WO1999001160A1

WO1999001160A1 - Saccharide conjugates, pharmaceuticals containing the same, process for preparing the same and their use

Info

Publication number: WO1999001160A1
Application number: PCT/EP1998/003142
Authority: WO
Inventors: Peter Mareski; Johannes Platzek; Bernd Radüchel; Dietmar Berndorff; Hanns-Joachim Weinmann
Original assignee: Schering Aktiengesellschaft
Priority date: 1997-06-30
Filing date: 1998-05-27
Publication date: 1999-01-14
Also published as: AU8210998A; DE19728954C1

Abstract

Conjugates consist of an amino-group-containing polymer, signal-generating group(s) which contain metal ion(s), and mono- or oligosaccharides, and optionally of cations of inorganic and/or organic bases, amino acids or amino acid amides. These conjugates are valuable compounds for diagnosis and therapy.

Description

Saccharide conjugates, pharmaceutical compositions containing them, processes for their preparation and their use

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.

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. They can promote lesions, particularly if they are applied too quickly, with regard to the vulnerability of the lymphatic vessels. A number of disadvantages are due to the oil character of these contrast media. Since the oil is only suspended in the blood, the size of the oil droplets cannot be determined in advance. If the oil droplets are too large, microembolism, e.g. in the lungs, is often unavoidable. Since the absorption of the large oil droplets from the interstitial space into the lymph capillaries is hardly possible, the representation of the Lymphatic vessels and lymph nodes, for example after subcutaneous or intra-parenchymal injection, only in exceptional cases.

The last-mentioned disadvantage can only be overcome by endoiymphatic application, although prior dye marking and surgical exposure of the lymphatic vessels under local anesthesia must also be accepted without complications. Another disadvantage is that the contrast agents based on iodized oils are only excreted very slowly after application. Depending on the form of preparation, the elimination time is weeks to months.

By emulsifying the iodized oils, attempts have been made to overcome the disadvantages shown. This has resulted in a reduction in viscosity and droplet size. In this way the capillary passage could be improved and the risk of embolization reduced if the emulsion was stable. However, these partial successes could only be bought with other disadvantages. Examples of this include the effective reduction of the iodine content per ml of contrast medium and the associated inevitable loss of contrast, greater local toxicity at the lymph nodes, hepatotoxic effects and histologically detectable foreign body reactions, which are enhanced by the added emulsifiers.

All contrast media based on iodized oils are not very stable and can only be used to a limited extent due to the side effects shown. The derivatives of triiodinated 5-aminoisophthalic acid proposed as lymphographics in EP 0 022 056 have not met the expectations placed on them in medical practice because they diffuse out of the lymphatic system again after application. Due to their inadequate storage capacity in the lymph nodes, these aqueous forms of preparation are at best limited for use in peripheral lymphography.

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. By means of infusion into the interstitial space (intracutaneous, subcutaneous or intramuscular), only the lymphatic vessels or nodes located in the infusion site's intake area are displayed in high contrast. 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.

In nuclear medicine, radioactive ^99m Tc tracers are used for indirect lymph node dissection. In addition to the limited spatial resolution, 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

(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 results of the tests obtained on animals so far indicate e ^; ne unsatisfactory imaging despite high dosage of the particles.

Various compounds proposed as 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.

There was therefore still the task of providing compounds which accumulate in the lymphatic tissue after parenteral administration and do not have the disadvantages mentioned above, e.g. have a more favorable safety margin between the diagnostic and lethal dose ("margin of safety") compared to the known structures. This object is achieved by the present invention.

It has been found that the 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.

Surprisingly, they have the following advantages:

sufficient accumulation in the lymphatic system for good imaging System, high tolerance (LD50), 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.

The conjugates according to the invention can be described by the general formula I:

P (K) _m (LZ) _n (I),

wherein

P for a polymer containing k amino groups - of which (n + m) are each reduced by one hydrogen atom - where (n + m) <k should be, n and m each for the integers 1-149, k for the numbers 12 to 150,

K for a signaling group containing metal ion (s),

L for a left and

Z represents a mono- or oligosaccharide reduced by one hydroxyl group.

The P, 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. There is a complete occupation of the amino groups contained in P. 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.

wherein

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,

V a -CH ₂ - (CH ₂ ) ₀ - (O) group

With

o in the meaning of the numbers 0-10, p and I in each case in the meaning of the numbers 0 or 1, with the proviso that p only stands for the number 1 if I means the number 1, T ^{1 is} an -NHCS or -CO group,

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-

Alkylene chain which is optionally substituted by 1-5 (CH2) ₀ -COOH, 1-5OR ² radicals or 1-8 oxygen atoms, 1-2-NH-, 1-2-C (= NH) -, 1-5 CONR ³ ", 1-5-NR ^{3 contains} CO, 1-2 phenylene or 1-2 phenyleneoxy groups, with the proviso that at least two of the radicals R1 stand for metal ion equivalents of the elements of the above-mentioned atomic numbers.

If the compound according to the invention is intended for use in NMR diagnostics, the metal ion of the signaling group must be paramagnetic. These are, in particular, the bivalent and trivalent loreπ of the elements of atomic numbers 21-29, 42, 44 and 58-70. 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. For example, 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.

If the compound according to the invention is intended for use in X-ray diagnosis, 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.

They accumulate in the lymphatic system, allow statements about the perfusion of tissues, give the possibility to determine the blood volume in tissues and to selectively shorten the relaxation times or densities of the blood. Such physiological information cannot be obtained through the use of extracellular contrast agents, e.g. Gd-DTPA [Magnevist®]. From these points of view, the areas of application for the modern imaging methods magnetic resonance imaging and computed tomography also result: more specific diagnosis of metastatic, in particular malignant tumors and early therapy control with cytostatic, anti-inflammatory or vasodilative therapy.

The saccharide-polymer complexes according to the invention are outstandingly suitable for the interstitial and especially for the i.v. Lymphography.

Another advantage compared to extracellular contrast agents, such as Gd-DTPA [Magnevist®], is the higher effectiveness as a contrast agent for magnetic resonance imaging (higher relaxivity), which leads to a significant reduction in the diagnostically necessary dose. At the same time _ _

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) ι 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.

M ¹ may be mentioned as examples

α- (CH ₂ ) ii o-ß, α-CH (CH ₃ ) -ß,

α-CH [CH ₂ CH (CH3) ₂ ] -ß, -CH- (C ₆ H ₅ ) -ß

α -CH ₂ -CH ₂ -0- Vθ-CH ₂ -ß,

α-CH ₂ -CH ₂ -O-CH2-ß, α- (CH ₂ ) 2-3- (OCH ₂ CH2) l -5-0- (CH ₂ ) 2-3-ß, -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ - _{ß) α} - _CH

where α indicates the link to the rest-CONR ³ and ß the link to T1.

The groups are preferred:

CH ₂ COOH

α CH-CH ₂ - ß, α-CH ₂ -CH ₂ -O-CH ₂ -ß, α- (CH ₂ ) i-2-CO-N-CH ₂ -ß,

CH2COOH

α-CH2-CH2-CO-NH (CH2) 6-ß-α- (CH ₂ ) 5-ß,

Examples of groups M ² are:

α - (CH ₂ ) ₁ . ₁₀ -ß, _α α -CH; -ß,

SO ₃ H α- CH ₂ -O 0-CH ₂ -ß, α - ß, _α -CH.-NHCO ^ CH ^. ^ - ß,

where α indicates the linkage to the rest-CH (OH) - and ß the linkage to Tl. The groups are preferred:

α -CH ₂ -ß,

CH ₂ COOH

α

α -CH ₂ -NHCO- (CH ₂ ),, -ß

α - CH - 0 ß -α - CH ₂ -NHCO-CH ₂ -O-CH ₂ - ß. a (CH ₂ ) _g - ß

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. If 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. Stahl et al, Angew. Chemie 1994, 1ß6_, 2186); Sialyl-Le ^x (see, for example, W. Stahl, J. ^~ prak. Chemie 1995, 332, 441); Gentiobiose (Fluka Chemie AG,

Switzerland); Lactose; Maltose; Lactulose (Fluka Chemie AG, Switzerland); LactNAc; α N, ^N, N '-Triacetyichitotriose; Gal (1 - + 4) Gal, N, N'-diacetylchitobiose;

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 linker L, via which the mono- or oligosacchaids reduced by one hydroxyl group are bound to P, is described by the group T ² -M ³ -X, where M ^{3 stands} for a direct bond or has the meaning given for M ^ , T ^{2 stands} for an -NHCS-, -C (= NH) -, -CH2- or CO group and binds to P, X stands for NH, CO, O and S and binds to Z. The groups M ³ are, for example

τ- (CH ₂ ) l-l5 - δ,

γ- (CH2CH ₂ O). ₅ -CH2-δ

γ - (CH ₂ ) _{1 Ϊ} ,

γ-CH ₂ - (C = NH) -δ, γ-C (= NH) -NH- (CH ₂ ) 3-δ,

γ-NHCO- (CH ₂ ) 2-δ, γ-CH ₂ CH2-O-CH2CH2-δ, γ-CH ₂ CH2-S-CH2CH2-δ,

γ -OCH ₂ - δ, γ -NH-CH (CH ₂ - <%) ^■

called, where γ indicates the junction at X and δ the junction at T ² . M ³ preferably stands for a direct bond and for the groups

Y - (CH ₂ CH ₂ 0) _M - CH ^ CH ^ -δ,

J— (CH ₂ ) ₂ -CONH- (CH ₂ ) ₆ -δ,

CH (OH) CH, OH I - CH-CH (OH) -CH (OH) -δ, γ- (CH ₂ ) 2-CO- (CH ₂ ) 3-δ

The conjugates of the general formula I according to the invention are prepared in a manner known per se that

a) a polymer complex (former) conjugate of the general formula VII

P (K ') m (VII), wherein K' is a radical of the general formula II '. III ', IV, V or VI ^*

RO

(ii) -

(V)

(VI ')

wherein

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,

39, 42, 44 or 57-83 stands and

R ² , V, o, p, T and U have the meaning given above, with n 'mono- or oligosaccharides of the general formula VIII

L * -Z '(VIII), _ _

L ^* -Z '(VIII),

where 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, L ^* for a group T ² ' -M ³ '-X with T ² ' in the meaning of - NCS, -C (= NH) OCH3, - CHO, a -CO-Fg group where

-O-CO-R ⁴ with R ⁴ meaning a straight-chain or branched C- | -C7-alkyl chain,

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

P (L'-Z ^, ) _n (IX),

wherein

L 'has the meaning given for L, but the carboxy groups which may be present in L are optionally protected and P, Z and n have the meaning given above, with m' complexes or complexing agents K ^* , where m '= 1-3 m and K ^* for compounds of the general formulas Fg— OC ^ / - \ / - ^ -COOR ¹ NNNR ^ OC- ⁷ l ^ -COOR ^{1 '}

COOR ^{1 '}

(II "),

R ^r OOC / - \ r Λ COOR ^{1 '}

N N N

ROOC COOR ^{1 '}

C = O

Fg

I "),

(IV),

(V)

(VI ")

wherein

R ¹ ″ R ² , V, U and Fg have the meaning given above, and T1 ′ represents -NCS, -CO-Fg, -C (= NH) OCH ₃ or -CHO or

c) a polymer of the general formula X

P- (H) _k (X),

wherein P and k have the meanings given above, in a one-pot reaction with n 'mono- or oligosaccharides of the general formula VIII

L ^* -Z '(VIII), wherein

L ^* and Z 'have the meanings given above, with m' complexes or complexing agents K ^* . where K ^* for compounds of the general formulas

Fg— OC ^ / - \ / - \ r COOR ^{1 '} NNNR ^r OOC ^ l ^ COOR ¹

COOR ¹

(H"),

i

Fg (III "),

(VI ")

wherein m ', R ¹ ', R ² , V, T ^"1 ', and Fg have the meaning given above, the metal ion introduction which may be necessary being carried out before or after the splitting off of the protective groups which may be necessary, with the proviso that if R1 'stands for protective groups, these must be split off before the metal ion is introduced.

If 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.

If desired, 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. Examples of 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, α-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 Fachz. Lab. 1996, 46) are available. In the case of polyols, the hydroxy groups can also be in the form of ketals with e.g. Acetone, acetaldehyde, cyclohexanone or benzaldehyde must be protected.

If carboxyl groups are present at the same time, 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. Wuts, Protective Groups in Organic Syntheses, 2nd ed, John Wiley and Sons (1991), pp. 309-385, E. Meinjohanns et al, J. Chem. Soc. Pekin Trans 1, 1995, 405; U. Ellensik et al, Carbohydrate Research 280, 1996, 251; R. Madsen et al, J. Org. Chem. 60, 1995, 7920, R.R. Schmidt, Tetrahedron Letters 1995, 5343].

The 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. Comm. 1995, 2571; CR McBroom et al, Methods Enzymol. 1972, 28, 212 are described. It is in solvents such as water, methylene chloride, acetonite l, chloroform, DMSO, pyridine, ethanol / water, ethanol / acetonitrile, dioxane, DMF, THF, lower alcohols, tetramethylurea, N-methylpyrrolidone, polyethylene glycols, 12-dimethoxyethane, Dimethylacetamide, 1, 2-dichloroethane or - if possible - their mixtures with water at temperatures from -10 ° C to 100 ° C, preferably 0 to 50 ° C, particularly preferably at room temperature within 5 minutes to 72 hours, preferably 1 to 24 hours, particularly preferably 1 to 14 hours, optionally with the addition of an organic or inorganic base, such as aromatic or aliphatic amines, alkali or alkaline earth metal hydroxides, carbonates or hydrogen carbonates and quaternary ammonium hydroxides. 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. 2154; RF Borch et al , JACS 1971, 93 2897). Examples of reducing agents used 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.

If Fg stands for an OH group, 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. Kim et al, Tetrahedron Letters 1995, 36, 6013; D. Papaioannou et al, Tetrahedron Letters, 1995, 36, 5187, G. Stemple et al, Bioorg. Med. Letters 1996, 6, 55; be performed.

The 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! / Water ^r , ethanol / acetonitrile, dioxane, DMF, THF, lower alcohols, tetramethyl urea, N-methylpyrrolidone, polyethylene glycols, 12-dimethoxyethane, dimethylacetane , 1, 2-dichloroethane or - if possible - their mixtures with water at temperatures from -10 ° C to 100 ° C, preferably 0 to 50 ° C, particularly preferably at room temperatures within 5 minutes to 72 hours, preferably 1 to 24 Hours, particularly preferably 1 to 14 hours, optionally with the addition of an organic or inorganic base, such as aromatic or aliphatic amines, alkali or alkaline earth metal hydroxides, carbonates or hydrogen carbonates and quaternary ammonium hydroxides. 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. If 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). Examples of 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 dropping reaction indicated under c) takes place under the reaction conditions listed under a) and b) by adding a polymer of the general formula X with a mixture of m '= 1 - 3 m K ^* and n' = 1 - 3 n L ^* - Z 'implements. The occupancy ratio of the amino groups contained in the polymer is controlled by the ratio n ': m'.

The introduction of metal ions which is necessary after the above-mentioned reactions a) - c) or has already been carried out in K 'or K ^{* is} carried out in the manner disclosed, for example, in German Offenlegungsschhft 34 01 052 by adding the metal oxide or a metal salt ( for example the nitrate, acetate, carbonate, chloride or sulfate) of the element of atomic numbers 20-32, 37-39, 42-44, 49, 57-83 in water and / or a lower alcohol (such as methanol, ethanol or isopropanol ) dissolves or suspended and reacted with the solution or suspension of the equivalent amount of the complex-forming ligand and then, if desired, substituted acidic hydrogen atoms of the acid groups by cations of inorganic and / or organic bases, amino acids or amino acid amides.

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. To prepare the complex compounds, for example, 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. It is often advantageous to neutralize the formed salts by adding 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.

If the 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.

This can be done, for example, by reacting the complex-forming ligand in aqueous suspension or solution with the oxide or salt of the element providing the central ion and half of the amount of an organic base required for neutralization, isolating the complex salt formed, cleaning it if desired and then to complete it Neutralization with the required amount of inorganic base. 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.

In the case of neutral compounds, it is often advantageous to use an anion exchanger, for example IRA 67 (OH ^~ form), to polymerize the complexes. and if necessary additionally to give via a cation exchanger, for example IRC 50 (H ⁺ form) for the separation of ionic components.

The preparation of the polymer-complex (former) conjugates of the general formula VII required as starting substances

P (K ') _m (VII)

and the polymer saccharide conjugates of the general formula IX

P (L '- Z) _n (IX)

is carried out in a manner known per se by using a polymer of the general formula X

P- (H) k (X)

with m 'complexes or complexing agents K ^{* of} the general formulas II "- VI" and II'a or with N' activated mono- or oligosacchaids of the general formula VIII

L ^* - Σ (VIII)

under the reaction conditions given above under a) and b).

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:

II "and ll'a: see e.g. EP 263 059,

III ": see e.g. DE 19507822, DE 19580858, DE19507819

IV: s. e.g. WO 91/14459

V: s. e.g. US-5,053,503, WO 96/02669, WO 96/01655,

EP 0430863, EP 255471, US-5,277,895, EP 0232751,

U.S. 4,885,363

VI ": see e.g. U.S. 4,923,985

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. Cell 1984, 51, 187; EP Dubois et al, Bioorganic and Medical Chemistry Letters 1996, 6, 1387; CR McBroom et al, Methods Enzymol. 1972, 28, 212, M. Ponpipom et al, J. Med. Chem. 1981, 24, 1388; J. Haensler et al, Bioconjugate Chem. 1993, 4, 85; Y. Miura et al, Carbohydrate Research 1996, 289, 193; R. Roy et al. Tetrahedron Letters 1995, 36, 4377; W. Stahl et al, Angew. Chemistry 1994, 106, 2186; U. Sprengard et al, Angew. Chemie 1996, 108,359; A. Toepfer et al, Tetrahedron Letters 1995, 36, 9161; U. Sprengard et al, Angew. Chemistry 1995, 107, 1104; D. Zanini et al, Tetrahedron Letters 1995, 3.6, 7383; R. Roy et al, J. Chem. Commun. 1996, 201; W. Spevak et al, J. Med. Chem. 1996, 39, 1018; EAL Biessen et al, J. Med. Chem. 1995, 38, 1846; K. Yamada et al, Tetrahedron Letters 1995, 36, 9496; Lemieux et al, JACS 1975, 97, 4076; S. Koto et al, Bull. Chem. Soc. Jap. 1976, 49, 2639; PW Austin et al, J. Chem. Soz. C 1965, 1419; H. Paulsen, Angew. Chem. 1990, 102, 851; RR Schmidt et al, Angew. Chem. 1986, 98, 213; H. Kunz, Angew. Chem. 1987, 99, 297; J. Banoub, Chem. Review 1992, 92, 1167; H. Paulsen, Angew. Chem. 1982, 94, 184, RR Schmidt et al, Liebigs Ann. Chem. 1983, 1249; HA van Doren et al, Carbohydrate Research 1989, 194, 71, FD Tropper et al, J. Car- bohydr. Chem. 1992, H, 751; T. Sugawara et al, Carbohydrate Research 1992, 230, 117, YC Lee et al, Biochemistry 1976, 15, 3956; Blomberg et al, J. Carbohydr. Chem. 1992, 11, 751.

The pharmaceutical 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.

If 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.

In principle, it is also possible to prepare the pharmaceutical compositions according to the invention without isolating the complex salts. In any case, special care must be taken to carry out the chelation in such a way that the salts and salt solutions according to the invention are practically free of non-complexed toxic metal ions.

This can be ensured, for example, with the help of color indicators such as xylenol orange through control titrations during the manufacturing process. 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 μmol - 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.

for NMR and X-ray diagnostics in the form of their complexes with the ions of the elements with atomic numbers 21 - 29, 39 42, 44 and 57 - 83;

2. for radio diagnostics and radiotherapy in the form of their complexes with the radioisotopes of the elements with atomic numbers 27, 29, 31, 32, 37 - 39, 43, 49, 62, 64, 70, 7δ and 77.

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 good water solubility and low osmolality of 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. Furthermore, 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.

In general, 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).

Particularly low doses (below 1 mg / kg body weight) of organ-specific NMR diagnostics can be used, for example, to detect tumors and heart attacks.

Because of their favorable radioactive properties and the good stability of the complex compounds contained in them, 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.

Another imaging method with radioisotopes is positron emission tomography, which is positron-emitting isotopes such as ⁴³ Sc, ⁴⁴ Sc,

£> ² Fe, 55co and 68Qa used (Heiss, WD; Phelps, ME; Positron Emission Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York 1983).

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.

Since 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). In order to generate the same radiation dose in the malignant tissue, the radiation exposure for healthy tissue can be considerably reduced when using such metal complexes, and adverse side effects for the patient can thus be avoided. 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 β-emitting ions are, for example, ⁴ 6sc, ⁴⁷ Sc, ⁴⁸ Sc, ⁷² Ga, ⁷³ Ga and 90γ. Suitable α-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.

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. 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.

Details of the use of 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.

In general, 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.

Details of the use of X-ray contrast media are discussed, for example, in Barke, X-ray contrast media, G. Thieme, Leipzig (1970) and P. Thurn, E. Bücheier "Introduction to X-ray diagnostics", G. Thieme, Stuttgart, New York (1977). Overall, it has been possible to synthesize new polymer-metal complexes that open up new possibilities in diagnostic and therapeutic medicine.

The following examples serve to explain the subject of the invention in more detail:

The abbreviations known to those skilled in the art and known in the following examples, certain, frequently recurring compound names, are explained below by name and / or by structural formulas;

where = in each case indicates the position in the molecules described below via which the binding to the polymer P takes place.

1) DTPA: [bis- (2-aminoethyl) amine-N, N, N ', N ", N" - pentaacetic acid]

2) Gd-DTPA: Gadolinium complex of [bis- (2-aminoethyl) amine-N, N, N ', N ", N" - pentaacetic acid] monosodium salt

3) DTPA monoanhydride monoethyl ester:

4) DTPA-tetra-tert-butyl ester (central carboxymethyl function): 3,9-bis (tert-butoxycarbonylmethyl) -6-carboxymethyl-3,6,9-triazaundecanoic acid di-tert-butyl ester

5) DTPA-tetra-tert-butyl ester (terminal carboxymethyl function):

6,9-bis (tert-butoxycarbonylmethyl) -3-carboxymethyl-3,6,9-triaza-undecanoic acid 3,9-di-tert-butyl ester

6) Gly-Me-DOTA-tri-tert-butyl ester:

10- [1 - (Carboxymethylcarbamoyl) -ethyl] -1, 4.7, 10-tetraazacyclododecane-1, 4,7-tri-tert-butyl ester, sodium bromide:

7) Gd-Gly-Me-DOTA:

Gadolinium complex of 10- [1 - (carboxymethylcarbamoyl) ethyl] -1, 4.7, 10- tetraaza-cyclododecane-1, 4,7-triacetic acid

8) Sialyl Lewis ^x = [sLe *]:

(α-Neu5Ac- (2-3) -ß-D-Gal- (1-4) - [α-L-Fuc- (1-3)] - ß-GlcNAc)

The polyamines used in the respective syntheses are named once in the following and the corresponding references for their synthesis are listed once:

a) 12-cascade polyamine (12-mer polyamine):

12-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) - ethyl] -trimesic acid amide cores with N, N'-dibenzyloxycarbonyl-L-lysine

Synthesis description in an analogous manner as described in DE 19525924 A1 in Example 1d) for the preparation of the 24-cascade polyamine, only using N, N'-dibenzyloxycarbonyl-L-lysine instead of a completely benzyloxycarbonyl-protected "tri-lysine".

b) 24-cascade polyamine (24-mer polyamine):

24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) - ethyl] -trimesic acid amide Synthesis description in: DE 19525924 A1; EP 0430 863 A1; WO 97/02051; DE 195 18 222 A1

c) 36-cascade polyamine (36-mer polyamine):

36-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) ethyl] thmesic acid amide cores with six 1- (carboxymethoxyacetyl) -4.7 , 10- tris (N, N'-dibenzyloxycarbonyl-lysyl) -1, 4,10-tetraazacyclododecane

Synthesis description in: EP 0430 863 A1; WO 97/02051

d) 48-cascade polyamine (48-mer polyamine):

48-polyamine based on 1- (carboxymethoxyacetyl) -4,7,10-tris (N, N'-dibenzyloxycarbonyl-lysyl) -1,4,7,10-tetraazacyclododecane-hexamine cores with 1,4,7 10-tetraazacyclododecane tetrakis (N, N'-dibenzyloxycarbonyl-lysyl)

Synthesis description in: EP 0271180

f) 24 Starburst Dendrimer:

Tomalia D.A. et al .; Polym. J. (Tokyo) 1985, IZ, 117; Tomalia D.A. et al .; Macromolecules 1986, 19, 2466; Tomalia D.A., et al .; Macromolecules 1987, 20, 1164; Tomalia D.A. et al. , J. Am. Chem. Soc. 1987, 109, 1601; Tomalia D.A. et al .; J. Org. Chem. 1987, 52, 5305.

e) 48 Starburst Dendrimer:

Tomalia DA et al .; Polym. J. (Tokyo) 1985, 17, 117; Tomalia DA et al .; Macromolecules 1986, Ü 2466; Tomalia DA et al .; Macromolecules 1987, 20, 1164. example 1

13 kD poly-L-lysine (Gd-DTPA amide) ₄₇ - [1 - (4-thioureidophenyl) - β-D-galactopyranosyl] ₃ 3 conjugate

a) Polyamide from 13 kD poly-L-lysine and DTPA

A solution of 5.0 g (0.38 mmol; corresponding to 30.4 mmol of free amino functions) poly-L-lysine hydrobromide (13 kD, purchased from Sigma) is dissolved in 400 ml of distilled water and a pH with 1 molar sodium hydroxide solution -Value set to 9.5. Then a total of 14.7 g (36.5 mmol) of DTPA monoanhydride monoethyl ester (preparation as described in EP 0263051 A1, EP 0450742 A1 and EP 0413405 A1) are added, the pH ^{value of} the reaction being added - Solution is 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 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%

Elemental analysis (calculated on anhydrous substance): calc .: C 42.61 H 5.68 N 13.14 Na 13.48 found: C 42.55 H 5.72 N 13.20 Na 13.61

After elemental analysis and colorimetric titration at a complexing temperature of 22 ° C with 0.0025 molar gadolinium sulfate standard solution in the presence of xylenol orange as an indicator, the degree of DTPA loading of the polymer is 58.7% (corresponding to 47 DTPA Units per molecule). After a quantitative ninhydrin reaction [cf. see: Chem. Rev., 60, 39 (1960); Tetrahydron, 34, 1285 (1978), 47, 8791 (1991)] as well as quantitative Amino group determination using the TNBS method (cf.Fields, R., J. Biochem. 1971, 124, 581-590 and further references: Chem. Rev., 60, 39 (1960); Tetrahedron, 34, 1285 (1978 ); 47, 8791 (1991)] have an average of 33 free amino functions per polymer molecule.

b) 13 kD poly-L-lysine (DTPA amide) ₄₇ - [1 - (4-thioureidophenyl) - β-D-galactopyranosyl] 33 conjugate

1.5 g (0.047 mmol; corresponding to 1.54 mmol of free amino functions) of the title compound from Example 1 a) are dissolved in 80 ml of deionized water and the pH of the solution is adjusted to 9.5 with 1 molar hydrochloric acid in portions with a total of 2.07 g (6.63 mmol) of p-isothiocyanatophenyl-β-D-galactopyranose (representation according to: M. Ponpipom et al., J. Med. Chem. 24 1388; 1981. For the general formation of Isothiocyanates from the corresponding aniline precursors of various hexapyranoses see, for example: DH Buss, IJ Goldstein; J. Chem. Soc., 1968, 1457-1461, McBroom CR, Samanen CH and Goldstein IJ, Methods Enzymol. 1972, 28, 212 -219) were added, the pH of the reaction solution being kept constant at 9.5 using 0.1 molar sodium hydroxide solution. After a reaction time of 12 hours at 22 ° C., the mixture is filtered and made up to a total volume of 250 ml with distilled water. Ultrafiltration of the reaction solution three times over a YM3 ultrafiltration membrane (AMICON®) followed by freeze-drying of the remaining residue gives 1.84 g (92.6% of theory) of an amorphous and colorless solid. Water content: 6.78%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.34 H 5.54 N 11.02 S 2.49 Na 10.18 found: C 44.27 H 5.70 N 19.97 S 2.53 Na 10.24

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% β-D-Ga lactose (equivalent to 33 galactose residues per molecule). The colorimetric phenol-sulfuric acid determination (Dubois et al., Anal. Chem. 1956, 28, 3, 350) for determining the average degree of pyranose loading of the polyamine provides a mean statistical degree of loading of 32.68% of D-galactose residues per molecule and is therefore to be regarded as identical to the degree of loading, which was determined solely by the percentage element ratio (found here: 33 D-galactose residues per molecule).

c) 13 kD poly-L-lysine (Gd-DTPA amide) ₄₇ - [1- (4-thioureidophenyl) - β-D-galactopyranosyl] 33 conjugate

1.27 g (0.0411 mmol; corresponding to 1.56 mmol of DTPA) of the title compound from Example 1 b) are dissolved in 40 ml of sodium citrate buffer (pH 5.3) and at room temperature with a solution of 0.42 g (1 , 59 mmol) of gadolinium chloride in 10 ml of distilled water. After a reaction time of 15 minutes at room temperature, the reaction solution is adjusted to pH 7.2 with 1 molar sodium hydroxide solution. After three times of ultrafiltration through a YM3 ultrafiltration membrane (AMICON ®), the remaining residue is freeze-dried. Yield: 1.44 g (97.2% of theory) as an amorphous powder Water content: 3.89%

Elemental analysis (calculated on anhydrous substance): calc .: C 41.00 H 5.45 N 10.11 S 2.31 Gd 16.53 Na 2.42 found: C 39.87 H 5.74 N 9.98 S 2.28 Gd 16.58 Na 2.42

The molar element ratio of gadolinium to sulfur thus results in an average degree of loading of the polymer of 58.9% Gd-DPTA and 41.1% D-galactose (corresponding to 47 Gd-DTPA units and 33 β-D-galactose residues per molecule) . No free amino functions can be detected in the title compound by means of a ninhydrin reaction. Example 2

13 kD poly-L-lysine (Gd-DTPA) ₄₇ - [1- (4-Thioureidophenyl) -α - D-mannopyranosyi] 33 conjugate

a) 13 kD poly-L-lysine (DTPA amide) ₄₇ - [1 - (4-thioureidophenyl) - -D-mannopyranosyi] 33 conjugate

In an analogous manner to that described for Example 1 b), the reaction of 0.75 g (0.023 mmol; corresponding to 0.77 mmol of free amine functions) of the title compound from Example 1 a) with 1.2 g (3.8 mmol) p-lsothiocyaπatophenyl-α-D-mannopyranose [Presentation according to: Monsigny, M. et al., Biol. Cell. 51, (1984), 187] after working up 1.29 g (92.4% d τ _n ) of an amorphous and colorless solid. Water content: 4.86%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.34 H 5.54 N 1 1.02 S 2.49 Na 10, 18 found: C 44.40 H 5.57 N 10.96 S 2, 58 Na 10.20

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).

b) 13 kDpoly-L-lysine (Gd-DTPA amide) ₄₇ - [1 - (4-thioureidophenyl) -α - D-mannopyranosyl] 33 conjugate

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. Water content: 6.14% Elemental analysis (calculated on anhydrous substance): calc .: C 40.39 H 5.05 N 10.04 S 2.27 Gd 15.86 Na 2.32 found: C 40.42 H 5.11 N 10.01 S 2.36 Gd 15.92 Na 2.28

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.

