HRP20030173A2 - Use of metal complexes containing perfluoroalkyl as contrast agents in mr-imaging for the representation of plaques, tumors and necroses - Google Patents

Description

The invention relates to the application of metal complexes, which create one critical micellar concentration < 10-3 mol/l, and show one hydrodynamic micellar diameter (2 Rh) > 1 nm and one proton plasma relaxation (R1) > 10 l/mmol s, as contrast agents for MR-imaging, as well as for the detection of plaque, lymph nodes, tissues damaged by infarction and necrotic tissues, as well as for the independent detection of necrotic tissue and tumor tissues. It has been shown that metal complexes containing perfluralkyl with so-called characteristics for the independent detection of plaques, tumors and necrosis with the help of MR-imaging are extremely suitable, they can simultaneously cover the same diagnostically significant area of infarction and imaging necrosis.

Arteriosclerosis is the most important and most common diseased change in the arteries with thickening, loss of elasticity and reduced flow. It is the most common cause of death in Western industrialized nations. Changes on the walls of the blood vessels lead to the instability of the walls, the narrowing of the vessels and the formation of deposits through fat deposits, the development of connective tissue and the accumulation of stones with an uneven distribution. The causes of diseases are numerous exogenous and endogenous noxias, i.e. diseases such as hypertension, hyperlipidemia, hyperfibrinogenic anemia, diabetes mellitus, toxins, nicotine, antigen-antibody complexes, inflammation, hypoxia, psychological stress, aging and family burden.

The same lead to disturbances in the integrity of the inner surfaces of the wall, to disturbances in the control of the growth of smooth muscle cells of the vessel walls and to the burden of decomposition of aged cell parts. Treatment of arteriosclerosis is not possible, but the goal of the doctor's efforts is to prevent it by reducing risk factors, for example by means of substances that lower the level of lipids in the blood.

The diagnosis of arteriosclerosis in clinical practice is currently made exclusively by angiography as the gold standard. The limit of all procedures, which are based on measurements of the reduction of the lumen of blood vessels, is the early detection of the disease, which is observed through the thickening of the cell wall in normal blood vessels (Glagov S., Zarins CK., Quantiting atherosclerosis. In: Bond MG, Insull W , Glagov S, Chandler AB, Cornhill JF (eds.). Clinical Diagnosis of Atherosclerosis. Quantitative Methods of Evaluations. New York: Springer-Verlag, 1983, 11-35). One of the further methods for diagnostic evaluation of the cell wall and lumen is intravascular or percutaneous ultrasound.

Magnetic resonance tomography (MRT) is a modern, non-invasive radiological procedure, which enables very good spatial and temporal resolution in the detection of physiological and pathophysiological structures. The use of specific contrast agents with selective accumulation in certain tissues and organs can significantly increase the diagnostic value of the results. The preparation of contrast agents with selective accumulation in the arteriosclerotic plaque, could enable localization and degree of recognition in an early period and thereby enable targeted therapy and prophylaxis, and therefore the search for appropriate contrast agents began early.

Thus, in US patent 4,577,636, hamatoporphyrin derivatives were claimed as contrast agents for the detection of arteriosclerotic plaque. Scintigraphy, X-ray, fluorescence and for paramagnetic metalloporphyrins and NMR-spectrometry are mentioned as methods. Gd, Cr, Co, Ni, Ag and Eu will be mentioned as para-magnetic ions.

The disadvantage of these compounds is that porphyrins accumulate in the skin and skin discoloration, which can last up to several weeks. Therefore, they lead to photosensitisation. Furthermore, there is a danger that metalloporphyrin loses its metal during a longer retention time in vivo.

In application WO 95/09856, metalloporphyrins (deuteroporphyrins) for plaque diagnosis and therapy were claimed. MRI will be indicated as a diagnostic method. The same applies to those porphyrins, as they can cause skin discoloration.

In application WO 95/09013, conjugates of specifically binding polypeptides and metal complexes were claimed. These compounds should also bind to the plaque and thus enable their diagnosis and therapy. Scintigraphy, computed tomography and MRI will be mentioned as diagnostic methods. While scintigraphy has been experimentally proven, there is a lack of data for MRI.

US patent 5,807,536 will label phytocyanins as contrast agents used for plaque imaging. X-ray, comp. Tomography, scintigraphy, SPECT and MRI. Scintigraphy has been experimentally proven.

Numerous contrast agents for infarction and imaging of necrosis are known from the literature. Already earlier experiments, the localization of infarction and necrosis through the use of contrast agents in non-invasive procedures, such as scintigraphy or core-spin-tomography, should have been improved. In the literature, experiments, porphyrins for use in necrosis imaging, occupy a larger space. The achieved results still give a vague picture. This is how Winkelman and Hoyes described in Nature, 200, 903 (1967), that manganese-5,10,15,20-tetrakis(4-sulfonatophenyl)-porphyrin (TPPS) accumulates selectively in the necrotic part of the tumor.

Lyon et al. (Magn. Res. Med. 4, 24 (1987)) on the other hand, they noticed that manganese-TPPS is distributed in the body in the kidneys, liver, tumor and only a small part in the muscles. It is interesting that the concentration in the tumor only reaches its maximum on the 4th day and that only after the authors increased the amount from 0.12 mmol/kg to 0.2 mmol/kg. Therefore, the authors talk about the non-specific uptake of TPPS into the tumor. Bockhurst et al. they report again in Acta Neurochir. 60, 347 (1994, Suppl.), that MnTPPS selectively binds to tumor cells.

Foster et al. (J. Nucl. Med. 26, 756 (1985)) found, for their part, that 111 In-5,10,15,20-ethrakis-(4-N-methyl-pyridine)-porphyrin (TMPyP) does not it accumulates in the necrotic part, rather than in the living marginal layers. It follows that a porphyrin-tissue interaction exists, it is very close, but it is not always present.

In Circulation Vol. 90, No. 4, part 2, p. 1468, summary No. 2512 (1994) Ni et al. report that with manganese-tetraphenyl-porphyrin (Mn-TPP) and one gadolinium-mesoporphyrin (Gd-MP) they were able to image infarct areas. In international patent application WO 95/31219 both infarction and necrosis-imaging substances were used. The authors Marchal and Ni write (see example 3) that for the compound Gd-MP the metal content of the kidney in the infarct is similarly high as that of the organ that was not infarcted, but for the myocardium in the infarcted tissue (example 1) it was 9x higher. It is surprising that the ratio of signal intensity in MRI for infected compared to healthy tissue in both cases with 2.10 and 2.19 was comparably high. Further metal porphyrins are described in application DE 19835082 (Schering AG).

Porphyrins tend to accumulate in the skin, which leads to photosensitisation. Sensitization can last for days or weeks. In addition, the therapeutic index for porphyrins is very small, so that, for example, Mn-TPPS only works at a quantity of 0.2 mmol/kg, but the LD50 is already at 0.5 mmol/kg.

Contrast agents not derived from the porphyrin skeleton for necrosis and infarct imaging are described in DE 19744003 (Schering AG), DE 19744004 (Schering AG) and WO 99/17809 (EPIX).

In DE 19744003, oligomeric compounds, which consist of one nucleus, are bound to 1-3 metal complexes, will be claimed.

In application 19744004, lipophilic metal complexes for necrosis and infarction-imaging will be required. These compounds include metal complexes of polyaminopolycarboxylic acids, polyaminopolyphosphonic acids, porphyrins, texaphyrins, sapphyrins, peptides.

In EPIX-application WO 99/17809, the application of DTPA-derivatives for imaging necrosis will be requested. The best-known compound is the complex of gadolinium, a phosphodiester of hydroxymethyl-DTPA (MS-325).

Perfluoroalkyl metal complexes are also known as contrast agents for MR imaging. Thus, WO 97/26017 (Schering) and WO 99/01161 (Schering) disclose the use of perfluorinated metal complexes as lymphography. WO 99/01161 also describe the applicability of these compounds for creating "vasal" spaces (blood pool agents).

The same is true for individual identification of tumors and necrosis, using MR-imaging, contrast agents are described.

In EP 417870 A1, compounds for tumor diagnosis and therapy will be disclosed. It was discovered that both incarceration and ischemia can be shown. Experimental evidence for such evidence application is not acceptable. The required compounds are chelates of N2S2 and N3S complexes with radioisotopes. Scintigraphy serves as a diagnostic method.

In DE 19646762 scintigraphy will also be applied as a diagnostic method. In the description, metal chelates are used as radiosensors for the therapy of hypoxic tumors and for the diagnosis of hypoxic conditions and necrosis. In the described part, NMR diagnostics, X-ray diagnostics and radio diagnostics will be mentioned as diagnostic procedures.

In the German application DE 19824653, porphyrins will be claimed as necrosis-affinity substances for tumor therapy. In the application, it is described that the compounds accumulate in necrotic and hypoxic tumor areas. Compounds can be used for diagnostic purposes in the form of their metal derivatives with paramagnetic ions, i.e. radioisotopes.

Both applications - DE 19646762 and DE 19824653 - have in common that the presentation of necrosis and tumor does not follow independently of each other, but that the necrosis is a part of the tumor.

The task of the presented invention was to produce contrast agents for MR-imaging, which are used for the detection of plaque, lymph nodes, infarcted or necrotic tissue, as well as being suitable, independently, for the detection of necrosis and tumors.

It is surprising that it was found that metal complexes containing perfluoroalkyl, which show a critical concentration of micelle formation < 10-3 mol/l, one hydrodynamic micelle diameter (2 Rh) > 1 nm and proton relaxivity in plasma (R1) > 10 l /mmol s, as contrast agents for MR-imaging for plaque identification are very well applicable. In addition, such compounds can also be used for the detection of lymph nodes, infarcted and necrotic tissue, as well as for the independent detection of necrotic tissues and tumor tissues.

Amphiphilic compounds of metal complexes containing perfluoroalkyl refer to the non-polar part of one perfluoroalkyl side chain in the molecule, which is also connected to the entire molecule via a lipophilic binding element. The polar part of the compounds presented by the invention will be built through one or more metal complexes and further polar groups that are also present.

In aqueous systems, these amphiphilic molecules show characteristic properties for classical surfactants (such as sodium dodecyl sulfate, SDS). Thus, they break down the surface tension of water. Through tensiometry, the so-called CMC (critical micelle formation concentration in mol/l) to determine. In addition, the surface tension will be determined depending on the concentration of the substance being measured. The CMC can be calculated from the obtained surface tension function ( c ). The critical concentration of the formation of micelles by the invention of the presented compounds must be < 10-3 mol/l, preferably < 10-4 mol/l.

The amphiphilic compounds presented by the invention are associated in solutions and come as aggregates. The size (2 Rh) of such aggregates (eg micelles, rods, plates, etc.) can be determined using photon-corrective-spectroscopy (PCS).

The hydrodynamic diameter of the micelle 2 Rh, which must be > 1 nm, serves as the second criterion. In particular, the perfluoroalkyl metal complexes presented by the invention are suitable, whose 2Rh ≥ 3 nm is, in particular, > 4 nm is preferred.

CMC determination as well as photon-correlation-spectroscopy will be in H.-D. Dörfler "Grenzflächen und Kolloidchemie", Weinheim, New York, Basel, Cambridge, Tokyo, VSH 1994 described.

The third criterion is the relaxivity of protons in the plasma (R1) at 40ºC and a field strength of 0.47 Tesla. The relaxivity, which is stated in (l/mmol·s), is a quantitative measure of the shortening of the T1 proton relaxation time. For the purpose presented by the invention, the relaxivity must preferably be high and amount to > 10 l/mmol·s, preferably > 13 l/mmol·s, and particularly advantageous > 15 l/mmol·s.

The relaxivity R1 (l/mmol·s) of the presented MR-contrast agent will be determined using the device Minispec P 20 from Bruker. The measurements were carried out at 40ºC and at a field strength of 0.47 Tesla. From each T1-sequence: 180ºC-IT-90ºC, Inversion Recovery, 8 measurement points will be made. Bovine plasma from Kraeber was used as a medium. The concentration of the contrast agent (mmol/l) in the measured aliquots was between 0.30 and 1.16.

In the original version of the presented invention, compounds of the general formula I according to claims 8 to 11 will be used as advantageous compounds. These are known compounds, which are described in WO 97/26017. Surprisingly, it turned out that these compounds can also be used very well as MRI-contrast agents for plaque visualization. Metal complexes I-IV and XI-XIII can be used as particularly suitable compounds (compare with Table 1).

In a further version of the presented invention, compounds of the general formula Ia according to claims 12 to 21 will be used as preferred compounds. These compounds are known and described in WO 99/1161. Their use as MRI-contrast agents for plaque imaging has not been described so far. Of these compounds, the metal complex XIV (compare table 1) can be singled out as one of the special ones, for use.

In another particular version of the invention, macrocyclic perfluoroalkyl compounds of the general formula Ib can

[image] (Ib)

whereby

K one complex builder or one metal complex of the general formula IIb

[image] (IIb)

It indicates

whereby

R1 for one hydrogen atom or one equivalent of metal ions with serial numbers 23-29, 42-46 or 58-70,

R2 and R3 for one hydrogen atom, one C1-C7-alkyl group, one benzyl group, one phenyl group, -CH2OH or –CH2OCH3 and

U2 for one residue L1, whereby L1 and U2 can be the same or different independently of each other, it says,

A1 one hydrogen atom, one straight-chain or branched C1-C30-alkyl group, which is also interrupted by 1-15 oxygen atoms, and/or also substituted with 1-10 hydroxy groups, 1-2 COOH-groups, one phenyl group, one benzyl group and/or 1-5-ORg-groups, with Rg meaning one hydrogen atom or one C1-C7-alkyl residue, or –L1-RF denotes,

L1 one straight-chain or branched C1-C30-alkyl group, which is also terminated via 1-10 oxygen atoms, 1-5 –NH-CO-group, 1-5 –CO-NH-group, via one also through COOH -groups substituted by phenyl groups, 1-3 sulfur atoms, 1-2 –N(B1)-SO2-groups, and/or 1-2 –SO2-N(B1)-groups with B1 having the meaning of A1, one NHCO -group, one CONH-group, one N(B1)-SO2-group, or one –SO2-N(B1)-group and/or is also substituted with an RF residue,

has meaning and

RF one straight-chain or branched perfluorinated alkyl residue of Formula CnF2nE,

whereby

n stands for i for numbers 3-40

E for one terminal fluorine atom, chlorine atom, bromine atom, iodine atom or one hydrogen atom stands for,

has meaning

and also present "acidic" groups as well as salts of organic and/or inorganic bases or amino acids or amino acid amides may be present,

be used.

Considering that the compounds presented by the invention are intended for use in NMR-diagnostics, the metal ion of the signal-giving group must be paramagnetic. These are primarily double or triple valence ions of elements with ordinal numbers 23-29, 42-46 and 58-70. Suitable ions are, for example, chromium(III)-, iron(II)-, cobalt(II)-, nickel(II)-, copper(II)-, praseodymium(III)-, neodymium(III)-, samarium(III) -, and ytterbium(III)-ion. Due to their strong magnetic moments with particular advantages of gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III), iron(III), and manganese(II) -ions.

Preference is given to manganese(II)-, iron(II)-, iron(III)-, praseodymium(III)-, neodymium(III)-, samarium(III)-, gadolinium(III)-, ytterbium(III)-ions , especially dysprosium(III) ions.

Alkyl groups R2, R3, Rg can be straight-chain or branched. Examples of the same are methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl.

R 2 , R 3 and R 8 are preferably hydrogen and C 1 -C 4 -alkyl groups, and hydrogen and a methyl group are particularly preferred.

Benzyl group and phenyl group R2, A1 and B1 can be substituted in the phenyl ring. COOH-groups are suitable as substituents.

If the compound of formula Ib simultaneously contains residues L1 and U2, then L1 and U2 can be mutually different.

The C1-C30-alkylene groups U2 can be straight-chain or branched. Examples include methylene, ethylene, propylene, isopropylene, n-butylene, 1-methylpropylene, 2-methylpropylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, 1,2-dimethylpropylene.

For U2 in the meaning of alkylene, C1-C10 alkylene groups will be preferred, especially C1-C4-alkylene groups.

Alkyl groups C1-C30 for A1 can be straight-chain or branched. Examples are methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, n-hexyl, listed.

C1-C30-alkyl groups for A1 can be interrupted by 1-15 oxygen atoms and/or substituted with 1-10 hydroxy-, 1-5 alkoxy- or 1-2 COOH-groups, such as

C2C4-O-CH3, C3H6-O-CH3,

C2H4-O-(C2H4-O)t-C2H4-OH, C2H4-O-(C2H4-O)t-C2H4-OCH3 with t=0 to 13

C2H4OH, C3H6OH, C4H8OH, C5H10OH, C6H12OH, C7H14OH, as well as their

branched isomers,

CH(OH)CH2OH,

CH(OH)CH(OH)CH2OH, CH2[CH(OH)]u 1CH2OH, with u1 = 1-10

CH[CH2(OH)]CH(OH)CH2OH,

C2H4CH(OH)CH2OH,

(CH2)SCOOH with s = 1 to 15,

C2H4-O-(C2H4-O)t-CH2COOH with t = 0 to 13,

C2H4-O-(C2H4-O)t-C2H4-CnF2nE

with t = 0 to 13, n = 4 to 20 and E = one fluorine, hydrogen, chlorine, bromine or iodine atom.

Preferred meanings of A1 are hydrogen, C1-C10-alkyl,

C2C4-O-CH3, C3H6-O-CH3,

C2H4-O-(C2H4-O)x-C2H4-OH, C2H4-O-(C2H4-O)x-C2H4-OCH3 with x=0 to 5

C2C4OH, C3H6OH,

CH2[CH(OH)]YCH2OH, WITH y = 1-6,

CH(OH)CH2OH,

CH[CH2(OH)]CH(OH)CH2OH,

(CH2)wCOOH with w = 1 to 10,

C2H4-O-(C2H4-O)x-CH2COOH with x = 0 to 5,

C2H4-O-(C2H4-O)x-C2H4-CnF2nE with x = 0 to 5, n = 4 to 15 and E = one fluorine atom.

If the compound of general formula Ib contains two residues L1-RF, they can be different from each other.

For L1 residues, for example, they are listed, where α stands for the bond to the nitrogen atom, and β for the bond to the RF residue:

α -(CH2)s-β, with s = 1-15

α –CH2-CH2-(O-CH2-CH2-)y-β, with s = 1-6

α –CH2-(O-CH2-CH2-)y-β, with s = 1-6

α –CH2-NH-CO-β

α –CH2-CH2-NH-SO2-β

α –CH2-NH-CO-CH2-N(CH2COOH)-SO2-β

α –CH2-NH-CO-CH2-N(C2H5)-SO2-β

α –CH2-NH-CO-CH2-N(C10H21)-SO2-β

α –CH2-NH-CO-CH2-N(C6H13)-SO2-β

α –CH2-NH-CO-(CH2)10-N(C2H5)-SO2-β

α –CH2-NH-CO-CH2-N(-CH2-C6H5)-SO2-β

α –CH2-NH-CO-CH2-N(-CH2-CH2-OH)-SO2-β

α –CH2-NHCO-(CH2)10-S-CH2CH2-β

α –CH2NHCOCH2-O-CH2CH2-β

α –CH2CH2NHCOCH2-O-CH2CH2-β

α –CH2-(CH2-CH2-O)Y-(CH2)3NHCO-CH2-O-CH2CH2-β with y=1-6

α –CH2NHCO(CH2)10-O-CH2CH2-β

α –CH2CH2NHCO(CH2)10-O-CH2CH2-β

α –CH2-C6H4-O-CH2CH2-β where the phenyl groups are 1,4 or 1,3 linked

α –CH2-O-CH2-C(CH2-OCH2CH2-C6F13)2-CH2-OCH2-CH2-β

α –CH2-NHCOCH2CH2CON-CH2CH2NHCOCH2N(C2H5)SO2C8F17-β

α –CH2-CH2NHCOCH2N(C2H5)-SO2-β

α –CH2-O-CH2-CH(OC10H21)-CH2-O-CH2-CH2-β

α –(CH2NHCO)4-CH2O-CH2CH2-β

α –(CH2NHCO)3-CH2O-CH2CH2-β

α –CH2-OCH2C(CH2OH)2-CH2-O-CH2CH2-β

[image]

[image]

Preference is given to:

[image]

According to the invention, special preference is given to the residue L1 which in the examples presented according to the invention described and mentioned compounds.

For U2, the above-mentioned residues for L1 and the residues marked with priority and special importance, as well as the above-mentioned and specially highlighted residues for the meaning of alkylene, with the criterion that no nitrogen atom in the α position and no final (on the β-atom) SO2- or the CO group may be present.

Residues B1 which are preferred are hydrogen, straight-chain or branched C1-C10-alkyl residues, which can also be interrupted through 1-5 oxygen atoms and/or are also substituted with 1-5 hydroxy groups each, 1-2 COOH- group, once also via one COOH-group of a substituted phenyl group, one benzyl group and/or 1-5-ORg-group, with Rg, which denotes one hydrogen atom or one C1-C3-alkyl residue.

Residues that have the advantage of RF are straight-chain or branched perfluorinated alkyl residues of the formula CnF2nE, where n stands for numbers 4 to 15 and E stands for one terminal fluorine atom.

Preparation of the compounds presented by the invention of the general formula Ib

[image] (Ib)

with

K in the meaning of one complex builder or one metal complex of the general formula II b

[image] (II b)

can follow the following procedure:

Procedure A

The carboxylic acid of formula IIIb already contains an equivalent of metal ions R1.

[image]

(IIIb) (IVb) (Ib)

Similarly, in situ activated carboxylic acid IIIb with R1 in the meaning of one equivalent of the metal complex will be converted into one amide Ib with one amine Ib in one connection reaction.

This process for preparing metal complexes of carboxylic acid amides is known from DE 196 52 386.

In the connection reaction, a mixture of metal complexes of carboxylic acid IIIb, which also contains carboxylic and/or hydroxy groups in a protected form, and at least one solution of a similar substance in an amount of up to 5, preferably 0.5-2 molar equivalents compared to metal complex of carboxylic acid, can be prepared in one previously included reaction step and (e.g. via evaporation, freeze-drying or spray-drying of an aqueous or water-mixed solution of the components or via precipitation with an organic solvent from such a solution) be isolated and continuous in DMSO with reagents that can be removed and also a substance that supports the coupling converts, as well as in situ by adding a solvent to promote the reaction to a DMSO suspension of metal carboxylic acid complexes, a reagent that splits water and also one auxiliary substances that support binding, to be built.

Each reaction mixture prepared in this way will be kept for pretreatment (acid activation) for 1 to 24, preferably 3 to 12 hours, at temperatures from 0 to 50ºC, that is, at room temperature.

Next will be the amine of the general formula Ivb

[image] (IVb)

wherein the residues R3, L1, RF and A1 have the above meaning, without solvent or dissolved, for example in dimethylsulfoxide, alcohols, such as for example methanol, ethanol, isopropanol or their mixtures, formamide, dimethylformamide, water or mixtures of said solvents, especially in dimethylsulfoxide, in water or in water-miscible solvents, added. For connecting the amide, a reaction solution at temp. from 0 to 70ºC, especially 30 to 60ºC, 1 to 48, especially 8 to 24 hours stored.

In some cases, it turned out to be advantageous for the amine in the form of its salts, for example as hydrobromide or hydrochloride, to be used in the reaction. A base such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, tripropylamine, tributylamine, lithium hydroxide, lithium carbonate, sodium hydroxide or sodium carbonate will be used to release the amine in the reaction.

The protective groups that are still present will continue to be split off.

Isolation of the reaction product follows according to methods known in the art, for example via precipitation with organic solvents, especially acetone, 2-butanone, diethyl ether, acetic ester, methyl-tert-butyl ether, isopropanol or their mixtures. Further purification procedures can be followed, for example, by chromatography, crystallization or ultrafiltration.

Suitable auxiliary solvents are alkalis, earth alkalis, trialkylammonium, tetraalkylammonium salts, uric acid, N-hydroxyimides, hydroxyaryltriazoles, substituted phenols and salts of heterocyclic amines. Examples include: lithium chloride, lithium bromide, lithium iodide, sodium tribromide, sodium iodide, lithium methanesulfonate, sodium methanesulfonate, lithium-p-toluenesulfonate, sodium-p-toluenesulfonate, potassium bromide, potassium iodide, sodium iodide, magnesium bromide, magnesium chloride, magnesium iodide, tetraethylammonium-p-toluenesulfonate, tetramethylammonium- p-toluenesulfonate, pyridinium-p-toluenesulfonate, triethylammonium-p-toluenesulfonate, 2-morpholinoethylsulfonic acid, 4-nitrophenol, 3,5-dinitrophenol, 2,4-dichlorophenol, N-hydroxysuccinimide, N-hydroxyphthalimide, uric acid, tetramethyluric acid , N-methylpyrrolidone, formamide as well as cyclic uric acids, with the first 5 being preferred.

All means known to the profession are used as compounds that serve to separate water. For example, these are carbodiimides and Onij reagents such as dicyclohexylcarbodiimide (DCCI), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-hydroxychloride (EDC), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP) and O -(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), for example DCCI.

In the literature, for example, the following appropriate procedures are described:

● Activation of carbonic acid. Review in Houben-Weyl, Methods of Organic Chemistry, vol XV/2, Georg Thieme Verlag Stuttgart, 1974 (and J. Chem. Research (S) 1996, 302):

● Activation with carbodiimides. R. Schwyzer in. H. Kappeler, Helv. 46: 1550 (1963).

● E. Wunsch et al., B 100: 173 (1967).

● Activation with Carbodiimides/Hydroxysuccinimide: J. Am. Chem. Soc. 86: 1839 (1964) as well as J. Org. Chem. 53: 3583 (1988). Synthesis 453 (1972).

● Anhydride, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline Methods: B. Belleau et al., J. Am. Chem. Soc., 90: 1651 (1986), H. Kunz et al., Int. J. Pept. Prot.Res., 26: 493 (1985) and J.R. Vaughn, Am. Soc. 73: 3547 (1951).

● Imidazolid-methods: B.F. Gisin, R.B. Menifield, D.C. Tosteon, Am. Soc. 91: 2691 (1969).

● Methods of acid chlorides, thionyl chloride: helv., 42: 1653 (1959).

● Oxalide chloride: J. Org. Chem., 29: 843 (1964).

As also used auxiliary substances for binding, all those known in the art can be used (Houben-Weyl, Methoden der organischen Chemie, Bd. XV/2, Georg Thieme Verlag, Stuttgart, 1974). Examples include 4-nitrophenol, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 1-hydroxy-7-aza-benzotriazole, 3,5-dinitrophenol and pentafluorophenol. Preference is given to 4-nitrophenol and N-hydroxysuccinimide, the first mentioned reagent being particularly preferred.

Separation of protective groups follows according to methods known in the art, for example by means of hydrolysis, hydrogenolysis, alkaline saponification of esters with alkalis in a water-alcohol solution at temperatures from 0ºC to 50ºC, by acid saponification with mineral salts or in the case of e.g. tert-butyl esters using trifluoroacetic acid (Protective Groups in Organic Synthesis, 2nd Edition, T.W. Greene and P.G.M. Wuts, John Wiley and Sons, Inc. New York, 1991), in the case of hydrogen/palladium/carbon bentyl ethers.

Preparation of starting substances, compounds of formula IIIb,

[image]

(IIIb),

is known from DE 196 52 386.

Amines of general formula Ivb

[image]

(ivb)

are products that can be purchased (Fluorochem, ABCR) or can be obtained according to the following procedures from compounds of general formula Vb through translation with one amine of general formula Vib and further reduction of compounds of general formula VIIb:

[image]

in which

RF, A1, L1 and R3, which have the above-mentioned meaning and L` which has the meaning of the group L1, in which the α-CH2-group is still missing, and Rg stands for hydrogen or one methyl group.

After the procedure for activating carboxylic acid IIIb was already published in the literature, acid Vb will be activated with Vib before translation. For Rg meaning one methyl group, aminolysis will be performed.

Compounds of the general formula Vb are products that can be purchased (Fluorochem, ABCR) or, as disclosed in DE 196 03 033, will be prepared.

Compounds of formula Vib are commercially available products (Fluorochem, ABCR) or can as in Houben-Weyl, Methoden der organischen Chemie, XI/2, Stickstoffverbindungen, Georg Thieme Verlag Stuttgart, 1957, S. 680; IS. Rickman and T. Atkins, Am. Chem. Soc., 96:2268, 1974, 96:2268; F. Chavez and A.D. Sherry, J. Org. Chem. 1989, 54:2990 described, will be made:

Compounds of the general formula IVb will be in a known manner [helv. Chem. Acta, 77:23(1994)] through the reduction of compounds of the general formula VII, e.g. diborane or lithium aluminum hydride and removal of the protective group obtained.

Procedure B

The starting material is a carboxylic acid of the formula IIIx with R1 denoting hydrogen - it does not yet contain any equivalent of metal ions R1. Carboxylic groups will be protected by methods known in the art and compounds of the formula IIIy will be obtained, where R5 stands for any protecting group and R5' stands for their intermediates.

[image]

(XI) (IIIy)

Carboxyl protecting groups include, for example, straight-chain or branched C1-C6-alkyl, aryl and aralkyl groups, for example methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bi(p-nitrophenyl)methyl groups, as well as trialkylsilyl groups in consideration. The t-butyl group is preferred.

[image]

(IIIy) (IVb) (Ix)

The conversion of the protected carboxylic acid IIIy with an amine of the formula Ivb and the removal of the protective group follows as described in procedure A, and in one of the following steps, the carboxylic acid Ix will be obtained with at least one metal oxide or metal salt of one element of the desired serial number converted, as in DE 195 25 924 revealed.

If the metal complex obtained from process A or B still contains free COOH groups, these groups can be present as well as salts of physiologically tolerable inorganic or organic bases.

Neutralization of the possibly still present free carboxyl groups then follows with the help of inorganic bases (e.g. hydroxide, carbonate or bicarbonate) of e.g. sodium, potassium, lithium, magnesium or calcium and/or organic bases, as with other primary, secondary and tertiary amines, such as ethanolamine, morpholine, glucamine, N-methyl and N,N-dimethylglucamine, as well as basic amino acids such as lysine, arginine and ornithine or from amides of originally neutral or acidic amino acids.

According to the invention, the metal complexes V, VII, VIII, IX, X (compare table 1) will be particularly advantageously used.

These compounds of the general formula Ib are very useful as MRI-contrast agents for determining plaque.

In another embodiment of the invention, perfluoroalkyl-containing complexes with sugar residues of the general formula Ic can be used

[image]

(c)

in which

R one via 1-OH or 1-SH-position connected mono or oligosaccharide residues represents,

RF one perfluorinated, straight-chain or branched carbon chain with the formula –CnF2nE, in which E represents the last one in the row of fluorine, chlorine, bromine, iodine or hydrogen atom and n stands for numbers 4-30,

K stands for a metal complex of the general formula Iic,

[image]

(IIc)

in which

R1 one hydrogen atom or one equivalent of metal ions with serial numbers 23-29, 42-46 or 58-70 means,

with the measure that at least two R1 for the equivalent of metal ions stand

R2 and R3 mutually independent hydrogen, C1-C7-alkyl, benzyl, phenyl, -CH2OH or –CH2OCH3 represent and

In -C6H4-O-CH2-ω-, -(CH2)1-5-ω, one phenyl group, -CH2-NHCO-CH2-CH(CH2COOH)-C6H4-ω-, -C6H4-(OCH2CH2)0- 1-N(CH2COOH)-CH2-ω or one likewise via one or more oxygen atoms, 1 to 3-NHCO-, 1 to 3-CONH-group interrupted and/or with 1 to 3 –(CH2)0-5COOH -substituted C1-C12-alkylene or C7-C12-C6H4-O-group represents, where ω stands for the site of attachment to –CO-,

or

general formula IIIc

[image]

(IIIc)

in which R1 has the above meaning, R4 represents hydrogen or an equivalent of metal ions named under R1 and represents U1 – C6H4-O-CH2-ω-, where ω represents the binding site on –CO-

or general formula Ivc

[image]

(IVc)

in which R1 and R2 have the above meaning

or the general formulas VcA or VcB

[image]

(VcA)

[image]

(VcB)

in R1, which has the above meaning

or general formulas VIc

[image]

(Joke)

wherein R1 has the above meaning,

or general formula VIIc

[image]

(VIIc)

wherein R 1 has the above meaning and

U1 – represents C6H4-O-CH2-ω-, where ω indicates the binding site to –CO-

or general formula VIIIc

[image]

(VIIIc)

in R1 having the above meaning,

and in the residue K also present free acidic groups as well as salts of organic and/or inorganic bases or amino acids or amides of amino acids may be present,

G for the case that K means metal complex IIc to VIIc, one at least triply functional residue selected from the following residues a) to j) represents

(And)

[image]

(b)

[image]

(c)

[image]

(d)

[image]

(e)

[image]

(f)

[image]

(Mr)

[image]

(h)

[image]

(and)

[image]

(j)

[image]

and

G for the case that K has the meaning of a metal complex, one at least triple functional residue selected from k) or l) represents,

(k)

[image]

(l)

[image]

where α denotes the binding site of G to complex K, β denotes the binding site of G to residue Y, and γ the binding site of G to residue Z

Y -CH2-, σ-(CH2)1-5-CO-β, σ-CH2-CHOH-CO-β or σ-CH(CHOH)-CH2OH)-CHOH-CHOH-CO- β denotes, where σ the binding site to the sugar residue R represents and β the binding site to the G residue

Z for

[image]

or

γ-NHCH2CH2-O-CH2CH2-ε

stands, where the γ binding site of Z to the G residue represents and the ε binding site of Z to the perfluorinated residue RF denotes

and

l1, m1 mutually independent all numbers 1 or 2 denote i

p1 integers 1 to 4 denote,

be used.

Considering that the compounds presented by the invention are intended for use in NMR-diagnostics, the metal ion of the signal-giving group must be paramagnetic. These are especially the double or triple ions of elements with ordinal numbers 23-29, 42-46 and 58-70. Suitable ions are, for example, chromium(III), iron(II), cobalt(II), nickel(II), copper(II), phraeodymium(III), neodymium(III), samarium(III), and ytterbium(III)- ions. Due to their strong magnetic moments, gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III), iron(III) and manganese(II)-ions are particularly advantageous.

Manganese(II), iron(II), iron(III), phraesodymium(III), neodymium(III), samarium(III), gadolinium(III) and ytterbium(III)-ions are preferred, especially dysprosium(III)- ions.

Acidic hydrogen atoms are also present in R1, which means that those, which are not substituted via the central ion, can also be substituted completely or partially via 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 especially sodium ion. Suitable cations of organic bases are, among others, those of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine and especially N-methylglucamine. Suitable cations of amino acids are, for example, those of lysine, arginine or ornithine, as well as amides of otherwise acidic or neutral amino acids.

Compounds of general formula Ic as such with macrocycle K of general formula IIc are particularly advantageous.

The U residue in the metal complex K denotes, for example, –CH2- or C6H4-O-CH2-ω, where ω stands for the binding site to –CO-.

Alkylene groups R2 and R3 in the macrocycle of the general formula IIc can be straight-chain or branched. Examples of this are methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl named. For example, R2 and R3 independently of each other denote hydrogen or C1-C4-alkyl.

In one particular embodiment, R2 stands for methyl and R3 stands for hydrogen.

Benzyl groups or phenyl groups R2 or R3 in macrocycle K of the general formula IIc can also be substituted in the ring.

The residue R of the general formula Ic is denoted by one via the 1-OH or 1-SH position of the connected mono- or oligosaccharide residues or thiosugar residues, whereby according to the invention presented, it is also deoxy sugars, which instead of one or more OH-groups contain one H-atom . In a preferred form of the invention, R is designated as a monosaccharide residue with 5 to 6 C-atoms, preferably glucose, mannose, galactose, ribose, arabinose or xylose or their deoxysugars such as, for example, 6-deoxygalactose (fucose) or 6- deoxymannose (rhamnose) or their thiosugars, with glucose, mannose and galactose being particularly preferred.

Of the compounds of the general formula Ic presented by the invention, those in which RF –CnF2n+1 denotes are further preferred. n stands for the numbers 4-15, for example. Particularly advantageous are the residues -C4F9, -C6F17, -C12F25 and -C14F29, as well as the residues listed in the above examples.

The at least triply functional residue G in the general formula Ic, which represents the "skeleton", indicates in that preferred embodiment of the invention a lysine residue (a) or (b).

Y and Z denote the linkers specified in the general formula Ic, where they are independent of each other for the Z residue

[image]

And for the Y residue σ-CH2CO-β are advantageous.

Metal complexes with sugar residues of the general formula Ic, containing perfluoroalkyl

[image]

with K denoting a metal complex of general formula Iic to VIIc and G whose designation is given in formula a) to j), where Y, Z, R, RF, m1, p1 and I1 having the above meaning, will be made, wherein, in a known manner, one carboxylic acid of the general formula IIi

[image]

(IIi)

where R5 denotes one equivalent of metal ions with serial numbers 23-29, 42-46 or 58-70 or one carboxyl protecting group, and R2, R3 and U which have the given meaning

or one carboxylic acid of the general formula IIIi

[image]

(IIIi)

wherein R4, R5 and U1 have the stated meaning

or one carboxylic acid of the general formula Ivi

[image]

(And you)

wherein R5 and R2 have the stated meaning

or a carboxylic acid of the general formula Vi or Vii

[image]

(vii)

wherein R 5 has the specified meaning

or a carboxylic acid of the general formula Vii

[image]

(vii)

wherein R 5 has the specified meaning

or one carboxylic acid of the general formula VIIi

[image]

(VIi)

where R5 and U1 have the above meaning,

in the same activated form with one amine of the general formula Ixc

[image]

(IXc)

in which G has the meaning from the formula a) to j) and R, RF, Y, Z, m1 and p1 have the given meaning, in one binding reaction and also the subsequent removal of the protective groups also present to a metal complex of the general formula Ic translations

or

if R5 has the meaning of one protecting group, after removing that protecting group in one of the following steps, in a known manner with at least one metal oxide or metal salt of one element with sequence number 23-29, 42-46 or 58-70 and so on, if is desired, the acidic hydrogen atoms also present are substituted by cations of inorganic and/or organic bases, amino acids or amino acid amines.

[image]

(VIIIi)

wherein R5 denotes one equivalent of metal ions with serial numbers 23-29, 42-46 or 58-70 or one carboxyl protecting group,

with one, likewise activated, carboxylic acid of the general formula Xc

[image]

(xc)

where G has the meaning from the formula k) or I) and R, RF, Y, Z, m1 and p1 have the given meaning, in one binding reaction and also the following separation of the protective groups also present to a metal complex of the general formula Ic will be translated

or

if R5 has the meaning of one protective group, after the removal of that protective group and one subsequent step, which is carried out in a known manner with at least one metal oxide or metal salt of one element with sequence number 23-29, 42-46 or 58-70, and so on , if desired, also present acidic hydrogen atoms are substituted via cations of inorganic and/or organic bases, amino acids or amino acid amides.

The used carboxylic acids of the general formulas IIi to VIIi are either known compounds or will be prepared according to the known procedures described. Thus, the preparation of carboxylic acids of the general formula IIi from DE 196 52 386 is known. Preparation of carboxylic acid of the general formula IVi is DE 197 28 954 exemptable.

Intermediates for compounds of the general formula VcA is N3-(2,6-dioxomorpholinoethyl)-N6-(ethoxycarbonylmethyl)-3,6-diaza-dioctanoic acid, which is described in EP 263 059.

Compounds of the general formula VcB are derived from isomeric diethylenetriamine-pentaacetic acid, which binds acetic acid through the middle N-atom. That DTPA is described in patents DE 195 07 819 and DE 195 08 058.

Compounds of general formula Vic are derived from N-(carboxymethyl)-N-[2-(2,6-dioxo-4-morpholinyl]-glycine, whose synthesis is in J.Am.Oil.Chem.Soc. (1982), 59 (2), 104-107, described.

Compounds of general formula VIIc are derived from 1-(4-carboxymethoxybenzyl)-ethylenediamine-tetraacetic acid, which is described in US patent 4,622,420.

Perbenzylated sugar acids can be used as a starting material, analogously to Lockhoff, Angew.Chem. 1998, 110 no. 24, p. 3634ff to be made. This follows, for example, the preparation of 1-O-acetic acid from perbenzyl-glucose, over 2 stages, via trichloroacetimidate and reaction with ethyl ester of hydroxyacetic acid, BF3-catalysis in THF and subsequent saponification with NaOH in MeOH/THF.

In a more favorable process, the perbenzylated sugar acids used as starting materials can also be prepared, whereby the perbenzylated 1-OH-sugar is dissolved in a solvent that cannot be mixed with water, and with one reagent for alkylation, of the general formula Xic

Nu-1-COO-Sg (Xic),

where Nu denotes one nucleotide, L –(CH2) (1-5), -CH2-CHOH-, -CH(CHOH-CH2OH)-CHOH-CHOH- is, and Sg is one protecting group, in the presence of one base and also one phase-transfer-catalyst will be translated. As a nucleofuge, the alkylating reagent of the general formula Xic can contain, for example, Cl, Br, J, OTs, OMs, OSO2CF3, OSO2C4F9 or OSO2C8F17 residues.

The protecting group is a common acidic protecting group. These protective groups are well known to those skilled in the art (Protective Groups in Organic Synthesis, second Edition, T.W.Greene and P.G.M. Wuts, John Wiley & Sons Inc., New York 1991).

The use envisaged by the invention can be at temp. from 0-50ºC, preferably at temp. 0ºC to room temp. to follow. The reaction time is from 10 min to 24 hours, preferably from 20 min to 12 hours.

The base will be in solid form, preferably fine powder or as 10-70%, preferably 30-50%, aqueous solution added. The preferred bases are NaOH and KOH.

For example, toluene, benzene, CF3-benzene, hexane, cyclohexane, diethyl ether, tetrahydrofuran, dichloromethane, MTB or their mixtures can be used as organic, water-immiscible solvents in the alkylation procedures presented in the invention.

Known quaternary ammonium or phosphonium salts or also "Kronene" ethers, such as (15)-Krone-5 or (18)-Krone-6, are used as phase-transfer catalysts in the process presented by the invention. For example, quaternary ammonium salts with 4 same or different hydrocarbon groups on the cation, separated from methyl, ethyl, propyl, isopropyl, butyl or isobutyl, are taken into account. The hydrocarbon groups on the cation must be large enough to obtain a good solubility of the alkylating reagent in the organic solvent. According to the invention, N(butyl)4+-Cl-, N(butyl)4+-HSO4-, or N(methyl)4+-Cl- is especially advantageous.

Compounds of the general formula Ic, represented by the invention as metal complex XV from tab., will be of particular benefit. 1 (example 1).

In a further, preferred embodiment are perfluoroalkyl-containing complexes with polar residues of the general formula Id

Application

[image]

(ID)

where

RF is a perfluorinated, straight-chain or branched carbon chain with the formula –CnF2nE, in which E is at the end of the chain, and can be fluorine, chlorine, bromine, iodine or a hydrogen atom, and n stands for the numbers 4-30,

K stands for a metal complex of the general formula Iid,

[image]

(IId)

in which

R1 one hydrogen atom or one equivalent of metal ions serial numbers 23-29, 42-46 or 58-70 means,

with the criterion that at least 2 R1 for the equivalent of metal ions stand,

R2 and R3 mutually independent hydrogens, C1-C7-alkyl, benzyl, phenyl, -CH2OH or –CH2OCH3 represent and

In -C6H4-O-CH2-ω-, -(CH2)1-5-ω, one phenyl group, CH2-NHCO-CH2-CH(CH2COOH)-C6H4-ω-, -C6H4-(OCH2CH2)0-1 -N(CH2COOH)-CH2-ω or one also via one or more oxygen atoms, 1 to 3 -NHCO-, 1 to 3 –CONH-groups unbroken and/or with 1 to 3

-(CH2)0-5COOH-group of substituted C1-C12-alkylene or C7-C12-C6H4-O-group represents, where ω stands for the site of attachment to –CO-

or

general formulas IIId

[image]

(IIId)

in which R1, which has the above meaning, R4 represents hydrogen or one equivalent of metal ions specified under R1 and U1 represents –C6H4-O-CH2-ω-,

where ω indicates the place of attachment to –CO-

or general formulas Ivd

[image]

(IVd)

wherein R1 and R2 have the above meaning

or the general formulas VdA or VdB

[image]

(VdA)

[image]

(VdB)

in which R1 has the above meaning,

or that of the general formula Vid

[image]

(Vision)

in which R1 has the above-mentioned meaning,

or that of the general formula VIId

[image]

(VIId)

wherein R 1 has the above meaning and

U1 represents –C6H4-O-CH2-ω-, where ω indicates the binding site to –CO-

and in the residue K also present free acidic groups as well as salts of organic and/or inorganic bases or amino acids or amino acid amides may be present,

G represents one at least triple functional residue, selected from the following residues a) to g).

(And)

[image]

(b)

[image]

(c)

[image]

(d)

[image]

(e)

[image]

(f)

[image]

(Mr)

[image]

(h) [image] (i) [image]

where α represents the binding site of G to complex K, β is the binding site of G to residue R, and γ is the binding site of G to residue Z

Z for

[image]

stands, where γ represents the binding site from Z to the G residue, and ε represents the binding site from Z to the perfluorinated residue RF

R represents one polar residue selected from the complex K of the general formulas Iid to VIId, where R1 here represents one hydrogen atom or one equivalent of metal ions of serial numbers 20, 23-29, 42-46 or 58-70,

and residues R2, R3, R4, U and U1 exhibiting the above properties

or

the rest of folic acid

or

one via –CO-, SO2- or one direct bond to the residue G of a connected carbon chain with 2-30 C-atoms, indicates straight-chain or branched, saturated or unsaturated,

likewise interrupted by 1-10 oxygen atoms, 1-5 –NHCO-groups, 1-5 –CONH-groups, 1-2 sulfur atoms, 1-5 –NH-groups or 1-2 phenylene-groups, which also with 1-2 –OH-groups, 1-2 NH2-groups, 1-2 –COOH-groups or 1-2 –SO3H-groups can be substituted

or

also substituted with 1-8 OH-groups, 1-5 –COOH-groups, 1-2 SO3H-groups, 1-5 NH2-groups, 1-5 C1-C4-alkoxy groups,

and

I1, m1, p2 independently represent the integers 1 or 2.

Considering that the compounds presented by the invention are used in NMR-diagnostics, the metal ion must be paramagnetic in relation to the signal-giving group. These are especially the divalent and trivalent ions of the elements with ordinal numbers 23-29, 42-46 and 58-70. Suitable ions are, for example, chromium(III), iron(II), cobalt(II), nickel(II), copper(II), praseodymium(III), neodymium(III), samarium(III) and ytterbium(III). Due to their strong magnetic moment, gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III), iron(III) and manganese(II)-ions are particularly advantageous.

Manganese(II), iron(II), iron(III), praseodymium(III), neodymium(III), samarium(III), gadolinium(III) and ytterbium(III) ions are preferred, especially dysprosium(III) ions . Acidic hydrogen atoms also present in R1, which means those that are not substituted through the central ion, can also be completely or partially 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 especially sodium ion. Suitable organic base cations are, in addition to others, primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine and especially N-methylglucamine. Suitable amino acid cations are, for example, those of lysine, arginine or ornithine, as well as amides of otherwise acidic or neutral amino acids.

Particularly advantageous over compounds of general formula Id are those with macrocycle K of general formula Iid, IIId, VdB or VIId.

The residue U in the metal complex K denotes, for example, –CH2- or C6H4-O-CH2-ω, where ω stands for the binding site to –CO.

Alkyl groups R2 and R3 in the macrocycle of the general formula Iid can be straight-chain or branched. Examples of this are methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl named. For example, R2 and R3, independently of each other, denote hydrogen or C1-C4-alkyl.

In one particularly suitable embodiment, R z2a is methyl and R3 is hydrogen.

Benzyl groups or phenyl groups R2 or R3 in macrocycle K of the general formula Iid can also be substituted in the ring.

The polar residue R in the general formula Id denotes a complex K in a special form, whereby it can be, for example, a Ca 2+ complex in addition to a Gd 3+ or Mn 2+ complex. They are particularly advantageous as polar residues of R complex K of the general formula IId, IIId, VdA or VIId. Those residues show distinct advantages as R1 one equivalent of metal ions or ordinal numbers 20, 25, 39 or 64.

In another preferred embodiment, the polar residue R has the following meaning:

[image]

[image]

for example -C(O)CH2O[(CH2)2O]4-CH3.

In a further embodiment, the polar residue R denotes a folic acid residue.

Of the compounds of the general formula Id presented by the invention, those in which RF stands for –CnF2n+1 are further preferred. n stands for the numbers 4-15, for example. The residues -C4F9, -C6F13, -C8F17, -C12F25 and -C14F29 are particularly preferred.

The at least triply functionalizing residue G in the general formula Id, which represents the "skeleton", denotes in one form, which is preferred, the embodiment of the invention of the lysine residue (a) or (b).

Z denotes the "linker" specified in the general formula Id, while the remainder

[image]

has an advantage.

Metal complexes containing perfluoroalkyl with polar residues of the general formula Id

[image]

(ID)

in which K, G, R, Z, RF, I1, m1 and p2 have the above meaning, will be prepared, in a manner in which a carboxylic acid of the general formula Iik

[image]

(IIk)

where R5 denotes the equivalent of metal ions of serial numbers 23-29, 42-46 or 58-70 or one carboxyl protecting group, and R2, R3 and U, which have the given meaning

or one carboxylic acid of the general formula IIIk

[image]

(IIIk)

wherein R4, R5 and U1 have the stated meaning

or one carboxylic acid of the general formula IVk

[image]

(IV k)

wherein R5 and R2 have the stated meaning

or one carboxylic acid of the general formula Vk or Vm

[image] [image]

(Vk) (Vm)

wherein R 5 has the specified meaning

or one carboxylic acid of the general formula VI k

[image]

(VI k)

wherein R 5 has the specified meaning

or one carboxylic acid of the general formula VIIk

[image] (VIIk)

where R5 and U1 have the above meaning,

in the same activated form with one amine of the general formula VIIId

[image] (VIIId)

in which G, R, Z, RF, m1 and p2 have the stated meaning, in one reaction of connection and also the subsequent cleavage of the protective groups also present to one metal complex of the general formula Id be translated

or

if R5 has the meaning of one protecting group, after the removal of that protecting group in one of the following steps, in one of the known ways with at least one metal complex or metal salt of one element with sequence number 23-29, 42-46 or 58-70, it is translated and then, if desired, also present "acidic" hydrogen atoms can be substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides.

The used carboxylic acids of the general formulas Iik to VIIk are either known compounds or will be prepared according to the procedures described in the above examples. Thus, the preparation of carboxylic acid of the general formula Iik from the subject DE 196 52 386 is known. Preparation of carboxylic acid of the general formula Ivk can be removed from the subject DE 197 28 954.

The intermediate for compounds of the general formula VdA is N3-(2,6-dioxomorpholino-ethyl)-N6-(ethoxycarbonylmethyl)-3,6-diaza-octadienoic acid, which is described in EP 263 059.

Compounds of the general formula VdB are derived from the diethylenetriamine-foam acetic acid isomer, which is bound via the middle N-atom on the acetic acid. That DTPA is described in patents DE 195 07 819 and DE 195 08 058.

Compounds of the general formula Vid are derived from N-(carboxymethyl)-N-[2-(2,6-dioxo-4-morpholinyl]-ethyl]-glycine, the preparation of which is described in J. Am. Oil. Chem. Soc. (1982), 59 (2), 104-107.

Compounds of the general formula VIId are derived from 1-(4-carboxymethoxybenzyl)-ethylenediamine-tetraacetic acid, the preparation of which was described in US patent 4,662,420.

As compounds of particular advantage among the compounds of the general formula Id, metal complexes XVI from Tab. 1.

In another embodiment of the invention, galenic formulations can be used, which contain paramagnetic and diamagnetic substances, which contain perfluoroalkyl. For example, paramagnetic and diamagnetic substances also come dissolved in one aqueous solvent.

As paramagnetic, perfluoroalkyl compounds, all following metal complexes of the general formula I, Ia, Ib, Ic and/or Id can be used in the formulations according to the invention.

Diamagnetic substances containing perfluoroalkyl are of such general formula XX:

RF – L2 – B2 (XX)

where RF represents one straight-chain or branched perfluoroalkyl residue with 4 to 30 carbon atoms, L2 stands for one linker and B2 stands for one hydrophilic group. Linker L2 is one direct bond, one –SO2-group or one straight-chain or branched chain with up to 20 carbon atoms, which can be substituted with one or more –OH, -COO-, -SO3-groups and/or also one or multiple –O-, -S-, -CO-, -CONH-, -NHCO-, -CONR9-, -NR9CO-, -SO2-, -PO4--, -NH-, -NR9-groups, one aryl ring or one piperazine contains, whereby R9 stands for one C1- to C20-alkyl residue, which again may contain one or more O-atoms and/or may be substituted with –COO- or SO3-groups.

Hydrophilic group B2 is one mono or disaccharide, one or more adjacent –COO- or –SO3— groups, one dicarboxylic acid, one isophthalic acid, one picolinic acid, one benzenesulfonic acid, one tetrahydropyrandicarboxylic acid, one 2,6-pyridinedicarboxylic acid, one quaternary ammonium ion, one aminopolycarboxylic acid, one aminodipolyethylene-glycosulfonic acid, one aminopolyethylene glycol group, one SO2-(CH2)2-OH-group, one polyhydroxyalkylene chain with at least two hydroxy groups or one or more polyethylene glycol chains with at least two glycol units, whereby the polyethylene glycol chain is terminated via one –OH or –OCH3-group. such substances are partly already known, partly such substances were newly synthesized for making the formulations presented by the invention. Known substances containing perfluoroalkyl and their preparation will be described in the following publications:

J. G. Riess, Journal of Drug Targeting, 1994, Vol. 2, pp. 455-468;

J.B. Nivet et al., Eur. J. Med. Chem., 1991, Vol. 26, pp. 953-960;

M.-P. Krafft et al., Angew. Chem., 1994, Vol. 106, No. 10, pp. 1146-1148;

M. Lanier et al., Tetrahedron Letters, 1995, Vol. 36, No. 14, pp. 2491-2492;

F. Guillod et al., Carbohydrate Research, 1994, Vol. 261, pp. 37-55;

S. Achilefu et al., Journal of Fluorine Chemistry, 1995, Vol. 70, pp. 19-26;

L. Clary et al., Tetrahedron, 1995, Vol. 51, No. 47, pp. 13073-13088;

F. Szoni et al., Journal of Fluorine Chemistry, 1989, Vol. 42, pp. 59-68;

H. Wu et al., Supramolecular Chemistry, 1994, Vol. 3, pp. 175-180;

F. Guilleri et al., Angew. Chem. 1994, Vol. 106, No. 14, pp. 1583-1585;

M.-P. Krafft et al., Eur. J. Med. Chem., 1991, Vol. 26, pp. 545-550;

J. Greiner et al., Journal of Fluorine Chemistry, 1992, Vol. 56, pp. 285-293;

A. Milius et al., Carbohydrate Research, 1992, Vol. 229,

J. Riess et al., Colloids and Surfaces A, 1994, Vol. 84, pp. 33-48;

G. Merhi et al., J. Med. Chem., 1996, Vol. 39, pp. 4483-4488;

V. Cirkva et al., Journal of Fluorine Chemistry, 1997, Vol. 83, pp. 151-158;

A. Ould Amanetoullah et al., Journal of Fluorine Chemistry, 1997, Vol. 84, pp. 149-153;

J. Chen et al., Inorg. Chem., 1996, Vol. 35, pp. 1590-161;

L. Clary et al., Tetrahedron Letters, 1995, Vol. 36, No. 4, pp. 539-542;

MM. Chaabouni et al., Journal of Fluorine Chemistry, 1990, Vol. 46, pp. 307-315;

A. Milius et al., New J. Chem., 1991, Vol. 15, pp. 337-344;

M.-P. Krafft et al., New J. Chem., 1990, Vol. 14, pp. 869-875;

J.-B. Nivet et al., New J. Chem., 1994, Vol. 18, pp. 861-869;

C. Santanaella et al., New J. Chem., 1991, Vol. 15, pp. 685-692;

C. Santanaella et al., New J. Chem., 1992, Vol. 16, pp. 399-404;

A. Milius et al., New J. Chem., 1992, Vol. 16, pp. 771-773;

F. Szonyi et al., Journal of Fluorine Chemistry, 1991, Vol. 55, pp. 85-92;

C. Santanaella et al., Angew. Chem., 1993, Vol. 105, No. 5, pp. 783-785;

EP 0 548 096 B1.

Preparation of new substances containing perfluoroalkyl follows analogously to the above-mentioned substances known in the literature and is described in the examples. These are substances of the general formula XXI

RF – X1 (XXI)

where RF is a straight-chain or branched perfluoroalkyl residue with 4 to 30 carbon atoms and X1 is a residue selected from the group of the following residues (n is a number between 1 and 10):

[image]

[image]

[image]

Diamagnetic substances, which contain perfluoroalkyl and which are preferred, are those with one monosaccharide, as the hydrophilic group B2.

Diamagnetic substances that contain perfluoroalkyl are particularly advantageous, and contain one perfluoroalkyl residue Rf with 6 to 12 carbon atoms, one linker L2, which represents one –SO2-group or one straight or branched carbon chain with up to 20 carbon atoms, which again one or more –O-, -CO-, -CONH-, -NHCO-, -CONR-, NRCO-, -SO2-groups or one piperazine contain, where R has the above meaning and one monosaccharide as the hydrophilic group B2.

Further suitable perfluoroalkyl-containing diamagnetic compounds are cyclodextrin conjugates and perfluoroalkyl-containing compounds. These conjugates consist of α-, β-, or γ-cyclodextrin and compounds of general formula XXII

A1-L3-RF (XXII)

where A1 for adamantane, biphenyl or anthracene molecule, L3 for one linker and RF for one straight-chain or branched perfluoroalkyl residue with 4 to 30 carbon atoms stands. Linker L3 is one straight or branched carbon chain with 1 to 20 carbon atoms, which via one or more oxygen atoms, one or more CO-, SO2-, CONH-, NHCO-, CONR-, NRCO-, NH-, NR- groups or one piperazine may be terminated, wherein R is one C1-C5-alkyl residue.

Substances that are advantageous are the following:

[image]

[image]

The galenic formulations of the present invention contain paramagnetic and diamagnetic perfluoroalkyl compounds in a ratio between 5:95 and 95:5. Ratios between 40:60 and 60:40 of both substances are advantageous. Both substances were applied in millimolar concentrations. Concentrations between 0.5 and 1000 mmol/l of solvent were achieved. The most common solvent used is water. Metal concentrations of the same formulations lie, under the most favorable conditions, in the range of 50-250 mmol/l.

Preference is given to mixtures of paramagnetic and diamagnetic compounds containing perfluoroalkyl, in which the chains with perfluoroalkyl have a length of 6 to 12 carbon atoms. Particular preference is given to mixtures in which paramagnetic as well as diamagnetic compounds with perfluoroalkyl show one perfluoroalkyl chain with 8 carbon atoms.

Preparation of galenic formulations follows the way that paramagnetic perfluoroalkyl compounds (component A) and diamagnetic perfluoroalkyl substances (component B) in molar proportions between 0.05 and 0.95 to components A or B are weighed and dissolved in one suitable solvent. One particularly good solvent is water. The usual galenic additives are then added to such a solution, such as buffer solutions and Ca-salts of complex builders, in larger quantities. At 10 to 100°C, the solutions will be strongly mixed. Alternatively, solutions at 10 to 100°C in an ultrasonic bath can be treated. A further alternative is to treat the solutions with microwaves.

For substances that do not dissolve in water as individual components, it has proven to be advantageous to add a solvent, such as alcohol (eg methanol or ethanol) or another solvent, which can be mixed with water, and then slowly distill it off. Distillation can follow in a vacuum. The rest will be continuously dissolved in water and the solution filtered. It is also possible to dissolve each component separately in one solvent, then mix and process as above. It turned out to be advantageous to prepare a relatively highly concentrated solution (> 100 mmol) of the metal complex (component A) and then add component B, pure, and as mentioned above, mix the solutions or treat them in an ultrasonic bath, i.e. microwaves.

In conclusion, it can be said that the gadolinium complexes I-XVI listed in Table 1 meet the criteria presented by the invention as compounds, which are given special preference. The physical parameters of those metal complexes I-XVI are in tab. 2 listed.

Likewise, the paramagnetic compounds of the general formula I, Ia, Ib, Ic and Id presented by the invention, as well as the formulations presented by the invention from paramagnetic and diamagnetic substances, which contain perfluoroalkyls, are exceptionally suitable as contrast agents for MR-imaging for plaque detection, tumors and necrosis.

Table 1: Metal complexes specially selected and applied by the invention

Kompeks Literary citation, name

I WO 97/26017, Example 33f

Gadolinium complex of 10-[1-methyl-2-oxo-3-aza-5-oxo-{4-perfluorooxyl-sulfonyl-piperazin-1-yl}pentyl]-1,4,7-tris(carboxymethyl)- 1,4,7,10-tetraazacyclododecane

II WO 97/26017, example 2c

Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,1112,12,13,13,14,14,15,15,16,16,17 ,17-heptadecafluoroheptacecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

III WO 97/26017, example 34b

Gadolinium complex of 10-[2-hydroxy-4-aza-5,9-dioxo-9-{4-perfluorooctyl)-piperazin-1-yl}nonyl]-1,4,7-tris(carboxymethyl)-1 ,4,7,10-tetraazacyclododecane

IV WO 97/26017, example 1c

Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctyl-sulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7 ,10-tetraazacyclododecane

V Example 2c, attached application

1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-hexan-5-yl)-acid-N-(2,3-dihydroxypropyl)-N-(1H,1H,2H, 2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex

VI WO 97/26017, example 3c

gadolinium complex of 10-[2-hydroxy-4-oxa-1H,1H,2H,3H,3H,5H,5H6H,6H-perfluorotetradecyl]-1,4,7-tris(carboxymethyl)-1,4,7 ,10-tetraazacyclododecane

VII example 5e, attached application

1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-N-(3,6,9,12,15-pentaoxa)-hexadecyl) -N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex

VIII example 3c, attached application

1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-N-(5-hydroxy-3-oxa-pentyl)-N-(1H ,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

IX example 6b, attached application

1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-[N-3,6,9,16-tetraoxa-13-aza-14 -oxo-C19-C26-hepta-decafluoro)hexacosyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

X example 1c, application attached

1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-yl)-acid-[N-2-methoxyethyl)-N-(1H,1H,2H,2H ,4H,4H,5H,5H-3-oxa)perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

XI WO 97/26017, Example 32c

gadolinium-complex of 10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15,15, 16,16 ,17,17,18,18,19,19-henicosafluoro-nonadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

XII WO 97/26017, example 38d

gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-11-aza-11(perfluorooctyl-sulfonyl)-tridecyl]-1,4,7-tris(carboxymethyl)-1,4,7, 10-tetraazacyclododecane

XIII WO 97/26017, example 35d

gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7(perfluorooctyl-sulfonyl)-8-phenyl-octyl]-1,4,7-tris(carboxymethyl)-1, 4,7,10-tetraazacyclododecane

XIV WO 99/01161, example 1g

1,4,7-tris{1,4,7-tris(N-(carboxylatomethyl)-10-[N-1-methyl-3,6-diaza-2,5,8-trioxooctane-1,8-diyl )-1,4,7,10-tetraazacyclododecane,Gd-complex}-10-N-2H,2H,4H,4H,5H,5H-3-oxa-perfluoro-tridecanoyl]-1,4,7,10- tetraazacyclododecane, Gd-complex

XV example 21f, attached application

6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -2-N-[1-O-α-D-carboxymethyl-manno-pyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

XVI example 54b, attached application

2,6-N,N'-bi-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl- 5-yl)]-lysine-[1-(4-perfluorooctylsulfonyl-piperazine]-amide, Gd-complex

Table 2:

Physico-chemical parameters of the complexes presented and applied by the invention according to table 1

[image]

CMC: critical concentration for micelle formation

2 Rh: hydrodynamic micellar diameter

R1: relaxivity

Performance examples

Example 1

2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid-N-(2-methoxy)-ethyl-amide

To 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, add 8.90 g (70 mmol) of oxalyl chloride and stir for 12 hours at room temperature. temp. The mixture is then evaporated to dryness under vacuum. The residue is dissolved in 100 ml of dichloromethane and at 0°C to a solution of 4.51 g (60 mmol) of 2-methoxyethylamine and 6.07 g (60 mmol) of triethylamine, which are added dropwise to 200 ml of dichloromethane. The mixture is stirred for 3 hours at 0°C and then for another 6 hours at room temperature. Add 300 ml of 5% hydrochloric acid and mix for the next 15 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographically developed on Kieselgel (TL-chromatogram developer: dichloromethane/acetone=20:1).

