CZ2003392A3 - Contrast formulation for representation of plaques, tumors, and necroses by making use of magnetic resonance - 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

Contrast medium for imaging plaques, tumors and necrosis by magnetic resonance imaging

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) greater than 1 nm and a proton relaxivity in plasma (R ¹ ) greater than 10 1 / mmol as a contrast agent in NMR imaging and plaque, lymph node, infarction and necrotic tissue imaging, as well as independent imaging of necrotic and tumor tissues. Metal complexes containing perfluoroalkyl radicals with said properties have been shown to be particularly suitable for independent monitoring of plaques, tumors and necroses by NMR imaging, and at the same time can cover an important area of heart attack and necrosis monitoring.

BACKGROUND OF THE INVENTION

Arteriosclerosis is a serious and frequent disease of arterial disease accompanied by stiffening, loss of elasticity and thinning of the diameter. It is a common cause of death in Western industrial society. Changes in vascular walls through uneven lipid deposition, connective tissue growth, and calcium fouling lead to wall instability, venous changes, and clot deposition. The cause of the disease are numerous endogenous and exogenous injuries or illnesses such as hypertonia, hyperlipidemia, hyperfibrinogenamy, diabetes mellitus, toxins, nicotine, antigen-antibody complexes, inflammation, hypoxia, psychological stress, old age and family load. These effects lead to impaired venous wall integrity, impaired control of venous smooth muscle cell growth, and disrupted aging of the aged cells. Treatment of arteriosclerosis alone is not possible, the aim of physicians' efforts is to prevent by reducing risk factors, eg by removing lipids.

The diagnosis of arteriosclerosis in clinical practice is currently made mainly by angiography as the main standard. However, the limit for all methods based on measuring venous clearance is the early stage of this disease, which is characterized by thickening of venous walls at normal venous clearance (Gladov S, Zarins CK, Quantitating atherosclerosis. In Bond MG, Insull W, Glagov S, Chandler AB, Cornhill JF (eds.), Clinical Diagnosis of Atherosclerosis, Quantitative Methods of Evaluation, New York: Springer Verlag, 1983, 11-35). Intravascular or percutaneous ultrasound is another method for diagnostic assessment of venous walls and lumen.

Nuclear Magnetic Resonance Tomography (NMRT) 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 contrast agents selective in the arteriosclerotic plaques of the disease at an earlier stage and allowed targeted therapy and prophylaxis, so that there is a need for suitable contrast agents.

This would result in fluorescence being used for enrichment

In US Patent 4,577,636 hematoporphyrin derivatives are claimed as contrast agents for the detection of atherosclerotic plaques. As methods of scintigraphy, X-ray spectroscopy, spectroscopy and in paramagnetic metalloporphyrins also NMR spectroscopy. Gd, Cr, Co, Ni, Ag and Eu were mentioned as paramagnetic ions. The 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. In addition, there is a risk that the metalloporphyrins lose metal during long periods of in vivo residence.

WO 95/09856 discloses metalloporphyrins (deuteroporphyrins) for use in the diagnosis and therapy of plaques. The NMR imaging 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 can also bind to plaques and thereby allow diagnosis and therapy. Scintigraphy, computed tomography and NMR imaging were used as diagnostic methods. While experimental conditions for scintigraphy are given, NMR imaging data is 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 NMR imaging 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 research has crawled that the localization of heart attack and necrosis is better due to the use of contrast agents in non-invasive methods such as scintigraphy or NMR tomography. The use of porphyrin for imaging necrosis occupies much of 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 (TPPS) accumulates selectively in the necrotic portion of the tumor.

Lyon et al. (Magn. Res. Med. 4, 24 (1987)), on the other hand, have observed that manganese-TPPS breaks down in the body in the kidneys, liver, tumors, and to a small extent in the muscles. Interestingly, the tumor concentration first reaches its maximum at day 4 after the dose was increased from 0.12 mmol / kg to 0.2 mmol / kg. The authors also describe

non-specific binding of TPPS in tumor. Bockhurst et al. also referují v Acta Neurochir 60, 347 (1994, suppl), that MnTPPS se selectively weighs in tumors • Foster et al. (J. Nucl. Copper. 26, 756 (1985). they found sz that

^1x1In -5,10,15,20-tetrakis- (4-N-methylpyridinium) porphyrin (TMPyP) is not enriched in the necrotic part, 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 vol. 90, no. 4, volume 2, page 1468, abstract no. 2512 (1994) that using infusion of mangantetrafenyl porphyrin (Mn-TPP) and gadolinium mesoporphyrin (GdMP), the infarct area can be visualized. In International Patent Application WO 95/31219, both φφφφ compounds were used for imaging infarction and necrosis. Marchal and Ni describe (see Example 3) that the Gd-MP compound has a metal content similar to that of uninfected organs in infarcted kidneys, but is nine times higher than in infarcted myocardial tissue (Example 1). Remarkably, the NMRI signal intensity ratio for infarcted and healthy tissue in both cases was 2.10 and 2.10 respectively. 2.19. Other metalloporphyrins have been described in DE 19835082 (Schering AG).

Porphyrins tend to deposit in the skin, leading to photosensitization. Sensitization may take 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, e.g. for Mn-TPPS, the effect is only achieved at doses of 0.2 mmol / kg, LD ₅₀ is already around 0.5 mmol / kg.

Necrosis and heart attack contrast agents which are not based on porphyrin residues are described in DE 19744003 (Schering AG), DE 19744004 (Schering AG) and WO 99/17809 (EPIX).

DE 19744003 describes oligomeric compounds composed of a core to which 1 to 3 metal complexes are attached.

Application 19744004 discloses lipophilic metal complexes for imaging necrosis and heart attack. These compounds include metal complexes of polyaminopolycarboxylic acids, polyaminopolyphosphoric acids, porphyrins, texaphyrins, safyrins and peptides.

• · ·· ····

EPIX application WO 99/17809 describes the use of DTPA derivatives for imaging necrosis. The best compound is the gadolinium complex with hydroxymethyl-DTPA phosphodiesters (MS-325).

Also, metal complexes containing perfluoroalkyl residues are known as contrast agents for NMR imaging. WO 97/26017 (Schering) and WO 99/01161 (Schering) disclose perfluoroalkyl metal complexes as lymphography. WO 99/01161 also describes the suitability of diester compounds for imaging vascular spaces (bloodstream agents).

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

EP 417870 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 can be considered as chelates of N2S2 and N3S type complexes with radioisotopes. Scintigraphy serves as a diagnostic method.

In German patent DE 19646762 scintigraphy was also used as a diagnostic method. The patent claims metallic chelates as radiosensitizers for the treatment of hypoxic tumors and for the diagnosis of hypoxic conditions and necroses.

The use of NMR diagnostics, X-ray diagnostics and radiodiagnostics is also mentioned in the description.

In German application DE 19824653 porphyrins are described as necroseaphine substances 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 19646762 and DE 19824653 - have in common that imaging of necrosis and tumor cannot be performed independently of each other, since it is a necrotic part of the tumor.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide NMR imaging contrast agents 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 1 / mmol.s they are very suitable for use as contrast agents for NMR imaging in plaque imaging. In addition, these compounds can be used for imaging of lymph nodes, infarcted and necrotic tissues, as well as for independent imaging of necrotic tissue and tumor tissue.

Metal complexes containing perfluoroalkyl radicals suitable according to the invention are amphiphilic compounds which have 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 suspended by other polar groups.

• · · · · · · · · · ·

In aqueous systems, these compounds exhibit the behavior of classical surfactants (such as sodium dodecyl sulfate, SDS). Thus, they reduce the surface tension of the water. The so-called critical micellar concentration (CMC in mol / l) can be determined by tensiometry. For this, 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 ^-4 mol / l.

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

The second criterion is the hydrodynamic 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 of 3 nm, particularly preferred having 2 Rh of> 4 nm.

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

The third criterion is proton relaxivity in plasma (R ¹ ) at 40 ° C and 0.47 Tesla field strength. Relaxation, which is expressed in units [l / mmol.s], is a quantitative measure of the reduction in the relaxation time of 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] NMR of the contrast agents of the invention was determined using a Minispec P 20 from Bruker. The measurement was performed at a temperature of 40 ° C and a field strength of 0.47 Tesla. For each T1-sequence: 180 ° -TI-90 °, inverse response, 8 points were obtained. Kraeber bovine plasma was used as the medium. The concentration of contrast media [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 the compounds known in WO 97/26017. This application also includes their preparation. It has surprisingly been found that these compounds are very suitable as NMR contrast agents for plaque imaging. Particular preference is given to metal complexes I to IV and XI to XIII (see also Table 1).

In another embodiment of the invention, compounds of the formula Ia according to claims 12 to 21 are particularly preferred. These compounds are known and described in WO 99/01161. Their use as NMRI contrast agents for plaque imaging has not been previously 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 1b are included

AND

I F

K-N-L-R (1b) wherein

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

wherein (Hb) denotes a hydrogen atom or a metal equivalent of atomic number 23 to 29, 42 to 46 or 58 to 70,

R ² and R ³ denote a hydrogen atom, an alkyl group having up to 7 carbon atoms, a benzyl group, a phenyl group, a -CH ₂ OH group or a -CH ₂ -O-CH _{3 group} , and

U ² is the radical L ¹ , where L ¹ and U ² are independently the same or different from each other,

A ¹ denotes a hydrogen atom, a straight or branched alkyl group having 1 to 1, interrupted, 1 to 15 carbon atoms, optionally oxygen and / or optionally substituted with 1 to 10 hydroxyl groups, 1 to 2 COOH groups, phenyl group, benzyl group and / or from 1 to 5 OR ⁹ groups, wherein R ⁹ 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 with 1 to 10 oxygen atoms, 1 to 5 -NH-CO- groups, 1 to 5 -CO-NH- groups, or a phenyl group if inserted substituted with a -COOH group, 1-3 sulfur atoms, 1-2 -N (B ¹⁾ -SO 2, and / or 1 to 2 groups -S02NÍB ¹⁾ - where 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 ^F , and

R ^f is a straight or branched perfluoroalkyl radical of formula CnF 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 atom or a hydrogen atom, and the optionally attached acidic groups may be as salts of organic and / or inorganic amines or amino acids or amino acid amides.

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 of atomic numbers 23 to 29, 42 to 46 and 58 to 70. Suitable ions are, for example, chromic, ferrous, cobalt, nickel, copper, praseodymium, neodymium, samarium and yterbite. Due to their strong magnetic moment, gadolinium, terbite, dyspropious, holmite, erbite, ferric and manganese ions are particularly suitable.

Particularly suitable are the manganese, ferrous, ferric, praseodymium, neodymium, samarium, gadolinium and ytterbitium ion, in particular the dysprosit 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.

·· · «··

9999

The benzyl and phenyl groups in R ^2, A ¹ and B ¹ may be substituted on the phenyl ring. Possible substituents are -COOH.

When the compound of formula (Ib) simultaneously contains a residue L ¹ and U ² , 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-methylbutylene, 1,2-dimethylpropylene.

For U ² in the definition of alkylene, alkyl groups having 1 to 10 carbon atoms are preferred, C ₂ to C ₄ alkylene groups being particularly preferred.

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

A ¹ alkyl groups having 1 to 30 carbon atoms may be interrupted by 1 to 15 oxygen atoms, and / or may be substituted with 1 to 10 hydroxy groups, 1 to 5 alkoxy groups or 1 to 2 -COOH groups such as C ₂ H ₄ - O-CH 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 where t = 0 to 13,

C ₂ H ₄ -OH, C ₃ H ₆ -OH, C ₄ H ₈ -OH, C ₅ H ₁₀ -OH, C ₆ H ₁₂ -OH, C ₇ H ₁₄ -OH, as well as their branched isomers, • fcfcfcfc Fcfcfcfc fcfc fcfc fcfc fcfcfcfc 4 f · fcfc fcfc

CH (OH) CH ₂ OH,

CH (OH) CH (OH) CH ₂ OH, CH ₂ [CH (OH)] / CHaOH, where u 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 = 1 to 15,

C ₂ H ₄ -O- (C ₂ H ₄ -O) _t -CH ₂ COOH where t = 0-13,

C ₂ H ₄ -O- (C ₂ H ₄ -O) _t -C ₂ H ₄ -C _n F _2n E where t = 0-13, n = 4-20 and e = a fluorine atom, hydrogen atom, chlorine atom , a bromine atom or an iodine atom. Particularly preferred for A ¹ are hydrogen, alkyl having 1 to 10 carbon atoms,

C ₂ H ₄ -O-CH ₃ , c ₃ H ₆ -O-CH ₃ ,

C ₂ H ₄ -O- (C ₂ H ₄ -O) _x -C ₂ H ₄ -OH, C ₂ H ₄ -O- (C ₂ H ₄ -O) _x -C ₂ H ₄ -OCH ₃ where x = 0 to

5,

C ₂ H ₄ OH, C ₃ H _with OH,

CH ₂ [CH (OH)] _y CH ₂ OH, where y = 1 to 6

CH [CH ₂ (OH)] CH (OH) CH ₂ OH, (CH ₂ ) _w COOH where w = 1 to 10, C ₂ H ₄ -O- (C ₂ H ₄ -O) X-CH ₂ COOH where x = 0 to 5

C ₂ H ₄ -O- (C ₂ H ₄ -O) _x -C ₂ H ₄ -C _n F _2n E wherein x = 0 to 5, n = 4 to 15 and E = fluorine atom.

If the compound of formula (1b) has two iZ-R * 'residues, then these residues may be different from each other.

For the remainder of L1, examples are given where α denotes the bond to nitrogen and β a bond to the remainder RF:

α- (CH ₂ ) _s -p where s = 1 to 15 α-CH ₂ -CH ₂ - (O-CH ₂ -CH ₂ -) _γ -β, where y = 1 to 6, α-CH ₂ - ( O-CH ₂ -CH ₂ -) ₇ -β, where y = 1 to 6, α-0Η ₂ -ΝΗ-0Ο-β, * · ** ·· ·· φφ ·· ···· α-CH ₂ -CH ₂ -NH-SO ₂ - ^, α - CH ₂ - NH - CO - CH ₂ - Ν (CH2 COOH) - S0 ₂ - β, CC-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 ₂₁ ) -so ₂ -p, α-CH ₂ -NH-CO-CH ₂ -N (C ₆ Hi ₃₎ -SO ₂ -p,

O-CH ₂ -NH-CO- (CH ₂ ) 10 -N (C ₂ H ₅ ) -δθ ₂ -β, α-CH ₂ -NH-CO-CH ₂ -N (-CH ₂ -C ₆ H ₅₎ ) -3Ο ₂ -β, α-CH ₂ -NH-CO-CH ₂ -N (-CH ₂ -CH ₂ OH) -εο ₂ -β, α-CH ₂ -NH-CO- (CH ₂ ) ₁₀ -S-CH ₂ CH ₂ -?, Α-CH ₂ -NH-CO-CH ₂ -O-CH ₂ CH ₂ -?, Α-CH ₂ -CH ₂ -NH-CO-CH ₂ -O-CH ₂ CH ₂ -, a-CH ₂ - (CH ₂ -CH ₂ O) _y - (CH ₂ ) ₃ -NH-CO-CH ₂ -O-CH ₂ CH ₂ , where y = 1 to 6, a-CH ₂ -NH-CO- _{(CH2) ι-0} -Ο ΟΗ ΟΗ ₂ -β _2, and -CH ₂ -CH ₂ -NH-CO- _{(CH2) ι-0} -Ο ΟΗ ΟΗ ₂ -β _2, α-CH ₂ -C ₆ H ₄ -O-CH ₂ -CH ₂ -, wherein the phenylene group is substituted at the 1,4 or 1,3 positions, 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 - β, 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 a-CH ₂ -CH ₂ -NH-CO-CH ₂ -N (C ₂ H ₅ ) -δθ ₂ -β, a - CH ₂ - O - CH ₂ - CH (OC ₁₀ H ₂₁ ) - CH ₂ - O - CH ₂ CH ₂ - β, α- (CH ₂ -NHCO) ₄ -CH ₂ O-CH ₂ CH ₂ ^, a- ( CH ₂ -NHCO) ₃ -ΟΗ ₂ Ο-0Η ₂ ΟΗ ₂ -β, a - CH ₂ - OCH ₂ C (CH ₂ OH) 2 - ch ₂ - o - ch ₂ ch ₂ - β,

COOH α-CH ₂ -NH-CO-CH ₂ -N (C ₆ H ₅ ) -SO ₂ -β, α-NH-CO-CH ₂ CH ₂ -β,

α-NH-CO-CH ₂ -O-CH ₂ CH ₂ -P, α-NH-CO-β, α-NH-CO-CH ₂ -N (CH ₂ COOH) -SO ₂ -p, α-NH -CO-CH ₂ -N (c ₂ h ₅ ) -so ₂ -p,

Ct-NH-CO-CH ₂ -N (C ₁₀ H ₂₁ ) -SOa-β, α-NH-CO-CH ₂ -N (C ₆ H ₁₃ ) -δθ ₂ -β, α-NH-CO- ( CH ₂ ) ₁₀ -N (C ₂ H ₅ ) -εο ₂ -β, α-NH-CO-CH ₂ -N (-CH ₂ C ₆ H ₅ ) -δθ ₂ -β, α-NH-CO-CH ₂ -N (-CH ₂ -CH ₂ OH) -SO ₂ -β, α-ΝΗ-ΟΟ-ΟΗ ₂ -β, α-CH ₂ -OC ₆ H ₄ -O-CH ₂ -CH ₂ -, α-CH ₂ -C ₆ H ₄ -O-CH ₂ -CH ₂ R, and N (C ₂ H ₅₎ -SO-β, N (C ₆ H _{5) 2} -β -3Ο, N (C ₁₀ H ₂ i) - δθ ₂ -β, aN (C ₆ H ₁₃ ) -SO ₂ -β, cc-n (c ₂ h ₄ oh) -εο ₂ -β, aN (CH ₂ COOH) -3Ο- ₂ -β, aN (CH ₂ C ₆ H _{5) 2} -β -5Ο, and N [CH (CH ₂ OH) _{2] 2} -β -εο, and N [CH (CH ₂ OH) CH (OH) (CH ₂ OH)] ₂ -β -δθ,

Preferred are:

α-ΟΗ ₂ -Ο-ΟΗ ₂ -ΟΗ ₂ -β, α-CH ₂ -CH ₂ - (O-CH ₂ -CH ₂ -) _γ -β, where y = 1 to 6, α-CH ₂ - ( O-CH ₂ -CH ₂ -) _ζ -β, where y = 1 to 6, α-CH ₂ -CH ₂ -NH-SO ₂ ^, eg 10 α-CH ₂ -NHCOCH ₂ -O-CH ₂ - CH ₂ - β,

α - CH ₂ - CH ₂ NHCOCH ₂ - Ο - ch ₂ - CH ₂ - β, α-CH ₂ - (CH ₂ CH ₂ O) y (CH ₂ ) 3 NHCO-CH 2 -O-CH ₂ -CH ₂ -p where y = 1 to 6 and-NHCO-CH (CH _{2) 10} -O-CH ₂ -CH 2 -R p, - _CH2 - _CH2 - NHCO (CH ₂₎ about 1 ~ O - _CH2 - _CH2 - β, and -CH _2- O-CH ₂ -CH (OCl ₂ H ₂ ) -CH ₂ -O-CH ₂ -CH ₂ -, a-CH ₂ -OC ₆ H ₄ -O-CH ₂ -CH ₂ -, a- CH ₂ -C ₆ H ₄ -O-CH ₂ -CH ₂ -.

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

For U ² , the aforementioned radicals for L ^{1 apply} and the preferred and especially preferred radicals have the same meaning as in the above alkylene, provided that they have no nitrogen atom in the α position and no terminal (β-position) SO 2 - or CO- group.

Preferred radicals B ¹ are hydrogen, straight or branched alkyl chains having 1 to 10 carbon atoms which may be interrupted by 1 to 5 oxygen atoms and / or optionally substituted with 1-5 hydroxy groups, 1-2 groups

COOH, phenyl optionally substituted with COOH, 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 are straight or branched perfluorinated alkyl radicals of the formula C _n F _2n E, wherein n is a number of 4 to 15 and E is a terminal fluorine atom.

♦ ·

Preparation of a Compound of Formula 1b of the Invention knlr ^f (ib) A wherein K is a complexing agent of Formula IIb or a metal complex of Formula

as follows:

(Hb)

Method A

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

Said acid IIIb optionally activated in situ with R ¹ as the metal ion equivalent is allowed to condense with amine IVb in the coupling reaction to form amide 1b.

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

The reaction mixture used for the condensation reactions comprises a mixture of a metal complex of the carboxylic acid 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 up to 2 molar equivalents, selected so that the metal carboxylic acid complex can be introduced into the present reagents and isolated (e.g., 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 react with a reagent cleavable with a condensation agent, optionally also in situ by addition of a substance to dissolve the metal carboxylic acid complex, a water cleavable agent, and optionally a condensation agent in DMSO.

finally, it is left in DMSO with water and optionally

The reaction mixture thus obtained is allowed to react (acid activation) for 1 to 24, 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

R '' N ^{/ L} ^ r ^f

AND

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

····

9

In one embodiment, it has proven advantageous to use the amine in the form of a salt thereof, e.g. with hydrobromic acid or as a hydrochloride salt. 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 protecting groups that are still present are cleaved at the end.

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, methyl tert-butyl 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 heterocyclic amine salts. For example, mention may be made of lithium chloride, lithium bromide, lithium iodide, sodium bromide, sodium iodide, lithium ethanesulfonate, sodium lithium p-toluenesulfonate, sodium potassium bromide, potassium iodide, sodium chloride, magnesium bromide, magnesium chloride, magnesium iodide, tetraethylammonium p-tetraethylammonium. -toluenesulfonate, tetramethylammonium ptoluenesulfonate, pyridinium p-toluenesulfonate, triethylammonium p-toluenesulfonate, 2-morpholinoethylsulfonic acid, 4-nitrophenol, 3,5-dinitrophenol, 2,4-dichlorophenol, N-methanesulfonate, toluenesulfonate,

N-hydroxyphthalimide, urea, ·· ··· ♦

tetramethylurea, N-methylpyrrolidone, formamide as well as cyclic ureas, the five of which are preferred.

All reagents known to those skilled in the art are used 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 O- ( benzotriazol-1-yl) 1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), preferably DCCI.

For example, the following procedures are described in the literature: Activation of cyarboxylic acids. Review in Houben-Weyl, Methoden der Organischen Chemie, vol. 1/2, Georg Thieme Verlag Stuttgart, 1974 (and J. Chem. Research (S) 1996, 302). Activation with carbodiimides. R. Schwyzer and H. Kappeler, Helv. 46: 1550 (1963).

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

Activation with carbodiimides / 1-Hydroxysuccinimide: J. Am. Chem. Soc. 86: 1839 (1964) as well as J. Org. Chem. 53: 3583 (1988). Synthesis 453 (1972).

Anhydride method, 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline:

B. Belteau et al. J. Am. Chem. Soc., 90: 1651 (1986);

Kunz et al. , Int. J. Pept. Prot. Res., 26: 493 (1985), and J.

R. Voughn, Am. Soc. 73: 3547 (1951).

Imidazole Method: B.F. Gisin, R. B. Menifield, D. C. Tosteon, Am. Soc. 91: 2691 (1969).

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

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

·· 444 · «4444

4 ·

All the 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 possible 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. Preference is given to 4-nitrophenol and N-hydroxysuccinimide, the latter being 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 from 0 ° C to 50 ° C, acidic saponification with a mineral acid. of butyl esters with trifluoroacetic acid [Protective Groups in Organic Synthesis, 2nd edition, TW Greene and PGM Wuts, John Wifey and Sons, Inc. New York, 1991], in the case of benzyl ethers using hydrogen and palladium on carbon.

Preparation of Starting Materials, Compound of Formula IIIb

COOR

COOR

COOR (Illb) is known from DE 196 52 386. Amines of the formula IVb according to the invention. fcfcfcfc

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

Vllb:

+ A + A R '

(Vb) (VIb) (VIIb) (IVb) wherein

R ^f, A ^1, L ¹ and R ³ have the same meanings as stated above and L 'is a group L ^1, lacking a -CH ₂ group and R9 is hydrogen or methyl.

Accordingly, the carboxylic acid IIIb is activated according to literature procedures prior to reaction with amine VIb. In the case that ^R is a methyl group, the aminolysis.

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

Compounds of formula VIb are commercially available (Fluorochem, ABCR) or can be prepared according to known methods such as Houben-Weyl, Methoden der Organischen Chemie, XI / 2, Stickstoffverbindungen, Georg Thieme Verlag Stuttgart, 1957, p. 680, JE Rickman and T Atkins, Am. Chem. Soc., 96:

* «·· * · ··

2268, 1974, 96: 2268; F. Chavez and A. D. Sherry, J. Org. Chem., 1989, 54: 2990

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

Method B.

The starting materials are the carboxylic acids of formula IIIx wherein R ¹ is hydrogen, which contains no equivalent of the metal ion R ¹ . The carboxyl groups were protected by known methods to give a compound of formula IIIa, wherein R ⁵ is any protecting group and R ⁵ 'is a prodrug thereof.

(»Lx> (lily)

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

• · · · ·

The reaction of the protected carboxylic acid lily with the amine of formula IVb and the cleavage of the protecting groups is carried out as in procedure A and in the next step the obtained carboxylic acid Ix is reacted with at least one metal oxide or metal salt of the desired atomic number element. 195 25 924

The metal complex prepared by Method A or Method B contains free -COOH groups which may exist as salts of physiologically acceptable inorganic or organic bases.

Neutralization of any free carboxyl groups present is carried out with the aid of inorganic bases (e.g. hydroxides, carbonates or bicarbonates) such as sodium, potassium, lithium, magnesium or calcium and / or organic bases, among others primary, secondary and tertiary amines such as ethanolamine, morpholine , glucamine, N-methyl- and N, N-dimethylglucamine, as well as basic amino acids such as lysine, arginine, ornithine, or amides of initially 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 Ib are very useful as contrast agents for NMR imaging of plaques.

In another preferred embodiment of the invention, the perfluoroalkyl complexes with sugar moieties of formula Ic include:

(YR) p ¹ (1c) where

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

R ^F is a perfluorinated, straight or branched hydrocarbon chain of the formula -C _n F _2n E, where E is fluoro, chloro, bromo, iodo, or hydrogen, and n is an integer of 4-30,

K is a metal complex of formula IIc,

ROOC

N - »- j— (IIc) where

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

R ¹ and R ³ are independently of each other hydrogen, alkyl having 1 to 7 carbon atoms, benzyl, phenyl, CH ₂ OH or -CH ₂ OCH ₃ , and

In the group -C ₆ H ₄ ~ _0-CH2 -CO, - (CH ₂₎ -ω ι- _5, phenyl, -CH ₂ -NHCO-CH ₂ -CH (CH ₂ COOH) ₄ -06Η - ω, C ₆ H ₄ - (OCH ₂ CH ₂ ) o N (CH ₂ COOH) -CH ₂ -co, or an alkylene group having 1 to 12 carbon atoms or C ₇ -C ₁₂ -C ₆ H ₄ -O- , optionally interrupted with one or more oxygen atoms, 1 to 3

Even -NHCO-, 1-3 -CO-NH and / or substituted with one to three groups - _(CH2) 0-5COOH, where ω is the binding site to -CO-, or of formula IIIc

ROOC

wherein R ¹ is as defined above, R ⁴ is hydrogen or a metal ion equivalent as defined in R ¹ and U ¹ is -C ₆ H ₄ -OCH ₂ -ro-, where ω is the binding site to the group -CO-, or compounds of formula IVc

ROOC

(IVc) wherein R ¹ and R ² are as defined above, or compounds of formula VcA or VcB

WHAT-**

COOR

R ¹ OOC n:

-COOR ¹

- COOR ¹ (VcA)

• · · · ·

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

ROOC— \ —CO — wv

ROOC ^'NN -COOR ^{1 (VIc)} wherein R ¹ is as defined above, or a compound of formula VIIc

ROOCROOCROOC-ROOCO (VHc) where R ¹ is as defined above,

U1 is -C ₆ H ₄ -0-CH2-O-, where ω is a binding site to -CO-, or of formula VIIIc

ROOC

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 of organic and / or inorganic bases or amino acids or amino acid amides,

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

and)

f <IH β

(b)

C)

and

d) 9 · 9 9 · φ * 9 φ φ

E)

-and

F)

NH-CO -C- (CHA-N 1 ^H NH 1, N- * T ');

H

-CO-C- (CH 2 -N 4 -a NH b)

G)

NH

^NH-CO-CH-X ÍCHjVNH N-CO-CH- _(CH2) 4-NH- ^ and

NH

Ϊ

NH-CO-CH- (CH _{2) 4} -NH-NH ^ *

(h)

(i) • (CHJ.

-S-CON NH

j) a ^ NH — CH — CO — ^ Y 4 β a

G when K is a metal complex VIIlc, at least three times the functionalized moiety is selected from the group consisting of k) and 1)

k) p-NH- _(CH2) 4-C _H '^ CO- and

NH i

Y

i) • ί »· • • ♦ A · A · * • • • • AAA A · A · •« • · · · ·· AA o ^ CO-CH = CH-CH-CO-NH ² YI

I ř

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

Y is -CH ₂ -, δ- (CH ₂ ) i -sCO-β, δ-ΟΗ ₂ - <ΖΉΟΗ-ΟΟ-β, or δ-CH (CHOH-CH ₂ OH) -CHOH-CHOH- CO-β, where δ denotes the binding site to the sugar residue R and β denotes the binding site 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,

O ^ N-SQ- £ or γ - NHCH ₂ CH ₂ - 0 - CH ₂ CH ₂ -ε where γ is the point of attachment of Z to the residue G and ε the point of attachment of Z to the polyfluorinated residue R ^{F and l} , m ¹ are independently where integers 1 or 2 p ¹ is an integer from 1 to 4.

• 4 4 4

4 *

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 the elements of 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, dyspropious, holmite, erbite, ferric and manganese ions are particularly suitable.

Particularly suitable are the manganese, ferrous, ferric, praseodymium, neodymium, samarium, gadolinium and ytterbitium ion, in particular the dysprosit ion.

Acidic hydrogen atoms optionally occurring in R1, 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 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 Ic are those having the macrocycle K of formula IIc.

The radical U in the metal complex K is preferably -CH ₂ - or C ₆ H ₄ -O-CH ₂ -o, where ω is the binding site to the -CO- group.

The alkyl groups R ² and R ³ in the macrocycle of formula (IIc) may be straight or branched. By way of example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl may be mentioned. Preferably R ² and R ³ are independently from each other hydrogen or alkyl having 1 to 4 carbon atoms. In one particularly preferred embodiment of the invention R ^{2 is} methyl and R ³ is hydrogen.

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

The radical R in formula (Ic) denotes a mono-, oligosaccharide or thiocug residue which is bonded via the 1-OH- or 1-SH- position, which may also be replaced by desoxy sugars and which contain one or more OH 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 their desoxy sugars such as 6-desoxygalactose (fucose) or 6desoxymannose (rhamnose), or thiocucrose thereof, with glucose, mannose and galactose being particularly preferred.

Compounds of formula Ic of this invention are preferred when R ^F is -C _n F _{2n +,} wherein n is preferably an integer of 4 to 15 are particularly preferred radicals -C ₄ F _9, -C ₆ Fi _{3 /}

C ₅ F ₁₇ z -C ₁₂ F ₂₅ and -C ₁₄ F ₂₉ as well as residues of the compounds exemplified.

At least three times a functionalized moiety Ic representing a "molecular scaffold" of an embodiment of the invention is a lysine residue

G in the general formula is in a preferred (a) or (b).

Y and Z are the linkers shown in formula Ic, wherein preferably independently of one another Z is a residue

7 — Νζ_ / N-SO ₂ - a and Y is the remainder δ- <ΖΉ ₂ ΟΟ-β.

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

I (Ic) (YR) p 'where K is a metal complex of formulas IIc to VIIc and G has the meanings of formulas a) to j) wherein Y, Z, R, R ^F , m ¹ , p ¹ and I ¹ have the same as defined above, are prepared by employing, in a known manner, the carboxylic acid of formula (II)

COOR ⁵

R 00C

nu ^ oh (Hi) where R ⁵ is the metal ion equivalent of atomic number 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 the formula III

COOR ⁵

R ^S OOC

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

R 00C

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

X ^ _K i - COOR OH - COOR ⁵ r ⁵ ooc ^ 7 ⁿ Kj-COOR ⁵ COOR ⁵ x ^ COORf Z - COOR ⁵

N

HOOC / \ x ~ _M COOR ⁵

COOR ⁵ (Vi) (Vii) wherein R ⁵ is as defined above or a carboxylic acid of formula VIIa

R ^{S S} OOCR OOC: nn:

-what-oh

-coor ⁵ ( ^{v, i} )

«.

· 9999 • fc • fcfc * fcfc fcfc

wherein R ⁵ has the abovementioned meaning or a carboxylic acid of the formula R ⁵ OOC Vili ^R5 ooc ooc R ⁵ R ⁵ OOC wherein ^R and U ¹ have the abovementioned meaning, optionally in activated form, is reacted with an amine of general formula IXc

H - G - (ZR ^F ) _m ¹

I (IXc) (YR) p ¹ wherein G has the meaning of formulas a) to j) and R, ^Rf, Y, Z, m ¹ and p ¹ are as above defined, by condensation reaction, and optionally after subsequent cleavage occurring protecting groups a metal complex of the formula Ic is formed 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 a metal salt of elements of atomic numbers 23 to 29, 42 to 46 or 58 to 70 and where appropriate, the acidic hydrogen atoms are 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) has the meaning of formulas (k)

• · · · · · ·.. <

Or 1) are prepared by reacting an amine of the general formula VIaI.

R OOC

_N - ^h

H (VIII) wherein R 5 is a metal ion equivalent of atomic number up to 29, 42 to 46 or 58 to 70, or a carboxyl protecting group is reacted with an optionally activated carboxyl group of formula Xc in a known manner

HO - G - (ZR ^F ) _m ' ¹ ( ^{X 0} ) (YR) _p ' where G is as defined in formulas k) or 1) and R, RF, Y, Z, ml and pl are as defined above, by condensation reaction and optionally cleavage of the occurring protecting groups results in a metal complex of formula (1c) or, when R ⁵ is a protecting group, after cleavage of this protecting group is reacted in a known manner with at least one metal oxide or metal salt of atomic number 23 to 29, 42 to 46 or 58 to 70 and finally, if desired, acidic hydrogen atoms are substituted with cations of inorganic and / or organic bases, amino acids or amino acid amides.

Said carboxylic acids of formula (III) to either known compounds or prepared according to the procedures of the Examples. The preparation of the carboxylic acid of formula (III) is known from DE 196 52 3 86.

The acids are described by Acid Preparation

999

The carboxylic acids of the formula IVi are possible as described in DE 197 28 954.

The starting material for the compounds of formula VcA is N ^3- (2,6-dioxomorpholinoethyl) -N ⁶ - (ethoxycarbonylmethyl) -3,6-diazaoctanedioic acid, which is described in EP 263 059.

The compounds of formula (VcB) are derived from the isomer of diethylenetriamine-pentaacetic acid, which is linked via acetic acid at the middle 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. (1982) 59 (2): 104-107.

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

Perbenzylated sugar acids used as starting compounds can be prepared analogously to Lockhoff, Angew. Chem. 1998, 110, no. 24, p. 3634. Thus, for example, synthesis of 1-O-acetic acid of perbenzylated glucose via two substances was carried out via trichloroacetamidate and reaction with ethyl acetate of hydroxyacetic acid under catalysis with BF ₃ in THF and final saponification. with NaOH in methanol-THF.

In a preferred embodiment of the invention said perbenzylated sugar acid is used as starting material, wherein the perbenzylated 1-OH-sugar is dissolved in a solvent

• 39 ·· ···· • · · ·· · ·· ·· • · · · · • · · · •; · · * · • · · · immiscible with water and allowed to stand respond with alkylation agent of formula XIc Nu-COO-Sg (XIc) where Nu is a leaving group, L is a group - (CH ₂ ) (1-5), group -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. For example, -Cl, -Br, -J, OTs, -OMs, -OSO ₂ CF ₃ , -OSO ₂ C ₄ H ₉ or -OSO ₂ C ₈ F ₇ may be used as a leaving group 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 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 ground to a powder, or as a 10% to 70%, preferably 30% to 50% aqueous solution. Preferred bases are NaOH and KOH.

Toluene, benzene, CF ₃ benzene, hexane, cyclohexane, diethyl ether, tetrahydrofuran, dichloromethane, MTB or mixtures thereof may be used as the water-immiscible organic solvent in the alkylation of the invention.

Known phase quaternary ammonium and phosphonium salts or crownethers such as [15] -crown-5 or [18] -crown-6 are used as phase transfer catalysts of the present invention. Preferably, quaternary ammonium salts with four identical or different hydrocarbon groups in the cation selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl or isobutyl are used. The hydrocarbon groups on the cation must be sufficiently large to guarantee good solubility of the alkylating agent in the organic solvent. Particularly preferred according to the invention are N (Butyl) ₄ ⁺ Cl ', N (butyl) 4 ⁺ HSO4', but also N (methyl) ₄ ⁺ d '.

Particularly preferred compounds of formula 1c 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 Id (K), '- G - (ZR ^F ) _m ' are used.

I (Id) (R) p ² wherein

R ^f is a perfluorinated, straight or branched hydrocarbon chain of the formula -CnF 2 nE, wherein 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 IId

ROOC

R ³

Ň-

Old) where ·· ....,.

ί! · · · · ·.

Her.· · " ·

Her! ··· ·.

.. ·; · · · ···

».

• three tiers three tiers

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

R ¹ and R ³ are independently of each other hydrogen, alkyl having 1 to 7 carbon atoms, benzyl, phenyl, CH ₂ OH or -CH ₂ OCH ₃ , and

-C ₆ H ₄ -O-CH ₂ -a>, - (CH ₂ ) ₁₅ -ω, phenyl, -CH ₂ -NHCO-CH ₂ -CH (CH ₂ COOH) -C ₆ H _4-a , C ₆ H ₄ - (OCH ₂ CH ₂ ) o N (CH ₂ COOH) -CH ₂ -o, or an alkylene group having 1 to 12 carbon atoms or C ₇ -C ₁₂ -C ₆ H ₄ -O-, optionally interrupted with one or more oxygen atoms, 1 to 3 -NHCO-, 1 to 3 groups -CO-NH- and / or substituted with 1 to 3 - (CH _{2) 0-5} COOH, wherein ω is the point of attachment to the group -CO-, or of the general formula IIId

COOR ¹ COOR ⁴ Q

ROOC '

COOR ¹ (IIId) wherein R ¹ is as defined above, R ⁴ is hydrogen or the metal ion equivalent given under R ¹ and U ¹ is -C _s H ₄ -O-CH ₂ -co-, where ω is the binding site to -COor the general formula IVd e 4 φ e · e e e · · · · · · · · · · · · · · · · * ··

(IVd) wherein R ¹ and R ² are as defined above, or of the general formula VdA or VdB (N, _N -CO-v) -COOR ¹

R ¹ OOC / \ _n ^ Coor ¹ ^ -COOR ¹ (VdA)

-COOR ¹

-COOR ¹

x-COOR ¹ Z ^ - COOR ¹ (VdB) wherein R ¹ is as defined above, or of the formula Vid

ROOC

ROOC

WHAT-

COOR ¹ (Vid) wherein R ¹ is as defined above, or of formula Vild

ROOCR ¹ OOCROOCROOC: n: n

(Vild) wherein R ¹ is as defined above and

U 1 is -C ₆ H ₄ -O-CH ₂ -w-, wherein w is a binding site to the group -CO-, and the acid groups optionally present in residue K may be present in the form of salts of 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)

and)

rilH β

(b)

α

C)

d) • ·

F)

G)

(h)

β

(CH ₂ ) ₄ -C-NO 2 ^H

Y

CO-C- (CH 3 -NH)

AND

• · · · γ -co- (CH ₂ ) ₂ . ₃ -ch-co- ^ 3

NH

I α

(i) β -A * CO- (CH ₂ ) ₂ . ₃ -CH-CO - ^, y NH where a denotes the binding site G to the complex K, β denotes the binding site G to the residue R and γ denotes the binding site G to the residue Z

Z is

Y - N - SO ₂ - £

YC (O) CH ₂ O (CH ₂ ) 2 -e, wherein γ denotes the Z-binding site to G and ε denotes the Z-binding site to the perfluoroalkyl radical R ^F R is a polar radical selected from complex K of formulas lid-Vild, wherein R ¹ is a hydrogen atom or an equivalent of a metal ion of atomic number 20, 23 to 29, 42 to 46 or 58 to 70, and the radicals R ² , R ³ , R ⁴ , U and U ¹ have the above meaning or folic acid or hydrocarbon residue a chain having 2 to 30 carbon atoms, straight or branched, saturated or unsaturated, bonded to the remainder of G by -CO-, -SO ₂ - or directly, optionally interrupted with 1 to 10 oxygen atoms, 1 to 5 NHCO-, 1 to 5 -CONH-, 1 to 2 sulfur atoms, up to 5 -NH- or 1 to 2 phenyl groups which may be optionally substituted with 1 to 2 OH groups, 1 to 2

NH ₂ groups, 1-2 -COOH groups, or 1-2 -SO ₃ H groups, or l ^1, m ^1, p ² are each independently integers 1 or 2 respectively.

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 of 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, dyspropious, holmite, erbitic, ferric and manganese ions are particularly suitable.

Particularly suitable are the manganese, ferrous, praseodymium, neodymium, samarium, gadolinium and ion, especially dysprosit ion.

ferric, ytterbit

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 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 IId, IIId, VdB or Vild.

The radical U in the metal complex K is preferably -CH ₂ - or C ₆ H ₄ -O-CH ₂ -ro, where ω is the binding site to the -CO- group.

The alkyl groups R ² and R ³ in the macrocycle of formula (IIc) may be straight or branched. By way of example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl may be mentioned. Preferably R ² and R ³ are independently from each other hydrogen or alkyl having 1 to 4 carbon atoms.

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

The benzyl group or the phenyl group R ² or R ³ in the macrocycle K of formula IId can also be substituted on the ring.

The polar residue R in formula Id is a particularly preferred embodiment of the complex K, which may be, inter alia, a Gd ³⁺ or Mn ²⁺ complex as well as Ca ²⁺ . Especially preferred as polar

the radicals R are the complexes K of the formula IId, IIId, VdA or Vild. Particularly preferred are those where, as R ^{1, the} metal ion equivalents of atomic number 20, 25, 39 or 64.

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

-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) CH ₂ OH

-C (0) CH ₂ NH-C (0) CH ₂ COOH

-C (O) CH ₂ CH (OH) ₂ OH

-c (O) ch ₂ and 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 ₅ 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 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 OH- ₉ -CH ₃

-C (O) CH ₂ O [(CH ₂ ) ₂ O] i. ₉ -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) ₂

-c (O) -ch ₂ o- (ch ₂ ) ₂ 0 (ch ₂ ) ₂ o- (ch ₂ ) ₂ o (ch ₂ ) ₂ and ₃ preferably -C (O) CH ₂ O [(CH ₂₎ ) ₂ O] ₄ -CH ₃ .

• 0 · ·

0 0 0 0 0 0 0 0 • 0 0 0 0 0

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

Compounds of formula ID according to this invention are preferred when R ^F is -C _n F _{2n + 1,} wherein n is preferably an integer of 4 to 15 are particularly preferred radicals -C4F9 -C ₆ Fi ₃

C ₆ F ₇ , -Ci ₂ F ₂ 5 and -Ci ₄ F ₂ 9.

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

Z denotes the linker represented by the general formula Id, wherein the radical y-N-SO ₂ -? Is preferred

Perfluoroalkyl metal complexes with polar radicals of general formula Id (K) "- G- (ZR ^{f) '1 1} (Id), (R) ² where K P, G, R, Z, prepared,

Ilk

R ^f , l ¹ , m ¹ and P ² are as defined above, wherein the carboxylic acid of the formula

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

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

wherein R ⁵ and R ² are as defined above, or a carboxylic acid of the general formula Vk or Vm

HOOC

COOR ⁵ '-COOR ⁵

COOR®

COOR ⁵ (V k) (V m) wherein R ⁵ is as defined above, or a carboxylic acid of formula Vlk

R ^S OOC

R ^S OOC

CO-OH

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

OOCR R ^{S S S} OOCR OOCR ^S OOC: n:

O

Where R ⁵ and U ¹ are as defined above, optionally in activated form, are reacted in a known manner with an amine of formula VIIId

H - G - (Z-RV | (VIIId) (R) p ^S where G, R, Z, R ^F , m ¹ and p ¹ have the meaning given above, by condensation reaction and after possible subsequent cleavage of the occurring protecting groups a complex of the 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 a metal salt of the elements of atomic numbers 23 to 23; 29, 42-46 or 58-70, and finally, as appropriate, acidic hydrogen atoms are substituted with cations of inorganic and / or organic bases, amino acids or amino acid amides.

Said carboxylic acids of the formulas IIk to VIIk 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 in DE 196 52 386.

The preparation of carboxylic acids of the general formula IVk is described in DE 197 28 954.

The compounds of formula VdA are N ^3- (2,6-dioxomorpholinoethyl) -N ⁶ - (ethoxycarbonylmethyl) -3,6-diazaoctanedioic acid as described in EP 263 059.

The compounds of formula (VdB) are derived from the isomer of diethylenetriamine-pentaacetic acid, which is linked via acetic acid to a central nitrogen atom. This DTPA is described in DE 195 07 819 and DE 195 08 058.

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

The compounds of formula Vild are derived from 1- (4-carboxymethoxybenzyl) -ethylenediamine-tetraacetic acid, which is described in US 4,622,420.

·· · 4 · ····

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 present invention, galenic formulations comprising paramagnetic and diamagnetic perfluoroalkylated compounds may be used. Preferably, the paramagnetic and diamagnetic materials are available in an aqueous solvent.

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

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. 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 with one or more -OH, -COO-, -SO 3 - and / or containing one or more groups -O-, -S-, -CO-, -CONH-, -NHCO-, -CONR ⁹ -, -NR ⁹ CO-, -SO 2, -PO ₄ '-, -NH-, -NR ⁹ -, aryl a ring or piperazine wherein R ⁹ is an alkyl radical having 1 to 20 carbon atoms, which may contain one or more O atoms and / or may be substituted with a -COO- group or a -SO ₃ group.

