DE10066210B4 - Use of perfluoroalkyl-containing metal complexes as contrast agents in MR imaging for plaque imaging - Google Patents

Abstract

wobei p die Zahlen 0 bis 10, q und u unabhängig voneinander die Zahlen 0 oder 1 und
R^a ein Wasserstoffatom, eine Methylgruppe, eine -CH₂-OH-Gruppe, eine -CH₂-CO₂H-Gruppe oder eine C₂-C₁₅-Kette ist,
die gegebenenfalls unterbrochen ist durch 1 bis 3 Sauerstoffatome, 1 bis 2 > CO-Gruppen oder eine gegebenenfalls substituierte Arylgruppe und/oder substituiert ist mit 1...Use of perfluoroalkyl-containing metal complexes having a critical micelle formation concentration <10 ^-3 mol / l, a hydrodynamic micelle diameter> 1 nm and a proton relaxivity in plasma> 10 l / mmol · s, as a contrast agent in MR imaging for imaging plaques,
in which
as perfluoroalkyl-containing metal complexes, the compounds of general formula I. R F -LK I be used, in which
R ^{F is} a perfluorinated, straight-chain or branched carbon chain of 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,
L is a direct bond, a methylene group, an -NHCO group, a group

where p is the numbers 0 to 10, q and u are independently the numbers 0 or 1 and
R ^a is a hydrogen atom, a methyl group, a -CH ₂ -OH group, a -CH ₂ -CO ₂ H group or a C ₂ -C ₁₅ 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 ...

Description

The invention relates to the use of perfluoroalkyl-containing metal complexes having a critical micelle formation concentration <10 ^-3 mol / l, a hydrodynamic micelle diameter (2 Rh)> 1 nm and a plasma proton relaxivity (R ¹ )> 10 l / mmol · s , as a contrast agent in MR imaging both for the representation of plaques, wherein as perfluoroalkyl-containing metal complexes, the compounds of formula I are used. It has been shown that perfluoroalkyl-containing metal complexes having the properties mentioned are outstandingly suitable for the independent display of plaques.

arteriosclerosis is the most important and most common pathological change arteries with hardening, thickening, loss of elasticity and glade narrowing. It is the most common cause of death in the world The vascular wall changes lead by lipid storage, connective tissue proliferation and calcification with irregular distribution to wall instability, vasoconstriction and for the deposition of clots. The cause of the disease are numerous exogenous and endogenous noxae or diseases, e.g. Hypertension, hyperlipidemia, hyperfibrinogenemia, diabetes mellitus, toxins, nicotine, antigen-antibody complexes, inflammation, hypoxia, mental Stress, Age and family burden. These lead to disorder of integrity the inner vessel wall, to the disturbance Growth control of smooth muscle cells of the vascular wall and to the impairment the degradation of aged cell components. A treatment of arteriosclerosis itself is not possible the goal of medical efforts Prevention is by reducing the risk factors, e.g. by means of Lipid-lowering agents.

The Diagnosis of arteriosclerosis in clinical practice is made to Time mainly by angiography as a gold standard. The limitation at all Procedures based on the measurement of vascular lumen reduction, is however the early stage the disease caused by a thickening of the vascular wall at normal Vascular lumen marked (Glagov S, Zarin 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 the intravascular or percutaneous ultrasound.

The Magnetic Resonance Imaging (MRI) is a modern, non-invasive radiological procedure, with a very good spatial and temporal resolution the representation of physiological and pathophysiological structures allows. The use of specific contrast media with selective enrichment in certain tissues and organs can do the diagnostic Significantly increase the value. Contrast agent preparations with selective accumulation in arteriosclerotic Plaques could Detect localization and degree of the disease at an early stage and so that a targeted therapy and prophylaxis allow and therefore sat early the search for suitable contrast agents.

So be in the U.S. Patent 4,577,636 Hematoporphyrin derivatives claimed as contrast agents for the detection of atherosclerotic plaques. As methods the scintigraphy, the X-ray, the fluorescence and for paramagnetic metalloporphyrins also the NMR spectrometry are called. As para-magnetic ions Gd, Cr, Co, Ni, Ag and Eu are listed.

disadvantage in these compounds is that The porphyrins deposit in the skin and cause discoloration, the up to can last for several weeks. About that lead out they cause photosensitization. Furthermore, there is a danger that at a long residence time in vivo the metalloporphyrin the metal loses.

In the application WO 95/09856 are claimed metalloporphyrins (deuteroporphyrins) for the diagnosis and treatment of plaques. The diagnostic method is called MRI. Also for these porphyrins is that they cause discoloration of the skin.

In the application WO 95/09013 For example, conjugates of specifically binding polypeptides and metal complexes are claimed. These compounds should also bind to plaques, thus enabling their diagnosis and therapy. Diagnostic methods are scintigraphy, computed tomography and MRI. While scintigraphy has been experimentally proven, data for MRI are missing.

By doing U.S. Patent 5,807,536 labeled phycocyanins are claimed as contrast agents for the imaging of plaques. As diagnostic methods here are called X-ray, computed tomography, scintigraphy, SPECT and MRI. The scintigraphy is proven experimentally.

Out Numerous contrast agents are available for infarction and necrosis imaging known. Early carried out experiments, the localization of infarcts and necrosis by using contrast agents in non-invasive procedures such as To improve scintigraphy or magnetic resonance imaging. In the literature Attempt to Use Porphyrins for Necrosis Imaging a big Room. The results obtained, however, give a contradictory Image. This is how Winkelman and Hoyes describe in Nature, 200, 903 (1967), that yourself Manganese-5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrin (TPPS) selective in the necrotic part of a tumor.

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

Foster et al. (J. Nucl. Med. 26, 756 (1985)), in turn, found that ¹¹¹ In-5,10,15,20-tetrakis- (4-N-methylpyridinium) porphyrin (TMPyP) does not exist in the necrotic portion but enriches in the living marginal layers. To conclude that there is a porphyrin-tissue interaction is obvious, but not mandatory.

In Circulation Vol. 90, no. 4, part 2, page 1468, abstract no. 2512 (1994) Ni et al. Report that they can display infarcted areas with a manganese tetraphenyl porphyrin (Mn-TPP) and a gadolinium mesoporphyrin (Gd-MP). In the international patent application WO 95/31219 both substances were used for infarction and necrosis imaging. The authors Marchal 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 noninfected organ, but nine times greater for the myocardium in the infarcted tissue (Example 1) was. It was astonishing that the ratio of signal intensities in MRI for infarcted compared to healthy tissue was comparably high in both cases at 2.10 and 2.19. Other metalloporphyrins are in the application DE 198 35 082 (Schering AG).

Porphyrins tend to deposit in the skin, resulting in photosensitization. Sensitization can last for days, even weeks. This is an undesirable side effect of using porphyrins as diagnostics. In addition, the therapeutic index for the porphyrins is very small, since, for example, for Mn-TPPS an effect only starts at a dose of 0.2 mmol / kg, but the LD ₅₀ is already at 0.5 mmol / kg.

Non-porphyrin scaffold-derived contrast agents for necrosis and infarct imaging are known in US Pat DE 197 44 003 (Schering AG), DE 197 44 004 (Schering AG) and WO 99/17809 (EPIX).

In DE 197 44 003 are claimed oligomeric compounds consisting of a core are bonded to the 1-3 metal complexes claimed.

In the application 197 44 004 lipophilic metal complexes are claimed for necrosis and infarct imaging. These compounds include metal complexes of polyaminopolycarboxylic acids, polyaminopolyphosphonic acids, porphyrins, texaphyrins, sapphyrins, peptides.

In the EPIX application WO 99/17809 the use of DTPA derivatives for necrosis imaging is claimed. 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. So reveal WO 97/26017 (Schering) and WO 99/01161 (Schering) the use of perfluoroalkyl-containing metal complexes as lymphographs. WO 99/01161 also describes the suitability of these compounds for the representation of the vasal space (blond-pool-agents).

Also for the Single representation of tumors and necroses using MR imaging are Contrast agents have been described.

In EP 417870 A1 compounds are disclosed for tumor diagnosis and therapy. It is stated that infarcts and ischaemias can also be visualized. An experimental confirmation for the se statement, however, the application is not removable. The claimed compounds are chelates of complexes of the types N2S2 and N3S with radioisotopes. The diagnostic method is scintigraphy.

In DE 196 46 762 Scintigraphy is also used as a diagnostic method. The document claims metal chelates as radiosensitizers for the therapy of hypoxic tumors and for the diagnosis of hypoxic conditions and necroses. In the descriptive part, diagnostic procedures are called NMR diagnostics, X-ray diagnostics and radiodiagnostics.

In the German application DE 198 24 653 Porphyrins are claimed as necrosis-deficient 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 196 46 762 and DE 198 24 653 - have in common that the representation of necroses and tumor is not independent of each other, but that the necrosis is part of the tumor.

task The present invention has been a contrast agent for MR imaging to disposal to provide for the representation of plaques are.

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 l / mmol · s , are very well suited as a contrast agent in MR imaging for the preparation of plaques, being used as perfluoroalkyl-containing metal complexes, the compounds of formula I.

When for the use according to the invention suitable perfluoroalkyl-containing metal complexes become amphiphilic Compounds understood as a non-polar part of a Perfluoralkylseitenkette in the molecule possibly over a lipophilic linker is linked to the whole molecule. The polar one Part of the invention used Compounds are characterized by one or more metal complexes and optionally existing additional polar groups formed.

In aqueous systems, these amphiphilic molecules exhibit the characteristics characteristic of classical surfactants (such as sodium dodecyl sulfate, SDS). So they lower the surface tension of the water. By tensiometry, the so-called CMC (critical micelle concentration in mol / l) can be determined. For this purpose, the surface tension is determined as a function of the concentration of the substance to be measured. The CMC can be calculated from the course of the surface tension (c) function 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 used in this invention Amphiphilic compounds are associated and residing in solution as aggregates. The size (2 Rh) such aggregates (e.g., micelles, sticks, wafers, etc.) can be with the help of photon correction spectroscopy (PCS).

When the second criterion is therefore the hydrodynamic micelle diameter 2 Rh,> 1 nm got to. Especially can According to the invention such perfluoroalkylhaltigen metal complexes are used, whose 2 Rh ≥ 3 nm, completely particularly preferably> 4 nm.

Either the determination of the CMC as well as the photon correlation spectroscopy become in H.-D. Dörfler, "Interface and Colloid chemistry " Weinheim, New York, Basel, Cambridge, Tokyo, VSH 1994.

The third criterion is the 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 high as possible and be> 10 l / mmol · s, preferably> 13 l / mmol · s, more preferably> 15 l / mmol · s.

The relaxivity R ¹ [l / mmol · s] of the MR contrast agents used 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. From each T1 sequence: 180 ° -TI-90 °, inversion recovery, 8 measurement points were recorded men. The medium used was bovine plasma from Kraeber. The contrast agent concentrations [mmol / l] were between 0.30 and 1.16 in the batches.

According to the invention, the compounds of general formula I according to claims 1 to 4 are used. These are known compounds that are known in WO 97/26017 are described. Their preparation can be found in this WO-font. Surprisingly, it has been shown that these compounds are also very well suited as MRI contrast agents for plaque imaging. As very particularly preferred compounds, the metal complexes I-IV, VI and XI-XIII (see also Table 1) are used.

The invention also provides the use of the metal complexes according to claim 5, which correspond to the complexes V, VII to X and XIV and XVI of Table 1. Complex V, VII to X and XVI are new, metal complex XIV is in WO 99/01161 described.

pharmaceutical Formulations contain the paramagnetic used in the invention and diamagnetic perfluoroalkyl containing compounds in one mixing ratio between 5:95 and 95: 5. Preference is given to mixing ratios between 40:60 and 60:40 of the two substances. Both substances will be used in millimolar concentrations. There are concentrations between 0.5 and 1000 mmol / l solvent reached. The solvent is preferably water. The metal concentration of the formulations is preferably in a range of 50-250 mmol / l.

Prefers are mixtures of paramagnetic and diamagnetic perfluoroalkyl-containing Compounds in which the perfluoroalkyl chains have a length of Have 6 to 12 carbon atoms. Particular preference is given to mixtures, where both the paramagnetic and the diamagnetic Perfluoralkylhaltigen connections a Perfluoralkylkette with 8 Have carbon atoms.

The Preparation of the galenic formulations takes place in that the paramagnetic perfluoroalkyl-containing compounds (component A) and the diamagnetic Perfluoralkylhaltigen substances (component B) in mole fractions between Weighed 0.05 and 0.95 of component A or B and in a suitable solvent solved become. A particularly suitable solvent is water. This solution then become common galenical additives such as. buffer solutions and the Ca salt of the complexing agent added in excess. Be at 10 to 100 ° C the solutions strongly stirred. Alternatively you can the solutions at 10 to 100 ° C be treated in an ultrasonic bath. Another alternative is that one the solutions treated with microwaves.

at Substances that do not dissolve in water as individual components it is advantageous to have a solubilizer such as alcohol (e.g., methanol or ethanol) or another with water miscible solvent Add and then distill this slowly. The distillation can be done under vacuum. The residue is then in Water dissolved and the solution filtered. It is also possible, every component for each in a solvent to solve separately then put together and proceed as above. It has proved to be advantageous a relatively highly concentrated solution (> 100 mmol) of the metal complex (component A) and then add component B pure and, as mentioned above, the solution stir or to treat with ultrasound or microwaves.

In summary It should be noted that as very particularly preferred compounds those listed in Table 1 Gadolinium complexes I-XIV and XVI used in the invention become. The physical parameters of these metal complexes are listed in Tab. 2.

• CMC: kritische Mizellbildungskonzentration
• 2 Rh: hydrodynamischer Mizelldurchmesser
• R¹: Relaxivität

Both the paramagnetic compounds of the general formulas I used according to the invention and the formulations, paramagnetic and diamagnetic perfluoroalkyl-containing substances used according to the invention are outstandingly suitable as contrast agents in MR imaging for the representation of plaques. Table 1: Metal complexes very particularly preferably used according to the invention complex Reference, name I WO 97/26017 Example 33f Gadolinium complex of 10- [1-methyl-2-oxo-3-aza-5-oxo {4-perfluorooctylsulfonyl-piperazin-1-yl} -pentyl] -1,4,7-tris (carboxymethyl ) -1,4,7,10-tetraazacyclododecane II WO 97/26017 Example 2c 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-heptadecafluorheptacecyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane III WO 97/26017 Example 34b Gadolinium complex of 10- [2-hydroxy-4-aza-5,9-dioxo-9- {4-perfluorooctyl) -piperazin-1-yl} -nonyl] -1,4,7-tris ( carboxymethyl) -1,4,7,10-tetraazacyclododecane IV WO 97/26017 Example 1c Gadolinium complex of 10- [2-hydroxy-4-aza-5-oxo-7-aza-7- (perfluorooctylsulfonyl) nonyl] -1,4,7-tris (carboxymethyl) -1,4, 7,10-tetraazacyclododecane V Example 2c, present application 1,4,7-Tris (carboxylatomethyl) -10- (3-aza-4-oxo-hexan-5-yl) acid N- (2,3-dihydroxypropyl) -N- (1H , 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) perfluorotridecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex VI WO 97/26017 Example 3c Gadolinium complex of 10- [2-hydroxy-4-oxa-1H, 1H, 2H, 2H, 3H, 3H, 5H, 5H, 6H, 6H-perfluorotetradecyl] -1,4,7-tris (carboxymethyl ) -1,4,7,10-tetraazacyclododecane VII Example 5e, present application 1,4,7-tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acryloxy- [N- (3,6,9,12,15- pentaoxa) -hexadecyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluorotridecyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex VIII Example 3c of the present application 1,4,7-tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) acid N- (5-hydroxy-3-oxa-pentyl) - N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluorotridecyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex IX Example 6b, present application 1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid- [N-3,6,9,16-tetraoxa] 13-aza-14-oxo-C ₁₉ -C ₂₆ -hepta-decafluoro) hexacosyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex X Example 1c, present application 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-hexan-5-yl] -acid N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluorotridecyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex XI WO 97/26017 , Example 32c Gadolinium complex of 10- [2-hydroxy-4-aza-5-oxo-7-oxa-10, 10, 11, 11, 12, 12, 13, 13, 14, 14, 15, 15, 16,16,17,17,18,18,19,19-henicosafluor-nonadecyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane XII WO 97/26017 Example 38d Gadolinium complex of 10- [2-hydroxy-4-aza-5-oxo-11-aza-11- (perfluorooctylsulfonyl) tridecyl] -1-4-7-tris (carboxymethyl) 1,4,7 , 10-tetraazacyclododecane XIII WO 97/26017 Example 35d Gadolinium complex of 10- [2-hydroxy-4-aza-5-oxo-7-aza-7- (perfluorooctylsulfonyl) -8-phenyl-octyl] -1-4-7-tris (carboxymethyl) - 1,4,7,10-tetraazacyclododecane XIV WO 99/01161 Example 1g 1,4,7-tris {1,4,7-tris (N- (carboxylatomethyl) -10- [N-1-methyl-3,6-diaza-2,5,8-trioxooctan-1, 8-diyl] -1,4,7,10-tetraazacyclododecane, Gd complex} -10-N-2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoyl] -1,4,7 , 10-tetraazacyclododecane, Gd complex XVI Example 54b, present application 2,6-N, N'-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo) 5-methyl-5-yl)] - lysine [1- (4-perfluorooctylsulfonylpiperazine] -amide, Gd complex Table 2: Physicochemical parameters of the complexes used according to the invention according to Table 1 Complex No. CMC (mol / l) 2 Rh (nm) R ¹ plasma (l / mmol · s) I 1.86 · 10 ^-6 4.6 35.7 II 2.30 · 10 ^-5 14 33 III 7.06 · 10 ^-6 3.2 24.9 IV 1.0 · 10 ^-6 31.5 29.7 V 3.9 x 10 ^-6 4.4 19.6 VI 1.44 · 10 ^-5 3.2 27.5 VII 5.20 × 10 ^-5 3.0 30.3 VIII 2.92 x 10 ^-5 25 21.2 IX 2.65 · 10 ^-6 6.0 13.3 X 7.90 · 10 ^-6 5.4 25.7 XI 2.88 x 10 35.5 24.8 XII 1.07 x 10 ^-5 7.4 30.5 XIII 3.25 x 10 4.3 34.0 XIV 8.90 x 10 2.2 19.5 XVI 3.90 x 10 4.9 21.3

• CMC: critical micelle formation 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) -ethylamide

To 30 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 at room temperature. It is evaporated to dryness in vacuo. 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. The mixture is stirred for 3 hours at 0 ° C, then 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated, 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. calc .: C 31.10 H 2,44 N 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) perfluorotridecylamine

30 g (51.79 mmol) of the title compound of Example 1a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid and stirred at 40 ° C for 8 hours. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: 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

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

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 8.98 (15.88 mmol) of the title compound from Example 1b are added. The mixture is stirred for 10 minutes and gives dan 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: 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) 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 at room temperature. It is evaporated to dryness in vacuo. 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 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated, 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. 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 of Example 2a are dissolved in 300 ml of tetrahydrofuran and 50 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) was added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 300 ml of methanol, then it is evaporated to dryness in vacuo. The residue is dissolved in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid and stirred at 60 ° C for 8 hours. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol = 15: 1).
Yield: 24.07 g (85% of theory) of a colorless solid. 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

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) -perfluortridecyl) -amide] -1,4,7,10-tetraazacyclododecane, Gadolinium complex (metal complex V)

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 (15.88 mmol) of the title compound from Example 2b are added. The mixture is stirred for 10 minutes and gives dan 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: 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 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-oxa-pentyl) -amide

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane are added 8.90 g (70 mmol) of oxalyl chloride and stirred for 12 hours at room temperature. It is evaporated to dryness in vacuo. The residue is dissolved in 100 ml of dichloromethane and at 0 ° C to a solution of 6.25 g (60 mmol) of 5-hydroxy-3-oxa-pentylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane dripped. The mixture is stirred for 3 hours at 0 ° C, then 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1).
Yield: 32.20 g (92% of theory) of a colorless solid. calc .: C 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-oxa-pentyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -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) was added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid and stirred at 50 ° C for 10 hours. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue was chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1).
Yield: 26.09 g (89% of theory) of a colorless solid. 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) -acyl-N- (5-hydroxy-3-oxa-pentyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluortridecyl) -amide] -1,4,7,10-tetraazacyclododecane, Gadolinium Complex (Metal Complex VIII)

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 (15.88 mmol) of the title compound from Example 3b are added. The mixture is stirred for 10 minutes and gives dan 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: 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 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

To 30 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 at room temperature. It is evaporated to dryness in vacuo. 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 2-aminoethanol 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 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1).
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

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

28 g (49.54 mmol) of the title compound of Example 4a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) was added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid and stirred at 50 ° C for 10 hours. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: 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) -perfluortridecyl) -amine amide] -1,4,7,10-tetraazacyclododecane, gadolinium

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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. It is cooled to 15 ° C and 8.75 g (15.88 mmol) of the title compound of Example 4b to. The mixture is stirred for 10 minutes and gives dan 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: 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-perfluorotridecansäureamid

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane 8.90 g (70 mmol) of oxalyl chloride and stirred for 12 hours at room temperature. It is evaporated to dryness in vacuo. The residue is dissolved in 200 ml of dichloromethane. Then at 0 ° C ammonia gas is passed 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% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: 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 .: 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 5a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 400 ml of ethanol / 100 ml of 10% aqu. Hydrochloric acid and stirred at 60 ° C for 8 hours. It is evaporated to dryness in vacuo and the residue is recrystallized from a little ethanol / diethyl ether.
Yield: 26.75 g (95% of theory) of a colorless, crystalline solid. 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

c) 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 of Example 5b and 14.8 g (146.2 mmol) of triethylamine in 300 ml of dichloromethane is added dropwise, at 0 ° C 14.24 g (50 mmol) of 3,6,9,12,15-Pentaoxahexadecansäurechlorid and stir 3 hours at 0 ° C. 300 ml of 5% aqu. Hydrochloric acid and stirred for 30 minutes good by. The organic phase is separated, over magnesium sulfate dried and evaporated to dryness in vacuo.

The residue is chromatographed on silica gel (eluent: dichloromethane / acetone: 20: 1).
Yield: 32.03 g (87% of theory) of a colorless oil. 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. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid and stirred at 40 ° C for 8 hours. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: 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 431

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

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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. It is cooled to 15 ° C and 11.77 (15.88 mmol) of the title compound of Example 5d to. The mixture is stirred for 10 minutes and gives dan 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: 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 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-trioxa-dodecyl ) amide] 1,4,7,10-tetraazacyclododecane, gadolinium

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 at 60 ° C in 100 ml of dimethyl sulfoxide. It is cooled to 15 ° C and 3.51 (17 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 5 hours at 15 ° C. To separate the urea, the solution is filtered. To the filtrate is added 14.66 g (60 mmol) of 1,12-diamino-3,6,9-trioxa-dodecane and 2.02 g (20 mmol) of triethylamine and stirred for 12 hours at room temperature. The solution is poured into 1500 ml of diethyl ether / 50 ml of n-butanol and stirred for 30 minutes. The precipitated solid is filtered off and chromatographed on silica gel RP-18 (mobile phase: gradient of tetrahydrofuran / acetonitrile / water).
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-C ₁₉ -C ₂₆ -hepta-decafluoro) -hexacosyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex (metal complex IX)

11.3 g (21.64 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid, 0.85 g (20 mmol) of lithium chloride and 4.95 g (43 mmol) of N-hydroxysuccinimide dissolved at 25 ° C in 150 ml of dimethyl sulfoxide. It is cooled to 15 ° C and 6.19 (30 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 5 hours at 15 ° C. To separate the urea, the solution is filtered. To the filtrate are added 12.5 g (10.82 mmol) of the title compound from Example 6a and 3.29 g (32.47 mmol) of triethylamine and stirred for 12 hours at room temperature. 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 phase: gradient of 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

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 at 60 ° C in 100 ml of dimethyl sulfoxide. It is cooled to 15 ° C and 3.51 (17 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 5 hours at 15 ° C. To separate the urea, the solution is filtered. To the filtrate is added 8.63 g (15.88 mmol) of the title compound from Example 5b and 5.06 g (50 mmol) of triethylamine and 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 phase: gradient 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-pentahydroxy) -hexylamide

To 30 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 at room temperature. It is evaporated to dryness in vacuo. The residue is dissolved in 100 ml of dichloromethane and added dropwise at 0 ° C. to a solution of 10.87 (60 mmol) of glucamine and 6.07 g (60 mmol) of triethylamine dissolved in 150 ml of dichloromethane / 150 dioxane. The mixture is stirred for 3 hours at 0 ° C, then 8 hours at room temperature. 400 ml of 5% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: 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-1H, 1H, 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 added dropwise 500 ml of methanol, then it is evaporated to dryness in vacuo. The residue is dissolved in a mixture of 500 ml of ethanol / 100 ml of 10% aqu. Hydrochloric acid and stirred at 60 ° C for 15 hours. It is evaporated to dryness in vacuo, 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 (eluent: dichloromethane / methanol = 3: 1).
Yield: 19.69 g (67% of theory) of a colorless solid. 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- (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- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 15.88 (15.88 mmol) of the title compound from Example 8b are added. The mixture is stirred for 10 minutes and gives dan 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: gradient of tetrahydrofuran / acetonitrile / water).
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

To 30 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 at room temperature. It is evaporated to dryness in vacuo. The residue is dissolved in 100 ml of dichloromethane and added at 0 ° C to a solution of 9.67 (60 mmol) of 5-amino-2,2-dimethyl-1,3-dioxepan-6-ol and 6.07 g (60 mmol) of triethylamine, added dropwise in 200 ml of dichloromethane is stirred for 3 hours at 0 ° C, then at room temperature for 5 hours. 300 ml of water are added and the mixture is stirred well for 15 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1).
Yield: 27.62 g (85% of theory) Elemental analysis: calc .: C 34.30 H 30.03 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 of Example 9a are dissolved in 300 ml of tetrahydrofuran and 26 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) was added. It is refluxed for 20 hours. It is cooled to 0 ° C and added dropwise 300 ml of methanol, then it is evaporated to dryness in vacuo. The residue is dissolved in a mixture of 300 ml of ethanol / 100 ml of 10% aqu. Hydrochloric acid and stirred at 60 ° C for 6 hours. It is evaporated to dryness in vacuo, 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. 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) -acyl- [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- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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. It is cooled to 15 ° C and 9,71 (15,88 mmol) of the title compound of Example 9b to. The mixture is stirred for 10 minutes and gives dan 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: 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. It is cooled to room temperature and are directly on a silica gel column for chromatographic purification (eluent: dichloromethane / acetone = 20: 1).
Yield: 42.22 g (36% of theory) of a colorless solid. 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, hydrogenation is carried out overnight at room temperature. It is filtered off to the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 24.05 g (quantitative) of a colorless solid. Elemental analysis: 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-perfluorooctylsulfonylamino) -ethyl] -amide} -1 , 4,7,10-tetraazacyclododecane, gadolinium

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 at 60 ° C in 100 ml of dimethyl sulfoxide. It is cooled to 15 ° C and 3.51 (17 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 5 hours at 15 ° C. To separate the urea, the solution is filtered. To the filtrate are added 8.61 g (15.88 mmol) of the title compound of Example 10b and 2.02 g (20 mmol) of triethylamine and 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 phase: gradient 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): about .: 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-benzyloxycarboxylamino-ethyl) -amide

To 30 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 at room temperature. It is evaporated to dryness in vacuo. Of the Residue is dissolved in 100 ml of dichloromethane and at 0 ° C to a solution from 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 dripped. Man stirs 3 hours at 0 ° C, subsequently 5 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid to and stirs 15 Goodbye minutes. The organic phase is separated, over magnesium sulfate dried and evaporated to dryness in vacuo.

