EP1307236A2

EP1307236A2 - Use of metal complexes containing perfluoroalkyl as contrast agents in mr-imaging for the representation of plaques, tumours and necroses

Info

Publication number: EP1307236A2
Application number: EP01955366A
Authority: EP
Inventors: Johannes Platzek; Peter Mareski; Ulrich Niedballa; Bernd Radüchel; Hanns-Joachim Weinmann; Bernd Misselwitz
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 2000-08-11
Filing date: 2001-07-23
Publication date: 2003-05-07
Also published as: AU7754901A; ZA200301949B; BR0113188A; EE200300061A; WO2002013874A8; SK1572003A3; YU10603A; HUP0300736A3; IL154385A0; WO2002013874A2; JP2004506025A; NZ523932A; MXPA03001287A; BG107542A; NO20030604D0; CN1469757A; CA2419223A1; UA82642C2; RU2290206C2; DE10066210B4

Abstract

The invention relates to the use of metal complexes containing perfluoroalkyl, comprising a critical micelle formation concentration < 10<-3> mol/l, a hydrodynamic micelle dynameter of (2 Rh) > 1 nm and a proton relaxivity in plasma (R<1>) > 10 l/mmol.s, as contrast agents in MR imaging for the representation of plaque, lymph node, infarcted and necrotic tissue and for independent representation of necrotic tissue and tumoural tissue.

Description

Use of perfluoroalkyl-containing metal complexes as contrast media in MR imaging to display plaques, tumors and necrosis

description

The invention relates to the use of perfluoroalkyl-containing metal complexes which have a critical micelle concentration <10 ^"3 mol / l, a hydrodynamic micelle diameter (2 Rh)> 1 nm and a proton relaxivity in plasma (R ¹ )> 10 I / mmol-s , as a contrast medium in MR imaging for the display of plaques, lymph nodes, infarcted and necrotic tissue as well as for the independent display of necrotic tissue and tumor tissue. It has been shown that perfluoroalkyl-containing metal complexes with the properties mentioned for the independent display of plaques, tumors and necrosis with the help of MR imaging are outstandingly suitable and at the same time can also cover the diagnostically important area of infarct and necrosis imaging.

Atherosclerosis is the most important and most common pathological change in the arteries with hardening, thickening, loss of elasticity and narrowing of the glade. It is the most common cause of death in the western industrialized nations. Vascular wall changes lead to wall instability, vasoconstriction and clot deposition due to lipid storage, connective tissue growth and calcification with irregular distribution. The cause of the disease are numerous exogenous and endogenous noxa or diseases, such as hypertension, hyperlipidemia, hyperfibrinogenemia, diabetes mellitus, toxins, nicotine, antigen-antibody complexes, inflammation, hypoxia, psychological stress, old age and familial Burden. These lead to the disruption of the integrity of the inner wall of the vessel, the disruption of the growth control of smooth muscle cells in the wall of the vessel and the impairment of the degradation of aged cell components. Treatment of arteriosclerosis itself is not possible, the goal of medical efforts is prevention by reducing the risk factors, for example by means of lipid-lowering drugs.

The diagnosis of arteriosclerosis in clinical practice is currently mainly based on angiography as the gold standard. However, the limitation in all methods based on the measurement of the reduction of the vascular lumen is the early stage of the disease, which is characterized by a thickening of the vascular wall in normal vascular lumen (Glagov S, Zarins CK. Quantitating atherosclerosis. In: Bond MG, Insull W, Glagov S, Chandler AB, Cornhill JF (eds.). Clinical Diagnosis of Atherosclerosis. Quantitative Methods of Evaluation. New York: Springer-Verlag, 1983, 11-35). Another method for the diagnostic assessment of vascular wall and lumen is intravascular or percutaneous ultrasound.

Magnetic magnetic resonance imaging (MRI) is a modern, non-invasive radiological procedure that enables the display of physiological and pathophysiological structures with a very good spatial and temporal resolution. The use of specific contrast agents with selective enrichment in certain tissues and organs can significantly increase the diagnostic value. Contrast agent preparations with selective enrichment in arteriosclerotic plaques could detect the location and degree of the disease at an early stage and thus enable targeted therapy and prophylaxis, and the search for suitable contrast agents therefore began early on.

For example, US Pat. No. 4,577,636 claims hematoporphyrin derivatives as contrast agents for the detection of atherosclerotic plaques. Scintigraphy, X-ray, fluorescence and, for paramagnetic metalloporphyrins, NMR spectrometry are mentioned as methods. Gd, Cr, Co, Ni, Ag and Eu are listed as para-magnetic ions. The disadvantage of these compounds is that the porphyrins are deposited in the skin and cause discoloration that can last up to several weeks. In addition, they lead to photosensitization. Furthermore, there is a risk that the metalloporphyrin will lose the metal after a long residence time in vivo.

In application WO 95/09856, metalloporphyrins (deuteroporphyrins) are claimed for diagnosis and therapy of plaques. The MRI is mentioned as the diagnostic method. It also applies to these porphyrins that they cause discoloration of the skin.

Application WO 95/09013 claims conjugates of specifically binding polypeptides and metal complexes. These compounds are also said to bind to plaques and thus enable their diagnosis and therapy. Scintigraphy, computed tomography and MRI are mentioned as diagnostic methods. While scintigraphy has been experimentally proven, there is no information available for the MRI.

In US Pat. No. 5,807,536, labeled phycocyanins are claimed as contrast agents for the imaging of plaques. X-ray, computed tomography, scintigraphy, SPECT and MRI are mentioned here as diagnostic methods. Scintigraphy is experimentally proven.

Numerous contrast media for infarct and necrosis imaging are known from the literature. Attempts were made early on to improve the localization of infarcts and necroses by using contrast media in non-invasive procedures such as scintigraphy or magnetic resonance imaging. Attempts to use porphyrins for necrosis imaging occupy a large space in the literature. However, the results obtained give a contradictory picture. So Winkelman and Hoyes in Nature, 200. 903 (1967) describe that manganese-5,10,15,20-tetrakis (4-sulfonatophenyl) - porphyrin (TPPS) accumulates selectively in the necrotic part of a tumor.

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

Foster et al. (J. Nucl. Med. 26, 756 (1985)) for their part found that ¹¹¹ In- 5,10,15,20-tetrakis (4-N-methyl-pyridinium) -porphyrin (TMPyP) was not in the necrotic part , but enriched in the living marginal layers. It is obvious, but not mandatory, to conclude that there is a porphyrin-tissue interaction.

In Circulation Vol. 90, No. 4, part 2, page 1468, abstract no. 2512 (1994) Ni et al. Report that they can represent areas of infarction with a manganese tetraphenyl porphyrin (Mn-TPP) and a gadolinium mesoporphyrin (Gd-MP). In international patent application WO 95/31219, both substances were used for infarct and necrosis imaging. The authors Marchai and Ni write (see Example 3) that for the compound Gd-MP the metal content of the infarct kidney was similar to that of the uninfected organ, but that it was nine times as large for the myocardium in the infarcted tissue (Example 1) was. It was astonishing that the ratio of the signal intensities in the MRI for infarcted compared to the healthy tissue was comparable in both cases with 2.10 and 2.19. Further metalloporphyrins have been described in the application DE 19835082 (Schering AG).

Porphyrins tend to deposit in the skin, which leads to photosensitization. Sensitization can last for days, even weeks. This is an undesirable side effect when using porphyrins as diagnostics. In addition, the therapeutic index for the porphyrins is only very small, since for Mn-TPPS, for example, an effect only occurs at a dose of 0.2 mmol / kg, but the LD50 is already at 0.5 mmol / kg. Contrast agents for necrosis and infarct imaging that are not derived from the porphyrin scaffold have been described in DE 19744003 (Schering AG), DE 19744004 (Schering AG) and WO 99/17809 (EPIX).

DE 19744003 claims oligomeric compounds which consist of a core to which 1-3 metal complexes are bonded.

Application 19744004 claims lipophilic metal complexes for necrosis and infarct imaging. These compounds include metal complexes of polyaminopolycarboxylic acids, polyaminopolyphosphonic acids, porphyrins, texaphyrins, sapphyrins, peptides.

EPIX application WO 99/17809 claims the use of DTPA derivatives for necrosis imaging. The most prominent compound is the gadolinium complex of a phosphodiester of hydroxymethyl-DTPA (MS-325).

Perfluoroalkyl-containing metal complexes are also known as contrast agents for MR imaging. WO 97/26017 (Schering) and WO 99/01161 (Schering) disclose the use of perfluoroalkyl-containing metal complexes as lymphographics. WO 99/01161 also describes the suitability of these compounds for representing the vasal space (blood pool agents).

Contrast agents have also been described for the individual imaging of tumors and necrosis using MR imaging.

EP 417870 A1 discloses compounds for tumor diagnosis and therapy. It is said that infarcts and ischemia can also be represented. However, there is no experimental confirmation of this statement in the registration. The claimed compounds are chelates of complexes of the types N2S2 and N3S with radioisotopes. Scintigraphy serves as the diagnostic method. In DE 19646762, scintigraphy is also used as a diagnostic method. In the document, metal chelates are claimed as radio sensitizers for the therapy of hypoxic tumors and for the diagnosis of hypoxic conditions and necrosis. In the descriptive part, NMR diagnostics, X-ray diagnostics and radio diagnostics are mentioned as diagnostic methods.

German application DE 19824653 claims porphyrins as necrosis-affecting substances for the therapy of tumors. The application states that the compounds accumulate in the necrotic and hypoxic areas of tumors. The compounds can be used for diagnostic purposes in the form of their metal derivatives with paramagnetic ions or radioisotopes.

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

The object of the present invention was to provide contrast media for MR imaging which are suitable both for displaying plaques, lymph nodes, infarcted and necrotic tissue and for independently displaying necrosis and tumors.

Surprisingly, it has now been found that perfluoroalkyl-containing metal complexes which have a critical micelle formation concentration <10 ^"3 mol / l, a hydrodynamic micelle diameter (2 Rh)> 1 nm and a proton relaxivity in the plasma (R ¹ )> 10 1 / mmol s, are very suitable as contrast agents in MR imaging to display plaques, and can also be used to display lymph nodes, infarcted and necrotic tissue as well as for the independent display of necrotic tissue and tumor tissue.

Perfluoroalkyl-containing metal complexes which are suitable for the use according to the invention are understood to be amphiphilic compounds which, as the non-polar part, have a perfluoroalkyl side chain in the molecule which is optionally connected to the entire molecule via a lipophilic linker. The polar part The compounds according to the invention are formed by one or more metal complexes and any other polar groups which may be present.

In aqueous systems, these amphiphilic molecules show the properties that are characteristic of classic surfactants (such as sodium dodecyl sulfate, SDS). This is how they reduce the surface tension of the water. The so-called CMC (critical micelle formation concentration in mol / l) can be determined by tensiometry. For this purpose, the surface tension is determined depending on the concentration of the substance to be measured. The CMC can be calculated from the course of the surface tension function (c) obtained. The critical micelle formation concentration of the compounds according to the invention must be <10 ^-3 mol / l, preferably <10 ^{* 4} mol / l.

The amphiphilic compounds according to the invention are associated in solution and are present as aggregates. The size (2 Rh) of such aggregates (e.g. micelles, rods, wafers, etc.) can be determined with the help of Photon Correction Spectroscopy (PCS).

The hydrodynamic micelle diameter 2 Rh, which must be> 1 nm, therefore serves as the second criterion. Those perfluoroalkyl-containing metal complexes whose 2 Rh is> 3 nm are particularly suitable according to the invention, very particularly preferably> 4 nm.

Both the determination of the CMC and the photon correlation spectroscopy are described in H.-D. Dörfler, "interfacial and colloid chemistry", Weinheim, New York, Basel, Cambridge, Tokyo, VSH 1994.

The third criterion is proton relaxivity in plasma (R ¹ ) at 40 ° C and a field strength of 0.47 Tesla. The relaxivity, which is given in [l / mmol-s], is the quantitative measure for the shortening of the relaxation time T ^{1 of} the protons. For the purpose of the invention, the relaxivity must be as possible be high and be> 10 l / mmol-s, preferably> 13 l / mmol-s, particularly preferably> 15 l / mmol-s.

The relaxivity R ¹ [l / mmol-s] of the MR contrast agents according to the invention was determined using the Minispec P 20 device from Bruker. The measurements were carried out at 40 ° C and a field strength of 0.47 Tesla. 8 measurement points were recorded from each T1 sequence: 180 ° -TI -90 °, inversion recovery. Bovine plasma from Kraeber was used as the medium. The contrast medium concentrations [mmol / l] were between 0.30 and 1.16 in the batches.

In one embodiment of the present invention, the compounds of the general formula I according to claims 8 to 11 are used as preferred compounds. These are known compounds which are described in WO 97/26017. Their production can also be found in this WO document. Surprisingly, it has been shown that these compounds are also very suitable as MRI contrast agents for the display of plaques. The metal complexes I-IV, VI and Xl-Xlll (cf. also Table 1) are used as very particularly preferred compounds.

In a further embodiment of the present invention, preferred compounds are those of the general formula Ia according to Claims 12 to 21. These compounds are known and are described in WO 99/01161. Their use as an MRI contrast medium to display plaques has not yet been described. Of these compounds, the metal complex XIV (cf. Table 1) is very particularly preferably used.

In a further preferred embodiment of the invention, the macrocyclic perfluoroalkyl compounds of the general formula Ib

K— N— -R ^F (Ib) in which K is a complexing agent or a metal complex of the general formula IIb

means where

R ¹ for a hydrogen atom or a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70, R ² and R ³ for a hydrogen atom, a CrC ₇ alkyl group, a benzyl group, a phenyl group, -CH ₂ OH or -CH ₂ -OCH ₃ , and U ² for the radical L ¹ , where L ¹ and U ² can be the same or different independently of one another, A ^{1 is} a hydrogen atom, a straight-chain or branched C ¹ -C ₃ o-alkyl- group which is optionally interrupted by 1-15 oxygen atoms, and / or is optionally substituted with 1-10 hydroxyl groups, 1-2 COOH groups, a phenyl group, a benzyl group and / or 1-5 - OR ⁹ groups, with R ^{9 has} the meaning of a hydrogen atom or a CrCT-alkyl radical, or -L ¹ -R ^F , L ^{1 is} a straight-chain or branched CrC ₃ o-alkylene group which is optionally interrupted by 1-10 oxygen atoms, 1-5 -NH-CO - Groups, 1-5 -CO-NH groups, by a phenylene group optionally substituted by a COOH group , 1-3 sulfur atoms, 1-2 -N (B ¹ ) -S0 ₂ - groups, and / or 1-2 -S0 ₂ -N (B ¹ ) - groups with B ¹ as A ¹ , an NHCO -Group, a CONH group, an N (B ¹ ) -S0 ₂ group, or an -S0 ₂ -N (B ¹ ) group and / or optionally substituted with the radical R ^F , means and R ^{F is} a straight-chain or branched perfluorinated alkyl radical of the formula C _n F _2n E, where n stands for the numbers 4-30 and

E represents a terminal fluorine atom, chlorine atom, bromine atom, iodine atom or a hydrogen atom, and any acid groups present can optionally be present as salts of organic and / or inorganic bases or amino acids or amino acid amides.

Since the compounds according to the invention are intended for use in NMR diagnostics, the metal ion of the signaling group must be paramagnetic. These are in particular the divalent and trivalent ions of the elements of atomic 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. Because of their strong magnetic moment, gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), iron (III) and manganese (II) ions are particularly preferred ,

Manganese (II) -, iron (II) -, iron (III) -, praseodymium (III) -, neodymium (III) -, samarium (III) -, gadolinium (III) - and ytterbium (III) - are preferred ions, especially dyspro- sium (III) ions.

The alkyl groups R ² , R ³ , R ⁹ can be straight-chain or branched. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl.

Hydrogen and CrC alkyl groups are preferred for R ² , R ³ and R ⁹ , particularly preferably hydrogen and the methyl group. The benzyl group and the phenyl group R ² , A ¹ and B ¹ can be substituted in the phenyl ring. The COOH group can be used as a substituent.

If the compound of the formula Ib simultaneously contains the radicals L ¹ and U ² , L ¹ and U ² can be different from one another.

The CrC ₃ o-alkylene groups U ² 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 U ² as alkylene, C ₁ -C 10 alkylene groups are preferred, and C ₁ -C ₄ alkylene groups are particularly preferred.

The C ¹ -C ₃₀ -alkyl groups A ¹ can be straight-chain or branched. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, n-hexyl.

The CrC3o-alkyl groups A ¹ can be interrupted by 1-15 oxygen atoms and / or substituted with 1-10 hydroxyl, 1-5 alkoxy or 1-2 COOH groups such as

C ₂ H ₄ -O-CH ₃ , C ₃ H ₆ -O-CH ₃ ,

C2H4-0- (C ₂ H ₄ -O) _t -C ₂ H ₄ -OH, C ₂ H4-0- (C2H ₄ -0) tC ₂ H ₄ -OCH ₃ with t = 0 to 13

C ₂ H ₄ OH, C ₃ H ₆ OH, C ₄ H ₈ OH, C5H10OH, C ₆ Hι ₂ OH, C ₇ H ₁₄ OH, and their branched isomers,

CH (OH) CH ₂ OH,

CH (OH) CH (OH) CH ₂ OH, CH ₂ [CH (OH)] _u ¹ CH ₂ OH, with u ¹ = 1-10

CH [CH ₂ (OH)] CH (OH) CH ₂ OH,

C ₂ H ₄ CH (OH) CH ₂ OH,

(CH ₂ ) _s COOH with s = 1 to 15,

C ₂ H ₄ -0- (C ₂ H ₄ -0) rCH ₂ COOH with t = 0 to 13,

C ₂ H ₄ -0- (C ₂ H ₄ -0) _t -C ₂ H ₄ -C _n F _2n E with t = 0 to 13, n = 4 to 20 and E = a fluorine,

Hydrogen, chlorine, bromine or iodine atom. Preferred meanings for A ¹ are hydrogen, C _t -Cio alkyl, C ₂ H ₄ -O-CH _3, C ₃ H ₆ -O-CH _3,

C ₂ H ₄ -0- (C ₂ H ₄ -0) χ-C ₂ H ₄ -OH, C ₂ H ₄ -0- (C ₂ H ₄ -0) χ-C ₂ H ₄ -OCH3 with x = 0 to 5, CH ₂ [CH (OH)] _y CH ₂ OH, with y = 1-6 CH [CH ₂ (OH)] CH (OH) CH ₂ OH, (CH ₂ ) _w COOH with w = 1 to 10, C ₂ H ₄ -0- (C ₂ H ₄ -0) _x -CH ₂ COOH with x = 0 to 5,

C2H ₄ -0- (C ₂ H ₄ -0) _x -C ₂ H ₄ -CnF ₂ nE with x = 0 to 5, n = 4 to 15 and E = a fluorine atom.

If the compound of the general formula Ib contains two radicals L ¹ -R ^F , these radicals can be different from one another.

Examples of the radicals L ¹ are those where α is the bond to the nitrogen atom and β is the bond to the radical R ^F : α- (CH) s-ß it s = 1 - 15 α-CH2-CH2- ( 0-CH ₂ -CH2-) y-ß with y = 1-6 α-CH2- (0-CH2-CH ₂ -) y-ß with y = 1-6 α-CH ₂ -NH-CO-ß α -CH ₂ -CH ₂ -NH-S0 ₂ -ß α-CH ₂ -NH-CO-CH2-N (CH ₂ COOH) -Sθ2-ß α-CH2-NH-CO-CH ₂ -N (C2H ₅ ) -Sθ2-ß α-CH ₂ -NH-CO-CH ₂ -N (C ₁₀ H 1) -S0 -ß α-CH2-NH-C0-CH ₂ -N (C ₆ Hι 3) -Sθ2-ß α -CH ₂ -NH-CO- (CH ₂ ) lo-N (C2H5) -Sθ2-ß -CH2-NH-CO-CH ₂ -N (-CH2-C ₆ H5) -Sθ2-ß α-CH ₂ - NH-CO-CH ₂ -N (-CH2-CH ₂ -OH) Sθ2-ß -CH ₂ -NHCO- (CH ₂ ) 1 oS-CH2CH ₂ -ß α-CH ₂ NHCOCH ₂ -0-CH2CH2-ß α-CH2-CH ₂ NHCOCH2-0-CH ₂ CH2-ß α-CH ₂ - (CH ₂ -CH ₂ -0) _y - (CH ₂ ) 3NHC0-CH2-0-CH ₂ CH2-ß with y = 1 -6 α-CH ₂ NHCO (CH ₂ ) i o-0-CH CH ₂ -ß α-CH ₂ CH ₂ NHCO (CH2) ιo-0-CH2CH2-ß α-CH2-CgH4-0-CH2CH2-ß where the phenylene group 1, 4 or 1, 3 is linked -CH2-0-CH2-C (CH2-OCH2CH2-C ₆ F ₁₃ ) 2-CH2-OCH2-CH ₂ -ß α-CH2-NHCOCH2CH2CON-CH2CH2NHCOCH2N (C2H ₅ ) Sθ2C ₈ F-i7ß α-CH ₂ -CH ₂ NHCOCH ₂ N (C ₂ H ₅ ) -S0 ₂ -ß α-CH ₂ -0-CH ₂ -CH (OCι ₀ H ₂ 1) -CH ₂ -0- CH ₂ CH2-ß α- (CH ₂ NHCO) ₄ -CH2θ-CH2CH2-ß - (CH ₂ NHCO) 3-CH2θ-CH ₂ CH2-ß α-CH2-OCH2C (CH ₂ OH) 2-CH ₂ -0 -CH2CH2-ß

α-CH2NHCOCH ₂ N (C6H ₅ ) -Sθ2-ß α-NHCO-CH -CH ₂ -ß α-NHCO-CH ₂ -0-CH2CH ₂ -ß α-NH-CO-ß α-NH-CO-CH -N (CH2COOH) -S0 ₂ -ß α-NH-C0-CH2-N (C ₂ H ₅ ) -S02-ß α-NH-CO-CH ₂ -N (C- | ₀ H 1) -S0 ₂ -ß α-NH-CO-CH ₂ -N (C ₆ H- | ₃ ) -S0 ₂ -ß α-NH-CO- (CH ₂ ) ι oN (C ₂ H ₅ ) -Sθ2-ß α-NH -CO-CH ₂ -N (-CH2-C ₆ H ₅ ) -Sθ2-ß α-NH-CO-CH2-N (-CH2-CH ₂ -OH) S0 ₂ -ß α-NH-CO-CH ₂ -ß α-CH ₂ -0-C ₆ H ₄ -0-CH2-CH2-ß α-CH ₂ -C6H ₄ -0-CH2-CH2-ß -N (C ₂ H ₅ ) -S0 ₂ -ß -N (C ₆ H ₅ ) -S0 ₂ -ß α-N (C ₁₀ H ₂ i) -SO ₂ -ß α-N (C ₆ H ₁₃ ) -S0 ₂ -ß - N (C ₂ H ₄ 0H) -S02-ß α-N (CH ₂ COOH) -S0 ₂ -ß α-N (CH ₂ C ₆ H ₅ ) -S02-ß -N- [CH (CH ₂ 0H) ] -S02-ß α-N- [CH (CH ₂ OH) CH (OH) (CH ₂ OH)] - Sθ2-ß

The following are preferred: α-CH ₂ -0-CH ₂ CH2-β α-CH ₂ -CH2- (0-CH ₂ -CH2-) _y -ß with y = 1-6 -CH2- (0-CH ₂ -CH ₂ -) y-ß with y = 1 - 6 α-CH -CH2-NH-S0 ₂ -ß Example 10 α-CH ₂ NHCOCH2-0-CH2CH ₂ -ß α-CH2-CH2NHCOCH2-0-CH ₂ CH ₂ -ß α-CH ₂ - (CH ₂ -CH ₂ -0) _y - (CH2) 3NHCO-CH2-0-CH ₂ CH2-ß with y = 1-6 α-CH ₂ NHCO (CH2) io-0 -CH2CH -ß α-CH ₂ CH NHCO (CH2) ι 0-O-CH ₂ CH ₂ -ß α-CH ₂ -0-CH ₂ -CH (OC-ι ₀ H21) -CH ₂ -0-CH ₂ CH2-ß α-CH2-0-C ₆ H ₄ -0-CH2-CH2-ß α-CH2-C ₆ H ₄ -0-CH2-CH2-ß

The radicals L ^{1 of} the compounds mentioned in the examples of the present description of the invention are very particularly preferred according to the invention. For U ² , the radicals listed above apply to L ¹ and the preferred and particularly preferably marked radicals, and also the radicals listed above for the meaning alkylene and optionally preferred and particularly preferred radicals, with the proviso that no α-nitrogen atom and no terminal ( ß-permanent) S0 ₂ - or CO group may be present.

Preferred radicals B ¹ are hydrogen, straight or branched C ₁ -C ₁ 0-AI kylreste, optionally interrupted by 1-5 oxygen atoms, and / or are optionally substituted with 1-5 hydroxy groups, 1-2 COOH groups, a optionally substituted by a COOH group, a phenyl group, a benzyl group and / or 1-5-OR ⁹ groups, with R ⁹ in the meaning of a hydrogen atom or a C 1 -C 3 -alkyl radical.

Preferred radicals R ^F are straight-chain or branched perfluorinated alkyl radicals of the formula C _n F _2n E, where n represents the numbers 4 to 15 and E represents a terminal fluorine atom.

The preparation of the compounds of general formula Ib according to the invention

K - N - LR ^F I

^A (Ib)

With

K in the meaning of a complexing agent or a metal complex of the general formula IIb

can be done according to the following procedures:

Procedure A.

The carboxylic acid of formula IIIb already contains the metal ion equivalent R ¹ .

(lllb) (IVb) (Ib)

The carboxylic acid IIIb, optionally activated in situ, with R ¹ in the meaning of a metal ion equivalent, is reacted with an amine IVb in a coupling reaction to form an amide Ib.

This process for the production of metal complex carboxamides is known from DE 19652386.

The mixture of metal complex carboxylic acid IIIb used in the coupling reaction, which optionally contains carboxy and / or hydroxyl groups in protected form, and at least one solubilizing substance in an amount of up to 5, preferably 0.5-2 molar equivalents, based on the metal complex carboxylic acid both prepared in an upstream reaction stage and isolated (for example by evaporation, freeze-drying or spray-drying an aqueous or water-miscible solution of the constituents or by precipitation with an organic solvent from such a solution) and then in DMSO with water-releasing reagent and, if appropriate, a coupling agent. Auxiliary are implemented as well as formed in situ, if necessary, by adding solvent-imparting substance (s) to the DMSO suspension of metal complex carboxylic acid, water-releasing reagent and optionally a coupling auxiliary. The reaction solution prepared by one of these processes is kept for pretreatment (acid activation) for 1 to 24, preferably 3 to 12 hours at temperatures of 0 to 50 ° C., preferably at room temperature.

An amine of the general formula IVb

^R V i ^U R ^F ^A (IVb) in which the radicals R ³ , L ¹ , R ^F and A ^{1 have} the meanings given above, without solvent or dissolved, for example in dimethyl sulfoxide, alcohols such as, for example, methanol, ethanol, isopropanol or mixtures thereof, formamide, dimethylformamide, Water or mixtures of the solvents listed, preferably in dimethyl sulfoxide, in water or in solvents mixed with water, are added. For the amide coupling, the reaction solution thus obtained is kept at temperatures from 0 to 70 ° C., preferably 30 to 60 ° C., 1 to 48, preferably 8 to 24 hours.

In some cases it has proven advantageous to use the amine in the form of its salts, e.g. use as hydrobromide or hydrochloride in the reaction. A base such as e.g. Triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, tripropylamine, tributylamine, lithium hydroxide, lithium carbonate, sodium hydroxide or sodium carbonate are added.

The protective groups that may still be present are then split off.

The reaction product is isolated by the methods known to the person skilled in the art, preferably by precipitation with organic solvents, preferably acetone, 2-butanone, diethyl ether, ethyl acetate, methyl t-butyl ether, isopropanol or mixtures thereof. Further purification can be carried out, for example, by chromatography, crystallization or ultrafiltration. Alkali, alkaline earth, trialkylammonium, tetraalkylammonium salts, ureas, N-hydroxyimides, hydroxyaryltriazoles, substituted phenols and salts of heterocyclic amines are suitable as solubilizing substances. Examples include: lithium chloride, lithium bromide, lithium iodide, sodium bromide, sodium iodide, lithium methanesulfonate, sodium methanesulfonate, lithium p-toluenesulfonate, sodium p-toluenesulfonate, potassium bromide, potassium iodide, sodium chloride, magnesium bromide, magnesium chloride, magnesium iodide, tetraethyl amide toluenesulfonate, tetramethylammonium p-toluenesulfonate, pyridinium p-toluenesulfonate, triethylammonium p-toluenesulfonate, 2-morpholinoethylsulfonic acid, 4-nitrophenol, 3,5-dinitrophenol, 2,4-dichlorophenol, N-hydroxysuccinide Hydroxyphthalimide, urea, tetramethylurea, N-methylpyrrolidone, formamide and cyclic ureas, the first five being preferred.

All agents known to the person skilled in the art serve as water-releasing reagents. Examples include carbodiimides and onium reagents such as e.g. Dicyclohexylcarbodiimide (DCCI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydroxychloride (EDC), benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) and 0- (benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate (HBTU), preferably DCCI. The following suitable methods are described in the literature, for example:

♦ Activation of carboxylic acids. Overview in Houben-Weyl, Methods of Organic Chemistry, Volume XV / 2, Georg Thieme Verlag Stuttgart, 1974 (and J. Chem. Research (S) 1996, 302).

♦ Activation with carbodiimides. R. Schwyzer u. H. Kapier, Helv. 46: 1550 (1963).

♦ E. Wünsch et al., B. 100: 173 (1967).

♦ Activation with carbodiimides / hydroxysuccinimide: J. Am. Chem. Soc. 86: 1839 (1964) and J. Org. Chem. 53: 3583 (1988). Synthesis 453 (1972).

♦ anhydride method, 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydrochinoIin:

B. Belleau et al., J. Am. Chem. Soc, 90: 1651 (1986), H. Kunz et al., Int. J. Pept. Prot. Res., 26: 493 (1985) and JR Voughn, Am. Soc. 73: 3547 (1951).

♦ Imidazolid method: B.F. Gisin, R.B. Menifield, D.C. Tosteon, Am. Soc. 91: 2691 (1969).

♦ Acid chloride methods, thionyl chloride: Helv., 42: 1653 (1959).

♦ Oxalyl chloride: J. Org. Chem., 29: 843 (1964).

Suitable coupling auxiliaries to be used are all known to the person skilled in the art (Houben-Weyl, Methods of Organic Chemistry, Vol. 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. 4-nitrophenol and N-hydroxysuccinimide are preferred, the former reagent being particularly preferred.

The protective groups are cleaved off according to the processes known to the person skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline saponification of the esters with alkali in aqueous / alcoholic solution at temperatures from 0 ° to 50 ° C, acid saponification with mineral acids or in the case of e.g. tert-Butyl esters with the help of 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 benzyl ethers with hydrogen / palladium / carbon.

The preparation of the starting material, the compounds of the formula IIIb,

(lllb), is known from DE 19652386. The amines of the general formula IVb

R ³ N ' ^U R ^F i

A (IVb)

are commodities (Fluorochem, ABCR) or can be obtained by the following process from compounds of the general formula Vb by reaction with an amine of the general formula VIb and subsequent reduction of the compounds of the general formula VI Ib:

(Vb) (VIb) (Vllb) (IVb)

in which

R, A ¹ , L ¹ and R ^{3 have} the meaning given above, and L 'has the meaning of the group L ¹ in which the α-CH ₂ group is still missing, and

R ^{9 represents} hydrogen or a methyl group.

According to the processes already described in the literature for the activation of the carboxylic acid IIIb, the acid Vb is activated before the reaction with the amine VIb. For R ⁹ in the meaning of a methyl group, an aminolysis is carried out.

The compounds of the general formula Vb are commodities (Fluorochem, ABCR) or are produced as disclosed in DE 19603033.

The compounds of the formula VIb are commodities (Fluorochem, ABCR) or, as in Houben-Weyl, Methods of Organic Chemistry, XI / 2 nitrogen compounds, Georg Thieme Verlag Stuttgart, 1957, p. 680; JE Rickman and T. Atkins, Am. Chem. Soc, 96: 2268, 1974, 96: 2268; F. Chavez and AD Sherry, J. Org. Chem. 1989, 54: 2990: The compounds of the general formula IVb are prepared in a manner known per se [Helv. Chim. Acta, 77: 23 (1994)] by reducing the compounds of the general formula VII, for example with diborane or lithium aluminum hydride, and splitting off the protective groups.

Procedure B.

The carboxylic acid of formula II Ix with R ¹ in the meaning of hydrogen serves as the starting material - it does not yet contain any metal ion equivalent R ¹ . The carboxyl groups are protected by the processes known to the person skilled in the art and a compound of the formula Uly is obtained, where R ^{5 stands} for any protective group and R ^{5 stands} for its precursor.

(lllx) (Uly)

As a carboxyl protecting group e.g. straight-chain or branched C-j-Cβ-

Alkyl, aryl and aralkyl groups, for example the methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis (ρ-nitrophenyl) methyl group and trialkylsilyl groups in question. The t-butyl group is preferred.

(Uly) (IVb) (ix) The reaction of the protected carboxylic acid Uly with the amine of the formula IVb and the splitting off of the protective groups is carried out as described in process A and in a subsequent step the carboxylic acid Ix obtained is also reacted with at least one metal oxide or metal salt of an element of the desired atomic number, as described, for example, in DE 19525924 is disclosed.

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

Any free carboxy groups still present are then neutralized with the aid of inorganic bases (for example hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium, lithium, magnesium or calcium and / or organic bases, such as primary, secondary and tertiary amines, such as for example ethanolamine, morpholine, glucamine, N-methyl- and N, N-dimethylglucamine, as well as basic amino acids, such as lysine, arginine and ornithine or amides of originally neutral or acidic amino acids.

According to the invention, the metal complexes V, VII, VIII, IX and X (cf. Table 1) are very particularly preferably used.

These compounds of the general formula Ib are very suitable as MRI contrast agents for the display of plaques.

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

(Ic)

(YR) P ¹

in the R represents a mono- or oligosaccharide residue bonded via the 1-OH or 1-SH position,

R ^{F is} a perfluorinated, straight-chain or branched carbon chain with the formula -C _n F _2n E, in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n represents the numbers 4-30,

K represents a metal complex of the general formula IIc,

(llc) in the

R ^{1 is} a hydrogen atom or a metal ion equivalent of

Ordinal numbers 23-29, 42-46 or 58-70 means, with the proviso that at least two R ¹ stand for metal ion equivalents

R ² and R ³ independently represent hydrogen, CrC7-alkyl, benzyl, phenyl, -CH ₂ OH or -CH ₂ OCH ₃ and

U -C ₆ H4-0-CH ₂ -ω-, - (CH ₂ ) ι- ₅ -ω, a phenylene group, -CH ₂ -NHCO-

CH ₂ -CH (CH ₂ COOH) -C ₆ H ₄ -ω-, -C ₆ H ₄ - (OCH ₂ CH ₂ ) o-ι-N (CH ₂ COOH) - CH ₂ -ω or one optionally by a or more oxygen atoms, 1 to 3-NHCO, 1 to 3 -CONH groups interrupted and / or substituted by 1 to 3- (CH ₂ ) o- ₅ COOH groups C ₁ -C12 alkylene or C ₇ -Ci2 -C ₆ H ₄ -0 group, where ω stands for the binding site at -CO-, or of the general formula IIIc

(IIIc)

in which R ^{1 has} the meaning given above, R ^{4 represents} hydrogen or a metal ion equivalent mentioned under R ¹ and U ¹ -C ₆ H _{4 represents} -0-CH ₂ -ω-, where ω represents the binding site at -CO-

or the general formula IVc

(IVc)

in which R ¹ and R ^{2 have} the meaning given above

or the general formula VcA or VcB

(VCA)

(VcB) in which R ^{1 has} the meaning given above,

or the general formula Vlc

ROOC - / - \ - CO— ^ A, ROOC— ^ - COOR ¹

(Vlc) in which R ^{1 has} the meaning given above,

or the general formula VI Ic

(Vllc) in which R ^{1 has} the meaning given above and

U ¹ -C ₆ H4-0-CH ₂ -ω-, where ω is the binding site at -CO-

or the general formula VIIIc

(VIIIc)

in which R ^{1 has} the meaning given above, and any free acid groups which may be present in the radical K may be present as salts of organic and / or inorganic bases or amino acids or amino acid amides,

In the event that K denotes the metal complexes IIc to Vllc, it represents an at least triple-functionalized radical selected from the following radicals a) to j)

(A)

(B)

(C)

(D)

(E)

(F)

(G)

(H)

(0

0)

w ^ NH-CH - CO - ^ γ k ß

and

G in the event that K denotes the metal complex VI 11c represents an at least triple-functionalized radical selected from k) or I),

(K)

(0

α ^ CO-CH ^ CH-CH ^ CO- ^ y NH

ß

where α is the binding site of G to the complex K, ß is the binding site of G to the radical Y and γ is the binding site of G to the radical Z.

Y -CH ₂ -, δ- (CH ₂ ) ₁ . _{5 means} CO-ß, δ-CH ₂ -CHOH-CO-ß or δ-CH (CHOH-CH ₂ OH) - CHOH-CHOH-CO-ß, where δ represents the binding site to the sugar residue R and ß the binding site to the rest G is For

, y

-N ^ ^ N-S0 ₂ -ε

γ-COCH ₂ -N (C ₂ H ₅ ) -S0 ₂ -ε,

γ-COCH ₂ -0- (CH ₂ ) ₂ -S0 ₂ -ε,

or γ - NHCH ₂ CH ₂ -0-CH ₂ CH ₂ - ε, where γ represents the binding site of Z to the radical G and ε represents the binding site of Z to the perfluorinated radical R ^F and

I ¹ , m ¹ independently of one another are the integers 1 or 2 and p ^{1 is} the integers 1 to 4,

be used.

Since the compounds according to the invention are intended for use in NMR diagnostics, the metal ion of the signaling group must be paramagnetic. These are in particular the divalent and trivalent ions of the elements of atomic 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. Because of their strong magnetic moment, gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), iron (III) and manganese (II) ions are particularly preferred , Manganese (II), iron (II), iron (III), praseodymium (III), neodymium (III), samarium (III), gadolinium (III) and ytterbium (III) ions are preferred , especially dyspro- sium (III) ions.

Acidic hydrogen atoms which are optionally present in R ¹ , that is to say those which have not been substituted by the central ion, can optionally be wholly or partly replaced by cations of inorganic and / or organic bases or amino acids or amino acid amides.

Suitable inorganic cations are, for example, lithium ion, potassium ion, calcium ion and in particular sodium ion. Suitable cations of organic bases include those of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine and in particular N-methylglucamine. Suitable cations of amino acids are, for example, those of lysine, arginine and ornithine and the amides of otherwise acidic or neutral amino acids.

Particularly preferred compounds of the general formula Ic are those with the macrocycle K of the general formula IIc.

The radical U in the metal complex K preferably denotes -CH ₂ - or C ₆ H ₄ -O- CH ₂ -CD, where ω stands for the binding site at -CO-.

The alkyl groups R ² and R ³ in the macrocycle of the general formula IIc can be straight-chain or branched. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1, 2-dimethylpropyl. R ² and R ^{3 are} preferably, independently of one another, hydrogen or dC ₄ alkyl. In a very particularly preferred embodiment, R ^{2 is} methyl and R ^{3 is} hydrogen. The benzyl group or the phenyl group R ² or R ³ in the macrocycle K of the general formula IIc can also be substituted in the ring.

The radical R in the general formula Ic denotes a mono- or oligosaccharide radical or thio sugar radical which is bonded via the 1-OH or 1-SH position, which may also be deoxy sugar according to the invention which instead of one or more OH groups H atom included. In a preferred embodiment of the invention, R denotes a monosaccharide residue with 5 or 6 carbon atoms, preferably glucose, mannose, galactose, ribose, arabinose or xylose or their deoxy sugar such as 6-deoxygalactose (fucose) or 6-deoxymannose (rhamnose) or their Thio sugar, with glucose, mannose and galactose being particularly preferred.

Of the compounds of the general formula Ic according to the invention, preference is furthermore given to those in which R ^{F is} -C _n F _{2n +} ι, n is preferably the numbers 4-15. The radicals - CF ₉ , -C ₆ Fi3, -C ₈ Fi7, -C ₁₂ F ₂₅ and -C ₁₄ F29 and the radicals of the compounds mentioned in the examples are very particularly preferred.

The at least triple-functionalized radical G in the general formula Ic, which represents the “framework”, in a preferred embodiment of the invention means the lysine residue (a) or (b).

Y and Z denote the linkers indicated in the general formula Ic, where, independently of one another, Z is the rest

and δ-CH ₂ CO-ß is preferred for Y.

The perfluoroalkyl-containing metal complexes with sugar residues of the general formula Ic (K), ¹ -G - (ZR ^F ) _m ¹

I (Ic)

(YR) P ¹

with K in the meaning of a metal complex of the general formulas IIc to Vllc and G in the meaning of formulas a) to j), where Y, Z, R, R ^F m ¹ , p ¹ and I ^{1 have} the abovementioned meaning prepared by using a carboxylic acid of the general formula IN

wherein R ^{5 is} a metal ion equivalent of atomic numbers 23-29, 42-46, or 58- 70 or a carboxyl protecting group, and R ² , R ³ and U have the meaning given

or a carboxylic acid of the general formula Uli

wherein R ⁴ , R ⁵ and U ^{1 have} the meaning given or a carboxylic acid of the general formula IVi

wherein R ⁵ and R ^{2 have} the meaning given or a carboxylic acid of the general formula Vi or Vii

(Vi) (Vii)

where R has the meaning given

or a carboxylic acid of the general formula VIi

(Vli)

wherein R ^{5 has} the meaning given or a carboxylic acid of the general formula VIII

(Vlli)

wherein R ⁵ and U ^{1 have} the meanings mentioned, in optionally activated form with an amine of the general formula IXc

H - G - (ZR ^F ) _m ¹

I (IXc)

(YR) P ¹

in which G has the meaning of the formulas a) to j) and R, R ^F , Y, Z, m ¹ and p ^{1 have} the meaning given, in a coupling reaction and, if appropriate, subsequent cleavage of any protective groups which may be present to give a metal complex of the general formula Ic or if R ^{5 has} the meaning of a protective group, after splitting off these protective groups in a subsequent step in a manner known per se with at least one metal oxide or metal salt of an element of atomic numbers 23-29, 42-46 or 58-70, and then if Desired, any acidic hydrogen atoms present are substituted by cations of inorganic and / or organic bases, amino acids or amino acid amides.

The compounds of the general formula Ic with K in the meaning of a metal complex of the general formula VIIIc and G in the meaning of the formulas k) or I) are prepared by using an amine of the general formula VIIIi in a manner known per se (Vllli)

wherein R ^{5 is} a metal ion equivalent of atomic numbers 23-29, 42-46 or 58- 70 or a carboxyl protecting group,

with an optionally activated carboxylic acid of the general formula Xc

HO - G - (ZR ^F ) _m ¹

I (Xc)

wherein G has the meaning of the formulas k) or I) and R, R ^F , Y, Z, m ¹ and p ^{1 have} the meanings given, in a coupling reaction and, if appropriate, subsequent cleavage of any protective groups which may be present, to give a metal complex of the general formula Ic or if R ^{5 has} the meaning of a protective group, after splitting off these protective groups in a subsequent step in a manner known per se with at least one metal oxide or metal salt of an element of atomic numbers 23-29, 42-46 or 58-70, and then if desired , any acidic hydrogen atoms present are substituted by cations of inorganic and / or organic bases, amino acids or amino acid amides.

The carboxylic acids of the general formulas Mi to VIII used are either known compounds or are prepared by the processes described in the examples. This is how the carboxylic acids are made the general formula III from DE 19652386 known. The production of the carboxylic acids of the general formula IVi can be found in DE 19728954.

The precursor for compounds of the general formula VcA is N ³ - (2,6-dioxomorpholinoethyl) -N ⁶ - (ethoxycarbonylmethyl) -3,6-diaza-octanedioic acid, which is described in EP 263059.

The compounds of the general formula VcB are derived from the isomeric diethylenetriamine-pentaacetic acid, which binds via the acetic acid at the middle N atom. This DTPA is described in the patents DE 19507819 and DE 19508058.

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

Compounds of the general formula VIIIc are derived from the 1- (4-carboxymethoxybenzyl) ethylenediamine tetraacetic acid which is described in the patent US Pat. No. 4,622,420.

The perbenzylated sugar acids used as starting materials can be analogous to Lockhoff, Angew. Chem. 1998, 110 No. 24, pp. 3634ff. Getting produced. For example, the production of 1-O-acetic acid from perbenzyl-glucose takes place in two stages, via trichloroacetimidate and reaction with ethyl hydroxyacetate, BF ₃ catalysis in THF and subsequent saponification with NaOH in MeOH / THF.

In a more advantageous process, the perbenzylated sugar acids used as starting materials can also be prepared by dissolving the perbenzylated 1-OH sugars in a water-immiscible organic solvent and with an alkylating reagent of the general formula Xlc Nu-L-COO-Sg (Xlc),

where Nu is a nucleofug, L is - (CH ₂ ) ₍ ι- ₅ ), -CH ₂ -CHOH-, -CH (CHOH-CH ₂ OH) -CHOH-CHOH-, and Sg represents a protective group,

in the presence of a base and optionally a phase transfer catalyst. As a nucleophane, the residues -Cl, -Br, -J, -OTs, -OMs, - OS0 ₂ CF ₃ , -OS0 ₂ C ₄ F ₉ or -OS0 ₂ C ₈ F ₁₇ can be contained in the alkylation reagent of the general formula Xlc, for example , The protective group is a common acid protective group. These protective groups are well known to the person skilled in the art (Protective Groups in Organic Syntheses, second Edition, TWGreene and PGM Wuts, John Wiley & Sons Inc., New York 1991).

The reaction according to the invention can take place at temperatures from 0-50 ° C., preferably from 0 ° C. to room temperature. The reaction times are from 10 minutes to 24 hours, preferably from 20 minutes to 12 hours.

The base is either added in solid form, preferably finely powdered, or as a 10-70%, preferably 30-50%, aqueous solution. NaOH and KOH serve as preferred bases.

As organic, water-immiscible solvents, for example toluene, benzene, CF ₃ -benzene, hexane, cyclohexane, diethyl ether, tetrahydrofuran, dichloromethane, MTB or mixtures thereof can be used in the alkylation process according to the invention.

The phase transfer catalysts used in the process according to the invention are the quaternary ammonium or phosphonium salts known for this purpose or also crown ethers such as, for. B. [15] Crown-5 or [18] Crown-6. Quaternary ammonium salts with four identical or different hydrocarbon groups on the cation selected from methyl, ethyl, propyl, isopropyl, butyl or isobutyl are preferred. The hydrocarbon groups on Cations must be large enough to ensure good solubility of the alkylation reagent in the organic solvent. According to the invention, particular preference is given to using N (butyl) 4 ⁺ -Cr, N (butyl) ⁺ -HSθ ₄ ^" , but also N (methyl) ₄ ⁺ -CI ^' .

According to the invention, the metal complex XV of Table 1 (Example 1) is used as a very particularly preferred compound of the general formula Ic.

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

(K), ¹ -G - (ZR ^F ) _m ¹

I (Id)

(R) / p _P

in the

K represents a metal complex of the general formula IIId,

(lld) in the

R ^{1 is} a hydrogen atom or a metal ion equivalent of

Atomic numbers 23-29, 42-46 or 58-70 means with the proviso that at least two R ^{1 represent} metal ion equivalents,

R ² and R ^{3 are} independently hydrogen, -CC ₇ alkyl, benzyl, phenyl, -CH ₂ OH or -CH ₂ OCH ₃ and

U -C ₆ H ₄ -0-CH2-ω-, - (CH ₂ ) ι _-5 -ω, a phenylene group, -CH ₂ -NHCO-

CH2-CH (CH ₂ COOH) -C ₆ H4-ω-, -C ₆ H4- (OCH ₂ CH2) o-ι-N (CH2COOH) - CH ₂ -ω or one optionally by one or more oxygen atoms, 1 to 3-NHCO, 1 to 3 -CONH groups interrupted and / or with 1 to 3

- (CH ₂ ) o-5θ OH groups substituted CrC ₁₂ alkylene or C7-C12-C ₆ H -0 group, where ω stands for the binding site at -CO-, or the general formula II Id

(Hld) in which R ^{1 has} the meaning given above, R ^{4 represents} hydrogen or a metal ion equivalent mentioned under R ¹ and U ¹ -C ₆ H ₄ -0-CH ₂ -ω-, where ω is the binding site to -CO- means or the general formula IVd

(IVd) in which R ¹ and R ^{2 have} the meaning given above

or the general formula VdA or VdB

(Vd)

in which R ^{1 has} the meaning given above,

or the general formula Vld

ROOC- -CO ^^ «

: N ^' N:

RΌOC- -COOR ¹

(Vld) in which R ^{1 has} the meaning given above, or the general formula VI Id

(VIId)

in which R ^{1 has} the meaning given above and

U ¹ -C ₆ H _{4 represents} -0-CH2-ω-, where ω is the binding site at -CO-

and free acid groups which may be present in the rest K may optionally be present as salts of organic and / or inorganic bases or amino acids or amino acid amides,

G represents an at least triple-functionalized residue selected from the following residues a) to g)

(A)

(B)

(C)

(D)

(E)

(0

(G)

X ^" ^" \

HN N NH

ß

where α is the binding site of G to the complex K, ß is the binding site of G to the radical R and γ is the binding site of G to the radical Z.

for y— N:: N-sθ ₂ -ε

γ-C (0) CH ₂ 0 (CH ₂ ) ₂ -ε,

stands, where γ represents the binding site of Z to the radical G and ε represents the binding site of Z to the perfluorinated radical R ^F

R represents a polar radical selected from the complexes K of the general formulas Ild to VI Id, where R ¹ here Is hydrogen atom or a metal ion equivalent of atomic numbers 20, 23-29, 42-46 or 58-70, and the radicals R ² , R ³ , R ⁴ , U and U ^{1 have} the meaning given above or the folic acid radical or a -CO -, S0 ₂ - or a direct bond to the radical G bonded carbon chain with 2-30 C atoms means, straight or branched, saturated or unsaturated, optionally 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, optionally with 1-2 OH groups, 1-2 NH ₂ groups, 1-2 -COOH groups, or 1-2 - SOsH groups can be substituted or optionally substituted with 1-8 OH groups, 1-5 -COOH groups, 1-2 S0 ₃ H groups, 1-5 NH ₂ groups, 1-5 C1-C4 alkoxy groups, and I ¹ , m \ p ² independently of one another denote the integers 1 or 2.

Particularly preferred compounds of the general formula Id are those with the macrocycle K of the general formulas Ild, 11ld, VdB or Vlld.

The radical U in the metal complex K preferably denotes -CH ₂ - or C ₆ H -0- CH -ω, where ω stands for the binding site at -CO-.

The alkyl groups R ² and R ³ in the macrocycle of the general formula III can be straight-chain or branched. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1, 2-dimethylpropyl. R ² and R ^{3 are} preferably independently of one another hydrogen or CrC-alkyl.

In a very particularly preferred embodiment, R ^{2 is} methyl and R ^{3 is} hydrogen. The benzyl group or the phenyl group R ² or R ³ in the macrocycle K of the general formula III can also be substituted in the ring.

In a preferred embodiment, the polar radical R in the general formula Id denotes the complex K, which, in addition to a Gd ³ * or Mn ²⁺ complex, can preferably also be a Ca ²⁺ complex. Particularly preferred polar radicals R are the complexes K of the general formulas III, III, VdA or VIII. With very particular preference, these R ^{1 have} a metal ion equivalent of atomic numbers 20, 25, 39 or 64.

In another preferred embodiment, the polar radical R has the following meanings:

-C (0) CH ₂ CH ₂ S0 ₃ H

-C (O) CH ₂ OCH ₂ CH ₂ 0CH2CH ₂ OH

-C (O) CH ₂ OCH ₂ CH ₂ 0H

-C (0) CH ₂ OCH ₂ CH (OH) CH ₂ OH

-C (0) CH ₂ NH-C (0) CH ₂ COOH

-C (0) CH ₂ CH (OH) CH OH

-C (O) CH ₂ OCH ₂ C00H

-SO ₂ CH ₂ CH C00H

-C (O) -C ₆ H ₃ - (m-C00H) ₂

-C (O) CH ₂ 0 (CH ₂ ) ₂ -C ₆ H ₃ - (m-C00H) ₂

-C (O) CH ₂ O-C ₆ H ₄ -m-S0 ₃ H

-C (0) CH ₂ NHC (0) CH ₂ NHC (0) CH ₂ θCH ₂ COOH

-C (O) CH ₂ OCH ₂ CH ₂ 0CH ₂ COOH

-C (O) CH ₂ OCH2CH (0H) CH2θ-CH ₂ CH ₂ OH

-C (O) CH ₂ 0CH ₂ CH (0H) CH2θCH ₂ -CH (OH) -CH ₂ 0H

-C (0) CH ₂ S0 ₃ H

-C (O) CH ₂ CH ₂ C00H

-C (0) CH (OH) CH (OH) CH ₂ OH

-C (0) CH ₂ 0 [(CH ₂ ) ₂ θ] ι _-9 -CH ₃

-C (0) CH ₂ 0 [(CH ₂ ) ₂ 0] ι _-9 -H

-C (O) CH ₂ 0CH (CH ₂ 0H) ₂ -C (0) CH ₂ OCH (CH ₂ θCH ₂ COOH) ₂

-C (0) -C ₆ H ₃ - (m-OCH ₂ COOH) ₂

-CO-CH ₂ 0- (CH ₂ ) 2θ (CH2) 2θ- (CH ₂ ) ₂ 0 (CH ₂ ) 2θCH3

preferably -C (0) CH ₂ 0 [(CH2) 2θ] 4-CH ₃ .

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

Of the compounds of the general formula Id according to the invention, preference is furthermore given to those in which R ^F - C _n F ₂ n ₊ ι, n is preferably the numbers 4-15. The radicals - C4F9, -CβFi3, -CβFi7, -Cι ₂ F25 and - Ci4F ₂ g are very particularly preferred.

The at least triple-functionalized radical G in the general formula Id, which represents the “framework”, in a preferred embodiment of the invention means the lysine residue (a) or (b).

Z means the linkers indicated in the general formula Id, the rest

r— N:: N-so, -ε

is preferred.

The perfluoroalkyl-containing metal complexes with polar radicals of the general formula Id

(K), ¹ -G - (ZR ^F ) _m ¹

I (Id)

(R) / pP ²

in the K, G, R, Z, R ϊF ^{1 "} , I ι1, have the meaning given above, are prepared by using a carboxylic acid of the general formula IIk in a manner known per se

wherein R ^{5 is} a metal ion equivalent of atomic numbers 23-29, 42-46 or 58- 70 or a carboxyl protecting group, and R ² , R ³ and U have the meaning given

or a carboxylic acid of the general formula Ulk

wherein R ⁴ , R ⁵ and U ^{1 have} the meaning given

or a carboxylic acid of the general formula IVk

(IVk)

wherein R ⁵ and R ^{2 have} the meaning given or a carboxylic acid of the general formula Vk or Vm

(Vk) (Vm)

wherein R ^{5 has} the meaning given

or a carboxylic acid of the general formula VIk

(VIk)

(Vllk)

wherein R ⁵ and U ^{1 have} the meanings mentioned, in optionally activated form with an amine of the general formula VIII

H -G - (ZR ^F ) _m ¹

I (Vllld)

(R) P ²

in which G, R, Z, R ^F , m ¹ and p ^{2 have} the meaning given, in a coupling reaction and, if appropriate, subsequent cleavage of any protective groups which may be present, to give a metal complex of the general formula Id or if R ^{5 has} the meaning of a protective group, after Cleavage of these protective groups in a subsequent step in a manner known per se with at least one metal oxide or metal salt of an element of atomic numbers 23-29, 42-46 or 58-70, and then, if desired, acidic atoms which may be present by cations of inorganic and / or organic bases, amino acids or amino acid amides.

The carboxylic acids of the general formulas IIk to VIIIk used are either known compounds or are prepared by the processes described in the examples. This is how the carboxylic acids are made the general formula IIk known from DE 19652386. The production of the carboxylic acids of the general formula IVk can be found in DE 19728954.

The precursor for compounds of the general formula VdA is N ³ - (2,6-dioxomorpholinoethyl) -N ⁶ - (ethoxycarbonylmethyl) -3,6-diaza-octanedioic acid, which is described in EP 263059.

The compounds of the general formula VdB are derived from the isomeric diethylenetriamine-pentaacetic acid, which binds via the acetic acid at the middle N atom. This DTPA is described in the patents DE 19507819 and DE 19508058.

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

Compounds of the general formula VI Id are derived from 1- (4-carboxymethoxybenzyl) ethylenediamine tetraacetic acid, the preparation of which has been described in US Pat. No. 4,622,420.

The metal complex XVI of Table 1 is used according to the invention as a very particularly preferred compound of the general formula Id.

In another preferred embodiment of the invention, galenical formulations can be used which contain paramagnetic and diamagnetic perfluoroalkyl-containing substances. The paramagnetic and diamagnetic substances are preferably present dissolved in an aqueous solvent.

According to the invention, all of the above-mentioned metal complexes of the general formulas I, Ia, Ia, Ib, Ic and / or Id can be used as paramagnetic perfluoroalkyl-containing compounds in the formulations. The diamagnetic perfluoroalkyl-containing substances are of the general formula XX:

R ^F - L ² - B ² (XX)

wherein R ^{F represents} a straight-chain or branched perfluoroalkyl radical having 4 to 30 carbon atoms, L ^{2 stands} for a linker and B ² for a hydrophilic group. The linker L ² is a direct bond, a -SO ₂ group or a straight-chain or branched carbon chain with up to 20 carbon atoms, which can be substituted with one or more -OH, -COO ^" , -SO ₃ groups and / or optionally one or more -0-, -S-, -CO-, -CONH-, -NHCO-, -CONR ⁹ -, -NR ⁹ CO-, -S0 ₂ -, -P0 ₄ -, -NH-, - Contains NR ⁹ groups, an aryl ring or a piperazine, where R ^{9 represents} a Cr to C ₂ o -alkyl radical, which in turn can contain one or more O atoms and / or can be substituted with -COO ^" or S0 groups ,

The hydrophilic group B ² is a mono- or disaccharide, one or more adjacent -COO ^" or -S0 ₃ ^' groups, a dicarboxylic acid, an isophthalic acid, a picolinic acid, a benzenesulfonic acid, a tetrahydropyranedicarboxylic acid, a 2,6-pyridinedicarboxylic acid , a quaternary ammonium ion, an aminopolycarboxylic acid, an aminodipolyethylene-glycolsulfonic acid, an aminopoiyethylene glycol group, an S0 ₂ - (CH ₂ ) ₂ -OH group, a polyhydroxyalkyl chain with at least two hydroxyl groups or one or more polyethylene glycol chains with at least two glycol units, the polyethylene glycol chains being passed through a -OH or - OCH ₃ group are terminated, some of which substances are already known, some of which have been newly synthesized for the preparation of the formulations according to the invention, and known perfluoroalkyl-containing substances and their preparation are described in the following publications:

JG Riess, Journal of Drug Targeting, 1994, Vol. 2, pp. 455-468; JB 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. 13,073 to 13,088; 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. Guileri 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, pp. 323-336; 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., Jounal 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. Santaella et al., New J. Chem., 1991, Vol. 15, pp.685-692;

C. Santaella 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. Szönyi et al., Journal of Fluorine Chemistry, 1991, vol. 55, pp. 85-92;

C. Santaella et al., Angew. Chem., 1991, vol. 103, no. 5, pp. 584-586;

M.-P. Krafft et al., Angew. Chem., 1993, Vol. 105, No. 5, pp. 783-785;

EP 0548096 B1.