Yield: 30.28 g (91% d.Th.) of a colorless solid

Analysis of elements:

ber.: C 31.10 H 2.44 N 2.42 F 55.76

gef.: C 30.87 H 2.58 N 2.35 F 55.51

b) N-(2-methoxyethyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)perfluorotridecylamine

30 g (51.79 mmol) of the title substance from example 1a will be dissolved in 300 ml of tetrahydrofuran and 31 ml of 10M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 16 hours, with reverse cooling. It is then cooled to 0°C and 200 ml of methanol is added dropwise, and it is then evaporated to dryness under vacuum. The residue is dissolved in a mixture of 300 ml ethanol/50 ml 10% hydrochloric acid and stirred for 8 hours at 40°C. It is then evaporated to dryness under vacuum, the residue is dissolved in 300 ml of 5% sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phase is dried with magnesium persulfate, evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel (chromatogram developer: dichloromethane/2 propanol=20:1).

Yield: 26.93 g (92% d.Th.) of a colorless solid.

Analysis of elements (calculated according to dry substances):

ber.: C 31.87 H 2.85 N 2.48 F 57.14

gef.: C 31.69 H 3.10 N 2.27 F 56.88

c) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-yl)-acid-N-(2-methoxyethyl)-N-(1H,1H,2H ,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex

(metal complex X)

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride, will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The mixture is cooled to 15°C and 8.98 g (15.88 mmol) of the title substance from example 1b is added. The mixture was further stirred for 10 min and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. It is mixed for 12 hours at room temperature. The solution is then poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitated substance is filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (solvent: tetrahydrofuran/acetonitrile/water gradient).

Yield: 15.14 g (81% d.Th.), one colorless, amorphous powder

Water content: 5.7%

Analysis of elements (calculated according to dry substances):

ber.: C 34.70 H 3.77 N 7.14 F 27.44 Gd 13.36

gef.: C 34.51 H 3.94 N 7.02 F 27.25 Gd 13.18

Example 2

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa)-perfluorotridecanoic acid-N-(2,3-dihydroxypropyl)-amide

To 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, add 8.90 g (70 mmol) of oxalyl chloride and stir for 12 hours, at room temp. The mixture is then evaporated to dryness under vacuum. The residue is dissolved in 100 ml of dichloromethane and at 0°C to a solution of 5.47 g (60 mmol) of 2,3-dihydroxypropylamine and 6.07 g (60 mmol) of triethylamine, which are added dropwise to 200 ml of dichloromethane. The mixture is stirred for 3 hours at 0°C and then for another 6 hours at room temperature. Add 300 ml of 5% hydrochloric acid and mix for the next 15 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographically developed on Kieselgel (TL-chromatogram developer: dichloromethane/ethanol=15:1).

Yield: 29.70 g (87% d.Th.) of a colorless solid

Analysis of elements:

ber.: C 30.32 H 2.20 N 2.36 F 54.35

gef.: C 30.12 H 2.41 N 2.18 F 54.15

b) N-(2,3-dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amine

30 g (48.8 mmol) of the title substance from example 2a will be dissolved in 300 ml of tetrahydrofuran and 50 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 16 hours, with reverse cooling. It is then cooled to 0°C and 300 ml of methanol is added dropwise, and it is then evaporated to dryness under vacuum. The residue is dissolved in a mixture of 300 ml ethanol/50 ml 10% hydrochloric acid and stirred for 8 hours at 60°C. It is then evaporated to dryness under vacuum, the residue is dissolved in 300 ml of 5% sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phase is dried with magnesium persulfate, evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel (chromatogram developer: dichloromethane/methanol=15:1).

Yield: 24.07 g (85% d.Th.) of a colorless solid.

Analysis of elements:

ber.: C 31.05 H 2.61 N 2.41 F 55.66

gef.: C 31.91 H 2.78 N 2.33 F 55.47

c) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-yl)-acid-N-(2,3-dihydroxypropyl)-N-(1H,1H ,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex

(metal complex X)

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride, will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The mixture is cooled to 15°C and 9.21 g (15.88 mmol) of the title substance from example 2b is added. The mixture was further stirred for 10 min and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. It is mixed for 12 hours at room temperature. The solution is then poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitated substance is filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (solvent: tetrahydrofuran/acetonitrile/water gradient).

Yield: 16.09 g (85% d.Th.), one colorless, amorphous powder

Water content: 6.3%

Analysis of elements (calculated according to dry substances):

ber.: C 34.26 H 3.64 N 7.05 F 27.10 Gd 13.19

gef.: C 34.12 H 3.83 N 6.91 F 26.88 Gd 12.93

Example 3

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid-N-(5-hydroxy-3-oxapentyl)-amide

To 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, add 8.90 g (70 mmol) of oxalyl chloride and stir for 12 hours, at room temp. The mixture is then evaporated to dryness under vacuum. The residue is dissolved in 100 ml of dichloromethane and at 0°C to a solution of 6.25 g (60 mmol) of 5-hydroxy-3-oxa-pentylamine and 6.07 g (60 mmol) of triethylamine, which are added dropwise to 200 ml dichloromethane. The mixture is stirred for 3 hours at 0°C and then for another 6 hours at room temperature. Add 300 ml of 5% hydrochloric acid and mix for the next 15 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographically developed on Kieselgel (TL-chromatogram developer: dichloromethane/acetone=15:1).

Yield: 32.20 g (92%d.Th.) of a colorless solid

Analysis of elements:

ber.: C 31.54 H 2.65 N 2.30 F 53.01

gef.: C 31.61 H 2.84 N 2.14 F 52.85

b) N-(5-hydroxy-3-oxa-pentyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amine

30 g (49.24 mmol) of the title substance from example 3a will be dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 16 hours, with reverse cooling. It is then cooled to 0°C and 200 ml of methanol is added dropwise, and it is then evaporated to dryness under vacuum. The residue is dissolved in a mixture of 300 ml ethanol/50 ml 10% hydrochloric acid and stirred for 10 hours at 50°C. It is then evaporated to dryness under vacuum, the residue is dissolved in 300 ml of 5% sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phase is dried with magnesium persulfate, evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel (chromatogram developer: dichloromethane/2-propanol=20:1).

Yield: 26.09 g (89% d.Th.) of a colorless solid.

Analysis of elements:

ber.: C 32.28 H 3.05 N 2.35 F 54.25

gef.: C 32.12 H 3.21 N 2.18 F 54.09

c) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-yl)-acid-N-(5-hydroxy-3-oxa-pentyl)-N- (1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex

(metal complex VIII)

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride, will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The mixture is cooled to 15°C and 9.45 g (15.88 mmol) of the title substance from example 3b is added. The mixture was further stirred for 10 min and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. It is mixed for 12 hours at room temperature. The solution is then poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitated substance is filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (solvent: tetrahydrofuran/acetonitrile/water gradient).

Yield: 16.10 g (84% d.Th.), one colorless, amorphous powder

Water content: 5.7%

Analysis of elements (calculated according to dry substances):

ber.: C 34.83 H 3.84 N 6.96 F 26.76 Gd 13.03

gef.: C 34.65 H 3.96 N 6.84 F 26.62 Gd 12.91

Example 4

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid-N-(2-hydroxyethyl)-amide

To 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, add 8.90 g (70 mmol) of oxalyl chloride and stir for 12 hours, at room temp. The mixture is then evaporated to dryness under vacuum. The residue is dissolved in 100 ml of dichloromethane and at 0°C to a solution of 3.66 g (60 mmol) of 2-aminoethanol and 6.07 g (60 mmol) of triethylamine, which are added dropwise to 200 ml of dichloromethane. The mixture is stirred for 3 hours at 0°C and then for another 6 hours at room temperature. Add 300 ml of 5% hydrochloric acid and mix for the next 15 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographically developed on Kieselgel (TL-chromatogram developer: dichloromethane/acetone=20:1).

Yield: 28.90 g (89% d.Th.) of a colorless solid

Analysis of elements:

ber.: C 29.75 H 2.14 N 2.48 F 57.14

gef.: C 29.61 H 2.29 N 2.37 F 57.01

b) N-(2-hydroxyethyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amine

28 g (49.54 mmol) of the title substance from example 4a will be dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 16 hours, with reverse cooling. It is then cooled to 0°C and 200 ml of methanol is added dropwise, and it is then evaporated to dryness under vacuum. The residue is dissolved in a mixture of 300 ml ethanol/50 ml 10% hydrochloric acid and stirred for 10 hours at 50°C. It is then evaporated to dryness under vacuum, the residue is dissolved in 300 ml of 5% sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phase is dried with magnesium persulfate, evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel (chromatogram developer: dichloromethane/2-propanol=15:1).

Yield: 25.12 g (92% d.Th.) of a colorless solid.

Analysis of elements:

ber.: C 30.50 H 2.56 N 2.54 F 58.59

gef.: C 30.32 H 2.71 N 2.48 F 58.43

c) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-yl)-acid-N-(2-hydroxyenthyl)-N-(1H,1H,2H ,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amine-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride, will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The mixture is cooled to 15°C and 8.75 g (15.88 mmol) of the title substance from example 4b is added. The mixture was further stirred for 10 min and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. It is mixed for 12 hours at room temperature. The solution is then poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitated substance is filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (solvent: tetrahydrofuran/acetonitrile/water gradient).

Yield: 16.81 g (91% d.Th.), one colorless, amorphous powder

Water content: 7.2%

Analysis of elements (calculated according to dry substances):

ber.: C 34.08 H 3.64 N 7.23 F 27.77 Gd 13.52

gef.: C 33.91 H 3.82 N 7.14 F 27.58 Gd 13.41

Example 5

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluoroamide of tridecanoic acid

To 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-perfluorotridecanoic acid in 300 ml of dichloromethane, add 8.90 g (70 mmol) of oxalyl chloride and stir for 12 hours at room temperature . The mixture is then evaporated to dryness under vacuum. The residue is dissolved in 200 ml of dichloromethane. Gaseous ammonia is then introduced into the solution at 0°C for about 2 hours. It is then stirred for another 4 hours at 0°C and then for another 2 hours at room temperature. Add 300 ml of 5% hydrochloric acid and mix for the next 15 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographically developed on Kieselgel (TL-chromatogram developer: dichloromethane/acetone=20:1).

Yield: 27.85 g (93% d.Th.).

Analysis of elements:

ber.: C 27.66 H 1.55 N 2.69 F 61.97

gef.: C 27.49 H 1.72 N 2.54 F 61.81

b) 1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl amine, hydrochloride

27 g (51.8 mmol) of the title substance from example 5a will be dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 16 hours, with reverse cooling. It is then cooled to 0°C and 200 ml of methanol is added dropwise, and it is then evaporated to dryness under vacuum. The residue is dissolved in a mixture of 400 ml ethanol/100 ml 10% hydrochloric acid and stirred for 8 hours at 60°C. It is then evaporated to dryness under vacuum, and the residue is crystallized from a little ethanol/diethyl ether. Yield: 26.75 g (95% d.Th.) of a colorless, crystalline substance.

Analysis of elements:

ber.: C 26.51 H 2.04 N 2.58 F 59.41 Cl 6.52

gef.: C 26.37 H 2.21 N 2.46 F 59.25 Cl 6.38

c) 3,6,9,12,15-pentaoxahexadecanoic acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amine-amide

K 26.5 g (48.74 mmol) of the title substance from example 5b and 14.8 g (146.2 mmol) of triethylamine, dissolved in 300 ml of dichloromethane, are added at 0°C 14.24 g (50 mmol) 3 ,6,9,12,15-pentaoxahexadecane acid chloride and stirred for 3 hours at 0°C. Then add 300 ml of 5% hydrochloric acid and mix for the next 30 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (solvent: dichloromethane/acetone: 20:1).

Yield: 32.03 g (87% d.Th.), a colorless oil

Analysis of elements:

ber.: C 36.57 H 4.00 N 1.85 F 42.75

gef.: C 36.46 H 4.12 N 1.76 F 42.53

d) N-(3,6,9,12,15-pentaoxahexadecyl)-N-(1H,1H,2H,2H,4H,4H-3-oxa)-perfluorotridecyl)-amine

31 g (41.03 mmol) of the title substance from example 5c will be dissolved in 300 ml of tetrahydrofuran and 25 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 16 hours, with reverse cooling. It is then cooled to 0°C and 200 ml of methanol is added dropwise, and it is then evaporated to dryness under vacuum. The residue is dissolved in a mixture of 300 ml ethanol/50 ml 10% hydrochloric acid and stirred for 8 hours at 40°C. It is then evaporated to dryness under vacuum, and the residue is dissolved in 300 ml of 5% sodium hydroxide solution and extracted 3x with 300 ml of dichloromethane. The organic phase is dried over magnesium sulfate, evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel (chromatogram developer: dichloromethane/2-propanol=15:1).

Yield: 27.68 g (91% d.Th.).

Analysis of elements:

ber.: C 37.26 H 4.35 N 1.89 F 43.56

gef.: C 37.11 H 4.51 N 1.73 F 43.41

e) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-[N-3,6,9,12,15-pentaoxy)- hexadecyl-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex (metal complex VII)

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride, will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The mixture is cooled to 15°C and 11.77 g (15.88 mmol) of the title substance from example 5d is added. The mixture was further stirred for 10 min and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. It is mixed for 12 hours at room temperature. The solution is then poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitated substance is filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (solvent: tetrahydrofuran/acetonitrile/water gradient).

Yield: 18.05 g (84% d.Th.), one colorless, amorphous powder

Water content: 6.2%

Analysis of elements (calculated according to dry substances):

ber.: C 37.28 H 4.47 N 6.21 F 23.87 Gd 11.62

gef.: C 37.11 H 4.61 N 6.03 F 23.64 Gd 11.42

Example 6

a) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-yl)-acid-[N-12-amino-3,6,9-trioxa-dodecyl )-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex (metal complex VII)

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide will be dissolved at 60°C in 100 ml of dimethylsulfoxide. The mixture was cooled to 15°C and 3.51 g (17 mmol) of N,N'-dicyclohexylcarbodiimide was added and stirred for 5 hours. To separate the urinary substance, the solution is filtered. 14.66 g (60 mmol) of 1,12-diamino-3,6,9-trioxa-dodecane and 2.02 g (20 mmol) of triethylamine were added to the filtrate and stirred for 12 hours at room temperature. The solution is then poured into a mixture of 1500 ml diethyl ether/50 ml n-butanol and stirred for 30 minutes. The precipitated substance is filtered off and chromatographed on Kieselgel RP-18 (solvent: tetrahydrofuran/acetonitrile/water gradient).

Yield: 12.66 g (69% d.Th.), one colorless, amorphous powder

Water content: 3.5%

Analysis of elements (calculated according to dry substances):

ber.: C 30.16 H 4.54 N 8.49 F 27.96 Gd 13.61

gef.: C 30.02 H 4.68 N 8.35 F 27.81 Gd 13.45

d) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-[N-3,6,9,16-tetraoxa-13-aza -14-oxo-C19-C26-hepta-decafluoro)-hexacosyl]amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex (metal complex IX)

11.3 g (21.64 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid, 0.85 g (20 mmol) of lithium chloride and 4.95 g (43 mmol) of N- hydroxysuccinimide, will be dissolved at 25°C in 150 ml of dimethylsulfoxide. The mixture was cooled to 15°C and 6.19 g (30 mmol) of N,N`-dicyclohexylcarbodiimide were added and stirred for 5 hours at 15°C. To separate the urinary substance, the solution is filtered. 12.5 g (10.82 mmol) of the title substance from example 6a and 3.29 g (32.47 mmol) of triethylamine were added to the filtrate and stirred for 12 hours at room temperature. The solution is then poured into a mixture of 1300 ml diethyl ether/100 ml acetone and stirred for 30 minutes. The precipitated substance is filtered off and chromatographed on Kieselgel RP-18 (solvent: tetrahydrofuran/acetonitrile/water gradient).

Yield: 13.01 g (90%d.Th.).

Water content: 6.7%

Analysis of elements (calculated according to dry substances):

ber.: C 36.86 H 4.30 N 7.34 F 24.17 Gd 11.77

gef.: C 36.68 H 4.41 N 7.25 F 24.03 Gd 11.55

Example 7

1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-yl)-acid-N-(1H,1H,2H,2H,4H,4H,5H,5H -3-oxa-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of the gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide will be dissolved at 60°C in 100 ml of dimethylsulfoxide. The mixture was cooled to 15°C and 3.51 g (17 mmol) of N,N`-dicyclohexylcarbodiimide were added and stirred for 5 hours at 15°C. To separate the urinary substance, the solution is filtered. 8.63 g (15.88 mmol) of the title substance from example 5b and 5.06 g (50 mmol) of triethylamine were added to the filtrate and stirred for 12 hours at room temperature. The solution is then poured into a mixture of 1500 ml diethyl ether/100 ml acetone and stirred for 30 minutes. The precipitated substance is filtered off and chromatographed on Kieselgel RP-18 (solvent: tetrahydrofuran/acetonitrile/water gradient).

Yield: 13.86 g (78% d.Th.) of a colorless, amorphous powder.

Water content: 9.3%

Analysis of elements (calculated according to dry substances):

ber.: C 33.28 H 3.42 N 7.51 F 28.87 Gd 14.05

gef.: C 33.12 H 3.61 N 7.37 F 28.69 Gd 13.89

Example 8

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluoro tridecanoic acid-N-(2,3,4,5,6-pentahydroxy)-hexylamide

To 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, add 8.90 g (70 mmol) of oxalyl chloride and stir for 12 hours, at room temp. The mixture is then evaporated to dryness under vacuum. The residue is dissolved in 100 ml of dichloromethane and added at 0°C to a solution of 10.87 g (60 mmol) of glucamine and 6.07 g (60 mmol) of triethylamine, dissolved in 150 ml of dichloromethane/150 dioxane, which is added dropwise. It is then stirred for another 3 hours at 0°C and then for another 8 hours at room temperature. Add 400 ml of 5% hydrochloric acid and mix for the next 15 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographically developed on Kieselgel (TL-chromatogram developer: dichloromethane/methanol=5:1).

Yield: 30.71 g (78% d.Th.).

Analysis of elements:

ber.: C 31.55 H 2.94 N 2.04 F 47.13

gef.: C 31.44 H 3.09 N 1.97 F 47.01

b) N-(2,3,4,5,6-pentahydroxyhexyl)-N-1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amine

30 g (43.77 mmol) of the title substance from example 8a will be dissolved in 300 ml of tetrahydrofuran and 50 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 48 hours, with reverse cooling. It is then cooled to 0°C and 500 ml of methanol is added dropwise, and it is then evaporated to dryness under vacuum. The residue is dissolved in a mixture of 500 ml ethanol/100 ml 10% hydrochloric acid and stirred for 15 hours at 60°C. It is then evaporated to dryness under vacuum, and the residue is dissolved in 400 ml of 5% sodium hydroxide solution and extracted 5x with 400 ml of chloroform. The organic phase is dried over magnesium sulfate, evaporated to dryness under vacuum and the residue is chromatographed on Kieselgel (chromatography buffer: dichloromethane/methanol=3:1).

Yield: 19.69 g (67% d.Th.) of a colorless solid.

Analysis of elements:

ber.: C 32.20 H 3.30 N 2.09 F 48.41

gef.: C 32.05 H 3.43 N 1.97 F 47.93

c) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-N-2,3,5,6-pentahydroxy)-hexyl-N -(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of the gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The mixture is cooled to 15°C and 15.88 g (15.88 mmol) of the title substance from Example 8b is added. The solution is stirred for 10 min. and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Then for 12 hours at room temp. mixes. The solution is poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The resulting precipitate is then filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (solvent: tetrahydrofuran/acetonitrile/water gradient).

Yield: 16.10 g (79% d.Th.) of a colorless, amorphous powder.

Water content: 6.3%

Analysis of elements (calculated according to dry substances):

ber.: C 36.64 H 3.93 N 6.55 F 25.17 Gd 12.26

gef.: C 34.49 H 4.13 N 6.48 F 25.03 Gd 12.11

Example 9

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid-N-(2,2-dimethyl-5-hydroxy-1,3-dioxepan-6-yl)-amide

To 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, add 8.90 g (70 mmol) of oxalyl chloride and stir for 12 hours, at room temp. The mixture is then evaporated to dryness under vacuum. The residue is dissolved in 100 ml of dichloromethane and added at 0°C to a solution of 9.67 g (60 mmol) of 5-amino-2,2-dimethyl-1,3-dioxepan-6-ol and 6.07 g ( 60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane, added dropwise. It is then stirred for another 3 hours at 0°C and then for another 5 hours at room temperature. Add 300 ml of water and mix for the next 15 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographically developed on Kieselgel (TL-chromatogram developer: dichloromethane/acetone=5:1).

Yield: 27.62 g (85% d.Th.).

Analysis of elements:

ber.: C 34.30 H 3.03 N 2.11 F 48.54

gef.: C 34.15 H 3.19 N 2.04 F 48.37

b) N-(1-hydroxymethyl-2,3-dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amine

27 g (14.58 mmol) of the title substance from example 9a will be dissolved in 300 ml of tetrahydrofuran and 26 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 20 hours on a reflux condenser. Then the mixture is cooled to 0°C and 300 ml of methanol is added dropwise, and it is continuously evaporated to dryness under vacuum. The residue is dissolved in a mixture of 300 ml of ethanol/100 ml of 10% hydrochloric acid and stirred for 6 hours at 60°C. then the rest of the liquid is evaporated to dryness, the rest is dissolved in 400 ml of 5% sodium hydroxide solution and extracted 5x with 250 ml of chloroform. The organic phase is dried over magnesium sulfate, the salt is evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel to dryness (solvent: dichloromethane/methanol = 6:1).

Yield: 20.09 g (80%d.Th.) of a colorless solid.

Analysis of elements (calculated according to dry substances):

ber.: C 31.44 H 2.97 N 2.29 F 52.83

gef.: C 31.26 H 3.11 N 2.18 F 52.67

c) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-[N-1-hydroxymethyl-2,3-dihydroxypropyl)-N- (1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The mixture is cooled to 15°C and 15.88 g (15.88 mmol) of the title substance from Example 9b is added. The solution is stirred for 10 min. and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Then for 12 hours at room temp. mixes. The solution is poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The resulting precipitate is then filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (solvent: gradient from tetrahydrofuran/acetonitrile/water).

Yield: 13.40 g (69%d.Th.) of a colorless, amorphous powder.

Water content: 9.1%

Analysis of elements (calculated according to dry substances):

ber.: C 34.37 H 3.79 N 6.87 F 24.41 Gd 12.86

gef.: C 34.18 H 3.95 N 6.71 F 24.25 Gd 12.70

Example 10

a) Perfluorooctylsulfonic acid-N-(2-benzyloxycarbonylamino)-ethyl]-amide

40 g (173.4 mmol) of 1-benzyloxycarbonylamino-2-aminoethane, hydrochloride, 87.1 g (173.4 mmol) of perfluorooctylsulfofluoride and 35.42 g (350 mmol) of triethylamine will be heated at 80°C for 10 hours. Then the mixture is cooled to room temperature. and added directly to one Kieselgel column for chromatographic purification (buffer: dichloromethane/acetone=20:1).

Yield: 42.22 g (36%d.Th.) of a colorless solid.

Analysis of elements:

ber.: C 31.97 H 1.94 N 4.14 F 47.75 S 4.74

gef.: C 31.83 H 2.11 N 4.03 F 47.63 S 4.63

b) Perfluorooctylsulfonic acid-N-[(2-amino)-ethyl]-amide

30 g (44.36 mmol) of the title substance from example 10a will be dissolved in 300 ml of methanol and then 5 g of palladium catalyst (10% Pd/C) will be added, the mixture will then be hydrated overnight at room temperature. The catalyst is then filtered off, and the filtrate is evaporated to dryness under vacuum.

Yield: 24.05 g (quantitative) of a colorless solid.

Analysis of elements:

ber.: C 22.15 H 1.30 N 5.17 F 59.57

gef.: C 22.04 H 1.41 N 5.05 F 59.62

c) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-N-[(2-perfluorooctylsulfonylamino)-ethyl]-amide}-1 ,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide will be dissolved at 60°C in 100 ml of dimethylsulfoxide. The mixture is cooled to 15°C and 3.51 g (17 mmol) of N,N'-dicyclohexylcarbodiimide is added and then heated for 5 hours at temp. from 15°C mix. To separate the urinary substance, the solution is filtered. 8.61 g (15.88 mmol) of the title substance from example 10b and 2.02 g (20 mmol) of triethylamine were added to the filtrate and stirred for 12 hours at room temperature. The solution was then poured into a mixture of 1500 ml diethyl ether/100 ml acetone and stirred for 30 minutes. The resulting precipitate is then filtered off and chromatographed on Kieselgel RP-18 (solvent: tetrahydrofuran/acetonitrile/water gradient).

Yield: 15.76 g (86%d.Th.) of a colorless, amorphous powder.

Water content: 6.5%

Analysis of elements (calculated according to dry substances):

ber.: C 30.19 H 3.06 N 8.50 F 27.99 Gd 13.63 S 2.78

gef.: C 30.03 H 3.18 N 8.41 F 27.81 Gd 13.50 S 2.61

Example 11

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluoro tridecanoic acid-N-(2-benzyloxy-carboxylamino-ethyl)-amide

To 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, add 8.90 g (70 mmol) of oxalyl chloride and stir for 12 hours, at room temp. The mixture is then evaporated to dryness under vacuum. The residue is dissolved in 100 ml of dichloromethane and added at 0°C to a solution of 13.84 g (60 mmol) of 1-benzyloxycarbonylamine-2-aminoethane, hydrochloride and 12.14 g (120 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. , added. It is then stirred for another 3 hours at 0°C and then for another 5 hours at room temperature. Add 300 ml of 5% hydrochloric acid and mix for the next 15 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone=20:1).

Yield: 33.30 g (83%d.Th.) of a colorless solid.

Analysis of elements:

ber.: C 37.84 H 2.74 N 4.01 F 46.25

gef.: C 37.67 H 2.89 N 3.88 F 46.11

b) 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid-N-[(2-amino)-ethyl]-amide

30 g (42.96 mmol) of the title substance from example 11a will be dissolved in 500 ml of methanol and 5 g of palladium catalyst (10% Pd/C) will be added. The mixture is hydrated overnight, at room temperature. Then the catalyst is filtered off, and the filtrate is evaporated to dryness under vacuum.

Yield: 24.24 g (quantitative) of a colorless solid.

Analysis of elements:

ber.: C 29.80 H 2.32 N 4.96 F 57.24

gef.: C 29.67 H 2.41 N 4.88 F 57.15

c) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-N-[3-aza-6-oxa-4-oxo-( C9-C19-heptadecafluoro)-hexadecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of the gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide will be dissolved at 60°C in 100 ml of dimethylsulfoxide. The mixture is cooled to 15°C and 3.51 g (17 mmol) of N,N'-dicyclohexylcarbodiimide is added and then heated for 5 hours at temp. from 15°C mix. To separate the urinary substance, the solution is filtered. 8.96 g (15.88 mmol) of the title substance from example 11b and 2.02 g (20 mmol) of triethylamine were added to the filtrate and stirred for 12 hours at room temperature. The solution was then poured into a mixture of 1500 ml diethyl ether/100 ml acetone and stirred for 30 minutes. The resulting precipitate is then filtered off and chromatographed on Kieselgel RP-18 (solvent: tetrahydrofuran/acetonitrile/water gradient).

Yield: 15.31 g (82%d.Th.) of a colorless, amorphous powder.

Water content: 6.3%

Analysis of elements (calculated according to dry substances):

ber.: C 33.71 H 3.51 N 8.34 F 27.46 Gd 13.37

gef.: C 33.61 H 3.63 N 8.17 F 27.31 Gd 13.20

Example 12

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid-N-(2-hydroxy-ethyl)-amide

To 24.25 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, add 8.90 g (70 mmol) of oxalyl chloride and stir for 12 hours. , at room temp. The mixture is then evaporated to dryness under vacuum. The residue is dissolved in 100 ml of dichloromethane and added dropwise at 0°C to a solution of 3.66 g (60 mmol) of ethanolamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is then stirred for another 3 hours at 0°C and then for another 6 hours at room temperature. Add 300 ml of 5% hydrochloric acid and mix for the next 15 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone=20:1).

Yield: 24.86 g (93%d.Th.) of a colorless solid.

Analysis of elements:

ber.: C 30.98 H 2.60 N 3.01 F 53.09

gef.: C 30.71 H 2.81 N 2.87 F 52.82

b) N-(2-hydroxyethyl)-N-1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluoroundecyl)-amine

24 g (51.59 mmol) of the title substance from example 12a will be dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 12 hours at the reflux condenser. Then the mixture is cooled to 0°C and 300 ml of methanol is added dropwise, and it is continuously evaporated to dryness under vacuum. The residue is dissolved in a mixture of 300 ml of ethanol/50 ml of 10% hydrochloric acid and stirred for 8 hours at 40°C. Then the rest of the liquid is evaporated to dryness, the rest is dissolved in 300 ml of 5% sodium hydroxide solution and extracted 3x with 300 ml of dichloromethane. The organic phase is dried over magnesium sulfate, the salt is evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel to dryness (buffer: dichloromethane/2-propanol = 20:1).

Yield: 20.95 g (90%d.Th.) of a colorless solid.

Analysis of elements (calculated according to dry substances):

ber.: C 31.94 H 3.13 N 3.10 F 54.73

gef.: C 31.71 H 3.31 N 3.01 F 54.58

c) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-N-[(2-hydroxy)-ethyl-N-(1H, 1H,2H,2H,4H,4H,5H,5H-3-oxa)perfluoroundecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of the gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride, will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The mixture is cooled to 15°C and 8.98 g (15.88 mmol) of the title substance from Example 12b is added. It was then stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline was added. It is mixed for the next 12 hours at room temperature. The solution is then poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The resulting precipitate is then filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (buffer: gradient from tetrahydrofuran/acetonitrile/water).

Yield: 14.01 g (83%d.Th.) of a colorless, amorphous powder.

Analysis of elements (calculated according to dry substances):

ber.: C 35.03 H 3.98 N 7.91 F 23.24 Gd 14.79

gef.: C 34.85 H 4.19 N 7.75 F 23.05 Gd 14.58

Example 13

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluoroundecanoic acid-N-(3,6,9,12-tetraoxatridecyl)-amide

To 24.25 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, add 8.90 g (70 mmol) of oxalyl chloride and stir for 12 hours. , at room temp. The mixture is then evaporated to dryness under vacuum. The residue is dissolved in 100 ml of dichloromethane and added at 0°C to a solution of 12.44 g (60 mmol) of 3,6,9,12-tetraoxa-tridecylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane, added drop by drop. It is then stirred for another 3 hours at 0°C and then for another 6 hours at room temperature. Add 300 ml of 5% hydrochloric acid and mix for the next 15 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone=20:1).

Yield: 31.61 g (90%d.Th.) of a colorless solid.

Analysis of elements:

ber.: C 37.33 H 4.29 N 2.29 F 40.40

gef.: C 37.15 H 4.41 N 2.12 F 40.18

b) N-(3,6,9,12-tetraoxatridecyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluoroundecyl)-amine

31 g (50.7 mmol) of the title substance from example 13a will be dissolved in 300 ml of tetrahydrofuran and 32 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 16 hours on a reflux condenser. Then the mixture is cooled to 0°C and 300 ml of methanol is added dropwise, and it is continuously evaporated to dryness under vacuum. The residue is dissolved in a mixture of 300 ml of ethanol/50 ml of 10% hydrochloric acid and stirred for 8 hours at 40°C. Then the rest of the liquid is evaporated to dryness, the rest is dissolved in 300 ml of 5% sodium hydroxide solution and extracted 3x with 300 ml of dichloromethane. The organic phase is dried over magnesium sulfate, the salt is evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel to dryness (buffer: dichloromethane/2-propanol = 20:1).

Yield: 28.17 g (93%d.Th.) of a colorless solid.

Analysis of elements (calculated according to dry substances):

ber.: C 38.20 H 4.72 N 2.34 F 41.34

gef.: C 38.05 H 4.83 N 2.40 F 41.50

c) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-N-[(3,6,9,12-tetraoxa)-tridecyl -N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)perfluoroundecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of the gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride, will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The mixture was cooled to 15°C and 9.49 g (15.88 mmol) of the title substance from Example 13b was added. It was then stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline was added. It is mixed for the next 12 hours at room temperature. The solution is then poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The resulting precipitate is then filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (buffer: gradient from tetrahydrofuran/acetonitrile/water).

Yield: 16.13 g (84% d.Th.).

Analysis of elements (calculated according to dry substances):

ber.: C 37.75 H 4.67 N 6.95 F 20.43 Gd 13.01

gef.: C 37.91 H 4.81 N 6.83 F 20.60 Gd 13.15

Example 14

a) 2-N-(1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl)-amino-acetic acid-t. butyl ester

To 32.0 g (58.65 mmol) of the title substance from example 5b and 24.89 g (180 mmol) of potassium carbonate in 300 ml of acetonitrile, 6.523 g (40 mmol) of t. of butyl ester-bromoacetic acid and stirred for 3 hours at the same temperature. Then 300 ml of dichloromethane is added, the precipitated salts are removed by filtration, and the filtrate is evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/2-propanol=20:1).

Yield: 28.11 g (57%d.Th.) of a colorless solid.

Analysis of elements:

ber.: C 34.80 H 3.24 N 2.25 F 51.98

gef.: C 34.98 H 3.31 N 2.20 F 52.16

b) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-N-[(t.butyloxycarbonylmethyl)-N-(1H,1H, 2H,2H,4H,4H,5H,5H-3-oxa)perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of the gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride, will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The mixture was cooled to 15°C and 9.87 g (15.88 mmol) of the title substance from Example 14a was added. It was then stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline was added. It is mixed for the next 12 hours at room temperature. The solution is then poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The resulting precipitate is then filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (buffer: gradient from tetrahydrofuran/acetonitrile/water).

Yield: 16.64 g (85% d.Th.).

Analysis of elements:

ber.: C 36.04 H 3.92 N 6.82 F 26.19 Gd 12.72

gef.: C 35.92 H 3.83 N 6.91 F 26.29 Gd 12.84

c) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-N-[(carboxymethyl)-N-(1H,1H,2H, 2H,4H,4H,5H,5H-3-oxa)perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (8.11 mmol) of the title substance from example 14b will be dissolved in 50 ml of trifluoroacetic acid and left for 5 hours at room temperature. mixed. The mixture is then evaporated to dryness under vacuum and the residue is chromatographed on Kieselgel RP-18 (buffer: tetrahydrofuran/acetonitrile/water gradient). After evaporating the fractions containing the specified substance, the residue is dissolved in water, and the pH of the solution is adjusted to pH 7.2 using 5% sodium hydroxide solution. The solution is filtered, and the filtrate is freeze-dried.

Yield: 10.48 g (91 %d.Th.).

Analysis of elements (calculated according to dry substances):

ber.: C 33.06 H 3.28 N 7.01 F 26.94 Gd 13.12 Na 1.92

gef.: C 33.19 H 3.40 N 7.20 F 27.14 Gd 13.25 Na 2.00

Example 15

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid-N-(2-hydroxyethyl)-amide

To 32.0 g (56.61 mmol) of the title substance from example 4a, 2.96 g (74 mmol) of sodium hydride (from 60% sodium hydride in paraffin oil) in 300 ml of tetrahydrofuran was added and stirred for 3 hours at room temperature, under by the action of nitrogen. Then 7.67 g (74 mmol) of t-butyl ester-bromoacetic acid were added dropwise and stirred for 5 hours at 50°C. After that, add 50 ml of methanol and evaporate to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/2-propanol=20:1).

Yield: 23.46 g (61 %d.Th.).

Analysis of elements:

ber.: C 35.36 H 3.26 N 2.06 F 47.54

gef.: C 35.52 H 3.40 N 2.17 F 47.40

b) N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-N-[4-t.butyloxycarbonyl-3-oxa)butyl]-amine

35 g (51.52 mmol) of the title substance from example 15a will be dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 16 hours on a reflux condenser. Then the mixture is cooled to 0°C and 300 ml of methanol is added dropwise, and it is continuously evaporated to dryness under vacuum. The residue is dissolved in a mixture of 300 ml of ethanol/50 ml of 10% hydrochloric acid and stirred for 8 hours at 40°C. Then the rest of the liquid is evaporated to dryness, the rest is dissolved in 300 ml of 5% sodium hydroxide solution and extracted 3x with 300 ml of dichloromethane. The organic phase is dried over magnesium sulfate, the salt is evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel to dryness (buffer: dichloromethane/2-propanol = 20:1).

Yield: 31.88 g (93%d.Th.).

Analysis of elements:

ber.: C 36.10 H 3.64 N 2.11 F 48.54

gef.: C 35.90 H 3.75 N 2.20 F 48.71

c) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-N-[(4-t.butyloxycarbonyl-3-oxa)butyl) -N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of gadolinium complex 10-[1-carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) lithium chloride, will be dissolved in 100 ml of dimethylsulfoxide at 60°C. Then the mixture is cooled to 15°C and 10.57 g (15.88 mmol) of the title substance from example 15b is added. Everything was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Everything is mixed for 12 hours at room temperature. The solution is then poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitated residue is filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (buffer: gradient from tetrahydrofuran/acetonitrile/water).

Yield: 16.63 g (82 %d.Th.).

Analysis of elements:

ber.: C 36.68 H 4.10 N 6.58 F 25.29 Gd 12.31

gef.: C 36.81 H4.20 N 6.41 F 25.40 Gd 12.19

d) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-N-[(4-t.butyloxycarbonyl-3-oxa)butyl) -N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

12 g (9.40 mmol) of the title substance from example 15c will be dissolved in 50 ml of trifluoroacetic acid and left for 5 hours at room temperature. mixed. The mixture is evaporated to dryness in vacuo and the residue is chromatographed on Kieselgel RP-18 (buffer: tetrahydrofuran/acetonitrile/water gradient). After evaporation, the fractions containing the product are dissolved in water, and the pH is adjusted to 7.2, using 5% sodium hydroxide solution. The solution is filtered, and the filtrate is subjected to the freeze-dry process.

Yield: 11.41 g (92 %d.Th.).

Water content: 5.8%

Analysis of elements (calculated according to dry substances):

ber.: C 33.82 H 3.49 N 6.76 F 25.98 Gd 12.65 Na 1.85

gef.: C 33.95 H 3.60 N 6.88 F 26.15 Gd 12.49 Na 1.93

Example 16

a) 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid-N-(2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amide

To 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, add 8.90 g (70 mmol) of oxalyl chloride and stir for 12 hours at room temperature. temp. It is then evaporated in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added at 0°C to a solution of 32.62 g (60 mmol) of the title substance from example 5b and 6.07 g (60 mmol) of triethylamine, dissolved in 299 ml of dichloromethane. Everything is mixed for 3 hours at 0°C and further 6 hours at room temperature. After that, add 300 ml of 5% hydrochloric acid and mix well for the next 15 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone=15:1).

Yield: 52.87 g (91 %d.Th.).

Analysis of elements:

ber.: C 28.50 H 1.49 N 1.38 F 63.87

gef.: C 28.65 H 1.61 N 1.50 F 64.01

b) N-bi-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amine

52 g (51.42 mmol) of the title substance from example 16a will be dissolved in 500 ml of tetrahydrofuran and 31 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 16 hours on a reflux condenser. Then the mixture is cooled to 0°C and 200 ml of methanol is added dropwise, and it is continuously evaporated to dryness under vacuum. The residue is dissolved in a mixture of 400 ml of ethanol/70 ml of 10% hydrochloric acid and stirred for 8 hours at 40°C. Then the rest of the liquid is evaporated to dryness, the rest is dissolved in 400 ml of 5% sodium hydroxide solution and extracted 3x with 400 ml of dichloromethane. The organic phase is dried over magnesium sulfate, the salt is evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel to dryness (buffer: dichloromethane/2-propanol = 20:1).

Yield: 47.18 g (92%d.Th.) of a colorless solid.

Analysis of elements:

ber.: C 28.90 H 1.72 N 1.40 F 64.77

gef.: C 30.03 H 1.81 N 1.55 F 65.00

c) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-yl)-acid-N-bi-(1H,1H,2H,2H,4H,4H ,5H,5H-3-oxa-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride, will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The mixture is then cooled to 15°C and 15.84 g (15.88 mmol) of the title substance from Example 16b is added. Everything was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Everything is mixed for 12 hours at room temperature. The solution is then poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitated residue is filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (buffer: gradient from tetrahydrofuran/acetonitrile/water).

Yield: 20.95 g (82% d.Th.).

Analysis of elements:

ber.: C 32.10 H 2.82 N 5.22 F 40.14 Gd 9.77

gef.: C 29.87 H 2.91 N 5.09 F 40.28 Gd 9.98

Example 17

a) 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid-N-(5-hydroxy-3-oxa-pentyl)-amide

To 32 g (52.52 mmol) of the title substance from example 3a, add 2.80 g (70 mmol) of sodium hydride (from 60% sodium hydride in paraffin oil) in 300 ml of tetrahydrofuran and stir for 3 hours at room temperature under nitrogen money. Then 9.68 g (70 mmol) of t-butyl ester-bromoacetic acid, dissolved in 20 ml of tetrahydrofuran, were added dropwise and stirred for the next 5 hours at 50°C. after that, add 50 ml of methanol and evaporate to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/2-propanol=20:1).

Yield: 19.31 g (59 %d.Th.).

Analysis of elements:

ber.: C 32.76 H 2.91 N 2.25 F 51.82

gef.: C 32.98 H 2.99 N 2.36 F 51.98

b) N-(3,6-dioxa-heptyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amine

32 g (51.34 mmol) of the title substance from example 17a will be dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 16 hours on a reflux condenser. Then the mixture is cooled to 0°C and 200 ml of methanol is added dropwise, and it is continuously evaporated to dryness under vacuum. The residue is dissolved in a mixture of 300 ml of ethanol/50 ml of 10% hydrochloric acid and stirred for 8 hours at 40°C. Then the rest of the liquid is evaporated to dryness, the rest is dissolved in 300 ml of 5% sodium hydroxide solution and extracted 3x with 300 ml of dichloromethane. The organic phase is dried over magnesium sulfate, the salt is evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel to dryness (buffer: dichloromethane/2-propanol = 20:1).

Yield: 28.47 g (91%d.Th.).

Analysis of elements:

ber.: C 33.51 H 3.31 N 2.30 F 53.01

gef.: C 33.63 H 3.41 N 2.21 F 52.87

c) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-yl)-acid-N-(3,6-dioxa)-heptyl-N-(1H ,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride, will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The mixture is then cooled to 15°C and 9.68 g (15.88 mmol) of the title substance from Example 17b is added. Everything was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Everything is mixed for 12 hours at room temperature. The solution is then poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitated residue is filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (buffer: gradient from tetrahydrofuran/acetonitrile/water).

Yield: 16.09 g (83 %d.Th.).

Analysis of elements:

ber.: C 35.41 H 3.96 N 6.88 F 26.45 Gd 12.88

gef.: C 35.57 H 4.11 N 6.72 F 26.58 Gd 12.97

Example 18

a) 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid-N-(hexyl)-amide

8.90 g (70 mmol) of oxalyl chloride was added to 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane and stirred for 12 hours at room temperature . It is then evaporated to dryness in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added dropwise at 0°C to a solution of 6.07 g (60 mmol) of n-hexylamine and 6.07 g (60 mmol) of triethylamine dissolved in 200 ml of dichloromethane. The solution is stirred for the next 3 hours at 0°C and for a further 6 hours at room temperature. After that, add 300 ml of 5% hydrochloric acid and mix for the next 15 minutes. The organic phase is separated and evaporated to dryness over magnesium sulfate. The residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone=20:1).

Yield: 30.95 g (89% d.Th.).

Analysis of elements:

ber.: C 35.72 H 3.33 N 2.31 F 53.35

gef.: C 35.60 H 3.45 N 2.43 F 53.63

b) N-(hexyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amine

31 g (51.21 mmol) of the title substance from example 18a will be dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 16 hours on a reflux condenser. Then the mixture is cooled to 0°C and 200 ml of methanol is added dropwise, and it is continuously evaporated to dryness under vacuum. The residue is dissolved in a mixture of 300 ml of ethanol/50 ml of 10% hydrochloric acid and stirred for 8 hours at 40°C. Then the rest of the liquid is evaporated to dryness, the rest is dissolved in 300 ml of 5% sodium hydroxide solution and extracted 3x with 300 ml of dichloromethane. The organic phase is dried over magnesium sulfate, the salt is evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel to dryness (buffer: dichloromethane/2-propanol = 20:1).

Yield: 28.16 g (93%d.Th.).

Analysis of elements:

ber.: C 36.56 H 3.75 N 2.370 F 54.62

gef.: C 36.40 H 3.82 N 2.27 F 54.81

c) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-[N-(hexyl)-N-(1H,1H,2H, 2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride, will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The mixture is then cooled to 15°C and 10.98 g (15.88 mmol) of the title substance from Example 18b is added. Everything was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Everything is mixed for 12 hours at room temperature. The solution is then poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitated residue is filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (buffer: gradient from tetrahydrofuran/acetonitrile/water).

Yield: 16.29 g (84% d.Th.).

Analysis of elements:

ber.: C 36.94 H 4.19 N 6.99 F 26.85 Gd 13.07

gef.: C 37.18 H 4.31 N 7.18 F 26.67 Gd 13.19

Example 19

a) 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid-N-[(10-t.butyloxycarbonyl)-decyl]-amide

8.90 g (70 mmol) of oxalyl chloride was added to 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane and stirred for 12 hours at room temperature . It is then evaporated to dryness in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added dropwise at 0°C to a solution of 15.45 g (60 mmol) of 11-amino-t.butyl ester-undecanoic acid and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. The solution is stirred for the next 3 hours at 0°C and for a further 6 hours at room temperature. After that, add 300 ml of 5% hydrochloric acid and mix for the next 15 minutes. The organic phase is separated and evaporated to dryness over magnesium sulfate. The residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone=20:1).

Yield: 42.04 g (92 %d.Th.).

Analysis of elements:

ber.: C 42.58 H 4.76 N 1.84 F 42.41

gef.: C 42.74 H 4.90 N 1.73 F 42.61

b) N-(10-t.butyloxycarbonyl-decyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amine

39 g (51.21 mmol) of the title substance from example 19a will be dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 16 hours on a reflux condenser. Then the mixture is cooled to 0°C and 200 ml of methanol is added dropwise, and it is continuously evaporated to dryness under vacuum. The residue is dissolved in a mixture of 400 ml of ethanol/70 ml of 10% hydrochloric acid and stirred for 8 hours at 40°C. Then the rest of the liquid is evaporated to dryness, the rest is dissolved in 350 ml of 5% sodium hydroxide solution and extracted 3x with 400 ml of dichloromethane. The organic phase is dried over magnesium sulfate, the salt is evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel to dryness (buffer: dichloromethane/2-propanol = 20:1).

Yield: 34.84 g (91%d.Th.).

Analysis of elements:

ber.: C 43.38 H 5.12 N 1.87 F 43.20

gef.: C 43.22 H 5.23 N 1.96 F 43.33

c) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-[N-(10-t.butyloxycarbonyl)-decyl-N-( 1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride, will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The mixture is then cooled to 15°C and 11.87 g (15.88 mmol) of the title substance from Example 19b is added. Everything was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Everything is mixed for 12 hours at room temperature. The solution is then poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitated residue is filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on

Kieselgel RP-18 (buffer: gradient from tetrahydrofuran/acetonitrile/water).

Yield: 17.92 g (83% d.Th.).

Analysis of elements:

ber.: C 40.65 H 4.89 N 6.18 F 23.76 Gd 11.57

gef.: C 40.81 H 4.99 N 6.32 F 23.94 Gd 11.73

d) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-[N-(10-carboxy)-decyl-N-(1H, 1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex, sodium salt

12 g (8.83 mmol) of the title substance from example 19c will be dissolved in 50 ml of trifluoroacetic acid and left for 5 hours at room temperature. mixed. The mixture is then evaporated to dryness under vacuum and the residue is chromatographed on Kieselgel RP-18 (buffer: tetrahydrofuran/acetonitrile/water gradient). After evaporation of the fractions containing the product, the residue is dissolved in water, and the pH is adjusted to 7.2 with 5% sodium lye. The solution is filtered, and the filtrate is freeze-dried.

Yield: 12.48 g (92 %d.Th.).

Water content: 6.2%

Analysis of elements (calculated on the basis of dry substance):

ber.: C 38.07 H 4.34 N 6.34 F 24.37 Gd 11.87 Na 1.73

gef.: C 37.89 H 4.44 N 6.22 F 24.51 Gd 12.01 Na 1.80

Example 20

a) 15-benzyl-3,6,9,12,15-pentaoxa-hexadecyl acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl]-amide

To 19.67 g (57.45 mmol) of 15-benzyl-3,6,9,12,15-pentaoxa-hexadecyl acid in 250 ml of dichloromethane, add 8.90 g (70 mmol) of oxalyl chloride and stir for 12 hours at room temp. It is then evaporated to dryness in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added dropwise at 0°C to a solution of 32.62 g (60 mmol) of 1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluoro-tridecylamide, hydrochloride and 6 .07 (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. The solution is stirred for the next 3 hours at 0°C and for a further 6 hours at room temperature. After that, add 300 ml of 5% hydrochloric acid and mix for the next 15 minutes. The organic phase is separated and evaporated to dryness over magnesium sulfate. The residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone=20:1).

Yield: 44.91 g (94%d.Th.) of a colorless solid.

Analysis of elements:

ber.: C 41.89 H 4.12 N 1.68 F 38.84

gef.: C 42.02 H 4.25 N 1.83 F 39.07

b) N-15-benzyl-3,6,9,12,15-pentaoxa-hexadecyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)- Amen

43 g (51.72 mmol) of the title substance from example 20a will be dissolved in 400 ml of tetrahydrofuran and 31 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. The mixture is boiled for 16 hours on a reflux condenser. Then the mixture is cooled to 0°C and 200 ml of methanol is added dropwise, and it is continuously evaporated to dryness under vacuum. The residue is dissolved in a mixture of 400 ml of ethanol/50 ml of 10% hydrochloric acid and stirred for 8 hours at 40°C. Then the rest of the liquid is evaporated to dryness, the rest is dissolved in 350 ml of 5% sodium hydroxide solution and extracted 3x with 400 ml of dichloromethane. The organic phase is dried over magnesium sulfate, the salt is evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel to dryness (buffer: dichloromethane/2-propanol = 20:1).

Yield: 39.32 g (93%d.Th.).

Analysis of elements:

ber.: C 42.60 H 4.12 N 1.68 F 38.84

gef.: C 42.45 H 4.23 N 1.57 F 38.99

c) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-[N-15-benzyl-3,6,9,12,15 -pentaoxa)-hexadecyl-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-tridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex,

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) lithium chloride will be dissolved in 100 ml of dimethylsulfoxide at 60°C. The solution is cooled to 15°C and 12.98 g (15.88 mmol) of the title substance from Example 20b is added. It is then stirred for 10 min., and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline are added. It is mixed for the next 12 hours at room temperature. The solution is then poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitate is filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (buffer: gradient from tetrahydrofuran/acetonitrile/water).

Yield: 18.48 g (83 %d.Th.).

Analysis of elements:

ber.: C 40.34 H 4.51 N 5.88 F 22.60 Gd 11.00

gef.: C 40.50 H 4.62 N 5.76 F 22.73 Gd 11.16

d) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-[N-14-hydroxy-3,6,9,12-tetraoxa )-tetradecyl-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

12 g (8.40 mmol) of the title substance from example 20c will be dissolved in 150 ml of methanol and 1.0 g of palladium catalyst (10% Pd/C) will be added, then hydrated overnight at room temperature. The catalyst is filtered off and evaporated to dryness under vacuum.

Yield: 10.13 g (95 %d.Th.).

Analysis of elements:

ber.: C 38.80 H 4.61 N 1.10 F 25.45 Gd 12.39

gef.: C 38.87 H 4.73 N 1.20 F 25.58 Gd 12.50

Example 21

a) 2-N-trifluoroacetyl-6-N-benzyloxycarbonyl-1-lysine

100.0 g (356.7 mmol) of 6-N-benzyloxycarbonyl-1-lysine will be dissolved in a mixture of 1000 ml of trifluoroacetic acid ethyl ester and 500 ml of ethanol, and for 24 hours at room temp. mixed. The mixture is evaporated to dryness and the residue is crystallized from diisopropyl ether.

Yield: 128.9 g (96% theoretical) of a colorless crystalline powder.

Melting point: 98.5°C

Analysis of elements:

ber.: C 51.07 H 5.09 N 7.44 F 15.14

gef.: C 51.25 H 5.18 N 7.58 F 15.03

b) 2-N-trifluoroacetyl-6-N-benzyloxycarbonyl-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

K 125.0 g (332.0 mmol) of the title substance from example 21a and 188.7 g (332.0 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 750 ml of tetrahydrofuran are added at 0°C 164.2 g (0.664 mmol) EEDQ (2-ethoxy-1,2-dihydroquinoline-1-ethyl ester of carboxylic acid) and stirred overnight at room temperature. It is evaporated to dryness in a vacuum and chromatographed on Kieselgel (buffer: dichloromethane/methanol = 20:1).

Yield: 286.0 g (93% theoretical) of a colorless solid.

Melting point: 92°C

Analysis of elements:

ber.: C 36.30 H 2.83 N 6.05 F 41.01 S 3.46

gef.: C 36.18 H 2.94 N 5.98 F 40.87 S 3.40

c) 6-N-benzyloxycarbonyl-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

Into a solution of 280.0 g (302.2 mmol) of the title substance from example 21b in 2000 ml of ethanol, ammonia, as a gas, is introduced for one hour at 0°C. Then it is evaporated to dryness and the residue is separated from the water. Then the solid substance is filtered off and dried in a vacuum at 50°C.

Yield: 243.5 g (97% theoretical) amorphous solid.

Analysis of elements:

ber.: C 37.60 H 3.28 N 6.75 F 38.89 S 3.86

gef.: C 37.55 H 3.33 N 6.68 F 38.78 S 3.81

d) 6-N-benzyloxycarbonyl-2-N-[1-O-α-D-carbonylmethyl-(2,3,4,6-tetra-O-benzyl-mannopyranose]-1-lysine-[1-(4 -perfluorooctylsulfonyl)-piperazine]-amide

To a solution from 100.0 g (120.4 mol) of the title substance from Example 21c, 72.1 g (120.4 mol) of 1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O -benzyl-mannopyranose and 13.86 g (120.4 mol) of N-hydroxysuccinimide, dissolved in 500 ml of dimethylformamide, are added at 0ºC, 41.27 g (200 mmol) of N,N-dicyclohexylcarbodiimide. Then it is stirred for 3 hours at 0ºC and continuously overnight at room temperature. Then the precipitated urine substance is filtered off, the filtrate is evaporated in a vacuum to dryness and chromatographed on Kieselgel (buffer: dichloromethane/ethanol = 20:1).

Yield: 136.1 g (87% theoretical) of thick oil.

Analysis of elements:

ber.: C 57.32 H 4.89 N 4.31 F 24.86 S 2.47

gef.: C 57.38 H 5.07 N 4.22 F 24.78 S 2.39

e) 2-N-[1-O-α-D-carbonylmethyl-mannopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

130.0 g (100 mmol) of the title substance from example 21d will be dissolved in 2000 ml of ethanol and 10 g of palladium catalyst (10% Pd/C) will be added to it. Hydration is carried out for the next 12 hours at room temperature. The catalyst is then removed by filtration, and the filtrate is evaporated to dryness under vacuum.

Yield: 91.7 g (quantitative) of a colorless solid.

Analysis of elements:

ber.: C 34.07 H 3.63 N 6.11 S 3.50 F 35.24

gef.: C 33.91 H 3.72 N 6.04 S 3.40 F 35.31

f) 6-N-[1,4,7-tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5- il)]-2-N-[1-O-α-D-carbonylmethyl-mannopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex (metal complex XV)

50 g (54.55 mmol) of the title substance from example 21e, 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109 mol) of lithium chloride and 34.35 g (54.55 mol) of 1 ,4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methyl-pent-5-yl)-1,4,7,10-tetraazacyclododecane, Gd complex, will be zu gentle heating in 400 ml of dimethylsulfoxide dissolved. At 10ºC, 16.88 g (81.8 mol) of N,N-dicyclohexylcarbodiimide are added and stirred continuously overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated solid is filtered off and further purified by chromatography (RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 79.9 g (91%d.Th., theoretical) of a colorless solid.

Water content: 8.6%.

Analysis of elements (calculated according to dry substance):

ber.: C 35.34 H 4.09 N 8.24 S 2.10 F 21.12 Gd 10.28

gef.: C 35.28 H 4.15 N 8.19 S 2.15 F 21.03 Gd 10.14

Example 22

a) 6-N-[1,4,7-tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5- il)]-2-N-[1-O-α-D-carbonylmethyl-mannopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

50 g (54.55 mmol) of the title substance from example 21e, 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109 mol) of lithium chloride and 34.35 g (54.55 mol) of 1 ,4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methyl-pent-5-yl)-1,4,7,10-tetraazacyclododecane, Gd complex, will be zu gentle heating in 400 ml of dimethylsulfoxide dissolved. At 10ºC, 16.88 g (81.8 mol) of N,N-dicyclohexylcarbodiimide are added and stirred continuously overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated solid is filtered off and further purified by chromatography (RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 76.0 g (92%d.Th., theoretical) of a colorless solid.

Water content: 6.88%.

Analysis of elements (calculated according to dry substance):

ber.: C 34.90 H 3.93 N 8.32 S 2.12 F 21.33 Gd 10.38

gef.: C 34.81 H 4.02 N 8.27 S 2.09 F 21.22 Gd 10.19

Example 23

a) 2-[4-3-ethyl ester of oxapropionic acid]-methyl ester of phenylacetic acid

To 200.0 g (1204.0 mmol) of 4-methyl ester of hydroxyphenylacetic acid, 212.0 g (2000.0 mmol) of sodium carbonate in 2000 ml of acetone, add 233.8 g (1400.0 mmol) of 2-ethyl bromoacetic acid ester and cook for 5 hours, on a reflux condenser. The solid is filtered off and evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: n-hexane/ethyl acetate = 15:1)

Yield: 288.5 g (95% theoretical) of colorless oil.

Analysis of elements:

ber.: C 61.90 H 6.39

gef.: C 61.75 H 6.51

b) 2-[4-3-ethyl ester of oxapropionic acid]-phenyl-2-methyl ester of bromoacetic acid

To 285.0 g (1130.0 mmol) of the title substance from example 23a, dissolved in 2000 ml of carbon tetrachloride, 201.0 g (1130.0 mmol) of N-bromosuccinimide and 100 mg of dibenzoyl peroxide are added and boiled for 8 hours at reflux cooler. It is then cooled in an ice bath, the precipitated succinimide is filtered, and the filtrate is evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: n-hexane/acetone = 15:1)

Yield: 359.2 g (96% theoretical) of colorless thick oil.

Analysis of elements:

ber.: C 47.28 H 4.57 Br 24.16

gef.: C 47.19 H 4.71 Br 24.05

c) 2-[4-(3-ethyl ester of oxapropionic acid]-phenyl-2-[1-(1,4,7,10-tetraazacyclododecan-1-yl]-methyl ester of acetic acid)

To 603.0 g (3500.0 mmol) of 1,4,7,10-tetraazacyclododecane, in 6000 ml of chloroform, add 350.0 g (1057.0 mmol) of the title substance from example 23b and stir overnight at room temperature . Then it is extracted 3 times with 3000 ml of water each, the organic phase is dried over magnesium sulfate and evaporated in a vacuum to dryness. The residue is used without further purification in the next reaction (example 23d).

Usability: 448.0 g (quantitative) of thick oil.

Analysis of elements:

ber.: C 59.70 H 8.11 Br 13.26

gef.: C 59.58 H 8.20 Br 13.18

d) 2-[4-(3-oxapropionic acid]-phenyl-2-[1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-10-yl]-acetic acid

445 g (1053 mmol) of the title substance from example 23c and 496 g (5270.0 mmol) of chloroacetic acid will be dissolved in 4000 ml of water. Adjust the pH to 10 with 30% sodium lye and stir for 8 hours at 70ºC. Next, the pH value of the reaction solution is adjusted to 13 with the addition of 30% sodium lye and it is boiled for 30 min, on the reflux condenser. The solution is cooled in an ice bath and the addition of conc. of hydrochloric acid, adjust to a value of pH = 1. It is then evaporated to dryness in a vacuum. The residue is dissolved in 4000 ml of methanol and stirred for 1 hour at room temperature. The precipitated table salt (NaCl) is filtered off, the filtrate is evaporated to dryness and the residue is purified at RP-18 C (buffer: water/ethanol/acetonitrile gradient).

Yield: 403.0 g (69%d.Th., theoretical) of a colorless solid.

Water content: 10.2%.

Analysis of elements (calculated on the basis of dry substance):

ber.: C 51.98 H 6.18 Br 10.10

gef.: C 51.80 H 6.31 Br 10.01

e) 2-[4-(3-oxapropionic acid]-phenyl-2-[1,4,7-tris(carboxyatomethyl)-1,4,7,10-tetraazacyclododecan-10-yl]-acetic acid, Gd- complex

To 400 g (721.3 mmol) of the title substance from example 23d) in 2000 ml of water, 130.73 g (360.65 mmol) of gadolinium oxide is added and stirred for 5 hours at 80ºC. The solution is filtered, and the filtrate is freeze-dried.

Yield: 511 g (quantitative) amorphous solid.

Water content: 11.0%.