The hydrophilic group B ² is a mono- or disaccharide, a close group -COO 'or a group -SO ₃ ' -, a docarboxylic acid, isophthalic acid, picolinic acid, benzenesulfonic acid.

acid, tetrahydropyrandicarboxylic acid, 2,6-pyridinedicarboxylic acid, quaternary ammonium group, aminopolycarboxylic acid, aminodipolyethylene glycol sulfonic acid, aminopolyethylene glycol group, SO ₂ - (CH ₂ ) 2 -OH- group, polyhydroxyalkylene chain with at least two hydroxy groups with at least two hydroxy groups or one or more two glycol units, wherein the polyethylene glycol chain is terminated by -OH or OCH ₃ . Such compounds are already partially known, in part they have been newly synthesized to produce the compositions of the invention. Known perfluoroalkyl compounds and their preparations are described in the following publications:

J.G. Riess, Journal of Drug Targeting, 1994, Vol. 2, p. 455-468; J. B. Nivet et al., Eur. J. Med. Chem., 1991, Vol. 26, p 953-960; M.-P. Krafft et al., Angew. Chem., 1994, Vol. 106, C. 10,

pp. 1146-1148;

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

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

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

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

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

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

• 9,999

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

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

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

A. Milus et al., Carbohydrate Research, 1992, Vol. 229, pp. 323-336;

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

G. Merhi et al., J. Med. Chem., 1996, Vol. 39, pp. 44834488;

V. Cirkva et al., Jounal of Fluorine Chemistry, 1997, Vol.

83, pp. 151-158;

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

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

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

MM. Chaabouni et al., Journal of Fluorine Chemistry, 1990, Vol. 46, p. 307315;

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

M. -P. Krafft et al., New J. Chem., 1990, Vol. 14, pages 8698 75;

J: B. Nivet et al., New J. Chem., 1994, Vol. 18, pages 861869;

C. Santaella et al., New J. Chem., 1991, Vol. 15, p.685- 692; C. Santaella et al., New J. Chem., 1992, Vol. 16, pp. 399- 4 04; A. Milus et al., New J. Chem., 1992, Vol . 16, pp. 771-773;

· · · • • • · · · · ·

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

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

M.-P. Krafft et al., Angew. Chem., 1993, Vol. 105, No. 5, pp. 783-785; EP 0 548 096 B1.

The preparation of the new perfluoroalkyl compounds follows analogously to the literature preparation of the above known compounds and is described in the Examples. They are compounds of formula XXI ¹ -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 an integer from 1 to 10 ):

fcfc ··· ·· rf ··

·· ···· 44

4444

4 4 4 4 4 4 4

49

OH • · ··········

COO · ta ·

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 L ² 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-, -NRCO-, -SO ₂ - or piperazine, wherein R is as defined above and the monosaccharide residue as B ² .

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

A 1Z-RF (XXII) wherein A ¹ 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 30 carbon atoms. The linker L ³ is a straight hydrocarbon chain having 1 to 20 carbon atoms, which may be interrupted by one or more CO-, SO ₂ -, CONH-, NHCO-, CO-NR-, NRCO-, NH-, NR or piperazine groups, where R is an alkyl radical having 1 to 5 carbon atoms.

The following compounds are particularly preferred:

• · · · · · · ·

SoτΑτ ^ Sso, -c ₈ f ₁₇ | (^ 1 ^ ⁵ ° ^{C F '7}

····

\ _ / \ _ / Η θ8 Ί7

The galenical compositions of the present invention contain paramagnetic and diamagnetic perfluoroalkyl compounds in a mixed ratio 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 of the formulation ranges from 50 to 250 mmol / l.

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

The preparation of galenic preparations is carried out 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 stirred vigorously at 10 to 100 ° C. Alternatively, the solution is left in an ultrasonic bath. Another alternative is to treat the solution using microwaves.

For substances where the individual components do not dissolve in water, it is preferred to use a solvent such as an alcohol (e.g. methanol or ethanol) or another water-miscible solvent, which is then allowed to slowly distill off. The distillation can be carried out under vacuum. The residue was finally dissolved in water and the solution was filtered. It is also possible that the individual components are each separately dissolved in a solvent, then combined together and processed further as described above. It has been found to be advantageous to use relatively strong 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.

Overall, as particularly preferred compounds, the gadolinium complexes I to XVI listed in Table 1 which meet the criteria of the present invention are particularly preferred.

Both the paramagnetic compounds of the formulas I, Ia, 1b, Ic and Id of the present invention as well as the paramagnetic and diamagnetic perfluoroalkyl compounds are suitable for the above use as contrast agents in NMR imaging for plaque, tumor and necrosis imaging.

· Φ φ φ φ φ φ φ φ φ

Table 1: Particularly preferred metal complexes for use in the present invention Complex Literature, Name

WO 97/26017 Example 33f

Gadolinium complex with 10- [1-Methyl-2-oxo-3-aza-5-oxo- {4-fluorooctylsulfonyl-piperazin-1-yl} -pentyl] -1,4,7-tris (carboxymethyl) -1,4,7, 10-tetraazacyclododecane

II WO 97/26017, Example 2c

Gadolinium complex with 10- [2-Hydroxy-4-aza-5-oxo-7-oxa10,10,11,11,12,12,13,13,14,14,15,15,16,16,17, 17-heptadecafluoroheptadecyl] -1,4,7-tris (carboxymethyl) -1,4,7,10tetraazacyclododecane

III WO 97/26017, Example 34b

Gadolinium complex with 10- [2-Hydroxy-4-aza-5,9-dioxo-9- (4-fluorooctyl) piperazin-1-yl} nonyl] -1,4,7tris (carboxymethyl) -1,4,7, 10-tetraazacyclododecane

IV WO 97/26017, 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-oxo-hexan-5-yl) -acid-N- (2,3-dihydroxypropyl) -N- (1H, 1H, 2H, 2H, 4H, 4H,

5H, 5H-3-oxa-perfluorotridecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex

VI WO 97/26017, Example 3c

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

VII Example 5e, This Application

1.4.7- Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid- [N (3,6,9,12,15-pentaoxa) -hexadecyl] -N- (1H) , 1H, 2H, • · · · · · ·

2H, 4H, 4H, 5H, 5H-3-Oxa-Perfluorotridecyl] -amide} -1,4,7,10-Tetraazacyclododecane, gadolinium complex

VIII Example 3c, this application

1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid-N- (5-hydroxy-3-oxa-pentyl) -N- (1H, 1H) 2H, 2H, 4H,

4H, 5H, 5H-3-Oxa-perfluorotridecyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex

IX Example 6b, this application

1.4.7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -surea- [N-3,6,9,16-tetraoxa-13-aza-14-oxo-Ci ₉ -C ₂₆ -heptadecafluoro) hexacosyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex

X Example 1c, this application

1.4.7- Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-hexan-5-yl) -acid-N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H) {5H-3-oxo-perfluorotridecyl] amide} -1,4,7,10-tetraaza-cyclododecane, gadolinium complex

XI WO 97/26017, Example 32c

Gadolinium complex with 10- [2-Hydroxy-4-aza-5-oxo-7-oxa10,10,11,11,12,12,13,13,14,14,15,15,16,16,17, 17,18,18,19,19henicosafluornonadecyl] -1,4,7-tris (carboxymethyl) -1,4,7,10tetraazacyclododecane

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 (perfluorooctylsulfonyl) -8-phenyl-octyl] -1,4,7tris (carboxymethyl) -1,4,7,10 -tetraazacyclododecane

XIV WO 99/01161, Example 1g 4 4 44 4

4 4 4 4 4

4 4 4 4 4 4 4 4 4

4 4 44 4 4 44

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

XV Example 21f, this application

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

XVI Example 54b, this application

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

Table 2

Physicochemical parameters of the complexes of the present invention listed in Table 1

Complex number CMC (mol / 1) 2 Rh (nm) R ¹ plasma (1 / mmol) AND 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 10-6 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 10-6 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 10-6 4.4 15.9 XVI 3.90 X 10-6 4.9 21.3

CMC: critical micellar concentration

Rh: hydrodynamic micellar diameter

R ¹ : relaxation

4444

4 4 4

• 4

2H, 2H, 4H, 4H, 5H, 5H-3-oxa2H, 2H, 4H, 4H, 5H, 5H-3-oxa

Example 1

(a) Perfluorotridecanoic acid N- (2-methoxy) -ethylamide

To 30 g (57.45 mmol) of perfluorotridecanoic 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 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 chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1). Yield: 30.28 g (91% of theory) of a colorless solid.

Elementary analysis:

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-Methoxy-ethyl)-(- (1H, IH, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) pertluorotridecylamine g (51.79 mmol) of the title compound of Example 1a was dissolved in 300 ml of tetrahydrofuran and 31 ml of a 10 M solution of borane dimethyl sulfide (in tetrahydrofuran) was added. The mixture was boiled under reflux for 16 hours. Then the mixture was cooled to 0 ° C and 200 ml methanol was added dropwise, and the mixture was finally evaporated to dryness in vacuo. The remainder was put into a mixture of 300 ml ·· ·· ♦ ·

4% 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 then evaporated to dryness under vacuum, the residue was taken up in 300 ml of 5% sodium hydroxide 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 (eluent:

dichloromethane / 2-propanol = 20: 1). Yield: 26.93 g (92% of theory) of a colorless solid.

Elemental analysis (calculated on the anhydrous substance):

H, 2.85; N, 2.48; F, 57.14

Found: C 31.69 H 3.10 N 2.27 F 56.88

c) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-hexan-5-yl) -acetic acid N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H) 1,4,4,10,10-tetraazacyclododecane, gadolinium complex (metal complex X) 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 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 was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether, and the mixture was stirred at room temperature for 2 hours. The precipitate formed was filtered, dissolved in a small amount of ethanol and water and chromatographed on silica gel RP-18 (mobile phase: gradient of tetrahydrofuran / acetonitrile / three titers. Three titers.). Ti titititi water). Yield: 15.14 g (81% of theory) of a colorless, amorphous powder. Water content: 5.7%.

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-oxa) perfluorotridecanoic 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 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 at 0 ° C for 3 hours, and finally at room temperature for 6 hours. Then 300 ml of 5% aqueous hydrochloric acid 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 chromatographed on silica gel (mobile phase: dichloromethane / ethanol = 15: 1). Yield: 29.70 g (87% of theory) of a colorless solid.

Elementary analysis:

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-oxaperfluorotridecyl) -amine • fc ···· • fc ···· fcfcfcfcfcfcfcfcfcfcfcfcfc fcfcfcfcfcfcfcfcfc gc (48.8 mmol) of the title compound of Example 2a was dissolved in 300 ml of tetrahydrofuran and 50 ml was added in 50 ml. M solution of borane dimethyl sulfide (in tetrahydrofuran). The reaction mixture was heated to reflux for 16 hours. It was then cooled to 0 ° C and 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 10% aqueous hydrochloric acid and stirred at 60 ° C for 8 hours. 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 chromatographed on silica gel (Mobile phase: dichloromethane / methanol = 15: 1). Yield: 24.07 g (85% of theory) of a colorless solid.

Elementary 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-oxo-hexan-5-yl) -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 complex with 10 - [, 2 H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) 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 dimethylsulfoxide 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-1,2,444 was added (4,444 g). • dihydroquinoline • • • • • • • • • • • •. The mixture was then stirred at room temperature for 2 hours. The solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether, and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered, the precipitate dissolved in a small amount of ethanol / water and chromatographed 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 3

(a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid N- (5-hydroxy-3-oxa-pentyl) -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 at room temperature for 12 hours. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and 6.25 g (60 mmol) of 5-hydroxy-3-oxa-pentylamine and 6.07 g (60 mmol) of triethylamine in 200 mL of dichloromethane were added dropwise at 0 ° C. 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 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 chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1).

ΦΦ φ φ φ · · · · φ · · · · · · · ·

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

Elementary 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- (5-Hydroxy-3-oxa-pentyl) -Ν- (1H, IH, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -amine g (49.24 mmol) of the title compound of Example 3a was dissolved in 300 mL of tetrahydrofuran and 31 mL of a 10 M solution of borane dimethylsulfide (in tetrahydrofuran) was added. The reaction mixture was stirred at reflux for 16 hours. The reaction was cooled to 0 ° C and 200 mL of methanol was added dropwise, then 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 10% aqueous hydrochloric acid and heated at 50 ° C for 10 hours. The reaction mixture was evaporated to dryness in vacuo and 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 sulphate, evaporated to dryness under reduced pressure, and the residue was chromatographed on silica gel (Mobile phase: dichloromethane / 2-propanol = 20: 1).

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

Elementary 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-oxo-hexan-5-yl) -acid-N- (5-hydroxy-3-oxa-pentyl) -Ν- (1H) (1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -amide] -1,4,7,10-tetraazacyclododecane complex with gadolinium (metal complex VIII) this · ·· to 9 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 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 was added. The mixture was stirred at room temperature for 12 hours. 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, dissolved in a small amount of ethanol / water and chromatographed on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.10 g (84% of theory) of colorless amorphous powder: 5.7%

Elemental analysis (calculated on the anhydrous substance):

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, 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 at room temperature for 12 hours. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and added dropwise 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 at 0 ° C. The reaction mixture was stirred for 3 hours at 0 ° C and then for 6 hours at 9 ° C.

9 9 ·

9 9

9999 • 9 9

99 room temperature. Then 300 ml of 5% aqueous hydrochloric acid 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 chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1).

Yield: 28.90 g (89% of theory)

Elementary analysis:

H, 2.14; N, 2.48; F, 57.14

Found: C 29.61 H 2.29 N 2.37 F 57.01

b) N- (2-Hydroxyethyl) -N- (1H, 1H, 2H, 2H; 4H, 4H, 5H, 5H-3-oxa) perfluorotridecyl) -amine g (49.54 mmol) of the title compound of Example 4a was dissolved in 300 mL of tetrahydrofuran and 31 mL of a 10 M solution of borane dimethyl sulfide (in tetrahydrofuran) was added. The mixture was heated at reflux for 16 hours. It was then cooled to 0 ° C and 200 ml of methanol was added dropwise, then the reaction mixture was evaporated to dryness under reduced pressure. The residue was added to a mixture of 300 ml of ethanol and 50 ml of 10% aqueous hydrochloric acid, and the mixture was stirred at 50 ° C for 10 hours. 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 sulfate, evaporated to dryness under reduced pressure, and the residue was chromatographed on silica gel (Mobile phase: dichloromethane / 2-propanol = 15: 1). Yield: 25.12 g (92% of theory) of a colorless solid. Elemental analysis (calculated on 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 (carboxylateomethyl) -10 - [(3-aza-4-oxo-hexan-5-yl) -acid-N- (2-hydroxyethyl) -N- (1H, 1H, 2H) , 2H, 4H, 4H, 5H, 5H-3oxa-Pertluorotridecyl) amine] -1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of gadolinium complex with 10- [1 (carboxymethylcarboamoyl) 1-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 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 was added. The mixture was stirred at room temperature for 12 hours. The reaction solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether and stirred at room temperature for 2 hours. The precipitate formed was filtered, dissolved in a small amount of ethanol and water and chromatographed 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-oxa-perfluorotridecanoic acid amide To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid in 300 ml of dichloromethane Oxalyl chloride (8.90 g, 70 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was then 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 about 2 hours. The mixture was stirred at 0 ° C for 4 hours, and then stirred at room temperature for 2 hours. Then 300 ml of 5% aqueous hydrochloric acid was added and the mixture was stirred vigorously for 5 minutes. The organic phase was separated, dried over magnesium sulphate and then evaporated to dryness. The residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1). Yield: 27.85 g (93% of theory)

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, 5H-3-oxa-perfluorotridecylamine hydrochloride g (51.8 mmol) of the title compound of Example 5a was dissolved in 300 mL of tetrahydrofuran and 31 mL of 10M solution was added borane dimethyl sulfide (in tetrahydrofuran). The mixture was stirred at reflux for 16 hours. It was then cooled to 0 [deg.] C. and 200 ml of methanol was added dropwise, then 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 10% aqueous hydrochloric acid and stirred at 60 ° C for 8 hours. The mixture was evaporated in vacuo and the residue was crystallized from a small amount of ethanol / diethyl ether.

Yield: 26.75 g (95% of theory) of a colorless crystalline solid.

Elementary analysis:

Calculated: C 26.51 H 2.04 N 2.58 F 59.41 Cl 6.52

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

(c) 3,6,9,12,15-Pentaoxahexadecanoic acid N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluorotridecyl} -amide • · · · · · · · · · · ·

To a mixture of 26.5 g (48.74 mmol) of the title compound 2 of Example 5b and 14.8 g (146.2 mmol) of triethylamine dissolved in 300 ml of dichloromethane at 0 ° C was added dropwise 14.24 g (50 mmol). 3,6,9,12,15-pentaoxahexadecanoyl chloride was added and the mixture was stirred at 0 ° C for 3 hours. 300 ml of 5% aqueous hydrochloric acid was 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 chromatographed on silica gel (eluent: dichloromethane / acetone: 20: 1).

Yield: 32.03 g (87% of theory) of a colorless oil. Elementary 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) -Ν- (1H, IH, 2H, 2H, 4H, 4H-3oxa) -perfluorotridecyl) -amine g (41.03 mmol) of the title compound from Example 5c was dissolved in 300 mL of tetrahydrofuran and 25 mL of 10M borane dimethyl sulfide (in tetrahydrofuran) was added. The mixture was stirred at reflux for 6 hours. The mixture was then cooled to 0 ° C and methanol (200 mL) was added dropwise, then the reaction mixture was evaporated to dryness under reduced pressure. The mixture was poured into 300 ml of ethanol / 50 ml of 10% aqueous hydrochloric acid 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 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 chromatographed on silica gel (Mobile phase: dichloromethane / 2-propanol = 15: 1).

Yield: 27.68 g (91% of theory).

• ·

Elementary analysis:

H, 4.35; N, 1.89; F, 43.56

Found: C 37.11 H 4.51 N, 73 F 43.41

e) 1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid- [N-3,6,9,12,15-pentaoxa] -hexadecyl) -N (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxo) -perfluorotridecyl) -amide} 1,4,7,10-tetraazacyclododecane, gadolinium complex (Metal complex VII) g (15.88) mmol) of gadolinium complex of 10- [1 (carboxymethylcarboamoyl) -ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved at temperature 60 ° C in 100 mL 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 was added. The reaction mixture was stirred at room temperature for 12 hours. The mixture was poured into a solution of 200 ml of acetone and 1300 ml of diethyl ether and stirred at room temperature for 2 hours. The precipitate formed was filtered, dissolved in a small amount of ethanol / water and chromatographed 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 A AAAA

AAAA AAAA

AA A AA AAAA A · AA

(a) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-hexan-5-yl) -acid-N- (12-amino-3,6,9-trioxa-dodecyl) - amide] 1,4,7,10-tetraazacyclododecane, gadolinium complex 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 and 3.66 g (31.76 mmol) of N-hydroxysuccinimide were dissolved at 60 ° C in 100 ml of dimethylsulfoxide. The reaction was cooled to 15 ° C and 1, N'-dicyclohexylcarbodiimide (3.51 g, 17 mmol) was added and the mixture was stirred at 15 ° C for 5 hours. The reaction mixture was filtered to remove urea. To the filtrate was added 14.66 g (60 mmol) of 1,12-diamino-3,6,9-trioxa-dodecane and 2.02 g (20 mmol) of triethylamine, and the mixture was stirred at room temperature for 12 hours. The solution was poured into a mixture of 1500 ml of diethyl ether and 50 ml of n-butanol and stirred for 30 minutes. The precipitated solid was filtered and chromatographed 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 F 27.81 Gd 13.45

b) 1,4,7 Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid- [N-3,6,9,16-tetraoxa-13-aza-14] -oxo-C ₁₉ -C ₂₆ -heptadecafluoro) -hexacosyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex (metal complex IX)

11.3 g (21.64 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid, 0.85 g (20 mmol) of lithium chloride and 4, 95 g (43 mmol) of N-hydroxysuccinimide was dissolved at 25 ° C in 150 ml of dimethylsulfoxide. The reaction mixture was cooled to 15 ° C and 6.19 g (30 mmol) of N, N'-dicyclohexylcarbodiimide was added and the mixture was stirred at 15 ° C for 5 hours. 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 at room temperature for 12 hours. 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 and chromatographed on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient).

Yield: 13.01 g (90% of theory). Water content: 6.7%.

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-oxo-hexan-5-yl) acid-N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H- 3-oxa-perfluorotridecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex 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 and 3.66 g (31.76 mmol) of N-hydroxysuccinimide were at 60 ° C in 100 ml of dimethylsulfoxide. The mixture was cooled to 15 ° C and 3.51 g (17 mmol) of N, N'-dicyclohexylcarbodiimide was added and the reaction mixture was stirred at 15 ° C for 5 hours. The reaction mixture was filtered to remove urea. To the filtrate was added 8.63 g (15.88 mmol) of the title compound of Example 5b and 5.06 g (50 mmol).

4 · 4

4444

4,444 44 4

444 444 4444 triethylamine and the reaction mixture was stirred at room temperature for 12 hours. The solution was poured into 1500 ml diethyl ether and 100 ml acetone and the mixture was stirred for 30 minutes. The precipitated solid was filtered and chromatographed 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) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid N- (2,3,4,5,6-pentahydroxy) -hexylamide

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid in 300 ml of dichloromethane was added 8.90 g (70 mmol) of oxalyl chloride and the reaction mixture was stirred at room temperature for 12 hours. . 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 dioxane. The reaction mixture was stirred at 0 ° C for 3 hours, and then stirred at room temperature for 8 hours. Then 400 ml of 5% aqueous hydrochloric acid 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 chromatographed on silica gel (eluent: dichloromethane / methanol = 5: 1).

Yield: 30.71 g (78% of theory)

Elementary 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, β-pentahydroxyhexyl) -N-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) -amine g (43.77 mmol) title the compound of Example 8a was dissolved in 300 mL of tetrahydrofuran and 50 mL of a 10 M solution of borane dimethyl sulfide (in tetrahydrofuran) was added. The reaction mixture was heated at reflux for 48 hours. The reaction mixture was cooled to 0 ° C and 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 10% aqueous hydrochloric acid, and the mixture was stirred at 60 ° C for 15 hours. The reaction mixture was evaporated under reduced pressure, the residue 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 sulfate, evaporated to dryness under reduced pressure, and the residue was chromatographed on silica gel (Mobile phase: dichloromethane / methanol = 3: 1). Yield: 19.69 g (67% of theory) of a colorless solid.

Elementary analysis:

H, 3.30; N, 2.09; F, 48.11

Found: C 32.05 H 3.43 N 1.97 F 47.93

c) 1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid- [N-2,3,5, β-pentahydroxy) -hexyl-N ( 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl] -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) • 4,444

4444 lithium chloride was dissolved in 100 ml dimethylsulfoxide at 60 ° C. 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 then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether, and the reaction mixture was stirred at room temperature for 2 hours. The precipitate formed was filtered, the precipitate was dissolved in a small amount of ethanol / water and chromatographed 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) N- (2,2-dimethyl-5-hydroxy-1,3-dioxepan-6-yl) -amide

2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid

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 at room temperature for 12 hours. 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 at 0 ° C for 3 hours and then at room temperature for 5 hours. 300 mL of water was added and the mixture was stirred for 15 minutes. The organic phase was separated, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1).

Yield: 27.62 g (85% of theory).

Elementary analysis:

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) -Ν- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -amine g (40.58 mmol) of the title compound of Example 9a was dissolved in 300 mL of tetrahydrofuran and 26 mL of a 10 M solution of borane dimethyl sulfide (in tetrahydrofuran) was added. The mixture was stirred at reflux for 20 hours. It was then cooled to 0 ° C and methanol (300 ml) was added dropwise and 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 10% aqueous hydrochloric acid, and the mixture was stirred at 60 ° C for 6 hours. The mixture was evaporated to dryness under reduced pressure, the residue was dissolved in 400 ml of 5% aqueous sodium hydroxide 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 chromatographed on silica gel (Mobile phase: dichloromethane / methanol = 6: 1). Yield: 20.09 g (81% of theory) of a colorless solid.

Elementary 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-oxo-hexan-5-yl) -acid- [N 1 -hydroxymethyl-2,3-dihydroxypropyl] -N- ··

1119

H

II 1 9 19 9 11 1 11 11 1111

III 111 1111 11 1 11 1111 11 11 (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl] -amide} 1,4,7,10-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 and 1.35 g (31.76 mmol) of lithium chloride was Dissolved at 60 ° C in 100 mL dimethylsulfoxide, cooled to 15 ° C, and added 9.71 g (15.88 mmol) of the title compound of Example 9b. The reaction mixture was stirred for 10 minutes and 7.42 g was added. (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline The mixture was stirred at room temperature for 12 hours The solution was poured into a mixture of acetone (200 ml) and diethyl ether (1300 ml) and stirred at room temperature for 2 hours. filtered, dissolved in ethanol / water and chromatographed on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient) Yield: 13.40 g (69% of theory) 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) Perfluorooctylsulfonic 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 was directly poured onto a silica gel column for purification (mobile phase: dichloromethane / acetone = 20: 1).

• fc fcfcfc • fc fcfcfcfc • fc «fcfcfcfc fc · · • fcfc fcfcfc fcfcfcfc fc fcfcfc ··· fcfcfcfc • fcfc fcfc * fcfcfcfc

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

Elementary 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) perfluorooctylsulfonic acid N- [(2-amino) ethyl] -amide g (44.36 mmol) of the title compound of Example 10a was dissolved in 300 ml of methanol and 5 g of palladium catalyst (10% Pd / C) were added, The mixture was hadrogenated 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. Elementary 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-oxo-hexan-5-yl) -acid N - [(2-perfluorooctylsulfonylamino) -ethyl] -amide) 1,4, 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 and 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 15 ° C and 3.51 g (17 mmol) of N, N'-dicyclohexylcarbodiimide was added and stirred at 15 ° C for 5 hours. The reaction solution was filtered to remove urea. 8.61 g (15.88 mmol) of the title compound of Example 10b and 2.02 g (20 mmol) of triethylamine were added to the filtrate, and the mixture was stirred at room temperature for 12 hours. The solution was poured into a mixture of 1500 ml.

88 • · · • · · • · · ·· · • · · • · · · • · · • · · · · · • · · • · · · • · · · ·· ·· diethyl ether and 100 ml acetone and was stirred for 30 minutes minutes. A precipitate formed filtered and was cleaned silica gel chromatography RP-18 (Mobile phase: Gradient

tetrahydrofuran / acetonitrile / water).

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, 5H3-oxa-perfluorotridecanoic acid N- (2-benzyloxycarboxylamino-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 at room temperature for 12 hours. . 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 13.84 g (60 mmol) of 1-benzyloxycarbonylamine-2-aminoethane hydrochloride and 12.14 g (120 mmol) of triethylamine in 200 mL of dichloromethane. The reaction mixture was stirred at 0 ° C for 3 hours and then at room temperature for 5 hours. 300 ml of 5% aqueous hydrochloric acid 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 chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1).

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

Elementary 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-amino) ethyl] amide g (42.96 mmol) of the title compound of Example 11 was dissolved in 500 ml of methanol and 5 g of palladium catalyst (10% Pd / C) was added, then the mixture was hydrogenated overnight at room temperature. The catalyst was filtered and the filtrate was evaporated to dryness under reduced pressure.

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

H, 2.32; N, 4.96; F, 57.24

Found: C 29.67 H 2.4 N N 4.88 F 57.15

c) 1,4,7-Tris- (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acetic acid N- [3-aza-6-oxa-4-oxo- (C) _{9 - ( 6-} Heptadecafluoro) hexadecyl] -amide} -1,4,7,10-tetraazacyclododecane complex with gadolinium 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 and 3.66 g (31.76 mmol) of N-hydroxysuccinimide were dissolved at 60 ° C. in 100 ml of dimethylsulfoxide. The mixture was cooled to 15 ° C and 1, N'-dicyclohexylcarbodiimide (3.51 g, 17 mmol) was added and the mixture was stirred at 15 ° C for 5 hours. The solution was filtered to remove urea. 8.96 g (15.88 mmol) of the title compound of Example 11b was added to the filtrate, and 2.02 g (20 mmol) of triethylamine were added thereto, followed by stirring at room temperature for 12 hours. The reaction mixture was poured into a mixture of 1500 ml diethyl ether and 100 ml acetone, and the reaction mixture was stirred for 30 minutes. A precipitate formed

filtered and chromatographed 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):

H, 3.51; N, 8.34. F 27.46 Gd 13.37

Found: C 33.61 H 3.63 N 8.17 F 27.31 Gd 13.20

Example 12

(a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorodecanoic acid N - [(2-hydroxy) ethyl] 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 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 at 0 ° C for 3 hours and then at room temperature for 6 hours. 300 ml of 5% aqueous hydrochloric acid 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 chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1). Yield: 24.86 g (93% of theory) of a colorless solid.

Elementary 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 • ·

Φ ··········

b) Ν- (2-Hydroxyethyl) -Ν-1Η, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorodecyl) -amine g (51.59 mmol) of the title compound of Example 12a was dissolved in 300 mL of tetrahydrofuran and 31 mL of a 10 M solution of borane dimethyl sulfide (in tetrahydrofuran) was added. The mixture was heated at reflux for 12 hours. The mixture was cooled to 0 ° C and 200 mL of methanol was added dropwise and then evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of 300 ml of ethanol and 50 ml of 10% aqueous hydrochloric acid, 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 chromatographed on silica gel (Mobile phase: dichloromethane / 2-propanol = 20: 1).

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

Elementary 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- (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid-N - [(2-hydroxy) -ethyl-N- (1H, 1H) -1,4,7,10-tetraazacyclododecan-complex with gadolinium g (15.88 mmol) of gadolinium complex with 10- [1 (carboxymethylcarboamoyl), 2H, 2H, 4H, 4H, 5H, 5H3-oxa-perfluoradecyl] -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 dimethylsulfoxide at 60 ° C. The mixture was cooled to 15 ° C and 8.98 g (15.88 mmol) of the title compound of the example was added

12b. The mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline was added. The mixture was then stirred at room temperature for 12 hours. The solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether, and the mixture was stirred at room temperature for 2 hours. The precipitate formed was filtered, dissolved in a small amount of ethanol / water and chromatographed on RP-18 silica gel. (Mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 14.01 g (83% of theory) of a colorless, amorphous powder.

Elementary analysis:

Calculated: C 35.03 H 3.98 N 7.91 F 23.24 Gd 14.79

Found: C 34.85 H 4.19 N 7.75 F 23.05 Gd 14.58

Example 13

(a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorodecanoic acid N- (3,6,9,12-tetraoxa-tridecyl) -amide

To 24.25 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 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-tetraoxa-tridecylamine and 6.07 g (60 mmol) of triethylamine dissolved in 200 mL of dichloromethane. 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 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 chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1).

• · ·

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

Elementary analysis:

Calculated: C 37.33 H 4.29 N 2.29 F 40.40

Found: C 37.15 H 4.41 N 2.12 F 40.18

b) N- (3,6,9,12-Tetraoxatridecyl) -Ν- (1 H, 1 H, 2 H, 2 H, 4 H, 4 H, 5 H, 5 H 3 -oxa-perfluoroindecyl) -amine g (50.7 mmol) of the title compound of Example 13a was dissolved in 300 mL of tetrahydrofuran and 32 mL of a 10 M solution of borane dimethyl sulfide (in tetrahydrofuran) was added. The mixture was then heated under reflux for 16 hours. The reaction mixture was cooled to 0 ° C and 200 mL of methanol was added dropwise, then the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 300 mL of ethanol and 50 mL of 10% aqueous hydrochloric acid, and the mixture was stirred at 40 ° C for 8 hours. 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 chromatographed on silica gel (Mobile phase: dichloromethane / 2-propanol = 20: 1). Yield: 28.17 g (93% of theory) of a colorless solid. Elemental analysis (calculated on the anhydrous substance):

H, 4.72; N, 2.34; F, 41.34

Found: C 38.05 H 4.83 N 2.40 F 41.50

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

G (15.88 mmol) of complexugadolinium 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 was dissolved at 60 ° C in 100 ml of dimethylsulfoxide. 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 was added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was then poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether, and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered, dissolved in a small amount of ethanol-water and chromatographed on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.13 g (84% of theory).

Elementary 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, IH, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) -aminoacetic 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 bromoacetate at 50 ° C and the reaction mixture was stirred at this temperature for 3 hours. Then 300 ml of dichloromethane was added, the precipitated salts were filtered and the filtrate was evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1).

• • •

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

Elementary 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-oxo-hexan-5-yl) -acid-N [(tert-butyloxycarbonylmethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl] -amide} -1,4,7,10tetraazacyclododecane 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 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 was added.

The mixture was then stirred at room temperature for 12 hours. The 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 was filtered, dissolved in ethanol / water and chromatographed on silica gel RP18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.64 g (85% of theory)

Elementary analysis:

Calculated: C 36.04 H 3.92 N 6.82 F 26.19 Gd 12.72

Found: C 35.92 H 3.83 N 6.91 F 26.29 Gd 12.84

c) 1,4,7-Tris- (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid-N - [(carboxymethyl) -N- (1H, 1H, 2H, 2H) 4H, 4H, 5H, 5H-444

44 · 44 ·

4 · · ·

4 4

4444 oxa-Perfluorotridecyl] -amide} -1,4,7,10-tetraazacyclododecanecomplex gadolinium g (8.11 mmol) of the title compound of Example 14b was dissolved in 50 mL of trifluoroacetic acid and stirred for 5 hours at room temperature. The mixture was evaporated to dryness and chromatographed 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. 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) 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid N- (2-hydroxyethyl) amide

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 at room temperature for 3 hours. nitrogen atmosphere. Then 7.67 g (74 mmol) of tert-butyl bromoacetate dissolved in 20 ml of tetrahydrofuran was added, and the mixture was stirred at 50 ° C for 5 hours. 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: 23.46 g (61% of theory).

Elementary analysis:

H, 3.26; N, 2.06; F, 47.54

Found: C 35.52 H 3.40 N 2.17 F 47.40 • to ····

b) N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -N- [4terc. butyloxycarbonyl-3-oxa-butyl] -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 sulfide (in tetrahydrofuran) was added. The reaction was heated under reflux for 16 hours. It was then cooled to 0 [deg.] C. and 200 ml of methanol was added dropwise and finally evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of 300 ml of ethanol and 50 ml of 10% aqueous hydrochloric acid, 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 chromatographed on silica gel (Mobile phase: dichloromethane / 2-propanol = 20: 1).

Yield: 31.88 g (93% of theory).

Elementary analysis:

H, 3.64; N, 2.11; F, 48.54

Found: C 35.90 H 3.75 N 2.20 F 48.71

c) 1,4,7-Tris- (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid-N - [(4-tert-butyloxycarbonyl-3-oxa) -butyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluorotridecyl] -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 at 60 ° C in 100 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%) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline was added. The reaction mixture was stirred at room temperature for 12 hours. The solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether, and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered, dissolved in a small amount of ethanol / water and chromatographed on RP-18 silica gel. (Mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.63 g (82% of theory).

Elementary 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-oxo-hexan-5-yl) -acid- [N- (4-carboxy-3-oxa) -butyl} -N - (1 H, 1 H, 2 H, 2 H, 4H,

4H, 5H, 5H-3oxa-Perfluorotridecyl] -amide} -1,4,7,10-tetraazacyclododecane, the gadolinium g complex (9.40 mmol) of the title compound of Example 15c was dissolved in 50 mL of trifluoroacetic acid and the mixture was stirred for 5 hours The mixture was evaporated to dryness under reduced pressure and the residue was chromatographed 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 The solution was filtered and the filtrate was lyophilized Yield: 11.41 g (92% of theory) Water content: 5.8%.

Elemental analysis: (calculated on the anhydrous substance):

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 Na 1 , 93

Example 16

Ν- (2Η, 2Η, 4Η, 4Η, 5Η, 5H-3-oxa-perfluorotridecyl) -amide ·· ··· · ······

2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid

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 at room temperature for 12 hours. 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 at 0 ° C for 3 hours and then at room temperature for 6 hours. 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 sulphate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1). Yield: 52.87 g (91% of theory). Elementary 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-oxa) -perfluorotridecyl) amine g (51.42 mmol) of the title compound of Example 16a was dissolved in 500 mL of tetrahydrofuran and 31 mL of 10M borane dimethyl sulfide (in tetrahydrofuran) was added. The mixture was stirred at reflux for 6 hours. It was then cooled to 0 [deg.] C. and 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 at 40 ° C for 8 hours. The mixture was evaporated to dryness, the residue was dissolved in 400 ml.

100% aqueous sodium hydroxide solution and was 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 chromatographed on silica gel (Mobile phase: dichloromethane / 2-propanol = 20: 1). Yield: 47.18 g (92% of theory) of a colorless solid.

Elementary analysis:

H, 1.72; N, 1.40; F, 64.77

Found: C 30.03 H 1.81 N 1.55 F 65.00

c) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-hexan-5-yl) -acid-N-bis- (1H, 1H, 2H, 2H, 4H, 4H, 5H) 5H-3-oxaperfluorotridecyl) -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 at 100 ° C in 100 ml of dimethylsulfoxide. The mixture was cooled to 15 ° C and 15.84 g (15.88 mmol) of the title compound of Example 16b was added. The mixture was stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline was added. The mixture was stirred at room temperature for 12 hours. 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, dissolved in a small amount of ethanol / water and chromatographed on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient).

Yield: 20.95 g (82% of theory).

Elementary analysis:

Calcd: C 32.10 H 2.82 N 5.22 F 40.14 Gd 9.77 • · • · · ·

101

Found: C 29.87 H 2.91 N 5.09 F 40.28 Gd 9.98

Example 17

(a) 2H, 2H, 4H, 4H, 5H, 5H-3-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. 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 at 50 ° C for 5 hours. Methanol (50 ml) was added and the mixture was evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1). Yield: 19.31 g (59% of theory).

Elementary analysis:

Calculated: C 32.76 H 2.91 N 2.25 F 51.82

Found: C 32.98 H 2.99 N 2.36 F 51.98

b) N- (3,5-Dioxa-heptyl) -N- (1H, 1H, 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 dimethyl sulfide (in tetrahydrofuran) was added. The mixture was stirred at reflux for 16 hours. The mixture was cooled to 0 ° C and 200 ml of methanol was added dropwise and finally 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 at 40 ° C for 8 hours. The mixture was evaporated in vacuo, the residue was dissolved in 300 ml.

5% aqueous sodium hydroxide solution, and the mixture was 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 chromatographed on silica gel (Mobile phase: dichloromethane / 2-propanol = 20: 1). Yield: 28.47 g (91% of theory).

Elementary analysis:

Calculated: C 33.51 H 3.31 N 2.30 F 53.01

Found: C 33.63 H 3.41 N 2.21 F 52.87

c) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-hexan-5-yl) -acid-N- (3,6-dioxa) -heptyl-N- (1H, IH) , 2H, 2H, 4H, 4H, 5H, 5H3-Oxa-Perfluorotridecyl) -amide] -1,4,7,10-tetraazacyclododecane, gadolinium g complex (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 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 was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether and stirred at room temperature for 2 hours. The precipitate formed was filtered, dissolved in ethanol / water and chromatographed on silica gel RP18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient). Yield: 16.09 g (83% of theory).

Elementary 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 ·······

103

Example 18

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

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid in 300 ml of dichloromethane was added 8.90 g (70 mmol) of oxalyl chloride and the mixture was stirred at room temperature for 12 hours. 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 (6060 mmol) of n-hexylamine 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. 300 ml of 5% aqueous hydrochloric acid 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 chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1).

Yield: 30.95 g (89% of theory).

Elementary analysis:

H, 3.33; N, 2.31; F, 53.35

Found: C 35.60 H 3.45 N 2.43 F 53.63

b) N- (Hexyl) -N- (1 H, 1 H, 2 H, 2 H, 4 H, 4 H, 5 H, 5 H -3-oxaperfluorotridecyl) -amine g (51.21 mmol) of the title compound of Example 18a was dissolved in 300 mL tetrahydrofuran and 31 mL of a 10 M solution of borane dimethyl sulfide (in tetrahydrofuran) was added. The mixture was heated under reflux for 16 hours. The mixture was cooled to 0 ° C and 200 mL of methanol was added dropwise, then 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 at 40 ° C for 8 hours.

• ti ti ti ti ti ti ti ti ti ti

104

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 sulphate, evaporated to dryness under reduced pressure, and the residue was chromatographed on silica gel (Mobile phase: dichloromethane / 2-propanol = 20a). Yield: 28.16 g (93% of theory)

Elementary 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 (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid- [N- (hexyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium g complex (15.88 mmole) 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 60 mL of dimethyl sulfoxide at 60 ° C, cooled to 15 ° C and 10.98 g (15.88 mmol) of the title compound of Example 18b was added and 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 poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether and stirred for 2 hours at room temperature, and the precipitate formed was filtered, dissolved in ethanol / water and chromatographed on silica gel RP18 (mobile phase). : Gradie Yield: 16.29 g (84% of theory).

Elementary analysis:

Calculated: C 36.94 H 4.19 N 6.99 F 26.85 Gd 13.07 • A

105

A ·

AAA · A A AA ·· ·· ·

Found: C 37.18 H 4.31 N 7.18 F 26.67 Gd 13.19

Example 19

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid N - [(10-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 at room temperature for 12 hours. The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and added dropwise to a mixture of 15.45 g (60 mmol) of 11-amino-undecanoic acid tert-butyl ester and 6.07 g (60 mmol) of triethylamine dissolved in 200 mL of dichloromethane at 0 ° C. . The mixture was stirred at 0 ° C for 3 hours and then at room temperature for 6 hours. 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 chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1). Yield: 42.04 g (92% of theory).

Elementary 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, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxas-perfluorotridecyl) -amine g (51.21 mmol) of the title compound of Example 19 and was dissolved in 300 mL of tetrahydrofuran, and 31 mL of a 10 M solution of borane dimethyl sulfide (in tetrahydrofuran) was added. The mixture was stirred at reflux for 16 hours. It was then cooled to 0 ° C and 200 ml of methanol was added, at the end of which it was

106 the mixture was 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 at 40 ° C for 8 hours. The mixture was 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 chromatographed on silica gel (Mobile phase: dichloromethane / 2-propanol = 20: 1). Yield: 34.84 g (91% of theory).

Elementary 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-oxo-hexan-5-yl) -acid- [N- (10-tert-butyloxycarbonyl) -decyl-N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) gadolinium complex with 10- [1 (carboxymethylcarboamoyl) 1-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. 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 was added. The reaction solution was then poured into a mixture of 200 ml acetone and 1300 ml diethyl ether and stirred for 2 hours at room temperature. The precipitate formed was filtered, dissolved in ethanol / water and was chromatographed on silica lu RP18 (Mobile phase: tetrahydrofuran / acetonitrile / water gradient).

• «· · · · 4 4 4 · 4 ····« 4 ·

107

Yield: 17.92 g (83% of theory).

Elementary 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-oxo-hexan-5-yl) -acid- [N- (10-carboxy) -decyl-N- (1H, 1H)] 1, 4,7,10-tetraazacyclododecane, gadolinium complex, sodium salt g (8.83 mmol) of the title compound of Example 19c was dissolved, 2H, 2H, 4H, 4H, 5H, 5H-3oxa-perfluorotridecyl] 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 chromatographed 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 an aqueous solution of 5% sodium hydroxide. 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 Na 1 , 80

Example 20

a) 15-Benzyl-3,6,9,12,15-Pentaoxa-hexadecanoic acid N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3oxa) -perfluorotridecyl) amide

To 19.67 g (57.45 mol) of 15-Benzyl-3,6,9,12,15pentaoxahexadecanoic acid in 250 mL of dichloromethane was added 8.90 g (70 mmol) of oxalyl chloride and the mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 100 ml.

of dichloromethane and was added dropwise at 0 ° C to a mixture of 32.62 g (60 mmol) of 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecylamine hydrochloride and 6.07 g (60 mmol). 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. 300 ml of 5% aqueous hydrochloric acid was added and the mixture was stirred for 15 minutes. The organic phase was separated, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1).

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

Elementary 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-pentaoxa-hexadecyl) -N- (1H, 1H, 2H,

2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -amine (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 sulfide (in tetrahydrofuran) was added. The mixture was stirred under reflux for 16 hours. It was then cooled to 0 ° C and 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 10% aqueous hydrochloric acid and stirred at 40 ° C for 8 hours. The reaction mixture was evaporated to dryness under reduced pressure, 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 sulphate, evaporated to dryness under reduced pressure and the residue was 99 99 9999

9 9 9 9 9 9

109 chromatographed on silica gel (mobile phase:

dichloromethane / 2-propanol = 20: 1).

Yield: 39.32 g (93% of theory).

Elementary 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-oxo-hexan-5-yl) -acid- [N- (15-benzyl-3,6,9,12,15) -pentaoxa-hexadecyl-N (1H-, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -tridecyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium g complex (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 were at 60 ° C dissolved in 100 ml 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 at room temperature for 2 hours. The precipitate was filtered, dissolved in a small amount of ethanol / water and chromatographed on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient).

Yield: 18.84 g (83% of theory).

Elementary analysis:

Calculated: 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

110 • 4 44 44 4

4 4 43 4

• · 4 4 4 4 • 4 ···· 44 44

d) 1,4,7-Tris- (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid- [N- (14-hydroxy-3,6,9,12-tetraoxa)] ) -tetradecyl-N (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluorotridecyl] -amide} 1,4,7,10-tetraazacyclododecane, gadolinium g complex (8,40 mmot) of the title compound of Example 20c was dissolved in 150 mL of methanol and 1.0 g of palladium catalyst (10% Pd / C) was added, then the mixture was 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).

Elementary analysis:

Calculated: 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 at room temperature for 24 hours. The mixture was evaporated to dryness, and was crystallized from diisopropyl ether.

Yield: 128.9 g (96% of theory) of a colorless crystalline powder. Melting point: 98.5 ° C.

