SK1572003A3 - Use of metal complexes containing perfluoroalkyl as contrast agents in MR-imaging for the representation of plaques, tumours and necroses - Google Patents

Abstract

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

Description

Technical field

The present invention describes the use of metal complexes containing perfluoroalkyl residues having a critical micellar concentration of less than 10 ^-3 mol / l, a hydrodynamic micellar diameter (2 Rh) of greater than 1 nm and a proton relaxivity in plasma (R ¹ ) of greater than 10 1 / mmol.s, as a contrast agent in magnetic resonance imaging (MR imaging) and plaque, lymph node, infarction and necrotic tissue imaging as well as independent imaging of necrotic and tumor tissues. Metal complexes containing perfluoroalkyl residues with the above properties are shown to be particularly suitable for independent monitoring of plaques, tumors and necroses by MR imaging, and at the same time can cover an important area of heart and necrosis monitoring.

BACKGROUND OF THE INVENTION

Arteriosclerosis is a serious and frequent disease of arterial disease accompanied by stiffness, loss of elasticity and decrease in arterial brightness. It is a frequent cause of death in Western industrial society. Changes in vascular walls by uneven lipid deposition, connective tissue growth and calcium clogging lead to wall instability, venous changes, and clot deposition. The cause of the disease is numerous endogenous and exogenous pollutants or diseases such as hypertonia, hyperlipidemia, hyperfibrinogenemia, diabetes mellitus, toxins, nicotine, antigen-antibody complex, inflammation, hypoxia, psychological stress, aging and family burden. These effects lead to impaired venous wall integrity, impaired control of venous smooth muscle cell growth, and disrupted the degradation of aged cells. Treatment of arteriosclerosis alone is not possible, and the physicians endeavor to prevent them by reducing risk factors, for example by removing lipids.

The diagnosis of arteriosclerosis is currently made in clinical practice mainly by anciography as the main standard. However, the limit for all methods based on venous lumen reduction is the early stage of the disease, which is characterized by thickening of the venous walls at normal venous lumen (S. Glagov, C. K. Zarins, Quantitating atherosclerosis,

Bond M., G. Insull, W. Glagov, A. Chandler, A. F. Cornhill Eds., Clinical Diagnosis of Atherosclerosis. Quantitative Methods of Evaluation, Springer Verlag, New York 1953, p. 11-35). Another method for diagnostic assessment of venous arteries and lumen is intravascular or percutaneous ultrasound.

Magnetic Resonance Tomography (MRT) is a modern, non-invasive radiological method that allows very good spatial and temporal resolution of physiological and pathophysiological structures. The use of specific contrast agents with selective enrichment in certain tissues and organs significantly increases the diagnostic value of this method. The preparation of selectively enriched contrast agents in arterial-sclerotic plaques can lead to the localization of the disease at an earlier stage and thereby allow targeted therapy and prophylaxis, so that there is a need for suitable contrast agents.

US Patent 4,577,636 claims hematoporphyrin derivatives as contrast agents for the detection of atherosclerotic plaques. Scintigraphy, X-ray spectroscopy, fluorescence spectroscopy and, in the case of paramagnetic metalloporphyrins, NMR spectroscopy were used as methods. Paramagnetic ions include gadolinium, chromium, cobalt, nickel, silver and europium. A disadvantage of these compounds is that porphyrins are deposited in the skin and cause discoloration, which may persist for several weeks. In addition, they lead to photosensitization. At the same time, there is a risk that the metalloporphyrins lose metal during long-term in vivo persistence.

WO 95/09856 discloses metalloporphyrins (deuteroporphyrins) for use in the diagnosis and therapy of plaques. The MRI method was used as a diagnostic method. These porphyrins also cause skin discolouration.

WO 95/09013 describes conjugates of specifically bound polypeptides and metal complexes. These compounds may also bind to plaques and thereby facilitate diagnosis and therapy. As diagnostic method, scintigraphy, computed tomography and MRI were used. While experimental scintigraphy conditions are reported, data for MRI are missing.

In US Patent 5,807,536, labeled phthalocyanines were used as contrast agents for plaque imaging. X-ray spectroscopy, computed tomography, scintigraphy, SPECT and MRI were used as diagnostic methods. Scintigraphy is experimentally documented.

A variety of contrast agents for imaging myocardial infarction and necrosis are known in the literature. Early studies have shown that the localization of heart attack and necrosis is better due to the use of contrast agents for non-invasive methods such as scintigraphy or NMR tomography. The use of porphyrins for imaging necrosis is of great interest in the literature. However, the results obtained give a contradictory picture. As described by Winkelman and Hoyes in Nature, 200, 903 (1967), manganese-5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrin (Mn-TPPS) selectively accumulates in the necrotic portion of the tumor.

Lyon et al. In Magn. Res. Med. 4, 24 (1987), on the other hand, have observed that Mn-TPPS is distributed in the body into kidneys, liver, tumors and, to a small extent, into muscles. Interestingly, the tumor concentration first reaches its maximum at day 4 after the dose is increased from 0.12 mmol / kg to 0.2 mmol / kg. The authors also describe non-specific binding of Mn-TPPS in the tumor. Bockhurst et al. also refer to Acta Neurochir. 60, 347 (1994, Suppl.), That Mn-TPPS binds selectively in tumors.

Foster et al. in J. Nucl. Med. 26, 756 (1985) found that ^{µl of} In-5,10,15,2Q-tetrakis (4-N-methylpyridinium) porphyrin (TMPyP) does not enrich in the necrotic portion, but rather in the living edge layers. The conclusion that there is a porphyrin-tissue metabolism is obvious but not convincing.

Ni et al. describes in Circulation 90 (4), Volume 2, page 1468, abstract no. 2512 (1994) that infarct areas can be imaged using manganese-tetrafenylporphyrin (Mn-TPP) and gadolinium-mesoporphyrin (Gd-MP). In International Patent Application WO 95/31219 both compounds have been used for imaging infarction and necrosis. Marchal and Ni describe (see Example 3) that, in the case of Gd-MP, the metal content in the infarcted kidney is similarly high as in the uninfected organs, but is nine times higher than in the infarcted myocardial tissue ( Example 1). Remarkably, the signal intensity ratio at MRI for infarcted and healthy tissue in both cases was 2.10 and 2.19, respectively. Other metalloporphyrins have been described in DE 198 35 082 (Schering AG).

Porphyrins tend to deposit in the skin, leading to photosensitization. Sensitization may take several days to weeks. This is an undesirable side effect when using porphyrin as a diagnostic. In addition, the therapeutic index for porphyrins is very small, for example, for Mn-TPPS, the effect is only at doses of 0.2 mmol / kg, LD 50 already at about 0.5 mmol / kg.

Necrosis and infarct imaging contrast agents which are not based on porphyry residues are described in DE 197 44 003 (Schering AG), DE 197 44 004 (Schering AG) and WO 99/17809 (EPIX).

DE 197 44 003 describes oligomeric compounds composed of a core to which 1 to 3 metal complexes bind.

DE 197 44 004 discloses lipophilic. metal complexes for imaging necrosis and heart attack. These compounds include metal complexes of polyaminopolycarboxylic acids, polyaminopolyphosphoric acids, porphyrins, texaphyrins, saphyrins and peptides.

WO 95/17809 (EPIX) describes the use of DTPA derivatives for imaging necroses. The best compound is the gadolinium complex with hydroxymethyl-DTPA phosphodiesters (MS-325).

Metal complexes containing perfluoroalkyl residues are also known as contrast agents in MR imaging. WO 97/26017 (Schering) and WO 99/01161 (Schering) disclose perfluoroalkyl metal complexes as lymphographies. In addition, WO 99/01161 describes the suitability of diester compounds for imaging vascular spaces (bloodstream agents).

Contrast agents for imaging tumors and necrosis by MR imaging have also been described.

EP 417 870 A1 discloses compounds for tumor diagnosis and therapy. The patent implies that heart attacks and ischemia can also be imaged. However, the experimental confirmation of this statement is missing in the application. The claimed compounds may be considered as chelates of N2S2 and N3S type complexes with radioisotopes. Scintigraphy serves as a diagnostic method.

In German patent DE 196 46 762, scintigraphy was also used as a diagnostic method. The patent claims metal chelates as radiosensitizers for the treatment of hypoxic tumors and for the diagnosis of hypoxic conditions and necroses. Their use as NMR, X-ray and radiodiagnostics is also described.

German application DE 198 24 653 describes porphyrins as "necrosis-affine agents for tumor therapy. The application claims that the compounds accumulate in the necrotic and hypoxic regions of the tumors. The compounds can be used for diagnostic purposes in the form of their metal derivatives with paramagnetic isotopes or radioisotopes.

The two applications - DE 196 46 162 and DE 198 24 653 - have in common that imaging of necrosis and tumor cannot be performed independently of each other, since necrosis is part of the tumor.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide contrast agents in MR imaging that are suitable for imaging plaques, lymph nodes, infarcted and necrotic tissues, as well as independent imaging of necroses and tumors.

Surprisingly, it has been found that metal complexes containing perfluoroalkyl residues having a critical micellar concentration of less than 10 ^-3 mol / L, a hydrodynamic micellar diameter (2 Rh) of greater than 1 nm and a proton relaxivity (R ¹ ) of greater than 10 L / mmol. s, are very suitable for use as contrast agents in MR imaging for plaque imaging. In addition, these compounds can be used for imaging of lymph nodes, infarcted and necrotic tissues, as well as independent imaging of necrotic tissue and tumor tissue.

Metal complexes containing perfluoroalkyl radicals suitable according to the invention are amphiphilic compounds which are characterized by a non-polar part of the perfluoroalkyl chain in the molecule, which are optionally attached to the molecule by a lipophilic linker. The polar portion of the compounds of the invention is formed by one or more metal complexes and optionally bound by other polar groups.

Nu ^': odných systems, these compounds exhibit typical behavior of surfactants (e.g. sodium dodecyl sulfate, SDS). Thus, they reduce the surface tension of the water. Tensiometry can be used to determine the so-called. critical micellar concentration (CMC) in mol / l. The surface tension is determined in dependence on the concentration of the compound to be measured. The CMC is then calculated from the course of the surface tension function (c). The critical micellar concentration of the compounds of the invention must be less than 10 ^-3 mol / l, preferably less than 10 ^-3 mol / l.

The amphiphilic compounds of the invention associate in solution and exist as aggregates, and the size (2 Rh) of these aggregates (e.g. micelles, discs, bladders) is determined by photon-correlation spectroscopy (PCS).

The second criterion is the hydrodynamic micellar diameter of 2 Rh, which must be less than 1 nm. Particularly suitable according to the invention are those perfluoroalkyl metal complexes having 2 Rh > 3 nm, particularly preferred having 2 Rh > 4 nm.

Both the determination of CMC and photon-correlation spectroscopy are described in H. D. Döfer, Grenzflächen- und Kolloidchemie, VSH, Weinheim, New York, Basel, Camridge, Tokyo 1994.

The third criterion is proton relaxivity in plasma (R ¹ ) at a temperature of 40 ° C and a pole strength of 0.47 Celsius. The relaxivity, expressed in units of 1 / mmol.s, is a quantitative measure of the reduction in the relaxation time of the T ¹ protons. For the purposes of this invention, the relaxivity must be as high as possible and higher than 10 l / mmol.s, preferably higher than 13 l / mmol.s, particularly preferably higher than 15 l / mmol.s.

The relaxivity R ¹ [1 / mmol.s] of MR contrast agents of the invention was determined using a Minispec P 20 from Bruker. The measurement was carried out at a temperature of 40 ° C and a field strength of 0.47 ° C. For each T1-sequence: 180 ° -TI-90 °, "Inversion Recovery", 8 points were obtained. Kraeber bovine plasma was used as medium. The concentration of contrast agents [mmol / l] is in the range of 0.30 to 1.16.

In one embodiment of the invention, preferred compounds are compounds of formula I according to claims 8 to 11. These are known compounds and are described in WO 97/26017. This application also includes their preparation. It has surprisingly been found that these compounds are very suitable as MRI contrast agents for plaque imaging. Particularly preferred are the metal complexes I to IV, VI and XI to XIII (see Table 1).

In a further embodiment of the invention, the compounds of the general formula Ia according to claims 12 to 21 are particularly preferred. These compounds are known and described in WO 99/01161. Their use as MRI of contrast media for plaque imaging has not been described. Of these, the use of the metal complex XIV is particularly preferred (see Table 1).

In another preferred embodiment of the present invention, the macrocyclic perfluoroalkyl compounds of formula Ib are included

K - N - L - R (Ib) wherein

K is a complexing agent or a metal complex of formula IIb

COOR

COOR

COOR where it denotes a hydrogen atom or a metal ion equivalent having an atomic number of 23 to 29, 42 to 46 or 58 to 70,

R ² and R ³ denote a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a benzyl group, a phenyl group, a -CH ₂ OH group or a -CH 2 -OCH 3 group, and

U ² is a residue L ¹ , where L ¹ and U ² are independently the same or different,

A ¹ denotes a hydrogen atom, a straight or branched alkyl group having 1 to 30 carbon atoms, optionally interrupted by 1 to 15 oxygen atoms and / or optionally substituted by 1 to 10 hydroxyl groups, 1 to 2 carboxyl groups, phenyl group, benzyl group and / or 1 to 5 -OR ⁹ , wherein R ⁵ is a hydrogen atom or an alkyl radical having 1 to 7 carbon atoms or a radical -L ¹ -R ^F ,

L ¹ denotes a hydrogen atom, a straight or branched alkylene group having 1 to 30 carbon atoms, optionally interrupted by 1 to 10 oxygen atoms, 1 to 5 -NHCO- groups, 1 to 5 -CONH- groups, a phenyl group optionally substituted with a carboxyl group , from 1 to 3 sulfur atoms, 1 to 2 groups -Ν ^(Β Ί) -3Ο2- and / or 1 to 2 radicals -SO 2 -N (B ¹⁾ -, wherein B ¹ is a group a ^1, -NHCO-, -CONH-, -N (B 1) -SO 2 -, or -SO 2 -N (B ¹ ) -, and / or optionally substituted with R ', and

R ^f is a straight or branched perfluoroalkyl radical of the formula -C _n F ₂ nE, wherein n is a number of 4 to 30, and

E is a terminal fluorine atom, a chlorine atom, a bromine atom, an iodine aroma or a hydrogen atom, and the optionally attached acidic groups may be in the form of salts with organic and / or inorganic amines or amino acids or amino acid amides.

The compounds of the present invention are intended for use as NMR diagnostics, so the metal ion of the signal group must be paramagnetic. Such ions are in particular divalent and trivalent ions of elements having atomic numbers 23 to 29, 42 to 46 and 58 to 70. Suitable ions are, for example, chromium, iron, cobaitic, nickel, copper, praseodymium, neodymium, samarium and yterbite. Due to their strong magnetic moment, gadolinium, terbite, dysprozy, holmite, erbite, ferric and manganese ions are particularly suitable.

Particularly suitable are manganese, ferrous, ferric, praseodymium, neodymium, samarium, gadolinium and yterbitium ion, especially dysprozium ion.

The alkyl groups R ² , R ³ , R ⁹ may be straight or branched. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl 1,2-dimethylpropyl.

R @ ² , R @ ³ and R @ ⁹ are preferably hydrogen and alkyl groups having 1 to 4 carbon atoms, particularly preferred are hydrogen and methyl.

The benzyl and phenyl groups in R ¹ , A ¹ and B ¹ may be substituted on the phenyl ring. A substituent is a carboxyl group.

When a compound of the formula Ib simultaneously contains a residue L ¹ and L ¹ , then L ¹ and U ² may be different from each other.

Alkylene groups U ² having 1 to 30 carbon atoms can be straight or branched. Examples which may be mentioned are methylene, ethylene, propylene, isopropylene, n-butylene, 1-methylpropylene, 2-methylpropylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methyl 11 butylene, 1,2-dimethylpropylene.

For U ² as alkylene, alkylene groups having 1 to 10 carbon atoms are preferred, alkylene groups having 1 to 4 carbon atoms are particularly preferred.

Alkyl groups A ¹ having 1 to 30 carbon atoms can be straight or branched. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl 1,2-dimethylpropyl, n-hexyl.

The alkyl groups and ^one having 1 to 30 carbon atoms can be interrupted by 1 to 15 oxygen atoms and / or may be substituted with 1-10 hydroxy groups, 1-5 alkoxy groups or 1 to 2 carboxylic groups, such as e.g.

-C ₂ H ₄ -OCH ₃ , C ₃ H ₆ -OCH ₃ ,

-C ₂ H 4 -O- (C ₂ H 4 -O) ζ -C ₂ H 4 -OH, -C ₂ H 4 -O- (C ₂ H 4 -O) _t -C ₂ H 4 -OCH 3, wherein t is 0 to 13,

-C2H4-OH, -C ₃ H ₆ OH, -C4H8-OH, -C5H10-OH, -C ₆ H ₁₂ OH, -C7H14-OH, and also the branched isomers thereof.

-CH (OH) CH ₂ OH,

CH (OH) CH (OH) CH ₂ OH, CH ₂ [CH (OH) j ^ CHzOH, wherein the ^1, 1 to 10,

-CH [CH ₂ (OH)] CH (OH) CH ₂ OH,

-C ₂ H ₄ CH (OH) ^, CH ₂ OH,

- (CH ₂ ) _with COOH, where s is 1 to 15,

-C 2 H 4 -O- (C 2 H 4 -O) - CH 2 COOH, wherein t is 0 to 13,

-C-H 4 -O- (C ₂ H 4 -O) _c -C ₂ H, -C _n F _2r .Er wherein t is 0 to 13, n is 4 to 20 and E is fluorine, chlorine, bromine, atom iodine or a hydrogen atom.

Particularly preferred values for A ¹ are hydrogen, alkyl having 1 to 10 carbon atoms,

-C ₂ H ₄ -OCH ₃ , c ₃ h ₆ -och ₃ ,

-C ₂ H ₄ -O- (C ₂ H ₄ -O) _z -C ₂ H ₄ -OH, -C ₂ H ₄ -O- (C ₂ H ₄ -O) _z -C ₂ H ₄ -OCH ₃ where x is 0 to 5,

-C ₂ H ₄ OH, -C ₃ H ₆ OH,

-CH ₂ [CH (OH)] ₇ CH ₂ OH, wherein y is 1 to 6,

-CH [CH ₂ (OH)] CH (OH) CH ₂ OH,

- (CH ₂ ) _w COOH where w is 1 to 10,

-C ₂ H ₄ -O- (C ₂ H ₄ -O) _x -CH ₂ COOH, wherein x is 0 to 5,

C ₂ H ₄ -O- (C ₂ H ₄ O) _x -C ₂ H ₄ -C _R .F e _{2 n} wherein x is from O to 5, n is 4 to 15 and E is a fluorine atom.

If the compound of formula Ib has two radicals L ¹ -?, Then these radicals may be different from each other.

For residue L ¹ , examples are given where a denotes the bond to the nitrogen atom and β bond to the residue R ^F :

α- (0Η _{2) 3} -β, wherein p is 1 to 15, and -CH ₂ -CH ₂ - _{(O-CH2 -CH2} -) _γ -β wherein y is 1-6, and -CH ₂ - (O-CH ₂ -CH ₂ -) y-β, where y is 1 to 6, α-ΟΗ ₂ -ΝΗ-ΟΟ-β, α-ΟΗ ₂ -ΟΗ ₂ -ΝΗ-3Ο ₂ -β, a- CH ₂ -NH-CO-CH ₂ -N (CH ₂ COOH) ₂ -β -3Ο, and -CH ₂ -NH-CO-CH ₂ -N (C ₂ H _{5) 2} -β -εθ,

Cl-CH ₂ -NH-CO-CH ₂ -N (C ₁₀ H ₂₁₎ -SCč-β, _{.alpha.-CH2-NH-CO-CH 2} -N (C ₆ H _t3) -3Ο ₂ -β, and -CH? -NH-CO- _{(CH2) 0-N} (C ₂ H _{5) 2} -β -3Ο, and -CH ₂ -NH-CO-CH ₂ -N (-CH ₂ -C ₆ H ₅ ) -SO ₂ -p, and -CH ₂ -NH-CO-CH ₂ -N (CH ₂ CH ₂ OH) ₂ -β -3Ο, C CH ₂ -NH-CO- (CH _{2) 0} -S-CH ₂ CH _{2 -} , a-CH ₂ -NH-CO-CH ₂ -O-CH ₂ CH _{2 -} , a-CH ₂ -CH ₂ -NH-CO-CH ₂ -O-CH ₂ CH ₂ ,, α-CH ₂ - (CH ₂ -CH ₂ O) _y - (CH ₂ ) ₃ -NH-CO-CH ₂ -O-CH ₂ CH _{2 -} , wherein y is 1 to 6, gc-CH ₂ - NH-CO- (CH ₂ ) γ ₀ -Ο-ΟΗ ₂ ΟΗ ₂ -β,

Ct-CH ₂ -CH ₂ -NH-CO- (CH ₂ ) ₁₀ -O-CH ₂ CH ₂ -P, α-CH ₂ -C ₆ H ₄ -O-CH ₂ -CH ₂ -P wherein the phenylene group is substituted at positions 1,4 or 1,3, α-CH ₂ -O-CH ₂ -C (CH ₂ -OCH ₂ CH ₂ -C ₆ F 13) 2 (CH ₂ ) ₃ -CH ₂ -O-CH ₂ CH ₂ -p, α-CH ₂ -NK-CO-CH ₂ -CH ₂ -CON-CH ₂ -CH 2 -NHCOCH ₂ -N (C ₂ H ₅ ) SO ₂ C ₃ F ₁₇ -p a-CH ₂ - CH ₂ -NH-CO-CH ₂ -N (C ₂ H ₅ ) -SO ₂ -p, α-CH ₂ -O-CH ₂ -CH (OC ₁₀ H ₂ ) -CH ₂ -O-CH ₂ CH _2- p, α- (CH ₂ -NHCO) ₄ -CH ₂ O-CH ₂ CH ₂ -p, α- (CH ₂ -NHCO) ₃ -CH ₂ O-CH ₂ CH ₂ -p, α-CH ₂ -ocH ₂ c (ch ₂ oh) ₂ -ch ₂ -o-ch ₂ ch ₂ -P,

α-CH 2 -NH-CO-CH ₂ -N (C ₆ H ₅ ) -SO _; beta, and-NH-CO-CH ₂ CH ₂ -p, and _{-NH-CO-CH2 -O-CH2 CH2-p,} and NH-CO-β, and -NH-CO-CH ₂ -N (CH ₂ COOH) -SO ₂ -p, and -NH-CO-CH ₂ -N (C ₂ H _{5) 2} -β -3Ο, and -NH-CO-CH ₂ -N (C ₁₀ H ₂₁ ) -SO ₂ -P, c-NH-CO-CH ₂ -N (C ₆ H ₁₃ ) -so ₂ -p, α-NH-CO- (CH ₂ ) ₁₀ -N (C ₂ H ₅ ) -SO ₂ - p, α-NH-CO-CH ₂ -N (-CH ₂ C ₆ H ₅ ) -SO ₂ -p, α-NH-CO-CH ₂ -N (-CH ₂ -CH ₂ OH) -SO ₂ - P, α-NH-CO-CH ₂ -p, α-CH ₂ -OC ₆ H ₄ -O-CH ₂ -CH ₂ -p, α-CH ₂ -C ₆ H ₄ -O-CH ₂ -CH ₂ -P, aN (C ₂ H ₅ ) -SO ₂ -P, aN (C ₆ H ₅ ) -SO ₂ -P, aN (C ₁₀ H ₂ ) -SO ₂ -p, α-Ν (C ₅ H) ₁₃ ) -SO ₂ -p, α-Ν (C ₂ H ₄ OH) -SO ₂ -β, α-Ν (CH ₂ COOH) -SO ₂ -P, α-Ν (CH ₂ C ₆ H ₅ ) -SO ₂ -β, α-Ν [CH (CH ₂ OH) ₂ ] -SO ₂ -p, α-Ν [CH (CH ₂ OH) CH (OH) (CH ₂ OH)] -SO ₂ -p.

Preferred are those having 1 to 10 carbon atoms:

α-CH ₂ -O-CH ₂ -CH ₂ -p, α-CH ₂ -CH ₂ - (O-CH ₂ -CH ₂ -) _y -p where y is 1 to 6, α-CH ₂ - ( O-CH ₂ -CH ₂ -) _y -p where y is 1 to 6, a-CH ₂ -CH ₂ -NH-SO ₂ -P, for example 10 a-CH ₂ -NHCOCH ₂ -O-CH ₂ - CH ₂ -p, α-CH ₂ -CH ₂ NHCOCH ₂ -O-CH ₂ -CH ₂ -P, α-CH ₂ - (CH ₂ CH ₂ O) _y (CH ₂ ) ₃ NHCO-CH ₂ -O- _CH2-CH2-p, wherein y is 1-6, and -CH ₂ -NHC0 (CH _{2) 0 -O-CH2-CH2-p,} and -CH ₂ CH ₂ NHCO (CH _{2 10} -O-CH ₂ -CH ₂ -p, α-CH ₂ -O-CH ₂ -CH (OC ₁₀ H ₂₁ ) -CH ₂ -O-CH ₂ -CH ₂ -P, α-CH ₂ - 0-C ₆ H _! -O-CH ₂ -CH ₂ -p, α-CH ₂ -C ₆ H ₄ -O-CH ₂ -CH ₂ -p.

Particularly preferred residues L ¹ according to the invention are those shown in the compounds of the examples of the invention.

For U ^{2, the} radicals mentioned for L ¹ and the preferred and particularly preferred radicals have the same meaning as in the said alkylene group, provided that they have no nitrogen atom in the position and no terminal (P-position) -SO ₂ or -CO-.

Preferred radicals B ¹ are a hydrogen atom, a linear or branched alkyl chains having 1 to 10 carbon atoms, kro15 e may be optionally interrupted by 1-5 oxygen atoms and / or optionally substituted by 1-5 hydroxy, 1-2 carboxy groups, phenyl optionally substituted by carboxyl, benzyl, and / or 1 to 5 -OR ⁹ , wherein R ⁹ denotes a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms.

Preferred radicals R ^F is linear or branched perfluoroalkyl radicals of the formula -C _n F2nE wherein n is 4 to 15 and E is a terminal fluorine atom.

Preparation of a compound of formula Ib according to the invention

A

I, db)

K-N-L-R wherein K is a complexing agent or a metal complex of the formula ± Ib

may be carried out as follows:

Method A

The carboxylic acid of formula IIIb already contains a metal ion equivalent R ^first

(IIb) (IVb) (Ib)

Said acid of formula IIIb optionally activated in situ with R ¹ as the metal ion equivalent is reacted with an amine of formula IVb by a condensation reaction to form an amide of formula Ib.

This method of producing a metal complex of carboxylic acid amide is known from DE 196 52 386.

The reaction mixture used in the condensation reactions comprises a mixture of a metal complex of the carboxylic acid of formula IIIb optionally carrying a carboxy and / or hydroxy group in protected form and at least one solution-forming agent in an amount of up to 5 molar equivalents, preferably 0.5 to 2 molar equivalents. selected so that the metal carboxylic acid complex can be introduced into the present reagents and isolated (for example by evaporation, lyophilization or spray-drying of an aqueous or water-immiscible solution component or by addition of an organic solvent to the solution) and finally reacted with dimethylsulfoxide cleavable water and optionally with a condensation agent, optionally also with in situ addition of substances allowing dissolution into a metal carboxylic acid complex suspension, a water-cleavable agent and, optionally, a condensation agent in dimethy lsulfoxide.

The reaction mixture formed in this manner is allowed to react (acid activation) for 1 to 24 hours, preferably 3 to 12 hours, at a temperature of from 0 ° C to 50 ° C, preferably at room temperature.

Finally, an amine of formula IVb is added

wherein R ^3, L ^1, R ^R and A ¹ have the same meaning as above, without solvent or in a solvent such as dimethyl sulfoxide, alcohols such as methanol, ethanol, isopropanol or a mixture thereof, formamide, dimethylformamide, , water or mixtures of said solvents, preferably dimethylsulfoxide, water or water miscible solvents. To obtain the amide, the reaction mixture obtained is kept at a temperature of from 0 ° C to 70 ° C, preferably from 30 ° C to 60 ° C, for 1 to 48 hours, preferably 8 to 24 hours.

In one embodiment, it has proved to be advantageous that the amine is used in the reaction in the form of a salt thereof, for example, as a hydrobromide or hydrochloride. A base such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, tripropylamine, tributylamine, lithium hydroxide, lithium carbonate, sodium hydroxide or sodium carbonate is added to liberate the amine.

The protective groups which are still present are finally cleaved.

The isolation of the reaction products is carried out by methods known to those skilled in the art, in particular by precipitation with an organic solvent, preferably acetone, 2-butanone, diethyl ether, acetic acid, tert-butyl methyl ether, isopropanol or mixtures thereof. Further purification can be carried out, for example, by chromatography, crystallization or ultrafiltration.

Suitable solubilizers are alkali salts, alkaline earth salts, trialkylammonium salts, tetraalkylammonium salts, urea, N-hydroxyimide, hydroxyaryltriazole, substituted phenols and salts. heterocyclic amines. Examples which may be mentioned are lithium chloride, lithium bromide, lithium iodide, sodium bromide, sodium iodide, lithium ethanesulfonate, sodium methanesulfonate, lithium p-toluenesulfonate, sodium p-toluenesulfonate, potassium bromide, potassium iodide, sodium chloride, magnesium bromide, magnesium bromide, magnesium bromide. magnesium iodide, tetraethylammonium p-toluenesulfonate, tetramethylammonium p-toluenesulfonate, pyridinium p-toluenesulfonate, triethylammonium p-toluenesulfonate, 2-morpholinoethylsulfonic acid, 4-nitrophenol, 3,5-dinitrophenol, 3,5-dinitrophenol hydroxysuccinimide, N-hydroxyphthalimide, urea, tetramethylurea, N-methylpyrrolidone, formamide as well as cyclic ureas, preferably lithium chloride, lithium bromide, lithium iodide, sodium bromide, sodium iodide.

All reagents known to those skilled in the art serve as the water-cleavable reagent. Examples include carbodiimides and onium reagents such as dicyclohexylcarbodiimide (DCCI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) and BOP - (benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), preferably DCCI.

For example, the following procedures are described in the literature:

Activation of carboxylic acids: review in Houben-Weyl, Methoden der Organischen Chemie, Volume XV / 2, Georg Thieme Verlag, Stuttgart 1974; and J. Chem. Research (S) 1996, 302.

Activation with carbodiimides: R. Schwyzer and H. Kappeler, Helv. Chim. Acta, 46, 1550 (1963); E. Wunsch et al., Chem. Ber., 100, 173 (1967).

Activation with carbodiimides / 1-hydroxysuccinimide: J. Am. Chem. Soc., 86, 1839 (1964) and J. Org. Chem., 53, 3583 (1988);

Synthesis, 1972, 453.

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

Imidazolide method: B.F. Gisin, R.B. Menifield, D.C. Tosteon, J. Am. Chem. Soc., 91, 2691 (1969).

Acid chloride method, thionyl chloride: Helv. Chim. Acta, 42, 1653 (1959); Oxalyl chloride: J. Org. Chem., 29, 843 (1964).

All possible substances known to those skilled in the art (Houben-Weyl, Methoden der Organischen Chemie, Vol. XV / 2, Georg Thieme Verlag, Stuttgart 1974) are used as optional auxiliaries for use in condensation reactions. Examples which may be mentioned are 4-nitrophenol, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, 3,5-dinitrophenol and pentafluorophenol. 4-Nitrophenol and N-hydroxysuccinimide are preferred, 4-nitrophenol is particularly preferred.

The deprotection is carried out by methods known to those skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline saponification of an ester with a base in an aqueous-alcoholic solution at a temperature of 0 ° C to 50 ° C, acidic saponification with a mineral acid or tert-butyl esters. trifluoroacetic acid (Protective Groups in Organic Synthesis, 2nd edition, TW Greene and PGM Wuts, John Wiley & Sons, Inc. New York 1991), in the case of the benzylers with hydrogen and palladium on carbon.

Preparation of starting materials

Compound of Formula IIIb

(IHb) is known from DE 196 52 386.

Amines of formula IVb

A

R

IVb) are commercially available (Fluorochem, ABCR) or can be prepared by the following procedures, wherein the compound of formula Vb is reacted with an amine of formula VIb and finally reduced by the compound of formula VIIb by

r ^f .x

(IVb) (VIb) (VIb)

A (VIIb) where R ^f , A ¹ , L ¹ and R ³ have the same meaning as previously mentioned, and L is a group L ¹ , where α-CH? and R ⁹ is a hydrogen atom or a methyl group.

As mentioned above, the carboxylic acid of formula IIIb is activated according to literature procedures prior to reaction with an amine of formula VIb. When R 'is a methyl group, aminolysis is performed.

Compounds of formula Vb are commercially available (Fluorochem, ABCR) or are prepared according to the procedure described in DE 196 03 033.

Compounds of formula (VIb) are commercially available (Fluorochem, ABCR) or can be prepared according to known procedures, such as described in Houben-Weyl, Methoden der organischen Chemie, Vol. XI / 2, Stickstoffverbindungen, Georg Thieme Verlag,

Stuttgart 1957, p. 680. IS A . Rickman and T. Atkins, J. Am Chem. Soc. 2268 (1974 ); 96 2268 (1974), F. Chavez and A. D Sherry, J. Org. Chem. 54. 2990 ( 1989).

Compounds of formula IVb are prepared in a known manner (Helv. Chim. Acta, 77, 23 (1994)) by reduction of compounds of formula VII, for example, with diborane or lithium aluminum hydride and cleavage of the protecting groups.

Method B

The starting materials are used the carboxylic acid of the formula III * wherein R is hydrogen, containing no metal ion equivalent R ^first The carboxyl groups are protected by known methods to give a compound of formula (IIly) wherein R ⁵ is any protecting group and R ⁵ is a prodrug thereof.

Suitable carboxylic acid protecting groups are, for example, straight or branched alkyl groups having 1 to 6 carbon atoms, aryl groups and aralkyl groups, for example methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl a triphenylmethyl group, a bis (p-nitrophenyl) methyl group, such as a trialkylsilyl group. A tert-butyl group is preferred.

(IVb) (ix)

The reaction of the protected carboxylic acid of formula IIly with the amine of formula IVb and the cleavage of the protecting groups is carried out in the same manner as in Procedure A, and in the next step the resulting carboxylic acid of formula Ix is reacted with at least one metal oxide or metal salt of the element of the desired atomic number. as described, for example, in DE 195 25 924.

The metal complex prepared by Method A or Method B contains free carboxyl groups, which may exist in the form of salts with physiologically acceptable inorganic or organic bases.

Neutralization of any free carboxyl groups present is carried out using inorganic bases (e.g. hydroxides, carbonates or bicarbonates of e.g. sodium, potassium, lithium, magnesium or calcium) and / or organic bases (inter alia, primary, secondary and tertiary amines such as ethanolamine, morpholine, glucamine, N-methylglucamine and N, N-dimethylglucamine, as well as basic amino acids such as lysine, arginine and ornithine, or amides of originally neutral or acidic amino acids).

Metal complexes V, VII, VIII, IX and X are particularly preferred according to the invention (see Table 1).

These compounds of formula (1b) are very useful as MRI contrast agents in imaging of paws.

Another preferred embodiment of the invention includes perfluoroalkyl complexes with sugar moieties of the general formula Ic (K), ¹ -G - (ZR ^F ) _m ¹ > (Ic) (YR) p ¹ wherein:

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

R ⁷ is a perfluorinated linear or branched hydrocarbon chain of the formula -C _n F _2n E, in which E is F, Cl, Br, I or H and n is an integer of 4 to 30,

K is a metal complex of formula IIc

(llc) where

R ¹ is a hydrogen atom or a metal ion equivalent having an atomic number of 23 to 29, 42 to 46 or 58 to 70, with the proviso that at least two R ¹ are metal ion equivalents,

R ² and R ³ are independently a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, benzyl, phenyl, -CH ₂ OH or -CH ₂ OCH _3, and

U is-C _s H ₄ -O-CH ₂ s), the - (ΟΗ ₂₎ ι-5-ω, a phenyl group, -CH ₂ -NHCO-CH ₂ -CH (CH ₂ COOH) -CgH ₄ -ro, -C 8 H ₄ - (OCH ₂ CH ₂ ) 0-1 -N (CH ₂ COOH) -CH ₂ -g), or an alkylene group having 1 to 12 carbon atoms, or C 7 -C group _{; 2} -C; H ₄ -O-, optionally interrupted by one or more oxygen atoms, 1 to 3 -NHCO-, 1 to 3 -CONH- and / or substituted with 1 to 3 - (CH ₂ ) 0-5COOH, wherein ω is the point of attachment to the group -CO-, or compounds of formula IIIc

ROOC

wherein R ¹ is as defined above, R ⁴ is a hydrogen atom or a metal ion equivalent given in the definition of R ¹ and U ¹ is a group -CeH 2 -O-CHa-m-, wherein oj is the point of attachment to the group -CO-, or compounds of formula IVc

wherein R ¹ and R ² are as defined above, or a compound of formula VC and VCB

ROOC

CO in

COOR ¹ \ _n -COOR ¹ '- COOR ¹ (VCA)

Ο

I!

vw-C

\ ^ N:

COOR ¹

COOR ¹

-COOR ¹

-COOR ¹ (VcB) wherein R ¹ is as defined above, or compounds of formula VIc

ROOC— \ / \ _from —CO — vw

R'OOC ^ ^NN '-_COOR "(VIc) wherein R ¹ is as defined above, or a compound of formula Villa

ROOC

ROOC

ROOC

ROOC

O (VIIe) wherein R ¹ is as defined above and U ¹ is -C 5 H 2 -O-CH 3 -m-, where ω is the point of attachment to the -CO- group, or compounds of formula VIIIc

H (VIIIc) wherein R ¹ is as defined above, and wherein optionally the free carboxyl groups in K may be in the form of salts with organic and / or inorganic bases or amino acids or amino acid amides,

G when K is a metal complex IIe to VIIe, at least three times the functionalized moiety is selected from the group consisting of moieties a) to j):

a)

b) α m - N - (CH 2 -C - CO - Y ^H NH β

Y 2 CO-C- (CH 2) ₄ -Na-β IH

NH 1

α

c)

d)

β

e)

f)

g)

NH

NH-CO-CH- (CH ₂ ) _n NH- ^ 3'-CO-CH- (CH ₂ ) _n NH- ^ and NH

NH-CO-CH (CH _{2) 4} -NH- and NH ^ NO

β

HH avv - _N - (CH ₂ ) ₄ -CN-CO - (CH 2 -N-) β

C0 ^H

NH

i)

j) a-NH-CH-CO-Yi

β a

G when K is a metal complex VIIIc, at least a non-functionalized moiety is selected from the group consisting of moieties k) and 1):

p-NH- (CH ₂ ) ₄ -CH-CO-

k)

NH i

AWV-CO-CH-CH-CHS-CO ^ Y

1) NH β

where a denotes the point of attachment of G to the complex, β denotes the point of attachment of G to the remainder of Y and γ denotes the point of attachment of G to the remainder of Z,

Y is -CH ₂ -, δ- (CH ₂ ) 18 -CO-β, δ-CH ₂ -CHCH-CO-β, or δ-CH (CHOH-CH ₂ OH) -CKOH-CHOH-CO -β, where δ t denotes the point of attachment to the sugar residue R and β is the point of attachment to the residue G,

Z is y-n-s ₂ -s

Y-COCH ₂ -N (C ₂ H ₅ ) -SO ₂ -e,

Y-COCH ₂ -O- (CH ₂ ) 2 -SO ₂ -e,

OO y - NN - SC? -? Or y-NHCH ₂ CH ₂ -O-CH ₂ CH ₂ -s where γ is the point of attachment of Z to the residue G and ε is the point of attachment of Z to the polyfluorinated residue R ^F , and

l ¹ , m ¹ are independently integers 1 or 2, p ¹ is an integer from 1 to 4.

The compounds of the present invention are intended for use in NMR diagnostics, so the metal ion of the signal group must be paramagnetic. Such ions are, in particular, divalent and dihydrate ions of elements having atomic numbers 23 to 29, 42 to 46 and 58 to 70.

Suitable ions are, for example, chromium (III), iron (III), cobalt (II), nickel (II), copper (I), prazeodymium, neodymium, samarium and yterbite ions. Due to their strong magnetic moment, gadolinium, terbite, dysprozy, holmite, erbite, ferric and manganese ions are particularly suitable.

Particularly suitable are manganese, ferrous, ferric, praseodymium, neodymium, samarium, gadolinium and yterbitium ion, especially dysprozium ion.

Acidic hydrogen atoms optionally occurring in R ¹ , i.e., those which cannot be substituted by a central ion, may optionally exist partially or fully in the form of salts with cations of inorganic and / or organic bases or amino acids or amino acid amides.

Suitable inorganic cations are, for example, lithium ion, potassium ion, calcium ion and especially sodium ion. Suitable organic base cations are, inter alia, those derived from primary, secondary or tertiary amines, such as ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine, and in particular N-methylglucamine. Suitable amino acid cations are especially lysine, arginine and ornithine, as well as amides of originally acidic or neutral amino acids.

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

The radical U in the metal complex K is preferably -CH 2 - or -ΟδΗ ₄ -Ο-ΟΗ ₂ -ω, where ω is the point of attachment to the group

-WHAT-.

The alkyl groups R ² and R ³ in the macrocycle of formula IIc may be straight or branched. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl 1,2-dimethylpropyl. Preferably, R ² and R ^J are independently H or an alkyl group having 1 to 4 carbon atoms. In one particularly preferred embodiment of the present invention, R ^{2 is a} methyl group and R ³ is a hydrogen atom.

The benzyl or phenyl group R ² or R ³ in the macrocycle K of formula IIc may also be substituted on the core.

The radical R in the formula (Ic) denotes a mono- or oli31 gosaccharide residue or a thiocuck residue which binds through the 1-OH- or 1-SH- position, which can also be replaced according to the invention with deoxy sugars and containing one or more hydroxy groups containing hydrogen atom. In a preferred embodiment of the present invention, R is a monosaccharide residue of 5 or 6 carbon atoms, preferably glucose, mannose, galactose, ribose, arabinose or xylose, or deoxycucars thereof, such as 6-deoxygalactose (fucose) or 6-deoxymanose (rhamnose) or their thiocarbons, with glucose, mannose and galactose being particularly preferred.

Compounds of formula (Ic) according to the invention are preferred when R ^F is -C _n F ₂ n + iz wherein n is preferably a number from 4 to 15. Particularly preferred are the radicals -C ₄ F _g , -C ₆ F n, -C ₈ F ₇ , - (2 2 25 25 and -C 14 F 79), as well as residues of the compounds exemplified.

At least three times the functionalized moiety G in formula Ic, representing "molecular scaffolding", is in a preferred embodiment of the invention a lysine residue (a) or (b).

Y and Z are the linkers shown in the general formula Ic, wherein preferably independently of one another Z is the radical 1'-N

N = SO ₂ -? And Y is a residue of δ-CfUCO-β.

Perfluoroalkyl metal complexes containing sugar moieties of formula Ic 'm (Ic) (YR) p wherein K is a metal complex of formulas IIc to VIIe and G is of the formulas a) to j) wherein Y, Z, R, R ^F , m ¹ , p ¹ and I ¹ have the same meaning as previously described, by preparing a carboxylic acid of the formula Iii in a known manner

COOR ⁵

OH (III) wherein R ⁵ is a metal ion equivalent having an atomic number of 23 to 29, 42 to 46 or 58 to 70, or denotes a carboxyl protecting group and R ² , R ³ and U are as defined above, or a carboxylic acid of formula HLI

wherein R ⁴ , R ⁵ and U are as defined above, or a carboxylic acid of formula IVi

OH (IVi) wherein R ⁵ and R ² are as hereinbefore defined, or a carboxylic acid of formula VI or Vii

R 00C

COOR

HOOC (VI) / -N \

COOR ⁵

COOR ⁵

(Vii) wherein R ⁵ is as defined above, or a carboxylic acid of Formula Vii

R ⁵ OOC - / - CO-OH

R ⁵ OOC - ^{/ N -} COOR ⁵ ( ^{v, i} ) wherein R ⁵ is as defined above, or a carboxylic acid of the general formula R ⁵ ooc r ⁵ ooc r ⁵ ooc r ⁵ ooc

(VII) where R ⁵ and U ¹ are as previously defined, in the optionally activated form, are reacted with an amine of formula IXc

H - G - (ZR ^F ) _m ¹

I (IXc) (YR) p ¹ where G is as defined in formulas (a) to (j) and R, R ^F , Y, Z, m ¹ and ¹ are as defined above, by condensation reaction and subsequent cleavage of any protective groups, a metal complex of the formula Ic, or where R ⁵ is a protecting group, after cleavage of the protective group, is reacted in known manner with at least one metal oxide or metal salt of an element of atomic numbers 23-29, 42-46 or 58-70, and finally, acid hydrogen atoms are optionally substituted with cations of inorganic and / or organic bases, amino acids or amino acid amides.

Compounds of formula (Ic) according to the invention wherein K is a metal complex of formula (VIIIc) and G is of formula (k) or (1) are prepared by reacting an amine of formula (VHIi)

wherein R ⁵ is an equivalent of a metal ion having an atomic number of 23 to 29, 42 to 46 or 58 to 70 or a carboxylic acid protecting group, reacts with an optionally activated carboxyl group of formula Xc by known methods

HO - G - (Z-F ¹ (X 0) (Y R) p 'where G is of the general formulas k) or 1) and R, R ^F , Y, Z, m ¹ and ¹ are as defined above, by condensation reaction, and optionally cleaving the protecting groups occurring to form a metal complex of formula Ic, or

Although R ⁵ is a protecting group, after cleavage of this protecting group, it is reacted in a known manner with at least one metal oxide or metal salt of elements having an atomic number of 23 to 29, 42 to 46 or 58 to 70 and finally acidic hydrogen atoms as necessary. substituted with cations of inorganic and / or organic bases, amino acids or amino acid amides.

Said carboxylic acids of formulas (III) to (VII) are either known compounds or are prepared according to the procedures described in the Examples. The preparation of the carboxylic acid of the formula III is known from DE 196 52 386. The preparation of the carboxylic acid of the formula IVi can be carried out as described in DE 197 28 954.

The starting material for the compounds of formula VC is N ³ - (2,6-dioxomorfolinoetyl) N ^c - (ethoxycarbonylmethyl) -3, 6-diazaoktándiová, which is described in EP 263,059th

The compounds of formula (VcB) are derived from an isomer of diethylenetriaminepentaacetic acid, which is bound via acetic acid at a medium nitrogen atom. This DTPA is described in DE 195 07 819 and DE 195 08 058.

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

Compounds of formula Vile are derived from 1- (4-carboxymethoxybenzyl) ethylenediaminetetraacetic acid, which is described in US 4,622,420.

Perbenzylated sugar acids used as starting compounds can be prepared analogously to Lockhoff, Angew. Chem., 110 (24), 3634 (1998). Thus, for example, the synthesis of 1-O-acetic acid perbenzylated glucose was carried out via two substances, trichloroacetamidate and reaction with ethyl hydroxyacetate under catalysis with BF3 in tetrahydrofuran and final saponification with sodium hydroxide in methanol-tetrahydrofuran.

In a preferred embodiment of the present invention, the perbenzylated sugar is used as starting material, wherein the perbenzylated 1-OH-sugar is dissolved in a water-immiscible solvent and reacted with an alkylating agent of formula XIc

Nu-L-COO-Sg (XIc) wherein Nu is a leaving group, L is - (CH ₂ ) i -5, -CH 2 -CHOH-, -CH (CHOH-CH ₂ OH) -CHOH-CHOH and Sg is a protecting group, in the presence of a base and optionally a phase transfer catalyst. As the leaving group, for example, the radical -Cl, -Br, -J, -OTs, -OMs, -OSO ₂ CF _3, -OSO ₂ C ₄ H 9 or -OSO ₂ C ₈ Fi - may be used in the alkylating agent of formula XIc.

As a protecting group, conventional protecting groups known to those skilled in the art (Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, Inc., New York 1991) are used.

The substitution according to the invention is carried out at a temperature from 0 ° C to 50 ° C, preferably at a temperature from 0 ° C to room temperature. The reaction time is from 10 minutes to 24 hours, preferably from 20 minutes to 12 hours.

The base is used either in solid form, preferably powdered, or as a 10% to 70%, preferably 30% to 50% aqueous solution.

Preferred bases are sodium hydroxide and potassium hydroxide.

Toluene, benzene, trifluoromethylbenzene, hexane, cyclohexane, diethyl ether, tetrahydrofuran, dichloromethane, tert-butyl methyl ether or mixtures thereof may be used as the water-immiscible organic solvent in the alkylation of the invention.

I

Phase transfer catalysts used in the process of the present invention are the known quaternary ammonium and phosphonium salts or crown ethers such as 15-crown-5 or 18-crown-6. Preferably, quaternary ammonium salts with four identical or different hydrocarbon groups in a cation selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl or isobutyl are used. The hydrocarbon groups on the cation must be large enough to guarantee good solubility of the alkylating agent in the organic solvent. Particularly preferred according to the invention are N (butyl) ph, N (butyl) (HSO), but also I-1 (methyl).

Particularly preferred compounds of formula Ic according to the invention are the metal complexes XV of Table 1 (Example 1).

In another preferred embodiment of the present invention, perfluoroalkyl metal complexes with polar residues of the general formula Id (K), '- G - (Z-FOR' ') are used.

I (Id) (R) p ² wherein a perfluorinated straight or branched hydrocarbon chain of the formula -C _n F 2 _n E, wherein E is a terminal fluorine atom, chlorine atom, bromine atom, iodine atom or hydrogen atom and is a number from 4 to 30, is a metal complex of formula IIId

R ³ 0-juvv Nj (IId) wherein

R ¹ is a hydrogen atom or a metal ion equivalent having an atomic number of 23 to 29, 42 to 46 or 58 to 70,

R ² and R ³ are, independently of one another, a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a benzyl group, a phenyl group, a -CH ₂ OH group or a -CH ₂ OCH 3 group, and

U is -C 6 H ₄ -O-CH ₂ -m, - (CH ₂ ) 1-5 -ω, phenyl, -CH ₂ -NHCO-CH ₂ -CH (CH 2 COOH) -C ₅ H ₄ -m , -C _S H ₄ - (OCH ₂ CH ₂₎ 0-1 -N (CH ₂ COOH) -CH ₂ - (O, or alkylene group of 1 to 12 carbon atoms, or C ₇ -C ₂ -C ₁ H ₄ -O-, optionally interrupted by one or more oxygen atoms, 1 to 3 -NHCO- groups, 1 to 3 -CONH- groups, and / or substituted with 1 to 3 - (CH ₂ ) 0-5COOH groups, where ω is the point of attachment to the group -CO-, or the formula IIld

where R ¹ is as defined above, R ⁴ is a hydrogen atom or a metal ion equivalent given in the definition of R ¹ and (J ¹ is -C ₆ H ₄ -O-CH ₂ -m-, where ω is the point of attachment to the group -C0 or of the formula IVd group

wherein R ¹ and R ² are as defined above, or of the general formula VdA or VdB '-COOR ¹

ROOC

VNr ^C00R1

- COOR ¹ (VdA)

COOR ¹

COOR ¹ • w * —C

\ _n -COOR ¹ - - COOR ¹ (VdB) wherein R ¹ is as defined above, or of formula Vld

ROOC— \ j¾N

ROOC— ^x

CO-COOR ¹ (Vld) wherein R ¹ is as hereinbefore defined or of the general formula VIIId

Wherein R ¹ is as defined above, and U ¹ is -C 6 H 4 -O-CH 2 -W-, where w is the point of attachment to the -CO- group, and the acid groups optionally present in the residue K may be present in the form of salts with organic and / or inorganic bases or amino acids or amino acid amides,

G is at least three times a functionalized moiety selected from the following moieties a) to g):

a)

b)

H and N-fCi-γC-CO- ^H NH i β

H

Y ^ CO-C ^ their -nv ^ p

NH i

and

c)

d)

e)

f)

g)

2 / 2-3

H-CO- ^ β

h) γ -co- (CH.

NH f

i) β-y CO- (CH 2), -CH-CO-y> y

NH where a denotes the point of attachment of G to the complex K, β denotes the point of attachment of G to the remainder of R and γ denotes the point of attachment of G to the remainder of Z,

Z is y - ^ n-sq ₂ - £

YC (O) CH ₂ O (CH ₂ ) 2 -e, where γ denotes the point of attachment of Z to the radical G and ε denotes the point of attachment of Z to the perfluoroalkyl radical R ^F ,

R is a polar radical selected from complex K of the formulas Ild-VIIId, wherein R ¹ is a hydrogen atom or a metal ion equivalent having an atomic number of 20, 23-29, 42-46 or 58-

70, and the radicals R ² , R ³ , R ⁴ , U and U ¹ are as defined above, or a folic acid residue or a hydrocarbon chain having 2 to 30 carbon atoms, straight or branched, saturated or unsaturated, bound to radical G via -CO-, -SO2- or directly, optionally interrupted by 1 to 10 oxygen atoms, 1 to 5 -NHCO- groups, 1 to 5 -CONH- groups, 1 to 2 sulfur atoms, 1 to 5 -NH- groups, or 1 to 2 phenyl groups which may be optionally substituted with 1 to 2 hydroxy groups, 1 to 2 amino groups, 1 to 2 carboxyl groups or 1 to 2 SO 3 H groups, or optionally substituted with 1 to 8 hydroxy groups, 1 to 5 groups

-COOH, 1 to 2 SO ₃ H groups, 1 to 5 amino groups, 1 to 5 alkoxy groups having 1 to 4 carbon atoms ¹¹ , m ¹ , p ² are independently integers 1 or 2.

The compounds of the invention are intended for use as NMR diagnostics, so the metal ion of the signal group must be paramagnetic. Such ions are especially divalent and trivalent ions of elements having atomic numbers 23 to 29, 42 to 46 and 58 to 70. Suitable ions are, for example, chromium, ferrous, cobalt, nickel, copper, praseodymium, neodymium, samarium and yterbitium. Due to their strong magnetic moment, gadolinium, terbite, dysprozy, holmite, erbite, ferric and manganese ions are particularly suitable.

Particularly suitable are manganese, ferrous, ferric, praseodymium, neodymium, samarium, gadolinium and yterbitium ion, especially dysprozium ion.

Acidic hydrogen atoms optionally occurring in R ¹ , i.e., those which cannot be substituted by a central ion, may optionally exist partially or fully in the form of salts with cations of inorganic and / or organic bases or amino acids or amino acid amides.

Suitable inorganic cations are, for example, lithium ion, potassium ion, calcium ion and especially sodium ion. Suitable organic base cations include, but are not limited to, cations derived from primary, secondary, or tertiary amines, such as etanclamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine, and especially N-methylglucamine. Suitable amino acid cations are especially lysine, arginine and ornithine, as well as amides of originally acidic or neutral amino acids.

Particularly preferred compounds of formula Id are those having the macrocycle K of formula Ild, IIId, Vd3 or VIIId.

The radical U in the metal complex K is preferably -CH 2 - or -C 6 H 4 -O-CH 2 -O 1, where ω is the point of attachment to the group

-C0-.

The alkyl groups R ² and R ³ in the macrocycle of formula IIc may be straight or branched. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl 1,2-dimethylpropyl. Preferably, R ² and R ³ independently of one another are hydrogen or alkyl having 1 to 4 carbon atoms.

In a particularly preferred embodiment of the invention R ^{2 is a} methyl group and R ³ is a hydrogen atom.

The benzyl group or the phenyl group R ² or R ^J in the macrocycle K of formula (IIId) may also be substituted on the ring.

The polar radical R in formula Id represents a particularly preferred embodiment of the complex K, which may be, inter alia, a Gd ³⁺ or Mn ²⁺ complex as well as a Ca ²⁺ complex. Particularly preferred as the polar radicals R are the complexes K of the formula Ild, IIId, VdA or Vlld. Particularly preferred are polar residues, wherein R ¹ is as a metal ion equivalent of atomic numbers 20, 25, 39 and 64th

In another preferred embodiment of the invention, the group R has the following meaning:

-C (O) CH7CH2SO3H,

-C (O) CH2OCH2CH2OCH2CH2OH,

-C (O) CH2OCH2CH2OH,

-C (O) CH2OCH2CH (OH) CH ₂ OH,

-C (O) CK ₂ NH-C (O) ch ₂ cooh,

-C (O) CH ₂ CH (OH) CH ₂ OH,

-C (O) CH ₂ OCH ₂ COOH,

-so ₂ ch ₂ ch ₂ cooh

-C (O) -C ₆ H ₃ - (m-COOH) 2,

-C (O) CH ₂ O (CH ₂ ) 2 -C ₆ H ₃ - (m-COOH) ₂ ,

-C (O) CH ₂ OC ₆ H ₄ -m-SO ₃ H,

-C (O) CH ₂ NHC (O) CH ₂ NHC (O) CH ₂ OCH ₂ COOH,

-C (O) CH ₂ OCH ₂ CH ₂ OCH ₂ COOH,

-C (O) CH ₂ OCH ₂ CH (OH) ch ₂ o-ch ₂ ch? Oh,

-C (O) CH ₂ OCH ₂ CH (OH) CH ₂ O-CH ₂ CH (OH) -CH ₂ OH,

-C (O) CH ₂ SO ₃ H,

-C (O) CH ₂ CH ₂ COOH,

-C (O) CH (OH) CH (OH) CH ₂ OH,

C (O) CH ₂ O [(CH _{2) 2} 0H-9-CH _2,

C (O) CH ₂ O [(CH _{2) 2} O] _1-5 -H.

-C (O) CH ₂ OCH (CH ₂ OH) ₂ ,

-C (O) CH ₂ OCH (CH ₂ OCH ₂ COOH) 2,

-C (O) -C ₆ H ₃ - (m-OCH ₂ COOH) 7,

-C (O) -CH ₂ O- (CH ₂ ) ₂ O (CH ₂ ) ₂ O- (CH ₂ ) ₂ O (CH ₂ ) ₂ and ₃ , preferably -C (O) CH ₂ O [(CH ₂₎ ) _; O] ₄ -CH ₃ .

In another preferred embodiment, R is a folic acid residue.

Compounds of formula (Id) according to the invention are preferred when R ^F is -C _n F _2n + 1, where n is preferably a number from 4 to 15. Particularly preferred are the radicals -C ₄ F ₃ , -C ₆ F ₃ , - _C, Fn, F ₁₂ C ₂ 5, and

-c ₁₄ f ₂₉ . ''

At least three times the functionalized residue G in the general formula Id representing "molecular scaffolding" is in a preferred embodiment of the invention lysine residue (a) or (b).

Z denotes the linker represented by the general formula Id, where the radical y- is preferred

N-SO ₂ - £

Perfluoroalkyl metal complexes with polar groups of the general formula Id (K), '- G - (Z-R'). ¹ , ¹ Cd) (R) p ² wherein K, G, R, Z, R ^F , ¹¹ , m ¹ and P ² are as defined above, are prepared by preparing a carboxylic acid of the formula Tik

wherein R ⁵ is an equivalent of a metal ion having an atomic number of 23 to 29, 42 to 46 or 58 to 70, or a carboxylic acid protecting group and R ² , R ³ and U are as defined above, or a carboxylic acid of formula Illk

(IIIk) wherein R ⁴ , R ⁵ and U ¹ are as defined above, or a carboxylic acid of formula IVk

OH (IVk) wherein R ⁵ and R ² are as defined above, or a carboxylic acid of formula V k or V m

R OOC 1 R 6 z-COOH

Z ⁱⁿ -coor ⁵ —N

-COOR ⁵ -COOR ⁵ \ z

HOOC '

- _N x-C00R ⁵

Of --COOR ⁵ \ N / ₅ \ _K ^ - COOR ^{5 X} - ^'N' -COOR ⁵ (V?) (V m) wherein R ⁵ is as defined above, or a carboxylic acid of formula Wolf

R OOCR ⁵ OOC: nn;

-CO-OH

-COOR ⁵ (Vlk) wherein R ⁵ is as hereinbefore defined, or a carboxylic acid of formula VIIk

iP ^ OH (Vllk) wherein R ⁵ and U ¹ are as defined above, optionally in activated form, is allowed to react in a known manner with an amine of the formula VIIId

H - G - (ZR ^F ) _m ¹ | (VIIId) (R) p ² wherein G, R, Z, R ^F , m ¹ and p ¹ are as previously defined by a condensation reaction and, if appropriate, subsequent cleavage of the occurring protecting groups, to form a metal complex of formula Id, or when R ⁵ is a protecting group, after cleavage of this protecting group, it is reacted in a known manner with at least one metal oxide or metal salt of elements having atomic numbers 23 to 29, 42 to 46 or 58 to 70 and finally acidic hydrogen atoms as necessary substituted with cations of inorganic and / or organic bases, amino acids or amino acid amides.

Said carboxylic acids of the formulas Z1k to Vk1k are either known compounds or can be prepared by the procedures given in the examples. The preparation of carboxylic acids of the formula IIk is known from DE 196 52 386. The preparation of carboxylic acids of the formula IVk is described in DE 197 28 954.

