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WO1999001160A1 - Conjugues de saccharide, produits pharmaceutiques les contenant, leur procede de preparation et leur utilisation - Google Patents

Conjugues de saccharide, produits pharmaceutiques les contenant, leur procede de preparation et leur utilisation Download PDF

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Publication number
WO1999001160A1
WO1999001160A1 PCT/EP1998/003142 EP9803142W WO9901160A1 WO 1999001160 A1 WO1999001160 A1 WO 1999001160A1 EP 9803142 W EP9803142 W EP 9803142W WO 9901160 A1 WO9901160 A1 WO 9901160A1
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mmol
title compound
conjugate
amide
coor
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PCT/EP1998/003142
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German (de)
English (en)
Inventor
Peter Mareski
Johannes Platzek
Bernd Radüchel
Dietmar Berndorff
Hanns-Joachim Weinmann
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Schering Aktiengesellschaft
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Priority to AU82109/98A priority Critical patent/AU8210998A/en
Publication of WO1999001160A1 publication Critical patent/WO1999001160A1/fr

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    • 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
    • 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
    • A61K49/14—Peptides, e.g. proteins
    • A61K49/146—Peptides, e.g. proteins the peptide being a polyamino acid, e.g. poly-lysine

Definitions

  • the invention relates to the subject matter characterized in the claims, that is to say conjugates consisting of an amino group-containing polymer, metal ion (s) containing signaling group (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 polymer, metal ion (s) containing signaling group (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 are found in approx. 50-70% of patients with malignant tumors (Elke, M. lymph node diseases. In: W. Frommhold, H.- S. Stender and P. Thurn (eds.), Radiological diagnostics in clinic and practice, 7th edition, Vol. IV, pp. 475-512, Stuttgart-New York: Georg Thieme Verlag, 1984).
  • the involvement of 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 either can be compensated for by the sensitive method of computer tomography.
  • radioactive 99m Tc tracers are used for indirect lymph node dissection.
  • 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
  • lymphographics (Hanka, L. et al., Radiology 1996, 198. 365-370) show such an animal specificity (rat vs. guinea pig and rabbit) that their further development had to be stopped.
  • conjugates according to the invention consisting of an amino group-containing polymer, metal ion (s) containing signaling group (s) and mono- or oligosaccharides as well as optionally cations of inorganic and / or organic bases, amino acids or amino acid amides, surprisingly become excellent Production of NMR diagnostics, particularly suitable for lymphography.
  • LD50 high tolerance
  • low elimination time more than 98% of them are usually excreted from the body within 14 days
  • their high relaxivity allows them to be applied in low doses, they often make it possible even a morphological differentiation of the lymph node tissue, they show no deviating animal specificities.
  • Z represents a mono- or oligosaccharide reduced by one hydroxyl group.
  • polymer which contains k amino groups, of which (n + m) are each reduced by one hydrogen atom
  • polymer is a dendrimer (eg WO 96/01655, EP 0271180), polylysine (eg EP 0331616), polypeptide, polyalkylamine , Poly [N- (2-aminoethyl)] methacrylamide (eg US-5,364,613) or polysaccharide (eg EP 0535668).
  • 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.
  • the polymers preferably contain 12, 24, 32, 36, 40, 48, 64 or 80 amino groups, of which, for example, 3, 4, 6, 7, 8, 11, 13, 14, 16, 18, 19, 21, 47 signaling groups K and, for example, 9, 8, 18, 17, 16, 13, 1-1, 10, 20, 6, 29, 27, 33 are bound to mono- or polysaccharides Z which are bonded via L and each reduced by one hydroxyl group. If the amino groups are understaffed, the sum (n + m) is preferably> k - 4.
  • the signaling group K is a chelate complex consisting of a radical of the general formula 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,
  • R2 represents a hydrogen atom, a straight-chain or branched C1-C7 alkyl radical, a phenyl or benzyl radical,
  • U is a -CHR 3 -CONR 3 -M 1 or -CH 2 -CH (OH) -M 2 group with R 3 independently of one another in the meaning of R2 or the group -CH2- (CH2) 0 - COOH and M 1 and M 2 each represent a phenylene radical or a straight-chain, branched, saturated or unsaturated C1-C20-
  • 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) ions. Because of their strong magnetic moment, gadolinium (III), terbium (III), dysprosium (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) - 7 samarium (III) -, gadolinium (III) -, ytterbium (III) - are preferred or bismuth (III) ions, especially dysprosium (III) ions.
  • Acidic hydrogen atoms which may be present in R "1 that is to say those which have not been substituted by the central ion, can, if appropriate, be wholly or partly replaced 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 omithin 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.
  • Another advantage of the present invention is that complexes with hydrophilic or lipophilic, macrocyclic or open-chain, low molecular weight or high molecular weight ligands have now become accessible. This enables the tolerance and pharmacokinetics of these polymer complexes to be controlled by chemical substitution.
  • Preferred substituents for 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, (CH2) 6 and (CH2) ⁇ o group, the C6H4 group being bonded to T ⁇ .
  • Preferred substituents for R 3 are the hydrogen atom, the methyl, CH 2 COOH and (CH 2 ) 2COOH group.
  • ⁇ indicates the linkage to the rest-CH (OH) - and ß the linkage to Tl.
  • the groups are preferred:
  • the group is particularly preferred:
  • 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, 29, 1339); Deoxy-sialyl-Lewis x (see, for example, W.
  • N, N ', N ", N” -Tetraacetylchitotetraose; Maltotriose; Digalacturonic acid; Trigalacturonic acid (Carbohydrates International AB, Sweden).