The new perfluoroalkyl-containing substances are prepared analogously to the compounds known from the literature and are described in the examples. These are substances of the general formula XXI

R ^F - X ¹ (XXI) wherein R ^{F represents} a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms and X ^{1 is} a radical selected from the group of the following radicals (n is a number between 1 and 10):

OH o

0 ^ ° 3

Preferred diamagnetic perfluoroalkyl-containing substances are those with a monosaccharide as the hydrophilic group B ² .

Particularly preferred diamagnetic perfluoroalkyl-containing compounds contain a perfluoroalkyl radical Rf with 6 to 12 carbon atoms, a linker L ² , which represents a -S0 ₂ group or a straight-chain or branched carbon chain with up to 20 carbon atoms, which in turn is one or more -O-, - CO-, -CONH-, -NHCO-, -CONR-, -NRCO-, -S0 groups or a piperazine, in which R has the meaning given above, and a monosaccharide as the hydrophilic group B ² .

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

A ¹ -L ³ -R ^F (XXII)

wherein A ^{1 is} an adamantane, biphenyl or anthracene molecule, L ^{3 is} a linker and R ^{F is} a straight-chain or branched perfluoroalkyl radical having 4 to 30 carbon atoms. The linker L ³ is a straight-chain hydrocarbon chain with 1 to 20 carbon atoms, which by one or more oxygen atoms, one or more CO, SO2, CONH, NHCO, CONR, NRCO, NH, NR groups or one Piperazine can be interrupted, where R is a CrC ₅ alkyl radical.

Preferred compounds are the following compounds:

The pharmaceutical formulations of the present invention contain the paramagnetic and diamagnetic perfluoroalkyl-containing compounds in a mixing ratio between 5:95 and 95: 5. Mixing ratios between 40:60 and 60:40 of the two substances are preferred. Both substances are used in millimolar concentrations. Concentrations between 0.5 and 1000 mmol / l solvent are reached. The solvent is preferably water. The metal concentration of the formulations is preferably in a range from 50-250 mmol / l.

Mixtures of paramagnetic and diamagnetic perfluoroalkyl-containing compounds in which the perfluoroalkyl chains have a length of 6 to 12 carbon atoms are preferred. Mixtures in which both the paramagnetic and the diamagnetic perfluoroalkyl-containing compounds have a perfluoroalkyl chain with 8 carbon atoms are particularly preferred.

The pharmaceutical formulations are prepared by weighing the paramagnetic perfluoroalkyl-containing compounds (component A) and the diamagnetic perfluoroalkyl-containing substances (component B) in mole fractions between 0.05 and 0.95 on component A or B and dissolving them in a suitable solvent. A particularly suitable solvent is water. Common pharmaceutical additives such as buffer solutions and the Ca salt of the complexing agent are then added to this solution in excess. At 10 to 100 ° C the solutions are stirred vigorously. Alternatively, the solutions at 10 to 100 ° C in be treated with an ultrasonic bath. Another alternative is to treat the solutions with microwaves.

For substances that do not dissolve in water as individual components, it proves advantageous to add a solubilizer such as alcohol (e.g. methanol or ethanol) or another water-miscible solvent and then slowly distill it off. The distillation can be carried out under vacuum. The residue is then dissolved in water and the solution is filtered. It is also possible to separately dissolve each component in a solvent, then combine them and proceed as above. It has proven to be advantageous to present a relatively highly concentrated solution (> 100 mmol) of the metal complex (component A) and then to add component B pure and, as mentioned above, to stir the solution or to treat it with ultrasound or microwaves.

In summary, it can be stated that the gadolinium complexes I-XVI listed in Table 1 meet the criteria according to the invention as very particularly preferred compounds. The physical parameters of these metal complexes I-XVI are listed in Table 2.

Both the paramagnetic compounds according to the invention of the general formulas I, Ia, Ib, Ic and Id as well as the formulations according to the invention made of paramagnetic and diamagnetic perfluoroalkyl-containing substances are outstandingly suitable as contrast agents in MR imaging for the representation of plaques, tumors and necrosis.

Table 1: Metal complexes used with particular preference according to the invention

Table 2:

Physicochemical parameters of the complexes used according to the invention in accordance with Table 1

CMC: critical micelle concentration 2 Rh: hydrodynamic micelle diameter R ¹ : relaxivity embodiments

example 1

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

8.90 g (70 mmol) of oxalyl chloride are added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane and the mixture is stirred for 12 hours at room temperature. It is 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 4.51 g (60 mmol) of 2-methoxyethylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. Stir 3

Hours at 0 ° C, then 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stir well for 15 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1).

Yield: 30.28 g (91% of theory) of a colorless solid

Elemental analysis: calc .: C 31.10 H 2.44 2.42 F 55.76 found: 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) -perfluorotride-cylamine

30 g (51.79 mmol) of the title compound from Example 1a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 200 ml of methanol are added dropwise, then it is evaporated to the dry state in a vacuum. The residue is in a mixture of 300 ml

Ethanol / 50 ml 10% aqu. Hydrochloric acid added and 8 hours Stirred at 40 ° C. It is evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous solution. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / 2 propanol = 20: 1).

Yield: 26.93 g (92% of theory) of a colorless solid

Elemental analysis (calculated on anhydrous substance): calc .: C 31.87 H 2.85 N 2.48 F 57.14 found: C 31.69 H 3.10 N 2.27 F 56.88

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 the gadolinium complex of 10- [1- (carboxymethylcarboamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31, 76 mmol) of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 8.98 g (15.88 mmol) of the title compound from Example 1b are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile solvent: gradient of tetrahydrofuran / acetonitrile / water). Yield: 15.14 g (81% of theory) of a colorless, amorphous powder. Water content: 5.7%

Elemental analysis (calculated on anhydrous substance): calc .: C 34.70 H 3.77 N 7.14 F 27.44 Gd 13.36 found: 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) 2H, 2H, 4H, 4H , 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml dichloromethane are added 8.90 g (70 mmol) oxalyl chloride and stirred for 12 hours at room temperature. It is 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 5.47 g (60 mmol) of 2,3-dihydroxypropylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. Stir 3

Hours at 0 ° C, then 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stir well for 15 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: dichloromethane / ethanol = 15: 1).

Yield: 29.70 g (87% of theory) of a colorless solid

Elemental analysis: calc .: C 30.32 H 2.20 N 2.36 F 54.35 found: 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 compound from Example 2a are dissolved in 300 ml of tetrahydrofuran and 50 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 300 ml of methanol are added dropwise, then the mixture is evaporated to dryness in a vacuum. The residue is made up in a mixture

300 ml ethanol / 50 ml 10% aqu. Hydrochloric acid added and stirred at 60 ° C for 8 hours. It is evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous solution. Sodium hydroxide solution and extracted 3 times with 300 ml dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 15: 1). Yield: 24.07 g (85% of theory) of a colorless solid Elemental analysis: calc .: C 31.05 H 2.61 N 2.41 F 55.66 found: C 31.91 H 2.78 N 2.33 F 55.47

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 V)

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarboamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31, 76 mmol) of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 9.21 g (15.88 mmol) of the title compound from Example 2b are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate which has precipitated is filtered off and dissolved in a

Mixture of a little EthanoiVWasser and chromatographed on silica gel RP-18 (mobile solvent: gradient from tetrahydrofuran / acetonitrileΛ / Vasser). Yield: 16.09 g (85% of theory) of a colorless, amorphous powder. Water content: 6.3%

Elemental analysis (calculated on anhydrous substance): calc .: C 34.26 H 3.64 N 7.05 F 27.10 Gd 13.19 found: 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

8.90 g (70 mmol) of oxalyl chloride are added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane and the mixture is stirred for 12 hours at room temperature. It is evaporated to dryness in a vacuum. The residue is dissolved in 100 ml of dichloromethane and at 0 ° C. to a solution of 6.25 g (60 mmol)

5-Hydroxy-3-oxapentylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane, are added dropwise. The mixture is stirred for 3 hours at 0 ° C., then for 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stir well for 15 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The

The residue is chromatographed on silica gel (mobile phase: dichloromethane / acetone = 15: 1). Yield: 32.20 g (92% of theory) of a colorless solid

Elemental analysis: calc .: 0 31.54 H 2.65 N 2.30 F 53.01 found: C 31.61 H 2.84 N 2.14 F 52.85

b) N- (5-Hydroxy-3-oxapentyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-per-fluorotridecyl) amine

30 g (49.24 mmol) of the title compound from Example 3a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It's going on

Cooled 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid added and stirred at 50 ° C for 10 hours. It is evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous solution. Sodium hydroxide solution and extracted 3 times with 300 ml dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue Chromatographed on silica gel (eluent: dichloromethane / 2-propanol

20: 1).

Yield: 26.09 g (89% of theory) of a colorless solid

Elemental analysis: calc .: C 32.28 H 3.05 N 2.35 F 54.25 found: 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-oxapentyl) - 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 the gadolinium complex of 10- [1- (carboxymethylcarboamoyl) ethyl] -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1.35 g (31, 76 mmol) of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 9.45 g (15.88 mmol) of the title compound from Example 3b are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol and chromatographed on silica gel RP-18 (mobile solvent: gradient composed of tetrahydrofuran / acetonitrile / water).

Yield: 16.10 g (84% of theory) of a colorless, amorphous powder. Water content: 5.7%

Elemental analysis (calculated on anhydrous substance): calc .: C 34.83 H 3.84 N 6.96 F 26.76 Gd 13.03 found: 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 8.90 g (70 mmol) of oxalyl chloride are added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane and the mixture is stirred for 12 hours at room temperature. It is evaporated to dryness in a 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)

Triethylamine, dissolved in 200 ml of dichloromethane, added dropwise. The mixture is stirred for 3 hours at 0 ° C., then for 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stir well for 15 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is on silica gel (mobile solvent:

Dichloromethane / acetone = 20: 1) chromatographed. Yield: 28.90 g (89% of theory)

Elemental analysis: calc .: C 29.75 H 2.14 N 2.48 F 57.14 found: C 29.61 H 2.29 N 2.37 F 57.01

N- (2-Hydroxyethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluorotride-cyl) amine

28 g (49.54 mmol) of the title compound from Example 4a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 200 ml of methanol are added dropwise, then the mixture is evaporated to dryness in a vacuum. The residue is made up in a mixture

300 ml ethanol / 50 ml 10% aqu. Hydrochloric acid added and stirred at 50 ° C for 10 hours. It is evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous solution. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile phase: dichloromethane / 2 propanol = 15: 1). Yield: 25.12 g (92% of theory) of a colorless solid

Elemental analysis (calculated on anhydrous substance): calc .: C 30.50 H 2.56 N 2.54 F 58.59 found: 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-hydroxyethyl) -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 the gadolinium complex of 10- [1- (carboxymethylcarboamoyl) ethyl] -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1.35 g (31, 76 mmol) of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. It is cooled to 15 ° C. and 8.75 g (15.88 mmol) of the title compound from Example 4b are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel

RP-18 (mobile solvent: gradient of tetrahydrofuran / acetonitrile / water). Yield: 16.81 g (91% of theory) of a colorless, amorphous powder. Water content: 7.2%

Elemental analysis (calculated on anhydrous substance): calc .: C 34.08 H 3.64 N 7.23 F 27.77 Gd 13.52 found: 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-perfluorotridecanoic acid amide

8.90 g (70 mmol) of oxalyl chloride are added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane and the mixture is stirred

12 hours at room temperature. It is evaporated to dryness in a vacuum. The residue is dissolved in 200 ml of dichloromethane. Then ammonia gas is passed into the solution for about 2 hours at 0 ° C. The mixture is stirred for 4 hours at 0 ° C, then 2 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stir well for 15 minutes. The organic phase is separated off, dried over magnesium sulfate and in Vacuum evaporated to dryness. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone = 20: 1). Yield: 27.85 g (93% of theory)

Elemental analysis: calc .: C 27.66 H 1.55 N 2.69 F 61.97 found: 0 27.49 H 1.72 N 2.54 F 61.81

1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecylamine, hydrochloride

27 g (51.8 mmol) of the title compound from Example 5a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 200 ml of methanol are added dropwise, then it is evaporated to the dry state in a vacuum. The residue is in a mixture of 400 ml of ethanol / 100 ml of 10% aqu. Hydrochloric acid added and stirred at 60 ° C for 8 hours. It is evaporated to the dry state in a vacuum and the residue is recrystallized from a little ethanol / diethyl ether. Yield: 26.75 g (95% of theory) of a colorless, crystalline solid

Elementary arntaranalys «calc .: C 26.51 H 2.04 N 2.58 F 59.41 Cl 6.52 found: C 26.37 H 2.21 N 2.46 F 59.25 Cl. 6.38

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

To 26.5 g (48.74 mmol) of the title compound from Example 5b and 14.8 g

(146.2 mmol) of triethylamine, dissolved in 300 ml of dichloromethane, are added dropwise at 0 ° C., 14.24 g (50 mmol) of 3,6,9,12, 15-pentaoxahexadecanoic acid chloride and stirred for 3 hours at 0 ° C. 300 ml of 5% aqu. Hydrochloric acid and stir well for 30 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The The residue is chromatographed on silica gel (mobile phase: dichloromethane / acetone: 20: 1).

Yield: 32.03 g (87% of theory) of a colorless oil

Elemental analysis: calc .: C 36.57 H 4.00 N 1.85 F 42.75 found: 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 compound from Example 5c are dissolved in 300 ml of tetrahydrofuran and 25 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It's going on

Cooled 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid added and stirred at 40 ° C for 8 hours. It is evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous solution. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / 2 propanol = 15: 1). Yield: 27.68 g (91% of theory)

Elemental analysis: calc .: C 37.26 H 4.35 N 1.89 F 43.56 found: 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, gadolinium complex (metal complex VII) 10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarboamoyl) ethyl] -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1.35 g (31, 76 mmol) of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 11.77 g (15.88 mmol) of the title compound from Example 5d are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on

Silica gel RP-18 (mobile solvent: gradient made of tetrahydrofuran / acetonitrile / water).

Yield: 18.05 g (84% of theory) of a colorless, amorphous powder. Water content: 6.2%

Elemental analysis (calculated on anhydrous substance): calc .: C 37.28 H 4.47 N 6.21 F 23.87 Gd 11, 62 found: 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-trioxadodecyl ) -amide] - 1, 4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarboamoyl) ethyl] -1, 4,7,10-tetraazacyclododecan-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 are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 3.51 g (17 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is stirred at 15 ° C. for 5 hours. The solution is filtered to separate the urea. 14.66 g (60 mmol) of 1, 12-diamino-3,6,9-trioxadodecane and 2.02 g (20 mmol) of triethylamine are added to the filtrate and the mixture is stirred for 12 hours at room temperature. The solution is poured into 1500 ml of diethyl ether / 50 ml of n-

Butanol and stir for 30 minutes. The precipitated solid is filtered off and Chromatographed on silica gel RP-18 (eluent: gradient off

Tetrahydrofuran / AcetonitriiYWasser).

Yield: 12.66 g (69% of theory) of a colorless, amorphous powder

Water content: 3.5%

Elemental analysis (calculated on anhydrous substance): calc .: C 30.16 H 4.54 N 8.49 F 27.96 Gd 13.61 found: C 30.02 H 4.68 N 8.35 F 27.81 Gd 13.45

b) 1, 4,7-tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) acid- [N-

3,6,9,16-tetraoxa-13-aza-14-oxo-Cι ₉ -C ₂₆ -hepta-decafluor) -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 dissolved in 150 ml of dimethyl sulfoxide at 25 ° C. It is cooled to 15 ° C. and 6.19 g (30 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is stirred at 15 ° C. for 5 hours. The solution is filtered to separate the urea.

12.5 g (10.82 mmol) of the title compound from Example 6a and 3.29 g (32.47 mmol) of triethylamine are added to the filtrate and the mixture is stirred at room temperature for 12 hours. The solution is poured into 1300 ml of diethyl ether / 100 ml of acetone and stirred for 30 minutes. The precipitated solid is filtered off and chromatographed on silica gel RP-18 (mobile solvent: gradient from

Tetrahydrofuran / acetonitrile / water). Yield: 13.01 g (90% of theory) Water content: 6.7%

Elemental analysis (calculated on anhydrous substance): calc .: C 36.86 H 4.30 N 7.34 F 24.17 Gd 11.77 found: 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 of 10- [1 - (carboxymethylcarboamoyl) 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 are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 3.51 g (17 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is stirred at 15 ° C. for 5 hours. The solution is filtered to separate the urea. To the

Filtrate, 8.63 g (15.88 mmol) of the title compound from Example 5b and 5.06 g (50 mmol) of triethylamine are added and the mixture is stirred for 12 hours at room temperature. The solution is poured into 1500 ml of diethyl ether / 100 ml of acetone and stirred for 30 minutes. The precipitated solid is filtered off and chromatographed on silica gel RP-18 (mobile solvent: gradient composed of tetrahydrofuran / acetonitrile / water). Yield: 13.86 g (78% of theory) of a colorless, amorphous powder. Water content: 9.3%

Elemental analysis (calculated on anhydrous substance): calc .: C 33.28 H 3.42 N 7.51 F 28.87 Gd 14.05 found: 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-perfluorotridecanoic acid-N- (2,3,4,5,6-penta-hydroxy) -hexylamide

8.90 g (70 mmol) of oxalyl chloride are added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane and the mixture is stirred for 12 hours at room temperature. It is 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 10.87 g (60 mmol) of glucamine and 6.07 g (60 mmol) of triethylamine, dissolved in 150 ml of dichloromethane / 150 dioxane. You stir

3 hours at 0 ° C, then 8 hours at room temperature. 400 ml of 5% aqu. Hydrochloric acid and stir well for 15 minutes. The orga- African phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile phase: dichloromethane / methanol = 5: 1).

Yield: 30.71 g (78% of theory)

Elemental analysis: calc .: C 31.55 H 2.94 N 2.04 F 47.13 found: C 31.44 H 3.09 N 1.97 F 47.01

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

30 g (43.77 mmol) of the title compound from Example 8a are dissolved in 300 ml of tetrahydrofuran and 50 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 48 hours. It is cooled to 0 ° C. and 500 ml of methanol are added dropwise, then the mixture is evaporated to dryness in vacuo. The residue is in a mixture of 500 ml of ethanol / 100 ml of 10% aqu. Hydrochloric acid added and stirred at 60 ° C for 15 hours. It is evaporated to the dry state in a vacuum, the residue is taken up in 400 ml of 5% aqu. Sodium hydroxide solution and extracted 5 times with 400 ml of chloroform. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile phase: dichloromethane / methanol = 3: 1).

Yield: 19.69 g (67% of theory) of a colorless solid

Elemental analysis: calc .: C 32.20 H 3.30 N 2.09 F 48.11 found: 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-penthydroxy) -hexyl- N- (1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-per-fluorotridecyl] -amide} -1, 4,7,10-tetraazacyclododecane, gadolinium complex 10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarboamoyl) ethyl] -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1.35 g (31, 76 mmol) of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 15.88 g (15.88 mmol) of the title compound from Example 8b are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on

Yield: 16.10 g (79% of theory) of a colorless, amorphous powder. Water content: 6.3%

Elemental analysis (calculated on anhydrous substance): calc .: C 36.64 H 3.93 N 6.55 F 25.17 Gd 12.26 found: 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

8.90 g (70 mmol) of oxalyl chloride are added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane and the mixture is stirred for 12 hours at room temperature. It is evaporated to dryness in a vacuum. The residue is dissolved in 100 ml of dichloromethane and 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. The mixture is stirred for 3 hours at 0 ° C., then for 5 hours at room temperature. 300 ml of water are added and the mixture is stirred well for 15 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is on silica gel (mobile solvent:

Dichloromethane / acetone = 15: 1) chromatographed. Yield: 27.62 g (85% of theory) Elemental analysis: calc .: C 34.30 H 3.03 N 2.11 F 48.54 found: 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 (40.58 mmol) of the title compound from Example 9a are dissolved in 300 ml

Dissolved tetrahydrofuran and 26 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) added. The mixture is refluxed for 20 hours. It is cooled to 0 ° C. and 300 ml of methanol are added dropwise, then it is evaporated to the dry state in a vacuum. The residue is in a mixture of 300 ml of ethanol / 100 ml of 10% aqu. Hydrochloric acid added and stirred at 60 ° C for 6 hours. It is evaporated to the dry state in a vacuum, the residue is taken up in 400 ml of 5% aqu. Sodium hydroxide solution and extracted 5 times with 250 ml of chloroform. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 6: 1).

Yield: 20.09 g (81% of theory) of a colorless solid

Elemental analysis: calc .: C 31.44 H 2.97 N 2.29 F 52.83 found: 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 the gadolinium complex of 10- [1- (carboxymethylcarboamoyl) ethyl] -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1.35 g

(31, 76 mmol) lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. It is cooled to 15 ° C. and 9.71 g (15.88 mmol) of the title compound addition from Example 9b. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile solvent: gradient of tetrahydrofuran / acetonitrile / water). Yield: 13.40 g (69% of theory) of a colorless, amorphous powder. Water content: 9.1%

Elemental analysis (calculated on anhydrous substance): calc .: C 34.37 H 3.79 N 6.87 F 24.41 Gd 12.86 found: 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 are heated to 80 ° C. for 10 hours. The mixture is cooled to room temperature and placed directly on a silica gel column for chromatographic purification (mobile phase: dichloromethane / acetone = 20: 1). Yield: 42.22 g (36% of theory) of a colorless solid

Elemental analysis: calc .: C 31.97 H 1.94 N 4.14 F 47.75 S 4.74 found: 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 compound from Example 10a are dissolved in 300 ml of methanol and 5 g of palladium catalyst (10% Pd / C) are added hydrated overnight at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 24.05 g (quantitative) of a colorless solid

tieme intaranaiyse: calc .: C 22.15 H 1.30 N 5.17 F 59.57 found: 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-per-fluoroctylsulfonylamino) -ethyl] -amide} -1, 4,7,10-tetraazacyclododecane, gadolinium complex

(31.76 mmol) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolved in 100 ml of dimethyl sulfoxide at 60.degree. The mixture is cooled to 15 ° C. and 3.51 g (17 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is stirred at 15 ° C. for 5 hours. The solution is filtered to separate the urea. 8.61 g (15.88 mmol) of the title compound from Example 10b and 2.02 g (20 mmol) of triethylamine are added to the filtrate and the mixture is stirred for 12 hours at room temperature. The solution is poured into 1500 ml of diethyl ether / 100 ml of acetone and stirred for 30 minutes. The precipitated solid is filtered off and chromatographed on silica gel RP-18 (mobile solvent: gradient composed of tetrahydrofuran / acetonitrile / water).

Yield: 15.76 g (86% of theory) of a colorless, amorphous powder. Water content: 6.5%

Elemental analysis (calculated on anhydrous substance): calc .: C 30.19 H 3.06 N 8.50 F 27.99 Gd 13.63 S 2.78 found: 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-perfluorotridecanoic acid-N- (2-benzyloxy-carboxylamino-ethyl] -amide

12 hours at room temperature. It is evaporated to dryness in a vacuum. The residue is dissolved in 100 ml of dichloromethane and 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 was added dropwise. The mixture is stirred for 3 hours at 0 ° C., then 5

Hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stir well for 15 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone = 20: 1).

Yield: 33.30 g (83% of theory) of a colorless solid

Elemental analysis: calc .: C 37.84 H 2.74 N 4.01 F 46.25 found: 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 compound from Example 11a are dissolved in 500 ml of methanol and 5 g of palladium catalyst (10% Pd / C) are added, and the mixture is hydrogenated overnight at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 24.24 g (quantitative) of a colorless solid

Elemental analysis: calc .: C 29.80 H 2.32 N 4.96 F 57.24 found: 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 (C ₉ -Ci6-heptadecafluoro) hexadecyl] amide} -1, 4,7,10-tetraaza- cyclododecane-gadolinium complex

10 g (15.88 mmol) of the gadolinium complex of 10- [1 - (carboxymethylcarbo-amoyl) 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 are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 3.51 g (17 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is stirred at 15 ° C. for 5 hours. The solution is filtered to separate the urea. To the

8.96 g (15.88 mmol) of the title compound from Example 11b and 2.02 g (20 mmol) of triethylamine are added to the filtrate and the mixture is stirred at room temperature for 12 hours. The solution is poured into 1500 ml of diethyl ether / 100 ml of acetone and stirred for 30 minutes. The precipitated solid is filtered off and chromatographed on silica gel RP-18 (mobile solvent: gradient composed of tetrahydrofuran / acetonitrile / water).

Yield: 15.31 g (82% of theory) of a colorless, amorphous powder. Water content: 6.3%

Elemental analysis (calculated on anhydrous substance): calc .: C 33.71 H 3.51 N 8.34 F 27.46 Gd 13.37 found: 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-perfluorundecanoic 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 are added 8.90 g (70 mmol) of oxalyl chloride and stirred for 12 hours room temperature. It is 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 3.66 g (60 mmol) of ethanolamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. The mixture is stirred for 3 hours at 0 ° C., then for 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stir well for 15 minutes. The organic Phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone = 20: 1). Yield: 24.86 g (93% of theory) of a colorless solid

Elemental analysis: calc .: C 30.98 H 2.60 N 3.01 F 53.09 found: 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 compound from Example 12a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is boiled under reflux for 12 hours. It is cooled to 0 ° C. and 200 ml of methanol are added dropwise, then it is evaporated to the dry state in a vacuum. The residue is in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid was added and the mixture was stirred at 40 ° C. for 8 hours. It is evaporated to dryness in a vacuum and taken

Residue in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / 2-propanol = 20: 1).

Yield: 20.95 g (90% of theory) of a colorless solid

Elemental analysis: calc .: C 31.94 H 3.13 N 3.10 F 54.73 found: 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-3oxa) -perfluorundecyl] - amide} -1, 4.7, 10-tetraazacyclododecane-gadolinium complex 10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarboamoyl) ethylj-1, 4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 8.98 g (15.88 mmol) of the title compound from Example 12b are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel

RP-18 (mobile solvent: gradient of tetrahydrofuran / acetonitrile / water).

Yield: 14.01 g (83% of theory) of a colorless, amorphous powder. Elemental analysis: calc .: C 35.03 H 3.98 N 7.91 F 23.24 Gd 14.79 found: 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-perfluorundecanoic acid-N- (3,6,9,12-tetraoxa- tridecyl) -amide

8.90 g (70 mmol) of oxalyl chloride are added to 24.25 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorundecanoic acid in 300 ml of dichloromethane and the mixture is stirred for 12 hours room temperature. It is evaporated to dryness in a vacuum. The residue is dissolved in 100 ml of dichloromethane and 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 dropwise. The mixture is stirred for 3 hours at 0 ° C., then for 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stir well for 15 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone = 15: 1). Yield: 31.61 g (90% of theory) of a colorless solid

Elemental analysis: calc .: C 37.33 H 4.29 N 2.29 F 40.40 found: C 37.15 H 4.41 N 2.12 F 40.18 b) N- (3,6,9,12-tetraoxatridecyi) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-per-. fluorundecyl) amine

31 g (50.7 mmol) of the title compound from Example 13a are dissolved in 300 ml of tetrahydrofuran and 32 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 200 ml of methanol are added dropwise, then the mixture is evaporated to dryness in a vacuum. The residue is made up in a mixture

300 ml ethanol / 50 ml 10% aqu. Hydrochloric acid added and stirred at 40 ° C for 8 hours. It is evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous solution. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile phase: dichloromethane / 2-propanol = 20: 1). Yield: 28.17 g (93% of theory) of a colorless solid

Elemental analysis (calculated on anhydrous substance): calc .: C 38.20 H 4.72 N 2.34 F 41.34 found: 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-3oxa) -per-fluorundecyl] -amide} -1, 4.7 , 10-tetraazacyclododecane-gadolinium complex

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbomoyl) ethyl] -1,4.7,10-tetraazacyclododecane-1, 4,7-triacetic acid and 1.35 g

(31.76 mmol) lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 9.49 g (15.88 mmol) of the title compound from Example 13b are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyi-1,2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate which has precipitated is filtered off and dissolved in a Mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile solvent: gradient made of tetrahydrofuran / acetonitrile / water). Yield: 16.13 g (84% of theory)

Elemental analysis: calc .: C 37.75 H 4.67 N 6.95 F 20.43 Gd 13.01 found: 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

6.523 g (40 mmol) of t-butyl bromoacetate are added dropwise to 32.0 g (58.65 mmol) of the title compound from Example 5b and 24.89 g (180 mmol) of potassium carbonate in 300 ml of acetonitrile, and the mixture is stirred 3 hours at this temperature. 300 ml of dichloromethane are added, the precipitated salts are filtered off and the filtrate is evaporated to dryness in vacuo. The

The residue is chromatographed on silica gel (mobile phase: dichloromethane / 2-propanol = 20: 1). Yield: 28.11 g (57% of theory) of a colorless solid

Elemental analysis: calc .: C 34.80 H 3.24 N 2.25 F 51.98 found: 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-3oxa) -per-fluorotridecyl] -amide} -1, 4,7,10-tetraazacyclododecane-gadolinium complex

(31, 76 mmol) lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 9.87 g (15.88 mmol) of the title compound from Example 14a are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile solvent: gradient of tetrahydrofuran / acetonitrile water). Yield: 16.64 g (85% of theory) Elemental analysis: calc .: C 36.04 H 3.92 N 6.82 F 26.19 Gd 12.72 found: 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 - [(carb-oxymethyl) -N- (1H, 1H , 2H, 2H, 4H, 4H, 5H, 5H-3oxa) -perfluorotridecyl] -amide} - 1, 4,7,10-tetraazacyclododecane-gadolinium complex

10 g (8.11 mmol) of the title compound from Example 14b are dissolved in 50 ml

Trifluoroacetic acid dissolved and stirred for 5 hours at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel RP-18 (mobile solvent: gradient composed of tetrahydrofuran / acetonitrile / water). After evaporation of the product-containing fractions, the residue is dissolved in water and mixed with 5% aqu. Sodium hydroxide solution adjusted to pH 7.2. The solution is filtered and the filtrate freeze-dried. Yield: 10.48 g (91% of theory)

Elemental analysis (calculated on anhydrous substance): calc .: C 33.06 H 3.28 N 7.01 F 26.94 Gd 13.12 Na 1, 92 found: 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-perfiuortridecanoic acid-N- (2-hydroxyethyl) amide

2.96 g (74 mmol) of sodium hydride (from 60% sodium hydride in paraffin oil) in 300 ml of tetrahydrofuran are added to 32 g (56.61 mmol) of the title compound from Example 4a and the mixture is stirred for 3 hours at room temperature under nitrogen. 7.67 g (74 mmol) of t-butyl bromoacetate, dissolved in 20 ml of tetrahydrofuran, are added dropwise and the mixture is stirred at 50 ° C. for 5 hours. 50 ml of methanol are added and the mixture is evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile phase: dichloromethane (/ 2-propanoI = 20: 1).

Yield: 23.46 g (61% of theory) Elemental analysis: calc .: C 35.36 H 3.26 N 2.06 F 47.54 found: 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

35.0 g (51, 52 mmol) of the title compound from Example 15a are dissolved in 300 ml

Dissolved tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 200 ml of methanol are added dropwise, then it is evaporated to the dry state in a vacuum. The residue is in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid and 8

Stirred at 40 ° C for hours. It is evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous solution. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / 2-propanol = 20: 1). Yield: 31.88 g (93% of theory)

Elemental analysis: calc .: C 36.10 H 3.64 N 2.11 F 48.54 found: 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-3oxa) - perfluorotridecyl] -amide} -1, 4,7,10-tetraazacyclododecane, gadolinium complex

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarboamoyl) ethyl] -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1.35 g (31, 76 mmol) of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 10.57 g (15.88 mmol) are added Title compound from Example 15b. Stir for 10 minutes and then give

7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. It will

Stirred for 12 hours at room temperature. You pour the solution into one

Mixture of 200 ml acetone / 1300 ml diethyl ether and stirred for 2 hours

Room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on

Silica gel RP-18 (eluent: gradient off

Tetrahydrofuran / acetonitrile / water). Yield: 16.63 g (82% of theory)

Elemental analysis: calc .: C 36.68 H 4.10 N 6.58 F 25.29 Gd 12.31 found: C 36.81 H 4.20 N 6.41 F 25.40 Gd 12.19

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

12 g (9.40 mmol) of the title compound from Example 15c are dissolved in 50 ml of trifluoroacetic acid and stirred for 5 hours at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel RP-18 (mobile solvent: gradient composed of tetrahydrofuran / acetonitrile / water). After evaporation of the product-containing fractions, the residue is dissolved in water and mixed with 5% aqu. Sodium hydroxide solution adjusted to pH 7.2. The solution is filtered and the filtrate freeze-dried.

Yield: 11.41 g (92% of theory) Water content: 5.8%

Elemental analysis (calculated on anhydrous substance): calc .: C 33.82 H 3.49 N 6.76 F 25.98 Gd 12.65 Na 1.85 found: 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, 5H-3-oxa-perfluorotridecyl) -amide

8.90 g (70 mmol) of oxalyl chloride are added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane and the mixture is stirred for 12 hours at room temperature. It is evaporated to dryness in a vacuum. The residue is dissolved in 100 ml of dichloromethane and at 0 ° C. to a solution of 32.62 g (60 mmol) of the title compound from Example 5b and

6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane, are added dropwise. The mixture is stirred for 3 hours at 0 ° C., then for 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stir well for 15 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is on silica gel

(Mobile phase: dichloromethane / acetone = 15: 1) chromatographed. Yield: 52.87 g (91% of theory)

Elemental analysis: calc .: C 28.50 H 1.49 N 1.38 F 63.87 found: C 28.65 H 1.61 N 1.50 F 64.01

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

52 g (51, 42 mmol) of the title compound from Example 16a are dissolved in 500 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 200 ml of methanol are added dropwise, then it is evaporated to the dry state in a vacuum. The residue is in a mixture of 400 ml

Ethanol / 70 ml 10% aqu. Hydrochloric acid added and stirred at 40 ° C for 8 hours. It is evaporated to the dry state in a vacuum, the residue is taken up in 400 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 400 ml dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue

Chromatographed silica gel (eluent: dichloromethane / 2-propanol = 20: 1). Yield: 47.18 g (92% of theory) of a colorless solid Elemental analysis: calc .: C 28.90 H 1.72 N 1.40 F 64.77 found: 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-bis- (1 H, 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 of 10- [1- (carboxymethylcarboamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31, 76 mmol) of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 15.84 g (15.88 mmol) of the title compound from Example 16b are added. Stir for 10 minutes and then give

7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on

Silica gel RP-18 (mobile solvent: gradient made of tetrahydrofuran / acetonitrileΛ / Vasser). Yield: 20.95 g (82% of theory)

Elemental analysis: calc .: C 32.10 H 2.82 N 5.22 F 40.14 Gd 9.77 found: C 29.87 H 2.91 N 5.09 F 40.28 Gd 9.98

Example 17

2.80 g (70 mmol) of sodium hydride (from 60% sodium hydride in paraffin oil) in 300 ml of tetra- are added to 32 g (52.52 mmol) of the title compound from Example 3a. hydrofuran and stirred for 3 hours at room temperature under nitrogen. 9.68 g (70 mmol) of t-butyl bromoacetate dissolved in 20 ml of tetrahydrofuran are added dropwise and the mixture is stirred at 50 ° C. for 5 hours. 50 ml of methanol are added and the mixture is evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile phase: dichloromethane (/ 2-propanol = 20: 1). Yield: 19.31 g (59% of theory)

Elemental analysis: calc .: C 32.76 H 2.91 N 2.25 F 51.82 found: 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-perfiortride-cyl) amine

32 g (51, 34 mmol) of the title compound from Example 17a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 200 ml of methanol are added dropwise, then it is evaporated to the dry state in a vacuum. The residue is mixed in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid added and stirred at 40 ° C for 8 hours. It is evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous solution. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue

Chromatographed silica gel (eluent: dichloromethane / 2-propanol = 20: 1). Yield: 28.47 g (91% of theory)

Elemental analysis: calc .: C 33.51 H 3.31 N 2.30 F 53.01 found: 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- (1 H, 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 of 10- [1- (carboxymethylcarboamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31, 76 mmol) of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 9.68 g (15.88 mmol) of the title compound from Example 17b are added. Stir for 10 minutes and then give

Silica gel RP-18 (mobile solvent: gradient made of tetrahydrofuran / acetonitrile / water). Yield: 16.09 g (83% of theory)

Elemental analysis: calc .: C 35.41 H 3.96 N 6.88 F 26.45 Gd 12.88 found: 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

12 hours at room temperature. It is 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 mixture is stirred for 3 hours at 0 ° C., then for 6 hours at room temperature. 300 ml of 5 are added

% aqu. Hydrochloric acid and stir well for 15 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone = 20: 1). Yield: 30.95 g (89% of theory)

Elemental analysis: calc .: C 35.72 H 3.33 N 2.31 F 53.35 found: 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 compound from Example 18a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 200 ml of methanol are added dropwise, and the mixture is then added in vacuo

Evaporated to dryness. The residue is in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid added and stirred at 40 ° C for 8 hours. It is evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous solution. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / 2-propanol = 20: 1). Yield: 28.16 g (93% of theory)

Elemental analysis: calc .: C 36.56 H 3.75 N 2.37 F 54.62 found: 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- (1 H, 1 H, 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 of 10- [1- (carboxymethylcarboamoyl) ethyl] -1, 4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31, 76 mmol) of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 10.98 g (15.88 mmol) of the title compound from Example 18b are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours

Room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on Silica gel RP-18 (mobile solvent: gradient made of tetrahydrofuran / acetonitrile / water). Yield: 16.29 g (84% of theory)

Elemental analysis: calc .: C 36.94 H 4.19 N 6.99 F 26.85 Gd 13.07 found: 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 are added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane and the mixture is stirred for 12 hours at room temperature. It is evaporated to dryness in a vacuum. The residue is dissolved in 100 ml of dichloromethane and at 0 ° C. to a solution of 15.45 g (60 mmol) of t-butyl 11-amino-undecanoate and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane , dripped.

The mixture is stirred for 3 hours at 0 ° C., then for 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stir well for 15 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone = 20: 1).

Yield: 42.04 g (92% of theory)

Elemental analysis: calc .: C 42.58 H 4.76 N 1.84 F 42.41 found: 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 g (51.21 mmol) of the title compound from Example 19a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 200 ml of methanol are added dropwise, then it is evaporated to the dry state in a vacuum. The residue is in a mixture of 400 ml

Ethanol / 70 ml 10% aqu. Hydrochloric acid added and stirred at 40 ° C for 8 hours. It is evaporated to the dry state in a vacuum, the residue is taken up in 350 ml of 5% aqueous solution. Sodium hydroxide solution and extracted 3 times with 400 ml dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue

Chromatographed silica gel (eluent: dichloromethane / 2-propanol = 20: 1). Yield: 34.84 g (91% of theory)

Elemental analysis: calc .: C 43.38 H 5.12 N 1.87 F 43.20 found: C 43.22 H 5.23 N 1.96 F 43.33

1, 4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) acid- [N- (10- t.butyloxycarbonyl) decyl-N- (1 H , 1 H, 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 of 10- [1- (carboxymethylcarboamoyl) ethyl] -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1.35 g (31, 76 mmol) of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 11.87 g (15.88 mmol) of the title compound from Example 19b are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours

Room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile solvent: gradient of tetrahydrofuran / acetonitrile / water). Yield: 17.92 g (83% of theory)

Elemental analysis: calc .: C 40.65 H 4.89 N 6.18 F 23.76 Gd 11.57 found: 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-3oxa) -perfluorotridecyl] - amide} -1, 4,7,10-tetraazacyclododecane, gadolinium complex, sodium salt

12 g (8.83 mmol) of the title compound from Example 19c are dissolved in 50 ml of trifluoroacetic acid and stirred for 5 hours at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel RP-18 (mobile solvent: gradient composed of tetrahydrofuran / acetonitrile / water). After evaporation of the product-containing fractions, the residue is dissolved in water and with 5% aqu. Sodium hydroxide solution adjusted to pH 7.2. The solution is filtered and the filtrate freeze-dried.

Yield: 12.48 g (92% of theory) Water content: 6.2%

Elemental analysis (calculated on anhydrous substance): calc .: C 38.07 H 4.34 N 6.34 F 24.37 Gd 11.87 Na 1.73 found: 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-hexadecylic acid-N- (1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3oxa) -perfluorotridecyl) -amide

To 19.67 g (57.45 mmol) of 15-benzyl-3,6,9,12,15-pentaoxahexadecyl acid in

250 ml of dichloromethane are added to 8.90 g (70 mmol) of oxalyl chloride and stirred for 12 hours at room temperature. It is evaporated to dryness in a vacuum. The residue is dissolved in 100 ml of dichloromethane and at 0 ° C. to a solution of 32.62 g (60 mmol) of 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa- perfluorotridecylamine, hydrochloride and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane, were added dropwise. The mixture is stirred for 3 hours at 0 ° C., then for 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stir well for 15 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone = 20: 1). Yield: 44.91 g (94% of theory) of a colorless solid

Elemental analysis: calc .: C 41.89 H 4.12 N 1.68 F 38.84 found: C 42.02 H 4.25 N 1.83 F 39.07

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

43 g (51, 72 mmol) of the title compound from Example 20a) are in 400 ml

Dissolved tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 200 ml of methanol are added dropwise, then it is evaporated to the dry state in a vacuum. The residue is in a mixture of 400 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid added and stirred at 40 ° C for 8 hours. It is evaporated to the dry state in a vacuum, the residue is taken up in 350 ml of 5% aqueous solution. Sodium hydroxide solution and extracted 3 times with 400 ml dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile phase: dichloromethane / 2-propanol =

20: 1). Yield: 39.32 g (93% of theory)

Elemental analysis: calc .: C 42.60 H 4.12 N 1.68 F 38.84 found: 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 the gadolinium complex of 10- [1- (carboxymethylcarboamoyl) ethyl] -1, 4,7,10-tetraazacyclododecane-1, 4,7-triacetic acid and 1.35 g

(31, 76 mmol) lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 12.98 g (15.88 mmol) of the title compound from Example 20b) are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. You pour the solution into one

Mixture of 200 ml acetone / 1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile solvent: gradient of tetrahydrofuran / acetonitrile / water).

Yield: 18.84 g (83% of theory)

Elemental analysis: calc .: C 40.34 H 4.51 N 5.88 F 22.60 Gd 11.00 found: 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- (1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) - perfluorotridecyl] -amide} -1, 4,7,10-tetraazacyclododecane, gadolini- umkomplex

12 g (8.40 mmol) of the title compound from Example 20c are dissolved in 150 ml of methanol and 1.0 g of palladium catalyst (10% Pd / C) is added, and the mixture is hydrogenated overnight at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo.

Yield: 10.13 g (95% of theory)

Elemental analysis: calc .: C 38.80 H 4.61 N 1.10 F 25.45 Gd 12.39 found: C 38.87 H 4.73 N l, 20 F 25.58 Gd 12.50 Example 21 a) 2-N-Trifluoroacetyl -6-N-benzyloxycarbonyl-L-lysine

100.0 g (356.7 mmol) of 6-N-benzyloxycarbonyl-L-lysine are dissolved in a mixture of 1000 ml of ethyl trifluoroacetate and 500 ml of ethanol and stirred for 24 hours at room temperature. It is evaporated to dryness and the residue is crystallized from diisopropyl ether.

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

Melting point: 98.5 ° C.

Elemental analysis: calc .: C 51.07 H 5.09 N 7.44 F 15.14 found: C 51.25 H 5.18 N 7.58 F 15.03

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

To 125.0 g (332.0 mmol) of the title compound from Example 21a) and 188.7 g (332.0 mmol) of 1-perfluorooctylsulfonylpiperazine (produced according to DE 19603033) in 750 ml of tetrahydrofuran is 164.2 at 0 ° C. g (0.664 mmol) of EEDQ (2-ethoxy-1, 2-dihydroquinoline -1-carboxylic acid ethyl ester) and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 20: 1). Yield: 286.0 g (93% of theory) of a colorless solid. Melting point: 92 ° C. Elemental analysis: calc .: C 36.30 H 2.83 N 6.05 F 41.01 S 3.46 found: C 36.18 H 2.94 N 5.98 F 40.87 S 3.40

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

In a solution of 280.0 g (302.2 mol) of the title compound from Example 21b) in 2000 ml of ethanol, ammonia gas is passed in at 0 ° C. for one hour. The mixture is then stirred at 0 ° C. for 4 hours. It is evaporated to dryness and the residue was extracted from water. The solid is filtered off and dried in vacuo at 50.degree.

Yield: 243.5 g (97% of theory) of an amorphous solid.

Elemental analysis: calc .: C 37.60 H 3.28 N 6.75 F 38.89 S 3.86 found: C 37.55 H 3.33 N 6.68 F 38.78 S 3.81

d) 6-N-Benzyloxycarbonyl - 2-N- [1 -0-α-D-carbonylmethyl- (2,3,4,6-tetra-0-benzyl-mannopyranose) -L-lysine [1- (4th -perfluoroctylsulfonyl) -piperazine] amide

To a solution of 100.0 g (120.4 mol) of the title compound from Example 21c), 72.1 g (120.4 mol) of 1-0-α-D-carboxymethyl -2,3,4,6-tetra -0-benzyl-mannopyranose and 13.86 g (120.4 mol) of N-hydroxysuccinimide, dissolved in 500 ml of dimethylformamide, are added at 0 ° C to 41.27 g (200.0 mmol) of N, N -

Dicyclohexylcarbodiimide added. The mixture is stirred for 3 hours at 0 ° C. and then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo and chromatographed on silica gel. (Mobile phase: dichloromethane / ethanol = 20: 1).

Yield: 136.1 g (87% of theory) of a viscous oil.

Elemental analysis: calc .: C 57.32 H 4.89 N 4.31 F 24.86 S 2.47 found: C 57.38 H 5.07 N 4.22 F 24.78 S 2.39

e) 2-N- [1 -0-α-D-carbonylmethyl-mannopyranose] -L-lysine-1 - [(4-perfluorooctylsulfonyl) piperazine] amide

130.0 g (100.0 mmol) of the title compound from Example 21 d) are dissolved in 2000 ml of ethanol and 10.0 g of palladium catalyst (10% Pd / C) are added. The mixture is hydrogenated for 12 hours at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 91.7 g (quantitative) of a colorless solid.

Elemental analysis: calc .: C 34.07 H 3.63 N 6.11 S 3.50 F 35.24 found: 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- yl)] -2-N- [1-0-α-D-carbonylmethyl mannopyranose] -L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex (metal complex XV)

50.0 g (54.55 mmol) of the title compound from Example 21 e), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54 , 55 mol) 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methyl-pent-5-yl) -1, 4,7,10-tetraazacyclododecane, Gd Complex, are dissolved in 400 ml of dimethyl sulfoxide with gentle heating. 16.88 g (81.8 mol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred 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 then purified by chromatography (RP-18 mobile solvent: gradient from water / ethanol / acetonitrile).

Yield: 75.9 g (91.0% of theory) of a colorless solid. Water content: 8.6%. Elemental analysis (calculated on anhydrous substance): calc .: C 35.34 H 4.09 N 8.24 S 2.10 F 21.12 Gd 10.28 found: 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-tetraazacyclododecan-10-N- (pentanoyl -3-aza-4-oxo-5-methyl-5-yl )] -2-N- [1 -O-α-D-carbonylmethyl- mannopyranose] -L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

50.0 g (54.55 mmol) of the title compound from Example 21e), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54.55 mol) 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methyl-pent-5-yl) -1,4,7,10-tetraazacyclododecane, Gd complex dissolved in 400 ml of dimethyl sulfoxide with gentle heating. 16.88 g (81.8 mmol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred 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 then purified by chromatography (RP-18 mobile solvent: gradient from water / ethanol / acetonitrile. Yield: 76.0 g (92.0% of theory) of a colorless solid. Water content: 6.88%.

Elemental analysis (calculated on anhydrous substance): calc .: C 34.90 H 3.93 N 8.32 S 2.12 F 21.33 Gd 10.38 found: C 34.81 H 4.02 N 8.27 S 2.09 F 21.22 Gd 10.19

Example 23

a) Methyl 2- [4-3-oxapropionate] -phenylacetate

233.8 g (1400.0 mmol) of ethyl 2-bromoacetate are added to 200.0 g (1204.0 mmol) of methyl 4-hydroxyphenylacetate, 212.0 g (2000.0 mmol) of sodium carbonate in 2000 ml of acetone and the mixture is boiled for 5 hours reflux. The solid is filtered off and evaporated to dryness in vacuo. The residue is chromatographed on silica gel. (Mobile solvent: n-hexane / ethyl acetate = 15: 1).

Yield: 288.5 g (95.0% of theory) of a colorless oil.

Elemental analysis: calc .: C 61.90 H 6.39 found: C 61.75 H 6.51

b) Methyl 2- [4-3-oxapropionate)] - phenyl-2-bromoacetate

201.0 g (1130.0 mmol) of N-bromosuccinimide and 100.0 mg of dibenzoyl peroxide are added to 285.0 g (1130.0 mmol) of the title compound from Example 23a), dissolved in 2000 ml of carbon tetrachloride, and the mixture is boiled for eight hours reflux. The mixture is cooled in an ice bath, the precipitated succinimide is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is purified on silica gel (mobile solvent: n-hexane / acetone = 15: 1).

Yield: 359.2 g (96.0% of theory) of a colorless viscous oil.

Elemental analysis: calc .: C 47.28 H 4.57 Br 24.16 found: C 47.19 H 4.71 Br 24.05

c) Methyl 2- [4- (3-oxapropionate)] - phenyl-2- [1 - (1, 4,7, 10-tetraazacyclododecane-1-yl] -acetate

350.0 g (1057.0 mmol) of the title compound from Example 23b) are added to 603.0 g (3500.0 mmol) of 1,4,7,10-tetraazacyclododecane, in 6000 ml of chloroform and the mixture is stirred overnight at room temperature. It is extracted 3 times with 3000 ml of water each time, the organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is used in the next reaction (example 23d) without further purification. Yield: 448.0 g (quantitative) of a viscous oil. Elemental analysis: calc .: C 59.70 H 8.11 N 13.26 found: C 59.58 H 8.20 N 13.18

d) 2- [4- (3-oxapropionic acid)] - phenyl-2- [1, 4,7-tris (carboxmethyl) -1, 4,7,10-tetraazacyclododecan-10-yl] acetic acid 445.0 g (1053.0 mmol) of the title compound from Example 23c) and 496.0 g (5270.0 mmol) of chloroacetic acid are dissolved in 4000 ml of water. The pH is adjusted to 10 with 30% strength aqueous sodium hydroxide solution and the mixture is stirred at 70 ° C. for 8 hours. The pH of the reaction solution is then adjusted to 13 by adding 30% aqueous sodium hydroxide solution and the mixture is refluxed for 30 minutes. The solution is cooled in an ice bath and by adding conc. Hydrochloric acid adjusted to a pH of 1. It is evaporated to dryness in vacuo. The residue is taken up in 4000 ml of methanol and stirred for one hour at room temperature. The precipitated sodium chloride is filtered off, the filtrate is evaporated to dryness and the residue is purified on RP-18 C (mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 403.0 g (69.0% of theory) of a colorless solid. Water content: 10.2%. Elemental analysis (calculated on anhydrous substance): calc .: C 51.98 H 6.18 N 10.10 found: C 51.80 H 6.31 N 10.01

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

130.73 g (360.65 mmol) of gadolinium oxide are added to 400 g (721.3 mmol) of the title compound from Example 23d) in 2000 ml of water and the mixture is stirred at 80 ° C. for 5 hours. The solution is filtered and the filtrate freeze-dried. Yield: 511 g (quantitative) of an amorphous solid. Water content: 11.0%.

Elemental analysis (calculated on anhydrous substance): calc .: C 40.67 H 4.41 N 7.98 Gd 22.19 found: C 40.51 H 4.52 N 8.03 Gd 22.05

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

50.0 g (54.55 mmol) of the title compound from Example 21 e), 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). the title compound from Example 23e) are dissolved in 400 ml of dimethyl sulfoxide with gentle heating. 16.88 g (81.8 mmol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred 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 then purified by chromatography (RP-18; eluent: gradient from water / ethanol / acetonitrile). The product obtained is dissolved in a little water and the pH of the solution is adjusted to 7.4 with aqueous sodium hydroxide solution. The product solution is then freeze-dried. Yield: 79.1 g (89% of theory) of a colorless solid. Water content: 10.3%.

Elemental analysis (calculated on anhydrous substance): calc .: C 36.86 H 3.77 N 6.88 S 1.97 F 19.82 Gd 9.65 found: 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-Tris (t-butyloxycarbonylmethyl) -10-carboxymethyl-1,4,7,10-tetraazacyclododecane-10-carbonylmethyl] -2-N- (1 -0-α-D -carbonylmethyl-mannopyranose) -L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] -amide

15.0 g (26.19 mmol) of 1,4,7-tris (t-butyloxycarbonylmethyl) -10-carboxymethyl-1,4,7,10-tetraazacyclododecane, 24.0 g (26.19 mmol) of the title compound Example 21 e) and 3.01 g (26.19 mmol) of N-hydroxysuccinimide are dissolved in 150 ml of dimethylformamide and 8.25 g (40.0 mmol) of N, N-dicyclohexylcarbodiimide are added at 0 ° C. The mixture is stirred overnight at room temperature. The precipitated urea is filtered off and the filtrate is removed in vacuo Evaporated dry. The residue is chromatographed on silica gel.

(Mobile phase: dichloromethane / methanol = 20: 1).

Yield: 35.45 g (92.0% of theory) of a colorless solid.

Elemental analysis: calc .: C 44.08 H 5.69 N 7.62 F 21.95 S 2.18 found: 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 - [1-0-α-D-carbonylmethyl-mannopyranose ] -L-lysine [1-

(4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

30.0 g (20.39 mmol) of the title compound from Example 24a) are dissolved in 50 ml of chloroform and 300 ml of trifluoroacetic acid are added. The mixture is stirred for 10 minutes at room temperature. It is evaporated to dryness in vacuo and the residue is dissolved in 300 ml of water. 3.69 g (10.19 mmol) of gadolinium oxide are added and the mixture is stirred at 80 ° C. for 5 hours. The solution is evaporated to dryness in vacuo and purified on silica gel (RP-18; mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 11.0 g (37.0% of theory) of a colorless and amorphous solid.

Water content: 11.3%.

Elemental analysis (calculated on anhydrous substance): calc .: C 34.62 H 3.87 N 7.69 F 22.16 S 2.20 Gd 10.97 found: 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-triazaundecanedioic acid-1-carboxy-11 ^■ oyl] -2-N- [1-0-α-D-carbonylmethyl- mannopyranose] -L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide 12.10 g (30.0 mmol) of 3-N- (2,6-dioxomorpholinoethyl) - are added to 24.0 g (26.19 mmol) of the title compound from Example 21 e), dissolved in 100 ml of dimethylformamide / 30 ml of pyridine. 6-N- (ethoxycarbonylmethyl) -3,6-diazaoctanedioic acid and stirred for 5 hours at 50 ° C. It is evaporated to dryness in vacuo. The residue is dissolved in 200 ml of water and the pH of the resulting solution is adjusted to 13 by adding 20% aqueous sodium hydroxide solution. The mixture is stirred for 8 hours at 22 ° C. and a pH of 13. The solution is brought to a pH of 7.2 by adding concentrated hydrochloric acid and then evaporated to dryness in vacuo. The residue is chromatographed on silica gel RP-18 (mobile solvent: gradient from water / ethanol / acetonitrile).

Yield: 17.26 g (51.0% of theory) of a colorless solid. Water content: 9.3%. Elemental analysis (calculated on anhydrous substance): calc .: C 37.19 H 4.21 N 7.59 F 25.00 S 2.48 found: 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-triazaundecanedioic acid-1-carboxy-11-yl] -2-N- [1 -0-α-D-carbonylmethyl- mannopyranose] -L-lysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex, sodium salt

1.40 g (3.87 mmol) of gadolinium oxide are added to 10.0 g (7.74 mmol) of the title compound from Example 25a) in 100 ml of water and the mixture is stirred at 70 ° C. for 2 hours. The solution is filtered. The filtrate was adjusted to a pH of 7.4 with 2N sodium hydroxide solution and freeze-dried.

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

Water content: 10.5%.

Elemental analysis (calculated on anhydrous substance): calc .: C 32.72 H 3.43 N 6.68 S 2.18 Gd 10.71 Na 1.57 F 22.00 found: 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-3aza 4-oxo-5-methyl-5yl )] - L-lysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

50.0 g (60.20 mmol) of the title compound 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-tetraazacyclododecan- 10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl), Gd complex dissolved in 400 ml of dimethyl sulfoxide with gentle heating. 20.63 g (100.0 mmol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred at room temperature overnight. The solution is poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18; mobile solvent: gradient from water / ethanol / acetonitrile).

Yield: 75.53 g (87.0% of theory) of a colorless solid.

Water content: 10.1%.

Elemental analysis (calculated on anhydrous substance): calc .: C 37.48 H 3.84 N 8.74 S 2.22 F 22.39 Gd 10.90 found: 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 - ^ - oxo-5-methyl-5 -yl) -L-lysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide

70.0 g (48.53 mmol) of the title compound from Example 21 d) are dissolved in 500 ml of water / 100 ml of ethanol, mixed with 5.0 g of palladium catalyst (10% Pd / C) and for as long as at room temperature under a hydrogen atmosphere (1 atm) hydrogenated until no more hydrogen uptake can be observed. The catalyst is then filtered off with suction, washed thoroughly with ethanol (twice with 75 ml each) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous and colorless oil. Yield: 63.5 g (quantitative). Water content: 9.8%.

Elemental analysis (calculated on anhydrous substance): calc .: C 37.48 H 3.84 N 8.74 S 2.22 F 22.39 Gd 10.90 found: C 37.39 H 4.03 N 8.65 S 2.20 F 22.31 Gd 10.78

c) 6-N- (1-0-α-D-carbonylmethyl-2,3,4,6-tetra-0-benzyl-mannopyranose) -2-N- [1,4,7-tris (carboxylatomethyl) - 1, 4,7,10-tetraazacyclododecane, Gd complex

10- (pentanoyl-3-aza-4oxo-5-methyl-5yl)] - L-lysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide

50.0 g (38.22 mmol) of the title compound 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) 1 -0-α-D-carboxymethyl-2,3,4,6-tetra-0-benzyl-mannopyranose are dissolved in 400 ml of dimethyl sulfoxide with gentle heating (30 to 40 ° C). 10.32 g (50.0 mmol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred 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 then purified by chromatography (silica gel RP-18, mobile solvent: gradient from water / ethanol / acetonitrile).

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

Water content: 10.9%.

Elemental analysis (calculated on anhydrous substance): calc .: C 46.42 H 4.54 N 6.67 S 1.70 F 17.10 Gd 8.33 found: 046.36 H 4.71 N 6.60 S 1.61 F 17.19 Gd 8.21

d) 6-N- (1-0-α-D-carbonylmethyl-2,3,4,6-tetra-0-benzyl-mannopyranose) -2-N- [1,4,7-tris (carboxylatomethyl) - 1, 4,8,10-tetraazacyclododecan-10- (pentanoyl-3-aza-4oxo-5-methyl-5yl)] - L-lysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

60.0 g (31, 77 mmol) of the title compound from Example 26c) are dissolved in 500 ml of ethanol and 6.0 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen uptake can be observed. The catalyst is then suctioned off, washed thoroughly with ethanol (twice with 150 ml each) and concentrated to dryness in vacuo.

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

Water content: 3.9%.