A prodrug of the compounds of formula VdA is N ³ - (2, β-dioxomorfolinoetyl) ^e N - (ethoxycarbonylmethyl) -3,6-diazaoktándiová, which is described in EP 263,059th

The compounds of formula VdB are derived from an isomer of diethylenetriaminepentaacetic acid, which is bound via acetic acid at a medium nitrogen atom. This DTPA is described in DE 195 07 819 and DE 195 08 058.

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

Compounds of formula IIId are derived from 1- (4-carboxymethoxybenzyl) ethylenediaminetetraacetic acid, which is described in US 4,622,420.

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

In another preferred embodiment of the invention, galenical formulations containing paramagnetic and diamamic perfluoroalkylated substances may be used. Preferably, the paramagnetic and diamagnetic materials are available in an aqueous solvent.

As the paramagnetic perfluoroalkylated compounds in the compositions of the present invention, all of the metal complexes of formula I, Ia, Ib, Ic and / or Id described above can be used.

The diamagnetic perfluoroalkylated compounds are those of formula XX

R ^F -L ² -B ² (XX) wherein R ^f is a straight or branched perfluoroalkyl radical having 4 to 30 carbon atoms, L ² is a linker and B ² is a hydrophilic group. The linker L ² is a direct link, -SO ₂ - or a straight or branched hydrocarbon chain of up to 20 carbon atoms, which may be substituted by one or more hydroxy, -COO ', -SO ₃ and / or may contain one or more -O-, -S-, -CO-, -CONH-, -NHCO-, -CONR ⁹ -,

-NR ⁹ CO-, -SO 2 -, -PO 4 '-, -NH-, -NR ⁹ -, an aryl ring or piperazine, wherein R ⁹ is an alkyl radical having 1 to 20 carbon atoms, which may contain one or more oxygen atoms and / or may be substituted by a -COO 'or -SO3 group.

The hydrophilic group B ² is a mono- or disaccharide, a close -COO 'or -SO ₃ ' group, a dicarboxylic acid, isophthalic acid, picolinic acid, benzenesulfonic acid, tetrahydropyranedicarboxylic acid, 2,6-pyridinedicarboxylic acid, quaternary ammonium group, aminopolycarboxylic acid acid aminodipolyetylénglykolsulfónová, aminopolyetylénglykolová group, a group of -S0 ₂ - (CH _{2) 2} ^_ 0H, polyhydroxyalkylene chain with at least two hydroxyl groups or one or more polyethylene glycol chains with at least two glycol units, wherein the polyethylene glycol chain is terminated with hydroxy or methoxy. Such compounds are already partially known, in part these compounds have been newly synthesized in order to produce the formulations of the invention. Known per-

fluoroalkylic substances publications: and their preparations are described in following J. G. Riess, Journal of Drug Targeting, 2, 455-468 1994); J. B. Nivet et al., Eur. . J. Med. Chem. 26, 953-960 (1991); M. -P. Krafft et al., Angew. Chem (10), 1146-1148 (1994);

Lanier, M., et al., Tetrahedron Letters, 36 (14), 2491-2492 (1995);

F. Guillod et al., Carbohydrate Research, 261: 37-55 (1994);

S. Achilef et al., Journal of Fluorine Chemistry, 70, 19-26 (1995);

L. Cary et al., Tetrahedron, 51 (47), 13073-13088 (1995);

F. Szoni et al., Journal of Fluorine Chemistry, 42: 59-68 (1989);

H. Wu et al., Supramolecular Chemistry, 3: 175-180 (1994);

F. Guileri et al., Angew. Chem. 106 (14), 1583-1585 (1994);

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

J. Greiner et al., Journal of Fluorine Chemistry 56: 285-293 (1992);

A. Milius et al., Carbohydrate Research 229: 323-336 (1992);

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

G. Merhi et al., J. Med. Chem., 39, 4483-4488 (1996);

V. Church et al., Journal of Fluorine Chemistry, 83, 151-158 (1997);

A. Ould Amanetoullah et al., Journal of Fluorine Chemistry, 84,

149-153 (1997);

J. Chen et al., Inorg. Chem., 35, 1590-1610 (1996);

L. Cary et al., Tetrahedron Letters, 36 (4), 539-542 (1995);

M. M. Chaabouni et al., Journal of Fluorine Chemistry, 46, 307-315 (1990);

A. Milius et al., New J. Chem., 15, 337-344 (1991);

M.-P. Krafft et al., New J. Chem., 14: 869-875 (1990);

J. B. Nivet et al., New J. Chem., 18, 861-869 (1994);

C. Santaella et and 1., New J. Chem., 15, 685-692 (1991); c. Santaella et and 1., New J. Chem., 16, 399-404 (1992); A. Milius et al. r New J. Chem., 16: 771-773 (1992); F. Szonyi et al. r Journal of Fluorine Chemistry, 55, 85-92

(1991);

C. Santaella et al. Angew. Chem (5), 584-586 (1991); M. · -P. Krafft et al. . Angew. Chem (5), 783-785 (1993); • a EP 0 548 096 BI.

The preparation of the novel perfluoroalkyl compounds follows an analogous literature preparation of the already known compounds and is described in the Examples. They are compounds of the general formula XXI p-X ¹ (XXI) wherein R ^f is a straight or branched perfluoroalkyl radical having 4 to 30 carbon atoms and X ¹ is a radical selected from the group consisting of the following substituents (n is a number from 1 to 10) )

ΖΙ

OH

N 'H

θ-'Χ.ο

Preferred diamagnetic perfluoroalkylated compounds are those having a monosaccharide as the hydrophilic group B ² .

Particularly preferred diamagnetic perfluoroalkyl compounds comprise a perfluoroalkyl radical R ^F having 6 to 12 carbon atoms, a linker L ² wherein Im is -SO 2 - or a straight or branched hydrocarbon chain having up to 20 carbon atoms, which may contain one or more groups -O-, -CO-,

-CONH-, -NHCO-, -CONR-, -NRC0-, -SO2- or a piperazine, where R is as defined above and B monosaccharide residue as ^second

Other suitable diamagnetic perfluoroalkyl compounds are the cyclodextrin-perfluoroalkyl compound conjugates. These conjugates consist of α-, β- or γ-cyclodextrin and a compound of formula XXII

A ¹ -L ³ -R ^F (XXII) wherein A ¹ is an adamantane molecule, biphenyl molecule or anthracene molecule, L ³ is a linker and R ^F is a straight or branched perfluoroalkyl radical having 4 to 30 carbon atoms. The linker L ^J is a straight hydrocarbon chain having 1 to 20 carbon atoms, which may be interrupted by one or more -CO-, -SO ₂ -r -CONH-, -NHCO-, -CONR-, -NRCO-, - NH-, -NR- or picerazine, wherein R is an alkyl radical having 1 to 5 carbon atoms.

The following compounds are particularly preferred:

at

C ₈ Fi7

c ₃ f ₁₇

The galenical compositions of the present invention contain paramagnetic and diamagnetic perfluoroalkyl compounds in a mixture ratio of between 5: 95 to 95: 5. Mixed ratios between 40: 60 and 60: 40 of both are preferred. Both substances are used in millimolar concentrations. These are concentrations between 0.5 and 1000 mmol / l of solvent. Preferably, the solvent is water. The metal concentration in the formulation ranges from 50 to 250 mmol / l.

Preference is given to mixtures of a paramagnetic and diamagnetic perfluoroalkyl compound, wherein the perfluoroalkyl chain contains from 6 to 12 carbon atoms. Particularly preferred are mixtures wherein both the paramagnetic and diamagnetic perfluoroalkyl compound comprise a perfluoroalkyl chain having 8 carbon atoms.

The galenical preparations are prepared by weighing the paramagnetic perfluoroalkyl compound (component A) and the diamagnetic perfluoroalkyl compound (component B) in a molar fraction between 0.05 and 0.95 and dissolving in a suitable solvent. A particularly suitable solvent is water. Additional galenic components such as buffers and calcium salts of complexing agents are added in excess to this solution. The solution is then vigorously stirred at a temperature of 10 ° C to 100 ° C. Alternatively, the solution is left in an ultrasonic bath. Another alternative is to treat the solution by microwaves.

In the case of substances in which the individual components do not dissolve in water, the use of a solvent such as an alcohol (e.g. methanol or ethanol) or another water-miscible solvent, which is then slowly distilled off, proves to be advantageous. The distillation can be carried out under vacuum. The residue was finally dissolved in water and the solution was filtered. It is also possible to proceed by dissolving the individual components separately in a solvent, then combining them together and processing them further as described above. It has been found to be advantageous to use relatively high concentrations of solution (greater than 100 mmol) of the metal complex (component A) to which pure component B is added and the mixture is then stirred or treated by ultrasound or microwaves as mentioned above.

In general, it can be said that as particularly preferred compounds, the gadclinium I-XVI complexes listed in Table 1, which meet the criteria of the present invention, are particularly preferred.

As paramagnetic compounds of formula I, Ia, Ib, 1c and Id according to the present invention, as well as paramagnetic and camagnetic perfluoroalkyl compounds, they are suitable for the above-mentioned use as contrast agents in MR imaging for imaging of plaques, tumors and necroses.

Table 1: Particularly preferred metal complexes for use in accordance with the present invention

Complex Literature, title

I WO 97/26017, Example 33f

Gadolinium complex with 10- [1-methyl-2-oxo-3-aza-5-oxo- (4-perfluorooctylsulfonylpiperazin-1-yl) pentyl] -1,4,7-tris (carboxymethyl) -1,4, 7,10-tetraazacyclododecane

II WO 97/2601, Example 2c

Gadolinium complex with 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-heptadecafluorohep tadecyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

III WO 97/2601, Example 34b

Gadolinium complex with 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 97/2601, Example 1c

Gadolinium complex with 10- [2-hydroxy-4-aza-5-oxo-7-aza-7- (perfluorooctylsulfonyl) nonyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane '

In Example 2c, this application

1,4,7-Tris (carboxylatomethyl) -10- (3-aza-4-oxohex-5-yl) acid -N- (2,3-dihydroxypropyl) -N- (1 H, 17 H, 2 H, 2H, AH, AH, 5H, 5H-3-oxa-perfluorotridecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex

VI WO 97/26017, Example 3c

Gadolinium complex with 10- [2-Hydroxy-4-oxa-1 H, 2 H, 3 H, 3 H, 5 H, 5 H, 6 H, 6 H -fluorotetradecyl] -1,4,7-tris (carboxymethyl) -1,4, 7,10-tetraazacyclododecane

VII Example 5e, this application

1,4.7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohex-5-yl) -acid-N- (3,6,9,12,12-pentaoxa) hexadecyl] -N- , 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl] amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex

VIII Example 3c, this application

1.4.7- Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohex-5-yl) -acid-N- (5-hydroxy-3-oxapentyl) -N- (1H, IH, 2H, 2H) 1,4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl] amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex

IX Example 6b, this application

1,4.7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohex-5-yl) -acetic acid N- (3,6,9,16-tetraoxa-13-aza-14-oxo- ( C _and C i-heptadecafluoro) hexakozyl] -amide} -l, 4,7,10-tetraazacyclododecane, gadolinium complex

X Example 1c, this application

1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohex-5-yl) -acid-N- (2-methoxyethyl) -N- (1H, IH, 2H, 2H, 4H) [4H, 5H, 5H-3-oxaperfluorotridecyl] amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex

XI WO 97/26017, Example 32c

Gadolinium complex with 10- [2-hydroxy-4-aza-5-oxo-7-oxa-10, 10, II, 11,12,12,13,13,14,14,15,15,16,16, 17,17,18,18,19,19-henosafluoronadecyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetra61 with azacyclododecane

XII WO 97/26017, Example 38d

Gadolinium complex with 10- [2-hydroxy-4-aza-5-oxo-11-aza-11- (perfluorooctylsulfonyl) tridecyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

XIII WO 97/2607, Example 35d

Gadolinium complex with 10- [2-hydroxy-4-aza-5-oxo-7-aza-7- (p-fluoroctylsulfonyl) -8-phenyloctyl] -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- (carboxymethyl) -10- [N1-methyl-3,6-diaza-2,5,8-trioxooctane-1,8-diyl] - 1,4,7,10-tetraazacyclododecane-10- [N-2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluoridecanoyl] -1,4,7,10-tetraazacyclododecane, gadolinium complex

XV Example 21f, this application

6-N- [1,4,7-Tris (carboxymethyl (-1,4,7,10-tetraazacyclododeca) -10- [N- (pentanoyl-3-aza-4-oxo-5-methyl)] - 2- N- [1-O-α-D-carbomethylmanopyranose] -L-lysine-1- [1- (4-perfluorooctylsulfonyl) piperazine] amide, gadolinium complex

XVI Example 54b, this application

2,6-N, N'-Bis [1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl)] -lysine- [1- (4-perfluorooctylsulfonylpiperazine) amide, gadolinium complex

Table 2: Physico-chémieké complex parameters according to this of the invention shown in Table 1 complex CMC 2 Rh R * plasma number (Mol / 1) (Nm) (1 / mmol · s) I 1.86 x 10 ^-6 4.6 35, 7 II 2.30 x 10 ^-5 14 33 III 7.06 x 10 ^-6 3.2 24, 9 IV 1.0 x 10 ^-6 31.5 29.7 in 3.9 x 10 ' ^e 4.4 9.6 VI 1.44 x 10 ^-5 3.2 27.5 VII 5.20 x 10 ^-5 3.0 30, 3 VIII 2.92 x 10 ^-5 25 21.2 IX 2, 65 x 10 ^-6 6, 0 13, 3 x 7, 90 x 10 ^-6 5.4 25, 7 XI 2.88 x 1O ^'E 35, 5 24.8 XII 1.07 x 10 ^-5 7.4 30.5 XIII 3.25 x 10 ^-6 4.3 34.0 XIV 8, 90 x 10 ^-4 2.2 19, 5 XV 2.50 x 1Ο ' ^δ 4.4 15, 9 XVI 3.90 x 10 ^-6 4.9 21.3

CMC

Rh R ¹ critical micellar concentration hydrodynamic micellar mean relaxivity

DETAILED DESCRIPTION OF THE INVENTION

Example 1

(a) 2H, 2H, 42H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid N- (2-methoxyethyl) amide

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 57,5,5H-3-oxaperfluorotridecanoic acid in 300 mL of dichloromethane was added 8.90 g (70 mmol) of oxalyl chloride and the mixture was stirred for 12 hours at room temperature. . The mixture was evaporated to dryness under reduced pressure. The residue was 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 was stirred at 0 ° C for 3 hours and then at room temperature for 6 hours. Then 300 ml of 5% aqueous hydrochloric acid solution was added and the mixture was stirred vigorously for 15 minutes. The organic phase was separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 20: 1). Yield: 30.28 g (91% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) amine g (51.79 mmol) of the title compound of Example 1a) was treated with was dissolved in 300 mL of tetrahydrofuran and 31 mL of a 10 M solution of borane dimethyl dimethyl sulfide (in tetrahydrofuran) was added. The mixture was heated to boiling for 16 hours. Then the mixture was cooled to 0 ° C, 200 ml of methanol was added dropwise and the mixture was finally evaporated to dryness in vacuo. The residue was taken up in the mixture

300 ml of ethanol and 50 ml of a 10% aqueous hydrochloric acid solution and the reaction mixture was stirred for 8 hours at 40 ° C. The mixture was then evaporated to dryness in vacuo, the residue taken up in 300 ml of 5% sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The organic phases were combined and dried over magnesium sulfate, evaporated to dryness under reduced pressure and purified by silica gel chromatography (mobile phase: dichloromethane / 2-propanol 20: 1). Yield: 26.93 g (92% of theory) of a colorless solid.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-oxohex-5-yl) -acetic acid -N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H) 1,4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex (metal complex X) g (15.88 mmol) of gadolinium acid complex 10 - [1- (carboxymethylcarboamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml at 60 ° C dimethylsulfoxide. The mixture was cooled to 15 ° C and 8.98 g (15.88 mmol) of the title compound of Example 1b) was added. The mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The reaction mixture was stirred for 12 hours at room temperature. The reaction solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether, and the mixture was stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in a small amount of ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 15.14 g (81% of theory) of a colorless amorphous powder. Water content: 5.7 i.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-oxaperfluorodecanedioic acid N- (2,3-dihydroxypropyl) amide

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid in 300 mL of dichloromethane was added 8.90 g (70 mmol ·) of oxalyl chloride and the reaction mixture was stirred for 12 hours at room temperature. The mixture was then evaporated to dryness under reduced pressure. The residue was 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 was stirred for 3 hours at 0 ° C and finally for 6 hours at room temperature. Then 300 ml of 5% aqueous hydrochloric acid solution was added and the mixture was stirred for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 15: 1). Yield: 29.70 g (87% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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-Cxaperfluorotridecyl) amine g (48.8 mmol) of the title compound of Example 2a ) was dissolved in 300 mL of tetrahydrofuran and 50 mL of a 10 M solution of borane dimethylsulfide (in tetrahydrofuran) was added. The reaction mixture was heated to reflux for 16 hours. It was then cooled to 0 ° C, 300 ml of methanol was added dropwise and finally the mixture was evaporated to dryness under reduced pressure. The residue was taken up in a mixture of 300 ml of ethanol and 50 ml of a 10% aqueous hydrochloric acid solution and stirred for 8 hours at 60 ° C. The mixture was evaporated under reduced pressure and the residue was taken up in 5% aqueous sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The organic phase was dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: dichloromethane / methanol 15: 1). Yield: 24.07 g (85% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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-oxohex-5-yl) -acetic acid N- (2,3-dihydroxypropyl) -N- (1H, 1H, 2H) -1,4,7,10-tetraazacyclododecane, gadolinium complex (metal complex V) g (15.88 mmol) of gadolinium-10- acid complex, 2H, 4H, 4H, 5α, 5β-3-oxaperfluorotridecyl) amide : 1- (carboxymethylcarboamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. . The mixture was cooled to 15 ° C and 9.21 g (15.88 mmol) of the title compound of Example 2b) was added. The mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The mixture was then stirred for 2 hours at room temperature. The solution was poured into a mixture of 200 ml acetone and 1300 ml. diethyl ether, and the mixture was stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in a small amount of ethanol / water and purified by chromatography on RP-18 silica gel. (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.09 g (85% of theory) of a colorless amorphous powder. Water content: 6.3%

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-oxaperfluorotidecanoic acid N- (5-hydroxy-3-oxapentyl) amide

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5/7-3-oxaperfluorotridecanoic acid in 300 ml of dichloromethane was added 8.90 g (70 mmol) of oxalyl chloride and the mixture was stirred for 12 hours at room temperature. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and added dropwise at 0 ° C to a solution of 6.25 g (60 mmol) of 5-hydroxy-3-oxapentylamine and 6.07 g (60 mmol) of triethylamine in 200 mL of dichloromethane. The mixture was stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. Then 300 ml of 5% aqueous hydrochloric acid solution was added and the mixture was stirred vigorously for 15 minutes. The organic phase was separated, dried over magnesium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 15: 1). Yield: 32.20 g (92% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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- (S-Hydroxy-3-oxapentyl) -N- (l / s, lH, 2H _R 2H, 4H, 4H, 5H, 5H-2-oxaperfluórcridecyl) -amine g (49.24 mmol) of the The title of Example 3a) was dissolved in 300 mL of tetrahydrofuran and 31 mL of a 10 M solution of borane dimethyl dimethyl sulfide (in tetrahydrofuran) was added. The reaction mixture was heated to reflux for 16 hours. Then, the reaction mixture was cooled to 0 ° C, 200 mL of methanol was added dropwise, and finally the mixture was evaporated to dryness under reduced pressure. The residue was taken up in a mixture of 300 ml of ethanol and 50 ml of a 10% aqueous hydrochloric acid solution and heated at 50 ° C for 10 hours. The reaction mixture was evaporated to dryness in vacuo, the residue was taken up in 300 ml of 5% aqueous sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The organic phase was dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / 2-propanol 20: 1). Yield: 26.09 g (89% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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 (carboxylateomethyl) -10 - [(3-aza-4-oxohex-5-yl) -acetic acid N- (5-hydroxy-3-oxapentyl) -N- (1H, 1H) , 27 [mu], 2H, 4H, 4H, 57 [mu], 57 [3- (3-oxaperfluorotridecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex (metal complex VIII) g (15.88 mmol) of gadolinium acid complex 10 - [1- (carboxymethylcarboamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml at 60 ° C DMSO. The mixture was cooled to 15 ° C and 9.45 g (15.88 mmol) of the title compound of Example 3b) was added. The mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The mixture was stirred for 12 hours at room temperature. The solution was then poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether and then stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in a small amount of ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.10 g (84% of theory) of a colorless amorphous powder. Water content: 5.7 h

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-oxaperfluorotridecanoic acid N- (2-hydroxyethyl) amide

To 30 g (57.45 mmol) of 2H, 2H, 4H, AH, 5H, 57'-3-oxaperfluorotidecanoic acid in 300 mL of dichloromethane was added 8.90 g (70 mmol) of oxalyl chloride and the mixture was stirred for 12 hours at room temperature. temperature. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and added dropwise at 0 ° C to a mixture of 3.66 g (60 mmol) of 2-aminoethanol and 6.07 g (60 mmol) of triethylamine dissolved in 200 mL of dichloromethane. The reaction mixture was stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. Then 300 ml of 5% aqueous hydrochloric acid solution was added and the mixture was stirred vigorously for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 20: 1). Yield: 28.90 g (89% of theory).

Elemental analysis:

Calculated: 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- (17H, 1H, 2H, 2H, 4H, AH, 5H, 5H-3-oxaperluorotridecyl) amine g (49.54 mmol) of the title compound of Example 4a) was dissolved in 300 ml of tetrahydrofuran and 3 ml of a 10 M solution of boranedimethylsulfide (in tetrahydrofuran) was added. The mixture was heated to boiling for 16 hours. It was then cooled to 0 ° C, 200 ml of methanol was added dropwise, and then the reaction mixture was evaporated to dryness under reduced pressure. The residue was taken up in a mixture of 300 ml of ethanol and 50 ml of a 10% aqueous hydrochloric acid solution and the mixture was stirred for 10 hours at 50 ° C. The mixture was evaporated to dryness in vacuo, the residue was dissolved in 300 ml of 5% aqueous sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The organic phase was dried over magnesium sulphate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: dichloromethane / 2-propanol 15: 1). Yield: 25.12 g (92% of theory) of a colorless solid.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-oxohex-5-yl) acid-N- (2-hydroxyethyl) -N- (1H, 1H, 2H, 2H) -1,4,7,10-tetraazacyclododecane, complex with gadolinium g (15.88 mmol) of gadolinium-10- [1- (carboxymethylcarboamoyl) acid complex, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) amide] ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The reaction mixture was cooled to 15 ° C and 8.75 g (15.88 mmol) of the title compound of Example 4b) was added. The mixture was stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The mixture was stirred for 12 hours at room temperature. The reaction solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in a small amount of ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.81 g (91% of theory) of a colorless amorphous powder. Water content: 7.2%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-oxaperfluorotridecanoic acid amide

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorodecanoic acid in 300 mL of dichloromethane was added 8.90 g (70 mmol) of oxalyl chloride and the mixture was stirred for 12 hours at room temperature. Then, the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 200 mL of dichloromethane. Then ammonia gas was bubbled through the solution at 0 ° C for approximately 2 hours. The mixture was stirred for 4 hours at 0 ° C and then for 2 hours at room temperature. Then 300 ml of a 5% aqueous hydrochloric acid solution was added and the mixture was stirred vigorously for 5 minutes. The organic phase was separated, dried over magnesium sulfate and then evaporated to dryness. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 20: 1). Yield: 27.85 g (93% of theory).

Elemental analysis:

Calculated: 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, SH-3-Oxaperfluorotridecylamine hydrochloride g (51.8 mmol) of the title compound of Example 5a) was dissolved in 300 mL of tetrahydrofuran and 31 mL of 10 was added. M solution of borenedimethylsulfide (in tetrahydrofuran). The mixture was heated to boiling for 16 hours. It was then cooled to 0 ° C, 200 mL of methanol was added dropwise and finally the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of 400 ml of ethanol and 100 ml of a 10% aqueous hydrochloric acid solution and stirred for 8 hours at 60 ° C. The mixture was evaporated in vacuo and the residue was recrystallized from a small amount of ethanol / diethyl ether. Yield: 26.75 g (95% of theory) of a colorless crystalline solid.

Elemental analysis:

Calcd: 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- (1 H, 2 H, 2 H, 4 H, 4 H, 5 H, 5 H-3-O-oxafluorotridecyl) amide

To a mixture of 26.5 g (48.74 mmol) of the title compound of Example 5b) and 14.8 g (146.2 mmol) of triethylamine dissolved in 300 mL of dichloromethane was added dropwise 14.24 g (50 mL) at 0 ° C. mmol) of 3,6,6,9,12,15-pentaoxahexadecanoyl chloride and the mixture was stirred for 3 hours at 0 ° C. 300 ml of 5% aqueous hydrochloric acid solution were added and the mixture was stirred vigorously for 30 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 20: 1). Yield: 32.03 g (87% of theory) of a colorless oil.

Elemental analysis:

Calculated: 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- (1 H, 2 H, 2 H, 2 H, A H, A H-3-oxaperfluorotidecyl) amine g (41.03 mmol) of the title compound from Example 5c) was dissolved in 300 mL of tetrahydrofuran and 25 mL of a 10 M solution of boranedimethylsulfide (in tetrahydrofuran) was added. The mixture was heated to reflux for 6 hours. The mixture was then cooled to 0 ° C, 200 mL of methanol was added dropwise, and then the reaction mixture was evaporated to dryness under reduced pressure. The mixture was poured into a mixture of 300 ml of ethanol and 50 ml of a 10% aqueous hydrochloric acid solution, and the reaction mixture was stirred at 40 ° C for 8 hours. The mixture was evaporated to dryness under reduced pressure, the residue was dissolved in 300 ml of 5% aqueous sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The organic phase was dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: dichloromethane / 2-propanol 15: 1). Yield: 27.68 g (91% of theory).

Elemental analysis:

Calculated: C 37.26; H, 4.35; N, 1.89; F, 43.56

Found: C, 37.11; H, 4.51; N, 1.73; F, 43.41

e) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohex-5-yl) -acetic acid N- (3,6,9,12,15-pentaoxahexadecyl) -N- (If1, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex (metal complex VII) g (15.88 mmol) complex gadolinium with 10- [1- (carboxymethylcarboamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved at 60 ° C in 100 mL of dimethylsulfoxide. The mixture was cooled to 15 ° C and 11.77 g (15.88 mmol) of the title compound of Example 5d) was added. The mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The reaction mixture was stirred for 12 hours at room temperature. The mixture was poured into a solution of 200 ml of acetone and 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in a small amount of ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 18.05 g (84% of theory) of a colorless amorphous powder. Water content: 6.2%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-oxohex-5-yl) acid-N- (12-amino-3,6,9-trioxadodecyl) amide] - 1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of gadolinium complex with 10- [1- (carboxymethylcarboamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,774

-triacetate, 1.35 g (31.76 mmol) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide were dissolved in 100 ml of dimethylsulfoxide at 60 ° C. The reaction mixture was cooled to 15 ° C, 3.51 g (17 mmol) of N, N '-dicyclohexylcarbodiimide was added, and the mixture was stirred for 5 hours at 15 ° C. The reaction mixture was filtered to remove urea. To the filtrate were added 14.66 g (60 mmol) of 1,12-diamino-3,6,9-trioxadodecane and 2.02 g (20 mmol) of triethylamine, and the mixture was stirred for 12 hours at room temperature. The solution was poured into a mixture of 1500 ml diethyl ether and 50 ml n-butanol and stirred for 30 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 12.66 g (69% of theory) of a colorless amorphous powder. Water content: 3.5%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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; E, 27.81; Gd 13.45

b) 1,4,7-Tris (carboxylatomethyl) -10 - ((3-aza-4-oxohex-5-yl) acid-N - [(3,6,9,16-tetraoxa-13-aza- 14-oxo (C26-Cig ^_ heptadecafluor) hexakozyl] -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-oxaperfluorotridecanoic acid, 0.85 g (20 mmol) of lithium chloride and 4.95 g (43 mmol) of N-hydroxysuccinimide are added. Dissolve at 25 ° C in 150 mL of dimethylsulfoxide. The reaction mixture was cooled to 15 ° C, 6.19 g (30 mmol) of N, N'-dicyclohexylcarbodiimide was added, and the mixture was stirred for 5 hours at 15 ° C. The solution was filtered to remove urea. 12.5 g (10.82 mmol) of the title compound of Example 6a and 3.29 g (32.47 mmol) of triethylamine were added to the filtrate and the mixture was stirred for 12 hours at room temperature. The solution was poured into 1300 mL of diethyl ether and 100 mL of acetone and stirred for 30 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 13.01 g (90% of theory). Water content: 6.7 I.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-oxohex-5-yl) -acetic acid N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, S) 1,3,4,10,10-tetraazacyclododecane, gadolinium complex (15.88 mmol) of gadolinium complex with 10- [1- (carboxymethylcarboamoyl) ethyl] -1,4,7,10-oxo-fluorotridecyl) amide , 10-tetraazacyclododecane-1,4,7-triacetic acid, 1.35 g (31.76 mmol) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide were dissolved in 100 ml of dimethylsulfide at 60 ° C. oxide. The mixture was cooled to 15 ° C, 3.51 g (17 mmol) of N, N'-dicyclohexylcarbodiimide was added and the reaction mixture was stirred for 5 hours at 15 ° C. The reaction mixture was filtered to remove urea. 8.63 g (15.88 mmol) of the title compound of Example 5b) and 5.06 g (50 mmol) of triethylamine were added to the filtrate, and the reaction mixture was stirred for 12 hours at room temperature. The solution was poured into 1500 ml of diethyl ether and 100 ml of acetone and stirred for 30 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 13.86 g (78% of theory) of a colorless amorphous powder. Water content: 9.3%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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) N- (2,3,4,5,6-Pentahydroxy) hexylamide acid

2H, 2H, 4H, 4H, 5H, 5 / 7-3-oxaperfluorotridecane

To 30 g (57.45 mmol) of 2/7, 2/7, 4/7, 4/7, 5/7, 5 / 7-3-oxaperfluorotidecanoic acid in 300 mL of dichloromethane was added 8.90 g (70 mmol). of oxalyl chloride and the reaction mixture was stirred for 12 hours at room temperature. It was then evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and added dropwise at 0 ° C to a solution of 10.87 g (60 mmol) of glucamine and 6.07 g (60 mmol) of triethylamine in 150 mL of dichloromethane and 150 mL of dioxane. The reaction mixture was stirred for 3 hours at 0 ° C and then for 8 hours at room temperature. 400 ml of 5% aqueous hydrochloric acid solution were then added and the mixture was stirred vigorously for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / methanol 5: 1). Yield: 30.71 g (78% of theory).

Elemental analysis:

Calculated: 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, IH, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotidecyl) amine g (43.77 mmol) of compound The title compound of Example 8a) was dissolved in 300 mL of tetrahydrofuran and 50 mL of a 10 M solution of borane dimethyl dimethyl sulfide (in tetrahydrofuran) was added. The reaction mixture was heated at reflux for 48 hours. The reaction mixture was cooled to 0 ° C, 500 mL of methanol was added dropwise, and the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of 500 ml of ethanol and 100 ml of a 10% aqueous hydrochloric acid solution and stirred for 15 hours at 60 ° C. The reaction mixture was evaporated under reduced pressure, the residual shock was taken up in 400 ml of 5% sodium hydroxide solution and extracted five times with 400 ml of chloroform. The organic phase was dried over magnesium sulphate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: dichloromethane / methanol 3: 1). Yield: 19.69 g (67% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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-oxohex-5-yl) acid-N- (2,3,5,6-pentahydroxy) hexyl-N- (1H) , 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl] amide) -1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of gadolinium 10- [1- (carboxymethylcarboamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethylsulfate at 60 ° C. oxide. The reaction mixture was cooled to 15 ° C and 15.88 g (15.88 mmol) of the title compound of Example 8b) was added. The reaction mixture was stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The mixture was stirred for 12 hours at room temperature. The reaction mixture was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in a small amount of ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.10 g (79% of theory) of a colorless amorphous powder. Water content: 6.3%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-oxaperfluorotridecanoic 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-oxaperfluorotridecanoic acid in 300 mL of dichloromethane was added 8.90. g (70 mmol) of oxalyl chloride was added and the mixture was stirred for 12 hours at room temperature. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and added dropwise at 0 ° C to a solution of 9.67 g (60 mmol) of 5-amino-2,2-dimethyl-1,3-dioxepan-6-ol and 6.07 g ( 60 mmol) of triethylamine dissolved in 200 ml of dichloromethane. The mixture was stirred for 3 hours at 0 ° C and then for 5 hours at room temperature. 300 mL of water was added and the mixture was stirred for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 15: 1). Yield: 27.62 g (85% of theory).

Elemental analysis:

Calculated: C 34.30; H, 3.03; N, 2.11; F, 48.54

Found: C, 34.15; H, 3.19; N, 2.04; F, 48.37

b) N- (1-Hydroxymethyl-2,3-dihydroxypropyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotidecyl) amine g (40.58 mmol) of the title compound the title of Example 9a) was dissolved in 300 mL of tetrahydrofuran and 26 mL of a 10 M solution of borane dimethyl dimethyl sulfide (in tetrahydrofuran) was added. The mixture was heated to reflux for 20 hours. It was then cooled to 0 ° C, 300 ml of methanol was added dropwise and finally the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of 300 ml of ethanol and 100 ml of a 10% aqueous hydrochloric acid solution and stirred for 6 hours at 60 ° C. The mixture was evaporated to dryness under reduced pressure, the residue was dissolved in 400 ml of 5% aqueous sodium hydroxide solution and extracted five times with 250 ml of chloroform. The organic phase was dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / methanol 6: 1). Yield: 20.09 g (81% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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-oxohex-5-yl) -acetic acid N- (1-hydroxymethyl-2,3-dihydroxypropyl) -N- (17H) , 17i, 27i, 27i, 4i, 4i, 57i, 5i-3-oxaphtluorotridecyl] amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) gadolinium complex with 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved at 60 ° C in 100 mL of dimethylsulfoxide The mixture was cooled to 15 ° C and 9.71 g (15.88 mmol) of the title compound of Example 9b) was added. The reaction mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The mixture was stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether, and the mixture was stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in ethanol / water and purified by chromatography on a RP-18 silica gel column (mobile phase: tetrahydrofuran / acetohitrile / water gradient). Yield: 13.40 g (69% of theory) of a colorless amorphous powder. Water content: 9.1%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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) Perfluorooctylsulphonic acid N- [2- (Benzyloxycarbonylamino) ethyl] amide g (173.4 mmol) 1- (Benzyloxycarbonylamino) -2-aminoethane hydrochloride, 87.1 g (173.4 mmol) perfluorooctylsulfofluoride and 35.42 g ( 350 mmol) of triethylamine was heated at 80 ° C for 10 hours. The mixture was cooled to room temperature and directly poured onto a silica gel column for purification (mobile phase: dichloromethane / acetone 20: 1). Yield: 42.22 g (36% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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) N- (2-Aminoethyl) perfluorooctylsulfonic acid amide g (44.36 mmol) of the title compound of Example 10a) was dissolved in 300 ml of methanol, 5 g of palladium catalyst (10% Pd / C) were added and the mixture was hydrogenated overnight at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 24.05 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: 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-oxohex-5-yl) -A- [2- (perfluorooctylsulfonylamino) ethyl] amide} -1,4,7 10-tetraazacyclododecene, gadolinium complex g (15.88 mmol) of gadolinium complex with 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, 1.35 g (31.76 mmol) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide were dissolved in 100 ml of dimethylsulfoxide at 60 [deg.] C. The mixture was cooled to 15 [deg.] C. and 3.51 g were added. (17 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 5 hours at 15 ° C. To remove the urea the reaction solution was filtered and 8.61 g (15.88 mmol) of the title compound was added to the filtrate. Of Example 10b) and 2.02 g (20 mmol) of triethylamine and the mixture was stirred for 12 hours at room temperature. The solution was poured into a mixture of 1500 ml diethyl ether and 100 ml acetone and stirred for 30 minutes. The precipitate formed was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 15.76 g (86% of theory) of a colorless amorphous powder. Water content: 6.5%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-oxaperfluorotridecanoic acid N- [2- (benzyloxycarbonylamino) ethyl] amide

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid in 300 mL of dichloromethane was added 8.90 g (70 mmol) of oxalyl chloride, and the reaction mixture was stirred for 12 hours at room temperature. temperature. It was then evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and added dropwise to a solution of 13.84 g (60 mmol) of 1- (benzyloxycarbonylamino) -2-aminoethane hydrochloride and 12.14 g (120 mmol) of triethylamine in 200 mL of dichloromethane at 0 ° C. . The reaction mixture was stirred for 3 hours at 0 ° C and then for 5 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid solution were added and the mixture was stirred for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone: 1). Yield: 33.30 g (83% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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-oxaperfluorotridecanoic acid N- (2-Aminoethyl) amide g (42.96 mmol) of the title compound of Example 11a) was dissolved in 500 ml of methanol, added 5 g of palladium catalyst (10% Pd / C) and the mixture was hydrogenated overnight at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 24.24 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: 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 (carboxylateomethyl) -10 - {(3-aza-4-oxohex-5-yl) -acetic acid N- (3-aza-6-oxa-4-oxo- (C8-) Cis-heptadecafluoro) hexadeoyl} -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of gadolinium complex with 10- [1- (carboxymethylcarboamovl) ethyl] -1,4,7 , 10-tetraazacyclododecane-1,4,7-triacetic acid, 1.35 g (31.76 mmol) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide were dissolved in 100 ml of dimethylsulfoxide at 60 ° C. . The mixture was cooled to a 15 ° C replica, 3.51 g (17 mmol) of N, N'-dicyclohexylcarbociimide was added, and the mixture was stirred for 5 hours at 15 ° C. The solution was filtered to remove urea. 8.96 g (15.88 mmol) of the title compound of Example 11b) and 2.02 g (20 mmol) of triethylamine were added to the filtrate, and then the mixture was stirred for 12 hours at room temperature. The reaction mixture was poured into a mixture of 1500 ml diethyl ether and 100 ml acetone and stirred for minutes. The precipitate formed was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 15.31 g (82% of theory) of a colorless amorphous powder. Water content: 6.3%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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; E 27.31; Gd 13.20

Example 12

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

To 24.25 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid in 300 mL of dichloromethane was added 8.90 g (70 mmol) of oxalyl chloride and the mixture was stirred for 12 hours at room temperature. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and added dropwise at 0 ° C to a mixture of 3.66 g (60 mmol) of ethanolamine and 6.07 g (60 mmol) of triethylamine dissolved in 200 mL of dichloromethane. The mixture was stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid solution were added and the mixture was stirred vigorously for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 20: 1). Yield: 24.86 g (93% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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- (If, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorodecyl) amine g (51.59 mmol) of the title compound of Example 12a) was treated with was dissolved in 300 mL of tetrahydrofuran and 31 mL of a 10 M solution of borane dimethyl dimethyl sulfide (in tetrahydrofuran) was added. The mixture was heated to boiling for 12 hours. It was then cooled to 0 ° C, 200 ml of methanol was added dropwise and the mixture was evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of 300 ml of ethanol and 50 ml of a 10% aqueous hydrochloric acid solution and stirred at 40 ° C for 8 hours. The reaction mixture was evaporated to dryness, the residue was dissolved in 300 ml of 5% aqueous sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The organic phase was dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / 2-propanol 20: 1). Yield: 20.95 g (90% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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 (carboxylateomethyl) -10 - [(3-aza-4-oxohex-5-yl) -acid-N- (2-hydroxyethyl) -N- (1 H, 2H, 2H) 1,4,4,10,10-tetraazacyclododecane, complex with gadolinium g (15.88 mmol) of gadolinium complex with 10- [1- (carboxymethylcarboamoyl) ethyl], 4H, 4H, 5H, 5H-3-oxaperfluorodecyl) amide -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethylsulfoxide at 60 ° C. The mixture was cooled to 15 ° C and 8.98 g (15.88 mmol) of the title compound of Example 12b) was added. The mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Then the mixture was stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether, and the mixture was stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in a small amount of ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 14.01 g (83% of theory) of a colorless amorphous powder.

Elemental analysis:

Calculated: C 35.03; H, 3.98; N, 7.91; E, 23.24; Gd 14.79 Found: C 34.85; H, 4.19; N, 7.75; E, 23.05; Gd 14.58

Example 13

a) 2- (3,6,9,12-Tetraoxatridecyl) amide 2 77, 2 77, 4 77, 4 77, 577, 577-3-oxaperfluorodecanoic acid

To 24.25 g (57.45 mmol) of 277, 277, 477, 577, 577, 577-3-oxaperfluorodecanoic acid in 300 mL of dichloromethane was added 8.90 g (70 mmol) of oxalyl chloride and the mixture was stirred for 12 hours at room temperature. The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and added dropwise at 0 ° C to a mixture of 12.44 g (60 mmol) of 3,6,9,12-tetraoxatridecylamine and 6.07 g (60 mmol) of triethylamine dissolved in 200 mL of dichloromethane. The mixture was stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. Then 300 ml of 5% aqueous hydrochloric acid solution was added and the mixture was stirred vigorously for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 15: 1). Yield: 31.61 g (90% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 37.33; H, 4.29; N, 2.29; E 40.40

Found: C, 37.15; H, 4.41; N, 2.12; E 40.18

b) N- (3,6,9,12-Tetraoxatridecyl) -N- (177, 177, 277, 277, 477, 477, 577, 577-3-oxaperfluorodecyl) amine g (50.7 mmol) of the title compound the title of Example 13a) was dissolved in 300 mL of tetrahydrofuran and 32 mL of a 10 M solution of borane dimethyl dimethyl sulfide (in tetrahydrofuran) was added. The mixture was then heated to boiling for 16 hours. The reaction mixture was cooled to 0 ° C, 200 mL of methanol was added dropwise, and finally the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 300 ml of ethanol and 50 ml of a 10% aqueous hydrochloric acid solution and stirred for 8 hours at 40 ° C. The mixture was evaporated to dryness under reduced pressure, the residue was taken up in 300 ml of 5% aqueous sodium hydroxide and extracted three times with 300 ml of dichloromethane. The organic phase was dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / 2-propanol 20: 1). Yield: 28.17 g (93% of theory) of a colorless solid.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-oxohex-5-yl) -N- (3,6,9,12-tetraoxatridecyl) -N- (1H, 1H, 2H, 2H, AH, AH, 5H, 5H-3-oxaperfluorodecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) gadolinium 10- [1- (carboxymethylcarboamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethylsulfoxide at 60 ° C. The mixture was cooled to 15 ° C and 9.49 g (15.88 mmol) of the title compound of Example 13b) was added. The mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The mixture was stirred for 12 hours at room temperature. The reaction mixture was then poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in a small amount of ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.13 g (84% of theory).

Elemental analysis:

Calculated: 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-oxaperfluorotridecylamino) acetic acid tert-butyl ester

To 32.0 g (58.65 mmol) of the title compound of Example 5b) and 24.89 g (180 mmol) of potassium carbonate in 300 mL of acetonitrile was added dropwise 6.523 g (40 mmol) of tert-butyl ester at 50 ° C. bromoacetic acid and the reaction mixture was stirred for 3 hours at this temperature. Then, 300 ml of dichloromethane was added, the precipitated salts were filtered off and the filtrate was evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (eluent: dichloromethane / 2-propanol 2: 1).

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

Elemental analysis:

Calculated: 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-oxohex-5-yl) acid-N- (tert-butyloxycarbonylmethyl) -N- (1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of cadolinium-10- [1- (carboxymethylcarboamoyl) ethyl] ethyl] - 1,4,7,10-tetraazacyclododecane-1,4,7-triacetoacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethylsulfoxide at 60 ° C. The mixture was cooled to 15 ° C and 9.87 g (15.88 mmol) of the title compound of Example 14a) was added. The reaction mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The mixture was then stirred for 12 hours at room temperature. It was then poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.64 g (85% of theory).

Elemental analysis:

Calculated: C 36.04; H, 3.92; N, 6.82; E 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-oxohex-5-yl) acid-N-carboxymethyl-N- (1 H, 1 H, 2 H, 2 H, 4 H,%) -1,4,7,10-tetraazacyclododecane, complex with gadolinium g (8.11 mmol) of the title compound of Example 14b) was dissolved in 50 ml of trifluoroacetic acid H, 5H, 5 (3-oxa-perfluorotridecyl) amide and the mixture was stirred for 5 hours at room temperature. The mixture was evaporated to dryness and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). After evaporation of the product-containing fractions, the residue was dissolved in water and the pH was adjusted to 7.2 with 5% sodium hydroxide solution. The solution was filtered and the filtrate was lyophilized. Yield: 10.48 g (91% of theory).

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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) N- (2-Hydroxyethyl) amide 2H, 2H, 4tf, 4tf, 5H, 5H-3-oxaperfluorotidecanoic acid

To 32 g (56.61 mmol) of the title compound of Example 4a) was added 2.96 g (74 mmol) of sodium hydride (from 60% sodium hydride in paraffin oil) in 300 mL of tetrahydrofuran and the mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere. Then 7.67 g (74 mmol) of tert-butyl bromoacetate dissolved in 20 ml of tetrahydrofuran were added and the mixture was stirred for 5 hours at 50 ° C. Then 50 ml of methanol was added and the mixture was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / 2-propanol 20: 1). Yield: 23.46 g (61% of theory).

Elemental analysis:

Calculated: 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-Oxaperfluoridecyl) -N- [4- (tert-butyloxycarbonyl) -3-oxabutyl] amine

35.0 g (51.52 mmol) of the title compound of Example 15a) was dissolved in 300 mL of tetrahydrofuran and 31 mL of a 10 M solution of borane dimethyl dimethylsulfide (in tetrahydrofuran) was added. The reaction mixture was heated to reflux for 16 hours. It was then cooled to 0 ° C, 200 ml of methanol was added dropwise and finally evaporated to dryness under reduced pressure. The rest. was dissolved in a mixture of 300 ml of ethanol and 50 ml of a 10% aqueous hydrochloric acid solution and the mixture was stirred at 40 ° C for 8 hours. The reaction mixture was evaporated to dryness, the residue was dissolved in 300 ml of 5% aqueous sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The organic phase was dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / 2-propanol 20: 1). Yield: 31.88 g (93% of theory).

Elemental analysis:

Calculated: 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-oxohex-5-yl) -acid-N- [4- (tert-butyloxycarbonyl) -3-oxabutyl] -N- (1H, 1H, 2H, 2H, AH, AH, 5H, 5H-3-oxaperfluorotridecyl) amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) gadolinium 10- 1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetoacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 at 60 ° C. ml of dimethylsulfoxide. The mixture was cooled to 15 ° C and 10.57 g (15.88 mmol) of the title compound of Example 15b) was added. The mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The reaction mixture was stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in a small amount of ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.63 g (82% of theory).

Elemental analysis:

Calculated: 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-oxohex-5-yl) -acetic acid-N- (4-carboxy-3-oxabutyl) -N- (1H, 1H) -1,4,7,10-tetraazacyclododecane, complex with gadolinium g (9.40 mmol} of the title compound of Example 15c) was dissolved, 2H, 2H, AH, AH, 5H, 57- (3-oxaperfluorotridecyl) amide in 50 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 5 hours. The mixture was evaporated to dryness under reduced pressure and the residue was purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). After evaporation of the product-containing fractions, the residue was dissolved in water and the pH was adjusted to 7.2 with 5% sodium hydroxide solution. The solution was filtered and the filtrate was lyophilized. Yield: 11.41 g (92% of theory). Water content: 5.8%.

Elemental analysis: (calculated anhydrous):

Calculated: 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; At 1.93

Example 16

(a) 27I, 27I, 47I, 47I, 57I, 57I-3-Oxaperfluorotridecyl) N- (27I, 27I, AH, 5H, 57I-3-Oxaperfluorotridecyl) amide;

To 30 g (57.45 mmol) of 27,, 27,, 47,, 47,, 57 3, 57 lu -3-oxaperfluorotridecanoic acid in 300 mL of dichloromethane was added oxalyl chloride (8.90 g, 70 mmol) and stirred for 12 hours at room temperature. . The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and then added dropwise at 0 ° C to a mixture of 32.62 g (60 mmol) of the title compound of Example 5b) and 6.07 g (60 mmol) of triethylamine dissolved in 200 mL of dichloromethane. The mixture was stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid solution were added and the mixture was stirred for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 15: 1). Yield: 52.87 g (91% of theory).

Elemental analysis:

Calculated: 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-oxaperofluoridecyl) amine g (51.42 mmol) of the title compound of Example 16a) was dissolved in 500 mL of tetrahydrofuran and 31 mL of a 10 M solution of borane dimethyl dimethylsulfide (in tetrahydrofuran) was added. The mixture was heated to reflux for 6 hours. It was then cooled to 0 ° C, 200 ml of methanol was added dropwise and finally evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of 400 mL of ethanol and 70 mL of a 10% aqueous hydrochloric acid solution and stirred for 8 hours at 40 ° C. The mixture was evaporated to dryness, the residue was dissolved in 400 ml of 5% aqueous sodium hydroxide solution and extracted three times with 400 ml of dichloromethane. The organic phase was dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / 2-propanol 20: 1). Yield: 47.18 g (92% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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-oxohex-5-yl) -acid-N-bis (1H, IH, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaphtluorotridecyl) -amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of gadolinium complex with 10- [1- (carboxymethylcarboamoyl) ethyl -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethylsulfoxide at 60 ° C. The mixture was cooled to 15 ° C and the title compound of Example 16b) was added and 7.42 g (30 mmol) of hydroquinoline were added. The mixture was stirred at temperature. The reaction mixture was poured into 1300 mL of diethyl ether and stirred with;

15.84 g (15.88 mmol) of compound. The mixture was stirred for 10 minutes

2-ethoxy-1-ethoxycarbonyl-1,2-diphase for 12 hours at room temperature, to a mixture of 200 ml of acetone and for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in a small amount of ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient. Yield: 20.95 g (82% of theory)).

Elemental analysis:

Calculated: 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) 2Η, 2Η, 4Η, 4Η, 5Κ, 5Η-3-oxaperfluorotridecanoic acid N- (5-hydroxy-3-oxapentyl) amide

To 32 g (52.52 mmol) of the title compound of Example 3a) was added 2.80 g (70 mmol) of sodium hydride (from 60% sodium hydride in paraffin oil) in 300 mL of tetrahydrofuran and the mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere. Then 9.68 g (70 mmol) of tert-butyl bromoacetate dissolved in 20 ml of tetrahydrofuran was added and the mixture was stirred for 5 hours at 50 ° C. Methanol (50 ml) was added and the mixture was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / 2-propanol 20: 1). Yield: 19.31 g (59% of theory).

Elemental analysis:

Calculated: C 32.76; H, 2.91; N, 2.25; E, 51.82

Found: C, 32.98; H, 2.99; N, 2.36; F, 51.98

b) N- (3,6-Dioxaheptyl) -N- (12,11ff, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) amine g (51.34 mmol) of the title compound of Example 17a ) was dissolved in 300 ml of tetrahydrofuran and 31 ml of a 10 M solution of borane dimethylsulfide (in tetrahydrofuran) was added. The mixture was heated to boiling for 16 hours. It was then cooled to 0 ° C, 200 ml of methanol was added dropwise and finally the mixture was evaporated to dryness in vacuo. The residue was dissolved in a mixture of 300 mL of ethanol and 50 mL of a 10% aqueous hydrochloric acid solution and stirred for 8 hours at 40 ° C. The mixture was evaporated in vacuo, the residue was dissolved in 300 ml of 5% aqueous sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The organic phase was dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / 2-propanol 20: 1). Yield: 28.47 g (91% of theory).

Elemental analysis:

Calculated: C 33.51; H, 3.31; N, 2.30; F, 53.01

Found: C, 33.63; H, 3.41; N, 2.21; E, 52.87

c) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohex-5-yl) acid-N- (3,6-dioxaheptyl) -N- (1H, IH, 2H) -1,4,7,10-tetraazacyclododecane, complex with gadolinium g (15.88 mmol) of gadolinium-10- [1- (2-acetic acid) complex], 2H, 4H, 4H, 5H, [eta] &lt; 5 &gt; (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethylsulfoxide at 60 ° C. The mixture was cooled to 15 ° C and 9.68 g (15.88 mmol) of the title compound of Example 17b) was added. The mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The reaction mixture was stirred for 12 hours at room temperature. It was then poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.09 g (83% of theory).

Elemental analysis:

Calculated: 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-oxaperfluorotridecanoic acid N- (hexyl) amide

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid in 300 ml of dichloromethane was added 8.90 g (70 mmol) of oxalyl chloride and the mixture was stirred for 12 hours at room temperature. . It was then evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and added dropwise at 0 ° C to a mixture 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 was stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid solution were added and the mixture was stirred for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 20: 1). Yield: 30, 95 g (89% of theory).

Elemental analysis:

Calculated: C 35.72; H, 3.33; N, 2.31; F, 53.35

Found: C, 35.60; H, 3.45; N, 2.43; E 53.63

b) N-Hexyl-N- (1 H, 1 H, 2 H, 2 H, 4 H, 4 H, 5 H, 5 H-3-oxaperofluoridecyl) -amine g (51.21 mmol) of the title compound of Example 18a) was dissolved in 300 mL of tetrahydrofuran and 31 mL of a 10 M solution of boranedimethylsulfide (in tetrahydrofuran) was added. The mixture was heated to boiling for 16 hours. It was then cooled to 0 ° C, 200 ml of methanol were added dropwise and finally the mixture was evaporated to dryness under reduced pressure. The residue was poured into a mixture of 300 ml of ethanol and 50 ml of a 10% aqueous hydrochloric acid solution and stirred for 8 hours at 40 ° C. It was then evaporated to dryness under reduced pressure, the residue was dissolved in 300 ml of 5% aqueous sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The organic phase was dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / 2-propanol 20: 1). Yield: 28.16 g (93% of theory).

Elemental analysis:

Calculated: 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 (carboxylateomethyl) -10 - [(3-aza-4-oxohex-5-yl) -acetic acid-N-hexyl-N- (177, 177, 2H, 2H, 4H, 4H, 5H, 577-3-Oxaperfluoridecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) gadolinium complex with 10- [1- (carboxymethylcarboamoyl) ethyl- 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. The mixture was cooled to 15 ° C and 10.98 g (15.88 mmol) of the title compound of Example 18b) was added. The mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dinydroquinoline was added. The mixture was then stirred for 12 hours at room temperature. It was then poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether, and the mixture was stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.29 g (84% of theory).

Elemental analysis:

Calculated: C 36.94; H, 4.19; N, 6.99; F, 26.85; Gd 13.07

9Ί

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-oxaperfluorotridecanoic acid N- [10- (tert-butyloxycarbonyl) decyl] amide

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid in 300 mL of dichloromethane was added 8.90 g (70 mmol) of oxalyl chloride and the mixture was stirred for 12 hours at room temperature. . The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and added dropwise at 0 ° C to a mixture of 15.45 g (60 mmol) of 11-aminoundecanoic acid tert -butyl ester and 6.07 g (60 mmol) of triethylamine dissolved in 200 mL of dichloromethane. The mixture was stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid solution were added and the mixture was stirred for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 20: 1). Yield: 42.04 g (92% of theory).

Elemental analysis:

Calculated: 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- (tert-Butyloxycarbonyl) decyl] -N- (1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) amine g (51.21 mmol) of the compound The title compound of Example 19a) was dissolved in 300 mL of tetrahydrofuran and 31 mL of a 10 M solution of borane dimethyl dimethyl sulfide (in tetrahydrofuran) was added. The mixture was heated to boiling for 16 hours. It was then cooled to 0 ° C, methanol (200 ml) was added and finally the mixture was evaporated to dryness under reduced pressure. The residue was dissolved in the mixture

400 ml of ethanol and 70 ml of a 10% aqueous hydrochloric acid solution were stirred for 8 hours at 40 ° C. It was then evaporated to dryness in vacuo, the residue was dissolved in 350 ml of 5% aqueous sodium hydroxide solution and extracted three times with 400 ml of dichloromethane. The organic phase was dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (mobile phase: cichloromethane / 2-propanol 20: 1). Yield: 34.84 g (91% of theory).

Elemental analysis:

Calculated: 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-oxohex-5-yl) -acid-N- [10- (tert-butyloxycarbonyl) decyl] -N- (1 H, 2 H -tetyl) 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of gadolinium 10- [1- (carboxymethylcarboamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethylsulfoxide at 60 ° C. The mixture was cooled to 15 ° C and 11.87 g (15.88 mmol) of the title compound of Example 19b) was added. The mixture was stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The mixture was then stirred for 12 hours at room temperature. The reaction solution was then poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 17.92 g (83% of theory).

Elemental analysis:

Calculated: 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-oxohex-5-yl) -acid-N- (10-carboxydecyl) -N- (1 H, 2H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex, sodium salt g (8.83 mmol) of the title compound of Example 19c was dissolved in 50 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 5 hours. The mixture was evaporated to dryness under reduced pressure and the residue was purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). After evaporation of the product-containing fractions, the pH was adjusted to 7.2 with 5% aqueous sodium hydroxide solution. The solution was filtered and the filtrate was lyophilized. Yield: 12.48 g (92% of theory). Water content: 6.2%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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; At 1.80

Example 20

(a) 15-Benzyl-3,6,9,12,15-pentaoxahexadecanoic acid N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-Oxaperfluorotridecyl) amide

To 19.67 g (57.45 mmol) of 15-benzyl-3,6,9,12,15-pentaoxahexadecanoic acid in 250 ml of dichloromethane was added 8.90 g (70 mmol) of oxalyl chloride and the mixture was stirred for 12 hours at room temperature. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and added dropwise at 0 ° C to a mixture of 32.62 g (60 mmol) of 1H, 1E, 2E, -2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecylamine hydrochloride and 6.07 g (60 mmol) of triethylamine dissolved in 200 ml of dichloromethane. The mixture was stirred for 3 hours at 0 ° C and then for 6 hours

100 at room temperature. 300 ml of 5% aqueous hydrochloric acid solution were added and the mixture was stirred for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 20: 1). Yield: 44.91 g (94% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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-pentaoxahexadecyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotidecyl) amine g (51, 72 mmol) of the title compound of Example 20a) was dissolved in 400 mL of tetrahydrofuran and 31 mL of a 10 M solution of borane dimethyl dimethyl sulfide (in tetrahydrofuran) was added. The mixture was heated to boiling for 16 hours. It was then cooled to 0 ° C, 200 ml of methanol was added dropwise, and the reaction mixture was then evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of 400 ml of ethanol and 50 ml of a 10% aqueous hydrochloric acid solution and stirred for 8 hours at 40 ° C. The reaction mixture was evaporated to dryness under reduced pressure, the residue was dissolved in 350 ml of 5% aqueous sodium hydroxide solution and extracted three times with 400 ml of dichloromethane. The organic phase was dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / 2-propanol 20: 1). Yield: 39.32 g (93% of theory).

Elemental analysis:

Calculated: 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-oxohex-5-yl) -yl] -N- (15-benzyl-3,6,6,12,12,15) -pentaoxahexadecyl) -N- (15, 15, 2H, 2H, 4H, 4H, 5H, 55-3-oxatridecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium g complex (15.88 mmol) complex gadolinium with 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were added at 60 °. C was dissolved in 100 mL of dimethylsulfoxide. The mixture was cooled to 15 ° C and 12.98 g (15.88 mmol) of the title compound of Example 20b) was added. The mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The reaction mixture was then stirred for 12 hours at room temperature. The reaction solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in a small amount of ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 18.84 g (83% of theory).

Elemental analysis:

Calcd .: C 40, 34; H, 4.51; N, 5.88; F, 22.60; Gd 11,00

Found: C, 40.50; H, 4.62; N, 5.76; F, 22.73; Gd 11.16

d) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohex-5-yl) acid-N- (14-hydroxy-3,6,9,12-tetraoxatetradecyl) - N- (1H, 15 ', 25, 25, 45, 4,55, 55-3-oxapiperofluoridyl) amide] -1,4,4,7-tetraazacyclododecane, gadolinium complex g (8.40 mmol) of the title compound of Example 20c) was dissolved in 150 ml of methanol, 1.0 g of palladium catalyst (10% Pd / C) was added, and the mixture was then hydrogenated overnight at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 10.13 g (95% of theory).

Elemental analysis:

102

Calcd: 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) 2-N- (Trifluoroacetyl) -6-N- (benzyloxycarbonyl) -L-lysine

100.0 g (356.7 mmol) of 6-N- (benzyloxycarbonyl) -L-lysine was dissolved in a mixture of 1000 ml of trifluoroacetic acid ethyl ester and 500 ml of ethanol, and the mixture was stirred for 24 hours at room temperature. The mixture was evaporated to dryness and recrystallized from diisopropyl ether. Yield: 128.9 g (96% of theory) of a colorless crystalline powder. Melting point: 98.5 ° C.