  • 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
  • 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 *
  • R1 independently of one another for a hydrogen atom, an acid protecting group or a metal ion equivalent of the elements of atomic numbers 20-29,
  • 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
  • R 4 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
  • R 1 ' stands for an acid protecting group or if the caboxy groups contained in U, M 3 ' and Z 'are protected, lower alkyl, aryl and aralkyl groups come, 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.
  • Suitable hydroxyl protective groups are the benzyl, 4-methoxybenzyl, 4-nitrobenzyl, trityl, diphenylmethyl, trimethylsilyl, dimethyl-t-butyl-silyl, diphenyl-t-butysilyl group.
  • the methyl group is also suitable as a protective group for the 1-OH group of the mono- and / or oligosaccharides.
  • the hydroxy groups can also e.g. as THP ether, alkyl ether, ⁇ -alkoxyethyl ether, MEM and MOM ether or as ester with aromatic or aliphatic carboxylic acids, such as e.g. Acetic acid and chloroacetic acid, benzoic acid, levulinic acid or 2-chloroacetoxymethyl (or ethyl) benzoic acid (GIT horrz. Lab. 1996, 46) are available.
  • the hydroxy groups can also be in the form of ketals with e.g. Acetone, acetaldehyde, cyclohexanone or benzaldehyde must be protected.
  • the hydroxyl groups can also be protected by intramolecular esterification to give the corresponding lactones.
  • the hydroxyl protecting groups can be prepared according to the literature methods known to the skilled person, e.g. 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", T.W. Greene, John Wiley and Sons 1981).
  • the amine protecting groups are the benzyloxycarbonyl, tertiary butoxycarbonyl, trifluoroacetyl, fluorenylmethoxycarbonyl, benzyl, formyl, 4-methoxybenzyl, 2,2,2-trichloroethoxycarbonyl, phthaloyl, 1, 2- Oxazoline, tosyl, dithiasuccinoyl, allyloxycabonyl, sulfate, pent-4-encarbonyl, 2-chloroacetoxymethyl (or ethyl) benzoyl, tetrachlorophthaloyl, alkyloxycarbonyl groups [Th. W. Greene, P.G.M.
  • reaction indicated under a) is carried out according to the methods familiar to the person skilled in the art, as described, 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, 131.854; 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.
  • Examples include thethylamine, 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 Bomann 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. Khim 1991, 9.
  • 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.
  • in-situ activation can also be carried out using the coupling reagents known to the person skilled in the art, such as DCCI, EEDQ, Staab reagent, BOP, PyBOP, TBTU, TDBTU, HBTU (see, for example, Fournic-Zaluski et al , J. Med. Chem. 1996, 39, 2596; Houben-Weyl, Volume XV / 2, Part II, 1974; YM An gell et al, Tetrahedron Letters 1994, 35, 5981; LA Carpino et at, J. Chem. Soc. Commun. 1994, 201; HO.
  • reaction of the polymer saccharide conjugate of the general formula IX with the complexes or complexing agents K * of the general formula II "to VII" and II'a indicated under b) is also carried out in a manner known per se, for example as described in US Pat. No. 5,135,737, H. Takalo et al, Bioconjugate Chem. 1994, 5, 278; EP 0430863; EP 0331616; WO 96/01655; EP 0271 180; U.S. 5,364,613; WO 95/17451 and WO 96/02669. It is in solvents such as water, methylene chloride, acetonitrile, chloroform, DMS0, pyridine, ethano!
  • 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, bicarbonate.
  • the reaction can also take place in the buffer solutions known to the person skilled in the art, preferably at pH 8 to 11, particularly preferably at pH 8.5 to 9.
  • the pH value is preferably maintained using a pH state.
  • T 2 ' is 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).
  • reducing agents used are sodium borohydride, sodium cyanoborohydride, 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 times excess.
  • the occupancy ratio of the amino groups contained in the polymer is controlled by the ratio n ': m'.
  • the neutralization is carried out 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, such as, for example, ethanolamine, morpholine, glucamine, N-methyl- and N, N-dimethylglucamine, as well as basic amino acids, such as lysine, arginine and omithin, or amides of originally neutral or acidic amino acids, such as 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, such as, for example, ethanolamine, morpholine, glucamine, N-methyl- and N, N-dimethylglucamine, as
  • 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 such as lower alcohols (methanol, ethanol, isopropanol and others), lower ketones (acetone and others), polar ethers (tetrahydrofuran, dioxane, 1, 2- Dimethoxyethane and others) to precipitate and 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 thus obtained 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 of suitable pore size (for example Amicon-®XM30, Amicon® -YM10, Amicon®-YM3) or gel filtration on e.g. suitable Sephadex® gels.
  • suitable pore size for example Amicon-®XM30, Amicon® -YM10, Amicon®-YM3
  • suitable Sephadex® gels for example Amicon-®XM30, Amicon® -YM10, Amicon®-YM3
  • an anion exchanger for example IRA 67 (OH ⁇ form)
  • a cation exchanger for example IRC 50 (H + form) for the separation of ionic components.
  • 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 (for example polylysine: EP 0331 616; dendrimers: WO 96/01655, EP 0271 180, EP 0430863, polypeptide, polyallylamine, poly [N- (2-aminoethyl)] methacrylamide: US Pat. No. 5,364,613; polysaccharide : VD Nadkami et al, Carbohydrate Research 1996, 290, 87, EA Yates et al, Carbohydrate Research 1996, 294, 15, DJ. Tyrrell et al, TiPS 1995, 16, 198, JP Patent 06080705-A).
  • the complexes or complexing agents K * used are known from the literature or can be obtained analogously to methods known from the literature:
  • 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, for example, tromethamine), additions of complexing agents or weak complexes (such as, for example, diethylenetriaminepentaacetic acid or the corresponding calcium polysaccharide-polymer complexes) or - if necessary - electrolytes such as, for example, sodium fluoride or - if necessary - antioxidants such as ascorbic acid.