Elementary analysis:

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 21

a) and 188.7 g (332.0 mmol) of 1-perfluorooctylsulfonylpiperazine

4444 (prepared according to DE 19603033) in 750 ml tetrahydrofuran at 0 ° C was added 164.2 g (0.664 mmol) EEDQ (ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred overnight at room temperature temperature. The reaction mixture was then evaporated to dryness and chromatographed on silica gel (mobile phase: dichloromethane / methanol = 20: 1). Yield: 286.0 g (93% of theory) of a colorless solid. Melting point: 92 ° C. Elementary 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-fluorooctylsulfonyl) -piperazine] -amide

To a solution of 280.0 g (302.2 mmol) of the title compound of Example 21 b) in 2000 mL of ethanol, ammonia gas was introduced at 0 ° C for 1 hour. The reaction mixture was then stirred for an additional 4 hours at 0 ° C. It was then stripped to dryness and the residue was stirred with water. The mixture was filtered and the solid was dried under vacuum at 50 ° C. Yield: 243.5 g (97% of theory) of a colorless amorphous solid. Elementary 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-fluorooctylsulfonyl) -piperazine] - amid

To a solution of 100.0 g (120.4 mol) of the title compound of Example 21c), 72.1 g (120.4 mol) of 1-O-α-D-carboxymethyl-2,3,4,6-tetra-O-benzylmannopyranose and 13.86 g (120.4 mmol) of N-hydroxysuccinimide, dissolved in 500 ml of dimethylformamide, were filtered.

Φ I • φ φ «φφφ φφ φ

112.2 N, N -dicyclohexylcarbodiimide (41.27g, 200.0 mmol) was added at 0 ° C at 0 ° C. The mixture was stirred at 0 ° C for 3 hours and then at room temperature overnight. The precipitate was filtered off, the filtrate was evaporated to dryness in vacuo and the residue was chromatographed on silica gel. (Mobile phase: dichloromethane / ethanol = 20: 1).

Yield: 136.1 g (87% of theory) of a solid oil. Elementary analysis:

Calculated: C 57.32 H 4.89 N 4.31 F 24.86 S 2.47

Found: C 57.38 H 5.07 N 4.22 F 24.78 S 2.39

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

130.0 g (100.0 mmol) of the title compound of Example 21d) was dissolved in 2000 ml of ethanol and 10.0 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated at room temperature for 12 hours. The catalyst was then filtered off and the filtrate was evaporated to dryness in vacuo.

Yield 91.7 G (quantitatively ) colorless solids Elementary analysis: Calculated: C 34.07 H 3.63 N 6.11 N 3, 50 F 35.24 Found: C 33, 91 H 3.72 N 6.04 N 3, 40 F 35.31 Found: C 33, 91 H 3.72 N 6.04 N 3, 40

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

50.0 g (54.55 mmol) of the title compound of Example 21 e), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) · * Φ φ φ φ · · φ ·

113 Lithium chloride and 34.35 g (54.55 mmol) of 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methylpent-5-yl) -1,4,7,10-tetraazacyclododecane, Gd complex, was dissolved in 400 ml dimethylsulfoxide with slight heating. 16.88 g (81.8 mol) of N, N-dicyclohexylcarbodiimide was added at 10 ° C and the reaction mixture was then stirred overnight at room temperature. The solution was poured into 3000 mL of acetone and stirred for 10 minutes. The precipitated solid was filtered and then chromatographed 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

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

50.0 g (54.55 mmol) of the title compound of Example 21 e), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54 , 55 mmol) 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methylpent-5-yl) -1,4,7,10-tetraazacyclododecane, Gd-Complex was dissolved in 400 ml of dimethylsulfoxide under gentle 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.

114

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 Gd 10.38 Found: C 34.81 H 4.02 N 8.27 S 2.09 F 21.22 Gd 10 , 19

Example 23

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

To 200.0 g (1204.0 mmol) of 4-hydroxyphenylacetic acid ethyl ester, 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-bromoacetic acid ester and the mixture was refluxed for 5 hours. The solid was filtered off and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel. (Mobile phase: n-hexane / ethyl acetate = 15: 1). Yield: 288.5 g (95.0% of theory) of a colorless oil. Elementary analysis:

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, 201.0 g (1130.0 mmol) of N-bromosuccinimide and 100.0 mg of dibenzoyl peroxide were added and the mixture was heated to reflux. 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.

• · «·

(Mobile phase: n-hexane / acetone = 15: 1).

Yield: 359.2 g (96.0% of theory) of a colorless solid oil. Elementary 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-tetraazacyclododecan-1-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 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 solid oil.

Elementary analysis:

H, 8.11; N, 13.26

Found: C 59.58 H 8.20 N 13.18

d) 2- [4- (3-Oxapropionic acid)] phenyl-2- [1,4,7tris (carboxymethyl) -1,4,7,10-tetraazacyclododecan-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 at 70 ° C for 8 hours. Then the pH of the reaction was adjusted to 13 with 30% aqueous sodium hydroxide solution and the mixture was boiled under reflux for 30 minutes. The solution was cooled in an ice bath and the pH was evaporated by addition of concentrated hydrochloric acid.

hour at

The reaction mixture was then taken up in 4000 ml of methanol and stirred at room temperature. The precipitated salt was filtered off and the filtrate was evaporated to dryness, the residue was purified by chromatography on silica gel RP-18 C (mobile phase: water / ethanol / acetonitrile gradient).

Yield: 403.0 g (69.0% of theory) of a colorless solid. Water content: 10.2%.

Elemental analysis (calculated on the anhydrous substance):

H, 6.18; N, 10.10

Found: C 51.80 H 6.31 N 10.01

e) 2- [4- (3-Oxapropionic acid)] - phenyl-2- [1,4,7tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-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 at 80 ° C for 5 hours. The solution was filtered and the filtrate was evaporated to dryness under reduced pressure.

Yield: 511 g (quantitative) colorless amorphous solid. Water content: 11.0%.

Elemental analysis (calculated on the anhydrous substance):

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-tetraazacyclododecan-10-yl] acetic acid acid)] - 2-N- (1-Oa-D-carbonylmethyl-mannopyranose) -L-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] amide, Gd-Kompiex, sodium salt · ·

117

50.0 g (54.55 mmol) of the title compound of Example 21 e), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 38.66 g ( 54.55 mmol) of the title compound of Example 23e) was dissolved in 400 ml of dimethyl sulfoxide 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 silica gel chromatography (RP-18; Mobile phase: Water / ethanol / acetonitrile gradient). The obtained product was dissolved in a small amount of water and an 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 F 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-carbonylmethyl] -2-N- (1-O-α-D-carbonylmethyl- mannopyranose) L-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

15.0 g (26.19 mmol) of 1,4,7-tris (tert-butyloxycarbonylmethyl) -10-carboxymethyl-1,4,7,10-tetraazacyclododecane, 24.0 g (26.19 mmol) of the title compound from Example 21e) and 3.01 g (26.19 mmol) of N-hydroxysuccinimide were dissolved in 150 ml of dimethylformamide at 0 ° C and 8.25 g (40.0 mmol) of N, N-dicyclohexylcarbodiimide were added. The mixture was stirred overnight at room temperature. The precipitated urea was filtered off and the filtrate was evaporated to dryness under reduced pressure.

118 pressure. The residue was chromatographed on silica gel. (Mobile phase: dichloromethane / methanol = 20: 1).

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

Elementary 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-carbonylmethyl -] - 2-N- [1-Oa-D-carbonylmethylmannopyranose] -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 at room temperature for 10 minutes. 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 80 ° C for 5 hours. The solution was evaporated to dryness in vacuo and the residue was purified by silica gel chromatography (RP-18; Mobile phase: Water / ethanol / acetonitrile gradient). Yield: 11.0 g (37.0% of theory) of a colorless and 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

Example 25

a) 6-N- [3,6,9-Tris (carboxymethyl) -3,6,9-triazaundecanedioic acid-1-carboxy-11-oyl] -2-N- [1-O-α-D-carbonylmethyl] • • • fcfc

119 mancopyranose] -L-lysine- [1- (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-dioxomorpholinoethyl) -6 -N- (ethoxycarbonylmethyl) -3,6-diazaoctanedioic acid, 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 addition of 20% aqueous sodium hydroxide solution. The mixture was stirred at 22 ° C and pH 13 for 8 hours. The solution was acidified to pH 7.2 by the addition of concentrated hydrochloric acid and evaporated in vacuo. The residue was chromatographed 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 F 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-O-c-D-carbonylmethyl] -mannopyranose] -L-lysine- [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 and then lyophilized.

«· · · · · · ·

120 • · · · ..

«· ···· ·· ··

Yield: 11.36 g (quantitative) 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 (60 mmol) , 20 mmol) of 1,4,7-tris [carboxylatomethyl] -1,4,7,10-tetraazacyclododecane-10 (pentanoyl-3-aza-4-oxo-5-methyl-5-yl), Gd-Complex was Dissolve under gentle heating in 400 mL of dimethylsulfoxide. 20.63 g (100.0 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 of acetone and stirred for 10 minutes. The precipitate formed was filtered off and then chromatographed on silica gel (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 · · · ·

121 ·· ··· ·

b) 2-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-Gd-Complex, 10- (pentanoyl-3-aza-4-oxo-5-methyl-5yl) -L-Lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

70.0 g (48.53 mmol of the title compound of Example 21d) was dissolved in a mixture of 500 ml water and 100 ml ethanol, then 5.0 g palladium catalyst (10% Pd / C) was added and hydrogenated at room temperature under atmosphere of hydrogen (1 atm) until no consumption of hydrogen was observed. The catalyst was then filtered off, washed well with ethanol (twice with 75 ml) and evaporated to dryness in vacuo. The title compound was obtained as a colorless and strongly viscous oil.

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 N 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 Found: C 37, 39 H 4.03 N 8, 65 S 2.20 F 22.31 Gd 10.78

(c) 6-N- (10aD-Carbonylmethyl-2,3,4,6-tetra-O-benzylmannopyranose) -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 ( , 22 mmol) of 1-Oa-D-carboxymethyl-2,3,4,6-tetra-O-benzyl-mannopyranose was dissolved in 400 ml of dimethylsulfoxide under gentle heating (30-40 ° C). 10.32 g (50.0 mmol) of N, N-dicyclohexylcarbodiimide were added at 10 ° C and the mixture was stirred overnight at room temperature. The solution was poured into 3000 mL of acetone and stirred for 10 minutes. Precipitated precipitate · · · · · · · · · · · · · · · · ·

122 was filtered off and then purified by silica gel chromatography (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

d) 6-N- (10aD-Carbonylmethyl-2,3,4,6-tetra-O-benzylmannopyranose) -2-N- [1,4,7-tris (carboxylatomethyl) -1,4,8,10-tetraazacyclododecane- 10- (Pentanoy-13-aza-4-oxo-5-methyl-5-yl)] - L-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] amide, GdComplex

60.0 g (31.77 mmo) 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. The catalyst was then filtered off, washed with ethanol (twice with 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 F 21.05 Gd 10 , 20

Example 27

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

To 50.0 g (13.5 mmol) of 1,7-bis (benzyloxycarbonyl) 1,4,7,10-tetraazacyclododecane and 66.42 g (113.5 mmol) of 2- (NA A AAAA)

A A A A A

123 ethyl-N-perfluorooctylsulfonyl) aminoacetic acid (prepared according to DE 196 03 033) in 300 ml of tetrahydrofuran, was added at 0 ° C 49, 46 g (200.0 mmol) of EEDQ (2-ethoxy-1-ethyl ester), 2-dihydroquinoline-1-carboxylic acid) and stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue was chromatographed on silica gel (mobile phase: dichloromethane / methanol = 20: 1). Yield: 65.2 g (57% of theory) of a colorless solid.

Elementary 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

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

To 60.0 g (59.53 mmol) of the title compound of Example 27a) and 35.64 g (59.53 mmol) of 1-OaD-carboxymethyl-2,3,4,6-tetraO-benzyl-mannopyranose prepared according to DE 19728954., in 300 ml of tetrahydrofuran, 24.73 g (100 mmol of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester)) was added at 0 ° C and the mixture was stirred overnight at room temperature. The mixture was evaporated to dryness and chromatographed on silica gel (mobile phase: dichloromethane / methanol = 20: 1) Yield: 76.6 g (81.0% of theory) of a colorless solid.

Calculated: C 54.4.4 H 4.70 N 4.41 F 20.33 S 2.02

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

c) 1- [2- (N-Ethyl-N-perfluorooctylsulfonyl) -amino] -acetyl-7- (1Ο-α-D-carbonylmethyl-mannopyranose) -1,4,7,10-tetraazacyclododecane · ·· ··· ·

124

ΊΟ g (44.07 mmol) of the title compound of Example 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 and the filtrate was evaporated to dryness.

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

Elementary 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 2s

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-perfluorooctylsulfonyl) amino] acetyl-10- (1-Oa-D-carbonylmethyl-mannopyranose) -1,4,7,10-tetraazacyclododecane g (20.84 mmol) of the title compound from Example 27c), 5.09 g (120 mmol) of lithium chloride and 37.78 g (60 mmol) of 1,4,7Tris (carboxylatomethyl) -10-pentanoyl-3-aza-4-oxo-5-methyl-5-yl) - 1,4,7,10-tetraazacyclododecane, Gd-Complex was dissolved in 400 ml dimethylsulfoxide with slight heating. At 0 ° C, 29.67 g (120 mmol) of EEDQ were added and the mixture was stirred overnight at room temperature. The reaction mixture was poured into 3000 mL of acetone and stirred for 10 minutes. The precipitated solid was filtered and purified by silica gel chromatography (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 ti ·· · • ti ti

125 • ti ti ti ti ti ti ti ti ti ti ti ti ti ti

Example 28

(a) 1,7-Bis (benzyloxycarbonyl) -4- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-10- [pentanoyl-3-aza-4-oxo-5-methyl-5-yl- [ 1,4,7-tris (carboxylatomethyl) -Gd complex. 1,4,7,10-tetraazacyclododecan-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) mmol) and 1,4,7Tris (carboxylatomethyl) -10- (pentanoyl-3-aza-oxo-5-methyl-5-yl) -1,4,7,10-tetraazacyclododecane, Gd-Complex were dissolved under slight heating in 350 ml of dimethylsulfoxide. 15.47 g (75 mmol) of N, N-dicyclohexylcarbodiimide was added at 10 ° C 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 silica gel chromatography (Kieselgel RP-18, Mobile phase: Water / ethanol / acetonitrile gradient).

Yield: 65.1 g (81.0% of theory) of a colorless solid. 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-perfluorooctylsulfonyl) -amino] -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 a palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated at room temperature. The catalyst was filtered and the filtrate was evaporated to dryness under reduced pressure.

·· ···· ·· ··· ·

126

Φ Φ · · • • Φ

Yield: 50.06 g (quantitative) of water: 3.9%.

Elemental analysis (calculated on the basis of: Calculated: C 34.67 H 4.03 N 10.37 Found: C 34.58 H 4.15 N 10.28 colorless solids. Content anhydrous):

S 2.37 F 23, 90 Gd 11.64 S 2.30 F 23.84 Gd 11.57

c) 1- [2- (N-Ethyl-N-perfluorooctylsulfonyl) -amino] -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-tetraazacyclododecan-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 10-α-D-carboxymethyl-2,3, 4,6-tetra-O-benzyl-mannopyranose 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 silica gel chromatography (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-perfluorooctylsulfonyl) -amino] -acetyl-4,10-bis [10α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose] -7 {(pentanoyl-3-aza-4-oxo-5-methyl-5-yl) - [1,4,7-tris-

• fc fcfcfcfc

127 (fc) (Carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-yl] (G-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- [3,5-bis (carboxymethyl) -octane-1,8-dicarboxylic acid-1-carboxy-8-oyl] -2-N- (1-O-α-D-carboxymethyl-mannopyranose) - lysine- [1- (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 mL). (0 mmol) of ethylenediamine-N, Ν, etr ', Ν'-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 silica gel chromatography RP-18 (Mobile phase: Water / ethanol / acetonitrile gradient).

Yield: 18.22 g (51.0% of theory) of a colorless solid. Water content: 7.9%.

Elemental analysis (calculated on the anhydrous substance):

44 4 • 4444

4 4

4 4

4 4 4

44

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-carboxylate-8-oyl-] -2-N- (1-O-α-D-carboxymethyl- mannopyranose) -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] -amide, η-complex, sodium salt g (8.397 mmol) of the title compound of Example 29a} was dissolved in 200 mL of water. Manganese carbonate (965 mg, 8.397 mmol) was added and the mixture was stirred at 60 ° C for 3 hours. The solution was added 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 Na 1.8

Found: C 34.06 H 3.61 N 6.58 S 2.47 F 25.47 Mn 4.30 Na 1, 97

Example 30

(a) 1,2,3,4,6-Penta-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. Beiller, Eds.), Academic Press, New York, Vol. 11, 53, pp. 211-215, (1963)] gave the deployment of 150 g (832.5 mmol) of α, β-D-Mannopyranose with a mixture of absolute pyridine and 1500 ml acetic anhydride after treatment with 315 g (96.7%) ) of the above title compound as a crude product as a viscous colorless oil. Using NMR spectroscopic measurements it was found that fc fcfcfcfc fcfcfcfcfcfcfcfcfcfcfcf

129 fcfc fcfc fcfc The title compound contains both isomers a and β in a 4: 1 ratio. Separation of the a, b anomers of the title compound can be accomplished by carrying out the following reactions.

Elementary analysis:

H, 5.68

Found: C, 49.12; H, 5.78

b) 1-O-α-D- (5-Ethoxycarbonyl) -pentyl-2,3,4,6-tetra-O-acetylmannopyranose

In an analogous manner to that described in the literature for the synthesis of aryl glycopyranosides [J. Conchie and G.A. Levvy in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol. 90, pp. 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, β anomers with 67 ml (400 mmol) of 6-hydroxy-hexanoic acid ethyl ester and 60.8 ml (520 mmol) of tin (II) chloride in 600 ml of 1,2-dichloroethane after chromatographic purification on a silica gel column (Eluent: Hexane / ethyl acetate 2: 1) to give 100.05 g (51% of theory) of the above title compound as a colorless viscous oil. By 1 H NMR spectroscopy it was found that the title compound can be considered to be exclusively the α-anomer.

Elementary analysis:

H, 6.77

Found: C, 52.80; H, 6.78

c) 1-O-α-D- (5-Carboxy) -pentyl-2,3,4,6-tetra-O-benzylmannopyranose

A stirred suspension of 141.0 g (289 mmol) of the title compound of Example 30b) in 200 mL dioxane was at room temperature.

0000

130 e e

0

0

0 ·

«000 • 0« »· 0

0 0 0 0

The mixture was allowed to react portionwise with vigorous stirring 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 stirring efficiency, and the suspension thus obtained was heated to boiling, and 372 ml (3.128 mol) of benzyl bromide was added dropwise over two hours. After 4 hours at 110 ° C, the reaction was stirred for 12 hours at room temperature and then poured slowly into 2.5 liters of ice water for work-up and finally the aqueous phase was well extracted 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 using a 1:10 ethyl acetate / hexane eluent. Yield: 172.2 g (91% of theory) of the title compound as a colorless and very viscous oil.

Elementary analysis:

Calculated: C 75.68 H 7.16

Found: C, 75.79; H, 7.04

d) 6-N-Benzyloxycarbonyl-2-N- [1-O-α- (5-carbonyl) -pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose) -L-lysine- [1- ( (Perfluorooctylsulfonyl) -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 was added and the mixture was stirred at this temperature for 3 hours. To prepare the activated ester solution, a solution of 111.3 g (134.0 mmol) of the title compound of i

131

Of Example 21c) dissolved in 300 mL of dimethylformamide cooled to 0 ° C over 2 hours at 0 ° C and then stirred for 12 h at room temperature. Upon working up, the precipitated dicyclohexylurea was filtered off and the solvent was evaporated to dryness. The residue was finally chromatographed on silica gel (mobile phase: dichloromethane / ethanol 20: 1; chromatography was carried out under continuous gradient conditions with the addition of an ethanol portion). Yield: 132.5 g (67.4% of theory) of the title compound as a colorless and highly viscous oil.

Elementary analysis:

Calculated: C 54.02 H 4.88 N 3.82 E 22.01 S 2.19

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

e) 2-N- [1-O-α-D- (5-Carbonyl) pentyl-mannopyranose] -L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -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 (Pd 20%, C) were added and the mixture was hydrogenated at room temperature under a hydrogen atmosphere ( 1 atm) until no further hydrogen consumption was observed (approx. 8 hours). The catalyst was filtered off, washed well with ethanol (ca. 200 ml) and the filtrate was evaporated to dryness under reduced printing. The title compound was obtained as a strongly viscous and colorless oil.

Yield: 78.5 g (98.7% of theory).

Elementary 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 N 3.22 · · · · ·

132

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

99.8 g (158.4 mmol; 2.2 molar equivalent of the above amine component of Example 30e) Gd complex 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7 Of 10-tetraazacyclododecane-1,4,7-triacetic acid, described in patent application DE 197 28 954 under Example 31 h) and 6.7 g of anhydrous lithium chloride (158.4 mmol) were dissolved at 40 ° C at 800 ° C. ml of absolute dimethylsulfoxide with stirring. 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 at room temperature for 12 hours. The resulting suspension was treated with excess acetone until the title compound completely precipitated, the compound was filtered off, dried, dissolved in water, the undissolved dicyclohexylurea was filtered off and the low molecular weight was removed on an AMICON® YM-3 ultrafiltration membrane (limit limit: 3000 Da). The residue was then 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 F 20.38 N 2.02 Gd 9.92 Found: C 36.92 H 4.50 N 7.68 F 19.77 N 1.91 Gd 10.08

Example 31

133

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

A stirred suspension of 5.0 g (9.06 mmol) of the title compound of Example 23e) in 15 mL of absolute dimethylsulfoxide was reacted with 0.68 g (15.9 mmol) of lithium chloride at 70 ° C. The mixture was stirred at 70 ° C for 30 minutes and the clear reaction solution was treated portionwise with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide and stirred at this temperature for an additional hour. After cooling to 0 ° C, dicyclohexylcarbodiimide (4.52 g, 23.85 mmol) was added and the reaction mixture was stirred at 0 ° C for an additional hour, followed by 22 ° C for 12 hours. To the thus obtained N-hydroxysuccinimide ester reaction solution of the title compound of Example 3e), a solution of 4.0 g (4.12 mmol) of the title compound of Example 10e in 15 ml of absolute dimethylsulfoxide was added dropwise at 22 ° C and the reaction mixture was stirred for 12 hours at room temperature. For working up, the reaction mixture was added dropwise to 900 ml of acetone at 22 ° C, whereby the title compound was obtained as a colorless precipitate. The precipitate was aspirated, dissolved in 200 ml of distilled water and treated with 1 molar sodium hydroxide solution until pH 7.2. The thus obtained aqueous solution of the product was ultrafiltered three times on a YM3 ultrafiltration membrane (AMICON®: cut-off limit: 3000 Da) to remove salts and a lower molecular fraction. The residue thus obtained was lyophilized.

Yield: 6.33g (92.4% of theory, calculated on the amine component used) as a colorless lyophilisate with a water content of 7.38%.

tt this this it

134 • to · • · · • to · ·· · • «· · • · · • · · • · · «· · · ·· · * • • · • it ···· Elementary analysis (calculated on anhydrous substance): Calculated: C 38.48 H 4.13 N 6.65 F 19.16 N 1.90 Gd 9.33 On 1.36 Found: C 39.52 H 4.12 N 6.67 F 19.70 N 1.89 Gd 9.30 On

I. 41

Example 32

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

20 g (47.5 mmol) of 3,5-bisbenzyloxycarbonylamino-benzoic acid (dissolved according to a method known in the literature: Skulnick, Harvey I .; Johnson, Paul D) was dissolved in a solvent mixture formed from 125 ml of dry tetrahydrofuran and 125 ml of dry dioxane. Aristoff, Paul A, Morris, Jeanette K, Lovasz, Kristina D, et al .;

J. Med.Chem .; 40; 7; 1997; 1149-1164) and 4.78 g (47.5 mmol) of triethylamine. After cooling to -15 ° C, a solution of 6.56g (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 mmoles) of 1 amino- H 1 H, 2 H, 2 H, 4 H, 4 H, 5 H, 5 H-3-oxo -perfluorotridecane and 4.78 g were added dropwise. (47.5 mmol) of triethylamine in 100 mL of dry tetrahydrofuran at -20 ° C. After one hour at -15 ° C, the reaction mixture was stirred at room temperature for 2 hours and the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 300 mL of ethyl acetate and washed twice with 200 mL of saturated sodium bicarbonate solution and 300 mL of water. After drying the organic phase over sodium sulfate, it was filtered from the salts and purified by chromatography on silica gel using the eluent φ Φ · · · · · φ φ φ φ φ

135> dichloromethane / hexane / 2-propanol (10: 5: 1). Yield: 36.2 g (82.5% of theory) of the title compound as an oil.

Elementary 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-diamino-benzoic acid N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl)] - amide

30.0 g (32.4 mmol) of the amide prepared in Example 32a) was dissolved in 300 ml of ethanol and 1.2 g of Pearlman catalyst (Pd 20%, 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 aspirated, washed well with ethanol (ca. 300 mL) and the solvent was evaporated under reduced pressure. The title compound was obtained as a strongly viscous, yellowish oil.

Yield: 20.12 g (94.8% of theory).

Elementary 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) 3N - [- (10aD-Carbonylmethyl-2,3,4,6-tetra-O-) N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide benzylmannopyranose) -5-amino-benzoic acid

10.95 g (18.30 mmol) of 1-Carboxymethyloxy-2,3,4, -tetra-Obenzyl-α-D-mannopyranoside [prepared as described in patent application DE 197 28 954 C1] was dissolved in 150 ml of dimethylformamide and left to stand with 2.09 g (18.3 mmol) of N-hydroxysuccinimide. The mixture was cooled to 0 ° C and 3.78 g (18.3 mmol) was added.

136 dicyclohexylcarbodiimide. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 4 hours. The mixture was cooled to 0 ° C and a solution of 24.0 g (36.6 mmol, 2 molar equivalents based on the named carboxylic acid) of the diamino compound prepared in Example 32b) was dissolved in 350 mL of dimethylformamide over 3 hours. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature overnight. 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 (2 x 100 mL). The organic phase was dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (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, 10.15 g of unreacted diamine compound 32b) was recovered by chromatography, which can be reused in the above reaction step.

Elementary analysis:

Calculated: C 54.42 H 4.40 N 3.40 F 26.13

Found: C 54.32 H 4.49 N 3.48 F 25.94

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

An analogous procedure to that described for the synthesis of the title compound of Example 32b) gave 12.0 g (9.70 mmol) of the title compound of Example 32c by hydrogenolysis, in the presence of 0.5 g of Pearlman catalyst (Pd 20%, C) in the mixture. • · · · · · · · · ·

137

ethanol / water (9: 1) after treatment 8.08 g (96.7% of theory) of the title compound as a yellow colorless viscous oil.

Elementary analysis:

Calculated: C 37.64 H 3.28 N 4.88 F 37.49

Found: C 37.32 H 3.17 N 4.97 F 37.55

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

13.6 g (19.2 mmol; 2.2 molar equivalent based on the amine component used in Example 32d) of the Gd complex described in Example 23Ae) and 0.81 g of anhydrous lithium chloride (19.2 mmol) were dissolved with stirring at 40 ° C. A total of 2.2 g (19.2 mmol) of N-hydroxysuccinimide and 7.5 g (8.7 mmol) of the title compound of Example 32d) dissolved in 50 mL of absolute dimethylsulfoxide were added at 0 ° C in 100 mL of absolute dimethylsulfoxide. . After cooling to room temperature, 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 undissolved dicyclohexylurea was filtered off and purified from the low molecular weight fraction on the AMICON® YM-3 ultrafiltration membrane (limit: 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):

• · • ·

138

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 Na 1.42

Example 33

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

10 g (23.75 mmol) of 3,5-bisbenzyloxycarbonylaminobenzoic acid (synthesized according to the literature procedure: Skulnick, Harvey L; Johnson, Paul D.; Aristoff, Paul) were dissolved in a solvent mixture of 60 mL dry tetrahydrofuran and 70 mL dry Dioxane. A., Morris, Jeanette K., Lovasz, Kristina D.; et al .; J. Med.Chem .; 40; 7; 1997; 1149-1164) and 2.39 g (23.75 mmol) of triethylamine. After cooling to 15 ° C, a solution of 3.28g (24 mmol) of isobutyl chloroformate in 20 ml of dry tetrahydrofuran was slowly added dropwise with stirring, the internal temperature not exceeding -10 ° C. After 15 minutes at -15 ° C, a solution of 23.0 g (23.75 mmol) of perfluorooctylsulfonylpiperazine and 2.39 g (23.75 mmol) of triethylamine in 50 ml of dry tetrahydrofuran was added dropwise at -20 ° C. The reaction mixture was stirred for one hour at 15 ° C and then for two hours at room temperature and was evaporated to dryness under reduced pressure. The obtained residue 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 obtained residue was purified by silica gel chromatography using dichloromethane / hexane / 2-propanol (15: 5: 1) as eluent.

Yield: 18.35 g (79.6% of theory) of the title compound as an oil.

Elementary analysis:

• φ · φ • Φ φφφφ

139

Calculated: C 43.31 Η 2.80 Ν 5.77 F 33.27 S 3.30

Found: C 43.21 Η 2.75 Ν 5.61 F 33.38 S 3.22

b) 3,5-Di-amino-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 catalyst (Pd 20%, 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 well with ethanol (ca. 150 ml) and the mixture was evaporated to dryness under reduced pressure. The title compound was obtained as a strongly viscous, yellowish oil.

Yield: 6.9 g (98.2% of theory).

Elementary 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-N- (1-O-α-D-Carbonylmethyl-2,3,4,6-tetra-O-benzylmannopyranose} -benzoic acid N- (1- (4-perfluorooctylsulfonyl) piperazine) -amide

5.48 g (9.15 mmol) of 1-Carboxymethyloxy-2,3,4; tetra-Obenzyl-α-D-mannopyranoside [Preparation according to patent application DE 197 28 954 C1] was dissolved in 100 ml of dimethylformamide and treated with 1.04 g (9.15 mmol) of N-hydroxysuccinimide. The mixture was cooled to 0 ° C and dicyclohexylcarbodiimide (1.89 g, 9.15 mmol) was added. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 4 hours. The mixture was cooled again to 0 ° C and a solution of 12.85 g (18.30 mmol, 2 molar) was slowly added dropwise over 3 hours.

140

4444 · * ·· • 4 4 44 444

4 4 4 4 4

4 4> 04 5

4 4 · 4 4

4,444,444 equivalents based 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 one 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 precipitated urea 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 evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (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 (nhexane / isopropanol) yielded a total of 4.36 g of unreacted compound 33b), which can be reused in the above reaction step.

Elementary 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-N- (1-O-α-D-Carbonylmethyl-mannopyranose) -benzoic acid N- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

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

Elementary analysis:

Calculated: C 35.15 H 2.95 N 6.07 F 35.01 S 3.48

141 «· ··« ·

Found: C 35.32 H 3.02 N 5.89 F 35.05 S 3.58

e) 3N- (10-α-D-Carbonylmethyl-mannopyranose) -5-N- [1,4,7-tris (carboxylatomethyl) -10- (3-) - [1- (4-perfluorooctylsulfonyl) -piperazine] -amide 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, based on the amine component of Example 33d) of the Gd complex with 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4, The 7,10-tetraazacyclododecane-1,4,7-triacetic acid described in patent application DE 197 28954 Cl under Example 31 h) and 0.37 g of anhydrous lithium chloride (8.8 mmol) 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 3.7 g (4.0 mmol) of the title compound of Example 13Ad) dissolved in 40 ml of absolute dimethylsulfoxide were added. After cooling to room temperature, 1.82 (8.8 mmol) of N, N'-dicyclohexylcarbodiimide was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. 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 undissolved dicyclohexylurea was filtered off and 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 ·· ·· «· ·· ····

142

Example 34

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 and 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 at this temperature for 3 hours. To prepare the active ester solution, a solution of 5.57 g (53.95 mmol) of diethylenetriamine dissolved in 60 ml of dimethylformamide 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 at room temperature for 12 h. temperature. The precipitated dicyclohexylurea precipitate was filtered off and the solvent was evaporated to dryness. The residue thus obtained was chromatographed on silica gel (mobile phase: dichloromethane / ethanol 15: 1; the chromatography was carried out with a gradient such that the ethanol portion was continuously increased).

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

Elementary 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-fluorooctylsulfonyl) -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 tetrahydrofuran and 15 ml chloroform, was at 0 ° C under nitrogen.

9 · ···

A solution of 16.18 g (27.0 mmol) of 2- (N-ethyl-N-fluorooctylsulfonyl) aminoacetic acid (prepared according to DE 196 03 033) dissolved in 50 ml of tetrahydrofuran was added via a 143 atmosphere 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 and then evaporated to dryness in vacuum. The residue obtained was chromatographed on silica gel (mobile phase: 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.

Elementary 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-N-perfluorooctylsulfonyl) -amino) -acetyl-1,4,7-triazaheptane

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 residual oily residue was purified by silica gel chromatography using dichloromethane / hexane / 2-propanol (20: 10: 1) as eluent. Yield: 12.92 g (98.4% of theory) of the title compound as a colorless and highly viscous oil.

Elementary 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 • fc fcfcfcfc • · • fc fcfcfcfc

144 fcfc · ····· ♦ · · fcfcfc fcfc fcfcfc · ··· fcfcfc fcfcfcfc · · »fcfcfcfc · ·» fcfcfcfc · fc fc fcfc fc ··· fcfc ··

d) 1,7-Bis- [6-N-benzyloxycarbonyl-2-N- (1-O-α-Dcarbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose) -Llysine] -diamide- 4- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-1,4,7-triazaheptane

5.47 g (9.15 mmol) of 1-Carboxymethyloxy-2,3,4, -tetra-Obenzyl-α-D-mannopyranoside [Preparation of patent application DE 197 28954 C1] was dissolved in 80 ml of dimethylformamide and a total of 1, 05 g (9.15 mmol) of N-hydroxysuccinimide. The mixture was cooled to 0 ° C and dicyclohexylcarbodiimide (1.9 g, 9.15 mmol) was added. The reaction mixture was stirred at 0 ° C for 1 hour and then stirred at room temperature for 4 hours. 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 h. The reaction mixture was then stirred at 0 ° C for an additional hour and then stirred at room temperature. The reaction 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 solution. The organic phase was dried over magnesium sulphate and evaporated in vacuo to dryness. The residue was chromatographed on silica gel (mobile phase: 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.

Elementary 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-α-carbonylmethyl-mannopyranose) -Llysine] -diamide-4- [2- (N-ethyl-N-perfluorooctylsulfonyl) -amino] acetyl-1 , 4,7-triazaheptane

15.0 g (6.36 mmol) of the amide prepared in Example 34d) was dissolved in 150 ml of ethanol and 0.5 g of Pearlman catalyst (Pd 20%, 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 well with ethanol (ca. 100 ml) and the solution evaporated to dryness under reduced pressure. The title compound was obtained as a viscous yellowish oil. Yield: 8.54 g (97.2% of theory).

Elementary 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-O-α-carbonylmethyl-mannopyranose) -6-N [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo) -5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -L-lysine] -diamide-4- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-1,4, 7-Triazaheptane, Digadolinium Complex

To a stirred suspension of 5.7 g (9.06 mmol) of Gd complex with 10 (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid obtained according to patent application DE 197 28 954 C1 under Example 31 h) in 75 ml of absolute dimethylsulfoxide at 70 ° C was added 0.68 g (15.9 mmol) of lithium chloride. 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 at this temperature for an additional hour. After cooling to 0 ° C, dicyclohexylcarbodiimide (4.52 g, 23.85 mmol) was added and the reaction mixture was stirred at 0 ° C for an additional hour.

146

then 12 hours at 22 ° C. The reaction mixture of the 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid N-hydroxysuccinimide ester Gd complex at 22 ° C 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 and the reaction was stirred at room temperature for 12 hours. During work-up, 500 ml of acetone was added dropwise to the reaction solution at 22 ° C, the title compound precipitating as a colorless precipitate. The precipitate was aspirated, dissolved in 200 ml of distilled water and was ultrafiltered three times through a YM3- ultrafiltration membrane (AMICON ®: cutoff limit: 3000 Da) to remove salts and low molecular weight fraction. The resulting filtrate was purified by lyophilization.

Yield: 4.80g (89.6% of theory, calculated on the amine component) as a colorless lyophilisate with a water content of 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-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) piperazine] -amide} -1,4,7, 10-tetraazacyclododecane

To a solution of 10.75 g (24.4 mmol) of 1,7-bis- [benzyloxycarbonyl] -1,4,7,10-tetraazacyclododecane, dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, was at 0 ° C and below. 16.56 g (24.4 mmol) of the title compound of Example 35e) dissolved in 150 mL of tetrahydrofuran was added under a nitrogen atmosphere. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2] titanium was added at 0 ° C. · · · · ·

147 • You • · · • · · titi til tititi • ti titititi dihydroquinoline] and a mixture was stirred over night at and then vaporized to dry for reduced pressure. The oil obtained was chromatographed 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 collected together with 3.8 g (8.8% of theoretical) of the by-product diamide. The title compound was isolated as a colorless oil. Elementary 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-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) piperazine] -amide] -10- [1-0 -αD- (5-carbonyl) -pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose] -1,4,7,10-tetraazacyclododecane

10.0 g (13.4 mmol) of the carboxylic acid of Example 30c) and 3.24 g (28.1 mmol) of N-hydroxysuccinimide were dissolved in 100 ml of dimethylformamide and a total of 5.8 was added in portions at 0 ° C. g (28.1 mmol) of N, N'-dicyclohexylcarbodiimide and the mixture was stirred at this temperature 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 cooled to 0 ° C and the mixture was stirred at 0 ° C for 2 hours and then for 12 h. 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 chromatographed on silica gel (mobile phase: dichloromethane / ethyl acetate 20: 1; chromatography was carried out with a gradual solvent gradient as the ethyl acetate portion was gradually increased).

• ·

148

Yield: 18.3 g (78.2% of theory) of the title compound as a colorless and strongly viscous oil. Elementary analysis:

Calculated: C 55.11 H 5.03 N 4.82 F. 8.52 S 1.84

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

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

In 150 ml of ethanol, 17.0 g (9.75 mmol) of the compound prepared in Example 34b) was dissolved, 1.0 g of Peartman catalysate (Pd 20%, 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 with 75 ml) and the solvent was evaporated under reduced pressure. The title compound was obtained as a strongly viscous colorless oil. Yield: 10.76 g (99.0% of theory).

Elementary analysis:

Calculated: C 38.78 H 4.61 N 7.54 F8.97 S 2.88

Found: C 38.86 H 4.65 N 7.41 F 29.02 S 2.92

d) 1,7-Bis- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-Gd-Complex-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) - 4- [2- (N-ethyl-N-perfluorooctylsulfonyl] -amino] acetyl-2-oxa-acetyl] -10- [1- O-α-D-6-carbonylpentylmannopyranose] -1,4,7,10 tetraazacyclododecane

24.86 g (39.46 mmol; 4.4 molar equivalents based on amine component 35c) of the Gd complex of 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 1 97 28

149

954 Cl under Example 31 h) and 1.67 g of anhydrous lithium chloride (39.46 mmol) were dissolved at 40 ° C with stirring in 200 ml of absolute dimethylsulfoxide and 4.53g (39.46 mmol) was added at this temperature. N-hydroxysuccinimide and 10.0 g (8.97 mmol) of the title compound of Example 34c) dissolved in 100 mL of absolute dimethylsulfoxide. After cooling to room temperature, 8.14 g (39, 46 mmol) of Ν, N'-dicyclohexylcarbodiimide was added to the reaction solution, and the reaction mixture was stirred at room temperature for 12 hours. The resulting suspension was decanted with excess acetone until the title compound completely precipitated, the precipitate was filtered, dried, dissolved in water, the undissolved dicyclohexylurea was filtered off, and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cutoff limit: 3000 Da) to remove 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-Oxapentane-1,5-dicarboxylic acid mono- [1- (4-perfluoro-octylsulfonyl) -piperazine] -amide g (44.0 mmol) of 1-Perfluoro-octylsulfonyl-piperazine was dissolved in 150 ml of tetrahydrofuran and a total of 5 was added at room temperature. Diglycolic anhydride (1 g, 44.0 mmol) was added and the reaction mixture was heated at reflux for 12 h. After cooling to room temperature, the reaction mixture was evaporated to dryness in vacuo and the residue was purified by silica gel chromatography using dichloromethane / 2-propanol (16: 1) as eluent. Yield: 27.94

150 g (92.8% of theory) of the above title compound as a colorless viscous oil.

Elementary analysis:

Calculated: C 58.52 H 4.27 N 1.98 S 2.26 F 22.80

Found: C58.42 H 4.41 N 1.80 S 2.28 F 23.02

Example 36

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

687 g (91.79 mmol) of 1-carboxymethyloxy-2,3,4, -tetra-O-benzyl-α-Dmannopyranoside [prepared according to patent application DE 197 28 954 C1] were dissolved in 750 ml of dry tetrahydrofuran and added. 9.25 g (91.79 mmol) of triethylamine. 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 dropwise rate being such that the reaction temperature the mixture did not exceed -10 ° C. The mixture was stirred at -15 ° C for 15 minutes 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 dissolved in 500 mL of dry tetrahydrofuran was added dropwise. at -20 ° C. The reaction mixture was stirred for one hour at -15 ° C and then for two hours at room temperature, then the reaction mixture was 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 inorganics were filtered off and the ethyl acetate was evaporated to dryness under vacuum.

151 • ·

The residual oil was purified by chromatography on silica gel using dichloromethane / hexane / 2-propanol (10: 20: 1) as eluent. Yield: 130.6 g (81.6% of theory) of the above

of the title compound in the form colorless and highly viscous oils. Elementary analysis: Calculated: C 55.11 H 5.03 N 4, 82 F 18.52 N 1.84 Found: C, 55.20 5.09 N 4, 91 F 18.48 N 1.80

b) -1- {3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-fluorooctylsulfonyl) piperazine] -amide] -7- [1-O-α- (5carbonyl) - pentyl-mannopyranose] -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 Peartman catalyst (Pd 20%, C) were added and the mixture was hydrogenated until all hydrogen was consumed. The catalyst was filtered off, washed well with ethanol and the mixture was evaporated to dryness under reduced pressure. The title compound was obtained as a colorless oil.

Yield: 92.6 g (99.5% of theory).

Elementary 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-oxa-pentan-1) 5-Dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] amide} -10- [1-O-α- (5-carbonyl) -pentyl-mannopyranose] 1,4,7 , 10-tetraazacyclododecane, Digadolinium complex

55.4 g [88.0 mmol; 4.4 molar equivalents based on the diamine component of Example 33d)] Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclo

152 dodecane-1,4,7-triacetic acid described in patent application DE 197 28 954 C1 under Example 31 h) and 3.7 g of anhydrous lithium chloride (88.0 mmol) were dissolved in 500 ml of absolute dimethyl sulfoxide with stirring 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 at room temperature for 12 hours. The obtained suspension was treated with excess acetone until the title compound completely precipitated, the precipitate was filtered, 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) for removal of 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-α-Dmannopyranoside

In an analogous manner to that described in the literature for the synthesis of arylglycopyranosides [J. Conchie and GA Levvy in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol. 11, 90, pp. 34.5-347, (1963) led to the use of 156.2 g • · · ··

153 · * (400 mmol) D-mannosapentaacetate as α, β- (α, β-ratio = 4: 1) mixture of anomers [for synthesis of 1,2,3,4,6-Penta-O-acetyl-α, β -Dmannopyranoses see: ML Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (RL Whistler, ML Wotfrom and JN BeMiller, Eds.), Academic Press, New York, Vol. 11, 53, 211-215, (1963)] with 67 ml (400 mmol) of 6-hydroxyhexanoic acid ethyl ester and 60.8 ml (520 mmol) of tin (II) chloride in 600 ml of 1,2-dichloroethane after column chromatography purification Silica gel (Eluent: hexane / ethyl acetate 2: 1) gave 100.0.05 g (51% of theory) of the title compound as a colorless and viscous oil. It was found by IH NMR spectroscopy that the title compound can be considered as the pure α-anomer.

Elementary analysis:

H, 6.77

Found: C, 52.80; H, 6.78

b) 5- (Carboxy) pentyl-2,3,4,6-tetra-O-benzyl-α-Dmannopyranoside

A stirred suspension of 141.0 g (289 mmol) of the title compound of Example 37a) in 200 mL 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 two hours. The reaction mixture was stirred at 110 ° C for 4 hours and then at room temperature for 12 hours. The reaction mixture was then poured slowly into a total of 2.5 liters of ice water and was extracted with diethyl ether. The ether phase was washed and dried over

• · ·

W · 9

9 9

9 9 9 ·· ··· · sodium sulphate. The inorganics were filtered off and the diethyl ether was evaporated to dryness in vacuo. Excess benzyl bromide was distilled off from the reaction mixture at 180 ° C oil bath temperature. The residue thus obtained was purified by chromatography on silica gel using ethyl acetate / hexane (1:10) as eluent.

Yield: 172.2 g (91.0% of theory) of the title compound as a colorless and strongly viscous oil.

Elementary analysis:

Calculated: C 75.68 H 7.16

Found: C, 75.79; H, 7.04

c) 5 - [(Carboxy) -pentyl-2,3,4,6-tetra-O-benzyl-α-Dmannopyranoside-] N-hydroxysuccinamide 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 dicyclohexylcarbodiimide (18.9 g, 91.5 mmol) was added. The reaction mixture was stirred at 0 ° C for 4 hours and then at room temperature for 4 hours. The solvent was evaporated to dryness and the residue was dissolved in 100 mL of ethyl acetate and cooled to 0 ° C. The urea precipitate was aspirated and the filtrate was evaporated to dryness in vacuo. The residue thus obtained was purified by silica gel column chromatography using ethyl acetate / hexane (1:20) as eluent.

Yield: 61.23 g (89.0% of theory) of the title compound above as a viscous oil.

Elementary analysis:

H, 6.57; N, 1.86

Found: C 70.39 H 5.64 N 1.91 • ·

155

d) 2,6-Bis- {6- _ε- 2- _α - [- [10aD-6-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 cooled DMF A solution of 27.51 g (36.6 mmol) of the title compound of Example 37c) in 150 ml of dimethylformamide was added dropwise to 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 precipitated urea was filtered off, the filtrate was washed twice with 100 ml of 5% aqueous soda. The organic phase was dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (mobile phase: n-hexane / isopropanol 25: 1). 39.56 g (75.4% of theory) of the title compound were obtained as a colorless oil.