The residue is chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1).
Yield: 33.30 g (83% of th.) Of a colorless solid. 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, hydrogenation is carried out overnight at room temperature. It is filtered off to the catalyst 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 -C ₁₆ heptadecafluoro) hexadecyl] amide} -1,4,7,10-tetraazacyclododecane gadolinium complex

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 at 60 ° C in 100 ml of dimethyl sulfoxide. It is cooled to 15 ° C and 3.51 (17 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 5 hours at 15 ° C. To separate the urea, the solution is filtered. To the filtrate are added 8.96 g (15.88 mmol) of the title compound from Example 11b and 2.02 g (20 mmol) of triethylamine and 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 phase: gradient 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 at room temperature. It is evaporated to dryness in vacuo. 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 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1).
Yield: 24.86 g (93% of theory) of a colorless solid. 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-perfluorundecyl) -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. It is refluxed for 12 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid and stirred at 40 ° C for 8 hours. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1).
Yield: 20.95 g (90% of th.) Of a colorless solid. 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) -acryloxy-N - [(2-hydroxy) -ethyl-N- (1H , 1H, 2H, 2H, 4H, 4H, 5H, 5H-3oxa) -perfluorundecyl] -amide} -1,4,7,10-tetraazacyclododecane gadolinium

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 8.98 (15.88 mmol) of the title compound from Example 12b are added. The mixture is stirred for 10 minutes and gives dan 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: gradient of tetrahydrofuran / acetonitrile / water).
Yield: 14.01 g (83% of theory) of a colorless, amorphous powder. 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-tetraoxatridecyl) -amide

To 24.25 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorundecanoic acid in 300 ml of dichloromethane are added 8.90 g (70 mmol) of oxalyl chloride and stirred for 12 hours at room temperature. It is used in a vacuum Dry evaporated. 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, dropped. The mixture is stirred for 3 hours at 0 ° C, then 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1).
Yield: 31.61 g (90% of theory) of a colorless solid. 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-Tetraoxatridecyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorundecyl) -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) were added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid and stirred at 40 ° C for 8 hours. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: 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) -perfluorundecyl] -amide} -1,4,7,10-tetraazacyclododecane gadolinium

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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. It is cooled to 15 ° C and are 9.49 (15.88 mmol) of the title compound of Example 13b to. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline are added. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: gradient 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) -aminoacetic acid t.butyl ester

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 is added dropwise at 50 ° C to 6.523 g (40 mmol) of bromoacetic acid-t.butylester and stirred 3 hours at this temperature. 300 ml of dichloromethane are added, the mixture is filtered off from the precipitated salts and the filtrate is evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: 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) -perfluortridecyl] -amide} -1,4,7,10-tetraazacyclododecane gadolinium

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 9.87 (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. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: 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) -acY N- [(carboxymethyl) -N- (1H, 1H, 2H , 2H, 4H, 4H, 5H, 5H-3oxa) -perfluortridecyl] -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 of trifluoroacetic acid and stirred at room temperature for 5 hours. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel RP-18 (mobile phase: gradient of tetrahydrofuran / acetonitrile / water). After evaporation of the product-containing fractions, the residue is dissolved in water and washed 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-perfluorotridecanoic acid N- (2-hydroxyethyl) -amide

To 32 g (56.61 mmol) of the title compound from Example 4a are added 2.96 g (74 mmol) of sodium hydride (from 60% sodium hydride in paraffin oil) in 300 ml of tetrahydrofuran and 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 dryness in vacuo. The residue is chromatographed on silica gel (mobile phase: dichloromethane (/ 2-propanol = 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 of Example 15a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) was added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then it is added to dryness in vacuo evaporated. The residue is dissolved in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid and stirred at 40 ° C for 8 hours. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: 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) -acyl-N - [(4-t-butyloxycarbonyl-3-oxa) - butyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3oxa) -perfluortridecyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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. It is cooled to 15 ° C and 10.57 (15.88 mmol) of the title compound of Example 15b to. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline are added. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: gradient of 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

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

12 g (9.40 mmol) of the title compound from Example 15c are dissolved in 50 ml of trifluoroacetic acid and stirred at room temperature for 5 hours. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel RP-18 (mobile phase: gradient of tetrahydrofuran / acetonitrile / water). After evaporation of the product-containing fractions, the residue is dissolved in water and washed 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-3-oxa-perfluorotridecyl) -amide

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane are added 8.90 g (70 mmol) of oxalyl chloride and stirred for 12 hours at room temperature. It is evaporated to dryness in vacuo. The residue is dissolved in 100 ml of dichloromethane and added dropwise at 0 ° C. to a solution of 32.62 g (60 mmol) of the title compound from Example 5b 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 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1).
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) was added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 400 ml of ethanol / 70 ml of 10% aqu. Hydrochloric acid and stirred at 40 ° C for 8 hours. It is evaporated to dryness in vacuo, the residue is taken up in 400 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 400 ml dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1).
Yield: 47.18 g (92% of theory) of a colorless solid. 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 (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- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 15.84 (15.88 mmol) of the title compound from Example 16b 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. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: gradient of tetrahydrofuran / acetonitrile / water).
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

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

To 32 g (52.52 mmol) of the title compound from Example 3a are added 2.80 g (70 mmol) of sodium hydride (from 60% sodium hydride in paraffin oil) in 300 ml of tetrahydrofuran 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 dryness in vacuo. 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-perfluorotridecyl) -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) was added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid and stirred at 40 ° C for 8 hours. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on 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- (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- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 9.68 (15.88 mmol) of the title compound from Example 17b 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. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: gradient 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

To 30 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 at room temperature. It is evaporated to dryness in vacuo. 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 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: 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. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid absorbed men and 8 hours at 40 ° C stirred. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: 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- (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- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 10.98 (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. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: gradient 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

To 30 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 at room temperature. It is evaporated to dryness in vacuo. The residue is dissolved in 100 ml of dichloromethane and dissolved 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 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: 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

39 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) was added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 400 ml of ethanol / 70 ml of 10% aqu. Hydrochloric acid and stirred at 40 ° C for 8 hours. It is evaporated to dryness in vacuo, the residue is taken up in 350 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 400 ml dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on 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

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

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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. It is cooled to 15 ° C and 11.87 (15.88 mmol) of the title compound of Example 19b to. The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline are added. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: 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) -perfluortridecyl] -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 at room temperature for 5 hours. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel RP-18 (mobile phase: gradient of tetrahydrofuran / acetonitrile / water). After evaporation of the product-containing fractions, the residue is dissolved in water and washed 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-hexadecanoic acid N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3oxa) -perfluortridecyl) amide

To 19.67 g (57.45 mmol) of 15-benzyl-3,6,9,12,15-pentaoxahexadecylic acid in 250 ml of dichloromethane is added 8.90 g (70 mmol) of oxalyl chloride and stirred for 12 hours at room temperature. It is evaporated to dryness in vacuo. The residue is dissolved in 100 ml of dichloromethane and at 0 ° C to a solution of 32.62 g (60 mmol) 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. The mixture is stirred for 3 hours at 0 ° C, then 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1).
Yield: 44.91 g (94% of theory) of a colorless solid. 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- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3oxa) -perfluortridecyl) amine

43 g (51.72 mmol) of the title compound from example 20a) are dissolved in 400 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 400 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid and stirred at 40 ° C for 8 hours. It is evaporated to dryness in vacuo, the residue is taken up in 350 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 400 ml dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: 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- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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. It is cooled to 15 ° C and are added 12.98 (15.88 mmol) of the title compound of Example 20b). The mixture is stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline are added. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: gradient of tetrahydrofuran / acetonitrile / water).
Yield: 18.84 g (83% of theory) Elemental analysis: calc .: C40,34 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 -tetroxa) -tetradecyl-N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluortridecyl) -amide} -1,4,7,10-tetraazacyclododecane, gadolinium

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, hydrogenation is carried out overnight at room temperature. It is filtered off to the catalyst 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 1.20 F 25.58 Gd 12,50

Example 21

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

50.0 g (54.55 mmol) of 2-N- [1-0-α-D-carbonylmethyl-mannopyranose] -L-lysine-1 - [(4-perfluorooctylsulfonyl) -piperazine] -amide, 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) -1,4,7,10-tetraazacyc iododecane, Gd complex, are dissolved with gentle heating in 400 ml of dimethyl sulfoxide. At 10.degree. C., 16.88 g (81.8 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is subsequently 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 (RP-18 mobile phase: gradient of 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 22

a) 2- [4-3-Oxapropionsäureethylester] -phenylacetic acid methyl ester

To 200.0 g (1204.0 mmol) of 4-hydroxyphenylacetic acid methyl ester, 212.0 g (2000.0 mmol) of sodium carbonate in 2000 ml of acetone are added 233.8 g (1400.0 mmol) of 2-bromoacetic acid ethyl ester and boiled for 5 hours reflux. The solid is filtered off and evaporated to dryness in vacuo. The residue is chromatographed on silica gel. (Eluent: 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) 2- [4-3-oxapropionic acid ethyl ester)] - phenyl-2-bromoacetic acid methyl ester

To 285.0 g (1130.0 mmol) of the title compound of Example 22a), dissolved in 2000 ml of carbon tetrachloride are added 201.0 g (1130.0 mmol) of N-bromosuccinimide and 100.0 mg of dibenzoyl peroxide and boiled for eight hours reflux. It 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 phase: 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) 2- [4- (3-oxapropionic acid ethyl ester)] - phenyl 2- [1- (1,4,7,10-tetraazacyclododecan-1-yl] -acetic acid methyl ester

To 603.0 g (3500.0 mmol) of 1,4,7,10-tetraazacyclododecane, in 6000 ml of chloroform are added 350.0 g (1057.0 mmol) of the title compound of Example 23b) and stirred overnight 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 without further purification in the next reaction (Example 22d).
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 (carboxymethyl) -1,4,7,10-tetraazacyclododecan-10-yl] acetic acid

445.0 g (1053.0 mmol) of the title compound of Example 22c) and 496.0 g (5270.0 mmol) of chloroacetic acid are dissolved in 4000 ml of water. It is adjusted with 30% aqueous sodium hydroxide solution to a pH of 10 and stirred for 8 hours at 70 ° C. The pH of the reaction solution is then adjusted to 13 by addition of 30% aqueous sodium hydroxide solution and refluxed for 30 minutes. The solution is cooled in an ice bath and by adding conc. Hydrochloric acid to a pH of 1 provided. 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. It is filtered from the precipitated sodium chloride, the filtrate is evaporated to dryness and the residue is purified on RP-18 C (mobile phase: gradient of 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

To 400 g (721.3 mmol) of the title compound of Example 22d) in 2000 ml of water are added 130.73 g (360.65 mmol) of gadolinium oxide and stirred for 5 hours at 80 ° C. 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- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-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) 2-N- [1-0-α-D-carbonylmethyl-mannopyranose] -L-lysine-1 - [(4-perfluorooctylsulfonyl) -piperazine] -amide, 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 38.66 g (54.55 mmol). of the Title compound from Example 22e) are added with slight warming in 400 ml of dimethyl sulfoxide dissolved. At 10 ° C 16.88 g (81.8 mmol) of N, N-dicyclohexylcarbodiimide are added to and stirs then overnight at room temperature. You pour the solution in 3000 ml of acetone and stirred 10 mins. The precipitated solid is filtered off and then by Purified (RP-18, mobile phase: gradient of water / ethanol / acetonitrile). Man dissolves the product obtained in a little water and prepares with aqueous sodium hydroxide solution the pH of the solution to 7.4.

Subsequently, the product solution is 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 3.84 N 6.80 S 2.03 F 19,75 Gd 9,57

Example 23

a) 6-N- [1,4,7-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 2-N - [1-0-α-D-carbonylmethyl-mannopyranose] -L-lysine-1 - [(4-perfluorooctylsulfonyl) -piperazine] -amide and 3.01 g (26.19 mmol) of N-hydroxysuccinimide are dissolved in 150 ml Dissolved dimethylformide and added at 0 ° C 8.25 g (40.0 mmol) of N, N-dicyclohexylcarbodiimide. It is stirred overnight at room temperature temperature. The precipitated urea is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is chromatographed on silica gel. (Eluent: 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 .: 044.01 H 5.81 N 7.53 F 21.87 S 2.03

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

30.0 g (20.39 mmol) of the title compound from example 23a) 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 phase: gradient of 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 24

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

50.0 g (60.20 mmol) of 6-N-benzyloxycarbonyl-L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, 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) of 1,4,7-tris [carboxylatomethyl] -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4 -oxo-5-methyl-5-yl), Gd complex are dissolved with gentle heating in 400 ml of dimethyl sulfoxide. At 10.degree. C., 20.63 g (100.0 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is subsequently 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 phase: gradient of 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-4-oxo-5-methyl-5 -yl) -L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

70.0 g (48.53 mmol) of 6-N-benzyloxycarbonyl-2-N- [1-0-α-D-carbonylmethyl- (2,3,4,6-tetra-O-benzyl-mannopyranose] -L lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide are dissolved in 500 ml of water / 100 ml of ethanol, treated with 5.0 g of palladium catalyst (10% Pd / C) and at room temperature under a hydrogen atmosphere ( 1 atm) until hydrogen uptake is no longer observed, then the catalyst is filtered off with suction, washed thoroughly with ethanol (twice with 75 ml each time) and evaporated to dryness in vacuo to afford the title compound 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-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose) -2-N- [1,4,7-tris (carboxylatomethyl) -] 1,4,7,10-tetraazacyclododecane, Gd-complex-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

50.0 g (38.22 mmol) of the title compound from Example 24b), 4.40 g (38.22 mmol) of N-hydroxysuccinimide, 3.39 g (80.0 mmol) of lithium chloride and 22.88 g (38, 22 mmol) of 1-O-α-D-carboxymethyl-2,3,4,6-tetra-O-benzyl-mannopyranose are dissolved with gentle heating (30 to 40 ° C) in 400 ml of dimethyl sulfoxide. At 10 ° C., 10.32 g (50.0 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is subsequently 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 phase: gradient of 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 .: C 46,36 H 4.71 N 6.60 S 1.61 F 17,19 Gd 8,21

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

60.0 g (31.77 mmol) of the title compound from Example 24c) are dissolved in 500 ml of ethanol and admixed with 6.0 g of palladium catalyst (10% Pd / C). It is hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen uptake is observed. It is then filtered off from the catalyst, washed thoroughly with ethanol (twice with 150 ml) 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 25

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 (prepared according to DE 196 03 033 ) in 300 ml of tetrahydrofuran is added at 0 ° C 49.46 g (200.0 mmol) EEDQ (2-ethoxy-1,2-dihydro-quinoline-1-carboxylic acid ethyl ester) and stirred overnight at room temperature. It is evaporated to dryness in vacuo and chromatographed on silica gel (eluent: 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-perfluorooctylsulfonyl) -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 of Example 25a) and 35.64 g (59.53 mmol) of 1-O-α-D-carboxymethyl-2,3,4,6-tetra-O- benzyl-mannopyranose, prepared according to DE 197 28 954 , in 300 ml of tetrahydrofuran, 24.7 g (100 mmol EEDQ (2-ethoxy-1,2-dihydro-quinoline-1-carboxylic acid ethyl ester) are added at 0 ° C. and stirred overnight at room temperature chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).
Yield: 76.6 g (81.0% of theory) of a colorless solid. Elemental analysis: calc .: 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-carbonylmetyl-mannopyranose) -1,4,7,10-tetraazacyclododecane

70 g (44.07 mmol) of the title compound from Example 25b 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 mixture is filtered off from the catalyst 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- [1,4,7-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 of Example 25c), 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 complex are dissolved with gentle heating in 400 ml of dimethyl sulfoxide. At 10.degree. C., 29.67 g (120 mmol) of EEDQ are added, followed by stirring 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 of 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 26

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

50.0 g (49.61 mmol) of the title compound of Example 25a), 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, with gentle heating dissolved in 350 ml of dimethyl sulfoxide. At 10 ° C are added 15.47 g (75 mmol) of N, N-dicyclohexylcarbodiimide and 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 purified by chromatography (silica gel RP-18, mobile phase: gradient of 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-5-yl) -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 26a) are dissolved in 600 ml of ethanol and 6.0 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
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 mmol) of the title compound from Example 26b), 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 with gentle heating in 300 ml of dimethyl sulfoxide. At 10.degree. C., 24.77 g (100.0 mmol) EEDQ are added, followed by stirring 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 of 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-perfluorooctylsulfonyl) -amino] -acetyl-4,10-bis [1-O-α-D-carbonylmethyl-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 26c) are dissolved in 300 ml of ethanol / 30 ml of water and 4.0 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature, filtered from the catalyst 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 .: C 36,87 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 27

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

In a manner analogous to that 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. II, 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 work-up 315 g (96.7%) of the above Title compound as a crude product in the form of a viscous and colorless oil. By ¹ H-NMR spectroscopic examination of the title compound thus obtained, the α to β ratio of both anomers with 4: 1 was determined. A separation of the α, β-anomers of the title compound mentioned above can be dispensed with for carrying out the subsequent reaction steps. Elemental analysis: calc .: C 49,21 H 5.68 Found .: C 49,12 H 5.78

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

In an analogous manner, as described in the literature for the synthesis of aryl glycopyranosides [J. Conchie and GA Levvy in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol. II, 90, pp. 345-347, (1963)], 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 ethyl 6-hydroxyhexanoate and 60.8 ml ( 520 mmol) of tin (IV) chloride in a total of 600 ml of 1,2-dichloroethane after purification by column chromatography (eluent: hexane / ethyl acetate 2: 1) to give 100.05 g (51% of theory) of the abovementioned title compound colorless and viscous oil. By ¹ H-NMR spectroscopic examination of the title compound thus obtained it was possible to show that the abovementioned 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-O-α-D- (5-carboxy) -pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose

A stirred suspension of 141.0 g (289 mmol) of the title compound from Example 27b) in 200 ml of dioxane is added in portions at room temperature and vigorous stirring with a total of 238.5 g (4.26 mol) of finely powdered potassium hydroxide powder. To increase the stirrability, the reaction mixture is treated with a further 200 ml of dioxane, and the suspension thus obtained is subsequently heated to boiling heat and treated dropwise at this temperature with a total of 372 ml (3.128 mol) of benzyl bromide 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 slowly poured for the purpose of workup in a total of 2.5 liters of ice water and the water phase is subsequently extracted completely with diethyl ether. After washing the thus obtained ether phase and then drying derselbigen over sodium sulfate is filtered off with suction from the salt and the diethyl ether removed in vacuo. Excess benzyl bromide is then distilled off quantitatively in an oil pump vacuum at an oil bath temperature of 180 ° C from the reaction mixture. The resulting resinous-oily residue is purified on silica gel using ethyl acetate / hexane (1:10) as eluent.
Yield: 172.2 g (91.0% of theory) of the abovementioned 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- [1-0-α-D- (5-carbonyl) -pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose] -L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

100.0 g (134.0 mmol) of the carboxylic acid prepared under Example 30c) and 32.4 g (281.4 mmol) of N-hydroxysuccinimide are dissolved in 500 ml of dimethylformamide and treated at 0 ° C with a total of 58.0 g (281 , 4 mmol) N, N'-dicyclohexylcarbodiimide added in portions and it is stirred for 3 hours at this temperature. To the thus prepared active ester solution is added a cooled to 0 ° C solution of 111.3 g (134.0 mmol) of 6-N-benzyloxycarbonyl-L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide , dissolved in 300 ml of dimethylformamide added dropwise and stirred for 2 hours at 0 ° C and 12 h at room temperature. For working up, the precipitated dicyclohexylurea is filtered off, and the solvent is then stripped to dryness. The residue thus obtained is subsequently chromatographed on silica gel (mobile phase: dichloromethane / ethanol 20: 1, the chromatography being carried out using a solvent gradient with a continuous increase in the ethanol content).
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- [1-0-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 stirred at room temperature under a hydrogen atmosphere (1 atm). hydrogenated until no hydrogen uptake is observed (about 8 hours). It is suctioned off from the catalyst, washed thoroughly with ethanol (about 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-O-α-D- (5-carbonyl) -pentyl-mannopyranose] -6-N- [1,4,7-tris- (carboxylatomethyl) -10 - (-3-aza) 4-oxo-5-methyl-5-yl-pentanoyl) -1,4,7,10-tetraazacyclododecane] -L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd complex

99.8 g (158.4 mmol, 2.2 mol equivalents based on the amine component used from Example 27e) of the patent application DE 197 28 954 C1 Example 31h) described the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-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 added. After cooling to room temperature, the reaction solution is treated with 32.7 g (158.4 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. 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) desalted and purified from low molecular weight components. The retentate is then freeze-dried.
Yield: 93.0 g (81.6% of theory) as a colorless lyophilisate.
H ₂ O 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 28

a) 2-N- [1-O-α-D- (5-carbonyl) -pentyl-mannopyranose] -6-N- {2- [4- (3-oxapropionyl) -phenyl] -2- [1,4 , 7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-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 of Example 22e) in 15 ml of absolute dimethyl sulfoxide is added at 70 ° C with 0.68 g (15.9 mmol) of lithium chloride. After 30 minutes of stirring at 70 ° C, the now clear reaction solution is added in portions with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide and kept the reaction mixture for 1 hour at this temperature. After cooling to 0 ° C., 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide are added and the reaction solution is stirred for a further 1 hour at 0.degree. C., followed by 12 hours at 22.degree. The reaction solution thus obtained of the N-hydroxysuccinimide ester of the title compound from Example 3e) is now added dropwise at 22 ° C. to 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 at room temperature for hours. For workup, the reaction solution is added dropwise at 22 ° C in 900 ml of acetone, whereby the title compound precipitates as a colorless precipitate. The precipitate is filtered off, dissolved in 200 ml of distilled water and then adjusted with 1 molar sodium hydroxide solution, the pH of this solution to exactly 7.2. The aqueous product solution thus obtained is a YM3-ultrafiltration membrane (AMICON ^®; cut-off: 3,000 Da) to ultrafiltration for the purpose of desalination and separation of low-molecular components. The resulting retentate is then freeze-dried.
Yield: 6.33 g (92.4% of theory, based on the amine component used) as 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 29

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

In a mixed solvent of 125 ml of dry tetrahydrofuran and 125 ml of dry dioxane, 20 g (47.5 mmol) of 3,5-bisbenzyloxycarbonylaminobenzoic 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 4.78 g (47.5 mmol) of triethylamine. After cooling to -15 ° C is added dropwise with stirring, a solution of 6.56 g (48 mmol) of isobutyl chloroformate in 30 ml of dry tetrahydrofuran added slowly, keeping the internal temperature 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-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxo is added dropwise. perfluorotridecane and 4.78 g (47.5 mmol) of triethylamine in 100 ml of dry tetrahydrofuran at -20 ° C added. After a reaction time of one hour at -15 ° C and two hours at Raumqtemperatur the reaction solution is concentrated in vacuo to dryness. 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 drying the organic phase over sodium sulfate is filtered off with suction from the salt and the ethyl acetate in vacuo. The residual oily residue is purified on silica gel using dichloromethane / hexane / 2-propanol (10: 5: 1) as 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 prepared under 29a) are dissolved in 300 ml of ethanol, and 1.2 g of Pearlman catalyst (Pd 20%, C) are added. It is hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no hydrogen uptake is observed. It sucks from the catalyst Wash thoroughly with ethanol (about 300 ml) and concentrate 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-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose) -5-amino-benzoic acid N- (3-oxa-1H , 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide

10.95 g (18.30 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-α-D-mannopyranoside [representation as in the patent DE 197 28 954 C1 described] are dissolved in 150 ml of dimethylformamide and treated 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 to. It is stirred for one hour at 0 ° C and then for 4 hours at room temperature. It is cooled to 0 ° C and added dropwise within 3 h, a solution of 24.0 g (36.6 mmol, 2 molar equivalents based on carboxylic acid) of the diamino compound described in Example 29b), dissolved in 350 ml of dimethylformamide slowly added. The mixture is then stirred for one hour at 0 ° C, then overnight at room temperature. It is evaporated to dryness in vacuo and the residue taken up in 300 ml of ethyl acetate. It is filtered from the precipitated urea 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 (eluent: n-hexane / isopropanol 13: 1). This gives 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 chromatographic fractions, which can be reacted again according to the above 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 5.94

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

In a manner analogous to that described for the synthesis of the title compound of Example 29b), hydrogenolysis afforded 12.0 g (9.70 mmol) of the title compound of 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 abovementioned title compound in the form of a yellowish-colored and viscous oil. Elemental analysis: calc .: C 37.64 H 3:28 N 4,88 F 37,49 Found .: C 37,32 H 3,17 N 4,97 F 37.55

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

13.6 g (19.2 mmol, 2.2 molar equivalents based on the amine component from Example 29d)) of the Gd complex described under Example 22Ae) and 0.81 g of anhydrous lithium chloride (19.2 mmol) are heated at 40 ° C. in Dissolved 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 of Example 29d), dissolved in 50 ml of absolute dimethyl sulfoxide, added. After cooling to room temperature, 3.96 g (19.2 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 treated with sufficient acetone until complete precipitation of the title compound mentioned above, the precipitate is filtered off with suction, dried, poured into water filtered off from insoluble dicyclohexylurea and the filtrate through an AMICON ^® YM-3 ultrafiltration membrane (cut off 3000 Da) desalted and purified from low molecular weight components. The retentate is then freeze-dried.
Yield: 11.51 g (84.5% of theory) as a colorless lyophilisate.
H ₂ O 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 6,31 F 20,73 Gd 10.11 Na 1.42

Example 30

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

In a mixed solvent 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) of triethylamine , After cooling to -15 ° C is added dropwise with stirring, a solution of 3.28g (24 mmol) of isobutyl chloroformate in 20 ml of dry tetrahydrofuran added slowly, the internal temperature does not exceed -10 ° C. After a reaction time of 15 minutes at -15 ° C is added dropwise a solution of 23.0 g (23.75 mmol) perfluorooctylsulfonylpiperazine and 2.39 g (23.75 mmol) of triethylamine in 50 ml of dry tetrahydrofuran at -20 ° C added , After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is concentrated in vacuo to dryness. 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 drying the organic phase over sodium sulfate is filtered off with suction from the salt and the ethyl acetate in vacuo. The residual oily residue is purified on silica gel using dichloromethane / hexane / 2-propanol (15: 5: 1) as 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-perfluorooctylsulfonyl) -piperazine] -benzamide

In 100 ml of ethanol 9.70 g (10.0 mmol) of amide prepared under 30a) are dissolved and treated with 0.4 g Pearlman catalyst (Pd 20%, C). It is hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no hydrogen uptake is observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (about 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-O-benzyl-α-D-mannopyranoside [representation as in the patent DE 197 28 954 C1 described] are dissolved in 100 ml of dimethylformamide and treated 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. It is stirred for one hour at 0 ° C and then for 4 hours at room temperature. After renewed cooling to 0 ° C is added dropwise within 3 h, a solution of 12.85 g (18.30 mmol, 2 molar equivalents, based on the carboxylic acid) of the diamino compound described in Example 30b), dissolved in 250 ml of dimethylformamide slowly added. Then it is stirred for another hour at 0 ° C, then overnight at room temperature. It is evaporated to dryness in vacuo and the residue taken up in 100 ml of ethyl acetate. It is filtered from the precipitated urea and the filtrate 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 (eluent: n-hexane / isopropanol 13: 1). This gives 8.14 g (69.4% 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 during the chromatography to 6: 1 (n-hexane / isopropanol), a total of 4.36 g of unreacted diamino compound 30b) are recovered in the subsequent chromatographic fractions, which can be reacted again according to the above 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 a manner analogous to that described for the synthesis of the title compound from Example 30b), the hydrogenolysis of 6.4 g (5.0 mmol) of the title compound from Example 30c) using 0.3 g Pearlman catalyst (Pd 20%). C) in an ethanol / water (8: 1) mixture after work-up 4.43 g (96.2% of theory) of the abovementioned title compound in the form of a yellowish-colored 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-tetraazacyclododecane] -benzoic acid N- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd complex