  • suspensions or solutions of the agents according to the invention in water or physiological saline 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.
  • the pharmaceutical 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. After oral or parenteral application, they are ideally suited to improve the meaningfulness of the image obtained with the aid of an MRI scanner by increasing the signal intensity. 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 which the new contrast agents are completely excreted again, is extremely slow.
  • the agents according to the invention for use as NMR diagnostic agents in amounts of 0.0001-5 mmol / kg, preferably 0.005-0.5 mmol / kg, dosed. 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, 44 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. This effect significantly increases the local radiation dose at the location where the metal complex is located (eg in tumors).
  • the metal complex conjugates according to the invention are therefore also suitable as radiosensitive lising substance in radiation therapy of malignant tumors (Mössbauer effects or neutron capture therapy can also be used).
  • Suitable ⁇ -emitting ions are, for example, 4 6sc, 47 Sc, 48 Sc, 72 Ga, 73 Ga and 90 ⁇ .
  • Suitable ⁇ -emitting ions with short half-lives are, for example, 21 1 Bi, 212 Bi, 213 Bi and 214 Bi, with 212 Bi being preferred.
  • a suitable photon and electron-emitting ion is 1 58Gd, which can be obtained from 57Qd 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), whereby it should be emphasized that they show no signs of the anaphylaxis-like reactions known from the iodine-containing contrast agents in biochemical-pharmacological examinations. They are particularly valuable for digital subtraction techniques due to their favorable absorption properties in areas with higher tube voltages.
  • 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 megiumin diatrizoate.
  • Gd-DTPA Gadolinium complex of [bis- (2-aminoethyl) amine-N, N, N ', N ", N" - pentaacetic acid] monosodium salt
  • 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 is cut three times using a YM3 ultrafiltration membrane [cut off 3000 D; AMICON ®] ultrafiltered 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. Yield: 10.26 g (84.6%; based on the polyamine used) as an amorphous powder Water content: 7.44%
  • the ninhydrin reaction and the TNBS method which can generally be used for the quantitative and qualitative determination of free amino functions, are negative, ie there are no free amino functions in the polymer.
  • the percentage of sulfur in the elemental analysis of the title compound gives a degree of loading of the polymer with 40% ⁇ -D-Ga lactose (equivalent to 33 galactose residues per molecule).
  • the colorimetric phenol-sulfuric acid determination Dubois et al., Anal. Chem.
  • the ninhydrin reaction on 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-mannose (corresponding to 33 mannose residues per molecule).
  • Example 2a 0.85 g (0.020 mmol; corresponding to 0.94 mmol of DTPA) of the title compound from Example 2a) are described in analogy as for Example 1 c), with 10 ml of an aqueous gadolinium chloride solution which has a total content of 0.25 g (0 , 96 mmol) of gadolinium chloride, complexed. After working up and freeze-drying, 918 mg (98.5% of theory) of the title compound are obtained as an amorphous powder.
  • the molar elemental ratios of gadolinium to sulfur thus result in an average degree of loading of the polymer of 60.3% Gd-DPTA and 39.7% D-mannose (corresponding to 47 Gd-DTPA units and 33-D-mannose residues per molecule). No free amino functions can be detected in the title compound by means of the quantitative ninhydrin reactions.
  • and T2 relaxivities of the title compound were determined both in water and in plasma:
  • the measurements were carried out at 40 ° C, a magnetic field strength of 0.47 Tesla, the T1 sequence: 180 ° - Tl - 90 ° [inversion recovery] and the T2 sequence: 90 ° - TE - 180 ° [CPMG].
  • the ninhydrin reaction of the title compound is negative, i. H. the polymeric product no longer contains any 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-glucose (corresponding to 33 glucose residues per molecule).
  • Example 3a 1.0 g (0.023 mmol; corresponding to 1.10 mmol of DTPA) of the title compound from Example 3a) are described in analogy as for Example 1c), with 10 ml of an aqueous gadolinium chloride solution which has a total content of 0.298 g (1.12 mmol ) Has gadolinium chloride solution complexed. After working up and freeze-drying, 1.06 g (99.2% of theory) of the title compound is obtained as an amorphous powder. Water content: 5.47%
  • the pH of the reaction solution is adjusted to 11.5 by adding 1 molar sodium hydroxide solution.
  • the reaction solution is stirred for 12 hours at room temperature and made up to a total volume of 800 ml by adding distilled water.
  • the aqueous product solution thus obtained is 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 ninhydrin reaction 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 54.2% D-galactose (corresponding to 13 galactose residues per molecule).
  • Example 1c 1.0 g (0.077 mmol; corresponding to 0.85 mmol of DTPA) of the title compound from Example 4b) are described in analogy as for Example 1c) with 10 ml of an aqueous gadolinium chloride solution which has a total content of 0.232 g (0.88 mmol) Contains gadolinium chloride, complexed. After working up and freeze-drying, 978.4 mg (98.4% of theory) of the title compound are obtained as an amorphous powder.
  • the molar element ratio of gadolinium to sulfur thus results in an average degree of loading of the polymer of 46.4% Gd-DPTA and 53.6% D-galactose (corresponding to 11 Gd-DTPA units and 13-D-galactose residues per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction.
  • the ninhydrin reaction of the title compound is negative, ie the polymeric product does not contain any free amino functions.
  • a degree of loading results from the percentage sulfur value of the elemental analysis of the title compound of the polymer with 53.8% D-mannose (corresponding to 20 ⁇ -D-mannose units per molecule).