Elementary analysis:

H, 7.31; N, 1.95

Found: C 72.90 H 7.29 N 2.02

(e) 2,6-Bis- [6- _ε- 2- _α] - [10-α-D-6-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 indicated that the reaction was quantitative. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved.

156 • 9 · «·· ····

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 chromatographed on silica gel (mobile phase: n-hexane / isopropanol 13: 1). Yield: 25.56 g (88.5% of theory) of the title compound as a colorless oil.

Elementary analysis:

H, 7.31; N, 1.95

Found: C 72.78 H 7.33 N 1.96

f) 2,6-Bis- [6- _ε- 2- _alpha - [10aD-6-Carbonylpentyl- (2,3,4,6-tetra-O-benzyl) -mannopyranose] -L-lysine] -N- hydroxysuccinimidester

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 dicyclohexylcarbodiimide (1.89 g, 9.15 mmol) was added. The mixture was stirred at 0 ° C for 1 hour and then at room temperature for 4 hours. The solvent was evaporated to dryness in vacuo and the residue was dissolved in 100 mL 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 silica gel chromatography using ethyl acetate / n-hexane (1:20) as eluent.

Yield: 12.94 g (92.4% of theory) of the title compound as a colorless viscous oil.

Elementary analysis:

H, 7.05; N, 2.74

Found: C, 71.39; H, 7.14; N, 2.81

4 • 4444

157

4444

4

4

4

4444

g) 2,6-N, N'-Bis [1-OaD- (6-carbonyl) -pentyl-2,3,4,6-tetra-O-benzylmannopyranose) -L-lysine-1,7- (1,4) 7-triazaheptane) diamide

To a solution (cooled to 0 ° C) of 0.47 g (4.57 mmol) of diethylenetriamine in 25 mL of dimethylformamide was slowly added dropwise a solution of 14.0 g (9.15 mmol; 2 molar equivalents, based on amine used) of the title compound. of Example 37f) in 100 ml of dimethylformamide. After the addition was complete, the reaction mixture was stirred for one 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. The organic phase was dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (mobile phase: n-hexane / isopropanol 25: 1). 9.53 g (71.4% of theory) of the title compound were obtained as a colorless oil.

Elementary analysis:

H, 7.42; N, 3.36

Found: C 72.90 H 7.39 N 3.32

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

20.8 g (35.6 mmol) of 2- [N-Ethyl-N-perfluorooctylsulfonyl) aminoacetic acid and 3.60 g (35.6 mmol) of triethylamine were dissolved in 200 ml of dimethylformamide and 4.09 g ( 35.6 mmol) of N-hydroxysuccinimide. The mixture was cooled to 0 ° C and dicyclohexylcarbodiimide (7.34 g, 35.6 mmol) was added. The reaction mixture was stirred at 0 ° C for 1 hour and then stirred at room temperature for 4 hours. The mixture was cooled to 0 ° C and then a solution of 11.77g (35.6 mmol) of 6-N-benzyloxycarbonyl-L-lysine-methyl ester hydrochloride and 4.0 g (40.0 mmol) of triethylamine in a dropwise manner was added dropwise over 10 minutes. 100 ml • 4444

158 ·· ·· ► 4 4 5

I 4 9

4444

4 4

4 4

4444 dimethylformamide. 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 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 sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (Mobile phase: n-

hexane / ethyl acetate 20: 1) • It was obtained 27,43 g (88.0% of the theoretical quantity) colorless oils. Elementary analysis: H, 3.45 N 4,80 F 36.89 N 3.66 Found: C, 38.45; H, 3.38 N 4.88 F 37.02 S 3.71

i) 2-Na - {[2- (N-ethyl-N-perfluorooctylsulfonyl) -amino-acetyl} -6- (benzyloxycarbonyl) -L-lysine

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 at 50 ° C for 3 hours. The saponification is complete by thin layer chromatography. The reaction mixture was evaporated in vacuo and 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 inorganics were filtered and the mixture was evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (mobile phase: n-hexane / isopropanol 10: 1). 22.73g (92.4% of theory) of the title compound were obtained as a colorless oil.

Elementary 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 <··· • to ····

159 this to this this to this this to this this to this

j) 1,4,7-Triazaheptane-4- {2-N- [2- (N-ethyl-N-perfluorooctylsulfonyl) -amino] -acetyl-6-N-benzyloxycarbonyl} -L-lysine-amide 1,7- bis {2,6-N, N'-bis [1-O-α- (5-carbonyl) pentyl-2,3,4,6-tetra-O-benzylmannopyranose] -L-lysine diamide)

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 triehylamine. After cooling to 15 ° C to -20 ° C, a solution of 4.92 g (35.6 mmol) of isobutyl chloroformate dissolved in 50 ml of dry tetrahydrofuran was slowly added dropwise to the reaction mixture while stirring, the rate of addition being such that the temperature The reaction mixture did not exceed -10 ° C. After stirring at 15 ° C for 15 min, a solution of 52.0 g (17.8 mmol) of the title compound of Example 37g) and 80g (17.8 mmol) of triehylamine in 300 mL of dry tetrahydrofuran was slowly added dropwise at -20 ° C. The reaction mixture was stirred at -15 ° C for 1 hour and then stirred at room temperature for 2 hours and evaporated to dryness under reduced pressure.

The residue was dissolved in 500 mL of ethyl acetate and was 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, the ethyl acetate was evaporated in vacuo. The residual oily residue was purified by silica gel column chromatography using ethyl acetate / n-hexane (1:20) as eluent. Yield: 54.6 g (81.6% of theory) of the above title compound as a colorless, highly viscous oil.

Elementary 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 *

• · • ·

160

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 [10-α-D- (5-carbonyl) -pentyl-mannopyranose] -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 (Pd 20%, 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 well with ethanol (ca. 400 ml) and the mixture was evaporated to dryness in vacuo. The title compound was obtained as a strongly viscous and colorless oil.

Yield: 26.85 g (93.0% of theory).

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

5.54 g (8.8 mmol; 2.2 molar equivalents, based on the amine component of Example 37k) used) Gd complex 10 (4-carboxyl-methyl-2-oxo-3-azabutyl) -1,4, The 7,10-tetraazacyclododecane-1,4,7-triacetic acid described in patent application DE 197 28 954 Cl under Example 31 h) and 0.37 g of anhydrous lithium chloride (8.8 mmol) were dissolved at 40 ° C. 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 dimethyl sulfoxide were added under stirring at this temperature. ··

161 dimethylsulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. The resulting suspension was mixed with excess acetone until the title compound completely precipitated, the precipitate was filtered, dried, dissolved in water, the undissolved dicyclohexylurea was filtered off, and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cutoff limit: 3000 Da) to remove low molecular weight. share. The remainder was lyophilized.

Yield: 8.77g (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) 2-Na-6-Ns-Bis- [1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose] -L-lysine] -methyl ester

10.95 g (18.30 mmol) of 1-Carboxymethyloxy-2,3,4, -tetra-Obenzyl-α-D-mannopyranoside [prepared as described in patent application DE 197 28954 C1] was dissolved in 150 ml of dimethylformamide and a total of 2.09 g (18.3 mmol) of N-hydroxysuccinimide. The mixture was cooled to 0 ° C and 3.78 g (18.3 mmol) of dicyclohexylcarbodiimide was added. The mixture was stirred at 0 ° C for 1 hour and then at room temperature for 4 hours. The mixture was cooled to 0 ° C and a solution of 2.13 g (9.15 mmol; 0.5 molar equivalents, based on the carboxylic acid used) of L-lysine methyl ester dihydrochloride (commercially available from Bachem) was added dropwise over 1 hour. 02 g (20.13 mmol) of triethylamine in 70 ml of dimethylformamide. After the addition was complete, the reaction mixture was stirred for one 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 was filtered off and the filtrate was washed with 100 ml of 5% aqueous soda. The organic phase was dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (mobile phase: n-hexane / isopropanol 25: 1). 10.05 g (82.3% of theory) of the title compound were obtained as a colorless oil.

Elementary analysis:

H, 6.79; N, 2.10

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

b) 2-Na-6-Ns-Bis- [1-O-α-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 of Example 38a) afforded 13.69 g (93.6% of theory) of the title compound as colorless. and viscous oil.

Elementary analysis:

H, 6.71; N, 2.12

Found: C 71.84 H 6.69 N 2.15

c) 2-α-β-ε-Bis- [1-O-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose] -L-lysine-N-hydroxysuccinimide ester

12.09 g (9.15 mmol) of the title compound 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 dicyclohexylcarbodiimide (1.89 g, 9.15 mmol) was added. The mixture was stirred for an hour at room temperature

163 • ··

4 4

44 ° C and then 4 hours at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in 100 mL of ethyl acetate and the mixture was cooled to 0 ° 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 using ethyl acetate / n-hexane (1:20) as eluent. Yield: 12.24 g (94.4% of theory) of the title compound above as a viscous oil. Elementary analysis:

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 (10α-Dcarbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)] - Llysyl-} 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 at 0 ° C, L-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide. a solution (cooled to 0 ° C) of 11.13 g (13.4 mmol) of the title compound of Example 21 c) dissolved in 50.0 mL of dimethylformamide was added dropwise. The mixture was stirred for an additional 2 hours at 0 ° C and then the work up was dicyclohexylurea at room temperature. The precipitate formed was filtered off and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography [Mobile phase: dichloromethane / ethanol 28: 1;

wherein the chromatography was carried out by adding a more polar component (here ethanol) during chromatography.

Yield: 25.28 g (88.4% of theory) of the title compound as a colorless and strongly viscous oil.

9 ···

164

Elementary analysis:

Calculated: C 59.10 H 5.34 N 3.94 F 15.13 S 1.50

Found: C 59.18 H 5.35 N 4.02 F 15.15 S 1.56

e) 2-N - {[2,6-N, Ν'-bis (1-O-α-D-carbonylmethylmannopyranose)] - 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 (Pd 20%, 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 well with ethanol (twice with about 100 ml) and the mixture was evaporated to dryness under reduced pressure. The title compound was obtained as a strongly viscous and colorless oil.

Yield: 11.62 g (97.0% of theory).

Elementary analysis:

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-cis-D-carbonylmethyl-mannopyranose)] -Llysyl} -L-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd-complex

9.98 g (15.84 mmol; 2.2 molar equivalents, based on the amine component of Example 38e) used, Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4, Of 7,10-tetraazacyclododecane-1,4,7-triacetic acid described in patent application DE 197 28 954 Cl under Example 31 h) and 0.67 g of anhydrous lithium chloride (15.84 mmol) were dissolved at

AAAA

AAA

• A AAAA

165

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), dissolved in 50 ml of absolute, were added at 0 DEG C. in 100 ml of absolute dimethylsulfoxide under stirring. 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 at room temperature for 12 hours. The resulting suspension was mixed with excess acetone until the title compound completely precipitated, the precipitate was filtered, dried, dissolved in water, the undissolved dicyclohexylurea was filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cutoff limit: 3000 Da) to remove eventually 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-2H, 2H, 4H, 4H, 5H, 5Hperfluorotridecanoyl) -1,4,7,10-tetraazacyclododecane To a solution of 10.75 g (24.4 g) mmol) 1,7-bis- [benzyloxycarbonyl] 1,4,7,10-tetraazacyclododecane, dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, was added dropwise at 0 ° C and 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-ethoxycarbonyl-1,2-dihydroquinoline] was added in portions at 0 ° C and the mixture was stirred for three times. Titanium dioxide titanium dioxide three hours at room temperature and then evaporated to dryness under reduced pressure. The residual oil was chromatographed on silica gel (mobile phase: n-hexane / isopropanol 16: 1). 15.89 g (69.0% 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. Elementary 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, 5Hperfluorotridecanoyl) -10- [1-SaD- (2-carbonyl) ethyl-2,3], 4,6-Tetra-O-acetyl-mannopyranose] -1,4,7,10-tetraazacyclododecane

7.09 g (13.4 mmol) of 3- (2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranosyl) propionic acid N-hydroxysuccinimide ester (prepared according to: J. Haensler et al., Bioconjugate Chem., 4, 85, (1993), Chipowsky, S., and Lee, YC (1973), Synthesis of

1-thio-aldosides; Carbohydrate Research 31, 339-346) was dissolved in 100 mL of dimethylformamide and a cooled solution (0 ° C) of 12.65 g (13.4 mmol) of the title compound of Example 39a) dissolved in 100 mL was added dropwise at 0 ° C. dimethylformamide. The mixture was stirred at 0 ° C for 2 hours and then at room temperature for 12 hours. Upon work-up, the solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column (mobile phase: dichloromethane / ethyl acetate 20: 1; chromatography was performed with a solvent gradient with increasing ethyl acetate).

Yield: 16.23 g (88.9% of theory) of the title compound as a colorless and strongly viscous oil. Elementary analysis:

«· • ·

167

Calculated: C 46.70 H 4.36 N 4.11 F 23.69 S 2.35

Found: C, 46.66; H, 4.35; N, 4.12; F, 23.65; S, 2.30

c) 1- (3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) -7- [1- S-α-D- (2-carbonyl) ethyl-2,3,4,6-tetra -O-acetyl-mannopyranose] 1,4,7,10-tetraazacyclododecane

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 (Pd 20%, 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 well with ethanol (twice with about 75 ml) and the mixture was evaporated to dryness under reduced pressure. The title compound was obtained as a strongly viscous and colorless oil.

Yield: 11.56 g (96.0% of theory).

Elementary 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-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) -7- [1- S-α- (2-carbonyl) ethyl-mannopyranose] -1,4,7, 10-tetraazacyclododecane

10.0 g (9.13 mmol) of the title compound of Example 39c) was suspended in 100 mL of absolute methanol and a catalytic amount of sodium methoxide was added at 5 ° C. The mixture was stirred for 3h at room temperature and thin layer chromatography control showed (Eluent: chloroform / methanol 4: 1) quantitative reaction. The clear reaction solution was neutralized with Amberlite IR 120 (H + Form) cation exchanger, filtered from the ion exchanger, washed with methanol and the methanolic thus obtained.

The 168 filtrate 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; chromatography was performed with a solvent gradient with continuous addition of ethyl acetate). After examining the title compound by 1 H NMR spectroscopy, it was possible to say, based on the magnitude of the interaction constant J _x , ₂ = 0.9 Hz, that the anomeric center of D-mannopyranose has an configuration. Said α-configuration at the anomeric center is the exclusive configuration, i.e. the amount of potentially formed β-anomer of the title compound lies below the recognition limit of IH NMR spectroscopy. Thus, the aforementioned title compound was prepared in the form of the pure α-anomer.

Yield: 8.28 g (98.0% of theory) of the title compound as a colorless and strongly viscous oil. Elementary 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-perfluorotridecanoyl) -7- [1- S-α-D- (2-carbonyl) ethyl-mannopyranose] -4,10-bis [ 1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl)] - 1,4,7,10-tetraazacyclododecane, digadolinium Complex

1,4,7,10-tetraazacyclododecane-amide conjugate with [1,7-Bis [gadolinium complex 10- (4-carboxy-1-methyl-2-oxo-3azabutyl) -1,4,7,10-tetraazacyclododecane-1] 4,7-triacetic acid]; 3- (2,3,4,6-Tetra-O-acetyl-1-thio-α-D-mannopyranosyl) -propionic acid

2.48 g [(3.94 mmol); 4.4 molar equivalents, based on the diamine component of Example 39d)] Gd complex used ·· · ··

169

• φ ·

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 C1 under Example 31 h) and 167 mg of anhydrous lithium chloride (3.94 mmol) was dissolved in 40 ml of absolute dimethylsulfoxide at 40 ° C under stirring, at which temperature a total of 453 mg (3.94 mmol) of N-hydroxysuccinimide and 980 mg (0.895 mmol) were added. of the title compound of Example 19Ad) 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 at room temperature for 12 hours. The resulting suspension was mixed with excess acetone until the title compound completely precipitated, the precipitate was filtered, 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) for desalination and removing 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% 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-2H, 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] was dissolved in 250 ml of absolute toluene and a catalytic amount (about 0.75) was added at room temperature. g) tetra-n-butyl ammonium hydrogen sulfate. Then it was total at 0 ° C

170

7.55 g (134.6 mmol; 2.5 eq. based on alcoholic component used) of finely powdered potassium hydroxide, followed by 15.73 g (80.7 mmol; 1.5 eq. based on alcoholic component used) were added. -butyl bromoacetate and the mixture was stirred at 0 ° C for 2 hours. The reaction mixture was stirred at room temperature for 12 h 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 with sodium sulfate, the inorganics were filtered off and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography using ethyl acetate / hexane (1:10) as eluent. Yield: 26.3 g (84.6% of theory) of the title compound as a colorless and strongly viscous oil.

Elementary analysis:

H, 2.61; F, 55.85

Found: C 33.29 H 2.61 F 55.90

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

20.0 g (34.58 mmol) of the title compound of Example 39f) was suspended in 200 ml of a mixture consisting of methanol and 0.5 molar aqueous sodium hydroxide solution 2: 1 with stirring at room temperature and then heated. to 60 ° C. The reaction mixture was stirred at 60 ° C for 12 h and the clear reaction mixture was worked up by neutralization by adding Amberlite IR 120 (H ⁺ -form) -cationic ion exchanger, filtering the ion exchanger and evaporating the methanolic filtrate to dryness under reduced pressure. The obtained residue was purified by silica gel chromatography using ethyl acetate / hexane (1: 3) as eluent.

Fc fc

171 • fc • fc fcfcfcfc

Yield: 16.0 g (88.6% of theory) of the title compound as a colorless and strongly viscous oil.

Elementary 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-perfluorooctylsulfonyl) -amino] -acetyl-L-lysine-methyl ester

To 8.0 g (24.4 mmol) of ε-carbonyloxybenzyl-L-lysine methyl ester hydrochloride (commercially available from Bachem) dissolved in a mixture of 150 ml of tetrahydrofuran, 15 ml of chloroform and 2.62 g (26.0 mmol) of triehylamine, 16.18 g (27.0 mmol) of 2- [N-ethyl-N-perfluorooctylsulfonyl) aminoacetic acid (prepared according to: DE 196 03 033), dissolved in 50 ml of tetrahydrofuran, was added dropwise at 0 [deg.] C. under a nitrogen atmosphere. Then, a total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-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 chromatographed on silica gel (mobile phase: n-hexane / isopropanol 15: 1). 17.0 g (79.6% of theory, based on the primary amine used) of the title compound were obtained as a colorless oil.

Elementary 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

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

Fcfcfc fcfcfc

172

• fc • fc fc • fc fc fcfc

Fc fcfc

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 (Pd 20%, 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 well 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)

Elementary analysis:

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 30

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

21.31 g (35.6 mmol) of 1-carboxymethyloxy-2,3,4, -tetra-O-benzyl-α-Dmannopyranoside [preparation according to patent application DE 197 28 954 C1] were dissolved in 500 ml of dry tetrahydrofuran together 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 the mixture did not exceed -10 ° C. The mixture was stirred at -15 ° C for 15 minutes and then a solution of 26.39 g (35.6 mmol) of the title compound of Example 40b) and 3.60 g (35.6 mmol) of triehylamine in 100 mL of dry tetrahydrofuran was slowly added dropwise. at -20 ° C. The reaction mixture was stirred at -15 ° C for one hour and then at room temperature for two hours. The reaction mixture was then evaporated to dryness under reduced pressure. The obtained residue was dissolved in 250 ml of φφφ φφφ φφφ

ΦΦΦΦ

173

ΦΦ ethyl acetate and washed twice with 100 ml of saturated aqueous sodium bicarbonate solution and then with 200 ml of water. After the organic phase was dried over sodium sulfate, the inorganics were filtered off and the ethyl acetate was removed under reduced pressure. The obtained residue was purified by silica gel chromatography using ethyl acetate / n-hexane (1:10) as eluent.

Yield: 38.12 g (81.0% of theory)

of the title compound ve ! form colorless and highly viscous oils. Elementary analysis: H, 49.92; 3, 92 N 2, 53 F 29.18 N 2.90 Found: C 49.99 H 4, 11 N 2, 69 F 29.22 N 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 at 50 ° C for 3 hours. Thin-layer chromatography indicated complete saponification of the methyl ester. The reaction mixture was evaporated in vacuo and 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 inorganics were filtered and the mixture was evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (mobile phase: n-hexane / chloroform / isopropanol 15: 10: 1). 24.31 g (88.9% of theory) of the title compound were obtained as a colorless and viscous oil.

Elementary analysis:

9

9 99

9 99

174

9 ♦ · ♦ • 9 9 9

9 9

9 9

9 9 ·· ····

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-carbonylmethyl-mannopyranose) 2- [2- (N-ethyl-N-fluorooctylsulfonyl) -amino] -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 on charcoal) was added. The mixture was hydrogenated at room temperature under hydrogen atmosphere for 12 hours. 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.

Elementary 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-O-α-D-carbonylmethyl-mannopyranose) -2- [2- (N-ethyl-N-fluorooctylsulfonyl) -amino] -acetyl-L-lysine-N- {2-hydroxyprop-3-yl - [1,4,7-tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10-yl]} - amide, Gd complex

7.48 g (7.91 mmol) of the title compound of Example 40e) was dissolved in 50 ml of dimethyl sulfoxide at 40 ° C and 1.00 g (8.70 mol) of N-hydroxysuccinimide was added. The mixture was cooled to 20 ° C and then 1.959 g (8.7 mmol) of dicyclohexylcarbodiimide was added. The mixture was stirred at 20 ° C for 1 hour and then at 40 ° C for 4 hours. A solution of 4.53 g (7.91 mmol) of gadolinium complex with 10- (2-hydroxy-3-aminopropyl) -4,7,100 0 0 0 was then added dropwise over 10 minutes.

0 00

175 • 0

0 0

0 0 Φ 0 0 0000 tris (carboxymethyl) -1,4,7,10-tetraazacyclododecanine [preparation according to: WO 97/02051] in 20 ml dimethylsulfoxide. The mixture was stirred at 40 ° C for one hour and then at room temperature overnight. The resulting suspension was mixed with excess acetone until the title compound completely precipitated, the precipitate was filtered, 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) for desalination and removing 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 N7.42 F 21.49 Gd 10.48 S 2.09

Example 41

a) 6-N- [1-O-α- (5-carbonyl) -pentyl-2,3,4,6-tetra-O-benzylmannopyranose] -2N- [2- (N-ethyl-N-pertluorooctylsulfonyl)] amino] -acetyl-L-lysine-methyl ester

5.23 g (8.0 mmol) of 5- (carboxy) pentyl-2,3,4,6-tetra-O-benzyl-D-mannopyranoside 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 Limited, UK) were dissolved in 75 mL of DMF and the mixture was stirred for 15 minutes. This solution was reacted 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 at room temperature for 1.5 days. On working up, the solvent was evaporated to dryness and the residue was chromatographed on silica gel (mobile phase: dichloromethane / ethyl acetate 30: 1;

9

9

176

9 · ··

chromatography was carried out under gradient elution conditions with continuous addition of ethyl acetate).

Yield: 9.70 g (88.0% d.Th.) of the title compound was obtained as a colorless and strongly viscous oil. Elementary analysis:

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

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

b) 6-N- [1-O-α- (5-carbonyl) -pentyl-2,3,4,6-tetra-O-benzyl-manhopyranose] -2N- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] -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 and 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 inorganics were filtered and the mixture was evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (Mobile phase: n-hexane / chloroform / isopropanol 25: 10: 1). 15.88 g (93.9% of theory) of the title compound were obtained as a colorless and strongly viscous oil. Elementary analysis:

H, 4.88; N, 3.08; F, 23.67; S, 2.35

Found: C 51.99 H 4.91 N 3.09 F 23.70 S 2.33

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

177

13.0 g (9.52 mmol) of the title compound of Example 41 b) was dissolved in a mixture consisting of 150 ml of 2-propanol and 25 ml of water and 1.0 g of palladium catalyst (10% Pd on charcoal) was added. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure, and the obtained residue was chromatographed on silica gel (mobile phase: n-hexane / chloroform / isopropanol 15: 10: 1). Yield: 9.09 g (95.1% of theory) of the title compound as a colorless and highly viscous oil.

Calculated: G 37.10 H 4.22 N 4.19 F 32.18 S 3.10

Found: C 37.09 H 4.21 N 4.19 F 32.20 S 3.13

d) 6-N- [1-O-α- (5-carbonyl) -pentyl-mannopyranose] -2N- [2- (N-N-perfluorooctylsulfonyl) -amino] -acetyl-L-lysine-N- {2-hydroxy -prop-3-yl- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-yl]} - amide, Gd complex

7.93 g (7.91 mmol) of the title compound of Example 41 c) was dissolved in 75 ml of dimethylsulfoxide at 40 ° C and 1.00 g (8.70 mof) of N-hydroxysuccinimide was added. The mixture was cooled to room temperature and a total of 1.795 g (8.7 mmol) of dicyclohexylcarbodiimide was added. The mixture was stirred at 20 ° C for 1 hour and then at 40 ° C for 4 hours. A solution consisting of 4.53 g (7.91 mmol) of gadolinium complex with 10- (2-hydroxy-3-) was then added dropwise at 40 ° C over 10 minutes to the thus obtained active ester solution of the title compound of Example 41 c). aminopropyl) -4,7,10 tris (carboxymethyl) -1,4,7,10-tetraazacyclododecanine [preparation see: WO 97/02051] dissolved in 20 ml of dimethylsulfoxide. The mixture was stirred at 40 ° C for 1 hour and then at room temperature overnight. So obtained ·· · «» ·

·· ·· · · <

The slurry was treated with excess acetone / 2-propanol (2: 1) to complete the compound, the precipitate of the above title was filtered, washed with ethyl acetate, dried, dissolved in water, undissolved The dicyclohexylurea was filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da) to desalinate and remove any low molecular weight moieties present. The residue was lyophilized. Yield: 9.71 g (78.8% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 6.65% 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-oxa-propionyl-2-N- (1-aD) -carbonylmethyl-mannopyranose) -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] -amide

5.25 g (7.72 mmol) of tetra-tert-butyl ester of Tyr-EDTA carboxylic acid and 781 mg (7.72 mmol) of triehylamine were dissolved in 50 ml of methylene chloride. At -15 ° C, a solution of 1.16 g (8.5 mmol) of isobutyl chloroformate in 10 ml of methyl chloride 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 consisting of 7.07 g (7.72 mmol) of the title compound of Example 30e) and 2.12 g (21.0 mmol) of triehylamine in 70 mL of tetrahydrofuran was added dropwise. The mixture was stirred for 30 minutes at 5 ° C and then overnight at room temperature. For work-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 sulphate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (mobile phase: methylene chloride / ethanol = 20: 1).

Yield: 9.60 g (79.0% of theory) of a colorless and very solid oil.

Elementary 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- (Ν, Ν-bis (carboxymethyl) -amino) -propyl] phenyl] -3-oxa-propionyl-2-N- (1-α-carbonylmethyl) -mannopyranose) -L-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

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 at 60 ° C for 6 hours. TLC analysis showed that the saponification of the tert-butyl ester was quantitatively achieved after the above reaction time. The solvent was evaporated to dryness and the residue was dissolved in 50 ml of dimethylsulfoxide hot and then a large amount of acetone / ethyl acetate (1: 1) was added until the title compound was completely precipitated. The precipitate thus obtained was filtered, washed with ethyl acetate, dried, dissolved in water, the pH of the solution was adjusted to 3.5 with 1M aqueous hydrochloric acid, the insolubles were filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cut-off limit). : 3000 Da) to desalinate and remove any low molecular weight constituents present. The residue was lyophilized. Yield:

·· ····

180 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

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- (Ν, Ν-bis (carboxylatomethyl) amino) propyl] phenyl} -3-oxapropionyl-2-N- (1-α-carbonylmethylmannopyranose) - L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] -amide, komplexη-complex, disodium salt

3.0 g (2.22 mmol) of the title compound of Example 42b) was dissolved in 150 mL of water / ethanol (3: 1) at boiling and 0.25 g (2.22) was added portionwise at 80 ° C. mmol) of manganese carbonate. The reaction solution thus obtained was heated to reflux for 5 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was dissolved in 200 mL of distilled water and n-butanol (1: 1). With vigorous stirring, the pH of the reaction mixture was adjusted to 7.2 with 1N sodium hydroxide solution. After the n-butanol was completely removed under reduced pressure, the aqueous phase was ultrafiltered through an AMICON® YM3 ultrafiltration membrane (cut-off limit: 3000 Da) to clear low-molecular 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 • ·

181

Example 43

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

Intensely stirred solution of 25.0 g (94.96 mmol) of 3-N (benzyloxycarbonyl) glutaranhydride [synthesis by: Hatanaka, Minoru; Yamamoto, Yu-ichi; Nitta, Hajime; Ishimaru, Toshiyasu; TELEAY; Tetrahedron Lett .; EN; 22; 39; 1981; 38833886;] in 150 ml of absolute tetrahydrofuran was added dropwise to a solution of 53.97 g (95.0 mmol) of 1-perfluorooctylsulfonylpiperazine in 150 ml of tetrahydrofuran with stirring and the resulting mixture was heated under reflux for 12 h. After cooling to room temperature, the mixture was evaporated to dryness and the residual oily residue was purified by silica gel chromatography using dichloromethane / 2-propanol (20: 1) as eluent.

Yield: 75.80 g (96.0% of theory) of the title compound as a colorless and viscous oil. Elementary 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 F 38.82

b) 3-Aminoglutaric acid [1- (4-perfluorooctylsulfonyl) -piperazine] -mononoamide

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 (Pd 20%, 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 to dryness in vacuo. The title compound was obtained as a white-yellowish, viscous oil.

Yield: 25.22 g (95.5% of theory) ··· 9999

182

Elementary 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- (1α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose) glutaric acid [1- (4-perfluorooctylsulfonyl) -piperazine] -mononoamide

21.52 g (18.96 mmol) of 1-carboxymethyloxy-2,3,4, -tetra-Obenzyl-α-D-mannopyranoside [prepared according to patent application: DE 197 28 954 Cl] was dissolved in 100 ml of absolute dimethylformamide at room temperature. and at 0 ° C, 2.56 g (22.2 mmol) of N-hydroxysuccinimide was added, followed by the addition of 4.55 g (22.2 mmol) of dicyclohexylcarbodimide. The reaction mixture was stirred at 0 ° C for 60 minutes and then at 22 ° C for 3 hours, the insoluble dicyclohexylurea was filtered off, and the clear active ester solution of the title compound thus obtained was added dropwise to a stirred solution of 13.22 g at 0 ° C. (18.96 mmol) of the compound of Example 43b) dissolved in 100 mL of dimethylformamide. The reaction mixture was stirred at room temperature for 12 hours 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 and then 100 ml of 10% aqueous. citric acid solution and then 200 ml of water. After drying the organic phase over sodium sulfate, ethyl acetate was removed under reduced pressure. The obtained oily residue was purified by silica gel chromatography using ethyl acetate / n-hexane (1:15) as eluent.

183

Yield: 2.39 g (88.3% of theory) of the title compound as a colorless and strongly viscous oil.

Elementary 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- (1α-D-Carbonylmethyl-mannopyranose) -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, 1.5 g of palladium catalyst (10% Pd on charcoal) was added. The mixture was hydrogenated at room temperature under 1 atm of hydrogen for 12 hours. The catalyst was filtered off, 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, the solid thus obtained was dried under vacuum at 40 ° C.

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

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-tetraazacyclododecan-10-yl] [1- (4-perfluorooctylsulfonyl) -piperazine] -amide 3-N- (1-α-D-Carbonylmethylmannopyranose) -glutaric acid amide, Gd complex

14.43 g (15.84 mmol) of the title compound of Example 43d) and 0.67 g of anhydrous lithium chloride (15.84 mmol) were dissolved in 100 ml of absolute dimethylsulfoxide at 40 ° C with stirring and at this temperature was added this ·· this · · · «« to to to to to to to · · · ·

184 to 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 ( carboxymethyl) -1,4,7,10-tetraazacyclododecanine [for synthesis see: WO 97/02051], in 50 ml of dimethyl sulfoxide. After cooling to room temperature, 3.27 g (15.84 mmol) of N, N'-dicyclohexylcarbodiimide was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The resulting suspension was mixed with excess acetone until the title compound completely precipitated, the precipitate was filtered, 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) for desalination and removing 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-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) piperazine) -amide} -10- [2, 6-N, Ν'-bis (1-Oa-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)] - 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 consisting of 150 mL of tetrahydrofuran and 15 mL of chloroform, was added at 0 ° C under a nitrogen atmosphere of 33.04 g (25.0 mmol). ) title • · · ·

the compound of Example 18c) dissolved in 250 mL of tetrahydrofuran. Then 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] were 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 chromatographed on silica gel (mobile phase: n-hexane / isopropanol 25: 1). 45.87 g (78.0% of theoretical based on the secondary amine used) of the title compound were obtained as a colorless oil.

Elementary analysis:

Calculated: C 59.30 H 5.39 F 13.40 N 4.65 S 1.33

Found: C 59.32 H 5.37 F 13.37 N 4.70 S 1.34

b) 1- (3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-fluorooctylsulfonyl) piperazine] -amide] -7- [2,6-N, Ν'-bis ( 1-O-D-carbonylmethyl-mannopyranose) - 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 (Pd 20%, 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 to dryness in vacuo. The title compound was obtained as a yellowish, highly viscous oil.

Yield: 12.80 g (90.1% of theory).

Elementary analysis:

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

Found: C 39.72 H 4.87 F 22.77 N 7.90 S 2.24

c) 1- {3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-fluorooctylsulfonyl) piperazine] -amide} -7- [2,6-N, Ν'-bis ( 1-0 »fc

186 α-D-carbonylmethyl-mannopyranose)] - L-lysyl-4,10-bis [1,4,7tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl)] - 1 4,7,10-tetraazacyclododecane, digadolinium complex

5.54 g [8.8 mmol; 2.2 molar equivalents, based on the amine component of Example 44b)] Gd complex 10 (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1, The 4,7-triacetic acid described in patent application DE 197 28 954 Cl under Example 31 h) and anhydrous lithium chloride (0.37 g, 8.8 mmol) were dissolved in 60 ml of absolute dimethylsulfoxide at 40 ° C with stirring at this temperature, 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 5.68 g (4.0 mmol) of the title compound of Example 44b) dissolved in 40 ml of absolute dimethylsulfoxide were added. 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 at room temperature for 12 hours. The resulting suspension was mixed with excess acetone until the title compound completely precipitated, the precipitate was filtered, 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) for desalination and removing any low molecular weight moieties present. The residue was lyophilized. Yield: 8.52g (80.6% of theory; calculated 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

·· ·· «4 •

187

Example 45

(a) 1,7-Bis (benzyloxycarbonyl) -4- (3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) piperazine] -amide) -10- (2, 6-N, Ν'-bis (1-O-α- (5-carbonyl) pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose)} - Llysyl-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 consisting of 150 mL of tetrahydrofuran and 15 mL of chloroform was added 35.80 g (25.0 g) at 0 ° C under a nitrogen atmosphere. mmol) of 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 chromatographed on silica gel (mobile phase: n-hexane / isopropanol 20: 1). Yield: 49.48 g (80.4% of theory, based on secondary amine used) of the title compound as a colorless oil.

Elementary 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-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-trifluoroctylsulfonyl) piperazine] -amide) -7- [2,6-N, Ν'-bis ( 1-O-D- (5-carbonyl) -pentylmannopyranose)] - L-lysyl-1,4,7,10-tetraazacyclododecane

25.2 g (10.0 mmol) of the title compound prepared in Example 45a) was dissolved in 250 ml of ethanol, 1.8 g of Pearlman catalyst (Pd 20%, C) were added. The mixture was hydrogenated under a hydrogen atmosphere (1 atm) until quantitative consumption

9999

188

9 9

9

9 9 9 9 9

9999 99 99 hydrogen. The catalyst was filtered off, washed with ethanol and the solvent was removed to dryness in vacuo. The title compound was obtained as a yellowish-colored, highly viscous oil.

Yield: 14.11 g (92.5% of theory)

Elementary analysis:

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) N- {3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-fluorooctylsulfonyl) piperazine] -amide] -7- [2,6-N, N'-bis ( 1-O-D- (5-carbonyl) -pentyl-mannopyranose) L-lysyl-4,10bis [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl) 5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane, digadolinium complex

5.54 g [8.8 mmol; 2.2 molar equivalents, based on the amine component of Example 45b)] Gd complexed with 10 (4-carboxymethyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4 The 7-triacetic acid described in patent application DE 197 28 954 C1 under Example 31h) and anhydrous lithium chloride (0.37 g, 8.8 mmol) were dissolved in 60 ml of absolute dimethylsulfoxide at 40 ° C with stirring 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 of absolute dimethylsulfoxide, were added at room temperature. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicydohexylcarbodiimide was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. The resulting suspension was mixed with excess acetone until the title compound completely precipitated, the precipitate was filtered, dried, dissolved in water, the undissolved dicyclohexylurea was filtered off.

189 and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cutoff limit: 3000 Da) to desalinate and remove any low molecular weight moieties present. The residue was lyophilized.

Yield: 9.26 g (84.0% of theory; calculated on the diamine component used) as a lyophilisate.

Water content (Karl-Fischer): 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 (50.0 mmol) triehylamine,

Example 46

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

19.02 g (50.0 mmol) of α-N- (Benzyloxycarbonyl) -ε- (tert-butyloxycarbonyl) -L-lysine (commercially available from Bachem) was dissolved in 150 ml of absolute tetrahydrofuran. 8.31 g of carbonyldiimidazole and 5.03 g (50.0 mmol) dissolved in 75 ml of dry tetrahydrofuran were added at 0 ° C and the reaction mixture was stirred at this temperature for 10 minutes.

A solution of 48.42 g (50.0 mmol) of perfluorooctylsulfonylpiperazine and 5.03 g (50.0 mmol) of triehylamine in 250 ml of dry tetrahydrofuran was then added dropwise at 0 ° C. The mixture was stirred overnight, tetrahydrofuran was evaporated to dryness in vacuo and the residue was chromatographed on silica gel (mobile phase: n-hexane / isopropanol 15: 1). Yield: 49.48 g (80.4% of theory, based on 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

190

b) 6-N-tert-Butyloxycarbonyl-L-lysine- [1- (4-fluorooctylsulfonyl) -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 catalyst (20% paldium hydroxide on carbon) were added. The mixture was stirred at room temperature for 10 hours, and TLC analysis showed that the above reaction time resulted in quantitative removal of benzyloxy protecting groups. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel. (Mobile phase: n-hexane / isopropanol) 25.13g (98.0% of theory) of the title compound was obtained as a colorless oil.

Elementary 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- [1-SaD- (2-carbonyl) ethyl-2,3,4, β-tetra-O-acetyl-mannopyranose] -L-lysine- [1- (4-Fluoro-octylsulfonyl) -piperazine] -amide

In 300 ml dry tetrahydrofuran was dissolved 15.53 g (35.60 mmol) of 3- (2,3,4,6-Tetra-O-acetyl-1-thio-α-Dmannopyranosyl) -propionic acid (preparation according to: J .

Haensler et al., Bioconjugate Chem. 4.85 (1993); Chipowsky,

S., and Lee, Y.C (1973), Synthesis of 1-thio-aldosides; Carbohydrate Research 31.339346, together with 3.60 g (35.60 mmol) of triehylamine. 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, the rate of addition being such that the temperature of the reaction mixture did not exceed -10 ° C. The reaction mixture was stirred for 15 minutes at -15 ° C.

J · · · φ «φφφ

A solution of 28.35 g (35.60 mmol) of the title compound of Example 42b) and 3.60 g (35.60 mmol) was slowly added dropwise thereto. triethylamine in 200 ml dry tetrahydrofuran at 20 ° C. The reaction mixture was stirred at -15 ° C and then at room temperature for 2 hours. The reaction mixture was then evaporated to dryness under reduced pressure. The obtained residue was dissolved in 250 ml of ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate and then washed with 200 ml of water. After drying the organic phase over sodium sulfate, the ethyl acetate was evaporated in vacuo. The remaining oily residue was purified by silica gel chromatography using ethyl acetate / n-hexane (1:25) as eluent. Yield: 34.21 g (79.1% of theory) of the title compound as a colorless and highly viscous oil.

Elementary 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-t-Butyloxycarbonyl-2-N- [1-S-α-D- (2-carbonyl) ethylmannopyranose] -L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] -amide

29.93 g (24.64 mmol) of the title compound of Example 46c) 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 3h at room temperature and thin layer chromatography control showed (Eluent: chloroform / methanol = 9: 1) that the progress of the reaction was quantitative. The clear reaction mixture was worked up by neutralization by adding Amberlite ® IR 120 (H ⁺ -form) -cationic ion exchanger, 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, using 1-propanol / ethyl acetate / n-hexane (1: 1: 15) as eluent. Yield: 23.42 g (90.8% of theory) of a colorless and viscous oil.

Elementary 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 F 30.82 S 6.11

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

20.93 g (20.0 mmol) of the title compound 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 the addition of a 2 molar aqueous solution of sodium hydroxide. The aqueous product solution was purified by filtration through an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da) to desalinate and remove any low molecular components present. The residue was lyophilized.

Yield: 17.79 g (94.2% of theory) of the free amine as a lyophilisate. Water content (Karl-Fischer): 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

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

f) 2-N- [1-SaD- (2-carbonyl) ethyl-mannopyranose] -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

193 φφφφ • «φφ φφφφ φφ

5.54 g of 1 (8.8 mmol, 2.2 molar equivalent, calculated on the amine compound of Example 46e)] Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4, Of 7,10-tetraazacyclododecane-1,4,7-triacetic acid described in patent application DE 197 28 954 C1 under Example 31h) and 0.37 g of anhydrous lithium chloride (8.8 mmol) were dissolved in 60 ° C at 40 ° C. 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 of absolute dimethylsulfoxide were added under stirring at this temperature. 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 at room temperature for 12 hours. The resulting suspension was mixed with excess acetone until the title compound completely precipitated, the precipitate was filtered, 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) for desalination and removing any low molecular weight moieties present. The residue was lyophilized. Yield: 5.17 g (83.0% of theory) as a colorless lyophilisate. Water content (KarlFischer): 4.43%.

Elemental analysis (calculated on the anhydrous substance):

Calculated: C 35.45 H 4.07 N 8.09 F20.72 Gd 10.09 S 4.11 Found: C 35.50 H 4.01 N 8.12 F 20.6 Gd 10.13 S 4, i4

Example 47

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

4444

4444> 4444 44 44 44 4444

194 • 4 4 44 4 • 4 4 * 44 · 4444 44 44 8.02 g (13.4 mmol) title compounds described in patent DE 197 28 954 Cl pod An example 46a)

carboxymethyloxy-2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside] and 3.24 g (28.14 mmol) of N-hydroxysuccinimide were dissolved in 100 mL of dimethylformamide and added in portions at 0 ° C total 5.80 g (28.14 mmol) of N, N-dicyclohexylcarbodiimide. The reaction mixture was stirred for an additional 3 hours at this temperature. To the thus obtained active ester solution at 0 ° C was added dropwise a cooled solution of 11.13 g (13) 4 mmol) of the title compound of Example 21 c) dissolved in 50 ml of dimethylformamide, and the 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 filtrate was evaporated to dryness under reduced pressure. The obtained residue was purified by silica gel chromatography using a mobile phase: dichloromethane / ethanol, 20: 1; the chromatography was carried out under gradient conditions with gradual increase in ethanol).

Yield: 12.67 g (67.0% of theory) of the title compound as a colorless and strongly viscous oil. Elementary analysis:

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

Found: C 52.75 H 4.6 N N 3.98 F 22.94 S 2.26

b) 2-N- (1-O-cis-D-carbonylmethyl-glucopyranose) -L-lysine- [1- (4-fluorooctylsulfonyl) -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 (Pd 20%, C) was added, and the mixture was hydrogenated at room temperature under hydrogen (1). atm) until no further consumption of hydrogen is observed. The catalyst was filtered off, the catalyst was washed.

195 1 tititi with ethanol (3 times 40 ml ethanol). The title compound was obtained as a strongly viscous and colorless oil.

Yield: 7.36 g (98.4% of theory).

Elementary analysis:

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

Found: C 34.11 H 3.59 N 6.08 F 35.23 S 3.52

c) 2-N- (1-O-α-D-carbonylmethyl-glucopyranose) -6-N- [1,4,7 tris (carboxylatomethyl) -10- (aza-4-oxo-5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -L-lysine- [1- (4-fluorooctylsulfonyl) -piperazine] -amide, Gd-complex

9.98 g [(15.84 mmol; 2.2 molar equivalent, based on amine component used in Example 47b)] Gd complex 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 C1 under Example 31h) and 0.67 g (15.84 mmol) of anhydrous lithium chloride were dissolved at 40 ° C. in 80 ml of absolute dimethylsulfoxide and at this temperature 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 were added. 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 mixed with excess acetone until the title compound completely precipitated, the precipitate was filtered, 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) for desalination and removing any low molecular weight moieties present. The residue was lyophilized.

0 «0000« 0

196 * ·· 000 0000 ··

Yield: 9.11 g (83.0% of theory) of the colorless lyophilisate.

Water content (Karl-Fischer): 4.02%.

Elemental analysis (calculated on the anhydrous substance): 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 With 2.06 Gd 10.34 form

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 21 b) was dissolved in 100 ml of ethanol, 1.0 g of Pearlman catalyst (Pd 20% / C) was added, and the mixture was hydrogenated under a hydrogen atmosphere (1 atm). up to quantitative hydrogen consumption. The catalyst was filtered off, washed with ethanol and the solvent was removed to dryness in vacuo. The title compound was obtained as a colorless oil.

Yield: 8.85 g (97.5% of theory).