Elemental analysis (calculated on anhydrous substance): calc .: C 35.37 H 4.02 N 8.25 S 2.10 F 21.13 Gd 10.29 found: C 35.28 H 4.13 N 8.17 S 2.03 F 21 , 05 Gd 10.20

Example 27

a) 1, 7-bis (benzyloxycarbonyl) - 4- [2- (N-ethyl-N-perfluorooctylsulfonyl] amino] - acetyl] -1, 4.7, 10 tetraazacyclododecane)

To 50.0 g (113.5 mmol) of 1,7-bis (benzyloxycarbonyl) -1, 4,7,10-tetraazacyclododecane and 66.42 g (113.5 mmol) of 2- (N-ethyl-N-perfluorooctylsulfonyl) ) -Aminoacetic acid (manufactured according to DE 19603033) in 300 ml of tetrahydrofuran, 49.46 g (200.0 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) are added at 0 ° C. and the mixture is stirred Night at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 20: 1). Yield: 65.2 g (57% of theory) of a colorless solid. Elemental analysis: calc .: C 42.91 H 3.80 N 6.95 F 32.05 S 3.18 found: C 42.85 H 3.90 N 6.87 F 31.98 S 3.15

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

1,4,7,10-tetraazacyclododecane To 60.0 g (59.53 mmol) of the title compound from Example 27a) and 35.64 g (59.53 mmol) of 1-0-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 of EEDQ (2-ethoxy-1,2-dihydroquinoline -1-carboxylic acid ethyl ester) are added at 0 ° C.) and the mixture is stirred overnight It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 20: 1). Yield: 76.6 g (81.0% of theory) of a colorless solid. Elemental analysis: calculated: C 54.44 H 4.70 N 4.41 F 20.33 S 2.02 found: C 54.37 H 4.81 N 4.35 F 20.27 S 1.96

c) 1 - [2- (N-Ethyl-N-perfluorooctylsulfonyl) amino] acetyl-7- (1-O-α-D-carbonylmethyl-mannopyranose) -1, 4.7, 10- tetraazacyclododecane

70 g (44.07 mmol) of the title compound from Example 27b are dissolved in 800 ml of ethanol and 8 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo.

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

Elemental analysis: calc .: C 35.04 H 3.99 N 7.30 F 33.65 S 3.34 found: C 35.15 H 4.13 N 7.13 F 33.48 S 3.26

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

20 g (20.84 mmol) of the title compound from Example 27c), 5.09 g (120 mmol) of lithium chloride and 37.78 g (60 mmol) of 1, 4,7-tris (carboxylatomethyl) -10-pentanoyl-3-aza -4-oxo-5-methyl-5yl) - 1,4,7,10-tetraazacyclododecane, Gd- The complexes are dissolved in 400 ml of dimethyl sulfoxide with gentle heating.

At 10 ° C, 29.67 g (120 mmol) of EEDQ are added and the mixture is then stirred 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 then purified by chromatography (silica gel RP-18, mobile phase: gradient from

Water / ethanol / acetonitrile).

Yield: 13.2 g (29.0% of theory) of a colorless solid.

Water content: 11.8%.

Elemental analysis (calculated on anhydrous substance): calc .: C 36.31 H 4.34 N 9.62 S 1.47 F 14.79 Gd 14.41 found: C 36.24 H 4.27 N 9.58 S 1.51 F 14.85 Gd 14.25

Example 28

a) 1,7-bis (benzyloxycarbonyl) -4- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] - acetyl-10- [pentanoyl-3-aza-4-oxo-5-methyl-5yl- [1,4,7-tris (carboxylatomethyl) -Gd complex. 1, 4,7,10-tetraazacyclododecan-10-yl] -1,4,7,10-tetraazacyclododecane.

50.0 g (49.61 mmol) of the title compound 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, Gd complex are heated gently dissolved in 350 ml of dimethyl sulfoxide. 15.47 g (75 mmol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred overnight at room temperature. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then through Chromatography cleaned (silica gel RP-18, mobile phase: gradient from water / ethanol / acetonitrile).

Yield: 65.1 g (81.0% of theory) of a colorless solid. Water content: 7.9%. Elemental analysis (calculated on anhydrous substance): calc .: C 40.79 H 4.11 N 8.65 S 1.98 F 19.94 Gd 9.72 found: C 40.71 H 4.20 N 8.58 S 2.03 F 19.87 Gd 9.68

b) 1- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] - acetyl - 7 {(- pentanoyl-3-aza-4-oxo-5-methyl-5yl) -10 - [1, 4, 7-tris (carboxylatomethyl) -1, 4.7, 10-tetra-azacyclododecane, Gd complex]} - 1, 4,7,10-tetraazacyclododecane.

60.0 g (37.05 mmol) of the title compound from Example 28a) are in 600 ml

Dissolved ethanol and 6.0 g of palladium catalyst (10% Pd / C) added. It is hydrogenated at room temperature. The catalyst is filtered off and this is evaporated

Filtrate to dryness in a vacuum.

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

Water content: 3.9%.

Elemental analysis (calculated on anhydrous substance): calc .: C 34.67 H 4.03 N 10.37 S 2.37 F 23.90 Gd 11.64 found: C 34.58 H 4.15 N 10.28 S 2.30 F 23.84 Gd 11.57

c) 1 - [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-4,10 - bis [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 (carboxylatomethyl) -

1, 4,7,10-tetraazacyclododecane - 10-yl] -Gd complex} -1, 4,7,10-tetraazacyclododecane

40.0 g (29.60 m mol) of the title compound from Example 28b), 2.54 g (60.0 mmol) of lithium chloride and 44.9 g (75.0 mmol) of 1-O-α-D-carboxymethyl - 2,3,4,6-tetra-O-benzyl-mannopyranose are dissolved in 300 ml of dimethyl sulfoxide with gentle heating. At 10 ° C, 24.73 g (100.0 mmol) of EEDQ are added and the mixture is then stirred overnight at room temperature. You pour it Solution in 3000 ml acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 31.98 g (43.0% of theory) of a colorless solid. Water content: 3.5%.

Elemental analysis (calculated on anhydrous substance): calc .: C 53.06 H 5.05 N 5.57 S 1.28 F 12.85 Gd 6.26 found: C 52.95 H 5.19 N 5.48 S 1.23 F 12.77 Gd 6.14

d) 1 - [2- (N-ethyl-N-perf luorooctylsulfonyl) amino] acetyl-4,10 - bis [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 (carboxylatomethyl) - 1,4,7,10-tetraazacyclododecane - 10-yl] - Gd complex} -1,4,7,10-tetraazacyclododecane

30.0 g (11.94 mmol) of the title compound from Example 28c) are dissolved in 300 ml of ethanol / 30 ml of water and 4.0 g of palladium catalyst (10% Pd / C) are added. The mixture is hydrogenated at room temperature, the catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 21, 39 g (quantitative) of a colorless solid. Water content: 3.4%.

Elemental analysis (calculated on anhydrous substance): calc .: 036.87 H 4.39 N 7.82 S 1.79 F 18.03 Gd 8.78 found: C 36.80 H 4.50 N 7.85 S 1.68 F 17.91 Gd 8.70

Example 29

a) 6-N- [3,6-bis (carboxymethyl) octane-1,8-dicarboxylic acid-1-earboxy-8-oyl] -2- N- (1 -O-α-D-carboxymethyl-mannopyranose) -lysine - [1 - (4perfluorooctylsulfonyl) piperazine] - amide To 27.5 g (30.0 mmol) of the title compound from Example 21 e), dissolved in 300 ml of dimethylformamide / 100 ml of pyridine, 25.62 g (100.0 mmol) of ethylenediamine-N, N, N ', N are added '- Tetraacetic acid dianhydride and stirred for 5 hours at 50 ° C. It is evaporated to dryness in vacuo. The residue is dissolved in 300 ml of water, adjusted to a pH of 10 by adding 20% aqueous sodium hydroxide solution, and then the basic product solution is added by adding. conc. Hydrochloric acid brought to a pH of 3 and evaporated to dryness in vacuo. The residue is chromatographed on silica gel RP-18 (mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 18.22 g (51.0% of theory) of a colorless solid. Water content: 7.9%.

Elemental analysis (calculated on anhydrous substance): calc .: C 36.31 H 3.98 N 7.06 F 27.12 S 2.69 found: C 36.23 H 4.07 N 6.98 F 27.05 S 2.62

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

10 g (8.397 mmol) of the title compound from Example 29a) are dissolved in 200 ml of water. 965 mg (8.397 mmol) of manganese (II) carbonate are added and the mixture is stirred at 60 ° C. for 3 hours. The solution is adjusted to a pH of 7.4 with 5% aqueous sodium hydroxide solution, filtered and then freeze-dried. Yield: 10.52 g (99.0% of theory) of a colorless solid. Water content: 7.8%.

Elemental analysis (calculated on anhydrous substance): calc .: C 34.16 H 3.50 N 6.64 S 2.53 F 25.52 Mn 4.34 Na 1.82 found: 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-0-acetyl-α, β-D-mannopyranose In an analogous manner, as described in the literature [ML Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol.ll, 53, pp. 211-215, (1963)] provides the reaction of 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 working up 315 g (96.7%) of the above-mentioned title compound as a crude product in the form of a viscous and colorless oil. The α to β ratio of the two anomers was determined to be 4: 1 by ¹ H-NMR spectroscopic examination of the title compound thus obtained. A separation of the α, β-anomers of the above-mentioned title compound can be dispensed with in order to carry out the subsequent reaction steps. Elemental analysis: calc .: C 49.21 H 5.68 found: C 49.12 H 5.78

b) 1-0-α-D- (5-ethoxycarbonyl) pentyl-2,3,4,6-tetra-0-acetyl-mannopyranose

In an analogous manner as described in the literature for the synthesis of aryl glycopyranosides [J. Conchie and GA Lewy in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol.ll, 90, pp. 345-347, (1963)] leads the reaction of 156.2 g (400 mmol) of the title compound from Example 21a) as α, β-anomer mixture with 67 ml (400 mmol) of 6-hydroxy-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 form 100.05 g (51% of theory) of the above Title compound as a colorless and viscous oil. By ¹ H-NMR spectroscopic examination of the title compound thus obtained it could be shown that the above-mentioned title compound is exclusively the pure α-anomer. Elemental analysis: calc .: C 52.94 H 6.77 found: C 52.80 H 6.78

c) 1-0-α-D- (5-carboxy) pentyl-2,3,4,6-tetra-0-benzyl-mannopyranose

A stirred suspension of 141.0 g (289 mmol) of the title compound from Example 30b) in 200 ml of dioxane is admixed in portions with a total of 238.5 g (4.26 mol) of finely powdered potassium hydroxide powder at room temperature and with vigorous stirring at the same time. To increase the stirrability, the reaction mixture is mixed with a further 200 ml of dioxane and the suspension thus obtained is subsequently heated to boiling point and a total of 372 ml (3.128 mol) of benzyl bromide are added dropwise at this temperature over a period of two hours. After a reaction time of 4 hours at 110 ° C., followed by 12 hours at room temperature, the reaction mixture is poured slowly into a total of 2.5 liters of ice water for the purpose of working up, and the water phase is subsequently extracted completely with diethyl ether. After washing the ether phase thus obtained and then drying it over sodium sulfate, the salt is filtered off with suction and the diethyl ether is stripped off in vacuo. Excess benzyl bromide is then quantitatively distilled off from the reaction mixture in an oil pump vacuum at an oil bath temperature of 180 ° C. The resinous-oily residue thus obtained is purified on silica gel using ethyl acetate / hexane (1:10) as the eluent. Yield: 172.2 g (91.0% of theory) of the above-mentioned title compound in the form of a colorless and extremely viscous oil. Elemental analysis: calc .: C 75.68 H 7.16 found: C 75.79 H 7.04

d) 6-N-benzyloxycarbonyl-2-N- [1 -O-α-D - (5-carbonyl) pentyl-2,3,4,6-tetra-0-benzyl-mannopyranose] -L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide 100.0 g (134.0 mmol) of the carboxylic acid prepared in Example 30c) and 32.4 g (281.4 mmol) of N-hydroxysuccinimide are dissolved in 500 ml of dimethylformamide and at 0 ° C with a total of 58.0 g (281 , 4 mmol) of N, N'-dicyclohexylcarbodiimide are added in portions and the mixture is stirred for 3 hours at this temperature. A solution of 111.3 g (134.0 mmol) of the title compound from Example 21c), cooled to 0 ° C., dissolved in 300 ml of dimethylformamide is added dropwise to the active ester solution prepared in this way and the mixture is stirred at 0 ° C. for 2 hours and 12 h at room temperature. For working up, the precipitated dicyclohexylurea is filtered off and the solvent is then drawn off to dryness. The residue obtained in this way is then chromatographed on silica gel (mobile solvent: dichloromethane / ethanol 20: 1; the chromatography is carried out using a solvent gradient with a continuous increase in the proportion of ethanol). Yield: 132.5 g (67.4% of theory) of the title compound in the form of a colorless and highly viscous oil. Elemental analysis: calc .: C 54.02 H 4.88 N 3.82 F 22.01 S 2.19 found: 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] -L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] -ami

120.0 g (81.77 mmol) of the compound prepared under 30d) are dissolved in 800 ml of ethanol, 4.5 g of Pearlman catalyst (Pd 20%, C) are added and the mixture is at room temperature under a hydrogen atmosphere (1 atm) hydrogenated until no more hydrogen uptake can be observed (approx. 8

Hours). It is suctioned off from the catalyst, washed thoroughly with ethanol (approx. 200 ml) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous and colorless oil. Yield: 78.5 g (98.7% of theory). Elemental analysis: calc .: C 37.04 H 4.25 N 5.76 F 33.20 S 3.30 found: C 36.96 H 4.85 N 5.41 F 34.13 S 3.22 f) 2-N- [1 -0-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] -L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd complex

99.8 g (158.4 mmol; 2.2 molar equivalents based on the amine component used from Example 30e) of the Gd complex of 10- (4-carboxy-1-methyl-2-) described in Patent Application DE 19728954 C1 under Example 31h) oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 6.7 g of anhydrous lithium chloride (158.4 mmol) are dissolved at 40 ° C. in 800 ml of absolute dimethyl sulfoxide with stirring , At this temperature, a total of 18.2 g (158.4 mmol) of N-hydroxysuccinimide and 70.0 g (71.96 mmol) of the title compound from Example 30e), dissolved in 250 ml of absolute dimethyl sulfoxide, are then added. After cooling to room temperature, 32.7 g (158.4 mmol) of N, N'-dicyclohexylcarbodiimide are added to the reaction solution and the mixture is stirred at room temperature for 12 hours. The suspension obtained is then mixed with sufficient acetone until the above-mentioned title compound has completely precipitated, the precipitate is filtered off with suction, dried, taken up in water, filtered off from insoluble dicyclohexylurea and the filtrate is passed through an AMICON® YM-3 ultrafiltration membrane (cut off: 3000 Da) desalted and cleaned of low molecular components. The retentate is then freeze-dried. Yield: 93.0 g (81.6% of theory) as a colorless lyophilisate. H2θ content (Karl Fischer): 9.53%.

Elemental analysis (calculated on anhydrous substance): calc .: C 37.15 H 4.39 N 7.96 F 20.38 S 2.02 Gd 9.92 found: C 36.92 H 4.50 N 7.68 F 19.77 S 1.91 Gd 10.08

Example 31 a) 2-N- [1 -0-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} -L-lysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex, sodium salt

A stirred suspension of 5.0 g (9.06 mmol) of the title compound from Example 23e) in 15 ml of absolute dimethyl sulfoxide is mixed at 70 ° C. with 0.68 g (15.9 mmol) of lithium chloride. After stirring for 30 minutes at 70 ° C., the now clear reaction solution is mixed in portions with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide and the reaction mixture is kept at this temperature for 1 hour. After cooling to 0 ° C., 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide are added and the reaction solution is stirred for a further hour at 0 ° C., followed by 12 hours at 22 ° C. The reaction solution of the N-hydroxysuccinimide ester of the title compound from Example 3e) thus obtained is then added dropwise at 22 ° C. with a solution of 4.0 g (4.12 mmol) of the title compound from Example 10Ae) in 15 ml of absolute dimethyl sulfoxide and a further 12 Stirred for hours at room temperature. For working up, the reaction solution is added dropwise in 900 ml of acetone at 22 ° C., the title compound precipitating out as a colorless precipitate. The precipitate is filtered off, dissolved in 200 ml of distilled water and then the pH of this solution is adjusted to exactly 7.2 with 1 molar sodium hydroxide solution. The aqueous product solution thus obtained is over a YM3

Ultrafiltration membrane (AMICON ®; cut off: 3000 Da) ultrafiltered three times for the purpose of desalination and the separation of low-molecular components. The retentate thus obtained is then freeze-dried.

Yield: 6.33 g (92.4% of theory, based on the amine component used) as a colorless lyophilisate with a water content of 7.38%. Elemental analysis (calculated on anhydrous substance): calc .: C 38.48 H 4.13 N 6.65 F 19.16 S 1.90 Gd 9.33 Na 1.36 found: 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-bis-benzyloxycarbonylamino-benzoic acid N- (3-oxa- 1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide

In a solvent mixture of 125 ml of dry tetrahydrofuran and 125 ml of dry dioxane, 20 g (47.5 mmol) of 3,5-bisbenzyloxycarbonylamino-benzoic acid (synthesis according to the following literature reference: 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) and 4.78 g (47.5 mmol) triethylamine dissolved. After cooling to -15 ° C., a solution of 6.56 g (48 mmol) isobutyl chloroformate in 30 ml of dry tetrahydrofuran is slowly added dropwise with stirring, the internal temperature being kept below -10 ° C. After a reaction time of 15 minutes at -15 ° C., a solution of 58.6 g (47.5 mmol) of 1-amino-1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3- add oxo-perfluorotridecane and 4.78 g (47.5 mmol) triethylamine in 100 ml dry tetrahydrofuran at -20 ° C. After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is evaporated to dryness in vacuo. The remaining residue is taken up in 300 ml of ethyl acetate and washed twice with 200 ml of saturated sodium bicarbonate solution and once with 300 ml of water. After the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the ethyl acetate is stripped off in vacuo. The remaining oily residue is purified on silica gel using dichloromethane / hexane / 2-propanol (10: 5: 1) as an eluent. Yield: 36.2 g (82.5% of theory) of the title compound as a colorless oil. Elemental analysis: calc .: C 46.82 H 3.27 N 4.55 F 34.97 found: 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 produced under 32a) are dissolved in 300 ml of ethanol and 1.2 g of Pearlman catalyst (Pd 20%, C) are added. Hydrogenation is carried out at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen uptake can be observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (approx. 300 ml) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous, yellowish oil.

Yield: 20.12 g (94.8% of theory). Elemental analysis: calc .: C 36.66 H 2.77 N 6.41 F 49.28 found: C 36.07 H 2.87 N 6.23 F 49.43

c) 3-N - [- (1-0-α-D-carbonylmethyl-2,3,4,6-tetra-0-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-0-benzyl-α-D-mannopyranoside [representation as described in patent specification DE 19728954 C1] are dissolved in 150 ml of dimethylformamide and with a total of 2.09 g (18.3 mmol) of N-hydroxysuccinimide. It is cooled to 0 ° C. and 3.78 g (18.3 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred at 0 ° C. for one hour and then at room temperature for 4 hours. The mixture is cooled to 0 ° C. and a solution of 24.0 g (36.6 mmol, 2 mol equivalents based on the carboxylic acid used) of the diamino compound described in Example 32b), dissolved in 350 ml of dimethylformamide, is slowly added dropwise over the course of 3 h. The mixture is then stirred for a further hour at 0 ° C., then overnight at room temperature. It is evaporated to dryness in vacuo and the residue is taken up in 300 ml of ethyl acetate. The precipitated urea is filtered off and the filtrate is washed twice with 100 ml of 5% aqueous sodium carbonate solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 13: 1). You get 16.8 g (74.3% of theory, based on the carboxylic acid used) of the title compound 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 unreacted diamino compound 32b) are recovered in the subsequent chromatography fractions, which can be reactivated again according to the above-mentioned reaction procedure. Elemental analysis: calc .: C 54.42 H 4.40 N 3.40 F 26.13 found: C 54.32 H 4.49 N 3.48 F 25.94

d) 3-N - [- (1-0-α-D-carbonylmethyl-mannopyranose)] - 5-amino-benzoic acid- N- (3-oxa-1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) amide

In an analogous manner as described for the synthesis of the title compound from Example 32b), the hydrogenolysis of 12.0 g (9.70 mmol) of the title compound from Example 32c) using 0.5 g Pearlman catalyst (Pd 20% , C) in an ethanol / water (9: 1) mixture after working up 8.08 g (96.7% of theory) of the above-mentioned title compound in the form of a yellowish and viscous oil. Elemental analysis: calc .: C 37.64 H 3.28N 4.88 F 37.49 found: C 37.32 H 3.17 4.97 F 37.55

e) 3-N- (1-0-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 based on the amine component from Example 32d)) of the Gd complex described under Example 23Ae) and 0.81 g of anhydrous lithium chloride (19.2 mmol) are added 40 ° C. in 100 ml of absolute dimethyl sulfoxide with stirring and at this temperature with a total of 2.2 g (19.2 mmol) of N-hydroxysuccinimide and 7.5 g (8.7 mmol) of the title compound from Example 32d), dissolved in 50 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 3.96 g (19.2 mmol) of N.N'-dicyclohexylcarbodiimide is added to the reaction solution and the mixture is stirred at room temperature for 12 hours. Sufficient acetone is then added to the suspension obtained until the above-mentioned title compound has completely precipitated, the precipitate is filtered off with suction, dried, taken up in water, filtered off from insoluble dicyclohexylurea and the filtrate is desalted via an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and cleaned of low molecular weight components. The retentate is then freeze-dried.

Yield: 11.51 g (84.5% of theory) as a colorless lyophilisate H2O content (Karl Fischer): 6.77%. Elemental analysis (calculated on anhydrous substance): calc .: C 40.05 H 3.94 N 6.29 F 20.71 Gd 10.08 Na 1.47 found: C 39.98 H 4.00 N 6.3 1 F 20, 73 Gd 10.11 Na 1.42

Example 33

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

In a solvent mixture of 60 ml of dry tetrahydrofuran and 70 ml of dry dioxane, 10 g (23.75 mmol) of 3,5-bis-benzyloxycarbonylaminobenzoic acid (synthesis according to the following reference: 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) and 2.39 g (23.75 mmol) triethylamine in solution , After cooling to -15 ° C., a solution of 3.28 g (24 mmol) of isobutyl chloroformate in 20 ml of dry tetrahydrofuran is slowly added dropwise with stirring, the internal temperature not exceeding -10 ° C. After a reaction time of 15 minutes at -15 ° C, 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 -20 ° C added. After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is evaporated to dryness in vacuo. The remaining residue is taken up in 200 ml of ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution and once with 300 ml of water. After the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the ethyl acetate is stripped off in vacuo. The remaining oily residue is purified on silica gel using dichloromethane / hexane / 2-propanol (15: 5: 1) as an eluent. Yield: 18.35 g (79.6% of theory) of the title compound as a colorless oil. Elemental analysis: calc .: C 43.31 H 2.80 N 5.77 F 33.27 S 3.30 found. : C 43.21 H 2.75 N 5.61 F 33.38 S 3.22

b) 3,5-Di-amino-1 - {N- [1 - (4-perf luorooctylsulfonyl) piperazine]} - benzamide

9.70 g (10.0 mmol) of the amide prepared under 33a) are dissolved in 100 ml of ethanol and 0.4 g of Pearlman catalyst (Pd 20%, C) are added. Hydrogenation is carried out at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen uptake can be observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (approx. 150 ml) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous, yellowish oil. Yield: 6.9 g (98.2% of theory). Elemental analysis: calc .: C 32.49 H 2.15 N 7.98 F 45.98 S 4.56 found: C 32.56 H 2.17 N 8.09 F 45.63 S 4.61

c) 5-Amino-3-N- (1-0-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose) -benzoic acid-N- [1 - (4-perfluorooctylsulfonyl) - piperazine] amide

5.48 g (9.15 mmol) of 1-carboxymethyloxy-2,3,4-tetra-0-benzyl-α-D-mannopyranoside [representation as in the patent DE 19728 954 C1 described] are dissolved in 100 ml of dimethylformamide and mixed with a total of 1.04 g (9.15 mmol) of N-hydroxysuccinimide. The mixture is cooled to 0 ° C. and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred at 0 ° C. for one hour and then at room temperature for 4 hours. After cooling again to 0 ° C., a solution of 12.85 g (18.30 mmol, 2 mol equivalents based on the carboxylic acid used) of the diamino compound described in Example 33b), dissolved in 250 ml of dimethylformamide, is slowly added dropwise within 3 h. The mixture is then stirred for a further hour at 0 ° C., then overnight at room temperature. It is evaporated to dryness in vacuo and the residue is taken up in 100 ml of ethyl acetate. The precipitated urea is filtered off and the filtrate is washed twice with 100 ml of 5% aqueous sodium carbonate solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 13: 1). 8.14 g (69.4% of theory, based on the carboxylic acid used) of

Title compound in the form of a colorless oil. By increasing the polarity of the eluent composition during the chromatography to 6: 1 (n-hexane / isopropanol), a total of 4.36 g of unreacted diamino compound 33b) are recovered in the subsequent chromatography fractions, which can be reactivated again according to the above-mentioned reaction procedure.

Elemental analysis: calc .: C 51.49 H 4.01 N 4.37 F 25.17 S 2.50 found: C 51.60 H 4.19 N 4.28 F 25.14 S 2.44

d) 5-Amino-3-N- (1 -0-α-D-carbonylmethyl-mannopyranose) -benzoic acid-N- [1 - (4-perfluorooctylsulfonyl) piperazine] amide

In an analogous manner to that described for the synthesis of the title compound 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 an ethanol / water (8: 1) mixture after working up 4.43 g (96.2% d. Th.) Of the above-mentioned title compound in the form of a yellowish and viscous oil. Elemental analysis: calc .: C 35.15 H 2.95 N 6.07 F 35.01 S 3.48 found: C 35.32 H 3.02 N 5.89 F 35.05 S 3.58

e) 3-N- (1 -0-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-tetraazacyclododecan] -benzoic acid N- [1 - (4-perf luoroctylsulfonyl) piperazine] amide, Gd complex

5.54 g (8.8 mmol; 2.2 molar equivalents based on the amine component from Example 33d)) of the Gd complex of 10- (4-carboxy-1-methyl-) described in Patent Application DE 19728 954 C1 under Example 31h) 2-oxo-3-azabutyl) -1, 4.7, 10-tetraazacyclododecan-1, 4.7-triacetic acid and 0.37 g of anhydrous lithium chloride (8.8 mmol) are at 40 ° C in 60 ml of absolute dimethyl sulfoxide Dissolved stirring and at this temperature with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.7 g (4.0 mmol) of the title compound from Example 13Ad), dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide is added and the mixture is stirred at room temperature for 12 hours. Sufficient acetone is then added to the suspension obtained until the above-mentioned title compound has completely precipitated, the precipitate is filtered off with suction, dried, taken up in water, filtered off from insoluble dicyclohexylurea and the filtrate is desalted via an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and cleaned of low molecular weight components. The retentate is then freeze-dried. Yield: 5.36 g (87.4% of theory) as a colorless lyophilisate. H2θ content (Karl Fischer): 6.77%. Elemental analysis (calculated on anhydrous substance): calc .: C 36.01 H 3.61 N 8.22 F 21.05 Gd 10.25 S 2.09 Found: 035.87 H 3.70 N 8.22 F 20.91 Gd 10.18 S 2.16

Example 34

a) 1,4,7-Triazaheptan-1,7-bis- (2-N-trifluoroacetyl -6-N-benzyloxycarbonyl-L-ϊysin) diamide

100 g (107.9 mmol) of the carboxylic acid prepared in Example 21a) and 26.1 g (226.59 mmol) of N-hydroxysuccinimide are dissolved in 500 ml of dimethylformamide and at 0 ° C. with a total of 46.7 g (226.59 mmol) of N, N'-dicyclohexylcarbodiimide was added in portions and the mixture was stirred at this temperature for 3 hours. A solution of 5.57 g (53.95 mmol) of diethylene triamine, dissolved in 60 ml of dimethylformamide, cooled to 0 ° C. is added dropwise to the active ester solution prepared in this way and the mixture is stirred for 2 hours at 0 ° C. and for 12 hours at room temperature. For working up, the precipitated dicyclohexylurea is filtered off and the solvent is then drawn off to dryness. The residue thus obtained is then chromatographed on silica gel (mobile phase: dichloromethane / ethanol 15: 1; the chromatography was carried out using a solvent gradient with a continuous increase in the proportion of ethanol).

Yield: 26.0 g (58.8% of theory, based on the amine component used) of the title compound in the form of a colorless and highly viscous oil.

Elemental analysis: calc .: C 52.74 H 5.78 N 11.96 F 13.90 found: C 52.66 H 5.89 N 11.88 F 14.02

b) 1, 4,7-triazaheptane-1,7-bis- (2-N-trifluoroacetyl -6-N-benzyloxycarbonyl-L-lysine) -diamide-4- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl 16.18 g (27.0 mmol) are dissolved in a solution of 20 g (24.4 mmol) of the diamide prepared under 34a), dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, at 0 ° C. and under a nitrogen atmosphere. 2- [N-ethyl-N-perfluorooctylsulfonyl) aminoacetic acid (preparation according to: DE 19603033), dissolved in 50 ml of tetrahydrofuran, is added. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is then added in portions at 0 ° C. and the mixture is stirred overnight at room temperature and then concentrated in vacuo. The remaining oil is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 15: 1). 24.74 g (72.4% of theory, based on the sec-amine used) of the title compound are obtained in the form of a colorless oil. Elemental analysis: calc .: C 42.01 H 3.96 F 31.19 N 8.00 S 2.29 found: C 41.92 H 4.07 F 31.22 N 7.87 S 2.34

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

22.0 g (15.7 mmol) of the title compound prepared under Example 34b) are dissolved in 100 ml of ethanol and ammonia gas is passed into this solution at 0 ° C. for 40 minutes. The mixture is then stirred for a further 4 hours at 0 ° C. and for 3 hours at room temperature and concentrated to dryness at a bath temperature of 40 ° C. in vacuo. The remaining oily residue is purified on silica gel using dichloromethane / hexane / 2-propanol (20: 10: 1) as an eluent

Yield: 12.92 g (98.4% of theory) of the above-mentioned title compound as a colorless and highly viscous oil. Elemental analysis: calc .: C 44.22 H 4.64 N 9.38 S 2.68 F 27.03 found: C 44.31 H 4.72 N 9.30 S 2.74 F 26.99 d) 1,7-bis- [6-N -benzyloxycarbonyl-2-N- (1 -0-α-D-carbonylmethyl-2,3,4,6-tetra-0-benzyl-mannopyranose) -L-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-0-benzyl-α-D-mannopyranoside [preparation as described in patent specification DE 19728 954 C1] are dissolved in 80 ml of dimethylformamide and a total of 1.05 g (9.15 mmol) of N-hydroxysuccinimide are added. The mixture is cooled to 0 ° C. and 1.9 g (9.15 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred for one hour at 0 ° C. and then for 4 hours at room temperature. The mixture is cooled to 0 ° C. and a solution of 7.65 g (9.15 mmol) of the amino compound described in Example 34e), dissolved in 50 ml of dimethylformamide, is slowly added dropwise over the course of 3 h. The mixture is then stirred for a further hour at 0 ° C., then overnight at room temperature. It is evaporated to dryness in vacuo and the residue is taken up in 100 ml of ethyl acetate. The precipitated urea is filtered off and the filtrate is washed twice with 50 ml of 5% aqueous sodium carbonate solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 20: 1). 17.01 g (78.9% of theory, based on the carboxylic acid used) of the title compound is obtained in the form of a colorless oil. Elemental analysis: calc .: C 59.13 H 5.43 N 4.76 F 13.71 S 1.36 found: C 59.22 H 5.39 N 4.85 F 13.70 S 1.40

e) 1,7-bis- [2-N- (1 -0-α-D-carbonylmethyl-mannopyranose) -L-lysine] -diamide-4- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino ] acetyl-1,4,7-triazaheptane

15.0 g (6.36 mmol) of the amide produced under 34d) are dissolved in 150 ml of ethanol and 0.5 g of Pearlman catalyst (Pd 20%, C) is added. Hydrogenation is carried out at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen uptake can be observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (approx. 100 ml) and concentrated in Vacuum to dryness. The title compound is a very viscous, yellowish

Get oil.

Yield: 8.54 g (97.2% of theory).

Elemental analysis: calc .: C 39.13 H 5.04 N 8.11 F 23.38 S 2.32 found: C 39.07 H 4.98 N 8.18 F 23.40 S 2.30

f) 1, 7-bis- [2-N- (1 -0-α-D-carbonylmethyl-mannopyranose) -6-N- [1, 4,7-tris (carboxylatomethyl) -10- (3-aza- 4-oxo-5-methyl-5-yl-pentanoyl) -1,4,7,10-tetraazacyclododecane] -L-lysine] -diamide-4- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] -acetyl-1, 4,7-triazaheptane, digadolinium complex

A stirred suspension of 5.7 g (9.06 mmol) of the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1 described in patent application DE 19728954 C1 under Example 31h), 4,7, 10-tetraazacyclododecan-1, 4,7-triacetic acid in 75 ml of absolute dimethyl sulfoxide is mixed at 70 ° C with 0.68 g (15.9 mmol) of lithium chloride. After stirring for 30 minutes at 70 ° C., the now clear reaction solution is mixed in portions with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide and the reaction mixture is kept at this temperature for 1 hour. After cooling to 0 ° C., 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide are added and the reaction solution is stirred for a further hour at 0 ° C., followed by 12 hours at 22 ° C. The reaction solution of the N-hydroxysuccinimide ester of the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7, 10-tetraazacyclododecane-1, 4,7-tri-acetic acid thus obtained a solution of 2.84 g (2.06 mmol) of the title compound from Example 34e) in 15 ml of absolute dimethyl sulfoxide is then added dropwise at 22 ° C. and stirring is continued for a further 12 hours at room temperature. For working up, the reaction solution is added dropwise at 22 ° C. in 500 ml of acetone, the title compound precipitating out as a colorless precipitate. The precipitate is filtered off, dissolved in 200 ml of distilled water and over a YM3 ultrafiltration membrane (AMICON ®; cut off: 3000 Da) for the purpose of desalination and the separation of low molecular weight Components ultrafiltered three times. The retentate thus obtained is then freeze-dried.

Yield: 4.80 g (89.6% of theory, based on the one used

Amine component) as a colorless lyophilisate with a water content of 8.98%.

Elemental analysis (calculated on anhydrous substance): calc .: C 38.28 H 4.84 N 9.68 F 12.40 S 1.23 Gd 12.07 found: C 38.20 H 4.91 N 9.77 F 12.45 S 1.19 Gd 12 10

Example 35

a) 1, 7-bis (benzyloxycarbonyl) - 4- {3-oxapentane-1,5-dicarboxylic acid-1-yl-5- [1 - (4-perfluorooctylsulfonyl) -piperazine] -amide} -1,4 , 7,10-tetraazacyclododecane

In a solution of 10.75 g (24.4 mmol) of 1,7-bis- [benzyloxycarbonyl] -1,4,7,10-tetraazacyclododecane, dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, at 0 ° C and 16.56 g (24.4 mmol) of the title compound from Example 35e), dissolved in 150 ml of tetrahydrofuran, were added under a nitrogen atmosphere. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is then added in portions at 0 ° C. and the mixture is stirred overnight at room temperature and then concentrated in vacuo. The remaining oil is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 12: 1). 17.22 g (64.3% of theory, based on the sec-amine used) of the monoamide and 3.8 g (8.8% of theory) of the diamide are obtained as a by-product. The title compound is isolated in the form of a colorless oil. Elemental analysis: calc .: C 43.41 H 3.92 F 29.18 N 7.59 S 2.60 found: C 43.52 H 4.07 F 29.24 N 7.67 S 2.55

b) 1, 7-bis (benzyloxycarbonyl) - 4- {3-oxapentane-1,5-dicarboxylic acid-1-yl-5- [1 - (4-perfluorooctylsulfonyl) -piperazine] -amide} -10- [ 1 -0-α-D- (5-carbonyl) - pentyl-2,3,4,6-tetra-0-benzyl-mannopyranose] -1, 4,7,10-tetraazacyclododecane

10.0 g (13.4 mmol) of the carboxylic acid prepared under Example 30c) and 3.24 g (28.1 mmol) of N-hydroxysuccinimide are dissolved in 100 ml of dimethylformamide and at 0 ° C. with a total of 5.8 g (28 , 1 mmol) of N, N'-dicyclohexylcarbodiimide are added in portions and the mixture is stirred for 3 hours at this temperature. A solution of 14.83 g (13.4 mmol) of the title compound, cooled to 0 ° C, is added to the solution thus prepared Example 35a), dissolved in 100 ml of dimethylformamide, is added dropwise and the mixture is stirred at 0 ° C. for 2 hours and at room temperature for 12 hours. For working up, the precipitated dicyclohexylurea is filtered off and the solvent is then drawn off to dryness. The residue thus obtained is then chromatographed on silica gel (mobile phase: dichloromethane / ethyl acetate 20: 1; the chromatography was carried out using a solvent gradient with a continuous increase in the proportion of ethyl acetate).

Yield: 18.3 g (78.2% of theory) of the title compound in the form of a colorless and highly viscous oil. Elemental analysis: calc .: C 55.11 H 5.03 N 4.82 F 18.52 S 1.84 found: C 54.87 H 4.85 N 4.92 F 18.55 S 1.86

c) 1 - {3-oxapentane-1,5-dicarboxylic acid-1-yl-5- [1 - (4-perfluorooctylsulfonyl) - piperazine] -amide} -7- [1-0-aD- (5- carbonyl) -pentyl-mannopyranose] -

1, 4,7,10-tetraazacyclododecane

17.0 g (9.75 mmol) of the compound prepared under 34b) are dissolved in 150 ml of ethanol, 1.0 g of Pearlman catalyst (Pd 20%, C) are added and the mixture is at room temperature under a hydrogen atmosphere (1 atm) hydrogenated until no more hydrogen uptake can be observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (twice with 75 ml) and evaporates to dryness in vacuo. The title compound is obtained as a highly viscous and colorless oil.

Yield: 10.76 g (99.0% of theory).

Elemental analysis: calc .: C 38.78 H 4.61 N 7.54 F8.97 S 2.88 found: C 38.86 H 4.65 N 7.41 F 29.02 S 2.92

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

24.86 g (39.46 mmol; 4.4 molar equivalents based on the amine component 35c) of the Gd complex of 10- (4-carboxy-1-methyl-2) described in patent application DE 19728 954 C1 under Example 31h) - oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1.67 g of anhydrous lithium chloride (39.46 mmol) are stirred at 40 ° C. in 200 ml of absolute dimethyl sulfoxide dissolved and at this temperature with a total of 4.53 g (39.46 mmol) of N-hydroxysuccinimide and 10.0 g (8.97 mmol) of

Title compound from Example 34c), dissolved in 100 ml of absolute dimethyl sulfoxide, added. After cooling to room temperature, 8.14 g (39.46 mmol) of N, N'-dicyclohexylcarbodiimide are added to the reaction solution and the mixture is stirred at room temperature for 12 hours. The suspension obtained is then mixed with sufficient acetone until the above-mentioned is completely precipitated

The title compound is added, the precipitate is filtered off with suction, dried, taken up in water, filtered off from insoluble dicyclohexylurea and the filtrate is desalted via an AMICON® YM-3 ultrafiltration membrane (cut off: 3000 Da) and cleaned of low molecular weight constituents. The retentate is then freeze-dried.

Yield: 16.37 g (79.3% of theory) as a colorless lyophilizate H ₂ O content (Karl Fischer): 7.65%. Elemental analysis (calculated on anhydrous substance): calc .: 0 38.01 H 4.61 N 9.58 F 13.81 S 1.37 Gd 13.45 found: C 37.92 H 4.55 N 9.58 F 13.77 S 1.31 Gd 13.48

e) 3-0xa-pentane-1,5-dicarboxylic acid mono- [1 - (4-perfluorooctylsulfonyl) piperazine] amide

25 g (44.0 mmol) of 1-perfluorooctylsulfonylpiperazine are dissolved in 150 ml of tetrahydrofuran, and a total of 5.1 g (44.0 mmol) of diglycolic anhydride are added at room temperature, and the reaction solution thus obtained is refluxed for 12 h. After cooling to room temperature, the mixture is evaporated to dryness and the remaining oily residue is purified on silica gel using dichloromethane / 2-propanol (16: 1) as the eluent. Yield: 27.94 g (92.8% of theory) the title compound mentioned above in the form of a colorless and viscous oil. Elemental analysis: calc .: C 58.52 H 4.27 N 1.98 S 2.26 F 22.80 found: C58.42 H 4.41 N 1.80 S 2.28 F 23.02

Example 36

a) 1, 7-Bis (benzyloxycarbonyl) - 4- {3- (oxapentane-1,5-dicarboxylic acid-1-yl-5- - [1 - (4-perfluorooctylsulfonyl) -piperazine] -amide} -10 - [1 -O-ß-D-6-carbonylpentyl-2,3,4,6-tetra-0-benzyl-glucopyranose] -1, 4,7,10-tetraazacyclododecane)

68.5 g (91.79 mmol) of 1-carboxymethyloxy-2,3,4-tetra-0-benzyl-α-D-mannopyranoside [representation as described in the patent DE 19728954 C1] are dissolved in 750 ml of dry tetrahydrofuran and then 9.25 g (91.79 mmol) of triethylamine was added. After cooling the reaction solution to -15 ° C to -20 ° C, a solution of 12.64 g (92.5 mmol) of isobutyl chloroformate in 150 ml of dry tetrahydrofuran is slowly added dropwise at this temperature with stirring, the The drop rate should be selected so that an internal temperature of -10 ° C is not exceeded. After a reaction time of 15 minutes at -15 ° C., a solution of 101.6 g (91.79 mmol) of the title compound from Example 35a) and 9.25 g (91, 79 mmol) of triethylamine, as a solution in 500, is then added dropwise ml of dry tetrahydrofuran slowly at -20 ° C. After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is evaporated to dryness in vacuo. The remaining residue is taken up in 450 ml of ethyl acetate and washed twice with 300 ml of saturated sodium hydrogen carbonate solution and once with 400 ml of water. After the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the ethyl acetate is stripped off in vacuo. The remaining oily residue is purified on silica gel using dichloromethane / hexane / 2-propanol (10: 20: 1) as the eluent. Yield: 130.6 g (81.6% of theory) of the above-mentioned title compound as a colorless and highly viscous oil. Elemental analysis: calc .: C 55.11 H 5.03 N 4.82 F 18.52 S 1.84 found: C 55.20 H 5.09 N 4.91 F 18.48 S 1.80

b) 1 - {3-Oxapentane-1,5-dicarboxylic acid-1-yl-5- [1 - (4-perfluorooctylsulfonyl) - piperazine] -amide} -7- [1 -0-α-D- ( 5-carbonyl) -pentyl-mannopyranose] -1, 4,7,10-tetraazacyclododecane

110.0 g (63.08 mmol) of the compound prepared under 36a) are dissolved in 1000 ml of ethanol, 5.0 g of Pearlman catalyst (Pd 20%, C) are added and the mixture is hydrogenated until it is quantitatively absorbed in hydrogen. It is suctioned off from the catalyst, washed with ethanol and concentrated to dryness in vacuo. The title compound is obtained as a viscous and colorless oil. Yield: 92.61 g (99.5% of theory). Elemental analysis: calc .: C 52.10 H 5.12 N 5.70 F 21.89 S 2.17 found: C 52.20 H 5.09 N 5.71 F 21.87 S 2.20 c) 1,7-bis- [1,7,4-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl-pentanoyl) -4- {3-oxapentane -1,5-dicarboxylic acid-1-yl-5- [1 - (4-perfluorooctylsulfonyl) piperazine] amide} -10- [1-0-α-D- (5-carbonyl) pentylmannopyranose] - 1, 4,7,10-tetraazacyclododecane, digadolinium complex

55.4 g [88.0 mmol; 4.4 molar equivalents based on the diamine component used from Example 33d)] of the Gd complex described in patent application DE 19728 954 C1 under Example 31h) of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4.7, 10-tetraazacyclododecan-1, 4,7-triacetic acid and 3.7 g of anhydrous lithium chloride (88.0 mmol) are dissolved at 40 ° C. in 500 ml of absolute dimethyl sulfoxide with stirring and at this temperature with a total of 10.1 g (88.0 mmol) of N-hydroxysuccinimide and 29.5 g (20.0 mmol) of the title compound from Example 36b), dissolved in 200 ml of absolute dimethyl sulfoxide, were added. After cooling to room temperature, 18.2 g (88.0 mmol) of N, N'-dicyclohexylcarbodiimide are added to the reaction solution and the mixture is stirred at room temperature for 12 hours. Sufficient acetone is then added to the suspension obtained until the above-mentioned title compound has completely precipitated, the precipitate is filtered off with suction, dried, taken up in water, filtered off from insoluble dicyclohexylurea and the filtrate is desalted via an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and cleaned of low molecular weight components. The retentate is then freeze-dried. Yield: 35.96 g (76.9% of theory) as a colorless lyophilisate H2O content (Karl Fischer): 5.98%

Elemental analysis (calculated on anhydrous substance): calc .: C 38.01 H 4.61 N 8.22 F 13.81 Gd 13.45 S 1.37 found: 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-0-acetyl-α-D-mannopyranoside

In an analogous manner as described in the literature for the synthesis of arylglycopyranosides [J. Conchie and GA Lewy in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol.ll, 90, pp. 345-347, (1963)] leads the reaction of 156.2 g (400 mmol) of D-mannose pentaacetate as an α, β- (α, β-ratio = 4: 1) anomer mixture [for the synthesis of 1, 2,3 , 4,6-Penta-O-acetyl-α, β-D-mannopyranose see: M.LWolfrom and A.Thompson in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol.ll, 53, pp. 211-215, (1963)] with 67 ml (400 mmol) of 6-hydroxy-hexanoic acid ethyl ester 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 form 100.05 g (51% of theory) of the above-mentioned title compound as a colorless and viscous oil. ¹ H-NMR spectroscopic examination of the title compound thus obtained showed that the above-mentioned title compound is exclusively the pure α-anomer. Elemental analysis: calc .: C 52.94 H 6.77 found: C 52.80 H 6.78

b) 5- (carboxy) pentyl-2,3,4,6-tetra-0-benzyl-α-D-mannopyranoside

A stirred suspension of 141.0 g (289 mmol) of the title compound from Example 37a) in 200 ml of dioxane is mixed with a total of 238.5 g (4.26 mol) of finely powdered potassium hydroxide powder at room temperature and with vigorous stirring at the same time. To increase the stirrability, the reaction mixture is mixed with a further 200 ml of dioxane and the suspension thus obtained is subsequently heated to boiling heat and a total of 372 ml (3.128 mol) of benzyl bromide are added dropwise at this temperature over a period of two hours. After a reaction time of 4 hours at 110 ° C followed by 12 hours at room temperature Pour the reaction mixture slowly into a total of 2.5 liters of ice water for the purpose of working up, and then completely extract the water phase with diethyl ether. After washing the ether phase thus obtained and then drying the ether phase over sodium sulfate, the salt is filtered off with suction and the diethyl ether is stripped off in vacuo. Excess benzyl bromide is then quantitatively distilled off from the reaction mixture in an oil pump vacuum at an oil bath temperature of 180 ° C. The resinous-oily residue thus obtained is purified on silica gel using ethyl acetate / hexane (1:10) as the eluent. Yield: 172.2 g (91.0% of theory) of the above-mentioned title compound in the form of a colorless and extremely viscous oil. Elemental analysis: calc .: C 75.68 H 7.16 found: C 75.79 H 7, 04

c) 5 - [(Carboxy) pentyl-2,3,4,6-tetra-0-benzyl-α-D-mannopyranoside-] N-hydroxysuccinimide ester

60.0 g (91.5 mmol) of the title compound from Example 37b) are in 750 ml

Dissolved dimethylformamide and mixed with a total of 10.4 g (91.5 mmol) of N-hydroxysuccinimide. The mixture is cooled to 0 ° C. and 18.9 g (91.5 mmol) are added.

Dicyclohexylcarbodiimide too. It is one hour at 0 ° C and then 4

Stirred for hours at room temperature. The solvent was removed in vacuo and the remaining residue was mixed with 100 ml of ethyl acetate and cooled to 0 ° C. The precipitated urea is filtered off and the filtrate obtained is evaporated to dryness in vacuo. The resinous-oily residue thus obtained is extracted on silica gel using

Ethyl acetate / hexane (1:20) as eluent.

Yield: 61.23 g (89.0% of theory) of the above-mentioned title compound in the form of a colorless and viscous oil. Elemental analysis: calc .: 070.29 H 6.57 N 1.86 found: C 70.39 H 5.64 N 1.91 d) 2,6-bis- {6-N _ε -2-N _α - [- [1 -0-α-D-6-carbonypentyl- (2,3,4,6-tetra-O-benzyl ) - mannopyranose} -L-lysine} methyl ester

In a solution cooled to 0 ° C. from 4.26 g (18.30 mmol; 0.5 mol equivalents based on the carboxylic acid used) L-lysine methyl ester dihydrochloride (commercially available from Bachern) 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 compound from Example 37c) in 150 ml of dimethylformamide. After the addition has ended, the mixture is stirred for a further hour at 0 ° C. and then overnight at room temperature. It is evaporated to dryness in vacuo and the residue is taken up in 300 ml of ethyl acetate. The precipitated urea is filtered off and the filtrate is washed twice with 100 ml of 5% aqueous sodium carbonate solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 25: 1). 39.56 g (75.4% of theory) of the title compound are obtained in the form of a colorless oil. Elemental analysis: calc .: C 72.88 H 7.31 N 1.95 found: C 72.90 H 7.29 N 2.02

e) 2,6-bis- [6-N _ε -2-N _α - [1 -0-α-D -6-carbony-pentyl- (2,3,4,6-tetra-0-benzyl) - mannopyranose]] - L-lysine

30.0 g (20.92 mmol) of the compound prepared in Example 37d) are dissolved in 150 ml of ethanol. The solution of 4 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water is then added and the mixture is stirred at 50 for 3 hours ° C. According to the thin layer chromatogram, the saponification is quantitative. The mixture is concentrated to dryness in vacuo, the residue which remains is taken up in 300 ml of ethyl acetate and the organic phase is extracted twice with 100 ml of dilute aqueous citric acid solution. After drying over sodium sulfate, the mixture is filtered and the mixture is concentrated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n- Hexane / isopropanol 13: 1). 25.56 g (88.5% of theory) of the title compound are obtained in the form of a colorless oil. Elemental analysis: calc .: C 72.88 H 7.31 N 1.95 found: C 72.78 H 7.33 N 1.96

f) 2,6-bis- [6-N _ε -2-N _α - [1 -0-α-D -6-carbonypentyl- (2,3,4,6-tetra-0-benzyl) - mannopyranose] -L-lysine] -N-hydroxysuccinimide

14.0 g (9.15 mmol) of the title compound from Example 37e) are dissolved in 100 ml of dimethylformamide and a total of 1.04 g (9.15 mmol) of N-hydroxysuccinimide are added. The mixture is cooled to 0 ° C. and added 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide. The mixture is stirred at 0 ° C. for one hour and then at room temperature for 4 hours. The solvent is then stripped off in vacuo and the remaining residue is mixed with 100 ml of ethyl acetate and cooled to 0.degree. The precipitated urea is filtered off and the filtrate obtained is evaporated to dryness in vacuo. The resinous-oily residue thus obtained is purified on silica gel using ethyl acetate / n-hexane (1:20) as the eluent. Yield: 12.94 g (92.4% of theory) of the above-mentioned title compound in the form of a colorless and viscous oil. Elemental analysis: calc .: C 71.40 H 7.05 N 2.74 found: C 71.39 H 7.14 N 2.81

g) 2,6-N, N-bis [1 -O-α-D - (6-carbonyl) -pentyl-2,3,4,6-tetra-0-benzyl-mannopyranose] -L-lysine-1 , 7- (1, 4,7-triazaheptane) diamide

A solution of 14.0 g (9.15 mmol; 2) is added dropwise to a solution of 0.47 g (4.57 mmol) of diethylenetriamine in 25 ml of dimethylformamide, cooled to 0 ° C

Mol equivalents based on the amine used) of the title compound from Example 37f) in 100 ml of dimethylformamide are slowly added. When the addition is complete, the mixture is stirred for a further hour at 0 ° C. and then overnight Room temperature. It is evaporated to dryness in vacuo and the residue is taken up in 200 ml of ethyl acetate. The precipitated urea is filtered off and the filtrate is washed twice with 50 ml of 5% aqueous sodium carbonate solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 25: 1). 9.53 g (71.4% of theory) of the title compound are obtained in the form of a colorless oil. Elemental analysis: calc .: C 72.79 H 7.42N 3.36 found: C 72.90 H 7.39 N 3.32

h) 2-N- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-6-N- (benzyloxycarbonyl) -L-lysine methyl ester

20.8 g (35.6 mmol) of 2- [N-ethyl-N-perfluorooctylsulfonyl) aminoacetic acid and 3.60 g (35.6 mmol) of triethylamine are dissolved in 200 ml of dimethylformamide and 4.09 g ( 35.6 mol) of N-hydroxysuccinimide was added. It is cooled to 0 ° C. and 7.34 g (35.6 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred at 0 ° C. for one hour and then at room temperature for 4 hours. The mixture is cooled to 0 ° C. and a solution of 11.77 g (35.6 mmol) of 6-N-benzyloxycarbonyl-L-lysine methyl ester hydrochloride and 4.0 g (40.0 mmol) of triethylamine are added dropwise within 10 minutes in 100 ml of dimethylformamide. The mixture is stirred for one hour at 0 ° C., then overnight at room temperature. It is evaporated to dryness in vacuo and the residue is taken up in 100 ml of ethyl acetate. The precipitated urea is filtered off and the filtrate is washed twice with 100 ml of 5% aqu. Soda solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n-hexane / ethyl acetate 20: 1). 27.43 g (88.0% of theory) of a colorless oil are obtained. Elemental analysis: calc .: C 38.41 H 3.45 N 4.80 F 36.89 S 3.66 found: 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) -L-lysine

25.0 g (28.55 mmol) of the compound prepared in Example 37h) are dissolved in 150 ml of ethanol. The solution of 4 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water is then added and the mixture is stirred at 50 ° C. for 3 hours. According to the thin layer chromatogram, the saponification is quantitative. The mixture is concentrated to dryness in vacuo, the residue which remains is taken up in 300 ml of ethyl acetate and the organic phase is extracted twice with 100 ml of dilute aqueous citric acid solution. After drying over sodium sulfate, the mixture is filtered and the mixture is concentrated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 10: 1). 22.73 g (92.4% of theory) of the title compound are obtained in the form of a colorless oil. Elemental analysis: calc .: C 37.64 H 3.28 N 4.88 F 37.49 S 3.72 found: C 37.65 H 3.38 N 4.88 F 37.52 S 3.73

j) 1,4,7-triazaheptan-4- {2-N- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-

6-N-benzyloxycarbonyl} -L-lysine amide-1,7-bis {2,6-N, N -bis [1-0-α-D- (5-carbonyl) pentyl-2,3,4 , 6-tetra-0-benzyImannopyranose] -L-lysine-diamide}

In 250 ml of dry tetrahydrofuran, 15.33 g (17.8 mmol) of the

Title compound from Example 37i) and 1.80 g (17.8 mmol) of triethylamine dissolved. After the reaction solution has been cooled to -15 ° C. to -20 ° C., a solution of 4.92 g (35.6 mmol) of isobutyl chloroformate, dissolved in 50 ml of dry tetrahydrofuran, is slowly added dropwise at this temperature with stirring, the dropwise rate It should be chosen so that an internal temperature of -10 ° C is not exceeded. After a reaction time of 15 minutes at -15 ° C., a solution of 52.0 g (17.8 mmol) of the title compound from Example 37g) and 1.80 g (17.8 mmol) is then added dropwise Triethylamine, in 300 ml dry tetrahydrofuran at -20 ° C slowly. After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is evaporated to dryness in vacuo. The remaining residue is taken up in 500 ml of ethyl acetate and washed twice with 200 ml of saturated sodium bicarbonate solution and once with 200 ml of water. After the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the ethyl acetate is stripped off in vacuo. The remaining oily residue is purified on silica gel using ethyl acetate / n-hexane (1:20) as the eluent.

Yield: 54.6 g (81.6% of theory) of the above-mentioned title compound as a colorless and highly viscous oil.

Elemental analysis: calc .: C 65.09 H 6.45 N 3.72 F 8.58 S 0.85 ge: C 65.13 H 4.41 N 3.69 F 8.52 S 0.90

k) 1,4,7-triazaheptan-4- {2-N- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl} - L-lysine amide-1,7-bis {2, 6-N, N -bis [1-0-α-D- (5-carbonyl) -pentyl-mannopyranose] - L-lysine-diamide}

50.0 g (13.28 mmol) of the compound prepared under 37j) are dissolved in 500 ml of ethanol, 4.0 g of Pearlman catalyst (Pd 20%, C) are added and the mixture is kept at room temperature under a hydrogen atmosphere (1 atm) hydrogenated until no more hydrogen uptake can be observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (approx. 400 ml) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous and colorless oil. Yield: 26.85 g (93.0% of theory). Elemental analysis:

calc .: C 45.85 H 6.35 N 6.44 F 14.86 S 1.47 found: C 45.76 H 6.35 N 6.41 F 14.92 S 1.39 I) 1,4,7-Triazaheptan-4- {2-N- [2- (N-ethyI-N-perfluorooctylsulfonyl) amino] acetyl-6-N- [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl-pentanoyl) -1,4,7,0-tetraazacyclododecane} -L-lysine amide-1,7-bis {2,6- N, N ^v -bis [1 -0-α-D- (5-carbonyl) -pentyl-mannopyranose] -L-lysine-diamide}, gadolinium complex

5.54 g (8.8 mmol; 2.2 molar equivalents based on the amine component used from Example 37k)) of the Gd complex of 10- (4-carboxy-1-methyl-) described in Patent Application DE 19728 954 C1 under Example 31h) 2-oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 0.37 g anhydrous lithium chloride (8.8 mmol) are at 40 ° C in 60 ml of absolute dimethyl sulfoxide Dissolved stirring and at this temperature with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 1.84 g (4.0 mmol) of the title compound from Example 37k), dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 12 hours. Sufficient acetone is then added to the suspension obtained until the above-mentioned title compound has completely precipitated, the precipitate is filtered off with suction, dried, taken up in water, filtered off from insoluble dicyclohexylurea and the filtrate is desalted via an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and cleaned of low molecular weight components. The retentate is then freeze-dried.

Yield: 8.77 g (78.7% of theory) as a colorless lyophilisate H2O content (Karl Fischer): 4.43%. Elemental analysis (calculated on anhydrous substance): calc .: C 43.98 H 5.97 N 7.54 F 11.59 Gd 5.64 S 1.15 ge: 043.97 H 6.02 N 7.62 F 11.61 Gd 10.18 S 1.15

Example 38 a) 2-Nα-6-Nε-bis- [1 -O-α-D - carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose] -L-lysine] methyl ester

10.95 g (18.30 mmol) of 1-carboxymethyloxy-2,3,4-tetra-0-benzyl-α-D-mannopyranoside [representation as in the patent DE 19728

954 C1 described] are dissolved in 150 ml of dimethylformamide and mixed with a total of 2.09 g (18.3 mmol) of N-hydroxysuccinimide. It is cooled to 0 ° C. and 3.78 g (18.3 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred at 0 ° C. for one hour and then at room temperature for 4 hours. It is cooled to 0 ° C. and a solution of 2.13 g (9.15 mmol; 0.5 mol equivalents based on the carboxylic acid used), L-lysine methyl ester dihydrochloride (commercially available from Bachern) and 2.02 g (20.13 mmol) of triethylamine in 70 ml of dimethylformamide are added. After the addition has ended, the mixture is stirred for a further hour at 0 ° C. and then overnight at room temperature. It is evaporated to dryness in vacuo and the residue is taken up in 300 ml of ethyl acetate. The precipitated urea is filtered off and the filtrate is washed twice with 100 ml of 5% aqueous sodium carbonate solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 25: 1). 10.05 g (82.3% of theory) of the title compound are obtained in the form of a colorless oil. Elemental analysis: calc .: C 71.94 H 6.79 N 2.10 get: C 71.90 H 6.79 N 2.09 b) 2-Nα-6-Nε-bis- [1 -O-α-D - carbonylmethyl- 2,3,4,6-tetra-O-benzyl-mannopyranose] -L-lysine The methyl ester saponification of 15 g (11.23 mmol) is carried out in a manner analogous to that described in Example 37e) for the synthesis of the title compound relevant there. the title compound from Example 38a) to form 13.89 g (93.6% of theory) of the above-mentioned title compound in the form of a colorless and viscous oil.