The T- | 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].

All relaxivity determinations were carried out on a Minispec PC 20 and in all cases a solution of Gd-DTPA with a concentration of 1 mmol / L served as a reference sample.

R ₁ (water) = 14.4 ± 0.0 (LJmmol-s) R ₁ (plasma) = 17.4 ± 0.2 (LJmmol-s) R ₂ (water) = 16.4 ± 0.2 (LJmmol-s) R ₂ (plasma) = 21.4 ± 1.9 (L / mmol-s)

Example 3

13 kD poly-L-lysine (Gd-DTPA amide) ₄₇ - [1- (4-thioureidophenyl) - β-D-glucopyranosyl] ₃ 3 conjugate

a) 13 kD poly-L-lysine (DTPA amide) ₄₇ - [1 - (4-thioureidophenyl) - β-D-glucopyranosyl] ₃ 3 conjugate

In an analogous manner to that described for Example 1b), the reaction of 0.9 g (0.028 mmol; corresponding to 0.92 mmol of free amine functions) of the title compound from Example 1a) with 1.44 g (4.56 mmol) of p- isothiocyanatophenyl-ß- D-glucopyranose [Representation in analogy to: M. Ponpipom et al., J. Med. Chem. 24, 1388; 1981 and Monsigny et al., Bio. Cell, 51, 187, 1984] after working up 1.08 g (90.6% of theory) of an amorphous and colorless solid. Water content: 3.75%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.34 H 5.54 N 11.02 S 2.49 Na 10.18 found: C 44.40 H 5.51 N 11.03 S 2.55 Na 10.20

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).

b) 13-kD poly-L-lysine (Gd-DTPA amide) ₄₇ - [1 - (4-thioureidophenyl) - ß-D-glucopyranosyl] ₃ 3 conjugate

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%

Elemental analysis (calculated on anhydrous substance): calc .: C 40.39 H 5.05 N 10.04 S 2.27 Gd 15.86 Na 2.32 found: C 40.44 H 5.12 N 10.09 S 2.31 Gd 15.90 Na 2.31

The molar element ratio of gadolinium to sulfur thus results in an average degree of loading of the polymer of 59.7% Gd-DPTA and 40.3% D-glucose (corresponding to 47 Gd-DTPA units and 33-D-glucose residues per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction. Example 4

24-cascade amine (Gd-DTPA amide) _{1 1} - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] i3 conjugate

a) 24-cascade amine (DTPA amide) _{1 1} conjugate

At room temperature, 5.0 g (1.06 mmol; corresponding to 25.44 mmol of free amine functions) 24-cascade amine [as HBr salt] are dissolved in 300 ml of distilled water. The pH of the resulting solution is 1.6. A pH of 9.5 is set by dropwise adding this solution with 1 molar sodium hydroxide solution. A total of 12.3 g (30.53 mmol) of DTPA monoanhydride monoethyl ester is then added in portions, as described in European Patent Application No. 0263051 A1, European Patent Application No. 0450742 A1 and European Patent Application No. 0413405 A1). wherein the pH of the reaction solution is 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 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.

Yield: 5.50 g (86.4 based on the polyamine used) as an amorphous powder Water content: 9.33%

Elemental analysis (calculated on anhydrous substance): calc .: C 43.20 H 5.66 N 13.88 Na 12.86 found: C 43.01 H 5.70 N 14.03 Na 12.84

After elemental analysis and colorimetric titration with 0.0025 molar gadolinium sulfate standard solution in the presence of xylenol orange as an indicator, the degree of DTPA loading of the polymer is 45.8% (corresponding to 11 DTPA units per molecule). After a quantitative ninhydrin reaction, an average of 13 free amino functions are available per polymer molecule.

b) 24-cascade amine (DTPA amide) _{1 1} - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] - | 3 conjugate

In an analogous manner as described for Example 1 b), the reaction of 1.0 g (0.12 mmol; corresponding to 1.65 mmol of free amine functions) of the title compound from Example 4a) with 2.3 g (7, 26 mmol) p-isothiocyanatophenyl-β-D-galactopyranose after working up 1.33 g (93.2% of theory) of an amorphous and colorless solid. Water content: 7.41%

Elemental analysis (calculated on anhydrous substance): calculated: C 45.46 H 5.38 N 10.67 S 3.49 Na 8.47 found: C 45.32 H 5.28 N 10.71 S 3.44 Na 8.51

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).

c) 24-cascade amine (Gd-DTPA amide) ₁₁ - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] - | ₃ conjugate

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. Water content: 4.36% Elemental analysis (calculated on anhydrous substance): calc .: C 42.04 H 4.97 N 9.87 S 3.23 Gd 13.40 Na 1, 96 found: C 42.12 H 5.03 N 9.81 S 3.26 Gd 13.54 Na 1.93

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.

Example 5

24-cascade amine (Gd-DTPA amide) _{1 1} - [1- (4-thioureidophenyl) -α - D-mannopyranosyl] - | 3 conjugate

a) 24-cascade amine (DTPA amide) _{1 1} - [1- (4-thioureidophenyl) -α D-mannopyranosyl] ι ₃ conjugate

In an analogous manner as described for Example 1 b), the reaction of 1.0 g (0.12 mmol; corresponding to 1.65 mmol of free amine functions) of the title compound from Example 4a) with 2.3 g (7, 26 mmol) p-isothiocyanatophenyl-α-D-mannopyranose after working up 1.31 g (91.8% of theory) of an amorphous and colorless solid. Water content: 4.89%

Elemental analysis (calculated on anhydrous substance): calc .: C 45.46 H 5.38 N 10.67 S 3.49 Na 8.47 found: C 45.27 H 5.40 N 10.58 S 3.40 Na 8.60

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 α-D-mannose units per molecule).

b) 24-cascade amine (Gd-DTPA amide) _{1 1} - [1- (4-thioureidophenyl) -α - D-mannopyranosyl] 33 conjugate

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%

Elemental analysis (calculated on anhydrous substance): calc .: C 42.04 H 4.97 N 9.87 S 3.23 Gd 13.40 Na 1.96 found: C 41, 98 H 5.02 N 10.01 S 3.27 Gd 13.42 Na 1.91

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.

The T and T 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 and the T1 sequence: 180 ° - Tl - 90 ° [inversion recovery] and the T2 sequence: 90 ° - TE - 180 ° [CPMG]. All relaxivity determinations were carried out on a Minispec PC 20. In all cases, a solution of Gd-DTPA with a concentration of 1 mmol / L served as the reference sample.

R-, (water) = 15.4 ± 0.0 (L / mmol-s) R., (plasma) = 17.7 ± 1.1 (IJmmol-s) R ₂ (water) = 17.6 ± 0.2 (LJmmol-s) R ₂ (plasma) = 19.3 + 1 .2 (LJmmol-s)

Example 6

24-cascade amine (Gd-DTPA amide) ₁ -, - [1 - (4-thioureidophenyl) -N-acetyl-ß-D-glucosaminopyranosyl] ^ conjugate

a) 24-cascade amine (DTPA amide) _{1 1} - [1 - (4-Thioureidopheπyl) -N-acetyl-ß-D-glucosaminopyranosyl] - \ 3 conjugate

In an analogous manner to that described for Example 1b), the reaction of 1.3 g (0.156 mmol; corresponding to 2.03 mmol of free amine functions) of the title compound from Example 4a) with 3.15 g (8.92 mmol) ) 2- [acetylamino-2-deoxy] -1 - [4- (isothiocyanatophenyl)] -ß-D-glucosaminopyranose [representation in analogy to: M. Ponpipom et al., J. Med. Chem. 24, 1388; 1981 and Monsigny et al., Biol. Cell, 51, 187, 1984] after working up 1.74 g (89.6% of theory) of an amorphous and colorless solid. Water content: 3.94%

Elemental analysis (calculated on anhydrous substance): calc .: C 45.97 H 5.56 N 1 1.66 S 3.34 Na 8, 10 found: C 46.03 H 5.60 N 1 1, 62 S 3 , 30 Na 8.07

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).

b) 24-cascade amine (DTPA amide) ₁ - [1 - (4-thioureidophenyl) -N-acetyl-β-D-glucosaminopyranosyl] ₁₃ conjugate

1.5 g (0.120 mmol; corresponding to 1.32 mmol of DTPA) of the title compound from Example 6a) are, in analogy to that described for Example 1 c), with 10 ml of a aqueous gadolium chloride solution complexed, which contains a total of 0.356 g (1.35 mmol) of gadolinium chloride. After working up and freeze-drying, 1.57 g (97.3% of theory) of the title compound are obtained as an amorphous powder. Water content: 4.91%

Elemental analysis (calculated on anhydrous substance): calc .: C 42.65 H 5.16 N 10.82 S 3.10 Gd 12.85 Na 1.88 found: C 42.71 H 5.20 N 10.86 S 3.14 Gd 12.91 Na 1.85

From the molar element ratios of gadolinium to sulfur, an average degree of loading of the polymer of 46% Gd-DTPA and 54% N-acetyl-D-glucosamine, i.e. there are on average 11 Gd-DTPA units and 13-

N-Acetyl-D-Glucosamine units per molecule vc In the title compound, no free amino functions can be detected using the ninhydrin reaction.

Example 7

24-cascade amine (Gd-DTPA amide) ₁₁ - [1- (4-thioureidophenyl) - β-D-glucopyranosyrj-13 conjugate

a) 24-cascade amine (DTPA amide) ₁ - [1- (4-thioureidophenyl) - ß-D-glucopyranosyl] - | 3 conjugate

In an analogous manner to that described for Example 1b), the reaction of 1.2 g (0.144 mmol; corresponding to 1.872 mmol of free amine functions) of the title compound from Example 4a) with 2.61 g (8.24 mmol) of p- Isothiocyanatophenyl-β-D-glucopyranose after working up 1.49 g (87.1% of theory) of an amorphous and colorless solid. Water content: 8.37%

Elemental analysis (calculated on anhydrous substance): calc .: C 45.46 H 5.38 N 10.67 S 3.49 Na 8.47 found: C 45.52 H 5.44 N 10.73 S 3.55 Na 8.60

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).

b) 24-cascade amine (Gd-DTPA amide) _{1 1} - [1- (4-thioureidophenyl) - ß-D-glucopyranosyl] -i3 conjugate

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.

Example 8

36-cascade amine (Gd-DTPA amide) ₁₆ - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] ₂ o-conjugate

a) 36-cascade amine (DTPA amide) ₁₆ conjugate

At room temperature, 4.0 g (0.54 mmol; corresponding to 19.41 mmol of free amine functions) 36-cascade amine [used as hydrobromide; Representation according to: Schmitt-Willich et al., Schering AG, European Patent Application No. 0430 863 A1; WO 97/02051; German patent application No. 195 18 222 A1] dissolved in 300 ml of distilled water. The pH of the resulting Solution is 1.8. A pH of 9.5 is set by dropwise adding this solution with 1 molar sodium hydroxide solution. 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. The remaining residue is made up to a volume of 500 ml with deionized water and the aqueous product solution is freeze-dried. Yield: 5.50 g (86.4% of theory: based on the polyamine used) 3ιs amorphous powder

Water content: 9.33%

Elemental analysis (calculated on anhydrous substance): calc .: C 43.23 H 5.63 N 13.88 Na 12.46 found: C 43.40 H 5.68 N 13.92 Na 12.30

After elemental analysis and colorimetric titration with 0.0025 molar gadolinium sulfate standard solution in the presence of xylenol orange as an indicator, the degree of DTPA loading of the polymer is 45.1% (corresponding to 16 DTPA units per molecule). After the ninhydrin reaction of the title compound, an average of 20 free amino functions per molecule are present in the polymer.

b) 36-cascade amine (DTPA amide) ₆ - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] ₂ o-conjugate

In an analogous manner to that described for Example 1b), the reaction of 1.5 g (0.12 mmol; corresponding to 2.54 mmol of free amine functions) of the title compound from Example 8a) with 3.55 g (11.2) mmol) p-isothiocyanatophenyl-cc-D-mannopyranose after working up 1.87 g (86.3% of theory) of an amorphous and colorless solid. Water content: 4.93% Elemental analysis (calculated on anhydrous substance): calc .: C 45.52 H 5.35 N 10.62 S 3.55 Na 8.14 found: C 45.60 H 5.41 N 10.58 S 3.49 Na 8.22

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).

c) 36-cascade amine (Gd-DTPA amide) ₁₆ - [1- (4-thioureidophenyl) - β-D-galactopyranosyl] 2o conjugate

1.5 g (0.10 mmol; corresponding to 1.32 mmol of DTPA) of the titanium compound from Example 8b) are described in analogy to that described for Example 1c) with a solution of 358.5 mg (1.36 mmol) of gadolinium chloride in 10 ml of water complexed. After working up and freeze-drying, 1.57 g (97.3% of theory) of the title compound are obtained as an amorphous powder. Water content: 7.71%

Elemental analysis (calculated on anhydrous substance): calc .: C 42.22 H 4.96 N 9.85 S 3.29 Gd 12.91 Na 1.89 found: C 42.30 H 5.02 N 9.78 S 3.31 Gd 13.01 Na 1.78

The molar element ratios of gadolinium to sulfur thus result in an average degree of loading of the polymer of 44% Gd-DPTA and 56% D-mannose (corresponding to 16 Gd-DTPA units and 20 D-mannose residues per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction. Example 9

36-cascade amine (Gd-DTPA amide) ₁₆ - [1- (4-thioureidophenyl) - ß-D-glucopyranosyl] ₂ o-conjugate

a) 36-cascade amine (DTPA amide) ₁₆ - [1- (4-thioureidophenyl) - ß-D-glucopyranosyl] ₂ o-conjugate

In an analogous manner to that described for Example 1b), the reaction of 2.5 g (0.20 mmol; corresponding to 4.0 mmol of free amine functions) of the title compound from Example 8a) with 5.58 g (17.6 mmol) p-Isothiocyanatophenyl-ß-D-glucooyranose after working up 3.26 g (90.2% of theory) of an amorphous and colorless solid. Water content: 8.44%

Elemental analysis (calculated on anhydrous substance): calc .: C 45.52 H 5.35 N 10.62 S 3.55 Na 8.14 found: C 45.61 H 5.42 N 10.57 S 3.49 Na 8.13

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).

b) 36-cascade amine (Gd-DTPA amide) ₁₆ - [1- (4-thioureidophenyl) - β-D-glucopyranosyl] g conjugate

3.0 g (0.166 mmol; corresponding to 2.65 mmol of DTPA) of the title compound from Example 9a) are complexed in a manner analogous to that described for Example 1 c) with a solution of 717 mg (2.72 mmol) of gadolinium chloride in 15 ml of water. After working up and freeze-drying, 3.18 g (98.4% of theory) of the title compound are obtained as an amorphous powder. Water content: 6.43% Elemental analysis (calculated on anhydrous substance): calc .: C 42.22 H 4.96 N 9.85 S 3.29 Gd 12.91 Na 1.89 found: C 42.24 H 4.93 N 10.01 S 3.27 Gd 12.99 Na 1.91

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.

Example 10

24-cascade amine (Gd-Gly-Me-DOTA amide) -] - _] - ( ^α 'D-annopyranosyl-1 - thio-3-propionic acid amide) ₃ conjugate

a) 24-cascade amine (Gly-Me-DOTA-tri-t.-butyl ester amide) _{1 1}

20.0 g (26.8 mmol) of Gly-Me-DOTA-tri-tert.butyl ester (title compound from Example 31f) are dissolved in 100 ml of absolute dimethylformamide at room temperature and stirred with 3.7 g (32.16 mmol) N-hydroxysuccinimide added. The clear reaction mixture is then cooled to 0 ° C. and a total of 6.6 g (32.16 mmol) of dicyclohexylcarbodiimide is added at this temperature in portions. After a reaction time of 30 minutes at 0 ° C. and 2.5 hours at room temperature, the precipitated dicyclohexylurea is filtered off. The filtrate thus obtained is now slowly added dropwise at room temperature to a stirred solution of 8.8 g (1.86 mmol; corresponding to 44.8 mmol of free amino functions) 24-cascade polyamine and 4.5 g (44.8 mmol) triethylamine in 60 ml of absolute DMF. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in vacuo and 250 ml of dichloromethane are added to the remaining residue. After the insoluble constituents have been filtered off, the organic phase is washed successively with 5% hydrochloric acid, saturated sodium bicarbonate solution and twice with water. After the organic product phase has dried over sodium sulfate, the mixture is filtered and the solvent is stripped off in vacuo. 14.03 g (84.3% of theory; based on the polyamine used) of a slightly yellow-colored oil is obtained, which is immediately used for the subsequent synthesis steps without further purification. After quantitative ninhydrin crack tion of the above-mentioned title compound there are an average of 13 free amine functions per molecule.

Elemental analysis: calc .: C 63.06 H 9.68 N 15.65 found: C 63.20 H 10.02 N 15.71

b) 24-cascade amine (Gly-Me-DOTA-tri-t.-butyl ester amide) -

[3- (2,3,4,6-Tetra-O-acetyl-1-thio) -α-D-mannopyranosyl-3-propionamide] ₁₃ - conjugate

A stirred solution of 3.5 g (0.39 mmol; corresponding to 5.1 mmol of free amine functions) of the title compound from Example 10a) in 100 ml of absolute dichloromethane is mixed with 617 mg (6.1 rmole) of triethylamir at room temperature : offset. Then with a solution of 2.97 g (5.61 mmol) of 3- (2, 3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranosyl) -propionic acid-N-hydroxysuccinimide- ester (representation in analogy to: J. Haensler et al., Bioconjugate Chem. 4, 85, (1993); Chipowsky, S., and Lee, YC (1973), Synthesis of 1-Thio-aldosides; Carbohydrate Research 31, 339-346) in 60 ml dichloromethane, added dropwise at room temperature. 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 in vacuo to dryness. 5.0 g (89.7% of theory) of the title compound are obtained as a colorless oil. The ninhydrin reaction of the title compound is negative, i. H. free amino functions are no longer detectable in the polymer.

Elemental analysis: calc .: C 57.67 H 8.03 N 9.73 S 2.90 found: C 57.53 H 7.92 N 9.79 S 2.87

The percentage sulfur value of the elemental analysis of the abovementioned title compound thus gives an average degree of loading of the polymer with 55% D-mannose tetraacetate residues (corresponding to 13 D-mannose units per molecule). c) 24-cascade amine (Gly-Me-DOTA amide) _{1 1} -

(-α-D-Mannopyranosyl-1-thio-3-propion-amide) i3 conjugate

4.5 g (0.312 mmol) of the title compound from Example 10b) are dissolved in 100 ml of absolute dichloromethane. A total of 75 ml of trifluoroacetic acid is then added dropwise at 0 ° C. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in vacuo. The remaining residue is mixed with 100 ml of water and stripped again to dryness in vacuo. 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 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%.

Elemental analysis (calculated on anhydrous substance): calc .: C 49.42 H 7.09 N 12.67 S 3.77 found: C 49.18 H 7.13 N 12.81 S 3.69

After elemental analysis and colorimetric titration with 0.0025 molar gadolinium sulfate standard solution in the presence of xylenol orange as an indicator, the degree of loading with Gly Me-DOTA of the polymer is 44.8% (corresponding to 1 1 Gly-Me DOTA units per molecule ). After the ninhydrin reaction, there are no free amino functions in the polymer.

d) 24-cascade amine (Gd-Gly-Me-DOTA amide) ι ₁ - (α-D-mannopyranosyl-1-thio-3-propionic acid amide) ₁₃ conjugate

2.5 g (0.22 mmol; corresponding to 2.48 mmol of Gly-Me-DOTA) of the title compound from Example 10c) are dissolved in 70 ml of distilled water and the pH The value of the solution is adjusted to 2.0 by dropwise addition with 10% aqueous hydrochloric acid. Finally, 670 mg (2.55 mmol) of gadolinium chloride dissolved in 10 ml of water are added at room temperature and the reaction solution is stirred for 12 hours at 60 ° C. 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. 2.7 g (97.3% of theory) of the title compound are obtained as an amorphous, colorless powder with a water content of 9.37%.

Elemental analysis (calculated on anhydrous substance): calc .: C 42.77 H 6.05 N 19.96 S 3.26 Gd 13.54 found: C 42.69 H 6.18 N 11, 04 S 3.33 Gd 13, 67

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% α-D-mannose (corresponding to 1 1 Gd-Gly -Me-DOTA units and 13-α-D-mannose residues per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction.

Example 11

24-cascade amine (Gd-Gly-Me-DOTA amide) ^ - (ß-D-glucopyranosyl-1-thio-3-propionic acid amide) 3 conjugate

a) 24-cascade amine (Gly-Me-DOTA-tri-t.-butyl ester amide) ₁ -

[3- (2,3,4,6-Tetra-O-acetyl-1-thio) - β-D-glucopyranosyl-3-propionamide] ₁₃ - conjugate

In an analogous manner to that described for Example 10b), the reaction of 3.0 g (0.33 mmol; corresponding to 4.3 mmol of free amine functions) of the title compound from Example 10a) with 2.76 g (5.2 mmol) 3- (2,3,4,6-Tetra-O-acetyl-1-thio-β-D-glucopyranosyl) propionic acid N-hydroxysuccinimide ester, 4.0 g (85.3% of theory) of the title compound as a colorless oil. Elemental analysis: calc .: C 57.67 H 8.03 N 9.73 S 2.90 found: C 57.39 H 8.14 N 9.87 S 2.96

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.

b) 24-cascade amine (Gly-Me-DOTA amide) _{1 1} - (ß-D-glucopyranosyl-1-thio-3-propionic acid amide) ₁₃ conjugate

In an analogous manner as described for Example 10c), the deprotection of 3.5 g (0.24 mmcl) of the title compound from Example 11a) after freeze-drying leads to the formation of 2.2 g (83.6% of theory). Th.) Of the above title compound as an amorphous powder. Water content: 4.73%

Elemental analysis (calculated on anhydrous substance): calc .: C 49.42 H 7.09 N 12.67 S 3.77 found: C 50.01 H 7.14 N 12.62 S 3.81

c) 24-cascade amine (Gd-Gly-Me-DOTA amide) ^ - (ß-D-glucopyranosyl-1-thio-3-propionic acid amide) ₁₃ conjugate

In an analogous manner to that described for Example 10d), the complexation of 2.0 g (0.176 mmol; corresponding to 1.94 mmol of Gly-Me-DOTA) of the title compound from Example 11 b) with 520 mg (1.98 mmol) Gadolinium chloride dissolved in 10 ml of water to form the title compound mentioned above. Yield: 2.75 g (98.1% of theory) as a colorless and amorphous powder. Water content: 9.36%

Elemental analysis (calculated on anhydrous substance): calc .: C 42.77 H 6.05 N 10.96 S 3.26 Gd 13.54 found: C 42.73 H 6.14 N 1 1.06 S 3.30 Gd 13.61 Average degree of loading per molecule of the above title compound:

11 Gd-Gly-Me-DOTA units and 13 D-glucopyranosyl residues

Example 12

24-cascade amine (Gd-Gly-Me-DOTA amide) ^ - (ß-D-galactopyranosyl-1-thio-3-propionic acid amide) ^ conjugate

a) 24-cascade amine (Gly-Me-DOTA-tri-t.-butyl ester amide) ₁ -

[3- (2,3,4,6-Tetra-O-acetyl-1-thio) - β-D-galactopyranosyl-3-propionamide] ₃ - conjugate

In an analogous manner to that described for Example 10b), the reaction of 1.5 g (0.165 mmol; corresponding to 2.14 mmol of free amine functions) of the title compound from Example 10a) with 1.36 g (2.57 mmol) of 3- (2,3,4,6-Tetra-O-acetyl-1-thio-β-D-galactopyranosyl) propionic acid N-hydroxysuccinimide ester 2.0 g (87.2% of theory) of the title compound as a colorless oil .