Elemental analysis:

Calculated: C 51.07; H, 5.09; N, 7.44; F, 15.14

Found: C, 51.25; H, 5.18; N, 7.58; F, 15.03

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

To 125.0 g (332.0 mmol) of the title compound of Example 21a) and 188.7 g (332.0 mmol) of 1- (perfluorooctylsulfonyl) piperazine prepared according to patent application DE 196 03 033 in 750 ml of tetrahydrofuran at 164.2 g (0.664 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) was added at 0 ° C and the mixture was stirred overnight at room temperature. The reaction mixture was then evaporated to dryness. It was purified by silica gel chromatography (eluent: dichloromethane / methanol 20: 1). Yield: 286.0 g (93% of theory) of a colorless solid. Melting point: 92 ° C.

Elemental analysis:

Calculated: C 36.30; H, 2.83; N, 6.05; F, 41.01; S, 3.46

Found: C, 36.18; H, 2.94; N, 5.98; F, 40.87; S, 3.40

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

To a solution of 280.0 g (302.2 mmol) of the title compound of Example 21b) in 2000 mL of ethanol at 0 ° C was added ammonia gas for 1 hour. The reaction mixture was then stirred for an additional 4 hours at 0 ° C. It was then evaporated to dryness and the residue was stirred with water. The mixture was filtered and the solid was dried under vacuum at 50 ° C. Yield: 24 3.5 g (97% of theory) of a colorless amorphous solid.

Elemental analysis:

Calculated: C 37.60; H, 3.28; N, 6.75; F, 38.89; S, 3.86

Found: C, 37.55; H, 3.33; N, 6.68; F, 38.78; S, 3.81

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

To a solution of 100.0 g (120.4 mmol) of the title compound of Example 21c), 72.1 g (120.4 mmol) of 1-OaD-carbonylmethyl- (2,3,4,6-tetra-O-). benzyl) manopyranose and 13.86 g (120.4 mmol) of N-hydroxysuccinimide in 500 ml of dimethylformamide were added at C ^: 3 at 41.27 g (200.0 mmol) of N, N'-dicyclohexylcarbodiimide. The mixture was stirred for 3 hours at 0 ° C and then overnight at room temperature. The precipitate was filtered off, the filtrate was evaporated to dryness in vacuo and the residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 136.1 g (87% of theory) of a viscous oil.

Elemental analysis:

Calculated: C 57.32; H, 4.89; N, 4.31; E, 24.86; S, 2.47

Found: C, 57.38; H, 5.07; N, 4.22; E, 24.78; S, 2.39

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

130.0 g (100.0 mmol) of the title compound of Example

104

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

Elemental analysis:

Calculated: C 34.07; H, 3.63; N, 6.11; S, 3.50; F, 35.24

Found: C, 33.91; H, 3.72; N, 6.04; S, 3.40; F, 35.31

f) 6-N- [1,4,7-Tris (carboxylatomethyl)] - 1,4,7,10-tetraazacyclododecane-10-Ν- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl) -2-N- (1-O-α-D-carboxymethylmanopyranose) -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine) amide, gadolinium complex (metal complex XV)

50.0 g (54.55 mmol) of the title compound of Example 21e), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol) of gadolinium complex with 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methylpent-5-yl) -1,4,7,10- tetraazacyclododecane was dissolved in 400 ml of dimethylsulfoxide with slight heating. 16.88 g (81.8 mmol) of N, N'-dicyclchexylcarbodiimide was added at 10 ° C and the reaction mixture was then stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitated solid was filtered off and then purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 75.9 g (91.0% of theory) of a colorless solid. Water content: 8.6%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 35.34; H, 4.09; N, 8.24; S, 2.10; F, 21.12; Gd 10.28

Found: C, 35.28; H, 4.15; N, 8.19; S, 2.15; F, 21.03; Gd 10.14

Example 22

105

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

50.0 g (54.55 mmol) of the title compound of Example 21e), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol) gadolinium complex with 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methylpent-5-yl) -1,4,7,10-tetraazacyclododecane was dissolved in 400 ml of dimethylsulfoxide with slight heating. Then, 16.88 g (81.8 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was stirred overnight at room temperature. The reaction solution was poured into 3000 mL of acetone and stirred for 10 minutes. The precipitate formed was filtered off and then purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 76.0 g (92.0% of theory) of a colorless solid. Water content: 6.88% .

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 34.90; H, 3.93; N, 8.32; S, 2.12; F, 21.33; C-d 10.38

Found: C, 34.81; H, 4.02; N, 8.27; S, 2.09; F, 21.22; C-d 10.19

Example 23

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

To 200.0 g (1204.0 mmol) of ethyl 4-hydroxyphenylacetic acid and 212.0 g (2000.0 mmol) of sodium carbonate in 2000 mL of acetone was added 233.8 g (1400.0 mmol) of ethyl 2-bromoacetate. and the mixture was refluxed for 5 hours. The solid was filtered off and the filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate 15: 1). Yield: 288.5 g (95.0% of theory) of a colorless oil.

Elemental analysis:

Calculated: 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 23a) dissolved in 2000 mL of carbon tetrachloride was added 201.0 g (1130.0 mmol) of N-bromosuccinimide and 100.0 mg of dibenzcylperoxide and the mixture was heated to boiling for 8 hours. The mixture was then cooled in an ice bath, the precipitated succinimide was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / acetone 15: 1). Yield: 359.2 g (96.0% of theory) of a colorless viscous oil.

Elemental analysis:

Calculated: 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- 1,4,4,10-tetraazacyclododec-10-yl] methyl acetate

To 603.0 g (3500.0 mmol) of 1,4,7,10-tetraazacyclododecane in 6000 mL of chloroform was added 350.0 g (1057.0 mmol) of the title compound of Example 23b) and the mixture was stirred overnight at room temperature. The mixture was extracted three times with 3000 ml of water, the organic phase was dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was used in the next reaction without further purification (Example 23d). Yield: 448.0 g (quantitative) of a colorless viscous oil.

Elemental analysis:

Calculated: C 59.70; H, 8.11; N, 13.26

107

Found: C, 59.58; H, 8.20; N, 13.18

d) 2- [4- (3-Oxapropionic acid)] - phenyl-2- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododec-10-yl] acetic acid

445.0 g (1053.0 mmol) of the title compound of Example 23c) and 496.0 g (5270.0 mmol) of chloroacetic acid were dissolved in 4000 ml of water. A 30% aqueous sodium hydroxide solution was added until pH 10 and the mixture was stirred for 8 hours at 70 ° C. Then the pH of the reaction was adjusted to 13 with 30% aqueous sodium hydroxide and the mixture was heated to boiling for 30 minutes. The solution was cooled in an ice bath and the pH was adjusted to 1 by addition of concentrated hydrochloric acid. The reaction mixture was then evaporated. The residue was taken up in 4000 ml of methanol and stirred for 1 hour at room temperature. The precipitated salt was filtered off, the filtrate was evaporated to dryness and the residue was purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 403.0 g (69.0% of theory) of a colorless solid. Water content: 10.2 I.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-tetraazacyclododec-10-yl] acetic acid, Gd complex

To 400 g (721.3 mmol) of the title compound of Example 23d) in 2000 mL of water was added 130.73 g (360.65 mmol) of gadolinium complex and the mixture was stirred for 5 hours at 80 ° C. The solution was filtered and the filtrate was evaporated to dryness under reduced pressure. Yield: 511 g (quantitative) of a colorless amorphous solid. Water content: 11.0%.

Elemental analysis (calculated on the anhydrous substance):

108

Calculated: 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-tetraazacyclododec-10-yl] acetic acid ]] - 2-N- (1-Oa-D-carboxymethylmanopyranose) -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex, sodium salt

50.0 g (54.55 mmol) of the title compound of Example 21e), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 38.66 g (54.55 mmol) of the title compound of Example 23e) was dissolved in 400 mL of dimethylsulfoxide with slight heating. Then, 16.88 g (81.8 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was then stirred overnight at room temperature. The reaction solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and then purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). The obtained product was dissolved in a small amount of water and aqueous sodium hydroxide solution was added until pH 7.4. The product solution was then lyophilized. Yield: 79.1 g (89% of theory) of a colorless solid. Water content: 10.3%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 36.86; H, 3.77; N, 6.88; S, 1.97; E 19.82; Gd 9.65

Found: C, 36.75; H, 3.80; N, 6.80; S 2.03; F, 19.75; Gd 9.57

Example 24

a) 6-N- [1,4,7-Tris (tert-butyloxycarbonylmethyl) -10-carboxymethyl-1,4,7,10-tetraazacyclododecane-10-carboxymethyl] -2-N- (1-O-a- Dkarboxymetylmanopyranóza) L-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

15.0 g (26.19 mmol) 1,4,7-tris (tert-butyloxycarbonylmethyl) 109

-10-carboxymethyl-1,4,7,10-tetraazacyclododecane, 24.0 g (26.19 mmol) of the title compound of Example 21e) and 3.01 g (26.19 mmol) of N-hydroxysuccinimide were added at Dissolve 0 ° C in 150 mL of dimethylformamide and add 8.25 g (40.0 mmol) of N, N'-dicyclohexylcarbodiimide. The mixture was stirred overnight at room temperature. The precipitated urea was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / methanol 20: 1). Yield: 35.45 g (92.0% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 44.08; H, 5.69; N, 7.62; F, 21.95; S, 2.18

Found: C, 44.01; H, 5.81; N, 7.53; F, 21.87; S, 2.03

b) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-carboxymethyl] -2-N- [1-Oa-D-carboxymethylmanopyranose] -L-lysine - [1- (4-Perfluorooctylsulfonyl) piperazine] amide, Gd complex

30.0 g (20.39 mmol) of the title compound of Example

24a) was dissolved in 50 ml of chloroform and 300 ml of trifluoroacetic acid was added. The mixture was stirred for 10 minutes at room temperature. It was then evaporated to dryness under reduced pressure and the residue was dissolved in 300 ml of water. 3.69 g (10.19 mmol) of gadolinium complex was added and the mixture was stirred at rt for 5 h. temperature 80 ° C. The solution was evaporated to dryness in vacuo and the residue was purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 11.0 g (37.0% of theory) of a colorless amorphous solid. Water content: 11.3%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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

110

Example 25

(a) 6-N- [3,6,9-Tris (carboxylatomethyl) -3,6,9-triazaundecanedioic acid-1-carboxy-11-oyl] -2-N- (1-O-α-D-carboxymethylmanopyranose) - L-lysine- [l- (4-perfluorooctylsulfonyl) -piperazine] -amide

To 24.0 g (26.19 mmol) of the title compound of Example 21e) dissolved in a mixture of 100 mL of dimethylformamide and 30 mL of pyridine was added 12.10 g (30.0 mmol) of 3-N- (2.6 mmol). -dioxomorpholinoethyl) -6-N- (ethoxycarbonylmethyl) -3,6-diazaoctanedio and the mixture was stirred at 50 ° C for 5 hours. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 200 mL of water and the pH of the solution was adjusted to 13 by the addition of 20% aqueous sodium hydroxide solution. The mixture was stirred for 8 hours at 22 ° C and pH 13. The solution was acidified to pH 7.2 by addition of concentrated hydrochloric acid and evaporated in vacuo. The residue was purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 17.26 g (51.0% of theory) of a colorless solid. Water content: 9.3%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 37.19; H, 4.21; N, 7.59; F, 25.00; S, 2.48

Found: C, 37.10; H, 4.30; N, 7.48; E, 25.07; S, 2.42

b) 6-N- [3,6,9-Tris (carboxylatomethyl) -3,6,9-triazaundecanedioic acid-1-carboxy-11-oyl] -2-N- (1-Oa-D-carboxymethylmanopyranol) -L -lyzín- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide,

Gd complex, sodium salt

To 10.0 g (7.74 mmol) of the title compound of Example 25a) in 100 mL of water was added 1.40 g (3.87 mmol) of gadolinium oxide and the mixture was stirred at 70 ° C for 2 hours. The solution was filtered. The filtrate was adjusted to pH 7.4 by addition of 2N sodium hydroxide solution and then lyophilized. Yield: 11.36 g (quantitative) of an amorphous solid. Water content: 10.5%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 32.72; H, 3.43; N, 6.68; S, 2.18; Gd 10.71; Na 1.57; F, 22.00

Found: C, 32.65; H, 3.51; N, 6.77; S, 2.08; Gd 10.61; Na 1.68;

F, 21.87

Example 26

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

50.0 g (60.20 mmol) of the title compound of Example 21c), 6.93 g (60.20 mmol) of N-hydroxysuccinimide, 5.09 g (120.0 mmol) of lithium chloride and 37.91 g (50.20 mmol) 1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) Gd complex was dissolved in 400 ml of dimethylsulfoxide with slight heating. 20.63 g (100.0 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was stirred overnight at room temperature; tepicce. The solution was poured into 3000 mL of acetone and stirred for 10 minutes. The precipitate formed was filtered off and then purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 75.53 g (87.0% of theory) of a colorless solid. Water content: 10.1%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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) -vl) -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide,

112

70.0 g (48.53 mmol of the title compound of Example 21d) was dissolved in a mixture of 500 mL of water and 100 mL of ethanol, then 5.0 g of palladium catalyst (10% Pd / Cl) was added and the mixture was hydrogenated at The catalyst was then filtered off, washed well with ethanol (2 x 75 mL) and evaporated to dryness in vacuo. The title compound was obtained as a colorless, very viscous product, at room temperature under a hydrogen atmosphere (1 atm). Yield: 63.5 g (quantitative) Water content: 9.8%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-Oa-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 of Example 26b), 4.40 g (38.22 mmol) of N-hydroxysuccinimide, 3.39 g (80.0 mmol) of lithium chloride and 22.88 g (38.22 mmol) of 1-OaD-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose was dissolved in 400 ml of dimethylsulfoxide with gentle heating (30-40 ° C). At 10 ° C, 10.32 g (50.0 mmol) of N, N'-dicyclinexylcarbodiimide was added and the mixture was stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitate formed was filtered off and then purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 64.25 g (89.0% of theory) of a colorless solid. Water content: 10.9%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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

113

d) 6-N- [1-O-cis-D-Carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -2-N- [1,4,7-tris (carboxylatomethyl)] -1,4,8,10-tetraazacyclododecane-10- (pentanoyl-13-aza-4-oxo-5-methyl-5-yl)] - L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

60.0 g (31.77 mmol) of the title compound of Example 26c) was dissolved in 500 mL of ethanol and 6.0 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no consumption of hydrogen was observed. Then the catalyst was filtered off, washed with ethanol (twice 150 ml) and evaporated to dryness in vacuo. Yield: 48.55 g (quantitative) of a colorless solid. Water content: 3.9%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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; E, 21.05; Gd 10.20

Example 27

a) 1,7-Bis (benzyloxycarbonyl) -4- [2- (N-ethyl-N-perfluorooczyisulfonylamino) acetyl] -1,4,7,10-tetraazacyclododecane

To 50.0 g (13.5 mmol) of 1,7-bis (benzyloxycarbonyl) -1,4,10,4-tetraazacyclododecane and 66.42 g (113.5 mmol) of 2- (N-ethyl-N-) acid of perfluorooctylsulfonylamino) acetic acid prepared according to patent application DE 196 03 033 in 300 ml of tetrahydrofuran was added at 0 ° C 49.46 g (200.0 mmol) of EEDQ (ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography (eluent: dichloromethane / methanol 20: 1). Yield: 65.2 g (57% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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

114

b) 1,7-Bis (benzyl) -4- [2- (N-ethyl-N-perfluorooctylsulfonylamino) acetyl] -10- [1-Oa-D-carbonylmethyl- (2,3,4,6-tetra-O-) benzyl) -manopyranose] -1,4,7,10-tetraazacyclododecane

To 60.0 g (59.53 mmol) of the title compound of Example 27a) and 35.64 g (59.53 mmol) of 1-OaD-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) ) of manopyranose prepared according to patent application DE 197 28 954 in 300 ml of tetrahydrofuran at 0 ° C was added 24.73 g (100 mmol of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester)) and the mixture was stirred The mixture was evaporated to dryness and purified by silica gel chromatography (mobile phase: dichloromethane / methanol 20: 1) Yield: 76.6 g (81.0% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 54.44; H, 4.70; N, 4.41; F, 20.33; S, 2.02

Found: C, 54.37; H, 4.81; N, 4.35; F, 20.27; S, 1.96

c) 1- [2- (N-Ethyl-N-perfluorooctylsulfonylamino) acetyl] -7- (10-α-D-carbonylmethylmanopyranose) -1,4,7,10-tetraazacyclododecane g (44.07 mmol) of the title compound of title 27b) was dissolved in 800 ml of ethanol and 8 g of a palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness. Yield: 42.3 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: 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- 5-yl) -4- (2- (N-ethyl-N-perfluorooctylsulfonylamino) acetyl) -10- (1-Oa-D-carbonylmethyl-manopyranose) -1,4,7,10-tetraazacyclododecane,

115 g (20.84 mmol) of the title compound of Example 27c), 5.09 g (120 mmol) of lithium chloride and 37.78 g (60 mmol)

1,4,7-Tris (carboxylatomethyl) -10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl, -1,4,7,10-tetraazacyclododecane, Gd complex dissolved with slight heating in 400 mL of dimethylsulfoxide, 29.67 g (120 mmol) of EEDQ was added at 0 ° C and the mixture was stirred overnight at room temperature The reaction mixture was poured into 3000 mL of acetone and stirred for 10 minutes. It was filtered and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient) Yield: 13.2 g (29.0% of theory) of a colorless solid Water content: 11.8%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 36.31; H, 4.34; N, 9.62; S, 1.47; F, 14.79; Gd 14.41

Found: C, 36.24; H, 4.27; N, 9.58; S 1.51; F, 14.85; Gd 14.25

Example 28

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

50.0 g (49.61 mmol) of the title compound of Example 27a), 5.71 g (49.61 mmol) of N-hydroxysuccinimide, 4.24 g (100 mmol) of lithium chloride and 31.24 g (49 , 61 mmol) 1,4,7-tris (carboxylatomethyl) -10- (pentanoyl-3-azaoxo-5-methyl-5-yl) -1,4,7,10-tetraazacyclododecane, Gd complex dissolved with slight heating in 350 ml of dimethylsulfoxide. At 10 ° C, 15.47 g (75 mmol) of N,--dicyclohexylcarbodiimide was added and the mixture was stirred overnight at room temperature. The solution was poured into 2000 mL of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 65.1 g (81.0% of theory) colorless

116 solids. Water content: 7.9%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-perfluorooctylsulfonylamino) acetyl] -7 - {(pentanoyl-3-aza-4-oxo-5-methyl-5-yl) -10- (1,4,7) -tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane, Gd-complex]} -1,4,7,10-tetraazacyclododecane

60.0 g (37.05 mmol) of the title compound of Example 28a) was dissolved in 600 ml of ethanol and 6.0 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 50.06 g (quantitative) of a colorless solid. Water content: 3.9 *.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-perfluorooctylsulfonylamino) acetyl] -4,10-bis [1-O-α-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -7- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) -10- (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 of Example 28b), 2.54 g (60.0 mmol) of lithium chloride and 44.9 g (75.0 mmol) of 1-OaD-carbonylmethyl- (2 3,4,6-tetra-O-benzyl) manopyranose was dissolved in 300 ml of dimethylsulfoxide with slight heating. At 10 ° C, 24.73 g (100.0 mmol) of EEDQ were added and the mixture was stirred overnight at room temperature. The solution was poured into 3000 mL of acetone and stirred for 10 minutes. The precipitate formed was filtered off and purified by chromatography on MgSO4

117 silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 31.98 g (43.0% of theory) of a colorless solid. Water content: 3.5%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-perfluorooctylsulfonylamino) acetyl] -4,10-bis [1-Oa-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-tetraazacyclododec-10-yl] - Gd complex} -1,4,7,10-tetraazacyclododecane

30.0 g (11.94 mmol) of the title compound of Example 28c) was dissolved in 300 mL of ethanol and 30 mL of water and 4.0 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated at room temperature, the catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 21.39 g (quantitative) of a colorless solid. Water content: 3.4.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 29

a) 6-N- [3,6-Bis (carboxymethyl) octane-1,8-dicarboxylic acid-1-carboxy-8-oyl] -2-N- (1-Oa-D-carboxymethylmanopyranose) -L-lysine- [ l- (4-perfluorooctylsulfonyl) -piperazine] -amide

To 27.5 g (30.0 mmol) of the title compound of Example 21e) dissolved in 300 mL of dimethylformamide and 100 mL of pyridine was added 25.62 g (100.0 mmol) of ethylenediamine-N, N, N ^' , N ^t- tetraacetate dianhydride and the mixture was stirred at 50 ° C for 5 hours. The mixture was evaporated to dryness in vacuo. The residue was dissolved in 300 ml of water and the pH of the mixture was adjusted to 10 by the addition of 20% aqueous sodium hydroxide solution. The basic solution was then adjusted to pH 3 by the addition of concentrated hydrochloric acid and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 13.22 g (51.0% of theory) of a colorless solid. Water content: 7.9%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 36.31; H, 3.98; N, 7.06; F, 27.12; S, 2.69

Found: C, 36.23; H, 4.07; N, 6.98; F, 27.05; S, 2.62

b) 6-N- [3,6-Bis (carboxylatomethyl) octane-1,8-dicarboxylic acid-1-carboxy-8-oyl] -2-N- (1-Oa-D-carboxymethylmanopyranose) -L-lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, Mn-complex, sodium salt g (8.397 mmol) of the title compound of Example 29a) was dissolved in 200 mL of water. 9.65 mg (8.37 mm.ci) of manganese carbonate was added and the mixture was stirred for 3 hours at 60 ° C. The solution was adjusted to pH 7.4 by addition of aqueous sodium hydroxide solution, filtered and finally lyophilized. Yield: 10.52 g (99.0% of theory) of a colorless solid. Water content: 7.8%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 34.16; H, 3.50; N, 6.64; S, 2.53; F, 25.52; Mn 4,34;

At 1.82

Found: C, 34.06; H, 3.61; N, 6.58; S, 2.47; F, 25.47; Mn 4,30;

At 1.97

Example 30

a) (1,2,3,4,6-Penta-O-acetyl) -α, β-D-manopyranose

In an analogous manner to that described in the literature [M. L. Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (R.

119

Whistler, L.L. Wolfrom and J.N. De Miller Eds., Academic Press, New York, Vol. 11, 53, p. 211-215 (1963)] gave the deposition of 150 g (832.5 mmol) of α, β-D-manopyranose with a mixture of absolute pyridine and 1500 mL of acetic anhydride after treating 315 g (96.7%) of the title compound as crude product as a viscous colorless oil. 1 H-NMR spectroscopy showed that the compound contained both an α and β anomers in a 4: 1 ratio. Separation of the α and β anomers of the title compound can be accomplished by the following reactions.

Elemental analysis:

Calculated: 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) -manopyranose

In an analogous manner to that described in the literature for the synthesis of arylglycopyranosides [J. Conchie and G. A. Levvy in Methods in Carbohydrate Chemistry (R.L. Whistler, M.L. Wolfrom and J.N. De Miller Eds.), Academic Press, New York, Vol. 11, 90, p.

345-347 (1963)] led to the use of 156.2 g (400 mmol) of the title compound of Example 21a) as a mixture of α and β anomers with 67 mL (400 mmol) of ethyl 6-hydroxyhexanoate and 60.8 mL (520 mmol) ) of tin tetrachloride in 600 ml of 1,2-dichloroethane after purification by silica gel column chromatography (mobile phase: hexane / ethyl acetate 2: 1) to give 100.05 g (51% of theory) of the title compound as a colorless viscous oil. It has been found by means of 1 H-NMR spectroscopy that the title compound can only be regarded as the α-anomer.

Elemental analysis:

Calculated: C 52.94; H, 6.77

Found: C, 52.80; H, 6.78

120

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

A suspension of 141.0 g (289 mmol) of the title compound of Example 30b) in 200 mL of dioxane was treated at room temperature with vigorous stirring in portions with a total of 238.5 g (4.26 mol) of finely powdered potassium hydroxide. An additional 200 ml of dioxane was added to the reaction mixture to increase the stirring efficiency, and the suspension thus obtained was heated to boiling and 372 ml (3.128 mol) of benzyl bromide was added dropwise over 2 hours. After 4 hours at 110 ° C, the reaction mixture was stirred for 12 hours at room temperature, then slowly poured into 2.5 L of ice water and the aqueous phase was finally extracted thoroughly with diethyl ether. After washing the ether phase so obtained, the organic phase was dried over sodium sulfate and the diethyl ether was evaporated under reduced pressure. Excess benzyl bromide was quantitatively distilled off from the reaction mixture at 180 ° C oil bath temperature. The oily residue thus obtained was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 1: 10). Yield: 172.2 g (91% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: C 75.68; H, 7.16

Found: C, 75.79; H, 7.04

d) 6-N- (Benzyloxycarbonyl) -2-N- [10aD-5-carbonylpentyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine- [1- (4-perflucroctylsulfonyl) ) -piperazine] amide

100.0 g (134.0 mmol) of the carboxylic acid obtained in Example 30c) and 32.4 g (281.4 mmol) of N-hydroxysuccinimide were dissolved in 500 ml of dimethylformamide and a total of 58 was added in portions at 0 ° C. 0 g (281.4 mmol) of N, N'-dicyclohexylcarbodiimide and the mixture was stirred for 3 hours at this temperature. For preparation

121 of the activated ester solution was added dropwise a solution of 111.3 g (134.0 mmol) of the title compound of Example 21c) in 300 mL of dimethylformamide cooled to 0 ° C over 2 hours at 0 ° C and the mixture was then stirred for 12 hours at room temperature. On working up, the precipitated cyclohexylurea was filtered off and the solvent was evaporated to dryness. The residue obtained was finally purified by chromatography on silica gel (mobile phase: dichloromethane / ethanol 20: 1, where chromatography was carried out under continuous gradient conditions with the addition of an ethanol fraction). Yield: 132.5 g (67.4% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: C 54.02; H, 4.88; N, 3.82; F, 22.01; S, 2.19

Found: C, 53.87; H, 4.85; N, 4.02; F, 22.55; S, 2.06

e) 2-N- (1-O-α-D-5-Carbonylpentylmanopyranose) -L-lysine- [1- (4-fluorooctylsulfonyl) piperazine] amide

120.0 g (81.77 mmol) of the compound obtained in Example 30d were dissolved in 800 ml of ethanol, 4.5 g of Pearlman catalyst (20% Pd / C) were added and the mixture was hydrogenated at room temperature under a hydrogen atmosphere (1). atm) until no further consumption of hydrogen was observed (about 8 hours). The catalyst was filtered off, washed thoroughly with ethanol (ca. 200 ml) and the filtrate was evaporated to dryness under reduced pressure. The title compound was obtained as a colorless, very viscous oil. Yield: 78.5 g (98.7% of theory).

Elemental analysis:

Calculated: 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- (10-cis-D-5-Carbonylpentylmanopyranose) -6-N- [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5) -ylpentanoyl) 122

-1,4,7,10-tetraazacyclododecane] -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

99.8 g (158.4 mmol, 2.2 molar equivalents, calculated on the amine component of Example 30e), gadolinium complex with 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, The 4,7,10-tetraazacyclododecane-1,4,7-triacetic acid described in patent application DE 197 28 954 in Example 31h) and 6.7 g (158.4 mmol) of anhydrous lithium chloride were dissolved with stirring at 40 ° C. in 800 ml of absolute dimethylsulfoxide. A total of 18.2 g (158.4 mmol) of N-hydroxysuccinimide and 70.0 g (71.96 mmol) of the title compound of Example 30e) dissolved in 250 mL of absolute dimethylsulfoxide were added at this temperature. After cooling to room temperature, 32.7 g (158.4 mmol) of N, N'-dicyclohexylcarbodiimide was added and the mixture was stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off, and the low molecular weight material was removed on an AMICON® YM-3 ultrafiltration membrane (cutoff limit: 3000). Will give). The residue was finally lyophilized. Yield: 93.0 g (81.6% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 9.53%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 37.15; H, 4.39; N, 7.96; E 20.38; S 2.02; Gd 9.92

Found: C, 36.92; H, 4.50; N, 7.68; F, 19.77; S, 1.91; Gd 10.08

Example 31

(a) 2-N- (10aD-5-Xarbonylpentylmanopyranose) -6-N- {2- [4- (3-oxapropionyl) phenyl] -2- [1,4,7-tris (carboxylatomethyl) -1,4, 7,10-tetraazacyclododec-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 was added

The title compound of Example 23e) (123e) in absolute dimethylsulfoxide (15 ml) was treated with lithium chloride (0.68 g, 15.9 mmol) at 70 ° C. The mixture was stirred for 30 minutes at 70 ° C, the clear reaction solution was treated portionwise with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide, and the reaction mixture was stirred for an additional hour at this temperature. After cooling to C C C, 4.52 g (23.85 mmol) of N, N'-dicyclohexylcarbodiimide was added and the reaction mixture was stirred for an additional hour at 0 C C and then for 12 hours at 22 ° C. To the thus obtained reaction solution of the N-hydroxysuccinimide ester of the title compound of Example 23e), a solution of 4.0 g (4.12 mmol) of the title compound of Example 10e) in 15 ml of absolute dimethylsulfoxide and a reaction mixture were added dropwise at 22 ° C. was stirred for 12 hours at room temperature. Upon work-up, the reaction mixture was added dropwise to 900 ml of acetone at 22 ° C to give the title compound as a colorless precipitate. The precipitate was filtered off with suction, dissolved in 200 ml of distilled water and treated with 1 M sodium hydroxide solution until a pH of 7.2 was reached. The aqueous product solution thus obtained was ultrafiltered three times on an AMICON 'YM-3 ultrafiltration membrane (cut-off limit: 3000 Da) to remove salts and low molecular weight fraction. The residue thus obtained was lyophilized. Yield: 6.33 g (92.4% of theory, calculated on the amine component used) as a colorless lyophilisate. Water content 7.38%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 38.48; H, 4.13; N, 6.65; F, 19.16; S, 1.90; Gd 9.33;

At 1.36

Found: C, 39.52; H, 4.12; N, 6.67; F, 19.70; S, 1.89; Gd 9.30;

At 1.41

Example 32

(a) 3,5-bis (benzyloxycarbonylamino) benzoic acid N- (15,15, 25, 25, 45, 45, 55, 55-3-Oxaperfluorotridecyl) amide

124

In a mixture of 125 mL dry tetrahydrofuran and 125 mL dry dioxane was dissolved 20 g (47.5 mmol) of 3,5-bis (benzyloxycarbonylamino) benzoic acid prepared according to literature procedures (HI Skulnick, PD Johnson, PA Aristoff, JK Morris, KD Lovasz et al., J. Med. Chem., 40 (7), 1149-1164 (1997)) and 4.78 g (47.5 mmol) of triethylamine. After cooling to -15 ° C, a solution of 6.56 g (48 mmol) of isobutyl chloroformate in 30 ml of dry tetrahydrofuran was slowly added dropwise with stirring, keeping the temperature of the reaction mixture below -10 ° C. After 15 minutes at -15 ° C, a solution of 58.6 g (47.5 mmol) of 1-amino-1 H, 2 H, 2 H, AH, 5 H, 5 H -3-oxoperfluorotridecane and 4.78 g was added dropwise. (47.5 mmol) triethylamine in 100 mL dry tetrahydrofuran at -20 ° C. After 1 hour at -15 ° C, the reaction mixture was stirred for 2 hours at room temperature and evaporated to dryness under reduced pressure. The residue was dissolved in 300 mL ethyl acetate and washed twice with 200 mL saturated sodium bicarbonate solution and 300 mL water. After drying the organic phase over sodium sulfate, it was filtered from the salts and purified by silica gel chromatography (mobile phase: dichloromethane / hexane / 2-propanol 10: 5: 1). Yield: 36.2 g (82.5% of theory) of the title compound as an oil.

Elemental analysis:

Calculated: 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-diaminobenzoic acid N- (1H, IH, 2H, 2H, AH, AH, 5H, 5'-3-Oxaperfluorotridecyl) amide

30.0 g (32.4 mmol) of the amide prepared in Example 32a) was dissolved in 300 ml of ethanol and 1.2 g of Pearlman's catalyst (20% Pd / C) were added. The reaction mixture was hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no further consumption of hydrogen was observed. The catalyst was filtered off with suction, washed thoroughly with ethanol (ca. 300 ml) and the solvent was evaporated

125 under reduced pressure. The title compound was obtained as a very viscous yellowish oil. Yield: 20.12 g (94.8% of theory).

Elemental analysis:

Calculated: 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) -carbonylmethyl] -amide (N- (1 H, 2 H, 2 H, 2 H, 5 H, 5 H-3-Oxaperfluorotridecyl) amide tetra-O-benzyl) mannopyranose) -5-aminobenzoic acid

10.95 g (18.30 mmol) of 1-Carboxymethyloxy- (2,3,6,6-tetra-O-benzyl) - α-D-manopyranoside prepared as described in patent application DE 197 28 954 Cl was dissolved in 150 ml of dimethylformamide and treated with 2.09 g (18.3 mmol) of N-hydroxysuccinimide. The mixture was cooled to 0 ° C and 3.78 g (18.3 mmol) of N, N'-dicyclohexylcarbodiimide was added. The reaction mixture was stirred for 1 hour at 0 ° C and then for 4 hours at room temperature. The mixture was cooled to 0 ° C and a solution of 24.0 g (36.6 mmol, 2 molar equivalents, calculated on the carboxylic acid) of the diamino compound prepared in Example 32b) dissolved in 350 mL of dimethylformamide was added dropwise over 3 hours. The reaction mixture was stirred for 1 hour at 0 ° C and then overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 300 mL of ethyl acetate. The precipitated urea was filtered off and the filtrate was washed twice with 5% aqueous soda solution (twice with 100 ml). The organic phase was dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: n-hexane / isopropanol 13: 1). 16.8 g (74.3% of theory, calculated on the carboxylic acid used) of the title compound were obtained as a colorless oil. By increasing the polarity of the mobile phase to n-hexane / isopropanol 5: 1, it was recovered by chromatography

126

10.15 g of unreacted diamino compound of Example 32b), which can be used again in the reaction step.

Elemental analysis:

Calculated: C 54.42; H, 4.40; N, 3.40; F, 26.13

Found: C, 54.32; H, 4.49; N, 3.48; E, 25.94

d) 3-N- (1-O-α-D-carbonylmethylmanopyranose) -5-aminobenzoic acid N- (IV, 1H, 2H, 4H, 4H, 5H, 5H-3-Oxaperfluorotridecyl) amide

In an analogous manner to that described in the title compound of Example 32b), by hydrogenolysis, 12.0 g (9.70 mmol) of the title compound of Example 32c) was obtained in the presence of 0.5 g of Pearlman's catalyst (20% Pd / C) in ethanol / water 9: 1 after treatment with 8.08 g (96.7% of theory) of the title compound as a colorless to yellowish and viscous oil.

Elemental analysis:

Calculated: C 37.64; H, 3.28; N, 4.88; E, 37.49

Found: C, 37.32; H, 3.17; N, 4.97; F, 37.55

e) 3-N- (1-Oa-D-carbonylmethyl-mannopyranose) -5-N- (2- [4- (3-oxapropionyl) phenyl] -2- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododec-10-yl] acetic acid, benzoic acid, Gd complex, sodium salt

13.6 g (19.2 mmol, 2.2 molar equivalents based on the amine component of Example 32d), the gadolinium complex described in Example 23e) and 0.81 g (19.2 mmol) of anhydrous lithium chloride were dissolved with stirring a total of 2.2 g (19.2 mmol) of N-hydroxysuccinimide and 7.5 g (8.7 mmol) of the title compound dissolved in Example 32d at 40 ° C in 100 ml of absolute dimethylsulfoxide were added at this temperature. in 50 ml of absolute dimethylsulfoxide. After cooling to room temperature127 here, the reaction solution was treated with 3.96 g (19.2 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off and purified from the low molecular weight fraction of the AMICON® YM-3 ultrafiltration membrane: 3000 Da). The residue was lyophilized. Yield: 11.51 g (84.5% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 6.77%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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; At 1.42

Example 33

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

In mixture. 60 ml of dry tetrahydrofuran and 70 ml of dry dioxane were dissolved 10 g (23.75 mmol) of 3,5-bis (benzyloxycarbonylamino) benzoic acid prepared according to the literature procedure (HL Skulnick, PD Johnson, PA Aristoff, JK Morris, KD Lovasz) et al., J. Med. Chem., 40 (7), 1149-1164 (1997)) and 2.39 g (23.75 mmol) of triethylamine. After cooling to -15 ° C, it was slowly added dropwise with stirring. solution of 3.28 g (24 mmol) of isobutyl chloroformate in 20 ml of dry tetrahydrofuran, the internal temperature not exceeding -10 ° C. After 15 minutes at -15 ° C, a solution of 23.0 g (23.75 mmol) of 1- (perfluorooctylsulfonyl) piperazine and 2.39 g (23.75 mmol) of triethylamine in 50 mL of dry tetrahydrofuran was added dropwise at -20 ° C. The reaction mixture was stirred for 1 hour at -15 ° C and then for 2 hours at room temperature and evaporated to dryness under reduced pressure. The residue obtained was dissolved in 200 ml of ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution and then with 300 ml of water. After drying the organic phase over sodium sulfate, the salts were filtered off and the ethyl acetate was removed under reduced pressure. The residue obtained was purified by silica gel chromatography (eluent: dichloromethane / hexane / 2-propanol 15: 5: 1). Yield: 18.35 g (79.6% of theory) of the title compound as an oil.

Elemental analysis:

Calculated: C 43.31; H, 2.80; N, 5.77; P, 33.27; S, 3.30

Found: C, 43.21; H, 2.75; N, 5.61; F, 33.38; S, 3.22

b) 3,5-Diamino-1- {N- [1- (4-perfluorooctylsulfonyl) piperazine]} - benzamide

9.70 g (10.0 mmol) of the amide prepared in Example 33a) was dissolved in 100 ml of ethanol and 0.4 g of Pearlman &apos; s catalyst (20% Pd / C) was added. The reaction mixture was hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no consumption of hydrogen was observed. The catalyst was filtered off, washed thoroughly with ethanol (ca. 150 ml) and the mixture was evaporated to dryness under reduced pressure. The title compound was obtained as a very viscous yellowish oil. Yield: 6.9 g (98.2% of theory).

Elemental analysis:

Calculated: 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-Ν- (1-O-ω-D-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) N- [1- (4-perfluorooctylsulfonyl) piperazine] amide -mancpyranóza} benzoate

5.48 g (9.15 mmol) of 1-carboxymethyloxy- (2,3,4,6-tetra-O-benzyl) -α-D-manopyranoside prepared according to patent application DE 197 28 954 C1 was dissolved in 100 ml of dimethylformamide and was reacted with 1.04 g (9.15 mmol) of N-hydroxysuccinimide. The mixture was cooled to 0 ° C and N, N'-dicyclohexylcarbodiimide (1.89 g, 9.15 mmol) was added. The reaction mixture was stirred for 1 hour at 0 ° C and then for 4 hours at room temperature. The mixture was recooled to 0 ° C and a solution of 12.85 g was slowly added dropwise over 3 hours)

(18.30 mmol, 2 molar equivalents, calculated on the carboxylic acid used) of the diamino compound prepared in Example 33b) dissolved in 250 mL of dimethylformamide. The reaction mixture was stirred for 1 hour at 0 ° C and then overnight at room temperature. The mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 100 mL of ethyl acetate. The resulting urea was filtered off and the filtrate was washed twice with 100 ml of 5% aqueous soda. The organic phase was dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: n-hexane / isopropanol 13: 1). Yield: 8.14 g (69.4% of theory, calculated on the carboxylic acid used) of the title compound as a colorless oil. Increasing the polarity during chromatography to 6: 1 n-hexane / isopropanol gave a total of 4.36 g of unreacted compound 33b, which can be reused in the reaction step.

Elemental analysis:

Calculated: 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-Ν- (1-O-α-D-carbonylmethylmanopyranose) benzoic acid N- [1- (4-perfluorooctylsulfonyl) piperazine] amide

In an analogous manner to that described for the synthesis of the title compound of Example 33b), hydrogenolysis yielded 6.4 g (5.0 mmol) of the title compound of Example 33c) by treatment with 0.3 g of Pearlman catalyst (20% Pd / C). in ethanol / water 8: 1 after treatment with 4.43 g (96.2% of theory) of the title compound as a yellowish viscous oil.

130

Elemental analysis:

Calculated: 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-O-α-D-carbonylmethylmanopyranose) -5-N- [1,4,7-tris (carboxylatomethyl) -10- (N- [1- (4-perfluorooctylsulfonyl) piperazine] amide) 3-aza-4-oxo-5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazacydododecane] benzoic acid, Gd complex

5.54 g (8.8 mmol, 2.2 molar equivalents, calculated on the amine component of Example 33d), gadolinium complex with 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7, 10-tetraazacyclododecane-1,4,7-triacetic acid as described in patent application DE 197 28 954 Cl in Example 31h) and 0.37 g (8.8 mmol) of anhydrous lithium chloride at 40 ° C dissolved in 60 ml of absolute dimethylsulfoxide with stirring and a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.7 g (4.0 mmol) of the title compound of Example 13d) dissolved in 40 ml were added at this temperature. ml of absolute dimethylsulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide was added to the reaction solution, and the mixture was stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until all the title compound precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off and the filtrate was purified from the low molecular weight fraction on the AMICON® YM-3 ultrafiltration membrane (cut-off limit). : 3000 Da). The residue was lyophilized. Yield: 5.36 g (87.4% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 6.77%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 34

131

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

100 g (107.9 mmol) of the carboxylic acid obtained in Example 21a) and 26.1 g (226.59 mmol) of N-hydroxysuccinimide were dissolved in 500 ml of dimethylformamide, a total of 46.7 g was added in portions at 0 ° C. (226, 59 mmol) of N, N'-dicyclohexylcarbodiimide and the reaction mixture was stirred for 3 hours at this temperature. To prepare the active ester solution, a solution of 5.57 g (53.95 mmol) of diethylenetriamine dissolved in 60 ml of dimethylformamide and cooled to 0 ° C was added dropwise to the reaction mixture, and the reaction mixture was stirred at 0 ° C for 2 hours and then 12 hours at room temperature. The precipitated dicyclohexylurea precipitate was filtered off and the solvent was evaporated to dryness. The residue thus obtained was purified by silica gel chromatography (mobile phase: dichloromethane / ethanol 15: 1, whereby the chromatography was carried out with a gradient such that the proportion of ethanol was continuously increased). Yield: 26.0 g (58.8% of theoretical based on the amine component used) of the title compound as a colorless and very viscous oil.

Elemental analysis:

Calculated: 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]

To a solution of 20 g (24.4 mmol) of the diamide prepared in Example 34a) dissolved in a mixture of 150 mL of tetrahydrofuran and 15 mL of chloroform at 0 ° C under a nitrogen atmosphere was added a solution of 16.18 g (27.0 mmol) of 2- Of (N-ethyl-N-perfluorooctylsulfonylamino) acetic acid prepared according to patent application DE 196 03 033 and dissolved in 50 ml of tetrahydrofuran. A total of 18.0 g (36.6 mmol) of EEDQ was then added portionwise at 0 ° C

132 (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline), stirred overnight at room temperature and then evaporated to dryness in vacuo. The residue obtained was purified by silica gel chromatography (eluent: n-hexane / isopropanol 15: 1). 24.74 g (72.4% of theoretical based on the secondary amine used) of the title compound were obtained as a colorless oil.

Elemental analysis:

Calculated: 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-perfluorooctylsulfonylamino) acetyl] -1,4,7-triazaheptene

22.0 g (15.7 mmol) of the title compound prepared in Example 34b) was dissolved in 100 ml of ethanol and ammonia gas was introduced into the reaction mixture at 0 ° C for 40 minutes. The reaction mixture was then stirred at 0 ° C for 4 hours and then at room temperature for 3 hours and then evaporated to dryness under reduced pressure at 40 ° C. The oily residue was purified by silica gel chromatography (eluent: dichloromethane / hexane / 2-propanol 20: 10: 1). yield:

12.92 g (98.4% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: 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-Oa-D-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine} diamide -4- [2- (N-ethyl-N-perfluorooctlsulfonylamino) acetyl] -1,4,7-triazaheptane

5.47 g (9.15 mmol) of 1-Carboxymethyloxy- (2,3,4,6-tetra-O-benzyl) -α-D-manopyranoside prepared according to patent application DE 197 28 954 C1 were dissolved in 80 ml of dimethylformamide a total of 1.05 g (9.15 mmol) of N-hydroxysuccinimide was added. The mixture was cooled to 0 ° C and N, N'-dicyclohexylcarbodiimide (1.9 g, 9.15 mmol) was added. The reaction mixture was stirred for 1 hour at 0 ° C and then for 4 hours at room temperature. The mixture was cooled to 0 ° C and then a solution of 7.65 g (9.15 mmol) of the amino compound prepared in Example 34e) dissolved in 50 mL of dimethylformamide was slowly added dropwise over 3 hours. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 100 mL of ethyl acetate. The precipitated urea was filtered off and the filtrate was washed twice with 50 ml of 5% aqueous soda. The organic phase was dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (eluent: n-hexane / isopropanol 20: 1). Yield: 17.01 g (78.9% of theory, calculated on the carboxylic acid used) of the title compound as a colorless oil.

Elemental analysis:

Calculated: 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-cis-D-carbonylmethylmanopyranose) -L-lysine] -diamide-4- [2- (N-ethyl-N-perfluorooctylsulfonylamino) acetyl] -1, 4,7-triazaheptan

15.0 g (6.36 mmol) of the amide prepared in Example 34d) was dissolved in 150 ml of ethanol, and 0.5 g of Pearlman's catalyst (20% Pd / C) was added. The reaction mixture was hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until consumption of hydrogen was observed. The catalyst was then filtered off, washed thoroughly with ethanol (ca. 100 ml) and the solution was evaporated to dryness under reduced pressure. The title compound was obtained as a viscous yellowish oil. Yield: 8.54 g (97.2% of theory).

134

Elemental analysis:

Calculated: 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-Oa-D-carbonylmethylmanopyranose) -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-perfluorooctylsulfonylamino) acetyl] -1,7,7-triazaheptane , digadolinium complex

To a stirred suspension of 5.7 g (9.06 mmol) of gadolinium complex with 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4 0.68 g (15.9 mmol) of lithium chloride was added at 75 ° C to the 7-triacetate obtained according to DE 197 28 954 C1 in Example 31h) in 75 ml of absolute dimethylsulfoxide. After stirring at 70 ° C for 30 minutes, a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide was added portionwise and the reaction mixture was stirred for an additional hour at this temperature. After cooling to 0 ° C, 4.52 g (23.85 mmol) of N, N ^? -dicyclohexylcarbodiimide and the reaction mixture was stirred for an additional hour at 0 ° C and then for 12 hours at 22 ° C. 10- (4-Carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetoacetic acid N-hydroxysuccinimide ester reaction mixture thus obtained. A solution of 2.84 g (2.06 mmol) of the title compound of Example 34e) in 15 mL of absolute dimethylsulfoxide was added dropwise at 22 ° C and the reaction mixture was stirred for 12 hours at room temperature. Upon work-up, 500 ml of acetone was added dropwise to the reaction solution at 22 ° C, whereby the title compound precipitated as a colorless precipitate. The precipitate was aspirated, dissolved in 200 ml of distilled water and ultrafiltered three times through an AMICON® YM-3 ultrafiltration membrane (cutoff limit: 3000 Da) to remove salts and low molecular weight fraction. The filtrate obtained was lyophilized. Yield: 4.80 g (89.6% of the theoretical calculated on ami135 new component) as a colorless lyophilisate. Water content 8.98%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 38.28; H, 4.84; N, 9.68; F, 12.40; S 1.23; Gd 12.07 Found: C 38.20; H, 4.91; N, 9.77; F, 12.45; S 1.19; Gd 12,10

Example 35

(a) 1,7-Bis (benzyloxycarbonyl) -4- {3-oxapentane-1,5-dicarboxylic acid-1-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 at 0 ° C and under a nitrogen atmosphere added 16.56 g (24.4 mmol) of the title compound of Example 35e) dissolved in 150 mL of tetrahydrofuran. Then a total of 18.0 g (36.6 mmol) of EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) was added at 0 ° C, the mixture was stirred overnight at room temperature and then evaporated to dryness at room temperature. reduced pressure. The oil obtained was purified by chromatography on silica gel (mobile phase: n-hexane / isopropanol 12: 1). 17.22 g (64.3% of theoretical based on the secondary amine used) of the monoamide were obtained together with 3.8 g (8.8% of theoretical) of the diamide by-product. The title compound was isolated as a colorless oil.

Elemental analysis:

Calculated: C 43.41; H, 3.92; F, 29.18; N, 7.59; S, 2.60

Found: C, 43.52; H, 4.07; F, 29.24; N, 7.67; S, 2.55

b) 1,7-Bis (benzyloxycarbonyl) -4- (3-oxapentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) piperazine] amide) -10- [10aD- 5-Carboxylpentyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -1,4,7,10-tetraazacyclododecane

10.0 g (13.4 mmol) of the carboxylic acid of Example 30c) a

136

3.24 g (28.1 mmol) of N-hydroxysuccinimide was dissolved in 100 ml of dimethylformamide, a total of 5.8 g (28.1 mmol) of N, N'-dicyclohexylcarbodiimide was added portionwise at 0 ° C and the mixture was stirred at This temperature was stirred for 3 hours. To the thus obtained active ether solution was added dropwise a solution of 14.83 g (13.4 mmol) of the title compound of Example 35a) dissolved in 100 ml of dimethylformamide and cooled to 0 ° C and stirred for 2 hours at 0 ° C and then for 12 hours at room temperature. On working up, the precipitated dicyclohexylurea precipitate was filtered off and the solvent was evaporated to dryness under reduced pressure. The residue thus obtained was purified by chromatography on silica gel (mobile phase: dichloromethane / ethyl acetate 20: 1, whereby the chromatography was carried out in a stepwise manner to gradually increase the proportion of ethyl acetate). Yield: 18.3 g (78.2% of theory) of the title compound as a colorless and very viscous oil.

Elemental analysis:

Calculated: C 55.11; H, 5.03; N, 4.82; F, 18.52; S, 1.84

Found: C, 54.87; H, 4.85; N, 4.92; F, 18.55; S, 1.86

c) 1- {3-Oxapentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) piperazine] amide} -7- (10aD-5-carbonylpentylmanopyranose) -1,4,7 , 10-tetraazacyclododecane

17.0 g (9.75 mmol) of the compound prepared in Example 34b) was dissolved in 150 ml of ethanol, 1.0 g of Pearlman catalyst (20% Pd / C) was added, and the reaction mixture was hydrogenated at room temperature under a hydrogen atmosphere ( 1 atm) until no further consumption of hydrogen was observed. The catalyst was filtered off, washed with ethanol (twice 75 ml) and the solvent was evaporated under reduced pressure. The title compound was obtained as a very viscous colorless oil. Yield: 10.76 g (99.0% of theory).

Elemental analysis:

137

Calculated: 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, 9.02; 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-) 5-yl) -4- [2- (N-ethyl-N-perfluóroktylsulfonylamino) acetyl] -2-oxaacetyl) -10- (5-load-karbonylpentylmanopyranóza) -1,4,7,10 tetraazacyclododecane

24.86 g (39.46 mmol, 4.4 molar equivalents, calculated on the amine component of Example 35c), gadolinium complex with 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, The 4,7,10-tetraazacyclododecane-1,4,7-triacetic acid described in patent application DE 197 28 954 Cl in Example 31h) and 1.67 g (39.46 mmol) of anhydrous lithium chloride were dissolved at 40 [deg.] C. of stirring in 200 ml of absolute dimethylsulfoxide and 4.53 g (39.46 mmol) of N-hydroxysuccinimide and 10.0 g (8.97 mmol) of the title compound of Example 34c) dissolved in 100 ml of absolute dimethylsulfoxide were added at this temperature. . After cooling to room temperature, 8.14 g (39.46 mmol) of N, N2O was added to the reaction solution ^. -dicyclohexylcarbodiimide and the reaction mixture was stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da). ) to remove the low molecular weight fraction. The residue was lyophilized. Yield: 16.37 g (79.3% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 7.65%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-1,3-pentane-1,5-dicarboxylic acid [1- (4-perfluorooctylsulfonyl) piperazine] amide g (44.0 mmol) of 1- (perfluorooctylsulfonyl) piperazine was dissolved in 150 ml of tetrahydrofuran, total temperature was added at room temperature Diglycolic anhydride (5.1 g, 44.0 mmol) was heated at reflux for 12 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness in vacuo and the residue was purified by silica gel chromatography (eluent: dichloromethane / 2-propanol 16: 1). Yield: 27.94 g (92.8% of theory) of the title compound as a colorless viscous oil.

Elemental analysis:

Calculated: 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

Example 36

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

68.5 g (91.79 mmol) of 1-carboxymethyloxy- (2,3,4,6-tetra-O-benzyl) -α-D-manopyranoside prepared according to patent application DE 197 28 954 C1 were dissolved in 750 ml of dry tetrahydrofuran and 9.25 g (91.79 mmol) of triethylamine was added. After cooling the reaction mixture to -15 ° C to -20 ° C, a solution of 12.64 g (92.5 mmol) of isobutyl chloroformate in 150 ml of dry tetrahydrofuran was slowly added dropwise at this temperature, the dropping rate being such that the reaction temperature was the mixture did not pass -10 ° C. The mixture was stirred for 15 minutes at -15 ° C and then a solution of 101.6 g (91.79 mmol) of the title compound of Example 35a) and 9.25 g (91.79 mmol) of triethylamine in 500 mL was added dropwise. dry tetrahydrofuran at

139 at -20 ° C. The reaction mixture was stirred for 1 hour at -15 ° C and then for 2 hours at room temperature and then evaporated to dryness under reduced pressure. The residue was dissolved in 450 mL of ethyl acetate and washed twice with 300 mL of saturated sodium bicarbonate solution and then with 400 mL of water. After drying the organic phase over sodium sulfate, the inorganic salts were filtered off and the ethyl acetate was evaporated to dryness in vacuo. The residual oil was purified by silica gel chromatography (eluent: dichloromethane / hexane / 2-propanol 10: 20: 1). Yield: 130.6 g (81.6% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: C 55.11; H, 5.03; N, 4.82; F, 18.52; S, 1.84

Found: C, 55.20; H, 5.09; N, 4.91; F, 18.48; S, 1.80

b) 1- {3-Oxapentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) piperazine] amide} -7- (10aD-5-carbonylpentylmanopyranose) -1,4,7 , 10-tetraazacyclododecane

110.0 g (63.08 mmol) of the compound prepared in Example 36a) was dissolved in 1000 ml of ethanol, 5.0 g of Pearlr.an catalyst (20% Pd / C) were added, and the mixture was hydrogenated until all the consumption was complete. hydrogen. The catalyst was filtered off, washed thoroughly with ethanol and the mixture was evaporated to dryness under reduced pressure. The title compound was obtained as a colorless oil. Yield: 92.61 g (99.5% of theory).

Elemental analysis:

Calculated: 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-ylpentanoyl) -4- (3-oxapentane-1,5) -dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) piperazine] amide) -10- (1-O-α-D-5-carbonylpentylmanopyranose) -1,4,7,10-tetraazacyclododecane,

140 digadolinium complex

55.4 g (88.0 mmol, 4.4 molar equivalents based on the diamine component of Example 33d), gadolinium-10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1-acid complex, 4,7,10-terraazacyclododecane-1,4,7-triacetic acid described in patent application DE 197 28 954 C1 in Example 31h) and 3.7 g (88.0 mmol) of anhydrous lithium chloride are stirred at 40 DEG C. with stirring. ° C was dissolved in 500 mL of absolute dimethylsulfoxide and the reaction mixture was treated 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 of Example 36b. ) dissolved in 200 ml of absolute dimethylsulfoxide. After cooling to room temperature, the reaction solution was treated with 18.2 g (88.0 mmol) of N, N'-dicyclohexylcarbodiimide and the mixture was stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the undissolved dicyclohexylurea was filtered off and the filtrate was ultrafiltered on an AMICON 'YM-3 ultrafiltration membrane (cut-off limit: 3000 Da). ) to remove the low molecular weight fraction. The residue was lyophilized. Yield: 35.96 g (76.9% of theory as a colorless lyophilisate) Water content (Karl-Fischer): 5.98%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 38.01; H, 4.61; N, 8.22; F, 13.81; Gd 13.45; S, 1.37. Found: C, 37.87; H, 4.70; N, 8.22; F, 13.90; Gd 13.48; S, 1.36

Example 37

a) 5- (Ethoxycarbonyl) pentyl- (2,3,4,6-tetra-O-acetyl) -? - D-manopyranoside

In an analogous manner to that described in the literature for the synthesis of arylglycopyranosides [J. Conchie and G. A. Levvy in Methods in Carbohydrare Chemistry (R. L. Whistler, M. L. Wolfrom and J. N. De

141

Miller Eds., Academic Press, New York, Vol. 11, 90, p. 345 -

-347 (1963)) resulted in 156.2 g (400 mmol) of D-mannosapentaacetate as a 4: 1 mixture of α, β-anomers [synthesis (1,2,3,4,6-Penta-O-acetyl)] -a, β-D-manopyranoses, see ML Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN De Miller Eds.), Academic Press, New York, Vol. 11, 53, p. 211-215 (1963)] with 67 ml (400 mmol) of ethyl 6-hydroxyhexanoate and 60.8 ml (520 mmol) of tin tetrachloride in 600 ml of 1,2-dichloroethane after chromatography on a silica gel column (mobile phase: n- hexane / ethyl acetate 2: 1) to give 100.05 g (51% of theory) of the title compound as a colorless viscous oil. ¹ H-NMR spectroscopy revealed that the title compound can be considered a pure α-anomer.

Elemental analysis:

Calculated: C 52.94; H, 6.77

Found: C, 52.80; H, 6.78

b) 5-Carboxypentyl- (2,3,4,6-tetra-O-benzyl) -α-D-manopyranoside

A suspension of 141.0 g (289 mmol) of the title compound of Example 37a) in 200 mL of dioxane was treated portionwise with a total of 238.5 g (4.26 mol) of finely powdered potassium hydroxide at room temperature with vigorous stirring. To increase the stirring efficiency, 200 mL of dioxane was added to the reaction mixture, and the mixture was heated to boiling and a total of 372 mL (3.128 mol) of benzyl bromide was added dropwise over 2 hours. The reaction mixture was stirred for 4 hours at 110 ° C and then for 12 hours at room temperature. The reaction mixture was then poured slowly into a total of 2.5 L of ice water and extracted with diethyl ether. The ether phase was washed and dried over sodium sulfate. The inorganic salts were filtered off and the diethyl ether was evaporated to dryness in vacuo. Excess benzyl bromide was distilled off from the reaction mixture at an oil bath temperature of 180 ° C. The residue thus obtained was purified by chromatography on silica gel (mobile phase: ethyl acetate / hexane 1:10). Yield: 172.2 g (91.0% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: C 75.68; H, 7.16

Found: C, 75.79; K 7.04

c) 5-Carboxypentyl- (2,3,4,6-tetra-O-benzyl) -α-D-manopyranoside-N-hydroxysuccinimide ester

60.0 g (91.5 mmol) of the title compound of Example 37b) was dissolved in 750 ml of dimethylformamide and a total of 10.4 g (91.5 mmol) of N-hydroxysuccinimide was added. The mixture was cooled to 0 ° C and 18.9 g (91.5 mmol) of N, N'-dicyclohexylcarbodiimide was added. The reaction mixture was stirred for 4 hours at 0 ° C and then for 4 hours at room temperature. The solvent was evaporated to dryness and the residue was dissolved in 100 mL of ethyl acetate and cooled to 0 ° C. The resulting urea was filtered off with suction and the filtrate was evaporated to dryness in vacuo. The residue thus obtained was purified by silica gel chromatography (eluent: ethyl acetate / hexane 1:20). Yield: 61.23 g (89.0% of theory) of the title compound as a viscous oil.

Elemental analysis:

Calculated: C 70.29; H, 6.57; N, 1.86

Found: C, 70.39; H, 5.64; N, 1.91

d) 2,6-Bis {β- ^ε- 2-β - [10aD-5-carbonylpentyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine} -methyl ester

To a solution of 4.26 g (18.30 mmol, 0.5 molar equivalent based on carboxylic acid) of L-lysine methyl ester dihydrochloride commercially available from Bachem and 4.05 g (40.26 mmol) of triethylamine in 100 mL of dimethylformamide cooled to the temperature

143

A solution of 27.51 g (36.6 mmol) of the title compound of Example 37c) in 150 mL of DMF was added dropwise at 0 ° C. After the addition was complete, the reaction mixture was stirred for an additional hour at 0 ° C and then overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 300 mL of ethyl acetate. The resulting urea was filtered off and the filtrate was washed twice with 100 ml of 5% aqueous soda. The organic phase was dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / isopropanol 25: 1). 39.56 g (75.4% of theory) of the title compound were obtained as a colorless oil.