Elementary 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- [1-O-α- (5-carbonyl) -pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose] -L-lysine- [1- ( (4-Fluoro-octylsulfonyl) -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 triehylamine in 100 mL of dimethylformamide cooled to 0 ° C was added dropwise a solution of 27.51 g (36.6 mmol). mmol) of the title compound of Example 37c) in 150 ml of dimethylformamide. After the addition was complete, the mixture was stirred for one hour at 0 ° C and then stirred overnight at room temperature. The reaction was evaporated to dryness under vacuum

197

9999

9999

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 solution. The organic phase was dried over magnesium sulphate and then evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: n-hexane / isopropanol 25: 1). Yield: 42.05 g (80.4% of theory) of the title compound as a colorless oil. Elementary 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- (5-carbonyl) -pentyl-2,3,4,6-tetra-O-benzylmannopyranose] -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 at 50 ° C for 0.5 h. According to thin-layer chromatography, the deprotection at this reaction time is 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 chromatographed on silica gel (mobile phase: n-hexane / isopropanol 20: 1). 16.66 g (89.3% of theory) of the title compound were obtained as a colorless oil. Elementary analysis:

Calculated: C 52.25 H 4.91 N 4.20 E 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- (5-Carbonyl) -pentyl-mannopyranose] -L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide Μ

198

15.0 g (11.25 mmol) of the compound obtained in Example 48c) was dissolved in 150 ml of a 10: 1 mixture of ethanol and water and 1.0 g of Pearlman catalyst (Pd 20% / 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 to dryness in vacuo. The title compound was obtained as a colorless oil.

Yield: 10.77 g (98.4% of theory).

Elementary 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- [1-OaD- (5-Carbonyl) -pentyl-mannopyranose] -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 equivalent, based on the amine component of Example 48d used)] Gd complex 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 C1 under Example 31h) and 0.37 g (8.8 mmol) of anhydrous lithium chloride were polluted at 40 ° C. in 60 ml of absolute dimethylsulfoxide with stirring at this temperature were added 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. 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 at room temperature for 12 hours. The resulting suspension was mixed with excess acetone until the title compound completely precipitated.

199 · 0 · aaa aaa aaaa aaa aaaa aa aaaa aa aa compounds, the precipitate was filtered, dried, dissolved in water, undissolved dicyclohexylurea was filtered off and the filtrate was ultrafiltered on an AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da) to desalinate 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 (KarlFischer): 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: 0 37.27 H 4.40 N 8.02 F 20.31 Gd 10.00 S 1.98

Example 49

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

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 nitrogen atmosphere 35.80 g (25.0 mmol) of 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 chromatographed on silica gel (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.

Elementary analysis:

Calculated: C 54.09 H 4.72 F 19.14 N 4.98 S 1.90 • · ·······

200

Found: C 54.12 H 4.77 F 19.17 N 5.03 S 1.90

b) 1- (1-O-α-D-carbonylmethyl-galactopyranose) -7- {3-oxapentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] - amide) -1,4,7,10-tetraazacyclododecane 30.0 g (17.77 mmol) of the title compound prepared in Example 49a) was dissolved in 250 ml of ethanol and 3.0 g of Pearlman catalyst (Pd 20% / C) were added. ) and the mixture was hydrogenated under a hydrogen atmosphere (1 atm) at room temperature until quantitative consumption of hydrogen. The catalyst was filtered off, washed with ethanol and the solvent removed to dryness in vacuo. The title compound was obtained as a colorless and very viscous oil.

Yield: 17.89 g (95.1% of theory).

Elementary 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- (3-D-carbonylmethyl-galactopyranose) -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, di-gadolinium complex

5.54 g [8.8 mmol; 4.4 molar equivalents, based on the amine component used in Example 49b)], the 1-O- (4-carboxymethyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4 Gd complex, Of 7-triacetic acid described in patent application DE 197 28 954 C1 under Example 31 h) and 0.37 g (8.8 mmol) of anhydrous lithium chloride were dissolved in 60 ml of absolute dimethylsulfoxide at 40 ° C with stirring. 1.01 g (8.8 mmol) of N ·· «· was added

201 of hydroxysuccinimide and 2.11 g (2.0 mmol) of the title compound of Example 49b) dissolved in 25 mL of absolute dimethylsulfoxide. After cooling to room temperature, the reaction solution was treated with 1.82 g (8.8 mmol) of N, N-dicyclohexylcarbodiimide and the reaction was stirred for 12 hours at room temperature. The resulting suspension was mixed with excess acetone until the title compound completely precipitated, the precipitate was filtered, 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) for desalting and removing any low molecular weight moieties present. The residue was lyophilized. Yield: 3.29 g (72.2% of theory, calculated on the amine component used) as a colorless lyophilisate.

Water content (Karl-Fischer): 5.99%. Elemental analysis (calculated on the anhydrous substance):

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

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-mannopyranose (prepared according to: F. Kong et al., J. Carbohydr. Chem.) Was dissolved in 500 ml of dry acetonitrile. 16; 6; 1997; 877-890). After cooling the reaction mixture to 5 ° C, a solution of 13.23 g (59.52 mmol) of trifluoromethanesulfonic acid trimethylsilyl ester 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 Nbenzyloxycarbonyl-L- of serine methyl ester (commercially available from Bachem) in 50 ml of acetonitrile, the rate of addition being such that the reaction temperature did not exceed 10 ° C.

• ° C. The reaction was stirred at room temperature for 15 hours and the reaction was 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 inorganics were filtered off and the ethyl acetate was removed in vacuo. The resulting oily residue was purified by silica gel chromatography using ethyl acetate / n-hexane (1: 5) as eluent.

Yield: 23.60 g (76.8% of theory) of the title compound as a colorless oil.

Elementary analysis:

H, 6.37; N, 1.81

Found: C 71.19 H 6.41 N 1.79

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

In a mixture consisting of 20 ml of methanol, 20 ml of water and 50 ml of tetrahydrofuran, 10.0 g (12.90 mmol) of the compound prepared in Example 50a) was dissolved. 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 at 60 ° C for 6 hours. Examination by thin layer chromatography (Eluent: methylene chloride / methanol 10: 1) revealed that the saponification of the methyl ester of Example 30a) was quantitative after the above reaction time, the reaction product was evaporated to dryness and the residue dissolved in 250 ml of ethyl acetate with heating (approx. 60 ° C). The ethyl acetate phase thus obtained was washed twice with 50 ml of 15% aqueous hydrochloric acid, then with 100 ml of distilled water. The organic phase was dried over magnesium sulfate, filtered, and evaporated to dryness under reduced pressure.

pressure. The residue was chromatographed on silica gel (mobile phase: n-hexane / ethyl acetate 5: 1). Yield: 8.40 g (85.7% of theory) of the title compound as a colorless oil.

Elementary analysis:

H, 6.22; N, 1.84

Found: C 70.97 H 6.30 N 1.78

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

To 13.86 g (24.40 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033), dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, was added dropwise at 0 ° C under a nitrogen atmosphere 20.57 g ( 27.0 mmol) of the carboxylic acid prepared in Example 50b) dissolved in 50 ml of tetrahydrofuran. Then, 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. For work-up, the reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography using n-hexane / isopropanol (15: 1) as eluent. 17.0 g (79.6% of theory, based on the primary amine used) of the title compound were obtained as a colorless viscous oil.

Elementary analysis:

Calculated: C 51.53 H 4.23 N 3.15 F 25.65 S 2.41

Found: C 51.48 H 4.27 N 3.10 F 25.71 S 2.35

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

15.0 g (11.41 mmol) of the compound prepared according to Example 50c were dissolved in 200 ml of ethanol, 1.5 g of Pearlman catalyst (Pd 20%, 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 and viscous oil.

Yield: 8.79 g (94.0% of theory). Elementary 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 F 39.50 S 3.88

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

Stirred suspension 5.7 g [9.06 mmol; corresponding to 1.5 molar equivalent corresponding to the title compound (primary amine) of Example 50d)] Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1 The 4,7-triacetic acid described in patent application DE 197 28 954 C1 under Example 31h) in 75 ml of absolute dimethylsulfoxide was reacted at 70 ° C with 0.68 g (15.9 mmol) of lithium chloride. The mixture was stirred at 70 ° C for 30 minutes and then a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide was added portionwise and the reaction mixture was stirred at 70 ° C for an hour. After cooling the reaction mixture to 10 ° C, 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide was added and the reaction solution was stirred for an additional hour at 0 ° C and then for 12 hours at 22 ° C.

• · • ·

205

The solution of the N-Hydroxysuccinimide ester Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid 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 at room temperature for 12 hours. For work-up, the reaction mixture was slowly added dropwise at 22 ° C to a solvent mixture consisting of 250 ml of acetone and 250 ml of 2-propanol, after 12 hours at 10 ° C the title compound separated as a pale yellowish-colored oil. The excess solvent mixture was decanted and the oily product was taken up in 200 ml of distilled water whereupon the oil completely dissolved to give a light yellowish-colored solution of the title compound. Finally, the aqueous product solution was purified by triple ultrafiltration through an ultrafiltration membrane (AMICON® cut-off 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 with a water content of 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

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 at room temperature. Galactopyranosyl- (1 → 4) -D-glucono-1,5-lactone [lactobionolactone; prepared according to: (a) Williams, T. J .; Plessas, N.R., Goldstein, I.J. Carbohydr. Res. 1978, 67,

Cl. (b) Kobayashi, K .; Sumitomo, H .; Ina, Y. Polym. J. 1985, 17, 567, (c) Hiromi Kitano, Katsuko Sohda, and Ayako Kosaka,

Bioconjugate Chem. 1995, 6, 131-134] in 40 ml of absolute dimethylsulfoxide. The reaction solution thus obtained was stirred at 40 ° C for 14 hours. 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 well with a total of 250 ml of absolute 2-propanol. The thus obtained solid was dissolved in 300 ml of distilled water and purified by triple ultrafiltration through an ultrafiltration membrane (AMICON® cutoff 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 51 a) was dissolved in 100 ml of ethanol, 0.5 g of Pearlman catalyst (Pd 20%, 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

207

The mixture was evaporated to dryness under reduced pressure. The title compound was obtained as a viscous, colorless oil.

Yield: 4.36 g (98.5% of theory).

Elementary 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- [1,4,7tris (carboxylatomethyl) -10- (3-aza-4-oxo-5) -methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -L-lysine- [1- (4-fluorooctylsulfonyl) -piperazine] -amide, Gd complex 5.54 g (8.8 mmol; 2 molar equivalent, calculated on the mine compound of Example 51b)] 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, Gd complex described in patent application DE 197 28 954 Cl under 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 a total of 1.01 was added at this temperature g (8.8 mmol) of N-hydroxysuccinimide and 3.85 g (4.0 mmol) of the title compound of Example 31Ab), dissolved in 60 ml of absolute dimethylsulfoxide. After cooling to room temperature, the reaction mixture was treated with 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide and the reaction mixture was stirred at room temperature for 12 hours. The resulting suspension was treated with an excess of acetone / 2-propanol (1: 1) until all of the title compound precipitated, filtered, dried, dissolved in undissolved dicyclohexylurea, filtered and the filtrate was purified three times from low molecular weight by ultrafiltration on an AMICON® Y ultrafiltration membrane. -3 (limit limit: 3000 Da). During ultrafiltration the title compound precipitate was 300 ml of water,

208 • · «·« · · · ····

free of excess Gd complex and possibly present

low molecular weight shares. Residue after ultrafiltration was dissolved in 500 ml distilled water; and was lyophilized. Yield: 4.64 g (70.4 % d.Th.) ve 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 was 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 and the residue was crystallized from diisopropyl ether.

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

Elementary analysis:

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-fluorooctylsulfonyl) piperazine] -amide

To 125 g (332 mmol) of the title compound of Example 52a) and 188.7 g (332 mmol) of 1-perfluorooctylsulfonyl-piperazine (prepared according to DE 19603033) in 800 mL of tetrahydrofuran was added 164.2 g (0 ° C) at 0 ° C. 0.664 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was chromatographed on silica gel (mobile phase: dichloromethane / methanol = 20: 1). Yield: 286 g (93% of theory) of a colorless solid.

Elementary analysis:

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

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

Elementary 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 triehylamine, dissolved in 350 mL of dichloromethane, was added dropwise a solution of 79.93 g (70 mmol) 3 at 0 ° C, 6,9,12,15-pentaoxahexadecanoyl chloride [prepared according to Liebigs Ann. Chem, (1980), (6), 852-62] in 50 mL of dichloromethane and the mixture was stirred at 0 ° C for 3 hours. 200 ml of 5% aqueous hydrochloric acid was added and the mixture was stirred at room temperature for 5 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated

210

Φ · φ φ φ φ φ φ ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve ve in vacuum. The residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1)

Yield: 53.7 g (93% of theory) of a colorless solid oil.

Elementary 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-fluorooctylsulfonyl) -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) 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) colorless solid.

Elementary 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-fluorooctylsulfonyl) -piperazine] -amide, Gd-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 15.27g (24.25 mmol) of 1,4,7 tris (carboxylatomethyl) -10 - [(3-aza-4-oxo) 5-methyl-5-yl)] pentanoic acid] -1,4,7,10-tetraazacyclododecane, The G-complex was dissolved in 200 ml of dimethyl sulfoxide with slight heating. At 10 ° C, 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide was added, and the mixture was stirred through přes * * φφφφφφφφφφφφφφφφφφφφ

211

Φ φ φ φ φ Φ Φ Φ Φ Φ Φ při night at room temperature. The solution was poured into 3000 mL of acetone and stirred for 10 minutes. The precipitated solid was filtered and purified by silica gel chromatography (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

(a) 6-N- [1- (4-perfluorooctylsulfonyl) piperazine] -amide 6-N- bis (tert-butyl ester) -6-carbonylmethyl] -2-N- [3,6,9,12,15pentaoxahexa-decanoyl] -lysine [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 bis (tert-butyl ester)

3,9-bis (tert-butyloxycarbonylmethyl-3,6,9-triazaundecane-1,11-dicarboxylic acid) and 2.77 g (24.08 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide, were added at 0 ° C. 25 g (40 mmol) of N, N-dicyclohexylcarbodiimide was stirred at 0 ° C for 3 hours and then at room temperature overnight.

The precipitate was filtered off, the filtrate was evaporated to dryness in vacuo and the residue was chromatographed on silica gel (mobile phase: = dichloromethane / ethanol = 20: 1).

Yield: 31.61 g (91% of theory) of a solid oil. Elementary analysis:

Calculated: 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 • fc fcfcfcfc fcfc fcfcfcfc

212 · * fcfc fcfc · cfcfcfc fcfc fc • fcfc ··· «fcfc · · • fcfc fcfcfc ···· fcfc fc fcfc fcfcfcfc fcfc fcfc

b) 6-N- [6-Carbonylmethyl-3,9-bis (carboxylatomethyl) -3,6,9-triazaundecanedioic acid-1-carboxy-11-carboxylato] -2-N- (3,6,9,12,15) -pentaoxahexadecanoyl) -lysine- [1- (4-fluorooctylsulfonyl) -piperazine] -amide, Gd-complex, sodium salt, g (20.8 mmol) of the title compound of Example 53a) was dissolved in 300 ml of trifluoroacetic acid and stirred for 5 hours 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 was added and the mixture was stirred at 60 ° C for 3 hours. The reaction mixture was then allowed to cool 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 silica gel RP18 chromatography. (Mobile phase: Water / acetonitrile gradient). Yield: 19.18 g (67% of theory, colorless amorphous solid) Water content 9.8%

Elemental analysis: (calculated on the anhydrous substance)

Calculated: C 28.80 H 4.25 F 23.47 N 7.12 S 2.33 Gd 11.48 Na 1.67

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

1.74

Example 54

a) Lysine [1- (4-perfluorooctylsulfonyl-piperazine) -amide 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) was added. The mixture was hydrogenated at room temperature. Catalyst was filtered, filtrate • · · ·

213

was evaporated to dryness in vacuo. Yield: 16.77 g (quantitative) of a colorless solid.

Elementary 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-5yl) -] - lysine- [1- (4-perfluorooctylsulfonylpiperazine) -amide, Gdcomplex (metal complex XVI) g (14.36 mmol) of the title compound of Example 54a), 3.34 g (29 mmol) of N-hydroxysuccinimide, 2, 54 g (mmol) of lithium chloride and 18.26 g (29 mmol) of 1,4,7-tris (carboxylatomethyl) 10- (3-aza-4-oxo-5-methyl-5-yl-) -1 The 4,7,10-tetraazacyclododecane-Gd complex was dissolved in 200 ml of dimethyl sulfoxide 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 of acetone and stirred for 10 minutes. The precipitate formed was filtered off and purified by silica gel chromatography (silica gel RP-18, mobile phase: water / ethanol / acetonitrile gradient). Yield: 19.02 g (69% of theory) of a colorless solid.

2o 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

214

To 200 g (1.204 mol) of 4-hydroxyphenylacetic acid methyl ester, 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 heated at reflux for 5 hours. . The solid was filtered off and the residue was evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (mobile phase: n-hexane / ethyl acetate = 15: 1).

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

Elementary analysis:

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 dibenzyl 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 silica gel chromatography (Mobile phase: n-hexane / acetone = 15: 1).

Yield: 359.2 g (96% of theory) of a colorless solid oil.

Elementary 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-tetraazacyclododecan-7-yl) -acetic acid methyl ester

215 • · * ··· ·· · * ·· · · · ·

Κ 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 in vacuo to dryness. The residue was used in the next step (reaction 3d) without further purification.

Yield: 448 g (quantitative) of a solid oil.

Elemental analysis::

H, 8.11; N, 13.26

Found: C 59.58 H 8.20 N 13.18

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

445 g (1.053 mol) of the title compound 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 stirred at reflux 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 and the residue was dissolved in 4000 ml of methanol and stirred for 1 hour at room temperature. The salt was filtered off and the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography 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 • · · ·

216

Found: C 51.80 H 6.31 N 10.01

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

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 at 80 ° C for 5 hours.

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, Ν'-Bis {2- [4- (3-oxapropionyl) phenyl] -2- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10 -yl] acetic acid) -lysine- [4-perfluoro-octylsulfonyl) piperazine] amide, Digadolinium complex, disodium salt g (14.36 mmol) of the title compound of Example 54a) 3.45 g (30 mmol) of N-hydroxysuccinimide 2.54 g (60 mmol) of lithium chloride and 21.26 g (30 mmol) of the title compound of Example 4Be were dissolved in 250 ml of dimethyl sulfoxide with slight heating. 16.51 g (80 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 2000 mL of acetone and stirred for 10 minutes. The precipitated solid was filtered off and was purified by silica gel chromatography (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.

• tititi • ti • tititi *

217 • ti

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 F 15.22 Gd 14.82 N 7.92 Na 2.17 S 1.51

Found: C 37.28 H 3.74 F 15.14 Gd 14.75 N 8.03 Na 2.23 S 1.46

Example 56

a) '2,6-N, N'-Bis [6-carbonylmethyl-3,9-bis (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 bis (tert-butyl ester) 3,9-bis (tert-butyloxycarbonylmethyl) -6-carboxymethyl-3,6 9-triazaundecan-1,11-dicarboxylic acid and 3.45 g (30 mol) of N-hydroxysuccinimide dissolved in 150 ml of dimethylformamide were added 10.32 g (50 mmol) of N, N-dicyclohexylcarbodiimide at 0 ° C. The mixture was stirred at 0 ° C for 3 hours and then stirred at room temperature overnight. The precipitated urea precipitate was filtered off, the filtrate was evaporated to dryness under reduced pressure and chromatographed on silica gel (Mobile phase: dichloromethane / ethanol = 20: 1)

Yield: 19.60 g (72% of theory) of a solid oil. Elementary 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-carbo;

218 xylato-lysine- [1- (4-perfluorooctylsulfonyl} -piperazine] -amide, Gd complex, sodium salt] g (7.91 mol) of the title compound of Example 56a) was dissolved in 50 ml of chloroform and 200 ml was added trifluoroacetic acids. The mixture was stirred at room temperature for 10 minutes. It was then evaporated to dryness in vacuo and the residue was dissolved in 150 ml of water. 2.87g (7.91 mmol) of gadolinium complex was added and the mixture was stirred at 80 ° C for 5 hours. The reaction mixture was allowed to cool to room temperature and the pH was adjusted to 7.4 with 2N sodium hydroxide. 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)] -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-1,11-dicarboxylic acid bis (tert-butyl ester) and 2.88 g (25 mol) of N-hydroxysuccinimide dissolved in 100 ml of dimethylformamide were added at 0 ° C 8.25 g of 40 mol) of N, N-dicyclohexylcarbodiimide. The mixture was stirred for 3 hours.

219 at 0 ° C, and then stirred overnight at room temperature. The precipitate was filtered off and the filtrate was evaporated to dryness under reduced pressure and the residue was

silica gel chromatography (Mobile phase: dichloromethane (ethanol = 20: 1). Yield: 27,21 g (79% theoretical amount) of a solid oil. Elementary analysis: H, 5.64; F, 22.58 N, 6.85 N 2.24 Found: C, 46.94; H, 5.58; F, 22.65 N, 6.84 2.31

b) 2-N- [Carbonylmethyl-3,9-bis (tert-butyloxycarbonylmethyl) 3,6,9-triazaundecane-1,1-dicarboxylic acid-bis (tert-butyloxycarbonylmethyl) -3,6-triazaundecane

butyl ester)] - lysine- [1- (4-perlfluorooctylsulfonyl) -piperazine] amide 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. Elementary 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,

Gd complex 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)

220 lithium chloride and 9.72 g (15.43 mmol) 1,4,7-Tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) -pentanoic acid 1,4,7,10- tetraazacyclododecane, Gd complex 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 was purified by silica gel chromatography (silica gel RP-18, mobile phase: Water / ethanol / acetonitrile 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-carboxy-11-carboxylato-z] -lysine- [1- (4-fluorooctylsulfonyl) -piperazine] -amide, digadolinium 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 at room temperature for 60 minutes. 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 at 80 ° C for 5 hours.

The reaction was allowed to cool to room temperature and the pH was adjusted to 7.4 by addition of sodium hydroxide. The solution was evaporated to dryness and was purified

221 • ·

RP-18 silica gel chromatography. (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) target; 5,6-Bis (benzyloxy) -3-oxahexanoic acid butyl ester

100 g (376.2 mmol) of 1,2-di-O-benzyl-glycerin [prepared according to Chem. Phys. Lipids (1987), 43 (2), 113-277] and 5 g of tetrabutylammonium hydrogen sulfate were dissolved in a mixture of 400 ml of toluene and 200 ml of 50% aqueous sodium hydroxide solution. At 0 ° C, 78g (400 mmol) of the target was added dropwise over 30 minutes. of 2-bromoacetic acid butyl ester and the mixture was stirred at 0 ° C for 3 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. (Mobile phase: n-hexane / acetone = 20: 1).

Yield: 133.4 g (94% of theory) of a colorless oil.

Elementary analysis:

H, 7.82

Found: C, 71.61; H, 7.92

b) 5,6-Bis (benzyloxy) -3-oxa-hexanoic acid

130 g (336.4 mmol) of the title compound of Example 58a) were dissolved in 200 mL of dichloromethane at 0 ° C

9999

9 99

222

100 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 4 hours and then evaporated to dryness under reduced pressure. The residue was crystallized from pentane / diethyl ether.

Yield: 102.2 g (92% of theory) of a waxy solid.

Elementary analysis:

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, Gd complex g (60.20 m mmol) of the title compound of Example 52c) 6.93 g (60.20 mmol) of N- hydroxysuccinimide, 5.09 g (120 mmol) of lithium chloride and 37.91 g (60.20 mmol) of 1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-pentanoyl-3-aza- 4-oxo-5-methyl-5-yl), the Gd complex 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 of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by silica gel chromatography (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 fcfc ····

223

d) 2-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) - lysine- [1- (4-perfluorooctylsulfonyl) piperazine] -amide, Gd-complex g (48.53 mmol) of the title compound of Example 58c) was dissolved in a mixture of 500 ml water / 100 ml ethanol and 5 g palladium catalyst ( 10% Pd / Cl). 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, Gd-complex g (7.64 mmol) of the title compound of Example 58d )

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, N, N'-dicyclohexylcarbodiimide (3.10 g, 15 mmol) was added and the mixture was stirred at room temperature for 8 hours. The reaction solution was poured into 2000 ml of acetone and the precipitate formed was collected by filtration. 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%.

4 994

4949

Elemental analysis: (calculated on the anhydrous compound) 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 F 19.84 N 7.70 Gd 9.58 S 1.90

f) 6-N- (5,6, -Dihydroxy-3-oxahexanoyl) -2-N- [1,4,7-tris carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-pentanoyl-3-aza- 4-oxo-5-methyl-5-yl)] - lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd complex 10g (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-oxahexanoyl] -lysine- [1- (4-perfluoro-octylsulfonyl) -piperazine] -amide

To a solution of 20 g (24.08 mmol) of the title compound of Example 52c), 9.91 g (30 mmol) of the title compound of Example 7b and 3.45 g (30 mmol) of N-hydroxysuccinimide, dissolved in 100 mL of dimethylformamide, 9.28 g (45 mmol) of N, N-dicyclohexylcarbodiimide was added at 0 ° C. The mixture was stirred at 0 ° C for 3 hours and then stirred at room temperature overnight. The precipitated urea precipitate was filtered off, the filtrate was evaporated to dryness and chromatographed on silica gel (Mobile phase: dichloromethane). fcfc ·· • fc fcfcfcfc / ethanol = 20: 1). Yield: 24, 50 g (89% of theory) of a solid oil.

Elementary 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-perfluorooctylsulfonyl) piperazine] -amide g (17.5 mmol) of the title compound of Example 52d) was dissolved in 300 ml 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, the filtrate was evaporated to dryness in vacuo. Yield: 17.65 g (quantitative) of a colorless solid.

Elementary 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, Gd-complex g (14.87 mmol) of the title compound of Example 59b) 1.73 g (15 mmol) N-hydroxysuccinimide, 1.27 g (30 g) mmol) of lithium chloride and 9.48 g (15 mmol) of 1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) -pentanoic acid-1,4 The 7,10-tetraazacyclododecane, Gd complex was dissolved in 100 ml of dimethyl sulfoxide with slight heating. 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 the mixture was stirred for 10 minutes. The precipitated solid was filtered off and purified by silica gel chromatography.

226 (silica gel RP-18, Mobile phase: Gradient water / ethanol / acetonitrile).

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 triehylamine were dissolved in 200 ml of tetrahydrofuran (THF) and 14.46 g (27 mmol) of diN, N'-Z-Lysine-paranitrophenol ester were added. The mixture was stirred at 50 ° C for 5 hours. The mixture was evaporated to dryness and chromatographed on silica gel. Mobile phase: dichloromethane / methanol = 20: 1).

Yield: 28.07 g (95% of theory) of a colorless solid.

Elementary 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 hydrogen bromide in acetic acid (48%) and the mixture was stirred at 40 ° C for 2 hours. 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%) were obtained.

227 »·· theoretical amount) light yellow colored crystalline solids.

Elementary analysis:

Calculated: C 27.01 H 3.40 Br. N, 7.87; S, 3.00. Found: C, 26.92; H, 3.53. 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 -] - 2,6N, 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) 1,4,7-Tris (carboxylatomethyl) -10- (3aza-4-oxo-5-methyl-) - 5-yl) -pentanoic acid, Gd complex 6,91 g ( 60 mmol) of N-hydroxysuccinimide and 4.24 g (100 mmol) of lithium chloride were dissolved in 350 ml of dimethylsulfoxide with slight heating. 16.51 g (80 mmol) of N, N-dicyclohexylcarbodiimide was added at 10 ° C and the mixture was stirred at 10 ° C for 5 hours. To this mixture was added 10 g (9.37 mmol) of the title compound Example 60b) and 3.03 g (30 mmol) of triehylamine, and the mixture was stirred at 60 ° C for 12 hours. The mixture was allowed to cool to room temperature and poured into 3000 mL of acetone. The precipitate formed was filtered off and purified by chromatography on silica gel RP18 (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

228

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

To 18.13 g (68.1 mmol) of 3,6,9,12,15-pentaoxahexadecanoic acid and 30 g (68.1 mmol) of 1,7 di-Z-Cyclene prepared according to Z. Kovacs and AD Sherry, J Chem. Soc. Chem. Commun. (1995), 2, 185, in 300 mL of tetrahydrofuran, 24.73 g (100 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 at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was chromatographed on silica gel (mobile phase: dichloromethane / methanol = 20: 1). Yield: 19.13 g (42% of theory) of a colorless solid.

Elementary analysis:

H, 7.61; N, 8.13

Found: C 60.92 H 7.75 N 8.04

b) 1,7-Bis (benzyloxycarbonyl) -4- (3,6,9,12,15-pentaoxahexadecanoyl) -10- (2H, 2H, 4H, 5H, 5H-3-oxa-perfluorotridecanoyl) 1,4, 7,10-tetraazacyclododecane

To 18 g (26.91 mmol) of the title compound of Example 61 a) and 14.05 g (26.91 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-Oxa-perfluorotridecanoic acid, prepared according to DE 19603033 In 300 mL of tetrahydrofuran, 12.36 g (50 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 was evaporated to dryness under reduced pressure and the residue was chromatographed on silica gel (mobile phase: dichloromethane / methanol = 20: 1). Yield:

21.51 g (67% of theory) of a colorless solid. Elementary analysis:

Calculated: C 47.32 H 4.82 F 27.07 N 4.70

229

Found: C 47.26 H 5.01 F 26.94 N 4.59

c) 1-3,6,9,12,15-Pentaoxahexadecanoyl) -7- (2H, 2H, 4H, 4H, 5H, 5H3-oxaperfluorotridecanoyl) -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.

Elementary 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- (2H, 2H, 4H, 4H, 5H, 5H, -3-oxaperfluorotridecanoyl) -1,4,7,10-tetraazacyclododecane, Gdcomplex g (16 , 22 mmol) of the title compound of Example 61 c), 4.60 g (40 mmol) of N-hydroxysuccinimide, 3.39 g (80 mmol) of lithium chloride and 25.19 g (40 mmol) of 1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) pentanoic acid, the G-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 of acetone and stirred for 10 minutes. The precipitate was filtered off and then purified by silica gel chromatography (RP-18). Mobile phase: Water / ethanol / acetonitrile gradient).

230 · a a a a a a φ φ φ φ φ a φ

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

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

To 20 g (35.2 mmol) and 8.1 g (80 mmol) of triehylamine 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. dichloromethane and the mixture was stirred at 0 ° C for 3 hours. 200 ml of 5% aqueous hydrochloric acid was added and the mixture was stirred at room temperature for 5 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1)

Yield: 24.96 g (93% of theory) of a colorless solid.

Elementary 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.

231 í ··· ··· «·« ·· · ·· ······

Elementary 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- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide (pentanoyl-3-aza-4-oxo-5-methyl-5-yl-)] benzoic acid, Gd-complex g (14.24 mmol) of the title compound of Example 62b), 3.45 g (30 mmol) of N- hydroxysuccinimide, 2.54 g (60 mol) of lithium chloride and 18.89 g (30 mmol) of 1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) 1-Pentanoic acid, the Gd complex 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 chromatographed on silica gel (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

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 sulfate. It was then added at

232 at 0 ° C a total of 7.55 g (134.6 mmol; 2.5 equivalents per alcohol component used) of finely powdered potassium hydroxide, followed by the addition of 15.73 g (80.7 mmol; 1.5 equivalents based on the alcohol used) alcohol component) of 2-bromoacetic acid tert-butyl ester and the mixture was stirred at 0 ° C for 2 hours. 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 for workup. 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 resulting oily residue was purified by chromatography on silica gel using ethyl acetate / hexane (1:10) as eluent. Yield: 26.3 g (84.6% of theory) of the title compound as a colorless and highly viscous oil.

Elementary analysis:

H, 2.61; F, 55.85

Found: C 33.29 H 2.61 F 55.90

b) 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanecarboxylic 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 molar sodium hydroxide, stirred at room temperature and heated to 60 ° C. The mixture was stirred at 60 ° C for 12 h and the clear reaction solution was treated by neutralization by addition of a cationic ion exchanger Amberlite ® IR 120 (H ⁺ form), filtering the ion exchanger and evaporating the obtained methanol / water filtrate to dryness under reduced pressure. The amorphous residue obtained was • φ

233 was purified by silica gel chromatography using ethyl acetate / n-hexane (1: 3) as eluent.

Yield: 16.0 g (88.6% of theory) of the title compound as a thick viscous oil. Elementary analysis:

Calculated: C 27.60 H 1.35 F 61.85

Found: C 27.58 H 1.36 F 61.90

c) 1,7-Bis {[1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl)] - 1,4,7,10-tetraazacyclododecane } diethylenetriamine, Digadolinium complex

2.48 g [(3.94 mmol); 2.05 molar equivalents based on diethylenetriamine] Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid described in U.S. Pat. DE 197 28 954 C1 under Example 31 h) and 167 mg of anhydrous lithium chloride (3.94 mmol) were dissolved in 40 ml of absolute dimethylsulfoxide at 40 ° C and a total of 453 mg (3.94) was added at this temperature with stirring. mmol) of N-hydroxysuccinimide. 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 at room temperature for 2 hours. The resulting active ester suspension was then treated with 198.3 mg (1/92 mmol) of absolute hours while treating with diethytentriamine dissolved in 5 mL of dimethylsulfoxide and stirred at room temperature for 12 hours. The resulting suspension was with excess acetone until all of the title compound precipitated, the precipitate was filtered off, dried, dissolved in water, the undissolved dicyclohexylurea was filtered off, and the filtrate was freed from salt and purified from the low molecular weight AMICON® YM-3 ultrafiltration membrane:

• · • those three

234

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):

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- (3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) -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, was added dropwise at 50 ° C and under nitrogen atmosphere 1.27 g (2.44 mmol). 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-ethoxycarbonyl-1,2-dihydroquinoline] was added portionwise at 0 ° C and the mixture was stirred overnight at room temperature. The resulting reaction mixture was then treated with excess acetone until the title compound was completely precipitated, the precipitate was filtered off, dried, dissolved in water, the undissolved dicyclohexylurea was filtered off, and the filtrate was freed from salt and purified from the low molecular weight ultrafiltration membrane AMICON® YM-3. 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 17.18

235 ·· ··· · · · · tt

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 crystallized from diisopropyl ether.

Yield: 128.9 g (96% of theory) of a colorless crystalline powder. Melting point: 98.5 ° C.

Elementary analysis:

Calculated: C 51.07 H 5.09N 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-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 750 mL of tetrahydrofuran was added 164 at 0 ° C. 2 g (0.664 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 chromatographed on silica gel (mobile phase: dichloromethane / methanol = 20: 1). Yield: 286.0 g (93% of theory) of a colorless solid.

Melting point: 92 ° C.

Elementary 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 ················ · · · · · · · · · ·

236 • 0 0 0 0 0 0 0 0

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

To a solution of 280.0 g (302.2 mol) of the title compound of Example 52b) in 2000 ml of ethanol, ammonia gas was introduced at 0 ° C 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. Elementary analysis:

Calculated: C 37.60 H 3.28 N 6.75 E 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-pertluorooctylsulfonyl) -piperazine] -amide

200.0 g (240.8 mmol) of the compound prepared in Example 64c) was dissolved in 1000 ml of ethanol and 5.0 g of Pearlman Catalyst (Pd 20% / 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 well with ethanol (three times 100 ml) and the mixture was evaporated to dryness in vacuo. The title compound was obtained as a strongly viscous and yellowish-colored oil.

Yield: 162.5 g (96.9% of theory).

Elementary 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 E 46.33 S 4.62 e} 6N-2N-Bis- {4- [2,3-bis- (N, N-bis (tert-butyloxycarbonylmethyl) (amino) -propyl] phenyl} -3-oxa-propionyl-L-lysine- [1- (4-fluorooctylsulfonyl) -piperazine] -amide

5.25 g (7.72 mmol) of 4- [2,3-Bis- (N, N-bis (tert-butoxycarbonylmethyl) amino) propyl] phenyl} -3-oxa-propionic acid ·· ··· ·

237 of the acid and 781.0 mg (7.72 mmol) of triethylamine were dissolved in 50 ml of methylene chloride. At -15 ° C, a solution of 1.16 g (8.5 mmol) of isobutyl chloroformate in 10 ml of methyl chloride was added dropwise over 5 minutes, and the mixture was stirred for an additional 20 minutes at -15 ° C. The reaction solution was then cooled to -25 ° C and a solution consisting of 2.68 g (3.86 mmol) of the title compound of Example 64d) and 2.12 g (21.0 mmol) of triehylamine in 70 mL of tetrahydrofuran was added dropwise. The mixture was stirred for 30 minutes at -15 ° C and then overnight at room temperature. For work-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 a 10% aqueous ammonium chloride solution, dried over magnesium sulfate and then evaporated to dryness in vacuo. The residue was chromatographed on silica gel (mobile phase: methylene chloride / ethanol = 20: 1). Yield: 5.37 g (68.8% of theory) of a colorless and very solid oil. Elementary analysis:

Calculated: C 52.27 H 6.43 N 5.54 F 15.97 S 1.59

Found: C 52.22 H 6.51 N 5.49 F 15.99 S 1.63

f) 6N-2N-BIS- {4- [2,3-bis- (N, N-bis (carboxylatomethyl) amino) propyl] phenyl} -3-oxa-propionyl-L-lysine- [1- ( 4-perfluorooctylsulfonyl) -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 was stirred at room temperature for 12 hours 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 fcfcfcfc.

238 distilled water and an aqueous solution of the above title compound was extracted twice with 60 ml of diethyl ether. The resulting aqueous product solution was made up to a total volume of 300 ml with water, stripped of insoluble matter by filtration, the filtrate was de-salted and purified from the low molecular weight fraction of the AMICON® YM-3 ultrafiltration membrane (cut-off limit: 3000 Da). The filtrate was made up to 200 ml with water 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 F 18.47 S 1.83 Na 10.52 Found: C 38.42 H 3.31 N 6.39 F 18.51 S 1.87 Na 10 38 g) 6N-2N-Bis- {4- [2,3-bis- (N, N-bis (carboxymethyl) amino) propyl] phenyl} -3-oxa-propionyl-L-lysine- [1] - (4-perfluorooctylsulfonyl) -piperazine] -amide, dimangan 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 molar 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 was stirred at reflux 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 (limit of 3000 Da) to desalinate the product and has been stripped 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%.

·· · «« · · · · ·

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 in 300 mL of dimethylsulfoxide and at 10 ° C was added 9.49 g (46 mmol) of N, N-dicyclohexylcarbodiimide. 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 at 50 ° C for 3 hours. 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 silica gel chromatography (RP-18) (mobile phase = water / ethanol / tetrahydrofuran gradient). Yield: 21.59 g (38% of theory), yellow solid.

Water content: 2.1%.

Elemental analysis: (calculated on the anhydrous substance).

Calculated: C 43.10 H 3.54 F 25.76 N 11.29 S 2.56

Found: C 43.02 H 3.62 F 25.68 N 11.21 S 2.48

b) 2-N - [(N-Pteroyl) -L-glutaminyl] -lysine- [1- (4-perfluorooctylsulfonyl) piperazine] -amide

To 20 g (15.95 mmol) of the title compound of Example 65a) was added 200 mL of a solution of hydrogen bromide in acetic acid (48%) and the mixture was stirred at 40 ° C for 2 hours. The mixture was cooled to 0 ° C, 2000 ml was added dropwise.

240

* Diethyl ether and eliminated * 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · the precipitate was filtered off. After drying under vacuum at 60 ° C, 18.96 g (99% of theory) of a yellow crystalline solid was obtained.

Elementary 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 - [(Npteroyl] -L-glutaminyl] -lysine- [1- (4-perfluorooctylsulfonylpiperazine) -amide, Gd-complex

0.92 g (8 mmol) of N-hydroxysuccinimide, 0.68 g (16 mol) of lithium chloride and 5.04 g (8 mmol) of 1,4,7-tris (carboxylatomethyl-O- (3-aza-4-) oxo-5-methyl-5-yl) -1,4,7-10-tetraazacyclododecane, Gd complex was dissolved in 80 mL of dimethylsulfoxide with gentle heating, and 2.06 g (10 mol) of N were added at 10 ° C N-dicyclohexylcarbodiimide was then stirred at room temperature for 3 hours, to which 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 of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by silica gel chromatography (silica gel RP-18, mobile phase: water / ethanol / acetonitrile gradient). The substance was dissolved in a little water, the pH of the solution was adjusted to 7.4 and 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 ·· ····

9999

241 · *

9 9 9 9 9

9 9 9 9 9

9 99 9900 99 99

Found: C 38.28 H 3.85 F 18.33 Gd 8.85 N 12.69 Na 1.42 S 1.75

Example 66

(a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoic 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 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 triehylamine dissolved in 200 mL of dichloromethane. The mixture was stirred at 0 ° C for 3 hours and then at room temperature for 6 hours. 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 chromatographed on silica gel (eluent: dichloromethane / ethanol = 15: 1).

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

Elementary analysis:

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-oxaperfluorotridecyl) -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 sulfide (in tetrahydrofuran) was added. Mixture

242 was heated under reflux for 16 hours. The mixture was cooled to 0 ° C and 300 mL of methanol was added dropwise, and then 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 10% aqueous hydrochloric acid, and the mixture was 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 sulfate, evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (Mobile phase: dichloromethane / methanol = 15: 1). Yield: 24.07 g (85% of theory) of a colorless solid.

Elementary 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-oxo-hexan-5-yl) -acid-N- (2,3-dihydroxypropyl) -N- (1H, 1H, 2H) , 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -amide] -1,4,7,10-tetraazacyclododecane, Gadolinium complex g (15.88 mmol) gadolinium 10- [1- (carboxymethylcarboamoyl) complex 1-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 9.21 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 was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was poured into a mixture of 200 ml of acetone and 1300 ml of diethyl ether and stirred at room temperature for 2 hours.

243

The precipitate was filtered, dissolved in a little ethanol / water and chromatographed on silica gel RP-18 (mobile phase: tetrahydrofuran / acetonitrile / water gradient).

Yield: 6.09 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-oxo-hexan-5-yl)] - N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H- 3-oxa-perfluorotridecyl) 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 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 15 ° C and 3.51 g (17 mmol) of N, N'-dicyclohexylcarbodiimide was added and the mixture was stirred at 15 ° C for 5 hours. The solution was filtered to remove urea. 8.63 g (15.88 mmol) of the title compound of Example 68b and 5.06 g (50 mmol) of triehylamine were added to the filtrate, and the mixture was stirred at room temperature for 12 hours. 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%.

• · · ·

244 o * o · o · o · o · · · · · · · · · to · to · to · to · to · to · to · this ·

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 68

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

To 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic 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 200 mL of dichloromethane. Ammonia gas was then introduced into the reaction mixture at 0 ° C for 2 hours. The mixture was stirred at 0 ° C for 4 hours, and then stirred at room temperature for 2 hours. Then 300 ml of 5% aqueous hydrochloric acid 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 chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1).

Yield: 27.85 g (93% of theory)

Elementary 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, 5H-3-oxa-perfluorotridecylamine hydrochloride g (51.8 mmol) of the title compound of Example 68a was dissolved in 300 mL of tetrahydrofuran and 31 mL of 10M borane dimethyl sulfide solution was added (in tetrahydrofuran). The reaction mixture was refluxed for 16 hours. The mixture was cooled to 0 ° C and 200 ml of methanol was added dropwise.

245 • ·

and the mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 400 mL of ethanol and 100 mL of 10% aqueous hydrochloric acid, and the mixture was stirred at 60 ° C for 8 hours. The mixture was evaporated to dryness and the residue was crystallized from ethanol / diethyl ether.

Yield: 26.75 g (95% of theory) of a colorless, crystalline solid.

Elementary analysis:

Calculated: C 26.51 H 2.04 N 2.58 F 59.41 Cl 6.52

Found: C 26.37 H 2.21 N 2.46 F 59.25 Cl 6.38

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

To 26.5 g (48.74 mmol) of the title compound of Example 68b and 14.8 g (146.2 mmol) of triehylamine dissolved in 300 mL of dichloromethane were added dropwise at 0 ° C 14.24 g (50 mmol) 3. 6,9,12,15-pentaoxahexadecanoyl chloride was added and the mixture was stirred at 0 ° C for 3 hours. 300 ml of 5% aqueous hydrochloric acid was added and the mixture was stirred well for 30 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (eluent: dichloromethane / acetone: 20: 1).

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

Elementary 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, IH, 2H, 2H, 4H, 4H-3-oxa) perfluorotridecyl) -amide

246 g (41.03 mmol) of the title compound of Example 68c was dissolved in 300 mL of tetrahydrofuran and 25 mL of a 10 M solution of borane dimethyl sulfide (in tetrahydrofuran) was added. The mixture was boiled under reflux for 16 hours. It was then cooled to 0 ° C and 200 ml of methanol was added dropwise and then evaporated to dryness under reduced pressure. The residue was stirred in 300 ml of ethanol and 50 ml of 10% aqueous hydrochloric acid and stirred at 40 ° C for 8 hours. 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 was chromatographed on silica gel (Mobile phase: dichloromethane / propane = 15: 1).

Yield: 27.68 g (91% of theory)

Elementary analysis:

H, 4.35; N, 1.89; F, 43.56

Found: C 37.11 H 4.51 N 1.73 F 43.41

e) 1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid- [N-3,6,9,12,15-pentaoxyl] -hexadexyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluorotridecyl] -amide} -1,4,7,10tetraazacyclododecane, gadolinium complex g (15.88 mmol) gadolinium complex 10- [1- (carboxymethylcarbamoyl) -ethyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride 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 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 was added. The mixture was stirred at room temperature for 12 hours. The reaction solution was poured into a mixture of 200 ml of acetone, and

247

1300 ml of diethyl ether and stirred at room temperature for 2 hours. The precipitate formed was filtered, dissolved in a small amount of ethanol / water and chromatographed 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 4.6i N 6.03 F 23.64 Gd 11.42

Example 69

(a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoic acid N- (5-hydroxy-3-oxapentyl) -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 at room temperature for 12 hours. 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-oxa-pentylamine and 6.07 g (60 mmol) of triehylamine dissolved in 200 mL of dichloromethane was added dropwise at 0 ° C. 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 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 chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1).

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

Elementary analysis:

248 ·· ····

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- (5-Hydroxy-3-oxa-pentyl) -Ν- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) -amine g (49.24 mmol) of the title compound of Example 69a was dissolved in 300 mL of tetrahydrofuran and 31 mL of a 10 M solution of borane dimethyl sulfide (in tetrahydrofuran) was added. The mixture was heated under reflux for 16 hours. It was then cooled to 0 ° C and 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 10% aqueous hydrochloric acid, and the reaction mixture was stirred at 50 ° C for 10 hours. The mixture was evaporated to dryness, the residue was dissolved in 300 ml of 50 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 chromatographed on silica gel. (Mobile phase: dichloromethane / 2-propanol = 20: 1). Yield: 26.09 g (89% of theory) of a colorless solid.