Analysis of elements (calculated on the basis of dry substance):

ber.: C 40.67 H 4.41 N 7.98 Gd 22.19

gef.: C 40.51 H 4.52 N 8.03 Gd 22.05

f) 6-N-[2-[4-(3-oxapropionyl)-phenyl]-2-[1,4,7-tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecan-10-yl] -acetic acid)]-2-N-[1-O-α-D-carbonylmethyl-mannopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex, sodium salt

50 g (54.55 mmol) of the title substance from Example 21e, 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 38.66 g (54.55 mmol ) of the title substance from example 23e will be dissolved by gentle heating in 400 ml of dimethylsulfoxide. At 10ºC, 16.88 g (81.8 mmol) of N,N-dicyclohexylcarbodiimide are added and stirred continuously overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated solid substance is filtered off and further chromatographically purified (RP-18; buffer: gradient from water/ethanol/acetonitrile). The obtained product is dissolved in a little water and the pH value is adjusted to 7.4 with aqueous sodium alkali.

Finally, the product solution is freeze-dried.

Yield: 79.1 g (89%d.Th., theoretical) of a colorless solid.

Water content: 10.3%.

Analysis of elements (calculated on the basis of dry substance):

ber.: C 36.86 H 3.77 N 6.88 S 1.97 F 19.82 Gd 9.65

gef.: C 36.75 H 3.8 N 6.80 S 2.03 F 19.75 Gd 9.57

Example 24

a) 6-N-[1,4,7-tris(t-butyloxycarbonylmethyl)-10-carboxymethyl-1,4,7,10-tetraazacyclododecane-10-carbonylmethyl]-2-N-[1-O-α- D-carbonylmethyl-mannopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

15 g (26.19 mmol) of 1,4,7-tris(t-butyloxycarbonylmethyl)-10-carboxymethyl-1,4,7,10-tetraazacyclododecane, 24 g (26.19 mmol) of the title substance from examples 21e and 3 .01 g (26.19 mmol) of N-hydroxysuccinimide will be dissolved in 150 ml of dimethylformamide and at 0ºC, 8.25 g (40.0 mmol) of N,N-dicyclohexylcarbodiimide will be added. The mixture is stirred overnight at room temperature. The precipitated urine substance is filtered off, and the filtrate is evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel.

(buffer: dichloromethane/methanol = 20:1)

Yield: 35.45 g (92%d.Th., theoretical) of a colorless solid.

Analysis of elements:

ber.: C 44.08 H 5.69 N 7.62 F 21.95 S 2.18

gef.: C 44.01 H 5.81 N 7.53 F 21.87 S 2.03

b) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-carbonylmethyl]-2-N-[1-O-α-D-carbonylmethyl-mannopyranose] -1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

30 g (20.39 mmol) of the title substance from example 24a will be dissolved in 50 ml of chloroform and 300 ml of trifluoroacetic acid will be added. The mixture is stirred for 10 min at room temperature. Then it is evaporated to dryness in a vacuum, and the residue is dissolved in 300 ml of water. Then 3.69 g (10.19 mmol) of gadolinium complex was added and stirred for 5 hours at 80ºC. The solution is evaporated to dryness under vacuum and purified on Kieselgel (RP-18; buffer: water/ethanol/acetonitrile gradient).

Yield: 11.0 g (37%d.Th., theoretical) of a colorless and amorphous solid.

Water content: 11.3%

Analysis of elements (calculated according to dry substances):

ber.: C 34.62 H 3.87 N 7.69 F 22.16 S 2.20 Gd 10.97

gef.: C 34.57 H 3.95 N 7.60 F 22.05 S 2.13 Gd 10.90

Example 25

a) 6-N-[3,6,9-tris(carboxymethyl)-3,6,9-triazaundecanedicyl-1-carboxy-11-oyl)-2-N-[1-O-α-D-carbonylmethyl- mannopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

To 24.0 g (26.19 mmol) of the title substance from example 21e, dissolved in 100 ml of dimethylformamide / 30 ml of pyridine, 12.10 g (30.0 mmol) of 3-N-(2,6-dioxomorpholinoethyl) is added. -6-N-(ethoxycarbonylmethyl)-3,6-diazaoctane acid and stirred for 5 hours at 50ºC. then it is evaporated to dryness in a vacuum. The residue is dissolved in 200 ml of water, and the pH value of the resulting solution is adjusted to 13 with the addition of 20% aqueous sodium alkali solution. It is stirred for 8 hours at 22ºC and the pH value is 13. The solution will be conc. of hydrochloric acid to a pH value of 7.2 and continuously evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel RP-18 (buffer: water/ethanol/acetonitrile gradient).

Yield: 17.26 g (51.0% theoretical) of a colorless solid.

Water content: 9.3%

Analysis of elements (calculated according to dry substances):

ber.: C 37.19 H 4.21 N 7.59 F 25.00 S 2.48

gef.: C 37.10 H 4.30 N 7.48 F 25.07 S 2.42

b) 6-N-[3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedic acid-1-carboxy-11-oyl)-2-N-[1-O-α-D-carbonylmethyl- mannopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex, sodium salt

To 10.0 g (7.74 mmol) of the title substance from example 25a in 100 ml of water, 1.40 g (3.87 mmol) of gadolinium oxide is added and stirred for 2 hours at 70ºC. The solution is filtered. The filtrate is adjusted to a pH value of 7.4 with 2N sodium alkali and freeze-dried.

Yield: 11.36 g (quantitative) of an amorphous solid.

Water content: 10.5%

Analysis of elements (calculated according to dry substances):

ber.: C 32.72 H 3.43 N 6.68 S 2.18 Gd 10.71 Na 1.57 F 22.00

gef.: C 32.65 H 3.51 N 6.71 S 2.08 Gd 10.61 Na 1.68 F 21.87

Example 26

a) 6-N-benzyloxycarbonyl-2-N[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane]-10-pentanoyl-3-aza-4-oxo-5-methyl- 5-yl)]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

50.0 g (60.20 mmol) of the title substance from example 21c, 6.93 g (60.20 mmol) of N-hydroxysuccinimide, 5.09 g (120.0 mmol) of lithium chloride and 37.91 g (60, 20 mmol) 1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl), Gd complex, be will zu gentle heating in 400 ml of dimethylsulfoxide dissolved. At 10ºC, 20.63 g (100.0 mmol) of N,N-dicyclohexylcarbodiimide are added and stirred continuously overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and further chromatographically purified (Kieselgel RP-18: gradient from water / ethanol / acetonitrile).

Yield: 75.73 g (87.0% theoretical) of a colorless solid.

Water content: 10.1%

Analysis of elements (calculated according to dry substances):

ber.: C 37.48 H 3.84 N 8.74 S 2.22 F 22.39 Gd 10.90

gef.: C 37.39 H 4.02 N 8.70 S 2.16 F 22.29 Gd 10.75

b) 2-N-[1,4,7-tris(carboxylatomethyl]-1,4,7,10-tetraazacyclododecane-Gd-complex, 10-(pentanoyl-3-aza-4-oxo-5-methyl-5 -yl)]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

70.0 g (48.53 mmol) of the title substance from example 21d will be dissolved in 500 ml of water / 100 ml of ethanol, mixed with 5.0 g of palladium catalyst (10% Pd / C) and kept at room temperature for a long time. hydrated in a hydrogen atmosphere (1 atm), until no more water absorption occurs. Next, the catalyst is removed, thoroughly washed with ethanol (2x with 75 ml each) and reduced to dryness in a vacuum. The title substance is obtained as a highly viscous and colorless oil.

Usability: 63.5 g (quantitative).

Water content: 9.8%

Analysis of elements (calculated according to dry substances):

ber.: C 37.48 H 3.84 N 8.74 S 2.22 F 22.39 Gd 10.90

gef.: C 37.39 H 4.03 N 8.65 S 2.20 F 22.31 Gd 10.78

c) 6-N-(1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)-2-N-[1,4,7-tris(carboxylatomethyl)- 1,4,7,10-tetraazacyclododecane, Gd-complex-10-pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine ]-amide

50.0 g (38.22 mmol) of the title substance from example 26b, 4.40 g (38.22 mmol) of N-hydroxysuccinimide, 3.39 g (80.0 mmol) of lithium chloride and 22.88 g (38, 22 mmol) of 1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose will be dissolved under gentle heating (30 to 40 ºC) in 400 ml of dimethylsulfoxide. At 10ºC, 10.32 g (50 mmol) of N,N-dicyclohexylcarbodiimide are added and stirred continuously overnight at room temperature. then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated solid substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: gradient from water / ethanol / acetonitrile).

Yield: 64.25 g (89.0% theoretical) of a colorless solid.

Water content: 10.9%

Analysis of elements (calculated according to dry substances):

ber.: C 46.42 H 4.54 N 6.67 S 1.70 F 17.10 Gd 8.33

gef.: C 46.36 H 4.71 N 6.60 S 1.61 F 17.19 Gd 8.21

d) 6-N-(1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)-2-N-[1,4,7-tris(carboxylatomethyl)- 1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide , Gd-complex

60.0 g (31.77 mmol) of the title substance from example 26c will be dissolved in 500 ml of ethanol and mixed with 6.0 g of palladium catalyst (10% Pd/C). For so long, it will continue to be hydrated in an atmosphere saturated with hydrogen (1 atm), until it stops absorbing water. Next, the catalyst is removed, washed thoroughly with ethanol (2 x 150 ml each) and reduced in a vacuum.

Yield: 48.55 g (quantitative) of a colorless solid.

Water content: 3.9%

Analysis of elements (calculated according to dry substances):

ber.: C 35.37 H 4.02 N 8.25 S 2.10 F 21.13 Gd 10.29

gef.: C 35.28 H 4.13 N 8.17 S 2.03 F 21.05 Gd 10.20

Example 27

a) 1,7-bi-(benzyloxycarbonyl)-4-[2-(N-ethyl-N-perfluorooxylsulfonyl]-amino]-acetyl]-1,4,7,10-tetraazacyclododecane

K 50 g (113.5 mmol) of 1,7-bi-(benzyloxycarbonyl)-1,4,7,10-tetraazacyclododecane and 66.42 g (113.5 mmol) of 2-(N-ethyl-N-perfluorooxylsulfonyl) -aminoacetic acid (prepared according to DE 196 03 033) in 300 ml of tetrahydrofuran, add 49.46 g (200 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-ethyl ester of carboxylic acid) at 0ºC and stir over overnight at room temperature. The mixture is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane / methanol = 20:1).

Yield: 65.2 g (57% theoretical) of a colorless solid.

Analysis of elements:

ber.: C 42.91 H 3.80 N 6.95 F 32.05 S 3.18

gef.: C 42.85 H 3.90 N 6.87 F 31.98 S 3.15

b) 1,7-bi-(benzyloxy)-4-[2-(N-ethyl-N-perfluorooxylsulfonyl]-amino]-acetyl-10-[1-O-α-D-carbonylmethyl-2,3,4 ,6-tetra-O-benzyl-mannopyranose)-1,4,7,10-tetraazacyclododecane

K 60 g (59.53 mmol) of the title substance from example 27a and 35.64 g (59.53 mmol) of 1-O-α-D-carboxymethyl-2,3,4,6-tetra-O-benzyl-mannopyranose , prepared according to DE 19728954, in 300 ml of tetrahydrofuran, 24.73 g (100 mmol EEDQ (2-ethoxy-1,2-dihydroquinoline-1-ethyl ester of carboxylic acid)) are added at 0ºC and stirred overnight at room temperature. All is evaporated to dryness and chromatographed on Kieselgel (buffer: dichloromethane/methanol = 20:1).

Yield: 76.6 g (81% theoretical) of a colorless solid.

Analysis of elements:

ber.: C 54.44 H 4.70 N 4.41 F 20.33 S 2.02

gef.: C 54.37 H 4.81 N 4.35 F 20.25 S 1.96

c) 1-[2-(N-ethyl-N-perfluorooxylsulfonyl]-amino]-acetyl-7-[1-O-α-D-carbonylmethyl-mannopyranose)-1,4,7,10-tetraazacyclododecane

70 g (44.07 mmol) of the title substance from example 27b will be dissolved in 800 ml of ethanol and 8 g of palladium catalyst (10% Pd/C) will be added. Hydration of the mixture is done at room temperature. The catalyst is filtered off and evaporated to dryness under vacuum.

Yield: 42.3 g (quantitative) of a colorless solid.

Analysis of elements:

ber.: C 35.04 H 3.99 N 7.30 F 33.65 S 3.34

gef.: C 35.15 H 4.13 N 7.13 F 33.48 S 3.26

d) 1,7-bi-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-(pentanoyl-3-aza-4-oxo-5-methyl) -5-yl)-4-[2-(N-ethyl-N-perfluorooxylsulfonyl]-amino]-acetyl-10-[1-O-α-D-carbonylmethyl-mannopyranose)-1,4,7,10- tetraazacyclododecane

20 g (20.84 mmol) of the title substance from example 27c, 5.09 g (120 mmol) of lithium chloride and 37.78 g (60 mmol) of 1,4,7-tris(carbonylatomethyl)-10-pentanoyl-3-aza- 4-oxo-5-methyl-5yl)-1,4,7,10-tetraazacyclododecane-Gd complex will be zu gently heated in 400 ml of dimethylsulfoxide dissolved. At 10ºC, 29.67 g (120 mmol) of EEDQ are added to this and stirred continuously overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 13.2 g (29% theoretical) of a colorless solid.

Water content: 11.8%

Analysis of elements (calculated according to dry substance):

ber.: C 36.31 H 4.34 N 9.62 S 1.47 F 14.79 Gd 14.41

gef.: C 36.24 H 4.27 N 9.58 S 1.51 F 14.85 Gd 14.25

Example 28

a) 1,7-bi-(benzyloxycarbonyl)-4-[2-(N-ethyl-N-perfluorooxylsulfonyl]-amino]-acetyl-10-[pentanoyl-3-aza-4-oxo-5-methyl-5 -yl-[1,4,7-tris(carbonylatomethyl)-Gd-complex 1,4,7,10-tetraazacyclododecane-10-yl]-1,4,7,10-tetraazacyclododecane

50 g (49.61 mmol) of the title substance from example 27a, 5.71 g (49.61 mmol) of N-hydroxysuccinimide, 4.24 g (100 mmol) of lithium chloride and 31.24 g (49.61 mmol) and 1,4,7-tris(carboxylatomethyl)-10-(pentanoyl-3-aza-oxo-5-methyl-5-yl)-1,4,7,10-tetraazacyclododecane, the Gd-complex will be zu gently heated in 350 ml of dimethylsulfoxide dissolved. At 10ºC, 15.47 g (75 mmol) of N,N-dicyclohexylcarbodiimide were added and stirred continuously overnight at room temperature. Then the solution is poured into 2000 ml of acetone and stirred for 10 min. The precipitated solid is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 65.1 g (81% theoretical) of one solid.

Water content: 7.9%

Analysis of elements (calculated according to dry substance):

ber.: C 40.79 H 4.11 N 8.65 S 1.98 F 19.94 Gd 9.72

gef.: C 40.71 H 4.20 N 8.58 S 2.03 F 19.87 Gd 9.68

b) 1-[2-(N-ethyl-N-perfluorooxylsulfonyl]-amino]-acetyl-7-{pentanoyl-3-aza-4-oxo-5-methyl-5-yl-10-[1,4, 7-tris(carbonylatomethyl)-1,4,7,10-tetraazacyclododecane, Gd-complex]}-1,4,7,10-tetraazacyclododecane.

60 g (37.05 mmol) of the title substance from example 28a will be dissolved in 600 ml of ethanol and 6.0 g of palladium catalyst (10% Pd/C) will be added. Hydration is done at room temperature. Then the catalyst is filtered off, and the filtrate is evaporated to dryness under vacuum.

Yield: 50.06 g (quantitative) of a colorless solid.

Water content: 3.9%

Analysis of elements (calculated according to dry substance):

ber.: C 34.67 H 4.03 N 10.37 S 2.37 F 23.90 Gd 11.64

gef.: C 34.58 H 4.15 N 10.28 S 2.30 F 23.84 Gd 11.57

c) 1-[2-(N-ethyl-N-perfluorooxylsulfonyl]-amino]-acetyl-4,10-bi[1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O- benzyl-mannopyranose]-7-{pentanoyl-3-aza-4-oxo-5-methyl-5-yl)-[1,4,7-tris(carbonylatomethyl)-1,4,7,10-tetraazacyclododecane-10 -yl]-Gd-complex}-1,4,7,10-tetraazacyclododecane.

40 g (29.60 mmol) of the title substance from example 28b, 2.54 g (60 mmol) of lithium chloride and 44.9 g (75 mmol) of 1-O-α-D-carbonylmethyl-2,3,4,6 -tetra-O-benzyl-mannopyranose will be dissolved by gentle heating in 300 ml of dimethylsulfoxide. At 10ºC, 24.73 g (100 mmol) of EEDQ are added and stirred continuously overnight at room temperature. then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated solid is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 31.98 g (43% theoretical) of a colorless solid.

Water content: 3.5%

Analysis of elements (calculated according to dry substance):

ber.: C 53.06 H 5.05 N 5.57 S 1.28 F 12.85 Gd 6.26

gef.: C 52.95 H 5.19 N 5.48 S 1.23 F 12.77 Gd 6.14

d) 1-[2-(N-ethyl-N-perfluorooxylsulfonyl]-amino]-acetyl-4,10-bi[1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O- benzyl-mannopyranose]-7-{pentanoyl-3-aza-4-oxo-5-methyl-5-yl)-[1,4,7-tris(carbonylatomethyl)-1,4,7,10-tetraazacyclododecane-10 -yl]-Gd-complex}-1,4,7,10-tetraazacyclododecane.

30 g (11.94 mmol) of the title substance from example 28c will be dissolved in 300 ml of ethanol/30 ml of water and 4 g of palladium catalyst (10% Pd/C) will be added. It is hydrated at room temperature, the catalyst is filtered off, and the filtrate is evaporated to dryness under vacuum.

Yield: 21.39 g (quantitative) of a colorless solid.

Water content: 3.4%

Analysis of elements (calculated according to dry substance):

ber.: C 36.89 H 4.39 N 7.82 S 1.79 F 18.03 Gd 8.78

gef.: C 36.80 H 4.50 N 7.87 S 1.68 F 17.91 Gd 8.70

Example 29

a) 6-N-[3,6-bi(carboxymethyl)-octane-1,8-dicarboxylic acid-1-carboxy-8-oyl]-2-N-[1-O-α-D-carbonylmethyl-mannopyranose ]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

25.62 g (100 mmol) of ethylenediamine-N,N,N',N'-di-anhydride is added to 27.5 g (30 mmol) of the title substance from example 21e, dissolved in 300 ml of diethylformamide / 100 ml of pyridine tetraacetic acid and stir for 5 hours at 50ºC. The mixture is evaporated to dryness under vacuum. The residue is dissolved in 300 ml of water, with the addition of 20% sodium lye, until the pH value is 10, and then the basic solution is added with conc. salt vinegar. bring to a pH value of 3 and then evaporate to dryness in a vacuum. The residue is chromatographed on Kieselgel RP-18 (buffer: water/ethanol/acetonitrile gradient).

Yield: 18.22 g (51% theoretical) of a colorless solid.

Water content: 7.9%

Analysis of elements (calculated according to dry substance):

ber.: C 36.31 H 3.98 N 7.06 F 27.12 S 2.69

gef.: C 36.23 H 4.07 N 6.98 F 27.05 S 2.62

b) 6-N-[3,6-bi(carboxymethyl)-octane-1,8-dicarboxylic acid-1-carboxylato-8-oyl]-2-N-[1-O-α-D-carbonylmethyl-mannopyranose ]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Mn-complex, sodium salt

10 g (8.397 mmol) of the title substance from example 29a will be dissolved in 200 ml of water. Add 965 mg (8.397 mmol) of manganese(II) carbonate and stir for 3 hours at 60ºC. The solution will be adjusted to pH = 7.4 with 5% sodium lye, filtered and continuously freeze-dried.

Yield: 10.52 g (99% theoretical) of a colorless solid.

Water content: 7.8%

Analysis of elements (calculated according to dry substance):

ber.: C 34.16 H 3.50 N 6.64 S 2.53 F 25.52 Mn 4.34 Na 1.82

gef.: C 34.06 H 3.61 N 6.58 S 2.47 F 25.47 Mn 4.30 Na 1.97

Example 30

a) 1,2,3,4,6-penta-O-acetyl-α,β-D-mannopyranose

In an analogous way, as described in the literature (M.L. Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (R.L. Whistler, M.L. Wolfrom and J.N. BeMiller, Eds.), Academic Press, New York, Vol. lI, 53, pp. 211- 215, (1963) gives a method of converting 150 g (832.5 mmol) of α,β-D-mannopyranose with a mixture of 1500 ml of absolute pyridine and 1500 ml of acetic anhydride after processing 315 g (96.7%) of the above title substance as raw materials in the form of a viscous, colorless oil. Through 1H-NMR-spectroscopic studies of the thus obtained title substance, the ratio of α to β, both anomers can be determined as 1:4. By separating the α, β-anomers of the above-mentioned title substance, the following reactions can be carried out steps to be ignored.

Analysis of elements:

ber.: C 49.21 H 5.68

gef.: C 49.12 H 5.78

b) 1-O-α-D-(5-ethoxycarbonyl)-pentyl-2,3,4,6-tetra-O-acetyl-mannopyranose

In an analogous way, as described in the literature for the synthesis of aryl-glycopyranosides (J. Conchie and G.A. Levvy in Methods in Carbohydrate Chemistry (R.L. Whistler, M.L. Wolfrom and J.N. BeMiller, Eds.), Academic Press, New York, Vol.II, 90 , pp. 345-347, (1963) leads to the conversion of 156.2 g (400 mmol) of the title substance from Example 21a as an α,β-anomer mixture with 67 ml (400 mmol) of 6-hydroxy-ethyl ester of hexanoic acid and 60, 8 ml (520 mmol) of tin-IV-chloride in a total of 600 ml of 1,2-dichloroethane after purification by column chromatography (eluent: hexane/ethyl acetate, 2:1) to give 100.05 g (51% d. Th.) of the above-mentioned title substances as a colorless and viscous oil.Through 1H-NMR-spectroscopic studies of the thus obtained title substance, it was possible to prove that the above-mentioned title substances are exclusively pure α-anomer.

Analysis of elements:

ber.: C 52.94 H 6.77

gef.: C 52.80 H 6.78

c) 1-O-α-D-(5-carboxy)-pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose

One mixed suspension of 141.0 g (289 mmol) of the title substance from example 30b in 200 ml of dioxane will be at room temp. and under simultaneous vigorous stirring in smaller amounts with a total of 238.5 g (4.26 mol) of fine potassium hydroxide powder mixed. To increase the ability to mix, the reaction mixture will be mixed with 200 ml of dioxane and the thus obtained suspension will be continuously heated to boiling and at the same temperature. with a total of 372 ml (3.128 mol) of benzyl bromide mixed over a period of 2 hours, while the same amount is added dropwise. After a reaction of 4 hours at 110ºC, followed by a step of 12 hours at room temperature, during which the reaction mixture for the purpose of processing and a total of 2.5 l of ice water will be slowly poured out, and the aqueous phase will then be completely extracted with diethyl ether. After washing the thus obtained ether phase and further drying it over sodium sulfate, the salt will be removed, and the diethyl ether will be removed under vacuum. Excessive benzyl bromide will be continuously in the oil vacuum pump quantitatively at temp. oil bath of 180ºC distilled from the reaction mixture. The resulting resin-oily residue will be purified on Kieselgel using ethyl acetate/hexane (1:10) as eluent.

Yield: 172.2 g (91 % d.Th.) of the above title substance in the form of a colorless and highly viscous oil.

Analysis of elements:

ber.: C 75.68 H 7.16

gef.: C 75.79 H 7.04

d) 6-N-benzyloxycarbonyl-2-N-[1-O-α-D-(5-carbonyl)-pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose]-1-lysine- [1-(4-Perfluorooctylsulfonyl)-piperazine]-amide

100 g (134.0 mmol) of the carboxylic acid prepared in example 30c and 32.4 g (281.4 mmol) of N-hydroxysuccinimide will be dissolved in 500 ml of dimethylformamide and at 0ºC with a total of 58 g (281.4 mmol) of N, N'-dicyclohexylcarbodiimide in smaller amounts mixed and will be for 3 hours at the same temp. mixed. A solution of 111.3 g (134.0 mmol) of the title substance from example 21c, cooled to 0ºC, dissolved in 300 ml of dimethylformamide, was added dropwise to the active ester solution prepared in this way and stirred for 2 hours at 0ºC, as well as for 12 hours at room temp. For refinement, it is filtered from the precipitated dicyclohexyl-urine and the solvent is continuously "extracted" until dry. The resulting residue is continuously chromatographed on Kieselgel (eluent: dichloromethane / ethanol; 20:1; chromatography is performed using a single solvent gradient with continuous addition of ethanol).

Yield: 132.5 g (67.4 % d.Th.) of the title substance in the form of a colorless and highly viscous oil.

Analysis of elements:

ber.: C 54.02 H 4.88 N 3.82 F 22.01 S 2.19

gef.: C 53.87 H 4.85 N 4.02 F 22.55 S 2.06

e) 2-N-[1-O-α-D-(5-carbonyl)-pentyl-mannopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

In 800 ml of ethanol, 120 g (81.77 mmol) of the compound prepared for 30 days will be dissolved, mixed with 4.5 g of Pearlman-catalyst (Pd 20%, C) and for a long time at room temperature, under an atmosphere saturated with hydrogen (1 atm) hydrated, until no more water absorption takes place (approx. 8 hours). Then the catalyst is removed, washed thoroughly with ethanol (ca. 200 ml) and reduced to dryness under vacuum. The title substance is obtained as a highly viscous and colorless oil.

Yield: 78.5 g (98.7 % d.Th.)

Analysis of elements:

ber.: C 37.04 H 4.25 N 5.76 F 33.20 S 3.30

gef.: C 36.96 H 4.85 N 5.41 F 34.13 S 3.22

f) 2-N-[1-O-α-D-(5-carbonyl)-pentyl-mannopyranose]6-N-[1,4,7-tris-(carboxylatomethyl)-10-(3-aza-4 -oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10-tetraazacyclododecane]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

99.8 g (158.4 mmol; 2.2 molar equivalents in relation to the used amine components from example 30e in patent application DE 197 28 954 C1 in example 31h described Gd-complex 10-(4-carboxy-1-methyl- 2-oxo-3-azbutyl)-1,4,7-triacetic acid and 6.7 g of dry lithium chloride (158.4 mmol) will be dissolved at 40ºC in 800 ml of absolute dimethylsulfoxide with stirring. At the same temp. below with a total of 18.2 g (158.4 mmol) of N-hydroxysuccinimide and 70 g (71.96 mmol) of the title compound from Example 30e, dissolved in 250 ml of absolute dimethylsulfoxide, mixed After cooling to room temp., the reaction mixture with 32.7 g (158.4 mmol) of N,N'-dicyclohexylcarbondiimide and mixed for 12 hours at room temperature. dissolved in water, filtered from the insoluble dicyclohexylurin, and the filtrate passed through an AMICON® YM-3 ultrafiltration membrane (cut off : 3000 Da) freed from salt and cleaned of low molecular content. The retentate will be continuously freeze-dried.

Yield: 93.0 g (81.6 % d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 9.53%

Analysis of elements (calculated according to dry substance):

ber.: C 37.15 H 4.39 N 7.96 F 20.38 S 2.02 Gd 9.92

gef.: C 36.92 H 4.50 N 7.68 F 19.77 S 1.91 Gd 10.08

Example 31

a) 2-N-[1-O-α-D-(5-carbonyl)-pentyl-mannopyranose]6-N-{2-[4-(3-oxapropionyl)-phenyl]-2-[1,4 ,7-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-10-yl]acetic acid}-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex, sodium salt

A mixed suspension of 5 g (9.06 mmol) of the title substance from Example 23e in 15 ml of absolute dimethylsulfoxide will be mixed at 70°C with 0.68 g (15.9 mmol) of lithium chloride. After 30 min. mixing at 70ºC will be a clear reaction solution portioned with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide mixed, and the reaction mixture for another 1 hour at the same temp. retained. After cooling to 0ºC, 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide will be mixed and the reaction solution will be stirred for another 1 hour at 0ºC, followed by 12 hours at 22ºC. The thus obtained reaction mixture of N-hydroxysuccinimide ester, the title substance from example 3e, will be mixed at 22ºC with one solution of 4 g (4.12 mmol) of the title substance from example 10Ae in 15 ml of absolute dimethylsulfoxide and further 12 hours at room temperature. mixed. For processing, the reaction mixture at 22ºC will be added to 900 ml of acetone, whereby the title substance will precipitate as a colorless precipitate. The precipitate is removed by suction, in 200 ml dest. dissolve in water and continue with 1M sodium alkali, the pH value of that solution is adjusted to exactly 7.2. The resulting aqueous solution of the product will be ultrafiltered 3x through a YM3-ultrafiltration membrane (AMICON®; cut off: 3000 Da) for the purpose of salt removal and separation of low molecular weight components. The retentate thus obtained will be continuously freeze-dried.

Yield: 6.33 g (92.4% d.Th, which refers to the amine components used) as a colorless lyophilisate.

Water content: 7.38%

Analysis of elements (calculated according to dry substance):

ber.: C 38.48 H 4.13 N 6.65 F 19.16 S 1.09 Gd 9.33 Na 1.36

gef.: C 39.52 H 4.12 N 6.67 F 19.70 S 1.89 Gd 9.30 Na 1.41

Example 32

a) 3,5-bi-benzyloxycarbonylamino-benzoic acid N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide

In a solution mixture of 125 ml of dry tetrahydrofuran and 125 ml of dry dioxane, there will be 20 g (47.5 mmol) of 3,5-bibenzyloxycarbonylamino-benzoic acid (synthesis according to the following references: Skulnick, Harvey I.; Johnson, Paul D .; Aristoff, Paul A.; Morris, Jeanette K.; Lovasz, Kristine D.; et. al.; J. Med. Chem.; 40; 7; 1997; 1149-1164), as well as 4.78 g ( 47.5 mmol) of triethylamine, dissolved. After cooling to -15ºC, a solution of 6.56 g (48 mmol) isobutyl ester of chloro-formic acid in 30 ml of dry tetrahydrofuran is added slowly, while the internal temperature, below -10ºC, must be maintained. After a reaction time of 15 min at -15ºC, a solution of 58.6 g (47.5 mmol) of 1-amino-1H,1H,2H,2H,4H,4H,5H,5H-3-oxo-perfluoro is added dropwise. -tridecane and 4.78 g (47.5 mmol) of triethylamine in 100 ml of dry tetrahydrofuran at -20ºC, in addition. After a reaction time of 1 hour at -15ºC, as well as 2 hours at room temperature, the reaction mixture will be reduced to dryness in a vacuum. The remaining residue will be added to 300 ml of ethyl ester of acetic acid and washed twice with 200 ml of saturated sodium hydrogen carbonate solution and once with 300 ml of water. After drying the organic phase over sodium sulfate, the salt will be removed, and the ethyl ester of acetic acid will be sucked off under vacuum. The remaining oily residue will be purified on Kieselgel using dichloromethane/hexane/2-propanol (10:5:1) as eluent.

Yield: 36.2 g (82.5% d.Th) of the title substance as a colorless oil.

Analysis of elements:

ber.: C 46.82 H 3.27 N 4.55 F 34.97

gef.: C 47.21 H 3.31 N 4.61 F 34.48

b) 3,5-di-amino-benzoic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)]amide

30.0 g (32.4 mmol) of the amide prepared in example 32a will be dissolved in 300 ml of ethanol and mixed with 1.2 g of Pearlman catalyst (Pd 20%, C). Hydration is carried out for such a long time at room temperature. under a hydrogen atmosphere (1 atm), until the absorption of water is no longer visible. The mixture is separated from the catalyst, washed thoroughly with ethanol (ca. 300 ml) and reduced to dryness under vacuum. The title substance will be obtained as a highly viscous, yellowish oil.

Yield: 20.12 g (94.8%, d.Th.)

Analysis of elements:

ber.: C 36.66 H 2.77 N 6.41 F 49.28

gef.: C 36.07 H 2.87 N 6.23 F 49.43

c) 3-N-(1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)-5-amino-benzoic acid-N-(3-oxa-

1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide

10.95 g (18.30 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-α-D-mannopyranoside (preparation as described in patent document DE 197 28 954 C1) will be in 150 ml of dimethylformamide dissolved and mixed with a total of 2.09 g (18.3 mmol) of N-hydroxysuccinimide. The mixture was cooled to 0°C and 3.78 g (18.3 mmol) of dicyclohexylcarbodiimide was added. Then 1 hour at 0ºC and 4 hours at room temperature. mixes. The solution is cooled to 0ºC and a solution of 24.0 g (36.6 mmol, 2 mol-equivalents, in relation to the carbonic acid used) of the diamino compound described in example 32b, dissolved in 350 ml of dimethylformamide, is added dropwise within 3 hours. slowly. Stir continuously for another hour at 0ºC, then overnight at room temperature. It is then evaporated to dryness under vacuum, and the residue is dissolved in 300 ml of ethyl acetic acid. Then the precipitated urine substance is filtered and the filtrate is washed twice with 100 ml of 5% aqueous soda solution. The organic phase will be dried over magnesium sulfate and evaporated to dryness under vacuum. The residue will be chromatographically purified on Kieselgel (buffer: n-hexane/isopropanol 13:1). 16.8 g (74.3% d.Th., which refers to the carbonic acid used) of the title substance are obtained in the form of a colorless oil. By increasing the polarity of the eluent composition to n-hexane/isopropanol, 5:1, a total of 10.15 g of unused diamino compounds 32b will be recovered in the following chromatographic fractions, which can be used again according to the above reaction steps.

Analysis of elements:

ber.: C 54.42 H 4.40 N 3.40 F 26.13

gef.: C 54.32 H 4.49 N 3.48 F 25.94

d) 3-N-[-(1-O-α-D-carbonylmethyl-mannopyranose)-5-amino-benzoic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H, 5H-perfluorotridecyl)-amide

In an analogous way as described for the synthesis of the title substance from example 32b, the hydrogenolysis of 12.0 g (9.70 mmol) of the title substance from example 32c, using 0.5 g of Pearlman catalyst (Pd 20%, C) in one ethanol /water (9:1) to the mixture after working up, 8.08 g (96.7% d.Th.) of the above title substances as a yellow, viscous oil.

Analysis of elements:

ber.: C 37.64 H 3.28 N 4.88 F 37.49

gef.: C 37.32 H 3.17 N 4.97 F 37.55

e) 3-N-(1-O-α-D-carbonylmethyl-mannopyranose)-5-N-{2-[4-(3-oxapropionyl)-phenyl]-2-[1,4,7-tris- (carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-10-yl]-acetic acid}-benzoic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl )-amide, Gd-complex, sodium salt

13.6 g (19.2 mmol; 2.2 molar equivalents, in relation to the used amino components from example 32d) in example 23Ae of the described Gd-complex and 0.81 g of dry lithium chloride (19.2 mmol) will be on 40ºC in 100 ml of absolute dimethylsulfoxide, with stirring, dissolved and at the same temp. with a total of 2.2 g (19.2 mmol) of N-hydroxysuccinimide and 7.5 g (8.7 mmol) of the title substance from example 32d, dissolved in 50 ml of absolute dimethylsulfoxide, mixed. After cooling to room temperature, the reaction mixture will be mixed with 3.96 g (19.2 mmol) of N,N'-dicyclohexylcarbodiimide for 12 hours at room temperature. mixed. The resulting suspension will be continuously mixed with sufficient acetone until the above-mentioned title substance is completely precipitated, the precipitate is suctioned off, dried, dissolved in water, filtered from insoluble dicyclohexylurins, and the filtrate is released through an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) salts and also purified from lower molecules. The retentate will be continuously freeze-dried.

Yield: 11.51 g (84.5% d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 6.77%

Analysis of elements:

ber.: C 40.05 H 3.94 N 6.29 F 20.71 Gd 10.08 Na 1.47

gef.: C 39.98 H 4.00 N 6.31 F 20.73 Gd 10.11 Na 1.42

Example 33

a) 3,5-bi-(benzyloxycarbonylamino)-1-{N-[1-(4-perfluoroxylsulfonyl)-piperazine]}-benzamide

In a solution mixture of 60 ml of dry tetrahydrofuran and 70 ml of dry dioxane, there will be 10 g (23.75 mmol) of 3,5-bi-benzyloxycarbonylamino-benzoic acid 8 synthesis according to the following literature: Skulnick, Harvey I.; Johnson, Paul D.; Aristoff, Paul A.; Morris, Jeanette K.; Lovasz, Kristine D.; et al.; J.Med.Chem.; 40; 7; 1997; 1149-1164) as well as 2.39 g (23.75 mmol) of triethylamine dissolved. After cooling to -15ºC, a solution of 3.28 g (24 mmol) isobutyl ester of chloroformic acid in 20 ml of dry tetrahydrofuran is slowly added to the mixture, whereby the internal temp. does not exceed -10º. After a reaction time of 15 min at -15ºC, a solution of 23.0 g (23.75 mmol) of perfluorooctylsulfonylpiperazine and 2.39 g (23.75 mmol) of triethylamine in 50 ml of dry tetrahydrofuran is added dropwise at -20ºC.

After a reaction time of 1 hour at -15ºC and 2 hours at room temperature, the reaction mixture will be reduced to dryness under vacuum. The remaining part will be dissolved in 200 ml of ethyl acetic acid and washed twice with 100 ml of saturated sodium hydrogen carbonate solution, as well as once with 300 ml of water. After drying the organic phase, the salt will be removed, and the ethyl ester of acetic acid will be sucked off under vacuum. The remaining oily residue will be purified on Kieselgel using dichloromethane/hexane/2-propanol (15:5:1) as eluent.

Analysis of elements:

ber.: C 43.31 H 2.80 N 5.77 F 32.27 S 3.30

gef.: C 43.21 H 2.75 N 5.61 F 33.38 S 3.22

b) 3,5-bi-amino-1-{N-[1-(4-perfluoroxylsulfonyl)-piperazine]}-benzamide

9.70 g (10.0 mmol) of the amide prepared in example 33a will be dissolved in 100 ml of ethanol and mixed with 0.4 g of Pearlman catalyst (Pd 20%, C). Hydration is carried out for such a long time, at room temperature, in a hydrogen atmosphere (1 atm), until no more water absorption takes place. Then the catalyst is sucked off, washed thoroughly with ethanol (ca. 150 ml) and reduced to dryness in a vacuum. The title substance is obtained as a highly viscous, yellow oil.

Usability: 6.9 g (98.2 % d.Th.)

Analysis of elements:

ber.: C 32.49 H 2.15 N 7.98 F 45.98 S 4.56

gef.: C 32.56 H 2.17 N 8.09 F 45.63 S 4.61

c) 5-amino-3-N-(1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)-benzoic acid-N-[1-(4-

perfluorooxylsulfonyl)-piperazine]-benzamide

5.48 g (9.15 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-α-D-mannopyranoside (preparation as described in patent document DE 197 28 954 C1) will be in 100 ml of dimethylformamide dissolved and mixed with a total of 1.04 g (9.15 mmol) of N-hydroxysuccinimide. The mixture was then cooled to 0ºC and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide was added. Then 1 hour at 0ºC and 4 hours at room temperature. mixes. After further cooling to 0ºC, a solution of 12.85 g (18.30 mmol), 2 molar equivalents in relation to the used carboxylic acid in example 33b of the described diamino compound, dissolved in 250 ml of dimethylformamide, was added slowly within 3 hours. Stir continuously for another 1 hour at 0ºC, then overnight at room temperature. It is then evaporated to dryness in a vacuum, and the residue is dissolved in 100 ml of ethyl acetic acid. The precipitated urine substance is filtered twice with 100 ml of 5% aqueous soda solution. The organic phase is dried over magnesium sulfate and dried to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: n-hexane/isopropanol 13:1). Thus, 8.14 g (69.4% d.Th., which refers to the carbonic acid used) of the title substance are obtained in the form of a colorless oil. By increasing the polarity of the eluent composition during chromatography to 6:1 (n-hexane/isopropanol), a total of 4.36 g of unused diamino compounds 33b will be recovered in the following chromatographic fractions, which can be used again according to the above reaction regulations.

Analysis of elements:

ber.: C 51.49 H 4.01 N 4.37 F 25.17 S 2.50

gef.: C 51.60 H 4.19 N 4.28 F 25.14 S 2.44

d) 5-amino-3-N-(1-O-α-D-carbonylmethyl-mannopyranose)-benzoic acid-N-[1-(4-perfluoroxylsulfonyl)-piperazine]-amide

In an analogous way as described in the synthesis of the title substance from example 33b, the hydrogenolysis of 6.4 g (5.0 mmol) of the title compound from example 33c, using 0.3 g of Pearlman catalyst (Pd 20%, C) in one mixture from ethanol/water (8:1), after working up 4.43 g (96.2% d.Th.) of the above title substance in the form of a yellow colored and viscous oil.

Analysis of elements:

ber.: C 35.15 H 2.95 N 6.07 F 35.01 S 3.48

gef.: C 35.32 H 3.02 N 5.89 F 35.05 S 3.58

e) 3-N-(1-O-α-D-carbonylmethyl-mannopyranose)-5-N-[1,4,7-tris-(carboxylatomethyl)-10-(3-aza-4-oxo-5- methyl-5-yl-pentanoyl)-1,4,7,10-tetraazacyclododecane]-benzoic acid-N-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

5.54 g (8.8 mmol; 2.2 molar equivalents, in relation to the used amino components from example 33d) in patent example DE 197 28 954 C1 in example 31h of the described Gd-component 10-(4-carboxy-1- methyl-2-oxo-3-azbutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.37 g of dry lithium chloride (8.8 mmol) will be at 40ºC in 60 ml of absolute dimethylsulfoxide, zu mixing, dissolved and at the same temp. with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.7 g (4.0 mmol) of the title substance from example 13Ad, dissolved in 40 ml of absolute dimethylsulfoxide, mixed. After cooling to room temperature, the reaction mixture will be mixed with 1.82 g (8.8 mmol) of N,N'-dicyclohexylcarbodiimide for 12 hours at room temperature. mixed. The obtained suspension will be continuously mixed with sufficient acetone until the above-mentioned title substance is completely precipitated, the precipitate is suctioned off, dried, dissolved in water, filtered from insoluble dicyclohexylurins, and the filtrate is released through an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) salts and also purified from lower molecules. The retentate will be continuously freeze-dried.

Yield: 5.36 g (87.4% d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 6.77%

Analysis of elements:

ber.: C 36.01 H 3.61 N 8.22 F 21.05 Gd 10.25 S 2.09

gef.: C 35.89 H 3.70 N 8.22 F 20.19 Gd 10.18 S 2.16

Example 34

a) 1,4,7-triazaheptane-1,7-bi-(2-N-trifluoroacetyl-6-N-benzyloxycarbonyl-1-lysine)-diamide

100 g (107.9 mmol) of the carboxylic acid prepared in example 21a and 26.1 g (226.59 mmol) of N-hydroxysuccinimide will be dissolved in 500 ml of dimethylformamide and at 0ºC with a total of 46.7 g (226.59 mmol ) of N,N'-dicyclohexylcarbodiimide in smaller amounts mixed and for 3 hours at the same temp. mixed. The active ester solution prepared in this way is added dropwise to a solution cooled to 0ºC from 5.57 g (53.95 mmol) of diethyltriamine, dissolved in 60 ml of dimethylformamide, and stirred for 2 hours at 0ºC and 12 hours at room temperature. For the purpose of treatment, the precipitated dicyclohexylurine substance is filtered and the solvent is "extracted" continuously until dry. The residue obtained in this way will be continuously chromatographed on Kieselgel (solvent: dichloromethane/ethanol, 15:1; the performance of the chromatography follows the application of a single gradient with a continuous increase in the proportion of ethanol).

Yield: 26.0 g (58.8 % d.Th., which refers to the components used) of the title substance in the form of a colorless and highly viscous oil.

Analysis of elements:

ber.: C 52.74 H 5.78 N 11.96 F 13.90

gef.: C 52.66 H 5.89 N 11.88 F 14.02

b) 1,4,7-triazaheptane-1,7-bi-(2-N-trifluoroacetyl-6-N-benzyloxycarbonyl-1-lysine)-diamide-4-[2-(N-ethyl-N-perfluorooctylsulfonyl) -amino]-acetyl

In a solution of 20 g (24.4 mmol) of the diamide prepared in example 34a, dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, at 0ºC and in an atmosphere enriched with nitrogen, 16.18 g (27.0 mmol) 2-[N-ethyl-N-perfluorooctylsulfonyl)-aminoacetic acid (preparation according to: DE 196 03 033), dissolved in 50 ml of tetrahydrofuran, was added. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is continuously added at 0ºC in portions and left overnight at room temperature. mix and continuously reduce in a vacuum. The remaining oil will then be chromatographed on Kieselgel (solvent: n-hexane/isopropanol 15:1). 24.74 g (72.4% d.Th., which refers to the amount of sec. amine used) of the title substance in the form of a colorless oil are obtained.

Analysis of elements:

ber.: C 42.01 H 3.96 F 31.19 N 8.00 S 2.29

gef.: C 41.92 H 4.07 F 31.22 N 7.78 S 2.34

c) 1,7-bi-(6-N-benzyloxycarbonyl-1-lysine)-diamide-4-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1,4,7-triazaheptane

In 100 ml of ethanol, 22 g (15.7 mmol) of the compound prepared in example 34b will be dissolved and ammonia introduced at 0ºC into that solution for 40 min. It will continue to be mixed for another 4 hours at 0ºC, as well as 3 hours at room temperature. and reduced to 40ºC temp. water bath until dry. The remaining oily residue will be purified on Kieselgel using dichloromethane/hexane/2-propanol (20:10:1) as eluent.

Yield: 12.92 g (98.4% d.Th.) of the above title substance as a colorless and highly viscous oil.

Analysis of elements:

ber.: C 44.22 H 4.64 N 9.38 S 2.68 F 27.03

gef.: C 44.31 H 4.72 N 9.30 S 2.74 F 26.99

d) 1,7-bi-[6-N-benzyloxycarbonyl-2-N-(1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)-1-lysine ]-diamide-4-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1,4,7-triazaheptane

5.47 g (9.15 mmol) of 1-carboxymethyloxy-2,3,4-tetra-1-O-benzyl-α-D-mannopyranoside (preparation as described in patent description DE 197 28 954 C1) will be dissolved in 80 ml of dimethylformamide and mixed with a total of 1.05 g (9.15 mmol) of N-succinimide. It is then cooled to 0ºC and 1.9 g (9.15 mmol) of dicyclohexylcarbodiimide is added. Then 1 hour at 0ºC and 4 hours at room temperature. mixes. The mixture is cooled to 0ºC and dropped over a period of 3 hours into a solution of 7.65 g (9.15 mmol) of the amino compound described in Example 34e, dissolved in 50 ml of dimethylformamide, slowly. Stir continuously for another hour at 0ºC, and then overnight at room temperature. It is evaporated to dryness in a vacuum, and the residue is mixed with 100 ml of ethyl ether of acetic acid. The precipitated urine substance is filtered, and the filtrate is washed twice with 50 ml of 5% aqueous soda solution. The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: n-hexane/isopropanol 20:1). 17.01 g (78.9% d.Th., relative to the carbonic acid used) of the title substance are obtained in the form of a colorless oil.

Analysis of elements:

ber.: C 59.13 H 5.43 N 4.76 F 13.71 S 1.36

gef.: C 59.22 H 5.39 N 4.85 F 13.70 S 1.40

e) 1,7-bi-[2-N-(1-O-α-D-carbonylmethyl-mannopyranose)-1-lysine]-diamide-4-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino ]-acetyl-1,4,7-triazaheptane

15.0 g (6.36 mmol) of the amide prepared in example 34d will be dissolved in 150 ml of ethanol and mixed with 0.5 g of Pearlman catalyst (Pd 20%, C). The mixture is hydrated for a long time at room temperature, in a hydrogen atmosphere (1 atm), until no more hydrogen is absorbed. The catalyst is then removed, the mixture is washed thoroughly with ethanol (ca. 100 ml) and reduced to dryness under vacuum. The title substance is obtained as a highly viscous, yellow oil.

Usability: 8.54 g (97.2 % d.Th.)

Analysis of elements:

ber.: C 39.13 H 5.04 N 8.11 F 23.38 S 2.32

gef.: C 39.07 H 4.98 N 8.18 F 23.40 S 2.30

f) 1,7-bi-[2-N-(1-O-α-D-carbonylmethyl-mannopyranose)-6-N-[1,4,7-tri(carboxylatomethyl)-10-(3-aza- 4-oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10-tetraazacyclododecane]-1-lysine]-diamide-4-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino] -acetyl-1,4,7-triazaheptane, digadolinium complex

Mixed suspension from 5.7 g (9.06 mmol) of the Gd-complex 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1 described in the patent application DE 197 28 954 C1 in example 31h, 4,7,10-tetraazacyclododecane-1,4,7-triacetic acid in 75 ml of absolute dimethylsulfoxide, will be mixed at 70ºC with 0.68 g (15.9 mmol) of lithium chloride. After 30 min. stirring at 70ºC, there will be a clear reaction solution in smaller amounts with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide mixed, and the reaction mixture for another 1 hour at that temp. retained. After cooling to 0ºC, it will be mixed with 4.52 g (23.85 mmol) of dicyclohexyldiimide, and the reaction solution will be stirred for another 1 hour at 0ºC, followed by 12 hours at 22ºC. The thus obtained reaction mixture of N-hydroxysuccinimide ester Gd-complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid is will at 22ºC, by adding dropwise with one solution from 2.84 g (2.06 mmol) of the title substance from example 34e in 15 ml of absolute dimethylsulfoxide mixed and for the next 12 hours at room temp. mixed. For work-up, the reaction solution will be added dropwise to 500 ml of acetone at 22ºC, whereby the title substance will precipitate as a colorless precipitate. The precipitate will be suctioned off, in 200 ml dest. dissolved in water and passed through a YM3-ultrafiltration membrane (AMICON®; cut off: 3000 Da) for the purpose of salt removal and separation of low molecular weight compounds, ultrafiltered 3x. The retentate thus obtained will be continuously freeze-dried.

Usefulness: 4.80 g (89.6% d.Th., in relation to the used amino components) as a colorless lyophilizate, with a water content of 8.98%.

Analysis of elements (calculated according to dry substances):

ber.: C 38.28 H 4.84 N 9.68 F 12.40 S 1.23 Gd 12.07

gef.: C 38.20 H 4.91 N 9.77 F 12.45 S 1.19 Gd 12.10

Example 35

a) 1,7-bi-(benzyloxycarbonyl)-4-{3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine-amide}-1, 4,7,10-tetraazacyclododecane

A solution of 10.75 g (24.4 mmol) of 1,7-bi-[benzyloxycarbonyl]-1,4,7,10-tetraazacyclododecane, dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, will be 0ºC and under a nitrogen atmosphere, 16.56 g (24.4 mmol) of the title compound from Example 35e, dissolved in 150 ml of tetrahydrofuran, was added. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is continuously added at 0ºC in smaller amounts and left overnight at room temperature. mix and reduce continuously in vacuum. The remaining oil will be chromatographed on Kieselgel (buffer: n-hexane/isopropanol 12:1). 17.22 g (64.3% d.Th., in relation to the used secondary amine) of monoamide and 3.8 g (8.8% d.Th.) of diamide are obtained as an additional product. The title compound will be isolated as a colorless oil.

Analysis of elements by dry substances):

ber.: C 43.41 H 3.92 F 29.18 N 7.59 S 2.60

gef.: C 43.52 H 4.07 F 29.24 N 7.67 S 2.55

b) 1,7-bi-(benzyloxycarbonyl)-4-{3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine-amide}-10- [1-O-α-D-(5-carbonyl)-pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose]-1,4,7,10-tetraazacyclododecane

10 g (13.4 mmol) of the carboxylic acid prepared in example 30c and 3.24 g (28.1 mmol) of N-hydroxysuccinimide will be dissolved in 100 ml of dimethylformamide and at 0ºC with a total of 5.8 g (28.1 mmol) N,N'-dicyclohexylcarbodiimide in smaller amounts mixed and it will be 3 hours at that temp. mixed. A solution of 14.83 g (13.4 mmol) of the title substance from example 35a, dissolved in 100 ml of dimethylformamide, cooled to 0ºC, dissolved in 100 ml of dimethylformamide, was added dropwise to the solution of the active ester and stirred for 2 hours at 0ºC, as well as for 12 hours at room temperature. temp. For processing, it is filtered from the precipitated dicyclohexylurine substance and the solvent is "extracted" until dry. The resulting residue will be continuously chromatographed on Kieselgel (buffer: dichloromethane/ethyl acetic acid ester 20:1; the implementation of the chromatography follows the application of a liquid gradient with a continuous increase in the proportion of ethyl acetic acid ester).

Yield: 18.3 g (78.2% d.Th.) of the title substance in the form of a colorless and highly viscous oil.

Analysis of elements:

ber.: C 55.11 H 5.03 N 4.82 F 18.52 S 1.84

gef.: C 54.87 H 4.85 N 4.92 F 18.55 S 1.86

c) 1-{3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-7-[1-O-a-D-(5-carbonyl) )-pentyl-mannopyranose]-1,4,7,10-tetraazacyclododecane

17.0 g (9.75 mmol) of the compound prepared in example 34b will be dissolved in 150 ml of ethanol, mixed with 1.0 g of Pearlamn-catalyst (Pd 20%, C) and kept at room temperature for a long time. under the influence of an atmosphere saturated with hydrogen (1 atm) hydrated, until no more hydrogen absorption is observed. Then the catalyst is sucked off, washed thoroughly with ethanol (2x with 75 ml each) and reduced in a vacuum until dry. The title substance will be obtained as a highly viscous and colorless oil.

Efficiency: 10.76% (99% d.Th.)

Analysis of elements:

ber.: C 38.78 H 4.61 N 7.54 F 8.97 S 2.88

gef.: C 38.86 H 4.65 N 7.41 F 29.02 S 2.92

d) 1,7-bi-[1,4,7-tri(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-Gd-complex-10-(pentanoyl-3-aza-4-oxo-5-methyl) -5-yl)-4-[2-(N-ethyl-N-perfluorooctylsulfonyl]-amino]-acetyl-2-oxa-acetyl]-10-[1-O-α-D-6-carbonylpentyl-mannopyranose) -1,4,7,10-tetraazacyclododecane

24.86 G (39.46 mmol; 4.4 mol-equivalents in relation to the used amine component 35c) in patent application De 197 28 954 C1 in example 31h of the described Gd-complex 10-(4-carboxy-1-methyl- 2-oxo-3-azbutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.67 g of dry lithium chloride (39.46 mmol) will be at 40ºC in 200 ml of absolute dimethylsulfoxide, zu mixing dissolved and at that temp. with a total of 4.53 g (39.46 mmol) of N-hydroxysuccinimide and 10.0 g (8.97 mmol) of the title substance from example 34c, dissolved in 100 ml of absolute dimethylsulfoxide, mixed. After cooling to room temperature, the reaction mixture will be mixed with 8.14 g (39.46 mmol) of N,N'-dicyclohexylcarbodiimide for 12 hours at room temperature. mixed. The obtained suspension will be continued with enough acetone until complete precipitation of the above-mentioned compound, mixed, the precipitate suctioned off, dried, dissolved in water, filtered from the insoluble dicyclohexylurin compound, and the filtrate passed through an AMICON®YM-3 ultrafiltration membrane (cut off: 3000 Da ) free from salt and low molecular weight parts. The retentate will be continuously freeze-dried.

Yield: 16.37 g (79.3% d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 7.65%.

Analysis of elements (calculated according to dry substance):

ber.: C 38.01 H 4.61 N 9.58 F 13.81 S 1.37 Gd 13.45

gef.: C 37.92 H 4.55 N 9.58 F 13.77 S 1.31 Gd 13.48

e) 3-oxa-pentane-1,5-dicarboxylic acid-mono-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

25 g (44.0 mmol) of 1-perfluoroxylsulfonylpiperazine will be dissolved in 150 ml of tetrahydrofuran and mixed with a total of 5.1 g (44 mmol) of diglycolic anhydride at room temperature, and the reaction solution thus obtained is refluxed for 12 hours. After cooling to room temp. will be reduced to dryness and the remaining oily residue will be purified on Kieselgel using dichloromethane/2-propanol (16:1) as eluent.

Yield: 27.94 g (92.8% d.Th.) of the above title substance in the form of a colorless and viscous oil.

Analysis of elements:

ber.: C 58.52 H 4.27 N 1.98 S 2.26 F 22.80

gef.: C 58.42 H 4.41 N 1.80 S 2.28 F 23.02

Example 36

a) 1,7-bi-(benzyloxycarbonyl)-4-{3-(oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}- 10-[1-O-β-D-6-carbonylpentyl-2,3,4,6-tetra-O-benzyl-glucopyranose]-1,4,7,10-tetraazacyclododecane

In 750 ml of dry tetrahydrofuran there will be 68.5 g (91.79 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-α-D-mannopyranoside (prepared as described in patent document DE 197 28 954 C1 ) cooled and then 9.25 g (91.79 mmol) of triethylamine was added. After cooling the reaction solution to -15ºC to -20ºC, it is added at that temp. by stirring one solution of 12.64 g (92.5 mmol) of isobutyl ester of chloroformic acid in 150 ml of dry tetrahydrofuran, slowly, whereby the rate of addition is determined so that the internal temp. does not exceed -10ºC. After a reaction time of 15 min at -15ºC, a solution of 101.6 g (91.79 mmol) of the title substance from example 35a and 9.25 g (91.79 mmol) of triethylamine, as a solution in 500 ml of dry tetrahydrofuran, is added dropwise. at -20ºC, slowly. After a reaction time of 1 hour at -15ºC, as well as 2 hours at room temp. the reaction solution will be reduced to dryness under vacuum. The remaining residue will be dissolved in 450 ml of acetic acid ethyl ester and washed twice with 300 ml of saturated sodium hydrogen carbonate solution and once with 400 ml of water. After drying the organic phase over sodium sulfate, the salt will be removed and the ethyl ester of acetic acid will be removed under vacuum. The remaining oily residue will be purified on Kieselgel using dichloromethane/hexane/2-propanol (10:20:1) as eluent.

Yield: 130.6 g (81.6% d.Th.) of the above title substance as a colorless and highly viscous oil.

Analysis of elements:

ber.: C 55.11 H 5.03 N 4.82 F 18.52 S 1.84

gef.: C 55.20 H 5.09 N 4.91 F 18.48 S 1.80

b) 1-{3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-7-[1-O-α-D- (5-carbonyl)-pentyl-mannopyranose]-1,4,7,10-tetraazacyclododecane

110.0 g (63.08 mmol) of the compound prepared in example 36a will be dissolved in 1000 ml of ethanol, mixed with 5 g of Pearlman-catalyst (Pd 20%, C) and hydrated until quantitative "taking over" to hydrogen. Then the catalyst is sucked off, washed with ethanol and reduced to dryness under vacuum.

The title substance is obtained as a thick and colorless oil.

Usability: 92.61 g (99.5% d.Th.)

Analysis of elements:

ber.: C 52.10 H 5.12 N 5.70 F 21.89 S 2.17

gef.: C 52.20 H 5.09 N 5.71 F 21.87 S 2.20

c) 1,7-bi-[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)-4-{3-(oxa- pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-10-[1-O-α-D-(5-carbonyl)-pentyl-mannopyranose ]-1,4,7,10-tetraazacyclododecane, Digadolinium-complex

55.4 g (88.0 mmol; 4.4 mol-equivalents in relation to the used diamino components from example 33d) in patent application DE 197 28 954 C1 in example 31h of the described Gd-complex 10-(4-carboxy-1-methyl) -2-oxo-3-azbutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 3.7 g of dry lithium chloride (88.0 mmol) will be at 40ºc in 500 ml of absolute of dimethylsulfoxide, with stirring, dissolved and at that temp. with a total of 10.1 g (88.0 mmol) of N-hydroxysuccinimide and 29.5 g (20.0 mmol) of the title substance from example 36b, dissolved in 200 ml of absolute dimethylsulfoxide, mixed. After cooling to room temperature, the reaction solution with 18.2 g (88.0 mmol) of N,N'-dicyclohexylcarbodiimide will be mixed and 12 hours at room temperature. mixed. The resulting suspension will be continued with sufficient acetone until complete precipitation, the above-mentioned compound is mixed, the precipitate is suctioned off, dried, dissolved in water, the insoluble dicyclohexylurin substance is filtered, and the filtrate is filtered through an AMICON® YM-3 ultrafiltration membrane (cut off 3000 da) freed from salt and cleaned from low molecular weight compounds. The retentate will be continuously freeze-dried.

Yield: 35.96 g (76.9% d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 5.98%

Analysis of elements (calculated according to dry substance):

ber.: C 38.01 H 4.61 N 8.22 F 13.81 Gd 13.45 S 1.37

gef.: C 37.87 H 4.70 N 8.22 F 13.90 Gd 13.48 S 1.36

Example 37

a) 5-(ethoxycarbonyl)pentyl-2,3,4,6-tetra-O-acetyl-α-D-mannopyranoside

in an analogous way, as described in the literature for the synthesis of arylglycopyranosides [J. Conchie and G.A. Levvy in Methods in Carbohydrate Chemistry (R.L. Whistler, M.L. Wolfrom and J.N. BeMiller, Eds.), Academic Press, New York, Vol. II, 90, pp. 345-347, (1963)] leads to the conversion of 156.2 g (400 mmol) of d-mannosepentaacetate as an α,β-(α,β-ratio = 4:1)- mixture of anomers [to the synthesis of 1,2,3,4 ,6-penta-O-acetyl-α,β-D-mannopyranose compare: M.L. Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (R.L. Whistler, M.L. Wolfrom and J.N. BeMiller, Eds.), Academic Press, New York, Vol. II, 53, pp. 211-215, (1963)] with 67 ml (400 mmol) of 6-hydroxy-ethyl ester of hexanoic acid and 60.8 ml (520 mmol) of tin-II-chloride in a total of 600 ml of 1,2-dichloroethane, after column chromatography (buffer: hexane/ethyl acetate 2:1) to give 100.05 g (51% d.Th.) of the above title compound as a colorless and viscous oil. Through 1H-NMR-spectroscopic studies of the thus obtained title compound, it could be proven that the above-mentioned title compound is exclusively a pure α-anomer.

Analysis of elements:

ber.: C 52.94 H 6.77

gef.: C 52.80 H 6.78

b) 5-(carboxy)pentyl-2,3,4,6-tetra-O-benzyl-α-D-mannopyranoside

The mixed suspension of 141.0 g (289 mmol) of the title substance from example 37a and 200 ml of dioxane will be at room temperature. and with simultaneous vigorous stirring in smaller amounts with a total of 238.5 g (4.26 mol) of blue powdery potassium hydroxide powder mixed. To increase the ability to mix, the reaction mixture will be mixed with a further 200 ml of dioxane, and the resulting suspension will then be heated to boiling at the same temperature. with a total of 372 ml (3.128 mol) of benzyl bromide, added dropwise over a period of 2 hours. A reaction time of 4 hours at 110ºC is followed by 12 hours at room temperature. the reaction mixture will be poured into a total of 2.5 l of ice water for processing reasons, and the water phase will be extracted completely with diethyl ether. After washing the thus obtained ether phase and continued drying of the ether phase over sodium sulfate, the salt will be removed, and diethyl ether will be removed under vacuum.

Excessive benzyl bromide will be continuously in the oil pump vacuum quantitatively, at temp. water bath at 180ºC from the reaction mixture distilled. The resulting resinous-oily residue will be purified on Kieselgel using ethyl acetic acid/hexane (1:10) as an eluent.