Elemental analysis:

Calculated: C 72.82; H, 7.31; N, 1.95

Found: C, 72.90; H, 7.29; N, 2.02

e) 2,6-Bis {6- ^ε- 2-β - [10aD-5-carbonylpentyl- (2,3,4,6-tetra-O-benzyl) mannopyranose]} - L-lysine

30.0 g (20.92 mmol) of the compound prepared in Example 37d) was dissolved in 150 ml of ethanol. A solution of 4 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water was then added and the mixture was stirred at 50 ° C for 3 hours. Thin layer chromatography showed the reaction to be quantitative. The reaction mixture was evaporated to dryness in vacuo, the residue was dissolved in 300 ml of ethyl acetate and the organic phase was extracted twice with 100 ml of dilute aqueous citric acid. After drying over sodium sulfate, the solution was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: n-hexane / isopropanol 13: 1). Yield: 25.56 g (88.5% of theory) of the title compound as a colorless oil.

Elemental analysis:

Calculated: C 72.88; H, 7.31; N, 1.95

Found: C 72.78; H, 7.33; N, 1.96

144

f) 2,6-Bis- {6-N ^E -2-N ^a - [10aD-5-carbonylpentyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine} -N hydroxysuccinimide

14.0 g (9.15 mmol) of the title compound of Example 37e) was dissolved in 100 mL of dimethylformamide and a total of 1.04 g (9.15 mmol) of N-hydroxysuccinimide was added. The mixture was cooled to 0 ° C and N, N'-dicyclohexylcarbodiimide (1.89 g, 9.15 mmol) was added. The mixture was stirred for 1 hour at 0 ° C and then for 4 hours at room temperature. The solvent was evaporated to dryness in vacuo and the residue was dissolved in 100 mL of ethyl acetate and cooled to 0 ° C. The precipitated urea was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue thus obtained was purified by chromatography on silica gel (mobile phase: ethyl acetate / n-hexane 1:20). Yield: 12.94 g (92.4% of theory) of the title compound as a colorless viscous oil.

Elemental analysis:

Calculated: 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-OaD- (6-carbonyl) pentyl- (2,3,4,6-tetra-Obenzyl) mannopyranose] -L-lysine-1,7- (1) 4- (7-triazaheptane) diamide

To a solution of 0.47 g (4.57 mmol) of diethylenetriamine in 25 mL of dimethylformamide cooled to 0 ° C was slowly added dropwise a solution of 14.0 g (9.15 mmol, 2 molar equivalents, based on amine used) of the title compound. Example 37f) in 100 ml of dimethylformamide. After the addition was complete, the reaction mixture was stirred for 1 hour at 0 ° C and then overnight at room temperature. The mixture was then evaporated to dryness under reduced pressure and the residue was dissolved in 200 mL of ethyl acetate. The precipitated urea precipitate was filtered off and the filtrate was washed twice with 50 ml of 5% aqueous soda solution. The organic phase was dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (mobile phase:

145 n-hexane / isopropanol 25: 1). 9.53 g (71.4% of theory) of the title compound were obtained as a colorless oil.

Elemental analysis:

Calculated: 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-perfluorooctylsulfonylamino) acetyl] -6-N- (benzyloxycarbonyl) -L-lysine methyl ester

20.8 g (35.6 mmol) of 2- [N-ethyl-N-perfluorooctylsulfonylamino) acetic acid and 3.60 g (35.6 mmol) of triethylamine were dissolved in 200 ml of dimethylformamide and 4.09 g (35 mmol) of tert-butylamine were added. , 6 mmol) of N-hydroxysuccinimide. The mixture was cooled to 0 ° C and 7.34 g (35.6 mmol) of N, N'-dicyclohexylcarbodiimide was added. The reaction mixture was stirred for 1 hour at 0 ° C and then for 4 hours at room temperature. The mixture was cooled to 0 ° C and then 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) was added dropwise over 10 minutes. mmol) of triethylamine in 100 ml of dimethylformamide. The reaction mixture was stirred for 1 hour at 0 ° C and then overnight at room temperature. It was then evaporated to dryness under reduced pressure and the residue was dissolved in 100 ml of ethyl acetate. The precipitated urea was filtered off and the filtrate was washed twice with 5% aqueous soda. The organic phase was dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate 20: 1). Yield: 27.43 g (88.0% of theory) of a colorless oil.

Elemental analysis:

Calculated: 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-N ° - [2- (N-Ethyl-N-perfluorooctylsulfonylamino) acetyl] -6-N ^c - (benzyloxycarbonyl) -L-lysine

146

25.0 g (28.55 mmol) of the compound prepared in Example 37h) was dissolved in 150 ml of ethanol. A solution of 4 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water was then added and the mixture was stirred for 3 hours at 50 ° C. According to thin-layer chromatography, the saponification is complete. The reaction mixture was evaporated in vacuo, the residue was dissolved in 300 ml of ethyl acetate and the organic phase was extracted twice with 100 ml of dilute citric acid solution. After drying over sodium sulfate, the inorganic salts were filtered off and the mixture was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: n-hexane / isopropanol 10: 1). Yield: 22.73 g (92.4% of theory) of the title compound as a colorless oil.

Elemental analysis:

Calculated: 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-Triazaheptane-4- {2-N- [2- (N-ethyl-N-perfluorooctylsulfonylamino) acetyl] -6-N- (benzyloxycarbonyl)} - L-lysine-1,7-bis (2,6-N, N'-bis [10-cis-D-5-carbonylpentyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine diamine}

In 250 mL of dry tetrahydrofuran was dissolved 15.33 g (17.8 mmol) of the title compound of Example 37i) along with 1.80 g (17.8 mmol) of triethylamine. After cooling to -15 ° C to -20 ° C, a solution of 4.92 g (35.6 mmol) of isobutyl chloroformate in 50 ml of dry tetrahydrofuran was slowly added dropwise to the reaction mixture with stirring at such a rate that the reaction temperature was the mixture did not exceed -10 ° C. After stirring at -15 ° C for 15 minutes, 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 was slowly added dropwise. temperature -20 ° C. The reaction mixture was stirred for 1 hour at -15 ° C and then for 2 hours at room temperature and evaporated to dryness under reduced pressure.

147 pressure. The residue was dissolved in 500 mL of ethyl acetate and washed twice with 200 mL of saturated sodium bicarbonate solution and then with 200 mL of water. After drying the organic phase over sodium sulfate, ethyl acetate was evaporated in vacuo. The oily residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane 1:20). Yield: 54.6 g (81.6% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: 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-Triazaheptane-4- {2-N- [2- (N-ethyl-N-perfluorooctylsulfonyl amino) acetyl]} - L-lysine-amide-1,7-bis {2,6- N, N'-bis (10aD-5-carbonylpentylmanopyranose) -L-lysine diamide]

50.0 g (13.28 mmol) of the compound prepared in Example 37j) was dissolved in 500 ml of ethanol, 4.0 g of Pearlman catalyst (20% Pd / C) were added and the mixture was hydrogenated at room temperature under a hydrogen atmosphere (1). atm) until hydrogen consumption was no longer observed. The catalyst was filtered off, washed thoroughly with ethanol (ca. 400 ml) and the mixture was evaporated to dryness in vacuo. The title compound was obtained as a very viscous colorless oil. Yield: 26.85 g (93.0% of theory).

Elemental analysis:

Calculated: 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-perfluorooctylsulfonylamino) acetyl] -6-N- [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl) -1,4,7,10 tetraazacyclododecane) -L-lysine amide-1,7-bis {2,6-N, N &apos; -bis ( 10aD-5-carbonylpentylmanopyranose) -L-lysine diamide}, gadolinium complex

148

5.54 g (8.8 mmol, 2.2 molar equivalents based on the amine component of Example 37k) used, gadolinium-10- (4-carboxylmethyl-2-oxo-3-azabutyl) -1,4 acid complex The 7,10-tetraazacyclododecane-1,4,7-triacetic acid described in DE 197 28 954 C1 in Example 31h) and 0.37 g (8.8 mmol) of anhydrous lithium chloride were dissolved at 40 ° C with stirring. in 60 ml of absolute dimethylsulfoxide and at this temperature a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 1.84 g (4.0 mmol) of the title compound of Example 37k) dissolved in 40 ml of absolute DMSO. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N2O was added to the reaction mixture ^. -dicyclohexylcarbodiimide and the mixture was stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da). ) to remove the low molecular weight fraction. The residue was lyophilized. Yield: 8.77 g (78.7% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 4.43%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 '38

a) 6-N ^£ 2-N "-bis [1-OaD-carbonylmethyl- (2,3,4, 6-tetra-O-benzyl) mannopyranose] -L-lysine] -methyl

10.95 g (18.30 mmol) of 1-Methoxycarbonyl- (2,3,4,6-tetra-O-benzyl) - α-D-manopyranoside prepared as described in patent application DE 197 28 954 Cl was dissolved in 150 ml of dimethylformamide and a total of 2.09 g (18.3 mmol) of N-hydroxysuccinimide was added. The mixture was cooled to 0 ° C and 3.78 g was added

149 (18.3 mmol) of N, N'-dicyclohexylcarbodiimide. The mixture was stirred for 1 hour at 0 ° C and then for 4 hours at room temperature. The mixture was cooled to 0 ° C and a solution of 2.13 g (9.15 mmol, 0.5 molar equivalent, calculated on the carboxylic acid used) of L-lysine methyl ester dihydrochloride (commercially available from Bachem) was added dropwise over 1 hour, and 2.02 g (20.13 mmol) of triethylamine in 70 ml of dimethylformamide. After the addition was complete, the reaction mixture was stirred for 1 hour at 0 ° C and then overnight at room temperature. The mixture was evaporated to dryness and the residue was dissolved in 300 mL of ethyl acetate. The precipitate formed was filtered off and the filtrate was washed with 100 ml of 5% aqueous soda. The organic phase was dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / isopropanol 25: 1). Yield: 10.05 g (82.3% of theory) of the title compound as a colorless oil.

Elemental analysis:

Calculated: C 71.94; H, 6.79; N, 2.10

Found: C, 71.90; H, 6.79; N, 2.09

b) 6-N ^c -2-N ^Q -Bis [1-Oa- ^D -carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine

In an analogous manner to that described in Example 37e) for the synthesis of the corresponding title compound, saponification of 15 g (11.23 mmol) of the title compound Example 38a yielded 13.69 g (93.6% of theory). the title compound as a colorless viscous oil.

Elemental analysis:

Calculated: C 71.80; H, 6.71; N, 2.12

Found: C, 71.84; H, 6.69; N, 2.15

c) 6-N- ^{1 '} -2-N' -Bis [1-Oa-D-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) 150 mannopyranose] -L-lysine-N-hydroxysuccinimide ester

12.09 g (9.15 mmol) of the title compound of Example 38b) was dissolved in 100 mL of dimethylformamide and a total of 1.04 g (9.15 mmol) of N-hydroxysuccinimide was added. The mixture was cooled to 0 ° C and N, N'-dicyclohexylcarbodiimide (1.89 g, 9.15 mmol) was added. The mixture was stirred for 1 hour at 0 ° C and then for 4 hours at room temperature. The solvent was removed under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate, and the mixture was cooled to 0 C. C. The precipitated urea precipitate was filtered off and the filtrate was evaporated to dryness under reduced pressure. The oily residue thus obtained was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane 1:20). Yield: 12.24 g (94.4% of theory) of the title compound as a viscous oil.

Elemental analysis:

Calculated: 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 N-hydroxysuccinimide ester of the carboxylic acid prepared in Example 38c) was dissolved in 75 ml of dimethylformamide and a solution of 11.13 g (13.4 mmol) of the title compound was added dropwise at 0 ° C. Of Example 21c) in 50.0 ml of dimethylformamide cooled to 0 ° C. The mixture was stirred for an additional 2 hours at 0 ° C and then for 12 hours at room temperature. Upon processing, the precipitated dicyclohexylurea precipitate was filtered off and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 28: 1; chromatography was performed by continuously adding ethanol). Yield: 25.28 g (88.4% of theory) of the title compound

151 in the form of a colorless and very viscous oil.

Elemental analysis:

Calculated: C 59.10; H, 5.34; N, 3.94; E, 15.13; S, 1.50

Found: C, 59.18; H, 5.35; N, 4.02; E 15.15; S, 1.56

é) 2-N - {[2,6-N, N´-Bis (1-O-α-D-carbonylmethylmanopyranose)] -L-lysyl-L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

20.0 g (9.37 mmol) of the compound prepared in Example 38d) was dissolved in 200 ml of ethanol, 1.5 g of Pearlman catalyst (20% Pd / C) were added and the reaction mixture was hydrogenated at room temperature under a hydrogen atmosphere ( 1 atm) until hydrogen consumption was no longer observed. The catalyst was filtered off, washed thoroughly with ethanol (twice about 100 ml) and the mixture was evaporated to dryness under reduced pressure. The title compound was obtained as a colorless, very viscous oil. Yield: 11.62 g (97.0% of theory).

Elemental analysis:

Calculated: 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-ylpentanoyl) -1,4,7,10-tetraazacyclododecane) -2 N - {[2,6-N, N'-bis (1-O-α-D-carbonylmethylmanopyranose)] -L-lysyl} -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd -complex

9.98 g (15.84 mmol, 2.2 'molar equivalent calculated with respect to the amine component of Example 38e), gadolinium-10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) acid complex. -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid described in patent application DE 197 28 954 Cl in Example 31h) and 0.67 g (15.84 mmol) of anhydrous lithium chloride were dissolved with stirring a total of 1.82 g (15.84 mmol) of N-hydroxysuccinimide and 9.19 g (7.19 mmol) of the title compound of Example 38e were added at 40 ° C in 100 mL of absolute dimethylsulfoxide.

152 dissolved in 50 ml of absolute dimethylsulfoxide. After cooling to room temperature, the reaction mixture was treated with 3.27 g (15.84 mmol) of N, N'-dicyclohexylcarbodiimide and the reaction mixture was stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da). ) to remove any low molecular weight moieties present. The residue was lyophilized. Yield: 11.85 g (87.2% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 5.54%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 39

a) 1,7-Bis (benzyloxycarbonyl) -4- (3-oxa-25, 25, 45, 45, 55, 55-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 in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform was added dropwise at 0 ° C under a nitrogen atmosphere. 12.74 g (24.4 mmol) of the title compound of Example 39g) dissolved in 150 mL of tetrahydrofuran. Then, a total of 18.0 g (36.6 mmol) of EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) was added portionwise at 0 ° C, stirred overnight at room temperature and then evaporated. to dryness under reduced pressure. The residual oil was purified by silica gel chromatography (mobile phase: n-hexane / isopropanol 16: 1). 15.89 g (69.0% of the theoretical amount calculated on the secondary amine used) of the monoamide were obtained together with 3.8 g (8.8% of the theoretical amount) of the diamide by-product. The title compound was isolated as a colorless oil.

153

Elemental analysis:

Calculated: 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- [1SaD-2-carbonylethyl- (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-SaD-manopyranosyl] propionic acid N-hydroxysuccinimide ester prepared according to J. Haensler et al., Bioconjugate Chem., 4, 85, (1993); S. Chipowsky and YC Lee, Synthesis of 1-thioaldosides, Carbohydrate Research 31, 339-346 (1973) was dissolved in 100 mL of dimethylformamide and a solution of 12.65 g (13.4 mmol) of the title compound was added dropwise at 0 ° C. in the title of Example 39a) in 100 ml of dimethylformamide cooled to 0 ° C. The mixture was stirred for 2 hours at 0 ° C and then for 12 hours at room temperature. Upon work-up, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane / ethyl acetate 20: 1, with a gradient gradient of increasing ethyl acetate). Yield: 16.23 g (88.9% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calcd, 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-perfluoridecanoyl) -7- [1-SaD-2-carbonylethyl- (2,3,4,6-tetra-O-acetyl)] mannopyranose] -1,4,7,10 tetraazacyclododecane

15.0 g (11.0 mmol) of the compound prepared in Example 39b) was dissolved in 150 ml of ethanol, 1.0 g of Pearlman catalyst (20% Pd / C) was added and the reaction mixture was hydrogenated at room temperature under a hydrogen atmosphere ( 1 atm) until hydrogen consumption was no longer observed. The catalyst was filtered off, washed thoroughly with ethanol (twice about 75 ml) and the mixture was evaporated to dryness under reduced pressure. The title compound was obtained as a colorless, very viscous oil. Yield: 11.56 g (96.0% of theory).

Elemental analysis:

Calculated: 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-2tf, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) -7- (1-S-α-D-2-carbonylethylmanopyranose) -1,4,7,10-tetraazacyclododecane

10.0 g (9.13 mmol) of the title compound of Example 39c) were suspended in 100 mL of absolute methanol and a catalytic amount of sodium methoxide was added at 5 ° C. The mixture was stirred for 3 hours at room temperature and checked by thin layer chromatography (eluent: chloroform / methanol 4: 1) showed a quantitative reaction. The clear reaction solution was neutralized with an Amberlite ³ IR 120 (H ⁺ form) cation exchanger, filtered from the ion exchanger, washed with methanol, and the methanolic filtrate thus obtained was evaporated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / n-hexane / ethyl acetate 15: 20: 1, the chromatography being carried out with a gradient with continuous addition of ethyl acetate). After examination of the title compound by ¹ H-NMR spectroscopy, the anomeric center of D-manopyranose could be concluded to have an α-configuration based on the size of the interaction constant J 1, 2 = 0.9 Hz. Said α-configuration at the anomeric center is the exclusive configuration, i.e. the amount of any α-anomer of the title compound formed is below the recognition limit of ¹ H-NMR spectroscopy. Thus, the title compound was prepared as the pure α-anomer. Yield: 8.28 g (98.0% of theory) of the title compound as a colorless, very viscous oil.

155

Elemental analysis:

Calculated: 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-perfluorotecanoyl) -7- (1-S-α-D-2-carbonylethylmanopyranose) -4,10-bis [1, 4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl)] - 1,4,7,10-tetraazacyclododecane, digadolinium complex

1,4,7,10-tetraazacyclododecane amide conjugate with 1,7- bis-gadolinium complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane- l, 4,7-triacetic acid; 3 - [(2,3,4,6-tetra-O-acetyl) -1-SaD-manopyranosyl) propionic acid, 2.48 g (3.94 mmol, 4.4 molar equivalents calculated on the diamine component used in the Example) 39d) gadolinium complex with 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid described in patent application DE 197 28 954 Cl of Example 31h) and 167 mg (3.94 mmol) of anhydrous lithium chloride were dissolved in 40 ml of absolute dimethylsulfoxide at 40 ° C with stirring and a total of 453 mg (3.94 mmol) of N-hydroxysuccinimide was added at this temperature. and 980 mg (0.895 mmol) of the title compound of Example 19d) dissolved in 10 mL of absolute dimethylsulfoxide. After cooling to room temperature, the reaction mixture was treated with 814 mg (3.946 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da). ) to desalination and remove any low molecular weight moieties present. The residue was lyophilized. Yield: 1.32 g (69.1% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 7.65%.

156

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-2tf, 2H, AH, AH, 5H, 5H-perfluorotridecanoic acid tert-butyl ester

25.0 g (53.8 mmol ·) of IH, IH, 2H, 2H-perfluoro-1-decanol commercially available from Lancaster were dissolved in 250 ml of absolute toluene and a catalytic amount (about 0.75) was added at room temperature. g) tetra-n-butylammonium hydrogen sulfate. Thereafter, 7.55 g (134.6 mmol, 2.5 equivalents per alcoholic component) of finely powdered potassium hydroxide was added at 0 ° C, followed by 15.73 g (80.7 mmol, 1.5 equivalents). to the alcoholic component used) bromoacetic acid tert-butyl ester and the mixture was stirred for 2 hours at 0 ° C. The reaction mixture thus obtained was stirred for 12 hours at room temperature and then 500 ml of ethyl acetate and 250 ml of water were added. The organic phase was separated and washed twice with water. After drying the organic phase over sodium sulfate, the inorganic salts were filtered off and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (mobile phase: ethyl acetate / hexane 1:10). Yield: 26.3 g (84.6% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: C 33.23; H, 2.61; F, 55.85

Found: C, 33.29; H, 2.61; F, 55.90

g) 3-Cxa-2H, 2H, AH, AH, 5H, 5H-perfluorodecanecarboxylic acid

20.0 g (34.58 mmol) of the title compound of Example 39f) was suspended in 200 mL of a 2: 1 mixture of methanol and 0.5 M aqueous sodium hydroxide with stirring at room temperature, and then the mixture was warmed to temperature 60 ° C. The reaction mixture was stirred for 12 hours at 60 ° C and clear

The reaction mixture was worked up by neutralization by adding a cation exchange resin Amberlite ® IR 120 (H ⁺ -form), filtering the ion exchanger and evaporating the methanolic filtrate to dryness under reduced pressure. The obtained residue was purified by silica gel chromatography (mobile phase: ethyl acetate / hexane 1: 3). Yield: 16.0 g (88.6% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: C 27.60; H, 1.35; F, 61.85

Found: C, 27.58; H, 1.36; F, 61.90

Example 40

a) 6- (Benzyloxycarbonyl) -2- [2- (N-ethyl-N-perfluorooctyl-sulfonyl) amino] acetyl-L-lysine-methyl ester

To 8.0 g (24.4 mmol) of ε-benzyloxycarbonyl-L-lysine-methyl ester hydrochloride commercially available from Bachem dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform and 2.62 g (26.0 mmol) of triethylamine was added at 16.18 g (27.0 mmol) of 2- (N-ethyl-N-perfluorooctylsulfonylamino) acetic acid prepared according to the patent application DE 196 03 033) dissolved in 50 ml of tetrahydrofuran was added dropwise under a nitrogen atmosphere. Then, a total of 18.0 g (36.6 mmol) of EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) was added portionwise at 0 ° C, and the mixture was stirred overnight at room temperature. The mixture was evaporated to dryness under reduced pressure and the residue was purified by silica gel chromatography (eluent: n-hexane / isopropanol 15: 1). Yield: 17.0 g (79.6% of theoretical based on the primary amine used) of the title compound as a colorless oil.

Elemental analysis:

Calculated: 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

158

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

15.0 g (20.23 mmol) of the compound prepared in Example 40a) was dissolved in 200 ml of ethanol, 800 mg of Pearlman catalyst (20% Pd / C) were added and the reaction mixture was hydrogenated at room temperature under a hydrogen atmosphere (1 atm). ) until the calculated amount of hydrogen has been consumed. The catalyst was filtered off, washed thoroughly with ethanol and the mixture was evaporated to dryness under reduced pressure. The title compound was obtained as a colorless oil. Yield: 14.68 g (97.9% of theory).

Elemental analysis:

Calculated: 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-perfluorooctylsulfonylamino) aceoyl] -1- iyzín methyl ester

21.31 g (35.6 mmol) of 1-carboxymethyloxy- (2,3,4,6-tetra-O-benzyl) - α -D-manopyranoside prepared according to DE 157 28 954 C1 were dissolved together in 500 ml of dry tetrahydrofuran. with 3.60 g (35.6 mmol) of triethylamine. After cooling the reaction mixture to -15 ° C to -20 ° C, a solution of 4.92 g (35.6 mmol) of isobutyl chloroformate in 75 ml of dry tetrahydrofuran was slowly added dropwise at this temperature, the rate of addition being such that the reaction temperature was the mixture did not exceed -10 ° C. The mixture was stirred for 15 minutes at -15 ° C and then a solution of 26.39 g (35.6 mmol) of the title compound of Example 40b) and 3.60 g (35 g) was slowly added dropwise at -20 ° C. 6 mmol) of triethylamine in 100 ml of dry tetrahydrofuran. The reaction mixture was stirred for 1 hour at -15 ° C and then for 2 hours at room temperature. Then, the reaction mixture was evaporated to dryness under reduced pressure. The residue obtained

159 was dissolved in 250 mL of ethyl acetate and washed twice with 100 mL of saturated aqueous sodium bicarbonate solution and then with 200 mL of water. After drying the organic phase over sodium sulfate, the inorganic salts were filtered off and the ethyl acetate was removed under reduced pressure. The residue obtained was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane 1:10). Yield: 38.12 g (81.0% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: 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

27.65 g (20.92 mmol) of the compound prepared in Example 40c) was dissolved in 250 ml of methanol. The solution was then added to a solution of 4.0 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water, and the mixture was stirred for 3 hours at 50 ° C. Thin-layer chromatography indicated complete saponification of the methyl ester. The reaction mixture was evaporated in vacuo, the residue was dissolved in 300 ml of ethyl acetate and the organic phase was extracted twice with 100 ml of dilute citric acid solution. After drying over sodium sulfate, the inorganic salts were filtered off and the mixture was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: n-hexane / chloroform / isopropanol: 10: 1). 24.31 g (88.9% of theory) of the title compound were obtained as a colorless viscous oil.

Calculated: 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-Carbonylmethylmanopyranose) -2- [2- (N-ethyl-N160)

-perfluóroktylsulfonylamino) acetyl] -L-lysine

20.0 g (15.30 mmol) of the title compound of Example 40d) was dissolved in a mixture of 250 ml of 2-propanol and 25 ml of water and 1.0 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated for 12 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in 200 ml of methanol and the reaction product was precipitated by the addition of 800 ml of diethyl ether. After filtering off the precipitate so obtained, the solid was dried under vacuum at 50 ° C. Yield: 14.32 g (99.0% of theory) of an amorphous solid.

Elemental analysis:

Calculated: 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-Oa-D-Carbonylmethylmanopyranose) -2- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-L-lysine-N- (2-hydroxy-prop-3-yl- [1, 4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododec-10-yl]} amide, Gd complex

7.48 g (7.91 mmol) of the title compound of Example 40e) was dissolved in 50 mL of dimethylsulfoxide at 40 ° C and 1.00 g (8.70 mmol) of N-hydroxysuccinimide was added. The mixture was cooled to 20 ° C and then N, N'-dicyclohexylcarbodiimide (1.795 g, 8.7 mmol) was added. The mixture was stirred for 1 hour at 20 ° C and then for 4 hours at 40 ° C. Then a solution of 4.53 g (7.91 mmol) of gadolinium complex with 10- (2-hydroxy-3-aminopropyl) -4,7,10-tris (carboxylatomethyl) -1,4 was added dropwise over 10 minutes. 7,10-tetraazacyclododane prepared according to patent application WO 97/02051 in 20 ml dimethylsulfoxide. The mixture was stirred for 1 hour at 40 ° C and then overnight at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off, and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cutoff limit: Da) due to desalination and removal of any low molecular weight moieties present. The residue was lyophilized. Yield: 9.71 g (81.7% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 3.97%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 41

a) 6-N- [10aD-5-carbonylpentyl- (2,3,4,6-tetra-O-benzyl) -manopyranose] -2-N- [2- (N-ethyl-N-perfluoroctylsulfonyl) amino] acetyl-L-lysine methyl ester

5.23 g (8.0 mmol) of 5-carbonylpentyl- (2,3,4,6-tetra-O-benzyl) -α-D-manopyranoside described in Example 30c), 1.3 g (8.0 mmol) )

1-hydroxybenzotriazole and 2.6 g (8.0 mmol) of 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU; Peboc Ltd., UK) were dissolved in 75 ml of dimethylformamide and the mixture was stirred for 15 minutes. This solution was treated with 5.16 ml (30 mmol) of N-ethyldiisopropylamine and 5.93 g (8.0 mmol) of the amine described in Example 40b) and the mixture was stirred for 1.5 days at room temperature. Upon work-up, the solvent was evaporated to dryness and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / ethyl acetate 30: 1, where the chromatography was carried out under gradient elution conditions with continuous addition of ethyl acetate). Yield: 9.70 g (88.0% of theory). The title compound was obtained as a colorless, very viscous oil.

Elemental analysis:

Calculated: C 52.29; H, 4.97; N, 3.05; F, 23.43; S, 2.33

162

Found: C, 52.33; H, 4.95; N, 3.12; F, 23.50; S, 2.30

b) 6-N- [10aD-5-carbonylpentyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -2-N- [2- (N-ethyl-N-perfluorooctylsulfonylamino) acetyl] L-lysine

9.0 g (12.40 mmol) of the compound prepared in Example 41a) was dissolved in 150 ml of methanol. A solution of 2.48 g (62.0 mmol) of sodium hydroxide in 15 ml of distilled water was then added and the mixture was stirred at 50 ° C for 3 hours. Thin-layer chromatography indicated that the saponification of the methyl ester was complete after the indicated reaction time. The reaction mixture was evaporated in vacuo, the residue was dissolved in 300 ml of ethyl acetate and the organic phase was extracted twice with 100 ml of dilute citric acid solution. After drying over sodium sulfate, the inorganic salts were filtered off and the mixture was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / chloroform / isopropanol 25: 10: 1). Yield: 15.88 g (93.9% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: 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-Carbonylpentylmanopyranose) -2-N- [2- (N-ethyl-Nperfluorooctyl sulfonylamino) acetyl] -L-lysine

13.0 g (9.52 mmol) of the title compound of Example 41b) was dissolved in a mixture of 150 ml of 2-propanol and 25 ml of water and 1.0 g of a palladium catalyst (10% Pd / C) was added. The mixture was then hydrogenated for 12 hours under a hydrogen atmosphere (i atm) and at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. The obtained residue was purified by silica gel chromatography (eluent: n-hexane / chloroform / isopropanol 15: 10: 1). 9.09 g were obtained

163 (95.1% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: C 37.10; H, 4.22; N, 4.19; E 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-Carbonylpentylmanopyranose) -2-N- [2- (N-ethyl-N-perfluorooctyl sulfonylamino) acetyl] -L-lysine-N- {2-hydrox Prop-3-yl- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclodod-10-yl]} amide, Gd complex

7.93 g (7.91 mmol) of the title compound of Example 41c) was dissolved in 75 mL of dimethylsulfoxide at 40 ° C and 1.00 g (8.70 mmol) of N-hydroxysuccinimide was added. The mixture was cooled to room temperature and a total of 1.795 g (8.7 mmol) of N, N'-dicyclohexylcarbodiimide was added. The mixture was stirred for 1 hour at 20 ° C and then for 4 hours at 40 ° C. A solution of 4.53 g (7.91 mmol) of gadolinium-10- (2-hydroxy-3-aminopropyl) complex was then added dropwise to the solution of the title compound of Example 41c) thus obtained at 40 ° C over a period of 1 min. -4,7,10-tris (carboxylateomethyl) -1,4,7,10-tetraazacyclododecane prepared according to patent application WO 97/02051 in 20 ml of dimethylsulfoxide. The mixture was stirred for 1 hour at 40 ° C and then over ncc at room temperature. The suspension thus obtained was treated with an excess of acetone / 2-propanol 2: 1 until the title compound completely precipitated, the precipitate was filtered off, washed with ethyl acetate, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off and the filtrate was ultrafiltrated AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da) to desalinate and remove any low-blood particles present. The residue was lyophilized. Yield: 9.71 g (78.8% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 6.65%.

164

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 42

(a) 6-N- (4- (2,3-Bis [N, N-bis (tert-butyloxycarbonylmethyl) amino] propyl} phenyl) -3-oxapropionyl-2-N- (1-α-carbonylmethylmanopyranose) - L-lysine- [l- (4-perfluorooctylsulfonyl) -piperazine] -amide

5.25 g (7.72 mmol) of Tyr-EDTA-carboxylic acid tetra (tert-butyl) ester and 781 mg (7.72 mmol) of triethylamine were dissolved in 50 ml of dichloromethane. At -15 ° C, a solution of 1.16 g (8.5 mmol) of isobutyl chloroformate in 10 ml of dichloromethane was added dropwise over 5 minutes, and the mixture was stirred for an additional 20 minutes at -15 ° C. The solution was then cooled to -25 ° C and a solution of 7.07 g (7.72 mmol) of the title compound of Example 30e) and 2.12 g (21.0 mmol) of triethylamine in 70 mL of tetrahydrofuran was added dropwise. The mixture was stirred for 30 minutes at 5 ° C and then overnight at room temperature. On working up, the solvent was evaporated to dryness and the residue was dissolved in 250 ml of chloroform. The chloroform phase was extracted twice with 100 ml of 10% aqueous ammonium chloride solution, the organic phase was dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 9.60 g (79.0% of theory) of a colorless, very viscous oil.

Elemental analysis:

Calculated: C 46.39; H, 5.55; N, 5.32; F, 20.45; S, 2.03

Found: C, 46.42; H, 5.51; N, 5.29; F, 20.49; S, 2.09

b) 6-N- (4- {2,3-Bis [N, N-bis (carboxylatomethyl) amino] propyl) phenyl) -3-oxapropionyl-2-N- (1-α-carbonylmethylmanopyranose) -L-lysine - [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

165

9.0 g (5.70 mmol) of the compound of Example 42a) was dissolved in 150 ml of methanol. A solution of 4.0 g (100.0 mmol) of sodium hydroxide in 25 ml of distilled water was then added and the mixture was stirred for 6 hours at 60 ° C. TLC analysis showed that the tetra (tert-butyl) ester was quantitatively saponified after the reaction time. The solvent was evaporated to dryness, the residue was dissolved in 50 ml of dimethylsulfoxide hot and then a large amount of 1: 1 acetone / ethyl acetate was added until precipitation of the title compound. The precipitate thus obtained was filtered off, washed with ethyl acetate, dried, dissolved in water, the pH of the solution was adjusted to 3.5 with 1 M aqueous hydrochloric acid solution, the insoluble matter was filtered off and the filtrate was ultrafiltered on an AMICON® YM- ultrafiltration membrane. 3 (threshold limit: 3000 Da) to desalination and remove any low molecular weight moieties present. The residue was lyophilized. Yield: 6.76 g (87.6% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 3.30%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 39.89; H, 4.09; N, 6.20; F, 23.84; S, 2.37

Found: C, 39.92; H, 4.15; N, 6.22; F, 23.92; S, 2.29

c) 6-N- (4- {2,3-Bis- [N, N-bis (carboxylatomethyl) amino] propyl} phenyl) -3-oxapropionyl-2-N- (1-α-carbonylmethylmanopyranose) -L -lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Mn complex, disodium salt; '

3.0 g (2.22 mmol) of the title compound of Example 42b) was dissolved in 150 ml of a 3: 1 mixture of water / ethanol at boiling point and 0.25 g (2, 22 mmol) of manganese carbonate The reaction solution thus obtained was heated at reflux for 5 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was dissolved in 200 ml of a 1: 1 mixture of distilled water and n-butanol. With vigorous stirring, the pH of the reaction mixture was adjusted to 7.2 with 1 N sodium hydroxide solution. After the n-butanol was completely removed under reduced pressure, the aqueous phase was ultrafiltered through an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da), thereby clearing low molecular weight impurities. The residue was lyophilized. Yield: 3.19 g (99.0% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 5.08%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 37.23; H, 3.54; F, 22.25; Mn 3.78; N, 5.79; Na 3.17; S, 2.21

Found: C, 37.30; H, 3.49; F, 22.29; Mn 3.81; N, 5.76; Na 3.19;

S, 2.18

Example 43

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

Intensively stirred solution of 25.0 g (94.96 mmol) of 3-N- (benzyloxycarbonyl) glutaric anhydride prepared according to M. Haranak, Y.-I. Yamamoto, H. Nitta, T. Ishimaru, Tetrahedron Lett., 22 (39), 3883-3886 (1981) in 150 mL of absolute tetrahydrofuran was added dropwise to a solution of 53.97 g (95.0 mmol) of 1- (perfluorooctylsulfonyl) with stirring. of piperazine in 150 ml of tetrahydrofuran and the resulting reaction mixture was heated at reflux for 12 hours. After cooling to room temperature, the mixture was evaporated to dryness and the residual oil was purified by silica gel chromatography (eluent: dichloromethane / 2-propanol 20: 1). Yield: 75.80 g (96.0% of theory) of the title compound as a colorless viscous oil.

Elemental analysis:

Calculated: 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; E 38.82

b) [1- (4-Perfluorooctylsulfonyl) piperazine] monoamide

167

3-aminoglutaric

31.50 g (37.88 mmol) of the compound prepared in Example 43b) was dissolved in 300 ml of ethanol, 2.5 g of Pearlman catalyst (20% Pd / C) were added, and the mixture was hydrogenated under a hydrogen atmosphere (1 atm) to into quantitative hydrogen consumption. The catalyst was filtered off, washed with ethanol and the solvent was removed in vacuo. The title compound was obtained as a white yellowish viscous oil. Yield: 25.22 g (95.5% of the theoretical amount).

Elemental analysis:

Calculated: 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-manopyranoside prepared according to patent application DE 197 28 954 Cl was dissolved in 100 at room temperature 2.65 g (22.2 mmol) of N-hydroxysuccinimide were added at 0 ° C, followed by 4.55 g (22.2 mmol) of N, N'-dicyclohexylcarbodimide. The reaction mixture was stirred for 1 hour at 0 ° C and then for 3 hours at 22 ° C, the insoluble dicyclohexylurea was filtered off and the clear active ester solution of the title compound thus obtained was added dropwise to the stirred solution 13 at 0 ° C. 22 g (18.96 mmol) of the compound of Example 43b) dissolved in 100 mL of dimethylformamide. The reaction mixture was stirred for 12 hours at room temperature and the solvent was removed under reduced pressure, the residue was dissolved in 300 ml of ethyl acetate, the precipitated urea precipitate was filtered off, and the organic filtrate was washed twice with 100 ml of saturated sodium bicarbonate solution, then 100 ml of 10% aq. citric acid solution; and

168 at the end 200 ml of water. After drying the organic phase over sodium sulfate, ethyl acetate was removed under reduced pressure. The oily residue obtained was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane 1: 15). Yield: 21.39 g (88.3% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: 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-carbonylmethylmanopyranose) glutaric acid [1- (4-perfluorooctylsulfonyl) piperazine] monoamide

19.55 g (15.30 mmol) of the title compound of Example 43c) was dissolved in a mixture of 250 ml of 2-propanol and 25 ml of water, and 1.5 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated for 12 hours at room temperature under a hydrogen atmosphere (1 atm). The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in 200 ml of methanol and the reaction product was precipitated by the addition of 800 ml of diethyl ether. After filtering off the precipitated solid, the solid thus obtained was dried under vacuum at 40 ° C. Yield: 17.49 g (97.5% of theory) of an amorphous solid.

Elemental analysis:

Calculated: 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) 5-N- (2-hydroxyprop-3-yl- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododec-10) - [1- (4-Perfluorooctylsulfonyl) piperazine] amide -yl]} 3-N- (1-α-D-carbonylmethylmanopyranose) glutaric acid amide, Gd complex

14.43 g (15.84 mmol) of the title compound of Example 43d) and 0.67 g (15.84 mmol) of anhydrous lithium chloride were dissolved in 100 ml of absolute dimethylsulfoxide and stirred at 40 ° C under stirring. a total of 1.82 g (15.84 mmol) of N-hydroxysuccinimide and a solution of 9.08 g (15.84 mmol) of gadolinium complex with 10- (2-hydroxy-3-aminopropyl) -4,7,10- tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane prepared according to patent application WO 97/02051 in 50 ml of dimethyl sulfoxide. After cooling to room temperature, 3.27 g (15.84 mmol) of N, N'-N, N'-dicyclohexylcarbodiimide was added to the reaction solution, and the mixture was stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclchexylurea was filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000). Da) due to desalination and removal of any low molecular weight moieties present. The residue was lyophilized. Yield: 18.71 g (80.2% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 4.87%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 44

a) 1,7-Bis (benzyloxycarbonyl) -4- (3-oxapentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) piperazine) amide) -10- (2,6 -N, N ^; -bis [1-Oa-D-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) -manopyranose]} - L-lysyl-1,4,7,10-tetraazacyclododecane

To a solution of 27.0 g (24.4 mmol) of the secondary amine prepared in Example 35a) in a mixture of 150 mL of tetrahydrofuran and 15 mL of chloroform at 0 ° C and under a nitrogen atmosphere was added 33.04 g (25.0 mmol) of the compound. The title compound of Example 18c) dissolved in 250 mL of tetrahydrofuran. Then, 18.0 g (36.6 mmol) of EEDQ (2-ethoxy-1-ethoxy-170-carbonyl-1,2-dihydroquinoline) was added portionwise at 0 ° C, and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residual oil was purified by silica gel chromatography (eluent: n-hexane / isopropanol 25: 1). 45.87 g (78.0% of the theoretical amount based on the secondary amine used) of the title compound were obtained as a colorless oil.

Elemental analysis:

Calculated: C 59.30; H, 5.39; E 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-Oxapentane-1,5-dicarboxylic acid-1-oyl-5- [1- (perfluorooctylsulfonyl) piperazine] amide} -7- [2,6-N, N'-bis (1) -O-α-D-carbonylmethylmanopyranose)] - L-lysyl-1,4,7,10-tetraazacyclododecane

24.1 g (10.0 mmol) of the compound prepared in Example 44a) was dissolved in 250 ml of ethanol, 1.4 g of Pearlman catalyst (20% Pd / C) were added, and the mixture was hydrogenated under 1 atmosphere of hydrogen. into quantitative hydrogen consumption. The catalyst was filtered off, washed with ethanol and the solvent was removed in vacuo. The title compound was obtained as a yellowish very viscous oil. Yield: 12.80 g (90.1% of theory).

Elemental analysis:

Calculated: C 39.72; H, 4.89; F, 22.73; N, 7.88; S, 2.26

Found: C, 39.72; K 4.87; F, 22.77; N, 7.90; S, 2.24

c) 1- {3-Oxapentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) piperazine] amide} -7- [2,6-N, N'-bis (1) O-α-D-karbonylmetylmanopyranóza)] - L-lysyl-4,10- bis [1,4,7-tris (karbcxylátometyl) -10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl -] - 1,4,7,10-Cecraazacyclododecane, digadolithium complex

5.54 g (8.8 mmol, 2.2 molar equivalents based on the amine component of Example 44b used), gadolinium complex with 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1 The 4,7,10-tetraaza171-cyclododecane-1,4,7-triacetic acid described in patent application DE 197 28 954 C1 in Example 31h) and 0.37 g (8.8 mmol) of anhydrous lithium chloride at 40 ° C. was dissolved in 60 mL of absolute dimethylsulfoxide and 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 were added with stirring at this temperature. absolute dimethylsulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide was added to the reaction mixture, and the reaction mixture was stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da). ) to desalination and remove any low molecular weight moieties present. The residue was lyophilized. Yield: 8.52 g (80.6% of theoretical based on the diamine component used) as a colorless lyophilisate. Water content (Karl-Fischer): 6.09%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 45

a) 1,7-Bis (benzyloxycarbonyl) -4- (3-oxapentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-fluorooctylsulfonyl) piperazine] amide} -10- {2, 6-N, N &apos; -bis (Load-5-carbonyl-pentyl- (2,3,4,6-tetra-O-benzyl) -manopyranóza)} - L-lysyl-1,4,7,10- tetraazacyclododecane

To a solution of 27.0 g (24.4 mmol) of the secondary amine prepared in Example 35a) in a mixture of 150 mL of tetrahydrofuran and 15 mL of chloroform was added 35.80 g (25.0 mmol) of the compound at 0 ° C under nitrogen. 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) was added portionwise in portions, and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residual oil was purified by silica gel chromatography (mobile phase: n-hexane / isopropanol 20: 1). Yield: 49.48 g (80.4% of theoretical based on the secondary amine used) of the title compound as a colorless oil.

Elemental analysis:

Calculated: 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-Oxapentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) piperazine} amide} -7- [2,6-N, N'-bis (10aD) 5-karbonylpentylmanopyranóza)] - L-lysyl-l, 4,7,10-tetraazacyclododecane

25.2 g (10.0 mmol) of the title compound of Example 45a) was dissolved in 250 mL of ethanol, 1.8 g of Pearlman's catalyst (20% Pd / C) were added. The mixture was hydrogenated under a hydrogen atmosphere (1 atm) until quantitative consumption of hydrogen. The catalyst was filtered off, washed with ethanol and the solvent was removed in vacuo. The title compound was obtained as a yellowish very viscous oil. Yield: 14.11 g (92.5% of theory).

Elemental analysis:

Calculated: 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-Oxapentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) piperazine] amide} -7- [2,6-N, N'-bis (1) -O-α-5-carbonylpentylmanopyranose] - L-lysyl-4,10-bis [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl) -] - 1,4,7,10-tetraazacyclododecane, digadolinium complex

173

5.54 g (8.8 mmol, 2.2 molar equivalents based on the amine component of Example 45b used), gadolinium complex with 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1 , 4,7,10-tetraazacyclododecane-1,4,7-triacetic acid described in patent application DE 197 28 954 Cl in Example 31h) and 0.37 g (8.8 mmol) of anhydrous lithium chloride are stirred at 40 ° with stirring. C was dissolved in 60 ml of absolute dimethylsulfoxide and at this temperature a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 6.10 g (4.0 mmol) of the title compound of Example 45b) dissolved in 40 ml were added. absolute dimethylsulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicydohexylcarbodiimide was added to the reaction mixture and stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da). ) to desalination and remove any low molecular weight moieties present. The residue was lyophilized. Yield: 9.26 g (84.0% of theoretical based on the diamine component used) as a lyophilizate. Water content (Karl-Eischer): 5.89%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 46

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

19.02 g (50.0 mmol) of α-N- (Benzyloxycarbonyl) -ε-Ν- (tert-butyloxycarbonyl) -L-lysine, commercially available from Bachem, were dissolved in 150 ml of absolute tetrahydrofuran. 8.31 g (50.0 mmol) of 1,1'-carbonyldiimidazole and 5.03 g (50.0 mmol) were added.

174 triethylamine dissolved in 75 ml dry tetrahydrofuran at 0 ° C and the reaction mixture was stirred for 10 minutes at this temperature. Then a solution of 48.42 g (50.0 mmol) of 1- (perfluorooctylsulfonyl) piperazine and 5.03 g (50.0 mmol) of triethylamine in 250 ml of dry tetrahydrofuran was added dropwise at 0 ° C. The mixture was stirred overnight, the tetrahydrofuran was evaporated in vacuo and the residue was purified by silica gel chromatography (mobile phase: n-hexane / isopropanol 15: 1). Yield: 49.48 g (80.4% of theoretical based on the secondary amine) of the title compound as a colorless oil.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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- (tert-Butyloxycarbonyl) -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

30.0 g (32.2 mmol) of the title compound of Example 46a) was dissolved in 300 ml of isopropanol and 1.5 g of Pearlman's catalyst (20% palladium hydroxide on carbon) was added. The mixture was stirred for 10 hours at room temperature, and TLC analysis showed that the reaction time indicated a quantitative removal of the benzyloxy protecting group. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography (mobile phase: n-hexane / isopropanol) to give 25.13 g (98.0% of theory) of the title compound as a colorless oil.

Elemental analysis:

Calculated: 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-N- (tert-Butyloxycarbonyl) -2-N- [1SaD-2-carbonylethyl- (2,3,4,6-tetra-O-acetyl) manopyranose] -L-lysine- [1- (4) -perfluoro175 octylsulfonyl) piperazine] amide

In 300 ml of dry tetrahydrofuran was dissolved 15.53 g (35.60 mmol) of 3 - [(2,3,4,6-tetra-O-acetyl) -1-SaD-manopyranosyl) propionic acid prepared according to J. Haensler et. al., Bioconjugate Chem., 4, 85 (1993); S. Chipowsky and Y.C. Lee, Synthesis of 1-thioaldosides, Carbohydrate Research 31, 339-346 (1973) together with 3.60 g (35.60 mmol) of triethylamine. After cooling the reaction mixture to -15 ° C to -20 ° C, a solution of 4.92 g (35.60 mmol) of isobutyl chloroformate in 75 ml of dry tetrahydrofuran was slowly added dropwise with stirring at this temperature, such that the addition rate was such that the temperature of the reaction mixture did not exceed -10 ° C. The reaction mixture was stirred for 15 minutes at -15 ° C and then slowly added dropwise a solution of 28.35 g (35.60 mmol) of the title compound of Example 42b) and 3.60 g (35.60 mmol) of triethylamine in 200 mL of dry tetrahydrofuran at -20 ° C. The reaction mixture was stirred for 1 hour at -15 ° C and then for 2 hours at room temperature. The reaction mixture was then evaporated to dryness under reduced pressure. The residue obtained was dissolved in 250 ml of ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution and then with 200 ml of water. After drying the organic phase over sodium sulfate, ethyl acetate was evaporated in vacuo. The oily residue obtained was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane 1:25). Yield: 34.21 g (79.1% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: 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- (tert-Butyloxycarbonyl) -2-N- (1-S-α-D-2-carbonylethyl-manopyranose) -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

29.93 g (24.64 mmol) of the title compound of Example

176

46c) was suspended in 400 ml absolute methanol and a catalytic amount of sodium methoxide was added at 5 ° C. The reaction mixture was stirred for 3 hours at room temperature, and thin layer chromatography (eluent: chloroform / methanol 9: 1) showed that the reaction was quantitative. The clear reaction mixture was worked up by neutralization by adding a cation exchanger Amberlite (R) IR 120 (1H-form), filtering the ion exchanger and evaporating the methanolic filtrate to dryness under reduced pressure. The amorphous residue obtained was purified by chromatography on silica gel (mobile phase: 2-propanol / ethyl acetate / n-hexane 1: 1: 15). Yield: 23.42 g (90.8% of theory) of a colorless and viscous oil.

Elemental analysis:

Calculated: 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; E, 30.82; S, 6.11

e) 2-N- (1-S-α-D-2-Carbonylethylmanopyranose) -L-lysine- [1- (4-

-perfluóroktylsulfonyl) -piperazine] amide

20.93 g (20.0 mmol) of the title compound of Example 46d) was dissolved in a mixture of 50 ml of trifluoroacetic acid and 100 ml of dichloromethane at 0 ° C with vigorous stirring, and the mixture was stirred at this temperature for 10 minutes. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 150 mL of water. The pH of the aqueous solution of the product was adjusted to 9.5 by addition of 2 M aqueous sodium hydroxide solution. The aqueous product solution was purified by filtration through an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da) to desalination and remove any low molecular weight components present. The residue was lyophilized. Yield: 17.79 g (94.2% of theory) of the free amine as a lyophilisate. Water content (Karl -ischer): 3.09%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 34.26; H, 3.73; N, 5.92; F, 34.12; S, 6.77

177

Found: C, 34.26; H, 3.79; N, 5.88; F, 34.07; S, 6.80

f) 2-N- (1SaD-2-Carbonylethylmanopyranose) -6-N- [1,4,7-tris- (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

I

5.54 g (8.8 mmol, 2.2 molar equivalent, calculated on the amine compound of Example 46e), gadolinium-10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4 acid complex 7,10-tetraazacyclododecane-1,4,7-triacetic acid described in patent application DE 197 28 954 C1 in Example 31h) and 0.37 g (8.8 mmol) of anhydrous lithium chloride are stirred at 40 ° with stirring. C was dissolved in 60 mL of absolute dimethylsulfoxide and a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.78 g (4.0 mmol) of the title compound of Example 46e) dissolved in 40 mL were added at this temperature. absolute dimethylsulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide was added to the reaction solution, and the mixture was stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da). ) to desalination and remove any low molecular weight moieties present. The residue was lyophilized. Yield: 5.17 g (83.0% of theory) as a colorless lyophilisate. Water content (Karl-Fisc’ner): 4.43 I.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 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, 20.60; Gd 10.13; S, 4.14

Example 47

178

a) 6-N- (Benzyloxycarbonyl) -2-N- (1-O-α-D-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) glucopyranose) -L-lysine- [1- (4) -perfluóroktylsulfonyl) -piperazine] amide

8.02 g (13.4 mmol) of 1-methoxycarbonyl- (2,3,4,6-tetra-O-benzyl) -α-D-glucopyranoside described in patent application DE 197 28 954 Cl in Example 46a) and 3.24 g (28.14 mmol) of N-N-hydroxysuccinimide was dissolved in 100 ml of dimethylformamide and a total of 5.80 g (28.14 mmci; N, N'-dicyclohexylcarbodiimide) was added portionwise at 0 ° C. A cooled solution of 11.13 g (13.4 mmol) of the title compound of Example 21c) dissolved in 50 ml of DMF was added dropwise at 0 ° C and the mixture was stirred for a further 3 hours at this temperature. 2 hours at 0 ° C and then for 12 hours at room temperature. The precipitated dicyclohexylurea precipitate was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue obtained was purified by chromatography on silica gel (mobile phase: dichloromethane / ethanol 20: 1, where the chromatography was carried out under gradient conditions with increasing proportion of ecanol). Yield: 12.67 g (67.0% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: C 52.77; H, 4.50; N, 3.97; F, 22.89; S, 2.27

Found: C, 52.75; H, 4.61; N, 3.98; F, 22.94; S, 2.26

b) 2-N- (1-O-α-D-Carbonylmethylglucopyranose) -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

11.52 g (8.17 mmol) of the compound obtained in Example 47a) was dissolved in 100 ml of ethanol, 0.5 g of Pearlman catalyst (20% Pd / C) was added and the mixture was hydrogenated at room temperature under a hydrogen atmosphere (1). atm) until no further consumption of hydrogen was observed. The catalyst was filtered off and washed with ethanol (three times 40 ml). The title compound is

179 obtained as a colorless, very viscous oil. Yield: 7.36 g (98.4% of theory).

Elemental analysis:

Calculated: C 34.07; H, 3.63; M, 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-α-D-Carbonylmethylglucopyranose) -6-N- [1,4,7-tris- (carboxylatomethyl) -10- (aza-4-oxo-5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

9.98 g (15.84 mmol, 2.2 molar equivalents, calculated on the amine component of Example 47b) used, gadolinium-10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) acid-1 complex, The 4,7,10-tetraazacyclododecane-1,4,7-triacetic acid described in patent application DE 197 28 954 Cl in Example 31h) and 0.67 g (15.84 mmol) of anhydrous lithium chloride were dissolved in 40 ° C at 40 ° C. 80 ml of absolute dimethyl sulfoxide was added at this temperature to a total of 1.82 g (15.84 mmol) of N-hydroxysuccinimide and 7.25 g (7.19 mmol) of the title compound of Example 47b) dissolved in 30 ml of absolute dimethylsulfoxide. After cooling to room temperature, the reaction mixture was treated with 3.27 g (15.84 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da). ) to desalination and remove any low molecular weight moieties present. The residue was lyophilized. Yield: 9.11 g (83.0% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 4.02%.

Elemental analysis (calculated on the anhydrous substance):

180

Calculated: 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 48

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

10.0 g (11.46 mmol) of the compound prepared in Example 21b) was dissolved in 100 ml of ethanol, 1.0 g of Pearlman's catalyst (20% Pd / C) was added, and the mixture was hydrogenated under 1 atmosphere of hydrogen. into quantitative hydrogen consumption. The catalyst was filtered off, washed with ethanol and the solvent was removed in vacuo. The title compound was obtained as a colorless oil. Yield: 8.85 g (97.5% of theory).

Elemental analysis:

Calculated: 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- [10aD-5-carbonylpentyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine- [1- (4-perfluorooctyisulfonyl) ) -piperazine] amide

To a solution of 29.0 g (36.6 mmol) of the title compound of Example 48a) and 4.05 g (40.26 mmol) of triethylamine in 100 mL of dimethylformamide cooled to 0 ° C was added dropwise a solution of 27.51 g ( 36.6 mmol) of the title compound of Example 37c) in 150 ml of dimethylformamide. After the addition was complete, the mixture was stirred for 1 hour at 0 ° C and then overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 300 mL of ethyl acetate. The insoluble matter was filtered off and the filtrate was washed twice with 100 ml of 5% aqueous soda. The organic phase was dried over magnesium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / isopropanol 25: 1). Yield: 42.05 g (80.4% of theory) of the title compound as a colorless oil.

Elemental analysis:

Calculated: 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-Carbonylpentyl- (2,3,4,6-tetra-O-benzyl) -manopyranose] -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] -amide

20.0 g (14.0 mmol) of the compound prepared in Example 48b) was dissolved in 150 ml of ethanol. A solution of 2.8 g (70.0 mmol) of sodium hydroxide in 25 ml of distilled water was then added and the mixture was stirred for 0.5 hour at 50 ° C. Thin layer chromatography indicated that the deprotection at this reaction time was quantitative. The reaction mixture was evaporated to dryness under reduced pressure and the residual water was removed by repeated distillation with ethanol. The residue was purified by silica gel chromatography (eluent: n-hexane / isopropanol 20: 1). Yield: 16.66 g (89.3% of theory) of the title compound as a colorless oil.

Elemental analysis:

Calculated: 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-D-5-Carbonylpentylmanopyranose) -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

15.0 g (11.25 mmol) of the compound obtained in Example 48c) was dissolved in 150 ml of ethanol / water 10: 1, 1.0 g of Pearlman catalyst (20% Pd / C) was added and the mixture was hydrogenated under atmosphere of hydrogen (1 atm) at room temperature until quantitative consumption of hydrogen. The catalyst was filtered off, washed with ethanol / water 10: 1 and the solvent was removed in vacuo. The title compound was obtained as a colorless oil. Yield: 10.77 g (98.4% of theory).

182

Elemental analysis:

Calculated: 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- [10aD-5-Carbonylpentylmanopyranose] -2-N- [1,4,7-tris- (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

5.54 g (8.8 mmol, 2.2 molar equivalents, based on the amine component of Example 48d used) of gadolinium-10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1, 4,7,10-tetraazacyclododecane-1,4,7-triacetic acid described in DE 197 28 954 C1 in Example 31h) and 0.37 g (8.8 mmol) of anhydrous lithium chloride are stirred at 40 ° C with stirring dissolved in 60 mL of absolute dimethylsulfoxide and at this temperature 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.89 g (4.0 mmol) of the title compound of Example 48d) dissolved in 60 mL of absolute dimethylsulfoxide were added. . After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide was added to the reaction solution, and the mixture was stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da). ) to desalination and remove any low molecular weight moieties present. The residue was lyophilized. Yield: 4.81 g (75.9% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 8.98%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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

183

Example 49

a) 1,7-Bis (benzyloxycarbonyl) -4- [1-Oa-D-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) galactopyranose] -10- {3-oxapentane-1,5-dicarboxylic acid acid-oyl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -l, 4,7,10-tetraazacyclododecane

To a solution of 27.0 g (24.4 mmol) of the secondary amine obtained in Example 35a) in a mixture of 150 mL of tetrahydrofuran and 15 mL of chloroform was added dropwise at 0 ° C and under a nitrogen atmosphere. The title compound of Example 37e) dissolved in 250 mL of tetrahydrofuran. Then, a total of 18.0 g (36.6 mmol) of EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) was added portionwise at 0 ° C and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residual oil was purified by silica gel chromatography (mobile phase: n-hexane / isopropanol 20: 1). 32.11 g (78.0% of theoretical based on the secondary amine used) of the title compound were obtained as a colorless oil.

Elemental analysis:

Calculated: 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-Oa-D-Carbonylmethylgalactopyranose) -7- {3-oxapentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsuifonyl) piperazine] amide} -1,4,7 , 10-tetraazacyclododecane

30.0 g (17.77 mmol) of the title compound prepared in Example 49a) was dissolved in 250 ml of ethanol, 3.0 g of Peariman catalyst (20% Pd / C) were added, and the mixture was hydrogenated under hydrogen (1). atm) at room temperature up to quantitative consumption of hydrogen. The catalyst was filtered off, washed with ethanol and the solvent was removed in vacuo. The title compound was obtained as a colorless, very viscous

184 oil. Yield: 17.89 g (95.1% of theory).

Elemental analysis:

Calculated: 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-cis-D-Carbonylmethylgalactopyranose) -7- {3-oxapentane-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-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -1,4 7,10-tetraazacyclododecane, digadolinium complex

5.54 g (8.8 mmol, 4.4 molar equivalents based on the amine component of Example 49b used) gadolinium-10- (4-carboxymethyl-2-oxo-3-azabutyl) -1,4,7 complex, The 10-tetraazacyclododecane-1,4,7-triacetic acid described in patent application DE 197 28 954 Cl in Example 31h) and 0.37 g (8.8 mmol) of anhydrous lithium chloride were dissolved at 60 ° C with stirring at 60 ° C. ml of absolute dimethylsulfoxide and 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 2.11 g (2.0 mmol) of the title compound of Example 49b) dissolved in 25 ml of absolute dimethylsulfoxide were added at this temperature. After cooling to room temperature, the reaction solution was treated with 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide and the reaction mixture was stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da). ) to desalination and remove any low molecular weight moieties present. The residue was lyophilized. Yield: 3.29 g (72.2% of theoretical based on the amine component used) as a colorless lyophilisate. Water content (Karl-Fischer): 5.99%.

Elemental analysis (calculated on the anhydrous substance):

185

Calculated: 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 50

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

21.42 g (39.61 mmol) of (2,3,4,6-tetra-O-benzyl) - α-D-manopyranose prepared according to F. Kong et al., J. Carbohydr were dissolved in 500 ml of dry acetonitrile. . Chem., 16 (6), 877-890 (1997). After cooling the reaction mixture to 5 ° C, a solution of 13.23 g (59.52 mmol) of trimethylsilyl trifluoromethanesulfonic acid in 30 ml of acetonitrile was added dropwise with stirring at this temperature, followed by a solution of 20.06 g (79.21 mmol) of N- ( benzyloxycarbonyl) -L-serine methyl ester commercially available from Bachem in 50 ml of acetonitrile at a rate such that the temperature of the reaction mixture did not exceed 10 ° C. The reaction mixture was stirred for 15 hours at room temperature and then evaporated to dryness under reduced pressure. The residue was dissolved in 250 ml of ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution and then with 200 ml of water. After drying the organic phase over sodium sulfate, the inorganic salts were filtered off and the ethyl acetate was removed in vacuo. The oily residue was purified by silica gel chromatography (solvent: into ethyl acetate / n-hexane 1: 5. Yield: 23.60 g (76.8% of theory) of ^the: title compound as a colorless oil.