Elemental analysis: calc .: C 57.67 H 8.03 N 9.73 S 2.90 found: C 57.78 H 8.14 N 9.80 S 2.97

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.

b) 24-cascade amine (Gly-Me-DOTA amide) _{1 1} - (ß-D-galactopyranosyl-1-thio-3-propionic acid amide) ₁ conjugate

In an analogous manner to that described for Example 10c), the deprotection of 1.8 g (0.12 mmol) of the title compound from Example 12a) leads to the formation of 1.15 g (87.2% of theory) after freeze-drying. ) of the above title compound as an amorphous powder. Water content: 4.22% Elemental analysis (calculated on anhydrous substance): calc .: C 49.42 H 7.09 N 12.67 S 3.77 found: C 49.66 H 7.13 N 12.54 S 3.70

c) 24-cascade amine (Gd-Gly-Me-DOTA amide) ^ - (ß-D-galactopyranosyl-1-thio-3-propionic acid amide) ₁₃ conjugate

In an analogous manner as described for Example 10d), the complexation of 1.0 g (0.088 mmol; corresponding to 1.94 mmol of Gly-Me-DOTA) of the title compound from Example 12b) with 262 mg (1.0 mmol) of gadolinium chloride dissolved in 10 ml of water to form the title compound mentioned above. Yield: 1.08 g (96.4% of theory) as a colorless and amorphous powder. Water content: 9.32%

Elemental analysis (calculated on anhydrous substance): calc .: C 42.77 H 6.05 N 10.96 S 3.26 Gd 13.54 found: C 42.56 H 6.12 N 10.93 S 3.24 Gd 13.51

Average degree of loading per molecule of the above-mentioned title compound: 11 Gd-Gly-Me-DOTA units and 13 D-galactopyranosyl residues

Example 13

24-cascade amine (Gd-dy-Me-DOTA amide) ^ - (N-acetyl-ß-D-glucosaminopyranosyl-1-thio-3-propionic acid amide) ₁₃ conjugate

a) 24-cascade amine (Gly-Me-DOTA-tri-t.-butyl ester amide) _{1 1} -

[3- (N-Acetyl-3,4,6-tetra-O-acetyl-1-thio) - β-D-glucosaminopyranosyl-3-propionamide] i3 conjugate

In an analogous manner to that described for Example 10b), the reaction of 2.0 g (0.22 mmol; corresponding to 2.86 mmol of free amine functions) of the title compound from Example 10a) with 1.74 g (3.43 mmol) 4 - [(Acetylamino-4-deoxy)] - 3- (2,3,4,6-tetra-O-acetyl-1-thio-ß-D-glucosaminopyranosyl) propionic acid N-hydroxysuccinimide ester 2,6 g (83.5% of theory) of the title compound as a colorless oil. Elemental analysis: calc .: C 57.77 H 8.04 N 11, 02 S 2.90 found: C 57.68 H 8.12 N 11, 13 S 2.87

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.

b) 24-cascade amine (Gly-Me-DOTA amide) _{1 1} - (N-acetyl-ß-D-glucosaminopyranosyl-1-thio-3-propionic acid amide) ₃ conjugate

In an analogous manner as described for Example 10c), the deprotection of 2.5 g (0.17 mmol) of the title compound from Example 13a) leads to the formation of 1.74 g (88.3% of theory) after freeze drying. ) of the above title compound as an amorphous powder. Water content: 10.02%

Elemental analysis (calculated on anhydrous substance): calc .: C 49.84 H 7.10 N 13.65 S 3.60 found: C 50.02 H 7.18 N 13.72 S 3.67

c) 24-cascade amine (Gd-Gly-Me-DOTA amide) ₁ -, - (N-acetyl-ß-D-glucosaminopyranosyl-1-thio-3-propionic acid amide) ₁ 3 conjugate

In an analogous manner as described for Example 10d), the complexation of 1.5 g (0.13 mmol; corresponding to 1.42 mmol of Gly-Me-DOTA) of the title compound from Example 13b) leads to 380 mg (1.45 mmol ) Gadolinium chloride, dissolved in 10 ml of water, to form the title compound mentioned above. Yield: 1.69 g (98.0% of theory) as a colorless and amorphous powder. Water content: 7.44%

Elemental analysis (calculated on anhydrous substance): calc .: C 43.48 H 5.95 N 11, 91 S 3.14 Gd 13.02 found: C 43.55 H 6.04 N 11, 88 S 3.18 Gd 12.98 Average degree of loading per molecule of the above-mentioned title compound: 11 Gd-Gly-Me-DOTA units and 13 N-acetyl-D-glucosaminopyranosyl residues

Example 14

48-Starburst dendrimer (Gd-DTPA amide) ₁₉ - [1- (4-thioureidophenyl) - β-D-galactopyranosyl] ₂ g conjugate

a) 48-Starburst dendrimer (DTPA amide) i9 conjugate

5.0 g (0.47 mmoi; corresponding to 22.6 mmol of free amine functions ^ 48-starburst cascade amine (Tomalia DA, et al .; Polym. J. (Tokyo) 1935, 17, 117; Tomalia DA et al. ; Macromolecules 1986, 19, 2466; Tomalia DA, et al .; Macromolecules 1987, 20, 1164) are dissolved in 400 ml of distilled water and the pH is adjusted to 9.5 with 1 molar sodium hydroxide solution. 9 g (27.12 mmol) of DTPA monoanhydride mono-ethyl ester are added in portions, the pH of the reaction solution being kept constant at 9.5 by adding 1 molar sodium hydroxide solution, and after the addition has ended, the mixture is left at room temperature for 15 minutes stirred and then the pH of the reaction solution is adjusted to 11.5 by adding 32% sodium hydroxide solution, and after a reaction time of 12 hours at room temperature, the mixture is made up to a total volume of 800 ml with distilled water a YM3 ultrafiltration smembran (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: 8.06 g (88.3%; based on the polyamine used) as an amorphous powder Water content: 7.32%

Elemental analysis (calculated on anhydrous substance): calc .: C 45.18 H 6.50 N 17.59 Na 8.99 found: C 45.26 H 6.61 N 17.32 Na 9.04 After elemental analysis and colorimetric titration with 0.0025 molar gadolinium sulfate standard solution, in the presence of xyienol orange as an indicator, the degree of DTPA loading of the polymer is 40.1% (corresponding to 19 DTPA units per molecule). After quantitative ninhydrin reaction [Lit .: Chem. Rev., 60, 39 (1960); Tetrahedron, 34, 1285 (1978); 4Z, 8791 (1991)] there are on average 29 free amino functions per molecule in the polyamine.

b) 48-Starburst dendrimer (DTPA amide) ₁₉ - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] g conjugate

1.0 g (0.051 mmol; corresponding to 1.5 mmol of free amino functions) of the title compound from Example 14a) are dissolved in 80 ml of deionized water and the pH of the solution is adjusted to 9.5 with 1 molar hydrochloric acid. A total of 1.55 g (4.9 mmol) of p-isothiocyanatophenyl-β-D-galactopyranose is then added in portions, the pH of the reaction solution being kept constant at 9.5 by means of 0.1 molar sodium hydroxide solution. After a reaction time of 12 hours at 22 ° C., the mixture is filtered and made up to a total volume of 250 ml with distilled water. Ultrafiltration of the reaction solution three times over a YM3 ultrafiltration membrane (AMICON®) followed by freeze-drying of the remaining residue gives 1.34 g (92% of theory) of an amorphous and colorless solid. Water content: 4.9%

Elemental analysis (calculated on anhydrous substance): calc .: C 46.62 H 6.06 N 13.39 S 3.26 Na 6.12 found: C 46.71 H 6.13 N 13.28 S 3.20 Na 6, 21

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). c) 48-Starburst dendrimer (Gd-DTPA amide) ₁₉ - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] ₂ 9 conjugate

1.0 g (6.035 mol; corresponding to 0.66 mmol of DTPA) of the title compound from Example 14b) are dissolved in 40 ml of sodium citrate buffer (pH 5.3) and at room temperature with a solution of 0.18 g (0.7 mmol) of gadolinium chloride, dissolved in 10 ml of distilled water. After a reaction time of 15 minutes at room temperature, the reaction solution is adjusted to pH 7.2 with 1 molar sodium hydroxide solution. After three times of ultrafiltration through a YM3 ultrafiltration membrane (AMICON ®), the remaining residue is freeze-dried. Yield: 1.0 g (95% of theory) as an amorphous powder Water content: 5.23%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.06 H 5.67 N 12.66 S 13.08 Gd 9.89 Na 1.45 found: C 44.20 H 5.71 N 12.59 S 13.11 Gd 10.01 Na 1.47

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.

Example 15

48-Starburst dendrimer (Gd-DTPA amide) ₁₉ - [1- (4-thioureidophenyl) -α - D-mannopyranosyl] ₂ g conjugate

a) 48-Starburst dendrimer (DTPA amide) ₁₉ - [1- (4-thioureidophenyl) -α - D-mannopyranosyl] ₉ conjugate

In an analogous manner to that described for Example 14b), the reaction of 0.75 g (0.038 mmol; corresponding to 1.22 mmol of free amine functions) of the title compound from Example 14a) with 1.2 g (3.8 mmol) of p- Isothiocyanatophenyl-α-D-mannopyranose [Presentation according to: Monsigny, M. et al., Biol. Cell, 5_1, 187 (1984)] after working up 0.94 g (89.2% of theory) of an amorphous and colorless

Solid.

Water content: 5.03%

Elemental analysis (calculated on anhydrous substance): calc .: C 46.62 H 6.06 N 13.39 S 3.26 Na 6.12 found: C 46.70 H 6.01 N 13.42 S 3.24 Na 6.09

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).

b) 48-Starburst dendrimer (Gd-DTPA amide) ι ₉ - [1- (4-thioureidophenyl) -α - D-mannopyranosyl] ₂₉ conjugate

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%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.06 H 5.76 N 12.66 S 3.08 Gd 9.89 Na 1.45 found: C 44.10 H 5.66 N 12.71 S 3.12 Gd 9.94 Na 1.38

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-mannose (corresponding to 19 Gd-DTPA units and 29-D-mannose residues per molecule). No free amino functions can be detected in the title compound by means of the ninhydrin reactions. Example 16

48-Starburst dendrimer (Gd-DTPA amide) ₁₉ - [1- (4-thioureidophenyl) - β-D-glucopyranosyl] ₉ conjugate

a) 48-Starburst dendrimer (DTPA amide) ₉ - [1- (4-thioureidophenyl) - ß-D-glucopyranosyl] ₂ g conjugate

In an analogous manner to that described for Example 14b), the reaction of 1.0 g (0.051 mmol; corresponding to 1.5 mmol of free amine functions) of the title compound from Example 14a) with 1.44 g (4.56 mmol) of p- Isothiocyanatophenyl-β-D-glucopyranose [purchased goods: Sigma or representation analogous to: Monsigny et al., Biol. Cell., 51, 187 (1984)] after working up 1.36 mg (34% of theory) of an amorphous and colorless solid. Water content: 5.08%

Elemental analysis (calculated on anhydrous substance): calc .: C 46.62 H 6.06 N 13.39 S 3.26 Na 6.12 found: C 46 "55 H 6.12 N 13.29 S 3.24 Na 6.01

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).

b) 48-Starburst dendrimer (Gd-DTPA amide) ₉ - [1- (4-thioureidophenyl) -ß -D-glucopyranosyl] ₂₉ conjugate

1.0 g (0.034 mmol; corresponding to 0.646 mmol of DTPA) of the title compound from Example 16a) are analogous to those described for Example 14c) with 0.17 g (0.66 mmol), dissolved in 10 ml of distilled water, a gadolinium - chloride solution complexed. After working up and freeze-drying, 998 mg (97.2% of theory) of the title compound are obtained as an amorphous powder. Water content: 3.94% Elemental analysis (calculated on anhydrous substance): calc .: C 44.06 H 5.67 N 12.66 S 3.08 Gd 9.89 Na 1.45 found: C 44.12 H 5.67 N 12.74 S 3.00 Gd 10.01 Na 1.38

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.

Example 17

48starburst dendrimer (Gd-DTPA amide) ₁₉ - [1- (4-thioureidophenyl) - u. -L- fucopyranosyl] ₂₉ conjugate

a) 48-Starburst dendrimer (DTPA amide) ₉ - [1- (4-thioureidophenyl) - α - L-fucopyranosyl] ₂₉ conjugate

In an analogous manner to that described for Example 14b), the reaction of 1.0 g (0.051 mmol; corresponding to 1.48 mmol of free amine functions) of the title compound from Example 14a) with 1.65 g (5.57 mmol) of p- Isothiocyanatophenyl-α-L-fucopyranose [Presentation according to: Tamio et al., Jpn. Kokai Tokyo Koho, Jp 4211099 and Hilditch et al., J. Appl. Phycol. 3 (4), 345, (1991)] after working up 1.36 g (94% of theory) of an amorphous and colorless solid. Water content: 7.24%

Elemental analysis (calculated on anhydrous substance): calc .: C 47.39 H 6.16 N 13.62 S 3.31 Na 6.22 found: C 47.42 H 6.08 N 13.57 S 2.98 Na 6.30

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 α-L-fucose residues per molecule). b) 48-Starburst dendrimer (Gd-DTPA amide) ₁₉ - [1- (4-thioureidophenyl) - α -L-fucopyranosyl] ₂₉ conjugate

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%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.72 H 5.81 N 12.89 S 3.12 Gd 10.04 Na 1, 47 found: C 44.81 H 5.79 N i 2. ^" SS 3 , 16 Gd 10.09 Na 1.40

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% α-L-fucose (corresponding to 19 Gd-DTPA units and 29 α-L-fucose residues per molecule). No free amino functions can be detected in the title compound by means of ninhydrin reactions.

Example 18

24-Starburst dendrimer (Gd-DTPA amide) ₁₀ - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] - _| -Conjugate

a) 24-Starburst dendrimer (DTPA amide) o conjugate

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. After the addition is complete, stirring is continued for 15 minutes at room temperature and then the pH The value of the reaction solution was 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 YMB 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: 4.6 g (92% of theory; based on the polyamine used) as an amorphous powder. Water content: 8.37%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.72 H 6.58 N 17.29 Na 9.38 found: C 44.64 H 6.51 N 17.36 Na 9.42

After elemental analysis and colorimetric titration with 0.0025 molar gadolinium sulfate standard solution in the presence of xylenol orange as an indicator, the degree of DTPA loading of the polymer is 41.6% (corresponding to 10 DTPA units per molecule). After a quantitative ninhydrin reaction, there are on average 14 free amino functions per molecule in the polymer.

b) 24-Starburst dendrimer (DTPA amide) ₁₀ - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] ₁ conjugate

In an analogous manner to that described for Example 1b), the reaction of 1.0 g (0.10 mmol; corresponding to 1.43 mmol of free amine functions) of the title compound from Example 18a) with 1.60 g (5.03 mmol) p-Isothiocyanatophenyl-β-D-galactopyranose after working up 1.32 g (93.3% of theory) of an amorphous and colorless solid. Water content: 7.31%

Elemental analysis (calculated on anhydrous substance): calc .: C 46.25 H 6.13 N 13.31 S 3.16 Na 6.47 found: C 46.32 H 6.19 N 13.28 S 3.09 Na 6.51

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).

c) 24-Starburst dendrimer (Gd-DTPA amide) ₁₀ - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] - _| -Conjugate

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%

Elemental analysis (calculated on anhydrous substance): calc .: C 43.59 H 5.77 N 12.53 S 2.98 Gd 10.42 Na 1, 52 found: C 43.61 H 5.81 N 12.49 S 2.94 Gd 10.48 Na 1.47

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.

Example 19

24-starburst dendrimer (Gd-DTPA amide) ₁₀ - [1- (4-thioureidophenyl) -α - D-mannopyranosyl] - | -Conjugate

a) 24-Starburst dendrimer (DTPA amide) ₁₀ - [1- (4-thioureidophenyl) -α D-mannopyranosyl] - | ₄ conjugate

In an analogous manner to that described for Example 14b), the reaction of 0.95 g (0.096 mmol; corresponding to 1.344 mmol of free amine functions) of the title compound from Example 18a) with 1.29 g (94.6 mmol) of p- isothiocyanato phenyl-α-D-mannopyranose after working up 1.29 g (94.6% of theory) of an amorphous and colorless solid. Water content: 6.88%

Elemental analysis (calculated on anhydrous substance): calc .: C 46.25 H 6.13 N 13.31 S 3.16 Na 6.41 found: C 46.09 H 6.07 N 13.33 S 3.24 Na 6, 51

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).

b) 24-Starburst dendrimer (Gd-DTPA amide) ₁₀ - [1- (4-thioureidophenyl) -α - D-mannopyranosyl] - | -Conjugate

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%

Elemental analysis (calculated on anhydrous substance): calc .: C 43.55 H 5.77 N 12.53 S 2.98 Gd 10.42 Na 1, 52 found: C 43.61 H 5.82 N 12.48 S 3.04 Gd 10.38 Na 1.49

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-mannose (corresponding to 10 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 ninhydrin reaction. Example 20

24-Starburst dendrimer (Gd-DTPA amide) ₁₀ - [1- (4-thioureidophenyl) - β-D-glucopyranosyl] ₁ conjugate

a) 24-Starburst dendrimer (DTPA amide) ₁₀ - [1- (4-thioureidophenyl) - ß-D-glucopyranosyl] ₁₄ conjugate

In an analogous manner to that described for Example 14b), the reaction of 1.2 g (0.12 mmol; corresponding to 1.21 mmol of free amine functions) of the title compound from Example 18a) with 1.92 g (6.03 mmol) p-lsothiocyanatophenyl-β-D-glucopyranose after working up 1.59 g (93.6% of theory) of an amorphous and colorless solid. Water content: 5.97%

Elemental analysis (calculated on anhydrous substance): calc .: C 46.25 H 6.13 N 13.31 S 3.16 Na 6.27 found: C 46.20 H 6.21 N 13.32 S 3.08 Na 6, 37

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).

b) 24-Starburst dendrimer (Gd-DTPA amide) ₁₀ - [1- (4-thioureidophenyl) - ß-D-glucopyranosyl] ₄ - conjugate

1.40 g (0.089 mmol; corresponding to 0.89 mmol of DTPA) of the title compound from Example 20a) are described in analogy as described for Example 14c) with 219 mg (0.90 mmol) of gadolinium chloride, dissolved in 10 ml of distilled water - plexed. After working up and freeze-drying, 1.32 g (98.7% of theory) of the title compound is obtained as an amorphous powder. Water content: 7.33% Elemental analysis (calculated on anhydrous substance): calc .: C 43.55 H 5.77 N 12.53 S 2.98 Gd 10.42 Na 1, 52 found: C 43.62 H 5.80 N 12.49 S 2.96 Gd 10.47 Na 1.58

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.

Example 21

24-Starburst dendrimer (Gd-DTPA amide) ₁₀ - [1- (4-thioureidophenyl) - α -L-fucopyranosyl] ₁ conjugate

a) 24-Starburst dendrimer (DTPA amide) ₀ - [1- (4-thioureidophenyl) - α -L-fucopyranosyl] ₁₄ conjugate

In an analogous manner to that described for Example 14b), the reaction of 1.0 g (0.10 mmol; corresponding to 1.4 mmol of free amine functions) of the title compound from Example 18a) with 1.50 g (5.03 mmol) p-lsothiocyanatophenyl-α -L-fucopyranose after working up 1.3 g (94.2% of theory) of an amorphous and colorless solid. Water content: 6.08%

Elemental analysis (calculated on anhydrous substance): calc .: C 47.00 H 6.23 N 13.53 S 3.21 Na 6.58 found: C 46.94 H 6.19 N 13.55 S 3.25 Na 6.60

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). b) 24-Starburst dendrimer (Gd-DTPA amide) ₀ - [1- (4-thioureidophenyl) - α - L-fucopyranosyl] - | ₄ conjugate

1.1 g (0.078 mmol; corresponding to 0.78 mmol of DTPA) of the title compound from Example 21a) are complexed with 197 mg (0.79 mmol) of gadolinium chloride, dissolved in 10 ml of distilled water, in a manner analogous to that described for Example 14c) . 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: 6.97%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.20 H 5.86 N 12.72 S 3.02 Gd 10.58 Na 1, 55 found: C 44.28 H 5.88 N 12.69 S 2.99 Gd 10.62 Na 1.51

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.

Example 22

24-Starburst dendrimer (Gd-DTPA amide) ₁₀ - [1- (4-thioureidophenyl) -N-acetyl-β-D-glucosaminopyranosyl] ₁₄ conjugate

a) 24-Starburst dendrimer (DTPA amide) ₁ o- [1- (4-thioureidophenyl) -N-acetyl-β-D-glucosaminopyranosyl] ₄ conjugate

In an analogous manner to that described for Example 14b), the reaction of 1.0 g (0.10 mmol; corresponding to 1.4 mmol of free amine functions) of the title compound from Example 18a) with 2.50 g (7.04 mmol) p-Isothiocyanatophenyl-β-D-glucopyranose after working up 1.4 g (95% of theory) of an amorphous and colorless solid. Water content: 8.06% Elemental analysis (calculated on anhydrous substance): calc .: C 46.73 H 6.18 N 14.12 S 3.04 Na 6.22 found: C 46.69 H 6.21 N 14.20 S 3.00 Na 6, 24th

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).

b) 24-Starburst dendrimer (Gd-DTPA amide) ₁₀ - [1- (4-thioureidophenyl) -N-acetyl-β-D-glucosaminopyranosyl] ₁₄ conjugate

1.6 g (0.10 mmol; corresponding to 1.08 mmol of DTPA) of the title compound from Example 22a) are described in analogy to that described for Example 14c) with 278 mg (1.10 mmol) of gadolinium chloride, dissolved in 10 ml of distilled water , complexed. After working up and freeze-drying, 1.54 g (98.7% of theory) of the title compound are obtained as an amorphous powder. Water content: 5.51%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.10 H 5.83 N 13.33 S 2.87 Gd 10.04 Na 1, 47 found: C 44.19 H 5.91 N 13.41 S 2.80 Gd 10.08 Na 1.44

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.

Example 23

36-cascade amine (Gd-Gly-Me-DOTA amide) ₁₆ - (α-D-mannopyranosyl-1-thio-3-propionic acid amide) ₂₀ conjugate

a) 36-cascade amine (Gly-Me-DOTA-tri-t.-butyl ester amide) ₁ 20.0 g (26.8 mmol) of Gly-Me-DOTA-tri-tert.butyl ester (title compound from Example 31f) are dissolved in 100 ml of absolute dimethylformamide at room temperature and stirred with 3.7 g (32.16 mmol) N-hydroxysuccinimide added. The clear reaction mixture is then cooled to 0 ° C. and a total of 6.6 g (32.16 mmol) of dicyclohexylcarbodiimide is added at this temperature in portions. After a reaction time of 30 minutes at 0 ° C. and 2.5 hours at room temperature, the precipitated dicyclohexylurea is filtered off. The filtrate thus obtained is now slowly added dropwise at room temperature to a stirred solution of 8.8 g (1.18 mmol; corresponding to 42.8 mmol of free amino functions) 36-cascade polyamine and 4.3 g (44.8 mmol) triethylamine in 60 ml of absolute DMF. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in vacuo and 250 ml of dichloromethane are added to the remaining residue. After filtering off insoluble constituents, the organized phase is washed successively with 5% hydrochloric acid, saturated sodium bicarbonate solution twice with water. After drying the organic product phase over sodium sulfate, the mixture is filtered and the solvent is stripped off in vacuo. 12.5 g (86.2% of theory; based on the polyamine used) of a slightly yellow-colored oil are obtained, which is immediately used for the subsequent synthesis steps without further purification. After quantitative ninhydrin reaction of the above-mentioned title compound, an average of 20 free amine functions per molecule are present.

Elemental analysis: calc .: C 67.65 H 10.32 N 8.72 found: C 67.50 H 10.41 N 8.91

b) 36-cascade amine (Gly-Me-DOTA-tri-t.-butyl ester amide) ₁₆ -

[3- (2,3,4,6-Tetra-O-acetyl-1-thio) -α-D-mannopyranosyl-3-propionamide] ₂₀ conjugate

A stirred solution of 3.5 g (0.28 mmol; corresponding to 5.6 mmol of free amine functions) of the title compound from Example 23a) in 100 ml of absolute dichloromethane is mixed with 708 mg (7.0 mmol) of triethylamine at room temperature. Then with a solution of 3.6 g (6.8 mmol) of 3- (2, 3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranosyl) propionic acid-N-hydroxysuccinimide- ester (representation in analogy to: J. Haensler et al., Bioconjugate Chem. 4, 85, (1993); Chipowsky, S., and Lee.YC (1973), "Synthesis of 1-Thio-aldosides"; Carbohydrate Research 31, 339-346) added dropwise in 60 ml 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. 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. 5.25 g (90.4% of theory) of the title compound are obtained as a colorless oil. The ninhydrin reaction of the title compound is negative, ie no free amino functions can be detected in the polymer.

Elemental analysis: calc .: C 59.99 H 8.38 N 5.19 S 3 09 found: C 60.41 H 8.52 N 5.08 S 3.00

An average degree of loading of the polymer with 55.5% D-mannose tetraacetate (corresponding to 20 D-mannose residues per molecule) results from the percentage sulfur value of the elemental analysis of the title compound.

c) 36-cascade amine (Gly-Me-DOTA amide) ₆ - (α-D-mannopyranosyl-1-thio-3-propionic acid amide) ₂ Q conjugate

5.0 g (0.24 mmol) of the title compound from Example 23b) are dissolved in 100 ml of absolute dichloromethane. A total of 75 ml of trifluoroacetic acid is then added dropwise at 0 ° C. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in vacuo. The remaining residue is mixed with 100 ml of water and again stripped to dryness in vacuo. 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 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.

Yield: 2.69 g (94.1% of theory) as an amorphous and colorless powder. Water content: 7.78%

Elemental analysis (calculated on anhydrous substance): calc .: C 47.03 H 6.62 N 9.06 S 5.19 found: C 46.98 H 6.73 N 9.10 S 5.24

d) 36-cascade amine (Gd-Gly-Me-DOTA amide) ₁₆ - (α-D-mannopyranosyl-1-thio-3-propionic acid amide J2o conjugate

2.0 g (0.16 mmol; corresponding to 2.6 mmol of Gly-Me-DOTA) of the title compound from Example 23c) are dissolved in 70 ml of distilled water and the pH of the solution is adjusted by dropwise addition with 10% aqueous hydrochloric acid adjusted to 5.0. Finally, 709 mg (2.7 mmol) of gadolinium chloride, dissolved in 10 ml of distilled water, 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. 2.31 g (97.5% of theory) of the title compound are obtained as an amorphous, colorless powder with a water content of 6.7%.

Elemental analysis (calculated on anhydrous substance): calc .: C 39.24 H 5.11 N 7.56 S 4.33 Gd 16.98 found: C 39.42 H 5.21 N 7.52 S 4.39 Gd 17.02

The molar element ratio of sulfur to gadolinium thus results in an average degree of loading of the polymer of 44% Gd-Gly-Me-DOTA and 56% D-mannose (corresponding to 16 Gd-Gly-Me-DOTA units and 20-D-mannose residues per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction. Example 24

36-cascade amine (Gd-Gly-Me-DOTA amide) ₁₆ - (ß-D-glucopyranosyl-1-thio-3-propionic acid amide) 2o conjugate

a) 36-cascade amine (Gd-Gly-Me-DOTA-tri-tert-butyl ester amide) ₁₆ - [- (2,3,4,6-tetra-O-acetyl-1-thio) -ß-D -glucopyranosyl-3-propionic acid amide)] 2o conjugate

In an analogous manner to that described for Example 23b), the reaction of 3.5 g (0.28 mmol; corresponding to 5.6 mmol of free amine functions) of the title compound from Example 23a) m> t 3.6 g (6.8 mmol) 3- (2.3,4,6-Tetra-O-acetyι-l - thio-ß-D-glucopyranosyl) propionic acid N-hydroxysuccinimide ester (representation in analogy to: J. Haensler et al., Bioconjugate Chem. 4 , 85, (1993); Chipowsky, S., and Lee, YC (1973), Synthesis of 1-Thio-aldosides; Carbohydrate Research 31, 339-346) 5.4 g (93% of theory) of the title compound as a colorless oil.

Elemental analysis: calc .: C 59.99 H 8.38 N 5.19 S 3.09 found: C 60.32 H 8.30 N 5.09 S 3.18

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.

b) 36-cascade amine (Gly-Me-DOTA amide) i6 - (ß-D-glucopyranosyl-1-thio-3-propionic acid amide) 2o conjugate

In an analogous manner as described for Example 23c), the deprotection of 5 g (0.24 mmol) of the title compound from Example 24b) after freeze-drying leads to the formation of 2.6 g (88.6% of theory) of the above title compound as an amorphous powder. Water content: 6.03% Elemental analysis (calculated on anhydrous substance): calc .: C 47.03 H 6.62 N 9.06 S 5.19 found: C 47.12 H 6.71 N 9.02 S 5.30

c) 36-cascade amine (Gd-Gly-Me-DOTA amide) ₆ - (ß-D-glucopyranosyl-1-thio-3-propionic acid amide) o-conjugate

In an analogous manner as described for Example 23d), the complexation of 2.0 g (0.16 mmol; corresponding to 2.6 mmol of Gly-Me-DOTA) of the title compound from Example 24b) with 709 mg (2.7 mmol ) Gadolinium chloride, dissolved in 10 ml of distilled water, to form the title compound mentioned above. Yield: 2.35 g (98% of theory) as a colorless and amorphous powder Water content: 5.2%

Elemental analysis (calculated on anhydrous substance): calcd: C 39.24 H 5.11 N 7.56 S 4.33 Gd 16.98 found: C 39.61 H 5.20 N 7.49 S 4.41 Gd 16.94

Average degree of loading per molecule of the above title compound:

16 Gd-Gly-Me-DOTA units (degree of polymer loading of 44.4%) and 20 D-glucopyranosyl residues (degree of polymer loading of 55.6%). The degrees of polymer loading were determined from the molar element ratios of sulfur to gadolinium.