  • Example 1c) 1.0 g (0.077 mmol; corresponding to 0.85 mmol of DTPA) of the title compound from Example 5a) are described in analogy as for Example 1c) with 10 ml of an aqueous gadolinium chloride solution which has a total content of 0.232 g (0.88 mmol) Contains gadolinium chloride, complexed. After working up and freeze-drying, 952.2 mg (96.4% of theory) of the title compound are obtained as an amorphous powder. Water content: 7.89%
  • the molar element ratio of gadolinium to sulfur results in an average degree of loading of the polymer of 45% Gd-DPTA and 55% D-mannose (corresponding to 11 Gd-DTPA units and 13-D-mannose residues per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction.
  • T and T relaxivities of the title compound were determined both in water and in plasma:
  • the 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, the degree of loading of the polymer is 54.1% N-acetyl-glucose units (corresponding to 13 N-acetyl-glucosamine residues per molecule).
  • the ninhydrin reaction of the title compound is negative, ie the polymeric product does not contain any free amino functions. From the percentage sulfur The elemental analysis of the title compound gives a degree of loading of the polymer with 54.9% D-glucose (corresponding to 13 glucose residues per molecule).
  • Example 7a 1.0 g (0.077 mmol; corresponding to 0.85 mmol of DTPA) of the title compound from Example 7a) are complexed in an analogy as described for Example 1c) with 232 mg (0.88 mmol) of an aqueous gadiolium chloride solution (10 ml). After working up and freeze-drying, 952.2 mg (96.4% of theory) of the title compound are obtained as an amorphous powder. Water content: 7 39%
  • the molar element ratio of gadolinium to sulfur results in an average degree of loading of the polymer of 45% Gd-DPTA and 55% D-glucose (corresponding to 11 Gd-DTPA units and 13-D-glucose residues per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction.
  • a total of 9.38 g (23.3 mmol) of DTPA monoanhydride monoethyl ester is then added in portions, the pH of the reaction solution being kept constant at 9.5 by adding 1 molar sodium hydroxide solution. After a reaction time of 20 minutes at room temperature, the pH of the reaction solution is adjusted to 1 1.5 by adding 1 molar sodium hydroxide solution. The reaction solution is stirred for 12 hours at room temperature and made up to a total volume of 800 ml by adding distilled water. The aqueous product solution thus obtained is ultrafiltered three times using a YM3 ultrafiltration membrane (AMICON ®) against distilled water.
  • AMICON ® YM3 ultrafiltration membrane
  • the degree of DTPA loading of the polymer is 45.1% (corresponding to 16 DTPA units per molecule).
  • an average of 20 free amino functions per molecule are present in the polymer.
  • the 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 59% N-acetyl-D-glucosamine (corresponding to 20 glucose residues per molecule).
  • the ninhydrin color reaction test for the presence of free amino functions in the title compound is negative, i. H. the polymeric product therefore no longer contains any free amino functions.
  • the percentage sulfur of the elemental analysis of the title compound gives a degree of loading of the polymer with 56.2% D-glucose (corresponding to 20 glucose residues per molecule).
  • the molar element ratios of gadolinium to sulfur result in an average degree of loading of the polymer of 44% Gd-DPTA and 56% ß-D-glucose (corresponding to 16 Gd-DTPA units and 20 ß-D-glucose residues per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction.
  • the aqueous product solution is extracted twice with 60 ml of diethyl ether each time.
  • the aqueous product solution is brought to a pH of 3.0 by adding 10% hydrochloric acid and made up to a total volume of 800 ml with water and ultrafiltered three times using a YM 3 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: 2.80 g (81.6% of theory) as an amorphous and colorless powder. Water content: 7.78%.
  • the molar element ratio of sulfur to gadolinium (1, 21) thus results in an average degree of loading of the polymer of 45.2% Gd-Gly-Me-DOTA and 54.8% ⁇ -D-mannose (corresponding to 1 1 Gd-Gly -Me-DOTA units and 13- ⁇ -D-mannose residues per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction.
  • the title compound shows a negative ninhydrin reaction.
  • An average degree of loading of the polymer with 13 D-glucose residues per molecule results from the percentage sulfur value of the elemental analysis.
  • the title compound shows a negative ninhydrin reaction.
  • An average degree of loading of the polymer with 13 D-galactose residues per molecule results from the percentage sulfur value of the elemental analysis.
  • 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 tetraacetyl-glucosamine residues per molecule.
  • the ninhydrin reaction of the title compound is negative, ie there are no free amino functions in the polymer.
  • the percentage sulfur value of the elemental analysis of the title compound gives a degree of loading of the polymer with 60% D-galactose (corresponding to 29 galactose residues per molecule).
  • the molar element ratios of gadolinium to sulfur thus result in an average degree of loading of the polymer of 40% Gd-DPTA and 60% D-galactose (corresponding to 19 Gd-DTPA units and 29-D-galactose residues per molecule). No free amino functions can be detected in the title compound by means of ninhydrin reactions.
  • the 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 60% D-mannose (corresponding to 29 mannose residues per molecule).
  • Example 15a 0.85 g (0.029 mmol; corresponding to 0.56 mmol of DTPA) of the title compound from Example 15a) are described in analogy as described for Example 14c) with 0.15 g (0.58 mmol) of gadolinium chloride, dissolved in 10 ml of distilled water , complexed. After working up and freeze-drying, 854 mg (97.5% of theory) of the title compound are obtained as an amorphous powder. Water content: 6.14%
  • the 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 60% D-glucose (corresponding to 29 glucose residues per molecule).
  • the molar element ratio of gadolinium to sulfur thus results in an average degree of loading of the polymer of 40% Gd-DPTA and 60% D-glucose (corresponding to 19 Gd-DTPA units and 29-D-glucose residues per molecule). No free amino functions can be detected in the title compound by means of the ninhydrin reactions.
  • the 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 degree of loading of the polymer with 60% L-fucose (corresponding to 29 ⁇ -L-fucose residues per molecule).