5.54 g (8.8 mmol, 2.2 mol equivalents based on the amine component from Example 30d)) used in the patent application DE 197 28 954 C1 Example 31h) described the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.37 g of anhydrous lithium chloride (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 3.7 g (4.0 mmol) the title compound of 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 are added to the reaction solution and the mixture is stirred at room temperature for 12 hours. The suspension obtained is then treated with sufficient acetone until complete precipitation of the title compound mentioned above, the precipitate is filtered off, dried, taken up in water, filtered from insoluble dicyclohexylurea and the filtrate over an AMICON ^® YM-3 ultrafiltration membrane (cut off 3000 Da) desalted and purified from low molecular weight components. The retentate is then freeze-dried.
Yield: 5.36 g (87.4% of theory) as colorless lyophilizate.
H ₂ O 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 .: C 35,87 H 3.70 N 8,22 F 20,91 Gd 10,18 S 2,16

Example 31

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

100 g (107.9 mmol) of 2-N-trifluoroacetyl-6-N-benzyloxycarbonyl-L-lysine and 26.1 g (226.59 mmol) of N-hydroxysuccinimide are dissolved in 500 ml of dimethylformamide and treated at 0 ° C with a total of 46.7 g (226.59 mmol) of N, N'-dicyclohexylcarbodiimide are added in portions and the mixture is stirred for 3 hours at this temperature. To the thus prepared active ester solution is added to a cooled to 0 ° C solution of 5.57 g (53.95 mmol) of diethylenetriamine, dissolved in 60 ml of dimethylformamide added dropwise and stirred for 2 hours at 0 ° C and 12 h at room temperature. For working up, the precipitated dicyclohexylurea is filtered off, and the solvent is then stripped to dryness. The residue thus obtained is subsequently chromatographed on silica gel (mobile phase: dichloromethane / ethanol 15: 1, the chromatography being carried out using a solvent gradient with a continuous increase in the ethanol content).
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

In a solution of 20 g (24.4 mmol) of the diamide prepared under 31a), dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, at 0 ° C and under nitrogen atmosphere 16.18 g (27.0 mmol) 2- [N-ethyl-N-perfluorooctylsulfonyl) -aminoacetic acid (prepared according to: DE 196 03 033 ) dissolved in 50 ml of tetrahydrofuran. Then, at 0 ° C., a total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] are added in portions and the mixture is stirred overnight at room temperature and then concentrated in vacuo. The remaining oil is chromatographed on silica gel (eluent: n-hexane / isopropanol 15: 1). This gives 24.74 g (72.4% of theory, based on secondary sec-amine) of the title compound 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 31b) are dissolved in 100 ml of ethanol, and ammonia gas is introduced at 0 ° C. into this solution for 40 minutes. The mixture is then stirred for a further 4 hours at 0 ° C and 3 hours at room temperature and concentrated at 40 ° C bath temperature in a vacuum to dryness. The residual oily residue is purified on silica gel using dichloromethane / hexane / 2-propanol (20: 10: 1) as eluent.
Yield: 12.92 g (98.4% of theory) of the abovementioned title compound as a colorless and strongly 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-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-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-O-benzyl-α-D-mannopyranoside [preparation as in the patent DE 197 28 954 C1 described] are dissolved in 80 ml of dimethylformamide and treated with a total of 1.05 g (9.15 mmol) of N-hydroxysuccinimide. It is cooled to 0 ° C. and 1.9 g (9.15 mmol) of dicyclohexylcarbodiimide are added. It is stirred for one hour at 0 ° C and then for 4 hours at room temperature. It is cooled to 0 ° C and added dropwise within 3 h, a solution of 7.65 g (9.15 mmol) of the amino compound described in Example 34e), dissolved in 50 ml of dimethylformamide slowly added. The mixture is then stirred for one hour at 0 ° C, then overnight at room temperature. It is evaporated to dryness in vacuo and the residue taken up in 100 ml of ethyl acetate. It is filtered from the precipitated urea 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 (eluent: n-hexane / isopropanol 20: 1). This gives 17.01 g (78.9% of theory, Bezo to the carboxylic acid used) of the title compound 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-O-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 prepared under 31d) are dissolved in 150 ml of ethanol, and 0.5 g of Pearlman catalyst (Pd 20%, C) are added. It is hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no hydrogen uptake is observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (about 100 ml) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous, yellowish 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-O-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 in the patent application DE 197 28 954 C1 under Example 31h) described Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid in 75 ml of absolute Dimethylsulfoxide is added at 70 ° C with 0.68 g (15.9 mmol) of lithium chloride. After 30 minutes of stirring at 70 ° C, the now clear reaction solution is added in portions with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide and kept the reaction mixture for 1 hour at this temperature. After cooling to 0 ° C., 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide are added and the reaction solution is stirred for a further 1 hour at 0.degree. C., followed by 12 hours at 22.degree. The thus-obtained 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-triacetic acid is now added dropwise at 22 ° C with a solution of 2.84 g (2.06 mmol) of the title compound of Example 34e) in 15 ml of absolute dimethyl sulfoxide and stirred for a further 12 hours at room temperature. For workup, the reaction solution is added dropwise at 22 ° C in 500 ml of acetone, whereby the title compound precipitates as a colorless precipitate. The precipitate is suctioned off, dissolved in 200 ml of distilled water and a YM3-ultrafiltration membrane (AMICON ^®: cut-off: 3,000 Da) to ultrafiltration for the purpose of desalination and separation of low-molecular components. The resulting retentate is then freeze-dried.
Yield: 4.80 g (89.6% of theory, based on the amine component used) as 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 32

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

To 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 are added at 0 ° C and under nitrogen atmosphere 16.56 g (24.4 mmol) of the title compound of Example 32e), dissolved in 150 ml of tetrahydrofuran was added. Subsequently, at 0 ° C, a total of 18.0 g (36.6 mmol) EEDQ [2-ethoxy-1-ethoxycarbo nyl-1,2-dihydroquinoline] in portions and allowed to stir overnight at room temperature and then concentrated in vacuo. The remaining oil is chromatographed on silica gel (eluent: n-hexane / isopropanol 12: 1). This gives 17.22 g (64.3% of theory, based on sec-amine used) of the monoamide and 3.8 g (8.8% of theory) of the diamide as a byproduct. The title compound is isolated as 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-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -10- [ 1-O-α-D- (5-carbonyl) -pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose] -1,4,7,10-tetraazacyclododecane

10.0 g (13.4 mmol) of the carboxylic acid prepared under Example 27c) and 3.24 g (28.1 mmol) of N-hydroxysuccinimide are dissolved in 100 ml of dimethylformamide and treated at 0 ° C with a total of 5.8 g (28 , 1 mmol) of N, N'-dicyclohexylcarbodiimide added in portions and it is stirred for 3 hours at this temperature. To the thus prepared active ester solution is added to a cooled to 0 ° C solution of 14.83 g (13.4 mmol) of the title compound of Example 35a), dissolved in 100 ml of dimethylformamide dropwise and stirred for 2 hours at 0 ° C and 12 h at room temperature. For working up, the precipitated dicyclohexylurea is filtered off, and the solvent is then stripped to dryness. The residue thus obtained is subsequently chromatographed on silica gel (mobile phase: dichloromethane / ethyl acetate 20: 1, the chromatography being carried out using a solvent gradient with a continuous increase in the ethyl acetate content).
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-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -7- [1-O-α-D- ( 5-carbonyl) -pentyl-mannopyranose] -1,4,7,10-tetraazacyclododecane

In 150 ml of ethanol are dissolved 17.0 g (9.75 mmol) of the compound prepared under 31b), admixed with 1.0 g Pearlman catalyst (Pd 20%, C) and at room temperature under a hydrogen atmosphere (1 atm) hydrogenated until no more hydrogen uptake is observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (twice with 75 ml each time) and evaporated 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 F 8,97 S 2,88 Found .: C 38,86 H 4.65 N 7.41 F 29.02 S 2,92

d) 1,7-bis- [1,4,7-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-oxa-acetyl] -10- [1-O-α-D-6-carbonylpentyl-mannopyranose] -1 , 4,7,10 tetraazacyclododecane

24.86 g (39.46 mmol, 4.4 mole equivalents based on the amine component 32c used) of the patent application DE 197 28 954 C1 Example 31h) described the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.67 g of anhydrous lithium chloride (39.46 mmol) are dissolved at 40 ° C in 200 ml of absolute dimethyl sulfoxide with stirring and at this temperature with a total of 4.53g (39.46 mmol) of N-hydroxysuccinimide and 10.0 g (8.97 mmol ) of the title compound from Example 31c), dissolved in 100 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution with 8,14 g (39.46 mmol) of N, N'-dicyclohexylcarbodiimide and Stirred for 12 hours at room temperature. 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) desalted and purified from low molecular weight components. 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 .: C 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-oxa-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 admixed at room temperature with a total of 5.1 g (44.0 mmol) of diglycolic anhydride and the resulting reaction solution is refluxed for 12 h. After cooling to room temperature, it is concentrated 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 above title compound 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 .: 058.42 H 4,41 N 1.80 S 2.28 F 23.02

Example 33

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

In 750 ml of dry tetrahydrofuran are 68.5 g (91.79 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-α-D-mannopyranoside [representation as in the patent DE 197 28 954 C1 described] and then added 9.25 g (91.79 mmol) of triethylamine. After cooling the reaction solution to -15 ° C to -20 ° C is added dropwise at this temperature with stirring, a solution of 12.64 g (92.5 mmol) of isobutyl chloroformate in 150 ml of dry tetrahydrofuran added slowly, to choose the dropping speed so is that an internal temperature of -10 ° C is not exceeded. After a reaction time of 15 minutes at -15 ° C is then added dropwise a solution of 101.6 g (91.79 mmol) of the title compound of Example 32a) and 9.25 g (91.79 mmol) of triethylamine, as a solution in 500 ml of dry tetrahydrofuran at -20 ° C slowly added. After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is concentrated in vacuo to dryness. The remaining residue is taken up in 450 ml of ethyl acetate and washed twice with 300 ml of saturated sodium bicarbonate solution and once with 400 ml of water. After drying the organic phase over sodium sulfate is filtered off with suction from the salt and the ethyl acetate in vacuo. The residual oily residue is purified on silica gel using dichloromethane / hexane / 2-propanol (10: 20: 1) as eluent.
Yield: 130.6 g (81.6% of theory) of the abovementioned title compound as a colorless and strongly 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-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-porfluorooctylsulfonyl) -piperazine] -amide} -7- [1-O-α-D- ( 5-carbonyl) -pentyl-mannopyranose] -1,4,7,10-tetraazacyclododecane

110.0 g (63.08 mmol) of the compound prepared under 33a) are dissolved in 1000 ml of ethanol, mixed with 5.0 g of Pearlman catalyst (Pd 20%, C) and hydrogenated until quantitative uptake of hydrogen. It is suctioned off from the catalyst, washed with ethanol and concentrated in vacuo to dryness. The title compound is obtained as a tough 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- [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl-pentanoyl) -4- {3-oxa-pentane -1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -10- [1-O-α-D- (5-carbonyl) -pentyl-mannopyranose] - 1,4,7,10-tetraazacyclododecane, Digadolinium complex

55.4 g [88.0 mmol; 4.4 mole equivalents based on the diamine component used from Example 30d)] of the patent application DE 197 28 954 C1 under Example 31h) described the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-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. The resulting suspension is then mixed with sufficient acetone until precipitation of the above titled 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 purified from low molecular weight components. The retentate is then freeze-dried.
Yield: 35.96 g (76.9% of theory) as a colorless lyophilizate.
H ₂ O 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 34

a) 5- (ethoxycarbonyl) pentyl-2,3,4,6-tetra-O-acetyl-α-D-mannopyranoside

In a manner analogous to that described in the literature for the synthesis of arylglycopyranosides [J. Conchie and GA Levvy in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol. II, 90, pp. 345-347, (1963)], the reaction of 156.2 g (400 mmol) of D-mannose pentaacetate as 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: ML Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York , Vol. II, 53, pp. 211-215, (1963)] with 67 ml (400 mmol) of ethyl 6-hydroxyhexanoate and 60.8 ml (520 mmol) of stannic chloride in a total of 600 ml of 1,2-dichloroethane after purification by column chromatography (eluent: hexane Ethyl acetate 2: 1) to give 100.05 g (51% of theory) of the title compound above as a colorless and viscous oil. By ¹ H-NMR spectroscopic examination of the title compound thus obtained it was possible to show that the abovementioned 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-O-benzyl-α-D-mannopyranoside

A stirred suspension of 141.0 g (289 mmol) of the title compound from Example 34a) in 200 ml of dioxane is added 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. To increase the stirrability is the Reak tion mixture with a further 200 ml of dioxane and heated the resulting suspension following boiling heat and at this temperature with a total of 372 ml (3.128 mol) of benzyl bromide, over a period of two hours, added dropwise. After a reaction time of 4 hours at 110 ° C followed by 12 hours at room temperature, the reaction mixture is slowly poured for the purpose of workup in a total of 2.5 liters of ice water and the water phase is subsequently extracted completely with diethyl ether. After washing the ether phase thus obtained and then drying the ether phase over sodium sulfate is filtered off with suction from the salt and the diethyl ether removed in vacuo.

Excess benzyl bromide is then distilled off quantitatively in an oil pump vacuum at an oil bath temperature of 180 ° C from the reaction mixture. The resulting resinous-oily residue is purified on silica gel using ethyl acetate / hexane (1:10) as eluent. Yield: 172.2 g (91.0% of theory) of the abovementioned title compound in the form of a colorless and extremely viscous oil. calc .: C 75.68 H 7,16 Found .: C 75.79 H 7.04

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

60.0 g (91.5 mmol) of the title compound from Example 34b) are dissolved in 750 ml of dimethylformamide and admixed 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) of dicyclohexylcarbodiimide are added. It is stirred for one hour at 0 ° C and then for 4 hours at room temperature. The solvent was removed in vacuo and the remaining residue was treated with 100 ml of ethyl acetate and cooled to 0 ° C. It is filtered from the precipitated urea and the resulting filtrate concentrated in vacuo to dryness. The resulting resinous-oily residue is purified on silica gel using ethyl acetate / hexane (1:20) as eluent.
Yield: 61.23 g (89.0% of theory) of the abovementioned title compound in the form of a colorless and viscous oil. Elemental analysis: calc .: C 70,29 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-carbonyl-pentyl- (2,3,4,6-tetra-O-benzyl ) -mannopyranose} -L-lysine methyl ester}

In a cooled to 0 ° C solution of 4.26 g (18.30 mmol, 0.5 molar equivalents based on carboxylic acid used) L-lysine methyl ester dihydrochloride (commercially available from Bachem) and 4.05 g (40.26 mmol) of triethylamine in 100 ml of dimethylformamide is added dropwise to a solution of 27.51 g (36.6 mmol) of the title compound from Example 34c) in 150 ml of dimethylformamide. After complete addition, the mixture is stirred for a further hour at 0 ° C and then at room temperature overnight. It is evaporated to dryness in vacuo and the residue taken up in 300 ml of ethyl acetate. It is filtered from the precipitated urea and the filtrate 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 (eluent: 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-carbonyl-pentyl- (2,3,4,6-tetra-O-benzyl) -mannopyranose ]] - L-lysine

In 150 ml of ethanol are dissolved 30.0 g (20.92 mmol) of the compound prepared under Example 34d). The solution of 4 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water is then added thereto and the mixture is stirred at 50 ° C. for 3 hours. According to the thin-layer chromatogram, saponification is quantitative. It is concentrated to dryness in vacuo and the remaining residue 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 About sodium sulfate is filtered and concentrated in vacuo to dryness. The residue is chromatographed on silica gel (eluent: 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-carbonyl-pentyl- (2,3,4,6-tetra-O-benzyl) -mannopyranose ] -L-lysine] -N-hydroxysuccinimide

14.0 g (9.15 mmol) of the title compound from Example 34e) are dissolved in 100 ml of dimethylformamide and admixed 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. It is stirred for one hour at 0 ° C and then for 4 hours at room temperature. The solvent is then removed in vacuo and the remaining residue is mixed with 100 ml of ethyl acetate and cooled to 0 ° C. It is filtered from the precipitated urea and the resulting filtrate concentrated in vacuo to dryness. The resulting resinous-oily residue is purified on silica gel using ethyl acetate / n-hexane (1:20) as eluent.
Yield: 12.94 g (92.4% of theory) of the abovementioned 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 [1-0-α-D- (6-carbonyl) -pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose] -L-lysine 1,7- (1,4,7-triazaheptane) -diamide

In a cooled to 0 ° C solution of 0.47 g (4.57 mmol) of diethylenetriamine in 25 ml of dimethylformamide is added dropwise a solution of 14.0 g (9.15 mmol, 2 molar equivalents based on the amine used) of the title compound Example 34f) in 100 ml of dimethylformamide added slowly. After complete addition, the mixture is stirred for a further hour at 0 ° C and then at room temperature overnight. It is evaporated to dryness in vacuo and the residue taken up in 200 ml of ethyl acetate. It is filtered from the precipitated urea 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 (eluent: 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 7,42 N 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 there are added 4.09 g ( 35.6 moles) of N-hydroxysuccinimide. It is cooled to 0 ° C. and 7.34 g (35.6 mmol) of dicyclohexylcarbodiimide are added. It is stirred for one hour at 0 ° C and then for 4 hours at room temperature. It is cooled to 0 ° C and added dropwise within 10 minutes, 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 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 taken up in 100 ml of ethyl acetate. It is filtered from the precipitated urea and the filtrate 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 (eluent: n-hexane / ethyl acetate 20: 1). This gives 27.43 g (88.0% of theory) of a colorless oil. 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-N _ε - (benzyloxycarbonyl) -L-lysine

In 150 ml of ethanol, 25.0 g (28.55 mmol) of the compound prepared under Example 34h) are dissolved. The solution of 4 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water is then added thereto and the mixture is stirred at 50 ° C. for 3 hours. According to the thin-layer chromatogram, saponification is quantitative. It is concentrated to dryness in vacuo and the remaining residue 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 is filtered and concentrated in vacuo to dryness. The residue is chromatographed on silica gel (eluent: 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-O-α-D- (5-carbonyl) -pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose] -L-lysine diamide}

In 250 ml of dry tetrahydrofuran are dissolved 15.33 g (17.8 mmol) of the title compound from Example 34i) and 1.80 g (17.8 mmol) of triethylamine. After cooling the reaction solution to -15 ° C to -20 ° C is added dropwise at this temperature with stirring, a solution of 4.92 g (35.6 mmol) of isobutyl chloroformate, dissolved in 50 ml of dry tetrahydrofuran, slowly added, 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 is then added dropwise a solution of 52.0 g (17.8 mmol) of the title compound of Example 37g) and 1.80 g (17.8 mmol) of triethylamine, in 300 ml of dry tetrahydrofuran slowly add at -20 ° C. After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is concentrated in vacuo to dryness. 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 drying the organic phase over sodium sulfate is filtered off with suction from the salt and the ethyl acetate in vacuo. The remaining oily residue is purified on silica gel using ethyl acetate / n-hexane (1:20) as eluent.
Yield: 54.6 g (81.6% of theory) of the abovementioned title compound as a colorless and strongly viscous oil. Elemental analysis: calc .: C 65.09 H 6,45 N 3.72 F 8,58 S 0.85 Found .: 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-O-α-D- (5-carbonyl) -pentyl-mannopyranose] -L-lysine-diamide}

50.0 g (13.28 mmol) of the compound prepared under 34j) are dissolved in 500 ml of ethanol, admixed with 4.0 g of Pearlman catalyst (Pd 20%, C) and reacted at room temperature under a hydrogen atmosphere (1 atm). hydrogenated until no more hydrogen uptake is observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (about 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

l) 1,4,7-triazaheptane-4- {2-N- [2- (N-ethyl-N-perfluorooctylsulfonyl) -amino] -acetyl-6-N- [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl-pentanoyl) -1,4,7,10-tetraazacyclododecane} -L-lysine-amide-1,7-bis {2,6- N, N'-bis [1-O-α-D- (5-carbonyl) -pentyl-mannopyranose] -L-lysine-diamide}, Gadolinium complex

5.54 g (8.8 mmol, 2.2 mol equivalents based on the amine component used in Example 34k)) of the patent application DE 197 28 954 C1 Example 31h) described the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.37 g of anhydrous lithium chloride (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 1.84 g (4.0 mmol) the title compound of Example 34k) 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 to the reaction solution 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 purified from low molecular weight components. The retentate is then freeze-dried.
Yield: 8.77 g (78.7% of theory) as a colorless lyophilisate.
H ₂ O 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 Found .: C 43,97 H 6.02 N 7.62 F 11,61 Gd 10.18 S 1,15

Example 35

a) 2-Nα-6-Nε-bis- [1-0-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-O-benzyl-α-D-mannopyranoside [representation as in the patent DE 197 28 954 C1 described] are dissolved in 150 ml of dimethylformamide and treated 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 to. It is stirred for one hour at 0 ° C and then for 4 hours at room temperature. It is cooled to 0 ° C. and dripped within 1 hour, a solution of 2.13 g (9.15 mmol, 0.5 molar equivalents based on the carboxylic acid used) L-lysine methyl ester dihydrochloride (commercially available from Bachem) and Added 2.02 g (20.13 mmol) of triethylamine in 70 ml of dimethylformamide. After complete addition, the mixture is stirred for a further hour at 0 ° C and then at room temperature overnight. It is evaporated to dryness in vacuo and the residue taken up in 300 ml of ethyl acetate. It is filtered from the precipitated urea and the filtrate 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 (eluent: 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 Found .: 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) of the title compound from Example 35a) results in the formation of 13.89 g (93.6% of theory) by analogous methods, as described in Example 37e) for the synthesis of the title compound relevant there. Th.) To above title compound in the form of a colorless and viscous oil. Elemental analysis: calc .: C 71.80 H 6,71 N 2,12 Found .: 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 35b) are dissolved in 100 ml of dimethylformamide and admixed 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. It is stirred for one hour at 0 ° C and then for 4 hours at room temperature. The solvent is then removed in vacuo and the remaining residue is mixed with 100 ml of ethyl acetate and cooled to 0 ° C. It is filtered from the precipitated urea and the resulting filtrate concentrated in vacuo to dryness. The resulting resinous-oily residue is purified on silica gel using ethyl acetate / n-hexane (1:20) as eluent.
Yield: 12.24 g (94.4% of theory) of the abovementioned title compound in the form of a colorless and viscous oil. Elemental analysis: calc .: C 70,27 H 6,47 N 2,96 Found .: C 70.31 H 6,44 N 3.01

d) 6-N-Benzyloxycarbonyl-2-N - {[2,6-N, N'-bis (1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-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 under Example 35c) are dissolved in 75 ml of dimethylformamide and incubated 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, was added dropwise. The resulting reaction solution is stirred for 2 hours at 0 ° C. and for 12 hours at room temperature. For work-up, the mixture is filtered off from the precipitated dicyclohexylurea and the solvent is then stripped to dryness in vacuo. The residue thus obtained is chromatographed on silica gel [eluent: dichloromethane / ethanol 28: 1; the chromatography is carried out here using a solvent gradient with a proportion of the polar eluent component (in this case ethanol) which is continuously increasing in the course of the chromatography.
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 Found .: C 59,18 H 5.35 N 4.02 F 15.15 S 1.56

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

20.0 g (9.37 mmol) of the compound prepared under 35d) are dissolved in 200 ml of ethanol, admixed with 1.5 g of Pearlman catalyst (Pd 20%, C) and reacted at room temperature under a hydrogen atmosphere (1 atm). hydrogenated until no more hydrogen uptake is observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (twice with approximately 100 ml each time) and evaporated 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 Found .: 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 mol equivalents based on the amine component used from Example 35e) of the patent application DE 197 28 954 C1 Example 31h) described the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.67 G anhydrous lithium chloride (15.84 mmol) are dissolved at 40 ° 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 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 are added to the reaction solution 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 while at the same time of possible, still present low molecular weight components, purified. The retentate is then freeze-dried.
Yield: 11.85 g (87.2% of theory) as a colorless lyophilisate.
H ₂ O 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 Found .: C 38,16 H 4.59 N 8,18 F 20.37 S 1.68 Gd 8:28

Example 36

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

To 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 are added at 0 ° C and under nitrogen atmosphere 12.74 g (24.4 mmol) of the title compound of Example 36g), dissolved in 150 ml of tetrahydrofuran was added. Then, at 0 ° C., a total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] are added in portions and the mixture is stirred overnight at room temperature and then concentrated in vacuo. The remaining oil is chromatographed on silica gel (eluent: n-hexane / isopropanol 16: 1). 15.89 g (69.0% of theory, based on 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 as a colorless oil. Elemental analysis: calc .: C 45,77 H 3.95 F 34,19 N 5.93 Found .: 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-O-acetyl-1-thio-α-D-mannopyranosyl) -propionic acid N-hydroxysuccinimide ester (according to: J. Med. 4, 85, (1993); Chipowsky, S., and Lee, YC (1973), Synthesis of 1-thio-aldosides; Carbohydrate Research 31, 339-346) are prepared 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 of Example 36a), dissolved in 100 ml of dimethylformamide, added dropwise. The mixture is stirred for 2 hours at 0 ° C and 12 h at room temperature. For working up, the solvent is removed in vacuo to dryness and the residue thus obtained is subsequently chromatographed on silica gel (mobile phase: dichloromethane / ethyl acetate 20: 1, the chromatography being carried out using a solvent gradient with a continuous increase in the ethyl acetate content).
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 4,36 N 4,11 F 23,69 S 2.35 Found .: C 46,66 H 4.35 N 4.12 F 23,65 S 2.30

c) 1- (3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) -7- [1-S-α-D- (2-carbonyl) -ethyl-2,3,4,6 tetra-O-acetyl-mannopyranose] -1,4,7,10-tetraazacyclododecane In 150 ml of ethanol, dissolve 15.0 g (11.0 mmol) of the compound prepared under 36b) with 1.0 g Pearlman catalyst (Pd 20%, C) and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen uptake is observed. It is suctioned off from the catalyst, washed thoroughly with ethanol (twice with 75 ml each time) and evaporated 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 Found .: 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 36c) are suspended in 100 ml of absolute methanol and treated at 5 ° C with a catalytic amount of sodium. After a reaction time of 3 h at room temperature, the thin-layer chromatographic control (eluent: chloroform / methanol 4: 1) of the course of the reaction already indicates quantitative conversion. For the purpose of workup, the now clear reaction solution is neutralized by addition of Amberlite IR 120 (H ⁺ form) cation exchange resin, sucked from the exchanger, washed with methanol and the methanolic filtrate thus obtained in vacuo to dryness. The resulting oily residue is purified by column chromatography on silica gel (eluent: dichloromethane / n-hexane / ethyl acetate 15: 20: 1; the chromatography is carried out using a solvent gradient with a continuous increase of the ethyl acetate content). According to ¹ H-NMR spectroscopic examination of the title compound, the size of the coupling constants of J _1.2 = 0.9 Hz clearly indicated the presence of the α-configuration at the anomeric center of D-mannopyranose. The present α configuration is the configuration exclusively present at the anomeric center, ie the amount of possibly formed and β-configured anomer of the title compound is thus below the ¹ H NMR spectroscopic detection limit. Accordingly, the above-mentioned title compound was represented only 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 Found .: C 37.57 H 4,28 N 6.02 F 34,85 S 3,44

e) 1- (3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) -7- [1-S-α-D- (2-carbonyl) -ethyl-mannopyranose] -4,10- 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-O-acetyl-1-thio-α-D-mannopyranosyl) -propionic acid 2.48 g [(3.94 mmol); 4.4 mole equivalents based on the diamine component 36d)] used in the patent application DE 197 28 954 C1 Example 31h) described the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-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 of Example 19Ad). , dissolved in 10 ml of absolute dimethyl sulfoxide, added. After cooling to room temperature, the reaction solution is treated with 814 mg (3.946 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. 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 purified from low molecular weight components. The retentate is then freeze-dried.
Yield: 1.32 g (69.1% of theory) as a colorless lyophilizate.
H ₂ O 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 Found .: 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 treated at room temperature with a catalytic amount (about 0, 75 g) of tetra-n-butylammonium hydrogen sulfate. A total of 7.55 g (134.6 mmol, 2.5 equiv., Based on the alcohol component used) of finely powdered potassium hydroxide powder are then added at 0 ° C., followed by 15.73 g (80.7 mmol, 1.5 equiv Based on the alcohol component used) bromoacetic acid tert-butyl ester and can be stirred for 2 hours at 0 ° C. The reaction solution thus obtained is stirred for 12 h at room temperature and for the purpose of work-up, a total of 500 ml of ethyl acetate and 250 ml of water are added. The org. Phase is separated and washed twice with water. After drying the organic phase over sodium sulfate is filtered off with suction from the salt and the solvent evaporated in vacuo. The remaining oily residue is purified on silica gel using ethyl acetate / hexane (1:10) as eluent.
Yield: 26.3 g (84.6% of theory) of the abovementioned title compound as a colorless and strongly viscous oil. 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 36f) are suspended in 200 ml of a mixture consisting of methanol and 0.5 molar sodium hydroxide 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 workup by addition of Amberlite IR 120 (H ⁺ form) cation exchange resin, filtered with suction from the exchanger and the methanolic-aqueous filtrate thus obtained in vacuo to dryness , The resulting amorphous oily residue is purified on silica gel using ethyl acetate / n-hexane (1: 3) as eluent.
Yield: 16.0 g (88.6% of theory) of the abovementioned title compound as a colorless and strongly viscous oil. calc .: C 27,60 H 1,35 F 61.85 Found .: C 27.58 H 1,36 F 61,90

Example 37

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 Bachem) dissolved in a mixture of 150 ml of tetrahydrofuran, 15 ml of chloroform and 2.62 g (26.0 mmol ) Triethylamine, at 0 ° C and under nitrogen atmosphere 16.18 g (27.0 mmol) of 2- [N-ethyl-N-perfluorooctylsulfonyl) aminoacetic acid (representation according to: DE 196 03 033 ) dissolved in 50 ml of tetrahydrofuran was added dropwise.