Elemental analysis: calc .: C 71.80 H 6.71 N 2.12 get: C 71.84 H 6.69 N 2.15

c) 2-Nα-6-Nε-bis- [1 -O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose] -L-lysine-N-hydroxysuccinimide ester

12.09 g (9.15 mmol) of the title compound from Example 38b) are dissolved in 100 ml of dimethylformamide and a total of 1.04 g (9.15 mmol) of N-hydroxysuccinimide are added. It is cooled to 0 ° C. and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred at 0 ° C. for one hour and then at room temperature for 4 hours. The solvent is then stripped off in vacuo and the remaining residue is mixed with 100 ml of ethyl acetate and cooled to 0 ° C. The urea which has precipitated is filtered off and the filtrate obtained is evaporated to dryness in vacuo. The resinous-oily residue thus obtained is purified on silica gel using ethyl acetate / n-hexane (1:20) as the eluent

Yield: 12.24 g (94.4% of theory) of the above-mentioned title compound in the form of a colorless and viscous oil. Elemental analysis: calc .: C 70.27 H 6.47 N 2.96 get: C 70.31 H 6.44 N 3.01

d) 6-N-Benzyloxycarbonyl-2-N - {[2,6-N, N ^* -bis (1-0-α-D-carbonylmethyl-2,3,4,6-tetra-0-benzyl-mannopyranose )] - L-lysyl -} - L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide

19.0 g (13.4 mmol) of the carboxylic acid N-hydroxysuccinimide ester prepared in Example 38c) are dissolved in 75 ml of dimethylformamide and at 0 ° C. with a solution of 11.13 g (13.4 mmol ) of the title compound from Example 21c)), dissolved in 50.0 ml of dimethylformamide, added dropwise. The resulting reaction solution is stirred for a further 2 hours at 0 ° C. and for 12 hours at room temperature. For working up, the precipitated dicyclohexylurea is filtered off and the solvent is drawn off then to dryness in a vacuum. The residue thus obtained is chromatographed on silica gel [mobile solvent: dichloromethane / ethanol 28: 1; The chromatography is carried out here using a solvent gradient with a proportion of the polar eluent component used (increasing here in the course of the chromatography (here: ethanol)).

Yield: 25.28 g (88.4% of theory) of the title compound in the form of a colorless and highly viscous oil. Elemental analysis: calc .: C 59.10 H 5.34 N 3.94 F 15.13 S 1.50 get: C 59.18 H 5.35 N 4.02 F 15.15 S 1.56

e) 2-N - {[2,6-N, N'-bis (1-0-α-D-carbonylmethyl-mannopyranose)] - L-lysyl-L-lysine [1 - (4-perf luoroctylsulfonyl) -piperazine] amide

20.0 g (9.37 mmol) of the compound prepared under 38d) are dissolved in 200 ml of ethanol, 1.5 g of Pearlman catalyst (Pd 20%, C) are added and the mixture is at room temperature under a hydrogen atmosphere (1 atm) hydrogenated until no more hydrogen uptake can be observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (twice with about 100 ml each) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous and colorless oil. Yield: 11.62 g (97.0% of theory). Elemental analysis: calc .: C 38.50 H 4.65 N 6.57 F 25.25 S 2.51 get: 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 -bis (1 -O-α-D carbonylmethyl-mannopyranose)] - L-lysyl} -L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex 9.98 g (15.84 mmol; 2.2 molar equivalents based on the amine component from Example 38e) of the Gd complex of 10- (4-carboxy-1-methyl-2) described in patent application DE 19728 954 C1 under Example 31h) -oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 0.67 g of anhydrous lithium chloride (15.84 mmol) are stirred at 40 ° C. in 100 ml of absolute dimethyl sulfoxide dissolved and at this temperature a total of 1.82 g (15.84 mmol) of N-hydroxysuccinimide and 9.19 g (7.19 mmol) of the title compound from Example 38e), dissolved in 50 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 3.27 g (15.84 mmol) of N, N'-dicyclohexylcarbodiimide is added and the mixture is stirred at room temperature for 12 hours. Sufficient acetone is then added to the suspension obtained until the above-mentioned title compound has completely precipitated, the precipitate is filtered off with suction, dried, taken up in water, filtered off from insoluble dicyclohexylurea and the filtrate is desalted via an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and at the same time cleaned of possible, still existing low molecular weight components. The retentate is then freeze-dried. Yield: 11.85 g (87.2% of theory) as a colorless lyophilisate. H ₂ 0 content (Karl Fischer): 5.54% elemental analysis (calculated on anhydrous substance): calc .: C 38.12 H 4.64 N 8.15 F 20.38 S 1.70 Gd 8.32 get: C 38.16 H 4.59 N 8.18 F 20.37 S 1.68 Gd 8.28

Example 39

a) 1, 7-bis (benzyloxycarbonyl) -4- (3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perf luortridecanoyl) -1, 4,7, 10-tetraazacyclododecane

In a solution of 10.75 g (24.4 mmol) of 1,7-bis- [benzyloxycarbonyl] -1,4,7,10-tetraazacyclododecane, dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, 12.74 g (24.4 mmol) of the title compound from Example 39g), dissolved in 150 ml of tetrahydrofuran, are added at 0 ° C. and under a nitrogen atmosphere. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is then added in portions at 0 ° C. and the mixture is stirred overnight at room temperature and then concentrated in vacuo. The remaining oil is chromatographed on silica gel (mobile phase: n-hexane / isopropanol 16: 1). 15.89 g (69.0% of theory, based on the sec-amine used) of the monoamide and 3.8 g (8.8% of theory) of the diamide are obtained as a by-product. The title compound is isolated in the form of a colorless oil. Elemental analysis: calc .: C 45.77 H 3.95 F 34.19 N 5.93 get: C 45.72 H 4.01 F 34.22 N 5.88

b) 1, 7-bis (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) of 3- (2,3,4,6-tetra-0-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. YC (1973), Synthesis of 1-thio-aldosides; Carbohydrate Research 31, 339-346) are dissolved in 100 ml of dimethylformamide dissolved and at 0 ° C with a pre-cooled to 0 ° C solution of 12.65 g (13.4 mmol) of the title compound from Example 39a), dissolved in 100 ml of dimethylformamide, added dropwise. The mixture is stirred at 0 ° C. for 2 hours and at room temperature for 12 hours. For working up, the solvent is removed to dryness in vacuo and the residue thus obtained is then chromatographed on silica gel (mobile phase: dichloromethane /

Ethyl acetate 20: 1; the chromatography was carried out using a solvent gradient with a continuous increase in the proportion of ethyl acetate). Yield: 16.23 g (88.9% of theory) of the title compound in the form of a colorless and highly viscous oil. Elemental analysis: calc .: C 46.70 H 436 N 4.11 F 23.69 S 2.35 get: 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-0-acety-l-mannopyranose] -1, 4.7, 10-tetraazacyclododecane

15.0 g (11.0 mmol) of the compound prepared under 39b) are dissolved in 150 ml of ethanol, 1.0 g of Pearlman catalyst (Pd 20%, C) are added and the mixture is at room temperature under a hydrogen atmosphere (1 atm) hydrogenated until no more hydrogen uptake can be observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (twice with 75 ml each) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous and colorless oil. Yield: 11.56 g (96.0% of theory). Elemental analysis: calc .: C 40.59 H 4.33 N 5.12 F 29.50 S 2.93 get: 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 compound from Example 39c) are suspended in 100 ml of absolute methanol and a catalytic amount of sodium methoxide is added at 5 ° C. After a reaction time of 3 hours at room temperature, the thin-layer chromatographic control (eluent: chloroform / methanol 4: 1) of the course of the reaction already shows quantitative conversion. For the purpose of working up, the now clear reaction solution is neutralized by adding Amberlite IR 120 (H ⁺ form) cation exchange resin, suctioned off from the exchanger, washed with methanol and the methanolic filtrate obtained in this way Vacuum drawn to dryness. The oily residue obtained is purified by column chromatography on silica gel (mobile phase: dichloromethane / n-hexane / ethyl acetate 15: 20: 1; the chromatography was carried out using a solvent gradient with a continuous increase in the proportion of ethyl acetate). After ¹ H-NMR spectroscopic examination the title compound, based on the size of the coupling constants of Jι _ι = 0.9 Hz, it was clearly possible to conclude that the α configuration was present at the anomeric center of D-mannopyranose. The present α configuration is the only configuration present at the anomer center, ie the amount of possibly formed and β-configured anomer of the title compound is therefore below the ¹ H-NMR spectroscopic detection limit. The above-mentioned title compound was therefore only prepared in the form of the pure α-configured anomer. Yield: 8.28 g (98.0% of theory) of the title compound in the form of a colorless and highly viscous oil. Elemental analysis: calc .: C 37.59 H 4.24 N 6.05 F 34.85 S 3.46 get: 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-carbony l) ethyl-mannopyranose] -4, 10 -bis [1, 4,7-tris (carboxylatomethyl) - 10- (3-aza-4-oxo-5-methyl-5-yl-pentanoyl)] - 1, 4,7,10-tetraazacyclododecane, digadolinium complex

Amide conjugate of 1, 4,7,10-tetraazacyclododecane with [1, 7-bis- [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-0-acetyl-1-thio-α-D-mannopyranosyl) propionic acid

2.48 g [(3.94 mmol); 4.4 molar equivalents based on the diamine component 39d)] of the Gd complex of 10- (4-carboxy-1-methyl-2-) described in patent application DE 197 28 954 C1 under Example 31h) oxo-3-azabutyl) -1, 4.7, 10-tetraazacyclododecan-1, 4,7-triacetic acid and 167 mg of anhydrous lithium chloride (3.94 mmol) are dissolved at 40 ° C. in 40 ml of absolute dimethyl sulfoxide with stirring and at this temperature with a total of 453 mg (3.94 mmol) of N-hydroxysuccinimide and 980 mg (0.895 mmol) of the title compound from Example 19Ad), dissolved in 10 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 814 mg ( 3.946 mmol) of N, N'-dicyclohexylcarbodiimide were added and the mixture was stirred at room temperature for 12 hours. Sufficient acetone is then added to the suspension obtained until the above-mentioned title compound has completely precipitated, the precipitate is filtered off with suction, dried, taken up in water, filtered off from insoluble dicyclohexylurea and the filtrate is desalted via an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and cleaned of low molecular weight components. The retentate is then freeze-dried. Yield: 1.32 g (69.1% of theory) as a colorless lyophilisate. H ₂ 0 content (Karl Fischer): 7.65% elemental analysis (calculated on anhydrous substance): calc .: C 37.43 H 4.45 N 9.12 F 15.02 S 1.49 Gd 14.63 get: 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

25.0 g (53.8 mmol) of 1H, 1H, 2H, 2H-perfluoro-1-decanol [commercially available from Lancaster] are dissolved in 250 ml of absolute toluene and at room temperature with a catalytic amount (approx. 75 g) tetra-n-butylammonium hydrogen sulfate were added. Subsequently, a total of 7.55 g (134.6 mmol; 2.5 equ., Based on the alcohol component used) of finely powdered potassium hydroxide powder is added at 0 ° C., followed by 15.73 g (80.7 mmol; 1.5 equ Based on the alcohol component used), tert-butyl bromoacetate and allowed to stir for a further 2 hours at 0 ° C. The reaction solution thus obtained is stirred for 12 h at room temperature and for the purpose of working up, a total of 500 ml of ethyl acetate and 250 ml Water added. The org. Phase is separated and washed twice with water. After the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the solvent is stripped off in vacuo. The remaining oily residue is purified on silica gel using ethyl acetate / hexane (1:10) as the eluent.

Yield: 26.3 g (84.6% of theory) of the above-mentioned title compound as a colorless and highly viscous oil. Elemental analysis: calc .: C 33.23 H 2.61 F 55.85 found: C 33.29 H 2.61 F 55.90

g) 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanecarboxylic acid

20.0 g (34.58 mmol) of the title compound from Example 39f) are suspended in 200 ml of a mixture consisting of methanol and 0.5 molar sodium hydroxide solution in a ratio of 2: 1 with stirring at room temperature and then heated to 60.degree , After a reaction time of 12 h at 60 ° C., the now clear reaction mixture is neutralized for working up by adding Amberlite IR 120 (H ⁺ form) cation exchange resin, suctioned off from the exchanger and the methanolic-aqueous filtrate thus obtained is drawn off to dryness in vacuo , The amorphous-oily residue obtained is purified on silica gel using ethyl acetate / n-hexane (1: 3) as the eluent.

Yield: 16.0 g (88.6% of theory) of the above-mentioned title compound as a colorless and highly viscous oil. Elemental analysis: calculated: C 27.60 H 1.35 F 61.85 get: C 27.58 H 1.36 F 61.90

Example 40

a) 6-Benzyloxycarbonyl-2- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-L-lysine methyl ester To 8.0 g (24.4 mmol) of ε-carbonyloxybenzyl-L-lysine methyl ester hydrochloride (commercially available from Bachern), dissolved in a mixture of 150 ml of tetrahydrofuran, 15 ml of chloroform and 2.62 g (26.0 mmol ) Triethylamine, 16.18 g (27.0 mmol) of 2- [N-ethyl-N-perfluorooctylsulfonyl) aminoacetic acid (representation according to: DE 19603033), dissolved in 50 ml of tetrahydrofuran, are added dropwise at 0 ° C. and under a nitrogen atmosphere , Are then added at 0 ° C a total of 18.0 g (36.6 mmol) of EEDQ [2- ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is added in portions and ^* ässt stir overnight at room temperature. It is then concentrated in vacuo and the remaining oil is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 15: 1). 17.0 g (79.6% of theory, based on the primary amine used) of the title compound are obtained in the form of a colorless oil. Elemental analysis: calc .: C 38.41 H 3.45 F 36.89 N 4.80 S 3.66 get: C 38.42 H 3.47 F 36.92 N 4.87 S 3.64

b) 2- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-L-lysine methyl ester

15.0 g (20.23 mmol) of the compound prepared under Example 40a) are dissolved in 200 ml of ethanol, 800 mg of Pearlman catalyst (Pd 20% on activated carbon) are added and the mixture is hydrogenated until the calculated amount of hydrogen has been taken up. It is suctioned off from the catalyst, washed thoroughly with ethanol and concentrated to dryness in vacuo. The title compound is obtained as a colorless oil.

Yield: 14.68 g (97.9% of theory)

Elemental analysis: calc .: C 32.40 H 3.26 F 43.56 N 5.67 S 4.32 get: C 32.42 H 3.27 F 43.60 N 5.67 S 4.34

c) 6- (1 -0-α-D-carbonyimethyl-2,3,4,6-tetra-0-benzyl-mannopyranose) 2- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl -L-lysine-methylester In 500 ml of dry tetrahydrofuran, 21.31 g (35.6 mmol) of 1-carboxymethyloxy-2,3,4-tetra-0-benzyl-α-D-mannopyranoside [representation as described in the patent DE 19728954 C1] and 3.60 g (35.6 mmol) triethylamine dissolved. After the reaction solution has cooled to -15 ° C. to -20 ° C., a solution of 4.92 g (35.6 mmol) of isobutyl chloroformate in 75 ml of dry tetrahydrofuran is slowly added dropwise at this temperature, with stirring, the dropwise rate being so chosen ^%, an internal temperature of -10 ° C is not exceeded. After a reaction time of 15 minutes at -15 ° C., a solution of 26.39 g (35.6 mmol) of the title compound from Example 40b) and 3.60 g (35.6 mmol) of triethylamine in 100 ml of dry tetrahydrofuran is then added dropwise slowly at -20 ° C. After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is evaporated to dryness in vacuo. The remaining residue is taken up in 250 ml of ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution and once with 200 ml of water. After the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the ethyl acetate is stripped off in vacuo. The remaining oily residue is purified on silica gel using ethyl acetate / n-hexane (1:10) as the eluent.

Yield: 38.12 g (81.0% of theory) of the above-mentioned title compound as a colorless and highly viscous oil

Elemental analysis: calc .: C 49.92 H 3.92 N 2.53 F 29.18 S 2.90 get: C 49.99 H 4.11 N 2.69 F 29.22 S 3.01

d) 6- (1 -0-α-D-carbonylmethyl-2,3,4,6-tetra-0-benzyl-mannopyranose) 2- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl -L-lysine

27.65 g (20.92 mmol) of the compound prepared in Example 40c) are dissolved in 250 ml of methanol. The solution of 4.0 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water is then added and the mixture is stirred for 3 hours at 50 ° C. After checking the course of the reaction by means of thin layer chromatography, the methyl ester saponification has already taken place quantitatively. The mixture is concentrated to dryness in vacuo, the residue which remains is taken up in 300 ml of ethyl acetate and the organic phase is extracted twice with 100 ml of dilute aqueous citric acid solution. After drying over sodium sulfate, the mixture is filtered and concentrated to dryness in vacuo. The residue obtained is chromatographed on silica gel (mobile solvent: n-hexane / chloroform / isopropanol 15: 10: 1). 24.31 g (88.9% of theory) of the title compound are obtained in the form of a colorless and viscous oil. Elemental analysis: calc .: C 51.46 H 4.70 N 3.21 F 24.71 S 2.45 get: C 51.49 H 4.71 N 3.19 F 24.72 S 2.41

e) 6- (1-0-α-D-carbonylmethyl-mannopyranose) 2- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-L-lysine

20.0 g (15.30 mmol) of the title compound from Example 40d) are dissolved in a mixture consisting of 250 ml of 2-propanol and 25 ml of water, and 1.0 g of palladium catalyst (10% Pd on activated carbon) is added. It is hydrogenated for 12 hours at room temperature and a hydrogen pressure from one atmosphere. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 200 ml of methanol and the reaction product is precipitated by adding a total of 800 ml of diethyl ether. After the solid thus obtained has been suctioned off, it is dried in vacuo at 50.degree

Yield: 14.32 g (99.0% of theory) of an amorphous solid.

Elemental analysis: calc .: C 35.56 H 3.84 N 4.44 S 3.39 F 34.15 get: C 35.58 H 3.81 N 4.45 S 3.40 F 34.17

f) 6- (1-0-α-D-carbonylmethyl-mannopyranose) 2- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-L-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 compound from Example 40e) are dissolved in 50 ml of dimethyl sulfoxide at 40 ° C. and 1.00 g (8.70 mol) of N-hydroxysuccinimide is added. It is cooled to 20 ° C. and 1.795 g (8.7 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred at 20 ° C. for one hour and then at 40 ° C. for 4 hours. A solution of 4.53 g (7.91 mmol) of the gadolinium complex of 10- (2-hydroxy-3-aminopropyl) -4,7, 10-tris (carboxymethyl) is then added dropwise at this temperature within 10 minutes. - 1,4,7,10-tetraazacyclododecanine [see illustration: WO 97/02051] in 20 ml of dimethyl sulfoxide. The mixture is stirred for one hour at 40 ° C., then overnight at room temperature. The resulting suspension is then mixed with sufficient acetone until the above-mentioned title compound has completely precipitated, the precipitate is filtered off with suction, dried, taken up in water, filtered off from insoluble dicyclohexylurea and the filtrate is passed through an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) desalted and cleaned of low molecular components. The retentate is then freeze-dried. Yield: 9.71 g (81.7% of theory) as a colorless lyophilisate. H ₂ 0 content (Karl Fischer): 3.97% elemental analysis (calculated on anhydrous substance): calc .: C 35.16 H 4.16 N 7.45 F 21.48 Gd 10.46 S 2.13 get: C 35.17 H 4.20 N7.42 F 21.49 Gd 10.48 S 2.09

Example 41

a) 6-N- [1-0-α-D- (5-carbonyl) pentyl-2,3,4,6-tetra-0-benzyl-mannopyranose] - 2N- [2- (N-ethyl- N-perfluorooctylsulfonyl) -amino] -acetyl-L-lysine methylester

5.23 g (8.0 mmol) of the 5- (carboxy) pentyl-2,3,4,6-tetra-0-benzyl-α-D-mannopyranoside described in Example 30c), 1.3 g (8, 0 mmol) 1-hydroxy-benzotriazole and 2.6 g (8.0 mmol) 2- (1H-benzotriazol-1-yi) -1,1,3,3-tetramethyl- uronium tetrafluoroborate (TBTU; Peboc Limited, UK) are dissolved in 75 ml DMF and stirred for 15 minutes. This solution is then mixed with 5.16 ml (30 mmol) of N-ethyldiisopropylamine and with 5.93 g (8.0 mmol) of the amine described in Example 40b) and stirred for 1.5 days at room temperature. For working up, the solvent is removed to dryness in vacuo and the residue thus obtained is then chromatographed on silica gel (mobile phase: dichloromethane / ethyl acetate 30: 1; the chromatography was carried out using a solvent gradient with a continuous increase in the proportion of ethyl acetate). Yield: 9.70 g (88.0% of theory) of the title compound in the form of a colorless and highly viscous oil. Elemental analysis: calc .: C 52.29 H 4.97 N 3.05 F 23.43 S 2.33 get: C 52.33 H 4.95 N 3.12 F 23.50 S 2.30

b) 6-N- [1 -0-α-D- (5-carbonyl) -pentyl-2,3,4,6-tetra-0-benzyl-mannopyranose] - 2N- [2- (N-ethyl- N-perfluorooctylsulfonyl) amino] acetyl-L-lysine

9.0 g (12.40 mmol) of the compound prepared in Example 41a) are dissolved in 150 ml of methanol. The solution of 2.48 g (62.0 mmol) of sodium hydroxide in 15 ml of distilled water is then added and the mixture is stirred at 50 ° C. for 3 hours. After checking the course of the reaction by means of thin layer chromatography, the methyl ester saponification has already taken place quantitatively after the above-mentioned reaction time. The mixture is concentrated to dryness in vacuo, the residue which remains is taken up in 300 ml of ethyl acetate and the organic phase is extracted twice with 100 ml of dilute aqueous citric acid solution. After drying over sodium sulfate, the mixture is filtered and concentrated to dryness in vacuo. The residue obtained is chromatographed on silica gel (mobile solvent: n

Hexane / chloroform / isopropanol 25: 10: 1). 15.88 g (93.9% of theory) of the title compound are obtained in the form of a colorless and highly viscous oil. Elemental analysis: calc .: C 51.95 H 4.88 N 3.08 F 23.67 S 2.35 get: C 51.99 H 4.91 N 3.09 F 23.70 S 2.33

c) 6-N- [1 -0-α-D- (5-carbonyl) -pentyl-mannopyranose] - 2N- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-L-lysine

13.0 g (9.52 mmol) of the title compound from Example 41b) are dissolved in a mixture consisting of 150 ml of 2-propanol and 25 ml of water, and 1.0 g of the palladium catalyst (10% Pd on activated carbon) is added. It is hydrogenated for 12 hours at 1 atmosphere of hydrogen pressure and room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue obtained is chromatographed on silica gel (mobile solvent: n-hexane / chloroform / isopropanol 15: 10: 1). 9.09 g (95.1% of theory) of the title compound are obtained in the form of a colorless and highly viscous oil. Elemental analysis: calc .: C 37.10 H 4.22 N 4.19 F 32.18 S 3.10 get: C 37.09 H 4.21 N 4.19 F 32.20 S 3.13

d) 6-N- [1 -0-α-D- (5-carbonyl) -pentyl-mannopyranose] - 2N- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-L-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 compound from Example 41c) are dissolved in 75 ml of dimethyl sulfoxide at 40 ° C., and 1.00 g (8.70 mol) of N-hydroxysuccinimide is added. The mixture is cooled to room temperature and a total of 1.795 g (8.7 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred at 20 ° C. for one hour and then at 40 ° C. for 4 hours. A solution consisting of 4.53 g (7.91 mmol) of the gadolinium complex of 10- (2-hydroxy-3) is then added dropwise to this solution of the active ester of the title compound from Example 41c) at 40 ° C. within 10 minutes - aminopropyl) -4,7,10-tris (carboxymethyl) -1, 4,7,10-tetraazacyclododecanine [for illustration, compare: WO 97/02051], in 20 ml of dimethyl sulfoxide. The mixture is stirred for one hour at 40 ° C., then overnight at room temperature. The resulting suspension is then mixed with the sufficient amount of a mixture of acetone / 2-propanol (2: 1) until the above-mentioned title compound has completely precipitated, the precipitate is filtered off with suction, washed with ethyl acetate, dried, taken up in water, from the insoluble dicyclohexylurea filtered off and the filtrate desalted over an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and cleaned of low molecular weight components. The retentate is then freeze-dried

Yield: 9.71 g (78.8% of theory) as a colorless lyophilisate. H2θ content (Karl Fischer): 6.65% elemental analysis (calculated on anhydrous substance): calc .: C 36.97 H 4.52 N 7.19 F 20.71 Gd 10.08 S 2.06 get: C 37 , 02 H 4.50 N 7.22 F 20.69 Gd 10.08 S 2.09

Example 42

a) 6-N- {4- [2,3-bis (N, N-bis (t-butyloxycarbonylmethyl) amino) propyl] phenyl} -3-oxa-propionyl-2-N- (1 - α-D-carbonylmethyl-mannopyranose) L-Iysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide

5.25 g (7.72 mmol) of the tetra-t.bu-ester of the 'Tyr-EDTA-carboxylic acid "and 781 mg (7.72 mmol) of triethylamine are dissolved in 50 ml of methylene chloride. The mixture is added dropwise at -15 ° C. a solution of 1.16 g (8.5 mmol) of isobutyl chloroformate in 10 ml of methyl chloride is added within 5 minutes and the mixture is stirred for a further 20 minutes at -15 ° C. The solution is then cooled to -25 ° C. and a solution is added dropwise, consisting of 7.07 g (7.72 mmol) of the title compound from Example 30e) and 2.12 g (21.0 mmol) of triethylamine in 70 ml of tetrahydrofuran was added over the course of 30 minutes and then stirred for a further 30 minutes at -15 ° C and then overnight at room temperature Working up, the solvent is removed in vacuo and the remaining oily residue is taken up in 250 ml of chloroform. The chloroform phase is extracted twice with 100 ml of a 10% aqueous ammonium chloride solution, the organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / ethanol = 20: 1). Yield: 9.60 g (79.0% of theory) of a colorless and very viscous oil. Elemental analysis: calc .: C 46.39 H 5.55 N 5.32 F 20.45 S 2.03 get: C 46.42 H 5.51 N 5.29 F 20.49 S 2.09

b) 6-N- {4- [2,3-bis- (N, N-bis (caboxymethyl) amino) propyl] phenyl} -3-oxapropionyl-2-N- (1 -α- D-carbonylmethyl-mannopyranose) L-Iysine [1 - (4- ρerfluorooctylsulfonyl) piperazine] amide

9.0 g (5.70 mmol) of the compound prepared in Example 42a) are dissolved in 150 ml of methanol. The solution of 4.0 g (100.0 mmol) of sodium hydroxide in 25 ml of distilled water is then added and the mixture is stirred at 60 ° C. for 6 hours. After checking the course of the reaction by means of thin layer chromatography, the saponification of the tetra-t-butyl ester has already taken place quantitatively after the above-mentioned reaction time. The mixture is concentrated to dryness in vacuo and the residue which remains is taken up in 50 ml of dimethyl sulfoxide under heat and then sufficient quantity of a mixture of acetone / ethyl acetate (1: 1) is added until the above-mentioned title compound has completely precipitated, which is so the precipitate obtained is filtered off with suction, washed thoroughly with ethyl acetate, dried, taken up in water, the pH of the product solution is adjusted to 3.5 using 1 molar hydrochloric acid, the insoluble constituents which may be present are filtered off and the filtrate is filtered through an AMICON® YM-3 ultrafiltration membrane (cut off: 3000 Da) desalted and cleaned of low molecular weight components. The retentate is then freeze-dried. Yield: 6.76 g (87.6% of theory) as a colorless lyophilisate H ₂ 0 content (Karl Fischer): 3.30%. Elemental analysis (calculated on anhydrous substance): calc .: C 39.89 H 4.09 N 6.20 F 23.84 S 2.37 get: C 39.92 H 4.15 N 6.22 F 23.92 S 2.29

c) 6-N- {4- [2,3-bis (N, N-bis (carboxylatomethyl) amino) propyl] phenyl} -3-oxa-propionyl-2-N- (1 -α- D-carbonylmethyl-mannopyranose) L-Iysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide, Mn complex, disodium salt

3.0 g (2.22 mmol) of the title compound from Example 42b) are dissolved in 150 ml of a water / ethanol (3: 1) mixture at the boiling point and at 80 ° C. in portions with 0.25 g (2.22 mmol) manganese ll carbonate added. The reaction solution thus obtained is then boiled under reflux for 5 hours. After cooling to room temperature, the solvent mixture is completely stripped off in vacuo and the remaining residue is dissolved in a mixture of 200 ml of distilled water / n-butanol (1: 1). With vigorous stirring, a pH of 7 is added by adding 1N sodium hydroxide solution , 2 set. After the n-butanol has been completely stripped off in vacuo, the remaining aqueous phase is desalted over an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and cleaned of low molecular weight components. The retentate is then freeze-dried. Yield: 3.19 g (99.0% of theory) as a colorless lyophilisate H2O content (Karl Fischer): 5.08%. Elemental analysis (calculated on anhydrous substance): calc .: C 37.23 H 3.54 F22.25 Mn 3.78 N 5.79 Na 3.17 S 2.21 get: 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-ρerfluorooctylsulfonyl) piperazine] monoamide A stirred solution of 25.0 g (94.96 mmol) of 3 -N- (benzyloxcarbonyl) glutaric anhydride [synthesis according to: Hatanaka, Minoru; Yamamoto, Yu-ichi; Nitta, Hajime; Ishimaru, Toshiyasu; TELEAY; Tetrahedron lett; EN; 22; 39; 1981; 3883-3886;] in 150 ml of absolute tetrahydrofuran, a solution of 53.97 g (95.0 mmol) of 1-perfluorooctylsulfonylpiperazine in 150 ml of tetrahydrofuran is added dropwise with stirring and the reaction solution thus obtained is refluxed for 12 h. After cooling to room temperature, the mixture is evaporated to dryness and the remaining oily residue is purified on silica gel using dichloromethane / 2-propanol (20: 1) as the eluent.

Yield: 75.80 g (96.0% of theory) of the above-mentioned title compound in the form of a colorless and viscous oil.

Elemental analysis: calc .: C 36.11 H 2.67 N 5.05 S 3.86 F 38.84 get: C 36.12 H 2.61 N 5.08 S 3.88 F 38.82

b) 3-Amino-glutaric acid- [1 - (4-perfluorooctylsulfonyl) piperazine] monoamide

31.50 g (37.88 mmol) of the compound prepared under 43b) are dissolved in 300 ml of ethanol, 2.5 g of Pearlman catalyst (Pd 20%, C) are added and the mixture is hydrogenated at 1 atmosphere of hydrogen pressure until quantitative absorption of hydrogen , It is suctioned off from the catalyst, washed with ethanol and concentrated to dryness in vacuo. The title compound is obtained as a whitish-yellow, viscous oil. Yield: 25.22 g (95.5% of theory) Elemental analysis: calc .: C 29.28 H 2.31 N 6.03 S 4.06 F 46.31 get: C 29.32 H 2, 29 N 6.08 S 4.08 F 46.28

c) 3-N- (1-α-D-carbonylmethyl-2,3,4,6-tetra-0-benzyl-mannopyranose) - glutaric acid- [1- (4-perfluorooctylsulfonyl) piperazine] monoamide 21.52 g (18.96 mmol) of 1-carboxymethyloxy-2,3,4, -tetra-0-benzyl-α-D-mannopyranoside [preparation as described in the patent DE 19728 954 C1] are at room temperature in 100 ml absolute dimethylformamide and mixed at 0 ° C with 2.56 g (22.2 mmol) of N-hydroxysuccinimide, followed by 4.55 g (22.2 mmol) of dicyclohexylcarbodimide. After a reaction time of 60 minutes at 0 ° C and 3 hours at 22 ° C, the insoluble dicyclohexylurea is filtered off and the clear active ester solution of the title compound obtained in this way is slowly added dropwise at 0 ° C to a stirred solution of 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 temperature, the solvent is removed in vacuo and the remaining residue is taken up in 300 ml of ethyl acetate, the urea is filtered off and the organic filtrate is twice with 100 ml of saturated sodium bicarbonate solution and once with 100 ml of 10% aqueous solution Citric acid solution and washed once with 200 ml of water. After the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the ethyl acetate is stripped off in vacuo. The remaining oily residue is purified on silica gel using ethyl acetate / n-hexane (1:15) as the eluent.

Yield: 21.39 g (88.3% of theory) of the above-mentioned title compound as a colorless and highly viscous oil.

Elemental analysis: calc .: C 49.81 H 4.10 N 3.29 F 25.27 S 2.51 get: C 49.89 H 4.11 N 3.32 F 25.22 S 2.51

d) 3-N- (1-α-D-carbonylmethyl-mannopyranose) -glutaric acid- [1 - (4-perfluorooctylsulfonyl) piperazine] monoamide

19.55 g (15.30 mmol) of the title compound from Example 43c) are dissolved in a mixture consisting of 250 ml of 2-propanol and 25 ml of water, and 1.5 g of palladium catalyst (10% Pd on activated carbon) are added. It is hydrogenated for 12 hours at room temperature and a hydrogen pressure of one The atmosphere. The catalyst is filtered off and the filtrate is removed in vacuo

Evaporated to dryness. The residue is dissolved in 200 ml of methanol and that

Reaction product by adding a total of 800 ml of diethyl ether

Brought precipitation. After the solid thus obtained has been suctioned off, it is dried in vacuo at 40.degree.

Yield: 17.49 g (97.5% of theory) of an amorphous solid.

Elemental analysis: calc .: C 32.73 H 3.08 N 4.58 S 3.49 F 35.20 get: C 32.68 H 3.15 N 4.55 S 3.50 F 35.17

e) 3-N- (1-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 compound from Example 43d) and 0.67 g of anhydrous lithium chloride (15.84 mmol) are dissolved at 100 ° C. in 100 ml of absolute dimethyl sulfoxide with stirring and at this temperature with a total of 1. 82 g (15.84 mmol) of N-hydroxysuccinimide and a solution of 9.08 g (15.84 mmol) of the gadolinium complex of 10- (2-hydroxy-3-aminopropyl) -4,7,10-tris ( carboxymethyl) -1,4,7,10-tetraazacyclododecanin [for illustration, see: WO 97/02051], in 50 ml of dimethyl sulfoxide. After cooling to room temperature, 3.27 g (15.84 mmol) of N, N ^* -dicyclohexylcarbodiimide is added and the mixture is stirred at room temperature for 12 hours. The resulting suspension is then mixed with sufficient acetone until precipitation of the above-mentioned title compound, the precipitate is suctioned off, dried, taken up in water, insoluble dicyclohexylurea is filtered and the filtrate concentrated over an Amicon ^® YM-3 ultrafiltration membrane (cut off 3,000 Da), and at the same time cleaned of possible, still existing low molecular weight components. The retentate is then freeze-dried.

Yield: 18.71 g (80.2% of theory) as a colorless lyophilisate. H2θ content (Karl Fischer): 4.87%.

Elemental analysis (calculated on anhydrous substance): calc .: C 34.24 H 3.83 N 7.61 F 21.92 S 2.18 Gd 10.67 get: - C 34.26 H 3.79 N 7.58 F 21.87 S 2.18 Gd 10.68

Example 44

a) 1,7-bis (benzyloxycarbonyl) -4- {3-oxapentane-1,5-dicarboxylic acid-1-yl-5- [1 - (4-perfluorooctylsulfonyl) -piperazine] -amide} -10- [2,6-N, N ^* -bis (1 -O-α-D-carbonylmethyl-2,3,4,6-tetra-0-benzyl-mannopyranose)] - L-lysyl-1, 4.7, 10- tetraazacyclododecane

In a solution of 27.0 g (24.4 mmol) of the sec. Amine prepared in Example 35a), in a mixture of 150 ml of tetrahydrofuran and 15 ml

Chloroform, 33.04 g (25.0 mmol) of the title compound from Example 18c), dissolved in 250 ml of tetrahydrofuran, are added at 0 ° C. and under a nitrogen atmosphere. A total of 18.0 g (36.6 mmol ) Add EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] in portions and stir overnight at room temperature. The mixture is then concentrated to dryness in vacuo and the remaining oil is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 25: 1). 45.87 g (78.0% of theory, based on the sec-amine used) of the title compound are obtained in the form of a colorless oil. Elemental analysis: calc .: C 59.30 H 5.39 F 13.40 N 4.65 S 1.33 get: C 59.32 H 5.37 F 13.37 N 4.70 S 1.34

b) 1 - {3-oxapentane-1,5-dicarboxylic acid-1-yl-5- [1 - (4-perfluorooctylsulfonyl) - piperazine] -amide} -7- [2,6-N, N ^' - bis (1-0-α-D-carbonylmethyl-mannopyranose)] -

L-lysyl-1, 4,7,10-tetraazacyclododecane 24.1 g (10.0 mmol) of the title compound prepared in Example 44a) are dissolved in 250 ml of ethanol, and 1.4 g of Pearlman catalyst (Pd 20%, C) are added. The mixture is hydrogenated until quantitative absorption of hydrogen, then suctioned off from the catalyst, washed well with ethanol and evaporated to dryness in vacuo. The product is obtained as a yellowish and extremely viscous oil. Yield: 12.80 g (90.1% of theory). Elemental analysis: calc .: C 39.72 H 4.89 F 22.73 N 7.88 S 2.26 get: C 39.72 H 4.87 F 22.77 N 7.90 S 2.24

c) 1 - {3-oxapentane-1,5-dicarboxylic acid-1-yl-5- [1 - (4-perfluorooctylsulfonyl) -piperazine] -amide} -7- [2,6-N, N ^, - bis (1-0-α-D-carbonylmethyl-mannopyranose)] - L-lysyl-4, 10-bis [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 based on the amine component used from Example 44b)] of the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1 described in patent application DE 19728 954 C1 under Example 31h) , 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and anhydrous lithium chloride (0.37 g, 8.8 mmol) are dissolved at 40 ° C. in 60 ml of absolute dimethyl sulfoxide with stirring and at this temperature with a total of 1 , 01 g (8.8 mmol) of N-hydroxysuccinimide and 5.68 g (4.0 mmol) of the title compound from Example 44b), dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide is added and the mixture is stirred at room temperature for 12 hours. Sufficient acetone is then added to the suspension obtained until the above-mentioned title compound has completely precipitated, the precipitate is filtered off with suction, dried, taken up in water, filtered off from insoluble dicyclohexylurea and the filtrate is desalted via an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and cleaned of low molecular weight components. The retentate is then freeze-dried.

Yield: 8.52 g (80.6% of theory; based on the one used

Diamine component) as a colorless lyophilisate.

H 0 content (Karl Fischer): 6.09%.

Elemental analysis (calculated on anhydrous substance): calc .: C 38.61 H 4.76 N 9.53 F 12.21 Gd 11.89 S 1.12 get: C 38.57 H 4.82 N 9.52 F 12, 21 Gd 11.93 S 1.15

Example 45

a) 1, 7-bis (benzyloxycarbonyl) -4- {3-oxapentane-1,5-dicarboxylic acid-1-yl-5- [1 - (4-perfluorooctylsulfonyl) -piperazine] -amide} -10- { 2,6-N, N ^' -bis (1-O-α-D- (5-carbonyl) pentyl-2,3,4,6-tetra-0-benzyl-mannopyranose)} - L-lysyl-1 , 4,7, 10-tetraazacyclododecane

In a solution of 27.0 g (24.4 mmol) of the sec. Amine prepared in Example 35a), in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, 35.80 g (25 , 0 mmol) of the title compound from Example 37e), dissolved in 250 ml of tetrahydrofuran. Then a total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2- dihydroquinoline] in portions and allowed to stir overnight at room temperature. The mixture is then concentrated to dryness in vacuo and the remaining oil is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 20: 1). 49.48 g (80.4% of theory, based on the sec-amine used) of the title compound are obtained in the form of a colorless oil. Elemental analysis: calc .: C 60.47 H 5.79 F 12.80 N 4.44 S 1.27 get: C 60.52 H 5.77 F 12.77 N 4.50 S 1.30 b) 1 - {3-oxapentane-1,5-dicarboxylic acid-1-yl-5- [1 - (4-perfluorooctylsulfonyl) - piperazine] -amide} -7- [2,6-N, N ^N - bis (1-0-α-D- (5-carbonyl) -pentyI-mannopyranose)] - L-jysyl-1, 4,7, 10-tetraazacyclododecane

25.2 g (10.0 mmol) of the title compound prepared under Example 45a) are dissolved in 250 ml of ethanol, and 1.8 g of Pearlman catalyst (Pd 20%, C) are added. The mixture is hydrogenated until quantitative absorption of hydrogen and then suctioned from the catalyst, washes well with ethanol and evaporates to dryness in vacuo. The product is obtained as a yellowish and extremely viscous oil.

Yield: 14.11 g (92.5% of theory)

Elemental analysis: calc .: C 49.60 H 7.20 F21.17 N 7.34 S 2.10 get: C 49.62 H 7.17 F 21.20 N 7.30 S 2.14

c) 1 - {3-oxapentane-1,5-dicarboxylic acid-1-yl-5- [1 - (4-perfluorooctylsulfonyl) - piperazine] -amide} -7- [2,6-N, N ^' - bis (1-0-α-D- (5-carbonyl) -pentyl-mannopyraηose)] - L-lysyl-4,10-bis [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 based on the amine component used from Example 45b)] of the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1 described in patent application DE 19728 954 C1 under Example 31h) , 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and anhydrous lithium chloride (0.37 g, 8.8 mmol) are dissolved at 40 ° C. in 60 ml of absolute dimethyl sulfoxide with stirring and at this temperature with a total of 1 , 01 g (8.8 mmol) of N-hydroxysuccinimide and 6.10 g (4.0 mmol) of the title compound from Example 45b), dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide is added and the mixture is stirred at room temperature for 12 hours. Sufficient acetone is then added to the suspension obtained until the above-mentioned title compound has completely precipitated, the precipitate is filtered off with suction, dried and in water absorbed, filtered off from insoluble dicyclohexylurea and the filtrate desalted over an AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and cleaned of low molecular weight components. The retentate is then freeze-dried. Yield: 9.26 g (84.0% of theory; based on the diamine component used) as a colorless lyophilisate H2O content (Karl-Fischer): 5.89%. Elemental analysis (calculated on anhydrous substance): calc .: C 40.52 H 5.16 N 9.15 F 11.72 Gd 11.41 S 1.16 ge: C 40.57 H 5.20 N 9.12 F 11, 69 Gd 11.43 S 1.18

Example 46

a) 6-N-t-Butyloxycarbonyl-2-N-benzyloxycarbonyl-L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide

19.02 g (50.0 mmol) of α-N- (benzyloxycarbonyl) -ε-N ^' - (tert.butyloxycarbonyl) -L-lysine (commercially available from Bachern) are dissolved in 150 ml of absolute tetrahydrofuran. 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 0 ° C. and the mixture is stirred for 10 minutes at this temperature. 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 then added dropwise at 0.degree. After stirring overnight, the tetrahydrofuran is removed in vacuo and the remaining oil becomes

Chromatographed silica gel (mobile solvent: n-hexane / isopropanol 15: 1). 49.48 g (80.4% of theory, based on the sec-amine used) of the title compound are obtained in the form of a colorless oil. Elemental analysis (calculated on anhydrous substance): calc .: C 40.01 H 3.79 N 6.02 F 34.70 S 3.45 get: C 40.07 H 3.82 N 6.02 F 34.67 S 3.48

b) 6-Nt-butyloxycarbonyl-L-lysine [1- (4-perfluorooctylsulfonyl) -ρiperazin] -amide 30.0 g (32.2 mmol) of the title compound from Example 46a) are dissolved in 300 ml of isopropanol and 1.5 g of Pearlman catalyst (20% palladium hydroxide on carbon) are added. The mixture is hydrogenated for 10 hours at room temperature, after checking the The course of the reaction by means of thin layer chromatography, the hydrogenolytic cleavage of the benzyloxycarbonyl protective group has already taken place quantitatively after the above-mentioned reaction time. The catalyst is filtered off and the filtrate is concentrated to dryness in vacuo. The remaining residue is chromatographed on silica gel. (Mobile solvent: n-hexane / isopropanol 25: 1). 25.13 g (98.0% of theory) of the title compound are obtained in the form of a colorless oil. Elemental analysis: calc .: C 34.68 H 3.67 F 40.55 N 7.03 S 4.03 get: C 34.72 H 3.70 F 40.60 N 7.01 S 3.98

c) 6-Nt-butyloxycarbonyl-2-N- [1-S-α-D- (2-carbonyl) ethyl-2,3,4,6-tetra-0-acetyl-mannopyranose] -L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

In 300 ml of dry tetrahydrofuran, 15.53 g (35.60 mmol) of the 3- (2,3,4,6-tetra-0-acetyl-1-thio-α-D-mannopyranosyl) propionic acid (representation according to: J Haensler et al., Bioconjugate Chem. 4.85, (1993); Chipowsky, S., and Lee. YC (1973), Synthesis of 1-thio-aldosides; Carbohydrate Research 31,339-346, and 3.60 g (35 , 60 mmol) of triethylamine After cooling the reaction solution to -15 ° C. to -20 ° C., a solution of 4.92 g (35.60 mmol) of isobutyl chloroformate in 75 ml of dry tetrahydrofuran is slowly added dropwise at this temperature with stirring, the dropping rate should be selected so that an internal temperature of -10 ° C is not exceeded. After a reaction time of 15 minutes at -15 ° C, a solution of 28.35 g (35.60 mmol) of the title compound is then dripped out Example 42b) and 3.60 g (35.60 mmol) of triethylamine in 200 ml of dry tetrahydrofuran at 20 ° C. slowly. After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is brought to dryness in vacuo concentrated. The remaining residue is taken up in 250 ml of ethyl acetate and saturated twice with 100 ml each

Sodium bicarbonate solution and washed once with 200 ml of water.

After the organic phase has dried over sodium sulfate, the salt is filtered off with suction and the ethyl acetate is stripped off in vacuo. The remaining oily residue is on silica gel using

Purified ethyl acetate / n-hexane (1:25) as eluent.

Yield: 34.21 g (79.1% of theory) of the above-mentioned title compound as a colorless and highly viscous oil. Elemental analysis: calc .: C 39.54 H 4.23 N 4.61 F 26.58 S 5.28 get: C 39.49 H 4.21 N 4.59 F 26.52 S 5.31

d) 6-N-t-Butyloxycarbonyl-2-N- [1-S-α-D- (2-carbonyl) ethyl mannopyranose] -L-lysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide

29.93 g (24.64 mmol) of the title compound from Example 46c) are dissolved in 400 ml of absolute

Suspended methanol and mixed with a catalytic amount of sodium methoxide at 5 ° C. After a response time of 3h at

The thin-layer chromatographic control (eluent: chloroform / methanol = 9: 1) of the course of the reaction shows room temperature already quantitative conversion. For the purpose of working-up, the now clear reaction solution is prepared by mixing with Amberlite ^® IR 120 (H ⁺ form) - neutralized cation exchanger suctioned off and the thus obtained methanolic filtrate in vacuo to dryness. The amorphous residue obtained is purified by chromatography on silica gel using 2-propanol / ethyl acetate / n-hexane (1: 1:15) as the eluent. Yield: 23.42 g (90.8% of theory) of a colorless and viscous oil. Elemental analysis: calc .: C 36.72 H 4.14 N 5.35 F 30.85 S 6.13 get: C 36.69 H 4.11 N 5.35 F 30.82 S 6.11 e) 2-N- [1 -S-α-D- (2-carbonyl) ethyl mannopyranose] -L-lysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide

20.93 g (20.0 mmol) of the title compound from Example 46d) are in one

Mixture of 50 ml trifluoroacetic acid and 100 ml dichloromethane at 0 ° C with vigorous stirring and stirred for 10 minutes at this temperature. It is then evaporated to dryness in vacuo and the residue is taken up in 150 ml of water. The pH value of this aqueous product solution is adjusted to 9.5 by the dropwise addition of 2 molar aqueous sodium hydroxide solution. The aqueous product solution is desalted via an AMICON ^® YM-3 ultrafiltration membrane (cut off: 3000 Da) and at the same time from possible still present , low molecular weight components cleaned. The retentate is then freeze-dried. Yield: 17.79 g (94.2% of theory) of the free amine as a colorless lyophilisate. H ₂ 0 content (Karl Fischer): 3.09%. Elemental analysis (calculated on anhydrous substance): calc .: C 34.26 H 3.73 N 5.92 F 34.12 S 6.77 get: C 34.26 H 3.79 N 5.88 F 34.07 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] -L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, gadolinium complex

5.54 g [(8.8 mmol, 2.2 molar equivalents based on the amine component from Example 46e)] of the Gd complex of 10- (4-carboxy-1. Described in Patent Application DE 19728 954 C1 under Example 31h) - Methyl-2-oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 0.37 g of anhydrous lithium chloride (8.8 mmol) are in 40 ml at 40 ° C absolute dimethyl sulfoxide dissolved with stirring and at this temperature with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.78 g (4.0 mmol) of the title compound from Example 46e), dissolved in 40 ml of absolute dimethyl sulfoxide, added. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide is added and the mixture is stirred at room temperature for 12 hours. The resulting suspension is then mixed with sufficient acetone until precipitation of the above-mentioned title compound, the precipitate is suctioned off, taken up in water, insoluble dicyclohexylurea is filtered and the filtrate concentrated over an Amicon ^® YM-3 ultrafiltration membrane (cut off 3,000 Da), and low molecular components cleaned. The retentate is then freeze-dried. Yield: 5.17 g (83.0% of theory) as a colorless lyophilisate. H ₂ 0 content (Karl Fischer): 4.43%. Elemental analysis (calculated on anhydrous substance): calc.: C 35.45 H 4.07 N 8.09 F20.72 Gd 10.09 S 4.11 found: C 35.50 H 4.01 N 8.12 F 20, 6 Gd 10.13 S 4.14

Example 47

a) ^' 6-N-Benzyloxycarbonyl-2-N- (1-0-ß-D-carbonyimethyl-2,3,4,6-tetra-0-benzylglucopyranose) - L-Iysin- [1 - (4-perf luoroctylsulfonyl) -piperazine] -amide

8.02 g (13.4 mmol) of the title compound described in patent application DE 19728954 C1 under example 46a) [1-carboxymethyloxy-2,3,4,6-tetra-O-benzyl-β-D-glucopyranoside] and 3 , 24 g (28.14 mmol) of N-hydroxysuccinimide are dissolved in 100 ml of dimethylformamide and a total of 5.80 g (28.14 mmol) of N, N'-dicyclohexylcarbodiimide are added in portions at 0 ° C. The mixture is stirred at this temperature for 3 hours. A solution of 11.13 g (13.4 mmol) of the title compound from Example 21c), cooled to 0 ° C. and dissolved in 50 ml of dimethylformamide, is added dropwise to the active ester solution prepared in this way and the mixture is stirred at 0 ° C. for 12 hours and at 12 Hours at room temperature. For working up, the precipitated dicyclohexylurea is filtered off and the solvent is then drawn off to dryness. The residue thus obtained is then on silica gel chromatographed (eluent: dichloromethane / ethanol, 20: 1; the chromatography was carried out using a solvent gradient with a continuous increase in the ethanol content).

Yield: 12.67 g (67.0% of theory) of the title compound in the form of a colorless and highly viscous oil. Elemental analysis: calc .: C 52.77 H 4.50 N 3.97 F 22.89 S 2.27 get.C 52.75 H 4.61 N 3.98 F 22.94 S 2.26

b) 2-N- (1-0-ß-D-carbonylmethyl-glucopyranose) - L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide

11.52 g (8.17 mmol) of those under 47a) are prepared in 100 ml of ethanol

Dissolved compound, mixed with 0.5 g Pearlman catalyst (Pd 20%, C) and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen uptake can be observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (three times with approx.

40ml) and evaporates to dryness in a vacuum. The title compound is obtained as a highly viscous and colorless oil. Yield: 7.36 g (98.4% of theory).

Elemental analysis: calc.: C 34.07 H 3.63 N 6.11 F 35.24 S 3.50 found. : C 34.11 H 3.59 N 6.08 F 35.23 S 3.52

c) 2-N- (1-0-ß-D-carbonylmethyl-glucopyranose) -6-N- [1,4,7-tris (carboxylatomethyl) -10- (aza-4-oxo-5-methyl-5 -yl-pentanoyl) -1, 4,7,10-tetraazacyclododecane] - L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

9.98 g [(15.84 mmol; 2.2 mol equivalents based on the one used

Amine component from Example 47b)] of the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10 described in patent application DE 19728 954 C1 under Example 31h) -tetraazacyclododecan-1, 4,7-triacetic acid and 0.67 g (15.84 mmol) of anhydrous lithium chloride are dissolved at 40 ° C in 80 ml of absolute dimethyl sulfoxide with stirring and at this temperature with a total of 1.82 g (15.84 mmol) of N-hydroxysuccinimide and 7.25 g ( 7.19 mmol) of the title compound from Example 47b), dissolved in 30 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 3.27 g (15.84 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is stirred for 12 hours Room temperature stirred. The resulting suspension is then mixed with sufficient acetone until precipitation of the above-mentioned title compound, the precipitate is suctioned off, taken up in water, insoluble dicyclohexylurea is filtered and the filtrate concentrated over an Amicon ^® YM-3 ultrafiltration membrane (cut-off: 3,000 Da) desalted and low molecular components cleaned. The retentate is then freeze-dried. Yield: 9.11 g (83.0% of theory) as a colorless lyophilizate H ₂ O content (according to Karl Fischer): 4.02%.

Elemental analysis (calculated on anhydrous substance): calc. C 35.37 H 4.02 N 8.25 F 21.13 S 2.10 Gd 10.29 get: C 35.42 H 4.07 N 8.18 F 21.09 S 2 , 06 Gd 10.34

Example 48

a) 2-N-Trifluoroacetyl-L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide

10.0 g (11.46 mmol) of the compound prepared under 21b) are dissolved in 100 ml of ethanol, 1.0 g of pearimane catalyst (Pd 20% / C) is added and the mixture is hydrogenated until it is quantitatively absorbed in hydrogen. You suck from

Catalyst, washed with ethanol and evaporated to dryness in vacuo.

The title compound is obtained as a viscous and colorless oil. Yield: 8.85 g

(97.5% of theory). Elemental analysis: calc .: C 30.31 H 2.54 N 7.07 F 47.95 S 4.05 get: C 30.36 H 2.50 N 7.11 F 47.99 S 4.00 b) 2-N-trifluoroacetyl-6-N- [1-0-α-D- (5-carbonyl) -pentyl-2,3,4,6-tetra-0-benzyl-mannopyranose] -L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

A solution of 27.51 g is added dropwise to a solution of 29.0 g (36.6 mmol) of the title compound from Example 48a) and 4.05 g (40.26 mmol) of triethylamine in 100 ml of dimethylformamide, cooled to 0 ° C (36.6 mmol) of the title compound from Example 37c) in 150 ml of dimethylformamide. After the addition has ended, the mixture is stirred for a further hour at 0 ° C. and then overnight at room temperature. It is evaporated to dryness in vacuo and the residue is taken up in 300 ml of ethyl acetate. Insoluble constituents are filtered off and the filtrate is washed twice with 100 ml of 5% aqueous sodium carbonate solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 25: 1). 42.05 g (80.4% of theory) of the title compound are obtained in the form of a colorless oil. Elemental analysis: calc .: C 50.42 H 4.51 N 7.96 F 26.59 S 2.24 get: C 50.38 H 4.50 N 7.91 F 26.62 S 2.20

c) 6-N- [1-0-α-D- (5-carbonyl) -pentyl-2,3,4,6-tetra-0-benzyl-mannopyranose] -L- lysine [1- (4- perfluorooctylsulfonyl) -piperazine] -amide

20.0 g (14.0 mmol) of the compound prepared in Example 48b) are dissolved in 150 ml of ethanol. The solution of 2.8 g (70.0 mmol) of sodium hydroxide in 25 ml of distilled water is then added and the mixture is stirred at 50 ° C. for 0.5 hour. According to the thin-layer chromatogram, the deprotection has already taken place quantitatively at this point. The mixture is concentrated to dryness in vacuo and traces of water are removed by repeated codistillation with ethanol. The residue is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 20: 1). 16.66 g (89.3% of theory) of the title compound are obtained in the form of a colorless oil. Elemental analysis: calc .: C 52.25 H 4.91 N 4.20 F 24.22 S 2.41 get: C 52.30 H 4.90 N 4.18 F 24.22 S 2.38

d) 6-N- [1 -0-α-D- (5-carbonyl) pentyl mannopyranose] -L-lysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide

15.0 g (11.25 mmol) of the compound prepared under 48c) are dissolved in 150 ml of a 10: 1 mixture of ethanol and water and 1.0 g of Pearlman catalyst (Pd 20% / C) is added. The mixture is then hydrogenated at room temperature and under an atmosphere of hydrogen pressure until quantitative absorption of hydrogen. It is suctioned off from the catalyst, washed with ethanol / water (10: 1) and concentrated to dryness in vacuo. The title compound is obtained as a viscous and colorless oil. Yield: 10.77 g (98.4% of theory). Elemental analysis: calc .: C 37.04 H 4.25 N 5.76 F 33.20 S 3.30 get: C 37.06 H 4.20 N 5.81 F 33.19 S 3.30

e) 6-N- [1-0-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] -L-lysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

5.54 g [(8.8 mmol; 2.2 molar equivalents based on the amine component from Example 48d)] of the Gd complex of 10- (4-carboxy-1. Described in Patent Application DE 19728 954 C1 under Example 31h) - Methyl-2-oxo-3-azabutyl) -1, 4,7, 10-tetraazacyclododecan-1, 4,7-triacetic acid and 0.37 g (8.8 mmol) anhydrous lithium chloride are in 40 ml at 40 ° C in 60 ml absolute dimethyl sulfoxide dissolved with stirring and a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.89 g (4.0 mmol) of the title compound from Example 48d), dissolved in 60 ml of absolute dimethyl sulfoxide, were added at this temperature. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide is added and the mixture is stirred at room temperature for 12 hours. The suspension obtained is then mixed with sufficient acetone until the above-mentioned is completely precipitated Title compound added, the precipitate is suctioned off, taken up in water, insoluble dicyclohexylurea is filtered and the filtrate concentrated over an Amicon ^® ultrafiltration membrane YM-3 (cut off: 3,000 Da) desalted and purified of low-molecular components. The retentate is then freeze-dried.

Yield: 4.81 g (75.9% of theory) as a colorless lyophilisate. H ₂ 0 content (Karl Fischer): 8.98%. Elemental analysis (calculated on anhydrous substance): calc .: C 37.15 H 4.39 N 7.96 F 20.38 Gd 9.92 S 2.02 get: C 37.27 H 4.40 N 8.02 F 20.31 Gd 10.00 a.m. 1.98

Example 49

a) 1, 7-bis (benzyloxycarbonyl) -4- (1 -0-ß-D-carbonylmethyl-2,3,4,6-tetra-0-benzyl-galactopyranose) -10- {3-oxapentane 1, 5-dicarboxylic acid-1-yl-5- [1 - (4-perfluorooctylsulfonyl) piperazine] amide} -1, 4,7, 10-tetraazacyclododecane

In a solution of 27.0 g (24.4 mmol) of the sec. Amine prepared in Example 35a), in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, 35.80 g (25 , 0 mmol) of the title compound from Example 37e), dissolved in 250 ml of tetrahydrofuran. Then a total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1, 2 -dihydroquinoline] in portions and allowed to stir overnight at room temperature. It is then concentrated to dryness in vacuo and the remaining oil is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 20: 1). 32.11 g (78.0% of theory, based on the sec-amine used) of the title compound are obtained in the form of a colorless oil. Elemental analysis: calc .: C 54.09 H 4.72 F 19.14 N 4.98 S 1.90 get: C 54.12 H 4.77 F 19.17 N 5.03 S 1.90 b) 1 - (1 -0-β-D-carbonylmethyl-galactopyranose) -7- {3-oxapentane-1,5-dicarboxylic acid-1-yl-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) are dissolved in 250 ml of ethanol, and 3.0 g of Pearlman catalyst (Pd 20%, / C) are added. The mixture is hydrogenated until quantitative absorption of hydrogen, then suctioned off from the catalyst, washed well with ethanol and evaporated to dryness in vacuo. The product is obtained as a yellowish and extremely viscous oil.