Elementary 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-oxo-hexan-5-yl) -acid-N- (5-hydroxy-3-oxa-pentyl) -Ν- (1H) 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -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-triacetic acid and 1.35 g (31.76 mmol)

The 9999 lithium chloride was dissolved in 100 ml of dimethyl sulfoxide 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 was added. The reaction mixture was then stirred at room temperature for 12 hours. 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, dissolved in ethanol / water and chromatographed on silica gel RP18 (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):

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 (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol. 11, 53, 211-215, (1963)] provided the use of 150 g (832.5 mmol) of α, β-D-mannopyranose with a mixture of 1500 ml of absolute Pyridine and 1500 ml of acetic anhydride after treatment with 315 g (96.7%) of the title compound as a viscous and colorless oil. IH NMR spectroscopy showed that it is a 4: 1 mixture of α and β anomers. Separation of α and β anomers of the aforementioned title • · · · · ····· ·

250

9 9 9 9 9 9 9 9 9 • 9 · 9999 99 99 compounds can be achieved by carrying out the following reaction steps.

Elementary analysis:

H, 5.68

Found: C, 49.12; H, 5.78

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

In an analogous manner to that described in the literature, the synthesis of aryl glycopyranosides [J. Conchie and GA Levvy in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol. 11, 90, pp. 345-347, (1963)] led to the use of 156,2 g (400 mmol) of the title compound of Example 70a as an α, β-isomer mixture with 67 ml (400 mmol) of 6-hydroxyhexanoic acid ethyl ester and 60.8 ml (520 mmol) of tin (II) chloride in a total of 600 ml of 1,2-dichloroethane Silica gel chromatography (Eluent: hexane / ethyl acetate 2: 1) to give 100.05 g (51% of theory) of the title compound as a colorless and viscous oil. 1 H NMR spectroscopy crawled that the title compound could be considered pure and anomer.

Elementary analysis:

H, 6.77

Found: C, 52.80; H, 6.78

c) 6- [1-O-α- (2,3,4,6-Tetra-O-benzyl-D-mannopyranosyl) hexanoic acid

To a stirred suspension of 141.0 g (289 mmol) of the title compound of Example 70b in 200 mL dioxane was added 235.5 g in portions at room temperature with vigorous stirring.

251 (4.26 mol) of finely powdered potassium hydroxide. To increase the stirring efficiency, an additional 200 mL 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 two hours. The reaction mixture was stirred at 110 ° C for 4 hours and then at room temperature for 12 hours. For work-up, the reaction mixture was poured slowly into 2.5 liters of ice water and the aqueous phase was extracted with diethyl ether. After the ether phase was washed and dried over sodium sulfate, the inorganics were filtered off and the solvent was evaporated under reduced pressure. Excess benzyl bromide was then distilled from the reaction mixture in a vacuum pump at an oil temperature of 180 ° C. The oily residue thus obtained was purified by chromatography on silica gel using ethyl acetate / hexane (1:10) as eluent.

Yield: 172.2 g (91.0% of theory) of the title compound as a colorless and very viscous oil.

Elementary analysis:

Calculated: C 75.68 H 7.16

Found: C, 75.79; H, 7.04

d) N- [3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl] -amide 6 [10-O-α- (2,3,4,6-Tetra-O-) benzyl-D-mannopyranosyl) -hexanoic acid

100 g (134 mmol) of the acid described in Example 70c were dissolved in 1200 ml of dry tetrahydrofuran, followed by 13.5 g (134 mmol) of triehylamine. 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 exceed -10 ° C. The mixture was stirred.

4 · 4 • ti ····

A solution of 165.5 g (134 mmol) of 1-amino-1H, 1H, 2H, 2H-perfluorodecane and 13.5 g (134 mmol) of triehylamine in 250 ml of dry tetrahydrofuran was added dropwise over 252 minutes at -15 ° C. at -20 ° C. The reaction mixture was stirred for 1 hour at -15 ° C and then for 2 hours at room temperature, and the mixture was then evaporated to dryness under reduced pressure. The obtained residue was dissolved in 300 ml of ethyl acetate and was 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 obtained residue was purified by silica gel chromatography using dichloromethane / hexane / 2-propanol (10: 5: 1) as eluent.

Yield: 143.8 g (86.9% of theory)

Elementary 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-c-D-mannopyranosyl] -hexanoic acid N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide

40.0 g (32.38 mmol) of the title compound 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 and 1 atm under a hydrogen atmosphere. The catalyst was filtered off and the residue was evaporated to dryness. The residue was dissolved in 300 ml of dimethyl sulfoxide and the product solution was treated with a total of 1000 ml of diethyl ether, and the precipitate 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.

Elementary analysis:

253

Φ · φ · · φφ φφφφφφφφφφφ ««ΦΦφΦφΦ

99 «ΦΦΦ« φφφ · Φ ΦΦ φ φφ

Calculated: C 36.01 Η 5.92 Ν 1.75 F 40.34 Found: C 36.07 Η 6.08 Ν 1.76 F 40.66

f) Preparation of the preparation of metal complex 1 H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide and N- (3-oxa-1H, 1-6- [1-O-D-mannopyranosyl) -hexanoic acid

To 35 ml of the metal complex I solution (280 mmol / l) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / l CaNajDTPA) was added 3.17 g (4.2 mmol) of the title compound. of the compound 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 at 60 ° C for 2 hours in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with 2N 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 for biological experiments (concentration is approximately 100 mmol Gd / L).

Example 71

(a) 1-O-αD - [(1-Perfluorooctylsulfonylpiperazine-4-carbonyl) pentyl-5] -2,3,4,6-tetra-O-benzyl-mannopyranose In 800 ml of tetrahydrofuran / acetonitrile (7: 3) 74.59 g (100 mmol) of the acid prepared in Example 71c was dissolved and 10.11 g (100 mmol) of triehylamine was added.

500 ml (102.0 mmol) 1g (100 mmol) dropwise

Finally, at room temperature of the tetrahydrofuran solution, 58.0 g of rerfluorooctylsulfonylpiperazine, 10.11 triehylamine and 16.84 g (110 mmol) of 1-hydroxybenzotriazole were present. The reaction solution thus obtained was reacted at -5 ° C with a solution of 22.7 g (110 mmol) of dicyclohexylcarbodiimide dissolved in 100 ml of tetrahydrofuran and the mixture.

254 ·· ·· ♦ 9 9 9 9 9

9

The mixture was then stirred at -5 ° C for an additional two hours. After dissolution of the reaction mixture, the reaction was stirred at room temperature for an additional 12 hours, the precipitated dicyclohexylurea was filtered, and the filtrate was evaporated to dryness in vacuo. The residue obtained was 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, the ethyl acetate was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography using a mixture of dichloromethane / acetone / 2-propanol (16: 2: 1) as eluent. Yield: 113.01 g (79.8% of theory) of a colorless and viscous oil.

Elementary 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-OaD - [(1-Perfluorooctylsulfonyl-piperazine-4-carbonyl) pentyl-5] 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 on charcoal) was added. The mixture was hydrogenated at room temperature for 12 hours. 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 treated with a total of 800 mL of diethyl ether to precipitate. After filtering off the precipitate, the material was dried under vacuum at 50 ° C.

Yield: 29.51 g (99% of theory) of an amorphous solid.

Elementary 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 • * ΦΦ ·· φφ ····

255 • Φ φ φ φ φ φ · · · · · φ φ φ φ φ φ · · · · · · · ·

c) Preparation of a preparation of metal complex II and 1-O-α-D - [(1-Perfluorooctylsulfonyl-piperazine-4-carbonyl) -pentyl-5] mannopyranose

To 47 mL of a solution of metal complex II (250 mmol / l) 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 in the microwave for 10 minutes. 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 for biological experiments. (concentration is approximately 250 mmol Gd / L).

Example 72

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

To a stirred suspension of 20.16 g (700 mmol; 80% suspension in mineral oil) of sodium hydride in 150 mL of dimethyl sulfoxide was added a total of 24.0 g (108.5 mmol) of 2-acetamido-2-deoxy-α, at room temperature, 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 at room temperature for a further 12 hours. For working up, the reaction solution was poured into 1.5 liters 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 salt, the solvent was evaporated to dryness in vacuo. The oily residue obtained was purified

256 fcfc fc fcfcfcfcfcfcfc • fcfcfcfc • fc fcfcfcfc fcfc fcfcfcfc fcfc fcfc chromatography on silica gel using ethyl acetate / hexane (1: 5) as eluent.

Yield: 48.68 g (73.6% of theory) of the title compound above as a viscous and colorless oil. Elementary analysis:

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 molar aqueous solution of perchloric acid was added at room temperature. After the addition was complete, the mixture was stirred at room temperature for 10 minutes and the homogeneous reaction mixture thus obtained was evaporated to dryness in vacuo. Treatment with a mixture of equal parts of hexane and dichloromethane led to crystallization. The crystalline reaction product was filtered off, washed with hexane and dried under vacuum at room temperature. Yield: 27.08g (86% of theory) of the title compound as a colorless crystalline compound. Melting point: 180.5-181.5 ° C

Elementary analysis:

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-methyl-N-perfluorooctylsulfonyl) -amino] -1-α, β-D-glucopyranose

20.8 g (35.6 mmol) of 2- [N-ethyl-N-perfluorooctylsulfonyl) aminoacetic acid and 3.60 g (35.6 mmol) of triehylamine were dissolved in 350 ml of dry tetrahydrofuran. After cooling φφ φφφφ

257 • φ φ φ φ φ φ φ φ φ

A solution of 4.92 g of isobutyl chloroformate in 75 tetrahydrofuran was added dropwise with stirring at this temperature (-15 ° C) at this temperature (35.6 mmol) at -15 ° C while the addition was so rapid that the temperature did not rise above -20 ° C. Low: 14 ° C. The mixture was stirred at -15 ° C for 15 minutes 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 100 ml of dry tetrahydrofuran was added dropwise). The mixture was stirred at -15 ° C for 1 hour and then at room temperature for 2 hours, then evaporated to dryness under reduced pressure, and the residue was dissolved in 250 ml of ethyl acetate and washed twice with 100 ml. 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. reagents.

Yield: 33.3 g (84.6% of theory) of the title compound as a colorless and strongly viscous oil.

Elementary 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) 2-Desoxy-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 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 at 22 ° C and 1 atm of hydrogen atmosphere for 12 hours. The catalyst was filtered off and the filtrate was evaporated.

0000 to dryness. The residue obtained was dissolved in 300 ml of dimethylsulfoxide and the product solution thus obtained was mixed with 750 ml of a mixture consisting of equal parts of diethyl ether and ethyl acetate. After filtering off the precipitate, 12.65 g (93.8% of theory) of the title compound are obtained as a colorless and crystalline powder. The aforementioned title compound occurs as a mixture of α and β anomers, and their ratio was determined to be approximately 1: 1 'by 1 H NMR spectroscopy. 2. The title compound is therefore considered to be a mixture of approximately equal parts of the α and β anomers. Melting point: 132.5 133 ° C.

Elementary 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) Production of the preparation of the metal complex XIV and 2-desoxy-2 [acetyl- (2-amino-N-ethyl-N-perfluorooctylsulfonyl) -amino] -α, β-D-glucopyranose

To a solution of XIV (300 mmol / l) metal complex solution (51 ml) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4 / 0.25 mg / l CaNasDTPA) was added a solution of 4.90 g (6.57 mmol). of the title compound of Example 3d, dissolved in 200 ml of ethanol, and the mixture was stirred at 50 ° C for 2 hours. 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 at 40 ° C for 10 minutes and filtered through a 0.2 µπ filter. The filtrate was filled into vials. The resulting solution can be directly used for biological experiments. (Concentration approximately 100 mmol Gd / L).

259 • fc ················· <<· · ··· ··· ·· · ·· ···· ·· ··

Example 73

a) 1,2,3,4,6-Penta-O-acetyl- and -D-glucopyranose

In an analogous manner to that described for the synthesis of the title compound described in 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 after treatment and crystallization from 95% aqueous ethanol 190.6 g (88.0%) of the title compound as a colorless crystalline compound. 1 H NMR spectroscopy revealed that the title compound was a 98: 2 mixture of α and β anomers. Thus, the title compound was considered to be exclusively ananomeric configuration.

Melting point: 110.5 ° C

Elementary analysis:

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, using 130.0 g (332.8 mmol) of the title compound of Example 4a) with 55.8 mL (332.8 mmol) of 6-hydroxyhexanoic acid ethyl ester and 50.6 mL (520 mmol) tin (II) chloride in 500 ml 1,2-dichloroethane after purification by column chromatography (eluent: hexane / ethyl acetate 2: 1) 101.85 g (62.4% of theory) of the title compound as a colorless and viscous oil. By 1 H NMR spectroscopy with the use of size coupling constants J ₂ = 8.8 Hz ₂ revealed that the title compound has a β configuration at the anomeric carbon, and that • 9 ··· "

260 ·· ··· <··· • »* fcfcfcfc fcfc 9 • fcfc ·· fcfc ·· ··· ·> -« · r ··· ♦ ·· ·· «· fcfc · fcfc ··· * · «fcfc is the only configuration of the anomeric center. Thus, the title compound has exclusively the β-configuration of the anomeric center.

Elementary analysis:

H, 6.77

Found: C, 52.77; H, 6.70

c) 5- (Carboxy) pentyl-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 was added portionwise 169.14 g (3.02 mol) of finely powdered potassium hydroxide. To increase the stirring efficiency, an additional 150 ml 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 two hours at this temperature. The reaction mixture was stirred at 110 ° C for 4 hours and then at room temperature for 12 hours. 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 the ether phase was washed and dried over sodium sulfate, the inorganics were filtered off and the solvent was evaporated under reduced pressure. Excess benzyl bromide was then distilled from the reaction mixture in a vacuum pump at an oil temperature of 180 ° C. The oily residue thus obtained was purified by chromatography on silica gel using ethyl acetate / hexane (1:10) as eluent.

Yield: 128.8 g (84.3% of theory) of the title compound as a thick viscous oil. Elementary analysis:

Calculated: C 75.68 H 7.16

Found: C, 75.66; H, 7.23

4 4

261

4

3s d) 2,3,4,6-Tetra-O-benzyl-10- [1-D- [6-hexanoic acid] -N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H) -perfluorotridecyl) -amide] glucopyranose

68.5 g (91.79 mmol) of the title compound described in Example 73c were dissolved in 825 mL of dry tetrahydrofuran together with 9.25 g (91.79 mmol) of triehylamine. 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 added dropwise with stirring at this temperature, the rate of addition being such that the mixture did not exceed -10 ° C. The mixture was stirred at -15 ° C for 15 minutes and then a solution of 46.40 g (91.79 mmol) of IH, IH, 2H, 2H-heptadecafluoro-1- (2-aminoethyoxy) decane and 9.25 g (91 g) was slowly added dropwise. (79 mmol) of triehylamine dissolved in 200 mL of dry tetrahydrofuran at -20 ° C. The mixture was stirred at -15 ° C for 1 hour and then at room temperature for 2 hours, and the mixture was 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 resulting oily residue was purified by chromatography on silica gel using dichloromethane / hexane / 2-propanol (10: 5: 1) as eluent.

Yield: 104.7 g (92.4% of theory) of the title compound as a colorless and viscous oil. Elementary 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 • · · · · · · ·

262

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

40.0 g (32.38 mmol) of the title compound of Example 73d 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 at 22 ° C and 1 atm of hydrogen atmosphere for 12 hours. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in 300 ml of dimethylsulfoxide and the product solution thus 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 and crystalline powder. Mp 122-124 ° C.

Elemental analysis: ...

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 the preparation of the title compound of Example 12 of WO 99/01161 (1,4,7-Tris {1,4,7-tris (N-carboxylatomethyl) -10- (N-1-methyl-3-aza-2,5) -dioxo-pentane-1,5-diyl] -1,4,7,10-tetraazacyclododecane, Gd-Complex} -10- [2- (N-ethyl-N-fluorooctylsulfonyl) -amino] -acetyl-1,4,7,10 -tetraazacyclododecane) and Ι-Ο-β-D- [6-hexanoic acid-N- (3-oxa1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide] -glucopyranose

To a solution of 37 ml of 1,4,7-tris (1,4,7-tris (N-carboxylatomethyl) -10- (N1-methyl-3-aza-2,5-dioxopentane-1,5-diyl) -1,5-yl) -1, 4,7,10-tetraazacyclododecane, Gd complex] -10- [2- (Nethyl-N-perfluorooctylsulfonyl} -amino] -acetyl-1,4,7,10tetraazacyclododecane (300 mmol / l) dissolved in 0.45% aq. sodium chloride solution (pH 7.4; 0.25 mg / L)

CaNa _{3 (} DTPA) was added 20.29 g (25.9 mmol) of the title compound of Example 73e and the mixture was treated with 0.9% aq.

263 ml of sodium chloride solution to a total volume of 111 ml. The mixture was stirred at 60 ° C for 2 hours in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 by addition of 2N sodium hydroxide. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The obtained solution can be directly used for biological experiments. (Concentration approximately 100 mmol Gd / 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, 1H, 2H, 2Hperfluorodecane in 150 ml of 1,2-dichloroethane and 19.47 g (166.53 mmol) of tin (II) chloride, analogous to the synthesis of the title compound of Example 1b) and 4b), after column chromatography (Eluent: hexane / ethyl ester) acetic acid 2: 1) to give 74.2 g (63.4% of theory) of the title compound as a viscous and colorless oil. 1 H NMR spectroscopy using an interaction constant size J ₁ , ₂ = 1.3 Hz found that the title compound had an α configuration at the anomeric center, so that it could be considered a pure α-anomer of the title compound.

Elementary analysis:

Calculated: C 44.65 H 2.53 F 35.32

Found: C, 44.77; H, 2.61; F, 35.09

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

The neutralized cationic g (27.33 mmol) of the title compound of Example 74a was suspended in 400 mL of absolute methanol and a catalytic amount of sodium methoxide was added at 5 ° C. The mixture was stirred for 3h at room temperature and the reaction was found to be quantitative by thin layer chromatography (eluent: chloroform / methanol 9: 1). For work-up, the clear reaction solution was an Amberlite IR 120 ion exchanger, the ion exchanger was a vigorous methanolic solution and evaporated to dryness under reduced pressure. The crystalline residue obtained was crystallized twice from ethanol. ^Spektr Η NMR spectroscopy based on the magnitude of the interaction constant J _x , ₂ = 1.0 Hz found that the title compound has a configuration at the anomeric center a. Named is the only configuration at the anomeric center The NMR (H-form) was filtered off and the configuration meant that the compound was spectroscopy. Thus, the title compound was prepared as the pure α-anomeric isomer.

Yield: 16.2 g (94.6% of theory) of a colorless and crystalline solid.

Melting point: 172-174 ° C with decomposition.

Elementary analysis:

Calculated: C 30.69 H 2.41 F 51.57 Found: C 30.57 H 2.48 F 51.65

(c) Preparation of metal complex II and 1-0 (1H, 1H, 2H, 2H-Perfluorodecyl) -αD-mannopyranose preparations To 50 ml of metal complex II solution (150 mmol / l) dissolved in 0.45% aqueous chloride solution sodium (pH 7.4 / 0.25 mg / l CaNa ₃ DTPA), a solution of 2.01 g (3.21 mmol) was added.

265 • · · «· · ti * • · • «« titi ···· «· ·· title compounds from Example 74b, dissolved in 200 ml ethanol and the mixture was stirred 2 hours at temperature 50 Deň: 32 ° 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 at 40 ° C for 10 minutes and filtered through a 0.2 µπ filter. The filtrate was poured into vials. The prepared solution is suitable for direct use in biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 7 5

a) 1-O- (1H, 1H, 2H, 2H-Perfluorododecyl) -2,3,4,6-tetra-O-acetyla-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-1H, 1H, 2H, 2H -perfluorododecane in 100 ml of 1,2-dichloroethane and a total of 13.63 g (16.61 mmol) of tin (II) chloride, analogous to that described for the synthesis of the title compound of Examples 1b), 4b) and 5b), resulted after treatment and purification by column chromatography (Eluent: hexane / ethyl acetate = 2: 1) to give 62.49 g (68.7% of theory) of the above-mentioned viscous and colorless oil. ¹ H NMR spectroscopy, based on the size of the interaction constant J ₁ , ₂ = 1.4 Hz, found that the title compound had an anomeric center configuration and that was the only configuration of the title compound at an anomeric center. Thus, the title compound can be prepared as the pure α-anomeric isomer.

Elementary analysis:

H, 2.28; F, 39.32

Found: C 42.55 H 2.38 F 39.40 • · · · «·

266 • «* · φ <·· · · · · ···

b) 1-O- (1H, 1H, 2H, 2H-Perfluorododecyl) -α-D-mannopyranose g (24.64 mmol) of the title compound of Example 75a was suspended in 400 mL of absolute methanol and a catalytic amount was added at 5 ° C sodium methoxide. The reaction was stirred for 3h at room temperature and was determined to be quantitative by checking the reaction mixture by thin layer chromatography (Eluent: chloroform / methanol-9: 1). For 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 resulting methanol solution was evaporated to dryness under reduced pressure. The obtained crystalline residue was crystallized twice from 2-propanol / ethanol (1: 1). ² H NMR spectroscopy based on the magnitude of the interaction constant J _{i (2} = 1.0 Hz found that the title compound has the α configuration at the anomeric center. The named configuration and is the exclusive configuration at the anomeric center, i.e. of the compound is below ³ H NMR spectroscopy, so the title compound was prepared as the pure α-anomeric isomer.

Yield: 16.96 g (90.8% of theory) of a colorless crystalline solid.

M.p .: 187-188 ° C with decomposition.

Elementary analysis:

C 29.77 H 2.08 F 54.93 Found: C 29.70 H 2.28 F 54.83

c) Production of a preparation of metal complex VI and 1-0 (1H, 1H, 2H, 2H-Perfluorododecyl) -α-D-mannopyranose

To 52 ml of a solution of metal complex VI (180 mmol / l) dissolved in 0.45% aqueous sodium chloride solution, was added 1.70 g.

• • · ··· * ·· · 267 • • to · to · to * ·········· · · · · (2.34 mmol) title of the compound of Example 75b and the mixture was heated 10 minutes in microwaves. Solution was cooled to laboratory temperature, was filtered through 0.2 μιη filter a

the filtrate was filled into vials. The solution thus prepared can be directly used for biological experiments. (Concentration approximately 180 mmol Gd / L).

Example 76

(a) 2,3,4,6-Tetra-O-acetyl) -1-O-α-D- [3,6,9-trioxa- (C12-C19heptadecafluoro) nonadecyl] -mannopyranose

Using 20 g (51.23 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 30.54 g (51.23 mmol) of 1-hydroxy-tris- (1H, 1H, 2H). , 2H-O) -1H, 1H, 2H, 2H-perfluorodecane in 100 ml of 1,2-dichloroethane and a total of 5.98 g (51.23 mmol) of tin (II) chloride, analogous to that described for the synthesis of the title compound of Examples 1b 4b) and 5b), after work-up and purification by column chromatography (Eluent: hexane / ethyl acetate = 1: 1) gave 34.22 g (72.1% of theory) of the title compound as a colorless and viscous oil. . ¹ H NMR spectroscopy, based on the magnitude of the interaction constant J ₁ , ₂ = 1.1 Hz, found that the title compound had an α configuration at the anomeric center. The said configuration is the exclusive configuration at the anomeric center. Thus, the title compound can be prepared as the pure α-anomeric isomer.

Elementary analysis:

H, 3.81; F, 34.86

Found: C 39.02 H 3.77 F 34.90

b) 1-O-α-D- [3,6,9-Trioxa- (C 1 -C 18 -heptadecafluoro) -nonadecyl) mannopyranose

The 268 neutralized cationic g (21.58 mmol) of the title compound of Example 76a was suspended in 350 mL of absolute methanol and a catalytic amount of sodium methoxide was added at 5 ° C. The reaction was stirred for 3h at room temperature and was determined to be quantitative by checking the reaction mixture by thin layer chromatography (Eluent: chloroform / methanol = 6: 1). For work-up, the clear reaction solution with an Amberlite IR 120 (H ⁺ -form) ion exchanger was filtered off, and the resulting methanolic solution was evaporated to dryness under reduced pressure. The obtained crystalline residue was crystallized twice from ethyl acetate / 2-propanol / ethanol (1: 0.5: 1). ¹ H NMR spectroscopy based on the magnitude of the interaction constant Ji, ₂ = 1.0 Hz found that the title compound has an α configuration at the anomeric center. The said configuration and is the exclusive configuration at the anomeric center, i.e. is below recognition by ¹ H NMR spectroscopy. Thus, the title compound was prepared as the pure α-anomeric isomer.

Yield: 15.20 g (92.9% of theory) of a colorless crystalline solid.

Melting point: 141 ° C.

Elementary 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 title compound of Example 68 and 1-O-α-D- [3,6,9-trioxa- (C ₁₂ -C ₁₉ -heptadecafluoro) -nonadecyl] mannopyranose

To a 38 ml solution of the title compound of Example 68 (300 mmol / l) dissolved in 0.45% aqueous sodium chloride solution

269 • 0 0 0 0 ··· 00 00 (pH 7.4; 0.25 mg / l CaNa ₃ DTPA), 3.71 g (4.89 mmol) of the title compound of Example 76b was added and 9% aqueous sodium chloride solution is made up to a total volume of 114 ml. The mixture was stirred at 60 ° C for 2 hours 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 2N sodium hydroxide. The solution was filtered through a 0.2 µm filter and the filtrate was filled into vials. The solution thus prepared was filled into vials. The solution can be directly used for biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 77

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

25.0 g (57.28 mmol) was dissolved in 500 mL dry tetrahydrofuran; [prepared by: Ponpipom, Mitree M.;

Bugianesi, Robert L .; Robbins, James C .; Doebber, T.W .; Shen, Τ. Y .; J. Med. Chem .; 24; 12; 1981; 1388-1395] 3 (tetra-O-acetyl-α-D-mannopyranosylmercapto) -propionic acid together with 5.77g (57.28 mmol) of triehylamine. 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 was stirred for 15 minutes at -15 ° C and a solution of 29.05 g (57.28 mmol) of ΙΗ, ΙΗ, 2H, 2H-heptadecafluoro-1- (2-aminoethyoxy) decane and 5.77g (57%) was slowly added dropwise. (28 mmol) of triethylamine as a solution in 200 mL of dry tetrahydrofuran at -20 ° C. The mixture was stirred at -15 ° C for 1 hour and then at room temperature for 2 hours

AAAA

AA AAAA

270 room temperature and the mixture was 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. The resulting oily residue was purified by silica gel chromatography using dichloromethane / hexane / 2-propanol (8: 5: 1) as eluent. Yield: 44.90 g (84.7% of theory) of the title compound as a colorless and strongly viscous oil.

Elementary 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- (3-oxa1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide] -mannopyranose 30 g (32.41 mmol) of the title compound of Example 77a was suspended in 400 mL of absolute methanol and a catalytic amount of sodium methoxide was added at 5 ° C. The reaction was stirred for 3h at room temperature and was determined to be quantitative by checking the reaction mixture by thin layer chromatography (Eluent: chloroform / methanol = 9: 1). For 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 resulting methanol solution was evaporated to dryness under reduced pressure. The obtained crystalline residue was crystallized from ethyl acetate / methanol (0.5: 1). NMR spectroscopy, based on the magnitude of the interaction constant J _{i / 2} = 1.1 Hz, found that the title compound has an α configuration at the anomeric center. The α configuration is the exclusive one at the anomeric configuration.

271 • φ · · · φ φφφφ φ φφ center, this means that possibly resulting β-configuration of the title compound is below the limit of detection with ^X H NMR spectroscopy. Thus, the title compound was prepared as the pure α-anomeric isomer.

Yield: 23.76 g (96.8% of theory) of a colorless crystalline solid. Melting point: 113 - 114,5 ° C

Calculated: C 33.30 H 3.19 N 1.85 S 4.23 F 42.64

Found: C 33.21 H 3.26 N 1.96 S 4.08 F 42.77

c) Preparation of the title compound of Example 66 and 1-α-D- [3-thiopropionic acid-N- (3-oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide ] -mannopyranoses

To a 47 mL solution of the title compound of Example 66 (330 mmol / L) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA) was added a solution

27.41 g (36.19 mmol) of the title compound of Example 77b dissolved in 200 mL of ethanol, and the mixture was stirred at 50 ° C for 2 hours. 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 at 40 ° C for 10 minutes and filtered through a 0.2 µπ filter. The filtrate was filled into vials. The resulting solution can be directly used for biological experiments (concentration approximately 100 mmol Gd / L).

Example 78

a) 2,3,4,6-Tetra-O-acetyl-1-β-D- [3,6,9-trioxa- (C12-C19heptadecafluoro) -nonadecyl] -glucopyranosyluronic acid

20.2 g (50.85 mmol) of methyl (1-bromo-2,3,4-tri-O-acetyl- and -D-glucopyranoside) uronate [prepared according to: Pelzer; HoppeSeyler's Z. Physiol. Chem .; 314; 1949; 234, 237 respectively. Goebel;

• ti ti «ti ·· · · ti

272 • the three titi • the three tititites • the tititites titititi titi titi

Babers; J. Biol. Chem .; 111; 1935; 347, 350 and Bollenback et al .; J. 7 \ mer. Chem. Soc .; 77; 1955; 3310, 3313th] and 60, 64 g (101.7 mmol) of 3, 6,9-trioxa- (C ₂ -C ₉ -heptadekafluor) nonadecan-1-ol were dissolved in 250 ml of aqueous acetonitrile at room temperature was added 13 0 g of freshly precipitated silver oxide. The reaction was stirred at room temperature for 12 hours and the undissolved 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 (Eluent: hexane / ethyl acetate = 3: 1).

Yield: 22.99 g (53.3% of theory) of the title compound as a colorless, highly viscous oil.

Elementary analysis:

H, 3.92; F, 38.06

Found: C, 41.20; H, 3.76; F, 38.22

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

10.0 g (11.78 mmol) of the title compound of Example 78a were suspended in 200 ml of a mixture of methanol and 0.5 molar sodium hydroxide solution 2: 1 with stirring at room temperature. The reaction was stirred for 12 h at room temperature and for 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 resulting methanol solution was evaporated to dryness under reduced pressure. The obtained crystalline residue was purified by crystallization from ethyl acetate / methanol (0.25: 1). ¹ H NMR spectroscopy based on the magnitude of the interaction constant Ji, ₂ = 9.2 Hz found that the title compound had a β configuration at the anomeric center.

φ ·· · φ * φφ φφφφ • φ φ · φ · · φ φ ·

273 φ · φ φ φ φ φ φ · ·

Said configuration of β is the exclusive configuration at the anomeric center, ie the possible α-configuration of the title compound is below the recognition limit by ^Χ Η NMR spectroscopy. Thus, the title compound was prepared as the pure β-anomeric isomer.

78.5 ° C

Elementary analysis:

H, 3.26; F, 41.81

Found: C 34.38 H 3.26 F 41.90

(c) Preparation of a preparation of metal complex I and 1-O- [β-D- [3,6,9-trioxa- (C12-C18-heptadecafluoro) -nonadecyl] glucopyranosyluronic acid

To 38 ml of the metal complex I solution (280 mmol / l) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / l CaNasDTPA) was added 19.18 g (24.83 mmol). of the title compound of Example 78b and the mixture was made up with a 0.9% sodium chloride solution to a total volume of 53.2 ml. The mixture was stirred at 60 ° C for 2 hours 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 2N sodium hydroxide. The solution was filtered through a 0.2 µm filter and the filtrate was filled into vials. The solution thus prepared was filled into vials. The solution can be directly used for biological experiments. (Concentration approximately 200 mmol Gd / L).

Example 79

a) 6- (2-0xa-H, H, 3H, 3H, 4H, 4H-perfluorodecyl) ^Χ -0, 0 ^2, 0 ^3, 0 ⁴ diisopropylidene-D-galactopyranose

To a stirred suspension of 2.01 g (70.0 mmol; 80% suspension in mineral oil) of sodium hydride in 25 ml of dimethylformamide.

274 fcfc fcfcfcfc fcfc · · • • fcfc fcfcfc fcfcfcfc fcfc fcfc fcfcfcfc fcfc fcfc at room temperature was slowly added dropwise a total of 12.15 g (46 66 mmol) of O ^1, 0 ^2, 0 ^3, 0 ⁴ -diisopropyliden-alpha-galactopyranose [preparation by: Levene; Meyer; J. Biol. Chem .; 64; 1925; 473 resp. McCreath; Smith; J. Chem. Soc .; 1939; 387, 389 and Freudenberg; Hixon; Chem. Ber .; 56; 1923; 2119, 2122] 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, 2Hperfluorododecane dissolved in 150 ml of absolute dimethylformamide was added dropwise. The reaction solution was stirred for an additional 12 hours at room temperature. For work-up, the reaction solution was poured slowly into 1 liter 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 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 resulting oily residue was purified by silica gel chromatography using ethyl acetate / hexane (1:10) as eluent.

Yield: 29.8 g (79.3% of theory) of the title compound as a viscous colorless oil. Elementary analysis:

H, 2.87; F, 49.47

Found: C 35.64 H 2.98 F 49.54

b) 6- (2-Oxa-1H, 1H, 3H, 3H, 4H, 4H-perfluordecyl) -α-D-galactopyranose g (24.8 mmol) of the title compound of Example 79a was stirred with 300 mL of 1% aqueous sulfuric acid and the mixture was stirred 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. Clear φ φ φ * φ φ

··· φ φ φ φ φ φ φ φ φ

The 275 aqueous filtrate was lyophilized. 1 H NMR spectroscopy showed that the title compound was a mixture of α and b anomers and that their ratio was 1: 1.4. Thus, the aforementioned title compound was isolated as a 1: 1.4 mixture of α and b anomers and no separation of the anomers was performed.

Yield: 15.28 g (98.4% of theory) of the title compound as a colorless lyophilisate. Elemental analysis (calculated on the anhydrous compound): Calculated: C 35.75 H 2.87 F 49.47

Found: C 35.64 H 2.98 F 49.54

c) Preparation of the title compound of Examples 67 and 6 (2-0xa-1H, 1H, 3H, 3H, 4H, 4H-perfluordecyl) -α-D-galactopyranose To 43 ml of the solution of the title compound of Example 67 (250 mmol / l) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA), a solution of 1.68 g (2.69 mmol) of the title compound of Example 79b, dissolved in 200 ml of ethanol, and the mixture was heated at 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 at 40 ° C for 10 minutes and filtered through a 0.2 µπ filter. The filtrate was filled into vials. The recovered solution can be directly used in biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 80

a) 1-OaD - [(1-perfluorooctylsulfonylpiperazine-4-carbonyl-) methyl] mannopyranose g (52.8 mmol) 1-Perfluorooctylsulfonylpiperazine (prepared as described in DE 196 03 033) and 31.73 g (53 mmol) 2 3,4,6-tetra-O-benzyl-α-D-carboxymethyl-mannopyranose

99

9 9 9 9 9 9 9 9 9 * * · ·· «·

276 • 9 · 9

9 9 9 99 99 9 9 (preparation as described in DE 197 28 954) was dissolved in 300 ml 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 at 0 ° C for 3 hours and then stirred 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 crystallized from acetone / diethyl ether.

Yield: 30.39 g (73% of theory) of a waxy solid.

Elementary analysis:

Calculated: C 30.47 H 2.68 F 40.96 N 3.55 S 4.07

Found: C 30.61 H 2.75 E 41.10 N 3.46 S 4.12

(b) Preparation of the preparation of metal complex I and 1-O-α-D - [(1perfluorooctylsulfonylpiperazine-4-carbonyl -) - methyl] mannopyranose

To 32 ml of a metal complex I solution (280 mmol / l) dissolved 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 of Example 80a and the mixture was made up to a total volume of 55 ml with 0.9% aqueous sodium chloride solution. The mixture was heated at 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 2N sodium hydroxide. The mixture was filtered through a 0.2 μπι filter and the filtrate · β β β · · β β β β β β

277 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · The prepared solution can be directly used for biological experiments (concentration approximately 200 mmol Gd / l).

Example 81

a) 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid, sodium salt g (38.3 mmol) of 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid (prepared as described in DE 196 03 033) was dissolved in 300 ml of ethanol and 7.7 ml of 5N aqueous sodium hydroxide was added. The mixture was evaporated to dryness and the residue was dried under vacuum (8 hours 60 ° C).

Yield: 20.85 g (quantitative) of anhydrous, crystalline powder.

Elementary analysis:

Calculated: C 26.49 H 1.11 F 59.35 Na 4.22

Found: C 26.60 H 1.19 F 59.47 Na 4.30

b) Preparation of the preparation of the title compound I and 3-0xa2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid, sodium salt

To 32 ml of a solution of metal complex I (280 mmol / l) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / l CaNa ₃ 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 at 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 2N 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 for biological experiments. (Concentration approximately 100 mmol Gd / L).

• fc fcfcfc · fcfc fcfc

I fcfc ·

I · · · fc fcfcfcfc

278 fc • fc • fc fcfcfcfc fcfc «fcfcfc

c) Production of a preparation of metal complex I and 3-0xa2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid, sodium salt

To 32 ml of a metal complex I solution (280 mmol / l) dissolved 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 at 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 2N 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 for biological experiments. (Concentration approximately 100 mmol Gd / L).

d) Preparation of the metal complex preparation I and 3-Oxa2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid, sodium salt

To 32 ml of a solution of metal complex I (280 mmol / l) dissolved 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 at 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 2N sodium hydroxide. The mixture was filtered through a 0.2 gm filter and the filtrate was filled into vials. The prepared solution can be directly used for biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 82 • 9 fcfcfcfc fc fcfc fcfc fcfc 9 9 9 9

279 ··· * ··· ’* ···· • fc9 ·· fcfcfcfc fc · fcfc

a) 1-Perfluorooctylsulfonyl-4- (3,6,9,12,15-pentaoxahexadecanoyl) -piperazine g (35.2 mmol) Perfluorooctylsulfonylpiperazine (see Example 80a) was dissolved in 300 mL of dichloromethane and 5.06 g ( 50 mmol) of triehylamine. The mixture was cooled to 0 ° C and 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 at 0 ° C for 3 hours. 400 ml of 5% aqueous hydrochloric acid 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 chromatographed on silica gel (eluent = dichloromethane / methanol: 15: 1).

Yield: 26.44 (92% of theory) of a waxy solid.

Elementary 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 the preparation of metal complex I and 1-perfluorooctylsulfonyl-4- (3,6,9,12,15-pentaoxahexadecanoyl) -piperazine

To 47 ml of the metal complex I solution (280 mmol / l) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / l CaNasDTPA) 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 at 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 2N sodium hydroxide. The mixture was filtered through a 0.2 µm filter and the filtrate was filled into vials. The prepared solution is possible directly • • • ·

280 used for biological experiments. (Concentration approximately 200 mmol Gd / L).

Example 83

a) p-toluenesulfonic acid 1 Η, Ι Η, 2H, 2H-Perfluordecyl ester g (43.1 mmol) of 1H, 1H, 2H, 2H-Perfluordecanol was dissolved in 200 ml of pyridine and 9 ° C was added portionwise at 0 ° C. 53 g (50 mmol) of p-toluenesulfonyl chloride. The mixture was stirred at room temperature for 5 hours. The solution was poured into 1000 ml of ice water and the mixture was 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.

Elementary 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) Ci8 ^- C ₂ 5 heptadecafluor-3, 6, 9,12,15-pentaoxo-pentakosan-l-ol g (37.94 mmol) of the title compound of Example 83a and 35.74 g (150 mmol) and pentaethylenglycolu 1 g of 18-crown-6 was dissolved in 300 ml of tetrahydrofuran and 10.1 g (180 mmol) of finely powdered potassium hydroxide was added. The mixture was stirred at room temperature for 10 hours. The solid was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: dichloromethane / methanol = 15: 1).

Yield: 5.45 g (21% of theory) of a colorless viscous oil.

Elementary analysis:

Calcd: C 35.10 H 3.68 F 47.19 • ·

281

Found: C 35.22 H 3.77 F 47.10

c) Preparation of the preparation of the title compound of Example 69 and C ₁₈ C 25 -heptadecafluoro-3,6,9,12,15-pentaoxa-pentacosan-1-ol

To 53 mL of a solution of the title compound of Example 69 (310 mmol) dissolved in 0.45% aqueous sodium chloride solution, 44.98 g (65.72 mmol) of the title compound of Example 83b was added and the mixture was heated under microwave for 10 minutes 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 for biological experiments. (Concentration approximately 310 mmol Gd / L).

Example 84

a) Ν, Ν-Bis (8-hydroxy-3,6-dioxa-octyl) perfluorooctylsulfonyl amide g (29.23 mmol) Perfluorooctylsulfonylamide and 22.16 g (87.7 mL) of 9- (tetrahydropyran-2-yl) -3,6,9-trioxanonyl chloride was dissolved in 200 mL acetonitrile. Potassium carbonate (41.46 g, 300 mmol) was added, and potassium iodide (1 g, 6 mmol) was added and the mixture was refluxed 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 10% aqueous hydrochloric acid was added. The mixture was stirred at room temperature for 2 hours. The pH was adjusted to 7 with sodium hydroxide and the solution was evaporated to dryness. The residue was chromatographed on silica gel (eluent: dichloromethane / methanol = 10: 1).

Yield: 1.38 g (51% of theory) of a colorless viscous oil.

Elementary analysis:

Calculated: C 31.46 H 3.43 N 1.83 F 42.30 S 4.20

282

Found: C 31.59 H 3.50 N 1.90 F 42.46 S 4.08

b) Preparation of the preparation of complex I and N, N-Bis (8-hydroxy-3,6, dioxa-octyl) -perfluorooctylsulfonylamide

To 37 ml of the metal complex I solution (280 mmol / l) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / l CaNasDTPA) was added 7.91 g (10.36 mmol). of the title compound 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 at 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 2N sodium hydroxide. The mixture was filtered through a 0.2 μπι filter and the filtrate was filled into vials. The prepared solution can be directly used for biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 85

a) N, N-Bis (tert-butyloxycarbonylmethyl) -perfluorooctylsulfonyl amide g (38.97 mmol) of Perfluorooctylsulfonylamide and 20.73 g (150 mol) of potassium carbonate were suspended in 200 ml of acetone and 17.56 g (90 ml) were added. mmol) of tert-butyl bromoacetate. The mixture was heated at reflux for 3 hours. The solid was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (Mobile phase: n-hexane / ethyl acetate = 10: 1).

Yield: 23.53 g (83% of theory) of a colorless waxy solid.

Elementary 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 • 999

283

9,999 * 999

99,999 99 9 ·

b) Ν, N-Bis (carboxymethyl) -perfluorooctylsulfonylamide, disodium salt

23g (31.62 mmol) of the title compound of Example 85a was dissolved in 300 mL of trifluoroacetic acid and stirred at room temperature for 5 hours. The mixture was evaporated to dryness and the residue was crystallized 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 3N aqueous sodium hydroxide solution was added. The mixture was stirred at room temperature for 20 minutes and was 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.

Elementary analysis:

Calculated: C 21.87 H 0.61 N 2.12 E 49.00 S 4.86 Na 6.98 Found: C 22.00 H 0.70 N 2.20 F 49.17 S 4.93 Na 7 , 10

c) Production of the preparation of metal complex II and N, Nbis (carboxymethyl) -perfluorooctylsulfonylamide, disodium salt

To 41 ml of the metal complex II solution (280 mmol / l) dissolved 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 at 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 2N sodium hydroxide. The mixture was filtered through a 0.2 gm filter and the filtrate was filled into vials. The prepared solution is possible directly •

284 used for biological experiments. (Concentration approximately 200 mmol Gd / L).

Example 86

a) 1 H, 1 H, 2 H, 2H-2-Perfluordodecyl monoester sulfuric acid sodium salt g (17.73 mmol) 1 H, 1 H, 2 H, 2 H -H 2 -fluorododecanol was dissolved in 300 ml chloroform and 2.82 g ( 17.73 mmol) of sulfur trioxide-pyridine complex. The mixture was stirred at 0 ° C for an hour 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 h).

Yield: 11.81 g (quantitative), Elemental analysis:

Calculated: C, 21.64; H, 0.61; F, 59.89 At 3.45 N 4.81 Found: C 21.70 H 0.72 F 60.00 At 3.57 N 4.92 (b) Production preparation of metal komplecu VI a 1 H, 1 H, 2H, 2H Sulfur perfluordodecyl monoester acids, sodium salts

To 38 ml of the metal complex VI solution (290 mmol / l) dissolved 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 86a and the mixture was heated in an ultrasonic bath for 10 minutes. The solution was cooled to room temperature and the mixture was filtered through a 0.2 μτη filter and the filtrate was filled into vials. The prepared solution can be directly used for biological experiments. (Concentration approximately 290 mmol Gd / L).

Example 87 • · • ·

285 • three * three * three * three * three * three

a) 2H, 2H, 4H, 4H, 5H, 5H-3-Oxa-perfluoropentadecanoic acid, sodium g- (16.07 mmol) 2H, 2H, 4H, 4H, 5H, 5H-3-Oxa-perfluoropentadecanoic 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 / 2h).

Yield: 10.35 g (quantitative) of a colorless amorphous powder. Elementary analysis:

C 26.10 H 0.94 F 61.94 Na 3.57

Found: C 26.22 H 1.00 F 62.05 Na 3.66

b) Preparation of the preparation of the title compound of Example 66 and 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluoropentadecanoic acid, sodium salt

To 45 mL of the title compound of Example 66 (270 mmol / l) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / l CaNaaDTPA) was added 3.36 g (5.21). mmol) of the title compound of Example 87a dissolved in 200 mL of ethanol and the mixture was heated at 50 ° C for 2 h. 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 and was filtered through a 0.2 µπ filter and the filtrate was filled into vials. The prepared solution can be directly used for biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 88

a) N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) mono-ethylenediamine-N, N-tetraacetic acid

To 30 g (117.1 mmol) of EDTA-Bisanhydride suspended in 200 ml of dimethylformamide and 50 ml of pyridine at 50 ° C was AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

• AAAA

AAA A A A A 10.14 g (20 mmol) of 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecylamine was added portionwise and the mixture was stirred at 50 ° C for 6 hours. Water (10 ml) was added, the mixture was stirred at 50 ° C for 10 minutes and evaporated to dryness. The residue was dissolved in a small amount of water and adjusted to 4 with acetic acid. The undissolved precipitate was filtered off and chromatographed on silica gel RP-18 (mobile phase: acetonitrile / water / gradient).