Then, at 0 ° C., a total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] are added in portions and the mixture is stirred overnight at room temperature. It is then concentrated in vacuo and the residual oil is chromatographed on silica gel (eluent: n-hexane / isopropanol 15: 1). This gives 17.0 g (79.6% of theory, based on prim amine used) of the title compound 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 Found .: 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

In 200 ml of ethanol are dissolved 15.0 g (20.23 mmol) of the compound prepared under Example 37a), mixed with 800 mg of Pearlman catalyst (Pd 20% on activated carbon) and hydrogenated until the calculated amount of hydrogen. It is suctioned off from the catalyst, washed thoroughly with ethanol and concentrated in vacuo to dryness. 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 Found .: C 32.42 H 3,27 F 43.60 N 5.67 S 4:34

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

In 500 ml of dry tetrahydrofuran are 21.31 g (35.6 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-α-D-mannopyranoside [representation as in the patent DE 197 28 954 C1 described] and 3.60 g (35.6 mmol) of triethylamine. After cooling the reaction solution to -15 ° C to -20 ° C is added dropwise at this temperature with stirring, a solution of 4.92 g (35.6 mmol) of isobutyl chloroformate in 75 ml of dry tetrahydrofuran slowly adding the dropping speed to choose is, an internal temperature of -10 ° C is not exceeded. After a reaction time of 15 minutes at -15 ° C is then added dropwise a solution of 26.39 g (35.6 mmol) of the title compound of Example 37b) and 3.60 g (35.6 mmol) of triethylamine, in 100 ml of dry tetrahydrofuran slowly add at -20 ° C. After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is concentrated in vacuo to dryness. 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 drying the organic phase over sodium sulfate is filtered off with suction from the salt and the ethyl acetate in vacuo. The residual oily residue is purified on silica gel using ethyl acetate / n-hexane (1:10) as eluent.
Yield: 38.12 g (81.0% of theory) of the abovementioned title compound as a colorless and strongly viscous oil. calc .: C 49.92 H 3.92 N 2.53 F 29,18 S 2,90 Found .: C 49.99 H 4,11 N 2.69 F 29,22 S 3.01

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

In 250 ml of methanol, 27.65 g (20.92 mmol) of the compound prepared under Example 37c) are dissolved. 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 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. It is concentrated to dryness in vacuo and the remaining residue 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 is filtered and concentrated in vacuo to dryness. The residue obtained is chromatographed on silica gel (mobile phase: 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 Found .: C 51.49 H 4.71 N 3,19 F 24,72 S 2.41

e) 6- (1-O-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 37d) 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 charcoal) are added. It is hydrogenated for 12 hours at room temperature and a hydrogen pressure of one atmosphere. It is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 200 ml of methanol and the reaction product by precipitation with a total of 800 ml of diethyl ether precipitated. After sucking off the solid thus obtained, it is dried in vacuo at 50.degree.
Yield: 14.32 g (99.0% of theory) of an amorphous solid. Elemental analysis: bar.: C 35.56 H 3.84 N 4,44 S 3.39 F 34,15 Found .: C 35.58 H 3.81 N 4,45 S 3.40 F 34,17

f) 6- (1-O-α-D-carbonylmethyl-mannopyranose) 2- [2- (N-ethyl-N-perfluorooctylsulfonyl) -amino] -acetyl-L-lysine-N- {2-hydroxy-propyl) 3-yl- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-yl]} - amide, Gd complex

7.48 g (7.91 mmol) of the title compound from Example 37e) are dissolved in 50 ml of dimethyl sulfoxide at 40 ° C. and 1.00 g (8.70 mol) of N-hydroxysuccinimide are added. It is cooled to 20 ° C and are added 1.795 g (8.7 mmol) of dicyclohexylcarbodiimide. It is stirred for one hour at 20 ° C and then at 40 ° C for 4 hours. Then 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 added dropwise at this temperature within 10 minutes. -1,4,7,10-tetraazacyclododecanin [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 suspension thus 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 dicyclohexylurea is filtered and the filtrate concentrated over an Amicon ^® YM-3 ultrafiltration membrane (cut-off 3,000 Da) desalted and purified from low molecular weight components. The retentate is then freeze-dried.
Yield: 9.71 g (81.7% of theory) as a colorless lyophilizate.
H ₂ O 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 Found .: C 35,17 H 4,20 N 7,42 F 21,49 Gd 10.48 S 2.09

Example 38

a) 6-N- [1-O-α-D- (5-carbonyl) -pentyl-2,3,4,6-tetra-O-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-O-benzyl-α-D-mannopyranoside described in Example 27c), 1.3 g (8, 0 mmol) of 1-hydroxy-benzotriazole and 2.6 g (8.0 mmol) of 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU; Peboc Limited, UK) dissolved in 75 ml of DMF and stirred for 15 minutes. This solution is then admixed with 5.16 ml (30 mmol) of N-ethyldiisopropylamine and with 5.93 g (8.0 mmol) of the amine described in Example 37b) and stirred at room temperature for 1.5 days. For working up, the solvent is removed in vacuo to dryness and the residue thus obtained is subsequently chromatographed on silica gel (mobile phase: dichloromethane / ethyl acetate 30: 1, the chromatography being carried out using a solvent gradient with a continuous increase in the ethyl acetate content).
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 Found .: C 52,33 H 4.95 N 3,12 F 23,50 S 2.30

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

9.0 g (12.40 mmol) of the compound prepared under Example 38a) 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 after the above-mentioned reaction time has already taken place quantitatively. It is concentrated to dryness in vacuo and the remaining residue 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 is filtered and concentrated in vacuo to dryness. The residue obtained is chromatographed on silica gel (eluent: 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 Found .: C 51.99 H 4.91 N 3.09 F 23,70 S 2.33

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

13.0 g (9.52 mmol) of the title compound from Example 38b) 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 charcoal) are added. It is hydrogenated for 12 hours at 1 atmosphere of hydrogen pressure and room temperature. It is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo. The residue obtained is chromatographed on silica gel (mobile phase: 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 Found .: C 37.09 H 4,21 N 4,19 F 32,20 S 3,13

d) 6-N- [1-O-α-D- (5-carbonyl) -pentyl-mannopyranose] -2 N - [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 38c) are dissolved at 40 ° C in 75 ml of dimethyl sulfoxide and it is mixed with 1.00 g (8.70 mol) of N-hydroxysuccinimide. Cool to room temperature and add a total of 1.795 g (8.7 mmol) of dicyclohexylcarbodiimide. It is stirred for one hour at 20 ° C and then at 40 ° C for 4 hours. To this solution of the active ester of the title compound of Example 41c) is then added dropwise at 40 ° C within 10 minutes, a solution consisting of 4.53 g (7.91 mmol) of the gadolinium complex of 10- (2-hydroxy-3 -aminopropyl) -4,7,10-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecanin [for comparison see: WO 97/02051 ], in 20 ml of dimethyl sulfoxide added. The mixture is stirred for one hour at 40 ° C, then overnight at room temperature. The suspension thus obtained is then treated with the sufficient amount of a mixture of acetone / 2-propanol (2: 1) until complete precipitation of the title compound mentioned above, 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 through an AMICON ^® YM-3 ultrafiltration membrane (cut off 3000 Da) desalted and purified from low molecular weight components. The retentate is then freeze-dried.
Yield: 9.71 g (78.8% of theory) as a colorless lyophilisate.
H ₂ O 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 Found .: C 37.02 H 4,50 N 7,22 F 20,69 Gd 10.08 S 2.09

Example 39

a) 3-Benzyloxycarbonylamino-glutaric acid [1- (4-perfluorooctylsulfonyl) -piperazine] -monoamide

A stirred solution of 25.0 g (94.96 mmol) of 3-N- (benzyloxcarbonyl) -glutaric anhydride [synthesis according to: Hatanaka, Minoru; Yamamoto, Yuichi; Nitta, Hajime; Ishimaru, Toshiyasu; TELEAY; Tetrahedron Lett .; EN; 22; 39; 1981; 3883-3886;] in 150 ml of absolute tetrahydrofuran is added dropwise with stirring to a solution of 53.97 g (95.0 mmol) of 1-perfluorooctylsulfonylpiperazine in 150 ml of tetrahydrofuran and the resulting reaction solution is refluxed for 12 h. After cooling to room temperature, it is concentrated to dryness and the remaining oily residue is purified on silica gel using dichloromethane / 2-propanol (20: 1) as eluent.
Yield: 75.80 g (96.0% of theory) of the abovementioned 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 Found .: 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 39b) are dissolved in 300 ml of ethanol, admixed with 2.5 g Pearlman catalyst (Pd 20%, C) and hydrogenated until the quantitative uptake of hydrogen at 1 atmosphere of hydrogen pressure , It is suctioned off from the catalyst, washed with ethanol and concentrated in vacuo to dryness. 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 Found .: 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-O-benzyl-mannopyranose) -glutaric acid [1- (4-perfluorooctylsulfonyl) -piperazine] -monoamide

21.52 g (18.96 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-α-D-mannopyranoside [representation as in the patent DE 197 28 954 C1 described] are dissolved at room temperature in 100 ml of absolute dimethylformamide and treated 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 is filtered from the insoluble dicyclohexylurea and the resulting clear active ester solution of the title compound added dropwise at 0 ° C slowly added to a stirred solution of 13.22 g (18 , 96 mmol) of the compound from Example 39b), 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 was taken up in 300 ml of ethyl acetate, it is filtered from the urea and the organic filtrate twice with 100 ml of saturated sodium bicarbonate solution and once with 100 ml of 10% aqueous Citric acid solution and washed once with 200 ml of water. After drying the organic phase over sodium sulfate is filtered off with suction from the salt and the ethyl acetate in vacuo. The residual oily residue is purified on silica gel using ethyl acetate / n-hexane (1:15) as eluent.
Yield: 21.39 g (88.3% of theory) of the abovementioned title compound as a colorless and strongly viscous oil. Elemental analysis: calc .: C 49.81 H 4,10 N 3,29 F 25,27 S 2.51 Found .: 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 39c) are dissolved in a mixture consisting of 250 ml of 2-propanol and 25 ml of water and admixed with 1.5 g of palladium catalyst (10% Pd on activated charcoal). It is hydrogenated for 12 hours at room temperature and a hydrogen pressure of one atmosphere. It is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 200 ml of methanol and the reaction product by precipitation with a total of 800 ml of diethyl ether precipitated. After sucking off the solid thus obtained, 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 Found .: 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-tetraazacyclododecane-10-yl]} - amide, Gd complex

14.43 g (15.84 mmol) of the title compound from Example 39d) and 0.67 g of anhydrous lithium chloride (15.84 mmol) are dissolved at 40 ° 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 [to compare: WO 97/02051 ], in 50 ml of dimethyl sulfoxide, added. After cooling to room temperature, 3.27 g (15.84 mmol) of N, N'-dicyclohexylcarbodiimide are added to the reaction solution 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 while at the same time of possible, still present low molecular weight components, purified. The retentate is then freeze-dried.
Yield: 18.71 g (80.2% of theory) as a colorless lyophilisate.
H ₂ O 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 Found .: C 34,26 H 3.79 N 7.58 F 21,87 S 2,18 Gd 10, 68

Example 40

a) 1,7-bis (benzyloxycarbonyl) -4- {3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -10- [2,6-N, N'-bis (1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)] - L-lysyl-1,4,7, 10-tetraazacyclododecane

In a solution of 27.0 g (24.4 mmol) of the sec. Amines prepared under Example 32a), in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, at 33 ° C. and under nitrogen atmosphere, 33.04 g (25, 0 mmol) of the title compound from Example 18c), dissolved in 250 ml of tetrahydrofuran. Then, at 0 ° C., a total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] are added in portions and the mixture is stirred overnight at room temperature. It is then concentrated to dryness in vacuo and the remaining oil is chromatographed on silica gel (eluent: n-hexane / isopropanol 25: 1). This gives 45.87 g (78.0% of theory, based on secondary sec-amine) of the title compound 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 Found .: C 59,32 H 5.37 F 13.37 N 4,70 S 1,34

b) 1- {3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -7- [2,6-N, N'- bis (1-O-α-D-carbonylmethyl-mannopyranose)] - L-lysyl-1,4,7,10-tetraazacyclododecane

In 250 ml of ethanol, 24.1 g (10.0 mmol) of the title compound prepared under Example 40a) are dissolved and treated with 1.4 g Pearlman catalyst (Pd 20%, C). The mixture is hydrogenated to quantitative uptake of hydrogen, then filtered from the catalyst, washed with ethanol well and concentrated in vacuo to dryness. The product is obtained as a yellowish colored 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 Found .: C 39,72 H 4,87 F 22,77 N 7,90 S 2.24

c) 1- {3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -7- [2,6-N, N'- bis (1-O-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 molar equivalents based on the amine component used from Example 40b)] of the patent application DE 197 28 954 C1 Example 31h) described the complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-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 of 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 are added to the reaction solution 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 purified from low molecular weight components. The retentate is then freeze-dried.
Yield: 8.52 g (80.6% of theory, based on the diamine component used) as colorless lyophilisate.
H ₂ O 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 Found .: C 38.57 H 4,82 N 9.52 F 12,21 Gd 11,93 S 1,15

Example 41

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

In a solution of 27.0 g (24.4 mmol) of sec. Amine prepared under Example 32a), in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, at 0 ° C and under nitrogen atmosphere 35.80 g (25 , 0 mmol) of the title compound of Example 37e), dissolved in 250 ml of tetrahydrofuran. Then, at 0 ° C., a total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] are added in portions and the mixture is stirred overnight at room temperature. It is then concentrated to dryness in vacuo and the remaining oil is chromatographed on silica gel (eluent: n-hexane / isopropanol 20: 1). This gives 49.48 g (80.4% of theory, based on secondary sec-amine) of the title compound 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 Found .: C 60.52 H 5,77 F 12,77 N 4,50 S 1,30

b) 1- {3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -7- [2,6-N, N'- bis (1-O-α-D- (5-carbonyl) -pentyl-mannopyranose)] - L-lysyl-1,4,7,10-tetraazacyclododecane

25.2 g (10.0 mmol) of the title compound prepared under Example 41a) are dissolved in 250 ml of ethanol, and 1.8 g of Pearlman catalyst (Pd 20%, C) are added. The mixture is hydrogenated to quantitative uptake of hydrogen, then filtered from the catalyst, washed with ethanol well and concentrated in vacuo to dryness. The product is obtained as a yellowish colored and extremely viscous oil.
Yield: 14.11 g (92.5% of theory) Elemental analysis: calc .: C 49.60 H 7,20 F 21,17 N 7,34 S 2,10 Found .: C 49.62 H 7,17 F 21,20 N 7,30 S 2,14

c) 1- {3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -7- [2,6-N, N'- bis (1-O-α-D- (5-carbonyl) -pentyl-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 molar equivalents based on the amine component used from Example 41b)] of the patent application DE 197 28 954 C1 Example 31h) described the complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-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 are added to the reaction solution 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 purified from 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 colorless lyophilizate.
H ₂ O 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 Found .: C 40.57 H 5.20 N 9,12 F 11,69 Gd 11:43 S 1,18

Example 42

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 Bachem) are dissolved in 150 ml of absolute tetrahydrofuran. 8.31 g (50.0 mmol) of carbonyldiimidazole and 5.30 g (50.0 mmol) of triethylamine, dissolved in 75 ml of dry tetrahydrofuran, are added dropwise at 0 ° C., and stirring is continued for 10 minutes at this temperature. Then 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 are added dropwise at 0 ° C. After stirring overnight, the tetrahydrofuran is removed in vacuo and the remaining oil is chromatographed on silica gel (eluent: n-hexane / isopropanol 15: 1). This gives 49.48 g (80.4% of theory, based on secondary sec-amine) of the title compound 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 Found .: C 40.07 H 3.82 N 6.02 F 34,67 S 3,48

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

30.0 g (32.2 mmol) of the title compound of Example 42a) are dissolved in 300 ml Isopropanol dissolved and with 1.5 g Pearlman catalyst (20% palladium hydroxide on carbon) added. Hydrogenated for 10 hours at room temperature, after checking the course of the reaction by thin layer chromatography Hydrogenolytic cleavage of the benzyloxycarbonyl protecting group already quantitatively after the above reaction time is. The mixture is filtered off from the catalyst and the filtrate is concentrated in vacuo to dryness. The remaining residue is chromatographed on silica gel.

(Eluent: 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 Found .: 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-O-acetyl-mannopyranose] -L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

In 300 ml of dry tetrahydrofuran are 15.53 g (35.60 mmol) of 3- (2,3,4,6-tetra-O-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 ( 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 in which the dropping speed is to be chosen such 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 added dropwise from 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 concentrated in vacuo to dryness. 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 drying the organic phase over sodium sulfate is filtered off with suction from the salt and the ethyl acetate in vacuo. The residual oily residue is purified on silica gel using ethyl acetate / n-hexane (1:25) as eluent.
Yield: 34.21 g (79.1% of theory) of the abovementioned 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 Found .: 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 42c) are suspended in 400 ml of absolute methanol and treated at 5 ° C with a catalytic amount of sodium. After a reaction time of 3 h at room temperature, the thin-layer chromatographic control (eluent: chloroform / methanol = 9: 1) of the course of the reaction already indicates quantitative conversion. For the purpose of working-up, the now clear reaction solution is neutralized by mixing with Amberlite ^® IR 120 (H ⁺ form) cation exchange resin, exchanger suctioned off and the thus obtained methanolic filtrate in vacuo to dryness. The resulting amorphous residue is purified by chromatography on silica gel using 2-propanol / ethyl acetate / n-hexane (1: 1: 15) as 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 Found .: 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 42d) are dissolved in a mixture of 50 ml of trifluoroacetic acid and 100 ml of dichloromethane at 0 ° C. with vigorous stirring and stirred for 10 minutes at this temperature. Then it is evaporated to dryness in vacuo and the residue is taken up in 150 ml of water. The pH 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 an AMICON ^® YM-3 ultrafiltration membrane (cut-off: 3,000 Da), and at the same time cleaned of possible, still present low-molecular components. The retentate is then freeze-dried.
Yield: 17.79 g (94.2% of theory) of the free amine as colorless lyophilisate.
H ₂ O 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 Found .: 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 mol equivalents based on the amine component used from Example 42e)] of the patent application DE 197 28 954 C1 Example 31h) described the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.37 g of anhydrous lithium chloride (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 3.78 g (4.0 mmol) of the title compound from Example 46e), 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 to the reaction solution and the mixture is stirred at room temperature for 12 hours. The suspension obtained is then treated with sufficient acetone until complete precipitation of the title compound mentioned above, the precipitate is filtered off, taken up in water, filtered from insoluble dicyclohexylurea and the filtrate over an AMICON ^® YM-3 ultrafiltration membrane (cut off 3000 Da) desalted and from purified low molecular weight components. The retentate is then freeze-dried.
Yield: 5.17 g (83.0% of theory) as a colorless lyophilisate.
H ₂ O content (Karl Fischer): 4.43%. Elemental analysis (calculated on anhydrous substance): calc .: 35.45 H 4.07 N 8.09 F 20,72 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 43

a) 6-N-Benzyloxycarbonyl-2-N- (1-O-β-D-carbonylmethyl-2,3,4,6-tetra-O-benzylglucopyranose) -L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] amide

8.02 g (13.4 mmol) of the in the patent application DE 197 28 954 C1 titled compound [1-carboxymethyloxy-2,3,4,6-tetra-O-benzyl-β-D-glucopyranoside] described in Example 46a) and 3.24 g (28.14 mmol) of N-hydroxysuccinimide are dissolved in 100 ml of dimethylformamide dissolved and mixed at 0 ° C with a total of 5.80 g (28.14 mmol) of N, N'-dicyclohexylcarbodiimide portionwise. It is stirred for 3 hours at this temperature. To the thus prepared active ester solution is added a cooled to 0 ° C solution of 11.13 g (13.4 mmol) 6-N-benzyloxycarbonyl-L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, dissolved in 50 ml of dimethylformamide, added dropwise and stirred for 2 hours at 0 ° C and 12 hours at room temperature. For working up, the precipitated dicyclohexylurea is filtered off, and the solvent is then stripped to dryness. The residue thus obtained is then chromatographed on silica gel (mobile phase: dichloromethane / ethanol, 20: 1, the chromatography being 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 incl .. C 52,75 H 4.61 N 3.98 F 22,94 S 2,26

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

11.52 g (8.17 mmol) of the compound prepared under 47a) are dissolved in 100 ml of ethanol, admixed with 0.5 g of Pearlman catalyst (Pd 20%, C) and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no hydrogen uptake is observed. It is sucked from the catalyst washed thoroughly with ethanol (three times with about 40ml) and concentrated in vacuo to dryness. 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-O-β-D-carbonylmethylglucopyranose) -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 amine component from Example 43b)] used in the patent application DE 197 28 954 C1 Example 31h) described the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.67 g (15.84 mmol) of 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 43b), 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 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 complete precipitation of the title compound mentioned above, the precipitate was filtered off, taken up in water, filtered from insoluble dicyclohexylurea and the filtrate over an AMICON ^® YM-3 ultrafiltration membrane (cut off: 3000 Da) desalted and purified from low molecular weight components. The retentate is then freeze-dried.
Yield: 9.11 g (83.0% of theory) as colorless lyophilisate.
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 Found .: C 35,42 H 4.07 N 8,18 F 21.09 S 2.06 Gd 10,34

Example 44

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

In 100 ml of ethanol, 10.0 g (11.46 mmol) of 2-N-trifluoroacetyl-6-N-benzyloxycarbonyl-L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide are dissolved, with 1.0 g Pearlman catalyst (Pd 20% / C) and hydrogenated until quantitative uptake of hydrogen. It is suctioned off from the catalyst, washed with ethanol and concentrated in vacuo to dryness. The title compound is obtained as a tough 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 Found .: C 30,36 H 2.50 N 7.11 F 47.99 S 4,00

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

In a cooled to 0 ° C solution of 29.0 g (36.6 mmol) of the title compound of Example 44a) and 4.05 g (40.26 mmol) of triethylamine in 100 ml of dimethylformamide is added dropwise a solution of 27.51 g (36.6 mmol) of the title compound of Example 34c) in 150 ml of dimethylformamide. After complete addition, the mixture is stirred for a further hour at 0 ° C and then at room temperature overnight. It is evaporated to dryness in vacuo and the residue taken up in 300 ml of ethyl acetate. It is filtered off from insoluble constituents and the filtrate 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 (eluent: n-hexane / isopropanol 25: 1). This gives 42.05 g (80.4% of theory) of the title compound 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 Found .: C 50,38 H 4,50 N 7.91 F 26,62 S 2,20

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

In 150 ml of ethanol are dissolved 20.0 g (14.0 mmol) of the compound prepared under Example 44b). 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 hours. According to the thin-layer chromatogram, the deprotection has already taken place quantitatively at this time. It is concentrated to dryness in vacuo and traces of water are removed by repeated co-distilling with ethanol. The residue is chromatographed on silica gel (eluent: n-hexane / isopropanol 20: 1). This gives 16.66 g (89.3% of theory) of the title compound 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 Found .: C 52,30 H 4,90 N 4,18 F 24,22 S 2.38

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

In 150 ml of a 10: 1 mixture of ethanol and water are dissolved 15.0 g (11.25 mmol) of the compound prepared under 44c) and treated with 1.0 g Pearlman catalyst (Pd 20% / C). Subsequently hydrogenation is carried out until the quantitative uptake of hydrogen at room temperature and under one atmosphere of hydrogen pressure. 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 tough 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 Found .: C 37.06 H 4,20 N 5.81 F 33,19 S 3.30

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

5.54 g [(8.8 mmol, 2.2 mol equivalents based on the amine component from Example 44d)] used in the patent application DE 197 28 954 C1 Example 31h) described the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.37 g (8.8 mmol) of 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 3.89 g (4.0 mmol) of the title compound from Example 48d), dissolved in 60 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 1.82 g (8.8 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 sufficient Acetone is added until complete precipitation of the title compound mentioned above, the precipitate is filtered off, taken up in water, filtered from insoluble dicyclohexylurea and the filtrate via an AMICON ^® YM-3 Utrafiltrationsmembran (cut off: 3000Da) desalted and purified from low molecular weight components. The retentate is then freeze-dried.
Yield: 4.81 g (75.9% of theory) as a colorless lyophilisate.
H ₂ O 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 Found .: C 37,27 H 4,40 N 8.02 F 20.31 Gd 10.00 S 1,98

Example 45

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

In a solution of 27.0 g (24.4 mmol) of sec. Amine prepared under Example 32a), in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, at 0 ° C and under nitrogen atmosphere 35.80 g (25 , 0 mmol) of the title compound from Example 37e), dissolved in 250 ml of tetrahydrofuran, was added. Then, at 0 ° C., a total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] are added in portions and the mixture is stirred overnight at room temperature. It is then concentrated to dryness in vacuo and the remaining oil is chromatographed on silica gel (eluent: n-hexane / isopropanol 20: 1). This gives 32.11 g (78.0% of theory, based on secondary sec-amine) of the title compound 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 Found .: C 54,12 H 4,77 F 19,17 N 5.03 S 1,90

b) 1- (1-O-β-D-carbonylmethyl-galactopyranose) -7- {3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -1,4,7,10-tetraazacyclododecane

30.0 g (17.77 mmol) of the title compound prepared under Example 45a) are dissolved in 250 ml of ethanol, and 3.0 g of Pearlman catalyst (Pd 20%, / C) are added. It is hydrogenated to quantitative uptake of hydrogen, then sucks from the catalyst, washed with ethanol well and concentrated in vacuo to dryness. The product is obtained as a yellowish colored 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 Found .: C 36,26 H 4,12 F 30.46 N 7,90 S 3.04

c) 1- (1-O-β-D-carbonylmethyl-galactopyranose) -7- {3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -4,10-bis [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl-pentanoyl) -1,4,7,10 -tetraazacyclododecan] -1,4,7,10-tetraazacyclododecane, di-gadolinium complex