Yield: 17.89 g (95.1% of theory).

Elemental analysis: calc .: C 36.30 H 4.09 F 30.50 N 7.94 S 3.03 get: C 36.26 H 4.12 F 30.46 N 7.90 S 3.04

c) 1 - (1 -0-ß-D-carbonylmethyl-galactopyranose) -7- {3-oxapentane-1,5-dicarboxylic acid-1-yl-5- [1 - (4-perfluorooctylsulfonyl) piperazine] -amide} -4,10- bis [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-gadolinium complex

5.54 g [8.8 mmol; 4.4 molar equivalents based on the amine component used from Example 49b)] of the Gd complex described in patent application DE 19728 954 C1 under Example 31h) of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4.7, 10-tetraazacyclododecan-1, 4,7-triacetic acid and 0.37 g (8.8 mmol) of anhydrous lithium chloride are dissolved at 40 ° C. in 60 ml of absolute dimethyl sulfoxide with stirring and at this temperature with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 2.11 g (2.0 mmol) of the title compound from Example 49b), dissolved in 25 ml of absolute dimethyl sulfoxide, were added. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 12 hours. Sufficient acetone is then added to the suspension obtained until the above-mentioned title compound has completely precipitated, the precipitate is filtered off with suction, dried and in water absorbed, filtered off from insoluble dicyclohexylurea and the filtrate desalted over an AMICON ^® YM-3 ultrafiltration membrane (cut off: 3000 Da) and cleaned of low molecular weight components. The retentate is then freeze-dried. Yield: 3.29 g (72.2% of theory; based on the amine component used) as a colorless lyophilisate. H ₂ 0 content (Karl Fischer): 5.99%. Elemental analysis (calculated on anhydrous substance): calc .: C 36.84 H 4.37 N 9.82 F 14.15 Gd 19.63 S 1.40 get: C 36.87 H 4.40 N 9.82 F 14.09 Gd 19.59 S 1.38

Example 50

a) 3- (1-0-α-D-2,3,4,6-tetra-0-benzyl-mannopyranose) -2-N-benzyloxycarbonyl-L-serine methyl ester

21.42 g (39.61 mmol) of 2,3,4,6-tetra-O-benzyl-α-D-mannopyranose are prepared in 500 ml of dry acetonitrile (preparation according to: F. Kong et al., J. Carbohydr. Chem.; 16; 6; 1997; 877-890). After the reaction solution has been cooled to 5 ° C., a solution of 13.23 g (59.52 mmol) of trifluoromethanesulfonic acid trimethylsilyl ester in 30 ml of acetonitrile is slowly added dropwise at this temperature with stirring, followed by a solution of 20.06 g (79. 21 mmol) of N-benzyloxycarbonyl-L-serine methyl ester (commercially available from Bachern) in 50 ml of acetonitrile, the dropping rate being chosen so that an internal temperature of 10 ° C is not exceeded. After a reaction time of 15 hours at room temperature, the reaction solution is evaporated to dryness in a vacuum. The remaining residue is taken up in 250 ml of ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution and once with 200 ml of water. After the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the ethyl acetate is stripped off in vacuo. The remaining oily residue is purified on silica gel using ethyl acetate / n-hexane (1: 5) as the eluent. Yield: 23.60 g (76.8% of theory) of the above-mentioned title compound as a colorless oil. Elemental analysis: calc .: C 71.21 H 6.37 N 1.81 get: C 71.19 H 6.41 N 1.79

b) 3- (1-0-α-D-2,3,4,6-tetra-0-benzyl-mannopyranose) -2-N-benzyloxycarbonyl-L-serine

10.0 g (12.90 mmol) of the compound prepared under Example 50a) are dissolved in a mixture of 20 ml of methanol, 20 ml of water and 50 ml of tetrahydrofuran. Then 0.47 g (19.35 mmol) of lithium hydroxide, dissolved in 25 ml of distilled water, is added at room temperature and the mixture is then stirred at 60 ° C. for 6 hours. After checking the course of the reaction by means of thin layer chromatography (eluent: methylene chloride / methanol 10: 1), the saponification of the methyl ester from Example 30a) has already taken place quantitatively after the above-mentioned reaction time. For the purpose of working up, the product solution is evaporated to dryness in vacuo and the remaining residue is taken up in 250 ml of ethyl acetate under heat (approx. 60 ° C.). The ethyl acetate phase thus obtained is washed twice with 50 ml of 15% aqueous hydrochloric acid and once with 100 ml of distilled water. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile phase: n-hexane / ethyl acetate 5: 1). 8.40 g (85.7% of theory) of the title compound are obtained in the form of a colorless oil. Elemental analysis: calc .: C 70.94 H 6.22 N 1.84 get: C 70.97 H 6.30 N 1.78 c) 3- (1-0-α-D-2,3,4,6-tetra-0-benzyl-mannopyranose-2-N-benzyloxycarbonyl-L-serine [1- (4-perfluorooctylsulfonyl) piperazine] - amide

To 13.86 g (24.40 mmol) of 1-perfluorooctylsulfonylpiperazine (produced according to DE 19603033), dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, 20.57 g (27.0 mmol) of the carboxylic acid shown in Example 50b), dissolved in 50 ml of tetrahydrofuran, are added dropwise. A total of 18.0 g (36.60 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is then added in portions at 0 ° C. and the mixture is stirred overnight at room temperature. For the purpose of working up, the reaction solution is concentrated in vacuo and the remaining, extremely viscous oil is chromatographed on silica gel using an n-hexane / isopropanol (15: 1) mixture as the eluent system. 17.0 g (79.6% of theory, based on the primary amine used) of the title compound are obtained in the form of a colorless and viscous oil.

Elemental analysis: calc .: C 51.53 H 4.23 N 3.15 F 25.65 S 2.41 get: C 51.48 H 4.27 N 3.10 F 25.71 S 2.35

d) 3- (1 -0-α-D-Mannopyranose) -L-serine [1 - (4-perfluorooctylsulfonyl) piperazine] amide

15.0 g (11.41 mmol) of the compound shown in Example 50c) are dissolved in 200 ml of ethanol, and 1.5 g of Pearlman catalyst (Pd 20%, C) are added. Then the reaction solution is as long as

Room temperature is hydrogenated under a hydrogen atmosphere (1 atm) until no more hydrogen absorption can be observed (approx. 8 hours). , For the purpose of working up, the catalyst is suctioned off, washed thoroughly with ethanol (twice with about 100 ml each) and the product-containing ethanolic filtrate is evaporated to dryness in vacuo. The title compound is obtained as a highly viscous and colorless oil. Yield: 8.79 g (94.0% of theory). Elemental analysis: calc .: C 30.78 H 3.20 N 5.13 F 39.41 S 3.91 get: C 30.87 H 3.14 N 5.19 F 39.50 S 3.88

e) 3- (1 -0-α-D-Mannopyranose) -2-N- [1,4-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl -pentanoyl) -1, 4.7, 10-tetraazacyclododecane] -L-serine [1 - (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

A stirred suspension of 5.7 g [9.06 mmol; corresponding to 1.5 mol equivalents with respect to the title compound used (primary amine) from Example 50d)] of the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3) described in patent application DE 19728954 C1 under Example 31h) -azabutyl) -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid in 75 ml absolute dimethyl sulfoxide is mixed at 70 ° C with 0.68 g (15.9 mmol) lithium chloride. After stirring for 30 minutes at 70 ° C., the now clear reaction solution is portioned with a total of 1.83 g (15.9 mmol) of N-

Hydroxysuccinimide added and the reaction mixture kept at 70 ° C for 1 hour. After the reaction solution has cooled to 10 ° C., 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide are added and the reaction solution is stirred for a further hour at 0 ° C., followed by 12 hours at 22 ° C. The solution of the N-hydroxysuccinimide ester of the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecane-1, 4,7-triacetic acid thus obtained a solution of 4.94 g (6.03 mmol) of the title compound from Example 30d), in 15 ml of absolute dimethyl sulfoxide, is then added dropwise at 22 ° C. and the mixture is stirred at room temperature for a further 12 hours. The reaction solution is worked up at 22 ° C.

Solvent mixture consisting of 250 ml of acetone and 250 ml of 2-propanol, slowly added dropwise, the title compound having settled completely as a slightly yellowish oil after 12 hours at 10 ° C. It is carefully decanted from the supernatant mixture and the oily product is taken up in 200 ml of distilled water, which completely dissolves, so that a slightly yellowish-colored aqueous solution of the above-mentioned title compound is obtained. Subsequently, the aqueous product solution is first filtered through a membrane filter and then, for the purpose of Desalting and the separation of low molecular weight components, ultrafiltered three times over a YM3 ultrafiltration membrane (AMICON ®; cut off: 3000 Da). The retentate thus obtained is then freeze-dried.

Yield: 8.63 g (80.2% of theory, based on the title compound used from Example 30d) as a colorless lyophilisate with a water content of 7.65

%.

Elemental analysis (calculated on anhydrous substance): calc .: 033.57 H 3.80 N 7.83 F 22.57 Gd 10.99 S 2.24 get: 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-ß-D-galactopyranosyl (1 → 4) -gluconosyl] -L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide

A solution of 13.3 g (37.2 mmol) of 0-β-D-galactopyranosyl- is added to a stirred solution of 4.98 g (6.0 mmol) of the title compound from Example 21c) in 40 ml of absolute dimethyl sulfoxide at room temperature. (1 → 4) -D-glucono-1,5-lactone [lactobionolactone; Representation 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] added dropwise in 40 ml of absolute dimethyl sulfoxide. The reaction solution thus obtained is then stirred at 40 ° C. for 14 hours. For working up, 500 ml of absolute 2-propanol are added at room temperature, and the resulting colorless precipitate is filtered off with a G4 frit and washed well with a total of 250 ml of absolute 2-propanol. The solid obtained in this way is then dissolved in 300 ml of distilled water and passed through a YM3

Ultrafiltration membrane (AMICON ®; cut off: 3000 Da) ultrafiltered a total of three times. The triple ultrafiltration process removes both the excess lactobionolactone and any low-molecular components that may still be present from the desired product. The in the residue remaining in the ultrafiltration membrane is then completely dissolved in 300 ml of distilled water and freeze-dried. Yield: 6.51 g (92.7% of theory) as a colorless lyophilisate water content: 10.03% elemental analysis (calculated on anhydrous substance): calculated: C 38.98 H 4.05 N 4.79 F 27.58 S 2.74 get: C 39.04 H 4.09 N 4.82 F 27.61 S 2.71

b) 2-N- [0-β-D-galactopyranosyl (1 → 4) -gluconosyl] -L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide

5.0 g (4.27 mmol) of the compound prepared under 51a) are dissolved in 100 ml of ethanol, 0.5 g of Pearlman catalyst (Pd 20%, C) are added and the mixture is hydrogenated at 1 atmosphere of hydrogen pressure until quantitative absorption of hydrogen , It is suctioned off from the catalyst, washed with ethanol and concentrated to dryness in vacuo. The title compound is obtained as a colorless and viscous oil. Yield: 4.36 g (98.5% of theory). Elemental analysis: calc .: 034.76 H 3.99 N 5.40 F 31.51 S 3.09 get: C 34.78 H 4.04 N 5.34 F 31.51 S 3.15

c) 2-N- [0-ß-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] -L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

5.54 g [(8.8 mmol; 2.2 molar equivalents based on the amine component from Example 51b)] of the Gd complex of 10- (4-carboxy-1. Described in patent application DE 19728 954 C1 under Example 31h) - Methyl-2-oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 0.37 g (8.8 mmol) anhydrous lithium chloride are in 40 ml at 40 ° C in 60 ml absolute dimethyl sulfoxide dissolved with stirring and at this temperature with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.85 g (4.0 mmol) of Title compound from Example 31 Ab), dissolved in 60 ml of absolute dimethyl sulfoxide, added. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide is added and the mixture is stirred at room temperature for 12 hours. Sufficient acetone / 2-propanol (1: 1) is then added to the suspension obtained until the above-mentioned title compound has completely precipitated and the precipitate is filtered off with suction. The precipitate thus obtained is then taken up in 300 ml of water and the insoluble dicyclohexylurea is filtered off. The filtrate is ultrafiltered three times over an AMICON ^® YM-3 ultrafiltration membrane (cut off: 3000Da). The ultrafiltration process carried out three times removes both the excess Gd complex and any low-molecular constituents that may still be present from the desired product. The residue remaining in the ultrafiltration membrane is then completely dissolved in 500 ml of distilled water and freeze-dried.

Yield: 4.64 g (70.4% of theory) as a colorless lyophilisate.

H ₂ 0 content (Karl Fischer): 10.08%.

Elemental analysis (calculated on anhydrous substance): calc .: C 35.70 H 4.22 N 7.65 F 19.59 Gd 9.54 S 1.95 get: C 35.77 H 4.17 N 7.71 F 19.61 Gd 9.60 S 1.99

Example 52

a) 2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-lysine

100 g (356.7 mmol) of 6-N-benzyloxycarbonyl-lysine are dissolved in a mixture of 1000 ml of ethyl trifluoroacetate / 500 ml of ethanol and stirred for 24 hours at room temperature. It is evaporated to dryness and the residue is crystallized from diisopropyl ether.

Yields 28.9 g (96% of theory) of a colorless crystalline powder.

Elemental analysis: calc. C 51.07 H 5.09 F 15.14 N 7.44 ge 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

To 125 g (332 mmol) of the title compound from Example 52a) and 188,7g (332 mmol) of 1-perfluorooctylsulfonyl - piperazine (produced according to DE 19603033) in 800 ml of tetrahydrofuran, are added at 0 ^Q C 164.2 g (0.664 mmol) of EEDQ (2-ethoxy-1, 2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 20: 1). Yield: 286 g (93% of theory) of a colorless solid.

Elemental analysis:

calcd. C 36.30 H 2.83 F 41.01 N 6.05 S 3.46 get 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

In a solution of 280 g (302.2 mmol) of the title compound from Example 52b) in 2000 ml of ethanol, it initiates for one hour ammonia gas at 0 ⁹ C. Then is stirred for 4 hours at 0 ^e C. It is evaporated to dryness and the residue is extracted from water. The solid is filtered off and dried in vacuo (50 ⁹ C). Yield: 243.5 g (97% of theory) of an amorphous solid. Elemental analysis:

calcd. C 37.60 H 3.28 F 38.89 N 6.75 S 3.86 found 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 compound from Example 52c) and 7.10 g (70 mmol) of triethylamine dissolved in 350 ml of dichloromethane is added dropwise at 0 ⁹ C a solution of 19.93 g (70 mmol) of 3 , 6,9,12,15 pentaoxahexadecanoic acid chloride [shown after Liebigs Ann. Chem. (1980), (6), 852-62] in 50 ml dichloromethane and stirred for 3 hours at 0 ⁹ C. 200 ml of 5% aqueous hydrochloric acid are added and the mixture is stirred for 5 minutes at room temperature. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile phase: dichloromethane / acetone = 15: 1 yield: 53.7 g (93% of theory) of a colorless, viscous oil.

Elemental analysis:

calcd. C 33.83 H 4.94 F 3.34 N 5.84 S 33.69 found. 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 compound from Example 52d) are dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. 5 Yield: 43.0 g (quantitative) of a colorless solid.

Elemental analysis:

calcd. C 27.68 H 5.01 F 39.17 N 6.79 S 3.89 found C 27.60 H 5.13 F 39.09 N 6.68 S 3.81

f) 6-N- [1,4-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10 - (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - 2-N- (3,6,9,12,15-15 pentaoxahexadecanoyl) lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

20 g (24.25 mmol) of the title compound 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

20 mmol) 1, 4,7-tris (carboxylatomethyl) - 10 - [(3-aza-4-oxo-5-methyl-5-yl)] - pentanoic acid] - 1,4,7,10-tetraazacyclododecane, Gd -Complex are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10 ⁹ C, 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is then stirred overnight at room temperature. The solution is poured into 3000 ml

25 acetone and stir for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 28.21 g (81% of theory) of a colorless solid. Water content: 11.0%

30

Elemental analysis (calculated on anhydrous substance) calcd. C 31.78 H 4.84 F 22.49 N 8.78 S 2.23 Gd 10.95 get 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 - bis (t butyloxycarbonylmethyl) -3,6,9- triazaundecane -1,11- dicarboxylic acid bis (t butyl ester) - 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 compound from Example 52e), 14.88 g (24.08 mmol) of 3.9- (t-butyloxycarbonylmethyl-3,6,9-triazaundecane-1, 11- Dicarboxylic acid bis (t-butyl ester) and 2.77 g (24.08 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide, are added at 0 ^S C to 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide the mixture is stirred for 3 hours at 0 ^° C., then overnight at room temperature, the precipitated urea is filtered off, the filtrate is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: = dichloromethane / ethanol = 20: 1). 61 g (91% of theory) of a viscous oil.

Elemental analysis:

calcd. C 40.80 H 6.71 F 22.39 N 6.80 S 2.22 found C 40.72 H 6.82 F 22.30 N 6.75 S 2.14 b) 6-N- [6-carbonylmethyl-3,9- bis (carboxylatomethyl) -3,6,9-triazaundecanedicarboxylic 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 compound from Example 53a) are dissolved in 300 ml of trifluoroacetic acid and stirred for 5 hours at room temperature. It is evaporated to dryness, the residue is taken up in 300 ml of water and the mixture is made up with 10% aqu. NaOH to pH 2.5. Then 3.77 g (10.4 mmol) of gadolinium oxide are added and the mixture is stirred for 3 hours at 60 ^° C. The mixture is allowed to come to room temperature and adjusted to a pH of 7.4 with sodium hydroxide solution. It is evaporated to dryness and the residue is purified on silica gel RP-18 (mobile solvent: gradient from water / acetonitrile). Yield: 19.18 g (67% of theory (a colorless, amorphous solid. Water content 9.8%

Elemental analysis: (calculated on anhydrous substance)

calc. C 28.80 H 4.25 F 23.47 N 7.12 S 2.33 Gd 11.48 Na 1.67 get 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-perfluorooctylsulfonylpiperazine] amide

20 g (24.08 mmol) of the title compound from Example 52c) are dissolved in 300 ml of ethanol and 4 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 16.77 g (quantitative) of a colorless solid.

Elemental analysis: calc. C 31.04 H 3.04 F 46.38 N 8.04 S 4.60 found C 30.97 H 3.15 F 46.31 N 7.98 S 4.51

b) 2,6-N, N '-Bis [1, 4,7-tris (carboxylatomethyl) -l, 4,7, 10-tetraazacyclododecane 10- (pentanoyl-3-aza-4-oxo-5-methyl -5-yl)] - lysin- [1 - (4-perf luoroctylsulfonylpiperazin] -amide, Gd complex (metal complex XVI)

10 g (14.36 mmol) of the title compound 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-5yl) 1,4,7,10-tetraazacyclododecane-Gd complex are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10 ⁹ C, 12.38 g (60 mmol) of N, N-dicyclohexlcarbodiimide are added and the mixture is then stirred 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 then purified by chromatography (silica gel RP-18, mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 19.02 g (69% of theory) of a colorless solid. Water content: 11.3%

Elemental analysis: (calculated on anhydrous substance)

calcd. C 35.03 H 4.04 F 16.82 N 10.21 S 1.67 Gd 16.38 found C 34.96 H 4.13 F 16.74 N 10.16 S 1.61 Gd 16.33

Example 55

a) Methyl 2- [4- (3-oxapropionate)] -phenylacetate To 200 g (1.204 mol) of methyl 4-hydroxyphenylacetate, 212 g (2 mol)

Sodium carbonate in 2000 ml acetone is added 233.8 g (1.4 mol) 2-

Ethyl bromoacetate and boiled under reflux for 5 hours. You filter the

Solid and evaporated to dryness in vacuo. The backlog is on

Chromatographed silica gel (eluent: -n-hexane / ethyl acetate logo CNRS logo INIST

15: 1).

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

Elemental analysis: calc. C 61.90 H 6.39 found C 61.75 H 6.51

b) Methyl 2- [4- (3-oxapropionate)] -phenyl-2-bromoacetate

201 g (1.13 mol) of N-bromosuccinimide and 100 mg of dibenzyl peroxide are added to 285 g (1.13 mol) of the title compound from Example 55a), dissolved in 2000 ml of carbon tetrachloride, and the mixture is refluxed for 8 hours. The mixture is cooled in an ice bath, the precipitated succinimide is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is purified on silica gel (mobile solvent: -n-hexane / acetone = 15: 1). Yield: 359.2 g (96% of theory) of a colorless, viscous oil.

Elemental analysis:

calcd. C 47.28 H 4.57 Br 24.16 found C 47.19 H 4.71 Br 24.05

c) Methyl 2- [4- (3-oxapropionate)] - phenyl-2- [1 - (1, 4,7, 10-tetraazacyclododecan 7-yl] -acetate

350 g (1,057 mol) of the title compound from Example 55b) are added to 603 g (3.5 mol) of 1,4,7,10-tetraazacyclododecane in 6000 ml of chloroform and the mixture is stirred Night at room temperature. It is extracted 3 times with 3000 ml of water, the organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is used in the next reaction (3d) without further purification. Yield: 448 g (quantitative) of a viscous oil.

Elemental analysis:

calcd C 59.70 H 8.11 N 13.26 found C 59.58 H 8.20 N 13.18

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

445 g (. 1, 053 mol) of the title compound from Example 55c) and 496 g (5.27 mol) of chloroacetic acid are dissolved in 4000 ml of water. It is with 30% aqu.Natronlauge to a pH of 10. The mixture is heated at 70 ^Q C and the pH-value by the addition of 30% sodium aqu.Natronlauge to pH 10. The mixture is stirred for 8 hours at 70 C. ⁹ The pH is then adjusted to 13 and the mixture is refluxed for 30 minutes. The solution is cooled in an ice bath and adjusted to pH 1 by adding concentrated hydrochloric acid. It is evaporated to dryness in vacuo. The residue is taken up in 4000 ml of methanol and stirred for one hour at room temperature. The precipitated sodium chloride is filtered off, the filtrate is evaporated to dryness and the residue is purified on silica gel RP-18 (mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 403 g (69% of theory) of a colorless solid. Water content: 10.2%

Elemental analysis: (calculated on anhydrous substance)

calcd. C 51.98 H 6.18 N 10.10 gef. C 51.80 H 6.31 N 10.01

e) 2- [4- (3-oxaproponic acid)] - phenyl-2- [1, 4,7-tris (carboxymethyl) -1, 4,7, 10-tetraaza-cyclododecan-10-yl] acetic acid, Gd -Complex

To 400 g (721, 3 mmol) of the title compound from Example 55d) in 2000 ml of water are added 130.73 g (360.65 mmol) of gadolinium oxide and stirred for 5 hours at 80 ⁹ C. The solution is filtered and freeze-drying the filtrate. Yield: 511 g (quantitative) of an amorphous solid. Water content: 11.0%

Elemental analysis: (calculated on anhydrous substance)

calcd. C 40.67 H 4.41 Gd 22.19 N 7.98 found. C 40.51 H 4.52 Gd 22.05 N 8.03

f) 2,6-N, N ^' -Bis {2- [4- (3-oxapropionyl) phenyl] -2- [1, 4,7-tris (carboxylatomethyl) - 1,4,7,10-tetraazacyclododecane -10-yl] -acetic acid] -lysine [4-perfluoro-octylsulfonyl) piperazine] amide, digadolinium complex, disodium salt

10 g (14.36 mmol) of the title compound 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 compound from Example 4Be dissolved in 250 ml of dimethyl sulfoxide with gentle heating. 16.51 g (80 mmol) of NN-dicyclohexylcarbodiimide are added at 10 ⁹ C and the mixture is then stirred in overnight

Room temperature. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient from water / ethanol / acetonitrile). The mixture is dissolved in a little water, adjusted to pH 7.4 with sodium hydroxide solution and freeze-dried Yield: 21.02 g (69% of theory) of a colorless solid. Water content: 11.2%

Elemental analysis: (calculated on anhydrous substance

calcd. C 37.36 H 3.66 F 15.22 Gd 14.82 N 7.92 Na 2.17 S 1.51 found 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 ^' - bis [6-carbonylmethyl-3,9-bis (t butyloxycarbonylmethyl) 3,6,9-triazaundecane-1,11-dicarboxylic acid bis (t butyl ester)] - lysine [ 1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 10 g (14.36 mmol) of the title compound from Example 54a), 18.53 g (30 mmol) of 3,9-bis (t-butyloxycarbonylmethyl) -6-carboxymethyl-3,6,9-triazaundecane -

1,11-dicarboxylic acid bis (t-butyl ester) and 3.45 g (30 mol) of N-hydroxysuccinimide dissolved in 150 ml of dimethylformamide are added at 0 ⁹ C to 10.32 g (50 mmol) of N, N dicyclohexylcarbodiimide. The mixture is stirred for 3 hours at 0 ^S C, then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile phase: dichloromethane / ethanol = 20: 1). Yield: 19.60 g (72% of theory) of a viscous oil.

Elemental analysis

calcd. C 49.41 H 6.75 F17.03 N 7.39 S 1.69 get C 49.35 H 6.82 F16.92 N 7.32 S 1.62

b) 2,6-N, N-bis [6-carbonylmethyl-3,9-bis (carboxylatomethyl) -3,6,9-triazaundecanedicarboxylic acid-1-carboxy-11-carboxylato-lysine [1 - (4-perfluorooctylsulfonyl ) -piperazine] -amide, Gd complex, sodium salt]

15 g (7.91 mol) of the title compound from Example 56a) are dissolved in 50 ml of chloroform and 200 ml of trifluoroacetic acid are added. The mixture is stirred for 10 minutes at room temperature. It is evaporated to the dry state in a vacuum and the residue is dissolved in 150 ml of water. 2.87 g (7.91 mmol) of gadolinium oxide are added and the mixture is stirred

5 hours at 80 ⁹ C. Allow to cool to room temperature and adjust to pH 7.4 with 2N sodium hydroxide solution. The solution is evaporated to dryness in vacuo and purified on RP-18 (mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 8.11 g (57% of theory) of a colorless amorphous solid. Water content: 9.6%

Elemental analysis: (calculated on anhydrous substance)

calc. C 30.70 H 3.08 Gd 17.48 N 7.78 Na 2.56 S 1.78 get 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-carboxylmethyl-3,9-bis (t butyloxycarbonylmethyl) -

3,6,9-triazaundecane-1, 11-dicarboxylic acid bis (t-butyl ester)] - lysine [1 (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 20 g (24.08 mmol) of the title compound from Example 52c), 14.88 g (24.08 mmol) of 3,9-bis (t butyloxycarbonylmethyl) -6-carboxymethyl-3,6,9- triazaun-decan-1, 11-dicarboxylic acid bis (t-butyl ester) and 2.88 g (25 mol) N-hydroxysuccinimide dissolved in 100 ml dimethylformamide are added at 0 ⁹ C 8.25 g 40 mol) N, N-dicyclo- hexylcarbodiimide. The mixture is stirred for 3 hours at 0 ⁹ C, then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile phase: dichloromethane / ethanol = 20: 1). Yield: 27.21 g (79% of theory) of a viscous oil

Elemental analysis:

calcd. C 47.03 H 5.64 F 22.58 N 6.85 S 2.24 found C 46.94 H 5.58 F 22.65 N 6.84 S 2.31

b) 2-N- [carbonylmethyl-3,9-bis (t butyloxycarbonylmethyl) -3,6,9-triazaundecane-1,11 -dicarboxylic acid bis (t butyl ester)] - lysine [1 - (4-perlfluorooctylsulfonyl) -piperazine] - amide

25 g (17.48 mmol) of the title compound from Example 57a) are dissolved in 350 ml of ethanol and 5 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 22.66 g (quantitative) of a colorless solid.

Elemental analysis:

calcd. C 44.48 H 5.75 F 24.92 N 7.56 S 2.47 found 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-5yl)] -2 -N- [6-carbonylmethyl-3,9-bis (t butyloxycarbonylmethyl) 3,6,9-triazaundecan-1,11-dicarboxylic acid bis (t butyl ester)] - lysine [1- (4-perfluorooctylsulfonyl) piperazine- ] amide, Gd complex

20 g (15.43 mmol) of the title compound from Example 57b), 1.78 g (15.43 mmol) of N-hydroxysuccininmide, 1.48 g (35 mmol) of lithium chloride and 9.72 g (15.43 mmol) 1 , 4,7-Tris (carboxylatomethyl) -10- (3-aza-4oxo-5methyl-5yl) pentanoic acid 1, 4,7, 10-tetraazacyclododecane, Gd complex are dissolved in 150 ml of dimethyl sulfoxide with gentle heating. 5.16 g (25 mmol) of N, N-dicyclohexylcarbodiimide are added at 10 ⁹ C and the mixture is then stirred overnight at room temperature. The solution is poured into 2500 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 22.94 g (78% of theory) of a colorless solid. Water content: 7.9%

Elemental analysis: (calculated on anhydrous substance)

calcd. C 42.22 H 5.29 F 16.95 Gd 8.25 N 8.82 S 1.68 found _, 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) -l, 4,7, 10-tetraazacyclododecan-10- (3-aza-4-oxo-5-methyl-5-yl-pentanoyl)] -2-N- [6-carbonylmethyl-3,9- bis (carboxylatomethyl) 3,6,9-triazaundecane dicarboxylic acid -carboxy-11-carboxylato-z] -lysine [1- (4-perfluorooctylsulfonyl) piperazine] - amide, digadolinium complex, sodium salt

20 g (10.49 mmol) of the title compound from Example 57c) are dissolved in 200 ml

Trifluoroacetic acid dissolved. The mixture is stirred for 60 minutes at room temperature. It will be in Evaporated to dryness in vacuo and the residue dissolved in 150 ml of water, 1.90 g (5.25 mmol) of gadolinium oxide are added and the mixture is stirred at 80 ^° C. for 5 hours. The mixture is allowed to cool to room temperature and is adjusted to pH 7 with sodium hydroxide solution ; 4. The solution is evaporated to dryness in vacuo and purified on silica gel RP-18 (mobile solvent: gradient consisting of water / ethanol / acetonitrile)

Yield: 11.89 g (61% of theory) of a colorless amorphous solid. Water content: 10.2%

Elemental analysis: (calculated on anhydrous substance) calc. C 32.97 H 3.47 F 17.39 Gd 16.93 N 9.05 Na 1.24 S 1.73 found 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-bis (benzyloxy) -3 oxa-hexanoic acid t-butyl ester

100 g (376.2 mmol) 1,2-di-O-benzylglycerol [manufactured according to Chem. Phys. Lipids (1987), 43 (2), 113-277] and 5 g of tetrabutylammonium hydrogen sulfate are dissolved in a mixture of 400 ml of toluene and 200 ml of 50% aqueous sodium hydroxide solution. At 0 ⁹ C, 78 g (400 mmol) of 2-bromoacetic acid t-butyl ester are added dropwise over 30 minutes and the mixture is then stirred for 3 hours at 0 ⁹ C. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel. (Mobile solvent: N-hexane / acetone = 20: 1).

Yield: 133.4 g (94% of theory) of a colorless oil.

Elemental analysis:

calcd. C 71.48 H 7.82 found C 71.61 H 7.92 b) 5,6-bis (benzyloxy) -3-oxa-hexanoic acid

130 g (336.4 mmol) of the title compound from Example 58a) are dissolved in 200 ml of dichloromethane and 100 ml of trifluoroacetic acid are added at 0 ^° C. The mixture is stirred for 4 hours at room temperature and then evaporated to dryness. The residue is crystallized from pentane / diethyl ether. Yield: 102.2 g (92% of theory) of a waxy solid

Elemental analysis: calc. C 69.07 H 6.71 found. C 69.19 H 6.82

c) 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)] - lysine [1 - (4-perf luoroctylsulfonyl) piperazine] amide, Gd complex

50 g (60.20 mmol) of the title compound from Example 52c) 6.93 g (60.20 mmol) N-hydroxysuccinimide, 5.09 g (120 mmol) lithium chloride and 37.91 g (60.20 mmol) 1 , 4,7-Tris (carboxylatomethyl) -1, 4,7,10-tetraazacyclododecan-10-pentanoyl-3-aza-4-oxo-5-methyl-5yl), Gd complex are heated in 400 ml of dimethyl sulfoxide with gentle heating solved. At 10 ^s C, 20.63 g (100 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is then stirred 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 then purified by chromatography (silica gel RP-18, mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 75.53 g (87% of theory) of a colorless solid. Water content: 10.1%

Elemental analysis: (calculated on anhydrous substance) calcd. C 37.48 H 3.84 F 22.39 Gd 10.90 N 8.74 S 2.22 found 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-tetraazacyclodOdecan-10- (pentanoyl-3aza-4-oxo-5methyl-5yl] -lysine [1- ( 4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

70 g (48.53 mmol) of the title compound from Example 58c) are dissolved in 500 ml of water / 100 ml of ethanol and 5 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 63.5 g (quantitative) of a colorless solid. Water content: 9.8%

Elemental analysis: (calculated on anhydrous substance)

calcd. C 37.48 H 3.84 F 22.39 Gd 10.90 N 8.74 S 2.22 found C 37.39 H 4.03 F 22.31 Gd 10.78 N 8.65 S 2.20

e) 6-N- [5,6-bis (benzyloxy) -3-oxahexanoyl] -2-N- [1,4,7-tris (carboxylatomethyl) -1,4,710-tetraazacyclododecane-10- (pentanoyl-3aza- 4-oxo-5-methyl-5yl)] lysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

10 g (7.64 mmol) of the title compound from Example 58d), 3.30 g (10 mmol) of the title compound from Example 7b, 0.85 g (20 mmol) of lithium chloride and 1.15 g (10 mmol) of N-hydroxysuccinimide are dissolved in 150 ml of dimethyl sulfoxide with gentle heating. At 10 ⁹ C, 3.10 g (15 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is stirred for 8 hours at room temperature. The The reaction solution is poured into 2000 ml of acetone and the precipitate is isolated. The title compound is purified on silica gel RP-18 (mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 11.14 g (90% of theory) of a colorless, amorphous solid. Water content: 4.3%

Elemental analysis: (calculated on anhydrous substance)

calcd. C 41.51 H 4.29 F 19.93 N 7.78 Gd 9.70 S 1.98 found C 41.45 H 4.38 F 19.84 N 7.70 Gd 9.58 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)] - lysiri [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

10 g (6.17 mmol) of the title compound from Example 58e) are dissolved in 200 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 8.89 g (quantitative) of a colorless solid. Water content: 3.1%

Elemental analysis: (calculated on anhydrous substance)

calcd. C 35.03 H 3.99 F 22.42 Gd 10.92 N 8.75 S 2.23 found 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-bis (benzyloxy) -3-oxa-hexanoyl] lysine [1- (4-perfluoro-octylsulfonyl) piperazine] amide

To a solution of 20 g (24.08 mmol) of the title compound from Example 52c), 9.91 g (30 mmol) of the title compound from Example 7b and 3.45 g (30 mmol) of N-hydroxysuccinimide, dissolved in 100 ml of dimethylformamide , 9.28 g (45 mmol) of N, N-dicyclohexylcarbodiimide are added at 0 ⁹ C. The mixture is stirred at O ⁹ C for 3 hours and then at room temperature overnight. The precipitated urea is filtered off, the filtrate is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile phase: dichloromethane / ethanol = 20: 1). Yield: 24.50 g (89% of theory) of a viscous oil.

Elemental analysis:

calcd. C 47.29 H 4.14 F 28.26 N 4.90 S 2.81. get C 47.14 H 4.26 F 28.17 N 4.91 S 2.69

b) 2-N- (5,6-Dihydroxy-3-oxahexanoyl) lysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide

20 g (17.5 mmol) of the title compound from Example 52d) are dissolved in 300 ml of ethanol and 5 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 17.65 g (quantitative) of a colorless solid.

Elemental analysis: calcd. C 44.05 H 4.10 F 32.02 N 5.55 S 3.18 found 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-tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] - lysine - [1- (4-perlfluorooctylsulfonyl) piperazine] amide, Gd complex

15 g (14.87 mmol) of the title compound 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 are dissolved in 100 ml of dimethyl sulfoxide with gentle heating , 5.16 g (25 mol) of NN-dicyclohexylcarbodiimide are added at 10 ⁹ C. The mixture is then stirred overnight at room temperature. The solution is poured into 1500 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18 mobile solvent: gradient from water / ethanol / acetonitrile).

Yield: 19.28 g (80% of theory) of a colorless solid. Water content: 10.3% elemental analysis: (calculated on anhydrous substance)

calcd. C 41.51 H 4.29 F 19.93 Gd 9.70 N 7.78 S 1.98 found 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'-bis (benzyloxycarbonyl) lysyl] lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide 20 g (24.08 mmol) of the title compound from Example 52c) and 2.53 g (25 mmol) of triethylamine are dissolved in 200 ml of tetrahydrofuran (THF) and 14.46 g (27 mmol) of Di-N, N ^' -Z -Lysine paranitrophenol ester added. The mixture is stirred for 5 hours at 50 ⁹ C. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel. Mobile phase: dichloromethane / methanol = 20: 1). Yield: 28.07 g (95% of theory) of a colorless solid.

Elemental analysis:

calcd. C 46.99 H 4.19 F 26.32 N 6.85 S 2.61 found 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

100 ml of hydrobromic acid in glacial acetic acid (48%) are added to 25 g (20.37 mmol) of the title compound from Example 60a) and the mixture is stirred at 40 ^° C. for 2 hours. The mixture is cooled to 0 ^° C. and 1500 ml of diethyl ester are added dropwise and the precipitated solid is filtered off. After drying in vacuo (60 ⁹ C), 21.52 g (99% of theory) of slightly yellow colored, crystalline solid.

Elemental analysis:

calc. C 27.01 H 3.40 Br. 22.46 F 30.26 N 7.87 S 3.00 found C 26.92 H 3.53 Br. 22.15 F 30.14 N 7.69 S 2.87

c) 6-N- [1,7,4-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] -2 -N-] 2,6-N, N - bis [1, 4,7-tris carboxylatomethyl) -1, 4,7,10-tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo 5-methyl-5yl)] - lysyl] -lysine [1- (4-perfluorooctylsulfonyl) -piρerazin] -amide, trigadolinium complex

31.49 g (50 mmol) 1,4,7-tris (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 are dissolved in 350 ml of dimethyl sulfoxide with gentle heating. At 10 ⁹ C, 16.51 g (80 mmol) of N, N-dicyclohexylcarbodiimide are added added and stirred for 5 hours at 10 ^Q C. to this mixture is added 10 g (9.37 mmol) of the title compound from example 60b) and 3.03 g (30 mmol) of triethylamine and stirred for 12 hours at 60 C. it is allowed to ⁹ Cool to room temperature and pour the mixture into 3000 ml acetone. The precipitate is filtered off, purified on silica gel RP-18 (mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 16.7 g (67% of theory) of a colorless solid. Water content: 7.9%

Elemental analysis: (calculated on anhydrous substance)

calcd. C 36.58 H 4.43 F 12.14 Gd 17.74 N 11.06 S 1.14 found C 36.47 H 4.54 F 12.03 Gd 17.65 N 10.95 S 1.21

Example 61

a) 1,7-bis (benzyloxycarbonyl) -4- (3,6,9,12,15-pentaoxahexadecanoyl) -1,4,7,10-tetraazacyclododecane

To 18.13 g (68.1 mmol) 3,6,9,12, 15-pentaoxahexadecanoic acid and 30 g (68.1 mmol) 1,7 Di-Z-Cycles prepared according to Z. Kovacs and AD Sherry, J. Chem. Soc .ehem. Commun. (1995), 2,185, in 300 ml of tetrahydrofuran, are added at 0 ^S. C add 24.73 g (100 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stir overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 20: 1). Yield: 19.13 g (42% of theory) of a colorless solid

Elemental analysis:

calcd. C 61.03 H 7.61 N 8.13 found C 60.92 H 7.75 N 8.04

b) 1, 7-bis (benzyloxycarbonyl) -4- (3,6,9, 12,15-pentaoxahexadecanoyl) -10- (2H, 2H, 4H, 5H, 5H-3-oxa-perfluorotridecanoyl) -1, 4 , tetraazacyclododecane 7.10-

To 18 g (26.91 mmol) of the title compound 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, are added at 0 ⁹ C 12.36 g (50 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1 -carboxylic acid ethyl ester) and stir overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 20: 1). Yield: 21.51 g (67% of theory) of a colorless solid

tiementar anaiyse:

calcd. C 47.32 H 4.82 F 27.07 N 4.70 found C 47.26 H 5.01 F 26.94 N 4.59

c) 1 - (3,6,9,12,15-Pentaoxahexadecanoyl) -7- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoyl) -1, 4,7,10-tetraazacyclododecane 20 g (16.77 mmol) of the title compound from Example 52d) are dissolved in 200 ml of ethanol and 2.5 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 15.5 g (quantitative) of a colorless solid.

Elemental analysis:

calcd. C 40.27 H 4.90 F 34.93 N 6.06 get C 40.15 H 4.99 F 34.87 N 5.94

d) 1, 7-bis (1, 4,7-tris (carboxylatomethyl) -l, 4,7,10-tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) ] -4- (3,6,9, 12,15-pentaoxahexadecanoyl) - 10- (2H, 2H, 4H, 4H, 5H, 5H, -3-oxaperfluorotridecanoyl) -1, 4,7,10-tetraazacyclododecane, Gd -Complex

15 g (16.22 mmol) of the title compound from Example 61c), 4.60 g (40 mmol) of N-

Hydroxysuccinimide, 3.39 g (80 mmol) lithium chloride and 25.19 g (40 mmol)

1,4,7-tris

(carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) pentanoic acid, Gd complex are dissolved in 300 ml of dimethyl sulfoxide with gentle heating. At 10 ⁹ C, 24.73 g (100 mmol ) EEDQ and then stir in overnight

Room temperature. The solution is poured into 3000 ml of acetone and stirred 10

Minutes.

The precipitated solid is filtered off and then purified by chromatography silica gel RP-18) mobile solvent: gradient from water /

Ethanol / acetonitrile).

Yield: 19.86 g (57% of theory) of a colorless solid. Water content: 11.3%

Elemental analysis: (calculated on anhydrous substance) calcd. C 38.58 H 4.74 F 15.04 Gd 14.64 N 9.13 found 0 38.47 H 4.91 F 14.95 Gd 14.57 N 9.04

Example 62

a) 3,5-Dinitrobenzoic acid 1 - [(4-perfluorooctysulfonyl) piperazine] amide

To 20 g (35.2 mmol) and 8.1 g (80 mmol) triethylamine, dissolved in 200 ml

Dichloromethane is added dropwise at 0 ⁹ C a solution of 8.76 g (38 mmol) of 3,5-dinitrobenzoyl chloride in 55 ml dichloromethane and stirred for 3 hours at 0 ⁹ C. 200 ml of 5% aqueous hydrochloric acid are added and the mixture is stirred 5 Minutes at room temperature.

The organic phase is separated off, dried over magnesium sulfate and in

Vacuum evaporated to dryness. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone = 15: 1)

Yield: 24.96 g (93% of theory) of a colorless solid.

Elemental analysis:

calcd. C 29.35 H 1.45 F 42.37 N 7.35 S 4.21 found 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 compound from Example 62a) are dissolved in 400 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) are added. The mixture is hydrogenated at room temperature. The catalyst is filtered off and this is evaporated Filtrate to dryness in a vacuum. Yield: 18.43 g (quantitative) of a cream colored solid.

Elemental analysis:

calcd. C 32.49 H 2.15 F 45.98 N 7.98 S 4.57 found C 32.29 H 2.35 F 45.69 N 7.81 S 4.40

c) 3,5-N, N ^* -Bis [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, Gd complex

10 g (14.24 mmol) of the title compound from Example 62b), 3.45 g (30 mmol) of N-

Hydroxysuccinimide, 2.54 g (60 mol) lithium chloride and 18.89 g (30 mmol)

1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5yl) -pentanoic acid, Gd complex are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10 ⁹ C. 10.32 g (50 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is then stirred overnight at room temperature. The solution is poured into 2000 ml

Acetone and stir for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent:

Gradient from water / ethanol / acetonitrile). Yield: 19.74 g (72% of

Theory) of a colorless solid.

Water content: 11.8%

Elemental analysis: (calculated on anhydrous substance)

calcd. C 35.55 H 3.72 F 16.77 Gd 16.33 N 10.18 S 1.67 found 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-perfluorotridecanecarboxylic acid t-butyl ester

25.0 g (53.8 mmol) of 1H, 1H, 2H, 2H-perfluoro-1-decanol [commercially available from Lancaster] are dissolved in 250 ml of absolute toluene and at room temperature with a catalytic amount (approx. 75 g) tetra-n-butylammonium hydrogen sulfate were added. A total of 7.55 g (134.6 mmol; 2.5 equ. Based on the alcohol component used) of finely powdered potassium hydroxide powder is then added at 0 ° C., followed by 15.73 g (80.7 mmol; 1.5 equ based on the alcohol component) bromoacetic acid tert-butyl ester and allowed to stir at 0 ° C. for a further 2 hours. The reaction solution thus obtained is stirred for a further 12 h at room temperature and a total of 500 ml of ethyl acetate and 250 ml of water are added for the purpose of working up. The org. Phase is separated and washed twice with water. After the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the solvent is stripped off in vacuo. The remaining oily residue is purified on silica gel using ethyl acetate / hexane (1:10) as the eluent. Yield: 26.3 g (84.6% of theory) of the above-mentioned title compound as a colorless and highly viscous oil. Elemental analysis: calc .: C 33.23 H 2.61 F 55.85 get: C 33.29 H 2.61 F 55.90

b) 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanecarboxylic acid

20.0 g (34.58 mmol) of the title compound from Example 63a) are suspended in 200 ml of a mixture consisting of methanol and 0.5 molar sodium hydroxide solution in a ratio of 2: 1 with stirring at room temperature and then heated to 60 ° C. , After a reaction time of 12 h at 60 ° C the now clear reaction mixture is neutralized for working-up by mixing with Amberlite ^® IR 120 (H ⁺ form) cation exchange resin, filtered off with suction from the exchanger, and the thus obtained methanolic-aqueous filtrate is drawn off in vacuo to dryness. The amorphous-oily residue obtained is purified on silica gel using ethyl acetate / n-hexane (1: 3) as the eluent.

Yield: 16.0 g (88.6% of theory) of the above-mentioned title compound as a colorless and highly viscous oil. Elemental analysis: calc .: C 27.60 H 1.35 F 61.85 get: C 27.58 H 1.36 F 61.90

c) 1, 7-bis {[1, 4,7-tris (carboxylatomethyl) - 10- (3-aza-4-oxo-5-methyl-5-yl-pentanoyl)] - 1, 4,7,10 -tetraazacyclododecane} -diethylenetriamine, digadoiinium complex

2.48 g [(3.94 mmol); 2.05 molar equivalents based on diethylenetriamine used] of the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4.7 described in patent application DE 19728954 C1 under Example 31h) , 10-tetraazacyclododecan-1, 4,7-triacetic acid and 167 mg of anhydrous lithium chloride (3.94 mmol) are dissolved at 40 ° C. in 40 ml of absolute dimethyl sulfoxide with stirring and at this temperature with a total of 453 mg (3.94 mmol) N-hydroxysuccinimide added. After cooling to room temperature, 814 mg (3.946 mmol) of N, N'-dicyclohexylcarbodiimide are added to the reaction solution thus obtained and the mixture is stirred at room temperature for 2 hours. The suspension of the active test obtained is then mixed with 198.3 mg (1.92 mmol) of diethylenetriamine, dissolved in 5 ml of absolute dimethyl sulfoxide, and stirred for 12 hours at room temperature. For the purpose of working up, sufficient acetone is added to the reaction mixture until the above-mentioned title compound has completely precipitated, the precipitate is filtered off with suction, dried, taken up in water, filtered off from insoluble dicyclohexylurea and the filtrate desalted via an AMICON ^® YM-3 ultrafiltration membrane (cut off 3000 Da) and cleaned of low molecular weight components. The retentate is then freeze-dried

Yield: 1.85 g (72.7% of theory) as a colorless lyophilisate.

H2θ content (Karl Fischer): 3.89%.

Elemental analysis (calculated on anhydrous substance): calculated: 038.03 H 5.24 N 13.73 Gd 23.71 get: 037.98 H 5.20 N 13.69 Gd 23.78

d) 1, 7-bis {[1, 4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl-pentanoyl)] - 1, 4,7, 10 -tetraazacyclododecan} -4- (3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) -diethylenetriarnine. digadolinium complex

In a solution of 3.23 g (2.44 mmol) of the title compound from Example 63c), in a mixture of 30 ml of dimethyl sulfoxide and 3 ml of tetrahydrofuran, 1.27 g (2.44 mmol ) of the title compound from Example 63b), dissolved in a mixture of 15 ml of tetrahydrofuran and 15 ml of dimethyl sulfoxide, is added dropwise. A total of 1.80 g (3.66 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is then added in portions at 0 ° C. and the mixture is stirred overnight at room temperature. The reaction solution obtained is then mixed with sufficient acetone until precipitation of the above-mentioned title compound, the precipitate is suctioned off, dried, taken up in water, insoluble components are filtered and the filtrate concentrated over an Amicon ^® YM-3 ultrafiltration membrane (cut off 3,000 Da), ultrafiltered , which serves both for complete desalination and for cleaning the title compound from low molecular weight constituents. The retentate is then freeze-dried.

Yield: 3.54 g (79.4% of theory) as a colorless lyophilisate.

H2θ content (Karl Fischer): 5.87%.

Elemental analysis (calculated on anhydrous substance): calc .: C 35.43 H 4.07 N 9.95 F 17.64 Gd 17.18 found: C 35.42 H 4.01 N 9.89 F 17.67 Gd 17.18

Example 64

a) 2-N-Trifluoroacetyl -6-N-benzyloxycarbonyl-L-lysine

100.0 g (356.7 mmol) of 6-N-benzyloxycarbonyl-L-lysine are dissolved in a mixture of 1000 ml of ethyl trifluoroacetate and 500 ml of ethanol and 24

Stirred for hours at room temperature. It is evaporated to dryness and the residue is crystallized from diisopropyl ether.

Yields 28.9 g (96% of theory) of a colorless crystalline powder.

Melting point: 98.5 ° C. Elemental analysis: calc .: C 51.07 H 5.09N 7.44 F 15.14 get: C 51.25 H 5.18N 7.58 F 15.03

To 125.0 g (332.0 mmol) of the title compound from Example 52a) and 188.7 g (332.0 mmol) of 1-perfluorooctylsulfonylpiperazine (produced according to DE 19603033) in 750 ml of tetrahydrofuran is 164.2 at 0 ° C. g (0.664 mmol) of EEDQ (2-ethoxy-1, 2-dihydroquinoline -1-carboxylic acid ethyl ester) and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 20: 1). Yield: 286.0 g (93% of theory) of a colorless solid. Melting point: 92 ° C. Elemental analysis: calc .: C 36.30 H 2.83 N 6.05 F 41.01 S 3.46 get: C 36.18 H 2.94 N 5.98 F 40.87 S 3.40 c) 6-N-Benzyloxycarbonyl-L-lysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide

In a solution of 280.0 g (302.2 mol) of the title compound from Example 52b) in 2000 ml of ethanol, ammonia gas is passed in at 0 ° C. for one hour. The mixture is then stirred at 0 ° C. for 4 hours. It is evaporated to dryness and the residue is extracted from water. The solid is filtered off and dried in vacuo at 50.degree. Yield: 243.5 g (97.0% of theory) of an amorphous solid. Elemental analysis: calc .: C 37.60 H 3.28 N 6.75 F 38.89 S 3.86 get: C 37.55 H 3.33 N 6.68 F 38.78 S 3.81

d) L-lysine [1 - (4-perfluorooctylsulfonyl) piperazine] amide

200.0 g (240.8 mmol) of those prepared under 64c) are prepared in 1000 ml of ethanol

Dissolved compound, mixed with 5.0 g Pearlman catalyst (Pd 20%, C) and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen uptake can be observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (three times with approx.

100 ml) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous and yellowish oil. Yield: 162.5 g (96.9% of theory).

Elemental analysis: calc. C 31.04 H 3.04 N 8.05 F 46.38 S 4.60 found C 31.11 H 3.09 N 8.08 F 46.33 S 4.62

e) 6N-2N-bis- {4- [2,3-bis- (N, N-bis (t-butyloxycarbonylmethyl) amino) propyl] phenyl} -3-oxa-propionyl-L-lysine [ 1- (4-perfluorooctylsulfonyl) -piperazine] -amide 5.25 g (7.72 mmol) of 4- [2,3-bis (N, N-bis (t-butyloxycarbonylmethyl) amino) propyl] phenyl} -3-oxa-propionic acid and 781.0 mg (7.72 mmol) of triethylamine are dissolved in 50 ml of methylene chloride. A solution of 1.16 g (8.5 mmol) of isobutyl chloroformate in 10 ml of methyl chloride is added dropwise at -15 ° C. in the course of 5 minutes and the mixture is stirred at -15 ° C. for a further 20 minutes. The solution is then cooled to -25 ° C. and a solution consisting of 2.68 g (3.86 mmol) of the title compound from Example 64d) and 2.12 g (21.0 mmol) of triethylamine is added dropwise in 70 ml Tetrahydrofuran added within 30 minutes and then stirred for a further 30 minutes at -15 ° C and then overnight at room temperature. For working up, the solvent is removed in vacuo and the remaining oily residue is taken up in 250 ml of chloroform. The chloroform phase is extracted twice with 100 ml of a 10% aqueous ammonium chloride solution, the organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / ethanol = 20: 1).

Yield: 5.37 g (68.8% of theory) of a colorless and very viscous oil. Elemental analysis: calc .: C 52.27 H 6.43 N 5.54 F 15.97 S 1.59 get: C 52.22 H 6.51 N 5.49 F 15.99 S 1.63

f) 6N-2N-bis- {4- [2,3-bis- (N, N-bis (carboxylatomethyl) amino) propyl] phenyl} -3-oxa-propionyl-L-lysine [1 - (4-perfluorooctylsulfonyl) plperazine] amide, octa sodium salt

5.0 g (2.47 mmol) of the title compound from Example 64e) are dissolved in 60 ml of absolute dichloromethane. A total of 75 ml of trifluoroacetic acid is then added dropwise at 0 ° C. After a reaction time of 12 hours at room temperature, the mixture is evaporated to dryness in a vacuum. The remaining residue is mixed with 100 ml of water and again drawn off to dryness in a vacuum. The residue thus obtained is in 200 ml distilled water and extracted the aqueous product solution of the above title compound twice with 60 ml of diethyl ether. The resulting aqueous product solution is filled ml by adding water to a total volume of 300, filtered to remove insolubles and the filtrate concentrated over an Amicon ^® YM-3 ultrafiltration membrane (cut off 3,000 Da), ultrafiltered, which both for complete desalination and for purification serves as the title compound of low molecular weight components. The retentate is made up to a total volume of 200 ml by adding water and the pH of this solution is then adjusted to 10.0 with 15% sodium hydroxide solution. The basic, aqueous product solution is then freeze-dried.

4.0 g (92.8% of theory) of the title compound are obtained in the form of the octa-sodium salt as an amorphous lyophilisate. Water content: 5.37%

Elemental analysis (calculated on anhydrous substance): calc .: C 38.46 H 3.28 N 6.41 F 18.47 S 1.83 Na 10.52 get: C 38.42 H 3.31 N 6.39 F 18.51 S 1.87 Na 10.38

g) 6N-2N-bis- {4- [2,3-bis- (N, N-bis (carboxymethyl) amino) propyl] phenyl} -3-oxa-propionyl-L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, di-manganese complex, tetra sodium salt

1.94 g (1.11 mmol) of the title compound from Example 64f) are dissolved in 100 ml of distilled water and the resulting solution is brought to a pH of 4.0 by adding 1 molar aqueous hydrochloric acid. At 80 ° C, 0.25 g (2.22 mmol) of manganese II carbonate is now added in portions. The reaction solution thus obtained is then under for 5 hours

Reflux cooked. After cooling to room temperature, the pH of the aqueous product solution is adjusted to 7.2 with vigorous stirring by adding 1N sodium hydroxide solution and using an AMICON® YM-3 Ultrafiltration membrane (cut off 3000 Da) desalted and of low molecular weight

Ingredients cleaned. The retentate is then freeze-dried.

Yield: 1.80 g (92.0% of theory) of the title compound as a colorless lyophilisate.

H2θ content (Karl Fischer): 7.28%.

Elemental analysis (calculated on anhydrous substance): calc .: C 38.07 H 3.25 F 18.28 Mn 6.22 N 6.34 Na 5.20 S1.81 get: C 38.01 H 3.29 F 18 , 29 Mn 6.21 N 6.36 Na 5.28 S 1.78

Example 65

a) 6-N- (Benzyloxycarbonyl) -2-N - [(N-pteroyl) - L-glutaminyl] -ysin [1- (4-perfluorooctylsulfonyl) piperazine] amide

20 g (45.31 mmol) folic acid are dissolved in 300 ml dimethyl sulfoxide and 9.49 g (46 mmol) N, N -dicyclohexylcarbodiimide are added at 10 ⁹ C. The mixture is stirred overnight at room temperature. 29.1 g (35 mmol) of the title compound from Example 52c) and 20 ml of pyridine are added to this mixture, and the mixture is stirred at 50 ^° C. for 3 hours. The mixture is cooled to room temperature and a mixture of 1500 ml of diethyl ether / 1500 ml of acetone is added. The precipitate is filtered off and on

(RP-18) cleaned (eluent = gradient from water / ethanol / tetrahydrofuran). Yield: 21.59 g (38% of theory), yellow solid. Water content: 2.1%

Elemental analysis: (calculated on anhydrous substance).

calcd. C 43.10 H 3.54 F 25.76 N 11.29 S 2.56 found C 43.02 H 3.62 F 25.68 N 11, 21 S 2.48

b) 2-N - [(N-pteroyl) -L-glutaminyl] -lysine [1- (4-perfluorooctylsulfonyl) piperazin] amide

200 ml of hydrobromic acid in glacial acetic acid (48%) are added to 20 g (15.95 mmol) of the title compound from Example 65a) and the mixture is stirred at 40 ^° C. for 2 hours. The mixture is cooled to 0 ^° C., 2000 ml of diethyl ether are added dropwise and the mixture is filtered the fancy

Solid off. After drying in vacuo (60 ⁹ C) 18.96 g (99% of theory) of a yellow colored, crystalline solid.

Elemental analysis:

calcd. C 37.01 H 3.27 Br 6.65 F 26.90 N 12.83 S 2.67 found C 36.91 H 3.42 Br 6.31 F 29.75 N 12.72 S 2.56

c) 6-N- [1, 4,7-tris (carboxylatomethyl) -l, 4,7,10 -tetraazacyclododecan -10- (pentanoyl-3-aza-4oxo-5-methyl-5yl] -2-N- [(N-pteroyl] -L-glutaminyl] lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

0.92 g (8 mmol) N-hydroxysuccinimide, 0.68 g (16 mol) lithium chloride and 5.04 g (8 mmol) 1, 4,7-tris (carboxylatomethyl-10- (3-aza - ^ - oxo -5-methyl-5-yl) - 1,4,7-10-tetraazacyclododecane, Gd complex are dissolved in 80 ml of dimethyl sulfoxide with gentle heating, 2.06 g (10 mol) of N, N are added at 10 ^° C. Dicyclohexylcarbodiimide and then stirred for 3 hours at room temperature 5 g (4.16 mmol) of the title compound from Example 65b) and 10 ml of pyridine are added to this reaction solution, which is stirred overnight at room temperature. The solution is poured into 1000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient from water / ethanol / acetonitrile. It is dissolved in a little water, the pH is adjusted to 7.4 with sodium hydroxide solution and freeze-dried. Yield: 3.87 g (53% of theory) of a yellow solid, water content: 5.8%,

Elemental analysis: (calculated on anhydrous substance)

calcd. C 38.36 H 3.74 F 18.42 Gd 8.97 N 12.78 Na 1.31 S 1.83 found C 38.28 H 3.85 F 18.33 Gd 8.85 N 12.69 Na 1.42 S 1.75

Example 66 a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluorotridecanoic acid-N- (2,3-dihydroxypropyl) -amide To 30 g (57.45 mmol) 2H, 2H, 4H, 4H , 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml dichloromethane are added 8.90 g (70 mmol) oxalyl chloride and stirred for 12 hours at room temperature. It is 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 5.47 g (60 mmol) of 2,3-dihydroxypropylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. The mixture is stirred for 3 hours at 0 ° C., then for 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stir well for 15 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / ethanol = 15: 1).