Yield: 172.2 g (91.0% d.Th.) of the above title substance in the form of a base-colored and extremely waxy oil.

Analysis of elements:

ber.: C 75.68 H 7.16

gef.: C 75.79 H 7.04

c) 5-[(carboxy)-pentyl-2,3,4,6-tetra-O-benzyl-α-D-mannopyranoside]-N-hydroxysuccinimide ester

60 g (91.5 mmol) of the title substance from example 37b will be dissolved in 750 ml of dimethylformamide and mixed with a total of 10.4 (91.5 mmol) of N-hydroxysuccinimide. The mixture is cooled to 0ºC and 18.9 g (91.5 mmol) of dicyclohexylcarbodiimide is added. It will be 1 hour at 0ºC and then 4 hours at room temperature. mixed. The solvent will be removed under vacuum and the remaining residue will be mixed with 100 ml of acetic acid ethyl ester and cooled to 0ºC. The precipitated urine substance will be filtered, and the resulting filtrate will be reduced to dryness in a vacuum. The oily residue thus obtained will be purified on Kieselgel using ethyl ester of acetic acid/hexane (1:20) as an eluent.

Yield: 61.23 g (89 % d.Th.) of the above title substance in the form of a colorless and viscous oil.

Analysis of elements:

ber.: C 70.29 H 6.57 N 1.86

gef.: C 70.39 H 5.64 N 1.91

d) 2,6-bi-{6-Nε-2-Nα-[-[1-O-α-D-6-carbonyl-pentyl-(2,3,4,6-tetra-O-benzyl)- mannopyranose}-1-lysine}-methyl ester

Into a solution cooled to 0ºC from 4.26 g (18.20 mmol; 0.5 mol-equivalents in relation to the carboxylic acid used) of L-lysine methyl ester dihydrochloride (commercially available from Bachem) and 4.05 g ( 40.26 mmol) of triethylamine in 100 ml of dimethylformamide is added dropwise to a solution of 27.51 g (36.6 mmol) of the title substance from example 37c in 150 ml of dimethylformamide. After the addition is complete, it is stirred for another 1 hour at 0ºC and then again at room temperature, overnight. Tda will be evaporated to dryness in a vacuum, and the residue dissolved in 300 ml of ethyl acetic acid ester.

The precipitated urine substance is filtered off, and the filtrate is washed twice with 100 ml of 5% aqueous soda solution. The organic phase will be dried over magnesium sulfate and then evaporated to dryness under vacuum. The residue will be chromatographed on Kieselgel (buffer: n-hexane/isopropanol 25:1). 39.56 g (75.4% d.Th.) of the title substance is obtained in the form of a colorless oil.

Analysis of elements:

ber.: C 72.88 H 7.31 N 1.95

gef.: C 72.90 H 7.29 N 2.02

e) 2,6-bi-[6-Nε-2-Nα-[-[1-O-α-D-6-carbonyl-pentyl-(2,3,4,6-tetra-O-benzyl)- mannopyranose]]-1-lysine

30.0 g (20.92 mmol) of the compound prepared in example 37d will be dissolved in 150 ml of ethanol. Then a solution of 4 g (100.0 mmol) of sodium hydroxide in 10 ml of dest. of water and stir for 3 hours at 50ºC. after thin layer chromatography, the saponification is quantitative. It is reduced to dryness in a vacuum, and the residue is dissolved in 300 ml of acetic acid ethyl ester and the organic phase is extracted 2x with 100 ml of diluted, aqueous citric acid solution. After drying over sodium sulfate, it will be filtered and reduced to dryness under vacuum. The residue is chromatographed on Kieselgel (Chromatogram developer: n-Hexane/isopropanol 13:1). 25.56 g (88.5% d.Th.) of the title substance are obtained in the form of a colorless oil.

Analysis of elements:

ber.: C 72.88 H 7.31 N 1.95

gef.: C 72.78 H 7.33 N 1.96

f) 2,6-bi-[6-Nε-2-Nα-[-[1-O-α-D-6-carbonyl-pentyl-(2,3,4,6-tetra-O-benzyl)- mannopyranose]-1-lysine]-N-hydroxysuccinimide ester

14.0 g (9.15 mmol) of the title substance from example 37e will be dissolved in 100 ml of dimethylformamide and mixed with a total of 1.04 g (9.15 mmol) of N-hydroxysuccinimide. The mixture was cooled to 0°C and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide was added. Then 1 hour at 0ºC and 4 hours at room temperature. mixes. The solvent was continuously removed under vacuum, and the residue was mixed with 100 ml of ethyl acetic acid and cooled to 0ºC. The precipitated urine substance is filtered off, and the resulting filtrate is reduced to dryness in a vacuum. The resulting resinous-oily residue will be purified on Kieselgel using ethyl acetic acid/n-hexane (1:20) as eluent.

Yield: 12.94 g (92.4% d.Th.) of the above title substance in the form of a colorless viscous oil.

Analysis of elements:

ber.: C 71.40 H 7.05 N 2.74

gef.: C 71.39 H 7.14 N 2.81

g) 2,6-N,N'-bi-[6-Nε-2-Nα-[-[1-O-α-D-(6-carbonyl)-pentyl-2,3,4,6-tetra -O-benzyl-mannopyranose]-1-lysine-1,7-(1,4,7-triazaheptane)-diamide

A solution of 14.0 g (9.15 mmol; 2 mol-equivalents in relation to the amine used) of the title substance from the example is added dropwise to a solution of 0.47 g (4.57 mmol) of diethylenetriamine in 25 ml of dimethylformamide cooled to 0ºC 37f in 100 ml of dimethylformamide, slowly. After the addition is complete, it is stirred for another 1 hour at 0ºC and then overnight at room temperature. It is then evaporated to dryness under vacuum, and the residue is dissolved in 200 ml of acetic acid ethyl ester. Then the precipitated urine substance is filtered, the afiltrate is washed twice with 50 ml of 5% aqueous soda solution. The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: n-hexane/isopropanol 25:1). 9.53 g (71.4% d.Th.) of the title substance is obtained in the form of a colorless oil.

Analysis of elements:

ber.: C 72.79 H 7.42 N 3.36

gef.: C 72.90 H 7.39 N 3.32

h) 2-N-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-6-N-(benzyloxycarbonyl)-1-lysine-methylester

20.8 g (35.6 mmol) of 2-[N-ethyl-N-perfluorooctylsulfonyl)-formic acid as well as 3.60 g (35.6 mol) of triethylamine will be dissolved in 200 ml of dimethylformamide and will be 4.09 g (35.6 mol) of N-hydroxysuccinimide added. The mixture will be cooled to 0ºC and continuously stirred for 4 hours at room temperature. It is then cooled to 0ºC and a solution of 11.77 g (35.6 mmol) of 6-N-benzyloxycarbonyl-1-lysine-methylester-hydrochloride and 4.0 g (40 mmol) of triethylamine and 100 ml of dimethylformamide. Stir for 1 hour at 0ºC, then overnight at room temperature. It is then dried in a vacuum, and the residue is dissolved in 100 ml of acetic acid ethyl ester. The precipitated urine substance is filtered, and the filtrate is washed twice with 100 ml of 5% soda solution. The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: n-hexane/ethyl acetate 20:1). 27.43 g (88.0 % d.Th.) of colorless oil are obtained.

Analysis of elements:

ber.: C 38.41 H 3.45 N 4.80 F 36.89 S 3.66

gef.: C 38.45 H 3.38 N 4.88 F 37.02 S 3.71

i) 2-Nα-{[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl}-6-Nε-(benzyloxycarbonyl)-1-lysine

In 150 ml of ethanol there will be 25.0 g (28.55 mmol) of the compound prepared in example 37h, dissolved. Then a solution of 4 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water is added and stirred for 3 hours at 50ºC. After thin-layer chromatogram, saponification is quantitative. The mixture is reduced to dryness in a vacuum and the remaining residue is dissolved in 300 ml of ethyl acetic acid and the organic phase is extracted twice with 100 ml of diluted aqueous citric acid solution. After drying over sodium sulfate, it is filtered and reduced to dryness in a vacuum. The residue will be chromatographed on Kieselgel (buffer: n-hexane/isopropanol 10:1). 22.73 g (92.4% d.Th.) of the title substance are obtained in the form of a colorless oil.

Analysis of elements:

ber.: C 37.64 H 3.28 N 4.88 F 37.49 S 3.72

gef.: C 37.65 H 3.38 N 4.88 F 37.52 S 3.73

j) 1,4,7-triazaheptane-4-{2-N-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-6-N-benzyloxycarbonyl}-1-lysine-amide-1, 7-bi{2,6-N,N'-bi[1-O-α-D-(5-carbonyl)-pentyl-2,3,4,6-tetra-O-benzylmannopyranose]-1-lysine- diamide}

In 250 ml of dry tetrahydrofuran, 15.33 g (17.8 mmol) of the title substance from example 37i as well as 1.80 g (17.8 mmol) of triethylamine will be dissolved. After cooling the reaction solution to -15ºC to -20ºC, it is added at that temp. zu stirring one solution of 4.92 g (35.6 mmol) of isobutyl ester of chloroformic acid, dissolved in 50 ml of dry tetrahydrofuran, slowly, whereby the rate of addition was chosen so that the internal temp. of -10ºC should not be exceeded. After a reaction time of 15 minutes at -15ºC, a solution of 52.0 g (17.8 mmol) of the title substance from example 37g and 1.80 g (17.8 mmol) of triethylamine in 300 ml of dry tetrahydrofuran is added dropwise, at - 20ºC, slow. After a reaction time of 1 hour at -15ºC, as well as 2 hours at room temp. the reaction solution will be reduced to dryness under vacuum. The remaining residue will be dissolved in 500 ml of ethyl ester of acetic acid and washed twice with 200 ml of saturated sodium hydrogencarbonate solution, as well as once with water. After drying the organic phase over sodium sulfate, it will be freed from salt, and the ethyl ester of acetic acid will be removed in a vacuum. The remaining oily residue will be purified on Kieselgel using ethyl acetate/n-hexane (1:20) as an eluent.

Yield: 54.6 g (81.6% d.Th.) of the above title substance as a colorless highly viscous oil.

Analysis of elements:

ber.: C 65.09 H 6.45 N 3.72 F 8.58 S 0.85

gef.: C 65.13 H 4.41 N 3.69 F 8.52 S 0.90

k) 1,4,7-triazaheptane-4-{2-N-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acet}-1-lysin-amide-1,7-bis{2, 6-N,N'-bi[1-O-α-D-(5-carbonyl)-pentyl-mannopyranose]-1-lysine-diamide}

In 500 ml of ethanol, 50.0 g (13.28 mmol) in 37 g of the prepared compound will be dissolved, mixed with 4 g of Pearlman-catalyst (Pd 20%, C) and for a long time at room temperature, in an atmosphere saturated with hydrogen (1 atm) hydrated, until hydrogen absorption is no longer noticeable. The catalyst is removed, washed thoroughly with ethanol (approx. 400 ml) and reduced to dryness under vacuum. The title substance will be obtained as a highly viscous and colorless oil.

Usability: 26.85 g (93.0 % d.Th.)

Analysis of elements:

ber.: C 45.85 H 6.35 N 6.44 F 14.86 S 1.47

gef.: C 45.76 H 6.35 N 6.41 F 14.92 S 1.39

l) 1,4,7-triazaheptane-4-{2-N-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-6-N-[1,4,7-tris(carboxylatomethyl) -10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10-tetraazacyclododecane}-1-lysine-amide-1,7-bi{2,6- N,N'-bi[1-O-α-D-(5-carbonyl)-pentyl-mannopyranose]-1-lysine-diamide}, gadolinium complex

5.54 g (8.8 mmol; 2.2 mol-equivalents in relation to the used amino components from example 37k in patent application DE 197 28 954 C1 in example 31h described Gd-complex 10-(4-carboxy-1-methyl -2-oxo-3-azbutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.37 g of dry lithium chloride (8.8 mmol) will be at 40ºC in 60 ml of absolute of dimethylsulfoxide with mixing dissolved and at that temperature with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 1.84 g (4.0 mmol) of the title substance from example 37k, dissolved in 40 ml of absolute dimethylsulfoxide, mixed. After cooling to room temperature, the reaction solution will be mixed with 1.82 g (8.8 mmol) of N,N'-dicyclohexyldiimide and stirred for 12 hours at room temperature. the listed title substances were mixed, the precipitate was suctioned off, dried, dissolved in water, filtered from the insoluble dicyclohexyl urinary substance, and the filtrate passed through an AMICON® YM3 ultrafiltration membrane (cu t off 3000 Da) free from salt and low molecular weight compounds. The retentate will be continuously freeze-dried.

Yield: 8.77 g (78.7% d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 4.43 %

Analysis of elements:

ber.: C 43.98 H 5.97 N 7.54 F 11.59 Gd 5.64 S 1.15

gef.: C 43.97 H 6.02 N 7.62 F 11.61 Gd 10.18 S 1.15

Example 38

a) 2-Nα-6-Nε-bi-[1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose-1-lysine]-methylester

10.95 g (18.30 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-α-D-mannopyranoside (preparation as described in patent application DE 197 28 954 C1) will be in 150 ml of dimethylformamide dissolved and mixed with a total of 2.09 g (18.3 mmol) of N-hydroxysuccinimide. It is then cooled to 0ºC and 3.78 g (18.3 mmol) of dicyclohexylcarbodiimide is added. Then it is continuously stirred for 1 hour at 0ºC, and continuously for another 4 hours at room temperature. Everything is cooled to 0ºC and a solution of 2.13 g (9.15 mmol; 0.5 mol-equivalents, with respect to the carboxylic acid used) of L-lysine methyl ester dihydrochloride (commercially available from Bachem) is added within 1 hour. ) and 2.02 g (20.13 mmol) of triethylamine in 70 ml of dimethylformamide. After the addition is complete, it is stirred for another hour at 0ºC and then overnight at room temperature. It is dried in a vacuum, and the residue is dissolved in 300 ml of ethyl acetic acid. The precipitated urine substance is filtered, and the filtrate is washed with 100 ml of 5% aqueous soda solution. The organic phase will be dried over magnesium sulfate and evaporated to dryness in a vacuum. The residue will be chromatographed on Kieselgel (buffer: n-hexane/isopropanol 25:1). 10.05 g (82.3% d.Th.) of the title substance is obtained in the form of a colorless oil.

Analysis of elements:

ber.: C 71.94 H 6.79 N 2.10

gef.: C 71.90 H 6.79 N 2.09

b) 2-Nα-6-Nε-bi-[1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose-1-lysine

In an analogous way, as in example 37e for the synthesis of the relevant title substance described there, the saponification of the methyl ester of 15 g (11.23 mmol) of the title substance from example 38a leads to the formation of 13.89 g (93.6 % d.Th. ) the aforementioned title substance in the form of a colorless and viscous oil.

Analysis of elements:

ber.: C 71.80 H 6.71 N 2.12

gef.: C 71.84 H 6.69 N 2.15

c) 2-Nα-6-Nε-bi-[1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose-1-lysine-N-hydroxysuccinimide ester

12.09 g (9.15 mmol) of the title substance from example 38b will be dissolved in 100 ml of dimethylformamide and mixed with a total of 1.04 g (9.15 mmol) of N-hydroxysuccinimide. It was then cooled to 0ºC and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide was added. Then 1 hour at 0ºC and 4 hours at room temperature. mixes. The solvent was continuously removed under vacuum, and the residue was mixed with 100 ml of acetic acid ethyl ester and cooled to 0ºC. The precipitated urinary substance is removed, and the resulting filtrate is evaporated to dryness under vacuum. The resulting resinous-oily residue is purified on Kieselgel using ethyl acetic acid/n-hexane (1:20) as an eluent.

Yield: 12.24 g (94.4% d.Th.) of the above title substance in the form of a colorless, viscous oil.

Analysis of elements:

ber.: C 70.27 H 6.47 N 2.96

gef.: C 70.31 H 6.44 N 3.01

d) 6-N-benzyloxycarbonyl-2-N{[2,6-N,N'-bi-(1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose) )]-1-lysine}-[1-(4-perfluorooxylsulfonyl)-piperazine]-amide

19.0 g (13.4 mmol) of the carboxylic acid-N-hydroxysuccinimide ester prepared in example 38c will be dissolved in 75 ml of dimethylformamide and cooled to 0ºC in a solution of 11.13 g (13.4 mmol) of the title substance from example 21c, dissolved in 50.0 ml of dimethylformamide, mixed dropwise. The resulting reaction solution is stirred for 2 hours at 0ºC and for 12 hours at room temperature. For processing, it is filtered from the precipitated dicyclohexyl urinary substance and the solvent is continuously evaporated to dryness under vacuum. The residue thus obtained is chromatographed on Kieselgel (buffer: dichloromethane/ethanol 28:1; the performance of the chromatography follows the application of one solvent gradient with one, during the course of chromatography, a continuously increasing partially used polar component as eluent (here: ethanol).

Yield: 25.28 g (88.4 % d.Th.) of the title substance in the form of a colorless, highly viscous oil.

Analysis of elements:

ber.: C 59.10 H 5.34 N 3.94 F 15.13 S 1.50

gef.: C 59.18 H 5.35 N 4.02 F 15.15 S 1.56

2-N{[2,6-N,N'-bi-(1-O-α-D-carbonylmethyl-mannopyranose)]-1-lysine-1-lysine-[1-(4-perfluoroxylsulfonyl)-piperazine] -amide

In 200 ml of ethanol there will be 20.0 g (9.37 mmol) of the compound prepared in example 38d, dissolved, with 1.5 g of Pearlman catalyst (Pd 20%, C) and mixed for a long time at room temperature. in an atmosphere saturated with hydrogen (1 atm) hydrated, until hydrogen absorption no longer takes place. The catalyst is removed, washed thoroughly with ethanol (2x with ca. 100 ml each) and reduced to dryness in a vacuum. The title substance is obtained as a highly viscous and colorless oil.

Yield: 11.62 g (97.0% d. Th.)

Analysis of elements:

ber.: C 38.50 H 4.65 N 6.57 F 25.25 S 2.51

gef.: C 38.46 H 4.65 N 6.51 F 25.23 S 2.52

f) 6-N-[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10-tetraazacyclododecane) -2-N-{2,6-N,N'-bi[1-O-α-D-carbonylmethyl-mannopyranose]-1-lysine}-1-lysine-[1-(4-perfluorooctylsulfonyl)piperazine]- amide, gadolinium complex

9.98 g (15.84 mmol; 2.2 mol-equivalents in relation to the used amino component from example 38e in patent document DE 197 28 954 C1 in example 31h of the described Gd-complex 10-(4-carboxy-1-methyl -2-oxo-3-azbutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.67 g of dry lithium chloride (15.84 mmol) will be at 40ºC in 100 ml of absolute of dimethylsulfoxide was dissolved and stirred at the same temperature with a total of 1.82 g (15.84 mmol) of N-hydroxysuccinimide and 9.19 g (7.19 mmol) of the title substance from example 38e, dissolved in 50 ml of absolute dimethylsulfoxide, mixed. After cooling to room temperature, the reaction solution with 3.27 g (15.84 mmol) of N,N'-dicyclohexylcarbodiimide will be mixed and stirred for 12 hours at room temperature. the above substances are mixed, the precipitate is suctioned off, dried, dissolved in water, filtered from the insoluble dicyclohexyl urinary substance, afiltrate through an AMICON YM 3 ultrafiltration m embrane (cut off 300 Da) freed from salt and at the same time purified from possible, still present low molecular weight compounds. The retentate will be continuously freeze-dried.

Yield: 11.85 g (87.2% d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 5.54 %

Analysis of elements (calculated according to dry substance):

ber.: C 38.12 H 4.64 N 8.15 F 20.38 S 1.70 Gd 8.32

gef.: C 38.16 H 4.59 N 8.18 F 20.37 S 1.68 Gd 8.28

Example 39

a) 1,7-bi(benzyloxycarbonyl)-4-(3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)-1,4,7,10-tetraazacyclododecane

A solution of 10.75 g (24.4 mmol) of 1,7-bi[benzyloxycarbonyl]-1,4,7,10-tetraazacyclododecane, dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, will be at 0ºC and in an atmosphere saturated with nitrogen 12.74 g (24.4 mmol) of the title substance from example 39g, dissolved and 150 ml of tetrahydrofuran added. A total of 18 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is continuously added at 0ºC in smaller quantities and left overnight at room temperature. mix and then reduce in a vacuum. The remaining oil will be chromatographed on Kieselgel (buffer: n-hexane/isopropanol 16:1). 15.89 g (69% d.Th., in relation to the sec. Amine used) of monoamide and 3.8 g (8.8 % d.Th.) of diamide are obtained as a side product. The title substance will be isolated in the form of a colorless oil.

Analysis of elements:

ber.: C 45.77 H 3.95 F 34.19 N 5.93

gef.: C 45.72 H 4.01 F 34.22 N 5.88

b) 1,7-bi(benzyloxycarbonyl)-4-(3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)-10-[1-S-α-D-(2-carbonyl)- ethyl-2,3,4,6-tetra-O-acetyl-mannopyranose]-1,4,7,10-tetraazacyclododecane

7.09 g (13.4 mmol) 3-(2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranosyl)-propionic acid-N-hydroxysuccinimide ester (preparation according to: J . Haensler et al., Bioconjugate Chem. 4, 85, (1993); Chipowsky, S. and Lee, Y.C. (1973); Synthesis of 1-thio-aldosides; Carbohydrate Research 31, 339-346) will be in 100 ml of dimethylformamide dissolved and at 0ºC with a cooled to 0ºC solution of 12.65 g (13.4 mmol) of the title substance from example 39a, dissolved in 100 ml of dimethylformamide, added dropwise. It is then stirred for 2 hours at 0ºC and 12 hours at room temperature. For processing, the solvent is removed under vacuum to dryness and the resulting residue is continuously chromatographed on Kieselgel (buffer: dichloromethane/acetic acid ethyl ester 20:1; chromatography is performed using one solvent gradient with the continuous addition of ethyl acetic acid ester).

Yield: 16.23 g (88.9% d.Th.) of the title substance in the form of a colorless, highly viscous oil.

Analysis of elements:

ber.: C 46.70 H 4.36 N 4.11 F 23.69 S 2.35

gef.: C 46.66 H 4.35 N 4.12 F 23.65 S 2.30

c) 1-(3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)-7-[1-S-α-D-(2-carbonyl)-ethyl-2,3,4,6 -tetra-O-acetyl-mannopyranose]-1,4,7,10-tetraazacyclododecane

15.0 g (11.0 mmol) of the compound prepared in example 39b will be dissolved in 150 ml of ethanol, mixed with 1.0 g of Pearlman catalyst (Pd 20%, C) and kept at room temperature for a long time. hydrated in a hydrogen atmosphere (1 atm), until hydrogen absorption no longer occurs. Then the catalyst is removed, washed thoroughly with ethanol (2x with 75 ml each) and reduced to dryness in a vacuum. The title substance is obtained as a highly viscous and colorless oil.

Usability: 11.56 g (96.0 % d.Th.)

Analysis of elements:

ber.: C 40.59 H 4.33 N 5.12 F 29.50 S 2.93

gef.: C 40.63 H 4.35 N 5.11 F 29.52 S 2.92

d) 1-(3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)-7-[1-S-α-D-(2-carbonyl)-ethyl-mannopyranose]-1,4, 7,10-tetraazacyclododecane

10.0 g (9.13 mmol) of the title substance from example 39c will be suspended in 100 ml of absolute methanol and mixed with one catalytic amount of sodium methanolate at 5ºC. After a reaction time of 3 hours at room temperature, control chromatography on a thin layer (eluent: chloroform/methanol 4:1) shows the progress of the reaction, which is quantitative. For processing purposes, the clear reaction solution by mixing with amberlite IR 120 (H+-form)- resin of the cation exchanger will be neutralized, separated from the exchanger, washed with methanol and the resulting methanol filtrate removed in a vacuum until dry. The obtained oily residue will be chromatographed on a Kieselgel column (buffer: dichloromethane/n-hexane/ethyl acetate 15:20:1); the implementation of chromatography follows the application of a solvent gradient with a continuous increase in the proportion of ethyl ester of acetic acid) purified. After 1H-NMR-spectroscopic verification of the title substance, the presence of an α-configuration at the anomeric center of D-mannopyranose could be concluded without doubt based on the magnitude of the coupling constant J1.2=0.9 Hz. The α-configuration present on the amomer center is the configuration always present, which means that the amount of the possibly formed β-configured anomer of the title substance lies below the limit where it is possible to prove something in 1H-NMR-spectroscopy. The above-mentioned title substance will eventually be prepared in the form of a pure α-configured anomer.

Yield: 8.28 g (98% d.Th.) of the title substance in the form of a colorless and highly viscous oil.

Analysis of elements:

ber.: C 37.59 H 4.24 N 6.05 F 34.85 S 3.46

gef.: C 37.57 H 4.28 N 6.02 F 34.85 S 3.44

e) 1-(3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)-7-[1-S-α-D-(2-carbonyl)-ethyl-mannopyranose]-4,10- bi[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl]-1,4,7,10-tetraazacyclododecane, gadolinium complex

Amide conjugate of 1,4,7,10-tetraazacyclododecane with [1,7-bi-[gadolinium complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10 -tetraazacyclododecane-1,4,7-triacetic acid]; 3-(2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranose)-propionic acid 2.48 g ((3.94 mmol); 4.4 mol-equivalents in the ratio to the used diamino components 39d)) in the patent application DE 197 28 954 C1 in example 31h of the described Gd-complex 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane -1,4,7-triacetic acid and 167 mg of dry lithium chloride (3.94 mmol) will be dissolved at 40ºC in 40 ml of absolute dimethylsulfoxide with stirring and at the same temp. with a total of 453 mg (3.94 mmol) of N-hydroxysuccinimide and 980 mg (0.895 mmol) of the title substance from example 19Ad), dissolved in 10 ml of absolute dimethylsulfoxide, mixed. After cooling to room temp. will be a reaction solution with 814 mg (3.946 mmol) of N,N'-dicyclohexylcarbodiimide mixed and 12 hours at room temp. mixed. The resulting suspension will be continuously mixed with enough acetone until the above-mentioned title substance is completely precipitated, the precipitate is suctioned off, dried, dissolved in water, filtered from insoluble dicyclohexyl urinary substances, the afiltrate through an AMICON YM3 ultrafiltration membrane (cut off 3000 Da) is freed from salt and purified from low molecular weight compounds. The retentate will be continuously freeze-dried.

Yield: 1.32 g (69.1 % d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 7.65%

Analysis of elements (calculated according to dry substances):

ber.: C 37.43 H 4.45 N 9.12 F 15.02 S 1.49 Gd 14.63

gef.: C 37.42 H 4.50 N 9.18 F 15.07 S 1.51 Gd 14.58

f) 3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid-t-butyl ester

25 g (53.8 mmol) of 1H,1H,2H,2H-perfluoro-1-decanol (commercially available from Lancaster), will be dissolved in 250 ml of absolute toluene and at room temperature. with catalyst. A quantity (ca. 0.75 g) of tetra-n-butyl-ammonium hydrogen sulfate mixed. A total of 7.55 g (134.6 mmol; 2.5 eq. Refers to the alcohol component used) of finely powdered potassium hydrogen is continuously added at 0ºC, followed by 15.73 g (80.7 mmol; 1.5 eq. depends on the alcohol component used) terc. butyl ester of bromo-acetic acid and leave for another 2 hours at 0ºC to mix. The resulting reaction mixture will be at room temperature for 12 hours. mixed and for reasons of finishing, a total of 500 ml of acetic acid ethyl ester and 250 ml of water will be added. Org. the phase will be separated and washed twice with water. After drying org. phase over sodium sulfate, the salt will be removed, and the solvent will be removed in vacuum. The remaining oily residue will be purified on Kieselgel using acetic acid ethyl ester/hexane (1:10) as an eluent.

Yield: 26.3 g (84.6% d.Th.) of the above title substance as a colorless and highly viscous oil.

Analysis of elements:

ber.: C 33.23 H 2.61 F 55.85

gef.: C 33.29 H 2.61 F 55.90

g) 3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid

20 g (34.58 mmol) of the title substance from example 39f will be in 200 ml of a mixture, which consists of methanol and 0.5 M sodium alkali in a ratio of 2:1 and mixed at room temperature. suspended and continuously heated to 60ºC. After a reaction time of 12 hours at 60ºC, the clear reaction mixture will be mixed with amberlite IR 120 (H+-form) for further processing - the resin of the cation exchanger will be neutralized, separated from the exchanger, and the methanol-water filtrate removed under vacuum until dry. The resulting amorphous-oily residue will be purified on Kieselgel using ethyl acetic acid/n-hexane (1:3) as an eluent.

Yield: 16.0 g (88.6 % d.Th.) of the above title substance as a colorless and highly viscous oil.

Analysis of elements:

ber.: C 27.60 H 1.35 F 61.85

gef.: C 27.58 H 1.36 F 61.90

Example 40

a) 6-benzyloxycarbonyl-2-[2-(N-ethyl-N-perfluoroxylsulfonyl)-amino]-acetyl-1-lysine-methylester

K 8.0 g (24.4 mmol) of ε-carbonyloxybenzyl-1-lysinemethylester hydrochloride (commercially available from Bachem) dissolved in a mixture of 150 ml of tetrahydrofuran, 15 ml of chloroform and 2.62 g (26.0 mmol) triethylamine, will be at 0ºC and in an atmosphere saturated with nitrogen 16.18 g (27.0 mmol) of 2-[N-ethyl-N-perfluoroxylsulfonyl)aminoacetic acid (preparation according to: DE 196 03 033), dissolved in 50 ml of tetrahydrofuran, adding dropwise added. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is continuously added at 0ºC in small amounts and left overnight at room temperature with stirring. The reduction is continued in a vacuum and the remaining oil is chromatographed on Kieselgel (buffer: n-hexane/isopropanol 15:1). 17.0 g (79.6% d.Th., in relation to the primary amine used) of the title substance are obtained in the form of a colorless oil.

Analysis of elements:

ber.: C 38.41 H 3.45 F 36.89 N 4.80 S 3.66

gef.: C 38.42 H 3.47 F 36.92 N 4.87 S 3.64

b) 2-[2-(N-ethyl-N-perfluoroxylsulfonyl)-amino]-acetyl-1-lysine-methylester

15.0 g (20.23 mmol) of the compound prepared in example 40a will be dissolved in 200 ml of ethanol, mixed with 800 mg of Pearlman catalyst (Pd 20% on activated carbon) and hydrated until the absorption of the calculated amount of hydrogen is complete. Then the catalyst is sucked off, the residue is washed thoroughly with ethanol and reduced to dryness under vacuum. The title substance is obtained as a colorless oil.

Usability: 14.68 g (97.9 % d.Th.)

Analysis of elements:

ber.: C 32.40 H 3.26 F 43.56 N 5.67 S 4.32

gef.: C 32.42 H 3.27 F 43.60 N 5.67 S 4.34

c) 6-[1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose]-2-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]- acetyl-1-lysine-methyl ester

In 500 ml of dry tetrahydrofuran there will be 21.31 g (35.6 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-α-D-mannopyranoside (preparation as described in patent document DE 197 28 954 C1 ) as well as 3.60 g (35.6 mmol) of triethylamine dissolved. After cooling the reaction solution to -15ºC to -20ºC, it is added at the same temp. zu stirring one solution of 4.92 g (35.6 mmol) of isobutyl ester of formic acid chloride in 75 ml of dry tetrahydrofuran, slowly, whereby the rate of addition was chosen so that the internal temp. does not exceed -10ºC. After a reaction time of 15 min at -15ºC, a solution of 26.39 g (35.6 mmol) of the title substance from example 40 b and 3.60 g (35.6 mmol) of triethylamine, in 100 ml of dry tetrahydrofuran, is added dropwise at - 20ºC, slow. After a reaction time of 1 hour at -15ºC, as well as 2 hours at room temperature, the reaction solution will be reduced to dryness in a vacuum. The remaining residue will be dissolved in 250 ml of acetic acid ethyl ester and washed twice with 100 ml of saturated sodium hydrogen carbonate solution and once with 200 ml of water. After drying the organic phase over sodium sulfate, the salts will be sucked off, and the ethyl ester will be acetic acid. removed in vacuum. The remaining oily residue will be purified on Kieselgel using acetic acid ethyl ester/n-hexane (1:10) as an eluent.

Yield: 38.12 g (81.0 % d.Th.) of the above title substance as a colorless and highly viscous oil.

Analysis of elements:

ber.: C 49.92 H 3.92 F 29.18 N 2.53 S 2.90

gef.: C 49.99 H 4.11 F 29.22 N 2.69 S 3.01

d) 6-[1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose]-2-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]- acetyl-1-lysine

27.65 g (20.92 mmol) of the prepared compound in example 40c will be dissolved in 250 ml of methanol. Add a solution of 4.0 g (100.0 mmol) of sodium hydroxide in 10 ml of dest. of water and stir for 3 hours at 50ºC. After monitoring the course of the reaction using thin layer chromatography, methyl ester saponification already followed quantitatively. Everything is reduced to dryness, and the remaining residue is dissolved in 300 ml of ethyl acetic acid and org. the phase is extracted 2x with 100 ml of diluted, aqueous solution of citric acid. After drying over sodium sulfate, it will be filtered and reduced to dryness in a vacuum. The resulting residue will be chromatographed on Kieselgel (buffer: n-hexane/chloroform/isopropanol 15:10:1). 24.31 g (88.9% d.Th.) of the title substance are obtained in the form of a colorless, viscous oil.

Analysis of elements:

ber.: C 51.46 H 4.70 F 24.71 N 3.21 S 2.45

gef.: C 51.49 H 4.71 F 24.72 N 3.19 S 2.41

e) 6-[1-O-α-D-carbonylmethyl-mannopyranose]-2-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1-lysine

20.0 g (15.30 mmol) of the title substance from example 40d will be in one mixture, which consists of 250 ml of 2-propanol and 25 ml of water, dissolved and with 1.0 g of palladium catalyst (10% Pd on activated carbon) mixed. It is then hydrated for 12 hours at room temperature. and hydrogen pressure of 1 atm. The catalyst is filtered off, and the filtrate is evaporated to dryness under vacuum. The residue will be dissolved in 200 ml of methanol, and the reaction product will be brought to precipitation by mixing with a total of 800 ml of diethyl ester. After the obtained solid substance is sucked off, it will be the same in a vacuum at 50ºC dried.

Yield: 14.32 g (99.0% d.Th.) of an amorphous solid.

Analysis of elements:

ber.: C 35.56 H 3.84 F 34.15 N 4.44 S 3.39

gef.: C 35.58 H 3.81 F 34.17 N 4.45 S 3.40

f) 6-[1-O-α-D-carbonylmethyl-mannopyranose]-2-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1-lysine-N-{2-hydroxy-prop -3-yl-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-10-yl]}-amide, Gd-complex

7.48 g (7.91 mmol) of the title substance from example 40e will be dissolved at 40ºC in 50 ml of dimethylsulfoxide and 1.00 g (8.70 mol) of N-hydroxysuccinimide will be added. It is then dried at 20ºC and 1.795 g (8.7 mmol) of dicyclohexylcarbodiimide is added thereto. It is then mixed for 1 hour at 20ºC and for a further 4 hours at 40ºC. It keeps reaching at that temp. within 10 min. one solution of 4.53 g (7.91 mmol) of the Gd-complex of 10-(2-hydroxy-3-aminopropyl)-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane ( for preparation compare: WO 97/02051) in 20 ml of dimethylsulfoxide. Everything is mixed for 1 hour at 40ºC, then overnight at room temperature. The thus obtained suspension will be continuously mixed with enough acetone until the above-mentioned substance is completely precipitated, the precipitate is suctioned off, dried, dissolved in water, the insoluble dicyclohexyl urinary substance is filtered, and the filtrate through an AMICON YM3 ultrafiltration membrane (cut off 3000 Da) is freed from salts and low molecular weight compounds purified. The retentate will continue to be freeze-dried.

Yield: 9.71 g (81.7% d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 3.97%

Analysis of elements (calculated according to dry substance):

ber.: C 35.16 H 4.16 F 21.48 N 7.45 S 2.13 Gd 10.46

gef.: C 35.17 H 4.20 F 21.49 N 7.42 S 2.09 Gd 10.48

Example 41

a) 6-[1-O-α-D-(5-carbonyl)-pentyl2,3,4,6-tetra-O-benzyl--mannopyranose]-2N-[2-(N-ethyl-N-perfluorooctylsulfonyl) )-amino]-acetyl-1-lysine-methyl ester

5.23 g (8.0 mmol) of the 5-(carboxy)pentyl-2,3,4,6-tetra-O-benzyl-α-D-mannopyranoside described in example 30c, 1.3 g (8.0 mmol ) of 1-hydroxy-benzotriazole and 2.6 g (8.0 mmol) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (TBTU; Teboc Limited, UK) to be will be dissolved in 75 ml DMF and 15 min. mixed. This solution will then be mixed with 5.16 ml (30 mmol) of N-ethyldiisopropylamine and 5.93 g (8 mmol) of the amine described in example 40b for 1.5 days at room temperature. mixed. For processing, the solvent is removed in a vacuum until dry and the resulting residue is continuously chromatographed on Kieselgel (buffer: dichloromethane/acetic acid ethyl ester 30:1; chromatography is performed using a single solvent gradient with a continuous increase in the proportion of ethyl acetic acid ester)

Yield: 9.70 g (88.0 % d.Th.) of the title substance in the form of a colorless and highly viscous oil.

Analysis of elements:

ber.: C 52.29 H 4.97 F 23.43 N 3.05 S 2.33

gef.: C 52.33 H 4.95 F 23.50 N 3.12 S 2.30

b) 6-[1-O-α-D-(5-carbonyl)-pentyl-2,3,4,6-tetra-O-benzyl--mannopyranose]-2N-[2-(N-ethyl-N -perfluorooctylsulfonyl)-amino]-acetyl-1-lysine

9.0 g (12.40 mmol) of the compound prepared in example 41a will be dissolved in 150 ml of ethanol. Then a solution of 2.48 g (62.0 mmol) of netrium hydroxide in 15 ml of dest. of water and stirred for 3 hours at 50ºC. After controlling the course of the reaction using thin-layer chromatography, the saponification of the methyl ester according to the above-mentioned reaction time, already followed quantitatively. It is then reduced to dryness in a vacuum and the remaining residue is dissolved in 300 ml of ethyl acetic acid and the organic phase is extracted twice with 100 ml of diluted aqueous citric acid solution. After drying over sodium sulfate, it will be filtered and reduced to dryness in a vacuum. The resulting residue will be chromatographed on Kieselgel (buffer: n-hexane/chloroform/isopropanol 25:10:1). 15.88 g (93.9% d.Th.) of the title substance are obtained in the form of a colorless and highly viscous oil.

Analysis of elements:

ber.: C 51.95 H 4.88 F 23.67 N 3.08 S 2.35

gef.: C 51.99 H 4.91 F 23.70 N 3.09 S 2.33

c) 6-[1-O-α-D-(5-carbonyl)-pentyl-mannopyranose]-2N-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1-lysine

13.0 g (9.52 mmol) of the title substance from example 41b will be dissolved in a mixture consisting of 150 ml of 2-propanol and 25 ml of water and will be 1.0 g of palladium catalyst (10% Pd on activated carbon ) added. It is then hydrated for 12 hours at 1 atm hydrogen pressure and room temp. Then the catalyst is filtered off, and the phytrate is evaporated to dryness under vacuum. The resulting residue will be chromatographed on Kieselgel (buffer: n-hexane/chloroform/isopropanol 15:10:1). 9.09 g (95.1 % d.Th.) of the title substance is obtained in the form of a colorless and highly viscous oil.

Analysis of elements:

ber.: C 37.10 H 4.22 F 32.18 N 4.19 S 3.10

gef.: C 37.09 H 4.21 F 32.20 N 4.19 S 3.13

d) 6-N-[1-O-α-D-(5-carbonyl)-pentyl-mannopyranose]-2N-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1-lysine- N-{2-hydroxy-prop-3-yl-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-10-yl]}-amide, Gd-complex

7.93 g (7.91 mmol) of the title substance from example 41c will be dissolved at 40ºC in 75 ml of dimethylsulfoxide and 1.00 g (8.70 mol) of N-hydroxysuccinimide will be added. It is then cooled to room temperature. and added 1.795 g (8.7 mmol) of dicyclohexylcarbodiimide thereto. It is then mixed for 1 hour at 20ºC and for a further 4 hours at 40ºC. The active ester title substance from example 41c is added continuously at 40ºC within 10 min. one solution, consisting of 4.53 g (7.91 mmol) of gadolinium from 10-(2-hydroxy-3-aminopropyl)-4,7,10-tris(carboxymethyl)-1,4,7,10- of tetraazacyclododecane (for the preparation compare: WO 97/02051) in 20 ml of dimethylsulfoxide. Everything is mixed for 1 hour at 40ºC, then overnight at room temperature. The thus obtained suspension will be continuously mixed with a mixture of acetone/2-propanol (2:1) until the above-mentioned substance is completely precipitated, the precipitate is suctioned off, dried, dissolved in water, the insoluble dicyclohexyl urea substance is filtered, and the filtrate is filtered through an AMICON YM3 ultrafiltration membrane (cut off 3000 Da) freed from salt and low molecular weight compounds purified. The retentate will continue to be freeze-dried.

Yield: 9.71 g (78.8% d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 6.65 %

Analysis of elements (calculated according to dry substance):

ber.: C 36.97 H 4.52 F 20.71 N 7.19 S 2.06 Gd 10.08

gef.: C 37.02 H 4.50 F 20.69 N 7.22 S 2.09 Gd 10.08

Example 42

a) 6-N-{4-[2,3-bi-(N,N-bi(t-butyloxycarbonylmethyl)-amino-propyl]-phenyl}-3-oxa-propionyl-2-N-(1-O -α-D-carbonylmethyl-mannopyranose)-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

5.25 g (7.72 mmol) of tetra-t.bu-ester "Tyr-EDTA-carboxylic acid" and 781 mg (7.72 mmol) of triethylamine will be dissolved in 50 ml of methylene chloride. At -15ºC, a solution of 1.16 g (8.5 mmol) of isobutyl ester of chloroformic acid in 10 ml of methyl chloride is added dropwise over a period of 5 minutes. and mix for another 20 min. at -15ºC. The solution is then cooled to -25ºC and a solution of 7.07 g (7.72 mmol) of the title substance from example 30e and 2.12 g (21.0 mmol) of triethylamine in 70 ml of tetrahydrofuran is added dropwise within 30 min and stir continuously for another 30 min. at 15ºC and overnight at room temperature. For processing, the solvent is removed under vacuum, and the remaining oily residue is dissolved in 250 ml of chloroform. The chloroform phase is then extracted twice with 100 ml of an aqueous ammonium chloride solution, the organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. The residue will be chromatographed on Kieselgel (buffer: methylene chloride/ethanol = 20:1).

Yield: 9.60 g (79.0 % d.Th.) of a colorless and very thick oil.

Analysis of elements:

ber.: C 46.39 H 5.55 F 20.45 N 5.32 S 2.03

gef.: C 46.42 H 5.51 F 20.49 N 5.29 S 2.09

b) 6-N-{4-[2,3-bi-(N,N-bi(carboxymethyl)-amino-propyl]-phenyl}-3-oxa-propionyl-2-N-(1-O-α) -D-carbonylmethyl-mannopyranose)-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

9.0 g (5.70 mmol) of the compound prepared in Example 42a will be dissolved in 150 ml of methanol. Then a solution of 4.0 g (100.0 mmol) of sodium hydroxide in 25 ml of dest. of water and stirred for 6 hours at 60ºC. After controlling the course of the reaction using chromium. on a thin layer, the saponification of tetra-t.-butyl ester according to the above-mentioned reaction time has already followed quantitatively. Then it is reduced in a vacuum up to the ear and the remaining residue is taken in 50 ml of dimethylsulfoxide, and then mixed with a sufficient amount of a mixture of acetone/ethyl ester of acetic acid (1:1) until the above-mentioned title compound is completely precipitated, the thus obtained precipitate is mixed suction, wash well with acetic acid ethyl ester, dry, dissolve in water, adjust the pH-value of the product solution using 1M hydrochloric acid to 3.5, filter off possible remaining insoluble particles, afiltrate through an AMICON YM3 ultrafiltration membrane (cut off 3000 Da ) free from salt and low-molecular compounds, purified. The retentate will be continuously freeze-dried

Yield: 6.76 g (87.6% d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 3.30%

Analysis of elements (calculated according to dry matter):

ber.: C 39.89 H 4.09 F 23.84 N 6.20 S 2.37

gef.: C 39.92 H 4.15 F 23.92 N 6.22 S 2.29

c) 6-N-{4-[2,3-bi-(N,N-bi(carboxylatomethyl)-amino-propyl]-phenyl}-3-oxa-propionyl-2-N-(1-O-α) -D-carbonylmethyl-mannopyranose)-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Mn-complex, disodium salt

3.0 g (2.22 mmol) of the title substance from example 42b will be dissolved in 150 ml of a water/ethanol mixture (3:1) at the boiling point and at 80ºC in smaller amounts with 0.25 g (2.22 mmol) of manganese-II-carbonate mixed. The resulting reaction solution will then be boiled for 5 hours in a reflux haldil. After cooling to room temp. will be a mixture of reaction solution from 200 ml dest. water/n-butanol (1:1) dissolved. With vigorous stirring, it will be mixed with 1N sodium alkali until the pH value is 7.2. After the complete removal of n-butanol in a vacuum, the remaining aqueous phase will be freed from salts and low-molecular compounds and cleaned through the AMICON YM3 ultra filtration membrane (cut off 3000 Da). The retentate will be continuously freeze-dried.

Yield: 3.19 g (99.0 % d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 5.08 %

Analysis of elements (calculated according to dry matter):

ber.: C 37.23 H 3.54 F 22.25 Mn 3.78 N 5.79 Na 3.17 S 2.21

gef.: C 37.30 H 3.49 F 22.29 Mn 3.81 N 5.76 Na 3.19 S 2.18

Example 43

a) 3-benzyloxycarbonylamino-glutaric acid-[1-(4-perfluorooctylsulfonyl)-piperazine]-monoamide

One mixed solution from 25.0 g (94.96 mmol) of 3-N-(benzyloxycarbonyl)-glutaric acid-anhydride (synthesis according to : Hatanaka, Minoru; Yamamoto; Yu-Ichi; Nitta, Hajime; Ishimaru, Toshijasu; TELAY; Tetrahedron Lett.; EN; 22; 39; 1981; 3883-3886) in 150 ml of absolute tetrahydrofuran will be mixed with a solution of 53.97 g (95.0 mmol) of 1-perfluorooctylsulfonylpiperazine in 150 ml of tetrahydrofuran added dropwise and thus the resulting reaction solution was boiled for 12 hours at the reflux condenser. After cooling to room temp. will be reduced to dryness, and the remaining oily residue will be purified on Kieselgel using dichloromethane/2-propanol (20:1) as eluent.

Yield: 75.80 g (96.0% d.Th.) of the above title substance in the form of a colorless and viscous oil.

Analysis of elements:

ber.: C 36.11 H 2.67 F 38.84 N 5.05 S 3.86

gef.: C 36.12 H 2.61 F 38.82 N 5.08 S 3.82

b) 3-amino-glutaric acid-[1-(4-perfluorooctylsulfonyl)-piperazine]-monoamide

31.50 g (37.88 mmol) of the compound prepared in example 43b will be dissolved in 300 ml of ethanol, mixed with 2.5 g of Pearlaman catalyst (Pd 20%, C) and until quantitative absorption of hydrogen at 1 atm of hydrogen pressure, hydrated. Then the catalyst is removed, washed with ethanol and reduced to dryness in vacuum. The title substance is obtained as a white-yellow viscous oil.

Usability: 25.22 g (95.5% d.Th.)

Analysis of elements:

ber.: C 29.28 H 2.31 F 46.31 N 6.03 S 4.06

gef.: C 29.32 H 2.29 F 46.28 N 6.08 S 4.08

c) 3-N-(1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)-glutaric acid-[1-(4-perfluorooctylsulfonyl)-piperazine]-monoamide

21.52 g (18.96 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-α-D-mannopyranoside (prepared according to patent document DE 197 28 954 C1 described) will be at room temp. in 100 ml of absolute dimethylformamide dissolved and at 0ºC with 2.56 g (22.2 mmol) of N-hydroxysuccinimide, followed by 4.55 g (22.2 mmol) of dicyclohexylcarbodiimide mixed. After a reaction time of 60 min. at 0ºC and 3 hours at 22ºC the insoluble dicyclohexyl urinary substance is filtered, the obtained solution of the active ester of the above-mentioned title substance is added slowly at 0ºC to a single solution, which is stirred, from 13.22 g (18.96 mmol) of the compound from example 43b , dissolved in 100 ml of dimethylformamide. After a reaction time of 12 hours at room temp. the solvent will be removed by vacuum and the remaining residue will be dissolved in 300 ml of ethyl acetic acid, it will be filtered from the urinary substance, and the organic filtrate will be diluted 2x with 100 ml of saturated sodium hydrogen carbonate solution as well as 1x with 100 ml of 10% aqueous solution of citric acid and 1x washed with water. After drying the organic phase over sodium sulfate, the salt will be sucked off, and the remaining ethyl ester of acetic acid will be removed in a vacuum. The remaining oily residue will be purified on Kieselgel using acetic acid ethyl ester/n-hexane (1:15) as eluent.

Yield: 21.39 g (88.3 % d.Th.) of the above title substance as a colorless and highly viscous oil.

Analysis of elements:

ber.: C 49.81 H 4.10 F 25.27 N 3.29 S 2.51

gef.: C 49.89 H 4.11 F 25.22 N 3.32 S 2.51

d) 3-N-(1-O-α-D-carbonylmethyl-mannopyranose)-glutaric acid-[1-(4-perfluorooctylsulfonyl)-piperazine]-monoamide

19.55 g (15.30 mmol) of the title substance from example 42c will be in one mixture, which consists of 250 ml of 2-propanol and 25 ml of water, dissolved and with 1.5 g of palladium catalyst (10% Pd on active coal) mixed. Hydration is carried out for the next 12 hours at room temperature. at a hydrogen pressure of 1 atm. Then the catalyst is filtered off, the afiltrate is evaporated to dryness under vacuum. The residue will be dissolved in 200 ml of methanol, and the reaction product will be precipitated by mixing with a total of 800 ml of diethyl ether. After removing the thus obtained solid substance, it will be dried in a vacuum at 40ºC.

Yield: 17.49 g (97.5% d.Th.) of an amorphous solid.

Analysis of elements:

ber.: C 32.73 H 3.08 F 35.20 N 4.58 S 3.49

gef.: C 32.68 H 3.15 F 35.17 N 4.55 S 3.50

e) 3-N-(1-O-α-D-carbonylmethyl-mannopyranose)-glutaric acid-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide-5-N-{2-hydroxy-prop-3- yl-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-10-yl]}-amide, Gd-complex

14.43 g (15.84 mmol) of the title substance from example 43d and 0.67 g of dry lithium chloride (15.84 mmol) will be dissolved at 40ºC in 100 ml of absolute dimethylsulfoxide with stirring and at the same temp. with a total of 1.82 g (15.84 mmol) of N-hydroxysuccinimide and one solution from 9.08 g (15.84 mmol) of the Gd-complex of 10-(2-hydroxy-3-aminopropyl)-4,7,10 -tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (for preparation compare: WO 97/02051), in 50 ml of dimethylsulfoxide, mixed. After cooling to room temperature, the reaction solution will be mixed with 3.27 g (15.84 mmol) of N,N'-dicyclohexylcarbodiimide for 12 hours at room temperature. mixed. The obtained solution will be continuously mixed with enough acetone until the above-mentioned title substance is completely precipitated, the precipitate is suctioned off, dried, dissolved in water, the insoluble dicyclohexyl urea substance is filtered, and the filtrate is freed from salt and at the same time, possible, still present low molecular weight compounds are cleaned. The retainer will continue to be freeze-dried.

Yield: 18.71 g (80.2% d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 4.87%

Analysis of elements (calculated according to dry substance):

ber.: C 34.24 H 3.83 F 21.92 N 7.61 S 2.18 Gd 10.67

gef.: C 34.26 H 3.79 F 21.87 N 7.58 S 2.18 Gd 10.68

Example 44

a) 1,7-bi(benzyloxycarbonyl)-4-{3oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-1,10- [2,6-N,N'-bi(1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)-1-lysine-1,4,7,10 -tetraazacyclododecane

In one solution from 27.0 g (24.4 mmol) in example 35a prepared check. Amine, in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, at 0ºC and in an atmosphere saturated with nitrogen, 33.04 g (25.0 mmol) of the title substance from example 18c, dissolved in 250 ml of tetrahydrofuran, was added. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is continuously added at 0ºC in smaller amounts and left overnight at room temperature. mix. It is then continuously reduced to dryness in a vacuum, and the remaining oil is chromatographed on Kieselgel (buffer: n-hexane/isopropanol 25:1). 45.87 g (78.0 % d.Th., in relation to the sec. Amine used) of the title substance are obtained in the form of a colorless oil.

Analysis of elements:

ber.: C 59.30 H 5.39 F 13.40 N 4.65 S 1.33

gef.: C 59.32 H 5.37 F 13.37 N 4.70 S 1.34

b) 1-{3oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-7-[2,6-N,N'-bi (1-O-α-D-carbonylmethyl-mannopyranose)-1-lysine-1,4,7,10-tetraazacyclododecane

24.1 g (10.0 mmol) of the title substance prepared in example 44a will be dissolved in 250 ml of ethanol and mixed with 1.4 g of Pearlman catalyst (Pd 20%, C). Hydration is carried out until hydrogen absorption no longer occurs, the catalyst is removed, washed with ethanol and reduced to dryness in a vacuum. The product is obtained as a yellowish and highly viscous oil.

Usability: 12.80 g (90.1 % d.Th.)

Analysis of elements (calculated according to dry substance):

ber.: C 39.72 H 4.89 F 22.73 N 7.88 S 2.26

gef.: C 39.72 H 4.87 F 22.77 N 7.90 S 2.24

c) 1-{3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-7-[2,6-N,N' -bi(1-O-α-D-carbonylmethyl-mannopyranose)-1-lysine-4,10-bi[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5- methyl-5-yl-pentanoyl)]-1,4,7,10-tetraazacyclododecane, digadolinium complex

5.54 g (8.8 mmol; 2.2 mol-equivalents in relation to the used amine component from example 44b) in patent application DE 197 28 954 C1 in example 31h of the described Gd-complex 10-(4-carboxy-1 -methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and dry lithium chloride (0.37 g, 8.8 mmol) will be at 40ºC in 60 ml of absolute dimethylsulfoxide was dissolved by mixing and at that temp. with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 5.68 g (4.0 mmol) of the title substance from example 44b, dissolved in 40 ml of absolute dimethylsulfoxide, mixed. After cooling to room temp. will be a reaction solution with 1.82 g (8.8 mmol) of N,N'-dicyclohexylcarbodiimide mixed for 12 hours at room temp. The resulting suspension will be continued with enough acetone until the above-mentioned compound is completely precipitated, mixed, the precipitate removed, dried, dissolved in water, filtered from insoluble dicyclohexyl urinary substances, and the filtrate through an AMICON YM-3 ultra filtration membrane (cut off 3000 Da ) purified from salts and low molecular weight compounds. The retentate will be continuously freeze-dried.

Yield: 8.52 g (80.6% d.Th.; in relation to the diamine components used) as a colorless lyophilizate.

Water content (Karl-Fischer): 6.09%.

Analysis of elements (calculated according to dry substance):

ber.: C 38.61 H 4.76 F 12.21 N 9.53 Gd 11.89 S 1.12

gef.: C 38.57 H 4.82 F 12.21 N 9.52 Gd 11.93 S 1.15

Example 45

a) 1,7-bi(benzyloxycarbonyl)-4-{3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-10- [2,6-N,N'-bi(1-O-α-D-(5-carbonyl)-pentyl-mannopyranose)-1-lysine-1,4,7,10-tetraazacyclododecane

In one solution from 27.0 g (24.4 mmol) in example 35a prepared sec. The amine, in a mixture of 150 ml of tetrahydrofuran in 15 ml of chloroform, will be at 0ºC and in an atmosphere saturated with nitrogen, 35.80 g (25.0 mmol) of the title substance from Example 37e, dissolved in 250 ml of tetrahydrofuran, is added. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is continuously added at 0ºC in smaller amounts and left overnight at room temperature. mix. The reduction is continued in a vacuum to dryness, the remaining oil will be chromatographed on Kieselgel (buffer: n-hexane/isopropanol 20:1). 49.48 g (80.4% d.Th., in relation to the used sec.-amine) of the title substance are obtained in the form of a colorless oil.

Analysis of elements:

ber.: C 60.47 H 5.79 F 12.80 N 4.44 S 1.27

gef.: C 60.52 H 5.77 F 12.77 N 4.50 S 1.30

b) 1-{3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-7-[2,6-N,N' -bi(1-O-α-D-(5-carbonyl)-pentyl-mannopyranose)]-1-lysine-1,4,7,10-tetraazacyclododecane

In 250 ml of ethanol will be 25.2 g (10.0 mmol) of the title substance prepared in example 45a, dissolved and mixed with 1.8 g of Pearman catalyst (Pd 20%, C). Hydrogenation is carried out until quantitative absorption of hydrogen, the catalyst is removed, washed with ethanol and then reduced to dryness in a vacuum. The product is obtained as a yellowish colored, extremely viscous oil.

Yield: 14.11 g (92.5% d.Th.)

element analysis:

ber.: C 49.60 H 7.20 F 21.17 N 7.34 S 2.10

gef.: C 49.62 H 7.17 F 21.20 N 7.30 S 2.14

c) 1-{3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-7-[2,6-N,N' -bi(1-O-α-D-(5-carbonyl)-pentyl-mannopyranose)-1-lysine-4,10-bi[1,4,7-tris(carboxylatomethyl)-10-(3-aza- 4-oxo-5-methyl-5-yl-pentanoyl)]-1,4,7,10-tetraazacyclododecane, digadolinium complex

5.54 g (8.8 mmol; 2.2 mol-equivalents in relation to the used amine component from example 45b) in patent application DE 197 28 954 C1 in example 31h of the described Gd-complex 10-(4-carboxy-1 -methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and dry lithium chloride (0.37 g, 8.8 mmol) will be at 40ºC in 60 ml of absolute dimethylsulfoxide was dissolved by mixing and at that temp. with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 6.10 g (4.0 mmol) of the title substance from example 45b, dissolved in 40 ml of absolute dimethylsulfoxide, mixed. After cooling to room temp. will be a reaction solution with 1.82 g (8.8 mmol) of N,N'-dicyclohexylcarbodiimide mixed for 12 hours at room temp. The resulting suspension will be continued with enough acetone until the above-mentioned compound is completely precipitated, mixed, the precipitate removed, dried, dissolved in water, filtered from insoluble dicyclohexyl urinary substances, and the filtrate through an AMICON YM-3 ultra filtration membrane (cut off 3000 Da ) purified from salts and low molecular weight compounds. The retentate will be continuously freeze-dried.

Yield: 9.26 g (84.0% d. Th.; in relation to the diamine components used) as a colorless lyophilizate.

Water content (Karl-Fischer): 5.89%.

Analysis of elements (calculated according to dry substance):

ber.: C 40.52 H 5.16 F 11.72 N 9.15 Gd 11.41 S 1.16

gef.: C 40.57 H 5.20 F 11.67 N 9.12 Gd 11.43 S 1.18

Example 46

6-N-t-butyloxycarbonyl-2-N-benzyloxycarbonyl-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

19.02 g (50.0 mmol) of α-N-(benzyloxycarbonyl)-ε-N'-(tert.butyloxycarbonyl)-1-lysine (commercially available from Bachem) will be dissolved in 150 ml of absolute tetrahydrofuran. Then 8.31 g (50.0 mmol) of carbonyldiimidazole and 5.03 g (50.0 mmol) of triethylamine, dissolved in 75 ml of dry tetrahydrofuran, are added dropwise at 0ºC and left for 10 min. at the same temp. mix. A solution of 48.42 g (50.0 mmol) of perfluorooctylsulfonylpiperazine and 5.03 g (50.0 mmol) of triethylamine in 250 ml of dry tetrahydrofuran is added dropwise under vacuum, and the remaining oil will be chromatographed on Kieselgel (buffer: n- hexane/isopropanol 15:1). 49.48 g (80.4% d.Th., in relation to the sec. amine used) of the title substance in the form of a colorless oil are obtained.

Analysis of elements (calculated according to dry substance):

ber.: C 40.01 H 3.79 F 34.70 N 6.02 S 3.45

gef.: C 40.07 H 3.82 F 34.67 N 6.02 S 3.48

b) 6-N-t-butyloxycarbonyl-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

30.0 g (32.2 mmol) of the title substance from example 46a will be dissolved in 300 ml of isopropanol and mixed with 1.5 g of Pearlamn catalyst (20% palladium hydroxide on charcoal). It is then hydrogenated for 10 hours at room temperature, and after controlling the course of the reaction using thin-layer chromatography, hydrogenolytic cleavage of the benzyloxycarbonyl-protecting group has already occurred quantitatively according to the above-mentioned reaction time. It is then filtered from the catalyst and the filtrate is reduced to dryness under vacuum. The remaining residue is chromatographed on Kieselgel.

(buffer: n-hexane/isopropanol 25:1). 25.13 g (98.0% d.Th.) of the title substance are obtained in the form of a colorless oil.

Analysis of elements:

ber.: C 34.68 H 3.67 F 40.55 N 7.03 S 4.03

gef.: C 34.727 H 3.70 F 40.60 N 7.01 S 3.98

c) 6-N-t-butyloxycarbonyl-2-N-[1-S-α-D-(2-carbonyl)-ethyl-2,3,4,6-tetra-O-acetyl-mannopyranose]-1-lysine- [1-(4-Perfluorooctylsulfonyl)-piperazine]-amide

In 300 ml of dry tetrahydrofuran there will be 15.53 g (35.60 mmol) of 3-(2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranosyl)-propionic acid (preparation according to : J. Haensler et al., Bioconjugate Chem. 4, 85, (1993); Chipowsky, S., and Lee, Y. C. (1973), Synthesis of 1-thio-aldosides; Carbohydrate Research 31, 339-346, as well as 3.60 g (35.60 mmol) of triethylamine dissolved After cooling the reaction solution to -15ºC to -20ºC, a solution of 4.92 g (35.60 mmol) of chloroformic acid isobutyl ester is added dropwise at the same temperature, with stirring into 75 ml of dry tetrahydrofuran slowly, while the rate of addition is chosen so that it does not exceed the internal temperature of -10ºC, after a reaction time of 15 min at -15ºC, one solution of 28.35 g (35.60 mmol) of the title substance from example 42b and 3.60 g (35.60 mmol) of triethylamine, in 200 ml of tetrahydrofuran at 20ºc, slowly. After a reaction time of 1 hour at -15ºC, as well as 2 hours at room temp., there will be reaction solution in vacuum to dryness Reduced And. The remaining residue will be dissolved in 250 ml of ethyl ester of acetic acid and 2x with a saturated solution of sodium hydrogen carbonate, as well as 1x with 200 ml of distilled water. After drying the organic phase over sodium sulfate, the salt will be sucked off, and the remaining ethyl ester of acetic acid will be removed under vacuum. The remaining oily residue will be purified on Kieselgel using acetic acid ethyl ester/n-hexane (1:25) as eluent.