  • Example 17a 1.2 g (0.042 mmol; corresponding to 0.81 mmol of DTPA) of the title compound from Example 17a) are described in analogy to that described for Example 14c) with 0.21 g (0.83 mmol) of an aqueous gadolinium chloride solution, dissolved in 10 ml distilled water, complexed. After working up and freeze-drying, 1.25 g (98.5% of theory) of the title compound is obtained as an amorphous powder. Water content: 4.39%
  • the molar element ratio of gadolinium to sulfur thus results in an average degree of loading of the polymer of 40% Gd-DPTA and 60% ⁇ -L-fucose (corresponding to 19 Gd-DTPA units and 29 ⁇ -L-fucose residues per molecule). No free amino functions can be detected in the title compound by means of ninhydrin reactions.
  • a solution of 5.0 g (0.97 mmol, corresponding to 23.3 mmol of free amine functions) 24-star burst dendrimer polyamine (representation according to: Tomalia DA et al.; Macromolecules 1986, 19, 2466; Tomalia DA et al .; Macromolecules 1987, 20, 1164) is dissolved in 400 ml of distilled water and adjusted to a pH of 9.5 with 1 molar sodium hydroxide solution. A total of 11.2 g (27.9 mmol) of DTPA monoanhydride monoethyl ester are then added in portions, the pH of the reaction solution being kept constant at 9.5 by adding 1 molar sodium hydroxide solution.
  • the ninhydrin reaction of the title compound is negative, ie the polymeric product does not contain any free amino functions. From the percentage sulfur The elemental analysis of the title compound gives a degree of loading of the polymer with 59% D-galactose (corresponding to 14 gaiactose residues per molecule).
  • Example 18b 1.0 g (0.07 mmol; corresponding to 0.7 mmol of DTPA) of the title compound from Example 18b) are dissolved in analogy as described for Example 14c) with 0.18 g (0.72 mmol) of an aqueous gadolinium chloride solution 10 ml of distilled water, complexed. After working up and freeze-drying, 1.05 g (97.3% of theory) of the title compound is obtained as an amorphous powder. Water content: 5.67%
  • the molar element ratio of gadolinium to sulfur thus results in an average degree of loading of the polymer of 41% Gd-DPTA and 59% D-galactose (corresponding to 10 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 ninhydrin reaction.
  • the 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 59% D-mannose (corresponding to 14 mannose residues per molecule).
  • Example 19a 1.1 g (0.077 mmol; corresponding to 0.77 mmol of DTPA) of the title compound from Example 19a) are described in analogy to that described for Example 14c) with 194.2 mg (0.79 mmol) of gadolinium chloride, dissolved in 10 ml of distilled water , complexed. After working up and freeze-drying, 1.14 g (98.6% of theory) of the title compound is obtained as an amorphous powder. Water content: 4.72%
  • the 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 59% D-glucose (corresponding to 14 glucose residues per molecule).
  • the molar element ratios of gadolinium to sulfur thus result in an average degree of loading of the polymer of 41% Gd-DPTA and 59% D-glucose (corresponding to 10 Gd-DTPA units and 14-D-glucose residues per molecule). No free amino functions can be detected in the title compound by means of ninhydrin reactions.
  • the ninhydrin reaction of the title compound is negative, ie the polymeric product does not contain any free amino functions.
  • the percentage of sulfur in the elemental analysis of the title compound gives a degree of loading of the polymer with 59% L-fucose (corresponding to 14 fucose residues per molecule).
  • 24-Starburst dendrimer (Gd-DTPA amide) 0 - [1- (4-thioureidophenyl) - ⁇ - L-fucopyranosyl] -
  • the molar element ratios of gadolinium to sulfur thus result in an average degree of loading of the polymer of 41% Gd-DPTA and 59% D-glucose (corresponding to 10 Gd-DTPA units and 14-D-glucose residues per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction.
  • the 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 59% N-acetyi-D-glucosamine (corresponding to 14 N-acetyl-D-glucosamine residues per molecule).
  • the molar element ratios of gadolinium to sulfur thus result in an average degree of loading of the polymer of 41% Gd-DPTA and 59% N-acetyl-D-glucosamine (corresponding to 10 Gd-DTPA units and 14 N-acetyl-D-glucosamine residues per Molecule).
  • No free amino functions can be detected in the title compound by means of a ninhydrin reaction.
  • the aqueous product solution is extracted twice with 60 ml of diethyl ether each time.
  • the aqueous product solution is brought to pH 3.0 by adding 10% hydrochloric acid and made up to a total volume of 800 ml with water and three times using a YM3 ultrafiltrate.
  • tion membrane AMICON ® ultrafiltered against distilled water. The remaining residue is made up to a volume of 500 ml with deionized water and freeze-dried.
  • the title compound shows a negative quantitative ninhydrin reaction.
  • An average degree of loading of the polymer with 20 D-glucose residues per molecule results from the percentage sulfur value of the elemental analysis.
  • the title compound shows a negative ninhydrin reaction.
  • An average degree of loading of the polymer with 20 D-galactose residues per molecule results from the percentage sulfur value of the elemental analysis.
  • the aqueous product solution is extracted twice with 60 ml of diethyl ether each time.
  • the aqueous product solution is brought to pH 3.0 by adding 10% hydrochloric acid and 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.
  • the molar element ratio of sulfur to gadolinium thus results in an average degree of loading of the polymer of 43.8% Gd-Gly-Me-DOTA and 56.2% D-mannose (corresponding to 21 Gd-Gly-Me-DOTA units and 27 - D-Mannosc3 ⁇ -est per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction.