Output: 29.70 g (87% of theory) of a colorless solid

Elemental analysis: calc .: C 30.32 H 2.20 N 2.36 F 54.35 get: 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 compound from Example 66a are dissolved in 300 ml of tetrahydrofuran and 50 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 300 ml of methanol are added dropwise, then it is evaporated to the dry state in a vacuum. The residue is in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid added and stirred at 60 ° C for 8 hours. you evaporates to dryness in vacuo, takes the residue in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 15: 1).

Yield: 24.07 g (85% of theory) of a colorless solid

Elemental analysis: calc .: C 31.05 H 2.61 N 2.41 F 55.66 get: 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

10 g (15.88 mmol) of the gadolinium complex of 10- [1 - (carboxymethylcarboamoyl) ethyl] -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1.35 g (31.76 mmol ) Lithium chloride are dissolved at 60 ° C in 100 ml of dimethyl sulfoxide. The mixture is cooled to 15 ° C. and 9.21 g (15.88 mmol) of the title compound from Example 66b are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile solvent: gradient of tetrahydrofuran / acetonitrile / water). Yield: 16.09 g (85% of theory) of a colorless, amorphous powder. Water content: 6.3%

Elemental analysis (calculated on anhydrous substance): calc .: C 34.26 H 3.64 N 7.05 F 27.10 Gd 13.19 get: C 34.12 H 3.83 N 6.91 F 26.88 Gd 12.93

Example 67

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 of 10- [1- (carboxymethylcarboamoyl) ethyl] -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1.35 g (31, 76 mmol ) Lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 3.51 g (17 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is stirred at 15 ° C. for 5 hours. The solution is filtered to separate the urea. 8.63 g (15.88 mmol) of the title compound from Example 68b and 5.06 g (50 mmol) of triethylamine are added to the filtrate and the mixture is stirred for 12 hours at room temperature. The solution is poured into 1500 ml of diethyl ether / 100 ml of acetone and stirred for 30 minutes. The precipitated solid is filtered off and chromatographed on silica gel RP-18 (mobile solvent: gradient consisting of tetrahydrofuran / acetonitrile / water).

Yield: 13.86 g (78% of theory) of a colorless, amorphous powder

Water content: 9.3% elemental analysis (calculated on anhydrous substance): calc .: C 33.28 H 3.42 N 7.51 F 28.87 Gd 14.05 get: 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 are added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane and the mixture is stirred for 12 hours at room temperature. It is evaporated to dryness in a vacuum. The ^"residue is dissolved in 200 ml of dichloromethane. Then, it is passed at 0 ° C ammonia gas for about 2 hours in the solution. The mixture is stirred for 4 hours at 0 ° C., then for 2 hours at room temperature. 300 ml of 5% hydrochloric acid and stirred thoroughly for 15 minutes, the organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone = 20: 1).

Yield: 27.85 g (93% of theory)

Elemental analysis: calc .: C 27.66 H 1.55 N 2.69 F 61.97 ge: C 27.49 H 1.72 N 2.54 F 61.81 b) 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecylamine, hydrochloride

27 g (51.8 mmol) of the title compound from Example 68a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 200 ml of methanol are added dropwise, then it is evaporated to the dry state in a vacuum. The residue is in a mixture of 400 ml of ethanol / 100 ml of 10% aqu. Hydrochloric acid added and stirred at 60 ° C for 8 hours. It is evaporated to the dry state in a vacuum and the residue is recrystallized from a little ethanol / diethyl ether.

Yield: 26.75 g (95% of theory) of a colorless, crystalline solid

Elemental analysis: calc .: C 26.51 H 2.04 N 2.58 F 59.41 Cl 6.52 get: 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

14.24 g (50 mmol) are added at 0 ° C. to 26.5 g (48.74 mmol) of the title compound from Example 68b and 14.8 g (146.2 mmol) of triethylamine, dissolved in 300 ml of dichloromethane. 3,6,9,12, 15-pentaoxahexadecanoic acid chloride and stirred for 3 hours at 0 ° C. 300 ml of 5% aqu. Hydrochloric acid and stir well for 30 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone: 20: 1).

Yield: 32.03 g (87% of theory) of a colorless oil

Elemental analysis: calc .: C 36.57 H 4.00 N 1.85 F 42.75 get: 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) amide 31 g (41.03 mmol) of the title compound from Example 68c are dissolved in 300 ml of tetrahydrofuran and 25 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 200 ml of methanol are added dropwise, then it is evaporated to the dry state in a vacuum. The residue is in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid added and stirred at 40 ° C for 8 hours. It is evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous solution. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / 2 propanol = 15: 1).

Yield: 27.68 g (91% of theory)

Elemental analysis: calc .: C 37.26 H 4.35 N 1.89 F 43.56 get: 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) -hexadexyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluorotridecyl] -amide} -1, 4, 7,10-tetraazacyclododecane,

gadolinium

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethy! Carboamoyl) -ethyl] -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1.35 g (31, 76 mmol) of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture is cooled to 15 ° C. and 11.77 g (15.88 mmol) of the title compound from Example 68d are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile solvent: gradient of tetrahydrofuran / acetonitrile / water). Yield: 18.05 g (84% of theory) of a colorless, amorphous powder. Water content: 6.2%

Elemental analysis (calculated on anhydrous substance): calc .: C 37.28 H 4.47 N 6.21 F 23.87 Gd 11.62 get: C 37.11 H 4.61 N 6.03 F 23.64 Gd 11.42

Example 69

5-Hydroxy-3-oxapentylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane, are added dropwise. The mixture is stirred for 3 hours at 0 ° C., then for 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stir well for 15 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone = 15: 1).

Yield: 32.20 g (92% of theory) of a colorless solid

Elemental analysis: calc .: 0 31, 54 H 2.65 N 2.30 F 53.01 get: 031.61 H 2.84 N 2.14 F 52.85

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

30 g (49.24 mmol) of the title compound from Example 69a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. The mixture is refluxed for 16 hours. It is cooled to 0 ° C. and 200 ml of methanol are added dropwise, then it is evaporated to the dry state in a vacuum. The residue is in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid added and stirred at 50 ° C for 10 hours. you evaporates to dryness in vacuo, takes the residue in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml dichloromethane each. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / 2-propanol = 20: 1).

Yield: 26.09 g (89% of theory) of a colorless solid

Elemental analysis: calc .: C 32.28 H 3.05 N 2.35 F 54.25 get: 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-oxapentyl) -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 of 10- [1- (carboxymethylcarboamoyl) ethyl] -1, 4,7,10-tetraazacyclododecan-1, 4,7-triacetic acid and 1.35 g (31.76 mmol ) Lithium chloride are dissolved at 60 ° C in 100 ml of dimethyl sulfoxide. The mixture is cooled to 15 ° C. and 9.45 g (15.88 mmol) of the title compound from Example 69b are added. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline are added. The mixture is stirred at room temperature for 12 hours. The solution is poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate which has separated out is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile solvent: gradient of tetrahydrofuran / acetonitrile / water).

Yield: 16.10 g (84% of theory) of a colorless, amorphous powder

Water content: 5.7% elemental analysis (calculated on anhydrous substance): calc .: C 34.83 H 3.84 N 6.96 F 26.76 Gd 13.03 get: 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-, ß -D-mannopyranose

In an analogous manner as described in the literature [ML Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol.ll, 53, pp. 211-215, (1963)] provides the reaction of 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 working up 315 g (96.7%) of the above Title compound as a crude product in the form of a viscous and colorless oil. The α to β ratio of the two anomers was determined to be 4: 1 by ¹ H-NMR spectroscopic examination of the title compound thus obtained. A separation of the α, β-anomers of the above-mentioned title compound can be dispensed with in order to carry out the subsequent reaction steps. Elemental analysis: calc .: C 49.21 H 5.68 get: C 49.12 H 5.78

b) 6- [1 -0-α- (2,3,4,6-tetra-0-acetyl-D-mannopyranosyl) hexanoic acid ethyl ester]

In an analogous manner, v / ie described in the literature for the synthesis of aryl glycopyranosides [J. Conchie and GA Lewy in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol.ll, 90, pp. 345-347, (1963)] carries out the reaction of 156.2 g (400 mmol) of the title compound from Example 70a as an α, β-anomer mixture with 67 ml (400 mmol) of 6-hydroxy-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 form 100.05 g (51% of theory) of the above-mentioned title compound as a colorless one and viscous oil. By ¹ H-NMR spectroscopic examination of the title compound thus obtained it could be shown that the above-mentioned title compound is exclusively the pure α-anomer. Elemental analysis: calc .: C 52.94 H 6.77 found: C 52.80 H 6.78

c) 6- [1 -0-α - (2,3,4,6-Tetra-0-benzy! -D-mannopyranosyl) hexanoic acid

A stirred suspension of 141.0 g (289 mmol) of the title compound from Example 70b in 200 ml of dioxane is mixed with a total of 238.5 g (4.26 mol) of finely powdered potassium hydroxide powder at room temperature and with vigorous stirring at the same time. To increase the stirrability, the reaction mixture is mixed with a further 200 ml of dioxane and the suspension thus obtained is subsequently heated to boiling point and a total of 372 ml (3.128 mol) of benzyl bromide are added dropwise at this temperature over a period of two hours. After a reaction time of 4 hours at 110 ° C., followed by 12 hours at room temperature, the reaction mixture is poured slowly into a total of 2.5 liters of ice water for the purpose of working up, and the water phase is subsequently extracted completely with diethyl ether. After washing the ether phase thus obtained and then drying it over sodium sulfate, the salt is filtered off with suction and the diethyl ether is stripped off in vacuo. Excess benzyl bromide is then quantitatively distilled off from the reaction mixture in an oil pump vacuum at an oil bath temperature of 180 ° C. The resinous-oily residue thus obtained is purified on silica gel using ethyl acetate / hexane (1:10) as the eluent.

Yield: 172.2 g (91.0% of theory) of the above-mentioned title compound in the form of a colorless and extremely viscous oil

Elemental analysis: calc .: C 75.68 H 7.16 found: ^" C 75.79 H 7.04

d) 6- [1 -O- - (2,3,4,6-Tetra-0-benzyl ~ D-mannopyranosyl) ~ hexanoic acid-N- (3-oxa-1H, 1H, 2H, 2H, 4H , 4H, 5H, 5H-perfluortridecyi) amide

100 g (134 mmol) of the acid described in Example 70c and 13.5 g (134 mmol) of triethylamine are dissolved in 1200 ml of dry tetrahydrofuran. After cooling to -15 ° C., a solution of 18.45 g (135 mmol) isobutyl chloroformate in 200 ml of dry tetrahydrofuran is slowly added dropwise with stirring, the internal temperature not exceeding -10 ° C. After a Reaction time of 15 minutes at -15 ° C, 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 at -20 ° C. After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is evaporated to dryness in vacuo. The remaining residue is taken up in 300 ml of ethyl acetate and washed twice with 400 ml of saturated sodium bicarbonate solution and once with 500 ml of water. After the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the ethyl acetate is stripped off in vacuo. The remaining oily residue is purified on silica gel using dichloromethane / hexane / 2-propanol (10: 5: 1) as an eluent.

Yield: 143.8 g (86.9% of theory)

Elemental analysis: calc .: C 57.38 H 4.98 N 1, 13 F 26.15 get: C 57.30 H 5.44 N 1, 01 F 26.25

e) 6- [1-0-α-D-mannopyranosyl) hexanoic acid N- (3-oxa- 1 H, 1 H ^ H ^ H ^ H ^ H.δH.δH-perfluorotridecyamide

40.0 g (32.38 mmol) of the title compound from Example 70d are dissolved in 750 ml of 2-propanol and 2.0 g of palladium catalyst (10% Pd / C) are added. The reaction solution is hydrogenated for 12 hours at 22 ° C. and 1 atmosphere of hydrogen pressure. The catalyst is then filtered off and the filtrate is evaporated to dryness. The remaining residue is taken up in 300 ml of dimethyl sulfoxide and 21.52 g (88.0% of theory) of the above-mentioned title compound are obtained as colorless from the resulting product solution by adding a total of 1000 ml of diethyl ether after the precipitated solid has been filtered off with suction and crystalline powder with the decomposition melting point of 88.5 ° C.

Elemental analysis: calc .: C 36.01 H 5.92 N 1.75 F 40.34 get: C 36.07 H 6.08 N 1.76 F 40.66 f) Preparation of a formulation from metal complex I and 6- [1-0-α-D-mannopyranosyl) hexanoic acid N- (3-oxa-1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl ) amide

To 35 ml of a solution of the metal complex I (280 mmol / L) dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) is added 3.17 g (4.2 mmol) of the title compound from Example 70e and filled with 0.9% aqu. Saline to a total of 98 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 71 a) 1 -O-α -D - [(1 -perfluorooctylsulfonylpiperazin-4-carbonyl) -pentyl-5] -2,3,4,6-tetra-O-benzyl-mannopyranose

74.59 g (100 mmol) of the acid described in Example 71c and 10.11 g (100 mmol) of triethylamine are dissolved in 800 ml of a mixture of tetrahydrofuran / acetonitrile (mixing ratio 7: 3). Then at room temperature dropwise with 500 ml of a tetrahydrofuran solution of 58.0 g (102.0 mmol) of 1-perfluorooctylsulfonylpiperazine; 10.11 g (100 mmol) of triethylamine and 16.84 g (110 mmol) of 1-hydroxybenzotriazole were added. A solution of 22.7 g (110 mmol) of dicyclohexylcarbodiimide, dissolved in 100 ml of tetrahydrofuran, is added to the reaction solution thus obtained, and the mixture is then stirred at -5 ° C. for a further two hours. After thawing the reaction solution, the mixture is stirred at room temperature for a further 12 hours, the precipitated dicyclohexylurea is filtered off and the filtrate obtained is evaporated to dryness in vacuo. The remaining residue is taken up in 600 ml of ethyl acetate and washed twice with 300 ml of saturated sodium bicarbonate solution and twice with 300 ml of water. After the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the ethyl acetate is stripped off in vacuo. The remaining oily residue is purified on silica gel using dichloromethane / acetone / 2-propanol (16: 2: 1) as the eluent

Yield: 113.01 g (79.8% of theory) of a colorless and viscous oil Elemental analysis: calc .: C 58.52 H 4.27 N 1.98 S 2.26 F 22.80 found: C 58.42 H 4.41 N 1.80 S 2.28 F 23.02

b) 1 -0-α -D - [(1 -perfluorooctylsulfonyl-piperazin-4-carbonyl) -pentyl-5] - mannopyranose

50 g (35.30 mmol) of the title compound from Example 71a are 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) are added. It is hydrogenated for 12 hours at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 200 ml of methanol and the reaction product is precipitated by adding a total of 800 ml of diethyl ether. After the solid obtained in this way has been suctioned off, it is dried in vacuo at 50.degree.

Yield: 29.51 g (99% of theory) of an amorphous solid. Elemental analysis: calc .: C 34.13 H 3.46 N 3.32 S 3.80 F 38.23 ge: C 34.28 H 3 , 81 N 3.25 S 3.80 F 38.01

c) Preparation of a formulation from metal complex II and 1-O-α -D - [(1- PerfIuoroctylsulfonyl-piperazin-4-carbonyl) -pentyl-5] -mannopyranose

To 47 ml of a solution of metal complex II (250 mmol / L) dissolved in 0.45% aqu. Sodium chloride solution), 9.92 g (11.75 mmol) of the title compound from Example 71b are added and the mixture is heated in the microwave for 10 minutes. The solution is cooled to room temperature, filtered through a 0.2 m filter and the filtrate is filled into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 250 mmol Gd / L).

Example 72

a) 2-Acetamido-2-deoxy-1, 3,4,6- (tetra-0-benzyl) -α, β -D-glucopyranose To a stirred suspension of 20.16 g (700 mmol; 80% in mineral oil) sodium hydride in 150 ml of dimethyl sulfoxide, a total of 24.0 g (108.5 mmol) of 2-acetamido-2-deoxy-α, β -D are added at room temperature dropwise add glucopyranose, dissolved in 500 ml of absolute dimethyl sulfoxide. The mixture is then left to stir at room temperature for a further 120 minutes, and 159.5 g (1.26 mol) of benzyl chloride are then added dropwise. The reaction solution thus obtained is then stirred for a further 12 hours at room temperature. For working up, the reaction solution is slowly poured into 1.5 liters of ice water and then exhaustively extracted with diethyl ether. The combined diethyl ether phases are then washed twice with 600 ml of saturated sodium bicarbonate solution and twice with 800 ml of water. After the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the solvent is stripped off in vacuo. The remaining oily residue is purified on silica gel using ethyl acetate / hexane (1: 5) as the eluent.

Yield: 48.68 g (73.6% of theory) of the above-mentioned title compound in the form of a viscous and colorless oil

Elemental analysis: calc .: C 70.92 H 6.45 N 6.89 ge: C 71.43 H 6.44 N 7.02

b) 1-0-Benzyl-3,4,6-tri-0-benzyl-2-amino-2-deoxy-α, β -D-glucopyranose

30.0 g (49.2 mmol) of the title compound from Example 72a are suspended in a mixture of 750 ml of methanol and 215 ml of water and a total of 440 ml (49.2 mmol) of a 0.112 molar aqueous perchloric acid solution are added dropwise at room temperature. After the addition has ended, the reaction solution is stirred for a further 10 minutes at room temperature and the reaction mixture which is now obtained and is now homogeneous is subsequently evaporated to dryness in vacuo. By adding a mixture of equal parts of hexane and dichloromethane to the remaining oily residue, it is brought to crystallization. The crystalline reaction product is filtered off, washed with hexane and dried in vacuo at room temperature. Yield: 27.08 g (86% of theory) of the above-mentioned title compound in the form of its perchlorate, which is present as a colorless, crystalline compound. Melting point: 180.5-181.5 ° C

Elemental analysis: calc .: C 63.68 H 5.98 N 2.19 Cl 5.54 get: C 63.43 H 6.04 N 2.02 Cl 5.71

c) 1, 3,4,6-tetra-0-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) aminoacetic acid and 3.60 g (35.6 mmol) of triethylamine are dissolved in 350 ml of dry tetrahydrofuran. After the reaction solution has been cooled to -15 ° C. to -20 ° C., a solution of 4.92 g (35.6 mmol) of isobutyl chloroformate in 75 ml of dry tetrahydrofuran is slowly added dropwise at this temperature, with stirring, the dropwise rate being so chosen is that an internal temperature of -10 ° C is not exceeded. After a reaction time of 15 minutes at -15 ° C., a solution of 22.78 g (35.6 mmol) of the perchlorate (title compound from Example 72b and 3.60 g (35.6 mmol) of triethylamine) in 100 ml of dry is then added dropwise Tetrahydrofuran slowly added at -20 ° C. After a reaction time of one hour at -15 ° C. and two hours at room temperature, the reaction solution is evaporated to the dry state in a vacuum, and the remaining residue is taken up in 250 ml of ethyl acetate and twice with 100 ml each saturated sodium bicarbonate solution and washed once with 200 ml of water, after the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the ethyl acetate is stripped off in vacuo cleaned.

Yield: 33.3 g (84.6% of theory) of the above-mentioned title compound as a colorless and highly viscous oil

Elemental analysis: calc .: C 49.92 H 3.92 N 2.53 F 29.18 S 2.90 get: 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

20.0 g (18.06 mmol) of the title compound from Example 72c are dissolved in 250 ml of 2-propanol and 1.5 g of palladium catalyst (10% Pd / C) are added. The

Reaction solution is for 12 hours at 22 ° C and 1 atmosphere

Hydrogen pressure hydrogenated. The catalyst is then filtered off and the filtrate is evaporated to dryness. The remaining residue is in 300 ml

Dimethyl sulfoxide is taken up and obtained from the product solution thus obtained by adding 750 ml of a mixture of equal parts

Diethyl ether and ethyl acetate after suction of the precipitated

Solid 12.65 g (93.8% of theory) of the above-mentioned title compound as a colorless and crystalline powder. The title compound mentioned above lies as α

/ β-anomer mixture, the ratio with respect to the two possible anomers being determined by ¹ H-NMR spectroscopic investigations to be approximately 1: 1.2. Accordingly, the title compound is an almost equally distributed α / β anomer mixture.

Melting point: 132.5 - 133 ° C.

Elemental analysis: calc .: C 28.97 H 2.57 N 3.75 F 43.27 S 4.30 get: C 29.09 H 2.56 N 3.84 F 43.36 S 4.42

e) Preparation of a 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 a solution of the metal complex XIV (300 mmol / L), dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA), a solution of 4.90 g (6 , 57 mmol) of the title compound from Example 3d, dissolved in 200 ml of ethanol, and the mixture is stirred at 50 ° C. for 2 hours. The solution is evaporated to dryness in vacuo and the residue with dist. Make up to a total of 153 ml of water. The mixture is stirred at 40 ° C. for 10 minutes and filtered through a 0.2 / m filter. The filtrate is filled into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L). Example 73

a) 1, 2,3,4,6-Penta-O-acetyl-α-D-glucopyranose

In an analogous manner, as described for the synthesis of the title compound 70a, the reaction 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 working up and recrystallization from 95% aqueous Ethanol 190.6 g (88.0%) of the above title compound as a colorless and crystalline compound. The α to β ratio of both possible anomers with D 98: 2 could be determined by ¹ H-NMR spectroscopic examination of the title compound thus obtained. Accordingly, the title compound is the exclusively α-configured anomer.

Melting point: 110.5 ° C

Elemental analysis: calc .: C 49.21 H 5.68 get: C 49.24 H 5.68

b) 5- (Ethoxycarbonyl) pentyl -2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside

In an analogous manner to that described in the synthesis of the title compound from Example 70b, the reaction of 130.0 g (332.8 mmol) of the title compound from Example 4a) with 55.8 ml (332.8 mmol) of 6-hydroxyhexanoic acid ethyl ester and 50.6 ml (520 mmol) of tin IV chloride in 500 ml of 1,2-dichloroethane after purification by column chromatography (eluent: hexane / ethyl acetate 2: 1) 101.85 g (62.4% of theory) of the above mentioned title compound as a colorless and viscous oil. After ¹ H-NMR spectroscopic examination of the title _compound, the size of the coupling constants of J _1ι = 8.8 Hz clearly indicated the presence of the β configuration at the anomeric center, which also represents the only configuration at the anomer center. So could the title compound mentioned above can only be prepared in the form of the β-configured anomer.

Elemental analysis: calc .: C 52.94 H 6.77 get: C 52.77 H 6.70

c) 5- (Carboxy) pentyl -2,3,4,6-tetra-O-benzyl-α -D-glucopyranoside

A stirred suspension of 100.0 g (204.96 mmol) of the title compound from Example 73b in 150 ml of dioxane is mixed with a total of 169.14 g (3.02 mol) of finely powdered potassium hydroxide powder at room temperature and with vigorous stirring at the same time. To increase the stirrability, the reaction mixture is mixed with a further 150 ml of dioxane and the suspension thus obtained is subsequently heated to boiling heat and a total of 264 ml (2.218 mol) of benzyl bromide are added dropwise at this temperature over a period of two hours. After a reaction time of 4 hours at 110 ° C., followed by 12 hours at room temperature, the reaction mixture is poured slowly into a total of 2.0 liters of ice water for the purpose of working up, and the water phase is then completely extracted with diethyl ether. After washing the ether phase thus obtained and then drying the organic phase over sodium sulfate, the salt is filtered off with suction and the diethyl ether is stripped off in vacuo. Excess benzyl bromide is then quantitatively distilled off from the reaction mixture in an oil pump vacuum at an oil bath temperature of 180 ° C. The remaining oily residue thus obtained is purified on silica gel using ethyl acetate / hexane (1:10) as the eluent

Yield: 128.8 g (84.3% of theory) of the above-mentioned title compound in the form of a colorless and extremely viscous oil. Elemental analysis: calc .: C 75.68 H 7.16 get: C 75.66 H 7, 23

d) 2,3,4,6-tetra-O-benzyl-1-0-β-D- [6-hexanoic acid-N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) amide] -glucopyranose 68.5 g (91.79 mmol) of the acid described in Example 73c and 9.25 g (91, 79 mmol) of triethylamine are dissolved in 825 ml of dry tetrahydrofuran. After the reaction solution has been cooled to -15 ° C. to -20 ° C., a solution of 12.64 g (92.5 mmol) of isobutyl chloroformate in 150 ml of dry tetrahydrofuran is slowly added dropwise at this temperature with stirring, the dropwise rate being so chosen is that an internal temperature of -10 ° C is not exceeded. After a reaction time of 15 minutes at -15 ° C, a solution of 46.40 g (91.79 mmol) of 1H.1H, 2H, 2H-heptadecafluoro-1- (2-aminoethyoxy) decane and 9.25 g ( 91, 79 mmol) triethylamine, as a solution in 200 ml dry tetrahydrofuran at -20 ° C slowly. After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is evaporated to dryness in vacuo. The remaining residue is taken up in 250 ml of ethyl acetate and washed twice with 300 ml of saturated sodium bicarbonate solution and once with 400 ml of water. After the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the ethyl acetate is stripped off in vacuo. The remaining oily residue is purified on silica gel using dichloromethane / hexane / 2-propanol (10: 5: 1) as an eluent.

Yield: 104.7 g (92.4% of theory) of the above. Title compound as a colorless and highly viscous oil

Elemental analysis: calc .: C 57.38 H 4.98 N 1.13 F 26.15 get: C 57.27 H 5.09 N 1.11 F 26.08

e) 1-O-ß -D- [6-hexanoic acid-N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) amide] -glucopyranose

40.0 g (32.38 mmol) of the title compound from Example 73d are dissolved in 750 ml of 2-propanol and 2.0 g of palladium catalyst (10% Pd / C) are added. The reaction solution is hydrogenated for 12 hours at 22 ° C. and 1 atmosphere of hydrogen pressure. The catalyst is then filtered off and the filtrate is evaporated to dryness. The remaining residue is taken up in 300 ml of dimethyl sulfoxide and obtained from the product solution thus obtained 22.05 g (90.2% of theory) of the title compound are added as a colorless and crystalline powder with a decomposition melting point of 122-124 ° C. by adding a total of 1000 ml of diethyl ether and then filtering off the precipitated solid.

Elemental analysis: calc .: C 36.01 H 5.92 N 1.75 F 40.34 get: C 36.07 H 6.08 N 1.76 F 40.66

f) Preparation of a formulation from the title compound of Example 12 from WO 99/01161 (1, 4,7-Tris {1, 4,7-tris (N-carboxylatomethyl) -10- (N-1 - methyl-3-aza -2,5-dioxopentane-1,5-diyl] -1,4,7,10-tetraazacyclododecane, Gd complex} -10- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyI - 1,4,7,10-tetraazacyclododecane) and 1-O-ß -D- [6-hexanoic acid-N- (3-oxa- 1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H- perfluorotridecyl) -amide] -glucopyranose

To 37 ml of a solution of 1,4,7-tris {1,4,7-tris (N-carboxylatomethyl) -10- (N-1-methyl-3-aza-2,5-dioxopentane-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% aqueous saline solution (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 20.29 g (25.9 mmol) of the title compound from Example 73e are added and the mixture is filled with 0.9% aqueous sodium chloride solution to a total of 111 ml, heated in an ultrasonic bath for 2 hours at 60 ° C. The solution is cooled to room temperature and adjusted to pH 7.4 with 2N aqueous sodium hydroxide solution 0.2 μm filter and fills the filtrate into vials, a solution prepared in this way can be used directly for biological experiments (the concentration is 100 mmol Gd / L).

Example 74

a) 1 -0- (1 H, 1 H, 2H, 2H-perfluorodecyl) - (2,3,4,6-tetra-0-acetyl) -α-D-mannopyranos

The reaction of 50 g (128.09 mmol) of the title compound from Example 70a, which is used as a 4: 1 mixture with respect to the α, β-anomers, with a

Solution of 75.84 g (128.1 mmol) of 1-hydroxy-1 H, 1H, 2H, 2H-perfluorodecane in 150 ml of 1, 2-dichloroethane and a total of 19.47 g (166.53 mmol) of tin IV chloride, in analogy to that described for the syntheses of the title compounds from Examples 1b) and 4b). After working up and purification by column chromatography ( Eluent: hexane / ethyl acetate, 2: 1) to form 74.2 g (63.4% of theory) of the above-mentioned title compound in the form of a viscous and colorless oil. After ¹ H-NMR spectroscopic examination of the title compound, it was possible to conclude unambiguously from the size of the coupling constants of Jι, ₂ = 1.3 Hz that the α configuration was present at the anomer center, which is also the only configuration present at the anomer center, so ^x Accordingly, the title compound mentioned above could only be prepared in the form of the pure α-configured anomer.

Elemental analysis: calc .: C 44.65 H 2.53 F 35.32 get: C 44.77 H 2.61 F 35.09

b) 1-0- (1H, 1H, 2H, 2H-perfluorodecyl) -α -D-mannopyranose

25 g (27.33 mmol) of the title compound from Example 74a are suspended in 400 ml of absolute methanol and a catalytic amount of sodium methoxide is added at 5 ° C. After a reaction time of 3 hours at room temperature, the thin-layer chromatographic control (eluent: chloroform / methanol 9: 1) of the course of the reaction already shows quantitative conversion. For the purpose of working up, the now clear reaction solution is neutralized by adding Amberlite IR 120 (H ⁺ form) cation exchange resin, suctioned off from the exchanger and the methanolic filtrate thus obtained is drawn off to dryness in vacuo. The crystalline residue obtained is purified by recrystallization twice from ethanol. After ¹ H-NMR spectroscopic examination of the title compound, it was possible to conclude unambiguously from the size of the coupling constants of J-ι, ₂ = 1.0 Hz that the α configuration was present at the anomeric center. The present α configuration is the only configuration present at the anomer center, ie the amount of β-configured anomers of the title compound which may be formed is below the ¹ H-NMR spectroscopic detection limit. The above-mentioned title compound was therefore only prepared in the form of the pure α-configured anomer. Yield: 16.2 g (94.6% of theory) of a colorless and crystalline solid. Melting point: 172-174 ° C. with decomposition. Elemental analysis: calc .: C 30.69 H 2.41 F 51, 57 get: C 30.57 H 2.48 F 51.65

c) Preparation of a formulation from metal complex II and 1-0- (1 H, 1 H, 2H, 2H-perfluorodecyl) -α -D-mannopyranose

To 50 ml of a solution of metal complex II (150 mmol / L), dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA), a solution of 2.01 g ( 3.21 mmol) of the title compound from Example 74b, dissolved in 200 ml of ethanol, and the mixture is stirred at 50 ° C. for 2 hours. The solution is evaporated to dryness in vacuo and the residue with dist. Water made up to a total of 75 ml. The mixture is stirred at 40 ° C. for 10 minutes and filtered through a 0.2 μm filter. The filtrate is filled into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 75

a) 1--0 (1H, 1H, 2H, 2H-perfluorododecyl) -2,3,4,6-tetra-0-acetyl-α-D-mannopyranose

The reaction of 35 g (89.66 mmol) of the title compound from Example 70a, which is used as a 4: 1 mixture with respect to the α, β-anomers, with a solution of 50.60 g (89.7 mmol) of 1-hydroxy -1H, 1H, 2H, 2H-perfluorododecane in 100 ml of 1, 2-dichloroethane and a total of 13.63 g (16.61 mmol) of tin IV chloride, in analogy to the synthesis of the title compounds from Examples 1b) , 4b) and 5b), after working up and purification by column chromatography (eluent: hexane / ethyl acetate = 2: 1) leads to the formation of 62.49 g (68.7% of theory) of the above-mentioned title compound in the form of a viscous and colorless oil. According to ¹ H-NMR Spectroscopic examination of the title _compound , based on the size of the coupling constants of J _1ι2 = 1.4 Hz, the existence of the α configuration at the anomeric center, which is also the only configuration at the anomer center, was clearly inferred, so that the title compound mentioned above can only be found in Form of the pure α - configured anomer could be represented.

Elemental analysis: calc .: C 42.62 H 2.28 F 39.32 get: C 42.55 H 2.38 F 39.40

b) 1 -0- (1 H, 1 H, 2H, 2H-perfluorododecyl) -α - D-mannopyranose

25 g (24.64 mmol) of the title compound from Example 75a are suspended in 400 ml of absolute methanol and a catalytic amount of sodium methoxide is added at 5 ° C. After a reaction time of 3 hours at room temperature, the thin-layer chromatographic control (eluent: chloroform / methanol = 9: 1) of the course of the reaction already shows quantitative conversion. For the purpose of working up, the now clear reaction solution is neutralized by adding Amberlite IR 120 (H ⁺ form) cation exchange resin, suctioned off from the exchanger and the methanolic filtrate thus obtained is drawn off to dryness in vacuo. The crystalline residue obtained is purified by recrystallization twice from a mixture of 2-propanol / ethanol (1: 1). After ¹ H-NMR spectroscopic examination of the title compound, it was possible to conclude unambiguously from the size of the coupling constants of J-ι, ₂ = 0.9 Hz that the α configuration was present at the anomeric center. The present α configuration is the only configuration present at the anomer center, ie the amount of β-configured anomers of the title compound which may be formed is below the ¹ H-NMR spectroscopic detection limit. The above-mentioned title compound was therefore only prepared in the form of the pure α-configured anomer. Yield: 16.96 g (90.8% of theory) of a colorless and crystalline solid. Melting point: 187-188 ° C. with decomposition. Elemental analysis: calc .: C 29.77 H 2.08 F 54.93 get: C 29.70 H 2.28 F 54.83

c) Preparation of a formulation from metal complex VI and 1-0- (1 H, 1 H, 2H, 2H-perfluorododecyl) -α -D-mannopyranose

To 52 ml of a solution of the metal complex VI (180 mmol / L) dissolved in 0.45% aqu. Sodium chloride solution, 1.70 g (2.34 mmol) of the title compound from Example 75b are added and the mixture is heated in the microwave for 10 minutes. The solution is cooled to room temperature, filtered through a 0.2 m filter and the filtrate is filled into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 180 mmol Gd / L)

Example 76

a) 2,3,4,6-Tetra-0-acetyl) -1-0-α-D- [3,6,9-trioxa (Ci2-C ₁₉ -heptadecafluor) - nonadecyl] -mannopyranose

The reaction of 20 g (51, 23 mmol) of the title compound from Example 70a, which is used as a 4: 1 mixture with respect to the β-anomers, with a solution of 30.54 g (51, 23 mmol) of 1 -hydroxy- tris- (1H, 1H, 2H, 2H-0) - 1H, 1H, 2H, 2H-perfluorodecane in 100 ml 1, 2-dichloroethane and a total of 5.98 g (51, 23 mmol) tin IV chloride, in Analogous to that described for the syntheses of the title compounds from Examples 1b), 4b) and 5b), after working up and purification by column chromatography (eluent: hexane / ethyl acetate = 1: 1), 34.22 g (72.1% of theory) are formed . Th.) Of the above-mentioned title compound in the form of a viscous and colorless oil. After ¹ H-NMR spectroscopic examination of the title _{compound, it was possible to conclude} unambiguously from the size of the coupling constants of J _1ι2 = 1.1 Hz that the α configuration was present at the anomeric center, which is also the only configuration present at the anomer center, so that the title compound mentioned above could only be prepared in the form of the pure α-configured anomer. Elemental analysis: calc .: C 38.89 H 3.81 F 34.86 get: C 39.02 H 3.77 F 34.90

b) 1-O-α -D- [3,6,9-trioxa- (Cι ₂ -Cιg-heptadecafluor) -nonadecyl] - mannopyranose

20 g (21.58 mmol) of the title compound from Example 76a are suspended in 350 ml of absolute methanol and a catalytic amount of sodium methoxide is added at 5 ° C. After a reaction time of 3 hours at room temperature, the thin-layer chromatographic control (eluent: chloroform / methanol = 6: 1) of the course of the reaction already shows quantitative conversion. For working up, the now clear reaction solution is neutralized by adding Amberlite IR 120 (H ⁺ form) cation exchange resin, suctioned off from the exchanger and the methanolic filtrate thus obtained is drawn off to dryness in vacuo. The crystalline residue obtained is purified by recrystallization twice from a mixture of ethyl acetate / 2-propanol / ethanol (1: 0.5: 1). After ¹ H-NMR spectroscopic examination of the title compound, it was possible to conclude unambiguously from the size of the coupling constants of Jι, ₂ = 1.0 Hz that the α configuration was present at the anomeric center. The present α configuration is the only configuration present at the anomer center, ie the amount of β-configured anomers of the title compound which may be formed is below the ¹ H-NMR spectroscopic detection limit. The above-mentioned title compound was therefore only prepared in the form of the pure α-configured anomer.

Yield: 15.20 g (92.9% of theory) of a colorless, crystalline solid. Melting point: 141 ° C. Elemental analysis: calc .: C 34.84 H 3.59 F 42.58 get: C 34.72 H 3.66 F 42.67

c) Preparation of a formulation from the title compound of Example 68 and 1-O-α -D- [3,6,9-trioxa- (Ci2-Cι ₉ -heptadecafluor) -nonadecyl] - mannopyranose To 38 ml of a solution of the title compound of Example 68 (300 mmol / L), dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 3.71 g (4.89 mmol) of the title compound from Example 76b are added and the mixture is treated with 0.9% aqu. Saline to a total of 114 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 77

a) 2,3,4,6-Tetra-0-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, 25.0 g (57.28 mmol); [Presentation according to:

Ponpipom, Mitree M .; Bugianesi, Robert L .; Robbins, James O; Doebber, TW; Shen, TY; J. Med .; 24; 12; 1981; 1388-1395] 3- (Tetra-0-acetyl-α-D-mannopyranosylmercapto) propionic acid and 5.77 g (57.28 mmol) triethylamine dissolved. After the reaction solution has been cooled to -15 ° C. to -20 ° C., a solution of 7.82 g (57.28 mmol) of isobutyl chloroformate in 100 ml of dry tetrahydrofuran is slowly added dropwise at this temperature with stirring, the dropwise rate being so chosen is that an internal temperature of -10 ° C is not exceeded. After a reaction time of 15 minutes at -15 ° C., a solution of 29.05 g (57.28 mmol) of 1H, 1H, 2H, 2H-heptadecafluoro-1- (2-aminoethyoxy) decane and 5, 77 g (57.28 mmol) of triethylamine, as a solution in 200 ml of dry tetrahydrofuran, are slowly added at -20 ° C. After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is evaporated to dryness in vacuo. The remaining residue is taken up in 250 ml of ethyl acetate and washed twice with 200 ml of saturated sodium bicarbonate solution and once with 300 ml of water. After drying the organic phase over sodium sulfate, the salt is filtered off and the ethyl acetate in Vacuum removed. The remaining oily residue is purified on silica gel using dichloromethane / hexane / 2-propanol (8: 5: 1) as the eluent.

Yield: 44.90 g (84.7% of theory) of the above-mentioned title compound as a colorless and highly viscous oil.

Elemental analysis: calc .: C 37.63 H 3.48 N 1.51 S 3.46 F 34.89 get: 0 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 compound from Example 77a are suspended in 400 ml of absolute methanol and a catalytic amount of sodium methoxide is added at 5 ° C. After a reaction time of 3 hours at room temperature, the thin-layer chromatographic control (eluent: chloroform / methanol = 9: 1) of the course of the reaction already shows quantitative conversion. For working up, the now clear reaction solution is neutralized by adding Amberlite IR 120 (H ⁺ form) cation exchange resin, suctioned off from the exchanger and the methanolic filtrate thus obtained is drawn off to dryness in vacuo. The crystalline residue obtained is purified by recrystallization from a mixture of ethyl acetate / methanol (0.5: 1). After ¹ H-NMR spectroscopic examination of the title compound, it was possible to conclude unambiguously from the size of the coupling constants of Jι, ₂ = 1.1 Hz that the α configuration was present at the anomeric center. The present α configuration is the only configuration present at the anomer center, ie the amount of β-configured anomers of the title compound which may be formed is below the ¹ H-NMR spectroscopic detection limit. The above-mentioned title compound was therefore only prepared in the form of the pure α-configured anomer.

Yield: 23.76 g (96.8% of theory) of a colorless and crystalline solid

Melting point: 113 - 114.5 ° C

Elemental analysis: calc .: C 33.30 H 3.19 N 1.85 S 4.23 F 42.64 get: C 33.21 H 3.26 N 1.96 S 4.08 F 42.77 c) Preparation of a formulation from the title compound from Example 66 and 1 -α -D- [3-thiopropionic acid-N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) amide] -mannopyranose

A solution of 27.41 is added to 47 ml of a solution of the title compound from Example 66 (330 mmol / L), dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA) g (36.19 mmol) of the title compound from Example 77b, dissolved in 200 ml of ethanol, and the mixture is stirred at 50 ° C. for 2 hours. The solution is evaporated to dryness in vacuo and the residue with dist. Make up to a total of 155 ml of water. The mixture is stirred at 40 ° C. for 10 minutes and filtered through a 0.2 μm filter. The filtrate is filled into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 78

a) 2,3,4,6-tetra-0-acetyl-1 -ß -D- [3,6,9-trioxa- (-Cι -Cι ₉ -heptadecafluor) - nonadecyl] -glucopyranosyluronic acid

20.2 g (50.85 mmol) methyl (1-bromo-2,3,4-tri-0-acety-α-D-glucopyranoside) uronate [representation according to: Pelzer; Hoppe-Seyler's Z. Physiol.Chem .; 314; 1949; 234, 237 and Goebel; Baber; J. Biol .; 111; 1935; 347, 350 and Bollenback et al .; J. Amer; 77; 1955; 3310, 3313.] and 60.64 g (101.7 mmol) of 3,6,9-trioxa- (Cι ₂ -C ₁₉ -heptadecafluor) - nonadecan-1-ol are dissolved in 250 ml of anhydrous acetonitrile and at room temperature with 13.0 g of freshly precipitated silver oxide are added. After a reaction time of 12 hours at room temperature, the insoluble silver salts are filtered off, the salts are washed well with dichloromethane and the filtrate thus obtained is drawn off to dryness in vacuo. The remaining residue is purified by column chromatography (eluent: hexane / ethyl acetate = 3: 1).

Yield: 22.99 g (53.3% of theory) of the above-mentioned title compound as a colorless, highly viscous oil

Elemental analysis: calc .: C 41.05 H 3.92 F 38.06 get: C 41.20 H 3.76 F 38.22

b) 1 -0-ß-D- [3,6,9-trioxa- (Ci ₂ -Cι ₉ -heptadecafluor) -nonadecyl] - glucopyranosyluronic acid

10.0 g (11.78 mmol) of the title compound from Example 78a are suspended in 200 ml of a mixture consisting of methanol and 0.5 molar sodium hydroxide solution in a ratio of 2: 1 with stirring at room temperature. After a reaction time of 12 h at room temperature, the now clear reaction mixture is neutralized for working up by adding Amberlite IR 120 (H ⁺ - form) cation exchange resin, suctioned off from the exchanger and the methanolic-aqueous filtrate thus obtained is drawn off to dryness in vacuo. The crystalline residue obtained is purified by recrystallization from a mixture of ethyl acetate / methanol (0.25: 1). After ¹ H-NMR spectroscopic examination of the title compound, it was possible to conclude unambiguously from the size of the coupling constants of Jι _{> 2} = 9.2 Hz that the β configuration was present at the anomeric center. The ß configuration at hand is the only configuration at the anomer center, ie the amount of ß - configured anomers of the title compound that may be formed is below the ¹ H NMR detection limit. The above-mentioned title compound was therefore only prepared in the form of the pure β-configured anomer.

Melting point: 78.5 ° C Elemental analysis: calc .: C 34.21 H 3.26 F 41, 81 get: C 34.38 H 3.26 F 41.90

c) Preparation of a formulation from metal complex I and 1-O-ß -D- [3,6,9- trioxa- (Cι ₂ -Cι ₉ -heptadecafluor) -nonadecyl] -glucopyranosyluronic acid

To 38 ml of a solution of the metal complex I (280 mmol / L), dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 19.18 g (24.83 mmol) of the title compound from Example 78b are added and the mixture is filled with 0.9% aqu.

Saline to a total of 53.2 ml. The mixture is heated at 60 ° C. for 2 hours Ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 200 mmol Gd / L).

Example 79

a) 6- (2-Oxa-1 H, 1 H, 3H, 3H, 4H, 4H-perfluorodecyl) -0 ¹ , 0 ² , 0 ³ , 0 ⁴ -diisopropylidene-α -D-galactopyranose

To a stirred suspension of 2.01 g (70.0 mmol; 80% in mineral oil) sodium hydride in 25 ml dimethylformamide, a total of 12.15 g (46.66 mmol) O ¹ , O ² , 0 ³ , 0 ⁴ -diisopropylidene-α - galactopyranose [representation according to: Levene; Meyer; J. Biol .; 64; 1925; 473 and McCreath; Smith; J.Chem.Soα; 1939; 387, 389 and Freudenberg; Hixon; Ber .; 56; 1923; 2119, 2122] dissolved in 200 ml of absolute dimethylformamide, added dropwise. The mixture is then left to stir at room temperature for a further 120 minutes and then a total of 30.09 g (48.0 mmol) of 1-bromo-1H, 1H, 2H, 2H-perfluorododecane, dissolved in 150 ml of absolute dimethylformamide, are slowly added dropwise. The reaction solution thus obtained is then stirred for a further 12 hours at room temperature. For working up, the reaction solution is slowly poured into 1 liter of ice water and then exhaustively extracted with diethyl ether. The combined organic phases are then washed twice with 200 ml of saturated sodium bicarbonate solution and twice with 200 ml of water. After the organic phase has been dried over sodium sulfate, the salt is filtered off with suction and the solvent is stripped off in vacuo. The remaining oily residue is purified on silica gel using ethyl acetate / hexane (1:10) as the eluent. Yield: 29.8 g (79.3% of theory) of the above-mentioned title compound in the form of a viscous, colorless oil

Elemental analysis: calc .: C 35.75 H 2.87 F 49.47 ge: C 35.64 H 2.98 F 49.54 b) 6- (2-Oxa-1H, 1H, 3H, 3H, 4H, 4H-perfluorodecyl) -α -D-galactopyranose

300 g of a 1% strength aqueous sulfuric acid solution are added to 20 g (24.8 mmol) of the title compound from Example 79a and the mixture is stirred at 80 ° C. for 3 hours. After cooling to room temperature, the mixture is neutralized by adding aqueous barium hydroxide solution and then filtered off from the precipitated barium sulfate, and the clear aqueous product solution thus obtained is freeze-dried. By ¹ H-NMR spectroscopic examination of the title compound, the existence of both possible configurations at the anomeric center was clearly shown, the present α / ß configuration ratio after ¹ H-NMR spectroscopic examination with 1: 1.4 (α: ß ) was determined at the anomerism center. The above-mentioned title compound was therefore isolated only in the form of the 1: 1.4 (α: β) anomer mixture, ie an anomer separation was dispensed with. Yield: 15.28 g (98.4% of theory) of the above title compound as a colorless lyophilisate

Elemental analysis (based on anhydrous substance): calc .: C 35.75 H 2.87 F 49.47 get: C 35.64 H 2.98 F 49.54

c) Preparation of a formulation from the title compound of Example 67 and 6- (2-oxa-1H, 1H, 3H, 3H, 4H, 4H-perfluorodecyl) -α -D-galactopyranose

A solution of 1.68 is added to 43 ml of a solution of the title compound of Example 67 (250 mmol / L), dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA) g (2.69 mmol) of the title compound from Example 79b, dissolved in 200 ml of ethanol, and the mixture is stirred at 50 ° C. for 2 hours. The solution is evaporated to dryness in vacuo and the residue with dist. Water made up to a total of 107.5 ml. The mixture is stirred at 40 ° C. for 10 minutes and filtered through a 0.2 μm filter. The filtrate is filled into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 80 a) 1 -0-α-D - [(1-perfluorooctylsulfonylpiperazin-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) are dissolved in 300 ml of tetrahydrofuran. At 0 ° C, 24.73 g (100 mmol) of EEDQ (= 1, 2-dihydro-2-ethoxyquinoline-1-carboxylic acid ethyl ester) are added and the mixture is stirred for 3 hours at 0 ° C, then for 6 hours at room temperature. The solution is evaporated to dryness in vacuo and the residue is purified by flash chromatography on silica gel (mobile phase: hexane / ethyl acetate = 10: 1). The product-containing fractions are evaporated to dryness, the residue is dissolved in a mixture of 200 ml of methanol / 150 ml of dichloromethane and hydrogenated over palladium / carbon (10% Pd / C 2 g) for 8 hours. The hydrogenation catalyst is filtered off and the filtrate is evaporated to dryness. The residue is recrystallized from acetone / diethyl ether.

Yield: 30.39 g (73% of theory) of a waxy, colorless solid

Elemental analysis: calc .: C 30.47 H 2.68 F 40.96 N 3.55 S 4.07 ge: C 30.61 H 2.75 F 41.10 N 3.46 S 4.12

b) Preparation of a formulation of metal complex I and 1-0-α-D - [(1- perfluorooctylsulfonylpiperazin-4-carbonyl -) - methyl] -mannopyranose

To 32 ml of a solution of the metal complex I (280 mmol / L), dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 4.71 g (5.97 mmol) of the title compound from Example 80a are added and the mixture is filled with 0.9% aqu. Saline to a total of 55 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. It is filtered through a 0.2 μ filter and the filtrate is filled into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 200 mmol Gd / L).

Example 81 a) 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid, sodium salt

20 g (38.3 mmol) of 3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid (preparation described in DE 196 03 033) are dissolved in 300 ml of ethanol and 7.7 ml of 5N aqu. Sodium hydroxide solution added. It is evaporated to dryness and the residue is dried in a vacuum drying cabinet (8 hours at 60 ° C.).

Yield: 20.85 g (quantitative) of a colorless, crystalline powder

Elemental analysis: calc .: C 26.49 H 1.11 F 59.35 Na 4.22 get: C 26.60 H 1.19 F 59.47 Na 4.30

b) Preparation of a formulation from metal complex I and 3-oxa- 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid, sodium salt

To 32 ml of a solution of the metal complex I (280 mmol / L), dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 2.09 g (3.84 mmol) of the title compound from Example 81a are added and the mixture is run with 0.9% aqu. Saline to a total of 90 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

c) Preparation of a formulation from metal complex I and 3-oxa- 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid, sodium salt

To 32 ml of a solution of the metal complex I (280 mmol / L) dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) is given 1.00 g (1.84 mmol) of the title compound from Example 81a and filled with 0.9% aqu. Saline to a total of 90 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

d) Preparation of a formulation from metal complex I and 3-oxa- 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid, sodium salt

To 32 ml of a solution of the metal complex I (280 mmol / L), dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 0.54 g (1.0 mmol) of the title compound from Example 81a is added and the mixture is filled with 0.9% aqu. Saline to a total of 90 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 82

a) 1 -Perf luoroctylsulfonyl-4- (3,6,9, 12,15-pentaoxahexadecanoyl) piperazine

20 g (35.2 mmol) of perfluorooctylsulfonylpiperazine (see Example 80a) are dissolved in 300 ml of dichloromethane and 5.06 g (50 mmol) of triethylamine are added. Man ^"is cooled to 0 ° C and added dropwise over 20 minutes 14.24 g (50 mmol) 3,6,9,12, 15-Pentaoxahexansäurechlorid added and stirred for 3 hours at 0 ° C. It is 400 ml of 5% aqueous sodium Hydrochloric acid and stirred well. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent = dichloromethane / methanol: 15: 1).

Yield: 26.44 (92% of theory) of a waxy solid

Elemental analysis: calc .: C 33.83 H 3.58 N 3.43 F 39.55 S 3.93 get: C 33.96 H 3.66 N 3.50 F 39.67 S 3.82 b) Preparation of a formulation from metal complex I and 1-perfluorooctylsulfonyl-4- (3,6,9,12,15-pentaoxahexadecanoyl) piperazine

To 47 ml of a solution of the metal complex I (280 mmol / L), dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 4.61 g (5.64 mmol) of the title compound from Example 82a are added and the mixture is mixed with 0.9% aqu. Saline to a total of 66 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 200 mmol Gd / L).

Example 83

a) 1 H, 1 H, 2H, 2H-perfluorodecyl-p-toluenesulfonic acid ester

20 g (43.1 mmol) of 1 H, 1 H, 2H, 2H-perfluorodecanol are dissolved in 200 ml of pyridine and 9.53 g (50 mmol) of p-toluenesulfonic acid chloride are added in portions at 0 ° C. The mixture is stirred for 5 hours at room temperature. The solution is poured into 1000 ml of ice water and stirred for 10 minutes. The precipitate is filtered off, washed with plenty of water and then recrystallized from acetone. Yield: 22.04 g (97% of theory) of a colorless crystalline solid

Elemental analysis: calc .: C 22.78 H 0.76 F 61, 26 S 6.08 get: C 22.89 H 0.70 F 61, 39 S 6.15

b) C ₁₈ -C ₂₅ heptadeca-fluoro-3,6,9,12,15-pentaoxa-pentacosan-1-ol

20 g (37.94 mmol) of the title compound from Example 83a, 35.74 g (150 mmol)

Pentaethylene glycol and 1 g of 18-crown-6 are dissolved in 300 ml of tetrahydrofuran and 10.1 g (180 mmol) of finely powdered potassium hydroxide are added. Stir 10 Hours at room temperature. The solid is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 15: 1).

Yield: 5.45 g (21% of theory) of a colorless, viscous oil

Elemental analysis: calc .: C 35.10 H 3.68 F 47.19 get: 0 35.22 H 3.77 F 47.10

c) Preparation of a formulation from the title compound of Example 69 and Ci ₈ -C ₅ -heptadeca-fluoro-3,6,9,12,15-pentaoxa-pentacosan-1-ol

To 53 ml of a solution of the title compound of Example 69 (310 mmol / L), dissolved in 0.45% aqu. Sodium chloride solution), 44.98 g (65.72 mmol) of the title compound from Example 83b are added and the mixture is heated in the microwave for 10 minutes. The solution is cooled to room temperature, filtered through a 0.2 μm filter and the filtrate is filled into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 310 mmol Gd / L).

Example 84

a). N, N-bis (8-hydroxy-3,6, -dioxa-octyl) -perfIuoroctylsulfonsäureamid

15 g (29.23 mmol) of perfluorooctylsulfonamide and 22.16 g (87.7 ml) of 9- (tetrahydropyran-2-yl) -3,6,9-trioxa-nonyl chloride are 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 the mixture is boiled under reflux for 10 hours. The solid is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 400 ml of ethanol and 30 ml of 10% aqu. Hydrochloric acid added. The mixture is stirred for 2 hours at room temperature. It is adjusted to pH 7 with sodium hydroxide solution and the solution is concentrated in vacuo. The residue is chromatographed on silica gel (mobile phase: dichloromethane / methanol = 10: 1). Yield: 11.38 g (51% of theory) of a colorless, viscous oil Elemental analysis: calc .: C 31.46 H 3.43 N 1.83 F 42.30 S 4.20 ge: C 31, 59 H 3.50 N 1.90 F 42.46 S 4.08

b) Preparation of a formulation from metal complex I and N, N-bis (8-hydroxy-3,6, -dioxa-octyl) perfluorooctylsulfonamide

To 37 ml of a solution of the metal complex I (280 mmol / L), dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 7.91 g (10.36 mmol) of the title compound from Example 84a are added and the mixture is filled with 0.9% aqu. Saline to a total of 104 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 85

a) N, N-bis (t-butyloxycarbonylmethyl) perfluorooctylsulfonic acid amide

20 g (38.97 mmol) of perfluorooctylsulfonamide and 20.73 g (150 mol) of potassium carbpnate are suspended in 200 ml of acetone and 17.56 g (90 mmol) of bromoacetic acid tert-butyl ester are added. The mixture is refluxed for 3 hours. The solid is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n-hexane / ethyl acetate = 10: 1). Yield: 23.53 g (83% of theory) of a colorless, waxy solid. Elemental analysis: calc .: C 33.02 H 3.05 F 44.40 N 1.93 S 4.41 get: C 33.19 H 3.11 F 44.30 N 1.99 S 4.32

b) N, N-bis (carboxymethyl) perfluorooctylsulfonic acid amide, disodium salt 23 g (31, 62 mmol) of the title compound from Example 85a are dissolved in 300 ml of trifluoroacetic acid and stirred for 5 hours at room temperature. It is evaporated to the dry state in a vacuum and the residue is recrystallized from acetone. The crystals are filtered off and dried in vacuo at 50 ° C. Yield: 17.7 g (91% of theory) of a colorless, crystalline powder

17 g (27.63 mmol) of the diacid thus obtained are dissolved in 100 ml of water / 300 ml of ethanol and 9.2 ml of 3 N aqu. Sodium hydroxide solution added. The mixture is stirred at room temperature for 20 minutes and then evaporated to dryness in vacuo. The residue is dried in vacuo (60 ° C / 8 hours). Yield: 18.2 g of colorless, crystalline powder

Elemental analysis: calc .: C 21.87 H 0.61 N 2.12 F 49.00 S 4.86 Na 6.98 get: C 22.00 H 0.70 N 2.20 F 49.17 S 4, 93 Na 7.10

c) Preparation of a formulation from metal complex II and N, N-bis (carboxymethyl) perfluorooctylsulfonamide, disodium salt

To 41 ml of a solution of metal complex II (250 mmol / L), dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 2.89 g (4.39 mmol) of the title compound from Example 85b are added and the mixture is filled with 0.9% aqu. Saline to a total of 52 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 200 mmol Gd / L).

Example 86

a) 1 H, 1 H, 2H, 2H-perfluorododecyl-sulfuric acid monoester, sodium salt

10 g (17.73 mmol) of 1H, 1H, 2H, 2H-perfluorododecanol are dissolved in 300 ml

Chloroform dissolved and at 0 ° C 2.82 g (17.73 mmol) sulfur trioxide-pyridine

Complex added. The mixture is stirred at 0 ° C. for one hour and then evaporated to dryness in vacuo. The residue is dissolved in 300 ml of ethanol and with 17.8 ml 1N aqu. Sodium hydroxide solution added. The solution is evaporated to dryness and the residue is dried in vacuo (60 ° C / 2 h).

Yield: 11.81 g (quantitative)

Elemental analysis: calc .: C 21.64 H 0.61 F 59.89 Na 3.45 S 4.81 get: C 21.70 H 0.72 F 60.00 Na 3.57 S 4.92

b) Preparation of a formulation from metal complex VI and 1 H, 1H, 2H, 2H-perfluorododecyl-sulfuric acid monoester, sodium salt

To 38 ml of a solution of the metal complex VI (290 mmol / L), dissolved in 0.45% aqu. Sodium chloride solution), 4.90 g (7.35 mmol) of the title compound from Example 86a are added and the mixture is heated in the microwave for 10 minutes. The solution is cooled to room temperature, filtered through a 0.2 m filter and the filtrate is filled into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 290 mmol Gd / L).

Example 87

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluoropentadecanoic acid, sodium salt

10 g (16.07 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluoropentadecanoic acid are dissolved in 300 ml of ethanol and mixed with 16.1 ml of 1N aqu. Sodium hydroxide solution added. The solution is evaporated to dryness and the residue is dried in vacuo (60 ° C / 2h).

Yield: 10.35 g (quantitative) of a colorless amorphous powder

Elemental analysis: calc .: C 26.10 H 0.94 F 61.94 Na 3.57 get: C 26.22 H 1.00 F 62.05 Na 3.66 b) Preparation of a formulation from the title compound of Example 66 and 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluoropentadecanoic acid, sodium salt

A solution of 3.36 is added to 45 ml of a solution of the title compound of Example 66 (270 mmol / L), dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA) g (5.21 mmol) of the title compound from Example 87a, dissolved in 200 ml of ethanol, and the mixture is stirred at 50 ° C. for 2 hours. The solution is evaporated to dryness in vacuo and the residue with dist. Make up to a total of 122 ml. The mixture is stirred at 40 ° C. for 10 minutes and filtered through a 0.2 μm filter. The filtrate is filled into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 88

a) Ethylenediamine-N, N-tetraacetic acid-N- (1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa- perfluorotridecyl) monoamide

10.14 g (20 mmol) of 1 H, 1H, 2H, 2H, 4H, 4H, 5H are added in portions to 30 g (117.1 mmol) of EDTA bisanhydride suspended in 200 ml of dimethylformamide and 50 ml of pyridine at 50 ° C. , 5H-3-oxa-perfluorotridecylamine and stirred for 6 hours at 50 ° C. 10 ml of water are added, the mixture is stirred at 50 ° C. for 10 minutes and the residue is evaporated to dryness. The residue is taken up in a little water and brought to pH 4 with glacial acetic acid. The insoluble precipitate is filtered off and chromatographed on RP-18 (mobile solvent: acetonitrile / water / gradient).