Yield: 34.21 g (79.1 % d.Th.) of the above title substance as a colorless and highly viscous oil.

Analysis of elements:

ber.: C 39.54 H 4.23 F 26.58 N 4.61 S 5.28

gef.: C 39.49 H 4.21 F 26.52 N 4.59 S 5.31

d) 6-N-t-butyloxycarbonyl-2-N-[1-S-α-D-(2-carbonyl)-ethyl-mannopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

29.93 g (24.64 mmol) of the title substance from example 46c will be suspended in 400 ml of absolute methanol and mixed with a catalytic amount of sodium methanolate at 5ºC. After a reaction time of 3 hours at room temp. control by means of thin layer chromatography (eluent: chloroform/methanol 9:1) shows the course of the reaction proceeding in the direction of quantitative translation. For the purpose of processing, the clear reaction solution will be neutralized by mixing it with amberlite IR 120 (H+-form)-resin of the cation exchanger, sucked off from the exchanger, and the resulting methanolic filtrate removed in a vacuum until dry. The resulting amorphous residue will be purified by chromatography on Kieselgel using 2-propanol/ethyl acetate/n-hexane (1:1:15) as eluent.

Yield: 23.42 g (90.8% d.Th.) of a colorless, viscous oil.

Analysis of elements:

ber.: C 36.72 H 4.14 F 30.85 N 5.35 S 6.13

gef.: C 36.69 H 4.11 F 30.82 N 5.35 S 6.11

e) 2-N-[1-S-α-D-(2-carbonyl)-ethyl-mannopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

20.93 g (20.0 mmol) of the title substance from example 46d will be dissolved in a mixture of 50 ml of trifluoroacetic acid and 100 ml of dichloromethane at 0ºC with vigorous stirring and 10 min at the same temp. mixed. It is continuously evaporated in a vacuum until dry, and the residue is dissolved in 150 ml of water. The pH value of that water product will be adjusted to 9.5 by adding a 2 M aqueous solution of sodium lye. The aqueous solution of the product will be freed from salt on an AMICON YM3 ultrafiltration membrane (cut off 3000 Da) and, at the same time, purified from possible low molecular weight compounds. The retentate will be continuously freeze-dried.

Yield: 17.79 g (94.2% d.Th.) of free amine as a colorless lyophilisate.

Water content (Karl-Fischer): 3.09%.

Analysis of elements (calculated before dry substance):

ber.: C 34.26 H 3.73 F 34.12 N 5.92 S 6.77

gef.: C 34.26 H 3.79 F 34.07 N 5.88 S 6.80

f) 2-N-[1-S-α-D-(2-carbonyl)-ethyl-mannopyranose]-6-N-[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4 -oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10-tetraazacyclododecane]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

5.54 g (8.8 mmol, 2.2 mol-equivalents in relation to the used amine components from example 46e)) in patent application DE 197 28 954 c1 in example 31h of the described Gd-complex 10-(4-carboxy-1- methyl-2-oxo-3-azabutyl)-1,4,7-tetraazacyclododecane-1,4,7-triacetic acid and 0.37 of dry lithium chloride (8.8 mmol) will be at 40ºC in 60 ml of absolute dimethylsulfoxide zu mixing dissolved and at full temp. with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.78 g (4.0 mmol) of the title substance from example 46e, dissolved in 40 ml of absolute dimethylsulfoxide, mixed. After cooling to room temp. will be a reaction solution with 1.82 g (8.8 mmol) of N,N'-dicyclohexylcarbodiimide mixed and 12 hours at room temp. mixed. The resulting suspension will be continuously mixed with enough acetone until the above-mentioned title substance is completely precipitated, the precipitate is suctioned off, dissolved in water, filtered from insoluble dicyclohexyl urinary substances, and the filtrate through an AMICON YM3 ultrafiltration membrane (cut off 3000 Da) is freed from salt and low molecular weight compounds purified. The retentate should not be continuously freeze-dried.

Yield: 5.17 g (83.0 % d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 4.43%.

Analysis of elements (calculated before dry substance):

ber.: C 35.45 H 4.07 F 20.72 N 8.09 Gd 10.09 S 4.11

gef.: C 35.50 H 4.01 F 20.6 N 8.12 Gd 10.13 S 4.14

Example 47

a) 6-N-benzyloxycarbonyl-2-N-(1-O-β-D-carbonylmethyl-2,3,4,6-tetra-O-benzylglucopyranose)-1-lysine-[1-(4-perfluorooctylsulfonyl) -piperazine]-amide

8.02 g (13.4 mmol) in patent application DE 197 28 954 C1 from example 46a of the described title compound (1-carboxymethyloxy-2,3,4,6-tetra-O-benzyl-β-D-glucopyranoside) and 3.24 g (28.14 mmol) of N-hydroxysuccinimide will be dissolved in 100 ml of dimethylformamide and mixed at 0ºC with a total of 5.80 g (28.14 mmol) of N,N'-dicyclohexylcarbodiimide in smaller quantities. Then for 3 hours at the same temperature. mixes. The thus obtained active ester solution is added dropwise to a solution of 11.13 g (13.4 mmol) of the title substance from example 21c, cooled to 0ºC, dissolved in 50 ml of dimethylformamide, and stirred for 2 hours at 0ºC and 12 hours at room temperature. temp. For processing, the precipitated dicyclohexyl urine substance is filtered off and the solvent is continuously "extracted" until dry. The residue thus obtained will be continuously chromatographed on Kieselgel (buffer: dichloromethane/ethanol, 20:1; the performance of the chromatography follows the application of a solvent gradient with a continuous increase in the ethanol content).

Yield: 12.67 g (67.0 % d.Th.) of the title substance in the form of a colorless and highly viscous oil.

Analysis of elements:

ber.: C 52.77 H 4.50 F 22.89 N 3.97 S 2.27

gef.: C 52.75 H 4.61 F 22.94 N 3.98 S 2.26

b) 2-N-(1-O-β-D-carbonylmethyl-glucopyranose)-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

11.52 g (8.17 mmol) of the compound prepared in example 47a will be dissolved in 100 ml of ethanol, mixed with 0.5 g of Pearlman catalyst (Pd 20%, C) and kept at room temperature for a long time. in an atmosphere saturated with hydrogen (1 atm) hydrated, until hydrogen absorption no longer takes place. Then the catalyst is sucked off, washed thoroughly with ethanol (3x with 40 ml each) and reduced to dryness in a vacuum. The title substance will be obtained as a viscous and colorless oil.

Usability: 7.36 g (98.4 % d.Th.)

Analysis of elements:

ber.: C 34.07 H 3.63 F 35.24 N 6.11 S 3.50

gef.: C 34.11 H 3.50 F 35.23 N 6.08 S 3.52

c) 2-N-(1-O-β-D-carbonylmethyl-glucopyranose)-6-N-[1,4,7-tris(carboxylatomethyl)-10-(aza-4-oxo-5-methyl-5 -yl-pentanoyl)-1,4,7,10-tetraazacyclododecane]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

9.98 g ((15.84 mmol; 2.2 mol-equivalents in relation to the used amine component from example 47b)) in patent application DE 197 28 954 C1 in example 31h of the described Gd-complex 10-(4-carboxy- 1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.67 g (15.84 mmol) of dry lithium chloride will be at 40ºC in 80 ml of absolute dimethylsulfoxide was dissolved and mixed at the same temperature. with a total of 1.82 g (15.84 mmol) of N-hydroxysuccinimide and 7.25 g (7.19 mmol) of the title substance from example 47b, dissolved in 30 ml of absolute dimethylsulfoxide, mixed. After cooling to room temp. will be a reaction solution with 3.27 g (15.84 mmol) of N,N'-dicyclohexylcarbodiimide mixed and 12 hours at room temp. mixed. The obtained suspension will be continuously mixed with enough acetone until the above-mentioned title substance is completely precipitated, the precipitate is suctioned off, dissolved in water, the insoluble dicyclohexyl urea substance is filtered, and the filtrate is purified through an AMICON YM3 ultrafiltration membrane. The retentate will be continuously freeze-dried.

Yield: 9.11 g (83.0 % d.Th.) as a colorless lyophilizate.

Water content (according to Karl-Fischer): 4.02 %

Analysis of elements (calculated according to dry substance):

ber.: C 35.37 H 4.02 F 21.13 N 8.25 S 2.10 Gd 10.29

gef.: C 35.42 H 4.07 F 21.09 N 8.18 S 2.06 Gd 10.34

Example 48

a) 2-N-trifluoroacetyl-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

10.0 g (11.46 mmol) of the compound prepared in example 21b will be dissolved in 100 ml of ethanol, mixed with 1.0 g of Pearlman catalyst (Pd 20%, C) and hydrated until the end of quantitative hydrogen absorption. Then the catalyst is removed, washed with ethanol and reduced to dryness under vacuum. The title substance is obtained as a thick, colorless oil.

Usability: 8.85 g (97.5 % d.Th.)

Analysis of elements:

ber.: C 30.31 H 2.54 F 47.95 N 7.07 S 4.05

gef.: C 30.36 H 2.50 F 47.99 N 7.11 S 4.00

b) 2-N-trifluoroacetyl-6-N-[1-O-α-D-(5-carbonyl)-pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose)-1-lysine- [1-(4-Perfluorooctylsulfonyl)-piperazine]-amide

A solution of 27.51 g (36 .6 mmol) of the title substance from example 37c in 150 ml of dimethylformamide. After the addition is complete, it is stirred for another 1 hour at 0ºC and then overnight at room temperature. It is then reduced in a vacuum and the residue is dissolved in 300 ml of acetic acid ethyl ester. The remaining insoluble parts are filtered off, the afiltrate is washed twice with 100 ml of aqueous soda solution. The organic phase will be dried over magnesium sulfate and reduced to dryness in a vacuum. The residue will be chromatographed on Kieselgel (buffer: n-hexane/isopropanol 25:1). 42.05 g (80.4% d.Th.) of the title substance is obtained in the form of a colorless oil.

Analysis of elements:

ber.: C 50.42 H 4.51 F 26.59 N 7.96 S 2.24

gef.: C 50.38 H 4.50 F 26.62 N 7.91 S 2.20

c) 6-N-[1-O-α-D-(5-carbonyl)-pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose)-1-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide

20.0 g (14.0 mmol) of the compound prepared in example 48b will be dissolved in 150 ml of ethanol. Then a solution of 2.8 g (70.0 mmol) of sodium hydroxide in 25 ml of dest. of water and stir for 0.5 hours at 50ºC. after chromatography on a thin layer, the detachment of protective groups already quantitatively followed at that moment. Everything is reduced to dryness in a vacuum, traces of water are removed by multiple co-distillation with ethanol. The residue will be chromatographed on Kieselgel (buffer: n-hexane/isopropanol 20:1). 16.66 g (89.3% d.Th.) of the title substance are obtained in the form of a colorless oil.

Analysis of elements:

ber.: C 52.25 H 4.91 F 24.22 N 4.20 S 2.41

gef.: C 52.30 H 4.90 F 24.22 N 4.18 S 2.38

d) 6-N-[1-O-α-D-(5-carbonyl)-pentyl-mannopyranose)-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

In 150 ml of a 10:1 mixture of ethanol and water, 15.0 g (11.25 mmol) of the compound prepared in example 48c will be dissolved and mixed with 1.0 g of Pearlman catalyst (Pd 20% / C). It will continue until the quantitative uptake of hydrogen at room temperature. and under 1 atm hydrogen pressure, hydrated. Then the catalyst is sucked off, washed with ethanol/water (10:1) and reduced to dryness under vacuum. The title substance is obtained as a thick and colorless oil.

Yield: 10.77 g (98.4 % d.Th.)

Analysis of elements:

ber.: C 37.04 H 4.25 F 33.20 N 5.76 S 3.30

gef.: C 37.06 H 4.20 F 33.19 N 5.81 S 3.30

e) 6-N-(1-O-α-D-(5-carbonyl)-pentyl-mannopyranose)-2-N-[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4 -oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10-tetraazacyclododecane]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

5.54 g ((8.8 mmol; 2.2 mol-equivalents in relation to the used amine component from example 48b)) in patent application DE 197 28 954 C1 in example 31h of the described Gd-complex 10-(4-carboxy- 1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.37 g (8.8 mmol) of dry lithium chloride will be at 40ºC in 60 ml of absolute dimethylsulfoxide was dissolved and mixed at the same temperature. with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.89 g (4.0 mmol) of the title substance from example 48d, dissolved in 60 ml of absolute dimethylsulfoxide, mixed. After cooling to room temp. will be a reaction solution with 1.82 g (8.8 mmol) of N,N'-dicyclohexylcarbodiimide mixed and 12 hours at room temp. mixed. The resulting suspension will be continuously mixed with enough acetone until the above title substance is completely precipitated, the precipitate is suctioned off, dissolved in water, the insoluble dicyclohexyl urea substance is filtered, and the filtrate is purified through an AMICON YM3 ultrafiltration membrane (cut off 3000 Da). The retentate will be continuously freeze-dried.

Yield: 4.81 g (75.9% d.Th.) as a colorless lyophilizate.

Water content (according to Karl-Fischer): 8.98 %

Analysis of elements (calculated according to dry substance):

ber.: C 37.15 H 4.39 F 20.38 N 7.96 S 2.02 Gd 9.92

gef.: C 37.27 H 4.40 F 20.31 N 8.02 S 1.98 Gd 10.00

Example 49

a) 1,7-bi-(benzyloxycarbonyl)-4-(1-O-β-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-galactopyranose)-10-{3-oxa-pentane -1,5-dicarboxylic acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-1,4,7,10-tetraazacyclododecane

In one solution from 27.0 g (24.4 mmol) in example 35a prepared sec. The amine, in a mixture of 150 ml of tetrahydrofuran in 15 ml of chloroform, will be at 0ºC and in an atmosphere saturated with nitrogen, 35.80 g (25.0 mmol) of the title substance from Example 37e, dissolved in 250 ml of tetrahydrofuran, is added. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is continuously added at 0ºC in smaller amounts and left overnight at room temperature. mix. It is then reduced to dryness in a vacuum, and the remaining oil is chromatographed on Kieselgel (Buffer: n-hexane/isopropanol 20:1). 32.11 g (78.0% d.Th., relative to the sec. amine used) of the title substance are obtained in the form of a colorless oil.

Analysis of elements:

ber.: C 54.09 H 4.72 F 19.14 N 4.98 S 1.90

gef.: C 54.12 H 4.77 F 19.17 N 5.03 S 1.90

b) 1-(1-O-β-D-carbonylmethyl-galactopyranose)-7-{3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4-

perfluorooctylsulfonyl)-piperazine]-amide}-1,4,7,10-tetraazacyclododecane

30.0 g (17.77 mmol) of the title compound prepared in example 49a will be dissolved in 250 ml of ethanol and mixed with 3.0 g of Pearlman catalyst (Pd 20%, C). Hydrogenation is carried out until quantitative absorption of hydrogen, the catalyst is then removed, the residue is washed well with ethanol and reduced to dryness in a vacuum. The product is obtained as a yellowish colored and extremely viscous oil.

Yield: 17.89 g (95.1 % d.Th.)

Analysis of elements:

ber.: C 36.30 H 4.09 F 30.50 N 7.94 S 3.03

gef.: C 36.26 H 4.12 F 30.46 N 7.90 S 3.04

c) 1-(1-O-β-D-carbonylmethyl-galactopyranose)-7-{3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4-

perfluorooctylsulfonyl)-piperazin]-amide}-4,10-bi[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)-1, 4,7,10-tetraazacyclododecane]-1,4,7,10-tetraazacyclododecane, di-Gd-complex

5.54 g ((8.8 mmol; 2.2 mol-equivalents in relation to the used amine component from example 49b)) in patent application DE 197 28 954 C1 in example 31h of the described Gd-complex 10-(4-carboxy- 1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.37 g (8.8 mmol) of dry lithium chloride will be at 40ºC in 60 ml of absolute dimethylsulfoxide was dissolved and mixed at the same temperature. with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 2.11 g (2.0 mmol) of the title substance from example 49b, dissolved in 25 ml of absolute dimethylsulfoxide, mixed. After cooling to room temp. will be a reaction solution with 1.82 g (8.8 mmol) of N,N'-dicyclohexylcarbodiimide mixed and 12 hours at room temp. mixed. The resulting suspension will be continuously mixed with enough acetone until the above title substance is completely precipitated, the precipitate is suctioned off, dissolved in water, the insoluble dicyclohexyl urea substance is filtered, and the filtrate is purified through an AMICON YM3 ultrafiltration membrane (cut off 3000 Da). The retentate will be continuously freeze-dried.

Yield: 3.29 g (72.2% d.Th., in relation to the amino component used) as a colorless lyophilizate.

Water content (according to Karl-Fischer): 5.99 %

Analysis of elements (calculated according to dry substance):

ber.: C 36.84 H 4.37 F 14.15 N 9.82 S 1.40 Gd 19.63

gef.: C 36.87 H 4.40 F 14.09 N 9.82 S 1.38 Gd 19.59

Example 50

a) 3-(1-O-α-D-2,3,4,6-tetra-O-benzyl-mannopyranose)-2-N-benzyloxycarbonyl-1-lysine-serine-methylester

In 500 ml of dry acetonitrile there will be 21.42 g (39.61 mmol) of 2,3,4,6-tetra-O-benzyl-α-D-mannopyranose (preparation according to: F. Kong et al., J. Carbohydr .Chem.;16;6;1997;877-890) dissolved. After cooling the reaction solution to 5ºC, it is added at that temperature. under slow stirring a solution of 13.23 g (59.52 mmol) of trimethylsilyl ester of trifluoromethane sulfonic acid in 30 ml of acetonitrile, followed by a solution of 20.06 g (79.21 mmol) of N-benzyloxycarbonyl-1-serine methyl ester ( commercially available from the company Bachem) in 50 acetonitrile, whereby the rate of addition is chosen so that the internal temp. is not exceeded. from 10ºC. After a reaction time of 15 hours at room temperature, the reaction solution will be reduced to dryness in a vacuum. The remaining residue will be washed in 250 ml of ethyl ester of acetic acid and 2x with 100 ml of saturated sodium hydrogen carbonate solution, as well as 1x with 200 ml of water. After drying org. phase over sodium sulfate, it will be freed from the salt, and the remaining ethyl ester of acetic acid will be removed in a vacuum.

The remaining oily residue will be purified on Kieselgel using acetic acid ethyl ester / n-hexane (1:5) as eluent.

Yield: 23.60 g (76.8 % d.Th.) of the above title substance as a colorless oil.

Analysis of elements:

ber.: C 71.21 H 6.37 N 1.81

gef.: C 71.19 H 6.41 N 1.79

b) 3-(1-O-α-D-2,3,4,6-tetra-O-benzyl-mannopyranose)-2-N-benzyloxycarbonyl-1-lysine-serine-methylester

In a mixture of 20 ml of methanol, 20 ml of water and 50 ml of tetrahydrofuran, 10.0 g (12.90 mmol) of the compound prepared in example 50a will be dissolved. Then, 0.47 g (19.35 mmol) of lithium hydroxide, dissolved in 25 ml of dest. water, at room temp. and stirred continuously for 6 hours at 60ºC. After controlling the course of the reaction, by means of TL-chromatography (buffer: methyl chloride/methanol 10:1), the saponification of the methyl ester from example 30a according to the above-mentioned reaction time already followed quantitatively. For the purpose of finishing, the product solution is reduced to dryness in a vacuum, and the remaining residue is added to 250 ml of ethyl acetic acid at heat (at 60ºC). Subsequently, the acetic acid ethyl ester phase thus obtained is washed twice with 50 ml of 15% aqueous solution, as well as once with 100 ml of dest. water. Org. the phase is dried over magnesium sulfate, filtered under vacuum and evaporated to dryness. The residue is chromatographed on Kieselgel (buffer: n-hexane/ethyl acetate 5:1). 8.40 g (85.7% d.Th.) of the title substance are obtained in the form of a colorless oil.

Analysis of elements:

ber.: C 70.94 H 6.22 N 1.84

gef.: C 70.97 H 6.30 N 1.78

c) 3-(1-O-α-D-2,3,4,6-tetra-O-benzyl-mannopyranose)-2-N-benzyloxycarbonyl-1-serine-[1-(4-perfluorooctylsulfonyl)piperazine] -amide

K 13.86 g (24.40 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 196 03 033), dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, will be at 0ºC and an atmosphere saturated with nitrogen 20.57 g (27 .0 mmol) of carboxylic acid prepared according to example 50b, dissolved in 50 ml of tetrahydrofuran, added dropwise. A total of 18.0 g (36.60 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is continuously added at 0ºC in smaller amounts and left overnight at room temperature. mix. For the purpose of refinement, the reaction solution is reduced in a vacuum and the remaining, extremely viscous oil is chromatographed on Kieselgel, using an n-hexane/isopropanol (15:1) mixture as an eluent system. 17.0 g (79.6% d.Th., in relation to the used prim. Amine) of the title substance are obtained in the form of a colorless viscous oil.

Analysis of elements:

ber.: C 51.53 H 4.23 N 3.15 F 25.65 S 2.41

gef.: C 51.48 H 4.27 N 3.10 F 25.71 S 2.35

d) 3-(1-O-α-D-mannopyranose)-1-serine-[1-(4-perfluorooctylsulfonyl)piperazine]-amide

15.0 g (11.41 mmol) of the prepared compound in example 50c will be dissolved in 200 ml of ethanol and mixed with 1.5 g of Pearlman catalyst (Pd 20%, C). It will continue to be a reaction solution for so long at room temperature. hydrated in an atmosphere saturated with hydrogen (1 atm), until there is no more hydrogen absorption (ca. 8 hours). For the purpose of finishing, the catalyst is sucked off, washed thoroughly with ethanol (2x with 100 ml each) and the ethanol filtrate containing the product is reduced to dryness in a vacuum. The title substance is obtained as a highly viscous and colorless oil.

Usability: 8.79 g (94.0 % d.Th.)

Analysis of elements:

ber.: C 30.78 H 3.20 N 5.13 F 39.41 S 3.91

gef.: C 30.87 H 3.14 N 5.19 F 39.50 S 3.88

e) 3-(1-O-α-D-mannopyranose)-2-N-[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl) -pentanoyl)-1,4,7,10-tetraazacyclododecane]-1-serine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

One mixed suspension from 5.7 g (9.06 mmol; corresponding to 1.5 mol-equivalents in relation to the used title substance (primary amine) from example 50d) in patent application DE 197 28 954 C1 in example 31h) of the described Gd -complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid in 75 ml of absolute dimethylsulfoxide will be at 70ºC with 0.68 g (15.9 mmol) of lithium chloride mixed. After 30 min. after stirring at 70ºC, there will be a clear reaction solution in smaller amounts with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide mixed, and the reaction mixture kept for another 1 hour at 70ºC. After cooling the reaction solution to 10ºC, it will be mixed with 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide, and the reaction solution will be stirred for another 1 hour at 0ºC, then 12 hours at 22ºC. The thus obtained solution of N-hydroxysuccinimide ester of Gd-complex 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid will be at 22ºC by adding dropwise a solution of 4.94 g (6.03 mmol) of the title substance from example 30d, in 15 ml of absolute dimethylsulfoxide, mixed for a further 12 hours at room temp. mixed. For processing, the reaction solution at 22ºC will be slowly added dropwise to a solution mixture consisting of 250 ml of acetone and 250 ml of 2-propanol, whereby the title substance will completely precipitate as a light yellow colored oil after 12 hours at 10ºC. It is decanted from the remaining solvent mixture and the oily product is mixed in 200 ml of dest. of water, whereby it completely dissolves, so that a yellowish-colored aqueous solution of the above-mentioned title substance is obtained. In the following, the aqueous solution of the product will first be filtered through a membrane filter, and then, for the purpose of removing salt and separating low molecular weight compounds, through a YM3 ultrafiltration membrane (AMICON; cut off: 3000 Da) 3 times ultrafiltered. The retentate thus obtained will be continuously freeze-dried.

Yield: 8.63 g (80.2 % d.Th., in relation to the used title substance from example 30d) as a colorless lyophilizate with a water content of 7.65 %.

Analysis of elements (in relation to dry substance):

ber.: C 33.57 H 3.80 N 7.83 F 22.57 Gd 10.99 S 2.24

gef.: C 33.57 H 3.76 N 7.82 F 22.63 Gd 11.06 S 2.18

Example 51

a) 6-N-benzyloxycarbonyl-2-N-[0-β-D-galactopyranose(1→4)-gluconosyl]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

A mixed suspension of 4.89 g (6.0 mmol) of the title substance from Example 21c in 40 ml of absolute dimethylsulfoxide will be at room temp. one solution from 13.3 g (37.2 mmol) O-β-D-galactopyranosyl-(1→4)-D-glucono-1,5-lactone (lactobionalcone; prepared according to: (a) Williams, T.J.; Plessas , N.R., Goldstein, I.J. Carbohydr. Res. 1978, 67, Cl.(b) Kobayashi, K.: Sumitomo, H.; Ina, Y. Polym. J. 1985, 17, 567, (c) Hiromi Kitano, Katsuko Sohda and Ayako Kosaka, Bioconjugate Chem., 1995, 6 131-134) in 40 ml of absolute dimethylsulfoxide, adding adiran dropwise. The resulting reaction solution will be continuously stirred for 14 hours at 40ºC. It will be at room temperature for finishing. mixed with 500 ml of absolute 2-propanol, and the resulting colorless precipitate was sucked off using a G4 frit and washed well with a total of 250 ml of absolute 2-propanol. The solid obtained in this way will be in 300 ml dest. of dissolved water and through a YM3- ultrafiltration membr. (AMICON; cut off: 3000 Da) total 3x ultrafiltered. Through triple ultrafiltration, excessive lactobionolactone as well as possibly still present low molecular weight parts will be separated from the desired product. In the ultrafiltration membrane, the remaining residue will be completely in 300 ml dest. dissolved in water and freeze-dried.

Yield: 6.51 g (92.7% d.Th.) as a colorless lyophilizate

Water content: 10.03%

Analysis of elements (in relation to dry substance):

ber.: C 38.98 H 4.05 N 4.79 F 27.58 S 2.74

gef.: C 39.04 H 4.09 N 4.82 F 27.61 S 2.71

b) 2-N-[O-β-D-galactopyranosyl(1→4)-gluconosyl]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

5.0 g (4.27 mmol) of the compound prepared in example 51a will be dissolved in 100 ml of ethanol, mixed with 0.5 g of Pearlman catalyst (Pd 20%, C) and hydrated by quantitative hydrogen absorption at 1 atm of hydrogen pressure. It is then filtered off the catalyst, washed with ethanol and reduced to dryness under vacuum. The title substance will be obtained as a colorless, viscous oil.

Usability: 4.36 g (98.5 % d.Th.)

Analysis of elements:

ber.: C 34.76 H 3.99 N 5.40 F 31.50 S 3.09

gef.: C 34.78 H 4.04 N 5.34 F 31.51 S 3.15

c) 2-N-[O-β-D-galactopyranosyl(1→4)-gluconosyl]-6-N-[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo- 5-methyl-5-yl-pentanoyl)-1,4,7,10-tetraazacyclododecane]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

5.54 g ((8.8 mmol; 2.2 mol-equivalents in relation to the used amine component from example 51b)) in patent application DE 197 28 954 C1 in example 31h of the described Gd-complex 10-(4-carboxy- 1-methyl-2-oxo-3-azabutyl)-1,4,7-tetraazacyclododecane-1,4,7-triacetic acid and 0.37 g (8.8 mmol) of dry lithium chloride will be at 40ºC in 60 ml of absolute dimethylsulfoxide zu mixing dissolved and at the same temp. with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.85 g (4.0 mmol) of the title substance from example 31Ab, dissolved in 60 ml of absolute dimethylsulfoxide, mixed. After cooling to room temp. will be a reaction solution with 1.82 g (8.8 mmol) of N,N'-dicyclohexylcarbodiimide mixed and 12 hours at room temp. mixed. The resulting suspension will be continuously mixed with enough acetone/2-propanol (1:1) until the above-mentioned title substance is completely precipitated, and the precipitate is suctioned off. The precipitate thus obtained will be continuously dissolved in 300 ml of water and the insoluble dicyclohexyl urinary substance will be filtered. The filtrate will be purified through an AMICON YM3 ultrafiltration membrane (cut off 3000 Da). Triple purification on ultrafiltration will separate the excessive Gd-complex, as well as possibly still present, low-molecular compounds from the desired product. In the ultrafiltration membrane, the remaining residues will continue to be completely in 500 ml dest. water thawed and freeze-dried.

Yield: 4.64 g (70.4% d.Th.) as a colorless lyophilizate.

Water content (according to Karl-Fischer): 10.08 %

Analysis of elements (calculated according to dry substance):

ber.: C 35.70 H 4.22 F 19.59 N 7.65 S 1.95 Gd 9.54

gef.: C 35.77 H 4.17 F 19.61 N 7.71 S 1.99 Gd 9.60

Example 52

2-N-trifluoroacetyl-6-N-benzyloxycarbonyl-lysine

100 g (356.7 mmol) of 6-N-benzyloxycarbonyl-lysine will be dissolved in a mixture of 1000 ml of acetic acid ethyl ester / 500 ml of ethanol and left at room temperature for 24 hours. mixed. It is then evaporated to dryness and the residue crystallized from diisopropyl ether.

Yield: 128.9 g (96% according to theory) of a colorless crystalline powder.

Analysis of elements:

ber.: C 51.07 H 5.09 F 15.14 N 7.44

gef.: C 51.25 H 5.18 F 15.03 N 7.58

b) 2-N-trifluoroacetyl-6-N-benzyloxycarbonyl-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

K 125 g (332 mmol) of the title substance from example 52a and 188.7 g (332 mmol) of 1-perfluorooctylsulfonyl-piperazine, (prepared according to DE 19603033) in 800 ml of tetrahydrofuran, are added at 0ºC, 164.2 g (0.664 mmol) ) EEDQ (2-ethoxy-1,2-dihydroquinoline-1-ethyl ester of carboxylic acid) and stirred overnight at room temperature. It is then evaporated to dryness in a vacuum and chromatographed on Kieselgel (buffer: dichloromethane/methanol 20:1).

Yield: 286 g (93% of theory) of a colorless solid.

Analysis of elements:

ber.: C 36.30 H 2.83 F 41.01 N 6.05 S 3.46

gef.: C 36.18 H 2.94 F 40.87 N 5.98 S 3.40

c) 6-N-benzyloxycarbonyl-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

Into a solution of 280 g (302.2 mmol) of the title substance from example 52b and 2000 ml of ethanol, is introduced at temp. from 0ºC for 1 hour ammonia gas. Then it is continuously stirred for 4 hours at 0ºC. Then it is evaporated to dryness and the rest is mixed in water. The solid substance is filtered off and dried in a vacuum (50ºC).

Yield: 243.5 g (97% of theory) of an amorphous solid.

Analysis of elements:

ber.: C 37.60 H 3.28 F 38.89 N 6.75 S 3.86

gef.: C 37.15 H 3.33 F 38.78 N 6.68 S 3.81

d) 6-N-benzyloxycarbonyl-2-N-(3,6,9,12,15-pentaoxahexadecanoyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

To 50 g (60.20 mmol) of the title substance from example 52c and 7.10 g (70 mmol) of triethylamine, dissolved in 350 ml of dichloromethane, a solution of 19.93 g (70 mmol) 3,6,9 is added dropwise at 0ºC. ,12,15-pentaoxa-chloride of hexadecanoic acid (prepared according to Liebigs Ann. Chem. (1980), (6), 852-62) in 50 ml of dichloromethane and stirred for 3 hours at 0ºC. Then 200 ml of 5% aqueous hydrochloric acid solution is added and mixed for 5 min. at room temp. Org. the phase is separated, dried over magnesium sulfate in a vacuum until it is evaporated to dryness. The residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone 15:1)

Yield: 53.7 g (93% according to theory) of colorless, thick oil.

Analysis of elements:

ber.: C 33.83 H 4.94 F 3.34 N 5.84 S 33.69

gef.: C 33.75 H 5.05 F 3.29 N 5.78 S 33.75

e) 2-N-(3,6,9,12,15-pentaoxahexadecanoyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

50 g (52.15 mmol) of the title substance from example 52d will be dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd/C) will be added. It is then hydrated at room temperature. The catalyst is filtered off and evaporated to dryness under vacuum.

Yield: 43.0 g (quantitative) of a colorless solid.

Analysis of elements:

ber.: C 27.68 H 5.01 F 39.17 N 6.79 S 3.89

gef.: C 27.60 H 5.13 F 39.09 N 6.68 S 3.81

f) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -2-N-(3,6,9,12,15-pentaoxahexadecanoyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

20 g (824.25 mmol) of the title substance from example 52e, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1, 4,7-tris(carboxylatomethyl)-10-[3-aza-4-oxo-5-methyl-5-yl)]-pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd-complex, will be zu gentle heating in 200 ml of dimethylsulfoxide dissolved. At 10ºC, 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide are added and stirred continuously overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 28.21 g (81% of theory) of a colorless solid.

Water content: 11.0%

Analysis of elements (calculated according to dry substance)

ber.: C 31.78 H 4.84 F 22.49 N 8.78 S 2.23 Gd 10.95

gef.: C 31.74 H 4.98 F 22.39 N 8.69 S 2.15 Gd 10.87

Example 53

a) 6-N-[3,9-bi(t-butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid bi(t-butylester)-6-carbonylmethyl]-2-N-[3,6 ,9,12,15-pentaoxahexadecanoyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

To a solution of 20 g (24.08 mmol) of the title substance from example 52e, 14.88 g (24.08 mmol) of 3,9-bi(t-butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11 -dicarboxylic acid bi (t butyl ester) and 2.77 g (24.08 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide, are added at 0ºC, 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide. It is mixed for 3 hours at 0ºC, then overnight at room temperature. It is then filtered from the precipitated substance, evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/ethanol 20:1).

Yield: 31.61 g (91% according to theory) of one thick oil.

Analysis of elements:

ber.: C 40.80 H 6.71 F 22.39 N 6.80 S 2.22

gef.: C 40.72 H 6.82 F 22.30 N 6.75 S 2.14

b) 6-N-[6-carbonylmethyl-3,9-bi(carboxylatomethyl)-3,6,9-triazaundecandicarboxylic acid-1-carboxy-11-

carboxylato]-2-N-[3,6,9,12,15-pentaoxahexadecanoyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-

complex, sodium salt

30 g (20.8 mmol) of the title substance from example 53a will be dissolved in 300 ml of trifluoroacetic acid and left for 5 hours at room temperature. mixed. Then it is evaporated to dryness, the residue is dissolved in 300 ml of water and the pH is adjusted to 2.5 with 10% aqueous NaOH. 3.77 g (10.4 mmol) of gadolinium oxide was continuously added and stirred for 3 hours at 60ºC. Let the solution come to room temperature. and adjusted with caustic soda to a pH of 7.4. It is then evaporated to dryness, and the residue is purified on Kieselgel RP-18 (buffer: water/acetonitrile gradient).

Yield: 19.18 g (67% of theory as a colorless, amorphous solid).

Water content: 9.8%

Analysis of elements (calculated according to dry substance):

ber.: C 28.80 H 4.25 F 23.47 N 7.12 S 2.33 Gd 11.48 Na 1.67

gef.: C 28.67 H 4.34 F 23.38 N 7.03 S 2.27 Gd 11.37 Na 1.74

Example 54

a) Lysine-[1-(4-perfluorooctylsulfonyl-piperazine]-amide).

20 g (24.08 mmol) of the title substance from example 52c will be dissolved in 300 ml of ethanol and 4 g of palladium catalyst (10% Pd/C) will be added. It hydrates at room temperature. The catalyst is filtered off, and the filtrate is reduced to dryness under vacuum.

Yield: 16.77 g (quantitative) solid.

Analysis of elements:

ber.: C 31.04 H 3.04 F 46.38 N 8.04 S 4.60

gef.: C 30.97 H 3.15 F 46.31 N 7.98 S 4.51

b) 2,6-N,N-bi[1,4,7-tris(carboxylatomethyl-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5 -yl)]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex (metal complex XVI)

10 g (14.36 mmol) of the title substance from example 54a, 3.34 g (29 mmol) of N-hydroxysuccinimide, 2.54 g (mmol) of lithium chloride and 18.26 g (29 mmol) of 1,4,7- tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl)-1,4,7,10-tetraazacyclododecane-Gd-complex will be zu gently heated in 200 ml of dimethylsulfoxide dissolved. At 10ºC, 12.38 g (60 mmol) of N,N-dicyclohexylcarbodiimide are added and stirred continuously overnight at room temperature. Then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated solid will be filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 19.02 g (69% of theory) of a colorless solid.

Water content: 11.3%

Analysis of elements (calculated according to solid matter):

ber.: C 35.03 H 4.04 F 16.82 N 10.21 S 1.67 Gd 16.38

gef.: C 34.96 H 4.13 F 16.74 N 10.16 S 1.61 Gd 16.33

Example 55

a) 2-[4-(3-ethyl ester of oxapropionic acid)]-methyl ester of phenyl acetic acid

To 200 g (1.204 mol) of 4-methyl ester of hydroxy phenyl acetic acid, 212 g (2 mol) of sodium carbonate in 2000 ml of acetone, add 233.8 g (1.4 mol) of 2-ethyl ester-bromoacetic acid and it is boiled for 5 hours on the return cooler. The solid is then filtered off and reduced to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: n-hexane/ethyl acetate = 15:1).

Yield: 288.5 g (95% according to theory) of colorless oil.

Analysis of elements:

ber.: C 61.90 H 6.39

gef.: C 61.75 H 6.51

b) 2-[4-(3-ethyl ester of oxapropionic acid)]-phenyl-2-methyl ester bromoacetic acid

To 285 g (1.13 mmol) of the title substance from example 55a, dissolved in 2000 ml of carbon tetrachloride, 201 g (1.13 mol) of N-bromosuccinimide and 100 mg of dibenzyl peroxide are added and boiled for 8 hours at reflux. It is then cooled in an ice bath, the precipitated succinimide is filtered and the filtrate is reduced to dryness under vacuum. The residue will be purified on Kieselgel (buffer: n-hexane/acetone 15:1).

Yield: 359.2 g (96% according to theory) of colorless, thick oil.

Analysis of elements:

ber.: C 47.28 H 4.57 Br 24.16

gef.: C 47.19 H 4.71 Br 24.05

c) 2-[4-(3-ethyl ester of oxapropionic acid)]-phenyl-2-[1-(1,4,7,10-tetraazacyclododecan-7-yl]-methyl ester of acetic acid

To 603 g (3.5 mol) of 1,4,7,10-tetraazacyclododecane in 6000 ml of chloroform is added 350 g (1.057 mol) of the title substance from example 55b and stirred overnight at room temperature. It is then extracted 3x with 3000 ml of water, dried org. phase over magnesium sulfate and reduce in vacuo to dryness. The residue will be used without further processing in the next reaction step (3d).

Usability: 448 g (quantitative) of one thick oil.

Analysis of elements:

ber.: C 59.70 H 8.11 N 13.26

gef.: C 59.58 H 8.20 N 13.18

d) 2-[4-(3-oxapropionic acid)]-phenyl-2-[1-(1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-10-yl]-octene) acid

445 g (1.053 mol) of the title substance from example 55c and 496 g (5.27 mol) of chloroacetic acid will be dissolved in 4000 ml of water. Then, using 30% NaOH, the pH-value of the solution is adjusted to 10. The solution is heated to 70ºC and the pH-value is maintained by adding 30% NaOH to pH 10. The solution is stirred for 8 hours at 70ºC. Then the pH is adjusted to 13 and boiled for 13 min. on the return cooler. The solution is cooled in an ice bath and with the addition of conc. of hydrochloric acid, the pH is lowered to 1. It is then evaporated to dryness under vacuum. The residue is dissolved in 4000 ml of methanol and left at room temperature for 1 hour. mixes. It is then filtered from the precipitated table salt, the filtrate is evaporated to dryness, and the residue is chromatographed on Kieselgel RP-18 (buffer: water/ethanol/acetonitrile gradient).

Yield: 403 g (69% of theory) of a colorless solid.

Water content: 10.2%

Analysis of elements (calculated according to dry substance):

ber.: C 51.98 H 6.18 N 10.10

gef.: C 51.80 H 6.31 N 10.01

e) 2-[4-(3-oxapropionic acid)]-phenyl-2-[1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-10-yl]-acetic acid, Gd -complex

To 400 g (721.3 mmol) of the title substance from example 55d in 2000 ml of water, 130.73 g (360.65 mmol) of gadolinium oxide is added and stirred for 5 hours at 80ºc. The solution is filtered, the afiltrate is freeze-dried.

Yield: 511 g (quantitative) of an amorphous solid.

Water content: 11.0%

Analysis of elements (calculated according to dry matter):

ber.: C 40.67 H 4.41 Gd 22.19 N 7.98

gef.: C 40.51 H 4.52 Gd 22.05 N 8.03

f) 2,6-N,N'-bi-{2-[4-(3-oxapropionyl)-phenyl]-2-[1,4,7-tris(carboxylatomethyl)-1,4,7,10- tetraazacyclododecan-10-yl]-acetic acid]-lysine-[4-perfluoro-octylsulfonyl)-piperazine]-amide, di-Gd-complex, disodium salt

10 g (14.36 mmol) of the title substance from example 54a, 3.45 g (30 mmol) of N-hydroxysuccinimide, 2.54 g (60 mmol) of lithium chloride and 21.26 g (30 mmol) of the title substance from example 4Be will be zu gently heated in 250 ml of dimethylsulfoxide dissolved. At 10ºC, 16.51 g (80 mmol) of N,N-dicyclohexylcarbodiimide are added and stirred overnight at room temperature. The solution is then poured into 2000 ml of acetone and stirred for 10 min. The precipitated solid is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient). It is dissolved in a little water, the pH is adjusted to 7.4 with NaOH and freeze-dried.

Yield: 21.02 g (69% of theory) of a colorless solid.

Water content: 11.2%

Analysis of elements (calculated according to dry substance):

ber.: C 37.36 H 3.66 F 15.22 Gd 14.82 N 7.92 Na 2.17 S 1.51

gef.: C 37.28 H 3.74 F 15.14 Gd 14.75 N 8.03 Na 2.23 S 1.46

Example 56

a) 2,6-N,N'-bi-[6-carboxymethyl-3,9-bi(t.butyloxycarbonylmethyl)3,6,9-triazaundecane-1,11-dicarboxylic acid-bi (t.butyl ester)] -lysine-[1-(4-perfluoro-octylsulfonyl)-piperazine]-amide

To a solution of 10 g (14.36 mmol) of the title substance from example 54a, 18.53 g (30 mmol) of 3,9-bi(t-butyloxycarbonylmethyl)-6-carboxymethyl-3,6,9-triazaundecane-1, 11-dicarboxylic acid-bi(t. butyl ester) and 3.45 g (30 mol) of N-hydroxysuccinimide dissolved in 150 ml of dimethylformamide, 10.32 g (50 mmol) of N,N-dicyclohexylcarbodiimide were added at 0ºC. It is mixed for 3 hours at 0ºC, then overnight at room temperature. Then the precipitated urine substance is filtered, the filtrate is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/ethanol = 20:1)

Yield: 19.60 g (72% according to theory) of one thick oil.

Analysis of elements:

ber.: C 49.41 H 6.75 F 17.03 N 7.39 S 1.69

gef.: C 49.35 H 6.82 F 16.92 N 7.32 S 1.62

b) 2,6-N,N-bi-[6-carbonylmethyl-3,9-bi(carboxylatomethyl)3,6,9-triazaundecanecarboxylic acid-1-carboxy-11-carboxylato-lysine-[1-(4- perfluoro-octylsulfonyl)-piperazine]-amide, Gd-complex, sodium salt

15 g (7.91 mol) of the title substance from example 56a will be dissolved in 50 ml of chloroform and 200 ml of trifluoroacetic acid will be added. Then it is mixed for 10 min at room temperature. It will be evaporated to dryness in a vacuum, and the rest dissolved in 150 ml of water. Then 2.87 g (7.91 mmol) of gadolinium oxide was added and stirred for 5 hours at room temperature. Allow the mixture to cool to room temperature, and adjust the pH to 7.4 with 2N NaOH. The solution will be reduced to dryness under vacuum and purified on RP-18 (buffer: water/ethanol/acetonitrile gradient).

Yield: 8.11 g (57% of theory) of a colorless amorphous solid.

Water content: 9.6%.

Analysis of elements (calculated according to dry substance):

ber.: C 30.70 H 3.08 Gd 17.48 N 7.78 Na 2.56 S 1.78

gef.: C 30.58 H 3.19 Gd 17.42 N 7.71 Na 2.68 S 1.72

Example 57

a) 6-N-benzyloxycarbonyl-2-N-[6-carbonylmethyl-3,9-bi(t.butyloxycarbonylmethyl)3,6,9-triazaundecane-1,11-dicarboxylic acid-bi(t.butylester)]-lysine -[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

To a solution of 20 g (24.08 mmol) of the title substance from Example 52c, 14.88 g (24.08 mmol) of 3,9-bi(t-butyloxycarbonylmethyl)-6-carboxymethyl-3,6,9-triazaundecane- 1,11-dicarboxylic acid-bi(t. butyl ester) and 2.88 g (25 mol) of N-hydroxysuccinimide dissolved in 100 ml of dimethylformamide, add 8.25 g (40 mol) of N,N-dicyclohexylcarbodiimide at 0ºC. It is mixed for 3 hours at 0ºC, then overnight at room temperature. Then the precipitated urine substance is filtered, the filtrate is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/ethanol = 20:1)

Yield: 27.21 g (79% according to theory) of one thick oil.

Analysis of elements:

ber.: C 47.03 H 5.64 F 22.58 N 6.85 S 2.24

gef.: C 46.94 H 5.58 F 22.65 N 6.84 S 2.31

b) 2-N-[carbonylmethyl-3,9-bi(t.butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid-bi(t.butylester)]-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide

25 g (17.48 mmol) of the title substance from example 57a will be dissolved in 350 ml of ethanol and 5 g of palladium catalyst (10% Pd/C) will be added. Hydration is done at room temperature. The catalyst is filtered off, and the filtrate is evaporated to dryness.

Yield: 22.66 g (quantitative) of a colorless solid.

Analysis of elements:

ber.: C 44.48 H 5.75 F 24.92 N 7.56 S 2.47

gef.: C 44.59 H 5.81 F 25.03 N 7.46 S 2.52

c) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -2-N-[6-carbonylmethyl-3,9-bi(t.butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid-bi(t.butylester)]-lysine-[1-(4 -perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

20 g (15.43 mmol) of the title substance from example 57b, 1.78 g (15.43 mmol) of N-hydroxysuccinimide, 1.48 g (35 mmol) of lithium chloride and 9.72 g (15.43 mmol) of 1 ,4,7-tris(carboxylmethyl)-10-(3-aza-4-oxo-5-methyl-5-yl)-pentanoic acid-1,4,7,10-tetraazacyclododecane, the Gd complex will be zu easy heating in 150 ml of dimethylsulfoxide dissolved. At 10ºC, 5.16 g (25 mmol) of N,N-dicyclohexylcarbodiimide were added and stirred continuously overnight at room temperature. The solution is then poured into 2500 ml of acetone and stirred for 10 min. The precipitated solid will be filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 22.94 g (78% of theory) of a colorless solid.

Water content: 7.9%

Analysis of elements (calculated according to dry substance):

ber.: C 42.22 H 5.29 F 16.95 Gd 8.25 N 8.82 S 1.68

gef.: C 42.15 H 5.41 F 16.87 Gd 8.13 N 8.70 S 1.60

d) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)] -2-N-[6-carbonylmethyl-3,9-bi(carboxylatomethyl)-3,6,9-triazaundecane dicarboxylic acid-carboxy-11-carboxylato-z]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine ]-amide, di-Gd-complex, sodium salt

20 g (10.49 mmol) of the title substance from example 57c will be dissolved in 200 ml of trifluoroacetic acid. Then it is mixed for 60 min at room temperature. Then it is evaporated to dryness, and the rest is dissolved in 150 ml of water. Add 1.90 g (5.25 mmol) of gadolinium oxide and stir for 5 hours at 80ºC. Cool to room temperature. and adjust the pH to 7.4 using NaOH. The solution will be evaporated to dryness in a vacuum and purified on Kieselgel RP-18. (buffer: water/ethanol/acetonitrile gradient).

Yield: 11.89 g (61% of theory) of a colorless and amorphous solid.

Water content: 10.2%

Analysis of elements (calculated according to dry substance):

ber.: C 32.97 H 3.47 F 17.39 Gd 16.93 N 9.05 Na 1.24 S 1.73

gef.: C 32.90 H 3.53 F 17.31 Gd 16.87 N 8.92 Na 1.33 S 1.67

Example 58

a) 5,6-bi(benzyloxy)-3-oxahexanoic acid.-t. butyl ester

100 g (376.2 mmol) of 1,2-di-O-benzyl-glycine (prepared according to Chem. Phys. Lipids (1987), 43(2), 113-227) and 5 g of tetrabutylammonium hydrogen sulfate will be in one mixture from 400 ml of toluene in 200 ml of 50% water. NaOH dissolved. At 0ºC it is added for 30 min. 78 g (400 ml) of 2-bromoacetic acid-t. butyl ester and stir continuously for 3 hours at 0ºC. Org. the phase will be separated, dried over magnesium sulfate and reduced in a vacuum. The residue will be chromatographed on Kieselgel (buffer: N-hexane/acetone 20:1).

Yield: 133.4 g (94% according to theory) of colorless oil.

Analysis of elements:

ber.: C 71.48 H 7.82

gef.: C 71.61 H 7.92

b) 5,6-bi(benzyloxy)-3-oxa-hexanoic acid

130 g (336.4 mmol) of the title substance from example 58a will be dissolved in 200 ml of dichloromethane and at 0ºC, 100 ml of trifluoroacetic acid will be added. Mix for 4 hours at room temperature. and reduces continuously until dry. The residue will be crystallized from pentane/diethylether.

Yield: 102.2 g (92% of theory) of a waxy solid.

Analysis of elements:

ber.: C 69.07 H 6.71

gef.: C 69.19 H 6.82

c) 6-N-benzyloxycarbonyl-2-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(3-aza-4-oxo-5-methyl-5 -yl)]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

50 g (60.20 mmol) of the title substance from example 52c 6.93 g (60.20 mmol) of N-hydroxysuccinimide, 5.09 g (120 mmol) of lithium chloride and 37.91 g (60.20 mmol) of 1, 4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-pentanoyl-3-aza-4-oxo-5-methyl-5yl), the Gd-complex will be zu gentle heating in 400 ml of dimethylsulfoxide dissolved. At 10ºC, 20.63 g (100 mmol) of N,N-dicyclohexylcarbodiimide is added and the mixture is continuously stirred overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated solid will be adfiltrated and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 75.53 g (87% of theory) of a colorless solid.

Water content: 10.1%

Water analysis (calculated according to solid matter)

ber.: C 37.48 H 3.85 F 22.39 Gd 10.90 N 8.74 S 2.22

gef.: C 37.39 H 4.02 F 22.29 Gd 10.75 N 8.70 S 2.22

d) 2-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

70 g (48.53 mmol) of the title substance from example 58c will be dissolved in 500 ml of water/100 ml of ethanol and 5 g of palladium catalyst (10% Pd/C) will be added. It hydrates at room temperature. The catalyst is filtered off and evaporated to dryness under vacuum.

Yield: 63.5 g (quantitative) of one solid.

Water content: 9.8%

Water analysis (calculated according to solid matter)

ber.: C 37.48 H 3.85 F 22.39 Gd 10.90 N 8.74 S 2.22

gef.: C 37.39 H 4.03 F 22.31 Gd 10.78 N 8.65 S 2.20

e) 6-N-[5,6-bi(benzyloxy)-3-oxahexanoyl]-2-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-( pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

10 g (7.64 mmol) of the title substance from example 58d, 3.30 g (10 mmol) of the title substance from example 7b, 0.85 g (20 mmol) of lithium chloride and 1.15 g (10 mmol) of N-hydroxysuccinimide will be zu gentle heating in 150 ml of dimethylsulfoxide dissolved. At 10ºC, 3.10 g (15 mmol) of N,N'-dicyclohexylcarbodiimide was added and stirred for 8 hours at room temperature. The reaction solution will be poured into 2000 ml of acetone and the precipitate isolated. The title substance will be purified on Kieselgel RP-18 (buffer: water/ethanol/acetonitrile gradient).

Yield: 11.14 g (90% of theory) of a colorless, amorphous solid.

Water content: 4.3%

Water analysis (calculated according to solid matter)

ber.: C 41.51 H 4.29 F 19.93 Gd 9.70 N 7.78 S 1.98

gef.: C 41.45 H 4.38 F 19.84 Gd 9.58 N 7.70 S 1.90

f) 6-N-[5,6-dihydroxy-3-oxahexanoyl]-2-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3 -aza-4-oxo-5-methyl-5-yl)]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

10 g (6.17 mmol) of the title substance from example 58e will be dissolved in 200 ml of ethanol and 3 g of palladium catalyst (10% Pd/C) will be added. Hydration is done at room temperature. Then the catalyst is filtered off and the filtrate is reduced to dryness under vacuum.

Yield: 8.89 g (quantitative) of a colorless solid.

Water content: 3.1%

Water analysis (calculated according to solid matter)

ber.: C 35.03 H 3.99 F 22.42 Gd 10.92 N 8.75 S 2.23

gef.: C 34.95 H 4.12 F 22.30 Gd 10.78 N 8.71 S 2.18

Example 59

a) 6-N-benzyloxycarbonyl-2-N-[5,6-bi(benzyloxy)-3-oxa-hexanoyl]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

To a solution of 20 g (24.08 mmol) of the title substance from example 52c, 9.91 g (30 mmol) of the title substance from example 7b and 3.45 g (30 mmol) of N-hydroxysuccinimide, dissolved in 1000 ml of dimethyl sulfoxide, was added at 0ºC, 9.28 g (45 mmol) of N,N-dicyclohexylcarbodiimide. It is mixed for 3 hours at 0ºC, then overnight at room temperature. Then the urine substance is filtered off, reduced to dryness in a vacuum and chromatographed on Kieselgel (buffer: dichloromethane/ethanol 20:1).

Yield: 24.50 g (89% according to theory) of thick oil.

Water analysis:

ber.: C 47.29 H 4.14 F 28.26 N 4.90 S 2.81

gef.: C 47.14 H 4.26 F 28.17 N 4.91 S 2.69

b) 2-N-[5,6-dihydroxy-3-oxa-hexanoyl]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

20 g (17.5 mmol) of the title substance from example 52d will be dissolved in 300 ml of ethanol and 5 g of palladium catalyst (10% Pd/C) will be added. Hydration is done at room temperature. The catalyst is filtered off and the filtrate is reduced to dryness under vacuum.

Yield: 17.65 g (quantitative) of a colorless solid.

Analysis of elements.

ber.: C 44.05 H 4.10 F 32.02 N 5.55 S 3.18

gef.: C 43.96 H 4.21 F 31.94 N 5.48 S 3.24

c) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]- lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

15 g (14.87 mmol) of the title substance from example 59b, 1.73 g (15 mmol) of N-hydroxysuccinimide, 1.27 g (30 mmol) of lithium chloride and 9.48 g (15 mmol) of 1,4,7- tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl)-pentanoic acid-1,4,7,10-tetraazacyclododecane, Gd-complex will be zu gentle heating in 100 ml of dimethylsulfoxide dissolved. At 10ºC, 5.16 g (25 mol) of N,N-dicyclohexylcarbodiimide are added and stirred overnight at room temperature. then the solution is poured into 1500 ml of acetone and stirred for 10 min. The precipitated solid will be filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 19.28 g (80% of theory) of a colorless solid.

Water content: 10.3%

Analysis of elements (calculated according to dry matter):

ber.: C 41.51 H 4.29 F 19.93 Gd 9.70 N 7.78 S 1.98

gef.: C 41.37 H 4.40 F 19.88 Gd 9.58 N 7.67 S 1.85

Example 60

a) 6-N-benzyloxycarbonyl-2-N-[2,6-N,N'-bi(benzyloxycarbonyl)-lysyl]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

20 g (24.08 mmol) of the title substance from example 52c and 2.53 g (25 mmol) of triethylamine will be dissolved in 200 ml of tetrahydrofuran (THF) and 14.46 g (27 mmol) of di-N,N'-Z -lysine paranitrophenol ester added. Then it is mixed for 5 hours at 50ºC. It is evaporated to dryness under vacuum and the residue is chromatographed on Kieselgel. Buffer: dichloromethane/methanol 20:1).

Yield: 28.07 g (95% of theory) of a colorless solid.

Analysis of elements.

ber.: C 46.99 H 4.19 F 26.32 N 6.85 S 2.61

gef.: C 47.08 H 4.32 F 26.21 N 6.75 S 2.54

b) 2-N-(lysyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, trihydrobromide

K 25 g (20.37 mmol) of the title substance from example 60a is added to 100 ml of hydrobromic acid in glacial acetic acid (48%) and stirred for 2 hours at 40º. The solution is cooled to 0ºC, 1500 ml of diethyl ester are added dropwise and the precipitated solid is filtered. After drying in a vacuum (60º C), 21.52 g (99% according to theory) of a slightly yellowish, crystalline solid are obtained.

Analysis of elements:

ber.: C 27.01 H 3.40 Br 22.46 F 30.26 N 7.87 S 3.00

gef.: C 26.92 H 3.53 Br 22.15 F 30.14 N 7.69 S 2.87

c) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]- 2-N]2,6-N,N'-bi[1,4,7-tris-carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5 -methyl-5-yl)]-lysyl]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, trigadolinium complex

31.49 g (50 mmol) 1,4,7-tri(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl)-5-yl)-pentanoic acid, Gd-complex 6.91 g (60 mmol) of N-hydroxysuccinimide and 4.24 g (100 mmol) of lithium chloride will be dissolved in 350 ml of dimethylsulfoxide under gentle heating. At 10ºC, 16.51 g (80 mmol) of N,N-dicyclohexylcarbodiimide were added and stirred for 5 hours at 10ºC. 10 g (9.37 mmol) of the title substance from example 60b and 3.03 g (30 mmol) of triethylamine were added to this solution and stirred for 12 hours at 60ºC. Then the mixture is cooled to room temperature. and poured into 3000 ml of acetone. The precipitated substance is filtered off, purified on Kieselgel RP-18 (buffer: water/ethanol/acetonitrile gradient).

Yield: 16.7 g (67% of theory) of a colorless solid.

Water content: 7.9%

Analysis of elements (calculated according to dry matter):

ber.: C 36.58 H 4.43 F 12.14 Gd 17.74 N 11.06 S 1.14

gef.: C 36.47 H 4.54 F 12.03 Gd 17.65 N 10.95 S 1.21

Example 61

a) 1,7-bi(benzyloxycarbonyl)-4-(3,6,9,12,15-pentaoxahexadecanoyl)-1,4,7,10-tetraazacyclododecane

K 18.13 g (68.1 mmol) of 3,6,9,12,15-pentaoxahexadecanoic acid and 30 g (68.1 mmol) of 1,7-di-Z-cyclene prepared according to z. Kovacs and A.D. Sherry, J. Chem. Soc. Chem. Commun. (1995), 2, 185 in 300 ml of tetrahydrofuran, add 24.73 g (100 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-ethyl ester of carboxylic acid) at 0º C and stir overnight at room temp. It is then evaporated to dryness in a vacuum and chromatographed on Kieselgel (buffer: dichloromethane/methanol 20:1).

Yield: 19.13 g (42% of theory) of a colorless solid.

Analysis of elements (calculated according to dry matter):

ber.: C 61.03 H 7.61 N 8.13

gef.: C 60.92 H 7.75 N 8.04

b) 1,7-bi(benzyloxycarbonyl)-4-(3,6,9,12,15-pentaoxahexadecanoyl)-10-(2H,2H,4H,5H,5H-3-oxa-perfluorotridecanoyl)-1,4 ,7,10-tetraazacyclododecane

K 18 g (26.91 mmol) of the title substance from example 61a and 14.05 g (26.91 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid, prepared according to DE 19603033, in 300 ml of tetrahydrofuran, added at 0ºc, 12.36 g (50 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-ethyl ester of carboxylic acid) and stirred overnight at room temperature. The mixture is then evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/methanol 20:1).

Yield: 21.51 g (67% of theory) of a colorless solid.

Analysis of elements:

ber.: C 47.32 H 4.82 F 27.07 N 4.70

gef.: C 47.26 H 5.01 F 26.94 N 4.59

c) 1-(3,6,9,12,15-pentaoxahexadecanoyl)-7-(2H,2H,4H,5H,5H-3-oxaperfluorotridecanoyl)-1,4,7,10-tetraazacyclododecane

20 g (16.77 mmol) of the title substance from example 52d will be dissolved in 200 ml of ethanol and 2.5 g of palladium catalyst (10% Pd/C) will be added. Hydration is done at room temperature. The catalyst is then filtered off and the filtrate is reduced to dryness under vacuum.

Yield: 15.5 g (quantitative) of a colorless solid.

Analysis of elements:

ber.: C 40.27 H 4.90 F 34.93 N 6.06

gef.: C 40.15 H 4.99 F 34.87 N 5.94

d) 1,7-bi(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl) ]-4-(3,6,9,12,15-pentaoxahexadecanoyl)-10-(2H,2H,4H,5H,5H-3-oxaperfluorotridecanoyl)-1,4,7,10-tetraazacyclododecane, gadolinium complex

15 g (16.22 mmol) of the title substance from example 61c, 4.60 g (40 mmol) of N-hydroxysuccinimide, 3.39 g (80 mmol) of lithium chloride and 25.19 g (40 mmol) of 1,4,7 -tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl)]-pentanoic acid, the Gd-complex will be dissolved in 300 ml of dimethylsulfoxide by gentle heating. At 10ºC, 24.73 g (100 mmol) of EEDQ are added and stirred continuously overnight at room temperature. It is then poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated substance is filtered off and further purified on Kieselgel RP-18 (buffer: water/ethanol/acetonitrile gradient).

Yield: 19.86 g (57% of theory) of a colorless solid.

Water content: 11.3%

Analysis of elements (calculated according to dry matter):

ber.: C 38.58 H 4.74 F 15.04 Gd 14.64 N 9.13

gef.: C 38.47 H 4.91 F 14.95 Gd 14.57 N 9.04

Example 62

a) 3,5-dinitrobenzoic acid-1-[1(4-perfluorooctylsulfonyl)-piperazine]-amide

K 20 g (35.2 mmol) and 8.1 g (80 mmol) of triethylamine, dissolved in 200 ml of dichloromethane, are added dropwise at 0ºC to a single solution of 8.76 g (38 mmol) of 3,5-dinitrobenzoyl chloride in 55 ml of dichloromethane. and stirred for 3 hours at 0ºC. Then add 200 ml of 5% hydrochloric acid solution and mix for 5 minutes at room temperature. Org. phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue will be chromatographed on Kieselgel (buffer: dichloromethane/acetone 15:1)

Yield: 24.96 g (93% of theory) of a colorless solid.

Analysis of elements.

ber.: C 29.35 H 1.45 F 42.37 N 7.35 S 4.21

gef.: C 29.28 H 1.61 F 42.15 N 7.25 S 4.15

b) 3,5-diaminobenzoic acid-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

20 g (26.23 mmol) of the title substance from example 62a will be dissolved in 400 ml of ethanol and 6 g of palladium catalyst (10% Pd/C) will be added. Hydration is done at room temperature. The catalyst is filtered off and the filtrate is reduced to dryness under vacuum.