Example 25

36-cascade amine (Gd-Gly-Me-DOTA amide) ₁₆ - (ß-D-galactopyranosyl-1 - thio-3-propionic acid amide) 2o conjugate

a) 36-cascade amine (Gd-Gly-Me-DOTA-tri-tert-butyl ester amide) ₁₆ - [3- (2,3,4,6-tetra-O-acetyl-1-thio) -ß- D-galactopyranosyl -3-propionic acid amide)] ₂ o-conjugate

In an analogous manner to that described for Example 23b), the reaction of 3.5 g (0.28 mmol; corresponding to 5.6 mmol of free amine functions) gives the title Compound from Example 23a) with 3.6 g (6.8 mmol) of 3- (2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranosyl) propionic acid N-hydroxysuccinimide ester [ Representation in analogy to: J. Haensler et al., Bioconjugate Chem. 4, 85, (1993); Chipowsky, S., and Lee, YC (1973), "Synthesis of 1-Thio-aldosides; Carbohydrate Research 31, 339-346] 5.1 g (87.8% of theory) of the title compound as a colorless oil.

Elemental analysis: calc .: C 59.99 H 8.38 N 5.19 S 3.09 found: C 60.03 H 8.46 N 5.24 S 3.14

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.

b) 36-cascade amine (Gly-Me-DOTA amide) ₁₆ - (ß-D-galactopyranosyl-1-thio-3-propionic acid amide) 2o conjugate

In an analogous manner as described for Example 23c), the deprotection of 5.0 g (0.24 mmol) of the title compound from Example 25b) after freeze drying leads to the formation of 2.64 g (90.2% of theory). ) of the above title compound as an amorphous powder. Water content: 8.3%

Elemental analysis (calculated on anhydrous substance): calc .: C 47.03 H 6.62 N 9.06 S 5.19 found: C 47.12 H 6.71 N 9.00 S 5.07

c) 36-cascade amine (Gd-Gly-Me-DOTA amide) ₁₆ - (ß-D-galactopyranosyl-1-thio-3-propionic acid amide) 2o conjugate

In an analogous manner as described for Example 23d), the complexation of 2.5 g (0.2 mmol; corresponding to 3.2 mmol of Gly-Me-DOTA) of the title compound from Example 24b) leads to 867 mg (3.3 mmol ) Gadolinium chloride, dissolved in 10 ml of distilled water, to form the title compound mentioned above. Yield: 2.88 g (97.3% of theory) as a colorless and amorphous powder. Water content: 9.3%.

Elemental analysis (calculated on anhydrous substance): calc .: C 39.24 H 5.11 N 7.56 S 4.33 Gd 16.98 found: C 39.21 H 5.04 N 7.63 S 4.41 Gd 17.07

Average degree of loading per molecule of the above-mentioned title compound: 16 Gd-Gly-Me-DOTA units (degree of polymer loading of 43.8%) and 20 D-galactopyranosyl residues (degree of polymer loading of 56.2%). The degree of polymer loading was determined from the molar element ratios of sulfur Gadolinium determined.

Example 26

48-cascade amine (Gd-Gly-Me-DOTA amide) 2i - (α-D-mannopyranosyl-1-thio-3-propionic acid amide) ₂₇ conjugate

a) 48-cascade amine (Gly-Me-DOTA-tri-tert-butyl ester amide) 2i

20.0 g (26.8 mmol) of Gly-Me-DOTA-tri-tert.butyl ester (title compound from Example 31f) are dissolved in 100 ml of absolute dimethylformamide at room temperature and stirred with 3.7 g (32.16 mmol) N-hydroxysuccinimide added. The clear reaction mixture is then cooled to 0 ° C. and a total of 6.6 g (32.16 mmol) of dicyclohexylcarbodiimide is added at this temperature in portions. After a reaction time of 30 minutes at 0 ° C. and 2.5 hours at room temperature, the precipitated dicyclohexylurea is filtered off. The filtrate thus obtained is now slowly added dropwise at room temperature to a stirred solution of 6.0 g (0.92 mmol; corresponding to 4.4 mmol of free amino functions), 48-cascade polyamine and 4.5 g (46.8 mmol) of triethylamine in 60 ml of absolute DMF. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in vacuo and 250 ml of dichloromethane are added to the remaining residue. After filtering off insoluble constituents, the organized phase is washed successively with 5% hydrochloric acid, saturated sodium bicarbonate solution twice with water. After drying the organic product phase over sodium sulfate, the mixture is filtered and the solvent is stripped off in vacuo. You get 13.75 g (83.2% of theory; based on the polyamine used) of a slightly yellow-colored oil, which is used immediately for the subsequent synthesis steps without further purification. After a quantitative ninhydrin reaction of the above-mentioned titi compound, an average of 27 free amine functions per molecule are present.

Elemental analysis: calc .: C 63.35 H 9.61 N 16.36 found: C 63.18 H 9.70 N 16.44

b) 48-cascade amine (Gd-Gly-Me-DOTA-tri-tert.butyl ester amide) ₂₁ -

[3- (2,3,4,6-Tetra-O-acetyl-1-thio) -α-D-mannopyranosyl-3-propionamide] ₂ - conjugate

A stirred solution of 3.5 g (0.19 mmol; corresponding to 5.13 mmol of free amine functions) of the title compound from Example 26a) in 100 ml of absolute dichloromethane is mixed with 657 mg (6.5 mmol) of triethylamine at room temperature. Then with a solution of 3.3 g (6.3 mmol) of 3- (2, 3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranosyl) propionic acid N-hydroxysuccinimide ester in 60 ml of dichloromethane are added dropwise. 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. 5.07 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.

Elemental analysis: calc .: C 58.65 H 7.98 N 10.21 S 3.00 found: C 58.90 H 8.08 N 10.14 S 2.96

The percentage sulfur value of the elemental analysis of the title compound gives an average degree of loading of the polymer with 56.2% D-mannose tetraacetate (corresponding to 27 D-mannose residues per molecule). c) 48-cascade amine (Gly-Me-DOTA amide) ₂₁ - (α-D-mannopyranosyl-1-thio-3-propionic acid amide) ₂₇ conjugate

5.0 g (0.17 mmol) of the title compound from Example 26b) are dissolved in 100 ml of absolute dichloromethane. A total of 75 ml of trifluoroacetic acid is then added dropwise at 0 ° C. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in vacuo. The remaining residue is mixed with 100 ml of water and again stripped to dryness in vacuo. 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 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.

Yield: 3.47 g (90.6% of theory) as an amorphous and colorless powder. Water content: 9.11%

Elemental analysis (calculated on anhydrous substance): calc .: C 51.08 H 7.12 N 13.32 S 3.92 found: C 50.97 H 7.21 N 13.30 S 3.86

d) 48-cascade amine (Gd-Gly-Me-DOTA amide) ₂ ι - (α-D-mannopyranosyl-1-thio-3-propionic acid amide) ₂₇ conjugate

3.0 g (0.136 mmol; corresponding to 285 mmol of Gly-Me-DOTA) of the title compound from Example 26c) are dissolved in 70 ml of distilled water and the pH of the solution is adjusted to 5 by dropwise addition with 10% aqueous hydrochloric acid , 0 set. Finally, 787 mg (3.0 mmol) of gadolinium chloride, dissolved in 10 ml of distilled water, are added at room temperature and the reaction solution is stirred for 12 hours at 60 ° C. at room temperature the reaction solution was 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. 3.31 g (96.3% of theory) of the title compound are obtained as an amorphous, colorless powder with a water content of 4.9%.

Elemental analysis (calculated on anhydrous substance): calc .: C 44.54 H 5.96 N 11, 62 S 3.42 Gd 13.04 found: C 44.59 H 6.04 N 11, 55 S 3.41 Gd 13, 10th

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 27

48-cascade amine (Gd-Gly-Me-DOTA amide) ₂₁ - (ß-D-glucopyranosyl-1-thio-3-propionic acid amide) ₂ conjugate

a) 48-cascade amine (Gd-Gly-Me-DOTA-tri-tert-butyl ester amide) ₂₁ - [3- (2,3,4,6-tetra-O-acetyl-1-thio) - ß- D-glucopyranosyl-3-propion-

Amide] ₂₇ conjugate

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-β-D-glucopyranosyl) propionic acid N-hydroxysuccinimide ester 5.57 g (93% of theory) of the title compound as colorless oil.

Elemental analysis: calc .: C 58.65 H 7.98 N 10.21 S 3.00 found: C 58.68 H 8.10 N 10.20 S 3.07 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 27 D-glucose residues per molecule.

b) 48-cascade amine (Gly-Me-DOTA amide) ₂₁ - (β-D-glucopyranosyl-1-thio-3-propionic acid amide) ₂₇ conjugate

In an analogous manner as described for Example 26c), the deprotection of 5 g (0.17 mmol) of the title compound from Example 27a) after freeze-drying leads to the formation of 2.23 g (84.7% of theory) of the above title compound as an amorphous powder. Water content: 7.44%

Elemental analysis (calculated on anhydrous substance): calc .: C 51, 08 H 7.12 N 13.32 S 3.92 found: C 51, 11 H 7.10 N 13.26 S 4.01

c) 48-cascade amine (Gd-Gly-Me-DOTA amide) ₂ - (ß-D-glucopyranosyl-1-thio-3-propionic acid amide) ₂₇ conjugate

In an analogous manner as described for Example 26d), the complexation of 3.0 g (0.136 mmol; corresponding to 2.85 mmol of Gly-Me-DOTA) of the title compound from Example 27b) leads to 787 mg (3.0 mmol ) Gadolinium chloride, dissolved in 10 ml of distilled water, to form the title compound mentioned above. Yield: 3.36 g (98% of theory) as a colorless and amorphous powder. Water content: 4.41%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.54 H 5.96 N 11, 62 S 3.42 Gd 13.04 found: C 44.39 H 5.88 N 11, 74 S 3.40 Gd 13.00

Average degree of loading per molecule of the above-mentioned title compound: 21 Gd-Gly-Me-DOTA units (degree of polymer loading of 43.8%) and 27 D-glucopyranosyl residues (degree of polymer loading of 56.2%). The degree of polymer loading was determined from the molar element ratios of sulfur Gadolinium determined. Example 28

48-cascade amine (Gd-Gly-Me-DOTA amide) ₂₁ - (ß-D-galactopyranosyl-1-thio-3-propionic acid amide) ₂₇ conjugate

a) 48-cascade amine (Gly-Me-DOTA-tri-tert-butyl ester amide) ₂₁ - [3- (2,3,4,6-tetra-O-acetyl-1-thio) - ß-D- galactopyranosyl-3-propione-amide] ₂₇ conjugate

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-β-D-gaiactopyranosyl) propionic acid N-hydroxysuccinimide ester 5.23 g (90.2% of theory) of the title compound as colorless oil.

Elemental analysis: calc .: C 58.65 H 7.98 N 10.21 S 3.00 found: C 58.66 H 8.00 N 10.31 S 3.11

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.

b) 48-cascade amine (Gly-Me-DOTA amide) ₂₁ - (β-D-galactopyranosyl-1-thio-3-propionic acid amide) ₂₇ conjugate

In an analogous manner as described for Example 26c), the deprotection of 5.0 g (0.17 mmol) of the title compound from Example 28a) after freeze-drying leads to the formation of 3.48 g (91.4% of theory). ) of the above title compound as an amorphous powder. Water content: 6.79%

Elemental analysis (calculated on anhydrous substance): calc .: C 51, 08 H 7.12 N 13.32 S 3.92 found: C 51, 12 H 7.19 N 13.27 S 3.99 c) 48-cascade amine (Gd-Gly-Me-DOTA amide) ₂₁ - (ß-D-galactopyranosyl-1-thio-3-propionic acid amide) ₂₇ conjugate

In an analogous manner as described for Example 26d), the complexation of 3.0 g (0.136 mmol; corresponding to 2.85 mmol of Gly-Me-DOTA) of the title compound from Example 28b) with 787 mg (3.3 mmol) of gadolinium chloride dissolved in 10 ml of distilled water to form the title compound mentioned above. Yield: 3.32 g (96.9% of theory) as a colorless and amorphous powder. Water content: 8.70%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.54 H 5.96 N 11, 62 S 3.42 Gd 13.04 found: C 44.50 H 5.94 N 11.58 S 3.37 Gd 12, 98

Average degree of loading per molecule of the above title compound:

21 Gd-Gly-Me-DOTA units (degree of polymer loading of 43.6%) and 27 D-galactopyranosyl residues (degree of polymer loading of 56.4%). The degrees of polymer loading were determined from the molar element ratios of sulfur to gadolinium.

Example 29

48-Starburst dendrimer (Gd-DTPA amide) ₁₉ - (O-ß-D-galactopyranosyl- (1 → 4) - D-glucono-1, 5-lactone amide) g conjugate

a) 48 Starburst Dendrimer (DTPA Amide) - _| g- (O-ß-D-galactopyranosyl- (1 → 4) -D-glucono-1, 5-lactone amide) _g conjugate

To a stirred solution of 4.0 g (0.20 mmol; corresponding to 6.0 mmol of free amino functions) of the title compound from Example 14a) are suspended in 40 ml of absolute dimethyl sulfoxide at room temperature. Then a solution of 13.3 g (37.2 mmol, corresponding to 6.26 g lactone per amino function present) becomes O-β-D-galactopyranosyl- (1-4) -D-glucono-1, 5-lactone (Representation according to (a) Williams, TJ; Plessas, NR, Goldstein, IJ Carbohydr. Res. 1978, 67, Cl. (B) Kobayashi, K .; Sumitomo, H .; Ina, Y. Poiym. J. 1985, 17, 567, (c) Hiromi Kitano, Katsuko Sohda, and Ayako Kosaka, Bioconjugate Chem. 1995,, 131-134) in 40 ml of absolute dimethyl sulfoxide at 22 ° C added dropwise. The reaction solution thus obtained is then stirred at 40 ° C. for 14 hours. For working up, 500 ml of absolute methanol are added at room temperature, and the resulting colorless precipitate is filtered off with a G4 frit and washed thoroughly with a total of 250 ml of absolute methanol. The solid obtained in this way is then dissolved in 500 ml of distilled water and ultrafiltered a total of three times through an ultrafiltration membrane (YM-3, Amicon, 3 kD exclusion limit). The remaining residue is completely dissolved in distilled water and freeze-dried. Yield: 5.42 g (92.7% of theory) as a colorless lyophilisate water content: 8.34%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.23 H 6.31 N 11, 66 Na 5.96 found: C 44.41 H 6.28 N 11, 60 Na 6.03

After elemental analysis and colorimetric titration with 0.0025 molar gadolinium sulfate standard solution in the presence of xylenol orange as an indicator, the degree of DTPA loading of the polymer is 39.4% (corresponding to 19 DTPA units per molecule). After a ninhydrin reaction, no more amino functions can be detected in the above-mentioned title compound.

b) 48-Starburst dendrimer (Gd-DTPA amide) ₁₉ - (O-β-D-galactopyranosyl- (1 → 4) -D-glucono-1, 5-lactone-amide) _g conjugate

4.0 g (0.136 mmol; corresponding to 2.6 mmol of DTPA) of the title compound from Example 29a) are complexed analogously to 691 mg (2.65 mmol) of gadolinium chloride, dissolved in 10 ml of distilled water, as described for Example 1c) . After working up and freeze-drying, 4.14 g (98.7% of theory) of the title compound are obtained as an amorphous powder. Water content: 6.94% Elemental analysis (calculated on anhydrous substance): calc .: C 41, 84 H 5.96 N 11.03 Gd 9.64 Na 1.41 found: C 41, 90 H 6.03 N 10.97 Gd 9.61 Na 1, 39

The ninhydrin reaction as well as the TNBS method of the title compound are negative, i. H. the polymeric product contains no free amino functions.

Example 30

24-Starburst dendrimer (Gd-DTPA amide) ₁₀ - (O-ß-D-galactopyranosyl- (1 →) -D-glucono-1, 5-lactone amide) ₄ conjugate

a) 24-Starburst dendrimer (DTPA amide) ₁₀ - (O-ß-D-galactopyranosyl- (1 → 4) -D-glucono-1, 5-lactone-amide) ₁ conjugate

To a stirred solution of 4.0 g (0.4 mmol), corresponding to 5.7 mmol of free amino functions) of the title compound from Example 18a), are suspended in 40 ml of absolute dimethyl sulfoxide at room temperature. A solution of 12.66 g (35.4 mmol, corresponding to 6.2 g lactone per amino function present) is then O-ß-D-galactopyranosyl- (1-4) -D-glucono-1, 5-lactone in 40 ml of absolute dimethyl sulfoxide added dropwise at 22 ° C. The reaction solution thus obtained is then stirred at 40 ° C. for 14 hours. For working up, 500 ml of absolute methanol are added at room temperature, and the resulting colorless precipitate is filtered off with a G4 frit and washed well with a total of 200 ml of absolute methanoi. The solid obtained in this way is then dissolved in 350 ml of distilled water and ultrafiltered a total of three times through an ultrafiltration membrane (YM-3, Amicon, 3 kD exclusion limit). The remaining residue is completely dissolved in distilled water and freeze-dried. Yield: 5.6 g (96.0% of theory) as a colorless lyophilisate Water content: 10.2%

Elemental analysis (calculated on anhydrous substance): calc .: C 43.95 H 6.37 N 11, 63 Na 6.31 found: C 44.06 H 6.22 N 11, 59 Na 6.40 After elemental analysis and colorimetric titration with 0.0025 molar gadolinium sulfate standard solution in the presence of xylenol orange as an indicator, the degree of DTPA loading of the polymer is 41.5% (corresponding to 10 DTPA units per molecule).

According to the ninhydrin reaction and the TNBS method, no more amino functions can be detected in the title compound mentioned above.

b) 24-Starburst dendrimer (Gd-DTPA amide) ₁₀ - (O-β-D-galactopyranosyl- (1 → 4) -D-glucono-1, 5-lactone-amide) ₁₄ conjugate

5.0 g (0.343 mmol; corresponding to 10.34 mmol of DTPA of the title compound from Example 30a) are complexed analogously to 272 g (10.45 mmol) of gadolinium chloride, dissolved in 10 ml of distilled water, as described for Example 1 c) . After working up and freeze-drying, 5.17 g (97.6% of theory) of the title compound are obtained as an amorphous powder. Water content: 8.11%

Elemental analysis (calculated on anhydrous substance): calc .: C 41, 44 H 6.00 N 10.97 Gd 10.18 Na 1.49 found: C 41, 51 H 5.96 N 11.03 Gd 10.24 Na 1, 46

Example 31

24-cascade amine (Gd-Gly-Me-DOTA amide) ₁₀ - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] ₁₄ conjugate

a) 24-cascade amine (Gd-Gly-Me-DOTA amide) ₁₀ conjugate

A stirred suspension of 5.0 g (7.95 mmol) of the title compound from Example 31 h) 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 A total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide was added in portions to the reaction solution, and the reaction mixture was kept at this temperature for 1 hour. After cooling to 0 ° C., 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide are added and the reaction solution is stirred for a further 1 hour at 0 ° C., followed by 12 hours at 22 ° C. The 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.

Yield: 4.0 g (82.0% based on the polyamine used) as an amorphous and colorless powder.

Water content: 7.38%

Elemental analysis (calculated on anhydrous substance): calc .: C 43.10 H 6.07 N 14.97 Gd 17.69 found: C 43.18 H 5.99 N 15.03 Gd 17.74

According to elemental analysis, there is a degree of loading of the polymer with 41.5% Gd-Gly-Me-DOTA (corresponding to 10 Gd-Gly-Me-DOTA units per molecule). The determination of the free amino functions remaining in the polymer using ninhydrin and the TNBS method gives an average of 58.1% of free amino groups, ie. H. There are 14 free amino functions in the polymer molecule.

b) 24-cascade amine (Gd-Gly-Me-DOTA amide) ₁₀ - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] ι ₄ conjugate

In an analogous manner to that described for Example 1 d), the reaction gives 1.0 g (0.112 mmol; correspondingly 1.57 mmol of free amine functions) Title compound from Example 31a) with 2.5 g (7.87 mmol; corresponding to 5 mol equivalents based on the polyamine used) p-isothiocyanatophenyl-β-D-galactopyranose after working up 1.33 g (93.2% of theory) of one amorphous and colorless solid. Water content: 7.41%

Elemental analysis (calculated on anhydrous substance): calc .: C 45.32 H 5.66 N 11, 50 S 3.78 Gd 11, 84 found: C 45.40 H 5.72 N 11, 61 S 3.42 Gd 11, 88

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

(corresponding to 14 galactose residues per molecule) and 41.7% Gd-Gly-DOTA (corresponding to 10 Gd-Gly-Me-DOTA complexes per molecule).

c) N- (2-bromopropionyl) glycine benzyl ester

60.97 g (355.7 mmol) of α-bromopropionyl chloride are added dropwise at 0 ° C. to 100 g (296.4 mmol) of glycine benzyl ester of p-toluenesulfonic acid salt and 89.98 g (889.2 mmol) of triethylamine in 500 ml of methyl chloride. The temperature is kept between 0 ° C - 5 ° C. 1000 ml of 5% aqu. Hydrochloric acid and separates the organic phase. The organic phase is again with 500 ml of 5% aqu. Hydrochloric acid extracted, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is recrystallized from di-isopropyl ether. Yield: 69.39 g (78% of theory)

Elemental analysis: calc .: C 48.02 H 4.70 N 4.67 Br 26.62 found: C 47.91 H 4.82 N 4.51 Br 26.47 d) 1- [1-Benzyloxycarbonylmethylcarbamoyl) ethyl] -1, 4,7,10-tetraazacyclododecane

50 g (166.6 mmol) of the title compound from Example 31 c) are added to 86.14 g (500 mmol) of 1,4,7,10-tetraazacyclododecane dissolved in 1000 ml of chloroform and the mixture is stirred for 24 hours at room temperature. It is extracted 3 times with 600 ml of water, the organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo.

Yield: 53.48 g (82% of theory) of a light yellow oil. Water content: 1.5%

Elemental analysis (calculated on anhydrous substance): calc .: C 61, 36 H 8.50 N 17.89 found: C 62.03 H 8.75 N 17.36

e) 10- [1-Benzyloxycarbonylmethylcarbamoyl) -ethyl] -1, 4.7, 10-tetraazacyclododecane-1, 4,7-tri-tert-butyl ester, sodium bromide

82.20 g (421.4 mmol) of tert-butyl bromoacetate are added to 50 g (127.7 mmol) of the title compound from Example 31d) and 54.14 g (510.8 mmol) of sodium carbonate in 500 ml of acetonitrile and stirred for 12 hours at 60 ° C. The mixture is cooled to 0 ° C. and the salts are filtered off. The filtrate is evaporated to dryness and the residue is chromatographed on silica gel (mobile solvent: methylene chloride / methanol = 20: 1). Yield: 90.83 g (85% of theory) of a colorless solid

Elemental analysis: calc .: C 54.54 H 7.59 N 8.37 Na 2.75 Br 9.55 found: C 54.37 H 7.71 N 8.21 Na 2.83 Br 9.69 f) 10- [1-carboxymethylcarbamoyl) ethyl] -1, 4.7, 10-tetraazacyclododecane-1, 4,7-tri-tert-butyl ester, sodium bromide

90 g (107.5 mmol) of the title compound from Example 31e) are dissolved in 1000 ml of isopropanol and 5 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated overnight at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is recrystallized from dioxane. Yield: 77.06 g (96% of theory) of a crystalline solid

Elemental analysis: calc .: C 49.86 H 7.69 N 9.38 Na 3.08 Br 10.70 found: C 49.73 H 7.79 N 9.21 Na 3.19 Br 10.83

g) 10- [1-Carboxymethylcarbamoyl) ethyl] -1, 4.7, 10-tetraazacyclododecane-1, 4.7-triacetic acid

77 g (103.1 mmol) of the title compound from Example 31f) are dissolved in 500 ml of trifluoroacetic acid and stirred for 3 hours at room temperature. It is evaporated to dryness, the residue is taken up in 300 ml of water and the solution is placed on a column filled with Reillex® 425 PVP. You elute with water. The product-containing fractions are combined and evaporated to dryness, the residue is recrystallized from methanol / acetone. Yield: 44.04 g (84% of theory) of a colorless, hygroscopic solid. Water content: 6.5%

Elemental analysis (calculated on anhydrous substance): calc .: C 47.99 H 6.99 N 14.73 found: C 47.83 H 7.12 N 14.55

h) Gadolinium complex of 10- [1-carboxymethylcarbamoyl) -ethyl] -1, 4,7, 10- tetraazacyclododecan-1, 4,7-triacetic acid

15.27 g (42.06 mmol) of gadolinium oxide are added to 40 g (84.12 mmol) of the title compound from Example 31g), dissolved in 400 ml of water, and the mixture is heated at 90 ° C. for 3 h. The mixture is evaporated to dryness (vacuum ) and crystallizes the residue from 90% aqu. Ethanol around. The crystals are filtered off with suction, washed once with ethanol, then with acetone and finally with dimethyl ether and dried in a vacuum oven at 130 ° C. (24 hours). Yield: 50.53 g (93% of theory) of a colorless crystalline powder Water content: 2.5%

Elemental analysis (calculated on anhydrous substance): calc .: C 36.24 H 4.80 N 11, 12 Gd 24.97 found: C 36.35 H 4.95 N 10.98 Gd 24.80

Example 32

24-cascade amine (Gd-Gly-Me-DOTA amide) ₁₀ - [1- (4-thicureidophenyl) - α - D-mannopyranosyl] ₁₄ conjugate

a) 24-cascade amine (Gd-Gly-Me-DOTA amide) ₁₀ - [1- (4-thioureidophenyl) - α -D-mannopyranosyl] ₁₄ conjugate

In an analogous manner to that described for Example 1b), the reaction of 1.0 g (0.11 mmol; correspondingly 1.57 mmol of free amine functions) of the title compound from Example 31g) with 2.5 g (7.87 mmol) p-Isothiocyanatophenyl-α-D-mannopyranose after working up 1.38 g (94.7% of theory) of an amorphous and colorless solid. Water content: 5.76%

Elemental analysis (calculated on anhydrous substance): calc .: C 45.32 H 5.66 N 11, 50 S 3.38 Gd 11, 84 found: C 45.42 H 5.72 N 11, 47 S 3.41 Gd 11, 81

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). Example 33

24-cascade amine (Gd-Gly-Me-DOTA amide) ₁₀ - [1- (4-thioureidophenyl) - ß-D-glucopyranosyl] ₁ conjugate

a) 24-cascade amine (Gd-Gly-Me-DOTA amide) ₁₀ - [1 - (4-thioureidophenyl) - ß-D-glucopyranosyl] ₁₄ - conjugate

In an analogous manner to that described for Example 1b), the reaction of 1.2 g (0.13 mmol; corresponding to 1.89 mmol of free amine functions) of the title compound from Example 31g) with 2.34 g (7.87 mmol) p-Isothiocyanatophenyl-ß-D-glucopyranose after working up 1. 53 g (88.9% of theory) of an amorphous and colorless solid. Water content: 6.44%

Elemental analysis (calculated on anhydrous substance): calc .: C 46.05 H 5.85 N 11, 68 S 7.44 Gd 12.03 found: C 45.96 H 5.90 N 11, 71 S 3.40 Gd 12.10

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).

Example 34

24-cascade amine (Gd-Gly-Me-DOTA amide) ₁₀ - [1- (4-thioureidophenyl) - α -L- fucopyranosyl] ι ₄ conjugate

a) 24-cascade amine (Gd-Gly-Me-DOTA amide) ₁₀ - [1- (4-thioureidophenyl) - α -L-fucopyranosyl] ₁₄ conjugate

In an analogous manner to that described for Example 1 b), the reaction of 1.0 g (0.1 12 mmol; correspondingly 1.57 mmol of free amine functions) of the titanium Tel compound from Example 31a) with 2.34 g (7.87 mmol) of p-isothiocyanatophenyl-α-L-fucopyranose after working up 1.37 g (93.7% of theory) of an amorphous and colorless solid. Water content: 4.92%

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% α-L-fucose (corresponding to 13 α-L-fucose residues per molecule) and 40.6% (corresponding to 10 Gd-Gly-Me-DOTA Complexes per molecule).