Yield: 9.58 g (61% of theory) of a colorless solid

Water content: 8% Elemental analysis: calc .: C 33.64 H 3.59 N 5.35 F 41, 12 ge: C 33.51 H 3.69 N 5.44 F 41.24 b) ethylenediamine-N, N-tetraacetic acid-N- (1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa- perfluorotridecyl) monoamide, calcium salt, sodium salt

9.0 g (11.46 mmol) of the title substance from Example 88a are suspended in 300 ml of water and 11.4 ml of 1N aqu. Sodium hydroxide solution added. Then 1.15 g (11.46 mmol) of calcium carbonate are added and the mixture is stirred at 50 ° C. for 5 hours. The solution is filtered and the filtrate freeze-dried.

Yield: 9.7 g (100% of theory) of a colorless, amorphous solid

Water content: 7.5% Elemental analysis: calc .: C 31, 25 H 2.98 N 4.97 F 38.20 Na 2.72 Ca 4.74 get: 0 31, 40 H 3.09 N 5.10 F 38.07 Na 2.81 Ca 4.82

c) Preparation of a formulation of metal complex I and ethylenediamine-N, N-tetraacetic acid-N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-5-3-oxa-perfluorotridecyl) - monoamide, calcium salt, sodium salt

To 43 ml of a solution of the metal complex I (280 mmol / L), dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 2.54 g (3.01 mmol) of the title compound from Example 88b are added and the mixture is filled with 0.9% aqu. Saline to a total of 121 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 89

a) 1 H, 1 H, 2H, 2H-perfluorodecyl (2,2-dimethyl-5-hydroxy-1, 3-dioxepan-6-yl) ether

30 g (64.64 mmol) of 1 H, 1 H, 2H, 2H-perfluorodecanoI are dissolved in 200 ml of tetrahydrofuran and 1.68 g (70 mmol) of sodium hydride are added at 0 ° C. The mixture is stirred for 2 hours at room temperature, then for 4 hours at 60 ° C. The solution is placed in a metal autoclave, then 9.31 g (64.64 mmol) of 2,2-dimethyl-1, 3,6-trioxabicyclo [5.1.0] octane are added and the mixture is then heated at 150 ° C. for 10 hours. The reaction solution is poured onto ice water and extracted twice with diethyl ether. The combined organic phases are evaporated to dryness and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone = 10: 1)

Yield: 16.12 g (41% of theory) of a colorless solid

Elemental analysis: calc .: C 33.57 H 2.82 F 53.10 get: 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 compound from Example 89a are dissolved in 300 ml of ethanol and 30 ml of 10% aqu. Hydrochloric acid added. The mixture is heated under reflux for 5 hours. It is adjusted to pH 7 with sodium hydroxide solution, then evaporated to dryness and the residue is chromatographed on RP-18 (mobile solvent: acetonitrile / water / gradient).

Yield: 12.75 g (91% of theory) of a colorless solid

Water content: 4.5%

Elemental analysis: calc .: C 29.59 H 2.31 F 56.84 get: C 29.48 H 2.37 F 56.99

c) Preparation of a formulation from the title compound of Example 12 from WO 99/01161 (1, 4,7-Tris {1, 4,7-tris (N-carboxylatomethyl) -10- (N-1 - methyl-3-aza -2,5-dioxopentane-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 H, 1 H, 2H, 2H-perfluorodecyl- (1 - hydroxymethyl-2,3-dihydroxypropyl) ether To 37 ml of a solution of 1,4,7-tris {1,4,7-tris (N-carboxylatomethyl) -10- (N-1-methyl-3-aza-2,5-dioxopentane-1, 5-diyl] -1, 4,7,10-tetraazacyclododecane, Gd complex} -! 0- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-1, 4,7,10-tetraazacyclododecane (300 mmol / L), dissolved in 0.45% aqueous saline solution (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 9.46 g (16.65 mmol) of the title compound from Example 89b are added and make up to a total of 111 ml with 0.9% aqueous sodium chloride solution, and the mixture is heated in an ultrasound bath for 2 hours at 60 ° C. The solution is cooled to room temperature and adjusted to pH 7.4 with aqueous 2 N sodium hydroxide solution through a 0.2 μm filter and fills the filtrate into vials, a solution prepared in this way can be used directly for biological experiments (the concentration is 100 mmol Gd / L).

Example 90

a) 1 H, 1 H, 2H, 2H-perfluorodecyl- [1,2-bis (2,2-dimethyl-1,3-dioxolan-4-yl) -2-hydroxyethyl] ether

30 g (64.64 mmol) of 1H, 1H, 2H, 2H-perfluorodecanol are dissolved in 200 ml of tetrahydrofuran and 1.68 g (70 mmol) of sodium hydride are added at 0 ° C. The mixture is stirred for 2 hours at room temperature, then for 4 hours at 60 ° C. The solution is placed in a metal autoclave, then 15.78 g (64.64 mmol) of 1,2-bis (2,2-dimethyl-1,3-dioxolan-4-yl) oxirane is added, and the mixture is then stirred for 10 hours Heated to 150 ° C. The reaction solution is poured onto ice water and extracted twice with diethyl ether. The combined organic phases are evaporated to dryness and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone = 10: 1)

Yield: 14.2 g (31% of theory) of a colorless solid

Elemental analysis: calc .: C 37.30 H 3.56 F 45.59 get: C 37.48 H 3.66 F 45.71

b) 1 H, 1 H, 2H, 2H-perfluorodecyl [1,2-bis (1,2-dihydroxyethyl) -2-hydroxyethyl] ether

14 g (19.76 mmol) of the title compound from Example 90a are dissolved in 300 ml of ethanol and 30 ml of 10% aqu. Hydrochloric acid added. One heats 5 Hours under reflux. It is adjusted to pH 7 with sodium hydroxide solution, then evaporated to dryness and the residue is chromatographed on RP-18 (mobile solvent: acetonitrile / water / gradient).

Yield: 10.55 g (85% of theory) of a colorless solid. Water content: 3.2%.

Elemental analysis: calc .: C 30.59 H 2.73 F 51.41 get: C 30.73 H 2.81 F 51.58

c) Preparation of a formulation from metal complex 11 and 1H, 1H, 2H, 2H-perfluorodecyl- [1,2-bis (1,2-dihydroxyethyl) -2-hydroxyethyl] ether

To 41 ml of a solution of metal complex II (300 mmol / L), dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 11.98 g (19.07 mmol) of the title compound from Example 90b are added and the mixture is filled with 0.9% aqu. Saline to a total of 64 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. It is filtered through a 0.2 μ filter and the filtrate is filled into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 200 mmol Gd / L).

Example 91

a) PerfIuoroctylsulfonic acid-N, N-bis [(8-sulfuric acid monoester, sodium salt) -3,6-dioxaoctyl] -amide

13.54 g (17.73 mmol) of the title compound from Example 84a are dissolved in 300 ml of chloroform and 2.82 g (17.73 mmol) of sulfur trioxide-pyridine complex are added at 0 ° C. The mixture is stirred at 0 ° C. for one hour and then evaporated to dryness in vacuo. The residue is dissolved in 300 ml of ethanol and 17.8 ml of 1N aqu. Sodium hydroxide solution added. The solution is evaporated to dryness and the residue is dried in vacuo (60 ° C / 2 h). Yield: 17.15 g (quantitative) Elemental analysis: calc .: C 24.83 H 2.50 F 33.83 N 1.45 S 9.94 Na 4.75 get: C 24.96 H 2.62 F 33.97 N 1.53 S 10.05 Na 4.86

b) Preparation of a formulation from metal complex I and perfluorooctylsulfonic acid-N, N-bis [(8-sulfuric acid monoester, sodium salt) -3,6-dioxaoctyl] -amide

To 43 ml of a solution of the metal complex I (380 mmol / L), dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 142.29 g (147.06 mmol) of the title compound from Example 91a are added and the mixture is filled with 0.9% aqu. Saline to a total of 164 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 92

a) Diethyl 2- (2H, 2H, 3H, 3H, 5.5H, 6H, 6H-1, 4, -dioxaperfluorotetradec-1-yl) amber

30 g (59.03 mmol) of 1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanol are dissolved in 300 ml of tetrahydrofuran and at 0 ° C 1.68 g (70 mmol) of sodium hydride added. Mna stirred for one hour at 0 ° C, then 5 hours at 40 ° C. 20.25 g (80 mmol) of diethyl 2-bromo-succinate are added dropwise to this solution at 40 ° C. in the course of 10 minutes and the mixture is then stirred at this temperature for 12 hours. 500 ml of ice water are added and the mixture is extracted twice with 300 ml of diethyl ether. The combined organic phases are evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: n-hexane / ethanol = 20: 1):

Yield: 12.05 g (30% of theory). Elemental analysis: calc .: C 35.31 H 3.11 F 47.47 found: 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) -succinic acid, disodium salt

50 ml of 3N aqu are added to 11.5 g (16.90 mmol) of the title compound from Example 92a, dissolved in 300 ml of methanol. Caustic soda and refluxed 8 hours. It is evaporated to dryness and the residue is taken up in 300 ml of water. The aqueous phase is extracted twice with 300 ml of diethyl ether. The aqueous phase is acidified with conc. Hydrochloric acid to pH 1 and extracted 2 times with 300 ml of chloroform. The combined chloroform phases are dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 300 ml of water and with 5% aqu. Sodium hydroxide solution adjusted to pH 7.4. It is then freeze-dried.

Yield: 10.50 g (93% of theory) of a colorless, amorphous solid

Water content: 5.7%

Elemental analysis: calc .: C 28.76 H 1.66 F 48.33 Na 6.88 get: C 28.88 H 1.71 F 48.25 Na 6.95

c) Preparation of a formulation from metal complex II and 2- (2H, 2H, 3H, 3H, 5H, 5H, 6H, 6H-1, 4-dioxa-perfluorotetradec-1-yl) -succinic acid, disodium salt

To 57 ml of a solution of metal complex II (300 mmol / L), dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 1.14 g (1.71 mmol) of the title compound from Example 92b are added and the mixture is filled with 0.9% aqu. Saline to a total of 154 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L). Example 93

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

To 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 0 ° C 16.51 g (80 mmol) of N.N'-dicyclohexylcarbodiimide and stirred for 3 hours at this temperature. A solution of 5.10 g (38.30 mmol) of L-aspartic acid, dissolved in 300 ml of 5% aqueous solution, cooled to 0 ° C. is added to the active ester solution thus prepared. Sodium carbonate solution and stirred for 2 hours at 0 ° C. It is poured onto 500 ml of ice water, filtered from the precipitated dicyclohexylurea and made up with conc. Hydrochloric acid to pH 1. It is extracted 3 times with 300 ml of chloroform. The combined organic phases are evaporated to dryness and the residue is chromatographed on RP-18 (mobile solvent: acetonitrile / water / gradient). The diacid thus obtained is dissolved in 400 ml of water and with 1N aqu. Sodium hydroxide solution adjusted to pH 7.4. It is filtered and the filtrate is freeze-dried.

Water content: 6.3%. Yield: 21.13 g (81% of theory) of a colorless amorphous powder

Elemental analysis: calc .: C 28.21 H 1.48 N 2.06 F 47.41 Na 6.75 ge: C 28.30 H 1.53 N 2.11 F 47.53 Na 6.83

b) Preparation of a formulation from metal 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 the metal complex XIV (300 mmol / L), dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), 422 mg (0.62 mmol) of the title compound from Example 93a are added and the mixture is filled with 0.9% aqu. Saline to a total of 111 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L). Example 94

Preparation of a formulation from the title compound of Example 67 and perfluorooctanesulfonic acid, sodium salt

A solution of 1.34 is added to 43 ml of a solution of the title compound of Example 67 (250 mmol / L), dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA) g (2.69 mmol) of perfluorooctanesulfonic acid, sodium salt, dissolved in 200 ml of ethanol, and stirred at 50 ° C. for 2 hours. The solution is evaporated to dryness in vacuo and the residue with dist. Make up water to a total of 108 ml. The mixture is stirred at 40 ° C. for 10 minutes and filtered through a 0.2 μm filter. The filtrate is filled into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 95

Preparation of a formulation from the title compound of Example 68 and perfluorodecanesulfonic acid, sodium salt

To 49 ml of a solution of the title compound of Example 68 (310 mmol / L), dissolved in 0.45% aqu. Sodium chloride solution), 3.03 g (5.06 mmol) of perfluorodecanesulfonic acid, sodium salt are added and the mixture is heated in the microwave for 10 minutes. The solution is cooled to room temperature, filtered through a 0.2 μm filter and the filtrate is filled into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 310 mmol Gd / L).

Example 96 a) (1H, 1H, 2H, 2H-perfluorodecyl) -5 - [(1, 3-dicarboxy, disodium salt) phenyl] ether

42.5 g (80.62 mmol) of the title compound from Example 14a are added to 20 g (80.62 mmol) of trisodium salt of 5-hydroxyisophthalic acid in 300 ml of dimethylformamide and the mixture is stirred at 60 ° C. for 10 hours. It is poured onto 1500 ml of ice water and made up with conc. Hydrochloric acid to pH 1. It is extracted 3 times with 300 ml of chloroform. The combined organic phases are evaporated and the residue is chromatographed on RP-18 (mobile solvent: acetonitrile / water / gradient). The diacid thus purified is dissolved in 400 ml of water and the pH with 1 N aqu. Sodium hydroxide solution brought to pH 7.4. It is filtered and the filtrate is freeze-dried.

Yield: 20.05 g (37% of theory) of a colorless amorphous solid

Water content: 5.0% elemental analysis: calc .: C 32.16 H 1.05 F 48.05 Na 6.84 ge: C 32.30 H 1.15 F 48.20 Na 6.95

b) Preparation of a formulation from the title compound of Example 12 from WO 99/01161 (1, 4,7-tris {1, 4,7-tris (N-carboxylatomethyl) -10- (N-1-methyl-3-aza -2,5-dioxopentane-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

To 51 ml of a solution of 1, 4,7-tris {1, 4,7-tris (N-carboxylatomethyl) -10- (N-1-methyl-3-aza-2,5-dioxopentane-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% aqueous sodium chloride solution (pH 7.4; 0.25 mg / L CaNa ₃ DTPA), are added 6.86 g (10.2 mmol) of the title compound from Example 96a and make up to a total of 153 ml with 0.9% aqueous sodium chloride solution, and the mixture is heated in an ultrasound bath for 2 hours at 60 ° C. The solution is cooled to room temperature and adjusted to pH 7.4 with aqueous 2 N sodium hydroxide solution a 0.2 μm filter and fills the filtrate into vials prepared solution can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 97

Preparation of a formulation from metal complex XIV and 3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid, sodium salt

To 4 ml of a solution of the metal complex XIV (320 mmol / L), dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNasDTPA), 434 mg (0.55 mmol) of the title compound from Example 80a are added and the mixture is filled with 0.9% aqu. Saline to a total of 12.8 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 98

a) (Adamant-1-yl) -3-oxa-propionic acid t-butyl ester

To 15.22 g (100 mmol) 1-adamantanol in 300 ml 50% aqu. Potassium hydroxide solution, 200 ml of toluene are added at 0 ° C 29.26 g (150 mmol) of bromoacetic acid tert. Butyl ester and stir vigorously for 2 hours. It is poured onto 1500 ml of water and extracted twice with 300 ml of diethyl ether. The combined organic phases are dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n-hexane / diethyl ether 20: 1).

Yield: 21.58 g (81% of theory) of a viscous, colorless oil. Elemental analysis: calculated: C 72.14 H 9.84 get: C 72.26 H 9.95 b) (Adamant-1-yl) -3-oxa-propionic acid

20 g (75 mmol) of the title compound from Example 98a are dissolved in 200 ml of trifluoroacetic acid at 0 ° C. and the mixture is stirred at room temperature for 8 hours. It is evaporated to dryness and the residue is recrystallized from diisopropyl ether.

Yield: 14.68 g (93% of theory) of colorless leaflets

Elemental analysis: calc .: C 68.55 H 8.63 get: C 68.41 H 8.74

c) 1 - (Perfluorooctylsulfonyl) -4 - [(adamant-1-yl) oxapropionyl] piperazine

14 g (66.6 mmol) of the title compound from Example 98b and 37.50 g (66.6 mmol) of 1-perfluorooctylsulfonylpiperazine are dissolved in 300 ml of tetrahydrofuran and 32.15 g (130 mmol) of 1 at 0 ° C. 2 Dihydro-2-ethoxyquinoline-1-carboxylic acid ethyl ester (= EEDQ) added. The mixture is stirred for 5 hours at room temperature. The solution is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent:

Dichloromethane / diethyl ether = 30: 1).

Yield: 43.05 g (85% of theory) of a colorless solid

Elemental analysis: calc .: C 37.90 H 3.31 N 3.68 S 4.22 F 42.47 get: C 38.04 H 3.42 N 3.49 S 4.11 F 42.30

d) preparation of 0.5 part of metal complex I and 0.5 part of inclusion compound of β-cyclodextrin hydrate and 1- (

Perfluorooctylsulfonyl) -4 - [(adamant-1-yl) -oxapropionyl] piperazine

To 32 ml of a solution of the metal complex l (280 mmol / L) dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) is added to 6.81 g (8.96 mmol) of the title compound from Example 98c, 10.33 g (8.96) from β-cyclodextrin monohydrate and filled with 0.9% aqu. Saline to a total of 98 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The Gd concentration is 100 mmol Gd / L).

Example 99

a) 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid-N- (1-adamantyl) -amide

To 15.12 g (100 mmol) of 1-amino-adamantane, 52.21 (100 mmol) of 3-oxa- 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid and 11.51 g (100 mmol) of N- Hydroxysuccinimide, dissolved in 300 ml of tetrahydrofuran, is added at 0 ° C to 30.95 g (150 mmol) of N, N-dicyclohexylcarbodiimide. The mixture is stirred for 2 hours at 0 ° C., then for 6 hours at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase: dichloromethane / acetone = 30: 1).

Yield: 54.4 g (83% of theory) of a waxy solid

Elemental analysis: calc .: C 40.32 H 3.38 N 2.14 F 49.28 ge: C 40.47 H 3.49 N 2.03 F 49.09

b) Preparation from 0.6 parts of metal complex II and 0.4 parts of inclusion compound from β-cyclodextrin hydrate and 3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid-N- (1-adamantyl) -amide

To 41 ml of a solution of metal complex II (250 mmol / L) dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) are added 4.48 g (6.83 mmol) of the title compound from Example 99a and 7.87 g (6.83 mmol) of β-cyclodextrin monohydrate and the mixture is filled with 0.9% aqu. Saline to a total of 103 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The Solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The Gd concentration is 100 mmol Gd / L).

Example 100

a) 2- [N- (Ethyl) -N- (perfIuoroctylsulfonyl) amino] acetic acid-N- (adamantyl) amide

To 15.12 g (100 mmol) of 1-aminoadamantane, 58.52 g (100 mmol) of N- (ethyl) -N- (perfluorooctylsulfonyl) -aminoacetic acid and 11.51 g (100 mmol) of N-hydroxysuccinimide, dissolved in 300 ml of tetrahydrofuran is added at 0 ° C to 30.95 g (150 mmol) of N, N-dicyclohyexylcarbodiimide. The mixture is stirred for 2 hours at 0 ° C., then for 6 hours at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase: dichloromethane / acetone = 30: 1).

Yield: 55.65 g (79% of theory) of an amorphous solid. Elemental analysis: calc .: C 37.51 H 3.29 F 45.85 N 1.99 S 4.55 get: C 37.64 H 3.41 F 45.99 N 2.12 S 4.43

b) Preparation from 0.6 parts of metal complex I and 0.4 parts of inclusion compound from β-cyclodextrin hydrate and 2- [N- (ethyl) -N- (perfluorooctylsulfonyl) amino] acetic acid-N- ( 1-adamantyl) amide

To 32 ml of a solution of the metal complex I (280 mmol / L) dissolved in 0.45% aqu. Saline (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) are added 4.20 g (5.97 mmol) of the title compound from Example 100a and 6.88 g (5.97 mmol) from ß - cyclodextrin monohydrate and fills with 0.9% aqu. Saline to a total of 90 ml. The mixture is heated in an ultrasonic bath at 60 ° C. for 2 hours. The solution is cooled to room temperature and washed with aqu. 2 N sodium hydroxide solution adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate into vials. A solution prepared in this way can be used directly for biological experiments. (The Gd concentration is 100 mmol Gd / L). Example 101

a) 6-N- a) Benzyloxycarbonyl-2-N- (3,6,9,12-tetraoxatridecanoyl) lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide

A solution of 16.85 g (70 mmol) 3 is added dropwise at 0 ° C. to 50 g (60.20 mmol) of the title compound from Example 1c and 7.10 g (70 mmol) of triethylamine, dissolved in 350 ml of dichloromethane. 6,9,12 tetraoxatridecanoic acid chloride in 50 ml dichloromethane and stirred for 3 hours at 0 ° C. 200 ml of 5% aqueous hydrochloric acid are added and the mixture is stirred for 5 minutes at room temperature. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile phase: dichloromethane / acetone = 15: 1 yield: 30.94 g (92% of theory) of a colorless, viscous oil.

Hlementa ranaryse:

calcd. C 40.63 H 4.19 F 31.21 N 5.41 S 3.10 found C 40.75 H 4.08 F 31.29 N 5.58 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 compound from Example 101a are dissolved in 500 ml of ethanol and 6 g palladium catalyst (10% Pd / C) added. It is hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 43.0 g (quantitative) of a colorless solid.

Elemental analysis:

calcd. C 36.01 H 4.14 F 35.86 N 6.22 S 3.56 found C 36.20 H 4.23 F 35.99 N 6.38 S 3.71

c) 6-N- [l, 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 compound from Example 101b, 2.79 g (24.25 mmol) of N-hydroxysuccimmide, 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

are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred 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 then purified by chromatography (silica gel RP-18, mobile solvent: gradient from water / ethanol / acetomtril). Yield: 28.21 g (81% of theory) of a colorless solid. Water content: 11.0%

Elemental analysis (calculated on anhydrous substance) calcd. C 36.53 H 4.33 F 21.36 N 8.34 S 2.12 Gd 10.40 found. C 36.64 H 4.48 F 21.39 N 8.29 S 2.15 Gd 10.57

Example 102

a) 6-N-Benzyloxycarbonyl-2-N- (propyl-3-sulfonic acid) - lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide

A solution of 7.33 g (60 mol) of propane sultone is added dropwise at 50 ° C. to 50 g (60.20 mmol) of the title compound from Example 1c and 7.10 g (70 mmol) of triethylamine, dissolved in 250 ml of dry tetrahydrofuran in 50 ml of tetrahydrofuran and stirred for 3 hours at 60 ° C. 200 ml of 5% hydrochloric acid are added and the mixture is stirred for 5 minutes at room temperature. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile phase: dichloromethane / acetone = 15: 1 yield: 45.16 g (79% of theory) of a colorless, viscous oil.

Elemental analysis:

calcd. C 36.56 H 3.49 F 33.90 N 5.88 S 6.73 found C 36.72 H 3.35 F 33.79 N 5.78 S 6.75 b) 2-N- (propyl-3-sulfonic acid) lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide

49.68 g (52.15 mmol) of the title compound from Example 102a are dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 42.69 g (quantitative) of a colorless solid.

basic analysis: calc. C 30.81 H 3.32 F 39.46 N 6.84 S 7.83 found C 30.64 H 4.1 F 39.29 N 6.68 S 7.89

c) 6-N- [l, 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 compound from Example 102b, 2.79 g (24.25 mmol) of N-hydroxysuccimmide, 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 are under slightly heated in 200 ml of dimethyl sulfoxide. 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred 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 then purified by chromatography (silica gel RP-18, mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 28.13 g (81% of theory) of a colorless solid. Water content: 11.0%

Elemental analysis (calculated on anhydrous substance) calcd. C 33.27 H 3.70 F 22.36 N 8.73 S 4.44 Gd 10.89 found. C 32.41 H 3.88 F 22.49 N 8.69 S 4.35 Gd 10.97 Example 103

a) 6-N-Benzyloxycarbonyl-2-N, N-bis (propyl-3-sulfonic acid) - lysine [1- (4-perfluorooctylsulfonyl) - piperazine] - amide

A solution of 14.65 g (120 mmol) 1 is added dropwise at 50 ° C. to 50 g (60.20 mmol) of the title compound from Example 1c and 12.14 g (120 mmol) of triethylamine, dissolved in 250 ml of dry tetrahydrofuran. 3-propanesultone in 100 ml of tetrahydrofuran and stirred for 3 hours at 60 ° C. 400 ml of 5% aqueous hydrochloric acid are added, the mixture is stirred for 5 minutes at room temperature, sodium chloride is added, the organic phase is separated off, dried over magnesium sulfate and evaporated dry them in a vacuum. The residue is chromatographed on silica gel (mobile phase: dichloromethane / acetone = 15: 1 yield: 52.24 g (81% of theory) of a colorless, viscous oil. Elemental analysis:

calcd. C 35.76 H 3.66 F 30.05 N 5.21 S 8.95 found C 35.75 H 3.55 F 30.19 N 5.08 S 9.04

b) 2-N, N bis (propyl-3-sulfonic acid) lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide

53.74 g (52.15 mmol) of the title compound from Example 103a are dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 49.06 g (quantitative) of a colorless solid.

ülementai ranalysis:

calcd. C 30.64 H 3.54 F 34.33 N 5.96 S 10.23 found C 30.69 H 3.71 F 34.19 N 6.08 S 10.38

c) 6-N- [l, 4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane 10 - (entanoyl- 3-aza-4-oxo-5-methyl-5-yl)] - 2-N, N bis (propyl-3-sulfonic acid) lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex, disodium salt 38.76 g (24.25 mmol) of the title compound from Example 103b 2.79 g (24.25 mmol) N-hydroxysuccinimide, 2.12 g (50 mmol) 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 become lighter under Warming dissolved in 200 ml of dimethyl sulfoxide. 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred 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 then purified by chromatography (silica gel RP-18, mobile solvent: gradient from water / ethanol / acetomtril). Yield: 31.63 g (81% of theory) of a colorless solid. Water content: 11.0%

Elemental analysis (calculated on anhydrous substance) calc .: C 32.07 H 3.57 F 20.06 N 7.83 S 5.97 Gd 9.76 Na 2.86 found. C 31.94 H 3.48 F 20.19 N 7.69 S 5.85 Gd 9.87 Na 2.99

Example 104

a) N-Trifluoroacetyl-L-glutamic acid 5-benzyl ester

100 g (421.5 mmol) of L-glutamic acid 5-benzyl ester are dissolved in a mixture of 1000 ml of ethyl trifluoroacetate / 500 ml of ethanol and stirred for 24 hours at room temperature. It is evaporated to dryness and the residue is crystallized from diisopropyl ether. Yield: 140.47 g (96% of theory) of a colorless crystalline powder.

Elemental analysis:

calcd. C 50.46 H 4.23 F 17.10 N 4.20 found. C 51.35 H 4.18 F 17.03 N 4.28

b) 2-N-TrMuoacetyl-L-glutamic acid 5-berιzylester-N-bis (2-hydroxyemyl) -amide

To a solution of 24.9 g (24.08 mmol) of the title compound 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 Dimethylformamide, 8.25 g (40 mmol) of N, N-dicyclohexylcabodiimide are added at 0 ° C. The mixture is stirred for 3 hours at 0 ° C., then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated in Vacuum to dryness and chromatographed on silica gel (eluent: = dichloromethane

Ethanol = 20: 1).

Yield: 9.11 g (90% of theory) of a viscous oil.

Elemental analysis:

calcd. C 51.43 H 5.51 F 13.56 N 6.66 found C 51.22 H 5.41 F 13.40 N 6.75

c) N-trifluoroacetyl-L-glutamic acid-N bis (2-hydroxyethyi) monoamide

21.92 g (52.15 mmol) of the title compound from Example 104b are dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) are added. One hydrogenates

Room temperature. The catalyst is filtered off and the filtrate is evaporated in vacuo

Dry one.

Yield: 43.0 g (quantitative) of a colorless solid.

Elemental analysis:

calcd. C 40.01 H 5.19 F 17.26 N 8.48 found C 39.84 H 5.13 F 17.09 N 8.68

c) Trifluoroacetyl-L-glutanic acid-N-bis (2-hy {koxyethyl) -amide-5- [l ~ (4- ρerfluorooctylsulfonyl) -piperazine] -amide

16.42 are added at 0 ° C. to 10.96 g (33.2 mmol) of the title compound from Example 104a and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (as described in DE 19603033) in 80 ml of tetrahydrofuran g (66.4 mmol) of EEDQ (2-ethoxy-l, 2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile phase: dichloromethane / methanol = 20: 1). Yield: 30.93 g (93% of theory) of a colorless solid.

Elemental analysis:

calcd. C 39.61 H 2.89 F 35.66 N 6.19 S 3.54 found C 39.68 H 2.74 F 35.81 N 6.13 S 3.40 e) L-glutamic acid-N- bis (2-hydroxyethyl) -amide-5- [l- (4-perfluorooctylsulfonyl) piperazine] - amide04 in 200 ml of ethanol, ammonia gas is passed in at 0 ° C. for one hour. The mixture is then stirred for 4 hours at 0 ° C. It is evaporated to dryness and the residue is extracted from water. The solid is filtered off and dried in vacuo (50 ° C.). Yield: 26.55 g (97% of theory) of an amorphous solid.

Elemental analysis:

calcd. C 41.12 H 2.89 F 35.66 N 6.19 S 3.54 found 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 - (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -L -glutamic acid-N-bis (2-hydroxyethyl) amide-5- [l- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

211.96 g (24.25 mmol) of the title compound 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 are under slightly heated in 200 ml of dimethyl sulfoxide. 8.25 g (40 mmol) of N, NDicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred 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 then purified by chromatography (silica gel RP-18, mobile solvent: gradient from water / ethanol / acetonitrile).

Yield: 27.43 g (81% of theory) of a colorless solid. Water content: 11.0%

Elemental analysis (calculated on anhydrous substance) calcd. C 34.41 H 3.83 F 23.13 N 9.03 S 2.30 Gd 11.26 found. C 34.34 H 3.98 F 23.29 N 9.19 S 2.15 Gd 11.07

Example 105 a) N -trifluoroacetyl-L-glutamic acid-5-benzyte ^^ amide [

To a solution of 8.03 g (24.08 mmol) of the title compound from Example 104a, 3.98 g (24.08 mmol) of dimethyl-bis (l, l-dihydroymethyl) amine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide, 8.25 g (40 mmol) of N, N-dicyclohexylcabodiimide are added at 0 ° C. The mixture is stirred for 3 hours at 0 ° C., then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile phase: dichloromethane / ethanol = 20: 1). Yield: 110.53 g (91% of theory) of a viscous oil.

Egg tai analysis: calc. C 50.00 H 5.66 F 11.86 N 7.18 found. C 50.17 H 5.82 F 11.80 N 7.15

b) N-trifluoroacetyl-L-glutamic acid-5-benzyl ester- [l- (4-perfluorooctylsulfonyl) piperazine] amide

25.05 g (52.15 mmol) of the title compound from Example 105a are dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) are added, hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 20.36 g (quantitative) of a colorless solid.

Elemental analysis:

calcd. C 40.00 H 5.42 F 14.60 N 7.18 found C 40.10 H 5.53 F 14.69 N 7.28

c) N-Trifluoroacetyl-L.glutamic acid-N-dimethyl-bis (l, l-dihydroxymethyl) -amide-5— [l- (4-perfluorooctylsuffonyl) piperazine] -amide To 12.96 g (33.2 mmol) of the title compound from Example 105b and 18.87g (33.2 mmol) of 1-perfluorooctylsulfonylpiperazine (produced according to DE 19603033) in 800 ml of tetrahydrofuran are added at 0 ° C. 16 , 42 g (66.4 mmol) of EEDQ (2-ethoxy-l, 2-dihydroquinoline-l-carboxylic acid ethyl ester) and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile phase: dichloromethane / methanol = 20: 1). Yield: 28.42 g (91% of theory) of a colorless solid.

Elemental analysis: calc. C 31.93 H 3.00 F 40.40 N 5.96 S 3.41 found. C 32.08 H 2.94 F 40.57 N 5.88 S 3.31

d) L-glutamic acid N- [dimemyl-bis (l, l-dmydroxymemyl)] - amide-5 - [(l-4-perfluorooctylsulfonyl) - piperazine] - amide

In a solution of 28.41 g (30.2 mmol) of the title compound from Example 105c in 200 ml of ethanol, ammonia gas is passed in at 0 ° C. for one hour. The mixture is then stirred for 4 hours at 0 ° C. It is evaporated to dryness and the residue is extracted from water. The solid is filtered off and dried in vacuo (50 ° C.). Yield: 24.74 g (97% of theory) of an amorphous solid. Elemental analysis:

calcd. C 32.71 H 3.46 F 38.24 N 6.63 S 3.80 found C 32.75 H 3.33 F 38.38 N 6.68 S 3.81

e) 2-N- [1,4-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10 - (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -L-glutamic acid-N- [dimethyl-bis (l, l-dihydroxymethyl) amide] -5- [l- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

20.48 g (24.25 mmol) of the title compound 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 become lighter under Warming dissolved in 200 ml of dimethyl sulfoxide. 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred 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 then purified by chromatography (silica gel RP-18, mobile solvent: gradient off

Water / ethanol / acetonitrile).

Yield: 29.05 g (83% of theory) of a colorless solid.

Water content: 11.0%

Elemental analysis (calculated on anhydrous substance) calcd. C 34.12 H 3.91 F 22.38 N 8.73 S 2.22 Gd 10.90 found. C 34.24 H 3.98 F 22.39 N 8.69 S 2.15 Gd 10.87

Example 106

a) N-Trifluormemylacetyl-L-glutanic acid 5-benzyl ester- [l- (4-perfluorooctylsulfonyl) piperazine] amide

To 11.06 g (33.2 mmol) of the title compound from Example 104a and 18.87g (33.2 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 80 ml of tetrahydrofuran are added at 0 ° C. 16 , 42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile phase: dichloromethane / methanol = 20: 1). Yield: 27.28 g (93% of theory) of a colorless solid.

Elemental analysis:

calcd. C 35.35 H 2.40 F 43.01 N 4.76 S 3.63 found C 35.48 H 2.51 F 42.87 N 4.73 S 3.50

b) N-trifluoroacetyl-L-glutanic acid-5- [l- [4-perfluorooctylsulfonyl) piperazine] amide

21.92 g (52.15 mmol) of the title compound from Example 106a are dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 41.37 g (quantitative) of a colorless solid.

Elemental analysis: calcd. C 28.76 H 1.91 F 47.89 N 5.30 S 4.04 found C 28.84 H 2.03 F 47.79 N 5.28 S 4.19

c) N-Trifluoace1 l-L-glutamic acid-N-bis (2-hyά ^ oxyemyl) -amide-5- [l- (4-perfluorooctyl-sulfonyl) -piperazine] -amide

To a solution of 24.9 g (24.08 mmol) of the title compound from Example 106a, 2.53 g (24.08 mmol) of diethanolamine and 2.77 g (24.08 mmol) of N-hydroxysuccimmide, dissolved in 150 ml Dimethylformamide, 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are added at 0 ° C. The mixture is stirred for 3 hours at 0 ° C., then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: = dichloromethane / ethanol = 20: 1). Yield: 9.11 g (90% of theory) of a viscous oil.

Elemental analysis:

calcd. C 31.37 H 2.75 F 43.15 N 6.36 S 3.64 found C 31.22 H 2.61 F 43.30 N 6.25 S 3.81

d) L-glutamic acid-N- bis (2-hydroxyethyl) amide-5- [1- (4-perfluorooctylsulfonyl) piperazine] amide

In a solution of 26.61 g (30.22 mmol) of the title compound from Example 106c in 200 ml of ethanol, ammonia gas is passed in at 0 ° C. for one hour. The mixture is then stirred for 4 hours at 0 ° C. It is evaporated to dryness and the residue is extracted from water. The solid is filtered off and dried in vacuo (50 ° C.). Yield: 23.93 g (97% of theory) of an amorphous solid.

Elemental analysis:

calcd. C 30.89 H 3.09 F 39.56 N 6.86 S 3.93 found C 30.75 H 3.13 F 39.78 N 6.75 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)] -L -glutamic acid-N-bis (2-hydroxyethyl) amide-5- [1 - (4-perfluoro-octylsulfonyl) piperazine] amide, Gd complex

16.43 g (24.25 mmol) of the title compound 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 are under slightly heated in 200 ml of dimethyl sulfoxide. 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred 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 then purified by chromatography (silica gel RP-18, mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 28.10 g (83% of theory) of a colorless solid. Water content: 11.0%

Elemental analysis (calculated on anhydrous substance) calcd. C 34.41 H 3.83 F 23.13 N 9.03 S 2.30 Gd 11.26 found. C 34.44 H 4.98 F 23.19 N 8.89 S 2.15 Gd 11.17

Example 107

a) N-Trifluoroacetyl-glutamic acid-5-benzyl ester- [l- (4-ρerfluorooctylsulfonyl) piperazine] amide

To 11.06 g (33.2 mmol) of the title compound from Example 104a and 18.87 g (33.2 mmol) 1-

Perfluorooctylsulfonylpiperazine, (manufactured according to DE 19603033) in 80 ml

Tetrahydrofuran, 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) are added at 0 ° C. and the mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent:

Dichloromethane / methanol = 20: 1)

Yield: 27.28 g (93% of theory) of a colorless solid.

Elemental analysis:

calcd. C 35.35 H 2.40 F 43.01 N 4.76 S 3.63 found C 35.48 H 2.54 F 42.87 N 4.73 S 3.40 b) N-TrMuoraceryl-L-glutamic acid 5- [l- [4-perfluorooctylsulfonyl) piperazine] amide

21.92 g (52.15 mmol) of the title compound from Example 107a are dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 41.37 g (quantitative) of a colorless solid.

Elementary analysis:

calcd. C 28.76 H 1.91 F 47.89 N 5.30 S 4.04 found C 28.84 H 1.81 F 47.79 N 5.28 S 4.16

Example 108

a) 6-N-Benzyloxycarbonyl - 2-N- (2,3,4,5-pentahydroxyhexanoyl) L-lysine [l- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 100.0 g (120.4 mol) of the title compound from Example 21c), in 500 ml of dry tetrahydrofuran, a solution of 21.45 g (120.4 mol) of 5-

Gluconolactone in 50 ml tetrahydrofuran. The mixture is stirred for 3 hours at 60 ° C. and then overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel.

(Mobile phase: dichloromethane / ethanol = 20: 1).

Yield: 98.37 g (82% of theory) of a viscous oil.

Elemental analysis: calc .: C 38.10 H 3.70 F 32.02 N 5.55 S 3.18 found :: C 38.22 H 3.79 F 32.02 N 5.42 S 3.29

b) 2-N- (2,3,4,5-pentahyα oxyhexanoyl) -L-lysine-1 - [(4-perfluorooctylsulfonyl) pipera2in] amide 100.9 g (100.0 mmol) of the title compound from Example 108a) are dissolved in 2000 ml of ethanol and 10.0 g of palladium catalyst (10% Pd / C) are added. The mixture is hydrogenated for 12 hours at room temperature. The catalyst is filtered off and this is evaporated

Filtrate to dryness in a vacuum.

Yield: 87.46 g (quantitative) of a colorless solid.

Elemental analysis: calc .: C 32.96 H 3.57 N 6.41 S 3.67 F 36.93 found: C 32.91 H 3.72 N 6.34 S 3.50 F 36.78

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

50.0 g (54.55 mmol) of the title compound from Example 21e), 6.28 g (54.55 mmol) of N-

Hydroxysuccimmide, 4.62 g (109.0 mol) lithium chloride and 34.35 g (54.55 mol) 1,4,7-tris

(carboxylatomethyl) -10- (carboxy - 3-aza-4-oxo-5-methyl-pent-5-yl) -l, 4,7,10-tetraazacyclododecane, Gd complex, are placed in 400 ml with gentle heating

Dissolved dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mol) of N, N-

Dicyclohexylcarbodiimid and then stirred 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 then purified by chromatography (RP-18 mobile solvent: gradient from water / ethanol / acetonitrile).

Yield: 75.9 g (91.0% of theory) of a colorless solid.

Water content: 8.6%.

Elemental analysis (calculated on anhydrous substance): calc .: C 35.34 H 4.09 N 8.24 S 2.10 F 21.12 Gd 10.28 found: C 35.28 H 4.15 N 8.19 S 2 , 15 F 21.03 Gd 10.14

Example 109

A solution is added dropwise at 50 ° C. to a solution of 100.0 g (120.4 mmol) of the title compound from Example 21c) and 12.18 g (120.4 mmol) of triethylamine in 500 ml of dry tetrahydrofuran Solution of 21.45 g (120.4 mol) 5-gluconolactone in 50 ml tetrahydrofuran. Stir 3

Hours at 60 ° C and then overnight at room temperature. Then you give 400 ml

5% aqu.

Add hydrochloric acid, stir for 5 minutes at room temperature, add sodium chloride, separate the organic phase, dry it over magnesium sulfate, evaporate it in vacuo

Dry and chromatograph the residue on silica gel.

(Mobile phase: dichloromethane / ethanol = 20: 1).

Yield: 100.97 g (82% of theory) of a viscous oil.

Elemental analysis: calc .: C 37.58 H 3.45 F 31.58 N 5.48 S 3.14 found: C 37.72 H 3.59 F 31.72 N 5.42 S 3.29

b) 2-N- (2,3,4,5-pentahyά ^ oxy-hexanoyl) -L-lysine-l - [(4-perfluorooctylsulfonyl) piperazine] amide

100.9 g (100.0 mmol) of the title compound from Example 108a) are dissolved in 2000 ml of ethanol and 10.0 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated for 12 hours at room temperature. The catalyst is filtered off and this is evaporated

Filtrate to dryness in a vacuum.

Yield: 87.46 g (quantitative) of a colorless solid.

Elemental analysis: calc .: C 32.96 H 3.57 N 6.41 S 3.67 F 36.93 found: C 32.91 H 3.72 N 6.34 S 3.50 F 3678

c) 6-N- [l, 4,7-tris (carboxylatomethyl)] -l, 4,7,10-tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] -2-N- [lO-α-D-carbonylmethyl-mannopyranose] -L-lysine [l- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

50.0 g (54.55 mmol) of the title compound from Example 21e), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54, 55 mol) 1,4,7-tris (carboxylatomethyl) -10- (carboxy - 3-aza-4-oxo-5-methyl-pent-5-yl) -l, 4,7,10-tetraazacyclododecane, Gd- Complex, are dissolved in 400 ml of dimethyl sulfoxide with gentle heating. 16.88 g (81.8 mol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred 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 then purified by chromatography (RP-18 mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 75.9 g (91.0% of theory) of a colorless solid.

Water content: 8.6%.

Elemental analysis (calculated on anhydrous substance): calc .: C 35.34 H 4.09 N 8.24 S 2.10 F 21.12 Gd 10.28 found: C 35.28 H 4.15 N 8.19 S 2.15 F 21.03 Gd 10.14

Example 110

a) 6-N-BenzyloxycarbonyI - 2-N- [l-0-α-D-carbonylmethyl- (2,3,4,6-tetra-O-benzylglucopyranose) -L-lysine [l- (4- perfluorooctylsulfonyl) -piperazine] -amide

To a solution of 100.0 g (120.4 mol) of the title compound from Example 21c), 72.1 g

(120.4 mol) 1-O-α-D-carboxymethyl - 2,3,4,6-tetra-O-benzyl-glucopyranose and 13.86 g

(120.4 mol) N-hydroxysuccinimide, dissolved in 500 ml of dimethylformamide, is added at 0 ° C

41.27 g (200.0 mmol) of N, N - dicyclohexylcarbodiimide. The mixture is stirred for 3 hours at 0 ° C. and then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo and chromatographed on silica gel.

(Mobile phase: dichloromethane / ethanol = 20: 1).

Yield: 136.1 g (87% of theory) of a viscous oil.

Elemental analysis: calc .: C 57.32 H 4.89 N 4.31 F 24.86 S 2.47 found: C 57.48 H 5.04 N 4.20 F 24.69 S 2.38

b) 2-N- [l-0-α-D-carbonylmemylglucopyranose] -L-lysine-l - [(4-perfluorooctylsulfonyl) piperazine] amide

130.0 g (100.0 mmol) of the title compound from Example 110a) are dissolved in 2000 ml of ethanol and 10.0 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated for 12 hours at room temperature. The catalyst is filtered off and this is evaporated

Filtrate to dryness in a vacuum.

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

Elemental analysis: calc .: C 34.07 H 3.63 N 6.11 S 3.50 F 35.24 found: C 33.92 H 3.71 N 6.02 S 3.42 F 35.33 c) 6-N- [l, 4,7-tris (carboxylatomethyl)] - 1,4,7, 10-tetraazacyclododecane 10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] -2-N- [lO-α-D-carbonylmethyl-glucopyranose] -L-lysine [l- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

50.0 g (54.55 mmol) of the title compound from Example 110b), 6.28 g (54.55 mmol) of N-

Hydroxysuccinimide, 4.62 g (109.0 mol) lithium chloride and 34.35 g (54.55 mol) 1,4,7-tris

Dissolved dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mol) of N, N-

Yield: 75.9 g (91.0% of theory) of a colorless solid.

Water content: 8.6%.

Elemental analysis (calculated on anhydrous substance): calc .: C 35.34 H 4.09 N 8.24 S 2.10 F 21.12 Gd 10.28 found: C 35.26 H 4.18 N 8.14 S 2.158 F 21.01 Gd 10.13

Example 111

a) 6-N-Benzyloxycarbonyl - 2-N- [l-0-α-D-carbonylmethyl- (2,3,4,6-tetra-O-benzyl-galactopyranose) -L-lysine [l- (4th -perfluoroctylsulfonyl) -piperazine] amide

To a solution of 50.0 g (60.2 mol) of the title compound from Example 21c), 36.05 g (60.2 mmol) of 1-O-α-D-carboxymethyl-2,3,4,6-tetra -O-benzyl-galactopyranose and 6.93 g (60.2 mmol) of N-hydroxysucciriimide, dissolved in 500 ml of dimethylformamide, are added at 0 ° C with 20.64 g (100.0 mmol) of N, N-dicyclohexylcarbodiimide. The mixture is stirred for 3 hours at 0 ° C. and then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo and chromatographed on silica gel. (Medium: dichloromethane / ethanol == 20: 1). Yield: 68.1 g (87% of theory) of a viscous oil. Elemental analysis: calc .: C 57.32 H4.89 N 4.31 F 24.86 S 2.47 found: C 57.47 H 5.05 N 4.19 F 24.72 S 2.29

b) 2-N- [1-0 -D-carbonylmemyl-galactopvranose] -L-lysine-1 - [(4-peιfluorooctylsulfonyl) piperazine] amide

65.0 g of 50.0 mmol) of the title compound from example lilac) are dissolved in 1000 ml of ethanol and 5.0 g of palladium catalyst (10% Pd / C) are added. Hydrogenate 12

Hours at room temperature. The catalyst is filtered off and the filtrate is evaporated in

Vacuum to dryness.

Yield: 45.85 g (quantitative) of a colorless solid.

Elemental analysis: calc .: C 34.07 H 3.63 N 6.11 S 3.50 F 35.24 found: C 33.93 H 3.74 N 6.01 S 3.39 F 35.05

fc 6-N- [l, 4,7-tris (carboxylatomethyl)] -l, 4,7,10-tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] -2-N- [lO-α-D-carbonylmethyI-galactopyranose3-L-Iysine [l- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

50.0 g (54.55 mmol) of the title compound from Example IIIb), 6.28 g (54.55 mmol) of N-

Dissolved dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mol) of N, N-

Dicyclohexylcarbodiimid and then stirred 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 then purified by chromatography (RP-18 mobile medium: gradient from water / ethanol / acetonitrile).

Yield: 37.95 g (91.0% of theory) of a colorless solid.

Water content: 8.6%.

Elemental analysis (calculated on anhydrous substance): calc .: C 35.34 H 4.09 N 8.24 S 2.10 F 21.12 Gd 10.28 found: C 35.22 H 4.17 N 8.18 S 2 , 19 F 20.91 Gd 10.12 Example 112

a) N-trifluoroacetyl-L-glutamic acid mono-benzyl ester

100 g (421.5 mmol) of L-glutamic acid monobenzyl ester are dissolved in a mixture of 1000 ml of ethyl trifluoroacetate / 500 ml of ethanol and stirred for 24 hours at room temperature. It is evaporated to dryness and the residue is crystallized from diisopropyl ether. Yield: 140.47 g (96% of theory) of a colorless crystalline powder.

Elemental analysis:

calcd. C 50.46 H 4.23 F 17.10 N 4.20 found. C 51.35 H 4.18 F 17.03 N 4.28

b) 2-N-Trifluoacetyl-L-glutammic acid mono-benzyl ester-5-N- (methyl) -N- (2,3,4,5,6-ρentahydroxyhexyl) ~ amide

To a solution of 24.9 g (24.08 mmol) of the title compound from Example 112a, 2x g (24.08 mmol) of N-methylglucamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide, dissolved in 150 ml Dimethylformamide, 8.25 g (40 mmol) of N, N-dicyclohexylcabodiimide are added at 0 ° C. The mixture is stirred for 3 hours at 0 ° C., then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: = dichloromethane / ethanol = 20: 1). Yield: 9, xx g (89% of theory) of a viscous oil.

Elemental analysis:

calcd. C 51.43 H 5.51 F 13.56 N 6.66 found C 51.22 H 5.41 F 13.40 N 6.75

c) N-Trifluoroacetyl-L-glutamic acid-N - (memyl) -N- (2,3,4,5,6-pentahydroxyhexyl) amide

21.9xxg (52.15 mmol) of the title compound from Example 112b are dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield: 43.0 g (quantitative) of a colorless solid.

Elemental analysis:

calcd. C 40.01 H 5.19 F 17.26 N 8.48 found C 39.84 H 5.13 F 17.09 ^ N 8.68

d) trifluoroaceryl-L-glutamic acid-5-N- (memyl) -N- (2,3,4,5,6-pent ^ ydroxyhexyl) -amide- [l- (4-perfluorooctylsulfonyl) -piperazine] -amidpiperazine] amide

To 0.96 g (33.2 mmol) of the title compound from Example 112c and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonylpiperazine (manufactured according to DE 19603033) in 80 ml of tetrahydrofuran are added at 0 ° C. 16, 42 g (66.4 mmol) of EEDQ (2-ethoxy-l, 2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 20: 1). Yield: 28.67 g (92% of theory) of a colorless solid.

Elemental analysis:

calcd. C 39.61 H 2.89 F 35.66 N 6.19 S 3.54 found C 39.68 H 2.74 F 35.81 N 6.13 S 3.40

e) L-Glutanoic acid-5-N- (methyl) -N- (2,3,4,5,6-pentahydroxyhexyl) amide - [1- (4-perfluorooctylsulfonyl) piperazine] amide

In a solution of 28.36 g (30.22 mmol) of the title compound from Example 112d in 200 ml of ethanol, ammonia gas is passed in at 0 ° C. for one hour. The mixture is then stirred for 4 hours at 0 ° C. It is evaporated to dryness and the residue is extracted from water. The solid is filtered off and dried in vacuo (50 ° C.). Yield: 24.19 g (95% of theory) of an amorphous solid.

Elemental analysis:

calcd. C 41.12 H 2.89 F 35.66 N 6.19 S 3.54 found 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 - (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -L -glutamic acid-5-N- (methyl) -N- (2,3,4,5,6-pntahydroxyhexyl) - amide-5- [l- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

20.43 g (24.25 mmol) of the title compound 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-5-yl)] - pentanoic acid] - 1,4,7,10-tetraazacyclododecane, Gd complex become lighter under Warming dissolved in 200 ml of dimethyl sulfoxide. 8.25 g (40 mmol) of N, NDicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred 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 then purified by chromatography (silica gel RP-18, mobile solvent: gradient from water / ethanol / acetonitrile). Yield: 28.45 g (79% of theory) of a colorless solid. Water content: 11.0%

Example 113

a) 6-N-Benzyloxycarbonyl - 2-N- [l -0-α-D -carbonylmethyl- (2,3,4 -triO benzyl-glucuron- säames-benzyl ester) -L-lysine [l- (4th -perfluoroctylsulfonyl) -piperazine] amide

To a solution of 100.0 g (120.4 mol) of the title compound from Example 21c), 73.77 g (120.4 mol) of 1-O-α-D-carboxymethyl-2,3,4-tri-O -benzyl-glucuronic acid benzyl ester and 13.86 g (120.4 mol) of N-HyαYoxysuccinirnid, dissolved in 500 ml of dimethylformamide, are added at 0 ° C 41.27g (200.0 mmol) of N, N - dicyclohexylcarbodiimide. The mixture is stirred for 3 hours at 0 ° C. and then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo and chromatographed on silica gel. (Mobile phase: dichloromethane / ethanol = 20: 1).

Yield: 147.58 g (86% of theory) of a viscous oil.

Elemental analysis: calc .: C 52.25 H 4.31 N 3.93 F 22.66 S 2.45 found: C 52.38 H 4.17 N4.12 F 22.78 S 2.39

b) 2-N- [l-0-α-D-carbonylmethyl-glucuronic acid] -L-lysine-l - [(4-perfluorooctylsulfonyl) piperazine] amide

142.52 g (100.0 mmol) of the title compound from Example 113a) are dissolved in 2000 ml of ethanol and 10.0 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated for 12 hours at room temperature. The catalyst is filtered off and this is evaporated

Filtrate to dryness in a vacuum.

Yield: 93.06 g (quantitative) of a colorless solid.

Elemental analysis: calc .: C 33.56 H 3.36 N 6.02 S 3.45 F 34.71 found: C 33.31 H 3.42 N 6.04 S 3.40 F 35.51

c) 6-N- [l, 4,7-tris (carboxylatomethyl)] -l, 4,7,10-tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] -2-N- [lO-α-D-carbonylmethyl-glucuronic acid] -L-lysine [l- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex, sodium salt

50.76 g (54.55 mmol) of the title compound from Example 113b), 6.28 g (54.55 mmol) of N-

(carboxylatomethyl) -10- (carboxy - 3-aza-4-oxo-5-methyl-pent-5-yl) - 1,4,7,10-tetraazacyclododecane, Gd complex, are placed in 400 ml with gentle heating

Dissolved dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mol) of N, N-

Yield: 75.14.9 g (88.0% of theory) of a colorless solid.

Water content: 8.6%.

Elemental analysis (calculated on anhydrous substance): calc .: C 34.53 H 3.80 N 8.05 Na 1.47 S 2.05 F 20.63 Gd 10.05 found: C 34.38 H 3.95 N 8, 19 Na 1.63 S 2.15 F 20.83 Gd 10.14 Example 114

a) 6-N-Benzyloxycarbonyl) - 2 - [2- (N-emyl-N-peιfluorocrylsulfonyl] amino] acetyl-L-lysine

31.82.0 g (113.5 mmol) 6-N-benzyloxycarbonyl) -L-lysine and 66.42 g (113.5 mmol) 2- (N-

Ethyl-N-perfluorooctylsulfonyl) aminoacetic acid (produced according to DE 19603 033) in 300 ml

Tetrahydrofuran, 49.46 g (200.0 mmol) of EEDQ (2-ethoxy-l, 2-dihydroquinone-1-carboxylic acid ethyl ester) are added at 0 ° C. and the mixture is stirred overnight at room temperature.

It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile phase

: Dichloromethane / methanol = 20: 1).

Yield: 55.79 g (58% of theory) of a colorless solid.

Elemental analysis: calc .: C 36.85 H 3.09 N 4.96 F 38.11 S 3.78 found: C 36.85 H 3.19 N 4.87 F 38.28 S 3.95

b) 6-N-Benzyloxycarbonyl - 2-N- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-L-lysine-N-methyl-N- (2,3,4,5, 6-pentahydroxy-hexyl) -amide

To a solution of 51.02 g (60.2 mol) of the title compound from Example 114a), 11.75 g

(60.2 mol) N-methyl-glucamine and 6.93 g (60.2 mol) N-hydroxysuccinimide, dissolved in 250 ml

Dimethylformamide, 20.64 g (100.0 mmol) of N, N -dicyclohexylcarbodiimide are added at 0 ° C. The mixture is stirred for 3 hours at 0 ° C. and then overnight at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo and chromatographed on silica gel.

(Medium: dichloromethane / ethanol = 20: 1).

Yield: 53.05 g (86% of theory) of a viscous oil.

Elemental analysis: calc .: C 38.68 H 4.03 N 5.47 F 31.52 S 3.13 found: C 38.49 H 4.17 N 5.32 F31.70 S 3.29 c) 2-N- [2- (N-emyl-N-perfluorooctylsulfonyl) amino] acetyl-L-lysine-N-memyl-N-pentahydroxyhexyl) amide

102.48 g (100.0 mmol) of the title compound from Example 114b) are dissolved in 2000 ml of ethanol and 10.0 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated for 12 hours at room temperature. The catalyst is filtered off and this is evaporated

Filtrate to dryness in a vacuum.

Yield: 89.06 g (quantitative) of a colorless solid.

Elemental analysis: calc .: C 33.72 H 3.96 N 6.29 S 3.60 F 36.26 found: C 33.91 H 3.82 N 6.14 S 3.47 F 36.31

d) 6-N- [l, 4,7-tris (carboxylatomethyl)] -l, 4,7,10-tetraazacy clododecan-10-N- (pentanoyI-3-aza-4-oxo-5-memyl-5 -yl)] -2-N- [2- (ne yl-N-perfluorooctylsulfonyl) amino] acetyl-L-lysm-N-methyl-N- (2,3,4,5,6-pentahydroxyhexyl ) -amide, Gd complex 48.58 g (54.55 mmol) of the title compound from Example 114), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 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) -l, 4.7 , 10-tetraazacyclododecane, Gd complex, are dissolved in 400 ml of dimethyl sulfoxide with gentle heating. 16.88 g (81.8 mol) of N, N -dicyclohexylcarbodiimide are added at 10 ° C. and the mixture is then stirred 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 then purified by chromatography (RP-18 mobile solvent: gradient from water / ethanol / acetonitrile).

Yield: 73.27 g (89.4% of theory) of a colorless solid. Water content: 8.6%.

Elemental analysis (calculated on anhydrous substance): calc .: C 35.18 H 4.23 N 4.23 S 2.13 F 21.50 Gd 10.47 found: C 35.28 H4.15 N 4.19 S 2.18 F 21.33 Gd 10.61 Example 115: MRI representation of arteriosclerotic plaques after intravenous administration of metal complexes according to the invention

In rabbits with genetically induced arteriosclerosis (Watanabe rabbits) 5-60 min as well as 24 h and 48 h after intravenous administration of 25 / mol Gd / kg body weight of the compounds according to the invention in Tj -weighted gradient echo recordings (TR 11.1 ms, TE 4.3 ms, flip angle α 15 °) a clear enhancement in the arteriosclerotic plaques can be observed. The healthy vessel wall showed little or no contrast medium uptake and therefore showed no or only a slight increase in signal in the T1-weighted images. Because of the contrast between signal-rich plaque and signal-poor healthy vascular wall, a diagnosis of arteriosclerotic changes in the vascular wall was possible.

The images in FIG. 1 show MR images of the aorta before and 24 h and 48 h after intravenous administration of 25 / mol Gd / kg body weight of the metal complex XV in Watanabe rabbits (genetically induced arteriosclerosis). The T- | -weighted gradient echo recordings (1.5 T; TR: 11.1 ms, TE: 4.3 ms; NA: 2; matrix: 213 * 256; layer thickness: 1.0 mm) illustrate a strong signal increase in arteriosclerotic plaque. The location of the plaques, especially in the aortic arch and at the vascular outlets, was confirmed by means of Sudan-3 staining.