Elemental analysis:

Calculated: 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 of 20 ml of methanol, 20 ml of water and 50 ml of tetrahydrofuran

186 g of the compound prepared in Example 50a) was dissolved (10.0 g, 12.90 mmol). Then, 0.47 g (19.35 mmol) of lithium hydroxide dissolved in 25 ml of distilled water was added at room temperature, and the mixture was then stirred for 6 hours at 60 ° C. Thin-layer chromatography control (eluent: dichloromethane / methanol 10: 1) revealed that the saponification of the methyl ester of Example 30a) after the indicated reaction time was quantitative. After working up, the reaction product was evaporated to dryness and the residue was dissolved in warm (ca. 60 ° C) in 250 ml of ethyl acetate. The ethyl acetate phase thus obtained was washed twice with 50 ml of a 15% aqueous hydrochloric acid solution and then with 100 ml of distilled water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: n-hexane / ethyl acetate 5: 1). Yield: 8.40 g (85.7% of theory) of the title compound as a colorless oil.

Elemental analysis:

Calculated: C 70.94; H, 6.22; N, 1.84

Found: C, 70.97; H, 6.30; N, 1.78

c) 3- [1-OaD- (2,3,4,6-Tetra-O-benzyl) mannopyranose] -2-N- (benzyloxycarbonyl) -L-serine- [1- (4-perfluorooctylsulfonyl) -piperazine] amide

To 13.86 g (24.40 mmol) of 1- (perfluorooctylsulfonyl) piperazine prepared according to DE 196 03 033 dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, 20.57 was added dropwise at 0 ° C under a nitrogen atmosphere. g (27.0 mmol) of the carboxylic acid prepared in Example 50b) dissolved in 50 ml of tetrahydrofuran. Then, a total of 18.0 g (36.60 mmol) of EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) was added portionwise at 0 ° C, and then the mixture was stirred overnight at room temperature. On working up, the reaction mixture was evaporated to dryness and the residue was purified by chromatography on silica gel 187 (mobile phase: n-hexane / isopropanol 15: 1). Yield: 17.0 g (79.6% of theoretical based on the primary amine used) of the title compound as a colorless viscous oil.

Elemental analysis:

Calculated: C 51.53; H, 4.23; Ν · 3.15; E, 25.65; S, 2.41

Found: C, 51.48; H, 4.27; N, 3.10; E, 25.71; S, 2.35

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

15.0 g (11.41 mmol) of the compound prepared according to Example 50c) was dissolved in 200 ml of ethanol, 1.5 g of Pearlman catalyst (20% Pd / C) were added and the mixture was hydrogenated under a hydrogen atmosphere (1 atm) at at room temperature until no hydrogen consumption was observed (8 hours). The catalyst was filtered off, washed with ethanol (twice 100 ml) and the ethanol solution containing the product was evaporated to dryness under reduced pressure. The title compound was obtained as a colorless viscous oil. Yield: 8.79 g (94.0% of theory).

Elemental analysis:

Calculated: 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; E 39.50; S, 3.88

e) 3- (1-Oa-D-Manopyranose) -2-N- [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-ox-5-methyl-5-ylpentanoyl) -1, 4,7,10-tetraazacyclododecane] -L-serine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

A stirred suspension of 5.7 g (9.06 mmol, 1.5 molar equivalents based on the primary amine of Example 50d) of gadolinium acid complex with 10-4 (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1 The 4,7,10-tetraazacyclododecane-1,4,7-triacetic acid described in patent application DE 197 28 954 C1 in Example 31h) in 75 ml of absolute dimethylsulfoxide was reacted with 0.68 g at 70 ° C.

188 (15.9 mmol) of lithium chloride. The mixture was stirred for 30 minutes at 70 ° C and then a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide was added in portions and the reaction mixture was stirred for 1 hour at 70 ° C. After cooling the reaction mixture to 10 ° C, 4.52 g (23.85 mmol) of N, N'-dicyclohexylcarbodiimide was added and the reaction solution was stirred for 1 hour at 0 ° C and then for 12 hours at 22 ° C. C. The solution of the gadolinium complex with the N-hydroxysuccinimide ester of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid was thus obtained at at 22 ° C was treated with a solution of 4.94 g (6.03 mmol) of the title compound of Example 30d) in 15 mL of absolute dimethylsulfoxide, and the mixture was stirred for 12 hours at room temperature. On working up, the reaction mixture was slowly added dropwise at 22 ° C to a mixture of 250 ml of acetone and 250 ml of 2-propanol, and the title compound separated after 12 hours at 10 ° C as a light yellow oil. The excess solvent mixture was decanted and the oily product was taken up in 200 mL of distilled water to completely dissolve the oil to give a light yellow solution of the title compound. Finally, the aqueous product solution was purified by triple ultrafiltration through an AMICON 'YR-3 ultrafiltration membrane (cutoff limit: 3000 Da) to remove inorganic salts and low molecular weight fractions. The solution thus obtained was lyophilized. Yield: 8.63 g (80.2% of theory, calculated on the title compound of Example 30d) as a colorless lyophilisate. Water content: 7.65%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 51

a) 6-N- (Benzyloxycarbonyl) -2-N- [Ο-β-D-galactopyranosyl- (1-> 4) -gluconosyl] -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

189

To a stirred solution of 4.98 g (6.0 mmol) of the title compound of Example 21c) in 40 mL of absolute dimethylsulfoxide was added dropwise a solution of 13.3 g (37.2 mmol) of Ο-β-D-galactopyranosyl- at room temperature. (1-> 4) -D-glucono-1,5-lactone (lactobionolactone) prepared according to: (a) TJ Williams, NR Plessas, IJ Goldstein, Carbohydr. Res., 67, Cl (1978); (b) K.Kobayashi, H.

Sumitomo, Y. Ina, Polym. J., 17, 567 (1985); (c) Hiromi K., Katsuko S., Ayako K., Bioconjugate Chem., 6, 131-134 (1995) in 40 mL of absolute dimethylsulfoxide. The reaction solution thus obtained was stirred for 14 hours at 40 ° C. For work-up, the reaction mixture was treated with 500 ml of absolute 2-propanol and the precipitated colorless precipitate was filtered off with a G4-frit and washed thoroughly with a total of 250 ml of absolute 2-propanol. The solid so obtained was dissolved in 300 ml of distilled water and purified by triple ultrafiltration through an AMICON® YR-3 ultrafiltration membrane (cut-off limit: 3000 Da) to remove excess lactobionolactone and low molecular weight fractions. The ultrafiltration residue was dissolved in 300 ml of distilled water and lyophilized. Yield: 6.51 g (92.7% of theory) as a colorless lyophilisate. Water content: 10.03%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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- [Ο-β-D-galactopyranosyl- (1- »4) -gluconosyl] -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

5.0 g (4.27 mmol) of the compound prepared in Example 51a) was dissolved in 100 ml of ethanol, and 0.5 g of Pearlman's catalyst (20% Pd / C) was added. The reaction mixture was hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no consumption of hydrogen was observed. The catalyst was filtered off, washed with ethanol and the mixture was evaporated to dryness under reduced pressure.

190

The title compound was obtained as a colorless viscous oil. Yield: 4.36 g (98.5% of theory).

Elemental analysis:

Calculated: 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- [β-D-galactopyranosyl- (1-> 4) -gluconosyl] -6-N- [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4- oxo-5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, gadolinium complex

5.54 g (8.8 mmol, 2.2 molar equivalents, calculated on the amine compound of Example 51b), 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4-gadolinium acid complex The 7,10-tetraazacyclododecane-1,4,7-triacetic acid described in DE 197 28 954 Cl in Example 31h) and 0.37 g (8.8 mmol) of anhydrous lithium chloride were dissolved at 40 ° C with stirring. in 60 ml of absolute dimethylsulfoxide and at this temperature a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.85 g (4.0 mmol) of the title compound of Example 31b) dissolved in 60 ml of absolute dimethylsulfoxide were added. . After cooling to room temperature, the reaction mixture was treated with 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide and then stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone / 2-propanol 1: 1 until all the title compound precipitated, the precipitate was filtered off, dried, dissolved in 300 ml of water, the insoluble dicyclohexylurea was filtered off and the filtrate was purified from low molecular weight three times by ultrafiltration on an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da). During ultrafiltration, the title compound was freed of excess gadolinium complex and possibly low molecular weight moieties present. The ultrafiltration residue was dissolved in 500 ml of distilled water and lyophilized. Yield: 4.64 g

191 (70.4% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 10.08%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 52

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

100 g (356.7 mmol) of 6-N- (benzyloxycarbonyl) -lysine were dissolved in a mixture of 1000 ml of ethyl trifluoroacetic acid ester and 500 ml of ethanol and stirred for 24 hours at room temperature. The reaction mixture was evaporated to dryness and the residue was recrystallized from diisopropyl ether. Yield: 128.9 g (96% of theory) of a colorless crystalline powder.

Elemental analysis:

Calculated: C 51.07; H, 5.09; F, 15.14; N, 7.44

Found: 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 52a) and 188.7 g (332 mmol) of 1- (4-perfluorooctylsulfonyl) piperazine prepared according to patent application DE 196 03 033 in 800 ml of tetrahydrofuran at 0 ° C 164.2 g (664 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) was added and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by silica gel chromatography (eluent: dichloromethane / methanol 20: 1). Yield: 286 g (93% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 36.30; H, 2.83; F, 41.01; N, 6.05; S, 3.46

192

Found: 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

To a solution of 280 g (302.2 mmol) of the title compound of Example 52b) in 2000 mL of ethanol was added at 0 ° C.

I ammonia gas for 1 hour. The mixture was then stirred for 4 hours at 0 ° C. The reaction mixture was then evaporated to dryness and the residue was stirred with water. The solid was filtered off and dried under vacuum at 50 ° C. Yield: 243.5 g (97% of theory) of a colorless amorphous substance.

Elemental analysis:

Calculated: C 37.60; H, 3.28; F, 38.89; N, 6.75; S, 3.86

Found: C, 37.15; H, 3.33; F, 38.78; N, 6.68; S, 3.81

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

To 50 g (60.20 mmol) of the title compound of Example 52c) and 7.10 g (70 mmol) of triethylamine dissolved in 350 ml of dichloromethane at 0 ° C was added dropwise a solution of 79.93 g (70 mmol) 3, 6,9,12,15-pentaoxahexadecanoyl chloride prepared according to Liebigs Ann. Chem., 1980 (6), 852-62 in 50 mL dichloromethane and stirred for 3 hours at 0 ° C. 200 ml of 5% aqueous hydrochloric acid solution were added and the mixture was stirred for 5 minutes at room temperature. The organic phase was separated, dried over magnesium sulphate and evaporated in vacuo. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 15: 1). Yield: 53.7 g (93% of theory) of a colorless viscous oil.

Elemental analysis:

Calculated: C 33.83; H, 4.94; F, 3.34; N, 5.84; S, 33.69

Found: C, 33.75; H, 5.05; F, 3.29; N, 5.78; S, 33.75

e) 2-N- (3,6,9,12,15-Pentaoxahexadecanoyl) -lysine- [1- (4-perfluoro-197-octylsulfonyl) -piperazine] -amide g (52.15 mmol) of the title compound of Example 52d) was dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 43.0 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 27.68; H, 5.01; F, 39.17; N, 6.79; S, 3.89

Found: C, 27.60; H, 5.13; F, 39.09; N, 6.68; S, 3.81

f) 6-N- [1,4,7-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, gadolinium complex g (24.25 mmol) of the title compound of Example 52e ), 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of the gadolinium-1,4,7-tris (carboxylatomethyl) complex -10 - [(3-aza-4-oxo-5-methyl-5-yl)] pentanoic acid] -1,4,7,10-tetraazacyclododecane was dissolved in 200 mL dimethylsulfoxide with slight heating. 8.25 g (40 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 28.21 g (81% of theory) of a colorless solid. Water content: 11.0%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 31.78; H, 4.84; F, 22.49; N, 8.78; S, 2.23; Gd 10.95

Found: C, 31.74; H, 4.98; F, 22.39; N, 8.69; S, 2.15; Gd 10.87

Example 53

194

a) 6-N- Acid Bis (tert-butyl ester) -6-carbonylmethyl-2-N- [3,6,9,12,15-pentaoxahexadecanoyl] -lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] amide [3,9-bis (tert-butyloxycarbonylmethyl) -3,6,9-triazaundecane-1,11-dicarboxylic acid

To a solution of 20 g (24.08 mmol) of the title compound of Example 52e), 14.88 g (24.08 mmol) of 3,9-bis (tert-butyloxycarbonylmethyl) -3,6-bis (tert-butyl ester) bis , 9-triazaurodecane-1,11-dicarboxylic acid and 2.77 g (24.08 mmol) of N-hydroxysuccinimide in 150 ml of dimethylformamide were added at 0 ° C 8.25 g (40 mmol) of N, N'- DCC. The mixture was stirred for 3 hours at 0 ° C and then overnight at room temperature. The precipitate was filtered off, the filtrate was evaporated to dryness in vacuo and the residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 31.61 g (91% of theory) of a viscous oil.

Elemental analysis:

Calcd: C 40.80; H, 6.71; F, 22.39; N, 6.80; S, 2.22

Found: C, 40.72; H, 6.82; F, 22.30; N, 6.75; S, 2.14

b) 6-N- [6-Carbonylmethyl-3,9-bis (carboxylatomethyl) -3,6,9-triazaundecanedicarboxylic acid-1-carboxy-11-carboxylate] -2-N- (3,6,9,12) 15-pentaoxahexadecanoyl) -lysine- [1- (4-perfluorooctylsulfonyl) piperazine) amide, gadolinic acid complex, sodium salt g (20.8 mmol) of the title compound of Example 53a) was dissolved in 300 mL of trifluoroacetic acid the mixture was stirred for 5 hours at room temperature. The reaction mixture was evaporated to dryness, the residue was dissolved in 300 ml of water and the pH of the solution was adjusted to 2.5 with 10% aqueous sodium hydroxide solution. Then, 3.77 g (10.4 mmol) of gadolinium oxide were added and the mixture was stirred for 3 hours at 60 ° C. The reaction mixture was then cooled to room temperature and the pH was adjusted to 7.4 by addition of sodium hydroxide. The mixture was evaporated to dryness under reduced pressure and the residue was purified by chromatography on silica gel RP-18 (mobile phase: gradient in 195 da / acetonitrile). Yield: 19.18 g (67% of theory) of a colorless amorphous solid. Water content: 9.8%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 28.80; H, 4.25; E, 23.47; N, 7.12; S, 2.33; Gd .11.48; At 1.67

Found: C, 28.67; H, 4.34; F, 23.38; N, 7.03; S, 2.27; Gd 11.37;

At 1.74

Example 54

a) Lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide g (24.08 mmol) of the title compound of Example 52c) was dissolved in 300 ml of ethanol and 4 g of palladium catalyst (10% Pd / C) were added. . The mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. Yield: 16.77 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 31.04; H, 3.04; F, 46.38; N, 8.04; S, 4.60

Found: C, 30.97; H, 3.15; F, 46.31; N, 7.98; S, 4.51

b) 2,6-N, N'-Bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl) -5-yl)] - lysine- [1- (4-perfluorooctylsulfonylpiperazine) amide, gadolinium complex (metal complex XVI) g (14.36 mmol) of the title compound of Example 54a), 3.34 g (29 mmol) N-hydroxysuccinimide, 2.54 g (60 mmol) of lithium chloride and 18.26 g (29 mmol) of gadolinium-1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5) complex (methyl-5-yl) -1,4,7,10-tetraazacyclododecane was dissolved in 200 ml of dimethylsulfoxide with slight heating. 12.38 g (60 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was then stirred overnight at room temperature. The mixture was poured into 3000 ml

196 acetone and stirred for 10 minutes. The precipitate formed was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). yield:

19.02 g (69% of theory) of a colorless solid. Water content: 11.3%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 35.03; H, 4.04; F, 16.82; N, 10.21; S, 1.67; Gd 16.38 Found: C 34.96; H, 4.13; F, 16.74; N, 10.16; S, 1.61; Gd 16.33

Example 55

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

To 200 g (1.204 mol) of 4-hydroxyphenylacetic acid methyl ester and 212 g (2 mol) of sodium carbonate in 2000 ml of acetone was added 233.8 g (1.4 mol) of ethyl 2-bromoacetate and the mixture was heated at boiling point. The solid was filtered off and the residue was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate 15: 1). Yield: 288.5 g (95% of theory) of a colorless oil.

Elemental analysis:

Calculated: 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-ethyl ester

To 285 g (1.13 mol) of the title compound of Example 55a) dissolved in 2000 ml of carbon tetrachloride were added 201 g (1.13 mol) of N-bromosuccinimide and 100 mg of dibenzoyl peroxide and the mixture was heated at reflux for 8 hours. The reaction mixture was cooled in an ice bath, the precipitated succinimide was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: n-hexane / acetone 15: 1). Yield: 359.2 g (96% of theory) of a colorless viscous oil.

Elemental analysis:

Calculated: 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-tetraazacyclododec-10-yl) acetic acid-methyl ester

To 603 g (3.5 mol) of 1,4,7,10-tetraazacyclododecane in 6000 ml of chloroform was added 350 g (1.057 mol) of the title compound of Example 55b) and the mixture was stirred overnight at room temperature. The mixture was extracted three times with 3000 ml of water, the organic phase was dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was used in the next step (reaction 55d) without further purification. Yield: 448 g (quantitative) of a viscous oil.

Elemental analysis:

Calculated: 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- (carboxylatomethyl) -1,4,7,10-tetraazacyclododec-10-yl] acetic acid

445 g (1.053 mol) of the title compound of Example 55c) and 496 g (5.27 mol) of chloroacetic acid were dissolved in 4000 ml of water. The pH of the solution was adjusted to 10 with 30% aqueous sodium hydroxide solution. The mixture was heated to 70 ° C and stirred for 8 hours. The pH was then adjusted to 13 and the mixture was heated to boiling for 30 minutes. The solution was cooled in an ice bath and the pH was adjusted to 1 by the addition of concentrated aqueous hydrochloric acid. The reaction mixture was evaporated to dryness, the residue was dissolved in 4000 ml of methanol and stirred for 1 hour at room temperature. The salt was filtered off, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 403 g (69% of theory) of a colorless solid. Water content: 10.2%.

Elemental analysis (calculated on the anhydrous substance):.

Calculated: 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-tetraazacyclododec-10-yl] acetic acid, complex with gadolinium

To 400 g (721.3 mmol) of the title compound of Example 55d) in 2000 mL of water was added 130.73 g (360.65 mmol) of gadolinium complex and the mixture was stirred for 5 hours at 80 ° C. The solution was filtered and the filtrate was lyophilized. Yield: 511 g (quantitative) amorphous solid. Water content: 11.0%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 40.67; H, 4.41; Gd 22.19; N, 7.98

Found: C, 40.51; H, 4.52; Gd 22.05; N, 8.03

f) 2,6-N, N'-Bis (2- [4- (3-oxapropionyl) phenyl) -2- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododec] -10-yl] acetic acid) -L- [4-perfluorooctylsulfonyl) piperazine] amide, digadolinium complex, disodium salt g (14.36 mmol) of the title compound of Example 54a) 3.45 g (30 mmol) N -hydroxysuccinimide, 2.54 g (60 mmol) of lithium chloride and 21.26 g (30 mmol) of the title compound of Example 55e) were dissolved in 250 ml of dimethylsulfoxide with slight heating. 16.51 g (80 mmol) of N, N ' -dicyclohexylcarbodiimide was added at 10 [deg.] C. and the mixture was then stirred overnight at room temperature. The solution was poured into 2000 mL of acetone and stirred for 10 minutes. The precipitated solid was filtered off and collected

199 was purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). The material was dissolved in a small amount of water, the pH was adjusted to 7.4 with sodium hydroxide, and the mixture was lyophilized. Yield: 21.02 g (69% of theory) of a colorless solid. Water content: 11.2%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 37.36; H, 3.66; E, 15.22; Gd 14.82; N, 7.92; Na 2.17; S, 1.51

Found: C, 37.28; H, 3.74; F, 15.14; Gd 14.75; N, 8.03; Na 2.23;

S, 1.46

Example 56

a) 2,6-N, N'-Eis [6-carbonylmethyl-3,9-bis (tert-butyloxycarbonylmethyl) -3,6,9-triazaundecane-1,1-dicarboxylic acid bis (tert-butyl ester)] -lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 10 g (14.36 mmol) of the title compound of Example 54a), 18.53 g (30 mmol) of 3,9-bis (tert-butyloxycarbonylmethyl) -6-carboxymethyl-3-bis (tert-butyl ester) , 6,9-triazaundecene-1,11-dicarboxylic acid and 3.45 g (30 mmol) of N-hydroxysuccinimide in 150 ml of dimethylformamide were added at 0 ° C 10.32 g (50 mmol) of N, N'-dicyclohexylcarbodiimide. The mixture was stirred for 3 hours at 0 ° C and then overnight at room temperature. The precipitated urea precipitate was filtered off, the filtrate was evaporated to dryness under reduced pressure and purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 19.60 g (72% of theory) of a viscous oil.

Elemental analysis:

Calculated: C 49.41; H, 6.75; F, 17.03; N, 7.39; S, 1.69

Found: C, 49.35; H, 6.82; F, 16.92; N, 7.32; S, 1.62

b) 2,6-N, N-Bis [6-carbonylmethyl-3,9-bis (carboxylatomethyl) -3,6,9-triazaundecanedicarboxylic acid-1-carboxy-11-carboxylate-lysine- [1- (4- perfluorooctylsulfonyl} piperazine] amide, complex with

200 gadolinium, sodium salt g (7.91 mmol) of the title compound of Example 56a) was dissolved in 50 ml of chloroform and 200 ml of trifluoroacetic acid was added. The mixture was stirred for 10 minutes at room temperature. It was then evaporated to dryness in vacuo and the residue was dissolved in 150 ml of water. 2.87 g (7.91 mmol) of gadolinium complex were added and the mixture was stirred for 5 hours at 80 ° C. The reaction mixture was cooled to room temperature and the pH was adjusted to 7.4 with 2 N sodium hydroxide solution. The solution was evaporated to dryness under reduced pressure, and the residue was purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 8.11 g (57% of theory) of a colorless amorphous solid. Water content: 9.6%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 30.70; H, 3.08; Gd 17.48; N, 7.78; Na 2.56; S, 1.78

Found: C, 30.58; H, 3.19; Gd 17.42; N, 7.71; Na 2.68; S, 1.72

Example 57

a) 6-N- (Benzyloxycarbonyl) -2-N- [6-carboxymethyl-3,9-bis (tert-butyloxycarbonylmethyl) -3,6,9-triazaundecane-1,1-dicarboxylic acid bis (tert-butyl ester) 1] - lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] amide

To a solution of 20 g (24.08 mmol) of the title compound of Example 52c), 14.88 g (24.08 mmol) of 3,9-bis (tert-butyloxycarbonylmethyl) -6-carboxymethyl-3,6,9- triazaundecane-1,1-dicarboxylic acid bis (tert-butyl ester) and 2.88 g (25 mol) of N-hydroxysuccinimide in 100 ml of dimethylformamide were added at 0 ° C 8.25 g (40 mol) of N, N ' dicyclohexylcarbodiimide. The mixture was stirred for 3 hours at 0 ° C and then overnight at room temperature. The precipitate was filtered off, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 27.21 g (79% of theory) of a viscous oil.

201

Elemental analysis:

Calculated: C 47.03; H, 5.64; E 22.58; N, 6.85; S, 2.24

Found: C, 46.94; H, 5.58; F, 22.65; N, 6.84; S, 2.31

b) 2-N- [6-Carbonylmethyl-3,9-bis (tert-butyloxycarbonylmethyl) -3,6,9-triazaundecene-1,11-dicarboxylic acid bis (tert-butyl ester)] -lysine- [1- G (17.48 mmol ·) of the title compound of Example 57a) was dissolved in 350 mL of ethanol and 5 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. Yield: 22.66 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 44.48; H, 5.75; F, 24.92; N, 7.56; S, 2.47

Found: C, 44.59; H, 5.81; F, 25.03; N, 7.46; S, 2.52

c) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) )] - 2-N- [6-carbonylmethyl-3,9-bis (tert-butyloxycarbonylmethyl) -3,6,9-triazaundecane-1,11-dicarboxylic acid bis (tert-butyl ester)] - lysine- [1 - (4-perfluorooctylsulfonyl) piperazine] amide, complex with gadolinium g (15.43 mmol) of the title compound of Example 57b), 1.78 g (15.43 mmol) of N-hydroxysuccinimide, 1.48 g (35 mmol) lithium chloride and 9.72 g (15.43 mmol) of gadolinium-1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) pentanoic acid- 1,4,7,7,10-tetraazacyclododecane was dissolved in 150 ml of dimethylsulfoxide with slight heating. 5.16 g (25 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was then stirred overnight at room temperature. The solution was poured into 2500 mL of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetone202 nitrile gradient). Yield: 22.94 g (78% of theory) of a colorless solid. Water content: 7.9%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 42.22; H, 5.29; F, 16.95; Gd 8.25; N, 8.82; S, 1.68 Found: C, 42.15; H, 5.41; F, 16.87; Gd 8.13; N, 8.70; S, 1.60

d) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl)] -2-N- [6-carbonylmethyl-3,9-bis (carboxylatomethyl) -3,6,9-triazaundecane dicarboxylic acid-1-carboxy-11-carboxylate] -lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, digadolithium complex, sodium salt g (10.49 mmol) of the title compound of Example 57c) was dissolved in 200 ml of trifluoroacetic acid. The mixture was stirred for 60 minutes at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 150 mL of water. 1.90 g (5.25 mmol) of gadolinium complex was added and the mixture was stirred for 5 hours at 80 ° C. The reaction mixture was cooled to room temperature and the pH was adjusted to 7.4 by addition of sodium hydroxide. The solution was evaporated to dryness and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 11.89 g (61% of theory) of a colorless amorphous solid. Water content: 10.2%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 32.97; H, 3.47; F, 17.39; Gd 16.93; N, 9.05; Na 1.24; S, 1.73

Found: C, 32.90; H, 3.53; F, 17.31; Gd 16.87; N, 8.92; Na 1.33;

S 1, 67

Example 58

a) 5,6-Bis (benzyloxy) -3-oxahexanoic acid tert-butyl ester

203

100 g (376.2 mmol) of 1,2- (di-O-benzyl) glycerin prepared according to Chem. Phys. Lipids 43 (2), 113-277 (1987) and 5 g of tetrabutylammonium hydrogen sulphate were dissolved in a mixture of 400 ml of toluene and 200 ml of 50% aqueous sodium hydroxide solution. At 0 ° C, 78 g (400 mmol) of 2-bromoacetic acid tert -butyl ester was added dropwise over 30 minutes, and the mixture was stirred at 0 ° C for hours. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / acetone 20: 1). Yield: 133.4 g (94% of theory) of a colorless oil.

Elemental analysis:

Calculated: C 71.48; H, 7.82

Found: C, 71.61; H, 7.92

b) 5,6-Bis (benzyloxy) -3-oxahexanoic acid

130 g (336.4 mmol) of the title compound of Example 58a) were dissolved in 200 mL of dichloromethane and 100 mL of trifluoroacetic acid was added at 0 ° C. The mixture was stirred for hours at room temperature and then evaporated to dryness under reduced pressure. The residue was recrystallized from pentane / diethyl ether. Yield: 102.2 g (92% of theory) of a waxy solid.

Elemental analysis:

Calculated: C 69.07; H, 6.71

Found: C, 69.19; H, 6.82

c) 6-N- (Benzyloxycarbonyl) -2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5) -methyl-5-yl)] - lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, gadolinium complex g (60.20 mmol) of the title compound of Example 52c, 6.93 g (60, 20) mmol) of N-hydroxysuccinimide, 5.09 g

204 (120 mmol) of lithium chloride and 37.91 g (60.20 mmol) of gadolinium complex with 1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5- yl) pentanoic acid-1,4,7,10-tetraazacyclododecane was dissolved in 400 ml of dimethylsulfoxide with slight heating. 20.63 g (100 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was then stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 75.53 g (87% of theory) of a colorless solid. Water content: 10.1%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 37.48; H, 3.84; F, 22.39; Gd 10.90; N, 8.74; S 2.22 Found: C 37.39; H, 4.02; F, 22.29; Gd 10.75; N, 8.70; S, 2.22

d) 2-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) ] -lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, gadolinium complex g (48.53 mmol) of the title compound of Example 58c) was dissolved in a mixture of 500 ml water and 100 ml ethanol and 5 g was added palladium catalyst (10% Pd / C). The mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness. Yield: 63.5 g (quantitative) of a colorless solid. Water content: 9.8%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 37.48; H, 3.84; F, 22.39; Gd 10.90; N, 8.74; S, 2.22

Found: C, 37.39; H, 4.03; F, 22.31; Gd 10.78; N, 8.65; S, 2.20

e) 6-N- [5,6-Bis (benzyloxy) -3-oxahexanoyl] -2-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - lysine [1- (4-perfluorooctylsulfonyl) -piperazine] amide, gadolinium complex g (7.64 mmol) of the title compound from Example 58d),

205

3.30 g (10 mmol) of the title compound of Example 7b), 0.85 g (20 mmol) of lithium chloride and 1.15 g (10 mmol) of N-hydroxysuccinimide were dissolved in 50 ml of dimethylsulfoxide with slight heating. At 10 ° C, 3.10 g (15 mmol) of N, N'-dicyclohexylcarbodiimide was added and the mixture was stirred for 8 hours at room temperature. The reaction solution was poured into 2000 ml of acetone and the precipitate formed was filtered off. The title compound was purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 11.14 g (90% of theory) of a colorless amorphous solid. Water content: 4.3%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 41.51; H, 4.29; F, 19.93; N, 7.78; Gd 9.70; S, 1.98

Found: C, 41.45; H, 4.38; E 19.84; N, 7.70; Gd 9.58; S, 1.90

f) 6-N- (5,6-Dihydroxy-3-oxahexanoyl) -2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-pentanoyl-3 -aza-4-oxo-5-methyl-5-yl)] - lysine [1- (4-perfluorooctylsulfonyl) -piperazine] amide, gadolinium complex g (6.17 mmol) of the title compound of Example 58e) was dissolved in 200 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) were added. The mixture was hydrogenated at room temperature. The catalyst was filtered off and the residue was evaporated to dryness under reduced pressure. Yield: 8.89 g (quantitative) of a colorless solid. Water content: 3.1%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 35.03; H, 3.99; F, 22.42; Gd 10.92; N, 8.75; S, 2.23

Found: C, 34.95; H, 4.12; F, 22.30; Gd 10.78; N, 8.71; S, 2.18

Example 59

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

To a solution of 20 g (24.08 mmol) of the title compound

206

Of Example 52c), 9.91 g (30 mmol) of the title compound

Example 7b) and N, N'-dicyclohexylcarbodiimide (9.28 g, 45 mmol) were added at 0 ° C and 3.45 g (30 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide. The mixture was stirred for 3 hours at 0 ° C and then overnight at room temperature. The precipitated urea precipitate was filtered off, the filtrate was evaporated to dryness and purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 24.50 g (89% of theory) of a viscous oil.

Elemental analysis:

Calculated: C 47.29; H, 4.14; F, 28.26; N, 4.90; S, 2.81

Found: C, 47.14; H, 4.26; F, 28.17; N, 4.91; S, 2.69

b) 2-N- (5,6-Dihydroxy-3-oxahexanoyl) -lysine- [1- (4-perfluoro-octylsulfonyl) -piperazine] -amide g (17.5 mmol) of the title compound of Example 52d) was dissolved in 300 ml of ethanol and 5 g of palladium catalyst (10% Pd / C) were added. The reaction mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. Yield: 17.65 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 44.05; H, 4.10; F, 32.02; N, 5.55; S, 3.18

Found: C, 43.96; H, 4.21; F, 31.94; N, 5.48; S, 3.24

c) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) ]] - lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, gadolinium complex g (14.87 mmol) of the title compound of Example 59b), 1.73 g (15 mmol) of N-hydroxysuccinimide, 1, 27 g (30 mmol) of lithium chloride and 9.48 g (15 mmol) of gadolinium-1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) complex pentanoic acid with 1,4,7,10-tetraazacyclododecane with slight heating

207 was dissolved in 100 mL of dimethylsulfoxide. 5.16 g (25 mol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was then stirred overnight at room temperature. The solution was poured into 1500 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 19.28 g (80% of theory) of a colorless solid. Water content: 10.3%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 41.51; H, 4.29; F, 19.93; Gd 9.70; N, 7.78; S, 1.98

Found: C, 41.37; H, 4.40; F, 19.88; Gd 9.58; N, 7.67; S, 1.85

Example 60

a) 6-N- (Benzyloxycarbonyl) -2-N- [2,6-N, N'-bis (benzyloxycarbonyl) lysyl] -lysine- [1- (4-perfluorooctylsulfonyl) piperazine] -amide g (24,08) mmol) of the title compound of Example 52c) and 2.53 g (25 mmol) of triethylamine were dissolved in 200 ml of tetrahydrofuran and 14.46 g (27 mmol) of N, N'-bis (benzyloxycarbonyl) lysine-p were added. -nitrophenyl ester. The mixture was stirred for 5 hours at 50 ° C. The mixture was evaporated to dryness and purified by chromatography on silica gel (mobile phase: dichloromethane / methanol 20: 1). Yield: 28.07 g (95% of theory) of a colorless solid.

Elemental analysis:

Calcd: C, 46.99; H, 4.19; F, 26.32; N, 6.85; S, 2.61

Found: C, 47.08; H, 4.32; F, 26.21; N, 6.75; S, 2.54

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

To 25 g (20.37 mmol) of the title compound of Example 60a) was added 100 mL of hydrobromic acid in acetic acid (48%), and the mixture was stirred for 2 hours at 40 ° C. The mixture was cooled to 0 ° C, 1500 ml diethyl ether was added dropwise and the precipitated solid was filtered off. After drying in vacuo (60 ° C), 21.52 g (99% of theory) of a light yellow crystalline solid was obtained.

Elemental analysis:

Calculated: C 27.01; H, 3.40; Br, 22.46; F, 30.26; N, 7.87; S, 3.00

Found: C, 26.92; H, 3.53; Br, 22.15; F, 30.14; N, 7.69; S, 2.87

c) 6-N- [1,4,7-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-10- (pentanoyl-3-aza- 4-Oxo-5-methyl-5-yl)] lysyl] -lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, trigadolinium complex

31.49 g (50 mmol) of gadolinium-1,4,7-tris- (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) pentanoic acid complex,

6.91 g (60 mmol) of N-hydroxysuccinimide and 4.24 g (100 mmol) of lithium chloride were dissolved in 350 ml of dimethylsulfoxide with slight heating. 16.51 g (80 mmol) of N, N'-dicyclohexylcarbodiimide were added at 10 ° C and the mixture was stirred for 5 hours at 10 ° C. To this mixture was added 10 g (9.37 mmol) of the title compound of Example 60b) and 3.03 g (30 mmol) of triethylamine, and the mixture was stirred for 12 hours at 60 ° C. The mixture was cooled to room temperature and poured into 3000 mL acetone. The precipitate formed was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 16.7 g (67% of theory) of a colorless solid. Water content: 7.9%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 36.58; H, 4.43; F, 12.14; Gd 17.74; N, 11.06; S 1.14 Found: C 36.47; H, 4.54; F, 12.03; Gd 17.65; N, 10.95; S, 1.21

Example 61

a) 1,7-Bis (benzyloxycarbonyl) -4- (3,6,9,12,15-pentaoxahexadeca209 noyl) -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-bis (benzyloxycarbonyl) cyclene prepared according to Z. Kovacs and AD Sherry, J. Chem. Soc., Chem. Commun., 1995 (2), 185 in 300 mL of tetrahydrofuran at 24 ° C was added 24.73 g (100 mmol) of EEDQ (ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and the mixture was stirred through overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by silica gel chromatography (eluent: dichloromethane / methanol 20: 1). Yield: 19.13 g (42% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 61.03; H, 7.61; N, 8.13

Found: C, 60.92; H, 7.75; N, 8.04

b) 1,7-Bis (benzyloxycarbonyl) -4- (3,6,9,12,15-pentaoxahexa-decanoyl) -10- (277,277,477,577,577-3-oxaperluoridecanoyl) -1,4,7,10-tetraazacyclododecane

To 18 g (26.91 mmol) of the title compound of Example 61a) and 14.05 g (26.91 mmol) of 277, 277, 477, 477, 577, 577-3-oxaperfluorotridecanoic acid prepared according to patent application DE 196 03 033 in 300 ml of tetrahydrofuran at 0 ° C was added 12.36 g (50 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and the mixture was stirred overnight at room temperature. . The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / methanol 20: 1). Yield: 21.51 g (67% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 47.32; H, 4.82; E 27.07; N, 4.70

Found: C, 47.26; H, 5.01; F, 26.94; N, 4.59

210

c) 1- (3,6,9,12,15-Pentaoxahexadecanoyl) -7- (27 β, 27 β, 47 β, 4H, 57 β, 57 β-3-oxaperfluorodecanoyl) -1,4,7,10-tetraazacyclododecane g (16 , 77 mmol) of the title compound of Example 52d) was dissolved in 200 mL of ethanol and 2.5 g of palladium catalyst (10% Pd / C) was added. The reaction mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 15.5 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 40.27; H, 4.90; F, 34.93; N, 6.06

Found: 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- (27,, 27,, 47,, 47,, 57,, 57--3-oxaperofluoridecanoyl) -1,4,7,10-tetraazacyclododecane, complex with gadolinium g (16.22 mmol) of the title compound of Example 61c), 4.60 g (40 mmol) of N-hydroxysuccinimide, 3.39 g (80 mmol) of lithium chloride and 25.19 g (40 mmol) gadolinium-1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) pentanoic acid complex was dissolved in 300 ml of dimethylsulfoxide with slight heating. At 10 ° C, 24.73 g (100 mmol) of EEDQ were added and the mixture was stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitate formed was filtered off and then purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 19.86 g (57% of theory) of a colorless solid. Water content: 11.3%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 38.58; H, 4.74; F, 15.04; Gd 14.64; N, 9.13

Found: C, 38.47; H, 4.91; F, 14.95; Gd 14.57; N, 9.04

Example 62

211

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 at 0 ° C was added dropwise a solution of 8.76 g (38 mmol) of 3,5-dinitrobenzoyl chloride in 55 ml of dichloromethane and the mixture was stirred for 3 hours at 0 ° C. 200 ml of 5% aqueous hydrochloric acid solution were added and the mixture was stirred for 5 minutes at room temperature. The organic phase was separated, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 15: 1). Yield: 24.96 g (93% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 29.35; H, 1.45; F, 42.37; N, 7.35; S, 4.21

Found: C, 29.28; H, 1.61; F, 42.15; N, 7.25; S 4.15

b) 3,5-diaminobenzoic acid [1- (4-Perfluorooctylsulfonyl) piperazine] amide g (26.23 mmol) of the title compound of Example 62a) was dissolved in 400 ml of ethanol and 6 g of palladium catalyst (10%) were added. Pd / C). The mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 18.43 g (quantitative) of a cream colored solid.

Elemental analysis:

Calculated: C 32.49; H, 2.15; F, 45.98; N, 7.98; S, 4.57

Found: C, 32.29; H, 2.35; F, 45.69; N, 7.81; S, 4.40

c) 3,5-N, N'-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl) [1- (4-perfluorooctylsulfonyl) piperazine] amide 3-aza-4-oxo-5-methyl-5-yl-benzoic acid, Gd complex g (14.24 mmol) of the title compound of Example

212

62b), 3.45 g (30 mmol) of N-hydroxysuccinimide, 2.54 g (60 mmol) of lithium chloride and 18.89 g (30 mmol) of gadolinium-1,4,7-tris (carboxylatomethyl) -10 The (3-aza-4-oxo-5-methyl-5-yl) pentanoic acid was dissolved in 200 mL of dimethylsulfoxide with slight heating. 10.32 g (50 mmol) of N, N'-dicyclohexylcarbodiimide were added at 10 ° C and the mixture was then stirred overnight at room temperature. The solution was poured into 2000 mL of acetone and stirred for 10 minutes. The precipitated solid was filtered off and then purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 19.74 g (72% of theory) of a colorless solid. Water content: 11.8%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 35.55; H, 3.72; F, 16.77; Gd 16.33; N, 10.18; S, 1.67 Found: C, 35.48; H, 3.84; F, 16.58; Gd 16.24; N, 10.07; S, 1.58

Example 63

(a) 3-oxa-2tf, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid tert-butyl ester

25.0 g (53.8 mmol) of 1H, 1H, 2H, 2H-perfluoro-1-decanol commercially available from Lancaster were dissolved in 250 ml of absolute toluene and the mixture was stirred at room temperature with a catalytic amount (ca. 0.75) g) tetra-n-butylammonium hydrogen sulphate. Then a total of 7.55 g (134.6 mmol) was added at 0 ° C.

2.5 equivalents (calculated on the alcohol component used) of finely powdered potassium hydroxide followed by 15.73 g (80.7 mmol,

1.5 equivalents per alcohol component of 2-bromoacetic acid tert-butyl ester used, and the mixture was stirred for 2 hours at 0 ° C. The reaction solution thus obtained was stirred for 12 hours at room temperature and a total of 500 ml of ethyl acetate and 250 ml of water were added during the work-up. The organic phase was separated and washed twice with water. After drying the organic phase over sodium sulfate, the solvent was evaporated to dryness under reduced pressure. The oily residue obtained was purified by silica gel chromatography (mobile phase: ethyl acetate / hexane 1:10). Yield: 26.3 g (84.6% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: C 33.23; H, 2.61; F 55.85 ¹

Found: C, 33.29; H, 2.61; F, 55.90

b) 3-Oxa-2H, 2tf, 4K, 4H, 5H, 5'-perfluoridecanecarboxylic acid

20.0 g (34.58 mmol) of the title compound of Example 63a) was suspended in 200 mL of a 2: 1 mixture of methanol and 0.5 M sodium hydroxide solution with stirring at room temperature, and the mixture was heated to 60 ° C. C. The mixture was stirred for 12 hours at 60 ° C and the clear reaction solution was treated by neutralization by addition of cation exchange Amberlite IR 120 (H ⁺ -form), filtering the ion exchanger and evaporating the obtained aqueous methanolic filtrate to dryness under reduced pressure. The amorphous residue obtained was purified by chromatography on silica gel (mobile phase: ethyl acetate / n-hexane 1: 3). Yield: 16.0 g (88.6% of theory) of the title compound as a very viscous oil.

Elemental analysis: Calculated: C 27.60;

Found: C, 27.58;

H, 1.35; F, 61.85; H, 1.36; E 61.90

c) 1,7-Bis {[1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl)] - 1,4,7,10- tetraazacyclododecane} diethylenetriamine, digadolinium complex

2.48 g (3.94 mmol, 2.05 molar equivalents per diethylenetriamine used) of gadolinium complex with 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7, 10-tetraazacyclodo decane-1,4,7-triacetic acid described in patent application DE 197 28 954 Cl in Example 31h) and 167 mg (3.94 mmol) of anhydrous

214 of lithium chloride was dissolved in 40 ml of absolute dimethylsulfoxide at 40 ° C and a total of 453 mg (3.94 mmol) of N-hydroxysuccinimide was added with stirring at this temperature. After cooling to room temperature, the reaction solution was treated with 814 mg (3.946 mmol) of N, N'-dicyclohexylcarbodiimide, and the mixture was stirred for 2 hours at room temperature. The resulting active ester suspension was then treated with 198.3 mg (1.92 mmol) of diethylenetriamine dissolved in 5 mL of absolute dimethylsulfoxide and stirred for 12 hours at room temperature. The resulting suspension was treated with excess acetone until all of the title compound precipitated, the precipitate was filtered off, dried, dissolved in water, the insoluble dicyclohexylurea was filtered off and the filtrate was freed from the salt and purified from the low molecular weight AMICON® Y ultrafiltration membrane. 3 (limit limit: 3000 Da). The residue was lyophilized. Yield: 1.85 g (72.7% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 3.89%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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-ylpentanoyl)) - 1,4,7,10-tetraazacyclododecane ) -4- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoyl) diethylenetriamine, digadolinium complex

To a solution of 3.23 g (2.44 mmol) of the title compound of Example 63c) in a mixture of 30 mL of dimethylsulfoxide and 3 mL of tetrahydrofuran at 50 ° C and under nitrogen atmosphere was added dropwise 1.27 g (2.44 mmol). of the title compound of Example 63b) dissolved in a mixture of 15 mL of tetrahydrofuran and 15 mL of dimethylsulfoxide. Then, a total of 1.80 g (3.66 mmol) of EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline) was added portionwise at 0 ° C, and the mixture was stirred overnight at room temperature. The resulting reaction mixture was then treated with an excess of acetone to

215 until the title compound is completely precipitated, the precipitate is filtered off, dried, dissolved in water, the insoluble dicyclohexylurea is filtered off and the filtrate is freed from salts and purified from the low molecular weight fraction of the AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da) ). The residue was lyophilized. Yield: 3.54 g (79.4% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 5.87%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 17.13

Example 64

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

100.0 g (356.7 mmol) of 6-N- (benzyloxycarbonyl) -L-lysine were dissolved in a mixture of 1000 ml of trifluoroacetic acid ethyl ester and 500 ml of ethanol, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated to dryness under reduced pressure and the residue was recrystallized from diisopropyl ether. Yield: 128.9 g (96% of theory) of a colorless crystalline powder. Melting point: 98.5 ° C.

Elemental analysis:

Calculated: C 51.07; H, 5.09; N, 7.44; F, 15.14

Found: C, 51.25; H, 5.18; N, 7.58; F, 15.03

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

To 125.0 g (332.0 mmol) of the title compound of Example 52a) and 188.7 g (332.0 mmol) of 1- (4-perfluorooctylsulfonyl) piperazine prepared according to patent application DE 196 03 033 in 750 ml of tetrahydrofuran 164.2 g (664 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) was added at 0 ° C and the mixture was stirred overnight at room temperature.

216 temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by silica gel chromatography (eluent: dichloromethane / methanol 20: 1). Yield: 286.0 g (93% of theory) of a colorless solid. Melting point: 92 C. C.

Elemental analysis:

Calculated: C, 36.30; H, 2.83; N, 6.05; F, 41.01; S 3,46 '

Found: C, 36.18; H, 2.94; N, 5.98; F, 40.87; S, 3.40

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

To a solution of 280.0 g (302.2 mmol) of the title compound of Example 52b) in 2000 mL of ethanol at 0 ° C was added ammonia gas for 1 hour. The mixture was evaporated to dryness and the residue was stirred with water. The solid was filtered off and dried under vacuum at 50 ° C. Yield: 243.5 g (97.0% of theory) of an amorphous solid.

Elemental analysis:

Calculated: C 37.60; H, 3.28; N, 6.75; F, 38.89; S, 3.86

Found: C, 37.55; H, 3.33; N, 6.68; F, 38.78; S, 3.81

d) L-Lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

200.0 g (240.8 mmol) of the compound prepared in Example 64c) was dissolved in 1000 ml of ethanol, 5.0 g of Pearlman catalyst (20% Pd / C) were added, and the mixture was hydrogenated at room temperature under hydrogen (1). atm) until hydrogen consumption was no longer observed. The catalyst was filtered off, washed well with ethanol (three times 100 ml) and the mixture was evaporated to dryness in vacuo. The title compound was obtained as a yellowish very viscous oil. Yield: 162.5 g (96.9% of theory).

Elemental analysis:

Calculated: C 31.04; H, 3.04; N, 8.05; F, 46.38; S, 4.60

Found: C, 31.11; H, 3.09; N, 8.08; F, 46.33; S, 4.62

217

e) 6-N-2-N-BIS- (4- {2,3-bis [Ν, Ν-bis (tert-butyloxycarbonylmethyl) amino] propyl} phenyl) -3-oxapropionyl-L-lysine- [ 1- (4-Perfluorooctylsulfonyl) piperazine] amide

5.25 g (7.72 mmol) of 4- {2,3-Bis [N, N-bis (tert-butyloxycarbonylmethyl) amino) propyl] phenyl} -3-oxapropionic acid and 781.0 mg (7.72 mmol) of triethylamine was dissolved in 50 ml of dichloromethane. At -15 ° C, a solution of 1.16 g (8.5 mmol) of tert-butyl chloroformate in 10 ml of dichloromethane was added dropwise over 5 minutes, and the mixture was stirred at the temperature for a further 20 minutes.

5 ° C. The reaction solution was then cooled to -25 ° C and a solution of 2.68 g (3.86 mmol) of the title compound of Example 64d) and 2.12 g (21.0 mmol) of triethylamine in 70 ml was added dropwise over 30 minutes. ml of tetrahydrofuran and the mixture was stirred for 30 minutes at -15 ° C and then overnight at room temperature. Upon working up, the reaction mixture was evaporated under reduced pressure and the resulting oily residue was dissolved in 250 ml of chloroform. The chloroform phase was extracted twice with 100 ml of 10% aqueous ammonium chloride solution, dried over magnesium sulfate and then evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 5.37 g (68.8% of theory) of a colorless, very viscous oil.

Elemental analysis:

Calculated: C 52.27; H, 6.43; N 5.54; E, 15.97; S, 1.59

Found: C, 52.22; H, 6.51; N, 5.49; F, 15.99; S, 1.63

f) 6-N-2-N-Bis (4- {2,3-bis [Ν, Ν-bis (carboxylatomethyl) amino] propyl} phenyl) -3-oxapropionyl-L-lysine- [1- (4) (perfluorooctylsulfonyl) piperazine] amide, octasodium salt

5.0 g (2.47 mmol) of the title compound of Example 64e) was dissolved in 60 mL of absolute dichloromethane. 75 ml of trifluoroacetic acid were then added dropwise at 0 ° C. The reaction mixture was stirred for 12 hours at room temperature and then evaporated to dryness under reduced pressure. The residue was stirred with 100 ml of water and evaporated to dryness again in vacuo. The residue thus obtained was dissolved in 200 ml of distilled water and the aqueous solution of the title compound was extracted twice with 60 ml of diethyl ether. The obtained aqueous solution of the product was made up to 300 ml with water, freed from insoluble matter by filtration, the filtrate was freed from salts and purified from the low molecular weight fraction of the AMICON ³ YM-3 ultrafiltration membrane (cut-off limit: 3000 Da). The filtrate was made up to volume with water

200 ml and the pH was adjusted to 10.0 with 15% aqueous sodium hydroxide. The basic aqueous solution of the product was finally lyophilized. 4.0 g (92.8% of theory) of the title compound were obtained as the octasodium salt as an amorphous lyophilisate. Water content: 5.37%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 38.46; H, 3.28; N, 6.41; E 18.47; S, 1.83; At 10.52

Found: C, 38.42; H, 3.31; N, 6.39; F, 18.51; S, 1.87; At 10.38

g) 6-N-2-N-BIS (4- (2,3-bis- [N, N-bis (carboxymethyl) amino] propyl} phenyl) -3-oxapropionyl-L-lysine- [1- ( 4-perfluorooctyl-sulfonyl) piperazine] amide, dimanganate complex, tetrasodium salt

1.94 g (1.11 mmol) of the title compound of Example 64f) was dissolved in 100 mL of distilled water and treated with 1 M aqueous hydrochloric acid until pH 4.0. At 80 ° C, 0.25 g (2.22 mmol) of manganese carbonate was added portionwise. The reaction mixture i

was heated to boiling for 5 hours. After cooling to room temperature, the pH of the aqueous solution of the product was adjusted to 7.2 with vigorous stirring by addition of 1 N sodium hydroxide, and the solution was purified by ultrafiltration on an AMICON® YM-3 ultrafiltration membrane (3000 Da limit) to desalinate the product. got rid of low molecular weight. The solution was then lyophilized. Yield: 1.80 g (92.0% of theory) of the title compound as a colorless lyophilisate. Water content (Karl-Fischer): 7.28%.

219

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 38.07; H, 3.25; F, 18.28; Mn 6.22; N, 6.34; Na 5.20; S, 1.81

Found: C, 38.01; H, 3.29; F, 18.29; Mn 6.21; N, 6.36; Na 5.28;

S, 1.78

Example 65 '

a) 6-N- (Benzyloxycarbonyl) -2-N - [(N-pteroyl) -L-glutaminyl] -lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide g (45.31 mmol) folic acid was dissolved 9.49 g (46 mmol) of N, N'-dicyclohexylcarbodiimide was added in 300 ml of dimethyl sulfoxide and at 10 ° C. The mixture was stirred overnight at room temperature. To this mixture was added 29.1 g (35 mmol) of the title compound of Example 52c) and 20 mL of pyridine, and the mixture was stirred for 3 hours at 50 ° C. The reaction mixture was then evaporated to dryness and treated with a mixture of 1500 ml diethyl ether and 1500 ml acetone. The precipitate formed was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / tetrahydrofuran gradient). Yield: 21.59 g (38% of theory) of a yellow solid. Water content: 2.1%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 43.10; H, 3.54; E, 25.76; N, 11.29; S, 2.56 Found: C, 43.02; H, 3.62; F, 25.68; N, 11.21; S, 2.48

b) 2-N - [(N-Pteroyl) -L-glutaminyl] -lysine- [1- (4-perfluorooctyl-sulfonyl) piperazine] amide

To 20 g (15.95 mmol) of the title compound of Example 65a) was added 200 mL of a solution of hydrobromic acid in acetic acid (48%) and the mixture was stirred for 2 hours at 40 ° C. The mixture was cooled to 0 ° C, 2000 mL of diethyl ether was added dropwise, and the precipitate formed was filtered off. After drying under vacuum at 60 ° C, 18.96 g (99% of theory) were obtained.

220 yellow crystalline solid.

Elemental analysis:

Calculated: C 37.01; H, 3.27; Br, 6.65; F, 26.90; N, 12.83; S, 2.67

Found: C, 36.91; H, 3.42; Br, 6.31; F, 29.75; N, 12.72; S, 2.56

c) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) ] -2- N - [(N-pteroyl] -L-glutamyl] -lyzín- [l- (4-perfluóroktylsulfonylpiperazín) amide,

Gd complex

0.92 g (8 mmol) of N-hydroxysuccinimide, 0.68 g (16 mmol) of lithium chloride and 5.04 g (8 mmol) of gadolinium-1,4,7-tris- (carboxylatomethyl) -O- (3) -aza-4-oxo-5-methyl-5-yl) -1,4,7-10-tetraazacyclododecane was dissolved in 80 mL of dimethyl sulfoxide with gentle heating. 2.06 g (10 mmol) of N, N'-dicyclohexylcarbodiimide were added at 10 ° C and the mixture was then stirred for 3 hours at room temperature. To this reaction solution was added 5 g (4.16 mmol) of the title compound of Example 65b) and 10 mL of pyridine. The mixture was stirred overnight at room temperature. The solution was poured into 1000 mL acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient. The material was dissolved in a small amount of water, the pH of the solution was adjusted to 7.4 and the mixture was lyophilized. Yield: 3.87 g (53% of theory) of a yellow solid Water content: 5.8%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 38.36; H, 3.74; F, 18.42; Gd 8.97; N, 12.78; Na 1.31; S, 1.83

Found: C, 38.28; H, 3.85; F, 18.33; Gd 8.85; N, 12.69; Na 1.42;

S, 1.75

Example 66

(a) 2H, 2H, 4H, 4H, 5H, 5H-3221 N- (2,3-dihydroxypropyl) amide

-oxaperfluórtridekánovej

To 30 g (57, 45 mmol) of 2H, 2H, 4/7, 4/7, 5H, 5 / 7-3-oxaperfluorotecanoic acid in 300 mL of dichloromethane was added oxalyl chloride (8.90 g, 70 mmol) and the mixture was stirred for 12 hours at room temperature. The reaction mixture was evaporated to dryness under reduced pressure. The residue was 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 in 200 mL of dichloromethane. The mixture was stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid solution were added and the mixture was stirred vigorously for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 15: 1). Yield: 29.70 g (87% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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- (1/7, 1/7, 2/7, 2/7, 4/7, 4/7, 5/7, 5H-3-oxaperfluorididyl) amine g (48.8 mmol) of the title compound of Example 66a) was dissolved in 300 mL of tetrahydrofuran and 50 mL of a 10 M solution of borane dimethyl dimethyl sulfide (in tetrahydrofuran) was added. The mixture was heated to boiling for 16 hours. It was then cooled to 0 ° C, 300 ml of methanol added dropwise and the mixture was evaporated to dryness under reduced pressure. The residue was stirred in a mixture of 300 ml of ethanol and 50 ml of a 10% aqueous hydrochloric acid solution and stirred at 60 ° C for 8 hours. The mixture was evaporated to dryness under reduced pressure, the residue was stirred with 300 ml of 5% aqueous sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The organic phase was dried over magnesium sulphate, evaporated to dryness under reduced pressure and the residue was evaporated

222 was purified by silica gel chromatography (eluent: dichloromethane / methanol 15: 1). Yield: 24.07 g (85% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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 (carboxylatomeryl) -10 - [(3-aza-4-oxohex-5-yl) acid-N- (2,3-dihydroxypropyl) -N- (17α, 17β, 27β) -1,7,7,10-tetraazacyclododecane, complex with gadolinium g (15.88 mmol) of gadolinium complex with 10- [1- (carboxymethylcarbamoyl) acid ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetoacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethylsulfoxide at 60 ° C. The mixture was cooled to 15 ° C and 9.21 g (15.88 mmol) of the title compound of Example 66b) was added. The mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The reaction mixture was stirred for 12 hours at room temperature. The reaction solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in a small amount of ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.09 g (85% of theory) of a colorless amorphous powder. Water content: 6.3%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 67

1, 4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohex-5-yl) acid-N- (17H, 17H, 27H, 27H, 47H, 4H, 57H), 5 T-3-Oxaperfluoridecyl) -amide] -1,4,223

7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of gadolinium complex with 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, 1 35 g (31.76 mmol) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide were dissolved in 100 ml of dimeryl sulfoxide at 60 ° C. The mixture was cooled to 15 ° C, 3.51 g (17 mmol) of N, N'-dicyclohexylcarbodiimide was added and the mixture was stirred for 5 hours at 15 ° C. The solution was filtered to remove urea. 8.63 g (15.88 mmol) of the title compound of Example 8b) and 5.06 g (50 mmol) of triethylamine were added to the filtrate and the mixture was stirred for 12 hours at room temperature. The solution was poured into 1500 ml of diethyl ether and 100 ml of acetone and stirred for 30 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 13.86 g (78% of theory) of a colorless amorphous powder. Water content: 9.3%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 33.28; H, 3.42; N, 7.51; E, 28.87; Gd 14.05 Found: C 33.12; H, 3.61; N, 7.37; E, 28.69; Gd 13.89

Example 68

(a) 2H, 2H, 4H, 4H, 5H, 57'-3-oxaperfluorotridecanoic acid amide;

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-zxaperfluorotridecanoic acid in 300 mL of dichloromethane was added 3.90 g (70 mmol) of oxalyl chloride and the mixture was stirred for 12 hours at room temperature. . The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 200 mL of dichloromethane. Ammonia gas was then introduced into the reaction mixture at 0 ° C for 2 hours. The mixture was stirred for 4 hours at 3 ° C and then for 2 hours at room temperature. Then 300 ml of 5% aqueous hydrochloric acid solution was added and the mixture was stirred for 15 minutes. The organic phase was separated, dried

224 over magnesium sulfate and evaporated to dryness under reduced pressure.

The residue was purified by silica gel chromatography (mobile phase:

dichloromethane / acetone 20: 1). Yield: 27.85 g (93% of theory).

Elemental analysis:

Calculated: C 27.66; H, 1.55; N, 2.69; F, 61.97

Found: C, 27.49; H, 1.72; N, 2.54; E, 61.81

b) 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecylamine hydrochloride g (51.8 mmol) of the title compound of Example 68a) was dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 ml were added. M solution of borane dimethylsulfide (in tetrahydrofuran). The reaction mixture was heated to reflux for 16 hours. The mixture was cooled to 0 ° C, 200 mL of methanol was added dropwise and the mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 400 ml of ethanol and 100 ml of a 10% aqueous hydrochloric acid solution and stirred for 8 hours at 60 ° C. The mixture was evaporated to dryness and the residue was recrystallized from ethanol / diethyl ether. Yield: 26.75 g (95% of theory) of a colorless crystalline solid.

Elemental analysis:

Calcd: C 26.51; H 2.04; N, 2.58; E 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-oxaperfluorotridecyl) amide

To 26.5 g (48.74 mmol) of the title compound of Example 68b) and 14.8 g (146.2 mmol) of triethylamine dissolved in 300 mL of dichloromethane were added dropwise at 0 ° C 14.24 g (50 mmol). 13,6,9,12,12,15-Pentaoxahexadecanoyl chloride and stirred for 3 hours at 0 ° C. 300 ml of a 5% aqueous hydrochloric acid solution were added and the mixture was stirred vigorously throughout

225 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 20: 1). Yield: 32.03 g (87% of theory) of a colorless oil.