5.54 g [8.8 mmol; 4.4 molar equivalents based on the amine component used in Example 45b)] of the patent application DE 197 28 954 C1 Example 31h) described the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.37 g (8.8 mmol) of 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) the title compound from Example 49b) dissolved in 25 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 1.82 g (8.8 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 complete precipitation of the title compound mentioned above, the precipitate abge sucks, dried, taken up in water, filtered off from insoluble dicyclohexylurea and the filtrate through a AMICON ^® YM-3 ultrafiltration membrane (cut off: 3000 Da) desalted and purified from 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 colorless lyophilizate.
H ₂ O 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 Found .: C 36,87 H 4,40 N 9.82 F 14.09 Gd 19.59 S 1,38

Example 46

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

In 500 ml of dry acetonitrile, 21.42 g (39.61 mmol) of 2,3,4,6-tetra-O-benzyl-α-D-mannopyranose (according to: F. Kong et al., J. Carbohydr. Chem., 16; 6; 1997; 877-890). After cooling the reaction solution to 5.degree. C., a solution of 13.23 g (59.52 mmol) of trifluoromethanesulphonylsilyl 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 ) N-benzyloxycarbonyl-L-serine methyl ester (commercially available from Bachem) in 50 ml of acetonitrile, wherein the dropping speed is to be 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 concentrated in vacuo to dryness. 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 drying the organic phase over sodium sulfate is filtered off with suction from the salt and the ethyl acetate in vacuo. The residual oily residue is purified on silica gel using ethyl acetate / n-hexane (1: 5) as eluent.
Yield: 23.60 g (76.8% of theory) of the abovementioned title compound as a colorless oil. Elemental analysis: calc .: C 71,21 H 6,37 N 1.81 Found .: C 71,19 H 6,41 N 1,79

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

In a mixture consisting of 20 ml of methanol, 20 ml of water and 50 ml of tetrahydrofuran 10.0 g (12.90 mmol) of the compound prepared under Example 46a) are dissolved. 0.47 g (19.35 mmol) of lithium hydroxide, dissolved in 25 ml of distilled water, are then added at room temperature and the mixture is subsequently 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) after the above-mentioned reaction time has already taken place quantitatively. For the purpose of working up, the product solution is concentrated to dryness in vacuo and the remaining residue is taken up in 250 ml of ethyl acetate in the presence of heat (about 60 ° C.). Subsequently, the thus obtained ethyl acetate phase 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 (eluent: 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 Found .: C 70.97 H 6,30 N 1,78

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

To 13.86 g (24.40 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 196 03 033 ) dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform are added dropwise at 0 ° C under a nitrogen atmosphere 20.57 g (27.0 mmol) of the carboxylic acid according to Example 46b), dissolved in 50 ml of tetrahydrofuran. Subsequently, at 0 ° C, a total of 18.0 g (36.60 mmol) EEDQ [2-Etho xy-1-ethoxycarbonyl-1,2-dihydroquinoline] in portions and allowed to stir overnight at room temperature. For workup, the reaction solution is concentrated in vacuo and the remaining viscous oil remaining on silica gel is chromatographed 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 Found .: C 51.48 H 4,27 N 3,10 F 25,71 S 2.35

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

In 200 ml of ethanol are dissolved 15.0 g (11.41 mmol) of the compound according to Example 46c) and treated with 1.5 g Pearlman catalyst (Pd 20%, C). Subsequently, the reaction solution is hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen uptake is observed (about 8 hours). For the purpose of work-up, the catalyst is filtered off with suction, washed thoroughly with ethanol (twice with approximately 100 ml each time) and the product-containing ethanolic filtrate is concentrated 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 Found .: C 30,87 H 3,14 N 5.19 F 39.50 S 3,88

e) 3- (1-O-α-D-Mannopyranose) -2-N- [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl pentanoyl) -1,4,7,10-tetraazacyclododecane] -L-serine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd complex

A stirred suspension of 5.7 g [9.06 mmol; corresponding to 1.5 molar equivalents with respect to the title compound used (primary amine) from Example 46d)] of the patent application DE 197 28 954 C1 under Example 31h) described Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid in 75 ml of absolute Dimethylsulfoxide is added at 70 ° C with 0.68 g (15.9 mmol) of lithium chloride. After 30 minutes of stirring at 70 ° C, the now clear reaction solution is added in portions with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide and kept the reaction mixture for 1 hour at 70 ° C. After cooling the reaction solution to 10 ° C., 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide are added and the reaction solution is stirred for a further 1 hour at 0 ° C., followed by 12 hours at 22 ° C. The resulting 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 is now added dropwise at 22 ° C with a solution of 4.94 g (6.03 mmol) of the title compound of Example 27d), in 15 ml of absolute dimethyl sulfoxide, and stirred for a further 12 hours at room temperature. For workup, the reaction solution is slowly added dropwise at 22 ° C in a solvent mixture consisting of 250 ml of acetone and 250 ml of 2-propanol, with the title compound after 12 hours at 10 ° C has completely settled as a slightly yellowish-colored oil. The mixture is carefully decanted from the supernatant eluent mixture and the oily product is taken up in 200 ml of distilled water, the latter dissolving completely to give a slightly yellowish aqueous solution of the abovementioned title compound. Subsequently, the aqueous product solution is first filtered through a membrane filter and then, for the purpose of desalination and separation of low-molecular components, via a YM3-ultrafiltration membrane (AMICON ^®; cut-off: 3000 Da) ultrafiltered three times. The resulting retentate is then freeze-dried. Yield: 8.63 g (80.2% of theory, based on the title compound used from Example 27d) as colorless lyophilisate with a water content of 7.65%. Elemental analysis (calculated on anhydrous substance): calc .: C 33.57 H 3.80 N 7,83 F 22.57 Gd 10.99 S 2.24 Found .: C 33.57 H 3.76 N 7.82 F 22,63 Gd 11.06 S 2,18

Example 47

a) 6-N-benzyloxycarbonyl-2-N- [O-β-D-galactopyranosyl (1 → 4) -gluconosyl] -L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

To a stirred solution of 4.98 g (6.0 mmol) of 6-N-benzyloxycarbonyl-L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide in 40 ml of absolute dimethylsulfoxide is added a solution of 13 at room temperature , 3 g (37.2 mmol) of O-β-D-galactopyranosyl- (1 → 4) -D-glucono-1,5-lactone [lactobionolactone; Preparation according to: (a) Williams, TJ; Plessas, NR, Goldstein, IJ 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] are added dropwise in 40 ml of absolute dimethyl sulfoxide. The reaction solution thus obtained is then stirred for 14 hours at 40 ° C. For working up, 500 ml of absolute 2-propanol are added at room temperature and the resulting colorless precipitate is filtered off with suction using a G4 frit and thoroughly washed with a total of 250 ml of absolute 2-propanol. The solid so obtained is then dissolved in 300 ml of distilled water and a YM3-ultrafiltration membrane (AMICON ^®; cut-off: 3000 Da) ultrafiltered a total of three times. Through the three-time ultrafiltration process, both the excess of lactobionolactone and, possibly still present, low molecular weight components are separated from the desired product. 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): calc .: C 38,98 H 4.05 N 4,79 F 27.58 S 2,74 Found .: C 39.04 H 4.09 N 4,82 F 27,61 S 2,71

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

5.0 g (4.27 mmol) of the compound prepared under 47a) are dissolved in 100 ml of ethanol, mixed with 0.5 g Pearlman catalyst (Pd 20%, C) and hydrogenated until the quantitative uptake of hydrogen at 1 atmosphere of hydrogen pressure , It is suctioned off from the catalyst, washed with ethanol and concentrated in vacuo to dryness. The title compound is obtained as a colorless and viscous oil.
Yield: 4.36 g (98.5% of theory). Elemental analysis: calc .: C 34,76 H 3.99 N 5.40 F 31.51 S 3.09 Found .: C 34.78 H 4.04 N 5.34 F 31.51 S 3,15

c) 2-N- [O-β-D-galactopyranosyl (1 → 4) -gluconosyl] -6-N- [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo) 5-methyl-5-yl-pentanoyl) -1,4,7,10-tetraazacyclododecane] -L-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd complex

5.54 g [(8.8 mmol, 2.2 mol equivalents based on the amine component from Example 47b)] used in the patent application DE 197 28 954 C1 Example 31h) described the Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 0.37 g (8.8 mmol) of 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 3.85 g (4.0 mmol) of the title compound from Example 31Ab), dissolved in 60 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide are added to the reaction solution and the mixture is stirred at room temperature for 12 hours. The resulting suspension is then treated with sufficient acetone / 2-propanol (1: 1) until complete precipitation of the title compound mentioned above and the precipitate is filtered off with suction. The resulting precipitate is then taken up in 300 ml of water and it is filtered from the insoluble dicyclohexylurea. The filtrate is an AMICON ^® YM-3 ultrafiltration membrane: ultrafiltered three times (cut-off 3,000 Da). The three-fold ultrafiltration process carried out, the excess of Gd complex as well as, possibly still existing, low molecular weight components are separated 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 colorless lyophilisate.
H ₂ O 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 Found .: C 35,77 H 4,17 N 7.71 F 19,61 Gd 9,60 S 1,99

Example 48

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

100 g (356.7 mmol) 6-N-benzyloxycarbonyl-lysine are dissolved in a mixture of 1000 ml ethyl trifluoroacetate / 500 ml 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. Elemental analysis: calc. C 51.07 H 5.09 F 15,14 N 7.44 gef. C 51,25 H 5:18 F 15.03 N 7.58

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

To 125 g (332 mmol) of the title compound of Example 48a) and 188.7 g (332 mmol) of 1-perfluorooctylsulfonyl-piperazine, (prepared according to DE 196 03 033 ) in 800 ml of tetrahydrofuran are added at 0 ° C 164.2 g (0.664 mmol) EEDQ (2-ethoxy-1,2-dihydro-quinoline-1-carboxylic acid ethyl ester) and stirred overnight at room temperature. It is evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).
Yield: 286 g (93% of theory) of a colorless solid. Elemental analysis: calc. C 36,30 H 2,83 F 41.01 N 6.05 S 3,46 gef. C 36,18 H 2,94 F 40,87 N 5.98 S 3.40

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

In a solution of 280 g (302.2 mmol) of the title compound of Example 48b) in 2000 ml of ethanol, is introduced at 0 ° C for one hour ammonia gas. It is then stirred for 4 hours at 0 ° C. It is evaporated to dryness and the residue is stirred out of water. The solid is filtered off and dried in vacuo (50 ° C).
Yield: 243.5 g (97% of theory) of an amorphous solid. Elemental analysis: calc. C 37,60 H 3:28 F 38,89 N 6.75 S 3.86 gef. C 37,15 H 3,33 F 38,78 N 6.68 S 3.81

d) 6-N-Benzyloxycarbonyl-2-N- (3,6,9,12,15-pentaoxahexadecanoyl) -lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

To 50 g (60.20 mmol) of the title compound from Example 48c) and 7.10 g (70 mmol) of triethylamine, dissolved in 350 ml of dichloromethane, is added dropwise at 0 ° C, a solution of 19.93 g (70 mmol) of 3 , 6,9,12,15 pentaoxahexadecanoic acid chloride [prepared according to Liebigs Ann. Chem. (1980), (6), 852-62] in 50 ml of dichloromethane and stirred for 3 hours at 0 ° C. 200 ml of 5% aqueous hydrochloric acid are added and stirred for 5 minutes at room temperature. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1
Yield: 53.7 g (93% of theory) of a colorless, viscous oil. Elemental analysis: calc. C 33,83 H 4,94 F 3,34 N 5.84 S 33,69 gef. C 33,75 H 5.05 F 3,29 N 5.78 S 33,75

e) 2-N- (3,6,9,12,15-pentaoxahexadecanoyl) -lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

50 g (52.15 mmol) of the title compound from Example 48d) 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 mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 43.0 g (quantitative) of a colorless solid. Elemental analysis: calc. C 27,68 H 5.01 F 39,17 N 6.79 S 3,89 gef. C 27,60 H 5:13 F 39.09 N 6.68 S 3.81

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

20 g (24.25 mmol) of the title compound from Example 48e), 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1, 4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl) -pentanoic acid] -1,4,7,10-tetraazacyclododecane, Gd complex becomes easier under Heating dissolved in 200 ml of dimethyl sulfoxide. 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C. 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 (silica gel RP-18, mobile phase: gradient of water / ethanol / acetonitrile). Yield: 28.21 g (81% of theory) of a colorless solid.
Water content: 11.0 Elemental analysis (calculated on anhydrous substance) calc. C 31.78 H 4,84 F 22,49 N 8,78 S 2,23 Gd 10.95 gef. C 31.74 H 4,98 F 22.39 N 8,69 S 2,15 Gd 10,87

Example 49

a) Lysine [1- (4-perfluorooctylsulfonyl-piperazine] -amide

20 g (24.08 mmol) of the title compound from Example 48c) 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 mixture is filtered off from the catalyst 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 gef. 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) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl -5-yl)] - lysine [1- (4-perfluorooctylsulfonyl-piperazine] -amide, Gd complex (metal complex XVI)

10 g (14.36 mmol) of the title compound from Example 49a), 3.34 g (29 mmol) of N-hydroxysuccinimide, 2.54 g (mmol) of lithium chloride and 18.26 g (29 mmol) of 1,4,7- Tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) 1,4,7,10-tetraazacyclododecane-Gd complex are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10 ° C., 12.38 g (60 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is subsequently 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 phase: gradient of water / ethanol / acetonitrile). Yield: 19.02 g (69% of theory) of a colorless solid
Water content: 11.3% Elemental analysis: (calculated on anhydrous substance) calc. C 35.03 H 4.04 F 16,82 N 10,21 S 1.67 Gd 16:38 gef. C 34.96 H 4,13 F 16.74 N 10,16 S 1.61 Gd 16:33

Example 50

a) 2- [4- (3-Oxapropionsäureethylester)] - phenylacetic acid methyl ester

To 200 g (1.204 mol) of methyl 4-hydroxyphenylacetate, 212 g (2 mol) of sodium carbonate in 2000 ml of acetone are added 233.8 g (1.4 mol) of 2-bromoacetic acid ethyl ester and refluxed for 5 hours. The solid is filtered off and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: n-hexane / ethyl acetate = 15: 1).
Yield: 288.5 g (95% of theory) of a colorless oil. Elemental analysis: calc. C 61,90 H 6,39 gef. C 61.75 H 6,51

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

To 285 g (1.13 mol) of the title compound of Example 50a), dissolved in 2000 ml of carbon tetrachloride, are added 201 g (1.13 mol) of N-bromosuccinimide and 100 mg of dibenzyl peroxide and refluxed for 8 hours. It 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 phase: n-hexane / acetone = 15: 1).
Yield: 359.2 g (96% of theory) of a colorless, viscous oil. Elemental analysis: calc. C 47,28 H 4.57 Br 24,16 gef. C 47,19 H 4.71 Br 24.05

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

To 603 g (3.5 mol) of 1,4,7,10-tetraazacyclododecane in 6000 ml of chloroform are added 350 g (1.057 mol) of the title compound from Example 50b) and stirred overnight 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 without further purification in the next reaction (3d).
Yield: 448 g (quantitative) of a viscous oil. Elemental analysis: calc. C 59.70 H 8,11 N 13,26 gef. C 59.58 H 8,20 N 13,18

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

445 g (1.053 mol) of the title compound from Example 50c) and 496 g (5.27 mol) of chloroacetic acid are dissolved in 4000 ml of water. It is adjusted to a pH of 10 with 30% strength aqueous sodium hydroxide solution. The mixture is heated to 70 ° C. and the pH is kept at pH 10 by adding 30% strength aqueous sodium hydroxide solution. The mixture is stirred at 70 ° C. for 8 hours. It is then adjusted to a pH of 13 and boiled for 30 minutes under reflux. The solution is cooled in an ice bath and by adding conc. Hydrochloric acid to a pH value of 1 provided. 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. It is filtered from the precipitated sodium chloride, the filtrate is evaporated to dryness and the residue is purified on silica gel
RP-18 (mobile phase: gradient of water / ethanol / acetonitrile).
Yield: 403 g (69% 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 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 50d) in 2000 ml of water are added 130.73 g (360.65 mmol) of gadolinium oxide and stirred for 5 hours at 80 ° C. The solution is filtered and the filtrate is 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 Gd 22:19 N 7.98 gef. 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] -lysin- [4-perfluoro-octylsulfonyl) -piperazine] -amide, Digadolinium complex, disodium salt

10 g (14.36 mmol) of the title compound from Example 49a) 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. At 10 ° C is added 16.51 g (80 mmol) of N, N-dicyclohexylcarbodiimide and 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 purified by chromatography (silica gel RP-18, mobile phase: gradient of water / ethanol / acetonitrile) Dissolve in a little water, adjust with sodium hydroxide solution to a pH of 7.4 and freeze-dried.
Yield: 21.02 g (69% of theory) of a colorless solid.
Water content: 11.2 Elemental analysis: (calculated on anhydrous substance calc. C 37,36 H 3.66 F 15,22 Gd 14,82 N 7.92 Na 2,17 S 1.51 gef. C 37,28 H 3.74 F 15,14 Gd 14.75 N 8.03 Na 2.23 S 1.46

Example 51

a) 6-N-benzyloxycarbonyl-2-N- [6-carboxymethyl-3,9-bis (t butyloxycarbonylmethyl) -3,6,9-triazaundecane-1,11-dicarboxylic acid bis (t butylester)] - lysine- [1 (4- perfluorooctylsulfonyl) -piperazine] -amide

To a solution of 20 g (24.08 mmol) of the title compound of Example 48c), 14.88 g (24.08 mmol) of 3,9-bis (t-butyloxycarbonylmethyl) -6-carboxymethyl-3,6,9-triazaune -decane-1,11-dicarboxylic acid bis (t-butyl ester) and 2.88 g (25 mol) of N-hydroxysuccinimide dissolved in 100 ml of dimethylformamide are added at 0 ° C 8.25 g 40 mol) N, N-dicyclo-hexylcarbodiimide to. The mixture is stirred for 3 hours at 0 ° C, then overnight at room temperature. It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloro-methane / ethanol = 20: 1). Yield: 27.21 g (79% of theory) of a viscous oil. calc. C 47.03 H 5.64 F 22.58 N 6,85 S 2.24 gef. C 46,94 H 5.58 F 22,65 N 6.84 S 2.31

b) 2-N- [carbonylmethyl-3,9-bis (t-butyloxycarbonylmethyl) -3,6,9-triazaundecane-1,11-dicarboxylic acid bis (t butylester)] - lysine- [1- (4-perlfluoroctylsulfonyl) -piperazine] -amide

25 g (17.48 mmol) of the title compound from Example 51a) are dissolved in 350 ml of ethanol and 5 g of palladium catalyst (10% Pd / C) are added. It is hydrogenated at room temperature. It is filtered from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 22.66 g (quantitative) of a colorless solid. Elemental analysis: calc. C 44.48 H 5.75 F 24.92 N 7.56 S 2,47 gef. C 44.59 H 5.81 F 25.03 N 7.46 S 2.52

c) 6-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - 2 -N- [6-carbonylmethyl-3,9-bis (t butyloxycarbonylmethyl) 3,6,9-triazaundecane-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 of Example 51b), 1.78 g (15.43 mmol) of N-hydroxysuccininamide, 1.48 g (35 mmol) of lithium chloride and 9.72 g (15.43 mmol) of 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. At 10 ° C., 5.16 g (25 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is subsequently stirred at room temperature overnight. The solution is poured into 2500 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and then purified by chromatography (silica gel RP-18, mobile phase: gradient of water / ethanol / acetonitrile).
Yield: 22.94 g (78% of theory) of a colorless solid.
Water content: 7.9% Elemental analysis: (calculated on anhydrous substance) calc. C 42,22 H 5.29 F 16.95 Gd 8,25 N 8,82 S 1.68 gef. C 42,15 H 5.41 F 16,87 Gd 8:13 N 8,70 S 1.60

d) 6-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (3-aza-4-oxo-5-methyl-5-yl-pentanoyl)] -2-N- [6-carbonylmethyl-3,9-bis (carboxylatomethyl) 3,6,9-triazaundecane dicarboxylic acid-carboxy-11-carboxylato-z] -lysin- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Digadolinium complex, sodium salt

20 g (10.49 mmol) of the title compound from Example 51c) are dissolved in 200 ml of trifluoroacetic acid. The mixture is stirred for 60 minutes at room temperature. It is 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 adjusted to a pH of 7.4 with sodium hydroxide solution. The solution is evaporated to dryness in vacuo and purified on silica gel RP-18. (Mobile phase: gradient 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 gef. C 32,90 H 3,53 F 17,31 Gd 16,87 N 8,92 Na 1.33 S 1.67

Example 52

a) 5,6-bis (benzyloxy) -3-oxa-hexanoic acid t-butyl ester

100 g (376.2 mmol) of 1,2-di-O-benzyl-glycerol [prepared 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 ° C is added dropwise over 30 minutes 78g (400 mmol) of 2-bromoacetic acid-t-butyl and then stirred for 3 hours at 0 ° C. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel. (Eluent: N-hexane / acetone = 20: 1).
Yield: 133.4 g (94% of theory) of a colorless oil. Elemental analysis: calc. C 71.48 H 7,82 gef. 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 52a) are dissolved in 200 ml of dichloromethane and added at 0 ° C to 100 ml of trifluoroacetic acid. 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 gef. 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-perfluorooctylsulfonyl) -piperazine] -amide, Gd complex

50 g (60.20 mmol) of the title compound from Example 48c) 6.93 g (60.20 mmol) of N-hydroxysuccinimide, 5.09 g (120 mmol) of lithium chloride and 37.91 g (60.20 mmol) of 1 , 4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-pentanoyl-3-aza-4-oxo-5-methyl-5-yl), Gd complex are added with slight heating in 400 ml of dimethylsulfoxide solved. At 10.degree. C., 20.63 g (100 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is subsequently 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 phase: gradient of water / ethanol / acetonitrile). Yield: 75.53 g (87% of theory) of a colorless solid. Water content: 10.1% Elemental analysis: (calculated on anhydrous substance) calc. C 37,48 H 3.84 F 22.39 Gd 10,90 N 8.74 S 2.22 gef. C 37,39 H 4.02 F 22,29 Gd 10,75 N 8,70 S 2.22

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

70 g (48.53 mmol) of the title compound from Example 52c) 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 mixture is filtered off from the catalyst 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) calc. 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 P 2.20

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

10 g (7.64 mmol) of the title compound from Example 52d), 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 with gentle heating in 150 ml of dimethyl sulfoxide. At 10 ° C., 3.10 g (15 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 8 hours. The reaction solution is poured into 2000 ml of acetone and the precipitate is isolated. It is purified on silica gel RP-18 (mobile phase: gradient of 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) calc. C 41.51 H 4,29 F 19,93 N 7,78 Gd 9,70 S 1,98 gef. 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-triscarboxylatomethyl] -1,4,7,10-tetraazacyclododecane-10-pentanoyl-3- aza-4-oxo-5-methyl-5-yl)] - lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd complex

10 g (6.17 mmol) of the title compound from Example 52e) 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 mixture is filtered off from the catalyst 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) calc. C 35.03 H 3.99 F 22,42 Gd 10,92 N 8,75 S 2,23 gef. C 34.95 H 4,12 F 22,30 Gd 10, 78 N 8,71 S 2,18

Example 53

a) 6-N-Benzyloxycarbonyl-2-N [-5,6-bis (benzyloxy) -3-oxa-hexanoyl] -lysin- [1- (4-perfluoro-octylsulfonyl) -piperazine] -amide

To a solution of 20 g (24.08 mmol) of the title compound of Example 48c), 9.91 g (30 mmol) of the title compound of Example 7b and 3.45 g (30 mmol) of N-hydroxysuccinimide dissolved in 100 ml of dimethylformamide , Are added at 0 ° C 9.28 g (45 mmol) of N, N-dicyclohexylcarbodiimide. The mixture is stirred for 3 hours at 0 ° C, then overnight at room temperature. It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / ethanol = 20: 1)
Yield: 24.50 g (89% of theory) of a viscous oil. Elemental analysis: calc. C 47,29 H 4,14 F 28,26 N 4,90 S 2,81 gef. C 47,14 H 4,26 F 28,17 N 4.91 S 2.69

b) 2-N- (5,6-dihydroxy-3-oxahexanoyl) -lysin- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

20 g (17.5 mmol) of the title compound from Example 48d) 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 mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo. Yield: 17.65 g (quantitative) of a colorless solid. Elemental analysis: calc. C 44.05 H 4,10 F 32.02 N 5.55 S 3,18 gef. C 43,96 H 4,21 F 31.94 N 5.48 S 3,24

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

15 g (14.87 mmol) of the title compound of Example 53b) 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 , At 10 ° C is added 5.16 g (25 mol) of N, N-dicyclohexylcarbodiimide and 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 eluent: gradient of water / ethanol / acetonitrile).
Yield: 19.28 g (80% of theory) of a colorless solid.
Water content: 10.3% Elemental analysis: (calculated on anhydrous substance) calc. C 41.51 H 4,29 F 19,93 Gd 9,70 N 7,78 S 1,98 gef. C 41,37 H 4,40 F 19,88 Gd 9,58 N 7,67 S 1.85

Example 54

a) 6-N-Benzyloxycarbonyl-2-N- [2,6-N, N'-bis (benzyloxycarbonyl) -lysyl] -lysin- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

20 g (24.08 mmol) of the title compound from Example 48c) 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 Added lysine paranitrophenol ester. The mixture is stirred for 5 hours at 50 ° C. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel. Eluent: dichloromethane / methanol = 20: 1).
Yield: 28.07 g (95% of theory) of a colorless solid. Elemental analysis: calc. C 46.99 H 4,19 F 26,32 N 6,85 S 2.61 gef. C 47.08 H 4,32 F 26,21 N 6.75 S 2.54

b) 2-N- (lysyl) -lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, trihydrobromide

To 25 g (20.37 mmol) of the title compound from Example 54a) is added 100 ml of hydrobromic acid in glacial acetic acid (48%) and stirred for 2 hours at 40 ° C. It is cooled to 0 ° C, added dropwise 1500 ml of diethyl ester and filtered off the precipitated solid. After drying in vacuo (60 ° C.), 21.52 g (99% of theory) of slightly yellow-colored, crystalline solid are obtained. Elemental analysis: calc. C 27.01 H 3,40 Br. 22.46 F 30,26 N 7,87 S 3.00 gef. C 26,92 H 3,53 Br. 22:15 F 30,14 N 7.69 S 2,87

c) 6-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - 2 -N-] 2,6-N, N'-bis [1,4,7-tris-carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-L0 (pentanoyl-3-aza-4-oxo-5 methyl-5-yl)] - lysyl] -lysin- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Trigadolinium complex

31.49 g (50 mmol) of 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 ° C., 16.51 g (80 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is stirred for 5 hours at 10 ° C. 10 g (9.37 mmol) of the title compound from Example 54b) and 3 are added to this mixture , 03 g (30 mmol) of triethylamine and stirred for 12 hours at 60 ° C. It is allowed to cool to room temperature and the mixture is poured into 3000 ml of acetone. The deposited precipitate is filtered off, purified on silica gel RP-18 (mobile phase: gradient of water / ethanol / acetonitrile). Yield: 16.7 g (67% of theory) of a colorless solid.
Water content: 7.9% Elemental analysis: (calculated on anhydrous substance) calc. C 36.58 H 4,43 F 12,14 Gd 17:74 N 11.06 S 1,14 gef. C 36.47 H 4.54 F 12.03 Gd 17,65 N 10.95 S 1,21

Example 55

a) 1,7-bis (benzyloxycarbonyl) -4- (3,6,9,12,15-pentaoxahexadecanoyl) -1,4,7,10-tetraazacyclododecane

To 18.13 g (68.1 mmol) of 3,6,9,12,15-pentaoxahexadecanoic acid and 30 g (68.1 mmol) of 1,7 di-Z-cyclic compounds prepared according to Z. Kovacs and AD Sherry, J. Chem. Soc. chem. Commun. (1995), 2, 185, in 300 ml of tetrahydrofuran, is added at 0.degree. C. 24.73 g (100 mmol) of ethyl EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylate) and stirred overnight at room temperature. It is evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1). Yield: 19.13 g (42% of theory) of a colorless solid Elemental analysis: calc. C 61.03 H 7.61 N 8,13 gef. 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 , 7,10-tetraazacyclododecane

To 18 g (26.91 mmol) of the title compound of Example 55a) and 14.05 g (26.91 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid, prepared according to DE 196 03 033 , 52n 300 ml of tetrahydrofuran are added at 0 ° C 12.36 g (50 mmol) EEDQ (2-ethoxy-1,2-dihydro-quinoline-1-carboxylic acid ethyl ester) and stirred overnight at room temperature. It is evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).
Yield: 21.51 g (67% of theory) of a colorless solid. calc. C 47,32 H 4,82 F 27.07 N 4,70 gef. C 47,26 H 5.01 F 26,94 N 4.59

c) 1- (3,6,9,12,15-pentaoxahexadecanoyl) -7- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoyl) -1,4,7,10-tetraazacyclododecane

20 g (16.77 mmol) of the title compound from Example 48d) are dissolved in 200 ml of ethanol and 2.5 g of palladium catalyst (10% Pd / C) was added. It is hydrogenated at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 15.5 g (quantitative) of a colorless solid. Elemental analysis: calc. C 40,27 H 4,90 F 34,93 N 6.06 gef. C 40,15 H 4.99 F 34,87 N 5.94

d) 1,7-bis (1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) ] -4- (3,6,9,12,15-pentaoxahexadecanoyl) -10- (2H, 2H, 4H, 4H, 5H, 5H, -3-oxaperfluortridecanoyl) -1,4,7,10-tetraazacyclododecane, Gd complex

15 g (16.22 mmol) of the title compound from Example 55c), 4.60 g (40 mmol) N-hydroxysuccinimide, 3.39 g (80 mmol) of lithium chloride and 25.19 g (40 mmol) of 1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) pentanoic acid, Gd complex are under slight warming dissolved in 300 ml of dimethyl sulfoxide. At 10 ° C Add 24.73 g (100 mmol) of EEDQ and then stir overnight at room temperature. You pour the solution in 3000 ml of acetone and stirred 10 mins.