Example 116: MRI imaging of arteriosclerotic plaques after intravenous administration of the metal complex XV in rats, and correlation of the post mortem image with Sudan HI staining

The images in FIG. 2 show MR images of the aorta before, and 35, 60 min and 24 h after intravenous administration of 10 // mol Gd / kg body weight of the Gad metal complex XV in Watanabe rabbits (genetically induced arteriosclerosis). The T- | -weighted gradient echo recordings (MPRage; 1.5 T; TR: 11.1 ms, TE: 4.3 ms; NA: 2; matrix: 213 * 256; layer thickness: 1.0 mm) illustrate a strong signal increase in arteriosclerotic plaque. The location of the plaques, especially in the aortic arch and at the vascular outlets, was confirmed by means of Sudan-3 staining. Subsequently, the MR imaging of the preparation embedded in agar was again carried out using a T- | - weighted gradient echo sequence (MPRage; 1.5 T; TR 11.1 ms, TE 4.3 ms, flip angle α 15 °; NA: 2; matrix: 213 ^* 256) and a spin echo sequence (1.5 T; TR: 400 ms, TE: 15 ms; NA: 16; matrix: 256 * 256) was examined (post mortem image). This showed an excellent correlation of the aortic sections with a strong signal increase and the stained plaques, which confirms the inclusion of the compounds according to the invention in the arteriosclerotic plaques.

Example 117: Infarct imaging (MRI) after intravenous administration of the metal complex XV in rats

The pictures in FIG. 3 show MR images of the heart (in vivo and post mortem) 24 h after intravenous application of 100 // mol Gd / kg bw of the metal complex XV in rats of acutely induced heart attack. The T- | -weighted spin echo recordings (1.5 T; TR: 400 ms, TE: 6 ms; NA: 4; matrix: 128 * 128; layer thickness: 2.5 mm) illustrate the strong signal increase in the infarct area. The successful induction of an acute myocardial infarction was confirmed by NBT staining.

Metal complex XV, 100 mol / kg IV; T1-SE, TR / TE 400/6 ms; Arrow: myocardial infarction.

Example 118: Infarction imaging (MRI) after intravenous administration of the metal complex I in rats

The pictures in FIG. 4 show MR images of the heart (in vivo and post mortem) 24 h after intravenous application of 100 // mol Gd / kg body weight of the metal complex I in rats of acutely induced heart attack. The Tj -weighted spin echo recordings (1.5 T; TR: 400 ms, TE: 6 ms; NA: 4; matrix: 128 ^* 128; layer thickness: 2.5 mm) illustrate the strong signal increase in the infarct area. The successful induction of an acute myocardial infarction was confirmed by NBT staining.

Example 119: Lvmphknotdarstellunq MRT) after intravenous administration of the metal complex XV in rabbits carrying VX2 tumor

5 shows MR images of iliac lymph nodes pre-contrast and up to 24 h after intravenous administration of 200 // mol Gd / kg body weight of the

Metal complex XV in rabbits with implanted VX2 tumor. The T- _| - Weighted gradient echo recordings (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, 15 °) illustrate the strong signal increase in healthy lymph node tissue. Zones with no signal increase within the lymph node were diagnosed as metastases and confirmed histologically (H / E staining of the lymph node sections). In contrast, a signal reversal was surprisingly observed at late times (24 h) after contrast medium application. The signal increase in healthy lymph node tissue was reduced, whereas the metastasis now showed a significant signal increase.

Surprisingly, a clear enhancement of the primary tumor (especially the periphery) was observed immediately after application. At later times (24 h pi), this enhancement also spreads towards the tumor center.

Example 120: Tumor imaging (MRI) after intravenous administration of the metal complex I in rabbits carrying VX2 tumors

6 shows MR images of an iliac lymph node and the primary tumor (im implanted VX2 tumor) pre-contrast, 60 min and 20 h after intravenous administration of 100 // mol Gd / kg body weight of

Metal complex I in rabbits. The T- | -weighted gradient echo recordings

(1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, 15 °) illustrate the strong signal increase in healthy lymph node tissue.

Significant enhancement of the primary tumor (especially the periphery) can be observed at an early point in time after application (60 min p.i.).

In the further course of time (20 h p.i.) the signal increase also extends to more central regions of the tumor.

The enhancement of a pathological structure is particularly noteworthy

(possibly secondary tumor or necrosis) on the contralateral side, which only becomes visible in the late exposure ("late enhancement").

Metal complex X

Example 121: Infarction imaging (MRI) after intravenous administration of the contrast medium in rats

The illustrations in FIG. 7 show MR images of the heart (in vivo and post mortem) 6 h after intravenous application of 100 // mol Gd / kg body weight of a polar Gd chelate with a perfluorinated side chain (metal complex X) in rats with acute induced Heart attack. The T- weighted, ECG-triggered spin echo recordings (1.5 T; TR (effective): 400 ms, TE: 12 ms; NA: 4; matrix: 128 * 128; layer thickness: 2.5 mm) illustrate the strong signal increase in the infarct area. The successful induction of an acute myocardial infarction was confirmed by NBT staining.

Example 122: Organ distribution (including lymph node enrichment) after intravenous administration of the contrast medium in rats

After intravenous application of 100 // mol total gadolinium / kg body weight of a polar Gd chelate with perfluorinated side chain (metal complex X) in rats, the metal content in various organs and in the lymph nodes was determined 24 hours after application (pooled as mesenteric and peripheral lymph nodes) ( MW, n = 2).

Example 123: Lymph node imaging (MRI) after intravenous administration of the contrast medium in rats

The illustrations in FIG. 8 show, by way of example, MR images of iliac lymph nodes pre-contrast and up to 60 min after intravenous administration of 100 _/ mol Gd / kg body weight of metal complex X in rats. The T- | -weighted Gradient echo recordings (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15 °) illustrate the strong signal increase in healthy lymph node tissue at very early times after injection. The enhancement was 263% at 15 min pi and 254% at 60 min pi.

Example 124: Lymph node imaging (MRI) after intravenous administration of the contrast medium in VX2-

Tumor-bearing rabbit

The illustrations in FIG. 9 show, by way of example, MR images of iliac lymph nodes pre-contrast and up to 60 min after intravenous administration of 200 mol / kg body weight of metal complex X in rabbits with the VX2 tumor implanted. The T- | -weighted gradient echo recordings (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, 15 °) illustrate the strong signal increase in healthy lymph node tissue. The enhancement in healthy lymph node tissue was 382% at 15 min pi and 419% at 60 min pi. Zones with no signal increase within the lymph node were diagnosed as metastases and confirmed histologically (H / E staining of the lymph node sections). The ratio of signal intensities of healthy lymph node tissue to metastasis was 3.0 at 15 min pi and 3.4 at 60 min pi. Surprisingly, a clear enhancement not only of the lymph nodes but also of the primary tumor (especially the periphery) was observed immediately after application (15 min pi: 277%). At later times (up to 24 h pi), this enhancement also spreads towards the tumor center (24 h pi: 217%). Metal complex V

Example 125: Infarction imaging (MRI) after intravenous administration of the contrast medium in rats

The figures in FIG. 10 show MR images of the heart (in vivo and post mortem) 24 h after intravenous application of 100 // mol Gd / kg body weight of a polar Gd chelate with a perfluorinated side chain (metal complex V) in rats with acute induced heart attack. The T- | -weighted, ECG-triggered spin echo recordings (1.5 T; TR (effective): 400 ms, TE: 12 ms; NA: 4; matrix: 128 * 128; layer thickness: 2.5 mm) illustrate the strong signal increase in the infarct area. The successful induction of an acute myocardial infarction was confirmed by NBT staining.

Example 126: Organ distribution (including lymph node enrichment) after intravenous administration of the

Contrast agent in rats

After intravenous application of 200 // mol total gadolinium / kg body weight of a polar Gd chelate with perfluorinated side chain (metal complex V) in rats, the metal content in various organs and in the lymph nodes was determined 24 hours after application (pooled as mesenteric and peripheral lymph nodes) ( MW, n = 2).

Example 127: Lymph node imaging (MRI) after intravenous administration of the contrast medium in rats

The images in FIG. 11 show, by way of example, MR images of iliac lymph nodes pre-contrast and up to 60 min after intravenous administration of 200 mol / kg body weight of metal complex V in rats. The Tj -weighted gradient echo recordings (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15 °) illustrate the strong signal increase in healthy lymph node tissue at very early times after injection. The enhancement was 147% at 15 min pi and 230% at 60 min pi. Example 128: Lymph node imaging (MRI) after intravenous administration of the contrast medium in VX2-

Tumor-bearing rabbit

The illustrations in FIG. 12 show exemplary MR images of iliac lymph nodes pre-contrast and up to 60 min after intravenous administration of 200 / mol Gd / kg body weight of metal complex V in rabbits with i.m. implanted VX2 tumor. The T-j weighted gradient echo recordings (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15 °) illustrate the strong signal increase in healthy lymph node tissue. The enhancement 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 confirmed histologically (H / E staining of the lymph node sections). The ratio of signal intensities of healthy lymph node tissue to metastasis was 2.5 at 15 min p.i. and 1.7 at 60 min p.i.

Surprisingly, a clear enhancement not only of the lymph nodes but also of the primary tumor (especially the periphery) was observed immediately after application (15 min pi: 350%). At later times (up to 24 h pi) this enhancement also spreads towards the tumor center (24 h pi: 106%).

Metal complex XIV

Example 129: Infarct imaging (MRI) after intravenous administration of the contrast medium in rats

The illustrations in FIG. 13 show MR images of the heart (in vivo and post mortem) 3 h after intravenous application of 100 mol / kg body weight / kg body weight of a polar Gd chelate with a perfluorinated side chain (metal complex XIV) in rats with acute induced Heart attack. The T- | -weighted, ECG-triggered spin echo recordings (1.5 T; TR (effective): 400 ms, TE: 12 ms; NA: 4; matrix: 128 * 128; layer thickness: 2.5 mm) illustrate the strong signal increase in the infarct area. The successful induction of an acute myocardial infarction was confirmed by NBT staining

Example 130: Organ distribution (including tumor and lymph node enrichment) after intravenous administration of the contrast agent in prostate cancer-bearing rats

After intravenous application of 200 // mol total gadolinium / kg body weight of a polar Gd chelate with perfluorinated side chain (metal complex XIV) in rats (cop inbreeding, with 12 days before in implanted prostate cancer Dunning R3327 MAT-Lu), 10 minutes, 1 and The metal content in various organs, in the tumor and in the lymph nodes (pooled as mesenteric and peripheral lymph nodes) was determined 24 hours after application (MW ± SD, n = 3). Metal complex XIV

Gd concentration f / mole / l]% dose

10min p.i. 1h p .i. 24h p. i. 10min p.i. 1h p i. 24h p. I.

Liver 192 ± 12 147 ± 7 64 ± 4 2.62 ± 0.11 2.04 ± 0.15 0.96 ± 0.05

Spleen 200 ± 13 123 ± 10 69 ± 5 0.13 + 0.01 0.08 ± 0.01 0.06 ± 0.00

Pancreas 191 ± 14 139 ± 26 25 ± 1 0.35 ± 0.02 0.21 ± 0.05 0.03 ± 0.01

Kidney 761 ± 60 1181 ± 232 338 ± 49 1.76 ± 0.14 2.84 + 0.61 0.81 ± 0.09

Lungs 603 + 30 415 ± 39 44 + 4 1.04 ± 0.02 0.80 ± 0.06 0.09 ± 0.01

Heart 320 ± 8 190 ± 15 19 ± 0 0.32 ± 0.01 0.19 ± 0.01 0.02 ± 0.00

Brain 38 ± 6 22 ± 2 4 ± 4 0.10 ± 0.03 0.06 ± 0.00 0.01 ± 0.01

Muscle **** 93 ± 5 56 ± 3 8 ± 1 0.06 ± 0.02 0.04 ± 0.00 0.00 ± 0.00

Tumor 246 ± 25 266 ± 87 56 ± 4 0.25 ± 0 05 0.37 ± 0.14 0.04 ± 0.01

Femur 115 ± 3 81 ± 10 9 ± 1 0.39 ± 0.02 0.28 ± 0.03 0.03 ± 0.00 mes. LK 291 ± 29 179 ± 16 50 ± 6 0.08 ± 0.01 0.05 ± 0.01 0.02 ± 0.00 peripheral. LK 284 ± 19 254 ± 14 51 ± 5 0.13 ± 0.00 0.14 ± 0.02 0.02 ± 0.00

Stomach (deflated) 244 ± 17 165 ± 21 19 ± 2 0.56 ± 0.07 0.40 ± 0.05 0.05 ± 0.00

Bowel (deflated) 242 ± 15 201 ± 32 36 ± 5 1.55 ± 0.09 1.16 ± 0.22 0.26 ± 0.04

Blood ** 957 ± 38 575 ± 56 22 ± 1 26.73 ± 0.84 16.13 ± 1.77 0.61 ± 0.03

Residual * 419 ± 27 392 ± 25 42 ± 0 70.71 ± 2.74 64.27 ± 5.50 6.81 ± 0.16

Urine 0-24 h - - 619 ± 19 - - 79.86 ± 3.13

Faeces 0-24 h - - 781 ± 611 - - 6.00 ± 4.91

Total organs *** 80.06 ± 2.84 72.94 _ 5.83 9.21 ± 0.27

Balance *** 95.07 ± 2.41

Blood samples are contained in the residual body * 58ml blood / kg body weight

'* Balance without blood values, since these contain orper in the rest "** only tissue aliquot

Example 131: Lymph node imaging (MRI) after intravenous administration of the contrast medium in

Guinea pig

The illustrations in FIG. 14 show, by way of example, MR images of iliac and inguinal lymph nodes pre-contrast and up to 24 h after intravenous administration of 200 mol / kg body weight / kg body weight of metal complex XIV in guinea pigs with stimulated lymph nodes (Freund's adjuvant). The T- | - weighted gradient echo recordings (2.0 T; TR 10 ms, TE 5 ms, α 40 °) illustrate the strong signal increase in healthy lymph node tissue at very early times after injection. The enhancement was 127% at 60 min pi. Example 132: Lymph node imaging (MRI) after intravenous administration of the contrast medium in VX2-t

Tumor-bearing rabbit

The images in FIG. 15 show, by way of example, MR images of iliac lymph nodes pre-contrast and up to 23 hours after intravenous administration of 200 mol / kg body weight of metal complex XIV in rabbits with i.m. implanted VX2 tumor. The T-j weighted gradient echo recordings (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15 °) illustrate the strong signal increase in healthy lymph node tissue. The enhancement in healthy lymph node tissue was 297% at 10 min p.i. and 269% at 60 min p.i .. Zones with no signal increase within the lymph node were diagnosed as metastases and confirmed histologically (H / E staining of the lymph node sections). The ratio of signal intensities of healthy lymph node tissue to metastasis was 5.1 at 10 min p.i. and 1.9 at 60 min p.i.

Surprisingly, a clear enhancement not only of the lymph nodes, but also of the primary tumor (especially the periphery) was observed immediately after application (15 min pi: 594%). At later times (up to 24 h pi) this enhancement also spreads towards the tumor center (120 min pi: 162%).

Metal complex III

Example 133: Infarction imaging (MRI) after intravenous administration of the contrast medium in rats

The images in FIG. 16 show MR images of the heart (in vivo and post mortem) 22 h after intravenous application of 100 // mol Gd / kg body weight of a polar Gd chelate with a perfluorinated side chain (metal complex III) in rats with acute induced Heart attack. The Tj -weighted, ECG-triggered spin echo recordings (1.5 T; TR (effective): 400 ms, TE: 12 ms; NA: 4; matrix: 128 ^* 128; layer thickness: 2.5 mm) illustrate the strong signal increase in infarcted area. The successful induction of an acute myocardial infarction was confirmed by NBT staining.

Example 134: Organ distribution (including lymph node enrichment) after intravenous administration of the contrast medium in rats

After intravenous application of 200 // mol total gadolinium / kg body weight of a polar Gd chelate with perfluorinated side chain (metal complex III) in rats, the metal content in various organs and in the lymph nodes was determined 24 hours after application (pooled as mesenteric and peripheral lymph nodes) ( MW, n = 2).

Example 135: Lymph node imaging (MRI) after intravenous administration of the contrast medium in rats

The illustrations in FIG. 17 show, by way of example, MR images of iliac lymph nodes pre-contrast and up to 60 min after intravenous administration of 200 mol / kg body weight of metal complex III in rats. The Ti-weighted gradient echo recordings (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15 °) illustrate the strong signal increase in healthy lymph node tissue at very early times after injection. The enhancement was 320% at 15 min pi and 401% at 60 min pi. Example 136 Lymph node imaging (MRI) after intravenous administration of the contrast agent in VX2 tumor-bearing rabbits

The illustrations in FIG. 18 show, by way of example, MR images of iliac lymph nodes pre-contrast and up to 60 min after intravenous administration of 200 / mol Gd / kg body weight of metal complex III in rabbits with i.m. implanted VX2 tumor. The T-j weighted gradient echo recordings (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15 °) illustrate the strong signal increase in healthy lymph node tissue. The enhancement in healthy lymph node tissue was 195% at 15 min p.i. and 233% at 60 min p.i .. Zones with no signal increase within the lymph node were diagnosed as metastases and confirmed histologically (H / E staining of the lymph node sections). The ratio of signal intensities of healthy lymph node tissue to metastasis was 1.9 at 15 min p.i. and 1.8 at 60 min p.i.

Surprisingly, a clear enhancement not only of the lymph nodes but also of the primary tumor (especially the periphery) was observed immediately after application (15 min p.i .: 232%).

Claims

claims

1. Use of perfluoroalkyl-containing metal complexes which have a critical micelle concentration <10 ^"3 mol / l, a hydrodynamic micelle diameter (2 Rh)> 1 nm and a proton relaxivity in the plasma (R ¹ )> 10 l / mmol-s, as Contrast agent in MR imaging to display plaques.

2. Use according to claim 1, characterized in that the metal complexes are also used as MRI contrast agents for the representation of lymph nodes.

3. Use according to claim 1 or 2, characterized in that the metal complexes are also used as MRI contrast agents for the representation of infarcted and necrotic tissue.

4. Use according to one of claims 1 to 3, characterized in that the metal complexes are also used as MRI contrast agents for the independent display of necrosis and tumors.

5. Use according to claim 1, characterized in that

Metal complexes are used, their micelle concentration

<10 ^{"is 4} mol / l.

6. Use according to claim 1, characterized in that

Metal complexes are used whose hydrodynamic micelle diameter is> 3 nm, preferably> 4 nm.

7. Use according to claim 1, characterized in that

Metal complexes are used which have a proton relaxivity in the plasma of> 13 l / mmol-s, preferably> 15 l / mmol-s.

8. Use according to one of claims 1 to 7, characterized in that the compounds of general formula I as perfluoroalkyl-containing metal complexes

R ^F -LK I where

RF is a perfluorinated, straight-chain or branched carbon chain with the formula -C _n F2nE in which

E is a terminal fluorine, chlorine, bromine, iodine or

Represents hydrogen atom and n represents the numbers 4 - 30,

L is a direct bond, a methylene group, an -NHCO group, a group

1

R

(CH ₂ ) -NHCOCH ₂ - (CH ₂ ) - N - S0 ₂ -

(Please change in formula R ¹ to R ^a !) Where p is the numbers 0 to 10, q and u independently of each other

Numbers 0 or 1 and R ^{a is} a hydrogen atom, a methyl group, a -CH2-OH group, a -CH2-Cθ2H group or a C2-Ci5 chain which is optionally interrupted by 1 to 3 oxygen atoms, 1 to 2 > CO groups or an optionally substituted aryl group and / or is substituted by 1 to 4 Hydroxyl groups, 1 to 2 C- | -C4-alkoxy groups, 1 to 2 carboxy groups, a group -SO3H-,

or is a straight-chain, branched, saturated or unsaturated C2-C30 carbon chain which optionally contains 1 to 10 oxygen atoms, 1 to 3 -NR ^a groups, 1 to 2 sulfur atoms, a piperazine, a -CONR ^a group, a -NR ^a CO group, a -SO2-

Group, a -NR ^a -Cθ2 group, 1 to 2 -CO groups, one group

__ CO - N - T - - N (R ^a ) - S0 ₂ - R ^{F or 1 to 2} if necessary

I contains substituted aryls and / or is interrupted by these groups, and / or is optionally substituted by

1 to 3 -OR ^a groups, 1 to 2 oxo groups, 1 to 2 -NH-COR ^a groups, 1 to 2 -CONHR ^a groups, 1 to 2 - (CH2) _p -Cθ2H groups, 1 to 2

Groups - (CH ₂ ) p- (0) q-CH2CH2-R ^F , where

R ^a , R ^F and p and q have the meanings given above and

T is a C2-Cιo ^chain , optionally by 1 to 2

Oxygen atoms or 1 to 2 NHCO groups is interrupted,

stands for a complexing agent or metal complex or their salts of organic and / or inorganic bases or amino acids or amino acid amides, specifically for a complexing agent or complex of the general formula II

in which R ^c > R ^" 1 and B are independent of one another and

R ^{c has} the meaning of R ^a or - (CH2) m "l-" ^RF , where m is 0, 1 or 2 and L and R ^{F have} the abovementioned meaning,

R ^" ! Independently of one another represents a hydrogen atom or a metal ion equivalent of atomic numbers 22-29, 42-46 or 58-70,

B -OR or

means, where R ¹ > L, R ^F and R ^{c have} the abovementioned meanings,

or

for a complexing agent or complex of the general formula III

CO _g Z ¹

^ COsZ ¹

^ (III) in which R ^c and R1 have the meanings given above and R ^{D has} the meaning of R ^a or for a complexing agent or complex of the general formula IV

in which R ^" ! has the meaning given above or for a complexing agent or complex of the general formula V

.1

-CO, Z

in which R ^" ! has the meaning given above and o and q stand for the digits O or 1 and the sum is o + q = 1, or for a complexing agent or complex of the general formula VI

in which R ^" ! has the meaning given above or for a complexing agent or complex of the general formula VII

in which R1 and B have the meanings given above or

for a complexing agent or complex of the general formula VIII

in which R ^c and R1 have the abovementioned meanings and R ^{D has} the abovementioned meaning of R ^a . or for a complexing agent or complex of the general formula IX

in which R ^c and R1 have the meanings given above,

or for a complexing agent or complex of the general formula X

in which R ^c and R ^{1 have} the meanings given above,

or for a complexing agent or complex of the general formula XI

in which R ¹ p and q have the meaning given above and R ^{D has} the meaning of R ^a . or for a complexing agent or complex of the general formula Xll

in which LR ^F and 2> have the meanings given above, or

for a complexing agent or complex of the general formula Xlll

in which R1 has the meaning given above.

9. Use according to claim 8, characterized in that the compounds of general formula I are used, in which L for

-CH ₂ -ß α-CH ₂ CH ₂ -ß α- (CH ₂ ) _s -ß s = 3 - 15 α-CH2-0-CH ₂ CH ₂ -ß α-CH2- (0-CH ₂ -CH ₂ -) t-ß t = 2 - 6 α-CH -NH-CO-ß -CH2-NH-CO-CH2-N (CH ₂ COOH) -S0 ₂ -ß α-CH2-NH-CO-CH2- N (C ₂ H5) -SO ₂ -ß α-CH ₂ -NH-CO-CH2-N (C- | ₀ H ₂ 1) -S0 ₂ -ß α-CH2-NH-CO-CH2-N (C ₆ H "| ₃ ) -S0 ₂ -ß α-CH2-NH-CO- (CH2) io-N (C ₂ H5) -Sθ2-ß -CH ₂ -NH-CO-CH2-N (-CH2-C ₆ H ₅ ) -Sθ2-ß α-CH ₂ -NH-CO-CH ₂ -N (-CH ₂ -CH2-OH) Sθ2-ß α-CH ₂ -NHCO- (CH ₂ ) ι oS-CH ₂ CH ₂ -ß α-CH2NHCOCH ₂ -0-CH ₂ CH2-ß α-CH NHCO (CH ₂ ) i o-0-CH ₂ CH ₂ -ß α-CH2-C ₆ H ₄ -0-CH ₂ CH2-ß -CH2-0-CH2-C (CH2-OCH ₂ CH2-C ₆ Fi3) 2-CH2-OCH2-CH2-ß α-CH2-NHCOCH ₂ CH2CON-CH2CH2NHCOCH2N (C2H5) Sθ2C ₈ F ₁₇

I

CH ₂ -CH ₂ NHCOCH ₂ N (C ₂ H ₅ ) -SO ₂ -ß α-CH -O-CH ₂ -CH (OCι ₀ H21) -CH2-0-CH ₂ CH -ß α- (CH ₂ NHCO ) 4-CH2θ-CH ₂ CH2-ß - (CH ₂ NHCO) 3-CH2θ-CH ₂ CH2-ß α-CH2-OCH2C (CH ₂ OH) 2-CH2-0-CH ₂ CH2-ß

(Please insert a and ß in this formula, we cannot access the F.! Α-CH ₂ NHCOCH2N (C ₆ H ₅ ) -Sθ2-ß -NHCO-CH ₂ -CH ₂ -ß α-NHCO-CH2 -O-CH CH ₂ -ß α-NH-CO-ß α-NH-CO-CH2-N (CH ₂ COOH) -S0 ₂ -ß α-NH-CO-CH ₂ -N (C2H ₅ ) -Sθ2-ß α-NH-CO- CH ₂ -N (C- | ₀ H21) -S0 -ß α-NH-CO-CH ₂ -N (C ₆ H- | 3) -S0 ₂ -ß -NH-CO- (CH ₂ ) ιo-N (C ₂ H5) -Sθ2-ß α-NH-CO-CH2-N (-CH2-C ₆ H ₅ ) -S0 ₂ -ß α-NH-CO-CH ₂ -N (-CH2-CH ₂ -OH ) Sθ2-ß -NH-CO-CH ₂ -ß α-CH ₂ -0-C ₆ H ₄ -O-CH2-CH2-ß α-CH2-C6H4-0-CH ₂ -CH ₂ -ß α-N (CH ₅ ) -Sθ2-ß α-N (C ₆ H ₅ ) -S0 ₂ -ß α-N (Cι ₀ H2l) -SO -ß α-N (C ₆ H ₁₃ ) -SO ₂ -ß α- N (C ₂ H ₄ OH) -SO ₂ -ß α-N (CH ₂ COOH) -SO ₂ -ß α-N (CH ₂ C ₆ H ₅ ) -S02-ß α-N- [CH (CH ₂ OH) ₂ ] -SO ₂ -ß α-N- [CH (CH20H) CH (CH ₂ 0H)] - S0 ₂ -ß and where the binding site to the complexing agent or

Metal complex K and ß represents the binding site to the fluorine residue.

10. Use according to claim 8 or 9, characterized in that the compounds of formula I are used, in which n in the formula -C _n F _2n E represents the numbers 4-15 and / or E in this formula represents a fluorine atom ,

11. Use according to one of claims 8 to 10, characterized in that the following compounds are used:

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

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

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

- Gadolinium complex of 10- [2-hydroxy-4-oxa-1 H, 1 H, 2H, 3H, 3H, 5H, 5H, 6H, 6H-perf luorotetradecyl] -1, 4,7-tris ( carboxymethyl) -1, 4.7, 10-tetraaza- cyclododecane,

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,

- Gadolinium complex of 10- [2-hydroxy-4-aza-5-oxo-11-aza-11 - (perfluoro-octylsulfonyl) tridecyl] -1 -4-7-tris (carboxymethyl) 1, 4.7 , 10-tetraazacyclododecane,

- Gadolinium complex of 10- [2-hydroxy-4-aza-5-oxo-7-aza-7- (perfluoro-octylsulfonyl) -8-phenyl-octyl] -1 -4-7-tris (carboxymethyl) - 1, 4,7,10-tetraazacyclododecane.

12. Use according to any one of claims 1-7, characterized in that the compounds of the general formula la as perfluoroalkyl-containing metal complexes

A - R ^F (la) in which

• A is a part of a molecule that contains 2-6 metal complexes that are bonded directly or via a linker to a nitrogen atom of a ring-shaped skeleton chain and

E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n represents the numbers 4 - 30,

where the molecular part A has the following structure:

K

I

I K where

q ^{1 is} a number 0, 1, 2 or 3,

K represents a complexing agent or metal complex or the salts thereof of organic and / or inorganic bases or amino acids or amino acid amides,

• X is a direct bond to the perfluoroalkyl group, a phenylene group or a C- _| -C- | o-alkylene chain, optionally 1-15 oxygen, 1-5

Sulfur atoms, 1 - 10 carbonyl, 1 - 10 (NR ^d ) -, 1 - 2 NR ^d SO ₂ -, 1 - 10 CONR ^d -, 1 piperidine, 1 - 3 SO2, 1 - 2 phenylene groups or optionally is substituted by 1-3 radicals R ^F , in which R ^{d is} a Is a hydrogen atom, a phenyl, benzyl or a C 1 -C 15 -alkyl group which may contain 1 to 2 NHCO, 1 to 2 CO groups,

Contains 1-5 oxygen atoms and optionally 1-5 hydroxy, 1-5

Methoxy, 1-3 carboxy, 1-3 R ^F radicals is substituted

V is a direct bond or a chain of the general formula IIIa or purple:

O ß-NH CH ₂ ) _k - (Z), - (CH ₂ ) _m -C— _α

,1

R (lla)

wherein

1 R ^{e is} a hydrogen atom, a phenyl group, a benzyl group or a CJ-C7 alkyl group which is optionally substituted by a carboxy, a methoxy or a hydroxy group,

ιW a direct bond, a polyglycol ether group with up to 5 glycol units or a

Molecular part of the general formula IVa

-CH (Rh) - (IVa) wherein R ^{n is} a Cj-Cy-carboxylic acid, a phenyl group, a benzyl group or a - (CH2) ι .5-NH-K group,

■ the bond to the nitrogen atom of the skeleton chain, ß the bond to

Represents complexing agent or metal complex K,

■ and in which the variables k and m stand for natural numbers between 0 and 10 and I for 0 or 1,

and where

D is a CO or Sθ2 group,

be used.

13. Use according to claim 12, characterized in that the compounds of general formula la are used, in which q is the number 1.

14. Use according to claim 12, characterized in that the compounds of the general formula Ia are used, in which the molecular part X is an alkylene chain which is 1-10 CH2CH2O- or 1-5

Contains COCH2NH groups, a direct bond or one of the following

structures

0 C ₂ H ₅ II r ⁵ γ -CH ₂ -0- (CH ₂ ) ₂ - 5. γ -CH ₂ -N N - SS00 ₂₂ - δδ, γ- (CH ₂ ) ₁₀ -NC-CH ₂ -N-SO

C ₂ H ₅ H

γ- (CH ₂ ) ₁₀ -O- (CH ₂ ) ₂ - _δ

where γ binds to D and δ binds to R.

15. Use according to claim 12, characterized in that the compounds of the general formula Ia are used, in which V is a part of the molecule having one of the following structures

II j α - C-CH -NH-ß, α- C -CH-NH - ß CH ₃ CH (CH ₃ ) ₂

_π COOH O CH ₉ C00H

TT I »I

"-C-CH ₂ -CH-NH- ß, α-C-CH ₂ -CH-NH- ß, O α-C-CH-NH-ß (CH ₂ ) ₄ -NH-K

16. Use according to claim 12, characterized in that the compounds of the general formula la are used, in which K represents a complex of the general formula Va, Via, Vlla or Villa

(Villa)

in which

R1 is independently a hydrogen atom or a metal ion equivalent of the elements of atomic numbers 23-29, 42-46 or 58- 70,

R8 is a hydrogen atom or a straight-chain, branched, saturated or unsaturated C-C3o-alkyl chain, which is optionally substituted by 1-5 hydroxy, 1-3 carboxy or 1 phenyl group (s) and / or optionally by 1-10 oxygen atoms , 1 phenylene or 1 phenylene oxy group is interrupted

R ^{6 is} a hydrogen atom, a straight-chain or branched C1-C7 alkyl radical, a phenyl or benzyl radical,

R ^{7 is} a hydrogen atom, a methyl or ethyl group which is optionally substituted by a hydroxyl or carboxy group, • U ^{3 is} optionally 1-5 imino, 1-3 phenylene, 1-3 phenyleneoxy, 1-3 phenyleneimino, 1-5 amide, 1-2 hydrazide, 1-5 carbonyl, 1-5 ethyleneoxy,

1 urea, 1 thiourea, 1 - 2 carboxyalkylimino, 1 - 2 ester groups, 1 - 10 oxygen, 1 - 5 sulfur and / or 1 - 5 nitrogen atoms and / or optionally with 1 - 5 Ηydroxy-, 1 - 2 mercapto, 1-5 oxo, 1-5 thioxo,

1 - 3 carboxy, 1 - 5 carboxyalkyl, 1 - 5 ester and / or 1 - 3 amino groups are substituted, straight-chain, branched, saturated or unsaturated C- | -C20-alkylene group, the optionally contained

Phenylene groups can be substituted by 1 - 2 carboxy, 1 - 2 sulfone or 1 - 2 hydroxy groups

• T ^{1 represents} a -CO-ß, -NHCO-ß or -NHCS-ß group, where ß represents the binding site on V.

17. Use according to claim 16, characterized in that the C ³ -C 8 -alkylene chain representing U ^{3 is} the groups

-CH ₂ NHCO-, -NHCOCH20-, -NHCOCH ₂ OC ₆ H ₄ -, -N (CH ₂ C0 ₂ H) -,

-CH OCH ₂ -,

-NHCOCH ₂ C ₆ H ₄ -, -NHCSNHC ₆ H -, -CH ₂ OC ₆ H ₄ -, -CH ₂ CH ₂ 0- β contains and / or is substituted by the groups -COOH, -CH2COOH.

18. Use according to claim 16, characterized in that U ³ for one

-CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -C ₆ H ₄ -, -C ₆ H ₁₀ -, -CH ₂ C ₆ H ₄ -, -CH2NHCOCH ₂ CH (CH2Cθ2H ) -C6H ₄ -, -CH ₂ NHCOCH ₂ OCH2-, -CH2NHCOCH ₂ C6H ₄ group.

19. Use according to claim 1, characterized in that the compounds of the general formula Ia are used, in which K has one of the following structures:

20. Use according to one of claims 12 to 19, characterized in that the compounds of the general formula Ia are used in which the perfluoroalkyl chain R is -CβF-o, -CβF-jy, -C- | nF21 or -C- | 2F25.

21. Use according to one of claims 12 to 20, characterized in that the gadolinium complex of 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-perfluorotridecanoylj-1,4,7,10-tetraazacyclododecane is used.

22. Use according to one of claims 1 to 7, characterized in that the compounds of the general formula Ib as perfluoroalkyl-containing metal complexes

AIK— N— LR ^F (Ib)

wherein

K is a complexing agent or a metal complex of the general formula IIb

where R ^{1 represents} a hydrogen atom or a metal ion equivalent of

Atomic numbers 23-29, 42-46 or 58-70,

R ² and R ^{3 represent} a hydrogen atom, a CrC ₇ alkyl group, a benzyl group, a phenyl group, -CH ₂ OH or -CH ₂ -OCH ₃ , U ^{2 represents} the radical L ¹ , but L ¹ and U ² can be the same or different independently of one another, means A ^{1 is} a hydrogen atom, a straight-chain or branched CrC ₃₀ alkyl group which is optionally interrupted by 1 -15 oxygen atoms, and / or optionally substituted with 1-10 hydroxyl groups, 1-2 COOH groups, a phenyl group, a benzyl group and / or 1-5 - OR ⁹ groups, with R ⁹ in the meaning of a hydrogen atom or one CrC -Alkylrestes, or -L ¹ -R ^F means, L ^{1 is} a straight-chain or branched C-C ₃ o-alkylene group, which is optionally interrupted by 1-10 oxygen atoms, 1-5 -NH-CO- groups, 1-5 -CO-NH groups, by a phenylene group optionally substituted by a COOH group, 1-3 sulfur atoms, 1-2 -N (B ¹ ) -S0 ₂ groups, and / or 1-2 -S0 ₂ -N ( B ¹ ) - groups with B ¹ in the meaning of A ¹ , an NHCO group, a CONH group, an N (B ¹ ) -S0 ₂ group, or an -S0 ₂ -N (B ¹ ) group and / ode r is optionally substituted by the radical R ^F , and R ^{F is} a straight-chain or branched perfluorinated alkyl radical of the formula C _n F _2n E, where n is the numbers 4-30 and

E represents a terminal fluorine atom, chlorine atom, bromine atom, iodatone or a hydrogen atom, and any acid groups present may optionally be present as salts of organic and / or inorganic bases or amino acids or amino acid amides,

be used.

23. Use according to claim 22, characterized in that the compounds of the general formula Ib are used in which R ² , R ³ and R ⁹ independently of one another are hydrogen or a C1-C4-alkyl group.

4. Use according to claim 22, characterized in that the compounds of the general formula Ib are used in which A ^{1 is} hydrogen, a CrCi ₅ -alkyl radical, the radicals C ₂ H ₄ -0-CH ₃ , C ₃ H6-0- CH ₃ ,

C ₂ H4-0- (C ₂ H4-0) rC ₂ H ₄ -OH,

C ₂ H ₄ -0- (C ₂ H ₄ -0) _t -C ₂ H ₄ -OCH ₃ ,

C ₂ HOH, C ₃ HβOH, C4H ₈ OH, C ₅ H ₁₀ OH, C ₆ H12OH, C ₇ H ₄ OH,

CH (OH) CH ₂ OH,

CH (OH) CH (OH) CH ₂ OH, CH ₂ [CH (OH)] _and ¹ CH ₂ OH,

CH [CH ₂ (OH)] CH (OH) CH ₂ OH,

C ₂ H ₄ CH (OH) CH ₂ OH,

(CH ₂ ) _s COOH,

C ₂ H ₄ -0- (C ₂ H ₄ -0) _t -CH ₂ COOH or

C ₂ H ₄ -0- (C ₂ H ₄ -0) _t -C ₂ H ₄ -CnF _2n E means, where s for the integers 1 to 15, t for the integers 0 to 13, u ¹ for the integers 1 to 10, n stands for the integers 4 to 20, and

E for a hydrogen, fluorine, chlorine, bromine or iodine atom and, if possible, their branched isomers.

25. Use according to claim 22, characterized in that the compounds of the general formula Ib are used in which A ^{1 is} hydrogen, C 1 -C 8 -alkyl, C ₂ H ₄ -0-CH ₃ , C ₃ H ₆ -O-CH ₃ .

C ₂ H ₄ -0- (C ₂ H ₄ -0) _x -C ₂ H ₄ -OH, C ₂ H4-0- (C ₂ H ₄ -0) _x -C2H4-OCH ₃ , C ₂ H ₄ θH , CsH _ß OH, CH ₂ [CH (OH)] _y CH ₂ OH, CH [CH ₂ (OH)] CH (OH) CH ₂ OH, (CH ₂ ) _w COOH, C ₂ H ₄ -0- (C ₂ H ₄ -0) _x -CH ₂ COOH, C ₂ H ₄ -0- (C ₂ H ₄ -0) χ-C2H ₄ -CnF ₂ nE, where x for the integers 0 to 5, y for the integers 1 to 6, w for the integers 1 to 10, n for the integers 4 to 15 and

E represents a fluorine atom and, if possible, its branched isomers.

26. Use according to claim 22, characterized in that the compounds of the general formula Ib are used, in which L ¹ α- (CH ₂ ) _s -β α-CH ₂ -CH2- (0-CH2-CH ₂ -) _y -ß α-CH ₂ - (0-CH2-CH ₂ -) y-ß, α-CH ₂ -NH-CO-ß -CH2-CH2-NH-S02-ß -CH2-NH-CO-CH ₂ - N (CH ₂ COOH) -Sθ2-ß α-CH2-NH-CO-CH ₂ -N (C2H ₅ ) -S02-ß α-CH ₂ -NH-CO-CH -N (Cι ₀ H21) -S0 ₂ -ß α-CH ₂ -NH-CO-CH2-N (C ₆ H- | 3) -S0 ₂ -ß α-CH2-NH-CO- (CH ₂ ) ιo-N (C2H ₅ ) -Sθ2-ß α-CH2-NH-CO-CH2-N (-CH2-C ₆ H ₅ ) -S0 ₂ -ß α-CH2-NH-C0-CH ₂ -N (-CH2-CH ₂ -0H) S02-ß α -CH2-NHCO- (CH2) ιo-S-CH CH2-ß

(X-CH ₂ NHCOCH2-0-CH2CH ₂ -ß -CH2-CH ₂ NHCOCH2-0-CH2CH ₂ -ß α-CH ₂ - (CH2-CH2-0) r (CH ₂ ) ₃ NHCO-CH2-0- CH ₂ CH ₂ -ß -CH ₂ NHCO (CH ₂ ) i o-0-CH ₂ CH ₂ -ß -CH ₂ CH ₂ NHCO (CH ₂ ) ι 0-O-CH ₂ CH ₂ -ß -CH2-C6H ₄ -0-CH2CH2-ß where the phenylene group 1, 4 or 1, 3 is linked α-CH2-0-CH2-C (CH2-OCH ₂ CH2-C6F- | ₃ ) 2-CH2-OCH2-CH2-ß α -CH2-NHCOCH ₂ CH2CON-CH2CH2NHCOCH2N (C2H ₅ ) Sθ2C8F- | 7ß α-CH ₂ -CH ₂ NHCOCH ₂ N (C ₂ H ₅ ) -S0 ₂ -ß α-CH -0-CH ₂ -CH (OC ₁ 0H21) -CH ₂ -0-CH ₂ CH2-ß α- (CH NHCO) ₄ -CH2θ-CH2CH ₂ -ß α- (CH ₂ NHCO) 3-CH2θ-CH ₂ CH ₂ -ß α-CH2-OCH2C (CH ₂ OH) 2-CH ₂ -0-CH2CH2-ß

α-CH ₂ NHC0CH2N (C ₆ H ₅ ) -S02-ß α-NHCO-CH ₂ -CH ₂ -ß α-NHCO-CH ₂ -0-CH ₂ CH2-ß α-NH-CO-ß α-NH -CO-CH ₂ -N (CH ₂ COOH) -Sθ2-ß α-NH-C0-CH2-N (C ₂ H ₅ ) -S02-ß α-NH-CO-CH ₂ -N (C- | 0H21 ) -S0 ₂ -ß α-NH-CO-CH ₂ -N (C6Hι 3) -S0 ₂ -ß α-NH-CO- (CH ₂ ) ι oN (C ₂ H ₅ ) -Sθ2-ß α-NH -C0-CH2-N (-CH2-C ₆ H ₅ ) -S02-ß α-NH-CO-CH ₂ -N (-CH2-CH2-OH) S0 ₂ -ß -NH-CO-CH ₂ -ß α-CH2-0-C6H ₄ -0-CH ₂ -CH ₂ -ß -CH2-C ₆ H ₄ -0-CH ₂ -CH2-ß α-N (C ₂ H ₅ ) -S02-ß α-N (C ₆ H ₅ ) -S0 ₂ -ß -N (C ₁₀ H2l) -SO -ß -N (C ₆ H ₁₃ ) -S0 ₂ -ß α-N (C ₂ H ₄ OH) -S0 ₂ -ß α-N (CH ₂ COOH) -S0 ₂ -ß α-N (CH ₂ C ₆ H5) -S0 ₂ -ß α-N- [CH (CH 0H) ₂ 3-S02-ß α-N- [CH (CH ₂ OH) CH (OH) (CH ₂ OH)] - S0 ₂ -ß, where s stands for the integers 1 to 15 and y stands for the integers 1 to 6.

27. Use according to claim 22, characterized in that the compounds of the general formula Ib are used, in which L ¹ -CH ₂ -0-CH ₂ CH2-ß, α-CH ₂ -CH2- (0-CH2-CH ₂ -) _y -ß, α-CH ₂ - (0-CH2-CH ₂ -) y-ß, α-CH ₂ -CH ₂ -NH-S02-ß, e.g. 10 α-CH ₂ NHCOCH2-0-CH ₂ CH2-ß, α-CH ₂ -CH2NHCOCH2-0-CH CH2-ß, α-CH ₂ - (CH ₂ -CH ₂ -0) y- (CH ₂ ) 3NHCO-CH ₂ -0-CH ₂ CH ₂ -ß, α-CH ₂ NHCO (CH ₂ ) ι o-0-CH ₂ CH ₂ -ß, α-CH ₂ CH ₂ NHCO (CH ₂ ) ι o-0-CH ₂ CH ₂ -ß, α-CH ₂ -0-CH2-CH (OC- | ₀ H ₂ 1) -CH ₂ -0-CH ₂ CH2-ß, α-CH ₂ -0-C6H ₄ -0-CH ₂ -CH2-ß or -CH ₂ -C6H -0-CH2-CH ₂ -ß means, where y stands for the integers 1 to 6.

28. Use according to claim 22, characterized in that the compounds of the general formula Ib are used in which R ^{F is} a straight-chain or branched perfluorinated alkyl radical of the formula C _n F _2n E, where n is the numbers 4 to 15 and E stands for a terminal fluorine atom.

29. Use according to one of claims 22 to 28, characterized in that the following compounds are used:

- 1,4-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) - (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-oxapentyl) -N- (1H , 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) - perfluorotridecyl] -amide} -1, 4.7, 10-tetraazacyclododecane, gadolinium complex - 1,4-tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid- [N- 3,6,9,15-tetraoxa-12-aza- 15-oxo-Cι ₇ -C 6-hepta-decafluor) hexacosyl] - amide} -1, 4,7,10-tetraazacyclododecane, gadolinium complex

- 1,4-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.

30. Use according to one of claims 1 to 7, characterized in that as the perfluoroalkyl-containing metal complexes the compounds with sugar residues of the general formula Ic

(K), -G - (ZR ^F ) _m ¹

I (Ic)

(YR) P ¹

in the

R represents a mono- or oligosaccharide residue bonded via the 1-OH or 1-SH position,

K represents a metal complex of the general formula IIc,

(llc) in the R ^{1 is} a hydrogen atom or a metal ion equivalent of

R ² and R ³ independently represent hydrogen, dC ₇ alkyl, benzyl, phenyl, -CH ₂ OH or -CH ₂ OCH ₃ and

U -C ₆ H ₄ -0-CH ₂ -ω-, - (CH ₂ ) ι _-5 -ω, a phenylene group, -CH ₂ -NHCO-

CH ₂ -CH (CH ₂ COOH) -C ₆ H ₄ -ω-, -C ₆ H4- (OCH ₂ CH ₂ ) o-ι-N (CH ₂ COOH) - CH ₂ -ω or one optionally by one or several oxygen atoms, 1 to 3-NHCO-, 1 to 3 -CONH groups interrupted and / or with 1 to 3- (CH ₂ ) _0-5 COOH groups substituted d -CC ₂ alkylene or C ₇ -Ci _2nd -C ₆ H represents -0 group, where ω stands for the binding site at -CO-, or the general formula IIIc

(IIIc)

in which R ^{1 has} the meaning given above, R ^{4 represents} hydrogen or a metal ion equivalent mentioned under R ¹ and U ¹ -C ₆ H4-0-CH ₂ -ω-, where ω represents the binding site at -CO-

or the general formula IVc

(IVc)

in which R ¹ and R ^{2 have} the meaning given above

or the general formula VcA or VcB

(VCA)

(VCB)

in which R ^{1 has} the meaning given above,

or the general formula Vlc

ROOC - / \ - CO - ^

J: N N ^

ROOC - ^ COOR ¹

(Vlc) in which R ^{1 has} the meaning given above, or the general formula Vllc

(VIIc)

in which R ^{1 has} the meaning given above and

U ¹ -C ₆ H _{4 represents} -0-CH ₂ -ω-, where ω denotes the binding site at -CO-

or the general formula VI llc

(VIIIc)

in which R ^{1 has} the meaning given above,

In the event that K denotes the metal complexes IIc to Vllc, it represents an at least triple-functionalized radical selected from the following radicals a) to j) (A)

ß

(c) α

(D)

(H)

(I)

0) ^ NH-CH - CO - ^ Y k ß

and

(K)

(I)

where the binding site of G to the complex means K, ß is the binding site of G to the radical Y and γ represents the binding site of G to the radical Z.

Y -CH ₂ -, δ- (CH ₂ ) _(1-5) CO-ß, δ-CH ₂ -CHOH-CO-ß or δ-CH (CHOH-CH ₂ OH) - CHOH-CHOH-CO-ß means, where δ represents the binding site to the sugar residue R and ß is the binding site to the rest G.

Z for

T— N:: N-so _^ -ε

γ-COCH ₂ -N (C ₂ H ₅ ) -S0 ₂ -ε,

γ-COCH ₂ -0- (CH ₂ ) ₂ -S0 ₂ -ε,

I ¹ , m ¹ independently of one another denote the integers 1 or 2 and p denotes the integers 1 to 4,

be used.

31. Use according to claim 30, characterized in that the compounds of general formula Ic are used, in which R represents a monosaccharide radical having 5 to 6 carbon atoms or its deoxy compound, preferably glucose, mannose or galactose.

32. Use according to claim 30, characterized in that the compounds of general formula Ic are used, in which R ² and R ³ independently of one another are hydrogen or C -C ₄ alkyl and / or E in the formula -C _n F _2n E represents a fluorine atom.

33. Use according to claim 30, characterized in that the compounds of general formula Ic are used, in which G represents the lysine residue (a) or (b).

34. Use according to claim 30, characterized in that the compounds of general formula Ic are used in which Z

YN: ^ -S0 ₂ -ε

means, where γ represents the binding site from Z to the radical G and ε denotes the binding site from Z to the perfluorinated radical R ^F and / or Y means δ-CH ₂ CO-ß, where δ represents the binding site to the sugar residue R and ß the binding site to the rest G.

35. Use according to claim 30, characterized in that the compounds of the general formula Ic are used in which U in the metal complex K represents -CH ₂ - or -C ₆ H -0-CH ₂ -ω, where ω stands for the binding site at -CO-.

36. Use according to claim 30, characterized in that the gadolinium complex of 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- [1-0-α-D-carbonylmethyl-mannopyranose] -L-lysine [1- (4-perfluorooctylsulfonyl) - piperazin] -amide is used.

37. Use according to one of claims 1 to 7, characterized in that as the perfluoroalkyl-containing metal complexes, the compounds with polar radicals of the general formula Id

I (Id)

(R) P ²

in the

K represents a metal complex of the general formula IIId,

(IId) in the

R ^{1 is} a hydrogen atom or a metal ion equivalent of

Ordinal numbers 23-29, 42-46 or 58-70 means, with the proviso that at least two R stand for metal ion equivalents

R ² and R ^{3 are} independently hydrogen, CrC ₇ alkyl, benzyl, phenyl, -CH ₂ OH or -CH ₂ OCH ₃ and

CH ₂ -CH (CH ₂ COOH) -C ₆ H ₄ -ω-, -C ₆ H4- (OCH ₂ CH ₂ ) o-rN (CH ₂ COOH) - CH ₂ -ω or one optionally by one or more oxygen atoms , 1 to 3-NHCO, 1 to 3 -CONH groups interrupted and / or with 1 to 3

- (CH ₂ ) _0-5 COOH groups substituted C C ₂ alkylene or C ₇ -C ₂ - C ₆ H ₄ -0 group, where ω is the binding site at -CO-, or the general formula IIId

(llld) in which R ^{1 has} the meaning given above, R ^{4 represents} hydrogen or a metal ion equivalent mentioned under R ¹ and U ¹ -C ₆ H ₄ -0-CH ₂ -ω-, where ω is the binding site to -CO- means or the general formula IVd

(IVd) in which R ¹ and R ^{2 have} the meaning given above

or the general formula VdA or VdB

(Vd)

in which R ^{1 has} the meaning given above,

or the general formula Vld

ROOC - s. / \ -CO— ^ t-

JNN: RΌOC - ^ -COOR ¹

(Vld) in which R ^{1 has} the meaning given above,

or the general formula VIII

(VIId)

in which R ^{1 has} the meaning given above and

U ¹ -C ₆ H _{4 represents} -0-CH ₂ -ω-, where ω denotes the binding site at -CO- and free acid groups which may be present in the rest K may optionally be present as salts of organic and / or inorganic bases or amino acids or amino acid amides,

(E)

(G)

α α

where the binding site of G to the complex means K, ß is the binding site of G to the radical R and γ represents the binding site of G to the radical Z.

for y— N: N-S0 _? -ε

γ-C (0) CH ₂ 0 (CH ₂ ) ₂ -ε,

where γ represents the binding site from Z to the radical G and ε the binding site from Z to the perfluorinated radical R _{f represents} R a polar radical selected from the complexes K of the general formulas Ild to Vlld, where R ¹ here is a hydrogen atom or a Metal ion equivalent of atomic numbers 20, 23-29, 42-46 or 58-70 means, and the radicals R ² , R ³ , R ⁴ , U and U ^{1 have} the meaning given above or the folic acid residue or a -CO-, S0 ₂ - or a direct bond to the radical G bonded carbon chain with 2-30 C atoms means straight or branched, saturated or unsaturated, optionally 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, optionally with 1-2 OH groups, 1-2 NH ₂ groups, 1-2 -COOH groups, or 1- 2 - S0 ₃ H groups can be substituted or optionally substituted with 1-8 OH groups, 1-5 -COOH groups, 1-2 S0 ₃ H groups, 1-5 NH ₂ groups, 1-5 C ₁ -C ₄ alkoxy groups, and I ¹ , m ¹ , p ² independently of one another denote the integers 1 or 2.

be used.

38. Use according to claim 37, characterized in that the compounds of the general formula Id are used, in which K represents a metal complex of the general formula IIID, IIID, VDB or VIID.

39. Use according to claim 37, characterized in that the compounds of the general formula Id are used, in which the polar radical R has the meaning of the complex K, preferably the complex K of the general formulas III, III, VdA or VIII.

40. Use according to claim 37, characterized in that the compounds of the general formula Id are used in which the polar radical R has the following meanings:

-C (0) CH ₂ CH ₂ S0 ₃ H

-C (0) CH2θCH ₂ CH2θCH ₂ CH ₂ OH

-C (0) CH ₂ OCH ₂ CH ₂ OH

-C (0) CH ₂ OCH ₂ CH (OH) CH ₂ OH

-C (0) CH ₂ NH-C (0) CH ₂ COOH

-C (0) CH ₂ CH (OH) CH ₂ OH

-C (0) CH ₂ OCH ₂ COOH

-SO ₂ CH ₂ CH ₂ COOH

-C (0) -C ₆ H ₃ - (m-COOH) ₂ -C (0) CH ₂ 0 (CH2) 2-C ₆ H3- (m-COOH) 2

-C (0) CH ₂ 0 -C ₆ H ₄ -m-S0 ₃ H

-C (0) CH ₂ NHC (0) CH ₂ NHC (0) CH ₂ OCH ₂ COOH

-C (0) CH ₂ OCH ₂ CH ₂ OCH ₂ COOH

-C (0) CH ₂ OCH ₂ CH (OH) CH ₂ 0-CH ₂ CH ₂ OH

-C (0) CH ₂ OCH ₂ CH (OH) CH ₂ OCH ₂ -CH (OH) -CH ₂ OH

-C (0) CH ₂ S0 ₃ H

-C (0) CH ₂ CH ₂ COOH

-C (0) CH (OH) CH (OH) CH ₂ OH

-C (0) CH ₂ 0 [(CH ₂ ) ₂ 0] ι _-9 -CH ₃

-C (0) CH ₂ 0 [(CH ₂ ) ₂ 0] ι _-9 -H

-C (0) CH ₂ OCH (CH ₂ OH) ₂

-C (0) CH ₂ OCH (CH ₂ OCH ₂ COOH) ₂

-C (0) -C ₆ H ₃ - (m-OCH ₂ COOH) ₂

-CO-CH ₂ 0- (CH ₂ ) ₂ 0 (CH ₂ ) ₂ O- (CH ₂ ) ₂ 0 (CH ₂ ) ₂ OCH ₃

preferably -C (0) CH ₂ 0 [(CH ₂ ) ₂ 0] ₄ -CH ₃ .

41. Use according to claim 37, characterized in that the compounds of the general formula Id are used in which the polar radical R is the folic acid radical.

42. Use according to claim 37, characterized in that the compounds of general formula Id are used, in which G represents the lysine residue (a) or (b).

43. Use according to claim 37, characterized in that the compounds of the general formula Id are used in which U in the metal complex K represents the group -CH ₂ - or -C ₆ H -0-CH ₂ -ω, where ω is for the Binding site at -CO-.

44. Use according to any one of claims 37-43, characterized in that the gadolinium complex of 2,6-N, N'-bis [1, 4,7-tris (carboxylatomethyl) - 1, 4,7,10- tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - lysine [1 - (4-perfluorooctylsulfonyl-piperazine] -amide is used.

45. Use according to any one of claims 1-7, characterized in that galenical formulations are used as perfluoroalkyl-containing metal complexes which contain paramagnetic perfluoroalkyl-containing metal complexes of the general formulas I, la, Ib, Ic and / or Id and diamagnetic perfluoroalkyl-containing substances, preferably dissolved in an aqueous solvent.

46. Use according to claim 45, characterized in that those of the general formula XX are used as diamagnetic perfluoroalkyl-containing substances:

R ^F -L ² -B ² (XX) wherein R ^{F represents} a straight-chain or branched perfluoroalkyl radical having 4 to 30 carbon atoms, L ^{2 stands} for a linker and B ² for a hydrophilic group.

47. Use according to claim 46, characterized in that the linker L ^{2 is} a direct bond, a -S0 ₂ group or a straight-chain or branched carbon chain with up to 20 carbon atoms, which with one or more -OH, -COO ^" , -S0 ₃ groups can be substituted and / or optionally one or more -O-, -S-, -CO-, -CONH-, -NHCO-, - CONR ⁹ -, -NR ⁹ CO-, -S0 ₂ -, -P0 ₄ ^" -, -NH-, -NR ⁹ groups, an aryl ring or a piperazine, wherein R ^{9 is} ad- to C ₂₀ -alkyl radical, which in turn one or more May contain O atoms and / or may be substituted with -COO ^" or S0 ₃ groups.

48. Use according to claim 46, characterized in that the hydrophilic group B ^{2 is} a mono- or disaccharide, one or more adjacent -COO ^" or -S0 ₃ ^" groups, a dicarboxylic acid, an isophthalic acid, a picolinic acid, a benzenesulfonic acid, one Tetrahydropyranedicarboxylic acid, a 2,6-pyridinedicarboxylic acid, a quaternary ammonium ion, an aminopolycarboxylic acid, an aminodipolyethylene glycol sulfonic acid, an aminopolyethylene glycol group, an S0 ₂ - (CH ₂ ) ₂ -OH group, a polyhydroxyalkyl chain with at least two hydroxyl groups or one or more polyethylene glycol chains Is glycol units, the polyethylene glycol chains being terminated by an -OH or -OCH ₃ group.

49. Use according to claim 45, characterized in that conjugates of -, β- or γ-cyclodextrin and compounds of the general formula XXII are used as diamagnetic perfluoroalkyl-containing substances:

A ² - L ³ -R ^F (XXII) wherein A ^{2 is} an adamantane, biphenyl or anthracene molecule, L ^{3 is} a linker and R ^{F is} a straight-chain or branched perfluoroalkyl radical having 4 to 30 carbon atoms; and wherein the linker L ^{3 is} a straight-chain hydrocarbon chain with 1 to 20 carbon atoms, which by one or more oxygen atoms, one or more CO-, S0 ₂ -, CONH-, NHCO-, CONR ¹⁰ -, NR ¹⁰ CO-, NH- . NR groups or a piperazine can be interrupted, where R ^{1ü is} a C ₅ -C ₅ alkyl radical.

50. Use according to claim 45, characterized in that those of the general formula XXI are used as diamagnetic perfluoroalkyl-containing substances:

R ^F - X ¹ (XXI) in which R ^{F represents} a straight-chain or branched perfluoroalkyl radical having 4 to 30 carbon atoms and X ^{1 is} a radical selected from the group of the following radicals (n is a number between 1 and 10):

O COO

-S-N

0 COO ^"

_O ^{/ S} ° 3