Yield: 9.58 g (61% of theory) of a colorless solid, water content: 8%

Elementary 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, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) monoamide ethylenediamine-N, N-tetraacetic acid, 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 was added. Then, 1.15 g (11.46 mmol) of calcium carbonate was added and the mixture was stirred at 50 ° C for 5 hours. The solution was filtered and the filtrate was evaporated to dryness. Yield: 9.7 g (100% of theory) of a colorless amorphous solid. Water content: 7.5%

Elementary 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 preparation of metal complex I and N (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) monoamide ethylenediamine-N, N-tetraacetic acid, calcium salt, sodium salt · Β •

287 · ti ti ti <<<<<<<<<<<<<<<<<

To 43 ml of the metal complex I solution (280 mmol / l) dissolved 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 at 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 2N 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 for biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 89

a) 1H, 1H, 2H, 2H-Perfluordecanol- (2,2-dimethyl-5-hydroxy-1,3-dioxepept-6-yl) ether g (64.64 mmol) of 1H, 1H, 2H, 2H-Perfluordecanol was dissolved in 200 ml of tetrahydrofuran and at 0 ° C was added 1.68 g (70 mmol) of sodium hydride. The mixture was stirred at room temperature for 2 hours and then at 60 ° C for 4 hours. 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. . The reaction solution was poured into ice water and was extracted twice with diethyl ether. The combined organic phases were evaporated to dryness and the residue was chromatographed on silica gel (mobile phase: dichloromethane / acetone = 10: 1).

Yield: 16.12 g (41% of theory) of a colorless solid.

Elementary analysis:

Calculated: C 33.57 H 2.82 F 53.10

Found: C 33.69 H 2.90 F 53.35 • · · · · · · · · ·

288 • · · · · · · · · · · · · · · · · · · ·

b) 1H, 1H, 2H, 2H-Perfluordecyl- (1-hydroxymethyl-2,3-dihydroxypropyl) -ether g (24.66 mmol) of the title compound of Example 89a was dissolved in 300 mL of ethanol and 30 mL of 10% was added aqueous hydrochloric acid. The mixture was heated under reflux for 5 hours. The pH was adjusted to 7 with sodium hydroxide, then evaporated to dryness and chromatographed 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%

Elementary analysis:

Calculated: C 29.59 H 2.31 F 56.84

Found: C 29.48 H 2.37 F 56.99

c) Preparation of the preparation of the title compound of Example 12 of WO

99/01161 (1,4,7-Tris {1,4,7-tris (N-carboxylatomethyl) -10- (N-1-methyl-3-aza-2,5-dioxo-pentane-1,5-) diyl] -1,4,7,10-tetraazacyclododecane, Gd-Complex} -10- [2- (N-ethyl-N-perfluorooctylsulfonyl) -amino] -acetyl-1,4,7,10-tetraazacyclododecane) and

1H, 1H, 2H, 2H-Perfluordecyl- (1-hydroxymethyl-2,3-dihydroxypropyl) ether

To 37 ml 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-solution 7,10-tetraazacyclododecane, Gd complex} -10- [2- (N-N-perfluorooctylsulfonyl) -amino] -acetyl-1,4,7,10-tetraazacyclododecane (300 mmol / l) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / L)

9.46 g (16.65 mmol) of the title compound of Example 89b was added and the mixture was made up to a total volume of 111 mL with 0.9% aqueous sodium chloride solution.

• «· ·

289

The mixture was heated at 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 2N 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 for biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 90

a) 1H, 1H, 2H, 2H-Perfluordecyl- [1,2-bis (2,2-dimethyl-1,3-dioxolan-4-yl) -2-hydroxyethyl] -ether g (64.64 mmol) 1H, 1H The 2H, 2H-Perfluordecanol 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 at room temperature for 2 hours and then at 60 ° C for 4 hours. The solution was placed in a metal autoclave, and 15.78 g (64.64 mmol) of 1,2-bis- (2,2-dimethyl-1,3-dioxolan-4-yl) -oxirane was added and the reaction was heated to temperature 150 ° C. The reaction mixture was poured into ice water and was extracted twice with diethyl ether. The combined organic phases were evaporated in vacuo to dryness and the residue was chromatographed on silica gel (Mobile phase: dichloromethane / Acetone = 10: 1)

Yield: 14.2 g (31% of theory) of a colorless solid.

Elementary analysis:

H, 3.56; F, 45.59

Found: C, 37.48; H, 3.66; F, 45.71

b) 1H, 1H, 2H, 2H-Perfluordecyl- [1,2-bis (1,2-dihydroxy-ethyl) -2-hydroxy-ethyl] -ether g (19.76 mmol) of the title compound of Example 90a was dissolved in 300 ml of ethanol and 30 ml of 10% aqueous φ * · · ····

290 hydrochloric acid. The mixture was heated under reflux for 5 hours. The pH was adjusted to 7 with sodium hydroxide, the reaction mixture was evaporated to dryness and chromatographed on RP-18 silica gel (mobile phase: acetonitrile / water / gradient).

Yield: 10.55 g (85% of theory) of a colorless solid.

Water content: 3.2%

Elementary analysis:

H, 2.73; F, 51.41

Found: C 30.73 H 2.81 F 51.58

c) Preparation of the metal complements II and 1H, 1H, 2H, 2Hperfluordecyl [1,2-bis (1,2-dihydroxyethyl) -2-hydroxyethyl] ether

To 41 ml of the metal complex II solution (300 mmol / l) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / l CaNa ₃ DTPA) 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 at 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 2N 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 for biological experiments. (Concentration approximately 200 mmol Gd / 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 was added at 0 ° C. The mixture was stirred for one 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 h). Yield: 17.15 g (quantitative)

Calculated: C 24.83 H 2.50 F 33.83 N 1.45 S 9.94 Na 4.75 Found: C 24.96 H 2.62 F 33.97 N 1.53 S 10.05 Na 4 , 86

b) Production of a preparation of 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) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / l CaNa ₃ DTPA) was added. 142.29 g (147.06 mmol) of the title compound of Example 91a were added and the mixture was made up to a total volume of 164 mL with 0.9% aqueous sodium chloride solution. The mixture was heated at 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 2N 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 for biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 92

a) 2- (2H, 2H, 3H, 3H, 3H, 5.5H, 6H, 6H-1,4, -dioxaperfluorotetradec-1-yl) -succinic acid diethyl ester

292 g (59.03 mmol) of 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanol was dissolved in 300 ml of tetrahydrofuran and 1.68 g (70 mmol) of hydride was added at 0 ° C. sodium. The mixture was stirred at 0 ° C for 1 hour and then at 40 ° C for 5 hours. 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 chromatographed on silica gel (Mobile phase: n-hexane / ethanol = 20: 1).

Yield: 12.05 g (30% of theory)

Elementary analysis:

H, 3.11; F, 47.47

Found: C 35.19 H 3.20 F 47.59

b) 2- (2H, 2H, 3H, 3H, 5H, 5H, 6H, 6H-1,4-dioxa-perfluorotetradec-1-yl) succinic acid, disodium salt

To 11.5 g (16.90 mmol) of the title compound of Example 92a dissolved in 300 mL of methanol was added 50 mL of 3N aqueous sodium hydroxide solution and the mixture was refluxed 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 with hydrochloric acid to pH 1 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 adjusted to pH 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.

·· ····

293

Water content: 5.7%

Elementary analysis:

Calculated: C 28.76 H 1.66 F 48.33 Na 6.88

Found: C 28.88 H 1.71 F 48.25 Na 6.95

c) Preparation of a preparation of metal complex II and 2- (2H, 2H, 3H, 3H, 5H, 5H, 6H, 6H-1,4-dioxa-perfluorotetradec-1-yl} -j antaric acid, disodium salt

To 57 ml of the metal complex II solution (300 mmol / l) dissolved 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 at 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 2N sodium hydroxide. The mixture was filtered through a 0.2 μπι filter and the filtrate was filled into vials. The prepared solution can be directly used for biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 93

(a) 2H, 2H, 4H, 4H, 5H, 5H-3-Oxa-perfluorotridecanoic acid N- (succin-2-yl) -amide

To 20 g (38.30 mmol) of perfluorotridecanoic acid and hydroxysuccinimide dissolved in 150 ml of dimethylformamide was added 16.51 g (80 mmol) of N, N-dicyclohexylcarbodiimide at 0 ° C and stirred at this temperature for 3 hours. To this active ester solution was added a cooled solution of 5.10 g (38.30 mmol) of L-aspartic acid dissolved in 300 mL of 5% aqueous carbonate solution to 0 ° C.

2H, 2H, 4H, 4H, 5H, 5H-3-oxa9.21 g (80 mmol) N ·· 44 4 · ·· 4444

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 1N 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.

Elementary 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 Na 6.83

b) Preparation of the preparation of the title compound XIV and N- (succin-2-yl) -amide 2H, 2H, 4H, 4H, 5H, 5H-3-Oxa-pertluorotridecanoic acid

To 37 mL of the metal complex XIV solution (300 mmol / L) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / L CaNasDTPA) was added 422 mg (0.62 mmol) of the title compound. of the compound 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 at 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 2N sodium hydroxide. The mixture was filtered through a 0.2 μπι filter and the filtrate was filled into vials. The prepared solution can be directly used for biological experiments. (Concentration approximately 100 mmol Gd / L).

····

295 • ·

9

> I ··

Example 94

Preparation of the title compound of Example 67 and perfluoroacetanesulfonic acid, sodium salt

To 43 mL of a solution of the title compound of Example 67 (250 mmol / L) dissolved 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 perfluorooctanesulfonic acid, sodium salt, dissolved in 200 ml of ethanol, and the mixture was stirred at 50 ° C for 2 hours. 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 at 40 ° C for 10 minutes and filtered through a 0.2 µπ filter and the filtrate was filled into vials. The prepared solution can be directly used for biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 95

Preparation of the title compound of Example 68 and Perfluordecanesulfonic acid, sodium salt

To 49 mL of a solution of the title compound of Example 68 (310 mmol) dissolved in 0.45% aqueous sodium chloride solution was added 3.03 g (5.06 mmol) of perfluordecanesulfonic acid, sodium salt, and the mixture was heated under microwave for 10 min. . 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 for biological experiments. (Concentration approximately 310 mmol Gd / L).

Example 96

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

· 9 9

9 9 9

296

9 9

9999

To 20 g (80.62 mmol) of the 5-hydroxy-isophthalic 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 at 60 ° C for 10 hours. 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 pH 7.4 by addition of 1N sodium hydroxide. 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%

Elementary analysis:

Calculated: C 32.16 H 1.05 F 48.05 Na 6.84

Found: C 32.30 H 1.15 F 48.20 Na 6.95

b) Preparation of the preparation of the title compound of Example 12 of WO 99/01161 (1,4,7-Tris {1,4,7-tris (N-carboxylatomethyl) -10- (N-1-methyl-3-aza-) 2,5-dioxo-pentane-1,5-diyl] -1,4,7,10tetraazacyclododecane, Gd-Complex] -10- [2- (N-ethyl-N-fluorooctylsulfonyl) -amino] -acetyl-1,4, 7,10tetraazacyclododecane) and (1H, 1H, 2H, 2H-perfluordecyl) -5 - [(1,3-dicarboxy, disodium salt) -phenyl] -ether

To 51 ml of a solution of 1,4,7-tris {1,4,7-tris (N-carboxylatomethyl) -10- (N1-methyl-3-aza-2,5-dioxopentane-1,5-diyl) 1,4,7,10-tetraazacyclododecane, Gd complex) -10- [2- (N-ethyl-Nperfluorooctylsulfonyl) -amino] -acetyl-1,4,7,10-tetraazacyclododecane (300 mmol / l), dissolved in 0 , 45% aq. • 6

·· ·

297 of sodium chloride solution (pH 7.4; 0.25 mg / l CaNa ₃ DTPA), 6.86 g (10.2 mmol) of the title compound of Example 96a was added and the mixture was treated with 0.9% aqueous sodium chloride solution added to a total of 153 ml. The mixture was heated at 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 2N 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 for biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 97

Production of the preparation of metal complex XIV and 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid, sodium salt

To 4 ml of the metal complex XIV solution (320 mmol / l) dissolved 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 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 at 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 2N 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 for biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 98

(a) (Adamant-1-yl) -3-oxa-propionic acid tert-butyl ester To 15.22 g (100 mmol) of 1-adamantanol in 300 ml of 50% aqueous potassium hydroxide solution, 200 ml of toluene at 0 ° C added to 29.26 g (150 mmol) of tert. of butyl bromoacetate and the mixture was stirred vigorously for 2 hours. The reaction 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 chromatographed on silica gel (mobile phase: n-hexane / diethyl ether 20: 1).

Yield: 21.58 g (81% of theory) of a viscous, colorless oil.

Elementary analysis:

H, 9.95. Found: C, 72.26; H, 9.95

b) (Adamant-1-yl) -3-oxa-propionic acid g (75 mmol) of the title compound of Example 98a was dissolved in 200 ml of trifluoroacetic acid at 0 ° C and the mixture was stirred at room temperature for 8 hours. The reaction was evaporated to dryness and the residue was crystallized from diisopropyl ether. Yield: 14.68 g (93% of theory) of colorless platelet-like crystals.

Elementary analysis:

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-perfluorooctylsulfonylpiperazine was dissolved in 300 mL of tetrahydrofuran and 32.15 g (130 mmol) of 1,2-dihydro-2-ethoxyquinoline-1-carboxylic acid ethyl ester (EEDQ) was added at 0 ° C. The mixture was stirred at room temperature for 5 hours. The solution was evaporated

299

Dry to dryness under reduced pressure and the residue was chromatographed on silica gel (mobile phase: dichloromethane / diethyl ether = 30: 1). Yield: 43.05 g (85% of theory) of a colorless solid.

Elementary 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 a preparation of 0.5 parts of metal complex I and 0.5 parts of cyclodextrin-hydrate clathrate and 1- (perfluorooctylsulfonyl) 4 - [(adamant-1-yl) -oxapropionyl] -piperazine

To 32 ml of a metal complex I solution (280 mmol / l) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / l CaNaaDTPA) was added 6.81 g (8.96 mmol). of the title compound of Example 98c from 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 at 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 2N 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 for biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 99

(a) 3-Oxa-2H, 2H, 4H, 4H, 5H, 5Hperfluorotridecanoic acid N- (1-adamantyl) -amide

To 15.12 g (100 mmol) of 1-Aminoadamantane, 52.21 (100 mmol) of 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-Perfluorotridecanoic acid and 11.51 g (100 mmol) of N-hydroxysuccinimide dissolved in 300 mL of tetrahydrofuran at 0 ° C was added 30.95 g (150 mmol) of N, N-dicyclohexylcarbodiimide. The mixture was stirred for 2 hours

300

at 0 ° C and then at room temperature for 6 hours.

The precipitated urea was filtered off, the filtrate was evaporated to dryness and the residue was chromatographed on silica gel (mobile phase: dichloromethane / acetone = 30: 1). Yield: 54.4 g (83% of theory) of a waxy solid.

Elementary analysis:

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 the preparation of 0.6 parts of metal complex II and 0.4 parts of cyclodextrin hydrate clathrate and 3oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid N- (1-adamantyl) -amide

To 41 ml of the metal complex II solution (250 mmol / l) dissolved 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 at 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 2N 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 for biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 100

a) 2- [N- (Ethyl) -N- (perfluorooctylsulfonyl) amino] -acetic acid N- (adamantyl) amide

To 15.12 g (100 mmol) of 1-aminoadamantane, 58.52 g (100 mmol) of N- (ethyl) -N- (perfluorooctylsulfonyl) aminoacetic acid and 11.51 g (100 mmol) of N-hydroxysuccinimide,

301

dissolved in 300 mL of tetrahydrofuran at 0 ° C was added 30.95 g (150 mmol) of N, N-dicyclohexylcarbodiimide. The mixture was stirred at 0 ° C for 2 hours and then at room temperature for 6 hours. The precipitated urea was filtered off, the filtrate was evaporated to dryness and the residue was chromatographed on silica gel (mobile phase: dichloromethane / acetone = 30: 1).

Yield: 55.65 g (79% of theory) of an amorphous solid.

Elementary 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 the preparation of 0.6 parts of metal complex I and 0.4 parts of clathrate of N- (1-adamantyl) -amide β-cyclodextrin hydrate and 2 [N- (ethyl) -N- (perfluorooctylsulfonyl) -amino] -acetic acids.

To 32 mL of metal complex I solution (280 mmol / L) dissolved 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) and 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 at 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 2N 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 for biological experiments. (Concentration approximately 100 mmol Gd / L).

Example 101 • · · ·

• · · ·

302 • · · 4 · · · · · ·

a) 6-N-a) 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 triehylamine dissolved in 350 mL of dichloromethane was added dropwise a solution of 16.85 g (70 mmol) 3.6 at 0 ° C. 9,12-tetraoxatridecanoyl chloride in 50 ml of dichloromethane and the mixture was stirred at 0 ^° C for 3 hours. 200 ml of 5% aqueous hydrochloric acid was added and the mixture was stirred at room temperature for 5 minutes. The organic phase was separated, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1). Yield: 30.94 g (92% of theory) of a colorless solid oil.

Elementary 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) was 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.

Elementary 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

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 *

303

99 9 (3,6,9,12-tetraoxatridecanoyl) -lysine- [1- (4-perfluorooctylsulfonyl} -piperazine] -amide, Gd-complex

21.84 (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 15.27g (24.25 mmol) of 1,4,7-tris (carboxylatomethyl) -10 - [(3 -aza-4-oxo-5-methyl-5-yl)] - pentanoic acid] -1,4,7,10-tetraazacyclododecane, The Gd complex was dissolved in 200 mL of dimethyl sulfoxide with slight heating. At 10 ° C, 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide was added 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 silica gel chromatography (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 triehylamine dissolved in 250 mL of dry tetrahydrofuran was added dropwise a solution of 7.33 g (60 mol) of propanesultone in 50 mL at 50 ° C. 50 ml of tetrahydrofuran and the mixture was stirred at 60 ° C for 3 hours. 200 ml of 5% aqueous hydrochloric acid solution was added and the mixture was stirred at room temperature for 5 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated in vacuo to

304::

• ·· · · »·· drought. The residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1)

Yield: 45.16 g (79% of theory) of a colorless solid oil.

Elementary 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-perfluorooctlsulfonyl) piperazine] -amide

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) 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: 42.69 g (quantitative) of a colorless solid. Elementary analysis:

Calculated: C 30.81 H 3.32 F 39.46 N 6.84 S 7.83

Found: C 30.64 H 4.1 F 39.29 N 6.68 S 7.89

c) 6-N- [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-pertluorooctylsulfonylpiperazine) -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 15.27g (24.25 mmol) of 1,4,7-tris (carboxylatomethyl) -10 - [(3 -aza-4-oxo-5-methyl-5-yl)] pentanoic acid] -1,4,7,10-tetraazacyclododecane, The Gd complex was dissolved in 200 mL of dimethyl sulfoxide with slight heating. 8.25 g (40 mmol) of N, N-dicycohexylcarbodiimide was added at 10 ° C and the mixture was then stirred.

305

0 · 0 · · 0 «0 · 00 0000 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 silica gel chromatography (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 acid) -lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide To 50 g (60.20 mmol) of the title compound from Example 1c and 12.14 g (120 mmol) of triehylamine dissolved in 250 ml of dry tetrahydrofuran were added at 50 ° C a solution of 14.65 g (120 mmol) of 1,3-propanesultone in 100 ml of tetrahydrofuran and the mixture was stirred for 3 hours. 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 chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1). Yield: 52.24 g (81% of theory) of a colorless and solid oil.

Elementary analysis:

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-sulphonic acid) -lysine- [1- (4-perfluorooctylsulphonyl) piperazine] -amide; and ·········· · · · And «

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 (14% 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. Elementary 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, Nbis (propyl-3-sulfonic acid) -lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd complex, disodium salt

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 15.27g (24.25 mmol) of 1,4,7-tris (carboxylatomethyl) -10 - [(3 -aza-4-oxo-5-methyl-5-yl)] - pentanoic acid] -1,4,7,10-tetraazacyclododecane, Gd complex was dissolved in 200 mL of dimethyl sulfoxide with slight heating. At 10 ° C, 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide was 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 precipitated solid was filtered off and purified by silica gel chromatography (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 · · ···

307

Found: C 31.94 H 3.48 F 20.19 N 7.69 S 5.85 Gd 9.87 Na 2, 99

Example 104

(a) Ν-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 trifluracetic acid ethyl ester and 500 ml of ethanol, and the mixture was stirred at room temperature for 24 hours. The reaction was evaporated to dryness under reduced pressure and the residue was crystallized from diisopropyl ether. Yield: 140.47 g (96% of theory) of a colorless crystalline powder.

Elementary 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-Nbis (2-hydroxyethyl) -amide

To a solution of 24.9 g (24.08 mmol) of the title compound of Example 104a, 2.53 g (24.08 mmol) of diethanolamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide dissolved in 150 ml of dimethylformamide, N, N-dicyclohexylcabodiimide (8.25 g, 40 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C for 3 hours, and then stirred overnight at room temperature. The precipitated urea precipitate was filtered off, the filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed on silica gel (mobile phase: dichloromethane / ethanol = 20: 1).

Yield: 9.11 g (90% of theory) of a solid oil. Elementary 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 · · · φ φ 4 4 4 «« 4 · · · · »· · · ·

c) N-Trifluoroacetyl-L-glutamic acid-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) was 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.

Elementary analysis:

H, 5.19; F, 17.26; N, 8.48

Found: C 39.84 H 5.13 F 17.09 N 8.68

c) Trifluoroacetyl-L-glutamic acid-N-bis (2-hydroxyethylamide-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

To 10.96g (33.2 mmol) of the title compound of Example 104a and 18.87g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (prepared by DE 19603033) in 80 mL of tetrahydrofuran was added 16 at 0 ° C. 42 g (66.4 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 and chromatographed on silica gel (mobile phase: dichloromethane / methanol = 20: 1). Yield: 30.93 g (93% of theory) of a colorless solid.

Elementary 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) L-Glutaminic acid-N-bis (2-hydroxyethyl) amide-5- [1- (4-fluoroctylsulfonyl) -piperazine] ············

To a solution of the amide in 200 mL of ethanol, ammonia gas was introduced at 0 ° C for 1 hour. The mixture was then stirred at 0 ° C for 4 hours. The mixture was evaporated to

drought under reduced pressure and the residue was mixed with water. Graphite the substance was filtered and dried to dryness under vacuum (50 ° C). Yield: 26.55 g (97% theoretical amount) amorphous rigid substances. Elementary 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-bis (2-hydroxyethylamide-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 15.27g (24.25 mmol) 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl)] pentanoic acid] -1,4,7,10-tetraazacyclododecane, Gd complex was dissolved in 200 ml of dimethylsulfoxide with slight heating. At 10 ° C, 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide was 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 precipitated solid was filtered off and purified by chromatography (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 • φ φφφφ

310

Example 105

a) N-Trifluoroacetyl-L-glutamine dimethyl-bis (1,1-dihydroxymethyl) amide

To a solution of 8.03g (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 (24.08 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide, were at 0 ° C. 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide was added. The mixture was stirred at 0 ° C for 3 hours and then at room temperature overnight. The precipitated urea precipitate was filtered off with suction, the filtrate was evaporated to dryness in vacuo and the residue was chromatographed on silica gel (mobile phase: dichloromethane / ethanol = 20: 1). Yield: 110.53 g (91% of theory) of a solid oil.

Elementary analysis:

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) was 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. Elementary analysis:

H, 5.42; F, 14.60; N, 7.18

Found: C 40.10 H 5.53 F 14.69 N 7.28-5-benzyl ester-N

311 fc

c) N-Trifluoroacetyl-L-glutamic acid-N-dimethylbis (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 DE 19603033) in 800 mL of tetrahydrofuran was at 16 ° C. 42 g (66.4 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 mixture was evaporated to dryness in vacuo and chromatographed on silica gel (mobile phase: dichloromethane / methanol = 20: 1). Yield: 28.42 g (91% of theory) of a colorless solid.

Elementary 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) L-Glutamic acid-N- [dimethyl-bis (1,1-dihydroxymethyl)] - amide-5 - ((1-4-pertluorooctylsulfonyl) -piperazine] -amide

To a solution of 28.41 g (30.2 mmol) of the title compound of Example 105c in 200 mL of ethanol, ammonia gas was introduced at 0 ° C for one hour. The mixture was then stirred at 0 ° C for 4 hours. The mixture was evaporated to dryness under reduced pressure and the residue was stirred with water. The solid was dried under vacuum (50 ° C).

Yield: 24.74 g (97% of theory) of an amorphous solid.

Elementary analysis:

Calculated: C 32.71 H 3.46 F 38.24 N 6.63 S 3.80

Found: C 32.75 H 3.33 F 38.38 N 6.68 S 3.81 ti tititi

312 • ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti

e) 2-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -Lglutamic acid-N- [dimethyl-bis (1,1-dihydroxymethyl) amide] -5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gdcomplex

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 15.27g (24.25 mmol) of 1 4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl)] pentanoic acid] -1,4,7,10-tetraazacyclododecane, the G-complex was under slight heating dissolved in 200 mL of dimethylsulfoxide. At 10 ° C, 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide was 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 precipitated solid was filtered off and was purified by silica gel chromatography (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 compound) 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 mmol) of 1-perfluorooctylsulfonyl-piperazine (prepared according to DE 19603033) in 80 ml of tetrahydrofuran were at 16 ° C. 42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and a mixture of fcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcff fcfcfcfc

313 fc fc fc was stirred overnight at room temperature. The reaction was evaporated to dryness under reduced pressure and the residue was chromatographed on silica gel (Mobile phase: dichloromethane / methanol = 20: 1)

Yield: 27.28 g (93% of theory) of a colorless solid.

Elementary 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-fluorooctylsulfonyl) 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 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 under vacuum. Yield: 41, 37 g (quantitative) colorless solids Elementary analysis: Calculated: C 28.76 Η 1.91 F 47.89 N 5.30 WITH 4.04 Found: C 28.84 H 2.03 F 47.79 N 5.28 WITH 4.19

c) N-Trifluoroacetyl-L-glutamic acid-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 dissolved in 150 ml of dimethylformamide, N, N-dicyclohexylcarbodiimide (8.25 g, 40 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C for 3 hours and then at room temperature overnight. The precipitated urea was filtered off, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by titi-titi. Titi-titi. Titi-titi. Titi-titi-titi

314 by chromatography on silica gel (mobile phase: = dichloromethane / ethanol = 20: 1).

Yield: 9.11 g (90% of theory) of a solid oil. Elementary analysis:

Calculated: C 31.37 H 2.75 F 43.15 N 6.36 S 3.64

Found: C 31.22 H 2.61 F 43.30 N 6.25 S 3.81

d) L-Glutaminic acid-N-bis (2-hydroxyethyl) amide-5- [1- (4-pertluorooctylsulfonyl) piperazine] amide

To a solution of 26.61 g (30.22 mmol) of the title compound of Example 106c in 200 mL of ethanol, ammonia gas was added at 0 ° C for one hour. The mixture was stirred at 0 ° C for 4 hours. The reaction mixture was evaporated to dryness under reduced pressure and the residue was stirred with water. The solid was filtered off and the filtrate was dried under vacuum (50 ° C). Yield: 23.93 g (97% of theory) of an amorphous solid.

Elementary 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)] - Lglutamine N-bis (2-hydroxyethyl) -amide-5- [1- (4-fluorooctylsulfonyl) -piperazine] -amide, Gd complex

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 15.27g (24.25 mmol) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl)] pentanoic acid] -1,4,7,10-tetraazacyclododecane, Gd complex was weak heating dissolved in 200 mL dimethylsulfoxide. 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide were added at 10 ° C and the mixture was then stirred

315 ··· ···················· It is this overnight at room temperature. The solution was poured into 3000 mL of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by silica gel chromatography (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 compound) 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-glutamic acid-5-benzyl ester- [1- (4-Fluoro-octylsulfonyl) -piperazine] -amide

To 11.06g (33.2 mmol) of the title compound of Example 104a and 18.87g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (prepared according to DE 19603033) in 80 mL of tetrahydrofuran was added 16 at 0 ° C. 42 g (66.4 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 and chromatographed on silica gel (Mobile phase: dichloromethane / methanol = 20: 1)

Yield: 27.28 g (93% of theory) of a colorless solid.

Elementary 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 9999

316 i: · ·

21.92 g (52.15 mmol) of the title compound of Example 107a was dissolved in 500 ml of ethanol and 3 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: 41.37 g (quantitative) of a colorless solid. Elementary 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

a) 6-N-Benzyloxycarbonyl-2-N- (2,3,4,5-pentahydroxy-hexanoyl) -L-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

To a solution of 100.0 g (120.4 mol) 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 mol) of 5-gluconolactone in 50 mL of tetrahydrofuran. The mixture was stirred at 60 ° C for 3 hours and then stirred at room temperature. The reaction was evaporated to dryness under reduced pressure and the residue was chromatographed on silica gel.

(Mobile phase: dichloromethane / ethanol = 20: 1). Yield: 98.37 g (82% of theory) of a solid oil.

Elementary analysis:

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-pentahydroxy-hexanoyl) -L-lysine-1 - [(4-fluorooctylsulfonyl) 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 at room temperature for about 4 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

Yield: 87.46 g (quantitative) of a colorless solid.

Elementary 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-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 2-N [1-O-α-D-carbonylmethyl-mannopyranose] -L-lysine- [1- (4-fluorooctylsulfonyl) -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 mol) of lithium chloride and 34.35 g (54.55 mol) of 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methylpent-5-yl) -1,4,7,10-tetraazacyclododecane, Gd complex, was dissolved in 400 ml of dimethylsulfoxide with slight heating. At 10 ° C, 16.88 g (81.8 mol) of N, N-dicyclohexylcarbodiimide was 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 silica gel chromatography (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 • φ ·· · ♦ ·· φφφφ

320 • «· ·· ·

a) 6-N-Benzyloxycarbonyl-2-N- (2,3,4,5-pentahydroxy-hexanoyl) -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 triehylamine in 500 mL of dry tetrahydrofuran was added a solution of 21.45 g (120 mL) at 50 ° C. (4 mol) of 5-gluconolactone in 50 ml of tetrahydrofuran. The mixture was stirred at 60 ° C for 3 hours and then stirred at room temperature overnight. Then 400 ml of 5% aqueous hydrochloric acid was added and the mixture was stirred at room temperature for 5 minutes. Sodium chloride was added, the organic phase was separated, the organic phase was dried over magnesium sulphate and evaporated to dryness under reduced pressure, and the residue was chromatographed on silica gel.

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

Yield: 100.97 g (82% of theory) of a solid oil. Elementary analysis:

Calculated: C 37.58 H 3.45 F 31.58 N 5.48 S 3.14

Found: C 37.72 H 3.5 9 F 31.72 N 5.42 S 3.29

b) 2-N- (2,3,4,5-pentahydroxy-hexanoyl) -L-lysine-1 - [(4-fluorooctylsulfonyl) -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 at room temperature for 12 hours. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure.

Yield: 87.46 g (quantitative) of a colorless solid.

Elementary 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

319 φφ · φφφ

ΦΦ »» »» »» »» »» »» »» »· · · · · · · · · · · ·

c) 6-Ν- [1,4,7-Tris (carboxylatomethyl)] - 1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl) -2-N [1-O-α-D-carbonylmethyl-mannopyranose] -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 mol) of lithium chloride and 34.35 g (54.55 mol) of 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methylpent-5-yl) -1,4,7,10-tetraazacyclododecane, Gd complex, was dissolved in 400 ml of dimethylsulfoxide with slight heating. At 10 ° C, 16.88 g (81.8 mol) of N, N-dicyclohexylcarbodiimide was 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 precipitated solid was filtered off and was purified by silica gel chromatography (RP18 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 110

(a) 6-N-Benzyloxycarbonyl-2-N- [1-Oa-D-carbonylmethyl (2,3,4,6-tetra-O-benzyl-glucopyranose) -L-lysine- [1- (4-fluorooctylsulfonyl) -piperazine] - amid

To a solution of 100.0 g (120.4 mol) of the title compound of Example 21c), 72.1 g (120.4 mol) of 1-OaD-carboxymethyl-2,3,4,6-tetra-O-benzyl-glucopyranose and 13 86 g (120.4 mol) of N-hydroxysuccinimide, dissolved in 500 ml of dimethylformamide, were added at 0 ° C 41.27g (200.0 mmol) of N, N-dicyclohexylcarbodiimide. The mixture was stirred for 3 hours at tt 9999

9 9 9 9 9

9 9 9 9 ₉

320 999 ° C and then stirred overnight at room temperature. The precipitate was filtered off, the filtrate was evaporated to dryness in vacuo and the residue was chromatographed on silica gel. (Mobile phase: dichloromethane / ethanol = 20: 1). Yield: 136.1 g (87% of theory) of a solid oil. Elementary 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-cis-D-Carbonylmethylglucopyranose] -L-lysine-1 - [(4-fluoroctylsulfonyl) 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 at room temperature for 12 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

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

Elementary 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-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 2-N [1-Oa-D-carbonylmethyl-glucopyranose] -L-lysine- [1- (4-fluorooctylsulfonyl) -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 mol) of lithium chloride and 34.35 g (54.55 mol) of 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methyl-pent-5-yl) -1,4,7,10-tetraazacyclododecane, Gd complex, was dissolved in 400 ml of dimethylsulfoxide with slight heating. 16.88 g (81.8 mol) of N, N were added at 10 ° C.

321

4 4

9

99

9 9 9 4 4 8

9 4

9 4 4 4 4 5

. 9 4 9 4 9 4

4449 49 49 dicyclohexylcarbodiimide and the mixture was stirred overnight at room temperature. The solution was poured into 3000 mL of acetone and stirred for 10 minutes. The precipitated solid was filtered off and was purified by silica gel chromatography (RP18, 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 compound): Calculated: C 35.34 H 4.09 N 8.24 S 2.10 F 21.12 Gd 10.28 Found: C 35.26 H 4.18 N 8.14 S 2.158 F 21.01 Gd 10.13

Example 111

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

To a solution of 50.0 g (60.2 mol) 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 dissolved in 500 ml of dimethylformamide were added at 0 ° C 20.64 g (100.0 mmol) of N, N-dicyclohexylcarbodiimide. The mixture was stirred at 0 ° C for 3 hours and stirred at room temperature overnight. The precipitate was filtered off, the filtrate was evaporated to dryness and chromatographed on silica gel. (Mobile phase: dichloromethane / ethanol = 20: 1).

Yield: 68.1 g (87% of theory) of a high solid oil.

Elementary 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 • · · · · · · · · · · ·

322 *

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

65.0 g of 50.0 mmol) of the title compound of Example IIIa) was dissolved in 1000 ml of ethanol and 5.0 g of palladium catalyst (10% Pd / C) was added. The mixture was hydrogenated at room temperature for 12 hours. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure.

Yield: 45.85 g (quantitative) of anhydrous solid.

Elementary 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-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 2-Ntl-O-α-D-carbonylmethyl-galactopyranose] -L-lysine- [1- (4-fluorooctylsulfonyl) -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 mol) of lithium chloride and 34.35 g (54.55 mol) of 1,4,7-tris (carboxylatomethyl-10- ( carboxy-3-aza-4-oxo-5-methylpent-5-yl) -1,4,7,10-tetraazacyclododecane, Gd complex, was dissolved in 400 ml of dimethylsulfoxide under gentle heating, at 10 ° C. 16.88 g (81.8 mol) of N, N-dicyclohexylcarbodiimide was stirred overnight at room temperature, the solution was poured into 3000 ml of acetone and stirred for 10 minutes, and the precipitated solid was filtered off and purified by chromatography on Silica gel (RP-18 Mobile phase: Water / ethanol / acetonitrile gradient).

Yield: 37.95 g (91.0% of theory) of a colorless solid. Water content: 8.6%.

Elemental analysis (calculated on dry compound):

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 L-Glutamic acid monobenzyl ester 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 mixture was evaporated to dryness under reduced pressure and the residue was crystallized from diisopropyl ether.

Yield: 140.47 g (96% of theory) of a colorless crystalline powder.

Elementary 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) 5-N- (methyl) -N- (2,3,4,5,6-pentahydroxyhexyl) -amide 2-N-Trifluoroacetyl-L-glutamic acid monobenzyl ester 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, dissolved in 150 ml of dimethylformamide, were added at 0 ° C 8.25 g ( 40 mmol) of N, N-dicyclohexylcabodiimide. The mixture was stirred at 0 ° C for 3 hours, stirred at room temperature overnight. The precipitate was filtered off, the filtrate was evaporated to dryness in vacuo and the residue was purified by silica gel chromatography (mobile phase: = dichloromethane / ethanol = 20: 1). Yield: 9.1 g (89% of theory) of a solid oil. Elementary 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 • · • · · tt ·

324

c) N-Trifluoroacetyl-L-glutamic acid N- (methyl) -N- (2,3,4,5,6-pentahydroxyhexyl) -amide

21.9xxg (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) 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.

Elementary analysis:

H, 5.19; F, 17.26; N, 8.48

Found: C 39.84 H 5.13 F 17.09 N 8.68

d) Trifluoroacetyl-L-glutamic acid-5-N- (methyl) -N (2,3,4,5,6-pentahydroxyhexyl) -amide- [1- (4-perfluorooctylsulfonyl) -piperazine) -amidepiperazine) -amide

To 10.96 g (33.2 mmol) of the title compound of Example 112c and 18.87 g (33.2 mmol) of 1-pertluorooctylsulfonyl-piperazine (prepared according to DE 19603033) in 80 ml of tetrahydrofuran were at 0 ° C. 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) was added and the mixture was stirred overnight at room temperature. The mixture was evaporated to dryness under reduced pressure and chromatographed on silica gel (Mobile phase: dichloromethane / methanol = 20: 1). Yield: 28.67 g (92% of theory) of a colorless solid.

Elementary 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) L-Glutamic acid-5-N- (methyl) -N- (2,3,4,5,6-pentahydroxyhexyl) -amide- (1- (4-perfluorooctylsulfonyl) -piperazine) amide · • ·

325

To a solution of 28.36 g (30.22 mmol) of the title compound of Example 112d in 200 mL of ethanol, ammonia gas was introduced at 0 ° C for 1 hour. The mixture was then stirred at 0 ° C for 4 hours. The reaction mixture was evaporated to dryness and the residue was stirred with water. The solid was filtered off and dried under vacuum (50 ° C). Yield: 24.19 g (95% of theory) of an amorphous solid.

Elementary analysis:

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)] - Lglutamine 5- [1- (4-Perfluorooctylsulfonyl) -piperazine] -amide, Gd-C-complex-5-N- (methyl) -N- (2,3,4,5,6-pentahydroxyhexyl) -amide

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) 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl)] pentanoic acid] -1,4,7,10-tetraazacyclododecane, the G-complex was weak heated in 200 ml of dimethylsulfoxide. At 10 ° C, 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide was 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 precipitated solid was filtered off and purified by silica gel chromatography (silica gel RP-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 compound) Calculated: C 34.41 H 3.83 F 23.13 N 9.03 S 2.30 Gd 11.26

AA AA

326 • A A A A ·

AA AAAA ·· «·

Found: C 34.34 H 3.98 F 23.29 N 9.19 S 2.15 Gd 11.07

Example 113

(a) 6-N-Benzyloxycarbonyl-2-N- [1-Oa-D-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 mol) of the title compound of Example 21c), 73.77 g (120.4 mol) of benzyl esters of 1-Oa-D-carboxymethyl-2,3,4-tri-O-benzyl-glucuronic acid and 13.86 g (120.4 mol) of N-hydroxysuccinimide, dissolved in 500 ml of dimethylformamide, were added at 0 ° C 41.27g (200.0 mmol) of N, N-dicyclohexylcarbodiimide. The mixture was stirred at 0 ° C for 3 hours and then stirred at room temperature overnight. The precipitated urea was filtered off, the filtrate was evaporated to dryness and chromatographed on silica gel.

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

Yield: 147.58 g (86% of theory) of a solid oil. Elementary 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-Carbonylmethyl-glucuronic acid] -Llysine-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 at room temperature for 12 hours. The catalyst was filtered off and the filtrate was evaporated to dryness.

Yield: 93.06 g (quantitative) of a colorless solid.

Elementary analysis:

Calculated: C 33.56 H 3.36 N 6.02 S 3.45 F 34.71

327 • • • to • · ····

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-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 2-N [1-Oa-D-carbonylmethyl-glucuronic acid] -L-lysine- [1- (4-fluorooctylsulfonyl) -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 mol) of lithium chloride and 34.35 g (54 , 55 mol) 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methylpent-5-yl) -1,4,7,10-tetraazacyclododecane, Gd-complex, 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 then stirred overnight at room temperature. The solution was poured into 3000 ml of acetone and the mixture was stirred for 10 minutes, the precipitate formed was filtered off and purified by silica gel chromatography (RP18, Mobile phase: Water / ethanol / acetonitrile gradient).

Yield: 75.14.9 g (8%, 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 F 20.83 Gd 10.14

Example 114

a) 6-N-Benzyloxycarbonyl) -2- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-L-lysine

To 31.82.0 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 DE 196 03 033) in 300 • · · ·

328 ml of tetrahydrofuran, 49.46 g (200.0 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) were added at 0 ° C and the reaction mixture was stirred overnight at room temperature. The mixture was evaporated to dryness and chromatographed on silica gel (mobile phase: dichloromethane / methanol = 20: 1).

Yield: 55.79 g (58% of theory) of a colorless solid. Elementary analysis:

Calculated: C 36.85 H 3.09 N 4.96 F 38.11 S 3.78

Found: C 36.85 H 3.19 N 4.87 F 38.28 S 3.95

b) 6-N-Benzyloxycarbonyl-2-N- [2- (N-ethyl-N-perfluorooctylsulfonyl) amino] acetyl-L-lysine-N-methyl-N- (2,3,4,5,6-pentahydroxy) (hexyl) -amide

To a solution of 51.02 g (60.2 mol) of the title compound of Example 114a), 11.75 g (60.2 mol) of N-methyl-glucamine and 6.93 g (60.2 mol) of N-hydroxysuccinimide, dissolved in 250 ml of dimethylformamide, 20.64 g (100.0 mmol) of N, N-dicyclohexylcarbodiimide was added at 0 ° C. The mixture was stirred at 0 ° C for 3 hours and then stirred at room temperature overnight. The precipitated urea precipitate was filtered off, the filtrate was evaporated to dryness in vacuo and chromatographed on silica gel.

(Mobile phase: dichloromethane / ethanol = 20: 1). Yield: 53.05 g (86% of theory) of a solid oil. Elementary 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-pertluorooctylsulfonyl) -amino] -acetyl-Llysine-N-methyl-N- (2,3,4,5,6-pentahydroxy-hexyl) -amide • · ···· · ·

329

102.48g (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 at room temperature for 12 hours. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure.

Yield: 89.06 g (quantitative) of a colorless solid.

Elementary 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-tetraazacyclododecane-10-N- (pentanoyl-3aza-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-pentahydroxy-hexyl) -amide, Gd -complex

48.58 g (54.55 mmol) of the title compound of Example 114), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54 , 55 mol) 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methylpent-5-yl) -1,4,7,10-tetraazacyclododecane, Gd complex was dissolved in 400 ml of dimethylsulfoxide under 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. The solution was poured into 3000 mL of acetone and stirred for 10 minutes. The precipitated solid was filtered off and was purified by silica gel chromatography (RP18 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 F 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), 6 to 60 minutes, as well as 24 hours and 48 hours after intravenous administration of 25 pmol Gd / kg body weight of the compound of the invention, was observed to enhance arteriosclerotic plaque while capturing Ti-weighted gradient echo. TR 11.1 ms, TE 4.3 ms, tilt angle α = 15 °). Healthy vascular walls exhibited either no or only weak absorption of the contrast agent, and thus showed either no or weak signal increase in T1-weighted sensing. Thus, on the basis of the contrast between the signal-rich plaque and the signal-weak vascular wall, a diagnosis of arteriosclerotic vascular wall changes is possible.

The figure in Figure 1 shows NMR measurements of aorta at 24 and 48 hours after administration of 25 μιηοΐ Gd / kg body weight of metal complex XV in Watanabe rabbits (genetically induced erteriosclerosis). Measurement of T1-weighted gradient echo (1.5 T, TR: 11.1 ms, TE: 4.3 ms, NA: 2, matrix: 213x256, layer thickness: 1.0 mm) shows a strong signal increase in arteriosclerotic plaque. Plaque localization, especially in the cardiac arch as well as in vascular defects, was confirmed with Sudan 3 stain.

Example 116

NMR imaging of arteriosclerotic plaque in rats following an intravenous dose of the metal complex XV of the present invention, as well as the correlation of post-mortem images with the dye Sudan III.

• «0 · ·· ····

331

The illustration in Figure 2 shows aortic NMR images 35 and 60 minutes and 24 hours after intravenous administration of 10 pmol Gd / kg live weight of the metal complex of gadolinium CV in Watanabe rabbits (genetically induced arteriosclerosis). Measurement of T1-weighted gradient echo (1.5 T, TR: 11.1 ms, TE: 4.3 ms, NA: 2, matrix: 213x256, layer thickness: 1.0 mm) shows a strong signal increase in arteriosclerotic plaque. Plaque localization, especially in the cardiac arch as well as vascular defects, was confirmed with Sudan 3 dye. Then, NMR imaging of preparations stored in agar was restored using the T1-weighted gradient echo sequence (MPRage, 1.5 T, TR: 11.1 ms, TE: 4.3 ms, inclination angle α = 15 ', NA: 2, nut: 213x256, layer thickness: 1.0 mm) as well as spin echo sequence (1.5 T, TR: 400 ms, TE: 15 ms, NA: 16, matrix: 256x256) (post-mortem images). There was an excellent correlation of aortic sections with a strong signal increase and plaque staining, since the compounds of the invention deposit in the arteriosclerotic plaque.