The precipitated solid is filtered off and then purified by chromatography silica gel RP-18) mobile phase: gradient of water / ethanol / acetonitrile).
Yield: 19.86 g (57% of theory) of a colorless solid
Water content: 11.3% Elemental analysis: (calculated on anhydrous substance) calc. C 38.58 H 4,74 F 15,04 Gd 14:64 N 9,13 gef. C 38.47 H 4.91 F 14.95 Gd 14,57 N 9.04

Example 56

a) 3,5-Dinitrobenzoic acid 1 - [(4-perfluorooctysulfonyl) -piperazine] -amide

To 20 g (35.2 mmol) and 8.1 g (80 mmol) of triethylamine, dissolved in 200 ml of dichloromethane is added dropwise at 0 ° 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 ° C. It gives 200 ml of 5% aqu. Hydrochloric acid and stirred for 5 minutes at room temperature. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel
(Eluent: dichloromethane / acetone = 15: 1)
Yield: 24.96 g (93% of theory) of a colorless solid. Elemental analysis: calc. C 29,35 H 1.45 F 42.37 N 7,35 S 4,21 gef. C 29,28 H 1.61 F 42,15 N 7.25 S 4,15

b) 3,5-diaminobenzoic acid [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

20 g (26.23 mmol) of the title compound of Example 56a) are dissolved in 400 ml of ethanol and 6 g of palladium catalyst (10% Pd IC) was added. It is hydrogenated at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo. Yield: 18.43 g (quantitative) of a cream-colored solid. Elemental analysis: calc. C 32.49 H 2,15 F 45,98 N 7.98 S 4,57 gef. C 32,29 H 2.35 F 45.69 N 7.81 S 4,40

c) 3,5-N, N'-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 of Example 56b), 3.45 g (30 mmol) of N-hydroxysuccinimide, 2.54 g (60 mol) of lithium chloride and 18.89 g (30 mmol) of 1,4,7 -Tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) -pentanoic acid, Gd-complex are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10 ° C., 10.32 g (50 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is subsequently stirred at room temperature overnight. 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 phase: gradient of water / ethanol / acetonitrile). Yield: 19.74 g (72% of theory) of a colorless solid.
Water content: 11.8% Elemental analysis: (calculated on anhydrous substance) calc. C 35.55 H 3.72 F 16.77 Gd 16:33 N 10,18 S 1.67 gef. C 35,48 H 3.84 F 16.58 Gd 16,24 N 10.07 S 1.58

Example 57

a) 3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecancarboxylic 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 treated at room temperature with a catalytic amount (about 0, 75 g) of tetra-n-butylammonium hydrogen sulfate. Then, at 0.degree. C., a total of 7.55 g (134.6 mmol, 2.5 equiv., Based on the alcohol component used) of finely powdered potassium hydroxide powder are added, followed by 15.73 g (80.7 mmol, 1.5 equiv Based on the alcohol component used) bromoacetic acid tert-butyl ester and can be stirred for 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 with a total of 500 ml of ethyl acetate and 250 ml of water. The org. Phase is separated and washed twice with water. After drying the organic phase over sodium sulfate is filtered off with suction from the salt and the solvent evaporated in vacuo. The remaining oily residue is purified on silica gel using acetic acid ethyl ester / hexane (1:10) as eluent.
Yield: 26.3 g (84.6% of theory) of the abovementioned title compound as a colorless and strongly viscous oil. Elemental analysis: calc .: C 33,23 H 2.61 F 55.85 Found .: C 33,29 H 2.61 F 55,90

b) 3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecancarboxylic acid

20.0 g (34.58 mmol) of the title compound from Example 57a) are suspended in 200 ml of a mixture consisting of methanol and 0.5 molar sodium hydroxide 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 workup by addition of Amberlite ^® IR 120 (H ⁺ form) cation exchange resin, sucked from the exchanger and the resulting methanolic-aqueous filtrate in vacuo to dryness deducted. The resulting amorphous oily residue is purified on silica gel using ethyl acetate / n-hexane (1: 3) as eluent.
Yield: 16.0 g (88.6% of theory) of the abovementioned title compound as a colorless and strongly viscous oil. Elemental analysis: calc .: C 27,60 H 1,35 F 61.85 Found .: 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 -tetraazacyclododecan} diethylenetriamine, Digadolinium complex

2.48 g [(3.94 mmol); 2.05 molar equivalents based on diethylenetriamine] used in the patent application DE 197 28 954 C1 under Example 31 h) described Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 167 mg Anhydrous lithium chloride (3.94 mmol) are dissolved at 40 ° C in 40 ml of absolute dimethyl sulfoxide with stirring and treated at this temperature with a total of 453 mg (3.94 mmol) of N-hydroxysuccinimide. After cooling to room temperature, the reaction solution thus obtained is treated with 814 mg (3.946 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 2 hours at room temperature. The resulting suspension of Aktivestetrs is then treated 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, the reaction mixture is treated with sufficient acetone until complete precipitation of the above title compound, the precipitate is filtered off, dried, taken up in water, filtered off from insoluble dicyclohexylurea and the filtrate through an AMICON ^® YM-3 ultrafiltration membrane (cut off 3000 Da Desalted and purified from low molecular weight components. The retentate is then freeze-dried.
Yield: 1.85 g (72.7% of theory) as colorless lyophilizate.
H ₂ O content (Karl Fischer): 3.89%. Elemental analysis (calculated on anhydrous substance): calc .: C 38.03 H 5.24 N 13,73 Gd 23,71 Found .: C 37,98 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-perfluortridecanoyl) -diethylenetriamine, Digadolinium complex

In a solution of 3.23 g (2.44 mmol) of the title compound of Example 57c), in a mixture of 30 ml of dimethyl sulfoxide and 3 ml of tetrahydrofuran, at 50 ° C and under nitrogen atmosphere 1.27 g (2.44 mmol ) of the title compound of Example 57b), dissolved in a mixture of 15 ml of tetrahydrofuran and 15 ml of dimethyl sulfoxide, was added dropwise. Subsequently, at 0.degree. C., a total of 1.80 g (3.66 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] are added in portions 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 ^® Ultrafilt ultrafiltered (cut off 3000 Da), which serves both for complete desalting and for purifying the title compound of low molecular weight components. The retentate is then freeze-dried.
Yield: 3.54 g (79.4% of theory) as a colorless lyophilizate.
H ₂ O 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

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 of Example 52a) and 188.7 g (332.0 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE

Example 58

a) 6-N- (Benzyloxycarbonyl) -2-N - [(N-pteroyl) -L-glutaminyl] -lysin- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

20 g (45.31 mmol) of folic acid are dissolved in 300 ml of dimethyl sulfoxide and added at 10.degree. C. 9.49 g (46 mmol) of N, N-dicyclohexylcarbodiimide. It is stirred overnight at room temperature. To this mixture are added 29.1 g (35 mmol) of the title compound from Example 48c) and 20 ml of pyridine and stirred for 3 hours at 50 ° C. It is cooled to room temperature and a mixture of 1500 ml of diethyl ether / 1500 ml of acetone. The precipitate is filtered off and on
(RP-18) (eluent = gradient of water / ethanol / tetrahydrofuran).
Yield: 21.59 g (38% of theory), yellow solid.
Water content: 2.1% Elemental analysis: (calculated on anhydrous substance). calc. C 43,10 H 3,54 F 25,76 N 11,29 S 2.56 gef. 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) piperazine] -amide

to 20 g (15.95 mmol) of the title compound from Example 58a) are added 200 ml of hydrobromic acid in Glacial acetic acid (48%) and stir 2 hours at 40 ° C.

It is cooled to 0 ° C, added dropwise 2000 ml of diethyl ether and filtered from the precipitated solid. After drying in vacuo (60 ° C.), 18.96 g (99% of theory) of a yellow-colored, crystalline solid are obtained. Elemental analysis: calc. C 37.01 H 3,27 Br 6,65 F 26,90 N 12,83 S 2,67 gef. 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) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl] -2-N- [(N-pteroyl] -L-glutaminyl] -lysin- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd complex

0.92 g (8 mmol) of N-hydroxysuccinimide, 0.68 g (16 mol) of lithium chloride and 5.04 g (8 mmol) of 1,4,7-tris (carboxylatomethyl-10- (3-aza-4-oxo 5-methyl-5-yl) -1,4,7-10-tetraazacyclododecane, Gd complex are dissolved in 80 ml of dimethylsulfoxide with gentle heating, at 10 ° C. 2.06 g (10 mol) of N, N are added And then stirred for 3 hours at room temperature To this reaction solution are added 5 g (4.16 mmol) of the title compound of Example 58b) and 10 ml of pyridine, it 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 phase: gradient of water / ethanol / acetonitrile.) Dissolve in a little water, adjust the pH 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) calc. C 38,36 H 3.74 F 18,42 Gd 8,97 N 12,78 Na 1.31 S 1.83 gef. C 38,28 H 3.85 F 18,33 Gd 8,85 N 12,69 Na 1.42 S 1.75

Example 59

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

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane are added 8.90 g (70 mmol) of oxalyl chloride and stirred for 12 hours at room temperature. It is evaporated to dryness in vacuo. 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 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated, 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. 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 59a are dissolved in 300 ml of tetrahydrofuran and 50 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 300 ml of methanol, then it is evaporated to dryness in vacuo. The residue is dissolved in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid and stirred at 60 ° C for 8 hours. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol = 15: 1).
Yield: 24.07 g (85% of theory) of a colorless solid. 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

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) -perfluortridecyl) -amide] -1,4,7,10-tetraazacyclododecane, gadolinium

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 (15.88 mmol) of the title compound from Example 59b are added. The mixture is stirred for 10 minutes and gives dan 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: 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 Found .: C 34,12 H 3,83 N 6.91 F 26,88 Gd 12,93

Example 60

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

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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 at 60 ° C in 100 ml of dimethyl sulfoxide. It is cooled to 15 ° C and 3.51 (17 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 5 hours at 15 ° C. To separate the urea, the solution is filtered. To the filtrate are added 8.63 g (15.88 mmol) of the title compound from Example 61b and 5.06 g (50 mmol) of triethylamine and 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 phase: gradient 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 61

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecansäureamid

To 30 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 at room temperature. It is evaporated to dryness in vacuo. The residue is dissolved in 200 ml of dichloromethane. Then at 0 ° C ammonia gas is passed 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% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: 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 .: 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 61a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 400 ml of ethanol / 100 ml of 10% aqu. Hydrochloric acid and stirred at 60 ° C for 8 hours. It is evaporated to dryness in vacuo and the residue is recrystallized from a little ethanol / diethyl ether.
Yield: 26.75 g (95% of theory) of a colorless, crystalline solid. 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

c) 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 61b and 14.8 g (146.2 mmol) of triethylamine, dissolved in 300 ml of dichloromethane dropwise, is added at 0 ° C 14.24 g (50 mmol) 3,6,9,12,15-Pentaoxahexadecansäurechlorid and stirred for 3 hours at 0 ° C. 300 ml of 5% aqu. Hydrochloric acid and stirred well for 30 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: dichloromethane / acetone: 20: 1).
Yield: 32.03 g (87% of theory) of a colorless oil. 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) -amide

31 g (41.03 mmol) of the title compound from Example 61c are dissolved in 300 ml of tetrahydrofuran and 25 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid and stirred at 40 ° C for 8 hours. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: 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 431

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

10 g (15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-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. It is cooled to 15 ° C and 11.77 (15.88 mmol) of the title compound of Example 61d to. The mixture is stirred for 10 minutes and gives dan 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: 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 Found .: C 37.11 H 4.61 N 6.03 F 23,64 Gd 11,42

Example 62

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

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane are added 8.90 g (70 mmol) of oxalyl chloride and stirred for 12 hours at room temperature. It is evaporated to dryness in vacuo. The residue is dissolved in 100 ml of dichloromethane and at 0 ° C to a solution of 6.25 g (60 mmol) of 5-hydroxy-3-oxa-pentylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane dripped. The mixture is stirred for 3 hours at 0 ° C, then 6 hours at room temperature. 300 ml of 5% aqu. Hydrochloric acid and stirred for 15 minutes well. The organic phase is separated off, over Magne dried sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1).
Yield: 32.20 g (92% of theory) of a colorless solid. calc .: C 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-oxa-pentyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -amine

30 g (49.24 mmol) of the title compound from Example 62a are dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borane dimethyl sulfide (in tetrahydrofuran) are added. It is refluxed for 16 hours. It is cooled to 0 ° C and added dropwise 200 ml of methanol, then evaporated to dryness in vacuo. The residue is dissolved in a mixture of 300 ml of ethanol / 50 ml of 10% aqu. Hydrochloric acid and stirred at 50 ° C for 10 hours. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% aqu. Sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1).
Yield: 26.09 g (89% of theory) of a colorless solid. 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-oxa-pentyl) -N- (1H , 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluortridecyl) -imide] -1,4,7,10-tetraazacyclododecane, gadolinium

10 g, 15.88 mmol) of the gadolinium complex of 10- [1- (carboxymethylcarbamoyl) -ethyl] -1,4,7,10-tetraazacyclododecane-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 (15.88 mmol) of the title compound from Example 62b are added. The mixture is stirred for 10 minutes and gives dan 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. It is stirred for 12 hours at room temperature. 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 is filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: 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 Found .: C 34.65 H 3.96 N 6.84 F 26,62 Gd 12,91

Example 63

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

In a manner analogous to that 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. II, 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 work-up 315 g (96.7%) of the above Title compound as a crude product in the form of a viscous and colorless oil. By ¹ H-NMR spectroscopic examination of the title compound thus obtained, the α to β ratio of both anomers with 4: 1 was determined. A separation of the α, β-anomers of the title compound mentioned above can be dispensed with for carrying out the subsequent reaction steps. Elemental analysis: calc .: C 49,21 H 5.68 Found .: C 49,12 H 5.78

b) 6- {1-O-α- (2,3,4,6-tetra-O-acetyl-D-mannopyranosyl) -hexanoic acid ethyl ester]

In an analogous manner, as described in the literature for the synthesis of aryl glycopyranosides [J. Conchie and GA Levvy in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol.II, 90, pp. 345-347, (1963)], the reaction of 156.2 g (400 mmol) of the title compound from Example 63a as an α, β-anomer mixture with 67 ml (400 mmol) of ethyl 6-hydroxyhexanoate and 60.8 ml (520 mmol) tin (IV) chloride in a total of 600 ml of 1,2-dichloroethane after purification by column chromatography (eluent: hexane / ethyl acetate 2: 1) to give 100.05 g (51% of theory) of the abovementioned title compound as a colorless compound and viscous oil. By ¹ H-NMR spectroscopic examination of the title compound thus obtained it was possible to show that the abovementioned 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-O-α- (2,3,4,6-tetra-O-benzyl-D-mannopyranosyl) -hexanoic acid

A stirred suspension of 141.0 g (289 mmol) of the title compound from Example 63b in 200 ml of dioxane is added 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. To increase the stirrability, the reaction mixture is treated with a further 200 ml of dioxane, and the suspension thus obtained is subsequently heated to boiling heat and treated dropwise at this temperature with a total of 372 ml (3.128 mol) of benzyl bromide 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 slowly poured for the purpose of workup in a total of 2.5 liters of ice water and the water phase is subsequently extracted completely with diethyl ether. After washing the thus obtained ether phase and then drying the same over sodium sulfate is filtered off with suction from the salt and the diethyl ether removed in vacuo. Excess benzyl bromide is then distilled off quantitatively in an oil pump vacuum at an oil bath temperature of 180 ° C from the reaction mixture. The resulting resinous-oily residue is purified on silica gel using ethyl acetate / hexane (1:10) as eluent.
Yield: 172.2 g (91.0% of theory) of the abovementioned title compound in the form of a colorless and extremely viscous oil. calc .: C 75.68 H 7,16 Found .: C 75.79 H 7.04

d) 6- [1-O-α- (2,3,4,6-tetra-O-benzyl-D-mannopyranosyl) -hexanoic acid N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) amide

100 g (134 mmol) of the acid described in Example 63c and 13.5 g (134 mmol) of triethylamine are dissolved in 1200 ml of dry tetrahydrofuran. After cooling to -15 ° C is added dropwise with stirring, a solution of 18.45 g (135 mmol) of isobutyl chloroformate in 200 ml of dry tetrahydrofuran added slowly, the internal temperature does not exceed -10 ° C. After a reaction time of 15 minutes at -15 ° C is added dropwise 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 - 20 ° C added. After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is concentrated in vacuo to dryness. 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 drying the organic phase over sodium sulfate is filtered off with suction from the salt and the ethyl acetate in vacuo. The residual oily residue is purified on silica gel using dichloromethane / hexane / 2-propanol (10: 5: 1) as eluent.
Yield: 143.8 g (86.9% of theory) Elemental analysis: calc .: C 57,38 H 4,98 N 1.13 F 26,15 Found .: C 57.30 H 5.44 N 1.01 F 26,25

e) 6- [1- O -α-D-mannopyranosyl] hexanoic acid N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide

40.0 g (32.38 mmol) of the title compound from Example 63d are dissolved in 750 ml of 2-propanol and admixed with 2.0 g of palladium catalyst (10% Pd / C). The reaction solution is hydrogenated for 12 hours at 22 ° C and 1 atmosphere of hydrogen pressure. The mixture is then filtered off from the catalyst and the filtrate is concentrated to dryness. The remaining residue is taken up in 300 ml of dimethyl sulfoxide and from the product solution thus obtained is obtained by addition of 1000 ml of diethyl ether after filtering off the precipitated solid 21.52 g (88.0% of theory) of the title compound above as colorless 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 Found .: C 36.07 H 6.08 N 1.76 F 40,66

f) Preparation of a formulation Metal complex I and 6- [1- O -α-D-mannopyranosyl] hexanoic acid N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide

To 35 ml of a solution of 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 3.17 g (4.2 mmol) of the title compound of Example 63e and filled with 0.9% aqu. Saline solution to a total of 98 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 64

a) 1-O-α-D - [(1-perfluorooctylsulfonylpiperazine-4-carbonyl) -pentyl-5] -2,3,4,6-tetra-O-benzyl-mannopyranose

In 800 ml of a mixture of tetrahydrofuran / acetonitrile (mixing ratio 7: 3) are dissolved 74.59 g (100 mmol) of the acid described in Example 64c and 10.11 g (100 mmol) of triethylamine. Then, at room temperature, dropwise with 500 ml of a tetrahydrofuran solution of 58.0 g (102.0 mmol) of 1-Perfluoroctylsulfonylpiperazin; 10.11 g (100 mmol) of triethylamine and 16.84 g (110 mmol) of 1-hydroxybenzotriazole were added. The reaction solution thus obtained is treated at -5 ° C. with a solution of 22.7 g (110 mmol) of dicyclohexylcarbodiimide, dissolved in 100 ml of tetrahydrofuran, and then stirred at -5 ° C. for a further two hours. After thawing the reaction solution is stirred at room temperature for a further 12 hours, filtered off from the precipitated Dicyclohexylharnstoff and the resulting filtrate concentrated in vacuo to dryness. 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 drying the organic phase over sodium sulfate is filtered off with suction from the salt and the ethyl acetate in vacuo. The residual oily residue is purified on silica gel using dichloromethane / acetone / 2-propanol (16: 2: 1) as eluent
Yield: 113.01 g (79.8% of theory) of a colorless and viscous oil. 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-O-α-D - [(1-perfluorooctylsulfonyl-piperazine-4-carbonyl) -pentyl-5] -mannopyranose

50 g (35.30 mmol) of the title compound from Example 64a 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 charcoal) are added. It is hydrogenated for 12 hours at room temperature. It is filtered off from the catalyst and the filtrate in vacuo evaporated to dryness. The residue is dissolved in 200 ml of methanol and the reaction product by precipitation with a total of 800 ml of diethyl ether precipitated. After sucking off the solid thus obtained, 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 Found .: 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-perfluorooctylsulfonyl-piperazine-4-carbonyl) -pentyl-5] -mannopyranose

To 47 ml of a solution of metal complex 11 (250 mmol / L) dissolved in 0.45% aqu. Sodium chloride solution) 9.92 g (11.75 mmol) of the title compound from Example 64b and heated for 10 Minutes in the microwave. The solution is cooled to room temperature, through a 0.2 μm filter filtered and the filtrate bottled in vials. A solution prepared in this way can directly for biological experiments are used. (The concentration is 250 mmol Gd / L).

Example 65

a) 2-acetamido-2-deoxy-1,3,4,6- (tetra-O-benzyl) -α, β-D-glucopyranose

To a stirred suspension of 20.16 g (700 mmol, 80% in mineral oil) of sodium hydride in 150 ml of dimethyl sulfoxide is added at room temperature, a total of 24.0 g (108.5 mmol) of 2-acetamido-2-deoxy-α, β-D Glucopyranose, dissolved in 500 ml of absolute dimethyl sulfoxide, added dropwise. Then allowed to stir for 120 minutes at room temperature and then added dropwise 159.5 g (1.26 mol) of benzyl chloride. The reaction solution thus obtained is subsequently stirred for a further 12 hours at room temperature. For workup, the reaction solution is poured slowly into 1.5 liters of ice water and then extracted exhaustively with diethyl ether. The combined diethyl ether phases are subsequently washed twice with 600 ml of saturated sodium bicarbonate solution and twice with 800 ml of water each time. After drying the organic phase over sodium sulfate is filtered off with suction from the salt and the solvent removed in vacuo. The remaining oily residue is purified on silica gel using ethyl acetate / hexane (1: 5) as eluent.
Yield: 48.68 g (73.6% of theory) of the abovementioned title compound in the form of a viscous and colorless oil. calc .: C 70.92 H 6,45 N 6.89 Found .: C 71.43 H 6,44 N 7.02

b) 1-O-Benzyl-3,4,6-tri-O-benzyl-2-amino-2-deoxy-α, β-D-glucopyranose

30.0 g (49.2 mmol) of the title compound from Example 65a are suspended in a mixture of 750 ml of methanol and 215 ml of water and treated dropwise at room temperature with a total of 440 ml (49.2 mmol) of a 0.112 molar aqueous perchloric acid solution. After completion of the addition, the reaction solution is stirred for 10 minutes at room temperature and the thus obtained, now homogeneous, reaction solution is subsequently concentrated to dryness in vacuo. By adding the remaining oily residue with a mixture of equal parts of hexane and dichloromethane, this is crystallized. 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 title compound mentioned above 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 Found .: C 63,43 H 6,04 N 2.02 Cl 5.71

c) 1,3,4,6-Tetra-O-benzyl-2-deoxy-2- [acetyl- (2-amino-N-ethyl-N-perfluorooctylsulfonyl) -amino] -1-α, β-D- glucopyranose

In 350 ml of dry tetrahydrofuran are dissolved 20.8 g (35.6 mmol) of 2- [N-ethyl-N-perfluorooctylsulfonyl) aminoacetic acid and 3.60 g (35.6 mmol) of triethylamine. After cooling the reaction solution to -15 ° C to -20 ° C is added dropwise at this temperature with stirring, a solution of 4.92 g (35.6 mmol) of isobutyl chloroformate in 75 ml of dry tetrahydrofuran slowly adding the dropping speed to choose is that an internal temperature of -10 ° C is not exceeded. After a reaction time of 15 minutes at -15 ° C is then added dropwise 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 Tetrahydrofuran is 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 concentrated to dryness in vacuo, the residue remaining is taken up in 250 ml of ethyl acetate and washed twice with 100 ml each time After the organic phase has been dried over sodium sulphate, 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 / hexane (1: 5) as eluent ,
Yield: 33.3 g (84.6% of theory) of the abovementioned title compound as a colorless and strongly viscous oil. calc .: C 49.92 H 3.92 N 2.53 F 29,18 S 2,90 Found .: 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 65c are dissolved in 250 ml of 2-propanol and admixed with 1.5 g of palladium catalyst (10% Pd / C). The reaction solution is hydrogenated for 12 hours at 22 ° C and 1 atmosphere of hydrogen pressure. The mixture is then filtered off from the catalyst and the filtrate is concentrated to dryness. The remaining residue is taken up in 300 ml of dimethyl sulfoxide and from the product solution thus obtained is obtained by addition of 750 ml of a mixture of equal parts of diethyl ether and ethyl acetate after filtering off the precipitated solid 12.65 g (93.8% of theory) above title compound as a colorless and crystalline powder. The abovementioned title compound is present as an α / β anomer mixture, the ratio with respect to the two possible anomers being determined to be about 1: 1.2 by ¹ H-NMR spectroscopic investigations. Thus, the title compound is an approximately equally distributed α / β anomeric 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 Found .: C 29.09 H 2.56 N 3.84 F 43.36 S 4,42

e) Preparation of a formulation 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) is added a solution of 4.90 g (6 , 57 mmol) of the title compound from Example 3d, dissolved in 200 ml of ethanol, and stirred for 2 hours at 50 ° C. The solution is concentrated to dryness in vacuo and the residue is filled up with water to a total of 153 ml. The mixture is stirred for 10 minutes at 40 ° C and filtered through a 0.2 micron filter. The filtrate is bottled in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 66

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 63a, 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 work-up and recrystallization from 95% aqueous Ethanol 190.6 g (88.0%) of the title compound mentioned above as a colorless and crystalline compound. By ¹ H NMR spectroscopic Examination of the title compound thus obtained allowed the α to β ratio of both possible anomers to be determined to be ≥98: 2. Thus, the title compound is the exclusively α-configured anomer.
Melting point: 110.5 ° C Elemental analysis: calc .: C 49,21 H 5.68 Found .: C 49,24 H 5.68