Elemental analysis:

Calculated: 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-oxaperfluorotridecyl) amide g (41.03 mmol) of the title compound from Example 68c) was dissolved in 300 mL of tetrahydrofuran and 25 mL of a 10 M solution of borane dimethyl dimethylsulfide (in tetrahydrofuran) was added. The mixture was heated to boiling for 16 hours. It was then cooled to 0 ° C, 200 ml of methanol was added dropwise, and then the mixture was evaporated to dryness under reduced pressure. The residue was stirred in 300 ml of ethanol and 50 ml of a 10% aqueous hydrochloric acid solution and stirred for 8 hours at 40 ° C. The mixture was evaporated in vacuo, the residue was dissolved in 300 mL of 5% aqueous sodium hydroxide solution and extracted three times with 300 mL of dichloromethane. The organic phase was dried over magnesium sulphate, evaporated to dryness in vacuo and the residue purified by silica gel chromatography (eluent: dichloromethane / 2-propanol 15: 1). Yield: 27.68 g (91% of theory).

Elemental analysis:

Calculated: C 37.26; H, 4.35; N, 1.89; F, 43.56

Found: C, 37.11; H, 4.51; N, 1.73; F, 43.41

e) 1,4,7-Tris (carboxylateomethyl) -10 - {(3-aza-4-oxohex-5-yl) -acid- [N- (3,6, 9, 12, 15-pentaoxa) hexadecyl] -N- (1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) perfluorotridecyl] amide} -1,4,7,10-tetraazacyclododecane complex with gadolinium

226 g (15.88 mmol) of gadolinium complex with 10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride was dissolved in 100 ml of dimethylsulfoxide at 60 ° C. The mixture was cooled to 15 ° C and 11.77 g (15.88 mmol) of the title compound of Example 68d) was added. The mixture was stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The mixture was stirred for 12 hours at room temperature. The reaction solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether, and the mixture was stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in a small amount of ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 18.05 g (84% of theory) of a colorless amorphous powder. Water content: 6.2%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 69

a) 2H, 2H, AH, AH, 5H, 5H-3-oxaperfluorotidecanoic acid N- (5-hydroxy-3-oxapentyl) amide

To 30 g (57.45 mmol) of 27,, 27,, 47,, 47,, 57 3, 57 lu -3-oxaperfluorotridecanoic acid in 300 mL of dichloromethane was added oxalyl chloride (8.90 g, 70 mmol) and stirred for 12 hours at room temperature. . The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and a solution of 6.25 g (60 mmol) of 5-hydroxy-3-oxapentylamine and 6.07 g (60 mmol) of triethylamine in 200 mL of dichloromethane was added dropwise at 0 ° C. The mixture was stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. Then 300 ml of 5% aqueous hydrochloric acid solution was added and the mixture was stirred for 15 minutes. The organic phase was separated, dried

227 over magnesium sulfate and evaporated to dryness under reduced pressure.

The residue was purified by silica gel chromatography (mobile phase:

dichloromethane / acetone 15: 1). Yield: 32.20 g (52% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 31.54; H, 2.65; N, 2.30; E 53.01

Found: C, 31.61; H, 2.84; N, 2.14; F, 52.85

b) N- (5-Hydroxy-3-oxapentyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotidecyl) amine g (49.24 mmol) of the title compound from Example 69a) was dissolved in 300 mL of tetrahydrofuran and 31 mL of a 10 M solution of borane dimethyl dimethyl sulfide (in tetrahydrofuran) was added. The mixture was heated to boiling for 16 hours. It was then cooled to 0 ° C, 200 ml of methanol was added dropwise, and then the mixture was evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of 300 ml of ethanol and 50 ml of a 10% aqueous hydrochloric acid solution and the reaction mixture was stirred for 10 hours at 50 ° C. The mixture was evaporated to dryness, the residue was dissolved in 300 ml of 5% aqueous sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The organic phase was dried over magnesium sulphate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: dichloromethane / 2-propanol 20: 1). Yield: 26.09 g (89% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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-oxohex-5-yl) -acid-N- (5-hydroxy-3-oxapentyl) -N- (1 H, 1H) , 2H, 2H, 4H, 4H, 5H, 5 (3-oxaperfluorotridecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex

228 g (15.88 mmol) of gadolinium-10- [1- (carboxymethylcarbamoyl) ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1,35 g (31, 76 mmol) of lithium chloride was dissolved in 100 ml of dimethylsulfoxide at 60 ° C. The mixture was cooled to 5 ° C and 9.45 g (15.88 mmol) of the title compound of Example 69b) was added. The mixture was stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The reaction mixture was then stirred for 12 hours at room temperature. The reaction solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether, and the mixture was stirred for 2 hours at room temperature. The precipitate formed was filtered off, dissolved in ethanol / water and purified by chromatography on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.10 g (84% of theory) of a colorless amorphous powder. Water content: 5.7%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: 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 70

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

In an analogous manner to that described in the literature [M. L. Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (R. L. Whistler, M. L. Wolfrom and J. N. De Miller Eds.), Academic Press, New York, Vol. 11, 53, p. 211-215 (1963)] provided use

150 g (832.5 mmol) of α, β-D-manopyranose with a mixture of 1500 ml of absolute pyridine and 1500 ml of acetic anhydride after treatment with 315 g (96.7% of theory) of the title compound as a colorless viscous oil. 1 H-NMR spectroscopy showed that it was a 4: 1 mixture of α and β anomers. Separation of the α and β anomers of the title compound can be achieved by carrying out the following reaction steps.

229

Elemental analysis:

Calculated: C 49.21; H, 5.68

Found: C, 49.12; H, 5.78

b) 6- [Ι-O-α- (2,3,4,6-Tetra-O-acetyl) -D-manopyranosyl] hexanoic acid ethyl ester

In an analogous manner to the synthesis of arylglycopyranosides [J. Conchie and G. A. Levvy in Methods in Carbohydrate Chemistry (R.L. Whistler, M.L. Wolfrom and J.N. De Miller Eds.), Academic Press, New York, Vol. 11, 90, p. 345-347 (1963)] led to the use of 156.2 g (400 mmol) of the title compound of Example 70a) as a mixture of α and β anomers with 67 mL (400 mmol) of 6-hydroxyhexanoic acid ethyl ester and 60.8 mL (520 mmol) of tin tetrachloride in a total of 600 ml of 1,2-dichloroethane after purification by column chromatography on silica gel (mobile phase: hexane / ethyl acetate 2: 1) to give 100.05 g (51% of theory) of the title compound as a colorless viscous oil. 1 H-NMR spectroscopy showed that the title compound can be considered a pure α-anomer.

Elemental analysis:

Calculated: C 52.94; H, 6.77

Found: C, 52.80; H, 6.78

(c) 6- [1-O-cis- (2,3,4,6-tetra-O-benzyl) -D-manopyranosyl] hexanoic acid;

To a stirred suspension of 141.0 g (289 mmol) of the title compound of Example 70b) in 200 mL of dioxane at room temperature with vigorous stirring was added portionwise 235.5 g (4.26 mol) of finely powdered potassium hydroxide. To increase the stirring efficiency, an additional 200 mL of dioxane was added to the reaction mixture, and the suspension thus obtained was heated to boiling and a total of 372 mL (3.128 mol) of benzyl bromide was added dropwise over 2 hours. The reaction mixture was stirred for 4 hours at 110 ° C and then for 12 hours at room temperature. For working up, the reaction mixture was poured slowly into 2.5 L of ice water and the aqueous phase was extracted with diethyl ether. After washing the ether phase so obtained and drying it over sodium sulfate, the inorganic salts were filtered off and the solvent was evaporated under reduced pressure. Excess benzyl bromide was then distilled from the reaction mixture in vacuo at an oil temperature of 180 ° C. The oily residue thus obtained was purified by chromatography on silica gel (mobile phase: ethyl acetate / hexane 1:10). Yield: 172.2 g (91.0% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: C 75.68; H, 7.16

Found: C, 75.79; H, 7.04

d) 6- [Ι-O-α- (2,3,4,6-tetra-O-) - N- (177,1H, 2H, 2H, 4H, 4H, 5H, 577-3-Oxaperfluorotridecyl) amide benzyl) -D-mannopyranosyl) hexanoic acid

In 1200 mL of dry tetrahydrofuran was dissolved 100 g (134 mmol) of the acid described in Example 70c) followed by 13.5 g (134 mmol) of triethylamine. After cooling the mixture to -15 ° C, a solution of 18.45 g (135 mmol) of isobutyl chloroformate in 200 ml of dry tetrahydrofuran was added dropwise with stirring, while the temperature of the mixture did not rise to -10 ° C. The mixture was stirred for 15 minutes at -15 ° C and then a solution of 165.5 g (134 mmol) of 1-amino-177, 177, 277, 277-perfluorodecane and 13.5 g (134 mmol) of triethylamine in a dropwise addition was added dropwise. 250 mL of dry tetrahydrofuran at -20 ° C. The reaction mixture was stirred for 1 hour at -15 ° C and then for 2 hours at room temperature and evaporated to dryness under reduced pressure. The residue obtained was dissolved in 300 ml of ethyl acetate and washed twice with 400 ml of saturated aqueous sodium bicarbonate solution and then once with 500 ml of water. After drying the organic phase over sodium sulfate, the salts were filtered off and the ethyl acetate was evaporated in vacuo. The residue obtained was purified by chromatography on silica gel (mobile phase:

231 dichloromethane / hexane / 2-propanol 10: 5: 1). Yield: 143.8 g (86.9% of theory).

Elemental analysis:

Calculated: 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- (1 H, 2 H, 2 H, 4 H, A H, 5 H, 5 H -3-Oxaperfluorotridecyl) amide

40.0 g (32.38 mmol) of the title compound of Example 70d) was dissolved in 750 mL of 2-propanol and 2.0 g of palladium catalyst (10% Pd / C) was added. The reaction mixture was hydrogenated for 12 hours at 22 ° C under a hydrogen atmosphere (1 atm). The catalyst was filtered off and the filtrate was evaporated to dryness. The residue obtained was dissolved in 300 ml of dimethylsulfoxide, the product solution thus obtained was treated with a total of 1000 ml of diethyl ether, and the precipitate formed was filtered off to give 21.52 g (88.0% of theory) of the title compound as a colorless crystalline powder. mp 88.5 ° C.

Elemental analysis:

Calculated: 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) Production of a formulation from a metal complex I and

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

To 35 ml of a solution of metal complex I (280 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNaaDTPA) was added 3.17 g (4.2 mmol) of the title compound. in the title of Example 70e) and 0.9% aqueous sodium chloride solution was added up to a total volume of 98 ml. The reaction mixture was stirred for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with 2 N

232 of sodium hydroxide solution. The solution was filtered through a 0.2 µm filter and the filtrate was filled into vials. The solution thus prepared can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 71

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

74.59 g (100 mmol) of the acid prepared in Example 71c) was dissolved in 800 mL of 7: 3 tetrahydrofuran / acetonitrile and 10.11 g (100 mmol) of triethylamine was added. Finally, 500 ml of a tetrahydrofuran solution of 58.0 g (102.0 mmol) of 1- (4-perfluorooctylsulfonyl) piperazine, 10.11 g (100 mmol) of triethylamine and 16.84 g (110 mmol; 1-hydroxybenzotriazole) were added dropwise at room temperature. The reaction solution thus obtained was treated at -5 ° C with a solution of 22.7 g (110 mmol) of N, N'-dicyclohexylcarbodiimide in 100 ml of tetrahydrofuran, and the mixture was then stirred at -5 ° C for a further 2 hours. After dissolution, the reaction mixture was stirred at room temperature for an additional 12 hours, the precipitated dicyclohexylurea was filtered off, and the filtrate was evaporated to dryness in vacuo, dissolved 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, ethyl acetate was evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / acetone / 2). (Propanol: 2: 1) Yield: 113.01 g (79.8% of theory) of a colorless viscous oil.

Elemental analysis:

Calculated: 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-Perfluorooctylsulfonylpiperazine-4-carbonyl) 233

-pent-5-yl] mannopyranose g (35.30 mmol) of the title compound of Example 71a) was dissolved in a mixture of 500 ml of 2-propanol and 50 ml of water and 2 g of palladium catalyst (10% Pd / C) were added. . The mixture was hydrogenated for 12 hours at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in 200 mL of methanol and treated with a total of 800 mL of diethyl ether to precipitate the reaction product. After the precipitate was filtered off, the material was dried under vacuum at 50 ° C. Yield: 29.51 g (99% of theory) of an amorphous solid.

Elemental analysis:

Calculated: 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-perfluorooctylsulfonylpiperazin-4-carbonyl) pent-5-yl] mannaprose

To 47 mL of a solution of metal complex II (250 mmol / l) in 0.45% aqueous sodium chloride solution was added 9.92 g (11.75 mmol) of the title compound of Example 71b) and the mixture was heated for 10 min. microwave oven. The solution was cooled to room temperature, filtered through a 0.2 µm filter, and the filtrate was filled into vials. The solution thus prepared can be directly used in biological experiments (gadolinium concentration approximately 250 mmol / l).

Example 72

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

To a stirred suspension of 20.16 g (700 mmol, 80% suspension in mineral oil) of sodium hydride in 150 mL of dimethylsulfoxide was added a total of 24.0 g (108.5 mmol) at room temperature.

234

2-acetamido-2-deoxy-α, β-D-glucopyranose dissolved in 500 mL of absolute dimethylsulfoxide. The mixture was then stirred for 120 minutes at room temperature and 159.5 g (1.26 mol) of benzyl chloride was added dropwise to the solution. The reaction solution was stirred for an additional 12 hours at room temperature. For working up, the reaction solution was poured into 1.5 L of ice water and the mixture was extracted with diethyl ether. The combined ether phases were washed twice with 600 ml of saturated sodium bicarbonate solution and then twice with 800 ml of water. After drying the organic phase over sodium sulfate and filtering out the salts, the solvent was evaporated to dryness in vacuo. The oily residue obtained was purified by silica gel chromatography (eluent: ethyl acetate / hexane 1: 5).

Yield: 48.68 g (73.6% of theory) of the title compound as a colorless viscous oil.

Elemental analysis:

Calculated: 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 of Example 72a) was suspended in a mixture of 750 mL of methanol and 215 mL of water and a total of 44.0 mL (49.2 mmol) of a 0.112 M aqueous solution was added at room temperature. perchloric acid. After the addition was complete, the mixture was stirred for 10 minutes at room temperature and the homogeneous reaction mixture thus obtained was evaporated in vacuo to dryness. Treatment with an equal volume mixture of hexane and dichloromethane led to crystallization. The crystalline reaction product was filtered off, washed with hexane and dried in vacuo at room temperature. Yield: 27.08 g (86% of theory) of the title compound as a colorless crystalline compound. Melting point: 180.5-181.5 ° C.

Elemental analysis:

235

Calculated: 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-a, β-D- glucopyranose

20.8 g (35.6 mmol) of 2- (N-ethyl-N-perfluorooctylsulfonyl) aminoacetic acid and 3.60 g (35.6 mmol) of triethylamine were dissolved in 350 ml of dry tetrahydrofuran. After cooling the reaction mixture to -15 ° C to -20 ° C, a solution of 4.92 g (35.6 mmol) of isobutyl chloroformate in 75 ml of dry tetrahydrofuran was added dropwise at this temperature, with the addition rate being such that did not rise above -10 ° C. The mixture was stirred for 15 minutes at -15 ° C and then a solution of 22.78 g (35.6 mmol) of perchlorate (the title compound of Example 72b) and 3.60 g (35.6 mmol) of triethylamine in a dropwise solution was added dropwise. 100 mL of dry tetrahydrofuran at -20 ° C. The mixture was stirred for 1 hour at -15 ° C and then for 2 hours at room temperature and then evaporated to dryness under reduced pressure. The residue obtained was dissolved in 250 ml of ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution and then once with 200 ml of water. After drying the organic phase over sodium sulfate, the salts were filtered off and the ethyl acetate was evaporated in vacuo. The oily residue obtained was purified by silica gel chromatography (eluent: ethyl acetate / hexane 1: 5). Yield: 33.3 g (84.6% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: C 49.92; H, 3.92; N, 2.53; E 29.18; S, 2.90

Found: C, 49.99; H, 4.11; N, 2.69; E, 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 of Example

236

72c) was dissolved in 250 ml of 2-propanol and 1.5 g of palladium catalyst (10% Pd / C) was added. The reaction solution was hydrogenated for 12 hours at 22 ° C and under a hydrogen atmosphere (1 atm). The catalyst was filtered off and the filtrate was evaporated to dryness. The residue obtained was dissolved in 300 ml of dimethyl sulfoxide, and the product solution thus obtained was mixed with 750 ml of a mixture of equal volumes of diethyl ether and ethyl acetate. Filtration of the deposited precipitate gave 12.65 g (93.8% of theory) of the title compound as a colorless crystalline powder. The title compound occurs as a mixture of α and β anomers, and their ratio to each other was determined to be approximately 1: 1.2 by ¹ H-NMR spectroscopy. Thus, the title compound can be considered as a mixture of approximately equal parts of the α and β anomers. Melting point 132.5-133 ° C.

Elemental analysis:

Calculated: 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 from the metal complex XIV and 2-deoxy-2- [acetyl (2-amino-N-ethyl-N-perfluorooctylsulfonyl) amino] -1-α, β-D-glucopyranose

To a 51 mL solution of the metal complex XIV (300 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNaaDTPA) was added a solution of 4.90 g (6.57 mmol) of the compound The title compound of Example 72d) in 200 ml of ethanol and stirred for 2 hours at 50 ° C. The solution was evaporated to dryness in vacuo and the residue was made up to a total volume of 153 ml with distilled water. The mixture was stirred for 10 minutes at 40 ° C and filtered through a 0.2 µm filter. The filtrate was filled into vials. The solution thus obtained can be directly used in biological experiments (gadolinium concentration approximately 100 mmcl / l).

Example 73

237

(a) (1,2,3,4,6-Penta-O-acetyl) -α-D-glucopyranose

In an analogous manner to that described for the synthesis of the title compound of Example 70a), the use 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 yielded after treatment and crystallization from 95 % aqueous ethanol 190.6 g (88.0% of theory) of the title compound as a colorless crystalline solid. 1 H-NMR spectroscopy revealed that the title compound is a 98: 2 mixture of a and p anomers. The title compound can thus be considered to be exclusively the α-anomer. Melting point: 110.5 ° C.

Elemental analysis:

Calculated: 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 to that described for the synthesis of the title compound of Example 70b), the use of 130.0 g (332.8 mmol) of the title compound of Example 73a) yielded 55.8 ml (332.8 mmol) of ethyl ester 6. -hydroxyhexane and 50.6 ml (520 mmol) of tin tetrachloride in 500 ml of 1,2-dichloroethane after purification by column chromatography (mobile phase: hexane / ethyl acetate 2: 1) 101.85 g (62.4% of theory) of the compound in the form of a colorless viscous oil. Using the ¹ H-NMR is based on the use size of the coupling constant Ji, _{2 to} 8.8 Hz has been found that the compound is characterized by a β configuration at the anomeric carbon, and it is only the configuration of the anomeric center. Thus, the title compound has exclusively the β-configuration of the anomeric center.

Elemental analysis:

Calculated: C 52.94; H, 6.77

238

Found: C, 52.77; H, 6.70

c) 5-Carboxypentyl- (2,3,4,6-tetra-O-benzyl) -α-D-glucopyranoside

To a stirred suspension of 100.0 g (204.96 mmol) of the title compound of Example 73b) in 150 mL of dioxane at room temperature with vigorous stirring in portions was added a total of 169.14 g (3.02 mol) of finely powdered hydroxide. potassium. To increase the stirring efficiency, an additional 150 mL of dioxane was added to the reaction mixture, and the suspension thus obtained was heated to boiling and a total of 264 mL (2.218 mol) of benzyl bromide was added dropwise over 2 hours. The reaction mixture was stirred for 4 hours at 110 ° C and then for 12 hours at room temperature. For work-up, the reaction mixture was poured slowly into 2.0 L of ice water and the aqueous phase was extracted with diethyl ether. After washing the ether phase so obtained and drying it over sodium sulfate, the inorganic salts were filtered off and the solvent was evaporated under reduced pressure. Excess benzyl bromide was then distilled off from the reaction mixture in vacuo at an oil bath temperature of 180 ° C. The oily residue thus obtained was purified by chromatography on silica gel (mobile phase: ethyl acetate / hexane 1:10). Yield: 128.8 g (84.3% of theory) of the title compound as a very viscous oil.

Elemental analysis:

Calculated: C 75.68; H 7 ,, 16

Found: C, 75.66; H, 7.23

d) (2,3,4,6-Tetra-O-benzyl) -1-O- [1-D- [6-hexanoic acid] -N- (1H, IE, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperofluoridecyl) amide] glucopyranose

68.5 g (91.79 mmol) of the title compound of Example 73c) was dissolved in 825 mL of dry tetrahydrofuran together with 9.25 g (91.79 mmol) of triethylamine. After cooling the reaction mixture to -15 ° C to -20 ° C, the reaction mixture was added dropwise with stirring

239 DEG C. is a solution of 12.64 g (92.5 mmol) of isobutyl chloroformate in 150 ml of dry tetrahydrofuran, the rate of addition being such that the temperature of the mixture does not exceed -10 ° C. The mixture was stirred for 15 minutes at -15 ° C and then slowly added dropwise a solution of 46.40 g (91.79 mmol) of 17, 17, 17, 27, 2-heptadecafluoro-1- (2-aminoethyloxy) decane and 9.25. g (91.79 mmol) of triethylamine in 200 ml of dry tetrahydrofuran at -20 ° C. The mixture was stirred for 1 hour at -15 ° C and then for 2 hours at room temperature and then evaporated to dryness under reduced pressure. The obtained residue was dissolved in 250 ml of ethyl acetate and washed twice with 300 ml of saturated sodium bicarbonate solution and then once with 400 ml of water. After drying the organic phase over sodium sulfate, the salts were filtered off and the ethyl acetate was evaporated in vacuo. The oily residue obtained was purified by silica gel chromatography (eluent: dichloromethane / hexane / 2-propanol 10: 5: 1). Yield: 104.7 g (92.4% of theory) of the title compound as a colorless viscous oil.

Elemental analysis:

Calculated: 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) Ι-Ο-β-D- [6-Hexanoic acid-N- (17β, 17β, 27β, 27β, 47β, 47β, 57β, 57β-3-oxaperfluorotridecyl) amide] glucopyranose

40.0 g (32.38 mmol) of the title compound of Example 73d) was dissolved in 750 ml of 2-propanol and 2.0 g of palladium catalyst (10% Pd / C) were added. The reaction mixture was hydrogenated for 12 hours at 22 ° C under a hydrogen atmosphere (1 atm). The catalyst was filtered off and the filtrate was evaporated to dryness. The residue obtained was dissolved in 300 ml of dimethylsulfoxide, the product solution thus obtained was precipitated by the addition of a total of 1000 ml of diethyl ether and the precipitate formed was filtered off to give 22.05 g (90.2% of theory) of the title compound as a colorless crystalline powder. melting point

240

Mp 122-124 ° C.

Elemental analysis:

Calculated: 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 of WO 99/01161 (1,4,7-tris [1,4,7-tris- (N-carboxylatomethyl) -10- (N1-methyl-3-) aza-2,5-dioxopentane-1,5-diyl) -1,4,7,10-tetraazacyclododecane] -10- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-1,4,7, 10-tetraazacyclododecane, Gd complex) and glucopyranose Ι-Ο-β-D- [6-hexanoic acid-N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotidecyl) amide]

To 37 ml of 1,4,7-tris [1,4,7-tris (N-carboxylatomethyl) -10- (N-1-methyl-3-aza-2,5-dioxopentane-1,5-diyl) solution -1,7,7,10-tetraazacyclododecane] -10- [2- (N-ethyl-N-perfluorooctylsulfonyl] amino] acetyl-1,4,7,10-tetraazacyclododecane, Gd complex (300 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l)

CaNa3DTPA) was added 20.29 g (25.9 mmol) of the title compound of Example 73e) and the mixture was diluted with 0.9% aqueous sodium chloride solution to a total volume of 111 mL. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The solution obtained can be used directly in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 74

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

Using 50 g (128.09 mmol) of the title compound of Example 70a), which was determined to be a 4: 1 mixture of α and β anomers, with a solution of 75.84 g (128.1 mmol) of 1-hydroxy-1H, m / z, 2H, 2H241

-perfluorodecane in 150 ml of 1,2-dichloroethane and 19.47 g (166.53 mmol) of tin tetrachloride in an analogous manner to the synthesis of the title compound of Example 1b) and 4b) resulted in column chromatography (mobile phase: hexane). ethyl acetate 2: 1) to give 74.2 g (63.4% of theory) of the title compound as a colorless viscous oil. 1 H-NMR spectroscopy, using the size of the coupling constant J _b 2 = 1.3 Hz, the title compound was found to have the α configuration at the anomeric center so that it can be considered a pure α-anomer.

Elemental analysis:

Calculated: C 44.65; H, 2.53; E 35.32

Found: C, 44.77; H, 2.61; 35 35.09

b) 1-O- (1H, 17H, 2H, 2H-Perfluorodecyl) -α-D-manopyranose g (27.33 mmol) of the title compound of Example 74a) was suspended in 400 mL of absolute methanol at 5 ° C a catalytic amount of sodium methanolate was added. The mixture was stirred for 3 hours at room temperature and the reaction was found to be quantitative by thin layer chromatography (eluent: chloroform / methanol 9: 1). Upon work-up, the clear reaction solution was neutralized with an Amberlite ® IR 120 (H ⁺ form) cation exchanger, the ion exchanger was filtered off and the methanolic solution obtained was evaporated to dryness under reduced pressure. The crystalline residue was recrystallized twice from ethanol. 1 H-NMR spectroscopy revealed that the title compound has an α configuration at the anomeric center based on the size of the interaction constant J 1, 2 ⁼ 1/0 Hz. Said configuration α is the exclusive configuration at the anomeric center, which means that any resulting β-configuration of the title compound is below the limit of recognition by 1 H-NMR spectroscopy. Thus, the title compound was prepared as the pure α-anomer. Yield: 16.2 g (94.6% of theory) of a colorless crystalline solid

242 fabric. Melting point:

172-174 ° C with decomposition.

Elemental analysis: Calculated: C 30.69;

Found: C, 30.57;

H, 2.41; F, 51.57; 2.48; F, 51.65

c) Production of a formulation from metal complex II and 1-O- (15,15,25,25-perfluorodecyl) -? - D-manopyranose

To a 50 mL solution of metal complex II (150 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / L CaNasDTPA) was added a solution of 2.01 g (3.21 mmol) of the compound The title compound of Example 74b) in 200 ml of ethanol and stirred for 2 hours at 50 ° C. The solution was evaporated in vacuo and the residue was made up to a total volume of 75 mL with distilled water. The mixture was stirred for 10 minutes at 40 ° C and filtered through a 0.2 µm filter. The filtrate was poured into vials. The prepared solution is suitable for direct use in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 75

a) 1-O- (15,15,25,25-Perfluorododecyl) -2,3,4,6-tetra-O-acetyl-α-D-mannopyranose

Using 35 g (89.66 mmol) of the title compound of Example 70a) which is a 4: 1 mixture of the respective α and β anomers with a solution of 50.60 g (89.7 mmol) of 1-hydroxy-15, 15, 25, 25-perfluorododecane in 100 ml 1,2-dichloroethane and a total of 13.63 g (16.61 mmol) of tin tetrachloride in an analogous manner to that described for the synthesis of the title compound of Examples 1b), 4b) and 5b ) after work-up and purification by column chromatography (mobile phase: hexane / ethyl acetate 2: 1) gave 62.49 g (68.7% of theoretical) of the title compound as a colorless viscous oil. 1 H-NMR spectroscopy based on the size of the interaction constant J _{1> 2} = 1.4 Hz revealed that the title compound had an a243 figure at the anomeric center and that was the only configuration of the title compound at the anomeric center. Thus, the title compound can be prepared as the pure α-anomer.

Elemental analysis:

Calculated: 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-manopyranose g (24.64 mmol) of the title compound of Example 75a) was suspended in 400 ml of absolute methanol at 5 ° C. ° C a catalytic amount of sodium methanolate was added. The reaction mixture was stirred for 3 hours at room temperature and by checking the reaction mixture by thin layer chromatography (eluent: chloroform / methanol 9: 1) the reaction was found to be quantitative. Upon work-up, the clear reaction solution was neutralized with an Amberlite ® IR 120 (H ⁺ form) cation exchanger, the ion exchanger was filtered off and the methanolic solution obtained was evaporated to dryness under reduced pressure. The crystalline residue was recrystallized twice from 2-propanol / ethanol 1: 1. 1 H-NMR spectroscopy based on the size of the interaction constant J 1, ₂ = 1.0 Hz revealed that the title compound has the α configuration at the anomeric center. Said configuration α is the exclusive configuration at the anomeric center, i.e. the potentially formed β-configuration of the title compound is below the recognition limit by 1 H-NMR spectroscopy. Thus, the title compound was prepared as the pure α-anomer. Yield: 16.96 g (90.8% of theory) of a colorless crystalline solid. M.p .: 187-188 ° C with decomposition.

Elemental analysis:

Calculated: C 29.77; H 2.08; F, 54.93

Found: C, 29.70; H, 2.28; F, 54.83

c) Preparation of the formulation from metal complex VI and 1-O- (1H, 2H, 2H244)

-perfluórododecyl) -α-D-mannopyranose

To 52 ml of the metal complex solution VI. (180 mmol / L) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / L CaNa ₂ DTPA) was added 1.70 g (2.34 mmol) of the title compound of Example 75b. ) and the mixture was heated for 10 minutes in a microwave oven. The solution was cooled to room temperature, filtered through a 0.2 μπ filter, and the filtrate was filled into vials. The solution thus prepared can be used directly in biological experiments (gadolinium concentration approximately 180 mmol / l).

Example 76

a) (2,3,4,6-Tetra-O-acetyl) -1-OaD- [3,6,9-trioxa (C ₁₂ -C ₂₂ -heptadecafluoro) nonadecyl] manopyranose

Using 20 g (51.23 mmol) of the title compound of Example 70a), which is a 4: 1 mixture of the appropriate α and β anomers, with a solution of 30.54 g (51.23 mmol) of 1-hydraxy-tris- ( 1H, 1H, 2H, 2H-O) -1H, 1H, 2H, 2H-perfluorodecane in 100 ml 1,2-dichloroethane and a total of 5.98 g (51.23 mmol) of tin tetrachloride in an analogous manner to describes for the synthesis of the title compound of Examples 1b), 4b) and 5b), after administration and purification by column chromatography (mobile phase: hexane / ethyl acetate 1: 1) to give 34.22 g (72.1% of theory) ) of the title compound in the form of a colorless viscous oil. ¹ H-NMR spectroscopy based on size. of the coupling constant J 1, ₂ = 1/1 Hz, the title compound was found to have the α configuration at the anomeric center. Said configuration is the exclusive configuration at the anomeric center. Thus, the title compound can be prepared as the pure α-anomer.

Elemental analysis:

Calculated: C 38.89; H, 3.81; F, 34.86

Found: C, 39.02; H, 3.77; F, 34.90

245

b) Ι-Ο-α-D- [3,6,9-Trioxa- (C 1 -C 18 -heptadecafluoro) nonadecyl) -manopyranose g (21.58 mmol) of the title compound of Example 76a) was suspended in 350 ml of absolute methanol was added and a catalytic amount of sodium methoxide was added at 5 ° C. The reaction mixture was stirred for 3 hours at room temperature and showed that the reaction was quantitative by checking the reaction mixture by thin layer chromatography (eluent: chloroform / methanol 6: 1). Upon work-up, the clear reaction solution was neutralized with an Amberlite ® IR 120 (H ⁺ form) cation exchanger, the ion exchanger was filtered off and the methanolic solution obtained was evaporated to dryness under reduced pressure. The crystalline residue was recrystallized twice from ethyl acetate / 2-propanol / ethanol 1: 0.5: 1). ^X H-NMR spectroscopy for the size of the coupling constant Ji, ₂ = 1.0 Hz, it was found that the compound has a configuration of the anomeric center of a. Said configuration α is the exclusive configuration at the anomeric center, which means that any resulting β-configuration of the title compound is below recognition by ¹ H-NMR spectroscopy. Thus, the title compound was prepared as the pure α-anomer. Yield: 15.20 g (92.9% of theory) of a colorless crystalline solid. M.p .: 141 ° C.

Elemental analysis:

Calculated: C 34.84; H, 3.59; F, 42.58

Found: C, 34.72; H, 3.66; F, 42.67

c) Preparation of the formulation from the title compound of Example 68 and 1-O-α-D- [3,6,9-trioxa (C 1 -C 18 -heptadecafluoro) nonadecyl] manopyranose

To 38 ml of a solution of the title compound of Example 68 (300 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa ₃ DTPA) was added 3.71 g (4 89 mmol) of the title compound of Example 76b) and 0.9% aqueous solution

246 of sodium chloride was made up to a total volume of 114 ml. The mixture was stirred for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH of the solution was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The solution was filtered through a 0.2 µm filter and the filtrate was filled into vials. The solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 77

a) (2,3,4,6-Tetra-O-acetyl) -α-D- [3-thiopropionic acid-N- (177, 177, 277, 2H, 4H, 4H, 5H, 577- 3-Oxaperfluoridecyl) amide] manopyranose

25.0 g (57.28 mmol) of 3- (2,3,4,6-tetra-O-acetyl) -. Alpha.-D-mancpyranosylmercapto) propionic acid prepared according to MM Ponpip, RL Bugianesi, were dissolved in 500 ml of dry tetrahydrofuran, JC Robbins, TW Doebber, TY Shen, J. Med. Chem., 24 (12), 1388-1395 (1981) together with 5.77 g (57.28 mmol) of triethylamine. The mixture was cooled to -15 ° C to -20 ° C, and a solution of 7.82 g (57.28 mmol) of isobutyl chloroformate in 100 ml of dry tetrahydrofuran was added dropwise with stirring at this temperature, the rate of addition being such that the mixture did not exceed -10 ° C. The reaction mixture was stirred for 15 minutes at -15 ° C and a solution of 29.05 g (57.28 mmol) of 177,177, 277, 277-heptadecafluoro-1- (2-aminoethyloxy) decane and 5.77 g was slowly added dropwise. (57.28 mmol) triethylamine in 200 mL dry tetrahydrofuran at -20 ° C. The mixture was stirred for 1 hour at -15 ° C and then for 2 hours at room temperature and then evaporated to dryness under reduced pressure. The obtained residue was dissolved in 250 ml of ethyl acetate and washed twice with 200 ml of saturated sodium bicarbonate solution and then once with 300 ml of water. After drying the organic phase over sodium sulfate, the salts were filtered off and the ethyl acetate was evaporated in vacuo

247 vacuum. The oily residue obtained was purified by chromatography on silica gel (mobile phase: dichloromethane / hexane / 2-propanol).

8: 5: 1). Yield: 44.90 g (84.7% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

Calculated: 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) Ι-α-D- [3-Thiopropionic acid-N- (1 H, 2 H, 2 F, 2 F, 4 F, 4 F, 5 F, 5 F - 3-oxaperfluorotridecyl) amide] manopyranose g (32.41 mmol) of title 77a) was suspended in 400 ml of absolute methanol and a catalytic amount of sodium methoxide was added at 5 ° C. The reaction mixture was stirred for 3 hours at room temperature and showed that the reaction was quantitative by checking the reaction mixture by thin layer chromatography (eluent: chloroform / methanol 9: 1). Upon work-up, the clear reaction solution was neutralized with an Amberlite IR 120 cation exchanger (K @ + form), the ion exchanger was filtered off and the methanolic solution obtained was evaporated to dryness under reduced pressure. The crystalline residue was recrystallized from ethyl acetate / methanol 0.5: 1. 1 H-NMR spectroscopy based on the size of the interaction constant J 1, ₂ = 1/1 Hz revealed that the title compound had an α configuration at the anomeric center. The configuration and the exclusion, the configuration at the anomeric center, which means that if the resulting β-configuration of the title compound was below the detection by ^X-NMR spectroscopy. Thus, the title compound was prepared as the pure α-anomer. Yield: 23.76 g (96.8% of theory) of a colorless crystalline solid. Melting point: 113-114.5 ° C.

Elemental analysis:

Calculated: C 33.30; H, 3.19; N, 1.85; S, 4.23; E, 42.64

248

Found: C, 33.21; H, 3.26; N, 1.96; S 4.08; F, 42.77

c) Preparation of the formulation from the title compound of Example 66 and Ι-α-D- [3-thiopropionic acid-N- (1H, 17H, 2H, 2H, 4H, 4H, 57H, 5H-3-) oxaperfluórtridecyl) -amide] mannopyranose

To a 47 mL solution of the title compound of Example 66 (330 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / L CaNa ₃ DTPA) was added a solution of 27.41 g ( 36.19 mmol) of the title compound of Example 77b) in 200 ml of ethanol and stirred for 2 hours at 50 ° C. The solution was evaporated to dryness and the residue was diluted with distilled water to a total volume of 155 ml. The mixture was stirred for 10 minutes at 40 ° C and filtered through a 0.2 µm filter. The filtrate was filled into vials. The solution obtained can be used directly in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 78

acid a) (2,3,4,6-tetra-O-acetyl) -Ι-β-D- [3, 6, 9-trioxa- (C ₂ -Ci9-heptadecafluoro) nonadecyl] glucopyranosyluronic

20.2 g (50.85 mmol) of methyl [1-bromo- (2,3,4-tri-O-acetyl-1-D-glucopyranosyl) uronate prepared according to Pelzer, Hoppe-Seyler's Z. Physiol. Chem., 314, 234-237 (1949) or Goebel, Babers, J. Biol. Chem., 111, 347-350 (1935) and Bollenback et al., J. Amer. Chem. Soc., 77, 3310-3313 (1955) and 60.64 g (101.7 mmol) of 3,6,9-trioxa- (C ₁₂ -C ₁₉ -heptadecafluoro) nonadecan-1-ol were dissolved in 250 mL aqueous acetonitrile and at room temperature 13.0 g of freshly precipitated silver oxide were added. The reaction mixture was stirred for 12 hours at room temperature and the insoluble silver salt was filtered off, the salts were washed well with dichloromethane and the filtrate thus obtained was evaporated to dryness in vacuo. The obtained residue was purified by column chromatography (mobile phase: hexane / ethyl acetate 3: 1). Yield: 22.99 g (53.3% of theory) of the title compound as a colorless, highly viscous oil without 249.

Elemental analysis:

Calculated: 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- (Cp-Cig-heptadecafluoro) nonadecyl] glucopyranosyluronic acid

10.0 g (11.78 mmol) of the title compound of Example 78a) were suspended in 200 ml of a 2: 1 mixture of methanol and 0.5 M sodium hydroxide solution with stirring at room temperature. The reaction mixture was stirred for 12 hours at room temperature and during work-up, the clear reaction solution was neutralized with a cation exchanger Amberlite ® IR 120 (H ⁺ -form), the ion exchanger was filtered off and the methanolic solution obtained was evaporated to dryness under reduced pressure. The crystalline residue was purified by crystallization from ethyl acetate / methanol 0.25: 1. 1 H-NMR spectroscopy based on the size of the interaction constant J ₁ = 9.2 Hz revealed the title compound to have a β configuration at the anomeric center. Said β configuration is the exclusive configuration at the anomeric center, meaning that any α-configuration of the title compound formed may be below recognition by -N-NMR spectroscopy. Thus, the title compound was prepared as the pure β-anomer. 78.5 ° C.

Elemental analysis:

Calculated: C 34.21; H, 3.26; F, 41.81

Found: C, 34.38; H, 3.26; F, 41.90

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

To 38 ml of a solution of metal complex I (280 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa 1 DTPA) was added 19.18 g (24.83 mmol) of the compound in the title of Pri250 of Example 78b) and the mixture was made up to a total volume of 53.2 ml with 0.9% sodium chloride solution. The mixture was stirred for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH of the solution was adjusted to 7.4 by addition of 2 N sodium hydroxide. The solution was filtered through a 0.2 µm filter and the filtrate was filled into vials. The solution can be directly used in biological experiments (gadolinium concentration approximately 200 mmol / l).

Example 79

a) 6- (H, 1 H, 3H, 3H, 4H, 4H-2-Oxaperfluórdecyl) O ^1, O ^2, O ^5, 0 ⁴ -diizopropylidén-D-galactopyranose

To a stirred suspension of 2.01 g (70.0 mmol, 80% in mineral oil) sodium hydride in 25 ml of dimethylformamide at room temperature was slowly dropped a total of 12.15 g (46, 66 mmol), O ^1, O ^2, 0 ³ 0 ⁴ -diizopropylidén-and-galactopyranose prepared according Levene, Meyer, J. Biol. Chem., 64, 473 (1925) or Mc Creat, Smith, J. Chem. Soc., 1939, 387, 389 and Ireudenberg, Hixon, Chem. Ber., 56, 2119, 2122 (1923) dissolved in 200 ml of absolute dimethylformamide. The mixture was stirred for an additional 120 minutes at room temperature and then a total of 30.09 g (48.0 mmol) of 1-bromo-1H, 1H, 2H, 2H-perfluorodecane dissolved in 150 ml of absolute dimethylformamide was added dropwise. The reaction solution was stirred for an additional 12 hours at room temperature. For working up, the reaction solution was slowly poured into 1 L of ice water and the mixture was extracted with diethyl ether. The combined organic phases were washed twice with 200 ml of saturated sodium bicarbonate solution and then twice with 200 ml of water. After drying the organic phase with sodium sulfate, the salts were filtered off and the solvent was evaporated to dryness in vacuo. The oily residue obtained was purified by chromatography on silica gel (mobile phase: ethyl acetate / hexane 1:10). Yield: 29.8 g (79.3% of theory) of the title compound as a colorless viscous oil.

Elemental analysis:

Calculated: C 35.75; H, 2.87; F, 49.47

Found: C, 35.64; H, 2.98; F, 49.54

b) 6- (17β, 17β, 37β, 37β, 47β, 47β-2-Oxaperfluorodecyl) -α-D-galactopyr-. g (24.8 mmol) of the title compound of Example 79a) was mixed with 300 mL of a 1% aqueous sulfuric acid solution and heated at 80 ° C for 3 hours. After cooling to room temperature, the reaction mixture was neutralized with a barium hydroxide solution and the precipitated barium sulfate was filtered off. The clear aqueous filtrate was lyophilized. ¹ H-NMR spectroscopy showed that the title compound was a mixture of α and β anomers and that their ratio was 1: 1.4. Thus, the title compound was isolated as a 1: 1.4 mixture of α and β anomers and anomer separation was not performed. Yield: 15.28 g (98.4% of theory) of the title compound as a colorless lyophilisate.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 35.75; H, 2.87; F, 49.47

Found: C, 35.64; H, 2.98; F, 49.54

c) Preparation of the preparation from the title compound of Example 67 and 6- (17β, 17β, 37β, 37β, 47β, 47β-2-oxaperfluorodecyl) -α-D-galactopyranose

To a 43 mL solution of the title compound of Example 67 (250 mmol / L) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / L CaNa ₃ DTPA) was added a solution of 1.68 g ( 2.69 mmol) of the title compound of Example 79b) in 200 mL of ethanol and heated to 50 ° C for 2 hours. The solution was evaporated to dryness under reduced pressure and the residue was diluted with distilled water to a total volume of 107.5 ml. The mixture was stirred for 10 minutes at 40 ° C and filtered through a 0.2 gm filter. The filtrate was filled into vials. The solution obtained can be used directly in the

252 biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 80

a) 1-OaD - [(1-Perfluorooctylsulfonylpiperazine-4-carbonyl) methyl] mannopyranose g (52.8 mmol) of 1- (4-Perfluorooctylsulfonyl) piperazine prepared as described in patent applications DE 196 03 033 and 31.73 g (53 mmol) of (2,3,4,6-tetra-O-benzyl) -α-D-carboxymethylmanopyranose prepared as described in patent application DE 197 28 954 was dissolved in 300 ml of tetrahydrofuran. At 0 ° C, 24.73 g (100 mmol) of EEDQ (1,2-dihydro-2-ethoxyquinoline-1-carboxylic acid ethyl ester) was added and the mixture was stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. The resulting solution was evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (mobile phase: hexane / ethyl acetate 10: 1). Product containing fractions were evaporated to dryness, the residue was dissolved in a mixture of 200 mL of methanol and 150 mL of dichloromethane and the mixture was hydrogenated for 8 hours in the presence of palladium on carbon (10% Pd / C, 2 g). The hydrogenation catalyst was filtered off and the filtrate was evaporated to dryness. The residue was recrystallized from acetone / diethyl ether. Yield: 30.39 g (73% of theory) of a waxy solid.

Elemental analysis:

Calculated: 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) Production of a formulation from metal complex I and 1-O-α-D - [(1-perfluorooctylsulfonylpiperazine-4-carbonyl) methyl] mannopyranose

To a 32 mL solution of metal complex I (280 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNasDTPA) was added 4.71 g (5.97 mmol) of the title compound. in the title of Example 80a) and the mixture was made up with 0.9% aqueous chloride solution

253 sodium to a total volume of 55 ml. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 200 mmol / l).

Example 81

a) 2H, 2H, AH, AH, 5H, 5H-3-oxaperfluorotridecanoic acid, sodium salt g (38.3 mmol) of 2H, 2H, AH, AH, 5H, 5H-3-oxaperfluorotridecanoic acid prepared as described in patent application DE 196 03 033 was dissolved in 300 ml of ethanol and 7.7 ml of 5 N aqueous sodium hydroxide solution was added. The mixture was evaporated to dryness and the residue was dried in vacuo (8 hours, 60 ° C). Yield: 20.85 g (quantitative) of a colorless crystalline powder.

Elemental analysis:

Calculated: C 26.49; H, 1.11; F, 59.35; At 4.22

Found: C, 26.60; H, 1.19; F, 59.47; At 4.30

b) Preparation of a formulation of metal complex I and of 2H, 2H, -AH, AH, 5H, 5H-3-oxaperfluorotridecanoic acid, sodium salt

To 32 ml of a solution of metal complex I (280 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaN? DTPA) was added 2.09 g (3.84 mmol). of the title compound of Example 81a) and the mixture was made up to a total volume of 90 ml with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments

254 (gadolinium concentration approximately 100 mmol / l).

c) Production of a formulation from metal complex I and 2H, 2H, 44H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid, sodium salt

To 32 ml of a solution of metal complex I (280 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa ₃ DTPA) was added 1.00 g (1.84 mmol) of the title compound of Example 81a) and the mixture was made up to a total volume of 90 ml with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

d) Preparation of a formulation from metal complex I and 2H, 2H, 44tf, 4H, 5H, 5'-3-oxaperfluorotidecanoic acid, sodium salt

To 32 ml of a solution of metal complex I (280 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa ₃ DTPA) was added 0.54 g (1.00 mmol) of the title compound of Example 81a) and the mixture was made up to a total volume of 90 ml with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 82

a) 1- (4-Perfluorooctylsulfonyl) -4- (3,6,9,12,15-pentaoxahexadecanoyl) piperazine

255 g (35.2 mmol) of 1- (4-Perfluorooctylsulfonyl) piperazine (see Example 80a) was dissolved in 300 mL of dichloromethane and 5.06 g (50 mmol) of triethylamine was added. The mixture was cooled to 0 ° C, a solution of 14.24 g (50 mmol) of 3,6,9,12,15-pentaoxahexanoyl chloride was added dropwise over 20 minutes, and the mixture was stirred for 3 hours at 0 ° C. 400 ml of 5% aqueous hydrochloric acid solution were then added and the mixture was stirred. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / methanol 15: 1). Yield: 26.44 g (92% of theory) of a waxy solid.

Elemental analysis:

Calculated: 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 metal complex I (280 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa ₃ DT? A) was added 4.61 g (5.64) mmol) of the title compound of Example 82a) and the mixture was made up to a total volume of 66 ml with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 200 mmol / l).

Example 83

a) IH, 1/7, 2H, 2/7-Perfluorodecyl p-toluenesulfonic acid g (43.1 mmol) 1/7, 1/7, 2/7, 2H-perfluorodecanol dissolved

256 in 200 ml of pyridine and 9.53 g (50 mmol) of p-toluenesulfonyl chloride were added portionwise at 0 ° C. The mixture was stirred for 5 hours at room temperature. The solution was poured into 1000 ml of ice water and stirred for 10 minutes. The compound was filtered off, washed with water and finally crystallized from acetone. Yield: 22.04 g (97% of theory) of a colorless crystalline solid.

Elemental analysis:

Calculated: 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) ( _C18 -C25-Heptadecafluoro) -3,6,9,12,15-pentaoxapentacosan-1-ol g (37.94 mmol) of the title compound of Example 83a), 35.74 g (150 mmol) pentaethylene glycol and 1 g of 18-crown-6 were dissolved in 300 ml of tetrahydrofuran and 10.1 g (180 mmol) of finely powdered potassium hydroxide was added. The mixture was stirred for 10 hours at room temperature. The solid was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (eluent: dichloromethane / methanol 15: 1). Yield: 5.45 g (21% of theory) of a colorless viscous oil.

Elemental analysis:

Calculated: C 35.10; H, 3.68; F, 47.19

Found: C, 35.22; H, 3.77; F, 47.10

c) Preparation of the formulation from the title compound of Example 69 a (C 18 -C 25 -heptadecafluoro) -3,6,6,9,12,15-pentaoxapentacosan-1-ol

To 53 mL of a solution of the title compound of Example 69 (310 mmol / l) in 0.45% aqueous sodium chloride solution was added 44.98 g (65.72 mmol) of the title compound of Example 83b) and the mixture was heated for 10 minutes in a microwave oven. The solution was cooled to room temperature, filtered through a 0.2 µπ filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 310 mmol / l).

Example 84

a) N, N-Bis (8-hydroxy-3,6-dioxaoctyl) perfluorooctylsulfonylamide g (29.23 mmol) Perfluorooctylsulfonylamide and 22.16 g (87.7 mmol) 9- (tetrahydropyran-2-yl) -3, 6,9-trioxanonyl chloride was dissolved in 200 ml acetonitrile. 41.46 g (300 mmol) of potassium carbonate and 1 g (6 mmol) of potassium iodide were added and the mixture was heated to reflux for 10 hours. The solid was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in 400 mL of ethanol and 30 mL of a 10% aqueous hydrochloric acid solution was added. The mixture was stirred for 2 hours at room temperature. The pH was adjusted to 7 with sodium hydroxide and the solution was evaporated to dryness. The residue was purified by silica gel chromatography (eluent: dichloromethane / methanol 10: 1). Yield: 11.38 g (51% of theory) of a colorless viscous oil.

Elemental analysis:

Calculated: 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, -dioxaoctyl) perfluorooctylsulfonylamide

To 37 ml of a solution of metal complex I (280 mmol / l) in both 0.45 and aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNasDTPA) was added 7.91 g (10.36 mmol) of the compound in the title of Example 84a) and the mixture was made up to a total volume of 104 ml with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be used directly in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 85

a) N, N-Bis (tert-butyloxycarbonylmethyl) perfluorooctylsulfonylamide g (38.97 mmol) Perfluorooctylsulfonylamide and 20.73 g (150 mmol) of potassium carbonate were suspended in 200 ml of acetone and 17.56 g (90 mmol) of tert. -butyl bromoacetate. The mixture was heated to boiling for 3 hours. The solid was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: n-hexane / ethyl acetate 10: 1). Yield: 23.53 g (83% of theory) of a colorless waxy solid.

Elemental analysis:

Calculated: 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) perfluorooctylsulfonylamide, disodium salt g (31.62 mmol) of the title compound of Example 85a) was dissolved in 300 ml of trifluoroacetic acid and stirred for 5 hours at room temperature. The mixture was evaporated to dryness and the residue was recrystallized from acetone. The crystals were filtered and dried under vacuum at 50 ° C. Yield: 17.7 g (91% of theory) of a colorless crystalline powder.

g (27.63 mmol) of the disodium salt thus obtained was dissolved in 100 ml of water and 300 ml of ethanol and 9.2 ml of 3 N aqueous sodium hydroxide solution were added. The mixture was stirred for 20 minutes at room temperature and evaporated to dryness under reduced pressure. The residue was dried under vacuum at 60 ° C for 8 hours. Yield: 18.2 g of a colorless crystalline powder.

Elemental analysis:

259

Calculated: 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; At 7.10

c) Preparation of the formulation from metal complex II and N, N-bis (carboxymethyl) perfluorooctylsulfonylamide, disodium salt

To a 41 mL solution of metal complex II (280 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa ₃ DTPA) was added 2.89 g (4.39 mmol) of the title compound of Example 85b) and the mixture was made up to a total volume of 52 mL with 0.9% aqueous sodium chloride solution. The mixture was heated for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 200 mmol / l).

Example 86

a) 17β, 17β, 2H, 277-Perfluododecyl monoester of sulfuric acid, sodium salt g (17.73 mmol) 17β, 17β, 27β, 2β-perfluorododecanol was dissolved in 300 mL of chloroform and 2 ° C were added at 0 ° C 82 g (17.73 mmol) of sulfur trioxide pyridine complex. The mixture was stirred for 1 hour at 0 ° C and evaporated to dryness in vacuo. The residue was dissolved in 300 mL of ethanol and 17.8 mL of 1 N aqueous sodium hydroxide solution was added. The solution was evaporated to dryness and the residue was dried in vacuo (60 ° C, 2 hours). Yield: 11.81 g (quantitative).

Elemental analysis:

Calculated: C, 21.64; H, 0.61; F, 59.89; Na 3.45; S, 4.81

Found: C, 21.70; H, 0.72; F, 60.00; Na 3.57; S, 4.92

b) Production of a formulation from a metal complex VI and 17i, 17i, 27i, 27i260

-fluorododecyl monoester of sulfuric acid, sodium salt

To 38 ml of a solution of metal complex VI (290 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa ₃ DTPA) was added 4.90 g (7.35 mmol) of the title compound of Example 36a) and the mixture was heated in an ultrasonic bath for 10 minutes. The solution was cooled to room temperature, the mixture was filtered through a 0.2 µm filter, and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 290 mmol / l).

Example 87

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluoropentadecanoic acid, sodium salt g (16.07 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluoropentadecanoic acid was dissolved in 300 ml of ethanol and 16.1 mL of 1 N aqueous sodium hydroxide solution was added. The solution was evaporated to dryness under reduced pressure and the residue was dried in vacuo (60 ° C, 2 hours). Yield: 10.35 g (quantitative) of a colorless amorphous powder.

Elemental analysis:

Calculated: C 26.10; H, 0.94; F, 61.94; At 3.57

Found: C, 26.22; H, 1.00; F, 62.05; At 3.66

b) Preparation of the formulation from the title compound of Example 66 and 2H, 2tf, 4H, 4H, 5H, 5tf-3-oxaperfluoropentadecanoic acid, sodium salt

To 45 mL of the title compound of Example 66 (270 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa ₃ DTPA) was added 3.36 g (5, 21 mmol) of the title compound of Example 87a) dissolved in 200 ml of ethanol and heated at 50 ° C for 2 hours. The solution was evaporated to dryness and the residue was made up to a volume of 122 ml with distilled water. The mixture was stirred for 10 minutes at 40 ° C, filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 88

(a) N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluoridecyl) ethylenediamine-N, N-tetraacetic acid monoamide

To 30 g (117.1 mmol) of EDTA-bisanhydride suspended in 200 ml of dimethylformamide and 50 ml of pyridine at 50 ° C was added portionwise 10.14 g (20 mmol) of 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5t-3-oxaperfluorotridecylamine and the mixture was stirred at 50 ° C for 6 hours. 10 ml of water were added, the mixture was stirred for 10 minutes at 50 ° C and evaporated to dryness. The residue was dissolved in a small amount of water and adjusted to pH 4 with acetic acid. The insoluble precipitate was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: acetonitrile / water gradient). Yield: 9.58 g (61% of theory) of a colorless solid. Water content: 8%.

Elemental analysis:

Calculated: 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) N- (1H, 17H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluoridecyl) ethylenediamine-N, N-tetraacetic acid monoamide, calcium salt, sodium, salt

9.0 g (11.46 mmol) of the title compound of Example 88a) was suspended in 300 mL of water and 11.4 mL of 1 N sodium hydroxide solution was added. Then, 1.15 g (11.46 mmol) of calcium carbonate was added and the mixture was stirred for 5 hours at 50 ° C. The solution was filtered and the filtrate was evaporated to dryness. Yield: 9.7 g (quantitative) of a colorless amorphous solid. Water content: 7.5%.

262

Elemental analysis:

Calculated: 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 of metal complex I and N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) ethylenediamine-N, N-tetraacetic acid monoamide, calcium salt, sodium salt

To 43 ml of a solution of metal complex I (280 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa ₃ DTPA) was added 2.54 g (3.01 mmol) of the title compound of Example 88b) and the mixture was made up to a total volume of 121 mL with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 89

a) 1H, 1H, 2H, 2H-2H-perfluoroecyl- (2,2-dimethyl-5-hydroxy-1,3-dioxepan-6-yl) ether g (64.64 mmol) 1H, 1H, 2H, 2H- of perfluorodecanol was dissolved in 200 mL of tetrahydrofuran and 1.68 g (70 mmol) of sodium hydride was added at 0 ° C. The mixture was stirred for 2 hours at room temperature and then for 4 hours at 60 ° C. The solution was placed in a metal autoclave, then 9.31 g (64.64 mmol) of 2,2-dimethyl-1,3,6-trioxabicyclo [5.1.0] octane was added and the mixture was heated at 150 ° C for 10 hours. C. The reaction solution was poured into ice water and extracted twice with diethyl ether. The combined organic phases were evaporated to dryness and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / acetone 10: 1). Yield: 16.12 g (41% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 33.57; H, 2.82; F, 53.10

Found: C, 33.69; H, 2.90; F, 53.35

b) 17β, 17β, 27β, 27β-Perfluorodecyl (1-hydroxymethyl-2,3-dihydroxypropyl) ether g (24.66 mmol) of the title compound of Example 89a) was dissolved in 300 mL ethanol and 30 mL 10 was added. % aqueous hydrochloric acid solution. The mixture was heated to reflux for 5 hours. The pH was adjusted to 7 with sodium hydroxide, then evaporated to dryness and the residue purified by chromatography on silica gel RP-18 (mobile phase: acetonitrile / water gradient). Yield: 12.75 g (91% of theory) of a colorless solid. Water content: 4.5%.

Elemental analysis:

Calcd: 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 of WO 99/01161 (1,4,7-tris [1,4,7-tris (N-carboxylatomethyl) -10- (N1-methyl-3-aza) -2,5-dioxo-pentane-1,5-diyl) -1,4,7,10-tetraazacyclododecane, Gd complex] -10- [2- (N-ethyl-N-perfluorooctyl-sulfonyl) amino] acetyl-1,4, 7,10-tetraazacyclododecan) and 17,17,17,27,2,21-Perfluoroecyl- (1-hydroxymethyl-2,3-dihydroxypropyl) ether

To 37 ml of a solution of 1,4,7-tris [1,4,7-tris (N-carboxylatomethyl) -10- (N1-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) ) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / L)

CaNa3DTPA) was added 9.46 g (16.65 mmol) of the title compound of Example 89b) and the mixture was made up with 0.9% aq.

264 ml of sodium chloride solution to a total volume of 111 ml. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 90

a) 17H, 1H, 2H, 2H-Perfluoroecyl- [1,2-bis (2,2-dimethyl-1,3-dioxolan-4-yl) -2-hydroxyethyl] ether g (64.64 mmol) 1H 1 H, 2H, 2 H-perfluorodecanol was dissolved in 200 mL of tetrahydrofuran and 1.68 g (70 mmol) of sodium hydride was added at 0 ° C. The mixture was stirred for 2 hours at room temperature and then for 4 hours at 60 ° C. The solution was placed in a metal autoclave, 15.78 g (64.64 mmol) of 1,2-bis- (2,2-dimethyl-1,3-dioxolan-4-yl) oxirane was added and the reaction mixture was stirred for 10 hours heated to 150 ° C. The reaction mixture was poured into ice water and extracted twice with diethyl ether. The combined organic phases were evaporated to dryness in vacuo and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / acetone 10: 1). Yield: 14.2 g (31% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 37.30; H, 3.56; F, 45.59

Found: C, 37.48; H, 3.66; F, 45.71

b) 17β, 17β, 27β, 27β-Perfluoroecyl- [1,2-bis (1,2-dihydroxyethyl) -2-hydroxyethyl] ether g (19.76 mmol) of the title compound of Example 90a) was dissolved in 300 ml of ethanol and 30 ml of a 10% aqueous hydrochloric acid solution were added. The mixture was heated to boiling for 5 hours. The pH was adjusted to 7 with sodium hydroxide, the reaction mixture was evaporated to dryness and purified by chromatography on silica gel RP-18 (mobile phase: acetonitrile / water gradient). Yield: 10.55 g (85% of theory) of a colorless solid. Water content: 3.2%.