  • Example 26b In an analogous manner as described for Example 26b), the reaction of 3.5 g (0.19 mmol; corresponding to 5.13 mmol of free amine functions) of the title compound from Example 26a) with 3.3 g (6.3 mmol) 3- (2,3,4,6-tetra-O-acetyl-1-thio- ⁇ -D-glucopyranosyl) propionic acid N-hydroxysuccinimide ester 5.57 g (93% of theory) of the title compound as colorless oil.
  • Example 26b In an analogous manner as described for Example 26b), the reaction of 3.5 g (0.19 mmol; corresponding to 5.13 mmol of free amine functions) of the title compound from Example 26a) with 3.3 g (6.3 mmol) 3- (2,3,4,6-Tetra-O-acetyl-1-thio- ⁇ -D-gaiactopyranosyl) propionic acid N-hydroxysuccinimide ester 5.23 g (90.2% of theory) of the title compound as colorless oil.
  • the title compound shows a negative ninhydrin reaction.
  • An average degree of loading of the polymer with 27 D-galactose residues per molecule results from the percentage sulfur value of the elemental analysis.
  • ninhydrin reaction as well as the TNBS method of the title compound are negative, i. H. the polymeric product contains no free amino functions.
  • ninhydrin reaction as well as the TNBS method of the title compound are negative, i. H. the polymeric product contains no free amino functions.
  • reaction solution thus obtained of the N-hydroxysuccinimide ester of the title compound from Example 31 h) is then added dropwise at 22.degree. C. with a solution of 2.61 g (0.55 mmol, corresponding to 13.23 mmol of free amine functions, 24 cascade polyamine) 15 ml of absolute dimethyl sulfoxide are added and the mixture is stirred for a further 12 hours at room temperature, and the reaction solution is added dropwise in 1.5 l of acetone at 22 ° C., the title compound precipitating as a colorless precipitate, the precipitate is filtered off with suction, dissolved in 200 ml of distilled water and Ultrafilter three times through a YM3 ultrafiltration membrane (AMICON ®), the remaining residue is dissolved in 300 ml of distilled water, filtered and freeze-dried.
  • AMICON ® YM3 ultrafiltration membrane
  • the ninhydrin reaction as well as in the TNBS method of the title compound are negative, i. H. the polymeric product contains no free amino functions.
  • a degree of loading of the polymer with 58.3% D-galactopyranose results from the molar sulfur value of the elemental analysis of the title compound
  • Gd-Gly-DOTA corresponding to 10 Gd-Gly-Me-DOTA complexes per molecule.
  • the ninhydrin reaction as well as in the TNBS method of the title compound are negative, ie the polymeric product does not contain any free amino functions.
  • the percentage sulfur content of the elemental analysis of the titite compound gives a degree of loading of the polymer with 56.8% D-mannopyranose (corresponding to 14 mannose residues per molecule) and 41.2% (corresponding to 10 Gd-Gly-Me-DOTA complexes per molecule).
  • the ninhydrin reaction as well as in the TNBS method of the title compound are negative, i. H. the polymeric product contains no free amino functions. From the percentage sulfur value of the elemental analysis of the titite compound, a degree of loading of the polymer results with 57.9% D-glucopyranose (corresponding to 14 glucose residues per molecule) and 42.1% (corresponding to 10 Gd-Gly-Me-DOTA complexes per molecule).
  • the ninhydrin reaction as well as in the TNBS method of the title compound are 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 54.1% ⁇ -L-fucose (corresponding to 13 ⁇ -L-fucose residues per molecule) and 40.6% (corresponding to 10 Gd-Gly-Me-DOTA Complexes per molecule).
  • the ninhydrin reaction as well as the TNBS method are negative, ie the polymeric product contains no free amino functions.
  • the ninhydrin reaction as well as the TNBS method are negative, ie the polymeric product contains no free amino functions. From the molar Sulfur value of the elemental analysis of the title compound results in a degree of loading of the polymer with 58.8% D-mannopyranose (corresponding to 14 mannose residues per molecule) and 41.2% Gd-Gly-DOTA (corresponding to 10 Gd-Gly-Me-DOTA complexes per molecule) .
  • the reaction is carried out analogously to that described in Example 1b), by reacting 4.0 g (0.45 mmol, corresponding to 6.3 mmol of free amine functions) of the title compound from Example 31a) with 15.86 g (31.5 mmol) ) of the title compound from Example 38a) to form 6.04 g (84.2% of theory, based on the polyamine used) of the above-mentioned title compound as a colorless lyophilisate.
  • a solution of 5.0 g (4.07 mmol; corresponding to 48.8 mmol of free amino functions) 12-part cascade polyamine (preparation according to: Schmitt-Willich et al.; EP 0271180) is dissolved in 400 ml of distilled water and with 1 molar sodium hydroxide solution a pH of 9.5 is set.
  • a total of 14.7 g (36.5 mmol) of DTPA-ivlcnoa ⁇ hydrid-mono-ethyl ester is then added, the pH of the reaction solution being constant at 9.5 by adding 1 molar sodium hydroxide solution is held.
  • 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 is ultrafiltered three times using 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. Yield: 11.2 g (89.3% of theory; based on the polyamine used) as an amorphous powder Water content: 9.41%
  • the ninhydrin reaction as well as the TNBS determination of the title compound are negative, ie there are no free amino functions in the polymer.
  • the percentage sulfur value of the elemental analysis of the title compound gives a degree of loading of the polymer with 67.4% sialyl -Le x units (corresponding to 8 sialyl -Le x residues per molecule).
  • Example 40 1 mg of the title compound from Example 39c) are dissolved in 2 ml of sodium citrate buffer (pH 5.3) and a solution of 11 l of indium chloride, which has an initial activity of 20.1 MBq, is added at room temperature. , After a stirring time of 15 minutes at room temperature, the reaction solution is adjusted to pH 7.2 with 1 molar sodium hydroxide solution and then sterile filtered. The solution prepared in this way can be used directly for the corresponding radiodiagnostic purposes.