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

In an analogous manner, as described in the synthesis of the title compound of Example 63b, the reaction of 130.0 g (332.8 mmol) of the title compound of Example 4a) with 55.8 ml (332.8 mmol) of ethyl 6-hydroxy-hexanoate 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) of 101.85 g (62.4% of theory) of the above mentioned title compound as a colorless and viscous oil. According to ¹ H NMR spectroscopic examination of the title compound, the size of the coupling constants of J _1.2 = 8.8 Hz clearly indicated the presence of the β configuration at the anomeric center, which is also the only configuration available at the anomeric center. Thus, the title compound mentioned above could be represented only in the form of the β-configured anomer. Elemental analysis: calc .: C 52,94 H 6,77 Found .: 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 66b in 150 ml of dioxane is added at room temperature and with simultaneous vigorous stirring in portions with a total of 169.14 g (3.02 mol) of finely powdered potassium hydroxide powder. To increase the stirrability, the reaction mixture is admixed with a further 150 ml of dioxane, and the resulting suspension is subsequently heated to boiling heat and treated dropwise at this temperature with a total of 264 ml (2.218 mol) of benzyl bromide 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 slowly poured for the purpose of work-up in a total of 2.0 liters of ice water and the water phase is subsequently extracted completely with diethyl ether. After washing the ether phase thus obtained and then drying the organic phase over sodium sulfate is filtered off with suction from the salt and the diethyl ether removed in vacuo. Excess benzyl bromide is then distilled off quantitatively in an oil pump vacuum at an oil bath temperature of 180 ° C from the reaction mixture. The resulting residual oily residue is purified on silica gel using ethyl acetate / hexane (1:10) as eluent.
Yield: 128.8 g (84.3% of theory) of the abovementioned title compound in the form of a colorless and extremely viscous oil. calc .: C 75.68 H 7,16 Found .: C 75.66 H 7,23

d) 2,3,4,6-tetra-O-benzyl-1-O-β-D- [6-hexanoic acid N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) amide] -glucopyranose

In 825 ml of dry tetrahydrofuran are dissolved 68.5 g (91.79 mmol) of the acid described in Example 66c and 9.25 g (91.79 mmol) of triethylamine. After cooling the reaction solution to -15 ° C to -20 ° C is added dropwise at this temperature with stirring, a solution of 12.64 g (92.5 mmol) of isobutyl chloroformate in 150 ml of dry tetrahydrofuran added slowly, to choose the dropping speed so 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-aminoethoxy) -decane and 9.25 g ( 91.79 mmol) of triethylamine, as a solution in 200 ml of dry tetrahydrofuran at -20 ° C slowly added. After a reaction time of one hour at -15 ° C and two hours At room temperature, the reaction solution is concentrated in vacuo to dryness. 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 drying the organic phase over sodium sulfate is filtered off with suction from the salt and the ethyl acetate in vacuo. The residual oily residue is purified on silica gel using dichloromethane / hexane / 2-propanol (10: 5: 1) as eluent.
Yield: 104.7 g (92.4% of theory) of the 0.g. Title compound as a colorless and highly viscous oil Elemental Analysis: calc .: C 57,38 H 4,98 N 1.13 F 26,15 Found .: C 57,27 H 5.09 N 1.11 F 26.08

e) 1-O-β-D- [6-hexanoic acid N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide] -glucopyranose

40.0 g (32.38 mmol) of the title compound from Example 66d are dissolved in 750 ml of 2-propanol and admixed with 2.0 g of palladium catalyst (10% Pd / C). The reaction solution is hydrogenated for 12 hours at 22 ° C and 1 atmosphere of hydrogen pressure. The mixture is then filtered off from the catalyst and the filtrate is concentrated to dryness. The remaining residue is taken up in 300 ml of dimethyl sulfoxide and 22.05 g (90.2% of theory) of the title compound are obtained as colorless and crystalline powder from the product solution thus obtained by addition of a total of 1000 ml of diethyl ether and subsequent suction of the precipitated solid with a decomposition melting point of 122-124 ° C. Elemental Analysis: calc .: C 36.01 H 5.92 N 1.75 F 40.34 Found .: 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-dioxo-1,5-diyl] - 1,4,7,10-tetraazacyclododecane, Gd complex} -10- [2- (N-ethyl-N-perfluorooctylsulfonyl) -amino] -acetyl-1,4,7,10-tetraazacyclododecane) and 1-O- β-D- [6-hexanoic acid-N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide] -glucopyranose

To 37 ml of a solution of 1,4,7-tris {1,4,7-tris (N-carboxylatomethyl) -10- (N-1-methyl-3-aza-2,5-dioxo-pentane-1, 5-diyl] -1,4,7,10-tetraazacyclododecane, Gd complex} -10- [2- (N-ethyl-N-perfluorooctylsulfonyl) -amino] -acetyl-1,4,7,10-tetraazacyclododecane ( 300 mmol / L) dissolved in 0.45% aqueous saline solution (pH 7.4, 0.25 mg / L CaNa ₃ DTPA) are added 20.29 g (25.9 mmol) of the title compound from Example 66e and filled with Saline solution to a total of 111 ml, heated 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 2 μm filter and fills the filtrate in vials A solution prepared in this way can be used directly for biological experiments (the concentration is 100 mmol Gd / L).

Example 67

a) 1-O- (1H, 1H, 2H, 2H-perfluorodecyl) - (2,3,4,6-tetra-O-acetyl) -α-D-mannopyranose

The reaction of 50 g (128.09 mmol) of the title compound of Example 63a, 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 1H, 1H, 2H, 2H-perfluorodecane in 150 ml of 1,2-dichloroethane and a total of 19.47 g (166.53 mmol) tin-IV chloride, in analogy as for the syntheses of the title compounds of Examples 1b) and 4b), after working up and purification by column chromatography (eluent: hexane / ethyl acetate, 2: 1) to give 74.2 g (63.4% of theory) of the abovementioned title compound in the form of a viscous and colorless oil. According to ¹ H-NMR-spectroscopic examination of the title compound, the size of the coupling constants of J _1.2 = 1.3 Hz clearly indicated the presence of the α-configuration at the anomeric center, which is the exclusive configuration at the anomeric center that therefore the title compound mentioned above could be represented only in the form of the pure α-configured anomer. Elemental analysis: calc .: C 44.65 H 2.53 F 35,32 Found .: C 44,77 H 2.61 F 35.09

b) 1-O- (1H, 1H, 2H, 2H-perfluorodecyl) -α-D-mannopyranose

25 g (27.33 mmol) of the title compound from Example 67a are suspended in 400 ml of absolute methanol and treated at 5 ° C with a catalytic amount of sodium. After a reaction time of 3 h at room temperature, the thin-layer chromatographic control (eluent: chloroform / methanol 9: 1) of the course of the reaction already indicates quantitative conversion. For the purpose of workup, the now clear reaction solution is neutralized by addition of Amberlite IR 120 (H ⁺ form) cation exchange resin, sucked from the exchanger and the methanolic filtrate thus obtained in vacuo to dryness. The resulting crystalline residue is purified by recrystallizing twice from ethanol. According to ¹ H-NMR spectroscopic examination of the title compound, the size of the coupling constants of J _1.2 = 1.0 Hz clearly indicated the presence of the α-configuration at the anomeric center. The present α configuration is the configuration exclusively at the anomeric center, ie the amount of possibly formed β-configured anomer of the title compound is below the ¹ H NMR spectroscopic detection limit. The above-mentioned title compound was thus represented only in the form of the pure α-configured isomer.
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 Found .: C 30.57 H 2,48 F 51.65

c) Preparation of a formulation from Metal complex II and 1-O- (1H, 1H, 2H, 2H-perfluorodecyl) -α-D-mannopyranose

To 50 ml of a solution of the metal complex 11 (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 of Example 67b, dissolved in 200 ml of ethanol and stirred for 2 hours at 50 ° C. The solution is concentrated to dryness in vacuo and the residue is washed with dist. Water to a total of 75 ml. The mixture is stirred for 10 minutes at 40 ° C and filtered through a 0.2 micron filter. The filtrate is bottled in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 68

a) 1-O- (1H, 1H, 2H, 2H-perfluorododecyl) -2,3,4,6-tetra-O-acetyl-α-D-mannopyranose

The reaction of 35 g (89.66 mmol) of the title compound from Example 63a, 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 syntheses of the title compounds from Examples 1b), 4b) and 5b), after working up and purification by column chromatography (eluent: hexane / ethyl acetate = 2: 1) to give 62.49 g (68.7% of theory) of the title compound mentioned above in the form of a viscous and colorless oil. According to ¹ H-NMR-spectroscopic examination of the title compound, the size of the coupling constants of J _1,2 = 1.4 Hz clearly indicated the presence of the α-configuration at the anomeric center, which is the exclusive configuration at the anomeric center that therefore the title compound mentioned above could be represented only in the form of the pure α-configured anomer. Elemental analysis: calc .: C 42,62 H 2.28 F 39,32 Found .: C 42.55 H 2.38 F 39.40

b) 1-O- (1H, 1H, 2H, 2H-perfluorododecyl) -α-D-mannopyranose

25 g (24.64 mmol) of the title compound from Example 68a are suspended in 400 ml of absolute methanol and treated at 5 ° C with a catalytic amount of sodium. After a reaction time of 3 h at room temperature, the thin-layer chromatographic control (eluent: chloroform / methanol = 9: 1) of the course of the reaction already indicates quantitative conversion. For the purpose of workup, the now clear reaction solution is neutralized by addition of Amberlite IR 120 (H ⁺ form) cation exchange resin, sucked from the exchanger and the methanolic filtrate thus obtained in vacuo to dryness. The resulting crystalline residue is purified by recrystallization twice from a mixture of 2-propanol / ethanol (1: 1). According to ¹ H NMR spectroscopic examination of the title compound, the size of the coupling constants of J _1.2 = 0.9 Hz clearly indicated the presence of the α configuration at the anomeric center. The present α configuration is the configuration exclusively at the anomeric center, ie the amount of possibly formed β-configured anomer of the title compound is below the ¹ H NMR spectroscopic detection limit. Accordingly, the above-mentioned title compound was represented only 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 Found .: C 29,70 H 2.28 F 54,83

c) Preparation of a formulation from Metal complex VI and 1-O- (1H, 1H, 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, gives 1.70 g (2.34 mmol) of the title compound from Example 75b and heated for 10 Minutes in the microwave. The solution is cooled to room temperature, through a 0.2 μm filter filtered and the filtrate bottled in vials. A solution prepared in this way can directly for biological experiments are used. (The concentration is 180 mmol Gd / L)

Example 69

a) 2,3,4,6-tetra-O-acety) -1-O-α-D- [3,6,9-trioxa- (C ₁₂ -C ₁₉ -heptadecafluoro) nonadecyl] -mannopyranose

The reaction of 20 g (51.23 mmol) of the title compound from Example 63a, which is used as a 4: 1 mixture with respect to the α, β-anomers, with a solution of 30.54 g (51.23 mmol) of 1-hydroxy -tris- (1H, 1H, 2H, 2H-O) -1H, 1H, 2H, 2H-perfluorodecane in 100 ml of 1,2-dichloroethane and a total of 5.98 g (51.23 mmol) of stannic chloride; in analogy as described for the syntheses of the title compounds from Examples 1b), 4b) and 5b), after work-up and purification by column chromatography (eluent: hexane / ethyl acetate = 1: 1) leads to the formation of 34.22 g (72.1%). d. Th.) of the title compound mentioned above in the form of a viscous and colorless oil. According to ¹ H-NMR spectroscopic examination of the title compound, the size of the coupling constants of J _1.2 = 1.1 Hz clearly indicated the presence of the α configuration at the anomeric center, which is also the exclusive configuration at the anomeric center. so that therefore the title compound mentioned above could be represented only in the form of the pure α-configured anomer. Elemental analysis: calc .: C 38,89 H 3.81 F 34,86 Found .: C 39.02 H 3,77 F 34,90

b) 1-O-α-D- [3,6,9-trioxa- (C ₁₂ -C ₁₉ -heptadecafluoro) nonadecyl] -mannopyranose

20 g (21.58 mmol) of the title compound from Example 69a are suspended in 350 ml of absolute methanol and treated at 5 ° C with a catalytic amount of sodium. After a reaction time of 3 h at room temperature, the thin-layer chromatographic control (eluent: chloroform / methanol = 6: 1) of the course of the reaction already indicates quantitative conversion. For workup, the now clear reaction solution is neutralized by addition of Amberlite IR 120 (H ⁺ form) cation exchange resin, sucked from the exchanger and the methanolic filtrate thus obtained in vacuo to dryness. He crystalline residue is purified by recrystallization twice from a mixture of ethyl acetate / 2-propanol / ethanol (1: 0.5: 1). According to ¹ H NMR spectroscopic examination of the title compound, the size of the coupling constants of J _1.2 = 1.0 Hz clearly indicated the presence of the α configuration at the anomeric center. The present α configuration is the configuration exclusively at the anomeric center, ie the amount of possibly formed β-configured anomer of the title compound is below the ¹ H NMR spectroscopic detection limit. Accordingly, the above-mentioned title compound was represented only 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 Found .: C 34.72 H 3.66 F 42.67

c) Preparation of a formulation from the title compound of Example 61 and 1-O-α-D- [3,6,9-trioxa- (C ₁₂ -C ₁₉ -heptadecafluoro) nonadecyl] -mannopyranose

To 38 ml of a solution of the title compound of Example 61 (300 mmol / L) dissolved in 0.45% aqu. Brine (pH 7.4, 0.25 mg / L CaNa ₃ DTPA), 3.71 g (4.89 mmol) of the title compound of Example 69b and leads with 0.9% aqu. Saline solution to a total of 114 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 70

a) 2,3,4,6-tetra-O-acetyl-1-α-D- [3-thiopropionic acid N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) amide] -mannopyranose

In 500 ml of dry tetrahydrofuran, 25.0 g (57.28 mmol); [Representation according to:
Ponpipom, Mitree M .; Bugianesi, Robert L .; Robbins, James C .; Doebber, TW; Shen, TY; J. Med .; 24; 12; 1981; 1388-1395] 3- (tetra-O-acetyl-α-D-mannopyranosylmercapto) -propionic acid and 5.77 g (57.28 mmol) of triethylamine were dissolved. After cooling the reaction solution to -15 ° C to -20 ° C is added dropwise at this temperature with stirring, a solution of 7.82 g (57.28 mmol) of isobutyl chloroformate in 100 ml of dry tetrahydrofuran added slowly, selecting the dropping speed so is that an internal temperature of -10 ° C is not exceeded. After a reaction time of 15 minutes at -15 ° C is then added dropwise a solution of 29.05 g (57.28 mmol) of 1H, 1H, 2H, 2H-heptadecafluoro-1- (2-aminoethyoxy) -decane and 5, 77g (57.28 mmol) of triethylamine, as a solution in 200 ml of dry tetrahydrofuran at -20 ° C slowly added. After a reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution is concentrated in vacuo to dryness. 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 is filtered off with suction from the salt and the ethyl acetate in vacuo. The residual oily residue is purified on silica gel using dichloromethane / hexane / 2-propanol (8: 5: 1) as eluent.
Yield: 44.90 g (84.7% of theory) of the abovementioned title compound as a colorless and strongly viscous oil. Elemental analysis: calc .: C 37.63 H 3,48 N 1.51 S 3,46 F 34,89 Found .: C 37,77 H 3.37 N 1.61 S 3,57 F 35,21

b) 1-α-D- [3-thiopropionic acid N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide] -mannopyranose

30 g (32.41 mmol) of the title compound from Example 70a are suspended in 400 ml of absolute methanol and treated at 5 ° C with a catalytic amount of sodium. After a reaction time of 3 h at room temperature, the thin-layer chromatographic control (eluent: chloroform / methanol = 9: 1) of the course of the reaction already indicates quantitative conversion. For workup, the now clear reaction solution is neutralized by addition of Amberlite IR 120 (H ⁺ form) cation exchange resin, sucked from the exchanger and the methanolic filtrate thus obtained in vacuo to dryness. The resulting crystalline residue is purified by recrystallization from a mixture of ethyl acetate / methanol (0.5: 1). cleaned. According to ¹ H NMR spectroscopic examination of the title compound, the size of the coupling constants of J _1.2 = 1.1 Hz clearly indicated the presence of the α configuration at the anomeric center. The present α configuration is the configuration exclusively at the anomeric center, ie the amount of possibly formed β-configured anomer of the title compound is below the ¹ H NMR spectroscopic detection limit. Accordingly, the above-mentioned title compound was represented only 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 Found .: C 33,21 H 3,26 N 1,96 S 4.08 F 42,77

c) Preparation of a formulation from the title compound of Example 59 and 1-α-D- [3-thiopropionic acid N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) amide] -mannopyranose

To 47 ml of a solution of the title compound of Example 59 (330 mmol / L), dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA), is added a solution of 27.41 g (36.19 mmol) of the title compound from Example 70b, dissolved in 200 ml of ethanol, and stirred for 2 hours at 50 ° C. The solution is concentrated to dryness in vacuo and the residue is washed with dist. Water to a total of 155 ml. The mixture is stirred for 10 minutes at 40 ° C and filtered through a 0.2 micron filter. The filtrate is bottled in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 71

a) 2,3,4,6-tetra-O-acetyl-1-β-D- [3,6,9-trioxa- (C ₁₂ -C ₁₉ -heptadecafluoro) nonadecyl] -glucopyranosyluronic acid

To a stirred solution of 20.2 g (50.85 mmol) of methyl (1-bromo-2,3,4-tri-O-acety-α-D-glucopyranoside) uronate [Preparation 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- (C ₁₂ -C ₁₉ -heptadecafluoro) nonadecan-1-ol are dissolved in 250 ml of anhydrous acetonitrile and stirred at room temperature 13.0 g of freshly precipitated silver oxide 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 resulting filtrate is removed in vacuo to dryness. The remaining residue is purified by column chromatography (eluent: hexane / ethyl acetate = 3: 1).
Yield: 22.99 g (53.3% of theory) of the abovementioned title compound as a colorless, highly viscous oil. calc .: C 41.05 H 3.92 F 38.06 Found .: C 41,20 H 3.76 F 38,22

b) 1-O-β-D- [3,6,9-trioxa- (C ₁₂ -C ₁₉ -heptadecafluoro) nonadecyl] -glucopyranosyluronic acid

10.0 g (11.78 mmol) of the title compound from Example 71a are suspended in 200 ml of a mixture consisting of methanol 0.5 molar sodium hydroxide solution in the ratio of 2: 1 with stirring at Taumtemperatur. After a reaction time of 12 h at room temperature, the now clear reaction mixture for workup by neutralization with Amberlite IR 120 (H ^± form) cation exchange resin is neutralized, aspirated from the exchanger and the methanolic-aqueous filtrate thus obtained in vacuo to dryness. The resulting crystalline residue is purified by recrystallization from a mixture of ethyl acetate / methanol (0.25: 1). According to ¹ H NMR spectroscopic examination of the title compound, the size of the coupling constants of J _1.2 = 9.2 Hz clearly indicated the presence of the β configuration at the anomeric center. The present β configuration is the configuration exclusively at the anomeric center, ie the amount of possibly formed β-configured anomer of the title compound is below the ¹ H NMR spectroscopic detection limit. Accordingly, the above-mentioned title compound was represented only 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 Found .: C 34,38 H 3,26 F 41.90

c) Preparation of a formulation of metal complex I and 1-O-β-D- [3,6,9-trioxa- (C ₁₂ -C ₁₉ -heptadecafluoro) nonadecyl] -glucopyranosyluronic acid

To 38 ml of a solution of the metal complex I (280 mmol / L) dissolved in 0.45% aqu. Brine (pH 7.4, 0.25 mg / L CaNa ₃ DTPA), 19.18 g (24.83 mmol) of the title compound of Example 71b and filled with 0.9% aqu. Saline to a total of 53.2 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 200 mmol Gd / L).

Example 72

a) 6- (2-oxa-1H, 1H, 3H, 3H, 4H, 4H-perfluorodecyl) -O ¹ , O ² , O ³ , O ⁴ -diisopropylidene-α-D-galactopyranose

To a stirred suspension of 2.01 g (70.0 mmol, 80% in mineral oil) of sodium hydride in 25 ml of dimethylformamide is added at room temperature a total of 12.15 g (46.66 mmol) of O ¹ , O ² , O ³ , O ⁴ -diisopropylidene-α-galactopyranose [Preparation according to: Levene; Meyer; J. Biol .; 64; 1925; 473 and McCreath; Smith; J. Chem .; 1939; 387, 389 and Freudenberg; Hixon; Ber .; 56; 1923; 2119, 2122] dissolved in 200 ml of absolute dimethylformamide, added dropwise. Then left to stir for 120 minutes at room temperature and then added dropwise 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 slowly added. The reaction solution thus obtained is subsequently stirred for a further 12 hours at room temperature. For workup, the reaction solution is poured slowly into 1 liter of ice water and then extracted exhaustively with diethyl ether. The combined organic phases are subsequently washed twice with 200 ml of saturated sodium bicarbonate solution and twice with 200 ml of water each time. After drying the organic phase over sodium sulfate is filtered off with suction from the salt and the solvent removed in vacuo. The remaining oily residue is purified on silica gel using ethyl acetate / hexane (1:10) as eluent.
Yield: 29.8 g (79.3% of theory) of the abovementioned title compound in the form of a viscous, colorless oil. calc .: C 35,75 H 2,87 F 49.47 Found .: C 35,64 H 2,98 F 49.54

b) 6- (2-oxa-1H, 1H, 3H, 3H, 4H, 4H-perfluorodecyl) -α-D-galactopyranose

20 g (24.8 mmol) of the title compound from Example 72a are admixed with 300 ml of a 1% strength aqueous sulfuric acid solution and stirred at 80 ° C. for 3 hours. After cooling to room temperature is neutralized by addition of aqueous barium hydroxide solution and filtered off from the precipitated barium sulfate and the resulting clear aqueous product solution is freeze-dried. The presence of both possible configurations at the anomeric center could be clearly demonstrated by ¹ H NMR spectroscopic examination of the title compound, the present α / β configuration ratio being 1: 1.4 (α: β) according to 1H NMR spectroscopic analysis. at the anomerie center. Accordingly, the abovementioned title compound was 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 0.g. Title compound as colorless lyophilisate Elemental analysis (based on anhydrous substance): calc .: C 35,75 H 2,87 F 49.47 Found .: C 35,64 H 2,98 F 49.54

c) Preparation of a formulation from of the title compound of Example 60 and 6- (2-oxa-1H, 1H, 3H, 3H, 4H, 4H-perforodecyl) -α-D-galactopyranose

To 43 ml of a solution of the title compound of Example 60 (250 mmol / L) dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA), a solution of 1.68 g (2.69 mmol) of the title compound of Example 79b, dissolved in 200 ml of ethanol, and stirred for 2 hours at 50 ° C. The solution is concentrated to dryness in vacuo and the residue is washed with dist. Water to a total of 107.5 ml. The mixture is stirred for 10 minutes at 40 ° C and filtered through a 0.2 micron filter. The filtrate is bottled in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 73

a) 1-0-α-D - [(1-perfluorooctylsulfonylpiperazine-4-carbonyl) -methyl] -mannopyranose

30 g (52.8 mmol) of 1-perfluorooctylsulfonylpiperazine (preparation described in DE 196 03 033 ) and 31.73 g (53 mmol) of 2,3,4,6-tetra-O-benzyl-α-D-carboxymethyl-mannopyranose (preparation described in U.S.P. DE 197 28 954 ) are dissolved in 300 ml of tetrahydrofuran. At 0 ° C., 24.77 g (100 mmol) of EEDQ (= 1,2-dihydro-2-ethoxyquinoline-1-carboxylic acid ethyl ester) are added and the mixture is stirred at 0 ° C. for 3 hours, then at room temperature for 6 hours. The solution is evaporated to dryness in vacuo and the residue is purified by flash chromatography on silica gel (eluent: 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. It is filtered from the hydrogenation catalyst 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. calc .: C 30,47 H 2,68 F 40,96 N 3,55 S 4.07 Found .: C 30.61 H 2,75 F 41,10 N 3.46 S 4,12

b) Preparation of a formulation from Metal complex I and 1-0-α-D - [(1-perfluorooctylsulfonylpiperazine-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 of Example 73a and filled with 0.9% aqu. Saline solution to a total of 55 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 200 mmol Gd / L).

Example 74

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 5 N aqu. Sodium hydroxide solution added. It is evaporated to dryness and the residue is dried in a vacuum oven (8 hours 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 Found .: 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 of Example 74a and leads with 0.9% aqu. Saline solution to a total of 90 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in 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) are added 1.00 g (1.84 mmol) of the title compound from Example 74a and filled with 0.9% aqu. Saline solution to a total of 90 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in 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 1 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), are added 0.54 g (1.0 mmol) of the title compound of Example 74a and filled with 0.9% aqu. Saline solution to a total of 90 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in 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-Perfluorooctylsulfonyl-4- (3,6,9,12,15-pentaoxahexadecanoyl) -piperazine

20 g (35.2 mmol) of perfluorooctylsulfonylpiperazine (see Example 73a) are dissolved in 300 ml of dichloromethane and 5.06 g (50 mmol) of triethylamine are added. It is cooled to 0 ° C and added dropwise within 20 minutes 14.24 g (50 mmol) of 3,6,9,12,15-Pentaoxahexansäurechlorid and stirred for 3 hours at 0 ° C. It is 400 ml of 5% aqu. Hydrochloric acid and stirred well. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent = dichloromethane / methanol: 15: 1).
Yield: 26.44 (92% of theory) of a waxy solid. calc .: C 33,83 H 3,58 N 3.43 F 39.55 S 3,93 Found .: 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 of Example 75a and leads with 0.9% aqu. Saline solution to a total of 66 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 200 mmol Gd / L).

Example 76

a) 1H, 1H, 2H, 2H-perfluorodecyl-p-toluenesulfonic acid ester

20 g (43.1 mmol) of 1H, 1H, 2H, 2H-perfluorodecanol are dissolved in 200 ml of pyridine and, at 0 ° C., 9.53 g (50 mmol) of p-toluenesulfonyl chloride are added in portions. It 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 Found .: 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 76a, 35.74 g (150 mmol) of 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. It is stirred for 10 hours at room temperature. It is filtered from the solid and the filtrate concentrated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: dichloromethane / methanol = 15: 1).
Yield: 5.45 g (21% of theory) of a colorless, viscous oil. calc .: C 35,10 H 3.68 F 47,19 Found .: C 35,22 H 3,77 F 47,10

c) Preparation of a formulation from the title compound of Example 62 and C ₁₈ -C ₂₅ -heptadeca-fluoro-3,6,9,12,15-pentaoxa-pentacosan-1-ol

To 53 ml of a solution of the title compound of Example 62 (310 mmol / L) dissolved in 0.45 % aqu. Sodium chloride solution), Are added 44.98 g (65.72 mmol) of the title compound from Example 76b and warmed up for 10 minutes in the microwave. The solution is cooled to room temperature, through a 0.2 μm filter filtered and the filtrate bottled in vials. A solution prepared in this way can directly for biological experiments are used. (The concentration is 310 mmol Gd / L).