Yield: 18.43 g (quantitative) of a creamy solid.

Analysis of elements.

ber.: C 32.49 H 2.15 F 45.98 N 7.98 S 4.57

gef.: C 32.29 H 2.35 F 45.69 N 7.81 S 4.40

c) 3,5-N,N'-bi-(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5- methyl-5-yl)]-benzoic acid-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, gadolinium complex

10 g (14.24 mmol) of the title substance from example 62b, 3.45 g (30 mmol) of N-hydroxysuccinimide, 2.54 g (60 mol) of lithium chloride and 18.89 g (30 mmol) of 1,4,7 -tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl)]-pentanoic acid, the gadolinium complex will be dissolved in 200 ml of dimethylsulfoxide by gentle heating. At 10ºC, 10.32 g (50 mmol) of N,N-dicyclohexylcarbodiimide are added and stirred continuously overnight at room temperature. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 19.74 g (72% of theory) of a colorless solid.

Water content: 11.8%

Analysis of elements (calculated according to dry matter).

ber.: C 35.55 H 3.72 F 16.77 Gd 16.33 N 10.18 S 1.67

gef.: C 35.48 H 3.84 F 16.58 Gd 16.24 N 10.07 S 1.58

Example 63

a) 3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecane carboxylic acid-t-butyl ester

25 g (53.8 mmol) of 1H,1H,2H,2H-perfluoro-1-decanol (commercially available from Lancaster) will be dissolved in 250 ml of absolute toluene and at room temp. with a catalytic amount (ca. 0.75 g) of tetra-n-butyl ammonium hydrogen sulfate mixed. A total of 7.55 g (134.6 mmol; 2.5 equivalents in relation to the alcohol component used) of fine powdered potassium hydroxide powder is continuously added at 0ºc, after which 15.73 g (80.7 mmol; 1.5 equiv. in relation to the alcohol component used) bromoacetene acid-tert-butylester and leave to stir for another 2 hours at 0ºC. the resulting reaction solution will be at room temperature for 12 hours. mixed and for the purpose of finishing, a total of 500 ml of acetic acid ethyl ester and 250 ml of water will be added. The phases will be separated and washed twice with water. After drying, the organic phase over sodium sulfate, the salt will be sucked off and the solvent removed under vacuum. The remaining oily substance will be purified on Kieselgel using acetic acid ethyl ester/hexane (1:10) as eluent.

Yield: 26.3 g (84.6% d.Th.) of the above title substance as a colorless and highly viscous oil.

Analysis of elements:

ber.: C 33.23 H 2.61 F 55.85

gef.: C 33.29 H 2.61 F 55.90

b) 3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecane carboxylic acid

20 g (34.58 mmol) of the title substance from example 63a will be in 200 ml of a mixture, which consists of methanol and 0.5 molar sodium alkali in a ratio of 2:1, with stirring at room temperature. suspended and continuously heated to 60ºC. After a reaction of 12 hours at 60ºC, the pure reaction mixture will be neutralized, removed from the exchanger, and the thus obtained methanolic-aqueous filtrate is removed in a vacuum until dry. The resulting amorphous-oily residue will be purified on Kieselgel using ethyl acetic acid/n-hexane (1:3) as eluent.

Yield: 16 g (88.6 % d.Th.) of the above title substance as a colorless and highly viscous oil.

Analysis of elements:

ber.: C 27.60 H 1.35 F 61.85

gef.: C 27.58 H 1.36 F 61.90

c) 1,7-bi-{[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)]-1,4,7, 10-tetraazacyclododecane}-diethylenetriamine, digadolinium complex

2.48 g ((3.94 mmol); 2.05 mol-equivalents in relation to the diethylenetriamine used) in patent application DE 197 28 954 C1 in example 31h described Gd-complex 10-(4-carboxy-1-methyl- 2-oxo-3-azbutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 167 mg of dry lithium chloride (3.94 mmol) will be at 40ºC in 40 ml of absolute dimethylsulfoxide under stirring dissolved and at the same temp. with a total of 453 mg (3.94 mmol) of N-hydroxysuccinimide mixed. After cooling to room temperature, the resulting reaction solution with 814 mg (3.946 mmol) of N,N'-dicyclohexylcarbodiimide will be mixed and for 2 hours at room temperature. mixed. The suspension of the active ester obtained will be continued with 198.3 mg (1.92 mmol) of diethylenetriamine, dissolved in 5 ml of absolute dimethyl sulfoxide, and mixed for 12 hours at room temperature. mixed. For the purpose of processing, the reaction mixture will be mixed with enough acetone until the above-mentioned substance is completely precipitated, the precipitate will be sucked off, dried, dissolved in water, the insoluble dicyclohexyl urinary substance will be filtered, and the filtrate will be filtered through an AMICON YM3- ultra filter membrane (cut off 3000 Da ) purified from salt and low molecular weight compounds. The retentate will be continuously freeze-dried.

Yield: 1.85 g (72.7% d.Th.) as a colorless lyophilisate.

Water content (Karl-Fischer): 3.89%

Analysis of elements (calculated according to dry substance):

ber.: C 38.03 H 5.24 N 13.73 Gd 23.71

gef.: C 37.98 H 5.20 N 13.69 Gd 23.78

d) 1,7-bi-{[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)]-1,4,7, 10-tetraazacyclododecane}-4-(3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)-diethylenetriamine, digadolinium complex

Into a solution of 3.23 g (2.44 mmol) of the title substance from example 63 c, in a mixture of 30 ml of dimethylsulfoxide and 3 ml of tetrahydrofuran, will be at 50ºC in an atmosphere saturated with nitrogen 1.27 g (2.44 mmol ) title substance from example 63b, dissolved in a mixture of 15 ml of tetrahydrofuran and 15 ml of dimethylsulfoxide, added dropwise. Subsequently, a total of 1.80 g (3.66 mmol) of EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) will be added in smaller amounts at 0ºC, and stirred overnight at room temperature. The resulting reaction mixture will be continuously mixed with enough acetone until the above-mentioned title substance is completely precipitated, the precipitate is removed, dried, dissolved in water, filtered from insoluble molecules, and the filtrate is filtered through an AMICON YM3 ultra filter membrane (cut off 3000 Da). , which serves to remove salt, as well as to clean the title substance from low-molecular compounds. The retentate will be continuously freeze-dried.

Yield: 3.54 g (79.4% d.Th.) as a colorless lyophilizate.

Water content (Karl-Fischer): 5.87%.

Analysis of elements (calculated according to dry matter):

ber.: C 35.43 H 4.07 N 9.95 F 17.64 Gd 17.18

gef.: C 35.42 H 4.01 N 9.89 F 17.67 Gd 17.18

Example 64

a) 2-N-trifluoroacetyl-6-N-benzyloxycarbonyl-1-lysine

100 g (356.7 mmol) of 6-N-benzyloxycarbonyl-1-lysine will be dissolved in a mixture of 1000 ml of trifluoroacetic acid ethyl ester and 500 ml of ethanol for 24 hours at room temperature. mixed. It is then evaporated to dryness and the residue crystallized from diisopropyl ether.

Yield: 128.9 g (96% theoretical) colorless crystalline powder.

Melting point: 98.5 ºC.

Analysis of elements:

ber.: C 51.07 H 5.09 N 7.44 F 15.14

gef.: C 51.25 H 5.18 N 7.58 F 15.03

b) 2-N-trifluoroacetyl-6-N-benzyloxycarbonyl-1-lysine[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

To 125 g (332 mmol) of the title substance from Example 52a and 188.7 g (332 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 750 ml of tetrahydrofuran, 164.2 g (0.664 mmol) of EEDQ (2) are added at 0ºC. -ethoxy-1,2-dihydroquinoline-1-ethyl ester of carboxylic acid) and stirred overnight at room temperature. It is then evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/methanol = 20:1).

Yield: 286 g (93% theoretical) of a colorless solid.

Melting point: 92 ºC.

Analysis of elements:

ber.: C 36.30 H 2.83 N 6.05 F 41.01 S 3.46

gef.: C 36.18 H 2.94 N 5.98 F 40.87 S 3.40

c) 6-N-benzyloxycarbonyl-1-lysine[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

Ammonia gas is introduced into a solution of 280 g (302.2 mol) of the title substance from example 52b in 2000 ml of ethanol at 0ºC for one hour. Then it is continuously stirred for 4 hours at 0ºC. Then it is evaporated to dryness, and the rest is removed from the water. Then the solid substance is filtered off and dried in a vacuum until dry at 50ºC.

Yield: 243.5 g (97% theoretical) amorphous solid.

Analysis of elements:

ber.: C 37.60 H 3.28 N 6.75 F 38.89 S 3.86

gef.: C 37.55 H 3.33 N 6.68 F 38.78 S 3.81

d) L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

200 g (240.8 mmol) of the compound prepared in example 64c) will be dissolved in 1000 ml of ethanol, mixed with 5 g of Pearlman catalyst (Pd 20%, C) and left for a long time at room temperature. stirred in a hydrogen atmosphere (1 atm) hydrated, until hydrogen absorption stops. Then the catalyst is removed, washed thoroughly with ethanol (3 times with 100 ml each) and reduced to dryness in a vacuum. The title substance will be obtained as a highly viscous and yellow colored oil.

Yield: 162.5 g (96.9% d.Th.).

Analysis of elements:

ber.: C 31.04 H 3.04 N 8.05 F 46.38 S 4.60

gef.: C 31.11 H 3.09 N 8.08 F 46.33 S 4.62

e) 6-N-2N-bi-{4-[2,3-bi-(N,N-bi(t-butyloxycarbonylmethyl)-amino)-propyl]-phenyl}-3-oxa-propionyl-1-lysine -[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

5.25 g (7.72 mmol) of 4-[2,3-bi-(N,N-bi(t-butyloxycarbonylmethyl)-amino)-propyl]-phenyl}-3-oxa-propionic acid and 781 mg ( 7.72 mmol) of triethylamine will be dissolved in 50 ml of methylene chloride. At -15ºC, a solution of 1.16 g (8.5 mmol) isobutyl ester of chloroformic acid in 10 ml of methyl chloride is added dropwise over a period of 5 minutes and stirred for another 20 minutes. at -15ºC. The solution is continuously cooled to -25ºC and a solution of 2.12 g (21 mmol) of triethylamine in 70 ml of tetrahydrofuran is added dropwise over a period of 30 minutes. and mix for the next 30 min. at -15ºC and continuously at room temp. over night. For finishing, the solvent will be evaporated in a vacuum, and the remaining oily residue will be dissolved in 250 ml of chloroform. Then the chloroform phase is extracted twice with 100 ml of a 10% aqueous solution of ammonia chloride, org. phase is dried over magnesium sulfate and reduced to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: methylene chloride/ethanol = 20:1)

Yield: 5.37 g (68.8 % d.Th.) of colorless very thick oil.

Analysis of elements:

ber.: C 52.27 H 6.43 N 5.54 F 15.97 S 1.59

gef.: C 52.22 H 6.51 N 5.49 F 15.99 S 1.63

f) 6-N-2N-bi-{4-[2,3-bi-(N,N-bi(carboxylatomethyl)-amino)-propyl]-phenyl}-3-oxa-propionyl-1-lysine-[ 1-(4-Perfluorooctylsulfonyl)-piperazine]-amide, octa-sodium salt

5 g (2.47 mmol) of the title substance from example 64e will be dissolved in 60 ml of absolute dichloromethane. It will continue to be at 0ºC with a total of 75 ml of trifluoroacetic acid added drop by drop. After a reaction time of 12 hours at room temp. it will be reduced to dryness in a vacuum. The remaining residue will be mixed with 100 ml of water and again evaporated to dryness in a vacuum. The resulting residue will be dissolved in 200 ml of distilled water, and the aqueous solution of the product of the above title substance will be extracted twice with 60 ml of diethyl ether. The resulting aqueous solution of the product will be mixed with water to a total volume of 300 ml, replenished and filtered from insoluble parts, and the filtrate will be ultrafiltered through an AMICON YM-3 ultrafiltration membrane (cut off 3000 Da), which serves both for complete salt removal and purification title substances from low molecular weight parts. The retentate will be mixed with water to a total volume of 200 ml, and the pH of the solution will be adjusted to 10 with 15% sodium lye. The basic, aqueous solution of the product will then be freeze-dried.

4 g (93.8% d.Th.) of the title substance are obtained in the form of the octasodium salt as an amorphous lyophilisate.

Water content: 5.37%

Analysis of elements (calculated according to dry substance):

ber.: C 38.46 H 3.28 N 6.41 F 18.47 S 1.83 Na 10.52

gef.: C 38.42 H 3.31 N 6.39 F 18.51 S 1.87 Na 10.38

g) 6-N-2N-bi-{4-[2,3-bi-(N,N-bi(carboxymethyl)-amino)-propyl]-phenyl}-3-oxa-propionyl-1-lysine-[ 1-(4-perfluorooctylsulfonyl)-piperazine]-amide, di-manganese complex, tetra-sodium salt

1.94 g (1.11 mmol) of the title substance from example 64f will be in 100 ml of dest. of water dissolved, and the resulting solution will be mixed with a 1M solution of hydrochloric acid. to the value 4 brought. It will be continued at 80ºC with a total of 0.25 g (2.22 mmol) of manganese-II-carbonate mixed. The resulting reaction solution will then be boiled for 5 hours in a reflux condenser. After cooling to room temperature, the pH-value of the aqueous solution of the product will be adjusted to 7.2 after strong mixing with 1N sodium hydroxide solution and freed from salt via an AMICON YM-3 ultrafiltration membrane (cut off 3000 Da). The retentate will be freeze-dried.

Yield: 1.80 g (92% d.Th.) of the title substance as a colorless lyophilizate.

H2O content (Karl-Fischer): 7.28%

Analysis of elements (calculated according to dry substance):

ber.: C 38.07 H 3.25 N 6.34 F 18.28 S 1.81 Na 5.20 Mn 6.22

gef.: C 38.01 H 3.29 N 6.36 F 18.29 S 1.78 Na 5.28

Mn 6:21

Example 65

a) 6-N-(benzyloxycarbonyl)-2N-[(N-pteroyl)-1-glutaminyl]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

20 g (45.31 mmol) of folic acid will be dissolved in 300 ml of dimethylsulfoxide and at 10ºC, 9.49 g (46 mmol) of N,N-dicyclohexylcarbodiimide will be added. It is then stirred overnight at room temperature. 29.1 g (35 mmol) of the title substance from example 52c and 20 ml of pyridine were added to this mixture and stirred for 3 hours at 50ºC. Then cool down to room temperature. and a mixture of 1500 ml diethyl ether/1500 ml acetone is added. The precipitated substance will be filtered and purified on RP-18 (buffer = gradient from water / ethanol / tetrahydrofuran).

Yield: 21.59 g (38% theoretical) of a yellow solid.

H2O content: 2.1%

Analysis of elements (calculated according to dry substance):

ber.: C 43.10 H 3.54 N 11.29 F 25.76 S 2.56

gef.: C 43.02 H 3.62 N 11.21 F 25.68 S 2.48

b) 2N-[(N-pteroyl)-1-glutaminyl]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

200 ml of hydrobromic acid in glacial acetic acid (48%) was added to 20 g (15.95 mmol) of the title substance from example 65a and stirred for 2 hours at 40ºC. It is then cooled to 0ºC, 2000 ml of diethyl ether is added dropwise and the precipitated substance is filtered off. After drying in vacuum (60ºC), 18.96 g (99% theoretical) of a yellow, crystalline solid is obtained.

Analysis of elements:

ber.: C 37.01 H 3.27 Br 6.65 N 12.83 F 26.90 S 2.67

gef.: C 36.91 H 3.42 Br 6.31 N 12.72 F 29.75 S 2.56

c) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl]- 2-N-[(N-pteroyl]-1-glutaminyl]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

0.92 g (8 mmol) of N-hydroxysuccinimide, 0.68 g (16 mol) of lithium chloride and 5.04 g (8 mmol) of 1,4,7-tris(carboxylatomethyl)-10-(3-aza-4 -oxo-5-methyl-5-yl)-1,4,7,10-tetraazacyclododecane, Gd-complex, will be zu gently heated in 80 ml of dimethylsulfoxide dissolved. At 10ºC, 2.06 g (10 mol) of N,N-dicyclohexylcarbodiimide is added and the mixture is continuously stirred for 3 hours at room temperature. 5 g (4.16 mmol) of the title substance from example 65b and 10 ml of pyridine were added to this reaction solution. Stir overnight at room temperature. Then the solution is poured into 1000 ml of acetone and stirred for 10 min. The precipitated solid will be filtered off and further purified by chromatography (Kieselgel RP-18, buffer: gradient from water/ethanol/acetonitrile. Then it is dissolved in some water, the pH value is adjusted to 7.4 with sodium alkali and freeze-dried.

Yield: 3.87 g (53% theoretical) of a yellow solid.

Water content: 5.8%

Analysis of elements (calculated according to dry substance):

ber.: C 38.36 H 3.74 N 12.78 F 18.42 S 1.83 Gd 8.97 Na 1.31

gef.: C 38.28 H 3.85 N 12.69 F 18.33 S 1.75 Gd 8.85 Na 1.42

Example 66

a) 2H,2H,4H,4H,5H,5H-3-oxa-perfluoro-tri-decanoic acid-N-(2,3-dihydroxypropyl)-amide

8.90 g (70 mmol) of oxalyl chloride was added to 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluoro-tri-decanoic acid in 300 ml of dichloromethane and mixed. 12 hours at room temperature. It is then evaporated in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added dropwise, at 0ºC, to a solution of 5.47 g (60 mmol) of 2,3-dihydroxypropylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is mixed for 3 hours at 0ºC, and then for 6 hours at room temperature. Then add 300 ml of 5% hydrochloric acid and mix for 15 minutes. Org. phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/ethanol = 15:1).

Yield: 29.70 g (87% d.Th) of a colorless solid.

Analysis of elements:

ber.: C 30.32 H 2.20 N 2.36 F 54.35

gef.: C 30.12 H 2.41 N 2.18 F 54.15

b) N-(2,3-dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluoro-tri-decyl)-amine

30 g (48.8 mmol) of the title substance from example 66a will be dissolved in 300 ml of tetrahydrofuran and 50 ml of 10M borane dimethyl sulfide (in tetrahydrofuran) will be added. It is then boiled for 16 hours in a return cooler. It is cooled to 0ºc and 300 ml of methanol is added dropwise, and it is continuously evaporated to dryness in a vacuum. The residue was added to a mixture of 300 ml ethanol/50 ml 10% hydrochloric acid. and stir for 8 hours at 60ºC.

It is then evaporated to dryness under vacuum, the residue is dissolved in 300 ml of 5% sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phase is dried over magnesium sulfate, evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel (buffer: dichloromethane/methanol = 15:1).

Yield: 24.07 g (85% d.Th) of a colorless solid.

Analysis of elements:

ber.: C 31.05 H 2.61 N 2.41 F 55.66

gef.: C 31.91 H 2.78 N 2.33 F 55.47

c) 1,4,7-tris(carboxylatomethyl)-10-[3-aza-4-oxo-hexan-5-yl]-acid-N-(2,3-dihydroxypropyl)-N-(1H,1H, 2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, Gd-complex

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride will be dissolved in 100 ml of dimethylsulfoxide at 60ºC. It is then cooled to 15ºC and 9.21 g (15.88 mmol) of the title substance from Example 66b is added. It was stirred for 10 min and then another 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline was added. Then for 12 hours at room temp. mixes. The solution is poured into a mixture of 200 ml acetone / 1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitated substance is filtered off, dissolved in a mixture of some ethanol/water and chromatographed on Kieselgel RP-18 (buffer: gradient from tetrahydrofuran/acetonitrile/water).

Yield: 16.09 g (85% d.Th.) colorless, amorphous powder

Water content: 6.3%

Analysis of elements (calculated according to dry substance):

ber.: C 34.26 H 3.64 N 7.05 F 27.10 Gd 13.19

gef.: C 34.12 H 3.83 N 6.91 F 26.88 Gd 12.93

Example 67

a) 1,4,7-tris(carboxylatomethyl)-10-[3-aza-4-oxo-hexan-5-yl]-acids-N-(1H,1H,2H,2H,4H,4H,5H, 5H-3-oxa-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, Gd-complex

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide will be dissolved at 60ºC in 100 ml of dimethylsulfoxide. It is then cooled to 15ºC and 3.51 g (17 mmol) of N,N'-dicyclohexylcarbodiimide is added and stirred for 5 hours at 15ºC. To separate the urinary substance, the solution is filtered. 8.63 g (15.88 mmol) of the title substance from example 68b and 5.06 g (50 mmol) of triethylamine were added to the filtrate and stirred for 12 hours at room temperature. The solution is poured into a mixture of 1500 ml diethyl ether / 100 ml acetone and stirred for 30 minutes. The precipitated substance is filtered off and chromatographed on Kieselgel RP-18 (buffer: tetrahydrofuran/acetonitrile/water gradient).

Yield: 13.86 g (78% d.Th.) colorless, amorphous powder

Water content: 9.3%

Analysis of elements (calculated according to dry substance):

ber.: C 33.28 H 3.42 N 7.51 F 28.87 Gd 14.05

gef.: C 33.12 H 3.61 N 7.37 F 28.69 Gd 13.89

Example 68

a) 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid amide

8.90 g (70 mmol) of oxalyl chloride was added to 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluoro-tri-decanoic acid in 300 ml of dichloromethane and mixed. 12 hours at room temperature. It is then evaporated in a vacuum. The residue is dissolved in 200 ml of dichloromethane. Then, at 0ºC, ammonia gas is added ca. 2 hours. Then it is mixed at 0ºC for 4 hours and then for another 2 hours at room temperature. Then add 300 ml of 5% hydrochloric acid and mix for 15 minutes. Org. phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone = 15:1).

Yield: 27.85 g (93% d.Th).

Analysis of elements:

ber.: C 27.66 H 1.55 N 2.69 F 61.97

gef.: C 27.49 H 1.72 N 2.54 F 61.81

b) 1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl amine, hydrochloride

27 g (51.8 mmol) of the title substance from example 68a will be dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. It is boiled for 16 hours on the return cooler. Then it is cooled to 0ºC and 200 ml of methanol is added, and it will then be evaporated to dryness in a vacuum. The residue will be added to a mixture of 400 ml ethanol/100 ml 10% hydrochloric acid and stirred for 8 hours at 60ºC. It is evaporated to dryness under vacuum and the residue is crystallized from a little ethanol/diethyl ether.

Yield: 26.75 g (95% d.Th) of a colorless, crystalline solid.

Analysis of elements:

ber.: C 26.51 H 2.04 N 2.58 F 59.41 Cl 6.52

gef.: C 26.37 H 2.21 N 2.46 F 59.25 Cl 6.38

c) 3,6,9,12,15-pentaoxahexadecanoic acid-N-(1H, 1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl amide

K 26.5 g (48.74 mmol) of the title substance from example 68b and 14.8 g (146.2 mmol) of triethylamine, dissolved in 300 ml of dichloromethane, are added at 0ºC 14.24 g (50 mmol) 3.6 ,9,12,15-pentaoxahexane chloride of decanoic acid and stirred for 3 hours at 0ºC. Then add 300 ml of 5% hydrochloric acid and mix well for 30 minutes. The organic phase is separated, dried over magnesium sulfate and reduced in a vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone 20:1).

Yield: 32.03 g (87% d.Th.) colorless oil.

Analysis of elements:

ber.: C 36.57 H 4.00 N 1.85 F 42.75

gef.: C 36.46 H 4.12 N 1.76 F 42.53

d) N-(3,6,9,12,15-pentaoxahexadecyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl amide

31 g (41.03 mmol) of the title substance from example 68c will be dissolved in 300 ml of tetrahydrofuran and 25 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. It is then boiled for 16 hours in a return cooler. It is cooled to 0ºC and 200 ml of methanol is added drop by drop, and it is continuously reduced to dryness in a vacuum. The residue is poured into a mixture of 300 ml of ethanol/50 ml of 10% hydrochloric acid and stirred for 8 hours at 40ºC. It is evaporated to dryness under vacuum, the residue is dissolved in 300 ml of 5% sodium hydroxide solution and extracted 3x with 300 ml of dichloromethane. The organic phase is dried over magnesium sulfate, evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel (buffer: dichloromethane/2-propanol 15:1).

Usability: 27.68 g (91% d.Th.)

Analysis of elements:

ber.: C 37.26 H 4.35 N 1.89 F 43.56

gef.: C 37.11 H 4.51 N 1.73 F 43.41

e) 1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-[N-3,6,9,12,15-pentaoxa-hexadecyl )-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, Gd-complex

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride will be dissolved at 60ºC and 100 ml of dimethylsulfoxide. It is cooled to 15ºC and 11.77 g (15.88 mmol) of the title substance from Example 68d is added. Mix for 10 min. and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitate is filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (buffer: gradient from tetrahydrofuran/acetonitrile/water).

Yield: 18.05 g (84% d.Th.) colorless, amorphous powder.

Water content: 6.2%

Analysis of elements (calculated according to dry substance):

ber.: C 37.28 H 4.47 N 6.21 F 23.87 Gd 11.62

gef.: C 37.11 H 4.61 N 6.03 F 23.64 Gd 11.42

Example 69

a) 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid-N-(5-hydroxy-3-oxa-pentyl)-amide

To 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, add 8.90 g (70 mmol) of oxalyl chloride and stir for 12 hours at room temp. It is then evaporated in a vacuum. The residue will be dissolved in 100 ml of dichloromethane and at 0ºC to a solution of 6.25 g (60 mmol) of 5-hydroxy-3-oxa-pentylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane, added dropwise. It is mixed for 3 hours at 0ºC, then for 6 hours at room temperature. Add 300 ml of 5% hydrochloric acid and stir for 15 minutes. Org. the phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone 15:1).

Yield: 32.20 g (92% d.Th.) colorless solid.

Analysis of elements:

ber.: C 31.54 H 2.65 N 2.30 F 53.01

gef.: C 31.61 H 2.84 N 2.14 F 52.85

b) N-(5-hydroxy-3-oxa-pentyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amine

30 g (49.24 mmol) of the title substance from example 69a will be dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M boranedimethylsulfide (in tetrahydrofuran) will be added. It is then boiled for 16 hours in a return cooler. It is cooled to 0ºC and 200 ml of methanol is added drop by drop, and it is continuously reduced to dryness in a vacuum. The residue is poured into a mixture of 300 ml of ethanol/50 ml of 10% hydrochloric acid and stirred for 10 hours at 50ºC. It is evaporated to dryness under vacuum, the residue is dissolved in 300 ml of 5% sodium hydroxide solution and extracted 3x with 300 ml of dichloromethane. The organic phase is dried over magnesium sulfate, evaporated to dryness under vacuum, and the residue is chromatographed on Kieselgel (buffer: dichloromethane/2-propanol 20:1).

Yield: 26.09 g (89% d.Th.) of a colorless solid

Analysis of elements:

ber.: C 32.28 H 3.05 N 2.35 F 54.25

gef.: C 32.12 H 3.21 N 2.18 F 54.09

c) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-yl]-acid-[5-hydroxy-3-oxa-pentyl)-N-(1H ,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, Gd-complex

10 g (15.88 mmol) of gadolinium complex 10-[1-(carboxymethylcarbamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol ) of lithium chloride will be dissolved at 60ºC and 100 ml of dimethylsulfoxide. Cool to 15ºC and add 9.45 g (15.88 mmol) of the title substance from Example 69b. Mix for 10 min. and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture of 200 ml acetone/1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitate is filtered off, dissolved in a mixture of a little ethanol/water and chromatographed on Kieselgel RP-18 (buffer: gradient from tetrahydrofuran/acetonitrile/water).

Yield: 16.10 g (84% d.Th.) colorless, amorphous powder.

Water content: 5.7%

Analysis of elements (calculated according to dry substance):

ber.: C 34.83 H 3.84 N 6.96 F 26.76 Gd 13.03

gef.: C 34.65 H 3.96 N 6.84 F 26.62 Gd 12.91

Example 70

a) 1,2,3,4,6-penta-O-acetyl-α,β-D-mannopyranose

In an analogous way, as described in the literature (M.L. Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (R.L. Whistler, M.L. Wolfrom and J.N. BeMiller, Eds.), Academic Press, New York, Vol II, 53, pp. 211-215 (1963). in the form of a viscous and colorless oil. 1H-NMR spectroscopy of the thus obtained title substance could determine the ratio of α and β anomers, which is 4:1. Separation of the α,β-anomer of the above title substance can be omitted for further reaction steps.

Analysis of elements:

ber.: C 49.21 H 5.68

gef.: C 49.12 H 5.78

b) 6-[1-O-α-(2,3,4,6-tetra-O-acetyl-D-mannopyranosyl)-ethyl ester of hexanoic acid]

In an analogous way, as described in the literature for the synthesis of aryl glycopyranosides (J. Conchie and G.A. Levvy in Methods in Carbohydrate Chemistry (R.L. Whistler, M.L. Wolfrom and J.N. BeMiller, Eds.), Academic Press, New York, Vol II, 90, pp . 345-347 (1963)) gives 156.2 g (400 mmol) of the title substance from Example 70a as an α,β-anomeric mixture with 67 ml (400 mmol) of 6-hydroxy-ethyl ester of hexanoic acid and 60.8 ml ( 520 mmol) of tin-IV-chloride in a total of 600 ml of 1,2-dichloroethane after purification by chromatography (eluent: hexane/ethyl acetate 2:1) to form 100.05 g (51% d.Th.) of the above title substance as a colorless and viscous oil. Through 1H-NMR spectroscopy of the thus obtained title substance, it was possible to prove that the obtained title substance is exclusively pure α-anomer.

Analysis of elements:

ber.: C 52.94 H 6.77

gef.: C 52.80 H 6.78

c) 6-[1-O-α-(2,3,4,6-tetra-O-benzyl-D-mannopyranosyl)-hexanoic acid

A mixed suspension of 141 g (289 mmol) of the title substance from example 70b in 200 ml of dioxane will be at room temperature. and zu simultaneous vigorous stirring in small amounts, with a total of 238.5 g (4.26 mol) of fine potassium hydroxide powder mixed. To increase the ability to mix, the reaction solution will be mixed with a further 200 ml of dioxane, and the resulting suspension will then be heated to boiling and at the same temperature. with a total of 372 ml (3.128 mol) of benzyl bromide over a period of 4 hours at 110ºC, followed by 12 hours at room temp. will be the reaction solution for the purpose of finishing in a total of 2.5 l of ice water slowly poured and the water phase below completely extracted with diethyl ether. After washing the ether phase obtained in this way and further drying it over sodium sulfate, it will be desalted and the diethyl ether removed under vacuum. Excess benzyl bromide will be continuously in the oil vacuum pump quantitatively at an oil bath temperature of 180ºC distilled from the reaction mixture. The resulting resinous-oily residue will be purified on Kieselgel using ethyl acetic acid/hexane (1:10) as an eluent.

Yield: 172.2 g (91 d.Th.) of the above title substance in the form of a colorless, highly viscous oil.

Analysis of elements:

ber.: C 75.68 H 7.16

gef.: C 75.79 H 7.04

d) 6-[1-O-α-(2,3,4,6-tetra-O-benzyl-D-mannopyranosyl)-hexanoic acid-N-(3-oxa-1H,1H,2H,2H,4H ,4H,5H,5H-perfluorotridecyl)-amide

100 g (134 mmol) of the acid described in example 70c as well as 13.5 g (134 mmol) of triethylamine will be dissolved in 1200 ml of dry tetrahydrofuran. After cooling to -15ºC and stirring, a solution of 18.45 g (135 mmol) isobutyl ester of chloroformic acid in 200 ml of dry tetrahydrofuran is added dropwise, whereby the internal temp. does not exceed -10ºC. After a reaction time of 15 min. at -15ºC, a solution of 165.5 g (134 mmol) of 1-amino-1H,1H,2H,2H-perfluorodecane and 13.5 g (134 mmol) of triethylamine in 250 ml of dry tetrahydrofuran is added dropwise at -20ºC. After a reaction time of 1 hour at -15ºC and 2 hours at room temp. the reaction solution will be reduced to dryness under vacuum. The remaining residue will be dissolved in 300 ml of ethyl ester of acetic acid and washed twice with 400 ml of saturated sodium hydrogen carbonate solution and once with 500 ml of water. After drying org. phase over sodium sulfate, the salt will be removed, and the acetic acid ethyl ester will be removed in vacuo. The remaining oily residue will be purified using dichloromethane/hexane/2-propanol (10:5:1) as eluent.

Yield: 143.8 g (86.9% d.Th.).

Analysis of elements:

ber.: C 57.38 H 4.98 N 1.13 F 26.15

gef.: C 57.30 H 5.44 N 1.01 F 26.25

e) 6-[1-O-α-D-mannopyranosyl)-hexanoic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide

40 g (32.38 mmol) of the title substance from example 70d will be dissolved in 750 ml of 2-propanol and mixed with 2 g of palladium catalyst (10% Pd/C). The reaction solution will be for 12 hours at 22ºC and under a hydrogen pressure of 1 atm. The catalyst is continuously filtered off, and the filtrate is reduced to dryness. The remaining residue will be dissolved in 300 ml of dimethylsulfoxide and the resulting reaction solution is obtained by mixing with a total of 1000 ml of diethyl ether, after removing the precipitated solid substance of 21.52 g (88% d.Th.) of the above-mentioned title substance as a colorless, crystalline powder with a melting and decomposition point of 88.5ºC.

Analysis of elements:

ber.: C 36.01 H 5.92 N 1.75 F 40.34

gef.: C 36.07 H 6.08 N 1.76 F 40.66

f) Preparation of one formulation from metal complex I and 6-[1-O-α-D-mannopyranosyl)-hexanoic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H- perfluorotridecyl)-amide

To 35 ml of a solution of metal complex I (280 mmol/L) dissolved in a 0.45% table salt solution (pH 7.4; 0.25 mg/L CaNa3DTPA) is added 3.17 g (4.2 mmol) of the title substance from example 70e and supplement with 0.9% aqueous table salt solution to a total of 98 ml. Then it is heated for 2 hours at 60ºC in an ultrasonic bath. The solution will be cooled to room temperature. and adjusted to pH 7.4 with an aqueous solution of 2N sodium alkali. It is then filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 71

a) 1-O-α-D-[(1-perfluorooctylsulfonylpiperazine-4-carbonyl)-pentyl-5-]-2,3,4,6-tetra-O-benzyl-mannopyranose

74.59 g (100 mmol) of the acid described in example 71c as well as 10.11 g (100 mmol) of triethylamine will be dissolved in 800 ml of the tetrahydrofuran/acetonitrile mixture (mix ratio 7:3). It will continue to be at room temperature. by adding dropwise with 500 ml tetrahydrofuran solution of 58 g (102 mmol) 1-perfluorooctylsulfonylpiperazine; 10.11 g (100 mmol) of triethylamine and 16.84 g (110 mmol) of 1-hydroxybenzotriazole were mixed. The reaction solution thus obtained will be at -5ºC with a solution of 22.7 g (110 mmol) of dicyclohexylcarbodiimide, dissolved in 100 ml of tetrahydrofuran, mixed and continued at -5ºC for another 2 hours. After dissolving the reaction solution will be at room temperature. stirred for a further 12 hours, the precipitated dicyclohexyl urinary substance was filtered off, and the resulting filtrate was reduced to dryness under vacuum. The remaining residue will be dissolved in 600 ml of ethyl ester of acetic acid and washed twice with 300 ml of saturated sodium hydrogen carbonate solution and twice with 300 ml of water. After drying org. phase over sodium sulfate, the salt will be removed, and the ethyl ester of acetic acid. using dichloromethane/acetone/2-propanol (16:2:1) as eluent, purified.

Yield: 113.01 g (79.8% d.Th.) colorless and viscous oil

Analysis of elements:

ber.: C 58.52 H 4.27 N 1.98 S 2.26 F 22.80

gef.: C 58.42 H 4.41 N 1.80 S 2.28 F 23.02

b) 1-O-α-D-[(1-perfluorooctylsulfonyl-piperazine-4-carbonyl)-pentyl-5-]-mannopyranose

50 g (35.30 mmol) of the title substance from example 71a will be dissolved in a mixture consisting of 500 ml of 2-propanol and 50 ml of water and 2 g of palladium catalyst (10% Pd on activated carbon) added. It is then hydrated for 12 hours at room temperature. The catalyst is removed, and the filtrate is evaporated to dryness under vacuum. The residue will be dissolved in 200 ml of methanol, and the reaction product will be precipitated by mixing with a total of 800 ml of diethyl ether. After separating the thus obtained solid substance, it will be dried in a vacuum at 50ºC.

Yield: 29.51 g (99% d.Th.) amorphous solid

Analysis of elements:

ber.: C 34.13 H 3.46 N 3.32 S 3.80 F 38.23

gef.: C 34.28 H 3.81 N 3.25 S 3.80 F 38.01

c) Preparation of one formulation from metal complex II and 1-O-α-D-[(1-perfluorooctylsulfonyl-piperazine-4-carbonyl)-pentyl-5-]-mannopyranose

To 47 ml of a solution of metal complex II (250 mmol/L) dissolved in a 0.45% sodium chloride solution is added 9.92 g (11.75 mmol) of the title substance from example 71b and heated for 10 min in a microwave oven. Then the solution is cooled to room temperature, filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 250 mmol/Gd/L).

Example 72

a) 2-acetamido-2-deoxy-1,3,4,6-(tetra-O-benzyl)-α,β-D-glucopyranose

To a stirred suspension of 20.16 g (700 mmol; 80% in mineral oil) of sodium hydride in 150 ml of dimethylsulfoxide was added at room temperature. a total of 24 g (108.5 mmol) of 2-acetamido-2-deoxy-α,β-D-glucopyranose, dissolved in 500 ml of absolute dimethylsulfoxide, added dropwise. Continue to leave for another 120 min. at room temp. mix and add 159.5 g (1.26 mol) of benzyl chloride. The reaction solution thus obtained will be kept at room temperature for a further 12 hours. mixed. For processing, the reaction solution will be slowly poured into 1.5 L of ice water and continuously extracted with diethyl ether. The combined phases of diethylether will be washed 2x with 600 ml of saturated sodium hydrogen carbonate solution and 2x with 800 ml of washed water. After drying org. phase over sodium sulfate, the salt will be removed, and the solvent will be removed in vacuo. The remaining oily residue will be purified on Kieselgel using acetic acid ethyl ester/hexane (1:5) as eluent.

Yield: 48.68 g (73.6% d.Th.) of the above title substance in the form of a viscous, colorless oil.

Analysis of elements:

ber.: C 70.92 H 6.45 N 6.89

gef.: C 71.43 H 6.44 N 7.02

b) 1-O-benzyl-3,4,6-tri-O-benzyl-2-amino-2-deoxy-α,β-D-glucopyranose

30 g (49.2 mmol) of the title substance from example 72a will be suspended in a mixture consisting of 750 ml of methanol and 215 ml of water at room temperature. with a total of 440 ml (49.2 mmol) of a 0.112 molar aqueous solution of perchloric acid. added by doping. After stopping the addition, the reaction solution will be at room temperature for another 10 min. the mixed, thus obtained homogeneous reaction solution will be further reduced to dryness in a vacuum. By mixing the remaining oily residue with a mixture of equal parts of hexane and dichloromethane, it will be brought to crystallization. The crystalline reaction product will be removed, washed with hexane and vacuumed at room temperature. dried.

Yield: 27.05 g (86% d.Th.) of the above title compound in the form of its perchlorate, which comes as a colorless, crystalline compound.

Melting point: 180.5-181.5ºC

Analysis of elements:

ber.: C 63.68 H 5.98 N 2.19 Cl 5.54

gef.: C 63.43 H 6.04 N 2.02 Cl 5.71

c) 1,3,4,6-O-tetra-O-benzyl-2-deoxy-2-[acetyl-(2-amino-N-ethyl-N-perfluorooctylsulfonyl)-amino]-1-α,β- D-glucopyranose

20.8 g (35.6 mmol) of 2-[N-ethyl-N-perfluorooctylsulfonyl)-amino acetic acid and 3.60 g (35.6 mmol) of triethylamine will be dissolved in 350 ml of dry tetrahydrofuran. After cooling the reaction solution to -15ºC to -20ºC, it is added at the same temp. by mixing a solution of 4.92 g (35.6 mmol) of isobutyl ester of chloroformic acid in 75 ml of dry tetrahydrofuran, whereby the rate of addition is selected so that the internal temp. does not exceed -10ºC. After a reaction time of 15 min. at -15ºC, a solution of 22.78 g (35.6 mmol) of perchlorate (title substance from example 72b) and 3.60 g (35.6 mmol) of triethylamine in 100 ml of dry tetrahydrofuran is added dropwise at -20ºC. after the reaction time for 1 hour at -15ºC, as well as for 2 hours at room temperature, the reaction solution will be reduced to dryness in a vacuum. The remaining residue will be dissolved in 250 ml of ethyl acetic acid and 2x with 100 ml of saturated sodium hydrogen carbonate solution as well as 1x washed with 200 ml of water. After drying the organic phase over sodium sulfate, the salt will be removed and the acetic acid ethyl ester will be removed under vacuum. The remaining oily residue will be on Kieselgel using acetic acid ethyl ester/hexane (1:5) as eluent, purified.

Yield: 33.3 g (84.6 % d.Th.) of the above title substance as a colorless and highly viscous oil.

Analysis of elements:

ber.: C 49.92 H 3.92 N 2.53 F 29.18 S 2.90

gef.: C 49.99 H 4.11 N 2.69 F 29.22 S 3.01

d) 2-deoxy-2-[acetyl-(2-amino-N-ethyl-N-perfluorooctylsulfonyl)-amino]-1-α,β-D-glucopyranose

20 g (18.06 mmol) of the title substance from example 72c will be dissolved in 250 ml of 2-propanol and mixed with 1.5 g of palladium catalyst (10% Pd/C). The reaction solution will be hydrated for 12 hours at 22ºC and 1atm of hydrogen pressure. The catalyst is then filtered off, and the filtrate is reduced to dryness. The remaining residue will be dissolved in 300 ml of dimethylsulfoxide and the product solution thus obtained is maintained by mixing with 750 ml of a mixture of the same parts of diethyl ester and ethyl ester of acetic acid, after removing the precipitated solid 12.65 g (93.8% d.Th.) the above title substance as a colorless and crystalline powder. The above-mentioned title substance comes as a mixture of polymers α/β, with the ratio of both polymers determined by 1H-NMR-spectroscopy to be 1:1.2. Therefore, the title substance is an almost uniform mixture of α/β anomers.

Melting point: 132.5-133ºC

Analysis of elements:

ber.: C 28.97 H 2.57 N 3.75 F 43.27 S 4.30

gef.: C 29.09 H 2.56 N 3.84 F 43.36 S 4.42

e) Preparation of one formulation from metal complex XIV and 2-deoxy-2-[acetyl-(2-amino-N-ethyl-N-perfluorooctylsulfonyl)-amino]-1-α,β-D-glucopyranose

To 51 ml of one solution of metal complex XIV (300 mmol/L) dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg/L CaNa3DTPA) is added 4.90 g (6.57 mmol) of the title substance from example 3d, dissolved in 200 ml of ethanol and stirred for 2 hours at 50ºC. Then the solution is reduced to dryness in a vacuum, and the residue is detd. with water to a total of 153 ml. It is mixed for 10 min at 40ºC, then filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 73

a) 1,2,3,4,6-penta-O-acetyl-α-D-glucopyranose

In an analogous way, as described in the synthesis of the title substance 70a, the conversion of 100 g (555.0 mmol) of α-D-glucopyranose with a mixture of 1000 ml of absolute pyridine and 1000 ml of acetic anhydride after treatment and recrystallization from a 95% aqueous solution gives of ethanol, 190.6 g (88%) of the above title substance as a colorless and crystalline compound. Through 1H-NMR spectroscopy of the thus obtained title substance, it could be determined that the obtained title substance is a mixture of α/β-anomers, in a certain ratio, which was determined to be 98:2. Therefore, the title substance is exclusively an α-configured anomer.

Melting point: 110.5ºC

Analysis of elements:

ber.: C 49.21 H 5.68

gef.: C 49.24 H 5.68

b) 5-(ethoxycarbonyl)pentyl-2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside

In an analogous way, as described in the synthesis of the title substance 70b, the conversion of 130 g (332.8 mmol) of the title substance from example 4a with 55.8 g (332.8 mmol) of 6-hydroxy-ethyl ester of hexanoic acid and 50.6 ml (520 mmol) of tin-IV-chloride in 500 ml of 1,2-dichloroethane, after column purification (eluent: hexane/ethyl acetate 2:1), 101.85 g (62.4% d.Th. ) of the above title substance as a colorless and viscous oil. After 1H-NMR-spectroscopic analysis of the thus obtained title substance, it was possible, based on the magnitude of the coupling constant of J1.2=8.8 Hz, to unambiguously conclude that the β-configuration on the anomeric center is the only configuration present on the anomeric center. This allowed us to establish that the title substance is exclusively a β-configured anomer form.

Analysis of elements:

ber.: C 52.94 H 6.77

gef.: C 52.77 H 6.70

c) 5-(carboxy)pentyl-2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside

A mixed suspension of 100 g (204.96 mmol) of the title substance from example 73b in 150 ml of dioxane will be at room temperature. and with simultaneous vigorous stirring in smaller amounts with a total of 169.14 g (3.02 mol) of fine potassium hydroxide powder mixed. In order to increase the ability to mix, the reaction solution will be mixed with a further 150 ml of dioxane, and the resulting suspension will then be heated to boiling and at the same temperature. with a total of 264 ml (2.218 mol) of benzyl bromide over a period of 2 hours by dropwise addition, mixed. After a reaction of 4 hours at 110ºC, followed by 12 hours at room temperature, the reaction solution will be slowly poured into a total of 2 liters of ice water for the purpose of finishing, and the aqueous phase will then be completely extracted with diethyl ether. After washing the thus obtained ether phase and subsequent drying of the org. phase over sodium sulfate, the salt will be removed, and the diethyl ether will be removed in vacuo. The remaining benzyl bromide will continue to be in the vacuum of the oil pump quantitatively at temp. oil bath of 180ºC distilled from the reaction solution. The remaining oily residue will be purified on Kieselgel using acetic acid ethyl ester/hexane (1:5) as eluent.

Yield: 128.8 g (84.3% d.Th.) of the above title substance in the form of an extremely viscous, colorless oil.

Analysis of elements:

ber.: C 75.68 H 7.16

gef.: C 75.66 H 7.23

d) 2,3,4,6-tetra-O-benzyl-1-O-β-D-[6-hexanoic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H ,5H-perfluorotridecyl)-amide]-glucopyranose

In 825 ml of dry tetrahydrofuran, 68.5 g (91.79 mmol) of the acid described in example 73c as well as 9.25 g (91.79 mmol) of triethylamine will be dissolved. After cooling the reaction solution to -15ºC to -20ºC, it is added at the same temp. zu stirring one solution of 12.64 g (92.5 mmol) of isobutyl ester of chloroformic acid in 150 ml of dry tetrahydrofuran, slowly, whereby the rate of addition is selected so that the internal temp. does not exceed -10ºC. after a reaction time of 15 min. at -15ºC, a solution of 46.40 g (91.79 mmol) of 1H,1H,2H,2H-heptadecafluoro-1-(2-aminoethoxy)-decane and 9.25 g (91.79 mmol) of triethylamine is added dropwise. , as a solution in 200 ml of dry tetrahydrofuran, at -20ºC, slowly. After a reaction time of 1 hour, at -15ºC, as well as 2 hours at room temperature, the reaction solution will be reduced to dryness in a vacuum. The remaining residue will be dissolved in 250 ml of ethyl ester of acetic acid and washed twice with 300 ml of saturated sodium hydrogen carbonate solution, as well as once with 400 ml of water. After drying org. phase over sodium sulfate, the salt will be removed, and the acetic acid ethyl ester will be removed in vacuo. The remaining oily residue will be purified on Kieselgel using dichloromethane/hexane/2-propanol (10:5:1) as eluent.

Yield: 104.7 g (92.4% d.Th.) of the above title substance as a colorless and highly viscous oil.

Analysis of elements:

ber.: C 57.38 H 4.98 N 1.13 F 26.15

gef.: C 57.27 H 5.09 N 1.11 F 26.08

e) 1-O-β-D-[6-hexanoic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide]-glucopyranose

40 g (32.38 mmol) of the title substance from example 73d will be dissolved in 750 ml of 2-propanol and mixed with 2 g of palladium catalyst (10% Pd/C). The reaction solution will be hydrated for 12 hours at 22ºC and 1 atm hydrogen pressure. The catalyst is removed by continuous filtration, and the filtrate is reduced to dryness. The remaining residue will be dissolved in 300 ml of dimethylsulfoxide and from the thus obtained product solution, 22.05 g (90.2% d.Th.) of the title substance as a colorless crystalline substance is obtained by mixing with a total of 1000 ml of diethyl ether and by suctioning the precipitated solid. powder with melting point and decomposition at 122-124ºC.

Analysis of elements:

ber.: C 36.01 H 5.92 N 1.75 F 40.34

gef.: C 36.07 H 6.08 N 1.76 F 40.66

f) Preparation of one formulation from the title substance from example 12 from WO 99/01161 (1,4,7-tris(N-carboxylatomethyl)-10-(N-1-methyl-3-aza-2,5-dioxo-pentane -1,5-diyl]-1,4,7,10-tetraazacyclododecane, Gd-complex}-10-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1,4,7,10 -tetraazacyclododecane) and 1-O-β-D-[6-hexanoic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide]-glucopyranose

To one solution 1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-10-(N-1-methyl-3-aza-2,5-dioxo-pentane-1,5-diyl ]-1,4,7,10-tetraazacyclododecane, Gd-complex}-10-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1,4,7,10-tetraazacyclododecane (300 mmol/ L, dissolved in 0.45% sodium chloride solution (pH 7.4; 0.25 mg/L CaNa3DTPA) is added to 20.2 g (25.9 mmol) of the title substance from example 73e and supplemented with 0.9% sodium chloride solution of salt to a total of 111 ml. It is then heated for 2 hours at 60ºC in an ultrasonic bath. The solution will be cooled to room temperature and adjusted to pH 7.4 with 2N sodium hydroxide solution. It is then filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). The resulting solution can be used directly for biological experiments. (Concentration is 100 mmol Gd/L).

Example 74

a) 1-O-(1H,1H,2H,2H-perfluorotridecyl)-(2,3,4,6-tetra-O-acetyl)-α-D-mannopyranose

Conversion of 50 g (128.09 mmol) of the title substance from example 70a, which as a 4:1 mixture, in the ratio of α,β-anomers used, with one solution of 75.84 g (128.1 mmol) of 1-hydroxy -1H,1H,2H,2H-perfluorodecane in 150 ml of 1,2-dichloroethane as well as a total of 19.47 g (166.53 mmol) of tin-IV-chloride, analogously to the synthesis of the title substance from examples 1b and 4b described , leads after treatment and column chromatography (eluent: hexane/ethyl acetic acid ester, 2:1) to the formation of 74.2 g (63.4 % d.Th.) of the above title substance in the form of a viscous and colorless oil. After 1H-NMR-spectroscopic analysis of the thus obtained title substance, it was possible, based on the magnitude of the coupling constant of J1.2=1.3 Hz, to unambiguously conclude that the α-configuration on the anomeric center is the only configuration present on the anomeric center. It could thus be concluded that the title substance comes in the form of a pure α-configuration of the anomer.

Analysis of elements:

ber.: C 44.65 H 2.53 F 35.32

gef.: C 44.77 H 2.61 F 35.09

b) 1-O-(1H,1H,2H,2H-perfluorotridecyl)-α-D-mannopyranose

25 g (27.33 mmol) of the title substance from example 74a will be suspended in 400 ml of absolute methanol and mixed with one catalytic amount of sodium methanolate at 5ºC. After a reaction time of 3 hours at room temperature, thin layer chromatography control (eluent: chloroform/methanol 9:1) shows a reaction path that is quantitative. For the purpose of processing, the pure reaction solution will be neutralized by mixing with amberlite IR 120 (H+-form)-resin of the cation exchanger, removed from the exchanger and the resulting metabolic filtrate evaporated to dryness under vacuum. The resulting crystalline residue will be purified through double recrystallization from ethanol. After 1H-NMR-spectroscopy of the thus obtained title substance, it was possible to unambiguously conclude the α-configuration at the anomeric center based on the magnitude of the coupling constant of J1.2=1.0 Hz. The α-configuration present on the anomeric center is the only configuration present, which means that the amount of β-configuration possibly present on the anomer of the title substance lies below the limit, by which it is possible to prove their presence by 1H-NMR-spectroscopy. It could thus be concluded that the title substance comes in the form of a pure α-configuration of the anomer.

Yield: 16.2 g (94.6% d.Th.) of a colorless crystalline solid.

Melting point: 172-174ºC, near decomposition.

Analysis of elements:

ber.: C 30.69 H 2.41 F 51.57

gef.: C 30.57 H 2.48 F 51.65

c) Preparation of the formulation from metal complex II and 1-O-(1H,1H,2H,2H-perfluorotridecyl)-α-D-mannopyranose

A solution of 2.01 g (3.21 mmol ) of the title substance from example 74b, dissolved in 200 ml of ethanol and stirred for 2 hours at 50ºC. Then the solution is reduced to dryness in a vacuum, and the residue is detd. with water to a total of 75 ml. It is mixed for 10 min at 40ºC, then filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 75

a) 1-O-(1H,1H,2H,2H-perfluorotridecyl)-2,3,4,6-tetra-O-acetyl-α-D-mannopyranose

Conversion of 35 g (89.66 mmol) of the title substance from example 70a, which as a 4:1 mixture, in the ratio of α,β-anomers used, with one solution of 50.60 g (89.7 mmol) of 1-hydroxy -1H,1H,2H,2H-perfluorodecane in 100 ml of 1,2-dichloroethane as well as a total of 13.63 g (16.61 mmol) of tin-IV-chloride, analogously to the synthesis of the title substance from examples 1b, 4b and 5b described, leads after treatment and column chromatography (eluent: hexane/ethyl acetic acid ester, 2:1) to the formation of 62.49 g (68.7% d.Th.) of the above title substance in the form of a viscous and colorless oil . After 1H-NMR-spectroscopic analysis of the thus obtained title substance, it was possible, based on the magnitude of the coupling constant of J1.2=1.4 Hz, to unambiguously conclude that the α-configuration on the anomeric center is the only configuration present on the anomeric center. It could thus be concluded that the title substance comes in the form of a pure α-configuration of the anomer.

Analysis of elements:

ber.: C 42.62 H 2.28 F 39.32

gef.: C 42.55 H 2.38 F 39.40

b) 1-O-(1H,1H,2H,2H-perfluorododecyl)-α-D-mannopyranose

25 g (24.64 mmol) of the title substance from example 75a will be suspended in 400 ml of absolute methanol and mixed with one catalytic amount of sodium methanolate at 5ºC. After a reaction time of 3 hours at room temperature, thin layer chromatography control (eluent: chloroform/methanol 9:1) shows a reaction path that is quantitative. For the purpose of processing, the pure reaction solution will be neutralized by mixing with amberlite IR 120 (H+-form)-resin of the cation exchanger, removed from the exchanger and the resulting metabolic filtrate evaporated to dryness under vacuum. The resulting crystalline residue will be purified through double recrystallization from a mixture of 2-propanol/ethanol (1:1). After 1H-NMR-spectroscopy of the thus obtained title substance, it was possible to unambiguously conclude on the α-configuration at the anomeric center based on the magnitude of the coupling constant of J1.2=0.9 Hz. The α-configuration present on the anomeric center is the only configuration present, which means that the amount of β-configuration possibly present on the anomer of the title substance lies below the limit, by which it is possible to prove their presence by 1H-NMR-spectroscopy. It could thus be concluded that the title substance comes in the form of a pure α-configuration of the anomer.

Yield: 16.96 g (90.8% d.Th.) of a colorless crystalline solid.

Melting point: 187-188ºC, near decomposition.

Analysis of elements:

ber.: C 29.77 H 2.08 F 54.93

gef.: C 29.70 H 2.28 F 54.83

c) Preparation of the formulation from metal complex VI and 1-O-(1H,1H,2H,2H-perfluorododecyl)-α-D-mannopyranose

To 52 ml of a solution of metal complex VI (180 mmol/L) dissolved in a 0.45% sodium chloride solution, a solution of 1.70 g (2.34 mmol) of the title substance from example 75b is added and heated for 10 min in a microwave ovens. Then the solution is cooled to room temperature, then it is filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 180 mmol/Gd/L).

Example 76

a) 2,3,4,6-tetra-O-acetyl)-1-O-α-D-[3,6,9-trioxa-(C12-C19-heptadecafluoro-nonadecyl]-mannopyranose

Conversion of 20 g (51.23 mmol) of the title substance from example 70a, which as a 4:1 mixture, in the ratio of α,β-anomers used, with one solution of 30.54 g (51.23 mmol) of 1-hydroxy -tris-(1H,1H,2H,2H-O)-1H,1H,2H,2H-perfluorodecane in 100 ml of 1,2-dichloroethane as well as a total of 5.98 g (51.23 mmol) of tin-IV-chloride , analogously to the synthesis of the title substance from examples 1b, 4b and 5b described, leads after treatment and column chromatography (eluent: hexane/ethyl acetic acid ester, 1:1) to the formation of 34.22 g (72.1 % d .Th.) of the above title substance in the form of a viscous and colorless oil. After 1H-NMR spectroscopy of the thus obtained title substance, based on the magnitude of the coupling constant of J1.2=1.1 Hz, it was possible to unambiguously conclude that the α-configuration on the anomeric center is the only configuration present on the anomeric center, so that could conclude that the title substance comes in the form of the pure α-configuration of the anomer.

Analysis of elements:

ber.: C 38.89 H 3.81 F 34.86

gef.: C 39.02 H 3.77 F 34.90

b) 1-O-α-D-[3,6,9-trioxa-(C12-C19-heptadecafluoro)-nonadecyl]-mannopyranose

20 g (21.58 mmol) of the title substance from example 76a will be suspended in 350 ml of absolute methanol and mixed with one catalytic amount of sodium methanolate at 5ºC. After a reaction time of 3 hours at room temperature, thin layer chromatography control (eluent: chloroform/methanol 6:1) shows a reaction path that is quantitative. For the purpose of processing, the pure reaction solution will be neutralized by mixing with amberlite IR 120 (H+-form)-resin of the cation exchanger, removed from the exchanger and the resulting metabolic filtrate evaporated to dryness under vacuum. The resulting crystalline residue will be purified through double recrystallization from a mixture of acetic acid ethyl ester/2-propanol/ethanol (1:0.5:1). After 1H-NMR-spectroscopy of the thus obtained title substance, it was possible to conclude unambiguously on the basis of the magnitude of the coupling constant of J1.2=1.0 Hz on the α-configuration at the anomeric center. The α-configuration present on the anomeric center is the only configuration present, which means that the amount of β-configuration possibly present on the anomer of the title substance lies below the limit, by which it is possible to prove their presence by 1H-NMR-spectroscopy. It could thus be concluded that the title substance comes in the form of a pure α-configuration of the anomer.

Yield: 15.20 g (92.9% d.Th.) of a colorless crystalline solid.

Melting point: 141ºC.

Analysis of elements:

ber.: C 34.84 H 3.59 F 42.58

gef.: C 34.72 H 3.66 F 42.67

c) Preparation of the formulation from the title substance of example 68 and 1-O-α-D-[3,6,9-trioxa-(C12-C19-heptadecafluoro)-nonadecyl]-mannopyranose

A solution of 3.71 g (4 .89 mmol) of the title substance from example 76b and add 0.9% table salt solution to a total of 114 ml. Then the solution is heated for 2 hours at 60ºC in an ultrasonic bath. After that, it is cooled to room temperature, with 2N sodium alkali, the pH is adjusted to 7.4. The solution is filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 77

a) 2,3,4,6-tetra-O-acetyl-1-α-D-[3-thiopropionic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H -perfluorotridecyl)-amide]-mannopyranose

In 500 ml of dry tetrahydrofuran there will be 25.0 g (57.28 mmol); (edited by Ponpip, Mitree M; Bugianesi, Robert L.; Pobbins, James C.; Doebber, T.W.; Shen, T.Y.; J. Med. Chem.; 24; 12; 1981; 1388-1395) 3-(tetra- O-acetyl-α-D-mannopyranosylmercapto)-propionic acid, as well as 5.77 g (57.28 mmol) of triethylamine dissolved. After cooling the reaction solution to -15ºC to -20ºC, it is added at that temperature. one solution of 7.82 g (57.28 mmol) isobutyl ester of chloroformic acid in 100 ml of dry tetrahydrofuran, slowly, while the rate of addition is chosen so that the internal temp. solution does not exceed -10ºC. After a reaction time of 15 min. at -15ºC, a solution of 29.05 g (57.28 mmol) of 1H,1H,2H,2H-heptadecafluoro-1-(2-aminoethoxy)-decane and 5.77 g (57.28 mmol ) of triethylamine, as a solution in 200 ml of dry tetrahydrofuran at -20ºC. After a reaction time of 1 hour at -15ºC, as well as 2 hours at room temp. the reaction solution will be evaporated to dryness under vacuum. The remaining residue will be dissolved in 250 ml of acetic acid ethyl ester and washed twice with 200 ml of saturated sodium hydrogen carbonate solution and once with 300 ml of water. After drying org. phase over sodium sulfate, the salt will be sucked off and the ethyl ester of acetic acid will be removed in a vacuum. The remaining oily residue will be purified on Kieselgel using dichloromethane/hexane/2-propanol (8:5:1) as eluent.

Yield: 44.90 g (84.7% d.Th.) of the above title substance as a colorless and highly viscous oil.

Analysis of elements:

ber.: C 37.63 H 3.48 N 1.51 S 3.46 F 34.89

gef.: C 37.77 H 3.37 N 1.61 S 3.57 F 35.21

b) 1-α-D-[3-thiopropionic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide]-mannopyranose

30 g (32.41 mmol) of the title substance from example 77a will be suspended in 400 ml of absolute methanol and mixed with one catalytic amount of sodium methanolate at 5ºC. After a reaction time of 3 hours at room temperature, thin layer chromatography control (eluent: chloroform/methanol 9:1) shows a reaction path that is quantitative. For the purpose of processing, the pure reaction solution will be neutralized by mixing with amberlite IR 120 (H+-form)-resin of the cation exchanger, removed from the exchanger and the resulting metabolic filtrate evaporated to dryness under vacuum. The resulting crystalline residue will be purified through double recrystallization from a mixture of ethyl acetic acid/methanol (0.5:1). After 1H-NMR-spectroscopy of the thus obtained title substance, it was possible to unambiguously conclude the α-configuration at the anomeric center based on the magnitude of the coupling constant of J1.2=1.1 Hz. The α-configuration present on the anomeric center is the only configuration present, which means that the amount of β-configuration possibly present on the anomer of the title substance lies below the limit, by which it is possible to prove their presence by 1H-NMR-spectroscopy. It could thus be concluded that the title substance comes in the form of a pure α-configuration of the anomer.

Yield: 23.76 g (96.8% d.Th.) of a colorless crystalline solid.

Melting point: 113-114.5ºC.