  • sodium citrate buffer pH 5.3
  • 11 l of indium chloride which has an initial activity of 20.1 MBq
  • Both the ninhydrin reaction and the TNBS determination of the title compound are negative, ie there are no longer any free amino functions in the polymer.
  • the percentage sulfur content of the elemental analysis of the title compound gives a degree of loading of the polymer with 67.3% D-mannose (corresponding to 8 mannose residues per molecule).
  • the colorimetric phenol-sulfuric acid determination to determine the mean pyranose loading level of the conjugate provides a loading level of 8 ⁇ -D-mannose residues per molecule and is therefore identical to the loading level (8 D-mannose residues per molecule), which by the percentage sulfur value of the elementary analysis was determined.
  • Example 40a In an analogous manner to that described for the synthesis of the titite compound from Example 39d), the title compound from Example 40a) is complexed with 1 1 ' ' indium chloride (as a solution with a specific initial activity of 19.83 MBq). After sterile filtration, a preparation is obtained which can be used directly for the corresponding radio diagnostic purposes.
  • the aqueous product solution thus obtained is made up to a total volume of 300 ml by adding water and ultrafiltered three times by means of a YM3 ultrafiltration membrane (AMICON®) against distilled water.
  • the remaining residue is made up to a volume of 300 ml with deionized water and a pH of 10.0 is set by adding 15% sodium hydroxide solution.
  • the basic product solution is ultrafiltered again twice and the remaining residue, after filling up with distilled water to a total volume of 500 ml, freeze-dried.
  • 1.42 g (82.8% of theory) of the title compound are obtained as amorphous lyophilisate in the form of the free polyamine.
  • Water content 5.37%
  • Elemental analysis (calculated on anhydrous substance): calc .: C 51, 94 H 7.83 N 17.92 S 3.77 Na 4.32 found: C 51, 89 H 7.80 N 18.01 S 3.69 Na 4.28
  • the title compound is free of fluoride ions.
  • the title compound shows a negative ninhydrin reaction.
  • An average degree of loading of the polymer with 13 D-galactose residues per molecule results from the percentage sulfur value of the elemental analysis.
  • the average degree of loading of the polymer of the above-mentioned title compound was determined from the molar element ratios of sulfur to gadolinium to 11 Gd-Gly-Me-DOTA units and 13 ⁇ -D-glucopyranosyl residues, which was very good with the loading levels of the title compound determined on the precursors correlated.
  • the ninhydrin reaction as well as the TNBS determination of the title compound are negative, i. H. there are no longer any free amino functions in the polymer.
  • the percentage sulfur of the elemental analysis of the title compound gives a degree of loading of the polymer of 55.2% D-galactose (corresponding to 13 galactose residues per molecule), while the percentage of ytterbium results in a degree of loading of the polymer with ytterbium DTPA of 44.8% ( corresponding to 11 Yb-DTPA units per molecule).
  • the colorimetric determination of phenol-sulfuric acid [Dubois et al., Anal. Chem. 1956, 28, 3, 350; Koch et al., Cereal Chem.
  • the molar elemental ratio of dysprosium to sulfur thus results in an average degree of loading of the polymer of 46.2% Gd-DPTA and 53.8% D-mannose (corresponding to 11 Dy-DTPA units and 13 D-mannose residues per molecule) .
  • the qualitative ninhydrin reaction as well as the TNBS determination of the title compound are negative, i. H. there are no longer any free amino functions in the polymer.
  • the coiorimetric phenol-sulfuric acid determination, as well as the quantitative carbohydrate determination method according to Nelson and Somogyi for determining the average pyranose loading level of the polyamine gives a loading level of 32.68 D-mannose residues per molecule and is therefore identical to the loading level, which is caused by the percentage element ratios was determined.
  • the ninhydrin reaction as well as the TNBS determination of the title compound are negative, i. H. there are no longer any free amino functions in the polymer.
  • the percentage sulfur of the elemental analysis of the title compound gives a degree of loading of the polymer with 53.8% N-acetylglucosamine (corresponding to 13 N-acetyl- ⁇ -D-glucosamine residues per molecule), while the percentage of manganese indicates a degree of loading of the polymer with manganese - DTPA of 46.0% results (corresponding to 11 Mn-DTPA units per molecule).
  • the molar element ratios of europium to sulfur thus result in an average degree of loading of the polymer of 45% Eu-DTPA units and 55% ß-D-glucose residues (corresponding to 11 DTPA units and 13 ß-D-glucose units per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction.
  • the qualitative ninhydrin reaction as well as the TNBS determination of the title compound are negative, i. H. there are no longer any free amino functions in the polymer.
  • the colorimetric phenol-sulfuric acid determination, as well as the quantitative carbohydrate determination method according to Nelson and Somogyi for determining the mean pyranose loading level of the conjugate results in an average loading level of 13 D-glucose residues per molecule and is therefore identical to the loading level, which is determined by the percentage element ratios was determined.
  • N N'-dicyclohexylcarbodiimide
  • the temperature is preactivated for 60 minutes.
  • a solution of 1.39 g (0.5 mmol) of the 24-mer polyamine based on the N, N, N ', N', N ", N is added to the N-hydroxysuccinimide ester solution thus prepared "-Hexakis [2nd (trilysylamino) ethyl] trimesic acid triamide and 7.28 g (72 mmol) triethylamine in 10 ml water and stirred overnight at room temperature.
  • N, N'-dicyclohexylcarbodiimide are added and the mixture is preactivated for 60 minutes.
  • a solution of 1 39 g (0.5 mmol) of the 24mer-polyamine based on N, N, N, N ', N ", N" -Hexakis [ 2. (trilysyl-amino) -ethyl] -trimesic acid triamide and 7.28 g (72 mmol) of triethylamine in 10 ml of water and stir overnight at room temperature.