Example 35

a) 1- [4-Nitrophenyl] tetraethylene glycol

863.2 (5 mol) of tetraethylene glycoi are dissolved in 2.5 l of anhydrous toluene, and 159.4 g (2.5 mol) of 88% potassium hydroxide powder and 7.5 g of tetrabutyiammonium hydrogen sulfate are added in succession at room temperature. A solution of 53 ml (500 mmol) of 4-fluoronitrobenzene in 500 ml of anhydrous toluene is then added dropwise at 0 ° C. with vigorous stirring. After the addition has ended, the mixture is stirred at 0 ° C. for 4 hours and at room temperature for 12 hours. For working up, the reaction mixture is stirred into 2000 ml of ice water and then the toluene phase is separated off and the aqueous phase is exhaustively extracted with toluene. After washing the combined organic phases with water, the mixture is dried over sodium sulfate, filtered and the solvent is drawn off to dryness in vacuo. The remaining, slightly yellowish, oily residue is purified by column chromatography (eluent: ethyl acetate / hexane = 3: 1). 135.8 g (86.1% of theory) of a slightly yellowish oil are obtained. Elemental analysis: calc .: C 53.33 H 6.71 N 4.44 found: C 53.27 H 6.68 N 4.50

b) 2,3,4,6-tetraacetyl-β-D-galactopyranosyl-1-O - [(4-nitrophenyl) - tetraethylene glycol]

10 g of β-D-galactose pentaacetate (purchased from Aldrich) is dissolved in 40 ml of absolute 1,2 dichloroethane and with a solution of 8.0 g (25.6 mmol) of the title compound from Example 35a) in 15 ml of 1,2 Dichloroethane added. 3.9 ml (33.3 mmol) of tin tetrachloride are then slowly added dropwise at room temperature and the reaction solution thus obtained is stirred for a further 12 h at room temperature. For working up, water is added, the organic phase is separated off and the remaining aqueous phase is exhaustively extracted with dichloromethane. After the organic phases have been dried over sodium sulfate, the mixture is filtered and the solvent is stripped off to dryness in vacuo. The remaining oily residue is purified by column chromatography (eluent: dichloromethanol / methanol = 20: 1). 14.6 g (88.2% of theory) of a colorless oil are obtained.

Elemental analysis: calc .: C 52.09 H 6.09 N 2.17 found: C 52.13 H 6.11 N 2.21

c) β-D-galactopyranosyl-1-O - [(4-nitrophenyl) tetraethylene glycol]

33.93 g (52.56 mmol) of the title compound from Example 35b) are dissolved in 680 ml of absolute methanol and mixed with 0.8 g of sodium methoxide. After a reaction time of 12 hours at room temperature, the reaction solution is neutralized by adding IRA-120 (H ⁺ ) cation exchanger in portions, suctioned off from the exchanger and the solvent removed in vacuo to dryness. The title compound thus obtained (23.3 g, 95.5% of theory) is used directly for the subsequent reduction step without further purification. Elemental analysis: calc .: C 50.31 H 6.54 N 2.93 found: C 50.48 H 6.74 N 3.07

d) β-D-galactopyranosyl-1-O - [(4-aminophenyl) tetraethylene glycol]

The reduction of 14.61 g (30.6 mmol) of the title compound from Example 35c) is carried out according to the procedures described in the literature (cf.: Taylor, JK et al., J. Chem. Soc, Chem. Commun .; 1993, 1410; Goldstein IJ, Methods in Enzymologie, Vol. XXVII, Part B., 212-219, 1972) using hydrogen (1 atm.) As reducing agent, palladium (10%) on barium sulfate as catalyst and anhydrous methanol as Solvent. After working up, 13.15 g (96% Th. D.) To obtain de ^r Titciver- compound as a colorless oil.

Elemental analysis (calculated on anhydrous substance): calc .: C 53.04 H 6.57 S 6.74 found: C 53.13 H 6.60 S 6.84

f) 24-cascade amine (Gd-Gly Me-DOTA amide) ₁₀ - [1-O- (4-thioureidotetraethylene glycolyl-pheny) - ß-D-galactopyranosyl] ₁₄ conjugate

In an analogous manner to that described in Example 1 b), the reaction of 4.0 g (0.448 mmol of the title compound from Example 31a) corresponding to 6.28 mmol of free amine functions) with 14.93 g (31.4 mmol) of the title compound from Example 35e) after working up, 6.01 g (86.3% of theory, based on the polyamine used) as a colorless lyophilisate.

Elemental analysis (calculated on anhydrous substance): calc .: C 47.36 H 6.28 N 8.56 S 2.89 Gd 10.11 found: C 47.41 H 6.31 N 8.49 S 2.93 Gd 10.18

The ninhydrin reaction as well as the TNBS method are negative, ie the polymeric product contains no free amino functions. The degree of loading of the polymer with 58.3% D-galactopyranose (corresponding to 14 Galactose residues per molecule) and 41.7% Gd-Gly-DOTA (corresponding to 10 Gd-Gly-Me-DOTA complexes per molecule).

Example 36

24-cascade amine (Gd-Gly Me-DOTA amide) ₁₀ - [1-O- (4-thioureidotetraethylene glycolyl-pheny) -α-D-mannopyranosyl] ₁ conjugate

a) α-D-Mannopyrannosyl-1-O - [(4-isothiocyanatophenyl) tetraethylene glycol]

In an analogous manner, as described in Examples 35b) - 35e) for the synthesis of the title compound from Example 35e), the reaction of 15 g of α-D-manno≤epentaacetate (38.4 mmol, Sigma commodity) leads to the formation of 13 , 22 g (72.4% of theory; over 4 synthesis steps) of the above-mentioned title compound as a colorless oil.

Elemental analysis (calculated on anhydrous substance): calc .: C 53.04 H 6.57 S 6.74 found: C 53.14 H 6.60 S 6.68

b) 24-cascade amine (Gd-Gly Me-DOTA amide) ₁₀ - [1-O- (4-thioureidotetraethylene glycolyl-pheny) -α -D-mannopyranosyl] - _| -Conjugate

By carrying out the reaction analogously as described in Example 1b), the reaction of 5.0 g (0.56 mmol, corresponding to 7.85 mmol of free amino functions, the title compound from Example 31a) with 18.66 g (39.25 mmol) of the title compound from Example 36a) to form 7.5 g (86.3% of theory), based on the polyamine used, of the above-mentioned title compound as a colorless lyophilisate.

Elemental analysis (calculated on anhydrous substance): calc .: C 47.36 H 6.28 N 8.56 S 2.89 Gd 10.11 found: C 47.31 H 6.36 N 8.49 S 2.94 Gd 10.22

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) .

Example 37

24-cascade amine (Gd-Gly Me-DOTA amide) ₁₀ - [1-O- (4-thioureidotetraethylene glycolyl-pheny) - N-acetyl-β-D-glucosaminopyranosyl] ₁₄ conjugate

a) 1-O- [4-Isothiocyanatophenyl] tetraetylene glycolyl-N-acetyl-β-D-glucosaminopyranose

In an analogous manner to that described in Examples 35b-35e), the reaction of 10 g (25.68 mmol) of N-acetyl-β-D-glucosamine pentaacetate leads to the formation of 9.85 g (74.3% of theory over 4 synthesis steps) of the above-mentioned title compound as a colorless oil.

Elemental analysis (calculated on anhydrous substance): calc .: C 53.48 H 6.63 N 2.71 S 6.21 found: C 53.60 H 6.59 N, 274 S 6.28

b) 24-cascade amine (Gd-Gly Me-DOTA amide) ₁₀ - [1-O- (4-thioureidotetraethylene glycolyl-pheny) - N-acetyl-β-D-glucosaminopyranosyl] ₁₄ - conjugate

By carrying out the reaction analogously to that described in Example 1b), the reaction of 4.0 g (0.45 mmol, corresponding to 6.3 mmol of free amine functions) of the title compound from Example 31a) with 16.2 g (31.5 mmol) the title compound from Example 37a) to form 6.15 g (85% of theory, based on the polyamine used) of the above-mentioned title compound as a colorless lyophilizate

Elemental analysis (calculated on anhydrous substance): calc .: C 47.75 H 6.32 N 9.47 S 2.78 Gd 9.75 found: C 47.84 H 6.38 N 9.59 S 2.86 Gd 9.80 Example 38

24-cascade amine (Gd-Gly Me-DOTA amide) ₁₀ - [1-O- (4-thioureidotetraethylene glycolyl-pheny) - ß-D-glucopyranosyl] ₁₄ conjugate

a) 1-O- [4-Isothiocyanatophenyl] tetraetylene glycolyl-β-D-glucopyranose

In an analogous manner to that described in Examples 35b-35e), the reaction of 8.52 g (25.68 mmol) of β-D-glucopyranosyltetraacetate (representation according to: Rosemann S., et al., Biochemistry, Vol. 8, No. 4, 1969, 1351-1359; Prihar, Behrmann, Biochemistry 1973, 12, 997-1000) to form 9.92 g (76.8% of theory over 4 synthesis steps) of the above-mentioned title compound as colorless oil (for analog synthesis see Lit Monsigny, M., et al., Biol. Cell., 51, 187 (1984)).

Elemental analysis (calculated on anhydrous substance): calc .: C 50.09 H 5.80 N 2.78 S 6.37 found: C 50.14 H 5.86 N 2.86 S 6.40

b) 24-cascade amine (Gd-Gly Me-DOTA amide) ₁₀ - [1 -O- (4-thioureidotetraethylene glycolyl-pheny) - ß-D-glucopyranosyl] ι ₄ conjugate

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.

Elemental analysis (calculated on anhydrous substance): calc .: C 46.19 H 5.95 N 9.58 S 2.82 Gd 9.87 found: C 46.28 H 5.91 N 9.63 S 2.76 Gd 9.80 Example 39

12-cascade polyamine ( ¹ 1 ¹ ln-DTPA amide) ₄ - [ß-1 -O- (6-thioureidohexyl) sialyl-Le ^x ] s conjugate

a) 12-cascade polyamine (DTPA amide) conjugate

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-ivlcnoaπhydrid-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. 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 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%

Elemental analysis (calculated on anhydrous substance): calc .: C 43.99 H 5.78 N 14.98 Na 11, 92 found: C 44.08 H 5.82 N 14.90 Na 11, 87

After elemental analysis and colorimetric titration with 0.0025 molar gadolinium sulfate standard solution in the presence of xylenol orange as an indicator, the degree of DTPA loading of the polymer is 32.94% (corresponding to 4 DTPA units per molecule). After quantitative ninhydrin reaction and quantitative amino group determination using the TNBS method (cf. Fields, R., J. Biochem. 1971, 124, 581-590) there are on average 13 free amino functions per polymer molecule.

b) β-1 -O- [6-isothiocyanatohexyl] sialyl Le ^x glycoside

150 mg (0.146 mmol) ß-1-O- [6-aminohexyl] sialyl-Le ^x glycoside (representation according to: Kunz, H. et al., Angew. Chem. 1994, 106, No. 20; Kretzschmar et al., Tetrahedron, Vol. 51, No. 47. 13015-13030, 1995) are dissolved in 20 ml of 80% aqueous ethanol and 0.028 ml (0.365 mmol) of thiophosgene are added at 0 ° C. by addition via a microsyringe. After a reaction time of 1 hour at 22 ° C, the ethanol is drawn off in vacuo and the aqueous residue of the crude isothiocyanate obtained is used directly for the subsequent reaction, the content of the above-mentioned title compound in the aqueous crude product solution thus obtained being 0.138 mmol (corresponding to a 95 % sales) is assumed. Thin layer chromatography (ethyl acetate / methanol / water / glacial acetic acid = 5: 3: 3: 0.5; Rf = 0.72) shows a uniform conversion to the title compound mentioned above.

Elemental analysis (sulfur determination; based on anhydrous substance): calculated: S 3.00 found: S 2.92

c) 12-cascade polyamine (DTPA amide) ₄ - [ß-1-O- (6-thioureidohexyl) sialyl-Le ^x ] ₈ conjugate

The reaction of 26.6 mg (0.00842 mmol; corresponding to 0.0673 mmol of free amino functions) of the title compound from Example 39a) with the entire aqueous solution of the crude product from Example 39b) (0.138 mmol) yields 88 after working up and freeze drying. 7 mg (90.6% of theory) of an amorphous and colorless solid. Water content: 8.74% Elemental analysis

(Sodium and sulfur determination; based on anhydrous substance): calc .: S 2.20 Na 3.16 found: S 2.17 Na 3.24

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).

From quantitative sialic acid determination using TBA (thiobarbituric acid) using a procedure known from the literature [cf. Lit. Aminoff, D (1961), "Methods for the quantitative estimation of N-acetylneuraminic acid and their application to hydrolysates of sialomucoids", J. Biochem. , 81 384-392; Uschida, Y. and Sugimori, T. (1977); "Distribution of neuraminidase in Arthrobacter and its purification by affinity chromatography", J. Biochem. (Tokyo), 82, 1425-1433] the degree of loading of the abovementioned title compound with 69.2% of tetrasaccharide (corresponding to 8 sialyl -Le ^x residues per molecule) is determined. After another colorimetric titration of the title compound with 0.0025 molar gadolinium sulfate standard solution, in the presence of xylenol orange as an indicator, the degree of DTPA loading of the polymer of 32.9% (corresponding to 4 DTPA units per molecule) was confirmed.

d) 12-cascade polyamine ( ^{1 in} DTPA amide) ₄ - [ß-1-O- (6-thioureidohexyl) sialyl-Le ^x ] 8 conjugate

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. Example 40

12-cascade polyamine (1 ^{1 1} 1n-DTPA amide) ₄ - [1- (4-thioureidophenyl) -α - D-mannopyranosyl] _Q conjugate

a) 12-cascade polyamine (DTPA amide) ₄ - [1- (4-thioureidophenyl) -α - D-mannopyranosyl] 3 conjugate

In an analogous manner to that described for the synthesis of the title compound from Example 1 b), the reaction of 0.5 g (0.16 mmol; corresponding to 1.3 mmol of free amine functions) of the title compound from Example 39a) with 2.07 g (6.63 mmol) p-isothiocyanatophenyl-α-D-mannopyranose after working up and freeze-drying 794 mg (88.7% of theory) of the title compound as a colorless and amorphous powder with a water content of 8.31%.

Elemental analysis (calculated on anhydrous substance): calc .: C 46.61 H 5.35 N 10.27 S 4.59 Na 6.58 found: C 46.57 H 5.41 N 10.30 S 4.63 Na 6.52

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 α-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. With the degree of loading of the title compound from Example 39a) of 32.94% determined in this way, a statistical, mean total loading of the polymer of 4-DTPA and 8-α-D-mannose residues per molecule is thus obtained. b) 12-cascade polyamine (1111n-DTPA amide) ₄ - [1 - (4-thioureidophenyl) -α - D-mannopyranosyl] conjugate

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.

Example 41

24-cascade amine (Gd-Gly-Me-DOTA-amide) ^ - [(ß-D-galactopyranosyl) -1- thio-2-imino -2-amidine] - _| 3 conjugate

a) 24-cascade amine (Gly-Me-DOTA amide) ^ conjugate

2.0 g (0.22 mmol) of the title compound from Example 10a) are dissolved in 60 ml of absolute dichloromethane. A total of 75 ml of trifluoroacetic acid is then added dropwise at 0 ° C. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in vacuo. The remaining residue is mixed with 100 ml of water and again drawn off to dryness in vacuo, then dissolved in 200 ml of distilled water and the aqueous product solution extracted twice with 60 ml of diethyl ether each time. 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

According to elemental analysis, the title compound is free of fluoride ions.

After a quantitative ninhydrin reaction, an average of 13 free amino functions are present in the title compound. After colorimetric titration of the title compound with 0.0025 molar gadolinium sulfate standard solution at 60 ° C in the presence of xylenol orange as an indicator, the degree of loading of the polymer with Gly-Me-DOTA is 46.3% (corresponding to 11 Gly-Me-DOTA Units) per molecule.

b) 24-cascade amine (Gly-Me-DOTA amide) _{1 1} - [(ß-D-galactopyraπosyl) - 1 -thio-2-imino -2-amidine] - | ₃ conjugate

In an analogous manner, as described in the literature for the reactions with proteins (see: Lee, YC et al., Methods of Enzymology, Vol. 83, 1982, 278), the reaction of 1.0 g (0.128 mmol corresponding to 1.66 mmol of free amine functions) of the title compound from Example 41a) with 11.4 g (42.8 mmol) of 2-imino-2-methoxyethyl-1-thio-β-D-galactopyranose (IME-thiogalactoside ) 1.06 g (76.3% of theory) of the title compound as a colorless lyophilisate [For the synthesis and the reaction conditions of analogous coupling reactions of IME thiopyranosides to proteins, see: YC Lee, CP. Stowell, M.J. Krantz, Biochemistry 1976, 5, 3956; R. Roger, D.G. Neilson, Chem. Rev. 1961, 61, 179; L. Wofsy, S.J. Singer, Biochemistry 1963, 2, 104; M.J. Hunter, M.L Ludwig, this series, vol. 25,585; J.E. Zull, J. Chung, J. Biol. Chem. 1975, 250. 1668; CP. Stowell, Doctoral Dissertation, The Johns Hopkins University, Baltimore, Maryland, 1978].

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. c) 24-Kaskadenamiπ- (Gd-Gly-Me-DOTA-amide) ^ - [(ß-D-galactopyra-nosyl) -1-thio-2-imino -2-amidine] ₃ conjugate

In an analogous manner to that described for Example 23d), the complexation of 900 mg (0.082 mmol; corresponding to 0.90 mmol of Gly-Me-DOTA) of the title compound from Example 41 b) with 241 mg (0.92 mmol) of gadolinium chloride leads to dissolved in 10 ml of distilled water to form the above title compound. Yield: 990 mg (96.0% of theory) as a colorless and amorphous powder. Water content: 9.32%

Elemental analysis (calculated on anhydrous Suostaπz) - calc .: C 42.19 H 6.06 N 12.58 S 3.31 Gd 13.75 found: C 42.23 H 6.10 N 12.57 S 3.28 Gd 13.80

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 β-D-glucopyranosyl residues, which was very good with the loading levels of the title compound determined on the precursors correlated.

Example 42

24-cascade amine (Yb-DTPA amide) ₁₁ - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] - | 3 conjugate

1.0 g (0.077 mmol; corresponding to 0.85 mmol of DTPA) of the title compound from Example 4b) are dissolved in 40 ml of sodium citrate buffer (pH 5.3) and at room temperature with a solution of 243 mg (0.87 mmol) of ytterbium chloride added to 10 ml of distilled water. After a reaction time of 15 minutes at room temperature, the reaction solution is adjusted to pH 7.2 with 1 molar sodium hydroxide solution. After three times of ultrafiltration through a YM3 ultrafiltration membrane (AMICON ®), the remaining residue is freeze-dried. Yield: 969 mg (96.2% of theory) as an amorphous powder Water content: 4.93% Elemental analysis (calculated on anhydrous substance): calc .: C 41, 48 H 4.91 N 9.74 S 3.19 Yb 14.54 Na 1, 93 found: C 41, 52 H 4.96 N 9.80 S 3, 22 Yb 14.60 Na 1.88

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. 1951, 28, 424] as well as the quantitative carbohydrate determination method according to Nelson and Somogyi [Cheronis et al., Mikrochim. Acta, 6, 769 (1957); Somogyi, J. Biol. Chem. 195, 19 (1952); Nelson, J. Biol. Chem., 153, 375 (1944); see. also Hodge et al., Meth. Carbohydrate Chem., Vol. 1,; Whistler and Wolfrom, eds. p. 388, Academic Press, New York, 1962; So and Goldstein, J. Biol. Chem. 242, 1617 (1967)] for determining the average degree of pyranose loading of the polyamine gives as a result a degree of loading of 32.68 D-galactose residues per molecule and is thus identical to the degree of loading caused by the percentage element ratios was determined.

Example 43

24-cascade amine (Dy-DTPA amide) _{1 r} [1 - (4-thioureidophenyl) -α D-mannopyranosyl] ₁₃ conjugate

1.4 g (0.108 mmol; corresponding to 1.18 mmol of DTPA) of the title compound from Example 5a) are dissolved in 40 ml of sodium citrate buffer (pH 5.3) and at room temperature with a solution of 325 mg (1.21 mmol) of dysprosium chloride added to 10 ml of distilled water. After a reaction time of 15 minutes at room temperature, the reaction solution is adjusted to pH 7.2 with 1 molar sodium hydroxide solution. After three times of ultrafiltration through a YM3 ultrafiltration membrane (AMICON ®), the remaining residue is freeze-dried. Yield: 1.35 g (97.0% of theory) as an amorphous powder Water content: 6.74%

Elemental analysis (calculated on anhydrous substance): calc .: C 41, 86 H 4.95 N 9.83 S 3.21 Dy 13.78 Na 1, 95 found: C 41, 84 H 4.99 N 9.78 S 3.25 Dy 13.81 Na 1.89

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.

Example 44

24-cascade amine (Mn-DTPA amide) _{1 1} - [1 - (4-thioureidophenyl) -N-acetyl-ß-D-glucosaminopyranosyl] - | 3 conjugate

1.0 g (0.077 mmol; corresponding to 0.85 mmol of DTPA) of the title compound from Example 4b) is dissolved in 40 ml of sodium citrate buffer (pH 5.3) and at room temperature with 100 mg (0.87 mmol) of manganese ll carbonate added. After a reaction time of 15 minutes at room temperature, the reaction solution is adjusted to pH 7.2 with 1 molar sodium hydroxide solution. After three times of ultrafiltration through a YM3 ultrafiltration membrane (AMICON ®), the remaining residue is freeze-dried. Yield: 911 mg (98.3% of theory) as an amorphous powder. Water content: 7.46% Elemental analysis (calculated on anhydrous substance): calc .: C 45.09 H 5.33 N 10.59 S 3.46 Mn 5.02 Na 4.20 found: C 45.11 H 5.38 N 10.61 S 3.42 Mn 5.10 Na 4.13

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-β-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 colorimetric phenol-sulfuric acid determination, as well as the quantitative carbohydrate determination method according to Nelson and Somogyi to determine the average pyranose loading level of the polyamine, results in a loading level of 13 N-acetyl-ß-D-glucosamine residues per molecule and is therefore identical to the degree of loading, which was determined by the percentage element ratios.

Example 45

24-cascade amine (Eu-DTPA amide) ₁ - [1- (4-thioureidophenyl) - ß-D-glucopyranosyl] - _| 3- conjugate

1.4 g (0.108 mmol; corresponding to 1.18 mmol of DTPA) of the title compound from Example 7b) are dissolved in 40 ml of sodium citrate buffer (pH 5.3) and at room temperature with a solution of 312 mg (1.21 mmol) of europium chloride added to 10 ml of distilled water. After a reaction time of 15 minutes at room temperature, the reaction solution is adjusted to pH 7.2 with 1 molar sodium hydroxide solution. After three times of ultrafiltration through a YM3 ultrafiltration membrane (AMICON ®), the remaining residue is freeze-dried. Yield: 1.30 g (97.6% of theory) as an amorphous powder. Water content: 8.34%

Elemental analysis (calculated on anhydrous substance): calculated: C 42.23 H 4.99 N 9.92 S 3.24 Eu 13.00 Na 1, 97 found: C 42.24 H 5.03 N 9.89 S 3.19 Eu 13.07 Na 1.93 - -

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.

Example 46

Amide conjugate of 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysyl-amino) -ethyl] trimesic acid triamide with the gadolinium complex of 10- (4-carboxy -1-methyl-2-oxo-3-azabutyl) -1, 4,7, 10-tetraazacyclododecan-1, 4,7-triacetic acid and 1-carboxymethyl-ß-D-glucopyranoside (m = 13, n = 11)

a) 1-Tert.butoxycarbonylmethyl-2,3,4,6-tetra-O-benzyl-ß-D-glucopyranoside

To a stirred solution of 661 mg (5.0 mmol) of tert-butyl glycolate in 25 ml of absolute 1, 2-dichloroethane, finely powdered molecular sieve 4 O (5.0 g) and silver silicate (5.0 g) are added in succession at room temperature. Then is added dropwise at 0 ° C. with a solution of 3.02 g (5.0 mmol) of 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl bromide, dissolved in 40 ml of absolute 1,2 Dichloroethane. The reaction solution thus obtained is then stirred at -10 ° C. for 3 hours. For working up, 250 ml of 1,2-dichloroethane are added at 0 ° C. and the reaction solution is filtered off with suction through Celite. The filtrate is washed successively with 200 ml of aqueous sodium bicarbonate solution and 220 ml of water, washed over sodium sulfate dries and filtered. After the solvent has been stripped off in vacuo, the remaining residue is chromatographed on silica gel (eluent: toluene: ethyl acetate = 10: 1).

488.7 mg (15.3% of theory) of the above-mentioned title compound are obtained as a colorless oil.

Elemental analysis: calc .: C 73.37 H 7.08 found: C 73.21 H 7.24

b) 1-carboxymethyl-2,3,4,6-tetra-O-beπzyl-ß-D-glucopyranoside

50 ml of trifluoroacetic acid are added to 30 g (45.81 mmol) of the title compound from Example 46 a) dissolved in 300 ml of 1,2-dichloroethane at -10 ° C. and the mixture is stirred for 2 hours at this temperature. The mixture is then stirred at 0 ° C for one hour. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: n-hexane / 2-propanol = 5: 1). Yield: 3.02 g (11.4% of theory) of a glassy solid.

Elemental analysis: calc .: C 72.22 H 6.40 found. C 72.09 H 6.61

c) Amide conjugate of the 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) ethyl] trimesic acid triamide with the gadolinium complex of 10- (4th -Carboxy-1-methyl-2-oxo-3-azabutyl) - 1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1-

Carboxymethyl-2,3,4,6-tetra-O-benzyl-β-D-glucopyranoside (m = 13, n = 1 1)

12.28 g (19.5 mmol) of the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecane-1 described in Example 31 h) , 4,7-triacetic acid, 2.0 g of sodium bromide (19.5 mmol), 8.28 g (72 mmol) of N-hydroxysuccinimide and 9.88 g (16.5 mmol) of the title compound from Example 46b) are dissolved in 200 ml of dimethyl sulfoxide dissolved at 50 ° C. After cooling to room temperature 14.86 g (72 mmol) of N, N'-dicyclohexylcarbodiimide are added and 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. 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. Yield: 8.13 g (95% of theory) H2O content (Karl Fischer): 7.8%

Elemental analysis (calculated on anhydrous substance): calc .: C 54.19 H 5.98 N 9.00 Gd 11.95 found: C 54.06 H 6.10 N 8.87 Gd 11.81

A ratio of m: n = 13:11 can be calculated from this.

d) amide conjugate of the 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) -ethyl] trimesic acid triamide with the gadolinium complex of 10- (4th Carboxy-1-methyl-2-oxo-3-azabutyl) -

1, 4, 7, 10-tetraazacyclododecan-1, 4,7-triacetic acid and 1-carboxymethyl-ß-D-glucopyranoside (m = 13, n = 1 1)

8.0 g (0.467 mmol) of the title compound from Example 46c) are dissolved in a mixture of 50 ml. Ethanol / 100 ml water and 2 g palladium catalyst (10% Pd on activated carbon) are added. The mixture is hydrogenated for 12 seconds at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 300 ml of water and freeze-dried. Yield: 6.08 g (99% of theory) of a glassy solid. H2θ content (Karl Fischer): 11% Elemental analysis (calculated on anhydrous substance): calc .: C 42.39 H 5.76 N 1 1.72 Gd 15.55 found: C 42.21 H 5.89 N 1 1.61 Gd 15.42

A ratio of m: n = 13: 1 1 can be calculated from this.

Example 47

Thiourea conjugate of the 24er-polyamine based on N, N, N ', ^N', N ", N" -Hexakis [2- (trilysyl-amino) -ethyl] trimesinsäuretriamids isothiocyanatobenzyl-4 with the gadolinium complex on the basis of - DOTA and 1-carboxymethyl-α-D-mannopyranoside (m = 10, n = 14)

a) Thiourea conjugate of 24mer polyamine based on

N, N, N ', ^N', N ", N" -Hexakis [2- (trilysyl-amino) -ethyl] -trimesinsäuretriamids with 1-carboxymethyl-2,3,4,6-tetra-O-benzyl-α - D-mannopyranoside (m = 10, n = 14).