Analysis of elements:

ber.: C 33.30 H 3.19 N 1.85 S 4.23 F 42.64

gef.: C 33.21 H 3.26 N 1.96 S 4.08 F 42.77

c) Preparation of the formulation from the title substance of example 66 and 1-α-D-[3-thiopropionic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide] -mannopyranoses

A solution of 27.41 g (36 .19 mmol) of the title substance from example 77b, dissolved in 200 ml of ethanol and stirred for 2 hours at 50ºC. The solution will be reduced to dryness in a vacuum, and the remainder with dest. topped up with water to a total of 155 ml. Then the solution is stirred for 10 min. at 40ºC, and then it is filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 78

a) 2,3,4,6-tetra-O-acetyl-1-β-D-[3,6,9-trioxa-(C12-C19-heptadecafluoro)-nonadecyl]-glucopyranosyl uronic acid

20.2 g (50.85 mmol) methyl (1-bromo-2,3,4-tri-O-acetyl-α-D-glucopyranoside)uronate (preparation according to: Pelzer; Hoppe-Seyler's Z. Physiol.Chem. : 314; 1949; 234,237 as well as Goebels; Babers; J. Biol. Chem.; 111; 1935; 347, 350 and Bollenback et al.; J. Amer.Chem.Soc.; 77; 1955; 3310-3313) and 60.64 g (101.7 mmol) of 3,6,9-trioxa-(C12-C19-heptadecafluoro)-nonadecan-1-ol will be dissolved in 250 ml of dry acetonitrile and at room temperature. with 13 g of freshly precipitated silver oxide mixed. After a reaction time of 12 hours at room temperature, the insoluble salts will be filtered off, the salts will be washed with dichloromethane and the resulting filtrate will be evaporated to dryness under vacuum. The remaining residue will be purified by column chromatography (eluent: hexane/ethyl acetate 3:1).

Yield: 22.99 g (53.3% d.Th.) of the above title substance as a colorless and highly viscous oil.

Analysis of elements:

ber.: C 41.05 H 3.92 F 38.06

gef.: C 41.20 H 3.76 F 38.22

b) 1-O-β-D-[3,6,9-trioxa-(C12-C19-heptadecafluoro)-nonadecyl]-glucopyranosyl uronic acid

10 g (11.78 mmol) of the title substance from example 78a will be suspended in 200 ml of a mixture of methanol and 0.5 M sodium alkali, in a ratio of 2:1, mixed with stirring at room temperature. After a reaction time of 12 hours at room temperature, the pure reaction solution will be neutralized by mixing with amberlite IR 120 (H+-form)-resin of the cation exchanger, removed from the exchanger, and the resulting metabolic-aqueous filtrate evaporated to dryness under vacuum. The resulting crystalline residue will be purified through double recrystallization from a mixture of ethyl acetic acid/methanol (0.25:1). After 1H-NMR-spectroscopy of the thus obtained title substance, it was possible to conclude unambiguously on the β-configuration at the anomeric center based on the magnitude of the coupling constant of J1.2=9.2 Hz. The β-configuration present is the configuration exclusively present on the anomeric center, which means that the amount of β-configuration possibly present on the anomer of the title substance lies below the limit, by which it is possible to prove their presence by 1H-NMR-spectroscopy. It could thus be concluded that the title substance comes in the form of a pure β -configuration of the anomer.

Yield: 23.76 g (96.8% d.Th.) of a colorless crystalline solid.

Melting point: 78.5ºC.

Analysis of elements:

ber.: C 34.21 H 3.26 F 41.81

gef.: C 34.38 H 3.26 F 41.90

c) Preparation of the formulation from metal complex I and 1-O-β-D-[3,6,9-trioxa-(C12-C19-heptadecafluor)-nonadecyl]-glucopyranosyl uronic acid

A solution of 19.18 g (24, 83 mmol) of the title substance from example 78b and add 0.9% table salt solution to a total of 53.2 ml. It is then heated for 2 hours at 60ºC in an ultrasonic bath. Then the solution is cooled to room temperature. and adjust to pH 7.4 with an aqueous solution of 2N sodium alkali. The solution is filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 200 mmol/Gd/L).

Example 79

a) 6-(2-oxa-1H,1H,2H,2H,4H,4H-perfluorotridecyl)-O1,O2,O3,O4-diisopropyldiene-α-D-galactopyranose

To a stirred solution of 2.01 g (70 mmol; 80% in mineral oil) of sodium hydride in 25 ml of dimethylformamide, was added at room temp. a total of 12.15 g (46.66 mmol) of O1,O2,O3,O4-diisopropyldiene-α-galactopyranose (preparation according to: Levene; Meyer; J.Biol.Chem.; 64; 1925; 473 as well as McCreath; Smith; J. Chem. Soc.; 1939; 387, 389 and Freudenberg; Hixon; Chem. Ber.; 56; 1923; 2119, 2122) dissolved in 200 ml of absolute dimethylformamide, dropwise. Continue mixing for 120 min. at room temp. and added dropwise a total of 30.09 g (48 mmol) of 1-bromo-1H,1H,2H,2H-perfluorododecane, dissolved in 150 ml of absolute dimethylformamide, slowly. The reaction solution obtained in this way will be continued for a further 12 hours at room temperature. mixed. For processing, the reaction solution will be slowly poured into 1 L of ice water and then generously extracted with diethyl ether. Thus obtained org. phases will be washed 2x each with 200 ml of saturated sodium hydrogen carbonate solution, as well as 2x each with 200 ml of water. After drying org. phase over sodium sulfate, the salt will be removed, and the solvent will be evaporated under vacuum. The remaining oily residue will be purified on Kieselgel using acetic acid ethyl ester/hexane (1:10) as an eluent.

Yield: 29.8 g (79.3% d.Th.) of the above title substance in the form of a viscous, colorless oil.

Analysis of elements:

ber.: C 35.75 H 2.87 F 49.47

gef.: C 35.64 H 2.98 F 49.54

b) 6-(2-oxa-1H,1H,3H,3H,4H,4H-perfluorodecyl)-α-D-galactopyranose

20 g (24.8 mmol) of the title substance from example 79a will be added to 300 ml of a 1% aqueous solution of sulfuric acid and stirred for 3 hours at 80ºC. After cooling to room temperature, it will be mixed with an aqueous solution of barium hydroxide, neutralized and subsequently filtered from the precipitated barium sulfate, and thus obtained a clear aqueous solution of the product, freeze-dried. Through 1H-NMR spectroscopy of the title substance, it was possible to unambiguously prove the presence of both configurations on the anomeric center, with the α/β configuration ratio after 1H-NMR spectroscopy, with 1:1,4 (α:β) on the anomeric center certain. Therefore, the above-mentioned title substance in the form of a 1:1,4 (α:β)-anomeric mixture was isolated, which means that the separation of the anomers was abandoned.

Yield: 15.28 g (98.4 % d.Th.) of the above title substance as a colorless lyophilisate.

Analysis of elements (in relation to dry substances):

ber.: C 35.75 H 2.87 F 49.47

gef.: C 35.64 H 2.98 F 49.54

c) Preparation of the formulation from the title substance from example 67 and 6-(2-oxa-1H,1H,3H,3H,4H,4H-perfluorodecyl)-α-D-galactopyranose

A solution of 1.68 g ( 2.69 mmol) of the title substance from example 79b, dissolved in 200 ml of ethanol, and stirred for 2 hours at temp. 50ºC. Then the solution is reduced to dryness in a vacuum, and the residue is detd. add water to a volume of 107.5 ml. The solution is stirred for 10 min. at 40ºC, filtered through a 0.2 μm filter. The filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 80

a) 1-O-α-D-[(1-perfluorooctylsulfonylpiperazine-4-carbonyl-)-methyl]-mannopyranose

30 g (52.8 mmol) of 1-perfluorooctylsulfonylpiperazine (preparation described in DE 196 03 033) and 31.73 g (53 mmol) of 2,3,4,6-tetra-O-benzyl-α-D-carboxymethyl-mannopyranose (preparation described in DE 197 28 954) will be dissolved in 300 ml of tetrahydrofuran. At 0ºC, 24.73 g (100 mmol) of EEDQ (1,2-dihydro-2-ethoxyquinoline-1-ethyl ester of carboxylic acid) are added and stirred for 3 hours at 0ºC, and for a further 6 hours at room temperature. After that, the solution is reduced to dryness in a vacuum, and the residue is purified by flash chromatography on Kieselgel (buffer: hexane/acetic ester 10:1). Fractions containing the product will be reduced to dryness, the residue dissolved in a mixture of 200 ml methanol/150 ml dichloromethane and hydrated over palladium/carbon (10% Pd/C, 2 g) for 8 hours. It is then filtered from the hydrogenation catalyst and the filtrate is reduced to dryness. The residue will be recrystallized from acetone/diethyl ether.

Yield: 30.39 g (73% d.Th.) wax-like, colorless solid.

Analysis of elements:

ber.: C 30.47 H 2.68 F 40.96 N 3.55 S 4.07

gef.: C 30.61 H 2.75 F 41.10 N 3.46 S 4.12

b) Preparation of the formulation from metal complex I and 1-O-α-D-[(1-perfluorooctylsulfonylpiperazine-4-carbonyl-)-methyl]-mannopyranose

4.71 g (5.97 mmol ) of the title substance from example 80a and add 0.9% table salt solution to a final volume of 55 ml. Then the mixture is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature. and with an aqueous 2N solution of sodium lye, adjust to pH 7.4. After that, it is filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 200 mmol/Gd/L).

Example 81

a) 3-oxa-2H,2H,4H,4H,5H,5H-perfluoro tridecanoic acid, sodium salt

20 g (38.3 mmol) of 3-oxa-2H,2H,4H,4H,5H,5H-perfluoro tridecanoic acid (preparation described in DE 196 03 033) will be dissolved in 300 ml of ethanol and 7.7 ml of 5N aqueous sodium lye solution added. Then it is evaporated to dryness, and the rest is dried in a vacuum dry cabinet (8 hours, 60ºC).

Yield: 20.85 g (quantitative) of a colorless, crystalline powder.

Analysis of elements:

ber.: C 26.49 H 1.11 F 59.35 Na 4.22

gef.: C 26.60 H 1.19 F 59.47 Na 4.30

b) Preparation of the formulation from metal complex I and 3-oxa-2H,2H,4H,4H,5H,5H-perfluoro tridecanoic acid, sodium salt

2.09 g (3.84 mmol ) of the title substance from example 81a and add 0.9% table salt solution to a final volume of 90 ml. Then the mixture is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature. and with an aqueous 2N solution of sodium lye, adjust to pH 7.4. After that, it is filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

c) Preparation of the formulation from metal complex I and 3-oxa-2H,2H,4H,4H,5H,5H-perfluoro tridecanoic acid, sodium salt

1.00 g (1.84 mmol ) of the title substance from example 81a and add 0.9% table salt solution to a final volume of 90 ml. Then the mixture is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature. and with an aqueous 2N solution of sodium lye, adjust to pH 7.4. After that, it is filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

d) Preparation of the formulation from metal complex I and 3-oxa-2H,2H,4H,4H,5H,5H-perfluoro tridecanoic acid, sodium salt

0.54 g (1.0 mmol ) of the title substance from example 81a and add 0.9% table salt solution to a final volume of 90 ml. Then the mixture is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature. and with an aqueous 2N solution of sodium lye, adjust to pH 7.4. After that, it is filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 82

a) 1-perfluorooctylsulfonyl-4-(3,6,9,12,15-pentaoxahexadecanoyl)-piperazine

20 g (35.2 mmol) of perfluorooctylsulfonylpiperazine (see example 80a) will be dissolved in 300 ml of dichloromethane and 5.06 g (50 mmol) of triethylamine will be added. It is then cooled to 0ºC and dripped, in a time of 20 min. 14.24 g (50 mmol) of 3,6,9,12,15-pentaoxahexanoic acid chloride and stirred for 3 hours at 0ºC. Then 400 ml of 5% aqueous solution of hydrochloric acid is added and mixed well. Org. phase is separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/methanol 15:1).

Yield: 26.44 (92% d.Th.) wax-like solid.

Analysis of elements:

ber.: C 33.83 H 3.58 N 3.43 F 39.55 S 3.93

gef.: C 33.96 H 3.66 N 3.50 F 39.67 S 3.82

b) Preparation of the formulation from metal complex I and 1-perfluorooctylsulfonyl-4-(3,6,9,12,15-pentaoxahexadecanoyl)-piperazine

4.61 g (5.64 mmol ) of the title substance from example 82a and add 0.9% table salt solution to a final volume of 66 ml. Then the mixture is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature. and with an aqueous 2N solution of sodium lye, adjust to pH 7.4. After that, it is filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 200 mmol/Gd/L).

Example 83

a) 1H,1H,2H,2H-perfluoro decyl-p-ester of toluene sulfonic acid

20 g (43.1 mmol) of 1H,1H,2H,2H-perfluorodecanol will be dissolved in 200 ml of pyridine and at 0ºC 9.53 g (50 mmol) of p-toluene sulfonic acid chloride will be added. Then it is mixed for 5 hours at room temperature. The solution will be poured into 1000 ml of ice water and left for 10 min. mixed. The precipitate is filtered off, washed with plenty of water and then crystallized from acetone.

Yield: 22.04 (97% d.Th.) colorless, crystalline solid.

Analysis of elements:

ber.: C 22.78 H 0.76 F 61.26 S 6.08

gef.: C 22.89 H 0.70 F 61.39 S 6.15

c) C18-C25-heptadeca-fluoro-3,6,9,12,15-pentaoxa-pentacosan-1-ol

20 g (37.94 mmol) of the title substance from example 83a), 35.74 g (150 mmol) of pentaethylene glycol and 1 g of 18-Krone-6 will be dissolved in 300 ml of tetrahydrofuran and 10.1 g (180 mmol) of fine potassium hydroxide powder added. It is then stirred for 10 hours at room temperature. The precipitate is filtered off, and the filtrate is reduced to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/methanol 15:1).

Yield: 5.45 (21% d.Th.) of colorless, viscous oil.

Analysis of elements:

ber.: C 35.10 H 3.68 F 47.19

gef.: C 35.22 H 3.77 F 47.10

c) Preparation of the formulation from the title substance from example 69 and C18-C25-heptadeca-fluoro-3,6,9,12,15-pentaoxa-pentacosan-1-ol

To 53 ml of a solution of the title substance from example 69 (310 mmol/L), dissolved in a 0.45% sodium chloride solution, 44.98 g (65.72 mmol) of the title substance from example 83b are added and heated for 10 min in microwave oven. Then the solution is cooled to room temperature, after which it is filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 310 mmol/Gd/L).

Example 84

a) N,N-bi(8-hydroxy-3,6-dioxa-octyl)-perfluorooctylsulfonic acid amide

15 g (29.23 mmol) of perfluorooctylsulfonic acid amide and 22.16 g (87.7 ml) of 9-(tetrahydropyrn-2-yl)-3,6,9-trioxa-nonyl chloride will be dissolved in 200 ml of acetonitrile. 41.46 g (300 mmol) of potassium carbonate and 1 g (6 mmol) of potassium iodide are added and boiled for 10 hours at reflux. The solid substance is filtered off, and the filtrate is evaporated to dryness under vacuum. The residue is dissolved in 400 ml of ethanol and 30 ml of a 10% aqueous solution of hydrochloric acid is added. Then it is mixed for 2 hours at room temperature. The pH is adjusted to 7 with sodium lye, and the solution is reduced in a vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/methanol 10:1).

Yield: 11.38 (51% d.Th.) colorless, viscous oil.

Analysis of elements:

ber.: C 31.46 H 3.43 N 1.83 F 42.30 S 4.20

gef.: C 31.59 H 3.50 N 1.90 F 42.46 S 4.08

b) Preparation of the formulation from metal complex I and N,N-bi(8-hydroxy-3,6-dioxa-octyl)-perfluorooctylsulfonic acid amide

7.91 g (10.36 mmol ) title substance from example 84a and add 0.9% aqueous table salt solution to a total of 104 ml. It is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is then cooled to room temperature, and the pH is adjusted to 7.4 with 2N sodium hydroxide solution. After that, it is filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 85

a) N,N-bi(t-butyloxycarbonylmethyl)-perfluorooctylsulfonic acid amide

20 g (38.97 mmol) of perfluorooctylsulfonic acid amide and 20.73 g (150 mol) of potassium carbonate will be dissolved in 200 ml of acetonitrile and 17.56 g (90 mmol) of bromoacetic acid tert.-butyl ester. The mixture is then boiled for 3 hours at a reflux condenser. The solid substance is filtered off, and the filtrate is evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: n-hexane/acetic ester 10:1).

Yield: 23.53 (83% d.Th.) colorless, wax-like solid.

Analysis of elements:

ber.: C 33.02 H 3.05 N 1.93 F 44.40 S 4.41

gef.: C 33.19 H 3.11 N 1.99 F 44.30 S 4.32

b) N,N-bi(carboxymethyl)-perfluorooctylsulfonic acid amide, disodium salt

23 g (31.62 mmol) of the title substance from example 85a will be dissolved in 300 ml of trifluoroacetic acid and left for 5 hours at room temperature. mixed. It is then evaporated to dryness in a vacuum and the residue is crystallized from acetone. The crystals are sucked off and dried in a vacuum at 50ºC.

Yield: 17.7 g (91% d.Th.) of a colorless, crystalline powder.

17 g (27.63 mmol) of the thus obtained di-acid will be dissolved in 100 ml of water/300 ml of ethanol and 9.2 ml of an aqueous solution of 3N sodium alkali will be added. Everything is mixed for 20 min. at room temp. and evaporate continuously in a vacuum until dry. The rest is dried in a vacuum (60ºC / 8 hours).

Usability: 18.2 g of colorless, crystalline powder.

Analysis of elements:

ber.: C 21.87 H 0.61 N 2.12 F 49.00 S 4.86 Na 6.98

gef.: C 22.00 H 0.70 N 2.20 F 49.17 S 4.93 Na 7.10

c) Preparation of the formulation from metal complex II and N,N-bi(carboxymethyl)-perfluorooctylsulfonic acid amide, disodium salt

2.89 g (4.39 mmol ) title substance from example 85b and add 0.9% aqueous table salt solution to a total of 52 ml. It is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is then cooled to room temperature, and the pH is adjusted to 7.4 with 2N sodium hydroxide solution. After that, it is filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 200 mmol/Gd/L).

Example 86

a) 1H,1H,2H,2H-perfluorododecyl monoester of sulfuric acid, sodium salt

10 g (17.73 mmol) of 1H,1H,2H,2H-perfluorododecanol will be dissolved in 300 ml of chloroform and 2.82 g (17.73 mmol) of sulfur trioxide-pyridine-complex added at 0ºC. It is stirred for 1 hour at 0ºC and continuously evaporated in a vacuum until dry. The residue is dissolved in 300 ml of ethanol and mixed with 17.8 ml of 1N aqueous sodium hydroxide solution. The solution is evaporated to dryness, and the rest is dried in a vacuum (60ºC / 2h).

Usability: 11.81 g (quantitative).

Analysis of elements:

ber.: C 21.64 H 0.61 F 59.89 S 4.81 Na 3.45

gef.: C 21.70 H 0.72 F 60.00 S 4.92 Na 3.57

b) Preparation of the formulation from metal complex VI and 1H,1H,2H,2H-perfluorododecyl monoester of sulfuric acid, sodium salt

To 38 ml of one solution of metal complex VI (290 mmol/L), dissolved in 0.45% sodium chloride solution, 4.90 g (7.35 mmol) of the title substance from example 86a is added and heated for 10 min. in a microwave oven. Then the solution is cooled to room temperature, after which it is filtered through a 0.2 μm filter, and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 290 mmol/Gd/L).

Example 87

a) 2H,2H,4H,4H,5H,5H-3-oxa-perfluoro-penta-decanoic acid, sodium salt

10 g (16.07 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluoro-penta-decanoic acid will be dissolved in 300 ml of ethanol and mixed with 16.1 ml of 1N aqueous sodium alkali solution. The solution is evaporated to dryness, and the residue is dried in a vacuum (60ºC/2h).

Yield: 10.35 g (quantitative) of one colorless, amorphous powder.

Analysis of elements:

ber.: C 26.10 H 0.94 F 61.94 Na 3.57

gef.: C 26.22 H 1.00 F 62.05 Na 3.66

b) Preparation of the formulation from the title substance from example 66 and 2H,2H,4H,4H,5H,5H-3-oxa-perfluoro-penta-decanoic acid, sodium salt

A solution of 3.36 g ( 5.21 mmol) of the title substance from example 87a, dissolved in 200 ml of ethanol and stirred for 2 hours at 50ºC. The solution is reduced to dryness under vacuum, and the residue is detd. add water up to 122 ml. It is mixed for 10 min at 40ºC, and then filtered through a 0.2 μm filter. The filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 88

a) Ethylenediamine-N,N-tetraacetic acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-monoamide

To 30 g (117.1 mmol) of EDTA-bis-anhydride suspended in 200 ml of dimethylformamide and 50 ml of pyridine, 10.14 g (20 mmol) of 1H,1H,2H,2H,4H,4H, 5H,5H-3-oxa-perfluorotridecylamine and stirred for 6 hours at 50ºC. Then add 10 ml of water, mix for 10 min at 50ºC and evaporate the rest to dryness. The rest will be dissolved in a little water and adjusted to pH 4 with glacial vinegar. The insoluble precipitate will be filtered off and chromatographed on RP-18 (buffer: acetonitrile/water/gradient).

Yield: 9.58 g (61% d.Th.) of a colorless solid.

Water content: 8%.

Analysis of elements:

ber.: C 33.64 H 3.59 N 5.35 F 41.12

gef.: C 33.51 H 3.69 N 5.44 F 41.24

b) Ethylenediamine-N,N-tetraacetic acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-monoamide, calcium salt, sodium salt

9 g (11.46 mmol) of the title substance from example 88a will be suspended in 300 ml of water and 11.4 ml of 1N aqueous sodium alkali solution will be added. 1.15 g (11.46 mmol) of calcium carbonate was continuously added and stirred for 5 hours at 50ºC. The solution will be filtered and the filtrate freeze-dried.

Yield: 9.7 g (100% d.Th.) colorless, amorphous solid.

Water content: 7.5%.

Analysis of elements:

ber.: C 31.25 H 2.98 N 4.97 F 38.20 Na 2.72 Ca 4.74

gef.: C 31.40 H 3.09 N 5.104 F 38.07 Na 2.81 Ca 4.82

c) Preparation of the formulation from the matal complex I and Ethylenediamine-N,N-tetraacetic acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-monoamide, calcium salt, sodium salt

2.54 g (3.01 mmol ) of the title substance from example 88b and topped up with a 0.9% table salt solution to a total volume of 121 ml. The solution is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature. and adjust the pH to 7.4 with 2N sodium hydroxide solution. After that, it is filtered through a 0.2 μm filter and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 89

a) 1H,1H,2H,2H-perfluorodecyl-(2,2-dimethyl-5-hydroxy-1,3-dioxepan-6-yl)-ether

30 g (64.64 mmol) of 1H,1H,2H,2H-perfluorodecanol will be dissolved in 200 ml of tetrahydrofuran and at 0ºC 1.68 g (70 mmol) of sodium hydride will be added. Then it is mixed for 2 hours at room temperature, then 4 hours at 60ºC. The solution will be placed in a metal autoclave, then 9.31 g (64.64 mmol) of 2,2-dimethyl-1,3,6-trioxa-bi-cyclo[5.1.0]octane will be added and continued for 10 hours at 150ºC heated. The reaction solution will be poured onto ice water and extracted twice with diethyl ether. The combined organic phases will be reduced to dryness, and the residue will be chromatographed on Kieselgel (buffer: dichloromethane/acetone 10:1)

Yield: 16.12 g (41% d.Th.) of a colorless solid.

Analysis of elements:

ber.: C 33.57 H 2.82 F 53.10

gef.: C 33.69 H 2.90 F 53.35

b) 1H,1H,2H,2H-perfluorodecyl-(1-hydroxymethyl-2,3-dihydroxypropyl)-ether

15 g (24.66 mmol) of the title substance from example 89a will be dissolved in 300 ml of ethanol and 30 ml of a 10% aqueous hydrochloric acid solution will be added. It is then heated for 5 hours on a reflux condenser. The pH is adjusted to 7 with sodium lye, then it is reduced to dryness, and the residue is chromatographed on RP-18 (buffer: acetonitrile (water/gradient).

Yield: 12.75 g (91% d.Th.) of a colorless solid.

Water content: 4.5%

Analysis of elements:

ber.: C 29.59 H 2.31 F 56.84

gef.: C 29.48 H 2.37 F 56.99

c) Preparation of the formulation from the title substance from example 12 from DE 99/01161 (1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-10-(N-1-methyl-3-aza- 2,5-dioxo-pentane-1,5-diyl]-1,4,7,10-tetraazacyclododecane, Gd-complex}-10-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl- 1,4,7,10-tetraazacyclododecane) and 1H,1H,2H,2H-perfluorodecyl-(1-hydroxymethyl-2,3-dihydroxypropyl)-ether

K 37 ml of one solution of 1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-10-(N-1-methyl-3-aza-2,5-dioxo-pentane-1,5 -diyl]-1,4,7,10-tetraazacyclododecane, Gd-complex}-10-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1,4,7,10-tetraazacyclododecane (300 mmol/L), dissolved in a 0.45% table salt solution (pH 7.4; 0.25 mg/L CaNa3DTPA), 9.46 g (16.65 mmol) of the title substance from example 89b are added and supplemented with with a 0.9% table salt solution to a total volume of 111 ml. The solution is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature and the pH is adjusted to 7.4 with 2N sodium hydroxide solution. After that, it is filtered through a filter of 0.2 μm and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). One solution thus obtained can be directly used in biological experiments. (Concent. is 100 mmol/Gd/L).

Example 90

a) 1H,1H,2H,2H-perfluorodecyl-[1,2-bi(2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyethyl]-ether

30 g (64.64 mmol) of 1H,1H,2H,2H-perfluorodecanol will be dissolved in 200 ml of tetrahydrofuran and at 0ºC 1.68 g (70 mmol) of sodium hydride will be added. Then it is mixed for 2 hours at room temperature, then 4 hours at 60ºC. The solution will be placed in a metal autoclave, then 15.78 g (64.64 mmol) of 1,2-bi-(2,2-dimethyl-1,3-dioxolan-4-yl)-oxirane will be added and continued for 10 hours heated to 150ºC. The reaction solution will be poured onto ice water and extracted twice with diethyl ether. The combined organic phases will be reduced to dryness, and the residue will be chromatographed on Kieselgel (buffer: dichloromethane/acetone 10:1)

Yield: 14.2 g (31% d.Th.) of a colorless solid.

Analysis of elements:

ber.: C 37.30 H 3.56 F 45.59

gef.: C 37.48 H 3.66 F 45.71

b) 1H,1H,2H,2H-perfluorodecyl-[1,2-bi(1,2-dihydroxy-ethyl)-2-hydroxyethyl]-ether

14 g (19.76 mmol) of the title substance from example 90a will be dissolved in 300 ml of ethanol and 30 ml of a 10% aqueous hydrochloric acid solution will be added. It is then heated for 5 hours on a reflux condenser. The pH is adjusted to 7 with sodium hydroxide, then it is reduced to dryness, and the residue is chromatographed on RP-18 (buffer: acetonitrile/water/gradient).

Yield: 10.55 g (85% d.Th.) of a colorless solid.

Water content: 3.2%

Analysis of elements:

ber.: C 30.59 H 2.73 F 51.41

gef.: C 30.73 H 2.81 F 51.58

c) Preparation of the formulation from the matal complex II and 1H,1H,2H,2H-perfluorodecyl-[1,2-bi(1,2-dihydroxy-ethyl)-2-hydroxyethyl]-ether

11.98 g (19.07 mmol ) of the title substance from example 90b and topped up with a 0.9% table salt solution to a total volume of 64 ml. The solution is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature. and adjust the pH to 7.4 with 2N sodium hydroxide solution. After that, it is filtered through a 0.2 μm filter and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 200 mmol/Gd/L).

Example 91

a) Perfluorooctyl sulfonic acid-N,N-bi[8-monoester-sulfuric acid, sodium salt)-3,6-dioxaoctyl]-amide

13.54 g (17.73 mmol) of the title substance from example 84a will be dissolved in 300 ml of chloroform and 2.82 g (17.73 mmol) of sulfur trioxide-pyridine-complex added at 0ºC. It is then mixed for 1 hour at 0ºC, and then dried in a vacuum. The residue is dissolved in 300 ml of ethanol and mixed with 17.8 ml of 1N sodium hydroxide solution. The solution is evaporated to dryness, and the residue is dried in a vacuum (60ºC/2h).

Usability: 17.15 g (quantitative).

Analysis of elements:

ber.: C 24.83 H 2.50 F 33.83 N 1.45 S 9.94 Na 4.75

gef.: C 24.96 H 2.62 F 33.97 N 1.53 S 10.05 Na 4.86

b) Preparation of the formulation from the material complex I and Perfluorooctyl sulfonic acid-N,N-bi[8-monoester-sulfuric acid, sodium salt)-3,6-dioxaoctyl]-amide

142.29 g (147.06 mmol ) of the title substance from example 91a and topped up with a 0.9% table salt solution to a total volume of 164 ml. The solution is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature. and adjust the pH to 7.4 with 2N sodium hydroxide solution. After that, it is filtered through a 0.2 μm filter and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 92

a) 2-(2H,2H,4H,4H,5H,5H,6H,6H-1,4-dioxaperfluorotetradec-1-yl)-Bernstein acid diethyl ester

30 g (59.03 mmol) of 1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorodecanol will be dissolved in 300 ml of tetrahydrofuran and at 0ºC 1.68 g (70 mmol) of sodium hydride will be added . Then it is mixed for 1 hour at 0ºC, then 5 hours at 40ºC. Into that 40ºC warm solution, it reaches within 10 minutes. 20.25 g (80 mmol) of 2-bromo-diethyl ester of bernsteinic acid and stirred continuously for 12 hours at the same temperature. Then add 500 ml of ice water and extract twice with 300 ml of diethyl ether. The combined organic phases will be reduced to dryness, and the residue will be chromatographed on Kieselgel (buffer: n-hexane/ethanol 20:1)

Yield: 12.05 g (30% d.Th.).

Analysis of elements:

ber.: C 35.31 H 3.11 F 47.47

gef.: C 35.19 H 3.20 F 47.59

b) 2-(2H,2H,3H,3H,5H,5H,6H,6H-1,4-dioxa-perfluorotetradec-1-yl)-Bernstein acid, disodium salt

To 11.5 g (16.90 mmol) of the title substance from example 92a, dissolved in 300 ml of methanol, 50 ml of a 3N aqueous sodium alkali solution was added and refluxed for 8 hours. It is then evaporated to dryness, and the residue is dissolved in 300 ml of water. The aqueous phase is extracted twice with 300 ml of diethyl ether. Then the aqueous phase is acidified with conc. with hydrochloric acid to pH 1 and extract twice with 300 ml of chloroform. The combined chloroform phases are dried over magnesium sulfate and reduced to dryness. Dissolve the residue in 300 ml of water and adjust the pH to 7.4 with 5% caustic soda. Finally, the rest is freeze-dried.

Yield: 10.50 g (93% d.Th.) colorless, amorphous solid.

Water content: 5.7%

Analysis of elements:

ber.: C 28.76 H 1.66 F 48.33 Na 6.88

gef.: C 28.88 H 1.71 F 48.25 Na 6.95

c) Preparation of the formulation from the matal complex II and 2-(2H,2H,3H,3H,5H,5H,6H,6H-1,4-dioxa-perfluorotetradec-1-yl)-Bernstein acid, disodium salt

1.14 g (1.71 mmol ) of the title substance from example 92b and topped up with a 0.9% table salt solution to a total volume of 154 ml. The solution is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature. and adjust the pH to 7.4 with 2N sodium hydroxide solution. After that, it is filtered through a 0.2 μm filter and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 93

a) 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid-N-(succin-2-yl)-amide

K 20 g (38.30 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid and 9.21 g (80 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide, are added at 0ºC. , 16.51 g (80 mmol) of N,N'-dicyclohexylcarbodiimide and stirred for 3 hours at the same temp. A solution of 5.10 g (38.30 mmol) of L-aspartic acid, dissolved in 300 ml of a 5% sodium carbonate solution, cooled to 0ºC, was added to the solution of the active ster prepared in this way and stirred for 2 hours at 0ºC. then everything is poured into 500 ml of ice water, the precipitated dicyclohexyl urinary substance is filtered and conc. adjust to pH 1 with hydrochloric acid. It is then extracted 3x with chloroform. United org. phases will be reduced to dryness, and the residue chromatographed on RP-18 (buffer: acetonitrile/water/gradient). The thus obtained di-acid will be dissolved in 400 ml of water and the pH adjusted to 7.4 with 1N sodium alkali. Then it is filtered, and the filtrate is freeze-dried.

Water content: 6.3%.

Yield: 21.13 g (81% d.Th.) colorless, amorphous powder.

Analysis of elements:

ber.: C 28.21 H 1.48 N 2.06 F 47.41 Na 6.75

gef.: C 28.30 H 1.53 N 2.11 F 47.53 Na 6.83

b) Preparation of the formulation from the material complex XIV and 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid-N-(succin-2-yl)-amide

To 37 ml of a solution of metal complex XIV (300 mmol/L), dissolved in a 0.45% common salt solution (pH 7.4; 0.25 mg/L CaNa3DTPA), 422 mg (0.62 mmol) of the title substance from example 93a and topped up with a 0.9% table salt solution to a total volume of 111 ml. The solution is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature. and adjust the pH to 7.4 with 2N sodium hydroxide solution. After that, it is filtered through a 0.2 μm filter and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 94

Preparation of the formulation from the title substance from example 67 and Perfluorooctane sulfonic acid, sodium salt

A solution of 1.34 g ( 2.69 mmol) of perfluorooctane sulfonic acid, sodium salt, dissolved in 200 ml of ethanol, stirred for 2 hours at 50ºC. The solution will be reduced to dryness in a vacuum, and the remainder with dest. filled with water to a volume of 108 ml. Then it is mixed for 10 min. at 40ºC and filtered through a 0.2 μm filter. The filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 95

Preparation of the formulation from the title substance from example 68 and Perfluorodecane sulfonic acid, sodium salt

To 49 ml of a solution of the title substance from example 68 (310 mmol/L), dissolved in a 0.45% sodium chloride solution, 3.03 g (5.06 mmol) of perfluorodecane sulfonic acid, sodium salt, is added and heated for 10 min. in a microwave oven. The solution is cooled to room temperature and filtered through a 0.2 μm filter. The filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 310 mmol/Gd/L).

Example 96

a) (1H,1H,2H,2H-perfluorodecyl)-5-[(1,3-dicarboxy, disodium salt)-phenyl]-ether

To 20 g (80.62 mmol) of the trisodium salt of 5-hydroxy-isophthalic acid in 300 ml of dimethylformamide, 42.5 g (80.62 mmol) of the title substance from example 14a was added and stirred for 10 hours at 60ºC. It is then poured into 1500 ml of ice water and the pH is adjusted to 1 using conc. hydrochloric acid. The extraction is done 3 times with 300 ml of chloroform. United org. phases will be reduced to dryness, and the residue chromatographed on RP-18 (buffer: acetonitrile/water/gradient). The thus obtained di-acid will be dissolved in 400 ml of water and the pH adjusted to 7.4 with 1N sodium alkali. Then it is filtered, and the filtrate is freeze-dried.

Water content: 5.0%.

Yield: 20.05 g (37% d.Th.) colorless, amorphous powder.

Analysis of elements:

ber.: C 32.16 H 1.05 F 48.05 Na 6.84

gef.: C 32.30 H 1.15 F 48.20 Na 6.95

b) Preparation of the formulation from the title substance from example 12 from WO 99/01161 (1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-10-(N-1-methyl-3-aza- 2,5-dioxo-pentane-1,5-diyl]-1,4,7,10-tetraazacyclododecane, Gd-complex}-10-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl- 1,4,7,10-tetraazacyclododecane) and 1H,1H,2H,2H-perfluorodecyl-5-[(1,3-dicarboxy, disodium salt)-phenyl]-ether

K 51 ml of one solution of 1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-10-(N-1-methyl-3-aza-2,5-dioxo-pentane-1,5 -diyl]-1,4,7,10-tetraazacyclododecane, Gd-complex}-10-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1,4,7,10-tetraazacyclododecane (300 mmol/L), dissolved in 0.45% common salt solution (pH 7.4; 0.25 mg/L CaNa3DTPA), 6.86 g (10.2 mmol) of the title substance from example 96a are added and supplemented with with a 0.9% table salt solution to a total volume of 153 ml. The solution is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature and adjusted to pH 7.4 with 2N sodium hydroxide solution. After that, it is filtered through a filter of 0.2 μm and fill the filtrate into tubes (small plastic containers of 1.5-2 ml).

A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 97

Preparation of formulation from matal complex XIV and 3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid, sodium salt

To 4 ml of one solution of metal complex XIV (320 mmol/L), dissolved in a 0.45% common salt solution (pH 7.4; 0.25 mg/L CaNa3DTPA), 434 mg (0.55 mmol) of the title substance from example 80a and add 0.9% table salt solution to a total volume of 12.8 ml. The solution is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature. and adjust the pH to 7.4 with 2N sodium hydroxide solution. After that, it is filtered through a 0.2 μm filter and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 98

a) (adamant-1-yl)-3-oxa-t-butyl ester-propionic acid

To 15.22 g (100 mmol) of 1-adamantol in 300 ml of 50% potassium hydroxide solution, 200 ml of toluene, add at 0ºC, 29.26 g (150 mmol) of tert. Bromoacetic acid butyl ester and stirred thoroughly for 2 hours. Then the mixture is poured into 1500 ml of water and extracted twice with 300 ml of diethyl ester. United org. phases will be dried over magnesium sulfate and evaporated to dryness in a vacuum. The residue will be chromatographed on Kieselgel (buffer: n-hexane/diethylether 20:1)

Yield: 21.58 g (81% d.Th.) of viscous, colorless oil.

Analysis of elements:

ber.: C 72.14 H 9.84

gef.: C 72.26 H 9.95

b) (adamant-1-yl)-3-oxa-propionic acid

20 g (75 mmol) of the title substance from example 98a will be dissolved at 0ºC in 200 ml of trifluoroacetic acid and left at room temperature for 8 hours. mixed. The mixture is evaporated to dryness and the residue is crystallized from diisopropyl ether.

Yield: 14.68 g (93% d.Th.) of colorless leaves.

Analysis of elements:

ber.: C 68.55 H 8.63

gef.: C 68.41 H 8.74

c) 1-(perfluorooctylsulfonyl)-4-[(adamant-1-yl)-oxa-propionyl]-piperazine

14 g (66.6 mmol) of the title substance from example 98b and 37.50 g (66.6 mmol) of 1-perfluorooctylsulfonyl-piperazine will be dissolved in 300 ml of tetrahydrofuran and at 0ºC 32.15 g (130 mmol) 1.2 -dihydro-2-ethoxyquinoline-1-ethyl ester of carboxylic acid (EEDQ) added. Then it is mixed for 5 hours at room temperature. The solution is reduced in a vacuum, and the residue is chromatographed on Kieselgel (buffer: dichloromethane/diethylether 30:1).

Yield: 43.05 g (85% d.Th.) of a colorless solid.

Analysis of elements:

ber.: C 37.90 H 3.31 N 3.68 S 4.22 F 42.47

gef.: C 38.04 H 3.42 N 3.49 S 4.11 F 42.30

d) Preparation of the formulation from 0.5 parts of metal complex I and 0.5 parts of the final compound from β-cyclodextrin hydrate and 1-(perfluorooctylsulfonyl)-4-[(adamant-1-yl)-oxa-propionyl]-piperazine

6.81 mg (8.96 mmol ) of the title substance from Example 98c, 10.33 g (8.96) of β-cyclodextrin monohydrate and add 0.9% common salt solution to a total volume of 98 ml. The solution is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature. and adjust the pH to 7.4 with 2N sodium hydroxide solution. After that, it is filtered through a 0.2 μm filter and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 99

a) 3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid-N-(1-adamantyl)-amide

K 15.12 g (100 mmol) of 1-amino-adamantane, 52.21 g (100 mmol) of 3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid and 11.51 g (100 mmol) N-hydroxysuccinimide, dissolved in 300 ml of tetrahydrofuran, was added at 0ºC, 30.95 g (150 mmol) of N,N-dicyclohexylcarbodiimide. Then it is mixed for 2 hours at 0ºC, and then for another 6 hours at room temperature. The precipitated urinary substance is filtered off, the filtrate is reduced to dryness and the residue is chromatographed on Kieselgel (buffer: dichloromethane/acetin 30:1).

Yield: 54.4 g (83% d.Th.) of a wax-like solid.

Analysis of elements:

ber.: C 40.32 H 3.38 N 2.14 F 49.28

gef.: C 40.47 H 3.49 N 2.03 F 49.09

b) Making a formulation from 0.6 parts of metal complex II and 0.4 parts of the final compound from β-cyclodextrin hydrate and 3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid-N-(1- adamantyl)-amide

4.48 mg (6.83

mmol) of the title substance from example 99a and 7.87 g (6.83 mmol) of β-cyclodextrin monohydrate and add 0.9% common salt solution to a total volume of 103 ml. The solution is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature. and adjust the pH to 7.4 with 2N sodium hydroxide solution. After that, it is filtered through a 0.2 μm filter and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 100

a) 2-[N-(ethyl)-N-(perfluorooctylsulfonyl)-amino]-acetic acid-N-(adamantyl)-amide

K 15.12 g (100 mmol) of 1-amino-adamantane, 58.52 g (100 mmol) of N-(ethyl)-N-(perfluorooctylsulfonyl)-amino-acetic acid and 11.51 g (100 mmol) of N- of hydroxysuccinimide, dissolved in 300 ml of tetrahydrofuran, added at 0ºC, 30.95 g (150 mmol) of N,N-dicyclohexylcarbodiimide. Then it is mixed for 2 hours at 0ºC, and then for another 6 hours at room temperature. The precipitated urinary substance is filtered off, the filtrate is reduced to dryness and the residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone 30:1).

Yield: 55.65 g (79% d.Th.) amorphous solid.

Analysis of elements:

ber.: C 37.51 H 3.29 N 1.99 F 45.85 S 4.55

gef.: C 37.64 H 3.41 N 2.12 F 45.99 S 4.43

b) Making a formulation from 0.6 parts of metal complex II and 0.4 parts of the final compound from β-cyclodextrin hydrate and 2-[N-(ethyl)-N-(perfluorooctylsulfonyl)-amino]-acetic acid-N-( adamantyl)-amide

4.20 g (5.97 mmol ) of the title substance from example 100a and 6.88 g (5.97 mmol) of β-cyclodextrin monohydrate and add 0.9% common salt solution to a total volume of 90 ml. The solution is heated for 2 hours at 60ºC in an ultrasonic bath. The solution is cooled to room temperature. and adjust the pH to 7.4 with 2N sodium hydroxide solution. After that, it is filtered through a 0.2 μm filter and the filtrate is filled into tubes (small plastic containers of 1.5-2 ml). A solution thus obtained can be used directly in biological experiments. (Conc. is 100 mmol/Gd/L).

Example 101

a) 6-N-benzyloxycarbonyl-2-N-(3,6,9,12-tetraoxatridecanoyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

To 50 g (60.20 mmol9) of the title substance from example 1c and 7.10 g (70 mmol) of triethylamine, dissolved in 350 ml of dichloromethane, a solution of 16.85 g (70 mmol) 3,6,9 ,12-tetraoxatridecanoic acid chloride in 50 ml of dichloromethane and stirred for 3 hours at 0ºC, then 200 ml of 5% hydrochloric acid solution was added and stirred for 5 min at room temperature. The organic phase was separated, dried over sodium sulfate and The residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone 15:1).

Yield: 30.94 g (92% d.Th.) colorless, thick oil.

Analysis of elements:

ber.: C 40.63 H 4.19 N 5.41 F 31.21 S 3.10

gef.: C 40.75 H 4.08 N 5.58 F 31.29 S 3.25

b) 2-N-(3,6,9,12-tetraoxatridecanoyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]

53.96 g (52.15 mmol) of the title substance from example 101a will be dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd/C) will be added. It is then hydrated at room temperature. The catalyst is filtered off, and the filtrate is evaporated to dryness under vacuum.

Yield: 43 g (quantitative) of a colorless solid.

Analysis of elements:

ber.: C 36.01 H 4.14 N 6.22 F 35.86 S 3.56

gef.: C 36.20 H 4.23 N 6.38 F 35.99 S 3.71

c) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -2-N-(3,6,9,12-tetraoxatridecanoyl)-lysine[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

21.84 (24.25 mmol) of the title substance from example 101b, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-5-methyl-5-yl)]-pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd-complex , will be dissolved in 200 ml of dimethylsulfoxide by gentle heating. At 10ºC, 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide are added and the mixture is continuously stirred overnight at room temperature. Then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 28.21 g (81% of theory) of a colorless solid.

Water content: 11.0%

Analysis of elements (calculated according to dry substance):

ber.: C 36.53 H 4.33 N 8.34 F 21.36 S 2.12 Gd 10.40

gef.: C 36.64 H 4.48 N 8.29 F 21.39 S 2.15 Gd 10.57

Example 102

a) 6-N-benzyloxycarbonyl-2-N-(propyl-sulfonic acid)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

To 50 g (60.20 mmol) of the title substance from example 1c and 7.10 g (70 mmol) of triethylamine, dissolved in 250 ml of dry tetrahydrofuran, a solution of 7.33 g (60 mmol) of propanesultone is added dropwise at 50ºC and mixed for 3 hours at 60ºC. Then add 200 ml of 5% hydrochloric acid solution and mix for 5 min. at room temp. Org. the phase is separated, dried over sodium sulfate and evaporated to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone 15:1).

Yield: 45.16 g (79% d.Th.) of colorless, thick oil.

Analysis of elements:

ber.: C 36.56 H 3.49 N 5.88 F 33.99 S 6.73

gef.: C 36.72 H 3.35 N 5.78 F 33.79 S 6.75

b) 2-N-(propyl-sulfonic acid)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

49.68 g (52.15 mmol) of the title substance from example 102a will be dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd/C) will be added. It is then hydrated at room temperature. The catalyst is filtered off, and the filtrate is reduced to dryness under vacuum.

Yield: 42.69 g (quantitative) of a colorless solid.

Analysis of elements:

ber.: C 30.81 H 3.32 N 6.84 F 39.46 S 7.83

gef.: C 30.64 H 4.1 N 6.68 F 39.29 S 7.89

c) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -2-N-(propyl-3-sulfonic acid)-lysine[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

19.85 g (24.25 mmol) of the title substance from example 102b, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol ) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-5-methyl-5-yl)]-pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd- complex, will be zu gentle heating in 200 ml of dimethylsulfoxide dissolved. At 10ºC, 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide are added and the mixture is continuously stirred overnight at room temperature. Then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 28.13 g (81% of theory) of a colorless solid.

Water content: 11.0%

Analysis of elements (calculated according to dry substance):

ber.: C 33.27 H 3.70 N 8.73 F 22.36 S 4.44 Gd 10.89

gef.: C 32.41 H 3.88 N 8.69 F 22.49 S 4.35 Gd 10.97

Example 103

a) 6-N-benzyloxycarbonyl-2-N,N-bi(propyl-3-sulfonic acid)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

A solution of 14.65 g (120 mmol) 1.3 -propanesultone in 100 ml of tetrahydrofuran and stirred for 3 hours at 60ºC. Then add 400 ml of 5% hydrochloric acid solution and mix for 5 min. at room temperature, mix with sodium chloride, separate org. phase, dry over magnesium sulfate and reduce to dryness under vacuum. The residue is chromatographed on Kieselgel (buffer: dichloromethane/acetone 15:1).

Yield: 52.24 g (81% d.Th.) of colorless, thick oil.

Analysis of elements:

ber.: C 35.76 H 3.66 N 5.21 F 30.05 S 8.95

gef.: C 35.75 H 3.55 N 5.08 F 30.19 S 9.04

b) 2-N,N-bi(propyl-3-sulfonic acid)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

53.74 g (52.12 mmol) of the title substance from example 103a will be dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd/C) will be added. It is then hydrated at room temperature. The catalyst is filtered off, and the filtrate is reduced to dryness under vacuum.

Yield: 49.06 g (quantitative) of a colorless solid.

Analysis of elements:

ber.: C 30.64 H 3.54 N 5.96 F 34.33 S 10.23

gef.: C 30.69 H 3.71 N 6.08 F 34.19 S 10.38

c) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -2-N,N-(propyl-3-sulfonic acid)-lysine[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex, disodium salt

38.76 g (24.25 mmol) of the title substance from example 103b, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol ) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-5-methyl-5-yl)]-pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd- complex, will be zu gentle heating in 200 ml of dimethylsulfoxide dissolved. At 10ºC, 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide are added and the mixture is continuously stirred overnight at room temperature. Then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 31.63 g (81% of theory) of a colorless solid.

Water content: 11.0%

Analysis of elements (calculated according to dry substance):

ber.: C 32.07 H 3.57 N 7.83 F 20.06 S 4.44 Gd 9.76 Na 2.86

gef.: C 31.94 H 3.48 N 7.69 F 20.19 S 5.85 Gd 9.87 Na 2.99

Example 104

a) N-trifluoroacetyl-1-glutamic acid-5-benzyl ester

100 g (421.5 mmol) of L-glutamic acid-5-benzyl ester will be dissolved in a mixture of 1000 ml of trifluoroacetic acid ethyl ester / 500 ml of ethanol and left for 24 hours at room temperature. mixed. The mixture is then evaporated to dryness, and the residue is crystallized from diisopropyl ether.

Yield: 140.47 g (96% of theory) of a colorless crystalline powder.

Analysis of elements:

ber.: C 50.46 H 4.23 N 4.20 F 17.10

gef.: C 51.35 H 4.18 N 4.28 F 17.03

b) 2-N-trifluoroacetyl-1-glutamic acid-5-benzyl ester-N-bi(2-hydroxyethyl)-amide

To a solution of 24.9 g (24.08 mmol) of the title substance from example 104a, 2.53 g (24.08 mmol) of diethanolamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide , 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide are added at 0ºC. Then it is mixed for 3 hours. at 0ºC, and continuously overnight at room temp. The precipitated urinary substance is filtered off, the filtrate is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/ethanol 20:1).

Yield: 9.11 g (90% theoretical) of colorless, thick oil.

Analysis of elements:

ber.: C 51.43 H 5.51 N 6.66 F 13.56

gef.: C 51.22 H 5.41 N 6.75 F 13.40

c) N-trifluoroacetyl-1-glutamic acid-N-bi(2-hydroxyethyl)-monoamide

21.92 g (52.15 mmol) of the title substance from example 104b will be dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd/C) will be added. It hydrates at room temperature. The catalyst is then filtered off, and the filtrate is reduced to dryness under vacuum.

Yield: 43.0 g (quantitative) of a colorless solid.

Analysis of elements:

ber.: C 40.01 H 5.19 N 8.48 F 17.26

gef.: C 39.84 H 5.13 N 8.68 F 17.09

d) Trifluoroacetyl-1-glutamic acid-N-bi(2-hydroxyethyl)-amide-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

K 10.96 g (33.2 mmol) of the title substance from example 104a and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl)-piperazine, (prepared according to DE 196 03 033) in 80 ml of tetrahydrofuran, are added to 0ºC 16.42 g (66.4 mmol) EEDQ (2-ethoxy-1,2-dihydroquinoline-1-ethyl ester of carboxylic acid) and stirred overnight at room temp. The precipitated substance is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/ethanol 20:1).

Yield: 30.93 g (93% theoretical) of a colorless solid.

Analysis of elements:

ber.: C 39.61 H 2.89 N 6.19 F 35.66 S 3.54

gef.: C 39.68 H 2.74 N 6.13 F 35.81 S 3.40

e) L-glutamic acid-N-bi(2-hydroxyethyl)-amide-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

4 in 200 ml of ethanol, ammonia gas is introduced at 0ºC for 1 hour. Then it is continuously stirred for 4 hours at 0ºC. It is reduced to dryness, and the rest is dissolved in water. The solid substance is filtered off and dried in a vacuum (50ºC).

Yield: 26.55 g (97% theoretical) of amorphous solid.

Analysis of elements:

ber.: C 41.12 H 2.89 N 6.19 F 35.66 S 3.54

gef.: C 41.15 H 2.83 N 6.28 F 35.78 S 3.71

e) N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-1 -glutamic acid-N-bi(2-hydroxyethyl)-amide-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amine, Gd-complex

211.96 g (24.25 mmol) of the title substance from example 104e, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol ) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-5-methyl-5-yl)]-pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd- complex, will be zu gentle heating in 200 ml of dimethylsulfoxide dissolved. At 10ºC, 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide are added and the mixture is continuously stirred overnight at room temperature. Then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 27.43 g (81% of theory) of a colorless solid.

Water content: 11.0%

Analysis of elements (calculated according to dry substance):

ber.: C 34.41 H 3.83 N 9.03 F 23.13 S 2.30 Gd 11.26

gef.: C 34.34 H 3.98 N 9.19 F 23.29 S 2.15 Gd 11.07

Example 105

a) N-trifluoroacetyl-1-glutamic acid-5-benzyl ester-N-dimethyl-bi(1,1-dihydroxymethyl)-amide

To a solution of 8.03 g (24.08 mmol) of the title substance from Example 104a, 3.98 g (24.08 mmol) of dimethyl-bi(1,1-dihydroxymethyl)-amine and 2.77 g (24, 08 mmol9 of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide, is added at 0ºC, 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide. Then it is stirred for 3 hours at 0ºC, then overnight at room temperature. Then the precipitated urine the substance is filtered off, the filtrate is reduced to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/ethanol 20:1).

Yield: 110.53 g (91% theoretical) of thick oil.

Analysis of elements:

ber.: C 50.00 H 5.66 N 7.18 F 11.86

gef.: C 50.17 H 5.82 N 7.15 F 11.80

b) N-trifluoroacetyl-1-glutamic acid-5-benzyl ester-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

20.05 g (52.15 mmol) of the title substance from example 105a will be dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd/C) will be added. Hydration is done at room temperature. then the catalyst is filtered off, and the filtrate is reduced to dryness under vacuum.

Yield: 20.36 g (quant.) of a colorless solid.

Analysis of elements:

ber.: C 40.00 H 5.42 N 7.18 F 14.60

gef.: C 40.10 H 5.53 N 7.28 F 14.69

c) N-trifluoroacetyl-1-glutamic acid-N-dimethyl-bi(1,1-dihydroxymethyl)-amide-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

K 12.96 g (33.2 mmol) of the title substance from example 105a and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl)-piperazine, (prepared according to DE 196 03 033) in 800 ml of tetrahydrofuran, are added to 0ºC 16.42 g (66.4 mmol) EEDQ (2-ethoxy-1,2-dihydroquinoline-1-ethyl ester of carboxylic acid) and stirred overnight at room temp. The precipitated substance is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/methanol 20:1).

Yield: 28.42 g (91% theoretical) of a colorless solid.

Analysis of elements:

ber.: C 31.93 H 3.00 N 5.96 F 40.40 S 3.41

gef.: C 32.08 H 2.94 N 5.88 F 40.57 S 3.31

d) L-glutamic acid-N-[dimethyl-bi(1,1-dihydroxymethyl)-amide-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

Into a solution of 28.41 g (30.2 mmol) of the title substance from example 105c in 200 ml of ethanol, ammonia in the form of gas is introduced at 0ºC for 1 hour. Then it is continuously stirred for 4 hours at 0ºC. It is reduced to dryness, and the rest is dissolved in water. The solid substance is filtered off and dried in a vacuum (50ºC).

Yield: 24.74 g (97% theoretical) amorphous solid.

Analysis of elements:

ber.: C 32.71 H 3.46 N 6.63 F 38.24 S 3.80

gef.: C 32.75 H 3.33 N 6.68 F 38.38 S 3.81

e) 2-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -1-glutamic acid-N-[dimethyl-bi(1,1-dihydroxymethyl)-amide]-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amine, Gd-complex

20.48 g (24.25 mmol) of the title substance from example 105d, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol ) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-5-methyl-5-yl)]-pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd- complex, will be zu gentle heating in 200 ml of dimethylsulfoxide dissolved. At 10ºC, 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide are added and the mixture is continuously stirred overnight at room temperature. Then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 29.05 g (83% of theory) of a colorless solid.

Water content: 11.0%

Analysis of elements (calculated according to dry substance):

ber.: C 34.12 H 3.91 N 8.73 F 22.38 S 2.22 Gd 10.90

gef.: C 34.24 H 3.98 N 8.69 F 22.39 S 2.15 Gd 10.87

Example 106

a) N-trifluoromethylacetyl-1-glutamic acid-5-benzyl ester-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

K 11.06 g (33.2 mmol) of the title substance from example 104a and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl)-piperazine, (prepared according to DE 196 03 033) in 80 ml of tetrahydrofuran, are added to 0ºC 16.42 g (66.4 mmol) EEDQ (2-ethoxy-1,2-dihydroquinoline-1-ethyl ester of carboxylic acid) and stirred overnight at room temp. The precipitated substance is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/methanol 20:1).

Yield: 27.28 g (93% theoretical) of a colorless solid.

Analysis of elements:

ber.: C 35.35 H 2.40 N 4.76 F 43.01 S 3.63

gef.: C 35.48 H 2.51 N 4.73 F 42.87 S 3.50

b) N-trifluoroacetyl-1-glutamic acid-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

21.92 g (52.15 mmol) of the title substance from example 106a will be dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd/C) will be added. Hydration is done at room temperature. The catalyst is filtered off, and the filtrate is reduced to dryness under vacuum.

Yield: 41.37 g (quantitative) of a colorless solid.

Analysis of elements (calculated according to dry substance):

ber.: C 28.76 H 1.91 N 5.30 F 47.89 S 4.04

gef.: C 28.84 H .03 N 5.28 F 47.79 S 4.19

c) N-trifluoroacetyl-1-glutamic acid-N-bi(2-hydroxyethyl)-amide-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

To a solution of 24.9 g (824.08 mmol) of the title substance from example 106a, 2.53 g (24.08 mmol) of diethanolamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide , 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide are added at 0ºC. It is mixed for 3 hours at 0ºC, then overnight at room temperature. The precipitated urine substance is filtered off, evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/ethanol 20:1).

Yield: 9.11 g (91% theoretical) of thick oil.

Analysis of elements:

ber.: C 31.37 H 2.75 N 6.36 F 43.15 S 3.64

gef.: C 31.22 H 2.61 N 6.25 F 43.30 S 3.81

d) L-glutamic acid-N-bi(2-hydroxyethyl)-amide-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

Into a solution of 26.61 g (30.22 mmol) of the title substance from example 106c in 200 ml of ethanol, ammonia in the form of gas is introduced at 0ºC for 1 hour. Then it is continuously stirred for 4 hours at 0ºC. It is reduced to dryness, and the rest is dissolved in water. The solid substance is filtered off and dried in a vacuum (50ºC).

Yield: 23.93 g (97% theoretical) of amorphous solid.

Analysis of elements:

ber.: C 30.89 H 3.09 N 6.86 F 39.56 S 3.93

gef.: C 30.75 H 3.13 N 6.75 F 39.78 S 3.81

e) N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-1 -glutamic acid-N-bi-(2-dihydroxyethyl)-amide-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amine, Gd-complex

16.43 g (24.25 mmol) of the title substance from example 106d, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol ) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-5-methyl-5-yl)]-pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd- complex, will be zu gentle heating in 200 ml of dimethylsulfoxide dissolved. At 10ºC, 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide are added and the mixture is continuously stirred overnight at room temperature. Then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 28.10 g (83% of theory) of a colorless solid.

Water content: 11.0%

Analysis of elements (calculated according to dry substance):

ber.: C 34.41 H 3.83 N 9.03 F 23.13 S 2.30 Gd 11.26

gef.: C 34.44 H 4.98 N 8.89 F 23.19 S 2.15 Gd 11.17

Example 107

a) N-trifluoroacetyl-glutamic acid-5-benzyl ester-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

K 11.06 g (33.2 mmol) of the title substance from example 104a and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (prepared according to DE 19603033) in 80 ml of tetrahydrofuran are added at 0ºC 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-ethyl ester of carboxylic acid) and stirred overnight at room temp. The precipitated substance is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/methanol 20:1).

Yield: 27.28 g (93% of theory) of a colorless solid.

Analysis of elements:

ber.: C 35.35 H 2.40 N 4.76 F 43.01 S 3.63

gef.: C 35.48 H 2.54 N 4.73 F 42.87 S 3.40

b) N-trifluoroacetyl-1-glutamic acid-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

21.92 g (52.15 mmol) of the title substance from example 107a will be dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd/C) will be added. Hydration is done at room temperature. The catalyst is filtered off, and the filtrate is reduced to dryness under vacuum.

Yield: 41.37 g (quantitative) of a colorless solid.

Analysis of elements (calculated according to dry substance):

ber.: C 28.76 H 1.91 N 5.30 F 47.89 S 4.04

gef.: C 28.84 H 1.81 N 5.28 F 47.79 S 4.16

Example 108

a) 6-N-benzyloxycarbonyl-2-N-(2,3,4,5-pentahydroxy-hexanoyl)L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

To a solution of 100 g (120.4 mmol) of the title substance from example 21c in 500 ml of dry tetrahydrofuran, a solution of 21.45 g (120.4 mol) of 5-gluconolactone in 50 ml of tetrahydrofuran is added dropwise at 50ºC. It is mixed for 3 hours at 60ºC and continuously overnight at room temperature. The precipitated substance is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/ethanol 20:1).

Yield: 98.37 g (82% theoretical) of thick oil.

Analysis of elements:

ber.: C 38.10 H 3.70 N 5.55 F 32.02 S 3.18

gef.: C 38.22 H 3.79 N 5.42 F 32.02 S 3.29

b) 2-N-(2,3,4,5-pentahydroxy-hexanoyl)L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

100.9 g (100 mmol) of the title substance from example 108a will be dissolved in 2000 ethanol and 10 g of palladium catalyst (10% Pd/C) will be added. Hydration is carried out for 12 hours at room temperature. The catalyst is filtered off, and the filtrate is reduced to dryness under vacuum.

Yield: 87.46 g (quant.) of a colorless solid.

Analysis of elements:

ber.: C 32.96 H 3.57 N 6.41 F 36.93 S 3.67

gef.: C 32.91 H 3.72 N 6.34 F 36.78 S 3.50

c) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl) )]-2-N-[1-O-α-D-carboxylmethyl-mannopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amine, Gd-complex

50 g (54.55 mmol) of the title substance from Example 21e, 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol ) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-5-methyl-5-yl)]-1,4,7,10-tetraazacyclododecane, Gd-complex, will be zu gentle heating in 400 ml of dimethylsulfoxide dissolved. At 10ºC, 16.88 g (81.8 mmol) of N,N-dicyclohexylcarbodiimide are added and the mixture is continuously stirred overnight at room temperature. Then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 75.9 g (91% of theory) of a colorless solid.