Elemental analysis:

Calculated: C 30.59; H, 2.73; F, 51.41

Found: C, 30.73; H, 2.81; F, 51.58

(c) Preparation of the formulation from metal complex II and ΙΕ, ΙΕ, 2E, 2E-perfluorodecyl [1,2-bis (1,2-dihydroxyethyl) -2-hydroxyethyl] ether

To 41 ml of a solution of metal complex II (300 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa; D? A) was added 11.98 g (19.07) mmol) of the title compound of Example 90b) and the mixture was made up to a total volume of 64 ml with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µπ filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 200 mmol / l).

Example 91

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 of Example 84a) was dissolved in 300 mL of chloroform, and 2.82 g (17.73 mmol) of pyridine-sulfur trioxide complex were added at 0 ° C. The mixture was stirred for 1 hour at 0 ° C and finally evaporated to dryness. The residue was dissolved in 300 mL of ethanol and 17.8 mL of 1 N aqueous sodium hydroxide solution was added. The solution was evaporated to dryness and the residue was dried in vacuo (60 ° C, 2 hours). Yield 266: 17.15 g (quantitative).

Elemental analysis:

Calculated: C 24.83; H, 2.50; F, 33.83; N, 1.45; S, 9.94; At 4.75

Found: C, 24.96; H, 2.62; F, 33.97; N, 1.53; S 10.05; At 4.86

b) Production of a formulation from metal complex I and perfluorooctylsulfonic acid-N, N-bis [(8-sulfuric acid-monoester, sodium salt) -3,6-dioxaoctyl] amide

To 43 ml of a solution of metal complex I (380 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa3DTPA) was added 142.29 g (147.06 mmol) of the compound in the title of Example 91a) and the mixture was made up to a total volume of 164 ml with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µπ filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 92

a) 2- (2H, 2H, 3H, 3H, 3H, 5H, 5H, 6H, 6H-1,4-dioxaperfluorotetradec-1-yl) succinic acid diethyl ester g (59.03 mmol) 1H, 1H, 2H, 2H, AH N, 5H, 5H-3-oxaperfluorotridecanol was dissolved in 300 ml tetrahydrofuran and 1.68 g (70 mmol) sodium hydride was added at 0 ° C. The mixture was stirred for 1 hour at 0 ° C and then for 5 hours at 40 ° C. To this solution was added dropwise a solution of 20.25 g (80 mmol) of 2-bromosuccinic acid diethyl ester at 40 ° C over 10 minutes, and the mixture was stirred at this temperature for 12 hours. 500 ml of ice water was added and the mixture was extracted twice with 300 ml of diethyl ether. The combined organic phases were evaporated to dryness under reduced pressure and the residue was purified by chromatography

267 on silica gel (mobile phase: n-hexane / ethanol 20: 1) · Yield: 12.05 g (30% of theory).

Elemental analysis:

Calculated: C 35.31; H, 3.11; F, 47.47

Found: C, 35.19; H, 3.20; F, 47.59

(b) 2- (25, 25, 35, 35, 55, 55, 65, 65-1,4-dioxaperfluorotetradec-1-yl) succinic acid, disodium salt

To 11.5 g (16.90 mmol) of the title compound of Example 92a) dissolved in 300 mL of methanol was added 50 mL of 3 N aqueous sodium hydroxide solution and the mixture was heated at reflux for 8 hours. The mixture was evaporated to dryness and the residue was dissolved in 300 ml of water. The aqueous phase was extracted twice with 300 ml of diethyl ether. The organic phase was acidified to pH 1 with hydrochloric acid and extracted twice with 300 ml of chloroform. The combined organic layers were dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in 300 mL of water and the pH was adjusted to 7.4 with 5% aqueous sodium hydroxide solution. Finally, the solution was lyophilized. Yield: 10.50 g (93% of theory) of a colorless amorphous solid. Water content: 5.7%.

Elemental analysis:

Calculated: C 28.76; H, 1.66; F, 48.33; At 6.88

Found: C, 28.88; H, 1.71; F, 48.25; At 6.95

c) Production of a formulation from metal complex II and 2- (25,25, 35, 35, 55, 55, 65, 65-1, 4-dioxaperfluorotetradec-1-yl) -succinic acid, disodium salt

To 57 ml of a solution of metal complex II (300 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa ₃ DTPA) was added 1.14 g (3.01 mmol) of the title compound of Example 92b) and the mixture was made up to a total volume of 154 ml with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 93

(a) 2H, 2H, 47I, 4H, 5H, 57'-3-oxa-perfluorotidecanoic acid N- (succin-2-yl) amide

To 20 g (38.30 mmol) of 27.1, 2H, 4H, 4H, 5H, 57β-3-oxaperfluorodecanoic acid and 9.21 g (80 mmol) of N-hydroxysuccinimide dissolved in 150 mL of dimethylformamide was added 16 ° C at 0 ° C. 51 g (80 mmol) of N, N'-dicyclohexylcarbodiimide and the mixture was stirred for 3 hours at this temperature. To this active ester solution was added a solution of 5.10 g (38.30 mmol) of L-aspartic acid in 300 mL of a 5% aqueous solution of sodium carbonate cooled to 0 ° C, and the mixture was stirred at 0 ° C for 2 hours. The solution was poured into 500 ml of ice water, the precipitated dicyclohexylurea was filtered off, and the pH of the solution was adjusted to 1 with concentrated hydrochloric acid. The mixture was extracted three times with 300 mL of chloroform. The combined organic phases were evaporated to dryness and the residue was purified by chromatography on silica gel RP-18 (mobile phase: acetonitrile / water gradient). The diacid thus obtained was dissolved in 400 ml of water and the pH was adjusted to 7.4 by addition of 1 N aqueous sodium hydroxide solution. The mixture was filtered and the filtrate was lyophilized. Water content: 6.3%. Yield: 21.13 g (81% of theory) of a colorless amorphous powder.

Elemental analysis:

Calculated: 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; At 6.83

269

b) Preparation of the formulation of the metal complex XIV and N- (succin-2-yl) amide 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluoridecanoic acid

To 37 mL of a solution of the metal complex XIV (300 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa ₃ DTPA) was added 422 mg (0.62 mmol) of the title compound. in the title of Example 93a) and the mixture was made up to a total volume of 111 ml with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 94

Preparation of the formulation from the title compound of Example 67 and perfluorooctane sulfonic acid, sodium salt

To 43 mL of a solution of the title compound of Example 67 (250 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa ₃ DTPA) was added 1.34 g (2 (69 mmol) of perfluorooctane sulfonic acid, sodium salt, dissolved in 200 ml of ethanol and stirred for 2 hours at 50 ° C. The solution was evaporated to dryness and the residue was made up to a total volume of 108 ml with distilled water. The mixture was heated to 40 ° C for 10 minutes, filtered through a 0.2 µm filter, and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 95

Preparation of the formulation from the title compound of Example 68 and perfluorodecanesulfonic acid, sodium salt

270

To a 49 mL solution of the title compound of Example 68 (310 mmol / l) in 0.45% aqueous sodium chloride solution was added 3.03 g (5.06 mmol) of perfluorodecanesulfonic acid, sodium salt, and the mixture was stirred for 10 min. was heated in a microwave oven. The solution was cooled to room temperature, filtered through a 0.2 µm filter, and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 310 mmol / l).

Example 96

a) (1 H, 1 H, 2 H, 2 H-Per Fluoroecyl) -5 - [(1,3-dicarboxy) phenyl] ether, disodium salt

To 20 g (80.62 mmol) of 5-hydroxyisophthalic acid trisodium salt in 300 mL of dimethylformamide was added 42.5 g (80.62 mmol) of the title compound of Example 14a) and the mixture was stirred for 10 hours at 60 ° C. The reaction mixture was poured into 1500 ml of ice water and the pH of the solution was adjusted to 1 with concentrated sulfuric acid. The mixture was extracted three times with 300 ml of chloroform. The combined organic phases were evaporated to dryness and the residue was purified by chromatography on silica gel RP-18 (mobile phase: acetonitrile / water gradient). The purified diacid was dissolved in 400 ml of water and the pH was adjusted to 7.4 by addition of 1 N sodium hydroxide solution. The mixture was filtered and the filtrate was lyophilized. Yield: 20.05 g (37% of theory) of a colorless amorphous solid. Water content: 5.0%.

Elemental analysis:

Calculated: C 32.16; H, 1.05; E 48.05; At 6.84

Found: C, 32.30; H, 1.15; F, 48.20; At 6.95

b) Preparation of the formulation from the title compound of Example 12 of WO 99/01161 (1,4,7-Tris [1,4,7-tris (N-carboxylatomethyl) -10- (N1-methyl-3-aza)) -2,5-dioxo-pentan-1,5-di271 yl) -1,4,7,10-tetraazacyclododecane, Gd complex] -10- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl- 1,4,7,10-tetraazacyclododecane) and (1H, 17H, 2H, 2H-perfluorodecyl) -5 - [(1,3-dicarboxy) phenyl] ether, disodium salt

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) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / L)

CaNa3DTPA) was added 6.86 g (10.2 mmol) of the title compound of Example 96a) and made up to a total of 153 mL with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 97

Production of a formulation of the metal complex and the acid XIV, 2 H, 2 H, 4 H _R 4H, 5H, 5H-3-oxaperfluórtridekánovej, sodium salt

To 4 ml of a solution of the metal complex XIV (320 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa ₃ DTPA) was added 434 mg (0.55 mmol) of the title compound. in the title of Example 80a) and the mixture was made up to a total volume of 12.8 ml with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

272

Example 98

(a) (Adamant-1-yl) -3-oxapropionic acid tert-butyl ester

To 15.22 g (100 mmol) of 1-adamantanol in 300 ml of 50% aqueous potassium hydroxide solution and 200 ml of toluene at 0 ° C was added 29.26 g (150 mmol) of tert-butyl bromoacetate and the mixture was was stirred vigorously for 2 hours. The reaction mixture was poured into 1500 ml of water and extracted twice with 300 ml of diethyl ether. The combined organic phases were dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / diethyl ether 20: 1). Yield: 21.58 g (81% of theory) of a colorless viscous oil.

Elemental analysis:

Calculated: C 72.14; H, 9.84

Found: C, 72.26; H, 9.95

b) (Adamant-1-yl) -3-oxapropionic acid (75 mmol) of the title compound of Example 98a) was dissolved in 200 mL of trifluoroacetic acid at 0 ° C and stirred for 8 hours at room temperature. The reaction mixture was evaporated to dryness and the residue was recrystallized from diisopropyl ether. Yield: 14.68 g (93% of theory) of colorless platelet-like crystals.

Elemental analysis:

Calculated: C 68.55; H, 8.63

Found: C, 68.41; H, 8.74

c) 1- (Perfluorooctylsulfonyl) -4 - [(adamant-1-yl) oxapropionyl] piperazine g (66.6 mmol) of the title compound of Example 98b) and 37.50 g (66.6 mmol) of 1- ( perfluorooctylsulfonyl) piperazine was dissolved in 300 mL of tetrahydrofuran and 32.15 g (130 mmol) of EEDQ (1,2-dihydro-2-ethoxyquinoline-1-carboxylic acid ethyl ester) was added at 0 ° C at 273 ° C. The mixture was stirred for 5 hours at room temperature. The solution was evaporated to dryness under reduced pressure and the residue was purified by silica gel chromatography (eluent: dichloromethane / diethyl ether 30: 1). Yield: 43.05 g (85% of theory) of a colorless solid.

Elemental analysis:

Calculated: 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 metal complex I and 0.5 parts clathrate β-cyclodextrin hydrate and 1- (perfluorooctylsulfonyl) -4 - [(adamant-1-yl) oxapropionyl] piperazine

To 32 mL of a solution of metal complex I (280 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNasDTPA) was added 6.81 g (8.96 mmol) of the title compound. in the title of Example 98c) and β-cyclodextrin hydrate and the mixture was made up to a total volume of 98 ml with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 99

a) 2H, 2tf, 4H, 47H, 5H, 5H-3-oxaperfluorotridecanoic acid N- (1-Adamantyl) amide

To 15.12 g (100 mmol) of 1-aminoadamantane, 52.21 g (100 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid is 11.51 g (100 mmol) of N -hydroxysuccinimide dissolved in 300 ml of tetrahydrofuran at 0 ° C was added 30, 95 g (150 mmol) of N, N'274

dicyclohexylcarbodiimide. The mixture was stirred for 2 hours at 0 ° C and then for 6 hours at room temperature. The resulting urea was filtered off, the filtrate was evaporated to dryness and the residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 30: 1). Yield: 54.4 g (83% of theory) of a waxy solid.

Elemental analysis:

Calculated: 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 metal complex II and 0.4 parts clathrate β-cyclodextrin hydrate and N- (1-adamantyl) amide 2H, 2H, AH, AH, 5H, 5fl-3-oxaperfluorotridecanoic acid

To 41 mL of a solution of metal complex II (250 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa ₃ DTPA) was added 4.48 g (6.83 mmol) of the title compound of Example 99a) and 7.87 g (6.83 mmol) of β-cyclodextrin monohydrate and the mixture was made up to a total volume of 103 ml with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 100

a) 2- [N-Ethyl-N- (perfluorooctylsulfonyl) amino] acetic acid N- (1-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. 30.95 g (150 mmol) of N, N'275 dicyclohexylcarbodiimide was added at 0 ° C. The mixture was stirred for 2 hours at 0 ° C and then for 6 hours at room temperature. The resulting urea was filtered off, the filtrate was evaporated to dryness and the residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 30: 1). Yield: 55.65 g (79% of theory) of an amorphous solid. .

Elemental analysis:

Calculated: 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 metal complex I and 0.4 parts clathrate of N- (1-adamantyl) amide β-cyclodextrin hydrate and 2- [N-ethyl-N- (perfluorooctylsulfonyl) amino] acetic acid

To 32 ml of a solution of metal complex I (280 mmol / l) in 0.45% aqueous sodium chloride solution (pH 7.4, 0.25 mg / l CaNa ₃ DTPA) was added 4.20 g (5.97 mmol) of the title compound of Example 100a) and 6.88 g (5.97 mmol) of β-cyclodextrin monohydrate and the mixture was made up to a total volume of 90 ml with 0.9% aqueous sodium chloride solution. The mixture was heated to 60 ° C in an ultrasonic bath for 2 hours. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2 N sodium hydroxide solution. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution can be directly used in biological experiments (gadolinium concentration approximately 100 mmol / l).

Example 101

a) 6-N- (Benzyloxycarbonyl) -2-N- (3,6,9,12-tetraoxatridecanoyl) -lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To 50 g (60.20 mmol) of the title compound of Example 1c) and 7.10 g (70 mmol) of triethylamine dissolved in 350 ml of dichloromethane at 0 ° C was added dropwise a solution of 16.85 g (70 mmol) 3, 6,9,12-tetraoxatridecanoyl chloride in 50 mL dichloromethane methane and stirred for 3 hours at 0 ° C. 200 ml of 5% aqueous hydrochloric acid solution were added and the mixture was stirred for 5 minutes at room temperature. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 15: 1). Yield: 30.94 g (92% of theory) of a colorless viscous oil.

Elemental analysis:

Calculated: C 40.63; H, 4.19; F, 31.21; N, 5.41; S, 3.10

Found: C, 40.75; H, 4.08; F, 31.29; N, 5.58; S, 3.25

b) 2-N- (3,6,9,12-Tetraoxatridecanoyl) -lysine- (1- (4-perfluorooctylsulfonyl) piperazine)

53.96 g (52.15 mmol) of the title compound of Example 101a) was dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) were added. The mixture was hydrogenated at room temperature. The catalyst was filtered off and the residue was evaporated to dryness under reduced pressure. Yield: 43.0 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 36.01; H, 4.14; F, 35.86; N, 6.22; S, 3.56

Found: C, 36.20; H, 4.23; F, 35.99; N, 6.38; S 3,71 cj 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraaza-cyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl- 5-yl)] - 2-N- (3 ', 6,9,12-tetraoxatridecanoyl) -lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd-complex

21.84 g (24.25 mmol) of the title compound of Example 101b), 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24 , 25 mmol) of gadolinium complex with 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl)] pentanoic acid] -1,4,7,10 -tetraazacyclododecane is replaced by

277 of mild heating dissolved in 200 mL of dimethylsulfoxide. 8.25 g (40 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was stirred overnight at room temperature. The reaction solution was poured into 3000 mL of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 28.21 g (81% of theory) of a colorless solid. Water content: 11.0%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 36.53; H, 4.33; F, 21.36; N, 8.34; S, 2.12; Gd 10.40

Found: C, 36.64; H, 4.48; F, 21.39; N, 8.29; S, 2.15; Gd 10.57

Example 102

a) 6-N- (Benzyloxycarbonyl) -2-N- (propyl-3-sulfonic acid) - lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To 50 g (60.20 mmol) of the title compound of Example 1c) and 7.10 g (70 mmol) of triethylamine dissolved in 250 mL of dry tetrahydrofuran at 50 ° C was added dropwise a solution of 7.33 g (60 mmol) of propanesulfon. in 50 ml of tetrahydrofuran and the mixture was stirred for 3 hours at 60 ° C. 200 ml of 5% aqueous hydrochloric acid solution were added and the mixture was stirred for 5 minutes at room temperature. The organic phase was separated, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 15: 1). Yield: 45.16 g (79% of theory) of a colorless viscous oil.

Elemental analysis:

Calculated: C 36.56; H, 3.49; F, 33.90; N, 5.88; S, 6.73

Found: C, 36.72; H, 3.35; F, 33.79; N, 5.78; S, 6.75

b) 2-N- (Propyl-3-sulfonic acid) -lysine- [1- (4-perfluorooctyl · sulfonyl) piperazine] amide

278

49.68 g (52.15 mmol) of the title compound of Example 102a) was dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) were added. The mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 42.69 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 30.81; H, 3.32; E, 39.46; N, 6.84; S, 7.83

Found: C, 30.64; H, 4.10; F, 39.29; N, 6.68; S, 7.89

c) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -2-N- (propyl-3-sulfonic acid) -lysine- [1- (4-perfluorooctylsulfonylpiperazine) amide, Gd complex

19.85 g (24.25 mmol) of the title compound of Example 102b), 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24 , 25 mmol) of gadolinium complex with 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl)] pentanoic acid] -1,4,7,10 -tetraazacyclododecane was dissolved in 200 ml of dimethylsulfoxide with slight heating. 8.25 g (40 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was then stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitate formed was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 28.13 g (81% of theory) of a colorless solid. Water content: 11.0%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 33.27; H, 3.70; F, 22.36; N, 8.73; S, 4.44; Gd 10.89

Found: C, 32.41; H, 3.88; F, 22.49; N, 8.69; S, 4.35; Gd 10.97

Example 103

a) 6-N- (Benzyloxycarbonyl) -2-N, N-bis (propyl-3-sulfonic acid279 na) -lyl- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To 50 g (60.20 mmol) of the title compound of Example 1c) and 12.14 g (120 mmol) of triethylamine dissolved in 250 mL of dry tetrahydrofuran at 50 ° C was added dropwise a solution of 14.65 g (120 mmol) 1. 3-propanesulphone in 100 ml of tetrahydrofuran and the mixture was stirred for 3 hours at 60 ° C. 400 ml of 5% aqueous hydrochloric acid solution were added, the mixture was stirred for 5 minutes at room temperature, sodium chloride was added, the separated organic phase was dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone 15: 1). Yield: 52.24 g (81% of theory) of a colorless viscous oil.

Elemental analysis:

Calculated: C 35.76; H, 3.66; F, 30.05; N, 5.21; S, 8.95

Found: C, 35.75; H, 3.55; F, 30.19; N, 5.08; S, 9.04

b) 2-N, N-Bis (propyl-3-sulfonic acid) -lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

53.74 g (52.15 mmol) of the title compound of Example 103a) was dissolved in 500 mL of ethanol and 6 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 49.06 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 30.64; H, 3.54; F, 34.33; N, 5.96; S 10.23 Found: C 30.69; H, 3.71; F, 34.19; N, 6.08; S 10.38

c) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -2-N, N-bis- (propyl-3-sulfonic acid) -lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex, disodium salt

280

38.76 g (24.25 mmol) of the title compound of Example 103b), 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24 , 25 mmol) of gadolinium complex with 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl)] pentanoic acid] -1,4, 7, 10 -tetraazacyclododecane was dissolved in 200 ml of dimethylsulfoxide with slight heating. 8.25 g (40 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 31.63 g (81% of theory) of a colorless solid. Water content: 11.0%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 32.07; H, 3.57; F, 20.06; N, 7.83; S, 5.97; Gd 9.76; Na 2.86

Found: C, 31.94; H, 3.48; F, 20.19; N, 7.69; S, 5.85; Gd 9.87;

At 2.99

Example 104

(a) N- (trifluoroacetyl) -L-glutamic acid 5-benzyl ester

100 g (421.5 mmol) of L-glutamic acid 5-benzyl ester were dissolved in a mixture of 1000 ml of trifluoroacetic acid ethyl ester and 500 ml of ethanol and stirred for 24 hours at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was recrystallized from diisopropyl ether. Yield: 140.47 g (96% of theory) of a colorless crystalline powder.

Elemental analysis:

Calculated: C 50.46; H, 4.23; F, 17.10; N, 4.20

Found: C, 51.35; H, 4.18; F, 17.03; N, 4.28

b) 2-N- (Trifluoroacetyl) -L-glutamic acid-5-benzyl ester-N-bis (2-hydroxyethyl) amide

281

To a solution of 24.9 g (24.08 mmol) of the title compound z

Example 104a), 2.53 g (24.08 mmol) of diethanolamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide in 150 ml of dimethylformamide were added at 0 ° C 8.25 g (40 mmol) of N, DCC. The mixture was stirred for 3 hours at 0 ° C and then overnight at room temperature. The precipitated urea precipitate was filtered off, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 9.11 g (90% of theory) of a viscous oil.

Elemental analysis:

Calculated: C 51.43; H, 5.51; F, 13.56; N, 6.66

Found: C, 51.22; H, 5.41; F, 13.40; N, 6.75

c) N- (Trifluoroacetyl) -L-glutamic acid-N, N-bis (2-hydroxyethyl) monoamide

21.92 g (52.15 mmol) of the title compound of Example 104b) was dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) were added. The mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. Yield: 43.0 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 40.01; H, 5.19; F, 17.26; N, 8.48

Found: C, 39.84; H, 5.13; F, 17.09; N 8, 68

c) N- (Trifluoroacetyl) -L-glutamic acid-N, N-bis (2-hydroxyethylamide-5- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To 10.96 g (33.2 mmol) of the title compound of Example 104a) and 18.87 g (33.2 mmol) of 1- (perfluorooctylsulfonyl) piperazine prepared according to patent application DE 196 03 033) in 80 ml of tetrahydrofuran are added. 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) were added at 0 ° C and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and purified by silica gel chromatography (eluent: dichloromethane / methanol 20: 1). Yield: 30.93 g (93% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 39.61; H 2, 89; F, 35.66; N, 6.19; S, 3.54

Found: C, 39.68; H, 2.74; F, 35.81; N, 6.13; S, 3.40

e) 5- [1- (4-Perfluorooctylsulfonyl) piperazine] -L-Glutamic acid-N, N-bis (2-hydroxyethyl) amide

To a solution of the amide of Example 104d) in 200 mL of ethanol at 0 ° C was added ammonia gas for 1 hour. The mixture was then stirred for 4 hours at 0 ° C. The mixture was evaporated to dryness under reduced pressure and the residue was stirred with water. The solid was filtered off and dried to dryness under vacuum (50 ° C). Yield: 26.55 g (97% of theory) of an amorphous solid.

Elemental analysis:

Calculated: C 41.12; H, 2.89; F, 35.66; N, 6.19; S, 3.54

Found: C, 41.15; H, 2.83; F, 35.78; N, 6.28; S, 3.71

f) N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -L -Glutamic acid-N, N-bis (2-hydroxyethyl) amide-5- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

211.96 g (24.25 mmol) of the title compound of Example 104e), 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24 , 25 mmol) of gadolinium complex with 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl)] pentanoic acid] -1,4,7,10 -tetraazacyclododecane was dissolved in 200 ml of dimethylsulfoxide with slight heating. 8.25 g (40 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was stirred overnight at room temperature.

283

The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 27.43 g (81% of theory) of a colorless solid. Water content: 11.0%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 34.41; H, 3.83; F, 23.13; N, 9.03; S, 2.30; Gd 11.26

Found: C, 34.34; H, 3.98; F, 23.29; N, 9.19; S, 2.15; Gd 11.07

Example 105

a) N- (Trifluoroacetyl) -L-glutamic acid-5-benzyl ester-N-dimethyl-bis (1,1-dihydroxymethyl) amide

To a solution of 8.03 g (24.08 mmol) of the title compound of Example 104a), 3.98 g (24.08 mmol) of dimethyl bis (1,1-dihydroxymethyl) amine and 2.77 g (24, N-hydroxysuccinimide (8.2 mmol) in DMF (150 ml) was added N, N'-dicyclohexylcarbodiimide (8.25 g, 40 mmol) at 0 ° C. The mixture was stirred for 3 hours at 0 ° C and then overnight at room temperature. The precipitated urea precipitate was filtered off with suction, the filtrate was evaporated to dryness in vacuo and the residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 110.53 g (91% of theory) of a viscous oil.

Elemental analysis:

Calculated: C 50.00; H, 5.66; F, 11.86; N, 7.18

Found: C, 50.17; H, 5.82; F 11.80; N, 7.15

b) N- (Trifluoroacetyl) -L-glutamic acid-5-benzyl ester- [1- (4-perfluorooctylsulfonyl) piperazine] amide

25.05 g (52.15 mmol) of the title compound of Example 105a) was dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) were added. The mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. Yield: 20.36 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 40.00; H, 5.42; F, 14.60; N, 7.18

Found: C, 40.10; H, 5.53; F, 14.69; N, 7.28

c) N- [Trifluoroacetyl] -L-glutamic acid-N, N-dimethyl-bis- (1,1-dihydroxymethyl) amide-5- [1- (4-perfluorooctylsulfonyl) -piperazine] amide

To 12.96 g (33.2 mmol) of the title compound of Example 105b) and 18.87 g (33.2 mmol) of 1- (perfluorooctylsulfonyl) piperazine prepared according to patent application DE 196 03 033 in 300 ml of tetrahydrofuran at 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) was added at 0 ° C and the mixture was stirred overnight at room temperature. The mixture was evaporated to dryness in vacuo and purified by chromatography on silica gel (mobile phase: dichloromethane / methanol 20: 1). Yield: 28.42 g (91% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 31.93; H, 3.00; F, 40.40; N, 5.96; S, 3.41

Found: C, 32.08; H, 2.94; F, 40.57; N, 5.88; S, 3.31

d) 5- [1- (4-Perfluorooctylsulfonyl) piperazine] amide L-Glutamic acid-N- [dimethyl-bis (1,1-dihydroxymezyl)] amide

To a solution of 28.41 g (30.2 mmol) of the title compound of Example 105c) in 200 mL of ethanol at 0 ° C was bubbled ammonia gas over 1 hour. The mixture was then stirred for 4 hours at 0 ° C. The mixture was evaporated to dryness under reduced pressure and the residue was stirred with water. The solid was filtered and dried under vacuum (50 ° C). Yield: 24.74 g (97% of theory) of an amorphous solid.

Elemental analysis:

Calculated: C 32.71; H, 3.46; F, 38.24; N, 6.63; S, 3.80

285

Found: C, 32.75; H, 3.33; F, 38.38; N, 6.68; S, 3.81

e) 2-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -L-glutamic acid-N- [dimethyl-bis (1,1-dihydroxymethyl) amide] -5- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd-complex

20.48 g (24.25 mmol) of the title compound of Example 105d), 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24 , 25 mmol) of gadolinium complex with 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl)] pentanoic acid] -1,4,7,10 -tetraazacyclododecane was dissolved in 200 ml of dimethylsulfoxide with slight heating. 8.25 g (40 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 29.05 g (83% of theory) of a colorless solid. Water content: 11.0%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 34.12; H, 3.91; F, 22.38; N, 8.73; S, 2.22; Gd 10.90

Found: C, 34.24; H, 3.98; F, 22.39; N, 8.69; S, 2.15; Gd 10.87

Example 106

a) N- (Trifluoromethylacetyl) -L-glutamic acid-5-benzyl ester- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To 11.06 g (33.2 mmol) of the title compound of Example 104a) and 18.87 g (33.2 mm.cl) of 1- (perfluorooctylsulfonyl) piperazine prepared according to patent application DE 196 03 033 in 80 ml tetrahydrofuran at 0 ° C was added 16.42 g (66.4 mmol) of EEDQ (ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol 20: 1). Yield: 27.28 g (93% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 35.35; H, 2.40; F, 43.01; N, 4.76; S, 3.63

Found: C, 35.48; H, 2.51; F, 42.87; N, 4.73; S, 3.50

b) N- (Trifluoroacetyl) -L-glutamic acid-5- [1- [4-perfluorooctylsulfonyl) piperazine] amide

21,92 g. (52.15 mmol) of the title compound of Example 106a) was dissolved in 500 mL of ethanol and 3 g of palladium catalyst (10% Pd / C) were added. The mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. Yield: 41.37 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 28.76; H, 1.91; F, 47.89; N, 5.30; S, 4.04

Found: C, 28.84; H, 2.03; F, 47.79; N, 5.28; S 4.19

c) N- (Trifluoroacetyl) -L-glutamic acid-N, N-bis (2-hydroxyethyl) amide 5- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 24.9 g (24.08 mmol) of the title compound of Example 106a), 2.53 g (24.08 mmol) of diethanolamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide in 150 mL of dimethylformamide 8.25 g (40 mmol) of N, N'-dicyclohexylcarbodiimide was added at 0 ° C. The mixture was stirred for 3 hours at 0 ° C and then overnight at room temperature. The precipitated urea was filtered off, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 9.11 g (90% of theory) of a viscous oil.

Elemental analysis:

Calculated: C 31.37; H, 2.75; F, 43.15; N, 6.36; S, 3.64

287

Found: C, 31.22; H, 2.61; F, 43.30; N, 6.25; S, 3.81

d) L-Glutamic acid-N, N-bis (2-hydroxyethyl) amide-5- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 26.61 g (30.22 mmol) of the title compound of Example 106c) in 200 mL of ethanol at 0 ° C was bubbled ammonia gas over 1 hour. The mixture was stirred for 4 hours at 0 ° C. The reaction mixture was evaporated to dryness under reduced pressure and the residue was stirred with water. The solid was filtered and dried under vacuum (50 ° C). Yield: 23.93 g (97% of theory) of an amorphous solid.

Elemental analysis:

Calculated: C 30.89; H, 3.09; F, 39.56; N, 6.86; S, 3.93

Found: C, 30.75; H, 3.13; F, 39.78; N, 6.75; S, 3.81

e) N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -L-glutamic acid -N, Nb is 5- (1- (4-perfluorooctylsulfonyl) piperazine) amide, Gd-complex (2-hydroxyethyl) amide

16.43 g (24.25 mmol) of the title compound of Example 106d), 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24 , 25 mmol) of gadolinium si complex, 4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl)] pentanoic acid] -1,4,7,10- tetraazacyclododecane was dissolved in 200 ml of dimethylsulfoxide with slight heating. 8.25 g (40 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was then stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 28.10 g (83% of theory) of a colorless solid. Water content: 11.0%.

Elemental analysis (calculated on the anhydrous substance):

288

Calculated: C 34.41; H, 3.83; F, 23.13; N, 9.03; S 2.30; Gd 11.26 Found: C 34.44; H, 4.98; F, 23.19; N, 8.89; S, 2.15; Gd 11.17

Example 107

a) N- (Trifluoroacetyl) -L-glutamic acid-5-benzyl ester- [1- (4-perfluorooctylsulfonyl) piperazine] amide ¹

To 11.06 g (33.2 mmol) of the title compound of Example 104a) and 18.87 g (33.2 mmol) of 1- (perfluorooctylsulfonyl) piperazine prepared according to patent application DE 196 03 033) in 80 ml of tetrahydrofuran are added. 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) was added at 0 ° C and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and purified by silica gel chromatography (eluent: dichloromethane / methanol 20: 1). Yield: 27.28 g (93% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 35.35; H, 2.40; F, 43.01; N, 4.76; S, 3.63

Found: C, 35.48; H, 2.54; F, 42.87; N, 4.73; S, 3.40

b) N- (Trifluoroacetyl) -L-glutamic acid-5- [1- [4-perfluorooctylsulfonyl) piperazine] amide

21.92 g (52.15 mmol) of the title compound of Example 107a) was dissolved in 500 ml of ethanol, and 3 g of a palladium catalyst (10% Pd / C) were added. The mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 41.37 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 28.76; H, 1.91; F, 47.89; N, 5.30; S, 4.04

Found: C, 28.84; H, 1.81; F, 47.79; N, 5.28; S, 4.16

Example 108

289

a) 6-N- (Benzyloxycarbonyl) -2-N- (2,3,4,5-pentahydroxyhexanoyl) -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 100.0 g (120.4 mmol) of the title compound of Example 21c) in 500 mL of dry tetrahydrofuran was added dropwise at 50 ° C a solution of 21.45 g (120.4 mmol) of 5-gluconolactone in

1 ml tetrahydrofuran. The mixture was stirred for 3 hours at 60 ° C and then overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 98.37 g (82% of theory) of a viscous oil.

Elemental analysis:

Calculated: C 38.10; H, 3.70; F, 32.02; N, 5.55; S, 3.18

Found: C, 38.22; H, 3.79; F, 32.02; N, 5.42; S, 3.29

b) 2-N- (2,3,4,5-Pentahydroxyhexanoyl) -L-lysine-1 - [(4-perfluorooctylsulfonyl) piperazine] amide

100.9 g (100.0 mmol) of the title compound of Example 108a) was dissolved in 2000 mL of ethanol and 10.0 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated for 12 hours at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. Yield: 87.46 g (quantitative) of a colorless solid.

Elemental analysis: '

Calculated: C 32.96; H, 3.57; N, 6.41; S, 3.67; F, 36.93

Found: C, 32.91; H, 3.72; N, 6.34; S, 3.50; F, 36.78

f) 6-N- [1,4,7-Tris (carboxylatomethyl)] -1,4,7,10-tetraazacyclododecane-10-Ν- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 2-N- [Ι-O-α-D-carbonylmethylmanopyranose] - L-lysine- [1- (4-perfluorooctyisulfonyl) piperazine] amide, Gd complex

50.0 g (54.55 mmol ·) of the title compound of Example 21e), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g

290 (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol) of gadolinium complex with 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methyl) (pent-5-yl) -1,4,7,10-tetraazacyclododecane was dissolved in 400 ml of dimethylsulfoxide with slight heating. 16.88 g (81.8 mol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitate formed was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 75.9 g (91.0% of theory) of a colorless solid. Water content: 8.6%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 35.34; H, 4.09; N, 8.24; S, 2.10; F, 21.12; Gd 10.28

Found: C, 35.28; H, 4.15; N, 8.19; S, 2.15; F, 21.03; Gd 10.14

Example 109

a) 6-N- (Benzyloxycarbonyl) -2-N- (2,3,4,5-pentahydroxyhexanoyl) -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 100.0 g (120.4 mmol) of the title compound of Example 21c) and 12.18 g (120.4 mmol) of triethylamine in 500 mL of dry tetrahydrofuran at 50 ° C was added a solution of 21.45 g ( 120.4 mol) of 5-gluconolactone in 50 ml of tetrahydrofuran. The mixture was stirred for 3 hours at 60 ° C and then overnight at room temperature. Then 400 ml of 5% aqueous hydrochloric acid solution was added and the mixture was stirred for 5 minutes at room temperature. Sodium chloride was added, the organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / ethanol 20: 1). Yield: 100.97 g (82% of theory) of a viscous oil.

Elemental analysis:

Calculated: C 37.58; H, 3.45; F, 31.58; N, 5.48; S, 3.14

Found: C, 37.72; H, 3.59; F, 31.72; N, 5.42; S, 3.29

291

b) 2-N- (2,3,4,5-Pentahydroxyhexanoyl) -L-lysine-1 - [(-4-fluoroctylsulfonyl) piperazine] amide

100.9 g (100.0 mmol) of the title compound of Example 108a) was dissolved in 2000 mL of ethanol and 10.0 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated for 12 hours at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 37.46 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 32.96; H, 3.57; N, 6.41; S, 3.67; F, 36.93

Found: C, 32.91; H, 3.72; N, 6.34; S, 3.50; F, 36.78

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

50.0 g (54.55 mmol) of the title compound of Example 21e), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol) gadolinium complex 1,4,4-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methylpent-5-yl) -1,4,7,10 -tetraazacyclododecane was dissolved in 400 ml of dimethylsulfoxide with slight heating. 16.88 g (81.8 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 75.9 g (91.0% of theory) of a colorless solid. Water content: 8.6%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 35.34; H, 4.09; N, 8.24; S, 2.10; F, 21.12; Gd 10.28

Found: C, 35.28; H, 4.15; N, 8.19; S, 2.15; F, 21.03; Gd 10.14

292

Example 110

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

To a solution of 100.0 g (120.4 mmol) of the title compound of Example 21c), 72.1 g (120.4 mmol) of 1-OaD-carboxymethyl- (2,3,4,6-tetra-O-). benzyl) glucopyranose and 13.86 g (120.4 mmol) of N-hydroxysuccinimide in 500 ml of dimethylformamide were added at 0 ° C 41.27 g (200.0 mmol) of N, N'-dicyclohexylcarbodiimide. The mixture was stirred for 3 hours at 0 ° C and then overnight at room temperature. The precipitate was filtered off, the filtrate was evaporated to dryness in vacuo and the residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 136.1 g (87% of theory) of a viscous oil.

Elemental analysis:

Calculated: C 57.32; H, 4.89; N, 4.31; F, 24.86; S, 2.47

Found: C, 57.48; H, 5.04; N, 4.20; F, 24.69; S, 2.38

b) 2-N- (1-O-α-D-Carbonylmethylglucopyranose) -L-lysine-1 - [(4-perfluorooctylsulfonyl) piperazine] amide

130.0 g (100.0 mmol) of the title compound of Example 110a) was dissolved in 2000 mL of ethanol and 10.0 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated for 12 hours at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. Yield: 91.7 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 34.07; H, 3.63; N, 6.11; S, 3.50; F, 35.24

Found: C, 33.92; H, 3.71; N, 6.02; S, 3.42; F, 35.33

c) 6-N- [1,4,7-Tris (carboxylatomethyl)] - 1,4,7,10-tetraazacyclo293 dodecan-10-Ν- (pentanoyl-3-aza-4-oxo-5-methyl-5) -yl)] - 2-N- [Ι-O-α-D-carbonylmethylglucopyranose] -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd-complex

50.0 g (54.55 mmol) of the title compound of Example 110b), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol) of gadolinium complex with 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methylpent-5-yl) -1,4,7, 10-tetraazacyclododecane was dissolved in 400 ml of dimethylsulfoxide with slight heating. 16.88 g (81.8 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 75.9 g (91.0% of theoretical) of a colorless solid. Water content: 8.6%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 35.34; H, 4.09; N, 8.24; S, 2.10; F, 21.12; Gd 10.28 Found: C 35.26; K 4.18; N, 8.14; S, 2.15; F, 21.01; Gd 10.13

Example 111

a) 6-N- (Benzyloxycarbonyl) -2-N- [1-O-α-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) galactopyranose] -L-lysine- [1- (4) -perfluorooczylsulfonyl) piperazine] amide ¹

To a solution of 50.0 g (60.2 mmol) of the title compound of Example 21c), 36.05 g (60.2 mmol) of 1-OaD-carboxymethyl- (2,3,4,6-tetra-O-). benzyl) galactopyranose and 6.93 g (60.2 mmol) of N-hydroxysuccinimide in 500 ml of dimethylformamide were added 20.64 g (100.0 mmol) of N, N'-dicyclohexylcarbodiimide at 0 ° C. The mixture was stirred for 3 hours at 0 ° C and then overnight at room temperature. The precipitate was filtered off, the filtrate was evaporated to dryness and purified by chromatography on

294 silica gel (mobile phase: dichloromethane / ethanol 20: 1). Yield: 68.1 g (87% of theory) of a very viscous oil.

Elemental analysis:

Calculated: C 57.32; H, 4.89; N, 4.31; F, 24.86; S, 2.47

Found: C, 57.47; H, 5.05; N, 4.19; F, 24.72; S, 2.29

b) 2-N- (1-O-α-D-Carbonylmethylgalactopyranose) -L-lysine-1 - [(4-perfluorooctylsulfonyl) piperazine] amide

65.0 g (50.0 mmol) of the title compound of Example 11a) were dissolved in 1000 ml of ethanol and 5.0 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated for 12 hours at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 45.85 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 34.07; H, 3.63; N, 6.11; S, 3.50; F, 35.24

Found: C, 33.93; H, 3.74; N, 6.01; S, 3.39; F, 35.05

c) 6-N- [1,4,7-Tris (carboxylatomethyl)] - 1,4,7,10-tetraazacyclododecane-10-Ν- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl) -2-N- (1-Oa-D-carbonylmethylgalactopyranose) -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd-complex

50.0 g (54.55 mmol) of the title compound of Example IIIb), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol) gadolinium complex with 1,4,7-tris (carboxylátomethyl-10- (carboxy-3-aza-4-oxo-5-methylpent-5-yl) -1,4,7,10-tetraazacyclododecane was dissolved in 400 ml of dimethylsulfoxide with gentle heating, and 16.88 g (81.8 mol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was stirred overnight at room temperature. and the mixture was stirred for 10 minutes, and the precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: gradient vo295 da / ethanol / acetonitrile) Yield: 37.95 g (91.0% · theoretical) ) colorless solid Water content: 8.6%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 35.34; H, 4.09; N, 8.24; S, 2.10; F, 21.12; Gd 10.28

Found: C, 35.22; H, 4.17; N, 8.18; S, 2.19; F, 20.91; Gd 10.12

Example 112

a) N- (Trifluoroacetyl) -L-glutamic acid monobenzyl ester

100 g (421.5 mmol) of N- (trifluoroacetyl) -L-glutamic acid monobenzyl ester were dissolved in a mixture of 1000 ml of ethyl trifluoroacetate and 500 ml of ethanol for 24 hours at room temperature.

The mixture was evaporated to dryness under reduced pressure and the residue was recrystallized from diisopropyl ether. Yield: 140.47 g of a colorless crystalline powder.

theoretical quantity)

Elemental analysis:

Calculated: C 50.46; H, 4.23; F, 17.10; N, 4.20

Found: C, 51.35; H, 4.18; F, 17.03; N, 4.28

b) 2-N- (Trifluoroacetyl) -L-glutamic acid monobenzyl ester-5-N-methyl-N- (2,3,4,5,6-pentahydroxyhexyl) amide

To a solution of 24.9 g (24.08 mmol ·) of the title compound of Example 112a), 2x g (24.08 mmol) of N-methylglucamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide in 150 mL of dimethylformamide was added at 0 ° C 8.25 g (40 mmol) of N, N'-dicyclohexylcarbodiimide. The mixture was stirred for 3 hours at 0 ° C and then overnight at room temperature. The precipitate was filtered off, the filtrate was evaporated to dryness in vacuo and the residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 9.1 g (89% of theory) of a viscous oil.

Elemental analysis:

296

Calculated: C 51.43; H, 5.51; F, 13.56; N, 6.66

Found: C, 51.22; H, 5.41; F, 13.40; N, 6.75

c) N- (trifluoroacetyl) -L-glutamic acid N-methyl-N- (2,3,4,5,6-pentahydroxyhexyl) amide

21.9 g (52.15 mmol) of the title compound of Example 112b) was dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) were added. The mixture was hydrogenated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 43.0 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 40.01; H, 5.19; F, 17.26; N, 8.48

Found: C, 39.84; H, 5.13; F, 17.09; N, 8.68

d) N- (Trifluoroacetyl) -L-glutamic acid-5- [N-methyl-N- (2,3,4,5,6-pentahydroxyhexyl)] - amide [1- (4-perfluorooctylsulfonyl) piperazine) amide

To 10.96 g (33.2 mmol) of the title compound of Example 112c) and 18.87 g (33.2 mmol) of 1- (perfluorooctylsulfonyl) piperazine prepared according to patent application DE 196 03 033 in 80 ml of tetrahydrofuran at 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) was added at 0 ° C and the mixture was stirred overnight at room temperature. The mixture was evaporated to dryness under reduced pressure and purified by silica gel chromatography (eluent: dichloromethane / methanol 20: 1). Yield: 28.67 g (92% of theory) of a colorless solid.

Elemental analysis:

Calculated: C 39.61; H, 2.89; F, 35.66; N, 6.19; S, 3.54

Found: C, 39.68; H, 2.74; F, 35.81; N, 6.13; S, 3.40

e) 1- (4-Perfluorooctylsulfonyl) piperazine] amide L-Glutamic acid-5- [N-methyl-N- (2,3,4,5, o-pentahydroxyhexyl)] amide

297

To a solution of 28.36 g (30.22 mmol) of the title compound of Example 112d) in 200 mL of ethanol at 0 ° C was bubbled ammonia gas over 1 hour. The mixture was then stirred for 4 hours at 0 C. C. The reaction mixture was evaporated to dryness and the residue was stirred with water. The solid was filtered and dried under vacuum (50 ° C). Yield: 24.19 g (95% of theory) of an amorphous solid.

Elemental analysis:

Calculated: C 41.12; H, 2.89; E 35.66; N, 6.19; S, 3.54

Found: C, 41.15; H, 2.83; F, 35.78; N, 6.28; S, 3.71

f) N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -L-glutamic acid-5- [N-methyl-N- (2,3,4,5,6-pentahydroxyhexyl)] -amide 5- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd-complex

20.43 g (24.25 mmol) of the title compound of Example 112e), 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24 , 25 mmol) of gadolinium complex with 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl)] pentanoic acid] -1,4,7,10 -tetraazacyclododecane was dissolved in 200 ml of dimethylsulfoxide with slight heating. 8.25 g (40 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel ŔP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 28.45 g (79% of theory) of a colorless solid. Water content: 11.0%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 34.41; H, 3.83; F, 23.13; N, 9.03; S, 2.30; Gd 11.26 Found: C 34.34; H, 3.98; F, 23.29; N, 9.19; S, 2.15; Gd 11.07

Example 113

298

a) 6-N- (Benzyloxycarbonyl) -2-N- [1-O-α-carbonylmethyl- (2,3,4-tri-O-benzyl) glucuronic acid benzyl ester] -L-lysine- [1- ( 4-perfluorooctylsulfonyl (-piperazine] amide

To a solution of 100.0 g (120.4 mmol) of the title compound of Example 21c), 73.77 g (120.4 mmol) of y-O-α-D-carboxymethyl- (2,3,4- tri-O-benzyl) glucuronic acid and 13.86 g (120.4 mmol) of N-hydroxysuccinimide in 500 ml of dimethylformamide were added at 0 ° C at 41.27 g (200.0 mmol) of N, N'-dicyclchexylcarbodiimide. The mixture was stirred for 3 hours at 0 ° C and then overnight at room temperature. The precipitated urea was filtered off, the filtrate was evaporated to dryness and purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 147.58 g (86% of theory) of a viscous oil.

Elemental analysis:

Calculated: C 52.25; H, 4.31; N, 3.93; F, 22.66; S, 2.45

Found: C, 52.38; H, 4.17; N, 4.12; F, 22.78; S, 2.39

b) 2-N- (1-O-α-D-Carbonylmethylglucuronic acid) -L-lysine-1 - [(4-perfluorooctylsulfonyl) piperazine] amide

142.52 g (100.0 mmol) of the title compound of Example 113a) was dissolved in 2000 mL of ethanol and 10.0 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated for 12 hours at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness. Yield: 93.06 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 33.56; H, 3.36; N, 6.02; S, 3.45; F, 34.71

Found: C, 33.31; H, 3.42; N, 6.04; S, 3.40; F, 35.51

c) 6-N- [1,4,7-Tris (carboxylatomethyl)] - 1,4,7,10-tetraazacyclododecane-10-Ν- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 2-N- [Ι-O-α-D-carbonylmethylglucuronic acid] -L-lysine- [1- (4-perfluoro299 octylsulfonyl) piperazine] amide, Gd-complex, sodium salt ·

50.76 g (54.55 mmol) of the title compound of Example 113b), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol) of gadolinium complex with 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methylpent-5-yl) -1,4,7 10-tetraazacyclododecane was dissolved in 400 ml of dimethylsulfoxide with slight heating. 16.88 g (81.8 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was then stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitate formed was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 75.14 g (84.0% of theory) of a colorless solid. Water content: 8.6%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 34.53; H, 3.80; N, 8.05; Na 1.47; S 2.05; F, 20.63;

Gd 10.05

Found: C, 34.38; H, 3.95; N, 8.19; Na 1.63; S, 2.15; E 20.83;

Gd 10.14

Example 114

a) 6-N- (Benzyloxycarbonyl) -2- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-L-lysine

To 31.82 g (113.5 mmol) of 6-N- (benzyloxycarbonyl) -L-lysine and 66.42 g (113.5 mmol) of 2- (N-ethyl-N-perfluorooctylsulfonyl) aminoacetic acid prepared according to the patent application DE 196 03 033 in 300 ml tetrahydrofuran at 0 ° C was added 49.46 g (200.0 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and the reaction mixture was stirred overnight at room temperature. The mixture was evaporated to dryness and purified by silica gel chromatography (eluent: dichloromethane / methanol 20: 1). Yield: 55.79 g (58% of theory) of a colorless solid.

300

Elemental analysis:

Calculated: C 36.85; H, 3.09; N, 4.96; E 38.11; S 3.78

Found: C, 36.85; H, 3.19; N, 4.87; F, 38.28; S, 3.95

b) 6-N- (Benzyloxycarbonyl) -2-N- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-L-lysine- [N-methyl-N- (2,3,4,5, 6-pentahydroxyhexyl)] -amide

To a solution of 51.02 g (60.2 mmol) of the title compound of Example 114a), 11.75 g (60.2 mmol) of N-methylglucamine and 6.83 g (60.2 mmol) of N-hydroxysuccinimide in 250 ml of dimethylformamide was added at 0 ° C 20.64 g (100.0 mmol) of N, N'-dicyclohexylcarbodiimide. The mixture was stirred for 3 hours at 0 ° C and then overnight at room temperature. The precipitated urea precipitate was filtered off, the filtrate was evaporated to dryness in vacuo and the residue was purified by silica gel chromatography (eluent: dichloromethane / ethanol 20: 1). Yield: 53.05 g (86% of theory) of a viscous oil.

Elemental analysis:

Calculated: C 38.68; H, 4.03; N, 5.47; F, 31.52; S, 3.13

Found: C, 38.49; H, 4.17; N, 5.32; F, 31.70; S, 3.29

c) 2-N- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-L-lysine- [N-methyl-N- (2,3,4,5,6-pentahydroxyhexyl)] amide

102.48 g (100.0 mmol) of the title compound of Example 114b) was dissolved in 2000 mL of ethanol and 10.0 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated for 12 hours at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. Yield: 89.06 g (quantitative) of a colorless solid.

Elemental analysis:

Calculated: C 33.72; H, 3.96; N, 6.29; S, 3.60; F, 36.26

Found: C, 33.91; H, 3.82; N, 6.14; S, 3.47; F, 36.31

d) 6-N- [1,4,7-Tris (carboxylatomethyl)] - 1,4,7,10-tetraazacyclo301 dodecane-10-Ν- (pentanoyl-3-aza-4-oxo-5-methyl-5) yl)] - 2-N- [2- (N-ethyl-N-perfluorooctylsulfonyl) -amino] -acetyl-L-lysine- [N-methyl-N- (2,3,4,5,6-pentahydroxyhexyl)] amide, Gd complex

48.58 g (54.55 mmol) of the title compound of Example 114c), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol) of gadolinium complex with 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methylpent-5-yl) -1,4,7, 10-Tetraazacyclododecane was dissolved in 400 ml of dimethylsulfoxide with slight heating and 16.88 g (81.8 mmol) of N, N'-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was stirred overnight at room temperature. The solution was poured into 3000 mL acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on silica gel RP-18 (mobile phase: water / ethanol / acetonitrile gradient). Yield: 73.27 g (89.4% of theory) of a colorless solid. Water content: 8.6%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 35.18; H, 4.23; N, 4.23; S, 2.13; 21 21.50; Gd 10.47

Found: C, 35.28; H, 4.15; N, 4.19; S, 2.18; F, 21.33; Gd 10.61

Example 115

NMR imaging of arteriosclerotic plaque following an intravenous dose of the metal complex of the invention

In rabbits with genetically induced arteriosclerosis (Watanabe rabbits), 5 to 60 minutes, as well as 24 hours and 48 hours after intravenous administration of a compound of the invention (25 μιηοΐ Gd per kg body weight), was observed to enhance arteriosclerotic plaque in Τι-weighted scans. gradient echo (TR: 11.1 ms, TE: 4.3 ms, α 15 ° tilt angle). Healthy vascular walls were characterized by either no or only weak absorption of the contrast agent, and thus were characterized by either no or weak signal increase in T1-weighted scanning. Due to the congestion between the signal-rich plaque and the signal-weak vascular wall, the diagnosis of arteriosclerotic changes in the vascular walls is possible.

The figure in Figure 1 shows MR aortic measurements 24 and 48 hours after application of metal complex XV (25 pmol gadolinium per kg body weight) in Watanabe rabbits (genetically induced arteriosclerosis). Measurement of Tl-weighted gradient echo (1.5 T, TR: 11.1 ms, TE: 4.3 ms, NA: 2, matrix: 213 x 256, layer thickness: 1.0 mm) shows a strong signal increase for arteriosclerotic plaque. Plaque localization, especially in the case of cardiac arch as well as in vascular defects, was confirmed with Sudan 3 dye.

Example 116

NMR imaging of arteriosclerotic plaque in rats following an intravenous dose of metal complex XV according to the invention, as well as correlation of post-mortem images with Sudan III dye

The figure in Figure 2 shows MR images of the aorta at 35 and 60 minutes and 24 hours after intravenous administration of the gadolinium XV metal complex (10 pmol gadolinium per kg body weight) for Watanabe rabbits (genetically induced arteriosclerosis). Measurement of Tl-weighted gradient echo (1.5 T, TR: 11.1 ms, TE: 4.3 ms, NA: 2, matrix: 213 x 256, layer thickness: 1.0 mm) is characterized by a strong signal increase in in the case of arteriosclerotic plaque. Plaque localization, especially in the case of cardiac arch as well as vascular defects, was confirmed with Sudan 3. Then MR imaging of preparations stored in agar was restored using the T1-weighted gradient echo sequence (MPRange, 1.5 T, TR: 11). , 1 ms, TE: 4.3 ms, tilt angle 15 °, NA: 2, matrix: 213 x 256, layer thickness: 1.0 mm), as well as spin echo sequence (1.5 T, TR: 400 ms, TE: 15 ms, NA: 16, matrix: 256 x 256; post-mortem images obtained). Here it manifested

303 excellent correlation of aortic sections with strong signal increase and plaque staining, since the compounds of the invention deposit in arteriosclerotic plaque.

Example 117:

Imaging myocardial infarction (MRT) following intravenous dose of metal complex XV in rats

The figure in Figure 3 shows MR imaging of the heart (in vivo and post mortem) 24 hours after intravenous administration of metal complex XV (100 pmol gadolinium per kg bodyweight) in rats with acutely induced cardiac infarction. Measurement of T1-weighted spin echo (1.5 T, TR: 400 ms, TE: 6 ms, NA: 4, matrix: 128 x 128, layer thickness: 2.5 mm) shows a strong signal increase in the infarct area. Successful induction of acute myocardial infarction was confirmed by NBT staining.

Metal complex XV, 100 pmol / kg i. v., T1-SE, TR / TE 400/6 ms, myocardial infarction

Example 118

Imaging myocardial infarction (MRT) following intravenous dose of metal complex I in rats

The figure in Figure 4 shows MR imaging of the heart (in vivo and post mortem) 24 hours after intravenous administration of metal complex I (100 pmol gadolinium per kg body weight) in rats with acutely induced heart attack. Measurement of T1-weighted spin echo (1.5 T, TR: 400 ms, TE: 6 ms, NA: 4, matrix: 128 x 128, layer thickness: 2.5 mm) shows a strong signal increase in the infarct area. Successful induction of acute myocardial infarction was confirmed by NBT staining.

Example 119

304

Imaging of lymph nodes (MRT) after intravenous dose of metal complex XV in rabbits carrying VX2-tumor

Figure 5 shows MR imaging of iliac lymph nodes prior to contrast agent administration up to 24 hours after intravenous administration of metal complex XV (200 gmol gadolinium per kg bodyweight) in i. Rabbits. m. implanted with VX2-tumor. Measurement of T1-weighted gradient echo (1.5 T, sequence: MPRange, TR 11.1 ms, TE 4.3 ms, tilt angle and 15 °) is characterized by a strong signal increase in healthy lymph nodes. Zones without signal increase within the lymph nodes were diagnosed as mecastases and confirmed histologic (H / E-staining of the lymph node sections). Surprisingly, signal reversal was observed at later times (24 hours) after contrast agent application. The signal increase in healthy lymph nodes was reduced, while in the case of metastasis, significant signal amplification is still visible.

Surprisingly, even immediately after application, a significant enhancement of the primary tumor (especially at the edges) can be observed. At later times (24 hours), this amplification also extends towards the tumor center.

Example 120

I

Tumor Imaging (MRT) following an intravenous dose of metal complex I in rabbits carrying a VX2-tumor.

Figure 6 shows MR imaging of lymph nodes as well as primary tumor (i. M. Implanted with VX2-tumor) before administration, 60 minutes to 20 hours after intravenous administration of metal complex I (100 pmol gadolinium per kg body weight) in rabbits. Measurement of T1-weighted gradient echo (1.5 T, sequence: MPRange, TR 11.1 ms, TE 4.3 ms, tilt angle and 15 °) is characterized by a strong signal increase in healthy lymphatic

305 nodules.

At an early post-administration time (60 minutes post-administration), a significant increase in the primary tumor (especially in the periphery) may be observed. At longer times (20 hours after administration), the signal increase also extends to the central areas of the tumor.

Particularly noteworthy is the enhancement of pathological structures (possibly secondary tumor or necrosis) on the contralateral side, which is only visible at later measurements ("late enhancement").

Metal complex X

Example 121

Imaging myocardial infarction (MRT) after intravenous dose of contrast agent in rats

The figure in Figure 7 shows MR measurement of the heart (in vivo and post mortem) 6 hours after application of the polar gadolinium chelate with perfluorinated side chain (metal complex X, 100 μπιοί gadolinium per kg body weight) in rats with acutely induced heart attack. Tl-weighted, ECG-triggered spin echo (1.5 T, TR (effective): 400 ms, TE: 12 ms, NA: 4, matrix: 128 x 128, layer thickness: 2.5 mm) is characterized by strong amplification Successful induction of acute myocardial infarction was demonstrated by NBT staining.

Example 122

Organ distribution (including lymph node enrichment) following intravenous dose of contrast agent in rats

Following intravenous administration of the polar gadolinium chelate with perfluorinated side chain (metal complex X, 100 μπιοί total gadolinium per kg bodyweight) in rats, ur306 or 24 hours after application, the metal content of the various organs and lymph nodes (divided as mesenterial and peripheral lymphatic) nodes) (MW, n = 2).

Table 1

body concentration % Benefits liver gadolinium [μπιοί / ΐ] 104 2.34 femur 3 0.01 kidney 150 0.65 Brain 1 0.01 skeleton 192 34.01 blood 1 0.01 stomach 49 0.18 Digestive tract 65 1.22 spleen 54 0.07 pancreas 6 0.02 Heart 3 0.01 lungs 18 0.05 muscles 1 0.00 mesenteric 19 0.01 lymph nodes Perí ferální 11 0.01 lymph nodes Overall . 38.58

Example 123

Imaging of lymph nodes (MRT) after intravenous dose of contrast agent in rats

The figure in Figure 8 shows NMR measurement of iliac lymph nodes before administration up to 60 minutes after intravenous administration of metal complex X (100 pmol gadolinium per kg body weight) in rats. Measurement of Tl-Weighted Grid Echo (1.5 T,

307 sequence: MPRange, TR 11.1 ms, TE 4.3 ms, tilt angle and 15 °) is characterized by a strong signal increase in healthy lymph nodes soon after injection. The increase at the time point of 15 minutes after application is 263% and at the time point of 60 minutes after application it is 254%.

Example 124

Imaging of lymph nodes (MRT) after intravenous dose of contrast agent in rabbits carrying VX2-tumor

The illustration in Figure 9 shows MR measurements of iliac lymph nodes before administration and up to 60 minutes after intravenous administration of metal complex X (200 pmol gadolinium per kg body weight) in rabbits with i. m. implanted with VX2-tumor. Measurement of T1-weighted gradient echo (1.5 T, sequence: MPRange, TR 11.1 ms, TE 4.3 ms, tilt angle and 15 °) is characterized by a strong signal increase in healthy lymph nodes. The amplification for healthy lymph nodes is 382% at the time point 15 minutes after application and 419% at the time point 60 minutes after application. Zones without signal amplification within the lymph nodes were diagnosed as metastases and confirmed histologic (H / E-staining of the lymph nodes). The signal intensity ratio for healthy lymph nodes to metastasis is 3.0 at a time point of 15 minutes to 3.4 at a time point of 60 minutes.