Dissolved to 1.39 g (0.5 mmol) of the 24mer polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) ethyl) trimesic acid triamide 5.46 g (54 mmol) of triethylamine are added to 50 ml of water. A mixture of 4.1 1 g (7.5 mmol) of 4-isothiocyanatobenzyl-DOTA (US Pat. No. 4,923,985; Gansow OA et al., J. Chem. Soc. Perkin Trans. 1. 1992, 1 173-1 178) and 3.28 g (10.5 mmol) of p-isothiocyanatophenyl-α-D-mannopyranose, dissolved in 75 ml of water / 50 ml of ethanol (dropping time: 2 hours). The mixture is stirred at room temperature for 12 hours. Then add 3.54 g (10.6 mmol) of gadolinium acetate and adjust to pH 4.5 with 10% hydrochloric acid. The mixture is stirred for 5 hours at 80 ° C., allowed to come to room temperature and adjusted to pH 7.5 with 5% aqueous NaOH. The solution is desalted via an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and cleaned of low molecular weight components. The retentate is then freeze-dried. Yield: 6.76 g (94% of theory) of a glassy solid. H2θ content (Karl Fischer): 9.8% _{Λ Λ n}

-116-

Elemental analysis: (calculated on anhydrous substance): calc .: C 46.01 H 4.91 N 10.61 Gd 10.93 S 5.35 Na 1.60 found: C 45.87 H 4.99 N 10.50 Gd 10.82 S 5.21 Na 1.42

A ratio of m: n = 10: 14 can be calculated from this.

Example 48

24-polyamine thiourea conjugate based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) -ethyl] trimesic acid triamide with the gadolinium complex based on the 4-isothiocyanatobenzyi - DTPA and 1-carboxymethyl-ß-D-galactopyranoside (m - 8. n = 16)

a) Thiourea conjugate of 24mer polyamine based on

N, N, N ', N', N ", N" -Hexakis [2- (trilysyl-amino) ethyl] -trimesic acid triamide with 4-isothiocyanatobenzyl-DTPA (π = 8, n = 16)

To 1.39 g (0.5 mmol) of the 24-mer polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) ethyl] -trimesic acid triamide dissolved in 50 ml of water are added to 5.46 g (54 mmol) of triethylamine. A mixture of 3.22 g (6.0 mmol) of 4-isothiocyanotobenzyl-DTPA (WO 91/14459; Gansow, OA et al., Bioconjugate Chem. 1992, 3, 108-117) is added dropwise to this solution at 10 ° C. ) and 3.75 g (12.0 mmol) of p-isothiocyanatophenyl-β-D-galactopyranose, dissolved in 75 ml of water / 50 ml of ethanol (dropping time: 2 hours). The mixture is stirred at room temperature for 12 hours. Then 2.04 g (6.1 mmol) of gadolinium acetate are added and the pH is adjusted to 4.5 with 10% hydrochloric acid. The mixture is stirred for 3 hours at 60 ° C. The mixture is allowed to come to room temperature and adjusted to pH 7.5 with 5% NaOH. The solution is desalted via an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and cleaned of low molecular weight components. The retentate is then freeze-dried. Yield: 6.55 g (96% of theory) of a glassy solid. H2θ content (Karl Fischer): 10%

Elemental analysis: (calculated on anhydrous substance): calc .: C 45.15 H 4.66 N 9.54 Gd 9.22 S 5.64 Na 2.70 found: C 45.03 H 4.81 N 9.44 Gd 9.10 S 5.48 Na 2.51 A ratio of m: n = 8:16 can be calculated from this.

Example 49

Amide conjugate of 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) -ethyl] trimesic acid triamide with the gadolinium complex of 10- (4-carboxy -1-methyl-2-oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1-carboxymethyl-α-D-mannopyranoside (m = 13, n = 11)

a) l-Tert.butoxycarbonylmethyl ^ .SAδ-tetra-O-benzyl-α-D-mannopyranoside

To a stirred solution of 661 mg (5.0 mmol) of tert-butyl glycolate in 25 ml of absolute 1, 2-dichloroethane, finely powdered molecular sieve 4 A (5.0 g) and silver silicate (5.0 g) are added in succession at room temperature. Then dropwise at 0 ° C with a solution of 3.02 g (5.0 mmol) of 2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl bromide, dissolved in 40 ml of absolute 1, 2 -Dichloroethane, added. The reaction solution thus obtained is then stirred at -10 ° C. for 3 hours. For working up, 250 ml of 1,2-dichloroethane are added at 0 ° C. and the reaction solution is filtered off with suction through Celite. The filtrate is washed successively with 200 ml of aqueous sodium hydrogen carbonate solution and 220 ml of water, dried over sodium sulfate and filtered. After the solvent has been stripped off in vacuo, the remaining residue is chromatographed on silica gel (eluent: toluene: ethyl acetate = 10: 1). 472.7 mg (14.8% of theory) of the above-mentioned title compound are obtained as a colorless oil. Elemental analysis: calc .: C 73.37 H 7.08 found: C 73.25 H 7.19 - -

b) 1-carboxycarbonylmethyl-2,3,4,6-tetra-O-benzyl-α-D-mannopyranoside

50 ml of trifluoroacetic acid are added to 28 g (42.76 mmol) of the title compound from Example 49 a) dissolved in 300 ml of 1,2-dichloroethane at -10 ° C. and the mixture is stirred at this temperature for 2 hours. Then one hour at 0 ° C. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: n-hexane / 2-propanol = 5: 1). Yield: 2.58 g (10.4% of theory) of a glassy solid.

Elemental analysis: calc .: C 72.22 H 6.40 found: C 72.10 H 6.58

c) amide conjugate of 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysyl-amiπo) -ethyl] trimesic acid triamide with the gadolinium complex of 10- (4th -Carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4.7, 10-tetraazacyclododecan-1, 4.7-triacetic acid and 1-carboxymethyl-2,3, 4,6-tetra-O- benzyl α-D-mannopyranoside (m = 13, n = 1 1)

10.39 g (16.5 mmol) of the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecane-1 described in Example 31 h) , 4,7-triacetic acid, 1.7 g of sodium bromide (16.5 mmol), 8.28 g (72 mmol) of N-hydroxysuccinimide and 11.67 g (19.5 mmol) of the title compound from Example 49b) are in 200 ml Dimethyl sulfoxide dissolved at 50 ° C. After cooling to room temperature, 14.86 g (72 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is preactivated for 60 minutes. To the thus prepared N-hydroxysuccinimide esterlösung is added 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. 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. Yield: 8.1 g (95% of theory) _ _

H2θ content (Karl Fischer: 9.7%

Elemental analysis (calculated on anhydrous substance): calc .: C 56.78 H 6.09 N 8.21 Gd 10.14 found: C 56.64 H 6.18 N 8.14 Gd 10.01

A ratio of m: n = 11:13 can be calculated from this.

d) amide conjugate of the 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) -ethyl] trimesic acid triamide with the gadolinium complex of 10- (4th -Carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4.7, 10-tetraazacyclododecan-1, 4.7-triacetic acid and 1-carboxymethyl-α-D-mannopyranoside (m = 13, n = 11)

7.0 g (0.41 mmol) of the title compound from Example 49c) are dissolved in a mixture of 50 ml. Ethanol / 100 ml water and 2 g palladium catalyst (10% Pd on activated carbon) are added. It is hydrogenated for 12 hours at room temperature and a hydrogen pressure of 1 atm. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 300 ml of water and freeze-dried. Yield: 5.03 g (99% of theory) of a glassy solid. H2θ content (Karl Fischer): 9.8%

Elemental analysis (calculated on anhydrous substance): calc .: C 42.94 H 5.86 N 11.33 Gd 13.99 found: C 42.86 H 5.97 N 11.24 Gd 13.74

A ratio of m: n = 11:13 can be calculated from this.

Example 50

Amide conjugate of 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) ethyl] trimesic acid triamide with the

Gadolinium complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1-carboxymethyl-ß-D-galactopyranoside ( m = 6, n = 18) a) 1-Tert.butoxycarbonylmethyl-2,3,4,6-tetra-O-benzyl-ß-D-galactopyranoside

To a stirred solution of 661 mg (5.0 mmol) of tert-butyl glycolate in 25 ml of absolute 1, 2-dichloroethane, finely powdered molecular sieve 4 Ä (5.0 g) and silver silicate (5.0 g) are added in succession at room temperature. Then is added dropwise at 0 ° C. with a solution of 3.02 g (5.0 mmol) of 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide, dissolved in 40 ml of absolute 1, 2-dichloroethane. The reaction solution thus obtained is then stirred at -10 ° C. for 3 hours. For working up, 250 ml of 1,2-dichloroethane are added at 0 ° C. and the reaction solution is filtered off with suction through Celite. The filtrate is washed successively with 200 ml of aqueous sodium bicarbonate solution and 220 ml of water, dried over sodium sulfate and filtered. After the solvent has been stripped off in vacuo, the remaining residue is chromatographed on silica gel (eluent: toluene: ethyl acetate = 10: 1).

456.7 mg (14.3% of theory) of the above-mentioned title compound are obtained as a colorless oil. Elemental analysis: calc .: C 73.37 H 7.08 found: C 73.18 H 7.19

b) 1-carboxymethyl-2,3,4,6-tetra-O-benzyl-β-D-galactopyranoside

50 ml of trifluoroacetic acid are added to 29 g (44.29 mmol) of the title compound from Example 50 a) dissolved in 300 ml of 1,2-dichloroethane at -10 ° C. and the mixture is stirred for 2 hours at this temperature. Then one hour at 0 ° C. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: n-hexane / 2-propanol = 5: 1.

Yield: 3.79 g (14.7% of theory) of a glassy solid.

Elemental analysis: calc .: C 72.22 H 6.40 found: C 72.10 H 6.51 c) Amide conjugate of the 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) ethyl] trimesic acid triamide with the gadolinium complex of 10- (4th -Carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7, 10-tetraazacyclododecan-1, 4,7-triacetic acid and 1-carboxymethyl-ß-D-

2,3,4,6-tetra-O-benzyl-galactopyranoside (m = 6, n = 18)

5.67 g (9 mmol) of the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecane-1 described in Example 31 h) , 4,7-tri-acetic acid, 0.93 g sodium bromide (9 mmol), 8.28 g (72 mmol) N-hydroxysuccinimide and 16.16 g (27 mmol) the title compound from Example 50b) are in 200 ml of dimethyl sulfoxide dissolved at 50 ° C. 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. 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. Yield: 8.03 g (95% of theory) H2O content (Karl Fischer): 9.0%

Elemental analysis (calculated on anhydrous substance): calc .: C 63.34 H 6.39 N 6.22 Gd 5.58 found: C 63.18 H 6.47 N 6.13 Gd 5.47

A ratio of m: n = 6:18 can be calculated from this.

d) amide conjugate of the 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) ethyl] trimesic acid triamide with the

Gadolinium complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7, 10-tetraazacyclododecan-1, 4,7-triacetic acid and 1-carboxymethyi-ß-D-galactopyranoside ( m = 6, n = 18) 7.0 g (0.414 mmol) of the title compound from Example 50c are dissolved in a mixture of 75 ml. Ethanol / 100 ml water and 2 g palladium catalyst (10% Pd on activated carbon) are added. It is hydrogenated for 12 hours at room temperature at a hydrogen pressure of 1 atm. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 300 ml of water and freeze-dried. Yield: 4.27 g (99% of theory) of a glassy solid. H ₂ O content (Karl Fischer): 10.3%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.67 H 6.19 N 10.09 Gd 9.07 found: C 44.53 H 6.28 N 9.91 Gd 8.94

A ratio of m: n = 6:18 can be calculated from this.

Example 51

Amide conjugate of 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) -ethyl] trimesic acid triamide with the gadolinium complex of 10- (4-carboxy -1-methyl-2-oxo-3-azabutyl) -1, 4,7, 10- tetraazacyclododecan-1, 4,7-triacetic acid and 1-carboxymethyl-α-L-fucopyranoside (m = 10, n = 14)

a) 1-tert.butoxycarbonylmethyl-2,3,4-tri-O-benzyl-α-L-fucopyranoside

To a stirred solution of 661 mg (5.0 mmol) of tert-butyl glycolate in 25 ml of absolute 1, 2-dichloroethane, finely powdered molecular sieve 4 A (5.0 g) and silver silicate (5.0 g) are added in succession at room temperature. Then at 0 ° C dropwise with a solution of 2.49 g (5.0 mmol) 2,3,4,6-tetra-O-benzyl-α-D-fucopyranosyl bromide, dissolved in 40 ml of absolute 1, 2-dichloroethane , offset. The reaction solution thus obtained is then stirred at -10 ° C. for 3 hours. For working up, 250 ml of 1,2-dichloroethane are added at 0 ° C. and the reaction solution is filtered off with suction through Celite. The filtrate is washed successively with 200 ml of aqueous sodium bicarbonate solution and 220 ml of water, dried over sodium sulfate and filtered. After the solvent has been stripped off in vacuo, the remaining residue is chromatographed on silica gel (eluent: toluene: ethyl acetate = 10: 1).

407.5 mg (15.3% of theory) of the above-mentioned title compound are obtained as a colorless oil.

Elemental analysis: calc .: C 72.24 H 7.35 found: C 72.10 H 7.45

b) (1-Carboxymethyl) -2,3,4-tri- (O-benzyl) - α-L-fucopyranoside

To 24 g (43.74 mmol) of the title compound from Example 51 a) dissolved in 300 ml

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

Vacuum to dryness and chromatograph the residue on silica gel

(Mobile solvent: n-hexane / 2-propanol = 5: 1).

Yield: 3.36 g (16.2% of theory) of a glassy solid.

Elemental analysis: calc .: C 70.71 H 6.55 found: C 70.58 H 6.71

c) Amide conjugate of 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) ethyl] trimesic acid triamide with the

Gadolinium complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7, 10-tetraazacyclododecan-1, 4,7-triacetic acid and 1-carboxymethyl-2,3,4- tri-O-benzyl-α-L-fucopyranoside (m = 10, n = 14)

9.45 g (15 mmol) of the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4.7, 10-tetraazacyclododecane-1 described in Example 31 h) , 4,7-triacetic acid, 1.54 g sodium bromide (15 mmol), 8.28 g (72 mmol) N-hydroxysuccinimide and 10.34 g (21 mmol) of the title compound from Example 51 b) are in 200 ml Dimethyl sulfoxide dissolved at 50 ° C. After cooling to room temperature, 14.86 g (72 mmol) of N.N'-dicyclohexylcarbodiimide are added and the mixture is preactivated for 60 minutes. 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 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. Yield: 7.3 g (94% of theory) H ₂ O content (Karl Fischer: 8.6%)

Elemental analysis (calculated on anhydrous substance): calc .: C 56.06 H 6.20 N 8.57 Gd 10.12 found: C 55.91 H 6.32 N 8.49 Gd 9.97

A ratio of m: n = 10: 14 can be calculated from this.

Gadolinium complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7, 10-tetraazacyclododecan-1, 4,7-triacetic acid and 1-carboxymethyl-α-L-fucopyranoside ( m = 10, n = 14)

7.0 g (0.41 mmol) of the title compound from Example 51 c) are dissolved in a mixture of 75 ml. Ethanol / 100 ml water and 2 g palladium catalyst (10% Pd on activated carbon) are added. It is hydrogenated for 12 hours at room temperature and a hydrogen pressure of 1 atm. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 300 ml of water and freeze-dried.

Yield: 5.24 g (99% of theory) of a glassy solid. H2θ content (Karl Fischer): 1 1, 1%

Elemental analysis (calculated on anhydrous substance):

calc .: C 44.06 H 6.03 N 1 1.33 Gd 13.38 found: C 43.95 H 6.17 N 1 1.24 Gd 13.29 A ratio of m: n = 10: 14 can be calculated from this.

Example 52

Amide conjugate of 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) -ethyl] trimesic acid triamide with the gadolinium complex of 10- (4-carboxy -1-methyl-2-oxo-3-azabutyl) -1, 4,7, 10-tetraazacyclododecan-1, 4,7-triacetic acid and 6-carboxyhexyl-β-D-galactopyranoside (m = 10, n = 14)

a) 6-Tertbutoxycarbonylhexyl-2,3,4,6-tetra-O-benzyl-β-D-galactopyranoside

To a stirred solution of 3.54 g (5.0 mmol) of 1-tert-butoxycarbonylhexan-6-ol in 25 ml of absolute 1, 2-dichloroethane, finely powdered molecular sieve 4 Ä (5.0 g) and silver silicate (5.0 g) are successively added at room temperature. Then is added dropwise at 0 ° C. with a solution of 3.02 g (5.0 mmol) of 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosylbromide, dissolved in 40 ml of absolute 1,2 Dichloroethane. The reaction solution thus obtained is then stirred at -10 ° C. for 3 hours. For working up, 250 ml of 1,2-dichloroethane are added at 0 ° C. and the reaction solution is filtered off with suction through Celite. The filtrate is washed successively with 200 ml of aqueous sodium bicarbonate solution and 220 ml of water, dried over sodium sulfate and filtered. After the solvent has been stripped off in vacuo, the remaining residue is chromatographed on silica gel (eluent: toluene: ethyl acetate = 10: 1).

449.6 mg (12.7% of theory) of the above-mentioned title compound are obtained as a colorless oil.

Elemental analysis: calc .: C 76.27 H 7.96 found: C 76.41 H 7.80

b) 6-carboxyhexyl-2,3,4,6-tetra-O-benzyl-β-D-galactopyranoside

50 ml of trifluoroacetic acid are added to 32.4 g (45.81 mmol) of the title compound from Example 52a) dissolved in 300 ml of 1,2-dichloroethane at -10 ° C. and the mixture is stirred for 2 hours. at this temperature. Then stirred for one hour at 0 ° C. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: n-hexane / 2-propanol = 5: 1). Yield: 3.52 g (11.8% of theory) of a glassy solid.

Elemental analysis: calc .: C 75.43 H 7.41 found. C 75.56 H 7.32

c) Amide conjugate of the 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) ethyl] trimesic acid triamide with the gadolinium complex of 10- (4th -Carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7, 10-tetraazacyclododecan-1, 4,7-triacetic acid and 6-carboxyhexyl-2, 3,4,6-tetra-O- benzyl-β-D-galactccyranoside (m = 10, n = 14)

9.45 g (15 mmol) of the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecane-1 described in Example 31 h) , 4,7-triacetic acid, 1, 54 g of sodium bromide (15 mmol) and 8.28 g (72 mmol) of N-hydroxysuccinimide and 14.88 g (21 mmol) of 6-carboxyhexyl-2,3,4,6-tetra -O-benzyl-ß-D-galactopyranoside are dissolved in 200 ml of dimethyl sulfoxide at 50 ° C. 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 1.386 g (0.5 mmol) of the 24-mer polyamine based on the N, N, N ', N', N ", N" -Hexakis [1] is added to the N-hydroxysuccinimide ester solution thus prepared. 2- (triiysyl-amino) -ethyl] -trimesic acid triamide and 7.28 g (72 mmol) of triethylamine in 10 ml of 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.

Yield: 8.55 g (96% of theory) H ₂ O content (Karl Fischer): 9.2%

Elemental analysis (calculated on anhydrous substance): calc .: C 59.30 H 6.52 N 7.47 Gd 8.83 found: C 59.15 H 6.69 N 7.38 Gd 8.74 A ratio of m: n = 10: 14 can be calculated from this.

d) amide conjugate of the 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) -ethyl] trimesic acid triamide with the gadolinium complex of 10- (4th -Carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4.7, 10-tetraazacyclododecan-1, 4.7-triacetic acid and 6-carboxyhexyl-β-D-galactopyranoside (m = 10, n = 14)

8.0 g (0.449 mmol) of the title compound from Example 52c) are dissolved in a mixture of 75 ml. Ethanol / 100 ml water and 2 g palladium catalyst (10% Pd on activated carbon) are added. It is hydrogenated for 12 hours at room temperature and a hydrogen pressure of 1 atm. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 300 ml of water and freeze-dried. Yield: 5.67 g (99% of dr.) Glassy solid. H2θ content (Karl Fischer): 10.5%

Elemental analysis (calculated on anhydrous substance): calc .: C 45.85 H 6.44 N 10.43 Gd 12.33 found: C 45.74 H 6.55 N 10.39 Gd 12.23

From this a ratio of m: π = 10: 14 can be calculated.

Example 53

Amide conjugate of 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) -ethyl] trimesic acid triamide with the gadolinium complex of 10- (4-carboxy -1-methyl-2-oxo-3-azabutyl) -1, 4,7, 10-tetraazacyclododecan-1, 4,7-triacetic acid and 6-carboxyhexyl-α-D-mannopyranoside (m = 7, n = 17)

a) 6-Tertbutoxycarbonyl-hex-1-ol-2,3,4,6-tetra-O-benzyl-α-D-mannopyranoside In an analogous manner to that described for the title compound from Example 52a), the reaction of 3.54 g (5.0 mmol) of 1-tert-butoxycarbonylhexan-6-ol leads to 3.02 g (5.0 mmol) of 2,3,4 , 6-Tetra-O-benzyl-α-D-mannopyranosyl bromide in absolute 1, 2-dichloroethane at room temperature to form 368.5 mg (11.9% of theory) of the title compound as a colorless oil.

Elemental analysis: calc .: C 76.27 H 7.96 found: C 76.38 H 7.89

b) 1-carboxymethyl-2,3,4,6-tetra-O-benzyl-α-D-mannopyranoside

50 ml of trifluoroacetic acid are added to 30 g (45.81 mmol) of the itel compound from Example 53a) dissolved in 300 ml of 1,2-dichloroethane at -10 ° C. and the mixture is stirred for 2 hours at this temperature. The mixture is then stirred at 0 ° C for one hour. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: n-hexane / 2-propanol = 5: 1). Yield: 3.86 g (14.6% of theory) of a glassy solid.

Elemental analysis: calc .: C 75.43 H 7.41 found. C 75.40 H 7.54

c) Amide conjugate of the 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) ethyl] trimesic acid triamide with the gadolinium complex of 10- (4th -Carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7, 10-tetraazacyclododecan-1, 4,7-triacetic acid and 6-carboxyhexyl-2, 3,4,6-tetra-O- benzyl-α-D-mannopyranoside (m = 7, n = 17)

6.61 g (10.5 mmol) of the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane described in Example 31 h) -1,4,7-triacetic acid, 1.08 g of sodium bromide (10.5 mmol), 8.28 g (72 mmol) of N-hydroxysuccinimide and 16.70 g (25.5 mmol) of the title compound from Example 53b ) are dissolved in 200 ml of dimethyl sulfoxide at 50 ° C. After cooling to room temperature, 14.86 g (72 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is preactivated for 60 minutes. To the N-hydroxy succinimide ester solution is added a solution of 1, 386 g (0.5 mmol) of the 24mer-polyamine based on N, N, ^N, N ', N ", N" -Hexakis [2- (triIysyl-amino ) - ethyl] -trimesic acid triamide and 7.28 g (72 mmol) of triethylamine in 10 ml of water and stirred overnight at room temperature. 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.

Yield: 8.49 g (95% of theory) H2O content (Karl Fischer): 7.6%

Elemental analysis (calculated on anhydrous substance): calc .: C 63.28 H 6.76 N 6.27 Gd 6.16 found: C 63.17 H 6.83 N 6.15 Gd 6.09

A ratio of m: n = 7:17 can be calculated from this.

d) Amide conjugate of the 24-polyamine based on the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) ethyl] trimesic acid triamide with the gadolinium complex of 10- (4th -Carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 6-carboxyhexyl-α-D-mannopyranoside (m = 7, n = 17)

8.0 g (0.447 mmol) of the title compound from Example 53c) are dissolved in a mixture of 75 ml of ethanol / 100 ml of water and 2 g of palladium catalyst (10% Pd on activated carbon) are added. The mixture is hydrogenated for 12 hours at room temperature and a hydrogen pressure of 1 atm. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 300 ml of water and freeze-dried. Yield: 5.21 g (99% of theory) of a glassy solid. H ₂ O content (Karl Fischer): 12%

Elemental analysis (calculated on anhydrous substance): calc .: C 47.63 H 6.78 N 9.54 Gd 9.37 found: C 47.52 H 6.88 N 9.48 Gd 9.28 A ratio of m: n = 7:17 can be calculated from this.

Example 54

24-cascade amine (Gd-Gly-Me-DOTA amide) ^ - (N-glutaroyl-2-aminoethyl-1-thio-ß-D-lactose amide) ₁₃ conjugate

a) N-Glutaroyl-2-aminoethyl-1-thio-β-D-lactose -2,3,6,2 ", 3", 4 ", 6" -heptaacetate

To a stirred solution of 12.0 g (15 mmol) (2-aminoethyl) -1-thio- ß-D-lactose heptaacetate (for synthesis see: Yoshiaki Miura, Tsutomu Arai, Tatsuya Ya agata, Carbohydrate Reserarch 289 ( 1996) 193 - 199) at 200 m! Absolute tetrahydrofuran is added at 22 ° C in total 2.05 g (18 mmol) of Giutsrsäureanhydrid in portions and the reaction solution is allowed to stir after 12 hours at room temperature.

For the preparation, 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.

Elemental analysis: calc .: C 49.01 H 5.73 N 1.73 S 3.96 found: C 49.10 H 5.89 N 1.83 S 3.92

b) 24-cascade amine (Gly-Me-DOTA-tri-t-butyl ester amide) ₁ - [N-glutaroyl- (2-aminoethyl-1-thio-β-D-lactose-2,3,6, 2 ", 3", 4 ", 6" -heptaacetyl) amide -] - _| 3 conjugate

14 mg (18.96 mmol) of the compound from Example 54 a) are dissolved in 100 ml of absolute dimethylformamide at room temperature and at 0 ° C. with 2.56 g (22.2 mmol) N-hydroxysuccinimide followed by 4.55 g (22.2 mmol) dicyclohexylcarbodimide. After a reaction time of 60 minutes at 0 ° C. and 3 hours at 22 ° C., the insoluble dicyclohexylurea is filtered off, and the clear active ester solution of the title compound obtained in this way is slowly added dropwise at 0 ° C. to a stirred solution of 4.0 g (0.446 mmol; corresponding to 5.8 mmol of free amine functions) of the title compound from Example 10a). After a reaction time of 12 hours at room temperature, the solvent is removed in vacuo and 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. 7.7 g (92.6% of theory) of the title compound are obtained as a colorless oil. The ninhydrin and TNBS determination of ^T itelverbindung run negative, ie in Po lymer are no free amino functions before. The percentage sulfur value of the elemental analysis of the title compound gives a degree of loading of the polymer with 53.4% lactose heptaacetate units (corresponding to 13 lactose esters per molecule).

Elemental analysis: calc .: C 57.35 H 7.74 N 8.41 found: C 57.41 H 7.78 N 8.37

c) 24-cascade amine (Gly-Me-DOTA amide) ₁ - (N-glutaroyl-2-aminoethyl-1-thio-β-D-lactose amide) ₃ conjugate

5.87 g (0.312 mmol) of the title compound from Example 54 b) are dissolved in 100 ml of absolute dichloromethane and then a total of 75 ml of trifluoroacetic acid are added dropwise at 0 ° C. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in vacuo. The remaining residue is mixed with 100 ml of water and stripped again to dryness in vacuo. 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 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.

Elemental analysis: calc .: C 47.58 H 6.61 N 8.27 S 3.62 found: C 47.61 H 6.58 N 8.32 S 3.68

Water content: 6.43%

Yield: 3.29 (89.6% of theory) as an amorphous and colorless powder.

An average degree of loading of the polymer of 45.4% Gly-Me-DOTA and 54.6% lactose (corresponding to 11 Gly-Me-DOTA units and 13-D-lactose residues per molecule) was determined for the above-mentioned title compound. No free amino functions can be detected in the title compound by means of the ninhydrin reaction.

d) 24-cascade amine (Gd-Gly-Me-DOTA amide) ^ - (N-glutaroy-2-aminoethyl-1-thio-β-D-lactose amide) - | ₃ conjugate

2.53 g (0.22 mmol; corresponding to 2.42 mmol of Gly-Me-DOTA) of the title compound from Example 54 c) are dissolved in 70 ml of distilled water and the pH of the solution is adjusted by dropwise addition with 10% aqueous hydrochloric acid adjusted to 5.0. Finally, 670 mg (2.55 mmol) of gadolinium chloride are added at room temperature and the reaction solution is stirred for 12 hours at 60 ° C. 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 with distilled water filled up from 500 ml. After three times ultrafiltration against distilled water over a YM3 ultrafiltration membrane (AMICON ®), the remaining residue is freeze-dried. 2.7 g (98.6% of theory) of the title compound are obtained as an amorphous, colorless powder with a water content of 6.12%. Elemental analysis (calculated on anhydrous substance): calc .: C 41, 47 H 5.51 N 7.21 S 3.16 Gd 13.10 found: C 41, 54 H 5.60 N 7.16 S 3.09 Gd 13.18

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.