Water content: 8.6%

Analysis of elements (calculated according to dry substance):

ber.: C 35.34 H 4.09 N 8.24 F 21.12 S 2.10 Gd 10.28

gef.: C 35.28 H 4.15 N 8.19 F 21.03 S 2.15 Gd 10.14

Example 109

a) 6-N-benzyloxycarbonyl-2-N-(2,3,4,5-pentahydroxy-hexanoyl)L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

To a solution of 100 g (120.4 mmol) of the title substance from example 21c and 12.18 g (120.4 mmol) of triethylamine in 500 ml of dry tetrahydrofuran, a solution of 21.45 g (120.4 mol) of 5-gluconolactone in 50 ml of tetrahydrofuran. It is mixed for 3 hours at 60ºC and continuously overnight at room temperature. Then add 400 ml of 5% aqueous solution of hydrochloric acid, mix for 5 minutes. at room temp., mixed with sodium chloride, separated org. phase, dried over magnesium sulfate, the precipitated substance is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/ethanol 20:1).

Yield: 100.97 g (82% theoretical) of thick oil.

Analysis of elements:

ber.: C 37.58 H 3.45 N 5.48 F 31.58 S 3.14

gef.: C 37.72 H 3.59 N 5.42 F 31.72 S 3.29

b) 2-N-(2,3,4,5-pentahydroxy-hexanoyl)L-lysine-1-[(4-perfluorooctylsulfonyl)-piperazine]-amide

100.9 g (100 mmol) of the title substance from example 108a will be dissolved in 2000 ethanol and 10 g of palladium catalyst (10% Pd/C) will be added. Hydration is carried out for 12 hours at room temperature. The catalyst is filtered off, and the filtrate is reduced to dryness under vacuum.

Yield: 87.46 g (quant.) of a colorless solid.

Analysis of elements:

ber.: C 32.96 H 3.57 N 6.41 F 36.93 S 3.67

gef.: C 32.91 H 3.72 N 6.34 F 36.78 S 3.50

c) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl) )]-2-N-[1-O-α-D-carboxylmethyl-mannopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

50 g (54.55 mmol) of the title substance from Example 21e, 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol ) 1,4,7-tris(carboxylatomethyl)-10-(3-carboxy-aza-4-oxo-5-methyl-pent-5-yl)]-1,4,7,10-tetraazacyclododecane, Gd-complex , will be dissolved in 400 ml of dimethylsulfoxide by gentle heating. At 10ºC, 16.88 g (81.8 mmol) of N,N-dicyclohexylcarbodiimide are added and the mixture is continuously stirred overnight at room temperature. Then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 75.9 g (91% of theory) of a colorless solid.

Water content: 8.6%

Analysis of elements (calculated according to dry substance):

ber.: C 35.34 H 4.09 N 8.24 F 21.12 S 2.10 Gd 10.28

gef.: C 35.28 H 4.15 N 8.19 F 21.03 S 2.15 Gd 10.14

Example 110

a) 6-N-benzyloxycarbonyl-2-N-[1-O-α-D-carboxylmethyl-(2,3,4,6-tetra-O-benzyl-glucopyranose]-1-lysine-[1-(4 -perfluorooctylsulfonyl)-piperazine]-amide

To a solution of 100 g (120.4 mol) of the title substance from example 21c, 72.1 g (120.4 mol) of 1-O-α-D-carboxylmethyl-2,3,4,6-tetra-O-benzyl -glucopyranose and 13.86 g (120.4 mol) of N-hydroxysuccinimide, dissolved in 500 ml of dimethylformamide, were added at 0ºC to 41.27 g (200 mmol) of N,N-dicyclohexylcarbidiimide. Then it is stirred for 3 hours at 0ºC and continuously overnight at room temperature. The precipitated urine substance is filtered off, the filtrate is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/ethanol 20:1).

Yield: 136.1 g (87% according to theory) of thick oil.

Analysis of elements:

ber.: C 57.32 H 4.89 N 4.31 F 24.86 S 2.47

gef.: C 57.48 H 5.04 N 4.20 F 24.69 S 2.38

b) 2-N-[1-O-α-D-carboxylmethylglucopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

130 g (100 mmol) of the title substance from example 110a will be dissolved in 2000 ethanol and 10 g of palladium catalyst (10% Pd/C) will be added. Hydration is carried out for 12 hours at room temperature. The catalyst is filtered off, and the filtrate is reduced to dryness under vacuum.

Yield: 91.7 g (quant.) of a colorless solid.

Analysis of elements:

ber.: C 34.07 H 3.63 N 6.11 F 35.24 S 3.50

gef.: C 33.92 H 3.71 N 6.02 F 35.33 S 3.42

c) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl) )]-2-N-[1-O-α-D-carboxylmethyl-mannopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

50 g (54.55 mmol) of the title substance from example 21e, 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol ) 1,4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methyl-pent-5-yl)]-1,4,7,10-tetraazacyclododecane, Gd-complex , will be dissolved in 400 ml of dimethylsulfoxide by gentle heating. At 10ºC, 16.88 g (81.8 mmol) of N,N-dicyclohexylcarbodiimide are added and the mixture is continuously stirred overnight at room temperature. Then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 75.9 g (91% of theory) of a colorless solid.

Water content: 8.6%

Analysis of elements (calculated according to dry substance):

ber.: C 35.34 H 4.09 N 8.24 F 21.12 S 2.10 Gd 10.28

gef.: C 35.26 H 4.18 N 8.14 F 21.01 S 2.158 Gd 10.13

Example 111

a) 6-N-benzyloxycarbonyl-2-N-[1-O-α-D-carboxylmethyl-(2,3,4,6-tetra-O-benzyl-galactopyranose]-1-lysine-[1-(4 -perfluorooctylsulfonyl)-piperazine]-amide

To a solution of 50 g (60.2 mol) of the title substance from example 21c, 36.05 g (60.2 mol) of 1-O-α-D-carboxylmethyl-2,3,4,6-tetra-O-benzyl -galactopyranose and 6.93 g (60.2 mmol) of N-hydroxysuccinimide, dissolved in 500 ml of dimethylformamide, were added at 0ºC to 20.64 g (100 mmol) of N,N-dicyclohexylcarbidiimide. Then it is stirred for 3 hours at 0ºC and continuously overnight at room temperature. The precipitated urine substance is filtered off, the filtrate is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/ethanol 20:1).

Yield: 68.1 g (87% according to theory) of thick oil.

Analysis of elements:

ber.: C 57.32 H 4.89 N 4.31 F 24.86 S 2.47

gef.: C 57.47 H 5.05 N 4.19 F 24.72 S 2.29

b) 2-N-[1-O-α-D-carboxylmethyl-galactopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

65 g (50 mmol) of the title substance from example 111a will be dissolved in 1000 ml of ethanol and 5 g of palladium catalyst (10% Pd/C) will be added. Hydration is carried out for 12 hours at room temperature. The catalyst is filtered off, and the filtrate is reduced to dryness under vacuum.

Yield: 45.85 g (quant.) of a colorless solid.

Analysis of elements:

ber.: C 34.07 H 3.63 N 6.11 F 35.24 S 3.50

gef.: C 33.93 H 3.74 N 6.01 F 35.05 S 3.39

c) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl) )]-2-N-[1-O-α-D-carboxylmethyl-galactopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

50 g (54.55 mmol) of the title substance from example 111b, 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol ) 1,4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methyl-pent-5-yl)]-1,4,7,10-tetraazacyclododecane, Gd-complex , will be dissolved in 400 ml of dimethylsulfoxide by gentle heating. At 10ºC, 16.88 g (81.8 mmol) of N,N-dicyclohexylcarbodiimide are added and the mixture is continuously stirred overnight at room temperature. Then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 37.95 g (91% of theory) of a colorless solid.

Water content: 8.6%

Analysis of elements (calculated according to dry substance):

ber.: C 35.34 H 4.09 N 8.24 F 21.12 S 2.10 Gd 10.28

gef.: C 35.22 H 4.17 N 8.18 F 20.91 S 2.19 Gd 10.12

Example 112

a) N-trifluoroacetyl-1-glutamic acid mono-benzyl ester

100 g (421.5 mmol) of L-glutamic acid-mono-benzyl ester will be dissolved in a mixture of 1000 ml of trifluoroacetic acid ethyl ester / 500 ml of ethanol and left for 24 hours at room temperature. mixed. It is then evaporated to dryness, and the residue is crystallized from diisopropyl ether.

Yield: 140.47 g (96% according to theory) of a colorless crystalline powder.

Analysis of elements (calculated according to dry substance):

ber.: C 50.46 H 4.23 N 4.20 F 17.10

gef.: C 51.35 H 4.28 N 8.18 F 17.03

b) 2-N-trifluoroacetyl-1-glutamic acid-mono-benzyl ester-5-N-(methyl)-N-(2,3,4,5-pentahydroxy-hexyl)-amide

To a solution of 24.9 g (24.08 mmol) of the title substance from example 112a and 2x g (24.08 mmol) of N-methylglucamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide, a solution of 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is added dropwise at 0ºC. It is mixed for 3 hours at 0ºC and continuously overnight at room temperature. The precipitated urinary substance is filtered off, the filtrate is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/ethanol 20:1).

Yield: 9.xx g (89 % theoretical.) of thick oil.

Analysis of elements:

ber.: C 51.43 H 5.51 N 6.66 F 13.56

gef.: C 51.22 H 5.41 N 6.75 F 13.40

c) N-trifluoroacetyl-1-glutamic acid-(N)-methyl-N-(2,3,4,5-pentahydroxy-hexyl)-amide

21.9xx g (52.15 mmol) of the title substance from example 112b will be dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd/C) will be added. It hydrates at room temperature. The catalyst is filtered off, and the filtrate is reduced to dryness under vacuum.

Yield: 43 g (quantitative) of a colorless solid.

Analysis of elements (calculated according to dry substance):

ber.: C 40.01 H 5.19 N 8.48 F 17.26

gef.: C 39.84 H 5.13 N 8.68 F 17.09

d) Trifluoroacetyl-1-glutamic acid-5-N-(methyl)-N-(2,3,4,5-pentahydroxy-hexyl)-amide-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

K 10.96 g (33.2 mmol) of the title substance from example 112c and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (prepared according to DE 19603033) in 80 ml of tetrahydrofuran are added at 0ºC 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-ethyl ester of carboxylic acid) and stirred overnight at room temperature. The precipitated substance is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/methanol 20:1).

Yield: 28.67 g (92% theoretical) of thick oil.

Analysis of elements:

ber.: C 39.61 H 2.89 F 35.66 N 6.19 S 3.54

gef.: C 39.68 H 2.74 F 35.81 N 6.13 S 3.40

e) L-glutamic acid-5-N-(methyl)-N-(2,3,4,5-pentahydroxy-hexyl)-amide-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

Ammonia gas is introduced into a solution of 28.36 g (30.22 mmol) of the title substance from example 112d and 200 ml of ethanol at 0ºC for 1 hour. It is then stirred for 4 hours at 0ºC. It is evaporated to dryness, and the rest is separated from the water. The precipitated substance is filtered off and dried in a vacuum (50ºC).

Yield: 24.19 g (95% theoretical) amorphous solid.

Analysis of elements:

ber.: C 41.12 H 2.89 F 35.66 N 6.19 S 3.54

gef.: C 41.15 H 2.83 F 35.78 N 6.28 S 3.71

f) N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -1-glutamic acid-5-N-(methyl)-N-(2,3,4,5-pentahydroxy-hexyl)-amide-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex

20.43 g (24.25 mmol) of the title substance from example 112e, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol ) 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-5-methyl-pent-5-yl)pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd- complex, will be zu gentle heating in 200 ml of dimethylsulfoxide dissolved. At 10ºC, 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide are added and the mixture is continuously stirred overnight at room temperature. Then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 28.45 g (79% of theory) of a colorless solid.

Water content: 11.0%

Analysis of elements (calculated according to dry substance):

ber.: C 34.41 H 3.83 N 9.03 F 23.13 S 2.30 Gd 11.26

gef.: C 34.34 H 3.98 N 9.19 F 23.29 S 2.15 Gd 11.07

Example 113

a) 6-N-benzyloxycarbonyl-2-N-[1-O-α-D-carboxylmethyl-(2,3,4-tri-O-benzyl-glucuronic acid-benzyl ester]-1-lysine-[1-( 4-Perfluorooctylsulfonyl)-piperazine]-amide

To a solution from 100 g (120.4 mol) of the title substance from example 21c, 73.77 g (120.4 mol) of 1-O-α-D-carboxylmethyl-2,3,4-tri-O-benzyl-glucuronic acid-benzyl ester and 13.86 g (120.4 mmol) of N-hydroxysuccinimide, dissolved in 500 ml of dimethylformamide, were added at 0ºC to 41.27 g (200 mmol) of N,N-dicyclohexylcarbidiimide. Then it is stirred for 3 hours at 0ºC and continuously overnight at room temperature. The precipitated urine substance is filtered off, the filtrate is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/ethanol 20:1).

Yield: 147.58 g (86% according to theory) of thick oil.

Analysis of elements:

ber.: C 52.25 H 4.31 N 3.93 F 22.66 S 2.45

gef.: C 52.38 H 4.17 N 4.12 F 22.78 S 2.39

b) 2-N-[1-O-α-D-carboxylmethyl-glucuronic acid]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

142.52 g (100 mmol) of the title substance from example 113a will be dissolved in 2000 ml of ethanol and 10 g of palladium catalyst (10% Pd/C) will be added. It is hydrated for 12 hours at room temperature. The catalyst is filtered off, and the filtrate is evaporated to dryness under vacuum.

Yield: 93.06 g (quantitative) of a colorless solid.

Analysis of elements:

ber.: C 33.56 H 3.36 N 6.02 S 3.45 F 34.71

gef.: C 33.31 H 3.42 N 6.04 S 3.40 F 35.51

c) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl) )]-2-N-[1-O-α-D-carboxylmethyl-glucuronic acid]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex, sodium salt

50.76 g (54.55 mmol) of the title substance from example 113b, 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54, 55 mmol) 1,4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methyl-pent-5-yl)]-1,4,7,10-tetraazacyclododecane, Gd -complex, will be dissolved in 400 ml of dimethylsulfoxide by gentle heating. At 10ºC, 16.88 g (81.8 mmol) of N,N-dicyclohexylcarbodiimide are added and the mixture is continuously stirred overnight at room temperature. Then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 75.14.9 g (88% of theory) of a colorless solid.

Water content: 8.6%

Analysis of elements (calculated according to dry substance):

ber.: C 35.53 H 3.80 N 8.05 Na 1.47 F 20.63 S 2.05 Gd 10.05

gef.: C 34.38 H 3.95 N 8.19 Na 1.63 F 20.83 S 2.15 Gd 10.14

Example 114

a) 6-N-benzyloxycarbonyl-2-N-[2-(N-ethyl-N-perfluorooctylsulfonyl]-amino]-acetyl-1-lysine

31.82 g (113.5 mmol) of 6-N-benzyloxycarbonyl-1-lysine and 66.42 g (113.5 mmol) of 2-(N-ethyl-N-perfluorooctylsulfonyl]-amino acetic acid (prepared according to DE 196 03 033) in 300 ml of tetrahydrofuran, add 49.46 g (200 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-ethyl ester of carboxylic acid) at 0ºc and stir overnight at room temperature. Precipitated substance is evaporated to dryness under vacuum and chromatographed on Kieselgel (buffer: dichloromethane/methanol 20:1).

Yield: 55.79 g (58% theoretical) of a colorless solid.

Analysis of elements:

ber.: C 36.85 H 3.09 F 38.11 N 4.96 S 3.78

gef.: C 36.85 H 3.19 F 38.28 N 4.87 S 3.95

b) 6-N-benzyloxycarbonyl-2-N-[2-(N-ethyl-N-perfluorooctylsulfonyl]-amino]-acetyl-1-lysine-N-methyl-N-(2,3,4,5,6 -pentahydroxy-hexyl)-amine

To a solution of 51.02 g (60.2 mol) of the title substance from example 114a, 11.75 g (60.2 mol) of N-methyl-glucamine and 6.93 g (60.2 mmol) of N-hydroxysuccinimide, dissolved in 250 ml of dimethylformamide, 20.64 g (100 mmol) of N,N-dicyclohexylcarbidiimide are added at 0ºC. Then it is stirred for 3 hours at 0ºC and continuously overnight at room temperature. The precipitated urine substance is filtered off, the filtrate is evaporated to dryness under vacuum and chromatographed on Kieselgel.

(buffer: dichloromethane/ethanol 20:1).

Yield: 53.05 g (86% according to theory) of thick oil.

Analysis of elements:

ber.: C 38.68 H 4.03 N 5.47 F 31.52 S 3.13

gef.: C 38.49 H 4.17 N 5.32 F 31.70 S 3.29

c) 2-N-[2-(N-ethyl-N-perfluorooctylsulfonyl]-amino]-acetyl-1-lysine-N-methyl-N-(2,3,4,5,6-pentahydroxy-hexyl)- amide

102.48 g (100 mmol) of the title substance from example 114a will be dissolved in 2000 ml of ethanol and 10 g of palladium catalyst (10% Pd/C) will be added. It is hydrated for 12 hours at room temperature. The catalyst is filtered off, and the filtrate is evaporated to dryness under vacuum.

Yield: 89.06 g (quantitative) of a colorless solid.

Analysis of elements:

ber.: C 33.72 H 3.96 N 6.29 S 3.60 F 36.26

gef.: C 33.91 H 3.82 N 6.14 S 3.47 F 36.31

d) 6-N-[1,4,7-tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5- il)]-2-N-[2-(N-ethyl-N-perfluorooctylsulfonyl]-amino]-acetyl-1-lysine-N-methyl-N-(2,3,4,5,6-pentahydroxy-hexyl )-amide, Gd-complex

48.58 g (54.55 mmol) of the title substance from Example 114, 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54, 55 mmol) 1,4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methyl-pent-5-yl)]-1,4,7,10-tetraazacyclododecane, Gd -complex, will be dissolved in 400 ml of dimethylsulfoxide by gentle heating. At 10ºC, 16.88 g (81.8 mmol) of N,N-dicyclohexylcarbodiimide are added and the mixture is continuously stirred overnight at room temperature. Then the solution is poured into 3000 ml of acetone and stirred for 10 min. The precipitated substance is filtered off and further purified by chromatography (Kieselgel RP-18, buffer: water/ethanol/acetonitrile gradient).

Yield: 73.27 g (89.4% of theory) of a colorless solid.

Water content: 8.6%

Analysis of elements (calculated according to dry substance):

ber.: C 35.18 H 4.23 N 4.23 F 21.50 S 2.13 Gd 10.47

gef.: C 35.28 H 4.15 N 4.19 F 21.33 S 2.18 Gd 10.61

Example 115:

MRT-display of arteriosclerotic plaque after intravenous application of the invention of the presented metal complexes

In rabbits with genetically induced arteriosclerosis (Watanabe rabbits), it was possible for 5-60 min. as well as 24 h and 48 h after intravenous application of 25 μmol Gd/kg KGW by the invention of the presented compounds in T1-valid-echo gradient-images (TR 11.1 ms, TE 4.3 ms, Flipwinkel α 15º) a significant increase in arteriosclerotic plaques was observed. The healthy vessel wall showed no or very little uptake of contrast agents and thus showed no or very little signal enhancement in T1-weighted images. Based on the contrast between the plaque, which is rich in signals, and the vessel wall, which did not show signals, the diagnosis of arteriosclerotic changes on the vessel walls was possible.

Figure 1 shows MR images of the aorta, as well as 24h and 48h after intravenous application of 25 μmol Gd/kg KGW metal complex XV in Watanabe-kunić (genetically induced arteriosclerosis). T1-weighted gradient-echo scans (1.5 T; TR: 11.1 ms, TE: 4.3 ms; NA:2; matrix: 213*256; layer thickness: 1.0 mm) showed a single strong signal enhancement in arteriosclerotic plaque. Plaque localization, especially in the arch of the aorta, as well as at the exits from the blood vessel, was confirmed by Sudan-3 staining.

Example 116:

MRT-image of arteriosclerotic plaque after intravenous application of metal complex XV in rats, as well as post mortem correlation. Formation with Sudan-III-staining

Figure 2 shows MR images of the aorta, as well as 35, 60 min and 24 h after intravenous application of 10 μmol Gd/kg KGW Gad metal complex XV in Watanabe-kunićia (genetically induced arteriosclerosis). T1-weighted-echo gradient-imaging (MPRage; 1.5 T; TR 11.1 ms, TE 4.3 ms, NA: 2; matrix: 213*256; layer thickness: 1.0 mm) showed a significant increase in arteriosclerotic plaques. Localization of the plaque, especially in the arch of the aorta, as well as at the exits from the blood vessel, was confirmed by Sudan-III staining. Next was the creation of MR, which was placed in agar preparations and repeated with one T1-gradient-echo sequence (MPRage; 1.5T; TR 11.1 ms, TE 4.3 ms, Flipwinkel α 15º; NA:2; matrix: 213*256 ), as well as one spin-echo sequence (1.5T; TR 400 ms, TE 15 ms, NA:16; matrix: 256*256) was investigated (post mortem image). At the same time, an extraordinary correlation of the aorta sections with a strong signal and colored plaque was shown, which confirms the imaging by the invention of the presented compounds in the arteriosclerotic plaque.

Example 117:

Image of infarction (MRT) after intravenous administration of metal complex XV in rats

Figure 3 shows cardiac MR images (in vivo and post mortem) 24 hours after intravenous administration of 100 μmol Gd/kg KGW metal complex XV in rats acutely induced with heart infarction. T1-spin-echo-scans (1.5T; TR 400 ms, TE 6 ms, NA: 4; layer thickness: 2.5 mm) revealed strong signal enhancement in the infarct area.

Successful induction of one acute myocardial infarction was confirmed by NBT-staining.

Metal complex XV, 100 μmol i.v.; T1-SE, TR/TE 400/6 ms; arrow: myocardial infarction.

Example 118:

Image of infarction (MRT) after intravenous administration of metal complex I in rats

Figures 4 show cardiac MR images (in vivo and post mortem) 24 hours after intravenous administration of 100 μmol Gd/kg KGW metal complex I in rats acutely induced with heart infarction. T1-spin-echo-scan (1.5T; TR 400 ms, TE 6 ms, NA: 4; matrix: 128*128; layer thickness: 2.5 mm) revealed a strong signal increase in the infarct area.

Successful induction of one acute myocardial infarction was confirmed by NBT-staining.

Example 119:

Image of a lymph node (MRT) after intravenous administration of metal complex XV in a rabbit bearing a VX2 tumor

Figure 5 shows MR images of iliac lymph nodes, precontrast as well as up to 24 h after intravenous application of 200 μmol Gd/kg KGW metal complex XV in rabbits with i.m. implanted VX2-tumor. T1-gradient-echo-scans (1.5T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15º) clarified a strong signal enhancement in a healthy lymph node. Zones without increased signal inside the lymph node were diagnosed as metastases and proved histologically (by H/E staining of the lymph node section). Later (24h) after the application of the contrast agent, a reversal of the signal could be observed, surprisingly. The signal increase in the healthy lymph node was reduced, in contrast, metastases now showed a significant increase in signal.

Surprisingly, immediately after the application, a significant increase in the primary tumor (especially the peripheral one) could be observed. Later (24 h p.i.), the enlargement spread towards the center of the tumor.

Example 120:

Imaging of tumors (MRT) after intravenous application of metal complex I in rabbits, carriers of VX2-tumors

Figure 6 shows MR images of one iliac lymph node as well as the primary tumor (i.m. implanted VX2-tumor) with pre-contrast; 60 min. as well as 20 h after intravenous application of 100 μmol Gd/kg KGW metal complex I in rabbits. T1-gradient-echo-images (1.5T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15º) clarified the strength of the signal increase in the healthy tissue of the lymph node.

Earlier after the application (60 min. p.i.) a significant increase of the primary tumor (especially in the periphery) could be observed.

In the second time period (20 h p.i.), the signal amplification also extends to the central region of the tumor.

It is particularly significant that the increase of one pathological structure (possibly secondary tumors or necrosis) on the contralateral side, which was only visible in later scans ("late enhancement").

Metal complex X

Example 121:

Image of infarction (MRT) after intravenous administration of contrast medium in rats

Figure 7 shows MR images of the heart (in vivo and post mortem) 6 h after intravenous administration of 100 μmol Gd/kg KGW of a polar Gd-chelate with perfluorinated side chains (metal complex X) in rats with acutely induced heart infarction. T1, EKG-spin-echo-recordings (1.5T; TR (effective) 400 ms, TE 12 ms, NA: 4; matrix: 128*128; layer thickness: 2.5 mm) clarified the strength of the signal increase in the infarct area . Successful induction of one acute myocardial infarction was confirmed by NBT-staining.

Example 122:

Organ distribution (including accumulation in lymph nodes) after intravenous contrast agent administration in rats

After intravenous administration of 100 μmol total gadolinium/kg KGW of a polar Gd-chelate with perfluorinated side chains (metal complex X) in rats, there was 24 h post-administration the metal content in various organs as well as in lymph nodes (collected as mesenteric and peripheral lymph nodes) determined (MW, n=2).

[image]

Example 123:

Imaging of lymph nodes (MRT) after intravenous contrast agent administration in rats

Figure 8 shows precontrast as well as 60 min. after intravenous application of 100 μmol Gd/kg KGW metal complex X in rats.

T1-gradient-echo-imaging (1.5T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15º) clarified the signal strength in healthy lymph node tissue already at a very early stage after injection. Thus, the increase amounted to 263% at the time of 15 min. p.i. (post injection) and 254% at 60 min. p.i.

Example 124:

Imaging of the lymph node (MRT) after intravenous contrast agent application in a rabbit with VX2-tumor

Figure 9 shows an example of an MR image of the iliac lymph nodes, precontrast as well as 60 min. after intravenous application of 200 μmol Gd/kg KGW metal complex X in rabbits with i.m. implanted VX2-tumor. T1-gradient-echo-image (1.5T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15º) clarify the strong signal in the healthy tissue of the lymph node. The increase in a healthy lymph node is 382% at the time of 15 min. p.i. and 419% at the time of 60 min. p.i.. The no-signal zone within the lymph node was diagnosed as a metastasis and histologically (H/E-staining of the lymph node section) proven. The signal intensity ratio of healthy lymph node tissue compared to metastasis was 3.0 at 15 min. p.i. and 3.4 at 60 min p.i.

Surprisingly, already after the application, a significant increase not only in the lymph node, but also in the primary tumor (especially the periphery) could be observed (up to 24 h p.i.), this increase also spreads in the direction of the center of the tumor (24 h p.i.: 217%).

Metal complex V

Example 125:

Image of infarction (MRT) after intravenous administration of contrast medium in rats

Figure 10 shows MR images of the heart (in vivo and post mortem) 24 h after intravenous administration of 100 μmol Gd/kg KGW of a polar Gd-chelate with perfluorinated side chains (metal complex V) in rats with acutely induced heart infarction. T1, EKG-spin-echo-recording (1.5T; TR (effective): 400 ms, TE 12 ms; NA: 4; matrix: 128*128; layer thickness: 2.5 mm) clarify the strong signal increase in the infarct area . The successful induction of an acute myocardial infarction will be demonstrated by means of NBT-staining.

Example 126:

Organ distribution (including accumulation in lymph nodes) after intravenous contrast agent administration in rats

After intravenous administration of 200 μmol of total gadolinium/kg KGW of a polar Gd-chelate with perfluorinated side chains (metal complex V) in rats, the metal content in various organs as well as in lymph nodes (accumulated in mesenteric and peripheral lymph nodes) will be 24 h after application ) determined (MW, n=2).

[image]

Example 127:

Imaging of lymph nodes (MRT) after intravenous contrast agent administration in rats

Figure 11 shows an example of an MR image of an iliac lymph node precontrast as well as up to 60 min after intravenous administration of 200 μmol Gd/kg KGW metal complex V in rats. T1-gradient-echo scan (1.5T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms; α 15º) clarify the strong signal increase in the healthy lymph node already at a very early moment after the injection. Thus, the increase was 147% at the time of 15 min. p.i. and 230% at the moment 60 min p.i..

Example 128:

Imaging of the lymph node (MRT) after intravenous contrast agent administration in rabbits with VX2-tumor

Figure 12 shows appropriate MR images of iliac lymph nodes pre-contrast as well as 60 min after intravenous administration of 200 μmol Gd/kg KGW metal complex V in rabbits with i.m. implanted VX2-tumor. T1-gradient-echo scan (1.5T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms; α 15º) clarify the strong signal enhancement in the healthy tissue of the lymph node. The increase in healthy lymph node tissue was 246% at 15 min p.i. and 282% at 60 min p.i.. Zones without signal increase within the lymph node were diagnosed as metastases and histologically (H/E-staining of lymph node sections) injured. The signal intensity ratio of healthy lymph node tissue to metastases was 2.5 at 15 min. p.i. and 1.7 at the moment 60 min p.i..

Surprisingly, immediately after the application, a significant increase not only in the lymph node, but also in the primary tumor (especially in the periphery) could be observed (15 min p.i. 350%). At a later point in time (up to 24 h p.i.), the increase also spread in the direction of the tumor center (24 h p.i.: 106%).

Metal complex XIV

Example 129:

Image of infarction (MRT) after intravenous administration of contrast medium in rats

Figure 13 shows MR images of the heart (in vivo and post mortem) after intravenous administration of 100 μmol Gd/kg KGW of a polar Gd-chelate with perfluorinated side chains (metal complex XIV) in rats with acutely induced heart infarction. T1-EKG-spin-echo recordings (1.5T; TR (effective): 400 ms, TE 12 ms; NA: 4; matrix: 128*128; layer thickness: 2.5 mm) clarify signal amplification in the infarct area. Successful induction of one acute myocardial infarction was confirmed by NBT-staining.

Example 130:

Accumulation in organs (including tumor and lymph node accumulation) after intravenous administration of contrast medium in rats with prostate cancer

After intravenous administration of 200 μmol Gd/kg KGW of a polar Gd-chelate with perfluorinated side chains (metal complex XIV) in rats (Cop-fertilization, with 12 days previously i.m. implanted prostate cancer Dunning R3327 MAT-Lu) was 10 min, 1 and 24 hours after application metal content in different organs, in tumor as well as in lymph nodes (collected as mesenteric and peripheral lymph nodes) was determined (MW ± SD, n=3).

[image]

Clarification: Leber=liver; Milz=spleen; Pancreas=pancreas; Niere=kidney; Lunge=lung; Herz=heart; Gehirn=brain; Muskel=muscle; Tumor = tumor; Femur=thigh bone; month LK= mezent. Lymph node; periph. LK= peripheral lymph node; Magen(entleert)=stomach, emptied; Blut=blood; Restkorper=rest of the body;

* Blutproben sind im Restkorper enthalten = blood samples are contained in the rest of the body

** 58 ml Blut/kg KGW = 58 ml blood/kg KGW (body weight)

*** Bilanz ohne Blutwerte, da diese im Restkorper enthalten = balance without values for blood, which are contained in the rest of the body

**** nur Gewebealiquot = tissue aliquot only

Example 131:

Imaging of lymph nodes (MRT) after intravenous contrast agent administration in guinea pigs

Figure 14 shows exemplary MR images of iliac and inlingual lymph nodes pre-contrast as well as up to 24 h after intravenous application of 200 μmol Gd/kg KGW metal complex XIV in guinea pigs with stimulated lymph nodes (Freund Adjuvant). T1-gradient-echo scans (2.0T; TR: 10 ms, TE 5 ms; α 40º) clarify the signal enhancement in the healthy tissue of the lymph nodes already at a very early moment after the injection. Thus, the increase was 127% at 60 min p.i..

Example 132:

Imaging of lymph nodes (MRT) after intravenous contrast agent application in rabbits with VX2-t-tumor

Figure 15 shows exemplary MR images of iliac lymph nodes pre-contrast as well as 23 h after intravenous application of 200 μmol Gd/kg KGW metal complex XIV in rabbits with i.m. of the implanted VX2-tumor. T1-gradient-echo scans (1.5T; sequence: MPRange; TR: 11.1 ms, TE 4.3 ms; α 15º) clarify signal enhancement in healthy lymph node tissue. The increase in healthy lymph node tissue is 297% at the time of 10 min. p.i. and 269% at the time of 60 min. p.i.. Zones without signal increase were diagnosed as metastases and confirmed histologically (by H/E-staining of lymph node sections). The signal intensity ratio of healthy lymph node tissue compared to metastases was 5.1 at 10 min. p.i. and 9.1 at 60 min p.i..

Surprisingly, already after the application, a significant increase not only in the lymph node, but also in the primary tumor (especially in the periphery) could be observed (15 min p.i.: 594%). At later times (up to 24 h p.i.), the increase also spread in the direction of the tumor center (120 min p.i.: 162 %):

Metal complex III

Example 133:

Image of infarction (MRT) after intravenous administration of contrast medium in rats

Figure 16 shows MR images of the heart (in vivo and post mortem) 22 hours after intravenous administration of 100 μmol Gd/kg KGW of a polar Gd-chelate with perfluorinated side chains (metal complex III) in rats with acutely induced heart infarction. T1, EKG-spin-echo-images (1.5T; TR (effective): 400 ms, TE 12 ms; NA: 4; matrix: 128*128; layer thickness: 2.5 mm) clarify the signal enhancement in the infarct area. Successful induction of one acute myocardial infarction was demonstrated by NBT-staining.

Example 134:

Organ distribution (including accumulation in lymph nodes) after intravenous administration of contrast medium in rats

After intravenous administration of 200 μmol of total gadolinium/kg KGW of a polar Gd-chelate with perfluorinated side chains (metal complex III) in rats, 24 hours after administration the metal content in various organs as well as in lymph nodes (accumulated as mesenteric and peripheral lymph nodes ) determined (MW, n=2).

[image]

Example 135:

Imaging of lymph nodes (MRT) after intravenous contrast agent administration in rats

The illustration in Example 17 shows exemplary MR images of iliac lymph nodes pre-contrast as well as 60 min after intravenous administration of 200 μmol Gd/kg KGW metal complex III in rats. T1-gradient-echo scans (1.5T; sequence: MPRange; TR : 11.1 ms, TE 4.3 ms; α 15º) clarifies the strong signal increase in the healthy tissue of the lymph node already in the early moments after the injection. Thus, it amounts to an increase of 320% at the moment 15 min p.i. and 401% at the moment 60 min p.i..

Example 136:

Imaging of lymph nodes (MRT) after intravenous contrast agent administration in rabbits with VX2-tumor

Figure 18 shows exemplary MR images of iliac lymph nodes precontrast as well as 60 min after intravenous administration of 200 μmol Gd/kg KGW metal complex III in rabbits with i.m. implanted VX2-tumor. T1 gradient-echo images (1.5T; sequence: MPRange; TR : 11.1 ms, TE 4.3 ms; α 15º) clarifies the strong signal enhancement in the healthy tissue of the lymph node. The increase in healthy lymph node tissue is 195% at 15 min p.i. and 233% at 60 min p.i.. Zones without signal enhancement were diagnosed as metastases and histologically (H/E-staining of lymph node sections) confirmed. The signal intensity ratio of healthy lymph node tissue in relation to metastasis is 1.9 at 15 min p.i. and 1.8 at 60 min p.i.

Surprisingly, immediately after the application, a significant increase not only in the lymph node, but also in the primary tumor (especially in the periphery) could be observed (15 min p.i.: 232%).

Claims (50)

1. The use of metal complexes, which contain perfluoroalkyls, have a critical concentration of micelle structure <10-3 mol/l, a hydrodynamic micelle diameter (2 Rh) > 1 nm and show proton relexivity in plasma (R1) > 10 l/mmol.s , as contrast agents in MR-imaging for plaque visualization. 2. Application according to claim 1, indicated by the fact that metal complexes as well as MRI-contrast agents for the display of lymph nodes are used. 3. Application according to claim 1 or 2, indicated by the fact that metal complexes as well as MRI-contrast agents for the display of infarcted and necrotic tissues are used. 4. Application according to claim 1 or 3, characterized in that metal complexes are used as well as MRI contrast agents for independent visualization of necrosis and tumors. 5. Application according to claim 1, indicated by the fact that metal complexes are used, the concentration of which micelles are formed < 10-4 mol/l. 6. Application according to claim 1, characterized by the fact that metal complexes are used, the hydrodynamic diameter of which is ≥ 3 nm, or preferably > 4 nm. 7. Application according to claim 1, indicated by the fact that metal complexes are used, which show proton relaxivity in plasma > 13 l/mmol·s, that is, preferably > 15 l/mmol·s. 8. Application according to claims 1 to 7, characterized in that the metal complexes containing perfluoroalkyl compounds of the general formula I RF-1-K (I) whereby RF is a perfluorinated, straight-chain or branched carbon chain of the formula –CnF2nE, in which E represents one end fluorine, chlorine, bromine, iodine or hydrogen atom and n stands for numbers 4-30, L direct bond, methyl group, one –NHCO-group, one group [image] where p numbers from 0 to 10, q and u independently of each other, numbers 0 or 1 and Ra is a hydrogen atom, a methyl group, one –CH2-OH-group, one –CH2-CO2H-group or one C2-C15-chain, which is interrupted by 1 to 3 oxygen atoms, 1 to 2 > CO-groups or one similarly substituted aryl groups and/or is substituted with 1 to 4 hydroxy groups, 1 to 2 C1-C4-alkoxy groups, 1 to 2 carboxy groups, one group -SO3H- denotes, or one straight-chain, branched, saturated or unsaturated C2-C30 carbon chain, which also has 1 to 10 oxygen atoms, 1 to 3 -Nra-groups, 1 to 2 sulfur atoms, one piperazine, one -CONRa-group, one - NRaCO-group, one –SO2-group, one –NRa-CO2-group, 1 to 2 –CO-groups, one group CO – N – T –N(Ra) – SO2 – RF or 1 to 2 likewise contains substituted aryls and/or is interrupted via that group, and/or is also substituted with 1 to 3 -Ora-group, 1 to 2 oxy-groups, 1 to 2 -NH-CORa-groups, 1 to 2 -CONHRa -groups, 1 to 2 –(CH2)p-CO2H-groups, 1 to 2 groups –(CH2)p-(O)q-CH2CH2-RF, whereby Ra, RF and p and q, having the above meaning and T stands for the C2-C10 chain, which is also interrupted by 1 to 2 oxygen atoms or 1 to 2 –NHCO groups, K for one complex builder or metal complex or their salts of organic and/or inorganic bases or amino acids or amino acid amides stands for one complex builder or complex of the general formula II [image] in which Rc, R1 and B are mutually dependent and Rc having the meaning of Ra has either –(CH2)m-1-RF denotes, where m is 0, 1 or 2 and L and RF have the above meaning, R1, independently of each other, one hydrogen atom or one equivalent of metal ions with ordinal numbers 22-29, 42-46 or 58-70 denote, B OR1 or [image] denotes, where R1, L, RF and Rc have the above meaning, or for one complex builder or general formula III complex [image] In which Rc and R1 show the above meaning and Rb, which has the meaning of Ra or for one complex builder or general formula IV complex [image] (IV) in which R1 has the above meaning or for one complex builder or general formula V complex [image] (V) in which R1 has the above meaning and o and q for the numbers O or 1 stand and the sum o+q = 1 gives, or for one complex builder or general formula VI complex [image] (YOU) wherein R 1 has the above meaning or for one complex builder or general formula VII complex [image] (VII) wherein R 1 and B have the above meaning or for one builder of the complex or complex of the general formula VIII [image] (VIII) wherein Rc and R1 have the above meaning and Rb has the above meaning of Ra. or for one complex builder or general formula IX complex [image] (IX) in which Rc and R1 have the above meaning, or for one complex builder or general formula X complex [image] (X) in which Rc and R1 have the above meaning, or for one complex builder or general formula XI complex [image] in which Rc p and q have the above meaning and Rb has the meaning of Ra, or for one builder of a complex or a complex of the general formula XII [image] (XII) in which L, RF and R1 have the above meaning, or for one builder of a complex or a complex of the general formula XIII [image] (XIII) in which R1 has the above meaning, be used. 9. Use according to claim 8, characterized in that compounds of the general formula I are used, in which L for [image] [image] also stands for the previous α binding site for the complex builder or metal complex K and β binding site for the fluorine residue, represents. 10. Application according to claim 8 or 9, thereby indicating that compounds of formula I are used, in which n in the formula –CnF2nE stands for numbers 4-15 and/or E in that formula represents one fluorine atom. 11. Application according to claims 8 to 10, thereby indicating that the following compounds are used: Gadolinium complex 10-[1-methyl-2-oxo-3-aza-5-oxo-{4-perfluorooctylsulfonyl-piperazin-1-yl}-pentyl]-1,4,7-tris(carboxymethyl)-1,4 ,7,10-tetraazacyclododecane, Gadolinium complex 10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15,15,16,16,17 ,17-heptadecafluoroheptacecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, Gadolinium complex 10-[2-hydroxy-4-aza-5,9-dioxo-9-{4-perfluorooctyl)-piperazin-1-yl}-nonyl]-1,4,7-tris(carboxymethyl)-1, 4,7,10-tetraazacyclododecane, Gadolinium complex 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctyl-sulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10 -tetraazacyclododecane, Gadolinium complex 10-[2-hydroxy-4-oxa-1H,1H,2H,2H,3H,3H,4H,4H,5H,5H,6H,6H-perfluoro-tetradecyl]-1,4,7-tris( carboxymethyl)-1,4,7,10-tetraazacyclododecane, Gadolinium complex 10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15, 15,16,16,17 ,17,18, 18,19,19-henicosafluoro-nonadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, Gadolinium complex 10-[2-hydroxy-4-aza-5-oxo-11-aza-11-(perfluorooctyl-sulfonyl)-tridecyl]-1,4,7-tris(carboxy methyl)-1,4,7, 10-tetraazacyclododecane, Gadolinium complex 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctyl-sulfonyl)-8-phenyl-octyl]-1,4,7-tris(carboxy methyl)-1, 4,7,10-tetraazacyclododecane, 12. Application according to claims 1 - 7, characterized in that as metal complexes containing perfluoroalkyl, compounds of the general formula Ia A – RF (Ia) whereby A is one part of the molecule, which contains 2 to 6 metal complexes, which are directly attached via a "linker" to one carbon atom of one chain of a circular skeleton and RF is a perfluorinated, straight-chain or branched carbon chain of the formula –CnF2nE, in which E is one terminal fluorine, chlorine, bromine, iodine or hydrogen atom presents and n stands for numbers 4-30 where part of molecule A shows the following structure: [image] whereby q1 is a number 0,1,2 or 3, K stands for one complex builder or metal complex or their salts of organic and/or inorganic bases or amino acids or amino acid amides, X one direct bond to a perfluoroalkyl group, one phenyl group or one C1-C10-alkyl chain, which also 1-15 oxygen, 1-5 sulfur atoms, 1-10 carbonyl, 1-10 (NRd), 1-2 NRdSO2 , 1-10 CONRd, 1 piperidine, 1-3 SO2, 1-2 phenyl groups contain or likewise over 1-3 residues RF is substituted, where Rd for one hydrogen atom, one phenyl, benzyl or one C1-C15- alkyl group, which also contains 1-2 NHCO, 1-2 CO-groups, 1-5 oxygen atoms and also over 1-5 hydroxy, 1-5 methoxy, 1-3 carboxy, 1-3 RF-residues is substituted V one direct bond or one chain of the general formula IIa or IIIa is: [image] whereby Re is a hydrogen atom, one phenyl group, one benzyl group or one C1-C7 alkyl group is, which is also substituted with one carboxy, one methoxy or one hydroxy group each, W one direct bond, one polyglycol ether group with up to 5 glycol elements or one part of the molecule of the general formula IVa - CH(Rh) – (IVa) wherein Rh is one C1-C7-carboxylic acid, one phenyl group, one benzyl group or one –(CH2)1-5-NH-K-group, α bond to the carbon atom of the skeleton chain, β bond to the builder of the complex or metal complex K represents, and in which the variables k and m stand for natural numbers between 0 and 10 and I for 0 or 1, and at what D for CO or SO2-groups is, be used. 13. Application according to claim 12, characterized in that compounds of the general formula Ia are used, in which q is the number 1. 14. Application according to claim 12, characterized in that compounds of the general formula Ia are used, in which part of the molecule X is an alkylene chain, which contains 1-10 CH2CH2O or 1-5 COCH2NH-groups, one direct bond or one of the following structures [image] [image] [image] whereby γ to D and b to RF bonds. 15. Application according to claim 12, characterized in that compounds of the general formula Ia are used, in which V is one part of the molecule with one of the following structures [image] [image] 16. Application according to claim 12, characterized in that compounds of the general formula Ia are used, in which K is a complex of the general formula Va, Via, VIIa or VIIIa [image] (Va) [image] (VIa) [image] (VIIa) [image] (VIIIa) whereby R1, independently of each other, for one hydrogen atom or one equivalent of metal ions of elements with serial number 23-29, 42-46 or 58-70 is, R8 is one hydrogen atom or one straight-chain, branched, saturated or unsaturated C1-C30-alkyl chain, which is also substituted via 1-5 hydroxy, 1-3 carboxy or 1 phenyl group(s) and/or also via 1-10 oxygen atom, 1 phenylene or 1 phenyleneoxy-group is interrupted R6 is one hydrogen atom, one straight-chain or branched C1-C7-alkyl residue, one phenyl or benzyl residue, R7 one hydrogen atom, one methyl or ethyl group, which is also substituted or via one hydroxy or carboxy group, U3 one also 1-5 imino, 1-3 phenylene, 1-3 phenylenoxy, 1-3 phenylenamino, 1-5 amide, 1-2 hydracid, 1-5 carbonyl, 1-5 ethyleneoxy, 1 uric substance, 1 thiouric substance, 1-2 carboxyalkylamino, 1-2 ester groups, 1-10 oxygen, 1-5 sulfur and/or 1-5 carbon atoms containing and/or also through 1-5 hydroxy, 1-2 mercapto, 1- 5 oxo, 1-5 thiooxo, 1-3 carboxy, 1-5 carboxyalkyl, 1-5 ester and/or 1-3 amino groups substituted, straight-chain, branched, saturated or unsaturated C1-C20-alkylene groups, wherein likewise contained phenylene groups can be substituted through 1-2 carboxy, 1-2 sulfone or 1-2 hydroxy groups. T1 stands for one –CO-β, -NHCO-β or –NHCS-β-group, where β represents the attachment site to V. 17. Application according to claim 16, characterized in that for U3 the existing C1-C20-alkylene chain, groups -CH2NHCO-, -NHCOCH2O-, -NHCOCH2OC6H4-, -N(CH2CO2H)-, -CH2OCH2-, -NHCOCH2C6H4-, - CH2OC6H4-, -CH2CH2O- contains and/or is substituted by –COOH, -CH2COOH groups. 18. Use according to claim 16, characterized in that U3 for one -CH2-, -CH2CH2-, -CH2CH2CH2-, -C6H4-, -C6H10-, -CH2C6H4-, -CH2NHCOCH2CH(CH2CO2H)-C6H4-, -CH2NHCOCH2OCH2- , -CH2NHCOCH2C6H4- groups stand. 19. Application according to claim 12, thereby indicating that compounds of the general formula Ia are used, in which K shows one of the following structures: [image] [image] [image] 20. Use according to one of claims 12 to 19, thereby indicating that compounds of the general formula Ia are used, in which the perfluoroalkyl chain is RF-C6F13, -C8F17, -C10F21 or C12F25. 21. Use according to one of claims 12 to 20, characterized in that the gadolinium complex 1,4,7-tris{1,4,7-tris(N-(carboxylatomethyl)-10-[N-1-methyl-3 ,6-diaza-2,5,8-trioxooctane-1,8-diyl)]-1,4,7,10-tetraazacyclododecane, Gd-complex}-10-[N-2H,2H,4H,4H,5H ,5H-3-oxa-perfluorotridecanoyl]-1,4,7,10-tetraazacyclododecane was used. 22. Application according to one of claims 1 to 7, characterized in that as perfluoroalkyl containing metal complexes, compounds of the general formula Ib [image] (b) whereby K one complex "builder" or one metal complex of the general formula IIb [image] (IIb) where R1 for one hydrogen atom or one equivalent of metal ions with serial numbers 23-29, 42-46 or 58-70, R2 and R3 for one hydrogen atom, one C1-C7-alkyl group, one benzyl group, one phenyl group, CH2OH or –CH2-OCH3, U2 for the rest of L1, where L1 and U2 can be the same or different independently of each other, stands denotes A1 one hydrogen atom, one straight-chain or branched C1-C30-alkyl group, which is also interrupted by 1-15 oxygen atoms, and/or it is also substituted with 1-10 hydroxy groups, 1-2 COOH-groups, one phenyl group, one benzyl group and/or 1-5-ORg-group, with Rg meaning one hydrogen atom or one C1- C7-alkyl residue, or –L1-RF-denotes, L1 one straight-chain or branched C1-C30-alkyl group, which is also interrupted or via 1-10 oxygen atoms, 1-5 –NH-CO-group, 1-5 –CO-NH-group, via one also through a COOH-group of a substituted phenyl group, 1-3 sulfur atoms, 1-2 –N(B1)-SO2-groups, and/or 1-2 –SO2-N(B1)-groups with B1 having the meaning of A1, one NHCO -group, one CONH-group, one N(B1)-SO2-group, or one –SO2-N(B1)-group and/or it is also substituted with the residue RF means i RF one straight-chain or branched perfluorinated alkyl residue of the formula CnF2nE, where n stands for the numbers 4-30 and e stands for one terminal fluorine atom, chlorine atom, bromine atom, iodine atom or one hydrogen atom, has meaning and also present "acidic" groups as well as salts of organic and/or inorganic bases or amino acids or amino acid amides may be present, be used. 23. Application according to claim 22, characterized in that compounds of the general formula Ib are used, in which R2, R3 and Rg independently of each other denote hydrogen or one of the C1-C4-alkyl groups. 24. Application according to claim 22, indicated by the fact that compounds of the general formula Ib are used, in which A1 is hydrogen, one C1-C15-alkyl residue, residues C2H4-O-CH3, C3H6-O-CH3, [image] denotes, whereby s for integers 1 to 15, t for integers 0 to 13, u1 for integers 1 to 10, n stands for whole numbers 4 to 20, i E for hydrogen, fluorine, chlorine, bromine or iodine atom as well as, if possible, their branched isomers. 25. Use according to claim 22, characterized in that compounds of the general formula Ib are used, in which A1 is hydrogen, C1-C10-alkyl, [image] C2H4-O-(C2H4-O)x-C2H4-CnF2nE means, whereby x for integers 0 to 5, y for integers 1 to 6, w for integers 1 to 10, n for integers 4 to 15 i E stands for one fluorine atom, as well as, if possible, their branched isomers. 26. Use according to claim 22, characterized in that compounds of the general formula Ib are used, in which L1 [image] wherein the phenyl group is 1,4 or 1,3 linked [image] [image] denotes, whereby s for integers 1 to 15 and y stands for integers 1 to 6. 27. Use according to claim 22, characterized in that compounds of the general formula Ib are used, in which L1 [image] denotes, whereby y stands for integers 1 to 6. 28. Application according to claim 22, indicated by the fact that compounds of the general formula Ib are used, in which RF denotes one straight-chain or branched perfluorinated alkyl residue of the formula CnF2nE, where n stands for the numbers 4 to 15, and E for one terminal fluorine atom. 29. Application according to one of claims 22 to 28, characterized in that the following compounds are used: -1,4,7-tris(carboxylatomethyl)-10-[3-aza-4-oxo-hexan-5-yl)-acid-N-(2,3-dihydroxypropyl)-N-(1H,1H,2H ,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex -1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-N-(3,6,9,12,15-pentaoxa)-hexadecyl )-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex -1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-N-5-hydroxy-3-oxa-pentyl)-N-(1H ,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex -1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-yl)-acid-[N-3,6,9,15-tetraoxa-12-aza- 15-oxo-C17-C26-hepta-decafluoro)hexacosyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex -1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-yl)-acid-N-(2-methoxyethyl)-N-(1H,1H,2H, 2H,3H,3H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex. 30. Application according to one of claims 1 to 7, characterized in that as perfluoroalkyl containing metal complexes compounds with sugar residues of the general formula Ic [image] (c) where R one bound via the 1-OH- or 1-SH-position of a mono- or oligosaccharide represents, RF is a perfluorinated, straight-chain or branched carbon chain of the formula –CnF2nE, in which E represents one terminal fluorine, chlorine, bromine, iodine, or hydrogen atom and n stands for numbers 4-30, K stands for a metal complex of the general formula IIc, [image] (IIc) where R1 one hydrogen atom or one metal ion equivalent of serial numbers 23-29, 42-46 or 58-70 means, with measure, that at least 2 R1 for metal ion equivalents are R2 and R3 independently represent hydrogen, C1-C7-alkyl, benzyl, phenyl, -CH2OH or -CH2OCH3 and In -C6H4-O-CH2-ω-, -(CH2)1-5-ω-, one phenyl group, -CH2-NHCO-CH2-CH(CH2COOH)-C6H4-ω-, -C6H4-(OCH2CH2)0 -1-N(CH2COOH)-CH2-ω or one likewise via one or more oxygen atoms, 1 to 3-NHCO-, 1 to 3 –CONH-groups terminated and/or with 1 to 3 –(CH2)0- 5COOH-groups substituted C1-C12-alkylene or C7-C12-C6H4-O-groups represent, where ω stands for the binding site on –CO-, or general formula IIIc [image] (IIIc) in which R1 has the above meaning, R4 represents hydrogen or one of the metal ion equivalents specified under R1 and U1 represents –C6H4-O-CH2-ω, where ω represents the binding site on –CO- or general formula IVc [image] (IVc) wherein R1 and R2 have the above meaning or the general formula VcA or VcB [image] (VcA) [image] (VcB) wherein R1 has the above meaning, or general formulas VIc [image] (Joke) wherein R1 has the above meaning, or general formula VIIc [image] (VIIc) wherein R 1 has the above meaning and U1 represents -C6H4-O-CH2-ω-, where ω represents the binding site to –CO- or general formula VIIIc [image] (VIIIc) wherein R1 has the above meaning, and in the residue K also present free acid groups as well as salts of organic and/or inorganic bases or amino acids or amino acid amides may be present, G for the case that K of the metal complexes Iic to VIIc denotes, one at least three-functional residue selected from the following residues a) to j) represents And) [image] b) SCAN [image] c) SCAN [image] d) SCAN [image] e) [image] f) [image] Mr) [image] h) [image] i) SCAN [image] j) [image] and G for the case that K metal complex VIIIc denotes, one at least triply functional residue selected from k) or l) represents, k) [image] i) [image] where α denotes the binding site of G on complex K, β denotes the binding site of G to residue Y, and γ represents the site of binding of G to residue Z Y -CH2-, b-(CH2)(1-5)CO-β, b-CH2-CHOH-CO-β or b-CH(CHOH-CH2Oh)-CHOH-CHOH-CO-β denotes, where b the binding site to the sugar residue R represents, and the β binding site to the G residue is Z for [image] stands, where γ represents the binding site of Z to the G residue and ε represents the binding site of Z to the perfluorinated residue RF and I1, m1 mutually independent integers 1 or 2 denote i p denotes integers 1 to 4, be used. 31. Application according to claim 30, characterized in that compounds of the general formula Ic are used, in which R represents one monosaccharide residue with 5 to 6 C-atoms or their deoxy-compounds, wherein glucose, mannose or galactose is preferred. 32. Use according to claim 30, characterized in that compounds of the general formula Ic are used, in which R2 and R3 independently of each other denote hydrogen or C1-C4-alkyl and/or E in the formula –CnF2nE denotes one fluorine atom. 33. Use according to claim 30, characterized in that compounds of the general formula Ic are used, in which G represents one lysine residue (a) or (b). 34. Use according to claim 30, characterized in that compounds of the general formula Ic are used, in which Z SCAN Denotes, where γ represents the binding site of Z to the G residue and ε represents the binding site of Z to the perfluorinated RF residue and/or Y b-CH2CO-β represents the binding site to the G residue. 35. Application according to claim 30, indicated by the fact that compounds of the general formula Ic are used, in which U in the metal complex K represents –CH2- or –C6H4-O-CH2-ω, where the binding site is on –CO-. 36. Application according to claim 30, indicated by the fact that the gadolinium complex 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza- 4-oxo-5-methyl-5-yl)]-2-N-[1-O-α-D-carbonylmethyl-mannopyranose]-1-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide is used. 37. Application according to one of claims 1 to 7, characterized in that the metal complexes containing perfluoroalkyls are compounds with polar residues of the general formula Id [image] (ID) in which RF is a perfluorinated, straight-chain or branched carbon chain of the formula –CnF2nE, in which E represents one terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n stands for numbers 4-30, K stands for a metal complex of the general formula Iid, [image] (IId) in which R1 one hydrogen atom or one metal ion equivalent of serial numbers 23-29, 42-46 or 58-70 means, with measure, that at least 2 R1 for metal ion equivalents are R2 and R3 independently represent hydrogen, C1-C7-alkyl, benzyl, phenyl, -CH2OH or -CH2OCH3 and In -C6H4-O-CH2-ω-, -(CH2)1-5-ω-, one phenyl group, -CH2-NHCO-CH2-CH(CH2COOH)-C6H4-ω-, -C6H4-(OCH2CH2)0 -1-N(CH2COOH)-CH2-ω or one likewise via one or more oxygen atoms, 1 to 3-NHCO-, 1 to 3 –CONH-groups terminated and/or with 1 to 3 –(CH2)0- 5COOH-groups substituted C1-C12-alkylene or C7-C12-C6H4-O-groups represent, where ω stands for the binding site on –CO-, or general formulas IIId [image] (IIId) in which R1 has the above meaning, R4 represents hydrogen or one of the metal ion equivalents specified under R1 and U1 represents –C6H4-O-CH2-ω, where ω represents the binding site on –CO- or the general formula Ivd [image] (IVc) wherein R1 and R2 have the above meaning or the general formula VdA or VdB [image] (VdA) [image] (VdB) wherein R1 has the above meaning, or general formulas VId [image] (Vision) wherein R1 has the above meaning, or general formula VIIc [image] (VIId) wherein R 1 has the above meaning and U1 -C6H4-O-CH2-ω- represents, where ω represents the binding site to –CO- and in the K residue also present free acid groups as well as salts of organic and/or inorganic bases or amino acids or amino acid amides can come, G represents one at least triple functional residue selected from the following residues a) to i). And) [image] b) [image] c) [image] d) [image] e) [image] f) [image] Mr) [image] h) [image] where α denotes the binding site of G on complex K, β denotes the binding site of G to residue Y, and γ represents the site of binding of G to residue Z Z for [image] stands, where γ represents the binding site of Z to the G residue and ε represents the binding site of Z to the perfluorinated residue Rf R is a polar residue selected from the complex K of the general formula Iid to VIId, where R1 here represents one hydrogen atom or one equivalent of metal ions of serial numbers 20, 23-29, 42-46 or 58-70, and residues R2, R3, R4, U and U1 showing the above meaning or the rest of folic acid or one via –CO-, SO2- or one direct bond to the G residue indicates a carbon chain with 2–30 atoms, straight chain or branched, saturated or unsaturated, also continuous over 1-10 oxygen atoms, 1-5 NHCO-groups, 1-5 –CONH-groups, 1-2 sulfur atoms, 1-5 NH-groups or 1-2 phenyl groups, which also with 1- 2 OH-groups, 1-2 NH2-groups, 1-2 –COOH-groups or 1-2-SO3H-groups can be substituted or also substituted with 1-8 OH-groups, 1-5 –COOH-groups, 1-2 SO3H-groups, 1-5 NH2-groups, 1-5 C1-C4-alkoxy groups and I1, m1, p2 mutually independent integers 1 or 2 denote i be used. 38. Application according to claim 37, characterized in that compounds of the general formula Id are used, in which K stands for one metal complex of the general formula IId, IIId, VdB or VIId. 39. Application according to claim 37, indicated by the fact that compounds of the general formula Id are used, in which R means the complex K, and the preference is given to the complex K of the general formula IId, IIId, VdA or VIId. 40. Application according to claim 37, characterized in that compounds of the general formula Id are used, in which the residue R has the following meaning: [image] [image] Preference is given to –C(O)CH2O[(CH2)2O]4-CH3. 41. Application according to claim 37, characterized in that compounds of the general formula Id are used, in which the polar residue R is a residue of folic acid. 42. Application according to claim 37, characterized in that compounds of the general formula Id are used, in which G represents a lysine residue (a) or (b). 43. Application according to claim 37, indicated by the fact that compounds of the general formula Id are used, in which U in the metal complex K represents the group –CH2- or –C6H4-O-CH2-ω, where ω stands for the site of attachment to –CO -. 44. Use according to one of claims 37-43, characterized in that the gadolinium complex 2,6-N,N'-bi[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10 -(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-lysine-[1-(4-perfluorooctylsulfonyl-piperazine]-amide) was used. 45. Application according to one of the claims 1-7, characterized in that metal complexes containing perfluoroalkyls of galenic formulations are used, paramagnetic metal complexes containing perfluoroalkyls of the general formulas I, Ia, Ib, Ic and/or Id and diamagnetic substances containing perfluoroalkyls, with the advantage being that they are dissolved in one aqueous solvent. 46. Application according to claim 45, characterized in that diamagnetic substances containing perfluoroalkyls, such general formula XX are used: RF-L2-B2 (XX) where RF is a straight-chain or branched perfluoroalkyl residue with 4 to 30 carbon atoms, L2 is a "linker" and B2 is a hydrophilic group. 47. Application according to claim 45, characterized in that the "linker" L2 is one direct bond, one -SO2-group or one straight or branched carbon chain with up to 20 carbon atoms, which with one or more -OH, -COOH-, -SO3-groups can be substituted and/or also one or more -O-, -S-, -CO-, -CONH-, -NHCO-, -CONR9-, -NR9CO-, -SO2-, -PO4- -, -NH-, -NR9-group, one aryl ring or one piperazine contains, where R9 stands for one C1 to C20-aryl residue, which again may contain one or more O-atoms and/or with –COO- or It can be substituted by SO3-group. 48. Use according to claim 46, characterized in that the hydrophilic group B2 is one mono- or disaccharide, one or more adjacent -COO- or -SO3-- groups, one dicarboxylic acid, one isophthalic acid, one picolinic acid, one benzosulfonic acid, one tetrahydropyrandicarboxylic acid, one 2,6-pyridinedicarboxylic acid, one quaternary ammonium ion, one aminopolycarboxylic acid, one aminodipolyethyleneglycolsulfonic acid, one aminopolyethyleneglycol group, one SO2-(CH2)2-OH-group, one polyhydroxyalkyl chain with at least 2 hydroxy groups or one or more polyethylene glycol chains with at least 2 glycol units is, wherein the polyethylene glycol chain is terminated via one –OH or –OCH3-group. 49. Application according to claim 45, characterized in that diamagnetic substances containing pefluoroalkyl, conjugates from α-, β-, or γ-cyclodextrin and compounds of the general formula XXII are used: A2-L3-RF (XXII) Where A2 for one adamantane, biphenyl or anthracene molecule, L3 for one "linker" and RF for one straight-chain or branched perfluoroalkyl residue with 4 to 30 carbon atoms stands; and the "linker" L3 is a straight-chain hydrocarbon chain with 1 to 20 carbon atoms, which via one or more oxygen atoms, one or more CO-, SO2-, CONH-, CONR10-, NR10CO-, NH-, NR10- groups or one piperazine can be terminated, wherein R10 is one C1-C5-alkyl residue. 50. Application according to claim 45, characterized in that diamagnetic perfluoroalkyl substances such as those of the general formula XXI are used: RF-X1 (XXI) wherein RF is a straight-chain or branched perfluoroalkyl residue with 4 to 30 carbon atoms and X1 is a residue selected from the group of the following residues (n is a number between 1 and 10): [image] [image] [image] [image]