  • N, N'-dicyclohexylcarbodiimide After cooling to room temperature, 14.86 g (72 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is preactivated for 60 minutes. A solution of i, 39 g (0.5 mmol) of the 24-mer polyamine based on the N, N, N ', N', N ", N” - is added to the N-hydroxysuccinimide ester solution thus prepared. Hexakis [2. (trilysylamino) ethyl] trimesic acid triamide and 7.28 g (72 mmol) triethylamine in 10 ml water and stirred overnight at room temperature.
  • 1,2-dichloroethane is added at -10 ° C to 50 ml of trifluoroacetic acid and stirred for 2 hours at this temperature. Then one hour at 0 ° C
  • N-hydroxysuccinimide ester solution To the thus prepared N-hydroxysuccinimide ester solution was added a solution of 1, 386 g (0.5 mmol) of the 24mer-polyamine based on N, N, N, N, N ", N” -Hexakis [ 2. (trilysylamino) ethyl] trimesic acid triamids and 7.28 g (72 mmol) triethylamine in 10 ml water and stirred overnight at room temperature.
  • the suspension obtained is filtered and then sufficient acetone is added until precipitation is complete, the precipitate is filtered off with suction, dried, taken up in water, filtered off from the insoluble dicyclohexylurea and the filtrate is desalted via an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and then low molecular components cleaned. The retentate is then freeze-dried.
  • N, N'-dicyclohexylcarbodiimide are added and the mixture is preactivated for 60 minutes.
  • the suspension obtained in this way is filtered and then sufficient acetone is added until precipitation is complete, the precipitate is filtered off with suction, dried, taken up in water, filtered off from the insoluble dicyclohexylurea and the filtrate is desalted via an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and cleaned of low molecular components. The retentate is then freeze-dried.
  • the solvent is removed in vacuo and the remaining residue is mixed with dichloromethane (250 ml) and 1N hydrochloric acid (100 ml). After the organic product phase has been separated off, it is washed twice with 75 ml of water each time and dried over sodium sulfate. The desiccant is filtered off and the solvent is removed in vacuo. Crystallization from diethyl ether / pentane (1:10) yields 13.86 g (92.4% of theory) of the title compound as a colorless and crystalline solid.
  • the aqueous product solution is washed twice with Weil extracted 60 ml of diethyl ether and then brought to pH 3.0 by adding 10% hydrochloric acid. It is 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.
  • AMICON ® YM3 ultrafiltration membrane
  • the molar element ratio of sulfur to gadolinium thus results in an average degree of loading of the polymer of 45.2% Gd-Gly-Me-DOTA and 54.8% lactose (corresponding to 11 Gd-Gly-Me-DOTA units and 13-D - Lactose residues per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction.
  • the aqueous product solution is extracted twice with 60 ml of diethyl ether and then brought to pH 3.0 by adding 10% hydrochloric acid. It gets on with water
  • the total volume of 800 ml was filled up 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. Water content: 9.30%
  • the aqueous product solution is extracted twice with 60 ml of diethyl ether each and then brought to pH 3.0 by adding 10% hydrochloric acid, 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 another 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 - 2.80 g (81.3% of theory) as an amorphous and colorless powder.
  • 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 45.2% Gd-DTPA and 54.8% D-mannose (corresponding to 11 Gd-DTPA units and 13-D-mannose residues per molecule ). No free amino functions can be detected in the title compound by ninhydrin reaction.
  • Example 56d In an analogous manner as described for Example 56d), the complexation of 2.0 g (0.180 mmol; corresponding to 1.97 mmol of DTPA) of the title compound from Example 57b) with 525 mg (2.00 mmol) of gadolinium chloride, dissolved in 10 ml of distilled water to form the above title compound. Yield: 2.14 g (98.4% of theory) of the title compound as a colorless and amorphous powder. Water content: 7.22%

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Abstract

L'invention concerne des conjugués comportant un polymère contenant des groupes amino, un ou des groupes émettant des signaux et contenant un ou des ions métal, et des mono- ou oligosaccharides, ainsi qu'éventuellement des cations de bases inorganiques et/ou organiques, des aminoacides ou des amides d'aminoacide. Ces conjugués sont des composés précieux pour le diagnostic et la thérapie.
PCT/EP1998/003142 1997-06-30 1998-05-27 Conjugues de saccharide, produits pharmaceutiques les contenant, leur procede de preparation et leur utilisation WO1999001160A1 (fr)

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DE1997128954 DE19728954C1 (de) 1997-06-30 1997-06-30 Saccharid-Konjugate, diese enthaltende pharmazeutische Mittel, Verfahren zu ihrer Herstellung und ihre Verwendung
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WO2008017122A1 (fr) * 2006-08-11 2008-02-14 Starpharma Pty Ltd Agent de contraste dendrimère de polylysine

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008017125A1 (fr) * 2006-08-11 2008-02-14 Starpharma Pty Ltd Agent ciblé thérapeutique dendrimère de polylysine
WO2008017122A1 (fr) * 2006-08-11 2008-02-14 Starpharma Pty Ltd Agent de contraste dendrimère de polylysine
EP2076557A1 (fr) * 2006-08-11 2009-07-08 Starpharma Pty Ltd Agent de contraste dendrimère de polylysine
EP2076557A4 (fr) * 2006-08-11 2012-08-29 Starpharma Pty Ltd Agent de contraste dendrimère de polylysine
US8420067B2 (en) 2006-08-11 2013-04-16 Starpharma Pty Ltd Targeted polylysine dendrimer therapeutic agent
US9127130B2 (en) 2006-08-11 2015-09-08 Starpharma Pty Ltd. Polylysine dendrimer contrast agent

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