Example 55

24-cascade amine (Gd-Gly-Me-DOTA amide) ^ - (N-glutaroyl-2-amiroe hyl-1-O-ß-D-lactose amide) ₃ conjugate

a) N-Glutaroyl-2-aminoethyl-1-O-β-D-lactose -2,3,6,2 ", 3", 4 ", 6" -heptaacetate

In an analogous manner to that described for Example 54a), the reaction gives 14.0 g (21.6 mmol) of (2-amino-ethyl) -ß-latosideheptaacetat (Yoshiaki Miura, Tsutomu Arai, Tatsuya Yamagata, Carbohydrate Reserarch 289 (1996) 193-199) in 250 ml of anhydrous THF with 2.96 g (26 mmol) of glutaric anhydride after working up 14.9 g (87.0% of theory) of the title compound as a colorless solid.

Elemental analysis (calculated on anhydrous substance): calc .: C 50.00 H 5.85 N 1.77 found: C 49.89 H 5.92 N 1.80

b) 24-cascade amine (Gly-Me-DOTA-tri-t-butyl ester amide) ₁₁ - [N-glutaroyl- (2-aminoethyl-1-O-ß-D-lactose-2,3, 6.2 ", 3", 4 ", 6" -heptaacetyl) amide] i3 conjugate

14.4 g (18.16 mmol) of the compound from Example 55a) are dissolved in 100 ml of absolute dimethylformamide at room temperature and at 0 ° C. with 2.51 g (21.8 mmol) of N-hydroxysuccinimide followed by 4.46 ( 28.8 mmol) dihydro hexylcarbodimide added. After a reaction time of 60 minutes at 0 ° C and 3 hours at 22 ° C, the insoluble dicyclohexylurea is filtered off and the clear active ester solution of the title compound obtained in this way is slowly added dropwise at 0 ° C to a stirred solution of 3.9 g (0.435 mmol; corresponding to 5.65 mmol of free amine functions) of the title compound from Example 10a). After a reaction time of 12 hours at room temperature, the solvent is removed in vacuo and 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. 7.48 g (90.4% of theory) of the title compound are obtained as a colorless oil. 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 of the elemental analysis of the title compound gives a degree of loading of the polymer with 54.5% lactose heptaacetate units (corresponding to 13 lactose residues per molecule).

Elemental analysis: calc .: C 56.72 H 7.65 N 8.31 found: C 56.82 H 7.69 N 8.41

c) 24-cascade amine (Gly-Me-DOTA amide) ₁ - (N-glutaroyl-2-aminoethyl-1-O-ß-D-lactose amide) _{1 3} conjugate

5.93 g (0.312 mmol) of the title compound from Example 55b) are dissolved in 100 ml of absolute dichloromethane and a total of 75 ml of trifluoroacetic acid are added dropwise at 0 ° C. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in vacuo. The remaining residue is mixed with 100 ml of water and stripped again to dryness in vacuo. The oily residue thus obtained 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 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%

Yield: 3.23 g (91.7% of theory) as an amorphous and colorless powder.

Elemental analysis (calculated on anhydrous substance): calc .: C 48.46 H 6.73 N 7.33 found: C 48.52 H 6.59 N 7.40

d) 24-cascade amine (Gd-Gly-Me-DOTA-amide) ^ - (N-glutaroyl-2-amino-e * yl-1-O-ß-D-lactose amide) ₁₃ conjugate

2.48 g (0.22 mmol; corresponding to 2.42 mmol of Gly-Me-DOTA) of the title compound from Example 55c) are dissolved in 70 ml of distilled water and the pH of the solution is adjusted by dropwise addition with 10% aqueous hydrochloric acid adjusted to 5.0. 670 mg (2.55 mmol) of gadolinium chloride, dissolved in 10 ml of distilled water, are then added and the reaction solution is stirred for 12 hours at 60 ° C. At room temperature, the reaction solution is mixed with 1 brought molar sodium hydroxide solution to pH 7.2 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. 2.75 g (96.1% of theory) of the title compound are obtained as an amorphous, colorless powder with a water content of 4.19%.

Elemental analysis (calculated on anhydrous substance): calc .: C 42.13 H 5.50 N 7.33 Gd 13.31 found: C 42.20 H 5.60 N 7.26 Gd 13.28

The molar element ratio of sulfur to gadolinium thus results in an average degree of loading of the polymer of 45.7% Gd-Gly-Me-DOTA and 54.3% 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 the quantitative ninhydrin reaction. """

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Example 56

24-cascade amine (Gd-DTPA amide) _{1 1} - (α-D-mannopyranose-1-thio-3-propionone amide) ^ 3 conjugate

a) 24-cascade amine (Gd-DTPA-tetra-t-butyl ester amide) _{1 1}

20.0 g (32.37 mmol) of 3,9-bis (t-butoxycarbonylmethyl) -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 4.47 g (38.84 mmol) of N-hydroxysuccinimide are added with stirring. The clear reaction mixture is then cooled to 0 ° C. and a total of 7.97 g (38.84 mmol) of dicyciohexylcarbodiimide is added at this temperature. After a reaction time of 30 minutes at 0 ° C. and 2.5 hours at room temperature, the precipitated dicyclohexylurea is filtered off. The filtrate thus obtained is now slowly added dropwise at room temperature to a stirred solution of 9.0 g (1.9 mmol; corresponding to 44.8 mmol of free amino functions), 24-cascade polyamine and 4.6 g (45.8 mmol) Triethylamine in 60 ml of absolute DMF. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in vacuo and 250 ml of dichloromethane are added to the remaining residue. After filtering off the insoluble constituents, the organic phase is washed successively with 5% hydrochloric acid, saturated sodium hydrogen carbonate solution and twice with water. After this

Drying the organic product phase over sodium sulfate is filtered and the solvent removed in vacuo. 14.0 g (79.2% of theory; based on the polyamine used) of a slightly yellow-colored oil are obtained, which is used immediately for the subsequent synthesis steps without further purification. After quantitative ninhydrin reaction of the above-mentioned title compound, an average of 13 free amine functions per molecule are present.

Elemental analysis: calc .: C 58.84 H 9.01 N 11, 66 found: C 57.79 H 9.24 N 11, 80 b) 24-cascade amine (DTPA-tetra-tert-butyl ester amide) _{1 r} [(3- (2,3,4, 6-tetra-O-acetyl) -1-thio-α-D-mannopyranosyl-3 -propion-amide) ₃ - conjugate

617 mg (6.1 mmol) of triethylamine are added to a stirred solution of 3.5 g (0.27 mmol; corresponding to 3.5 mmol of free amine functions) of the title compound from Example 56a) in 100 ml of absolute dichloromethane at room temperature. Then with a solution of 2.97 g (5.61 mmol) of 3- (2, 3,4,6-tetra-O-acetyl-1-thio-α-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) added dropwise in 60 ml 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. 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. 3.55 g (92.6% of theory) of the title compound are obtained as a colorless oil. The ninhydrin reaction of the title compound is negative, i. H. free amino functions are no longer detectable in the polymer.

Elemental analysis: calc .: C 55.10 H 7.73 N 7.37 S 2.81 found: C 55.20 H 7.78 N 7.31 S 2.79

An average degree of loading of the polymer with 55% D-mannose tetraacetate (corresponding to 13 D-mannose residues per molecule) results from the percentage sulfur value of the elemental analysis of the title compound.

c) 24-cascade amine (DTPA amide) ₁ - (α-D-mannopyranose-1-thio-3-propione amide) ₁ 3 conjugate

4.5 g (0.30 mmol) of the title compound from Example 56b) are dissolved in 100 ml of absolute dichloromethane. A total of 75 ml of trifluoroacetic acid is then added dropwise at 0 ° C. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in vacuo. The remaining residue is mixed with 100 ml of water and again in vacuo peeled off 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 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.

Water content 6.39%

Elemental analysis (calculated on anhydrous substance): calc .: C 43.20 H 5.65 N 9.82 Na 9.09 S 3.75 found: C 43.22 H 5.71 N 9.79 Na 9.12 S 3.70

The ninhydrin reaction of the title compound is negative, i. H. free amino functions are no longer detectable in the polymer.

d) 24-cascade amine (Gd-DTPA amide) ₁ ^ - (α-D-mannopyranose-1-thio-3-propione amide) - | 3 conjugate

2.5 g (0.22 mmol; corresponding to 2.47 mmol of DTPA) of the title compound from Example 56c) are dissolved in 70 ml of distilled water and the pH of the solution is adjusted to 5 by dropwise addition with 10% aqueous hydrochloric acid , 2 set. Finally, a solution of 670 mg (2.55 mmol) of gadolinium chloride in 10 ml of distilled water is added at room temperature and the reaction solution is stirred 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. 2.6 g (98.3% of theory) of the title compound are obtained as an amorphous, colorless powder with a water content of 8.11%.

Elemental analysis (calculated on anhydrous substance): calc .: C 39.73 H 5.20 N 9.03 S 3.45 Gd 14.30 found: C 39.81 H 5.20 N 9.07 S 3.49 Gd 14.28

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 57

24-cascade amine (Gd-DTPA amide) _r (β-D-galactopyranose-1-thio-3-propion-amide) - _| 3 conjugate

a) 24-cascade amine (DTPA-tetra-tert-butyl ester amide) -] _r [(3- (2,3,4,6-tetra-O-acetyl) -1-thio- ß-D-galactopyranosyl- 3-propion-amide) i3 conjugate

In an analogous manner to that described for example 56b), the reaction of 3.0 g (0.32 mmol; corresponding to 4.2 mmol of free amine functions) of the title compound from example 56a) with 2.76 g (5.2 mmol) 3- (2,3,4,6-Tetra-O-acetyl-1-thio-β-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 4.15 g (87.6% of theory) . Th.) Of the above-mentioned title compound as a colorless oil.

Elemental analysis: calc .: C 55.10 H 7.73 N 7.37 S 2.81 found: C 55.14 H 7.80 N 7.31 S 2.88 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 elementary analysis.

b) 24-cascade amine (DTPA amide) ₁ - (ß-D-galactopyranose-1-thio-3-propione amide) i3 conjugate

In an analogous manner to that described for example 56c), the deprotection of 3.5 g (0.23 mmol) of the title compound from example 56b) after freeze-drying leads to the formation of 2.26 g (88.6% of theory). ) of the above title compound as an amorphous powder. Water content: 5.74%

Elemental analysis (calculated on anhydrous substance): calc .: C 43.20 H 5.65 N 9.82 Na 9.09 S 3.75 found: C 43.22 H 5.68 N 9.77 Na 9.12 S 3.70

c) 24-cascade amine (Gd-DTPA amide) _{1 1} - (ß-D-galactopyranose-1-thio-3-propione amide) - | 3 conjugate

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%

Elemental analysis (calculated on anhydrous substance): calc .: C 39.73 H 5.20 N 9.03 Na 2.09 S 3.45 Gd 14.30 found: C 39.84 H 5.22 N 9.10 Na 2.12 S 3.40 Gd 14.27

Average degree of loading per molecule of the above title compound:

11 Gd-DTPA units and 13 D-galactopyranosyl residues Example 58

5 24-cascade polyamιπ- ( ^{1 1 1} indium-DTPA-Amιd) ₈ - [ß-ι, 1 -deoxy-1-thιoureιdo) -

a) 24-Kaskadenpolyamιn - (DTPA-tetra-t-butyl ester-Amιd) ₈ conjugate

10 12.35 g (20 00 mmol) 6 9-Bιs (t-butoxycarbonylmethyl) -3-carboxymethyl-3 6 9-tnazaundecandicarboxylic acid di-t-butyl ester are dissolved in 100 ml of absolute dimethylformamide at room temperature and stirred with 2 9 g (24 mmol) of N-hydroxysuccinimide are added. The clear reaction mixture is then cooled to 0 ° C. and a total of 49 g at this temperature in portions

15 (24 mmol) of dicyclohexylcarbodiimide are added. After a reaction time of 30 minutes at 0 ° C. and 2 5 hours at room temperature, the precipitated dicyclohexylurea is filtered off. The filtrate thus obtained is then slowly added dropwise at room temperature to a stirred solution of 9.0 g (1.9 mmol corresponding to 45 8 mmol 24e of free amino functions) and 4.6 g ^r -Kaskadenpoiyamιn

20 (45.8 mmol) of triethylamine in 60 ml of absolute DMF After a reaction time of 12 hours at room temperature the mixture is concentrated in vacuo to dryness and the remaining residue with 250 ml dichloromethane ve ^r sets After filtering off insolubles, the organic phase is washed successively sodium hydrogen carbonate solution saturated with 5% hydrochloric acid twice with

25 water washed After drying the organic product phase over sodium sulfate, the mixture is filtered and the solvent is stripped off in vacuo. 12.38 g (94 6% of theory, based on salted-in polyamine) of a slightly yellow-colored oil are obtained which, without further purification, is immediately used for the subsequent ones Synthetic steps is used After quantitative ninhydπnreak

30 tion of the abovementioned title compound there are an average of 16 free amine functions per molecule

b) 24-cascade Dθlyamιn- (DTPA-Amιd) ₈ conjugate

J3

4 5 g (0 58 mmol) of the title compound from Example 58a) are dissolved in 100 ml of absolute dichloromethane is then Dei tropfenwe'se 0 ° C with 75 ml of trifluoroacetic acid After eιπe ^r Response Time 12 STUN _{Λ n}

-142-

is evaporated to dryness at room temperature in vacuo. The remaining residue is mixed with 100 ml of water and stripped again to dryness in vacuo. The residue is dissolved in 200 ml of distilled water. The aqueous product solution is extracted twice with 60 ml of diethyl ether each. The aqueous product solution is 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 YMA ultrafiltration membrane (AMICON®) against distilled water. 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. After renewed ultrafiltration, the remaining residue is made up to a volume of 500 ml with deionized water and freeze-dried. Yield: 3.16 g (84.3% of theory) as an amorphous and colorless powder. Water content: 7.33%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.70 H 6.0 N 14.92 Na 11, 36 found: C 44.77 H 6.6 N 14.90 Na 11, 31

c) 1-deoxy-1-isothiocyanato-sialyl-Le ^x -

270 mg (0.293 mmol) 1-deoxy-1-amino-sialyl-Le ^x (representation according to: Kunz, H.; et al., Angew. Chem. 1994, 1JJJ No. 20; Kunz, H.; et al. , Angew. Chem. 1996, 108, No. 3, 359-362; Kunz, H.; et al., Angew. Chem. 1995, 107, No. 9; Kretzschmar et al., Tetrahedron, Vol. 51, No 47. 13015-13030, 1995) are dissolved in 40 ml of 80% aqueous ethanol and 0.056 ml (0.73 mmol) of thiophosgene are added at 0 ° C. by addition via a microsyringe. After a reaction time of 1 hour at 22 ° C, the ethanol is drawn off in vacuo and the aqueous residue of the crude isothiocyanate obtained is used directly for the subsequent reaction, the content of the above-mentioned title compound in the aqueous crude product solution thus obtained being 0.276 mmol (corresponding to a 95 % conversion) is assumed, which are contained in a total volume of 7.6 ml of aqueous solution. Thin layer chromatography (ethyl acetate / methanol / water / glacial acetic acid = 5: 3: 3: 0.5; Rf = 0.54) of the reaction solution shows complete and uniform conversion to the title compound mentioned above. Sulfur determination (based on anhydrous sample): calc .: S 3.31 found: S 3.24

d) 24-cascade polyamine (DTPA amide) ₈ - [ß- (1-Deoxy-1-thioureido) - sialyl-Le ^x ] ₁₆ conjugate

The reaction of 54.5 mg (0.00842 mmol; corresponding to 0.134 mmol of free amino functions) of the title compound from Example 58b) with the entire aqueous solution of the crude product of the title compound from Example 58c, corresponding to 0.276 mmol), provides after working up and freeze drying: 64, 7 mg (89% of theory) of an amorphous and colorless solid. Water content: 10.01%

Elemental analysis (determination of sodium and sulfur; based on anhydrous sample): calc .: S 2.34 Na 3.35 found: S 2.36 Na 3.29

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 (corresponding to 8 sialyl-Le ^x residues per molecule). The degree of loading of the above-mentioned title compound with 67.2% of tetrasaccharide (corresponding to 16 sialyl-Le ^x residues per molecule) is determined from the quantitative determination of sulfuric acid using TBA (thiobarbituric acid) using a procedure known from the literature (cf. Example 39). After another colorimetric titration of the title compound with 0.0025 molar gadolinium sulfate standard solution, in the presence of xylenol orange as an indicator, the degree of DTPA loading of the polymer of 32.8% (corresponding to 8 DTPA units per molecule) was confirmed. _{Λ Λ Λ}

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e) 24-cascade polyamine ( ¹¹¹ indium DTPA amide) ₈ - [ß- (1-deoxy-1-thioureido) sialyl-Le ^x ] ₁₆ conjugate

1 mg of the title compound from Example 58 d) are dissolved in 2 ml of sodium citrate buffer (pH 5.3) and a solution of ¹ 1 ^{1 of} indium chloride (initial activity: 17.2 MBq) is added at room temperature. After a reaction time of 15 minutes at room temperature, the reaction solution is adjusted to pH 7.2 with 1 molar sodium hydroxide solution and sterile filtered.

The solution prepared in this way can be used directly for the relevant radio diagnostic purposes

Example 59

24-cascade polyamine ( ¹⁵⁷ gadolinium DTPA amide) ₈ - [ß-1-O- (6-thioureidohexyl) sialyl-Le ^x ] i6 conjugate

a) 24-cascade polyamine - (DTPA amide) ₈ conjugate

5.0 g (1.80 mmol; corresponding to 43.2 mmol of free amino functions) 24-cascade polyamine are dissolved in 400 ml of distilled water and adjusted to a pH of 9.5 with 1 molar sodium hydroxide solution. A total of 8.0 g (20.0 mmol) of DTPA monoanhydride monoethyl ester is then added, 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 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. Yield: 10.63 g (91.2% of theory; based on the polyamine used) as an amorphous powder Water content: 7.88%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.70 H 6.04 N 14.92 Na 11, 36 found: C 44.81 H 6.10 N 14.90 Na 11, 32

After elemental analysis and colorimetric titration with 0.0025 molar gadolinium sulfate standard solution in the presence of xylenol orange as an indicator, the degree of DTPA loading of the polymer is 33.47% (corresponding to 8 DTPA units per molecule). After the quantitative ninhydrin reaction and the quantitative determination of the amino groups using the TNBS method, there are a statistical average of 16 free amino functions per polymer molecule.

b) β-1-O- (6-isothiocyanato-hexyl) sialyl-Le ^x

250 mg (0.243 mmol) ß-1-O- [6-aminohexyl] sialyl-Le ^x (representation according to: Kunz, H.; et al., Angew. Chem. 1994, 106. No. 20; Kretzschmar et al ., Tetrahedron, Vol.51, No. 47.13015-13030, 1995) are dissolved in 30 ml of 80% aqueous ethanol and 0.046 ml (0.60 mmol) of thiophosgene are added at 0 ° C. by addition via a microsyringe . After a reaction time of 1 hour at 22 ° C, the ethanol is removed in vacuo and the aqueous residue of the crude isothiocyanate obtained is used directly for the subsequent reaction, the content of the title compound mentioned above corresponding to the aqueous crude product solution thus obtained at 0.23 mmol ( a 95% conversion) is assumed, which are contained in a total volume of 5.6 ml of aqueous solution.

Thin layer chromatography (ethyl acetate / methanol Λ / water / glacial acetic acid = 5: 3: 3: 0.5; Rf = 0.72) of the reaction solution shows complete and uniform conversion to the above-mentioned title compound.

Elemental analysis (sulfur determination; based on an anhydrous sample): calculated: S 3.00 found: S 2.90 c) 24-cascade polyamine (DTPA amide) ₈ - [ß-1 -O- (6-thioureidohexyl) - sialyl-Le ^x ] - | ₆ conjugate

The reaction of 50.0 mg (0.00770 mmol; corresponding to 0.123 mmol of free amino functions) of the title compound from Example 59a) with the entire aqueous solution of the crude product of the title compound from Example 59b) (0.23 mmol) provides after working up and freeze drying 167 7 mg (92.4% of theory) of an amorphous and colorless solid. Water content: 9.04%

Elemental analysis (determination of sodium and sulfur; based on anhydrous sample): calc .: S 2.18 Na 6.95 found: S 2.29 Na 7.03

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 67.0% sialyl -Le ^x units (corresponding to 16 sialyl -Le ^x residues per molecule).

From quantitative sialic acid determination using TBA (thiobarbituric acid) using a procedure known from the literature [cf. Lit .: Aminoff, D., (1961), "Methods for the quantitative estimation of N-acetylneuraminic acid and their application to hydrolysates of sialomucoids", J. Biochem. , 81, 384-392; Uschida, Y. and Sugimori, T. (1977), "Distribution of neuraminidase in Arthrobacter and its purification by affinity chromatography", J. Biochem. (Tokyo), 82, 1425-1433] the degree of loading of the above-mentioned title compound with 68.1% of tetrasaccharide (corresponding to 16 sialyl -Le ^x residues per molecule) is determined. in the presence of xylenol orange as an indicator, the DTPA loading level of the polymer of 32.1% (corresponding to 8 DTPA units per molecule) was confirmed. d) 24-cascade polyamine ( ¹⁵⁷ gadolinium DTPA amide) ₈ - [sialyl-Le ^x -1 - (6-hexyl-thiourea)] ₁₆ - conjugate

1 mg of the title compound from Example 59c) are dissolved in 2 ml of sodium citrate buffer (pH 5.3) and a solution of 1 ⁵⁷ gadolinium chloride (initial activity: 16.2 MBq) is added at room temperature. After a reaction time of 15 minutes at room temperature, the reaction solution is adjusted to pH 7.2 with 1 molar sodium hydroxide solution and sterile filtered. The solution prepared in this way can be used directly for the relevant radio diagnostic purposes

Example 60

24-cascade polyamine (Gd-DTPA amide) - (N-G! Utaroyl-3-aminoethyl-ß-1-thiolactoside amide) - | 3 conjugate

a) 24-cascade polyamine (DTPA-tetra-t-butyl ester amide) (N-glutaroyl-3-aminoethyl-ß-1-thioiactoside-amide) ₁₃ conjugate

In an analogous manner to that described in Example 54b), the reaction gives 5.40 g (0.58 mmol, 7.54 mmol of free amine) of the title compound from Example 56a), which was previously in 25 ml of absolute N, N-dimethylformamide was dissolved and the solution thus contained was cooled to 0 ° C. with a solution of 12.16 g (13.92 mmol) of N-glutaroyl-3-aminoethyl-β-1-thiolactosylheptaacetate-glutaric acid-N-hydroxysuccinimide ester [(for the illustration see Example 54b)] in 75 ml of absolute N, N-dimethylformamide to form the desired titanium compound. For this purpose, after a reaction time of 12 hours at room temperature, the solvent is removed in vacuo and made up to a total volume of 500 ml with dichloromethane. For working up, 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. 10.0 g (90.1% of theory) of the title compound are obtained as a colorless oil. The ninhydrin reaction as well as the TNBS determination of the title compound are negative, ie there are no longer any free amino functions in the polymer. From the percentage sulfur value of the elementary analysis of the title compound results The degree of loading of the polymer with 52.9% lactose heptaacetate units (corresponding to 13 lactose residues per molecule).

b) 24-cascade polyamine (DTPA amide) _ι (N-glutaroyl-3-aminoethyl-ß-1-thiolactoside amide) ₃ conjugate

6.1 g (0.312 mmol) of the title compound from Example 60a) are dissolved in 100 ml of absolute dichloromethane and then a total of 75 ml of trifluoroacetic acid are added dropwise at 0 ° C. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in vacuo. The remaining residue is mixed with 100 ml of water and stripped again to dryness in vacuo. The oily residue thus obtained 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 60 ml of diethyl ether each time 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. Yield: 3.95 g (88.7% of theory) as an amorphous and colorless powder. Water content: 4.88%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.44 H 5.85 N 8.90 S 2.91 Na 7.06 found: C 44.49 H 5.92 N 8.79 S 2.87 Na 6.98

c) 24-cascade polyamine (Gd-DTPA amide) -π- (N-glutaroyl-3-aminoethyl-ß-1-thiolactoside amide) _{1 3} conjugate

3.15 g (0.22 mmol; corresponding to 2.42 mmol of DTPA) of the title compound from Example 60b) are dissolved in 70 ml of distilled water and the pH of the The solution is adjusted to 4.0 by dropwise addition with 10% aqueous hydrochloric acid. 670 mg (2.55 mmol) of gadolinium chloride, dissolved in 10 ml of distilled water, are then added, 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. 3.3 g (98.4% of theory) of the title compound are obtained as an amorphous, colorless powder with a water content of 7.39%.

Elemental analysis (calculated on anhydrous substance): calc .: C 41, 71 H 5.28 N 8.35 Na 1.66 S 2.73 Gd 11, 33 found: C 41, 81 H 5.34 N 8.29 Na 1, 62 5 2.69 00 11, 40

The molar element ratio of sulfur to gadolinium results in an average degree of loading of the polymer of 46% DTPA and 54% lactose (corresponding to 11 Gd-DTPA units and 13-lactose residues per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction.

Example 61

48-cascade polyamine (Gd-DTPA amide) ₁₈ - (α-D-mannopyranosyl-1-thiopropionic acid amide) 3 _Q conjugate

a) 48-cascade polyamine- [DTPA-tetra-t-butyl ester amide (terminal)] ₁₈ conjugate

16.55 g (26.8 mmol) of DTPA-tetra-tert-butyl ester (representation: German Patent Application No. 195 080 58 A) are dissolved in 100 ml of absolute dimethylformamide at room temperature and stirred with 3.7 g (32 , 16 mmol) of N-hydroxysuccinimide were added. The clear reaction mixture is then cooled to 0 ° C. and a total of 6.6 g (32.16 mmol) of dicyclohexylcarbodiimide is added at this temperature in portions. After a response time of 30 Minutes at 0 ° C and 2.5 hours at room temperature is filtered off from the precipitated dicyclohexylurea. The filtrate thus obtained is then slowly added dropwise at room temperature to a stirred solution of 6.5 g (0.99 mmol; corresponding to 47.8 mmol of free amino functions), 48-cascade polyamine and 4.8 g (50.0 mmol) of triethylamine in 60 ml of absolute DMF. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in vacuo and 250 ml of dichloromethane are added to the remaining residue. After filtering off insoluble constituents, the organic phase is washed successively with 5% hydrochloric acid, saturated sodium bicarbonate solution twice with water. After drying the organic product phase over sodium sulfate, the mixture is filtered and the solvent is stripped off in vacuo. 14.5 g (85.2% of theory; based on the polyamine used) of a slightly yellow-colored oil are obtained, which is immediately used for the subsequent synthesis steps without further purification. After quantitative ninhydrin reaction of the above-mentioned title compound, an average of 30 free amine functions per molecule are present.

Elemental analysis: calc .: C 59.87 H 9.20 N 8.88 found: C 59.80 H 9.28 N 8.90

b) 48 cascade polyamine- [DTPA-tetra-t-butyl ester amide (terminal)] ₁₈ - [3- (2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl) -1 - thiopropionic acid amide] ₃ g conjugate

A stirred solution of 3.26 g (0.19 mmol; corresponding to 5.7 mmol of free amine functions) of the title compound from Example 61 a) in 100 ml of absolute dichloromethane is mixed with 657 mg (6.5 mmol) of triethylamine at room temperature. Then with a solution of 3.3 g (6.3 mmol) of 3- (2, 3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranosyl) propionic acid-N-hydroxysuccinimide dropwise added ester in 60 ml 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. 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. 5.07 g (90.3% of theory) of the title compound are obtained as a colorless oil. The ninhydrin reaction of The title compound is negative, ie no free amino functions can be detected in the polymer.

Elemental analysis: calc .: C 53.52 H 7.48 N 7.22 S 3.16 found: C 53.90 H 7.52 N 7.18 S 3.21

An average degree of loading of the polymer with 62.83% α-D-mannose-tetraacetate units (corresponding to 30 α-D-mannose residues per molecule) results from the percentage sulfur value of the elemental analysis of the title compound.

c) 48-cascade polyamine (DTPA amide) ₁₈ - (α-D-mannopyranosyl-1-thio-3-propionic acid amide) _3C conjugate

5.17 g (0.17 mmol) of the title compound from Example 61 b) are dissolved in 100 ml of absolute dichloromethane. A total of 75 ml of trifluoroacetic acid is then added dropwise at 0 ° C. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in vacuo. The remaining residue is mixed with 100 ml of water and again stripped to dryness in vacuo. 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 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.