Example 77

a) N, N-bis (8-hydroxy-3,6, dioxa-octyl) perfluorooctylsulfonamide

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. Are added 41.46 g (300 mmol) of potassium carbonate and 1 g (6 mmol) of potassium iodide and boiled for 10 hours under reflux. 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. It is stirred for 2 hours at room temperature. It is adjusted to pH 7 with sodium hydroxide solution and the solution concentrated in vacuo. The residue is chromatographed on silica gel (eluent: dichloromethane / methanol = 10: 1).
Yield: 11.38 g (51% of theory) of a colorless, viscous oil. calc .: C 31.46 H 3,43 N 1.83 F 42.30 S 4,20 Found .: 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) perfluorooctylsulfonic acid amide

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 of Example 77a and filled with 0.9% aqu. Saline solution to a total of 104 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 78

a) N, N-bis (t-butyloxycarbonylmethyl) perfluorooctylsulfonamide

20 g (38.97 mmol) of perfluorooctylsulfonamide and 20.73 g (150 mol) of potassium carbonate are suspended in 200 ml of acetone and 17.56 g (90 mmol) of tert-butyl bromoacetate are added. It 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 (eluent: n-hexane / ethyl acetate = 10: 1).
Yield: 23.53 g (83% of th.) Of a colorless, waxy solid. calc .: C 33.02 H 3.05 F 44.40 N 1,93 S 4,41 Found .: C 33,19 H 3,11 F 44,30 N 1.99 S 4:32

b) N, N-bis (carboxymethyl) perfluorooctyl sulfonic acid amide, disodium salt

23 g (31.62 mmol) of the title compound from Example 78a are dissolved in 300 ml of trifluoroacetic acid and stirred at room temperature for 5 hours. It is evaporated to dryness in vacuo and the residue is recrystallized from acetone. The crystals are dried in vacuo (at 50 ° C / hours).
Yield: 17.7 g (91% of theory) of a colorless, crystalline powder

17 g (27.63 mmol) of the di-acid 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 for 20 minutes at room temperature 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 Found .: 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) perfluorooctyl sulfonic acid amide, disodium salt

To 41 ml of a solution of the metal complex 11 (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 of Example 78b and filled with 0.9% aqu. Saline solution to a total of 52 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 200 mmol Gd / L).

Example 79

a) 1H, 1H, 2H, 2H-perfluorododecyl-sulfuric acid monoester, sodium salt

10 g (17.73 mmol) of 1H, 1H, 2H, 2H-perfluorododecanol 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 for one hour at 0 ° C and then evaporated to dryness in vacuo. The residue is dissolved in 300 ml of ethanol and washed with 17.8 ml of 1N aqu. Sodium hydroxide added. The solution is evaporated to dryness and the residue dried in vacuo (60 ° C / 2 h).
Yield: 11.81 g (quantitative) Elemental analysis: calc .: C, 21.64 H 0.61 F 59.89 Well 3.45 S 4,81 Found .: C 21.70 H 0.72 F 60,00 Well 3,57 S 4,92

b) Preparation of a formulation from Metal complex VI and 1H, 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 and heated for 10 Minutes in the microwave. The solution is cooled to room temperature, through a 0.2 μm filter filtered and the filtrate bottled in vials. Such a solution can be made directly for biological experiments are used. (The concentration is 290 mmol Gd / L).

Example 80

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 washed with 16.1 ml of 1N aqu. Sodium hydroxide added. The solution is evaporated to dryness and the residue 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 Well 3,57 Found .: C 26,22 H 1.00 F 62.05 Na 3.66

b) Preparation of a formulation from the title compound of Example 59 and 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluoropentadecanoic acid, sodium salt

To 45 ml of a solution of the title compound of Example 59 (270 mmol / L) dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA), a solution of 3.36 g (5.21 mmol) of the title compound of Example 80a, dissolved in 200 ml of ethanol, and stirred for 2 hours at 50 ° C. The solution is concentrated to dryness in vacuo and the residue is washed with dist. Water to a total of 122 ml. The mixture is stirred for 10 minutes at 40 ° C and filtered through a 0.2 micron filter. The filtrate is bottled in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 81

a) Ethylenediamine-N, N-tetraacetic acid N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -monoamide

10.14 g (20 mmol) of 1H, 1H, 2H, 2H, 4H, 4H, 5H are added in portions at 50 ° C. to 30 g (117.1 mmol) of EDTA-bisanhydride suspended in 200 ml of dimethylformamide and 50 ml of pyridine. 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 phase: 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 Found .: C 33.51 H 3.69 N 5.44 F 41,24

b) ethylenediamine-N, N-tetraacetic acid N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -monoamide, Calcium salt, sodium salt

9.0 g (11.46 mmol) of the title substance from Example 81a are suspended in 300 ml of water and 11.4 ml of 1-N-aqu. Sodium hydroxide solution added. Subsequently, 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 Found .: C 31.40 H 3.09 N 5,10 F 38.07 Na 2.81 Ca 4,82

c) Preparation of a formulation from Metal complex I and ethylenediamine-N, N-tetraacetic acid N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -monoamide, calcium salt, sodium salt

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 of Example 81b and filled with 0.9% aqu. Saline solution to a total of 121 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 82

a) 1H, 1H, 2H, 2H-perfluorodecyl- (2,2-dimethyl-5-hydroxy-1,3-dioxepan-6-yl) ether

30 g (64.64 mmol) of 1H, 1H, 2H, 2H-perfluorodecanol are dissolved in 200 ml of tetrahydrofuran and added at 0 ° C 1.68 g (70 mmol) of sodium hydride. The mixture is stirred at room temperature for 2 hours, then at 60 ° C. for 4 hours. The solution is placed in a metal autoclave, then added to 9.31 g (64.64 mmol) of 2,2-dimethyl-1,3,6-trioxabicyclo [5.1.0] octane and then heated to 150 ° C for 10 hours. The reaction solution is poured into ice-water and extracted twice with diethyl ether. The combined organic phases are evaporated to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / acetone = 10: 1).
Yield: 16.12 g (41% of theory) of a colorless solid. calc .: C 33.57 H 2,82 F 53,10 Found .: 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 82a are dissolved in 300 ml of ethanol and 30 ml of 10% aqu. Hydrochloric acid added. The mixture is heated for 5 hours under reflux. It is adjusted to pH 7 with sodium hydroxide solution, then concentrated to dryness and the residue is chromatographed on RP-18 (mobile phase: 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 Found .: 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-dioxo-pentane-l, 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-Perfluordecyl- (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-dioxo-pentane-1, 5-diyl] -1,4,7,10-tetraazacyclododecane, Gd complex} -10- [2- (N-ethyl-N-perfluorooctylsulfonyl) -amino] -acetyl-1,4,7,10-tetraazacyclododecane ( 300 mmol / L), dissolved in 0.45% aqueous saline (pH 7.4, 0.25 mg / L CaNa ₃ DTPA), 9.46 g (16.65 mmol) of the title compound of Example 82b and The mixture is heated to a total of 111 ml with 0.9% strength aqueous sodium chloride solution and then heated 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 a 0.2 μm filter and fill the filtrate in vials A solution prepared in this way can be used directly for biological experiments (the concentration is 100 mmol Gd / L).

Example 83

a) 1H, 1H, 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 added at 0 ° C 1.68 g (70 mmol) of sodium hydride. The mixture is stirred at room temperature for 2 hours, then at 60 ° C. for 4 hours. The solution is placed in a metal autoclave, then added to 15.78 g (64.64 mmol) of 1,2-bis (2,2-dimethyl-1,3-dioxolan-4-yl) -oxirane, followed by 10 hours Heated to 150 ° C. The reaction solution is poured into ice-water and extracted twice with diethyl ether. The combined organic phases are evaporated to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / acetone = 10: 1).
Yield: 14.2 g (31% of th.) Of a colorless solid. calc .: C 37,30 H 3.56 F 45.59 Found .: C 37,48 H 3.66 F 45,71

b) 1H, 1H, 2H, 2H-perfluorodecyl [1,2-bis (1,2-dihydroxy-ethyl) -2-hydroxyethyl] ether

14 g (19.76 mmol) of the title compound from Example 83a are dissolved in 300 ml of ethanol and 30 ml of 10% aqu. Hydrochloric acid added. The mixture is heated for 5 hours under reflux. It is adjusted to pH 7 with sodium hydroxide solution, then concentrated to dryness and the residue is chromatographed on RP-18 (mobile phase: 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 Found .: C 30,73 H 2,81 F 51.58

c) Preparation of a formulation from Metal complex II and 1H, 1H, 2H, 2H-perfluorodecyl [1,2-bis (1,2-dihydroxy-ethyl) -2-hydroxyethyl] ether

To 41 ml of a solution of the 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 83b and filled with 0.9% aqu. Saline solution to a total of 64 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 200 mmol Gd / L).

Example 84

a) Perfluorooctylsulfonic 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 77a 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 for one hour at 0 ° C and then evaporated to dryness in vacuo. The residue is dissolved in 300 ml of ethanol and washed with 17.8 ml of 1N aqu. Sodium hydroxide added. The solution is evaporated to dryness and the residue 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 Found .: 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-dioxa-octyl] -amide

To 43 ml of a solution of the metal complex I (380 mmol / L), dissolved in 0.45% aqu. Brine (pH 7.4, 0.25 mg / L CaNa ₃ DTPA) is added 142.29 g (147.06 mmol) of the title compound from Example 84a and filled with 0.9% aqu. Saline to a total of 164 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 85

a) 2- (2H, 2H, 3H, 3H, 5,5H, 6H, 6H-1,4, -dioxaperfluorotetradec-1-yl) -succinic acid diethyl ester

30 g (59.03 mmol) of 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanol are added in 300 ml of tetrahydrofuran and at 0 ° C 1.68 g (70 mmol) of sodium hydride. Mna is stirred for one hour at 0 ° C, then for 5 hours at 40 ° C. In this 40 ° C hot solution is added dropwise within 10 minutes 20.25 g (80 mmol) of 2-bromo-succinic acid diethylester and then stirred for 12 hours at this temperature. 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 (eluent: 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

To 11.5 g (16.90 mmol) of the title compound from Example 85a, dissolved in 300 ml of methanol, are added 50 ml of 3-N-aqu. Sodium hydroxide solution and refluxed for 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 anal 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 washed 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 Found .: C 28,88 H 1.71 F 48.25 Well 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 the metal complex 11 (300 mmol / L), dissolved in 0.45% aqu. Brine (pH 7.4, 0.25 mg / L CaNa ₃ DTPA), 1.14 g (1.71 mmol) of the title compound from Example 85b and filled with 0.9% aqu. Saline solution to a total of 154 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 86

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'-dicyclohexyl carbodiimide and stirred for 3 hours at this temperature. To the active ester solution thus prepared is added to a cooled to 0 ° C solution of 5.10 g (38.30 mmol) of L-aspartic acid dissolved in 300 ml of 5% aqu. 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 provides with conc. Hydrochloric acid to pH 1. It is extracted 3 times with 300 ml of chloroform. The combined organic phases are concentrated to dryness and the residue is chromatographed on RP-18 (mobile phase: acetonitrile / water / gradient). The diacid thus obtained is dissolved in 400 ml of water and washed 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 Found .: 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 of Example 86a and filled with 0.9% aqu. Saline solution to a total of 111 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 87

Preparation of a formulation from the Title compound of Example 60 and perfluorooctanesulfonic acid, sodium salt

To 43 ml of a solution of the title compound of Example 60 (250 mmol / L) dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA) is added a solution of 1.34 g (2.69 mmol) perfluorooctanesulfonic acid, sodium salt, dissolved in 200 ml of ethanol, and stirred for 2 hours at 50 ° C. The solution is concentrated to dryness in vacuo and the residue is washed with dist. Water to a total of 108 ml. The mixture is stirred for 10 minutes at 40 ° C and filtered through a 0.2 micron filter. The filtrate is bottled in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 88

Preparation of a formulation from the Title compound of Example 61 and perfluorodecane sulfonic acid, sodium salt

To 49 ml of a solution of the title compound of Example 61 (310 mmol / L) dissolved in 0.45 % aqu. Sodium chloride solution), Add 3.03 g (5.06 mmol) of perfluorodecane sulfonic acid, sodium salt and heat for 10 minutes in the microwave. The solution is cooled to room temperature, through a 0.2 μm filter filtered and the filtrate bottled in vials. A solution prepared in this way can directly for biological experiments are used. (The concentration is 310 mmol Gd / L).

Example 89

 a) (1H, 1H, 2H, 2H-perfluorodecyl) -5 - [(1,3-dicarboxy, Disodium salt) phenyl] ether

To 20 g (80.62 mmol) of trisodium salt of 5-hydroxy-isophthalic acid in 300 ml of dimethylformamide are added 42.5 g (80.62 mmol) of the title compound of Example 14a and stirred for 10 hours at 60 ° C. It is poured onto 1500 ml of ice-water and concentrated 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 chromatographed on RP-18 (eluent: acetonitrile / water / gradient). The thus purified diacid is dissolved in 400 ml of water and the pH with 1N 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 Found .: C 32,30 H 1,15 F 48.20 Well 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-dioxo-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-dioxo-pentane-1, 5-diyl] -1,4,7,10-tetraazacyclododecane, Gd complex} -10- [2- (N-ethyl-N-perfluorooctylsulfonyl) -amino] -acetyl-1,4,7,10-tetraazacyclododecane ( 300 mmol / L), dissolved in 0.45% aqueous saline solution (pH 7.4, 0.25 mg / L CaNa ₃ DTPA), 6.86 g (10.2 mmol) of the title compound from Example 89a and Make up to a total of 153 ml with 0.9% aqueous saline and heat 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 a 0.2 μm filter and fill the filtrate in vials A solution prepared in this way can be used directly for biological experiments (the concentration is 100 mmol Gd / L).

Example 90

Preparation of a formulation of 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 CaNa ₃ DTPA), are added 434 mg (0.55 mmol) of the title compound of Example 73a and precipitated with 0.9% aqu. Saline solution to a total of 12.8 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The concentration is 100 mmol Gd / L).

Example 91

a) (Adamant-1-yl) -3-oxa-propionic acid t-butyl ester

29.26 g (150 mmol) of bromoacetic acid tert-butyl ester are added to 15.22 g (100 mmol of 1-adamantanol in 300 ml of 50% aqueous potassium hydroxide solution, 200 ml of toluene) at 0 ° C. and stirred vigorously for 2 hours. It is poured into 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 phase: n-hexane / diethyl ether 20: 1).
Yield: 21.58 g (81% of theory) of a viscous, colorless oil. calc .: C 72,14 H 9.84 Found .: C 72,26 H 9.95

b) (adamant-1-yl) -3-oxa-propionic acid

20 g (75 mmol) of the title compound from Example 91a are dissolved at 0 ° C in 200 ml of trifluoroacetic acid and stirred for 8 hours at room temperature. It is evaporated to dryness and the residue is recrystallized from diisopropyl ether.
Yield: 14.68 g (93% of theory) of colorless leaves Elemental analysis: calc .: C 68.55 H 8,63 Found .: 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 91b and 37.50 g (66.6 mmol) of 1-perfluorooctylsulfonyl-piperazine are dissolved in 300 ml of tetrahydrofuran and 32.15 g (130 mmol) of 1, 2 dihydro-2-ethoxyquinoline-1-carboxylic acid ethyl ester (= EEDQ) was added. It 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 phase: dichloromethane / diethyl ether = 30: 1).
Yield: 43.05 g (85% of theory) of a colorless solid. calc .: C 37,90 H 3.31 N 3.68 S 4,22 F 42.47 Found .: C 38.04 H 3,42 N 3.49 S 4,11 F 42.30

d) Preparation of 0.5 parts of metal complex I and 0.5 parts of inclusion compound from β-cyclodextrin hydrate and 1- (perfluorooctylsulfonyl) -4 - [(adamant-1-yl) -oxapropionyl] piperazine

To 32 ml of a solution of the metal complex 1 (280 mmol / L) dissolved in 0.45% aqu. Brine (pH 7.4, 0.25 mg / L CaNa ₃ DTPA) is added 6.81 g (8.96 mmol) of the title compound of Example 91c, 10.33 g (8.96) of β-cyclodextrin monohydrate and charged with 0.9% aqu. Saline solution to a total of 98 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The Gd concentration is 100 mmol Gd / L).

Example 92

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 30.95 g (150 mmol) of N, N-dicyclohexylcarbodiimide. The mixture is stirred for 2 hours at 0 ° C, then 6 hours at room temperature. It is filtered from the precipitated urea, the filtrate evaporated to dryness and the residue chromatographed on silica gel (eluent: dichloromethane / acetone = 30: 1).
Yield: 54.4 g (83% of theory) of a waxy solid. calc .: C 40,32 H 3.38 N 2,14 F 49,28 Found .: C 40.47 H 3,49 N 2.03 F 49.09

b) Preparation of 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 the metal complex 11 (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 of Example 92a and 7.87 g (6.83 mmol) of β-cyclodextrin monohydrate and filled with 0.9% aqu. Saline solution to a total of 103 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The Gd concentration is 100 mmol Gd / L).

Example 93

 a) 2- [N- (ethyl) -N- (perfluorooctylsulfonyl) -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 are added at 0.degree. C. 30.95 g (150 mmol) of N, N-dicyclohexylcarbodiimide. The mixture is stirred for 2 hours at 0 ° C, then 6 hours at room temperature. It is filtered from the precipitated urea, the filtrate evaporated to dryness and the residue chromatographed on silica gel (eluent: dichloromethane / acetone = 30: 1).
Yield: 55.65 g (79% of theory) of an amorphous solid. calc .: C 37.51 H 3,29 F 45,85 N 1.99 S 4,55 Found .: C 37.64 H 3.41 F 45.99 N 2,12 S 4,43

b) Preparation of 0.6 parts of metal complex I and 0.4 parts 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. Brine (pH 7.4, 0.25 mg / L CaNa ₃ DTPA) is added 4.20 g (5.97 mmol) of the title compound from Example 93a and 6.88 g (5.97 mmol) of β-cyclodextrin monohydrate and fills with 0.9% aqu. Saline solution to a total of 90 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution is cooled to room temperature and washed with aqu. 2N sodium hydroxide adjusted to pH 7.4. Filter through a 0.2 μm filter and fill the filtrate in vials. A solution prepared in this way can be used directly for biological experiments. (The Gd concentration is 100 mmol Gd / L).

Claims (5)

Use of perfluoroalkyl-containing metal complexes having a critical micelle formation concentration <10 ^-3 mol / l, a hydrodynamic micelle diameter> 1 nm and a proton relaxivity in plasma> 10 l / mmol · s, as a contrast agent in MR imaging for imaging plaques, wherein as perfluoroalkyl-containing metal complexes, the compounds of general formula I R F -LK I in which 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 L is a direct bond, a methylene group, an -NHCO group, a group

where p is the numbers 0 to 10, q and u independently of one another the numbers 0 or 1, and R ^a is a hydrogen atom, a methyl group, a -CH ₂ -OH group, a -CH ₂ -CO ₂ H group or a C ₂ -C ₁₅ chain which is optionally interrupted by 1 to 3 oxygen atoms, 1 to 2> CO groups or an optionally substituted aryl group and / or substituted by 1 to 4 hydroxyl groups, 1 to 2 C ₁ -C ₄ alkoxy groups , 1 to 2 carboxy groups, a group -SO ₃ H-, or a straight-chain, branched, saturated or unsaturated C ₂ -C ₃₀ -carbon chain which may optionally contain 1 to 10 oxygen atoms, 1 to 3 -NR ^a groups, 1 to 2 sulfur atoms, a piperazine, a -CONR ^a group, an -NR ^a CO group, an -SO ₂ group, an -NR ^a -CO ₂ group, 1 to 2 CO groups, a group - CO-NTN (R ^a ) -SO ₂ -R ^F or 1 to 2 optionally substituted aryls and / or interrupted by these groups, and / or optionally substituted with 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 (CH ₂ ) _p- CO ₂ H groups, 1 to 2 groups - (CH ₂ ) _p - (O) _q -CH ₂ CH ₂ -R ^F , wherein R ^a , R ^F and p and q are as defined above and T is a C ₂ -C ₁₀ chain, the optionally interrupted by 1 to 2 oxygen atoms or 1 to 2 -NHCO groups, K is a complexing agent or metal complex or salts thereof of organic and / or inorganic bases or amino acids or amino acid amides, namely a complexing agent or complex of general formula II

in which R ^{1 is} independently a hydrogen atom or a metal ion equivalent of atomic numbers 22-29, 42-46 or 58-70 or for a complexing agent or complex of the general formula III

in which R ^{1 has} the abovementioned meaning and B_OR 1 or

where L and R ^{F have} the abovementioned meanings and R ^{c has} the meaning of R ^a or - (CH ₂ ) _m -LR ^F , where m is 0, 1 or 2 and L and R ^{F have} the abovementioned meaning or for a complexing agent or complex of general formula IV

in which R ^c and R ^{1 have} the abovementioned meanings and R ^{b has} the abovementioned meaning of R ^a , or for a complexing agent or complex of the general formula V

in which R ^c and R ^{1 have} the meanings given above, or for a complexing agent or complex of general formula VI

in which R ^c and R ^{1 have} the abovementioned meanings, or for a complexing agent or complex of the general formula VII

in which R ¹ , p and q have the abovementioned meaning and R ^{b has} the meaning of R ^a . Use according to claim 1, characterized in that the compounds of general formula I are used in which L is α-CH ₂ -β α-CH ₂ CH ₂ -β α- (CH ₂ ) _s -β s = 3-15 α-CH ₂ -O-CH ₂ CH ₂ -β α-CH ₂ - (O-CH ₂ -CH ₂ -) _t -β t = 2-6 α-CH ₂ -NH-CO-β α-CH ₂ -NH-CO-CH ₂ -N (CH ₂ COOH) -SO ₂ -β α-CH ₂ -NH-CO-CH ₂ -N (C ₂ H ₅ ) -SO ₂ -β α-CH ₂ -NH- CO-CH ₂ -N (C ₁₀ H ₂₁ ) -SO ₂ -β α-CH ₂ -NH-CO-CH ₂ -N (C ₆ H ₁₃ ) -SO ₂ -β α-CH ₂ -NH-CO- (CH ₂ ) ₁₀ -N (C ₂ H ₅ ) -SO ₂ -β α-CH ₂ -NH-CO-CH ₂ -N (-CH ₂ -C ₆ H ₅ ) -SO ₂ -β α-CH ₂ -NH-CO-CH ₂ -N (-CH ₂ -CH ₂ -OH) SO ₂ -β α-CH ₂ -NHCO- (CH ₂ ) ₁₀ -S-CH ₂ CH ₂ -β α-CH ₂ NHCOCH ₂ -O-CH ₂ CH ₂ -β α-CH ₂ NHCO (CH ₂ ) ₁₀ -O-CH ₂ CH ₂ -β α-CH ₂ -C ₆ H ₄ -O-CH ₂ CH ₂ -β α-CH ₂ -O-CH ₂ -C (CH ₂ -OCH ₂ CH ₂ -C ₆ F ₁₃ ) ₂ -CH ₂ -OCH ₂ -CH ₂ -βα

α-CH ₂ -O-CH ₂ -CH (OC ₁₀ H ₂₁ ) -CH ₂ -O-CH ₂ CH ₂ -β α- (CH ₂ NHCO) ₄ -CH ₂ O-CH ₂ CH ₂ -β α- (CH ₂ NHCO) ₃ -CH ₂ O-CH ₂ CH ₂ -β α-CH ₂ -OCH ₂ C (CH ₂ OH) ₂ -CH ₂ -O-CH ₂ CH ₂ -β

α-CH ₂ NHCOCH ₂ N (C ₆ H ₅ ) -SO ₂ -β α-NHCO-CH ₂ -CH ₂ -β α-NHCO-CH ₂ -O-CH ₂ CH ₂ -β α-NH-CO- β α-NH-CO-CH ₂ -N (CH ₂ COOH) -SO ₂ -β α-NH-CO-CH ₂ -N (C ₂ H ₅ ) -SO ₂ -β α-NH-CO-CH ₂ -N (C ₁₀ H ₂₁ ) -SO ₂ -β α-NH-CO-CH ₂ -N (C ₆ H ₁₃ ) -SO ₂ -β α-NH-CO- (CH ₂ ) ₁₀ -N (C ₂ H ₅ ) -SO ₂ -β α-NH-CO-CH ₂ -N (-CH ₂ -C ₆ H ₅ ) -SO ₂ -β α-NH-CO-CH ₂ -N (-CH ₂ -CH ₂ -OH) SO ₂ -β α-NH-CO-CH ₂ -β α-CH ₂ -OC ₆ H ₄ -O-CH ₂ -CH ₂ -β α-CH ₂ -C ₆ H ₄ -O-CH ₂ -CH ₂ -β α-N (C ₂ H ₅ ) -SO ₂ -β α-N (C ₆ H ₅ ) -SO ₂ -β α-N (C ₁₀ H ₂₁ ) -SO ₂ -β α-N (C ₆ H ₁₃ ) -SO ₂ -β α-N (C ₂ H ₄ OH) -SO ₂ -β α-N (CH ₂ COCH) -SO ₂ -β α-N (CH ₂ C ₆ H ₅ ) -SO ₂ -β α-N- [CH (CH ₂ OH) ₂ ] -SO ₂ -β α-N- [CH (CH ₂ OH) CH (CH ₂ OH)] - SO ₂ -β and wherein α the binding site to the complexing agent or metal complex K and β represents the binding site to the fluorine residue. Use according to claim 1 or 2, characterized in that the compounds of the formula 1 are used, in which n in the formula -C _n F _2n E stands for the numbers 4-15 and / or E in this formula denotes a fluorine atom. Use according to any one of claims 1 to 3, characterized in that the following compounds are used: - gadolinium complex of 10- [1-methyl-2-oxo-3-aza-5-oxo {4-perfluorooctylsulfonyl-piperazine- 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-10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17,17-heptadecafluoroheptadecyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane, - gadolinium complex of 10- [2-hydroxy-4-aza-5,9-dioxo-9- {4-perfluorooctyl) -piperazin-1-yl} -nonyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane, - gadolinium complex of 10- [2-hydroxy-4-aza-5-oxo-7-aza-7- (perfluorooctyl -sulfonyl) nonyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane, - gadolinium complex of 10- [2-hydroxy-4-oxa-1H, 1H, 2H, 3H, 3H, 5H, 5H, 6H, 6H-perfluoro-tetradecyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane, - gadolinium complex of 10- [2-hydroxy- 4-aza-5-oxo-7-oxa-1 0,10,11,11, 12,12,13,13,14,14,15,15,16,16,17,17,18,18,19,19,19-henicosafluornonadecyl] -1,4,7 -tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane, - gadolinium complex of 10- [2-hydroxy-4-aza-5-oxo-11-aza-11- (perfluorooctylsulfonyl) -tride cyl] -1,4,7-tris (carboxymethyl) 1,4,7,10-tetraazacyclododecane, - gadolinium complex of 10- [2-hydroxy-4-aza-5-oxo-7-aza-7- ( perfluorooctylsulfonyl) -8-phenyl-octyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane. Use of perfluoroalkyl-containing metal complexes having a critical micelle formation concentration <10 ^-3 mol / l, a hydrodynamic micelle diameter> 1 nm and a proton relaxivity in plasma> 10 l / mmol · s, as a contrast agent in MR imaging for imaging plaques, the following compounds are used: - gadolinium complex of 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 of 1,4,7- Tris (carboxylatomethyl) -10-1 (3-aza-4-oxo-hexan-5-yl) acid- [N- (3,6,9,12,15-pentaoxa) -hexadecyl) -N- (1 H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluorotridecyl] -amide} -1,4,7,10-tetraazacyclododecane, - gadolinium complex of 1,4,7-tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acryloxy-N- (5-hydroxy-3-oxa-pentyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H , 5H-3-oxa) -perfluorotridecyl] -amide} -1,4,7,10-tetraazacyclododecane, - gadolinium complex of 1,4,7-tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid- [N-3,6,9,16-tetraoxa-13-aza- 14-oxo-C ₁₉ -C ₂₆ -heptadecafluoro) hexacosyl] -amide} -1,4,7,10-tetraazacyclododecane, - gadolinium complex of 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza- 4-oxo-hexan-5-yl] -acyl-N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluorotridecyl] -amide} -1,4,7,10-tetraazacyclododecane, - Gd complex of 1,4,7-tris {1,4,7-tris (N- (carboxylatomethyl) -10- [N-1-methyl-3,6 -diaza-2,5,8-trioxooctan-1,8-diyl] -1,4,7,10-tetraazacyclododecane, Gd complex} -10-N-2H, 2H, 4H, 4H, 5H, 5H-3 -oxa-perfluorotridecanoyl] -1,4,7,10-tetraazacyclododecane, - Gd 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.