Surprisingly, immediately after administration, significant enhancement can be observed not only in the case of lymph nodes, but also in the case of a primary tumor (especially in the periphery) (15 minutes after application: intensity 277%). At later time points (up to 24 hours after dosing), this enhancement also extends towards the tumor center (24 hours after dosing: 217% intensity).

Metal complex V

Example 125

308

Imaging myocardial infarction (MRT) after intravenous dose of contrast agent in rats

The figure in Figure 10 shows MR imaging of the heart (in vivo and post mortem) 24 hours after intravenous administration of polar gadolinium chelate with perfluorinated side chain (metal complex V, 100 gmol gadolinium per kg body weight) in rats with induced heart attack. weighted, ECG-triggered spin echo (1.5 T, TR (effective): 400 ms, TE: 12 ms, NA: 4, matrix: 128 x 128, layer thickness: 2.5 mm) is characterized by strong signal amplification in Successful induction of acute myocardial infarction was demonstrated by NBT staining.

Example 126

Organ distribution (including lymph node enrichment) following intravenous dose of contrast agent in rats

Following intravenous administration of the polar gadolinium chelate with perfluorinated side chain (metal complex V, 200 pmol of total gadolinium per kg bodyweight) in rats, the metal content of the various organs and lymph nodes (divided into mesenterial and peripheral lymph nodes) was determined 24 hours after administration. (MW, n = 2).

309

Table 2

body concentration % Benefits liver gadolinium [pmol / l] 344 6, 34 Eemur ' 13 ¹ 0.05 kidney 436 1.77 Brain 4 0.02 skeleton 268 37,93 blood 15 0.18 stomach 28 0.08 Digestive tract 113 1.56 spleen 116 0, 17 pancreas 30 0, 05 Heart 14 0, 02 lungs 62 0, 17 muscles 9 0.02 mesenteric 70 0.05 lymph nodes peripheral 44 0.02 lymph nodes Overall 48,43

Example 127

Imaging of lymph nodes (MRT) after intravenous dose of contrast agent in rats

The illustration in Figure 11 shows MR imaging of iliac lymph nodes before administration and up to 60 minutes after intravenous administration of metal complex V (200 μπιοί gadolinium per kg bodyweight) in rats. Measurement of the T1-weighted gradient echo (1.5 T, sequence: MPRange, TR 11.1 ms, TE 4.3 ms, tilt angle and 15 °) is characterized by a strong signal increase in healthy lymph node tissue early in the injection. Increase over time

310 minutes after injection is 147% and at 60 minutes after injection 230%.

Example 128

Imaging of lymph nodes (MRT) after intravenous dose of contrast agent in rabbits carrying VX2-tumor

The figure in Figure 12 shows MR measurements of iliac lymph nodes before administration and up to 60 minutes after intravenous administration of metal complex V (200 μπιοί gadolinium per kg body weight) in i. Rabbits. m. implanted with VX2-tumor. Measurement of T1-weighted gradient echo (1.5 T, sequence: MPRange, TR 11.1 ms, TE 4.3 ms, tilt angle and 15 °) is characterized by a strong signal increase in healthy lymph nodes. The amplification for healthy lymph nodes is 246% at the time point 15 minutes after application and 282% at the time point 60 minutes after application. Zones without signal amplification within the lymph nodes were diagnosed as metastases and confirmed histologically (H / E-staining of the lymph nodes). The signal intensity ratio for healthy lymph nodes to metastasis is 2.5 at a time point of 15 minutes to 1.7 at a time point of 60 minutes.

Surprisingly, immediately after administration, significant enhancement can be observed not only in the case of lymph nodes, but also in the case of a primary tumor (especially in the periphery) (15 minutes after application: intensity 350%). At later time points (up to 24 hours after dosing), this amplification also extends towards the tumor center (24 hours after dosing: 106% intensity).

Metal complex XIV

Example 129

Imaging myocardial infarction (MRT) after intravenous dose of contrast agent in rats

311

Figure 13 shows MR imaging of the heart (in vivo and post mortem) 3 hours after intravenous administration of polar gadolinium chelate with perfluorinated side chain (metal complex XIV, 100 pmol gadolinium per kg body weight) in rats with induced heart attack. Tl-weighted, ECG-triggered spin echo (1.5 T, TR (effective): 400 ms, TE: 12 ms, NA: 4, matrix: 128 x 128, layer thickness: 2.5 mm) is characterized by strong amplification signal in the heart attack area. Successful induction of acute myocardial infarction was demonstrated by NBT staining.

Example 130

Organ distribution (including lymph node enrichment) following intravenous dose of contrast agent in rats

Following intravenous administration of a polar gadolinium chelate with perfluorinated side chain (XIV metal complex, 200 pmol of total gadolinium per kg bodyweight) in rats (Cop-Inzucht who were implanted with R3327 MAT-Lu prostate cancer 12 days prior to the experiment), minutes, 1 hour and 24 hours after application, the metal content of the various organs and lymph nodes (divided into mesenterial and peripheral lymph nodes) (mean +/- standard deviation, n = 3).

312

Table 3

metal complex XIV Gadolinium concentration [pmol / l] % Benefits 10 min p.i. 1 h p. i. 24 h p.i. 10 min p.i. 1 h p. i. 24 h p.i. liver 192 ± 12. 147 + 7 64 + 4 2, 62 + 0.11 2.04 + 0.150 0.96 + 0.05, spleen 200 ± 13 123 ± 10 69 ± 5 0.13 + 0.01 , 08 + 0.01 0.06 ± 0.00 pancreas 191 ± 14 139 of 26 25 + 1 0.35 ± 0.02 0.21 + 0.05 0.03 ± 0.01 kidney 761 ± 60 1181 of 232 338 ± 49 1.76 ± 0.14 2, 84 + 0.61 0.31 ± 0.09 lungs 603 + 30 415 ± 39 44 + 4 1.04 ± 0.02 0.80 + 0.06 0.09 + 0.01 Heart 320 i 8 190 + 15 19 + 0 0.32 + 0.01 0.19 + 0.01 0.02 ± 0.00 Brain 38 ± 6 22 + 2 4 ± 4 0.10 ± 0.03 0.06 + 0.00 0.01 + 0.01 Muscles '' * ^{** *** ****} 93 + 5 56 ± 3 8 + 1 0.06 + 0.02 0.04 + 0.00 0.00 + 0.00 tumor 246 + 25 266 of 87 56 ± 4 0.25 ± 0.05 0. 37 + 0.14 0.04 ± 0.01 femur 115 + 3 81 + 10 9 + 1 0.39 ± 0.02 0.28 + 0.03 0.03 + 0.00 Mesentery. 291 + 29 179 + 16 50 + 6 0.08 ± 0.01 0.05 ± 0.01 0.02 ± 0.00 lymphatic nodes Peripherals. 284 ± 19 254 + 14 51 ± 5 0.13 ± 0.00 0.14 ± 0.02 0.02 ± 0.00 lymphatic nodes stomach 244 ± 17 165 + 21 19 + 2 0.56 + 0.07 0.40 + 0.05 0.05 ± 0.00 (empty) intestine 242 + 15 201 + 32 36 + 5 1.55 + 0.09 1.16 + 0.22 0.26 ± 0.04 (empty) * Blood ' 957 + 38 575 + 56 22 + 1 26.73 ± 0.84 16, 13 ± 1.77 0.61 + 0.03 Rest' 419 i 27 392 + 25 42 + 0 70.71 + 2.74 64.27 ± 5.50 6, 31 ± 0.16 Urine 0-24 h - - 619 + 19 - - 79.86 ± 3.13 secretions - - 781 + 611 - - 6.00 ± 4.91 0-24 h Sum of all \ ch crgéncv ” 80.06 + 2.84 72.94 + 5.83 9.21 + 0.27 balance 95.07 ± 2.41

* Blood samples from the rest of the body ** 58 ml of blood per kg bodyweight *** Balance without blood data included in body rest data **** tissue aliquot only

313

Example 131

Imaging of lymph nodes (MRT) after intravenous dose of contrast agent in guinea pigs

The illustration in Figure 14 shows an example of MR measurement of iliac lymph nodes before and up to 24 hours after intravenous administration of metal complex XIV (200 pmol gadolinium per kg bodyweight) in guinea pigs with stimulated lymph nodes (Freund Adjuvant). Measurement of T1-weighted gradient echo (2.0 T, TR 10 ms, TE 5 ms, tilt angle and 40 °) is characterized by a strong signal increase in healthy lymph node tissue early in the injection. The gain reaches 127% at a time point of 60 minutes after application.

Example 132

Imaging of lymph nodes (MRT) after intravenous dose of contrast agent in rabbits carrying VX2-tumor

The illustration in Figure 15 shows MR measurements of iliac lymph nodes before administration and up to 23 hours after intravenous administration of metal complex XIV (200 pmol gadolinium per kg bodyweight) in i. Rabbits. m. implanted with VX2-tumor. Measurement of T1-weighted gradient echo (1.5 T, sequence: MPRange, TR 11.1 ms, TE 4.3 ms, tilt angle and 15 °) is characterized by a strong signal increase in healthy lymph nodes. The amplification in healthy lymph nodes is 297% at the time point 10 minutes after application and 269% at the time point 60 minutes after application. Zones without signal amplification within the lymph nodes were diagnosed as metastases and confirmed histologically (H / E-staining of the lymph nodes). The signal intensity ratio for healthy lymph nodes to metastasis is 5.1 at a time point of 10 minutes to 1.9 at a time point of 60 minutes.

Surprisingly, it can be observed immediately after application

314 significant increase not only in the case of lymph nodes, but also in the case of a primary tumor (especially in the periphery) (15 minutes after application: intensity 594%). At later time points (up to 24 hours after application), this amplification also extends towards the tumor center (120 minutes after application: 162% intensity).

Metal complex III

Example 133

Imaging myocardial infarction (MRT) after intravenous dose of contrast agent in rats

The figure in Figure 13 shows MR imaging of the heart (in vivo and post mortem) 22 hours after intravenous administration of polar gadolinium chelate with perfluorinated side chain (metal complex III, 100 pmol gadolinium per kg bodyweight) in rats with acutely induced heart attack. Tl-weighted, ECG-triggered spin echo (1.5 T, TR (effective): 400 ms, TE: 12 ms, NA: 4, matrix: 128 x 128, layer thickness: 2.5 mm) is characterized by strong amplification signal in the heart attack area. Successful induction of acute myocardial infarction was demonstrated by NBT staining.

Example 134

Organ distribution (including lymph node enrichment) following intravenous dose of contrast agent in rats

Following intravenous administration of a polar gadolinium chelate with perfluorinated side chain (metal complex III, 200 pmol of total gadolinium per kg body weight) in rats, the metal content of the various organs and lymph nodes (divided into mesenterial and peripheral lymph nodes) was determined 24 hours after administration. (MW, n = 2).

315

Table 4

body concentration % Batch liver gadolinia [μιηοΐ / ΐ] 1222 26, 28 Femur ¹ 76 0.32 kidney 489 1, 97 Brain 10 0.05 skeleton 242 36.30 blood 83 1, 15 stomach 165 0.57 Digestive tract 230 3.56 spleen 464 0.89 pancreas 203 0.48 Heart 82 0, 13 lungs 338 0, 96 muscles 28 0, 04 mesenteric 455 0, 33 lymph nodes peripheral 279 0, 18 lymph nodes Overall 73,20

Example 135

Imaging of lymph nodes (MRT) after intravenous dose of contrast agent in rats

The illustration in Figure 17 shows an example of MR measurement of iliac lymph nodes before and up to 60 minutes after intravenous administration of metal complex III (200 μιηοΐ gadolinium per kg bodyweight) in rats. Measurement of T1-weighted Grid Echo (1.5 T, sequence: MPRange, TR 11.1 ms, TE 4.3 ms, tilt angle and 15 °) is characterized by a strong signal increase in healthy lymphatic tissue tissues very soon after

316 injection. The gain is 320% at the time point · 15 minutes after application and 401% at the time point 60 minutes after application.

Example 136

Imaging of lymph nodes (MRT) after intravenous dose of contrast agent in rabbits carrying VX2-tumor

The illustration in Figure 18 shows MR measurements of iliac lymph nodes before and up to 60 minutes after intravenous administration of metal complex III (200 gmol gadolinium per kg body weight) in i. Rabbits. m. implanted with VX2-tumor. Measurement of T1-weighted gradient echo (1.5 T, sequence: MPRange, TR 11.1 ms, TE 4.3 ms, tilt angle and 15 °) is characterized by a strong signal increase in healthy lymph node tissue. The amplification for healthy lymph nodes is 195% at the time point 15 minutes after application and 233% at the time point 60 minutes after application. Zones without signal amplification within the lymph nodes were diagnosed as metastases and confirmed histologically (H / E-staining of the lymph nodes). The signal intensity ratio for healthy lymph nodes to metastasis is 1.9 at the 15 minute time point and 1.8 at the 60 minute time point.

Surprisingly, immediately after administration, significant enhancement can be observed not only in the case of lymph nodes, but also in the case of a primary tumor (especially in the periphery) (15 minutes after application: intensity 232%).

Claims (50)

Use of metal complexes containing perfluoroalkyl residues whose critical micellar concentration is less than 10 ^-3 mol / l, the hydrodynamic micellar diameter (2 Rh) is greater than 1 nm and the proton relaxivity in plasma (R ¹ ) is greater than 10 1 / mmol.s for the preparation of contrast agents for MR imaging for plaque imaging. Use according to claim 1, for the preparation of contrast agents for MR imaging for imaging lymph nodes. Use according to claims 1 or 2, for the preparation of contrast agents for MR imaging for imaging of infarcted and necrotic tissues. Use according to claims 1 to 3, for the preparation of contrast agents for MR imaging for independent imaging of necroses and tumors. 5. The method of claim 1, wherein the metal complexes have a critical micelle concentration less than IO ^"4 mol / 1st Use according to claim 1, wherein the metal complexes have a hydrodynamic micellar diameter> 3 nm, preferably> 4 nm. I The use according to claim 1, wherein the metal complexes have a proton relaxivity in plasma of greater than 13 L / mmol, preferably greater than 15 L / mmol. Use according to claims 1 to 7, wherein the metal complexes containing perfluoroalkyl radicals are compounds of the general formula I 318 is a perfluorinated straight or branched hydrocarbon ^Rf -LK (wherein H chain of the formula -C _n F _2n E, where E is a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n is an integer from 4 to 30, L is a direct bond, methylene, -NHCO-, a group N-SO ₂ - q wherein p is an integer from 0 to 10, q and u are independently integers of 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 ₁₈ chain, which is optionally interrupted by 1 to 3 oxygen atoms, 1 to 2 -CO- groups, or is optionally substituted with aryl and / or is substituted with 1 to 4 hydroxy, 1 to 2 alkoxy of 1 to 4 carbon atoms, 1 to 2 carboxyl groups, -SO 3 H. or a straight, saturated or unsaturated C ₂ -C 3 _O- hydrocarbon chain optionally containing 1 to 10 oxygen atoms, 1 to 3 -NR ³ -, 1 to 2 sulfur atoms, piperazine, -CON ³ -, - NR ^and CO-, -SO 2 -, -NR ^and -CO 2 -, 1 to 2 -CO-, -CO-NTN (R ^a ) -SO 2 -R ^F, or 1 to 2 optionally substituted aryl groups, and / or is interrupted by these groups, and / or is optionally substituted by 1 to 3 -OR ^a , 1 to 2 oxo, 1 to 2 -NHCOR ³ , 1 to 2 -CONHR ", 1 to 2 - (CH 2) groups _p -CO ₂ H, 1-2 groups - (CH ₂ ) _p - (O) _q -CH ₂ CH ₂ -R ^F , 319 where R ^a, R ^£ p and q are as defined above, and T is a C ₂ -C 10 chain, optionally interrupted by 1 to 2 oxygen atoms or 1 to 2 -NHCO- groups. is a complexing agent or a metal complex or salts thereof with organic and / or inorganic bases or amino acids or amino acid amides, wherein the complexing agent or complex has the general formula II COB (II) wherein R ^c , R ¹ and B are independently of each other: R ^c has the meaning of R ^a or is - (CH ₂ ) _m -LR ^F where m is 0, 1 or 2 and L and R ^F are as defined above, R ¹ is, independently of one another, a hydrogen atom or a metal ion equivalent having an atomic number of 22 to 29, 42 to 46 or 58 to 70, B is -OR ¹ or ^ CH, CH-LR ^F A \ p - <or "N N-SO ₂ -LR ^F R ^c '' wherein R ¹ , L, R ^F and R ^c are as defined above, or a complexing agent or complex of formula III 320 wherein R ^c and R ¹ are as defined above and R ^b is R ^a , or a complexing agent or complex of formula IV as ₂ r ¹ wherein R ¹ is as defined above, or a complexing agent or complex of formula V wherein R ¹ has the above meaning, o and q are 0 or 1 and the sum of o + q = 1, 321 and a complexing agent or complex of general formula VI R ¹ ₂ C ^ o \ / - \ / ^ CO ₂ R ^1, wherein R vr ¹ is as defined above, or a complexing agent or complex of general formula VII R ¹ OC - ^ \ / \ / ~ CCLR ^{1 2} , n to 'NN CO ₂ R ¹ CO B (VII) wherein R ¹ and B are as defined above, or a complexing agent or complex of formula VIII CH3CH3 (Vin; where R ^c and R ¹ are as defined above and R ^b is as defined above for R ^a , 322 or a complexing agent or complex of formula IX (TX) wherein R ^c and R ¹ are as defined above, or a complexing agent or a complex of the general formula X r'o, C 1 R ³ CO 2 R ² N N. ² OH CO _Z R (X) wherein R ^c and R ¹ are as defined above, or a complexing agent or complex of the general formula XI R ¹ o _z c - / - co ₂ r ¹ N CO ₂ R '[NH-CH 3 -CH 2 -CO] q N N. xi) wherein R ¹ , p and Q are as defined above and R ^b is as defined in R ^a , or 323 complexing agent or complex of formula XII // (XII) wherein L, R ^F and R ¹ are as defined above, or a complexing agent or complex of formula XIII (XIII) wherein R ¹ is as previously defined. 9. The method of claim 8, wherein the use of the formula I in which L is α-ΟΗ ₂ -β, _α-2 ΟΗ -ΟΗ ₂ -β, α- (0Η _{2) 3} -β, wherein p is 3 to 15 , α-ΟΗ ₂ -Ο-ΟΗ ₂ -ΟΗ ₂ -β, α-CH ₂ - (O-CH ₂ -CH ₂ -) t-β, where t is 2 to 6, α-ΟΗ ₂ -ΝΗ-ΟΟ -β, α-CH ₂ -NH-CO-CH ₂ -N (CH ₂ COOH) -εθ ₂ -β, compounds 324 α-CH ₂ -NH-CO-CH ₂ -N (C ₂ H ₅ ) -SO ₂ -P, α-CH ₂ -NH-CO-CH ₂ -N (C ₁₀ H ₂ ) -εθ ₂ - β, α-CH ₂ -NH-CO-CH ₂ -N (C ₆ H ₁₃ ) -SO 2 -β, c-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 -p, α-CH ₂ -NH-CO-CH ₂ -N (-CH ₂ - CH ₂ OH) ₂ -β -3Ο, Ct-CH ₂ -NH-CO- (CH ₂ ) ₁₀ -ε-ΟΗ ₂ ΟΗ ₂ -β, α-CH ₂ -NH-CO-CH ₂ -O-CH ₂ CH ₂ ^, α-CH ₂ - NH-CO- _{(CH2) ι-0} -Ο ΟΗ ₂ <3Η -β _2, and -CH ₂ -C ₆ H ₄ -O-CH ₂ -CH ₂ -p, and -CH ₂ -O-CH ₂ -C (CH ₂ -OCH ₂ CH _{2 -S} F ₁₃ ) ₂ -CH ₂ -O-CH ₂ CH ₂ -p, α-CH ₂ -NH-CO-CH ₂ -CH ₂ -CON-CH ₂ - CH ₂ -NHCOCH ₂ -N (C ₂ H ₅ ) SO ₂ C ₈ F ₁₇ I CH ₂ -CH ₂ -NH-CO-CH ₂ -N (C ₂ H 5) -SO 2 -β, α-CH ₂ -O-CH ₂ -CH (OCi ₀ H ₂₁ ) -CH ₂ -O-CH ₂ CH ₂ , α- (CH ₂ -NHCO) ₄ -ch ₂ o-ch ₂ ch ₂ -P, α- (CH ₂ -NHCO) ₃ -ch ₂ o-ch ₂ ch ₂ -, α-CH ₂ -OCH ₂ C (CH ₂ OH) ₂ -CH ₂ -O-CH ₂ CH ₂ -? COOH α-CH ₂ -NH-CO-CH ₂ -N (C ₆ H ₅ ) -SO ₂ -β, α-ΝΗ-ΟΟ-ΟΗ ₂ ΟΗ ₂ -β, α-NH-CO-CH ₂ -O-CH _2- CH _{2 -} , 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 ) -δθ ₂ -β, and _-NH-CO-CH2-N (C10H21) -ΞΟζ-β, and -NH-CO-CH ₂ -N (C ₆ H _{13) 2} -β -δθ, and-NH-CO- ( _{CH2) 1o} N (C ₂ H ₅₎ -SO ₂ -p, and -NH-CO-CH ₂ -N (CH ₂ C ₆ H ₅₎ -SO-β, and -NH-CO-CH ₂ N _{(CH2 CH2} OH) ₂ -β -3Ο, 325 ct-NH-CO-CH ₂ -P, α-CH 2 -OC ₆ H ₄ -O-CH ₂ -CH ₂ -p, α-CH ₂ -C ₆ H ₄ -O-CH ₂ -CH ₂ -, α -N (C ₂ H ₅₎ -SO ₂ -p, N _(C H ₅₎ -SO β, N ₍₂ CioH i) -3Ο -β _2, and N (C ₆ H ₁₃₎ -SO ₂ -p , aN (C ₂ H ₄ OH) -ΞΟ ₂ -β, aN (CH 2 COOH) -3 Ο ₂ -β, aN (ch ₂ c ₆ h ₅ ) -so ₂ -p, aN [CH (CH ₂ OH) ₂ ] -3Ο ₂ -β, aN [CH (CH ₂ OH) CH (CH ₂ OH)] -SO ₂ -p, and wherein a is the point of attachment to the complexing agent or the metal complex K and β is the point of attachment to the fluorine moiety. Use according to claims 8 or 9, wherein compounds of formula I are used, wherein n in the formula -C _n E _2n E is an integer of 4 to 15 and / or E in this formula denotes a fluorine atom. Use according to claims 8 to 10, wherein the following compounds are used: gadolinium complex with 10- [1-methyl-2-oxo-3-aza-5-oxo- (4-perfluorooctylsulfonylpiperazin-1-yl) pentyl] -1,4,7-tris (carboxymethyl) -1,4,7 , 10-tetraazacyclododecane, gadolinium complex with 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-heptadecafluoroheptadecyl-1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane, gadolinium complex with 10- [2-hydroxy-4-aza-5,9- dioxo-9- (4-perfluóroktylpiperazin-yl) nonyl] -1,4,7-tris (carboxymethyl) -1,4,7,10326 -tetraazacyclododecane, gadolinium complex with 10- [2-hydroxy-4-aza-5-oxo-7-aza-7- (perfluorooctylsulfonyl) nonyl] -1,4,7-tris (carboxymethyl) -1,4,7, 10-tetraazacyclododecane, gadolinium complex with 10- (2-hydroxy-4-oxa-1 H, 2H, 3H, 3H, 5H, 5H, -) 6H, 6H-perfluorotetradecyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane, gadolinium complex with 10- [2-hydroxy-4-aza-5-oxo-7-oxa- 10,10, II, 11,12,12,13,13,14,14,15,15,16,16, 17,17,18,18,19,19-henosafluoronadecyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane, gadolinium complex with 10- [2-hydroxy-4-aza-5-oxo-11-aza-11- (perfluorooctylsulfonyl) tridecyl] -1,4,7- tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane, gadolinium complex with 10- [2-hydroxy-4-aza-5-oxo-7-aza-7- (perfluorooctylsulfonyl) -8-phenyloctyl] -1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane. Use according to claims 1 to 7, wherein the metal complexes containing perfluoroalkyl radicals are compounds of the general formula Ia AR ¹ (la) where A is a molecular moiety containing 2 to 6 metal complexes attached directly or via a linker to a nitrogen atom attached to the ring-forming backbone, and ^{R f} is a perfluorinated straight or branched chain hydrocarbon of the formula C _n P n E _2, 327 wherein E is a terminal fluorine atom, a chlorine atom, a bromine atom, an iodine atom or a hydrogen atom, and n is an integer from 4 to 30, wherein the molecular moiety A has the following structure: V i K-V-N N-D-X- I K where q ¹ is an integer of 0, 1, 2 or 3, K is a complexing agent or a metal complex or a salt thereof with an organic and / or inorganic base or an amino acid or amino acid amide, X is a direct bond to a perfluoroalkyl, phenyl or C 1 -C 10 alkylene chain optionally containing 1 to 15 oxygen atoms, 1 to 5 sulfur atoms, 1 to 10 -CO-, 1 to 10 -NR ^d groups -, 1 to 2 -NR ^d SO ₂ -, 1 to 10 -CONR ^d -, 1 piperidine, 1 to 3 -SO 2 -, 1 to 2 phenylene, or substituted with 1 to 3 R ^F , wherein: R ^d is a hydrogen atom, a phenyl group, a benzyl group or an alkyl group having 1 to 15 carbon atoms, which optionally contains 1 to 2 -NHCO-, 1 to 2 -CO-, 1 to 5 oxygen atoms and is optionally substituted with 1 up to 5 hydroxy groups, 1 to 5 methoxy groups, 1 to 3 carboxyl groups, 1 to 3 R ^F radicals, V is a direct bond or a chain of formula IIa or Hla: 328 R ^e (Ha) RN- (CH ₂ ) _k -W - (CH ₂ ) -C - (Hla) wherein R ^e is a hydrogen atom, a phenyl group, a benzyl group or an alkyl group having 1 to 7 carbon atoms, optionally substituted by a carboxyl group, a methoxy group or a hydroxy group, W is a direct bond, a polyglycol ether group with up to 5 glycol units, or a molecular moiety of formula IVa -CH (R ^h ) - (IVa) wherein R ^h is a carboxylic acid having 1 to 7 carbon atoms, a phenyl group, a benzyl group or a group - (CHzh-s-NH-K, 'a is the point of attachment to the nitrogen atom of the backbone, β is the point of attachment to the complexing agent or metal complex K, and variables where the natural numbers are between 0 and 10 and 1 is 0 or 1, and where 329 D is -CO- or -SO ₂ -. The use according to claim 12, wherein compounds of formula Ia wherein q is 1 are used. Use according to claim 12, wherein: use compounds of formula Ia wherein the molecular part X of the alkyl chain contains 1 to 10 -CH ₂ CH ₂ O- or 1 to 5 -COCH ₂ NH- groups, a direct bond or one of the following structures: ^ 6 ^ 11 Y- (CH ₂ ) ₁₀ -O- (CH ₂ ) ₂ - _{? Y} -CH ₂ -N-SO-δ, Y-CK-N-SO, -δ CH, \\ 7 where γ is the point of attachment to D, and δ is the point of attachment to R ^F. Use according to claim 12, wherein compounds of the formula Ia are used, wherein V is a molecular moiety with one of the following structures 330 0 about II II CL-C-CH ₂ -NH-3, alpha Ό- (3- ₂ -Ν-β CH ₂ COOH 0 NH-β, II α-C - <3 H-NH-β ch ₃ CH _{(CH3) 2} O COOH CI-LCOOH ii 1 H 1 'C-CH ₂ -CH-NH-β, α-Ο-ΟΗ ₂ -ΟΗ-ΝΗ-β 0 II a-ΟγΗ-ΝΗ-β (CH ₂ ) ₄ -NH-K The use according to claim 12, wherein the compounds of formula Ia are used, wherein K is a complex of formula Va, Via, Fairy or VIIIa. DB-U-T (Va) U-T- (Via) —COOR ⁴ N COOR ⁴ '—COOR ⁴ ( ^Vlla ) R OOCR OOC - ^{/ - 7-0} N N II - COOR ^{4 -} COOR ⁴ (VIIIa) where R ¹ is independently from each other a hydrogen atom or an equivalent of a metal ion having an atomic number of 23 to 29, 42 to 46 or 58 to 70, R ⁸ is a hydrogen atom or a straight, branched, saturated or unsaturated C 1 -C 6 -alkyl chain optionally substituted by 1 to 5 hydroxy, 1 to 3 carboxyl or 1 phenyl groups and / or interrupted by 1 to 10 oxygen atoms, 1 phenylene or 1 phenyloxy, R ⁶ is a hydrogen atom, a straight or branched alkyl radical having 1 to 7 carbon atoms, a phenyl radical or a benzyl radical, R ⁷ is a hydrogen atom, a methyl group or an ethyl group optionally substituted by a hydroxy or carboxyl group, U ³ is a straight or branched, saturated or unsaturated Ci-C ₂ o ^_ -alkylene group optionally containing 1-5 imino, 1-3 phenylene, 1-3 fenylénoxyskupín, fenyléniminoskupín 1-3, 1-5 amide groups, 1 to 2 hydrazido groups, 1 to 5 carbonyl groups, 1 to 5 ethyleneoxy332 groups, 1 urea group, 1 thiourea group, 1 to 2 carboxyalkalimino groups, 1 to 2 ester groups, 1 to 10 oxygen atoms, 1 to 5 sulfur atoms and / or 1 to 5 nitrogen atoms, and / or optionally substituted by 1 to 5 hydroxy groups, 1 to 2 mercapto groups, 1 to 5 oxo groups, 1 to 5 thioxo groups, 1 to 3 carboxyl groups, 1 to 5 carboxyalkyl groups, 1 to 5 ester groups and / or 1 to 3 amino groups, wherein optionally present phenyl groups may be substituted by 1 to 2 carboxyl groups, 1 to 2 sulfo groups or 1 to 2 hydroxy groups, T ¹ is -CO-β, -NHCO-β, or -NHCS-β, where β is the point of attachment to V. 17. The method of claim 16, wherein the C 1 -C 20 ^- alkylene chain in U ³ contains the groups -CH ₂ NHCO-, -NHCOCH ₂ O-, -NHCOCHaOCgH ,, -, -N (CH ₂ CO ₂ H) -, -CH _{2 OCH2} -, -NHC ₂ C ₆ h ₄ -, -nhcsnhc ₆ h ₄ -, -CH ₂ oC ₆ h '-, -CH ₂ CH ₂ O-, and / or is substituted by -COOH, -CH ₂ COOH. 18. Use according to claim 16, wherein U ³ is -CH ₂ -, -CH2CH2-, _{-CH2 CH2 CH2} -, -C ₆ H ₄ -, -C ₆ H ₁₀ -, -CH ₂ C ₆ H ₄ -, -ch ₂ nhcoch ₂ ch (ch ₂ co ₂ h) -c ₆ h ₄ -, -CH ₂ NHCOCH ₂ CCH ₂ -, -οη ₂ νηοοοη ₂ ο ₆ η ₄ -. Use according to claim 12, wherein compounds of formula Ia wherein K has one of the following structures are used: 333 r ⁴ ooc 'C. II o about II R ⁴ OOC-11z-A N N N II ¹ —COOR ⁴ ROOC — I Q COOR ⁴ ROOC COOR ⁴ -NIN «p. to COOR -C — II o COOR ROOC ⁰ 9 ii D, ο ^ σ ^ ο .... Use according to claims 12 to 19, wherein compounds of formula Ia wherein the perfluoroalkyl chain R ^F is -C 8 ^F 13, -C 8 ^F 11, -C 10 ^F 21 or -C 12 F 25 are used. Use according to claims 12 to 20, wherein a gadolinium complex with 1,4,7-tris {1,4,7-tris- [N- (carboxymethyl) -10- [N-1-methyls 1-3,6] is used. -diaza-2,5,8-trioxooctane-1,8-diyl] -1,4,7,10-tetraazacyclododecane, Gd-complex} -10 - [N-2Ti, 277, 4H, 477, 57i, 57i- 3-Oxa-perfluoro-trichloro-1,4-tetrahydro-cyclododecane. Use according to claims 1 to 7, wherein a perfluoroalkyl metal complex of the general formula Ib is used 334 is a complexing agent or a metal complex of formula IIb. where A I _F K-N-L-R COOR U (IIb) where R ¹ denotes a hydrogen atom or a metal ion equivalent having an atomic number of 23 to 29, 42 to 46 or 58 to 70, R ² and R 'are hydrogen, alkyl of 1 to 7 carbon atoms, benzyl, phenyl, -CH ₂ OH or -CH ₂ -O-CH ₃ , and U ² denotes the remainder L ¹ , wherein L ¹ and U ² may independently be the same or different from each other, A ¹ denotes a hydrogen atom, a straight or branched alkyl group having 1 to 30 carbon atoms, optionally interrupted by 1 to 15 oxygen atoms and / or optionally substituted by 1 to 10 hydroxy groups, 1 to 2 carboxyl groups, phenyl group, benzyl group and / or from 1 to 5 -OR ⁹ , wherein R ⁹ is a hydrogen atom or an alkyl radical having 1 to 7 carbon atoms or a radical -L ¹ -R ^{1 '} , L ¹ denotes a straight or branched alkylene group having 1 to 30 carbon atoms, optionally interrupted by 1 to 10 oxygen atoms, 1 to 5 -NHCO- groups, 1 to 5 -CONH- groups, optionally a phenyl group optionally substituted with a carboxy group, 1 to 3 sulfur atoms, 1 to 3 carbon atoms; 2 -N (B ¹⁾ -SO 2, and / or 1 to 2 radicals -SO 2 -N (B ¹⁾ -, wherein B ¹ is a group A ^1, -NHCO-, -CONH-, -N ( BD-SC ^ -, or -SO 2 -N (B ¹⁾ -, and / or substituted with R ^F, and EV is a straight or branched perfluoroalkyl "radical of the formula -C _n F _2n E, where n is 4 to 30, and E is a terminal fluorine atom, a chlorine atom, a bromine atom, an iodine atom or a hydrogen atom, and the optionally present acid groups may optionally be in the form of salts with organic and / or inorganic bases or amino acids or amino acid amides. 23. Use according to claim 22, using a compound of formula Ib wherein R ^2, R ^3, and R ^g are independently hydrogen or an alkyl group having 1 to 4 carbon atoms. Use according to claim 22, wherein the compounds of the general formula Ib, wherein A ¹ is a hydrogen atom, an alkyl radical having 1 to 15 carbon atoms, a radical -C ₂ H ₄ -OCH ₃ , -c ₃ h ₆ -o-ch ₃ , -C ₂ H ₄ -O- (C ₂ H ₄ -O) _t -C ₂ H ₄ -OH, -C ₂ H ₄ -O- (C ₂ H ₄ -O) _t -C ₂ H ₄ -OCH ₃ , -C ₂ H ₄ OH, -C ₃ H ₆ OH, -C ₄ H ₈ OH, -C ₅ H ₁₀ OH, -C ₆ H ₂ OH, -C ₇ H ₄ OH, -CH (OH) CH ₂ OH, CH (OK) CH (OH) CH ₂ OH, CH ₂ [CH (OH)] ^l _{of CH2} OH, -CH [CH ₂ (OH)] CH (OH) ₂ OH, -C ₂ H ₄ CH (OH) CH ₂ OH, - (CH ₂₎ 5 COOH, -C ₂ H ₄ -O- (C ₂ H ₄ -O) t -CH ₂ COOH, or C ₂ H ₄ -O- (C ₂ H ₄ -O) _t -C ₂ H ₄ -C _n F _2n E, 336 where with is a integer 1 to 15, T is a Integer 0-13 u ¹ is a an integer from 1 to 10, n is a an integer from 4 to 20, and E is a hydrogen, fluorine, chlorine, bromine or an iodine atom, as well as their branched isomers, if possible. Use according to claim 22, wherein compounds of formula 1b wherein A ¹ is a hydrogen atom, an alkyl radical having 1 to 10 carbon atoms, a radical -C2H4-OCH3, C3H6-O-CH3, -C2H4-O- (C2H4-O) _x -C ₂ H ₄ OH, -C2H4-O- (C2H4-O) _x -C ₂ H 4 OCH _3, -C2H4OH, C ₃ H ₅ OH, -CH ₂ [CH (OH)] _y CH ₂ OH, -CH [CH ₂ (OH)] CH (OH) CH ₂ OH, - (CH ₂ ) _w COOH, -C2H4-O- (C2H4-O) _x -CH ₂ COOH, -C2H4-O- (C2H4-O) _x -C ₂ H 4 -C _n F _2n E, in which x is a the whole number 0 to 5 y is a the whole number 1 to 6 / w is a the whole number from 1 to 10. n is a the whole number from 4 to 15 E is a atom F T as well as their branched isomers, if possible. 337 Use according to claim 22, wherein the general formula Ib, wherein L ¹ is α- (CH ₂ ) _s -p, α-CH ₂ -CH ₂ - (O-CH ₂ -CH ₂ -) y-β, are used, α-CH ₂ - (O-CH 2 -CH 2 -) _γ -β, α-CH ₂ -NH-CO-β, α-CH ₂ -CH ₂ -NH-SO ₂ -p, α-CH ₂ -NH- CO-CH ₂ -N (CH ₂ COOH) -so ₂ -p, α-CH ₂ -NH-CO-CH ₂ -N (C ₂ H ₅ ) -SO ₂ -p, α-CH ₂ -NH-CO-CH ₂ -N (C ₂ H ₀ i) -βθ -β _2, and -CH ₂ -NH-CO-CH ₂ -N (C ₆ H ₁₃₎ -SO ₂ ~ Z, and -CH ₂ -NH-CO- (CH ₂ ) _ΧΟ -Ν (C ₂ H ₅ ) -SO ₂ -p, α-CH ₂ -NH-CO-CH ₂ -N (-CH ₂ -C ₆ H ₅ ) -SO ₂ P, α-CH _2- NH-CO-CH ₂ -N (-CH ₂ -CH ₂ OH) -SO ₂ -p, α-CH ₂ -NH-CO- (CH ₂ ) ₁₀ -S-CH ₂ CH ₂ -p, α-CH ₂ -NH-CO-CH ₂ -O-CH ₂ CH ₂ -p, α-CH ₂ -CH ₂ -NH-CO-CH ₂ -O-CH ₂ CH ₂ -p, Ct-CH ₂ - (CH ₂ -CH ₂ O) _t - (CH ₂ ) 3 -NH-CO-CH ₂ -O-CH ₂ CH ₂ -p, α-CH ₂ -NH-CO- (CH ₂ ) ₁₀ -O -CH ₂ CH ₂ -p, a-CH ₂ -CH ₂ -NH-CO- (CH ₂ ) ₁₀ -Ο-0Η ₂ 0Η ₂ -β, a-CH ₂ -C ₅ H 4 -O-CH ₂ -CH _2- β, wherein the phenylene group is bound by 1,4 or 1,3, α-CH ₂ -O-CH ₂ -C (CH ₂ -OCH ₂ CH ₂ -C ₆ F ₁₃ ) 2-CH ₂ -O-CH ₂ CH ₂ -p, α-CH ₂ -NH-CO-CH ₂ -CH ₂ -CON-CH ₂ -CH ₂ -NHCOCH ₂ -N (C ₂ H ₅ ) SO ₂ C ₈ F ₇ -p, a-CH _2- CH ₂ -NH-CO-CH ₂ -N (C ₂ H ₅ ) -ΞΟ ₂ -β, α-CH ₂ -O-CH ₂ -CH (OC 10 H 21) -CH ₂ -O-CH ₂ CH ₂ - P, α- (CH ₂ -NHCO) 4 -CH ₂ O-CH ₂ CH ₂ -P, α- (CH 2 -NHCO) ₃ -CH ₂ O-CH ₂ CH ₂ -p, α-CH ₂ -OCH ₂ C _(CH2 OH) _{2 -CH2 -O-CH2 CH2-P,} compound via its 338 COOH α-CH ₂ -NH-CO-CH ₂ -N (C ₅ H ₅ ) -SO ₂ -p, α-NH-CO-CH ₂ CH ₂ -p, α-NH-CO-CH ₂ -O -CH ₂ CH ₂ -P, α-NH-CO-β, α-NH-co-cH ₂ -N (ch ₂ cooh) -εο ₂ -β, α-NH-CO-CH ₂ -N (C ₂ H ₅₎ -SO ₂ -P, and-NH-CO-CH ₂ -N (C ₂ H ₀ i) -3Ο -β _2, and -NH-CO-CH ₂ -N (C ₆ Hi ₃₎ -SO beta _2, and -NH-CO- _(CH2) n-ίο (C ₂ H ₅₎ -SO ₂ -p, and -NH-CO-CH ₂ -N (CH ₂ C ₆ H _{5) 2} -3Ο -β, α-NH-CO-CH ₂ -N (CH ₂ -CH ₂ OH) -SO ₂ -β, α-ΝΗ-ΟΟ-ΟΗ ₂ -β, α-ΟΗ ₂ -Ο-0 ₆ Η ₄ -Ο -0Η -ΟΗ ₂ -β _2, and -CH ₂ -C ₅ H _{4 -O-CH2 CH2} ^ N (C ₂ H ₅₎ -SO β, N (C ₆ H ₅₎ -SO β, N ₍₂ CioH i) -SO-β, N (C ₆ H _{13) 2} -β -3Ο, N (C2H4OH) -ΞΟζ-β, N (CH ₂ COOH) ₂ -β -3Ο, N (CH ₂ C ₆ H _{5) 2} -β -3Ο, and N [CH (CH ₂ OH) _{2] -SO2-p,} and N [CH (CH ₂ OH) CH (OH) _(CH2 OH)] _-SO2 - p, wherein s is an integer from 1 to 15, and is an integer from 1 to 6. 339 Use according to claim 22, wherein compounds of formula 1b are used, wherein L ¹ is α-CH ₂ -O-CH ₂ -CH ₂ -p, α-CH ₂ -CH ₂ - (O-CH ₂ -CH ₂ -) _γ -β, α-CH ₂ - (O-CH ₂ -CH ₂ -) _γ -β, α-CH ₂ -CH ₂ -NH-SO ₂ -p, e.g. 10 α-CH ₂ -NHCOCH ₂ -O-CH ₂ -CH ₂ -P, α-CH ₂ -CH ₂ NHCOCH ₂ -O-CH ₂ -CH ₂ -β, α-CH ₂ - (CH ₂ CH ₂ O) _y (CH ₂ ) 3NHCO-CH ₂ -O-CH ₂ -CH 2 -P, c-CH ₂ -NHCO (CH ₂ ) 10 -O-CH ₂ -CH ₂ -P, α-CH ₂ -CH ₂ -NHCO (CH ₂ ) io-O-CH ₂ -CH ₂ -p, α-CH ₂ -O-CH ₂ -CH (OC ₁₀ H 21) -CH ₂ -O-CH ₂ -CH ₂ -P, α-CH ₂ -OC ₆ H ₄ - O-CH ₂ -CH ₂ -P, α-CH ₂ -C ₆ H 4 -O-CH ₂ -CH ₂ -P, wherein y is an integer from 1 to 6. Use according to claim 22, wherein compounds of formula 1b are used, wherein R ^F is a straight or branched perfluoroalkyl radical of formula -C _n E _2n E, wherein n is a number from 4 to 15 and E is a terminal fluorine atom. Use according to claims 22 to 28, wherein the following compounds are used: 1,4,7-Tris (carboxylatomethyl) -10- (3-aza-4-oxohex-5-yl) -acid-N- (2,3-dihydroxypropyl) -N- (17β, 17β, 27β, 27β, 47β, 471,57,5,5-thi-3-oxaperfluorotridecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex, 1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxohex-5-yl) -acid-N - [(3,6, 9, 12, 15-pentaoxa) hexadecyl] - (17 ', 17i, 27i, 27i, 47i, 47i, 57i, 57i-3-oxaperfluorotridecyl) amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex, 340 1, 4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxohex-5-yl) -acid-N- (5-hydroxy-3-oxapentyl) -N- (1H, 1H, 2H) , 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex, 1,4,4-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxohex-5-yl) -acid-N - [(3,6,9,15-tetraoxa-12-aza-15-) - oxo _(Ci7-C26 -heptadekafiuór) hexakozyl] -amide} -l, 4,7,10-tetraazacyclododecane, Gd complex, 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohex-5-yl) -acid-N- (2-methoxyethyl) -N- (1H, IH, 2H, 2H, 4H) 1,4H, 5H, 5Η-3-oxaperfluorotridecyl) amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex. Use according to claims 1 to 7, wherein compounds of the general formula Ic (10i'-G-2-Z-R 2, 2 ') are used as perfluoroalkyl metal complexes with sugar residues. I (1c) (Y-R) p 'wherein R is a mono- or oligosaccharide residue attached via the 1-OH or 1-SH- position, R ^f is a polyfluorinated, a straight or branched hydrocarbon chain of the formula -C _n H _2n E, where E is a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n is a number from 4 to 30, K is a metal complex of formula IIc 341 Ic) R 'denotes a hydrogen atom or a metal ion equivalent by the number 23 to 29, 42 to 46 or 58 to 70, provided that at least two R ¹ are metal ion equivalents, R ² and R ³ are each independently hydrogen, alkyl having 1 to 7 carbon atoms, benzyl, phenyl, -CH ₂ OH or -CH ₂ -OCH ₃ , and U is -C 6 H _{4 -O-CH2} - <a, - (CH ₂₎ i ₅ -úí, the phenyl, -CH ₂ -NHCO-CH ₂ -CH (CH ₂ COOH) -ΟβΗή-ω , groups; - (OCH ₂ CH ₂ ) o N (CH ₂ COOH) -CH ₂ -co, or optionally one: with several oxygen atoms, 1 to 3 -NHCO- groups, -CONH- groups interrupted and / or 1 to 3 s; - (CH ₂ ) 0-5COOH substituted C 1 -C 11 alkylene or C 7 -C ₁₂ -C ₅ H ₄ -O-, where ω is attached to -CO-, = at least one of which is = -c ₆ h ₄ n or 1 to 3 scales of 12 or of the formula IIIc wherein R ¹ is as defined above, R ⁴ is a hydrogen atom or equivalent 342 of the metal ion given in the definition of R ¹ and U ¹ is -C ₆ H ₄ -O -CH ₂ -co-, where ω is the point of attachment to the -CO- group, or formula IVc wherein R ¹ and R ² have already or VcA or VcB ROOC ^ -COOR ¹ \ _n -COOR ¹ CO OR ¹ (VcA) COOR ¹ (VcB) wherein R ¹ is as hereinbefore defined, or of formula VIc ROOC— \ \ —CO— R ¹ OOC- ^NN- COOR ¹ ( ^{V c} ) wherein R ¹ is as defined above, or of the general formula Vile 343 R'OOC ROOC ROOC ROOC O (Villa) where R ¹ is as defined above, U ¹ is -06Η ₄ -Ο-0Η ₂ -ω-,. where ω is the point of attachment to the group -CO- or of formula VIIIc H (VIIIc) wherein R ¹ is as defined above, and wherein optionally the free acid groups in K may be in the form of salts with organic and / or inorganic bases or amino acids or amino acid amides, G when K is a metal complex IIe to VIIe, at least three times the functionalized moiety is selected from the group consisting of moieties a) to j) | _α - - (CHy-C-CO —'W γ ^{H H H} 4 β b) J_ | y ^ CO-CHCH 3 -N β NH 1 and 344 e) f) α NH-CO-S-Y-i-f * '' ' N-wy NH i jsl-CO-C- (CH 2 -N-) NH i 345 g) h) β s NH NH-CO-CH- (CH ₂ ) _n NH 4 3 -CO-CH- (CH ₂ ) ₄ -NH- NH k ^x NH-CO-CH- (CH3) -NH- & NH β _α n - (CH ₂ ) ₄ -CN-CO C-t CH 2 ^M 1 i) j) <χ% λ ** ΝΗ — CH — CO — Y 4 β G when K is a metal complex VIIIc, at least three times the functionalized moiety is selected from the group consisting of moieties k) or 1) 346 p ^ NH- _{(CH2) 4-CH-CO-} ^ k) ²⁴ | NH i Y and? CO-CH? -CH-CHx-CO? Y D I NH I p where a denotes the point of attachment of G to the complex K, β denotes the point of attachment of G to the remainder of Y and γ denotes the point of attachment of G to the remainder of Z, Y is -CH ₂ -, δ- (CH ₂ ) is -CO-β, δ-ΟΗ ₂ -ΟΗΟΗ-ϋΟ-β, or δ-CH (CHOH-CH ₂ OH) -CHOH-CHOH-CO -β where δ denotes the point of attachment to the sugar residue R and β denotes the point of attachment to the residue G, Z is Y - N - SO ₂ - £ Y-COCH ₂ -N (C ₂ H ₅ ) -SO ₂ -e, Y-COCH ₂ -O- (CH ₂ ) ₂ -SO ₂ -e, N - SO 3 - ε or γ-NHCH ₂ CH ₂ -O-CH ₂ CH ₂ -8 where γ is the point of attachment of Z to the residue G and ε is the point of attachment of Z to the perfluoroalkyl radical R ^F , 347 l ¹ , m ¹ are independently integers 1 or 2, and p is an integer from 1 to 4. Use according to claim 30, wherein a compound of formula 1c is used, wherein R is a monosaccharide radical having 5 to 6 carbon atoms or a deoxy compound thereof, preferably glucose, mannose or galactose. Use according to claim 30, wherein a compound of formula 1c is used, wherein R ² and R ³ are independently hydrogen or an alkyl group having 1 to 4 carbon atoms and / or E in the formula -C _n F _2n E is a fluorine atom. Use according to claim 30, wherein a compound of formula 1c is used, wherein G is a lysine residue (a) or (b). 34. The method of claim 30, wherein it is used a compound of formula Ic, wherein Z is N &apos; ~ N, N-S0 ₂ - £ where γ denotes the point of attachment of Z to the radical G and ε denotes the attachment from the perfluoroalkyl radical R ^F and / or Y is δ-ΟΗ ₂ - (ΖΟ-β, where δ is the point of attachment to the sugar moiety R and β is the point of attachment to the moiety G. Use according to claim 30, wherein a compound of formula 1c is used, wherein U in the metal complex K is -CH ₂ - or -C _s H ₄ -O-CH ₂ -ro, where ω is the point of attachment to the -CO- group. . Use according to claim 30, wherein the gadolinium complex with 6-N- [1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane-10-Ν- (pentanoyl-3-aza-) is used. 4-oxo-5-methyl-5-yl)] - 2-N- [10a-β-carbonylbutylmethyl-pyranose] -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide. Use according to claims 1 to 7, wherein compounds of the general formula Id (K), ^1- G- (2-R ^f VI (Id) (R) p ² ) are used as perfluoroalkyl metal complexes with polar residues. R ^f is a perfluorinated, straight or branched hydrocarbon chain of the formula -C _n F _2n E, where E is a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n is a number from 4 to 30, the metal complex of the formula Ild where R ¹ is a hydrogen atom or a metal ion equivalent having an atomic number of 23 to 29, 42 to 46 or 58 to 70, R ² and R ³ are independently a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, benzyl, phenyl, -CH ₂ OH or -CH2OCH3, and U is -C ₅ H ₄ -O-CH ₂ -m, - (CH ₂ ) 1-5 -ω, phenyl, -CH ₂ -NHCO-CH ₂ -CH (CH ₂ COOH) -ΟβΗή- ω, -C6H4- (OCH ₂ CH ₂ ) 0-1-N (CH ₂ COOH) -CH ₂ -co or optionally one or 349 more oxygen atoms, 1-3 -NHCO groups, 1-3 -CONH groups interrupted and / or 1 to 3 groups (~ _CH2) 0-5COOH substituted alkylene group of 1 to 12 carbon atoms or C? -C ₁₂ -C ₆ H ₄ -O-, where ω is the point of attachment to the group -CO-, or of the formula IIld wherein R ¹ is as defined above, R ⁴ is a hydrogen atom or a metal ion equivalent as defined in R ¹ and U ¹ is -C _S H ₄ -O-CH ₂ -CU-, wherein ω is the point of attachment to group -C0-, or the formula IVd R ¹ 00 C (IVd) wherein R ¹ and R ² are as defined above, or of the general formula VdA or VdB 350 ROOC z-CO - / - 'COOR ¹ \ _n ^ coor ^{1 V} ^^ COOR ¹ (VdA) COOR ¹ (VdB) wherein R ¹ is as hereinbefore defined, or of formula VId ROOC ROOC CO- ^and COOR ¹ (VId) wherein R ¹ is as hereinbefore defined, or of formula IIId R ¹ OOC ROOC ROOC ROOC (VIld) wherein R ¹ is as defined above and U ¹ is -C ₆ H 4 -O-CH ₂ -m-, where ω is the point of attachment to the -CO- group, and the acid groups optionally present in the remainder of K may be present in the form of salts with organic and / or inorganic bases or amino acids or amino acid amides, G is at least three times a functionalized moiety selected from the following moieties a) to i): 351 a) b) H and * ~ N— (Cby-C-CO — γ ^H NH 4 β γ ^ CO-C-CH 2 -N-va-β NH I α d) e) N ~ * 4V <X H 352 f) HH N _{(CH2) 4} -CN, -CO-C (CH,) ₄ N H · Λ ^ Η | ²⁴ H 'β g) h) WHAT NH γ -co- (CH ₂ ) ₂ . ₃ -f H-CO - **? NH i) β-α-CO- (CH ₂ ), _β- CH-CO-α-y NH where a denotes the point of attachment of G to the complex K, β denotes the point of attachment of G to the remainder of R and y denotes the point of attachment of G to the remainder of Z Z is y-n-s ₂ -s YC (O) CH ₂ O (CH ₂ ) 2 -e, where γ denotes the point of attachment of Z to the radical G and ε denotes the point of attachment of Z to the perfluoroalkyl radical R ^F , R is a polar radical selected from complex K of the formulas Ild-VIIId, wherein R ¹ is a hydrogen atom or a metal ion equivalent having an atomic number of 20, 23-29, 42-46 or 58- 70 353 and the radicals R ² , R ³ , R ⁴ , (J and U ¹ as defined above) or a folic acid residue or a hydrocarbon chain having 2 to 30 carbon atoms, straight or branched, saturated or unsaturated, bound to the residue G via -CO-, -SO ₂ - or directly, optionally interrupted by 1 to 10 oxygen atoms, 1 to 5 -NHCO-, 1 to 5 -CONH-, 1 to 2 sulfur atoms, 1 to 5 -NH or 1 to 2 phenyl groups which may be optionally substituted with 1 to 2 hydroxy groups, 1 to 2 amino groups, 1 to 2 carboxyl groups or 1 to 2 -SO 3 H groups, or optionally substituted with 1 to 8 hydroxy groups, 1 to 5 carboxyl groups, 1 to 2 2 sulfo groups, 1 to 5 amino groups, 1 to 5 alkoxy groups having 1 to 4 carbon atoms, and l ¹ , m ¹ , p ² are independently integers 1 or 2. The use according to claim 37, wherein compounds of formula Id are used, wherein K is a metal complex of formula Ild, IIld, VdB or Vlld. Use according to claim 37, wherein compounds of the formula Id are used, wherein the polar residue R has the meaning of the complex K, preferably the complex of the formulas Ild, IIld, VdA or VIId. The use according to claim 37, wherein the compounds of formula Id are used, wherein the polar residue is: 354 -C (O) CH ₂ CH ₂ SO ₃ H, -C (O) CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ OH, -C (O) CH ₂ OCH ₂ CH ₂ OH, -C (O) CH ₂ OCH ₂ CH (OH) ₂ OH, C (O) CH ₂ NH-C (O) CH ₂ COOH, -C (O) CH ₂ CH (OH) CH ₂ OH, -C (O) CH ₂ OCH ₂ COOH, -so ₂ ch ₂ ch ₂ cooh -C (O) -C ₆ H ₃ - (m-COOH) ₂ , -C (O) CH ₂ O (CH ₂ ) 2 -C ₆ H ₃ - (R ₁ -COOH) ₂ , -C (O) CH ₂ OC ₆ H ₄ -m-SO ₃ H, C (O) CH ₂ NHC (O) CH ₂ NHC (O) CH2OCH2COOH. -C (O) CH ₂ OCH ₂ CH ₂ OCH ₂ COOH, -C (O) CH ₂ OCH ₂ CH (OH) CH ₂ O-CH ₂ CH ₂ OH, -C (O) CH ₂ OCH ₂ CH (OH) CH ₂ O-CH ₂ CH (OH) -CH ₂ OH, -C (O) CH ₂ SO ₃ H, -C (O) CH ₂ CH ₂ COOH, -C (O) CH (OH) CH (OH) CH ₂ OH, -C (O) CH ₂ O [(CH ₂ ) ₂ O] 1-9-CH 3, -C (O) CH ₂ O [(CH ₂ ) ₂ O] 1-9-Η, -C (O) CH ₂ OCH (CH ₂ OH) 2, -C (O) CH ₂ OCH (CH ₂ OCH ₂ COOH) 2, -C (O) -C ₆ H ₃ - (m-OCH ₂ COOH) ₂ , -C (O) -CH 2 O- (CH ₂ ) ₂ O (CH ₂ ) ₂ O- (CH ₂ ) ₂ O (CH ₂ ) ₂ OCH ₃ , preferably -C (O) CH ₂ O [(CH ₂ ) ₂ O] 4-CH 3. . The use according to claim 37, wherein compounds of formula Id are used, wherein the polar residue R is folic acid. The use of claim 37, wherein compounds of formula Id are used wherein G is lysine residue (a) or (b). The use according to claim 37, wherein the compounds of formula Id, wherein U in the metal complex K is a group, are used 355 -CH 2 - or -C ₆ H ₄ -O-CH ₂ -O), where ω is the point of attachment to the group. -C0-. Use according to claims 37 to 43, wherein the gadolinium complex with 2,6-N, N'-bis [1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane-10- ( pentanoyl-3-aza-4-oxo-5-methyl-5-yl) -lysine- [1- (4-perfluorooctylsulfonylpiperazine) amide. Use according to claims 1 to 7, wherein the galenical formulation of the perfluoroalkyl metal complex is a formulation comprising a paramagnetic perfluoroalkyl metal complex of formula I, Ia, Ib, Ic and / or Id and a diamagnetic perfluoroalkyl compound, preferably dissolved in an aqueous solvent. The use of claim 45, wherein the diamagnetic perfluoroalkyl compound is a compound of formula XX R ^F -L ² -B ² (XX) wherein ^{R f} is a straight or branched perfluoroalkyl radical having 4 to 30 carbon atoms, L ² is a linker and B ² is a hydrophilic group. The use of claim 46, wherein the linker L ² is a direct bond, -SO 2 - or a straight or branched hydrocarbon chain of up to 20 carbon atoms, which may be substituted by one or more hydroxy groups by COO ', SO 3 H groups and / or contain one or more -O-, -S-, -CO-, -CONH-, -NHCO-, -CONR ⁹ -, -NR ⁹ CO-, -SO ₂ -, -PO _{4 '} -, -NH-, -NR ⁹ -, an aryl ring or piperazine, wherein R ⁹ is an alkyl radical having 1 to 20 carbon atoms, which may again contain one or more oxygen atoms and / or may be substituted by -COO 'or -SO 3. 356 The use of claim 46, wherein the hydrophilic group B ² is a mono- or disaccharide, one or more adjacent COO or -SO ₃ 'groups, a dicarboxylic acid, isophthalic acid, picolinic acid, benzenesulfonic acid, tetrahydropyranedicarboxylic acid, 2,6- pyridine dicarboxylic, quaternary ammonium, aminopolycarboxylic acid, aminodipolyethylene glycol sulfonic acid, aminopolyethylene glycol group, -SO ₂ - (CH ₂ ) 2 - OH, a polyhydroxyalkyl chain with at least two hydroxy groups or one or more polyethylene glycol polycolkylene glycol chains terminated with hydroxy or methoxy. Use according to claim 45, wherein the perfluoroalkyl compound is a conjugate of α-, dextrin and a compound of formula XXII A ² -L ³ -R ^F as diamagnetic β- or γ-cyclo (XXII) wherein A ² is an adamantane molecule, a biphenyl molecule or anthracene molecule, L ³ is a linker and R ^F is a straight or branched perfluoroalkyl radical having 4 to 5 And wherein the linker L ³ is a straight hydrocarbon chain having 1 to 20 carbon atoms, which may be interrupted by one or more oxygen atoms or one or more -CO-, -SO ₂ -, -CONH-, - NHCO-, -CONR ¹⁰ -, -NR ¹⁰ CO-, -NH-, -NR ¹⁰ - or piperazine, wherein R ¹⁰ is an alkyl radical having 1 to 5 carbon atoms. The use of claim 45, wherein the diamagnetic perfluoroalkyl compound is a compound of formula XXI R ^f -X ¹ (XXI) wherein R ^f is a straight or branched perfluoroalkyl radical having 4 to 30 carbon atoms and X ¹ is a radical selected from the group consisting of the following substituents (n is a number from 1 to 10):