Yield: 3.47 g (91.6% of theory) as an amorphous and colorless powder. Water content: 7.34%

Elemental analysis (calculated on anhydrous substance): calc .: C 43.91 H 6.09 N 9.82 S 4.29 Na 7.39 found: C 43.89 H 6.12 N 9.84 S 4.34 Na 7.42 d) 48-cascade polyamine (Gd-DTPA amide) ₁₈ - (α-D-mannopyranosyl-1-thio-3-propionic acid amide) ₃₀ conjugate

3.04 g (0.136 mmol; corresponding to 2.45 mmol of DTPA of the title compound from Example 61c) are dissolved in 70 ml of distilled water and the pH of the solution is adjusted to 5.0 by dropwise addition with 10% aqueous hydrochloric acid. Then 655.8 mg (2.5 mmol) of gadolinium chloride, in the form of 10 ml of an aqueous solution, are added at room temperature and the reaction solution is stirred for 12 hours at 60 ° C. At room temperature, the reaction solution is stirred up by adding 1 molar sodium hydroxide solution brought to pH 7.2 and made up to a total volume of 500 ml with distilled water. After three times ultrafiltration against distilled water over a YM3 ultrafiltratic membrane (AMICON ®), the remaining residue is freeze-dried.

3.21 g (98.6% of theory) of the title compound are obtained as an amorphous, colorless powder with a water content of 7.30%.

Elemental analysis (calculated on anhydrous substance): calc .: C 41.00 H 5.68 N 9.17 S 4.01 Gd 11, 80 Na 1.72 found: C 41.09 H 5.71 N 9.10 S 4.08 Gd 11, 74 Na 1, 74

The molar element ratio of sulfur to gadolinium thus results in an average degree of loading of the polymer of 37.8% Gd-DTPA and 62.2% α-D-mannose (corresponding to 18 Gd-DTPA units and 30 α-D-mannose residues per Molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction.

Example 62

48 cascade polyamine (Gd-DTPA amide) ₁₈ - [3- (1-thio-ß-D-glucopyranosyl) propionic acid amide] ₃₀ conjugate a) 48 cascade polyamine- [DTPA-tetra-t-butyl ester amide (terminal)] ₁₈ and [3- (2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranosyl ) -propionate] ₃₀ - conjugate

In an analogous manner to that described for Example 61b), the reaction of 3.26 g (0.19 mmol; corresponding to 5.70 mmol of free amine functions) of the title compound from Example 61a) with 3.3 g (6.3 mmol) ) 3- (2,3,4,6-Tetra-O-acetyl-1-thio-β-D-glucopyranosyl) propionic acid N-hydroxysuccinimide ester 5.45 g (94.3% of theory) of the title compound as a colorless Oil.

Elemental analysis: calc .: C 53.52 H 7.48 N 7.22 S 3.16 found: C 53.88 H 7.46 N 7.20 S 3.20

The title compound shows a negative ninhydrin reaction. An average degree of loading of the polymer of 30 β-D-glucose residues per molecule results from the percentage sulfur value of the elemental analysis.

b) 48-cascade polyamine (DTPA amide) ₁₈ - [3- (1-thio-ß-D-glucopyranosyl) propionic acid amide] ₃₀ conjugate

In an analogous manner as described for Example 61 c), the deprotection of 5.17 g (0.17 mmol) of the title compound from Example 62a) leads to the formation of 3.35 g (88.0% of theory) after freeze drying .) the above-mentioned title compound as an amorphous powder. Water content: 7.44%

Elemental analysis (calculated on anhydrous substance): calc .: C 43.91 H 6.09 N 9.82 S 4.29 found: C 43.94 H 6.11 N 9.77 S 4.30

c) 48-cascade polyamine (Gd-DTPA amide) ₁₈ - [3- (1-thio-ß-D-glucopyranosyl) propionic acid amide] ₃₀ conjugate

In an analogous manner as described for Example 61 d), the complexation of 3.04 g (0.136 mmol; corresponding to 2.45 mmol of DTPA) leads to the title compound from Example 62b) with 556 mg (2.5 mmol) of gadolinium chloride, dissolved in 10 ml of distilled water, to form the above-mentioned title compound. Yield: 3.21 g (98.4% of theory) as a colorless and amorphous powder. Water content: 5.03%

Elemental analysis (calculated on anhydrous substance): calc .: C 41, 00 H 5.68 N 9.17 S 4.01 Gd 11, 80 Na 1, 72 found: C 40.96 H 5.75 N 9.20 S 3.97 Gd 11.78 Na 1.69

Average degree of loading per molecule of the above-mentioned title compound: 18 Gd-DTPA units (degree of polymer loading of 43.8%) and 30 D-glucopyranosyl residues (degree of polymer loading of 56.2%)

The polymer loading levels were determined from the molar Elementve ^ ^{hältnisεe-,} of sulfur to gadolinium.

Example 63

13-kD-poly-L-lysine (Gd-DTPA amide) ₄₇ - [1- (4-thioureidophenyl) -N-acetyl-β-D-glucosaminopyranosyl] 33 conjugate

a) 13 kD poly-L-lysine - (DTPA amide) ₄₇ - [1- (4-thioureidophenyl) -N-acetyl-β-D-glucosaminopyranosyl] 33 conjugate

1.5 g (0.047 mmol; corresponding to 1.54 mmol of free amino functions) of the title compound from Example 1a) are dissolved in 80 ml of deionized water and the pH of the solution is adjusted to 9.5 with 1 molar hydrochloric acid. Then in portions with a total of 2.35 g (6.63 mmol) of p-isothiocyanatophenyl-N-acetyl-β-D-glucosaminopyranose (presentation according to: Jonas Adam J, Jobe Helgi, Biochem. J. (1990), 268 (1). 41-5) are added, the pH of the reaction solution being kept constant at 9.5 using 0.1 molar sodium hydroxide solution. After a reaction time of 12 hours at 22 ° C., the mixture is filtered and made up to a total volume of 250 ml with distilled water. Ultrafiltration of the reaction solution three times over a YM3 ultrafiltration membrane (AMICON®) followed by freeze-drying of the remaining residue gives 1.93 g (93.8% of theory) of an amorphous and colorless solid. Water content: 7.43%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.78 H 5.60 N 11, 74 S 2.42 Na 9.87 found: C 44.82 H 5.63 N 11, 70 S 2.37 Na 9.79

The ninhydrin reaction as well as the TNBS method, which can generally be used for the quantitative as well as for the qualitative 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 title compound gives a degree of loading of the polymer with 41.6% N-acetylglucosamine (corresponding to 26 N-acetylglucosamine residues per molecule). The colorimetric determination of phenol-sulfuric acid to determine the average pyranose loading level of the conjugate gives a mean statistical loading level of 41.1% N-acetylglucosamine per molecule and is therefore to be regarded as identical to the loading level (33 N-acetylglucosamine units per molecule). , which was determined from the percentage sulfur value of the elementary analysis.

b) 13 kD poly-L-lysine (Gd-DTPA amide) ₄₇ - [1 - (4-thioureidophenyl) -N-acetyl-β-D-glucosaminopyranosyl] 33 conjugate

1.03 g (0.023 mmol; corresponding to 1.50 mmol of DTPA) of the title compound from Example 63a) are described in an analogy as in Example 1c), with 0.40 g (1.51 mmol) of gadolinium chloride, dissolved in 10 ml of distilled Water, complexed. After working up and freeze-drying, 1.48 g (99.4% of theory) of the title compound are obtained as an amorphous powder. Water content: 0.31%

Elemental analysis (calculated on anhydrous substance): calc .: C 40.90 H 5.11 N 10.72 S 2.21 Gd 15.41 Na 2.25 found: C 40.87 H 5.03 N 10.68 S 2.27 Gd 15.48 Na 2.30

The molar elemental ratios of gadolinium to sulfur result in an average degree of loading of the polymer of 60% Gd-DPTA and 40% N-acetyl-glucosamine (corresponding to 47 Gd-DTPA units and 33 -N-acetyl-ß- , _ "

-l oo-

D-glucosamine residues per molecule). No free amino functions can be detected in the title compound by means of a ninhydrin reaction. The T- | and T ₂ relaxivities of the title compound were determined in both water and plasma. The measurements were carried out at 40 ° C, a magnetic field strength of 0.47 Tesla, and the T1 sequence: 180 ° - Tl - 90 ° [inversion recovery] and the T2 sequence: 90 ° - TE - 180 ° [CPMG]. All relaxivity determinations were carried out on a Minispec PC 20. In all cases, a solution of Gd-DTPA with a concentration of 1 mmol / L served as the reference sample.

R-, (water) = 13.8 ± 0.2 (L / mmol-s)

R ₁ (plasma) = 16.1 ± 0.3 (L / mmol-s) R ₂ (water) = 15.8 + 0.2 (L / mmol-s)

R ₂ (plasma) = 18.0 ± 0.1 (L / mmol-s)

Example 64

24-cascade polyamine- {10- [7- (4-isothiocyanatophenyl) -2-hydroxy-5-oxo-7- (carboxymethyl) -4-aza-heptyl] -1, 4,7-tris (carboxymethyl) -1, 4,7,10-tetraazacyclododecane-gadoiniium complex} - _j2 - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] ₁ conjugate

a) 24-cascade polyamine- {10- [7- (4-thioureidophenyl) -2-hydroxy-5-oxo 7- (carboxymethyl) -4-aza-heptyl] -1, 4,7-tris (carboxymethyl) - 1, 4,7,10-tetraazacyclododecane-gadolinium complex} ι ₂ conjugate

At room temperature, 5.0 g (1.06 mmol; corresponding to 25.44 mmol of free amine functions) 24-cascade polyamine are dissolved in 300 ml of distilled water. The pH of the resulting solution is adjusted by adding this solution with 1 molar sodium hydroxide solution dropwise to a pH of 9.5. Then a total of 15.77 g (20.0 mmol) of the 4-isothiocyanatophenyl-DO3A-β-hydroxy-gadolinium complex (preparation according to: German Patent Application No. 44 24 923 A1) is added in portions, the pH Value of the reaction solution by adding 1 molar sodium hydroxide solution is kept constant at 9.5. 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.

Yield: 10.2 g (78.6% based on the polyamine used) as an amorphous powder. Water content: 6.94%

Elemental analysis (calculated on anhydrous substance): calc .: C 45.38 H 5.77 N 12.58 S 3.05 Gd 14.35 found: C 45.42 H 5.81 N 13.02 S 2.98 Gd 14.90

From the content, which was determined by elemental analysis for gadolinium and sulfur, the degree of loading of the polymer with gadolinium complexes was 39.7% (corresponding to 12 Gd-DO3A units per molecule). After a quantitative ninhydrin reaction, there are on average 12 free amino functions per polymer molecule.

b) 24-cascade polyamine- {10- [7- (4-isothiocyanatophenyl) -2-hydroxy-5-oxo-7- (carboxymethyl) -4-aza-heptyl] -1, 4,7-tris (carboxymethyl) - 1, 4,7, 10-tetraazacyclododecane-gadolinium complex} - _{] 2} - [1- (4-thioureidophenyl) - ß-D-galactopyranosyl] - | 2-onjugate

In an analogous manner as described for Example 1 b), the reaction of 2.0 g (0.16 mmol; corresponding to 1.90 mmol of free amine functions) of the Tϊtel compound from Example 64a) with 2.65 g (8.36 mmol) ) p-isothiocyanatophenyl-β-D-galactopyranose after working up 2.34 g (89.3% of theory) of an amorphous and colorless solid. Water content: 4.97%

Elemental analysis (calculated on anhydrous substance): calc .: C 46.40 H 5.55 N 11.03 S 4.70 Gd 1 1.52 found: C 46.91 H 5.60 N 11.00 S 4.68 Gd 11, 49 _ _

The ninhydrin reaction of the title compound is negative, i.e. the polymeric product contains no free amino functions. The percentage sulfur value and the gadolinium content of the elemental analysis of the title compound give a degree of loading of the polymer of 51.2% ß-D-galactose (corresponding to 12 ß-D-galactose residues per molecule) and a degree of complex loading of the polymer of 48.8. % (corresponding to 12 gadolinium complexes per molecule).

Example 65

48 cascade polyamine (Gd-DTPA amide) ₁₈ - [1- (4-thioureidophenyl) -α - D-mannopyranosyl] 30 conjugate

a) 48 cascade polyamine (DTPA amide) ₁₈

A solution of 5.0 g (1.7 mmol; corresponding to 81.7 mmol of free amino functions) 48 cascade polyamine is dissolved in 400 ml of distilled water and a pH of 9.5 is set with 1 molar sodium hydroxide solution. A total of 16.5 g (41.0 mmol) of DTPA monoanhydride monoethyl ester is then added, 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 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.

Yield: 15.63 g (81.4%; based on the polyamine used) as amorphous

powder

Water content: 6.94%

Elemental analysis (calculated on anhydrous substance): calc .: C 40.82 H 5.26 N 12.64 Na 14.65 found: C 40.91 H 5.30 N 12.59 Na 14.58 After elemental analysis and colorimetric titration with 0.0025 molar gadolinium sulfate standard solution in the presence of xylenol orange as an indicator, the degree of DTPA loading of the polymer was 38.2% (corresponding to 18 DTPA units per molecule). After the quantitative ninhydrin reaction and the quantitative determination of the amino groups using the TNBS method, there are on average 30 free amino functions per polymer molecule.

b) 48-cascade polyamine (DTPA amide) ₁₈ - [1- (4-thioureidophenyl) -α - D-mannopyranosyl] 30 conjugate

3.0 g (0.134 mmol; corresponding to 4.03 mmol of free amino functions) of the title compound from Example 65a) are dissolved in 150 ml of deionized water and the pH of the solution is adjusted to 9.5 with 1 molar hydrochloric acid. A total of 5.4 g (17.33 mmol) of p-isothiocyanatophenyl-α-D-mannopyranose is then added in portions, the pH of the reaction solution being kept constant at 9.5 using 0.1 molar sodium hydroxide solution. After a reaction time of 12 hours at 22 ° C., the mixture is filtered and made up to a total volume of 250 ml with distilled water. Ultrafiltration of the reaction solution three times over a YM3 ultrafiltration membrane (AMICON®) followed by freeze-drying of the remaining residue gives 2.45 g (87.9% of theory) of an amorphous and colorless solid. Water content: 7.48%

Elemental analysis (calculated on anhydrous substance): calc .: C 44.65 H 5.18 N 8.88 S 4.62 Na 8.39 found: C 44.70 H 5.23 N 8.81 S 4.57 Na 8, 44

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 of sulfur in the elemental analysis of the title compound gives a degree of loading of the polymer with 61.9% α-D-mannose (corresponding to 30 α-mannose residues per molecule). The colorimetric determination of phenol-sulfuric acid to determine the average pyranose loading level of the polyamine gives a loading level of 62.3% α-D-mannose, ie there are 30 α-D-mannose residues per molecule. The degree of loading of the title compound determined in this way is identical to the degree of loading which was determined by the percentage element ratios. c) 48 cascade polyamine (Gd-DTPA amide) ₁₈ - [1- (4-thioureidophenyl) -α - D-mannopyranosyl] ₃₀ conjugate

2.0 g (0.096 mmol; corresponding to 1.73 mmol of DTPA) of the title compound from Example 64b) are dissolved in 60 ml of sodium citrate buffer (pH 5.3) and at room temperature with a solution of 465 mg (1.76 mmol) of gadolinium chloride in 10 ml of distilled water are added. After a reaction time of 15 minutes at room temperature, the reaction solution is adjusted to pH 7.2 with 1 molar sodium hydroxide solution. After three times of ultrafiltration through a YM3 ultrafiltration membrane (AMICON ®), the remaining residue is freeze-dried. Yield: 2.1 g (98.2% of theory) as an amorphous powder Water content: 4.55%

Elemental analysis (calculated on anhydrous substance): calc .: C 41.65 H 4.83 N 8.28 S 4.31 Gd 12.68 Na 1.85 found: C 41.72 H 4.88 N 8.24 S 4.30 Gd 12.71 Na 1.79

The molar elemental ratios of gadolinium to sulfur thus result in an average degree of loading of the polymer of 36.5% Gd-DPTA and 63.1% α-D-mannose (corresponding to 18 Gd-DTPA units and 30-α-D-Man - Nose residues per molecule). No free amino functions can be detected in the title compound by means of the ninhydrin reaction.

Claims

claims

1. 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.

2. Conjugates according to claim 1, characterized in that they are constructed according to the general formula I.

P (K) _m (LZ) _n (I),

where P for a k amino group - of which (n + m) are each reduced by one hydrogen atom - containing polymer, where (n + m) <k, n and m each for the integers 1 to 149, k for the Numbers 12 to 150,

K for a signaling group containing metal ion (s), L for a linker and

Z represents a mono- or oligosaccharide reduced by one hydroxyl group.

3. Conjugates of the general formula I according to claim 2, characterized in that the sum (n + m) of the signaling groups (K) and the mono- or polysaccharides (Z) bound by L each reduced by one hydroxyl group is equal to the number k is the amino groups contained in the polymer.

4. Conjugates according to claim 3, characterized in that k stands for the numbers 12, 24.32, 36, 40, 48, 64 or 80.

5. Conjugates of the general formula I according to claim 2, characterized in that P for a k amino groups, of which (n + m) are each reduced by one hydrogen atom, containing dendrimer, polylysine, polypeptide, polyallylamine, poly [N- (2-aminoethyl)] methacrylamide or polysaccharide. - lOZ-

6. Conjugates of the general formula I according to claim 2, characterized in that they contain, as signaling group K, a chelate complex consisting of a radical of the general formula II, III, IV, V or VI.

OC ^ / - \ / - \ ^ COOR ¹

NNNR ^ OC- ⁷ I ^ -COOR ¹

COOR ¹

(ll),

R ¹ OOC ^, \ / - \ ^ COOR ¹

N N N

R ^ OC- I ^ COOR ¹

R C = O

(ill),

(V),

wherein

Rl independently of one another is a hydrogen atom or a metal ion equivalent of the elements of atomic numbers 20-32, 37-39, 42-44, 49 or 57-83,

R ^{2 is} a hydrogen atom, a straight-chain or branched C- | -C7-alkyl radical, a phenyl or benzyl radical,

V a -CH2- (CH ₂ ) ₀ - (0) p group with

o in the meaning of the numbers 0 to 10, p and I in each case in the meaning of the numbers 0 or 1, with the proviso that p only stands for the number 1 if I means the number 1,

T-! a -NHCS or -CO group,

U is a -CHR ³ -C0NR -M1- _or -CH ₂ -CH (OH) -M ² - group with R ³ independently of one another in the meaning of R ² or the group -CH2- (CH2) o- COOH and Ml and M ² each represents a phenylene radical or a straight-chain, branched, saturated or unsaturated C1-C20-

Alkylene chain, which is optionally substituted by 1-5 (CH2) o-COOH, 1- 5 OR ² radicals or 1-8 oxygen atoms, 1-2-NH-, 1-2-C (= NH) -, 1- 5-CONR ³ -, 1-5-NR ^{3 contains} CO, 1-2 phenylene or 1-2 phenyleneoxy groups, with the proviso that at least two of the radicals R ^{1 are} metal ion equivalents of the elements of the above-mentioned atomic numbers stand.

7. Conjugates according to claim 6, characterized in that M ¹ for a group

CH ₂ COOH

α CH ₂ ß, α (CH ₂ ) ₂ ß, _{α α} - CH-CH ₂ - ß, _α -CH ₂ -CH ₂ -0-CH ₂ -ß,

α - (CH ₂ ) l-2-CO-N-CH ₂ -ß,

CH ₂ COOH

α - CH2-CH ₂ -CO-NH (CH ₂ ) 6-ß, α- (CH ₂ ) s-ß,

stands, where α the link to the rest-CONR ³ and ß the link parts to T-! indicates.

8. Conjugates according to claim 6, characterized in that M ² for a group

CH ₂ COOH

α - -CH ₂ ß. ^α - CH ₂ - ^N CO- (CH ₂ ) ₀ . CH (/ V-ß, α CH ₂ -NHCO - (, CH ₂ ) _{2 3} -ß

- CH, -NHCO-CH, -0-CH, - ß, α (CH, r - ß

stands, where α indicates the linkage to the rest-CH (OH) and ß the linkage to T ^" ϊ.

9. Conjugates according to claim 1, characterized in that they contain as monosaccharides hexoses, pentoses or N-acetyl-neuramino acid, which are each in the pyranose or furanose form, or their derivatives.

10. Conjugates according to claim 1, characterized in that they contain as monosaccharides hexoses, which are in the pyranose form, or their derivatives. -

11. Conjugates according to claim 9, characterized in that the monosaccharides as 2-amino-2-deoxy, N-acetyl-2-amino-2-deoxy, 6-deoxy, 2-deoxy, 5-carboxy or 1-amino-1-deoxy derivatives.

12. Conjugates according to claim 1, characterized in that they contain oligosaccharides built up from the monosaccharides according to claim 9.

13. Conjugates of the general formula I according to claim 2, characterized in that Z represents a mono- or oligosaccharide reduced by one hydroxyl group on the C-1 atom.

14. Conjugates of the general formula I according to claim 2, characterized in that Z for one at the C-2 atom is reduced by one hydroxyl group

Mono- or oligosaccharide.

15. Conjugates of the general formula I according to claim 2, characterized in that L stands for a group T -M -X, where M ^{3 stands} for a direct bond or has the meaning given for M ^, T ² for a -

NHCS-, -C (= NH) -, -CH2- or CO group and binds to P, X stands for NH, CO, O and S and binds to Z.

16. Conjugates according to claim 15, characterized in that M ³ for a direct bond or for the groups

δ

Y- (CH ₂ CH ₂ O) ^ - CH ₂ - (CH ₂ ) ₀ . _δ ,

Y— (CH ₂ ) ₂ -CONH- (CH ₂ ) ₆ -δ,

CH (OH) CH ₂ OH

- CH-CH (OH) -CH (OH) -δ,

γ - (CH ₂ ) 2-CO- (CH ₂ ) 3-δ

stands, where γ indicates the junction at X and δ the junction at T ² .

17. A process for the preparation of conjugates of the general formula I according to claim 1, P (K) _m (LZ) _n (I),

where P for a k amino group - of which (n + m) are each reduced by one hydrogen atom - containing polymer, where (n + m) <k, n and m each for the integers 1 to 149, k for the Numbers 12 to 150, K as a signal-generating group containing magnetic metal ion (s) for a chelate complex consisting of a radical of the general formula II,

III, IV, V or VI

OC ^ / \ / \ ^ COOR ¹

N N N

R ¹ OOC ^ l ^ COOR ¹

COOR ¹

(II).

ROOC - \ / \ ^ COOR

N N N

R OOC COOR

R 'C = O

(HD,

ROOC - \ -Λ / ^" COOR ¹ NNN

R OOC l ^ COOR ¹

COOR ¹ (IV),

(V),

R

V-T '

R ¹ OOC-HC / CH-COOR

N N

NNR ¹ OOC-HC ⁷ CH-COOR ¹

R ^ R ^ (VI),

where R1 independently of one another is a hydrogen atom or a metal ion equivalent of the elements of atomic numbers 20-32, 37 - 39, 42 - 44, 49 or 57-

83, R ^{2 is} a hydrogen atom, a straight-chain or branched C- | -C7-alkyl radical, a phenyl or benzyl radical,

V a -CH2- (CH ₂ ) ₀ - (0) _p group with

o in the meaning of the numbers 0 to 10, p and I each in the meaning of the numbers 0 or 1, with the proviso that p only stands for the number 1 if I means the number 1, T1 a -NHCS- or -CO group, U is a -CHR -CONR ³ -M ¹ - or -CH ₂ -CH (OH) -M ² - group with R ³ independently of one another in the meaning of R ² or the group -CH2- (CH2) ₀ -COOH and M ^ and M ² each have the meaning of a phenylene radical or a straight-chain, branched, saturated or unsaturated C 1 -C 20 -alkylene chain, which is optionally substituted by 1-5 (CH2) ₀ -COOH, 1-5 OR ² - radicals or 1-8 oxygen atoms, 1-2-NH, 1-2-C (= NH) -, 1-5-CONR ³ -, 1-5- NR ³ CO, 1-2 phenylene or 1-2 phenyleneoxy groups contains, with the proviso that at least two of the radicals R ^ stand for metal ion equivalents of the elements of the above-mentioned atomic numbers, L for a linker and

Z represents a mono- or oligosaccharide reduced by one hydroxyl group, characterized in that a) a polymer-complex (former) conjugate of the general formula VII

P (K ') _m (VII). wherein K 'for a radical of the general formula II', III ', IV, V or VI'

oc- _{\ /} - ^ r- _Γ ∞ ^ORV

NNNR ^r OOC - ^ L ^ ^ r COOR ^{1 '}

COOR ^{1 '}

(ll ') -

R ¹ OOOC ^ / \ / \ ^ COOR ¹

N N N

R ^r OOC - 1 ^ COOR ^{1 '}

R ² ^ C = O

(lll '),

rCnOnODR

COOR ^{1 '}

(IV)

(V)

(VI ')

wherein

R1 'independently of one another represents a hydrogen atom, an acid protecting group or a metal ion equivalent of the elements of atomic numbers 20-29, 39, 42, 44 or 57-83 and R ² , V, o, p, T and U have the meaning given above, with n 'mono- or oligosaccharides of the general formula VIII

L * -Z ^* (VIII),

where 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, L ^* for a group T ² '-M ³ ' -X with

T ² 'in the meaning of -NCS, -C (= NH) OCH3, - CHO, a -CO-Fg group where

-O-CO-R ^ with R ^ meaning straight-chain or branched

C ¹ -C 7 -alkyl chain, 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

P (L'-Z ') _n (IX),

wherein U has the meaning given for L, but the carboxy groups which may be present in L are optionally protected and P, Z 'and n have the meaning given above, with m' complexes or complexing agents K ^* , where m '= 1-3 m is and K ^* for compounds of the general formulas

Fg— OC - _/ - / -, ^ - COOR NNN

R OOC - ^y l ^ ^ - COOR ^{1 '} ^C00R (II "), R ^r OOC / - \ / - \ r∞ ^0R

N N N

R ^r OOC COOR ¹

R ² ^ t 0 i

Fg (III "),

(VI ")

wherein Rl '. R ² , V, U and Fg have the meaning given above, and T1 'stands for -NCS, -CO-Fg, -C (= NH) OCH ₃ or -CHO or

c) a polymer of the general formula X

P- (H) _{k (X) ι}

L * -Z '(VIII),

wherein n ", L * and Z have the meanings given above, with m 'complexes or complexing agents K ^* , where K ^* for compounds of the general formulas

Fg— OC -χ / - - Λ / - COOR ^{1 '} NNN

R ^r OOC - L ^ ^ - COOR ^{1 '}

COOR _{(| r) ι}

R ^r OOC - \ \ / \ - COOR

N N N

R ^r OOC - ^ 1 ^ COOR ^{1 '}

R ² ^ C = O i

Fg (Hl ").

(IV),

(VI ")

wherein m ', Rl', R ² , V, τ ', U and Fg have the meaning given above, is implemented, the possibly necessary introduction of metal ions taking place before or after the possibly necessary removal of the protective groups, with the proviso that if R ¹ 'stands for protective groups, these must be removed before the introduction of metal ions.

18. A pharmaceutical composition comprising at least one conjugate according to claim 1, optionally with the additives customary in galenics.

19. Diagnostic agent containing at least one conjugate according to claim 1, optionally with the additives commonly used in galenics for NMR imaging.

20. Diagnostic agent according to claim 19, characterized in that it is used for NMR lymphography.

21. Diagnostic agent containing at least one conjugate according to claim 1, optionally with the additives common in galenics for X-ray diagnostics.

22. Diagnostic agent containing at least one conjugate according to claim 1, optionally with the additives common in galenics for radio diagnostics and radio therapy.

23. Use of at least one physiologically compatible conjugate according to claim 1 for the production of diagnostic agents for NMR diagnostics.

24. Use of at least one physiologically compatible conjugate according to claim 1 for the production of diagnostic agents for NMR lymphography.

25. A method for producing the pharmaceutical composition according to claim _ ..

-175-

18, characterized in that the conjugate, dissolved or suspended in water or physiological saline solution, is brought into a form suitable for enteral or parenteral administration, optionally with the additives customary in galenics.