Example 117:

Infarct imaging (MRT) following intravenous dose of metal complex XV in rats

The figure in Figure 3 shows NMR imaging of the heart (in vivo and post mortem) 24 hours after intravenous administration of 100 μ μηοΐ Gd / kg body weight of metal complex XV 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 heart attack area. Successful induction of acute myocardial infarction was confirmed by NBT staining.

fc * fcfcfcfc fcfc fcfcfcfc

Metallic complex XV, 100 μιηοΐ / kg i.v., T1-SE, TR / TE 400/6 ms, myocardial infarction.

Example 118

Infarct imaging (MRT) following intravenous dose of metal complex I in rats

The figure in Figure 4 shows NMR imaging of the heart (in vivo and post mortem) 24 hours after intravenous administration of 100 μτηοΐ Gd / kg body weight of metal complex I 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 heart attack area. Successful induction of acute myocardial infarction was confirmed by NBT staining.

Example 119

Imaging of lymph nodes (MRT) after intravenous dose of metal complex XV in rabbits carrying VX2-tumor

The figure in Figure 5 shows NMR imaging of iliac lymph nodes prior to contrast agent administration up to 24 hours after intravenous administration of 200 μιηοΐ Gd / kg body weight of metal complex XV in rabbits with i.m. implanted with VX2-tumor. Measurement of T1-weighted gradient echo (1.5 T, sequence: MPRage, TR 11.1 ms, TE 4.3 ms, α-15 °) shows a strong signal increase in healthy lymph nodes. Zones without signal increase within the lymph nodes were diagnosed as metastasis and were histologically confirmed (H / E-staining of lymph node sections). Surprisingly, signal reversal was observed at later times (24 hours) after contrast agent application. Signal increase at · «·« <<

·· ·· ·· ····

333 healthy lymph nodes were reduced, while significant signal amplification is still visible in metastases.

Surprisingly, significant enhancement of the primary tumor (especially at the margins) was observed immediately after administration. At later times (24 hours) this amplification also extends towards the center of the tumor.

Example 120:

Tumor Imaging (MRT) following intravenous dose of metal complex I in rabbits bearing VX-2 tumor.

Figure 6 shows NMR imaging of lymph nodes as well as primary tumor (i.m. implanted with VX2-tumor) prior to administration, 60 minutes to 20 hours after intravenous administration of 100 pmol Gd / kg body weight of metal complex I in rabbits. Measurement of T1-weighted gradient echo (1.5 T, sequence: MPRange, TR 11.1 ms, TE 4.3 ms, α = 15 °) shows a strong signal increase in healthy lymph nodes.

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 application), the signal increase also extends to the central areas of the tumor.

Of particular note is the enhancement of the pathological structures (or secondary tumor or necrosis) on the contralateral side, which is only visible in later measurements ("late enhancement").

·· · ** · ·· ··· ·

334

Metal complex X

Example 121:

Infarct imaging (MRT) following intravenous dose of contrast agent in rats

The figure in Figure 7 shows NMR measurements of the heart (in vivo and post mortem) 6 hours after administration of 100 μg / kg Gd / kg live water of polar Gd chelate with perfluorinated side chain (metal complex X) in acutely induced heart attack rats. 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) shows strong signal amplification in a heart attack. 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

After intravenous administration of 100 μπιοί total gadolinium / kg body weight of polar Gd-chelate with perfluorinated side chain (metal complex X) in rats, the metal content of various organs and lymph nodes (divided as mesenteric and peripheral lymph nodes) was determined 24 hours after administration. MW, n = 2).

· · · · · · · ·

335

Organ µd Gd / L % Benefits Liver 104 2.34 Femur 3 0.01 Kidneys 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 Lung 18 0, 05 Muscles 1 0.00 Mesenterial lymph. nodules 19 Dec 0.01 Peripheral lymph. nodules 11 0.01 Total 38.58

Example 123:

Imaging of lymph nodes (MRT) after intravenous dose of contrast agent in rats

Figure 8 shows NMR measurements of iliac lymph nodes before administration up to 60 minutes after intravenous administration of 100 pmol Gd / kg body weight of metal complex X in rats. Measurement of T1-weighted gradient echo (1.5 T, sequence: MPRange, TR 11.1 ms, TE 4.3 ms, a = 15 °) shows a strong signal increase in healthy lymph nodes soon after injection. Increase at time 15 minutes after application = 263% and at time 60 minutes after application = 254%.

φφ φφ φφφφ

336 · * - »· * · · ΦΦΦΦ · · φ · ♦ · φ · · φ · * · φ φ

Φ · · Φ

Φ * ΦΦ

Example 124:

Imaging of lymph nodes (MRT) after intravenous dose of contrast agent in rabbits carrying VX2-tumor

The figure in Figure 9 shows NMR measurements of iliac lymph nodes before and up to 60 minutes after intravenous administration of 200 μιηοΐ Gd / kg body weight of metal complex X 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, α = 15 °) shows a strong signal increase in healthy lymph nodes. The gain in 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 histologically (H / E-staining of the lymph nodes). The signal intensity ratio in healthy lymph nodes to metastasis is 3.0 at the 15 minute time point to 3.4 at the 60 minute time point.

Surprisingly, a significant increase not only in the lymph nodes but also in the primary tumor (especially in the periphery) was observed immediately after administration (15 minutes after application: intensity of 277%). At later times (up to 24 hours after administration), this amplification also extends towards the tumor center (24 hours after administration: 217%).

337 · · · · · · · · · · · ·

Metal complex V

Example 125:

Infarct imaging (MRT) following intravenous dose of contrast agent in rats

The figure in Figure 10 shows the NMR imaging of the heart (in vivo and post mortem) 24 hours after intravenous administration of 100 µg Gd / kg body weight of perfluorinated side chain polar Gd chelate (metal complex V) in rats with induced heart attack. Tl-weighted, ECG trigger trigger echo (1.5 T, TR (effective): 400 ms, TE: 12 ms, NA: 4, matrix: 128 x 128, layer thickness: 2.5 mm) shows strong signal amplification in a heart attack. 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

After intravenous administration of 200 μιτιοί of total gadolinium / kg body weight of polar Gd-chelate with perfluorinated side chain (metal complex V) in rats, the metal content of various organs and lymph nodes (separated as mesenteric and peripheral lymph nodes) was determined 24 hours after application. MW, n = 2).

338

Organ Gd / L % Benefits Liver 344 6, 34 Eemur 13 0.05 Kidneys 436 1.77 Brain 4 0, 02 Skeleton 268 37.93 Blood 15 Dec 0, 18 Stomach 28 0.08 Digestive tract 113 1.56 Spleen 116 0.17 Pancreas 30 0.05 Heart 14 0.02 Lung 62 0.17 Muscles 9 0.02 Mesenterial lymph. nodules 70 0.05 Peripheral lymph. nodules 44 0, 02 Overall 48.43

Example 127:

Imaging of the lymph nodes of the contrast agent in rats

Illustration of Ilial lymph node of intravenous complex V in T, sequence: strong increase (MRT) after intravenous dose imaging minutes after metal echo (1.5 shows node already shows NMR before administration and up to 60 administration 200 μιηοΐ Gd / kg bodyweight rats Measurement of T1-weighted gradient MPRage, TR 11.1 ms, TE 4.3 ms, a = 15 °) signal in healthy lymphatic tissue

339 very soon after injection. The increase at 15 minutes is 147% after injection and 230% at 60 minutes after injection.

Example 128:

Lymph node imaging (MRT) following intravenous dose of contrast agent in rabbits carrying VX2-tumor

The figure in Figure 12 shows NMR measurements of iliac lymph nodes before and up to 60 minutes after intravenous administration of 200 gmol Gd / kg body weight of metal complex V 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, cc = 15 °) shows a strong signal increase in healthy lymph nodes. The gain in 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 in healthy lymph nodes to metastasis is 2.5 at the 15 minute time point to 1.7 at the 60 minute time point.

Surprisingly, even immediately after administration, a significant enhancement is observed not only in the lymph nodes but also in the primary tumor (especially in the periphery) (15 minutes after application: intensity 350%). At later time points (up to 24 hours after administration), this amplification also extends towards the tumor center (24 hours after administration: 10.6%).

Metal complex XIV

Example 129:

Infarct imaging (MRT) following intravenous dose of contrast agent in rats

340

The figure in Figure 13 shows the NMR imaging of the heart (in vivo and post mortem) 3 hours after intravenous administration of 100 μιηοΐ Gd / kg body weight of polar Gd-chelate with perfluorinated side chain (metal complex XIV) 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) shows strong signal amplification in a heart attack. 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

After intravenous administration of 200 pmol of total gadolinium / kg body weight of polar Gd-chelate with perfluorinated side chain (metal complex XIV) in rats (Cop-Inzucht implanted with prostate cancer R3327 MAT-Lu 12 days ago), 10 minutes were determined, 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).

«· ··· · · · · · ·

341 ··· · * · «» »· · · · ·«

Metal complex. XIV 10mln p.i. 3d-! Concentration 1h p.i. fy / mol / I] 24hp and. 10r nin p.i. % of the dose 1h p.i. 24h p.i. Liver 192 ± 12 147 ± 7 64 i 4 2.62 * 0.11 2.04 * 0.15 0.96 ± 0.05 Spleen 200 i 13 123 ± 10 69 ± 5 0.13 ± 0.01 0.08 ± 0.01 0.06 ± 0.00 Pankrcas 191 ± 14 139 ± 26 25 ± 1 0.35 ± 0.02 0.21 ± 0.05 0.03 ± 0.01 Kidney 761 ± 60 1181 ± 232 338 ± 49 1.76 ± 0.14 2.84 ± 0.61 0.81 ± 0.09 Lung 603 ± 30 415 ± 39 44 ± 4 1.04 ± 0.02 0.80 ± 0.06 0.09 * 0.01 Heart 320 ± S 190 ± 15 19 λ 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 t 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 rnes. Izmf. uzL 291 ± 29 179 ± 16 50 * 6 0.08 ± 0.01 0.05 λ 0.01 0.02 ± 0.00 perif. lymph. uzL 284 ± 19 254 * 14 51 ± 5 0.13 ± 0.00 0.14 ± 0.02 0.02 ± 0.00 Stomach (empty) 244 ± 17 165 ± 21 19 ± 2 0.56 ± 0.07 0.40 ± 0.05 0.05 and 0.00 Intestine (empty) 242 ± 15 201 ± 32 36 ± 5 1.55 ± 0.09 1.16 ± 0.22 0.26 ± 0.04 Blood** 957 ± 38 575 ± 56 22 ± 1 26.73 ± 0.84 16.13 ± 1.77 0.61 ± 0.03 Residue* 419 ± 27 392 ± 25 42 ± 0 70.71 ± 2.74 64.27 ± 5.50 6.81 ± 0.16 Sea 0-24 h - - 619 ± 19 Dec - - 79.86 ± 3.13 Excretions 0-24 h - - 781 ± 611 - - 6.00 ± 4.91 Sum of all institutions' * 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 / kg body weight *** Balance without blood data included in rest of body data **** Aliquot of tissue only

Example 131:

Imaging of lymph nodes (MRT) after intravenous dose of contrast agent in guinea pigs

The illustration in the Figure. 14 shows an example of NMR measurement of iliac lymph nodes before and up to 24 hours after intravenous administration of 200 μιηοΐ Gd / kg body weight of metal complex XIV in guinea pigs with stimulated lymph nodes (Ereund Adjuvant). Tl-weighted gradient echo measurements (2.0 T, TR 10 ms, TE 5 ms, a = 40 °) show a strong signal increase in healthy lymph node tissues very soon after

342 injection. The gain reaches 127% at the time point 60 minutes after application.

Example 132:

Lymph node imaging (MRT) following intravenous dose of contrast agent in rabbits bearing VX2-t tumor

The illustration in Figure 15 shows NMR measurements of iliac lymph nodes before and up to 23 hours after intravenous administration of 200 µmol Gd / kg body weight of metal complex XIV 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, α-15 °) shows a strong signal increase in healthy lymph nodes. The gain in healthy lymph nodes is 297% at the time point 10 minutes after administration and 269% at the time point 60 minutes after administration. 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 of 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, even immediately after administration, a significant enhancement was observed not only in the lymph nodes but also in the primary tumor (especially in the periphery) (15 minutes after application: intensity 594%). At later time points (up to 24 hours after administration), this amplification also extends towards the tumor center (120 minutes after administration: 162%).

343

Metal complex III

Example 133:

Infarct imaging (MRT) following intravenous dose of contrast agent in rats

The figure in Figure 13 shows the NMR imaging of the heart (in vivo and post mortem) 22 hours after intravenous administration of 100 μπιοί Gd / kg body weight of polar Gd-chelate with perfluorinated side chain (metal complex III) in acutely induced heart attack rats. 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) shows strong signal amplification in a heart attack. 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

After intravenous administration of 200 μπιοί of total gadolinium / kg body weight of polar Gd-chelate with perfluorinated side chain (metal complex III) in rats, the metal content of various organs and lymph nodes (separated as mesenteric and peripheral lymph nodes) was determined 24 hours after application. MW, n = 2).

• · · · ·

344

Organ Gd / L % Benefits Liver 1222 26.28 Femur 76 0, 32 Kidneys 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 Lung 338 0.96 Muscles 28 0.04 Mesenterial lymph. nodules 455 0.33 Peripheral lymph. nodules 279 0.18 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 NMR measurement of iliac lymph nodes before and up to 60 minutes after intravenous administration of 200 μπιοί Gd / kg body weight of metal complex III in rats. Measurement of T1-weighted gradient echo (1.5 T, sequence: MPRange, TR 11.1 ms, TE 4.3 ms, a = 15 °) shows a strong signal increase in healthy lymph node tissues very soon after injection. Gain reaches 320% • fcfcfc fcfc fcfcfcfc · · fcfc fcfc • fc · fcfcfcfc fcfc ·

345 at a time point of 15 minutes after application and a value of 401% at a time point of 60 minutes after application.

Example 136:

Lymph node imaging (MRT) following intravenous dose of contrast agent in rabbits bearing VX2-t tumor

The figure in Figure 18 shows NMR measurements of iliac lymph nodes before and up to 60 minutes after intravenous administration of 200 μιηοΐ Gd / kg body weight of metal complex III 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, a = 15 °) shows a strong signal increase in healthy lymph node tissue. The gain in 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 of healthy lymph nodes to metastasis is 1.9 at the 15 minute time point and 1.8 at the 60 minute time point.

Surprisingly, even immediately after administration, a significant enhancement was observed not only in the lymph nodes, but also in the primary tumor (especially in the periphery) (15 minutes after application: intensity 232%).

Claims (50)

Patent claims 346 Use of metal complexes containing perfluoroalkyl residues whose critical micellar concentration is less than 1CT ³ mol / l, the hydrodynamic micellar diameter (2 Rh) is greater than 1 nm and the proton relaxivity in plasma (R1) is greater than 10 1 / mmol. s, to prepare a contrast agent for MR-imaging for plaque imaging. Use according to claim 1 for the preparation of a contrast agent for MRI for lymph node imaging. Use according to claim 1 or 2 for the preparation of an MRI contrast agent for imaging infarcted and necrotic tissues. Use according to claims 1 to 3 for preparing an MRI contrast agent for independent imaging of necroses and tumors. Use according to claim 1, wherein metal complexes having a critical micellar concentration of less than 10 ^-4 mol / l are used. Use according to claim 1, wherein metal complexes having a hydrodynamic micellar diameter of nm 3 nm, preferably> 4 nm are used. • fc ···· «fc ·· ···· · · · ····· fc 347 Use according to claim 1, characterized in that metal complexes are used whose proton relaxivity in the plasma is greater than 13 l / mmol s, preferably greater than 15 l / mmol s. Use according to one of Claims 1 to 7, characterized in that compounds of the formula I are used as perfluoroalkyl-containing metal complexes. R ^F -LK (I) wherein R ^f is a perfluorinated straight or branched hydrocarbon chain of the formula C _n F _2n E, 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, L is a direct bond, a methylene group, an -NHCO- group, a group R = (CH ₂ ) -NHCOCH ₂ - (CH ₂ ) n -so - 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 methylene group, a -CH 2 -OH group, a -CH ² -CO ² H group or a C ₂ -C ₁₅ chain optionally interrupted by 1 to 3 oxygen atoms, 1 to 2> C0 groups or optionally substituted with an aryl group and / or 1 to 4 hydroxyl groups, 1 to 2 C 1 -C ₄ alkoxy groups, 1 to 2 carboxy groups, -SO ₃ H. or straight, saturated or unsaturated C ₂ -C ₃₀ hydrocarbon chain, which optionally contains 1-10 oxygen atoms, 1 ·· ·· · a · ···· ···· ·· ·· 348 • Up to 3 -NR ^and -, 1 to 2 sulfur atoms, piperazine, CONR ^and -, -NR ^and CO-, -SO2-, -NR ^and -CO 2 -, 1 to 2 -CO-, -CO-NTN (R ^a ) -SO 2 -R ^f or 1 to 2 optionally substituted aryl and / or is interrupted by these groups, and / or is optionally substituted with 1 up to 3 groups -ORa, 1 to 2 oxo groups, 1 to 2 -NH-COR ³ groups, 1 to 2 -CONHR groups ^and -, 1 to 2 groups - (CH 2) _p -CO ₂ H, 1 to 2 groups - ( CH ₂ ) _p - (O) _q -CH ₂ CH ₂ -R ^F , wherein R ^a , R ^{b and 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. K is a complexing agent or a metal complex or salts thereof of organic and / or inorganic bases or amino acids or amino acid amides, wherein the complexing agent or complex has the general formula II CHjjCHj N ()) wherein R ^c , R ¹ and B are independently of each other R ^c has the meaning of R ^a or is - (CH ₂ ) mL R ^F where m is 0, 1 or 2 and L and R ^f have the meanings given above, R ¹ is independently from each other a hydrogen atom or a metal ion equivalent of atomic number 22 to 29, 42 to 46 or 58 to 70, B is -OR ¹ or 44 4444 4,444 44 4 349 • 4 4 4 · »4444 44 4 4, CH, CH — LR / - —N < ^{2 2} or - N N-SO ₂ -LR ^F where R ¹ , L, R ^f and R ^c are as defined above , or a complexing agent or a complex of formula (III) γ-co ^ z ¹ CC 1 Z (HI) 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 (IV) wherein R ¹ is as defined above or a complexing agent or complex of formula V Fcfcfcfc fcfc fcfc fcfc fcfc 350 fcfc fcfc fcfc fcfc where ^ R ¹ is as defined above and o and q are numbers 0 or the sum of o + q = 1, or a complexing agent or complex of formula VI / o ₂ c ^ \ / - \ / ^ C0 ₂ Z ¹ (VI) wherein R ¹ is as defined above or a complexing agent or complex of general formula VII wherein R ¹ and B £ maj defined above, or COY (VII) complexing agent or complex of formula VIII 351 · · · * * * # # # # # # # # # # # # # # # # # # # # # I * · Φ ·· ·· CHjjCHj (VIII) wherein R ^c and R j £ ¹ mA as defined above and R ^b is as defined above ^and R, or a complexing agent or complex of general formula IX z'o ₂ c ^ \ / \ X ^ co / ² K > /? ^H (V ⁷ / \ COGZ ¹ R »c \ (IX) wherein R ^c and R ¹ are as defined above, or a complexing agent or complex of general formula X; nn; (X) wherein R ^c and R ¹ are as defined above, or a complexing agent or a complex of formula XI (XI) 352 W _{K χ} CO ₂ '[NH-CH = CH. .Alpha.-COfo- ^N1 SQ ^ - ΛΛΛΛΛΛ wherein R ^1, p and q are as defined above and R ^b is as R ^a, or a complexing agent or complex of general formula XII in which L, R ^F and Z ¹ have the abovementioned meanings, or a complexing agent or complex of general formula XIII Use according to claim 8, characterized in that the compounds of the formula I are used, wherein L is -CHa-β α-ΟΗ ₂ -ΟΗ ₂ -β α- (CH ₂ ) ₈ -β, where s = 3 to 15 α-α ₂ -ο-θ _2- α ₂ -β, α-CH ₂ - ( O-CH ₂ -CH ₂ -) t-β, where t = 2 to 6, α-CH ₂ -NH-CO-β, α-CH ₂ -NH-CO-CH ₂ -N (CH ₂ COOH) -SO ₂ -β, α-CH ₂ -NH-CO-CH ₂ -N (C ₂ H ₅ ) -εθ ₂ -β, α-CH ₂ -NH-CO-CH ₂ -N (C ₁₀ H ₂₁ ) -SO 3 -β, and -CH ₂ -NH-CO-CH ₂ -N (C ₆ H _{13) 2} -β -5Ο CC-CH ₂ -NH-CO- (CH _{2) 10} -N (C ₂ H _s) -SO ₂ -β, α-CH ₂ -NH-CO-CH ₂ -N (-CH ₂ -C ₆ H ₅ ) -5-2 -β, α-CH ₂ -NH-CO-CH ₂ -N (-CH ₂ -CH ₂ -OH) -SO ₂ -β, α-CH ₂ -NH-CO- (CH ₂ ) ₁₀ -S-CH ₂ CH ₂ , α-CH ₂ -NH-CO-CH ₂ -O-CH ₂ CH ₂ - β, α-CH ₂ -NH-CO- (CH ₂ ) ₁₀ -Ο-ΟΗ ₂ ΟΗ ₂ -β, α-ΟΗ ₂ -Ο ₆ Η ₄ -Ο-ΟΗ ₂ -ΟΗ ₂ -β, α-CH ₂ -O-CH ₂ -C (CH ₂ -OCH ₂ CH ₂ -C ₆ F ₁₃ ) ₂ -ΟΗ ₂ -Ο-ΟΗ ₂ ΟΗ ₂ -β, 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 CH ₂ -CH ₂ -NH-CO-CH ₂ -N (C ₂ H ₅ ) -SO ₂ -β, α-CH ₂ -O-CH ₂ -CH (OC ₁₀ H ₂₁ ) -CH ₂ -O-CH ₂ CH ₂ - β, α- (CH ₂ -NHCO) ₄ -ΟΗ ₂ 0-ΟΗ ₂ ΟΗ ₂ -β, α- (CH ₂ -NHCO) ₃ -ΟΗ ₂ Ο-ΟΗ ₂ ΟΗ ₂ -β, α-CH _2- OCH ₂ C (CH ₂ OH) ₂ -ΟΗ ₂ -Ο-ΟΗ ₂ ΟΗ ₂ -β, α-CH ₂ -NH-CO-CH ₂ -N (C ₆ H ₅ ) -δθ ₂ -β, · A · AA AA A · A · A 354 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) -SO ₂ -β, α-NH-CO-CH ₂ -N (C ₂ H ₅ ) -δθ ₂ -β, and -NH-CO-CH ₂ -N (C ₁₀ H ₂₁ ) -βθ ₂ -β, α-NH-CO-CH ₂ -N (C ₆ H ₁₃ ) -SO ₂ -p, α-NH-CO- ( _{CH2) 1o} N (C ₂ H _s) -SO ₂ -p, and -NH-CO-CH ₂ -N (-CH ₂ C ₆ H ₅₎ -SO ₂ -p, and -NH-CO-CH ₂ -N (-CH ₂ -CH ₂ OH) -so ₂ -p, α-NH-CO-CH ₂ -β, α-CH ₂ -OC ₆ H ₄ -O-CH ₂ -CH ₂ -p, and -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) ₂₁ ) -SO ₂ -p, aN (C ₆ H ₁₃ ) -SO ₂ -p, aN (C ₂ H ₄ OH) -SO ₂ -p, aN (CH ₂ COOH) -SO ₂ -β, aN (CH ₂ C ₆ H ₅ ) -SO ₂ -p, aN [CH (CH ₂ OH) ₂ ] -SO ₂ -P, aN [CH (CH ₂ OH) CH (CH ₂ OH)] -βθ ₂ -β, and wherein a is the point of attachment to the complexing agent or metal complex K and β is the point of attachment to the fluorinated moiety. 10. Use according to claims 8 and 9, characterized in that the used compounds of formula I wherein n in formula -C _n F _2n E is an integer of 4-15 and / or E in this formula means a fluorine. and · · · 355 • · Use according to claims 8 to 10, characterized in that the following compounds are used: gadolinium complex with 10- [1-methyl-2-oxo-3-aza-5-oxo- {4-fluorooctylsulfonyl-piperazin-1-yl} -pentyl] -1,4,7tris (carboxymethyl) -1,4,7, 10-tetraazacyclododecane, gadolinium complex with 10- [2-hydroxy-4-aza-5-oxo-7-oxa10,10,11,11,12,12,13,13,14,14,15,15,16, 16,17,17-heptadecafluoroheptadecyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-triazazacyclododecane, gadolinium complex with 10- [2-hydroxy-4-aza-5,9-dioxo-9- (4-Fluoro-octyl) piperazin-1-yl} -nonyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-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-1H, 1H, 2H , 3H, 3H, 5H, 5H, 6H, 6H-perfluorotetradecyl] -1,4,7tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane, gadolinium complex with 10- [2-hydroxy-4-aza-5 -oxo-7-oxa10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17,18,18,19,19henosafluornonadecyl] -1,4, 7-tris (carboxymethyl) -1,4,7,10tetraazacyclododecane, gadolinium complex with 10- [2-h ydroxy-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-phenyl-octyl] -1,4,7tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane. Use according to Claims 1 to 7, characterized by 356 by using compounds of the formula Ia as metal complexes containing perfluoroalkyl radicals AR ^F (Ia) wherein • A is a molecular moiety containing 2 to 6 metal complexes, attached directly or via a linker to a nitrogen atom bound to the ring-forming carrier chain and • R ^F is a perfluorinated straight or branched hydrocarbon chain of the formula C _n F _2n E, where 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 the following structure: TO AND Y P K where • q ¹ is an integer of 0, 1, 2 or 3 • K is a complexing agent or 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 group, phenyl or a C 1 -C ₁₀ alkylene chain optionally containing 1 to 15 oxygen atoms, 1 to 5 sulfur atoms, 1 to 10 carbonyl, 1 to 10 (NR ^d ) -, 1 to 2 NR ^d SO ₂ -, 1 up to 10 CONR ^d -, 1 piperidine, 1 to 3 groups Group 357 S0 ₂ -, 1-2 phenylene groups, or is substituted by 1-3 radicals R ^F, where R ^d is hydrogen, phenyl, benzyl or C1-C15 alkyl group which optionally contains 1-2 NHCO groups , 1-2 CO-, 1-5 oxygen atoms and optionally substituted with 1-5 hydroxy, 1-5 methoxy, 1-3 carboxy, 1-3 R ^F radicals, • V is a direct bond or a chain of general formula IIa or - lilac: O II 3-NHCH ₂ ) _k - (R, - (CH ₂ ) -C -a) R '(Ha) O II β-N-CHL-C-N, 1 * 1 O Η H / - \ II 0 you (CH ₂ ) 2 -C a 11 KbfN-CbL-C-hr 1 1 H i (lila) where • R ^e is hydrogen atom, phenyl group, benzylová group or C 1 -C ₇ alkyl group, eventual substituted with carboxy, methoxy or hydroxy; 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) · fcfc · · · · · · · · · · · · · · · · · · · 358 wherein R ^h is a C 1 -C ₇ carboxylic acid, a phenyl group, a benzyl group or - (CH ₂ ) 1-5 -NH -Kgroup • a is the point of attachment to the nitrogen atom of the support chain, 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 • D is CO- or S0 ₂ ~. Use according to claim 12, characterized in that compounds of the formula Ia wherein q is 1 are used. Use according to claim 12, characterized in that the compounds of formula (Ia) are used, 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 of the following structures γ ~ CH ₂ -O- (CH ₂ ) ₂ - §, γ -CH ₂ -N-SO ₂ —δ OC ₂ H ₅ II I ^{2 5} y- (CH ₂ ) ₁₀ -NC -ch ₂ -n-so c ₂ h _{5 y} - (CH ₂ ) ₁₀ -O- (CH ₂ ) ₂ - _δ · · · · · · · · · · <P ^H 5 ch ₂ -n-so ₂ —δ> γ-ch ₂ -n-so ₂ - § 359 Y-CH ₂ -N-SO ₂ - δ γ-0Η ₂ -Ν-? Η —δ CH. where ^- · γ is the binding site to D and δ is the binding site to RF. Use according to claim 12, characterized in that compounds of the formula Ia are used, wherein V is the molecular part of one of the following structures α-C-CH ₂ -NH- β, α-C-CH ₂ -N- β CH, COOH ch ₃ fH-NH-β, CH (CH ₃ ) ₂ µl and C-pH-NH-β (CH ₂ ) ₄ -NH-K 360 Use according to claim 12, characterized in that compounds of the formula Ia are used, K is a complex of the formula Va, Via, Vila or Vlila where: R 00 ' ROOC N N II — COOR ⁴ -COOR ’ Where R ¹ is, independently of one another, a hydrogen atom or a metal ion equivalent of atomic number 23 to 29, 42 to 46 or 58 to 70, • R ⁸ is a hydrogen atom or straight, branched saturated or unsaturated C1 -C30 alkyl chain which is optionally substituted with 1-5 hydroxy, 1-3 carboxy or 1 phenyl group and / or is interrupted with 1 to 10 oxygen atoms, 1 phenylene or 1 phenyloxy, • R ⁶ R ⁷ is a hydrogen atom, a methyl or ethyl group, optionally substituted with a hydroxy- or carboxy-group, • U ³ is a straight, branched, saturated or unsaturated Oχ -O ₃ ο alkylene group optionally containing 1 to 5 imino groups, 1 to 3 phenylene groups, 1 to 3 phenylenoxy groups, 1 to 3 phenylenimino groups, 1 to 5 amide groups, 1 to 2 hydrazido couples, 1 to 5 carbonyl groups, 1 to 5 ethyleneoxy groups, 1 urea group, 1 thiourea group, 1 to 5 sulfur or nitrogen atoms and / or optionally substituted with 1 to 5 hydroxy groups, 1 to 2 mercapto groups, 1 to 5 oxo - groups, 1 to 5 thioxo groups, 1 to 3 carboxy groups, 1 to 5-carboxyalkyl groups and / or 1 to 3 amino groups, wherein optionally present phenyl groups may be substituted with 1 to 2 carboxy groups, 1 to 2 sulfone groups or 1 to 2 hydroxy groups; T ¹ is -CO-β, -NHCO-β or -NHCSβ, where β is the point of attachment to V. ·· ··· · 362 · · · · ················· Use according to claim 16, characterized in that the C 1 -C ₂ alkylene chain in U ³ contains the groups -CH ₂ NHCO-, -NHCOCH ₂ O-, -NHCOCH ₂ OC ₆ H ₄ -, -N (CH ₂ CO ₂ H) -, -CH ₂ OCH ₂ -, -NHCOCH ₂ C ₈ H ₄ -, -NHCSNHC ₉ H ₄ -, -CH ₂ OC ₆ H ₄ -, -CH ₂ CH ₂ O-, and / or is substituted with -COOH groups, -CH ₂ COOH. Use according to claim 16, characterized in that U ³ is -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -C ₆ H ₄ -, -C ₆ H ₁₀ - , -CH ₂ C ₆ H ₄ -, -CH ₂ NHCOCH ₂ CH (CH ₂ CO ₂ H) -c _s h ₄ -, -CH ₂ NHCOCH ₂ OCH ₂ -, -CH ₂ NHCOCH ₂ C ₆ H ₄ -. Use according to claim 12, characterized in that compounds of the formula Ia are used, wherein K has one of the following structures: ROO iQ --- j N ROOC □ II / —C— · COOR ⁴ I — COOR ⁴ • COOR ´ ' ^X ' ^X -COOR ⁴ .COOR ' -N | \ r CO-OOR ⁴ ROOC / \ c \ II o Ch ³¹ N COOR COOR ⁴ N- ^ 2 OH 'COOR ⁴ ·· ··· · 363 Use according to claims 12 to 19, characterized in that compounds of the formula Ia are used, wherein the perfluoroalkylated chain RF is -C ₆ F ₃ , -C ₈ F ₁₇ , -C ₁₀ F ₂₁ or -C ₁₂ F ₂₅ . Use according to claims 12 to 20, characterized in that the gadolinium complex with 1,4,7tris {1,4,7-tris (N- (carboxylatomethyl) -10- [N1-methyl-3]) is used. 6-diaza-2,5,8-trioxooctane-1,8-diyl] -1,4,7,10-tetraazacyclododecane, Gd complex} -10- [N-2H, 2H, 4H, 4H, 5H, 5H- 3-oxa-perfluorotridecanoyl] -1,4,7,10-tetraazacyclododecane. Use according to one of Claims 1 to 7, characterized in that a perfluoroalkyl metal complex of the formula 1b is used. AND I F K-N-L-R (1b) wherein K is a complexing agent or a metal complex of formula IIb wherein R ¹ denotes a hydrogen atom or a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70, 364 φφ ·· * · φφ · ΦΦ · R ² and R ³ 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 radical L ¹ , wherein L ¹ and U ² may independently of one another be the same or different, A ¹ denotes a hydrogen atom, a straight or branched alkyl group having 1 to 30 carbon atoms, optionally interrupted with 1 to 15 oxygen atoms and / or optionally substituted with 1 to 10 hydroxyl groups, 1 to 2 COOH groups, phenyl group, benzyl group and / or 1 to 5 OR ³ groups, wherein R ³ is a hydrogen atom or an alkyl radical having 1 to 7 carbon atoms or a radical -L ¹ * ^F , L ¹ denotes a straight or branched alkylene group having 1 to 30 carbon atoms, optionally interrupted with 1 to 10 oxygen atoms, 1 to 5 -NH-CO- groups, 1 to 5 CO-NH- groups, optionally a phenyl group optionally substituted with -COOH, 1-3 sulfur atoms, 1-2 -N (B ¹⁾ -SO 2, and / or 1 to 2 groups -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 ^F , and R ^p is a straight or branched perfluorinated alkyl radical of formula C _n F _2n E, wherein n is an integer of 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 as salts of organic and / or inorganic bases or amino acids or amino acid amides. Use according to claim 22, characterized in that the compounds of formula (1b), wherein R ² , R ³ and R ⁹ are independently from each other hydrogen or an alkyl group having from 1 to 2, are used. 4 carbon atoms. Use according to claim 22, characterized in that compounds of the formula 1b are used, wherein A ¹ is hydrogen, an alkyl radical having 1 to 15 carbon atoms, the 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 ₁₂ OH, C ₇ H ₁₄ OH, CH (OH) _CH2 (OH) CH (OH) CH (OH) CH ₂ OH, CH ₂ [CH (OH)] ΟΗ ₂ ΟΗ, CH [CH ₂ (OH)] CH (OH) CH ₂ OH, C ₂ H ₄ CH (OH) 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, where s is an integer from 1 to 15, t is an integer from 0 to 13, ¹ is an integer from 1 to 10, n is an integer from 4 to 20, and E is hydrogen, fluorine, chlorine, bromine or iodine, as well as, when possible, branched isomers. Use according to claim 22, characterized in that compounds of formula 1b are used, wherein A ¹ is hydrogen, an alkyl radical having 1 to 10 carbon atoms C ₂ H ₄ -OCH ₃ , C ₃ H 6 -O-CH ₃ , C ₂ H ₄ -O- (C ₂ H ₄ -O) _X -C ₂ H ₄ -OH, C ₂ H ₄ -O- (C ₂ H ₄ -O) _x -C ₂ H ₄ -OCH ₃ , c ₂ hrs ₄ oh, c ₃ hrs ₆ oh, ·· 44 4 4 4 4 4 5 44 4444 43 4 44 4 CH ₂ [CH (OH)] _y CH ₂ OH, CH [CH ₂ (OH)] CH (OH) CH ₂ OH, (CH ₂ ) _W COOH, C ₂ H ₄ -O- (C ₂ H ₄ -O) _X -CH ₂ COOH, C ₂ H ₄ -O- (C ₂ H ₄ -O) χ-C ₂ H ₄ - CnF ₂ nE, where X Yippee whole number 1, in az 5, y Yippee whole number 1 in az 6, w Yippee whole number from 1 to 10, n Yippee whole number from 4 to 15, E Yippee atom fluorine, as well as, if possible, branched isomers thereof. Use according to claim 22, characterized in that compounds of the formula 1b are used, wherein L ¹ is α- (CH ₂ ) _s -3 α-CH ₂ -CH ₂ - (O-CH ₂ -CH ₂ -) _γ -β, α-CH ₂ - (O-CH ₂ -CH ₂ -) γ-β, α-ΟΊ ₂ -ΝΗ-00-β, α-CH ₂ -CH ₂ -NH-SO ₂ ^, and - CH ₂ - NH - CO - CH ₂ - N (CH ₂ COOH) - S0 ₂ - β, and -CH ₂ -NH-CO-CH ₂ -N (C ₂ H _{5) 2} -β -δθ, -CH _2- NH-CO-CH ₂ -N (C ₁₀ H ₂₁ ) -δθ ₂ -β, α-CH ₂ -NH-CO-CH ₂ -N (C ₆ H ₁₃ ) -δθ ₂ -β, α-CH ₂ -NH-CO- _(CH2) io-N (C ₂ H _{5) 2} -5Ο -β, -CH ₂ -NH-CO-CH ₂ -N (-CH ₂ -C ₆ H ₅₎ -δθ ₂ -β, α-CH ₂ -NH-CO-CH ₂ -N (-CH ₂ -CH ₂ OH) -SO ₂ -β, α-CH ₂ -NH-CO- (CH ₂ ) ₁₀ -S-CH ₂ CH ₂ R, and -CH ₂ -NH-CO-CH ₂ -O-CH ₂ CH ₂ R, -CH ₂ -CH ₂ -NH-CO-CH ₂ -O-CH ₂ CH ₂ R, • · fc ··· • fc «fcfcfc 367 • fc fcfc fcfc · ···· fcfc fc «fc fc ··" ··· •• * fc · w fcfcfcfc fcfcfc fcfcfc fcfcfcfc ·· * fcfc fcfcfcfc fcfc fcfc -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, Α-CH ₂ -CH ₂ -NH-CO- (CH ₂ ) ₁₀ -Ο-ΟΗ ₂ ΟΗ ₂ -β, 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, -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 ₁₇ -p α-CH ₂ -CH ₂ -NH -CO-CH ₂ -N (C ₂ H ₅ ) -SO ₂ -p, a - CH ₂ - O - CH ₂ - CH (OCi ₀ H ₂₁ ) - CH ₂ - O - CH ₂ CH ₂ - β, and - (CH ₂ -NHCO) ₄ -ΟΗ ₂₀ -ΟΗ ₂ ΟΗ ₂ -β, 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 R, and -CH ₂ -NH-CO-CH ₂ -N (C _e H ₅₎ -βθ ₂ -β, α-ΝΗ _ΟΟ-2-ΟΗ 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 ^, and -NH-CO-CH ₂ -N (C ₂ H ₅ ) -3-2-β, α-NH-CO-CH ₂ -N (C ₁₀ H ₂₁ ) -SO ₂ -β, α-NH-CO-CH ₂ -N (C ₆ H ₁₃ ) -δθ ₂ -β, α-NH-CO- (CH ₂ ) ₁₀ -N (C ₂ H ₅ ) -δθ ₂ -β, α-NH-CO-CH ₂ -N ( -CH ₂ C _e H _{5) 2} -β -3Ο GC-NH-CO-CH ₂ -N (-CH ₂ -CH ₂ OH) -δθ ₂ -β, α-ΝΗ-ΟΟ _ΟΗ-2 -β, and- CH ₂ -OC ₆ H 4 -O-CH ₂ -CH ₂ -; 368 · a · CH ₂ -C ₆ H 4 -O-CH ₂ -CH ₂ -P, oc-N (C ₂ H) ₅ ) -SO ₂ -β, α-N (C ₆ H ₅ ) -5-2 -β, α N (C ₁₀ H ₂₁ ) -SO ₂ -β, α N (C ₆ H ₃ ) -5-2 -β, α-N (C ₂ H ₄ OH) -SOa-β, N (CH ₂ COOH) -SO-β, N (CH ₂ C ₆ H _s) -SOa-β, α-N- [CH (CH ₂ OH) _2] - δθ ₂ -β, aN [CH (CH ₂ OH) CH (OH) (CH ₂ OH)] -δθ ₂ -β, where s is an integer from 1 to 15 and y is an integer from 1 to 6. Use according to claim 22, characterized in that the compounds of formula 1b are used, wherein L ¹ is α-ΟΗ ₂ -O-ΟΗ ₂ -ΟΗ- ₂ -β, cc-CH ₂ -CH ₂ - (O- CH ₂ -CH ₂ -) y-β, α-CH ₂ - (O-CH ₂ -CH ₂ -) _γ -β, α-CH ₂ -CH ₂ -NH-SO ₂ - ^, eg 10 α - CH ₂ - NHCOCH ₂ - O - CH ₂ - CH ₂ - β, α - ch ₂ - ch ₂ nhcoch ₂ - o - ch ₂ - ch ₂ - β, α-CH ₂ - (CH ₂ CH ₂ O) _y ( CH ₂ ) ₃ NHCO-CH 2 -O-CH ₂ -CH ₂ -, a-ch ₂ -nhco (ch ₂ ) ₁₀ -o-ch ₂ -ch ₂ -β, a-CH ₂ -CH ₂ -NHCO (CH _{2) 10} -O-CH ₂ -CH ₂ -P, and-CH ₂ -O-CH ₂ -CH (OC ₁₀ H ₂₁₎ -CH ₂ -O-CH ₂ -CH ₂ -P, and-CH ₂ - OC ₆ H ₄ -O-CH ₂ -CH ₂ -, a-CH ₂ -C ₆ H ₄ -O-CH ₂ -CH ₂ -p wherein y is an integer from 1 to 6. • · · · 369 Use according to claim 22, characterized in that compounds of formula 1b are used, wherein R ^F is a straight or branched perfluorinated alkyl radical of the formula C _n F _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, characterized in that the following compounds are used: 1.4.7- Tris (carboxylatomethyl) -10- (3-aza-4-oxo-hexan-5-yl) -acid-N- (2,3-dihydroxypropyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex 1.4.7- Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) acid- [N (3,6,9,12,15-pentaoxa) -hexadecyl] -Ν- (ΙΗ) , ΙΗ, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl] -amide} -1,4,7,10tetraazacyclododecane, gadolinium complex 1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -acid-N- (5-hydroxy-3-oxa-pentyl) -N- (1H, 1H) 2H, 2H, 4H, 4H, 5H, 5H-3-Oxa-perfluorotridecyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex 1.4.7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) -surea- [N-3,6,9,16-tetraoxa-13-aza-14-oxo-C17] -C ₂₆ -heptadecafluoro) hexacosyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex 1.4.7- Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-hexan-5-yl) -acid-N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H) -1,4,7,10-tetraaza-cyclododecane, gadolinium complex, 5H-3-oxo-perfluorotridecyl] amide. Use according to one of Claims 1 to 7, characterized in that the compounds of the formula 1c are used as perfluoroalkyl metal complexes with sugar residues. 370 (K), ^1- G - (ZR ^F ) _m ' I (1c) (Y-R) p 'wherein R is a mono- or oligosaccharide residue attached via the 1OH- or 1-SH- position, R ^f is a polyfluorinated, straight or branched hydrocarbon chain of the formula -C _n H _2n E, wherein 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 wherein R ¹ denotes a hydrogen atom or a metal ion equivalent of atomic 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, C 1 -C 7 alkyl, benzyl, phenyl, -CH ₂ OH or -CH ₂ -O-CH ₃ , and U is -C ₆ H ₄ -0-CH ₂ -CO-, - (CH ₂₎ i -CO _5, phenyl, -CH ₂ -NHCO-CH ₂ -CH (CH ₂ COOH) -Ο ₆ Η -ω ₄ group, -C ₆ H ₄ - (OCH ₂ CH ₂ ) o N (CH ₂ COOH) -CH ₂ -O>, or an alkylene group having 1 to 12 carbon atoms or a C ₇ -C ₁₂ -C ₆ H ₄ -O- group, optionally interrupted with one or more oxygen atoms, 1 to 3 -NHCO-, 1 to 3 -CO-NH- and / or Substituted with 1 to 3 groups - (CH ₂ ) 0-5COOH, where ω is the site of attachment to the -CO- group, or of formula IIIc wherein R ¹ is as defined above, R ⁴ is hydrogen or an equivalent the metal ion given in the definition of R ¹ and U ¹ is -C ₆ H ₄ -OCH ₂ -co-, where ω is the binding site to the group -CO-, or formula IVc ROOC (IVc) wherein R ¹ and R ² are as defined above, or of the general formula VcA or VcB COv COOR ROOC n: -COOR -COOR (VCA) 372 • and a · ^ x-COOR ’ OZ ⁿ '-COOR' / (VcB) m -COOR ^{1 zIN 4} COOR ¹ wherein R ¹ is as defined above, or of formula VIc or formula VIc ROOC R ¹ OOC ROOC ROOC O (Villa) wherein R ¹ is as defined above, U ¹ is the group -C ₆ H ₄ -O-CH ₂ -o, where ω is the binding site to the group -CO-, or of the general formula VIIIc wherein R ¹ is as defined above, (VIIIc) ···· · · · · · · · · · · · · · · · And wherein the optionally free carboxyl groups in residue K may be in the form of salts of 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) and) H _α (CH 2) - C-CO — Y ^H NH i β (b) Y - ^ CO - C - CH3 --N - NH i α d) β 374 ti ti ti titititi E) g) »ti ti ti ti ti ti ti ti ti« H NH-CO-C- (CH-N-N in H-a-1H) N- ^ Y NH H JM-CO -C-tCH3-NH4b AND NH NH-CO-CH- _(CH2) -NH- ^ 3 N-CO-CH- _(CH2) 4 --NH - ^ <x NH AND NH-CO-CH- _(CH2) -NH- ^ B · NH • «• · · h) —N- (CH ₂ ) ₄ -SN-ω ₅ - (CH ₃ ) -N- β π π | π <r ° NH Y i β and) j) <χτΜ ~ ΝΗ — CH — CO — Y β and G when K is a metal complex VIIIc, is at least a triple functionalized moiety selected from the group consisting of k) or 1) k) p-NH- (CH ₂ ) _n CH-CO-α NH i Y i) • fc 376 ^ and CO-CH = _CH-CO-R-Y NH i β where a denotes binding site G to complex K, β denotes binding site G to residue Y and γ denotes binding site G to residue Z Y is -CH ₂ -, δ- (CH ₂ ) _{( 1-5} ) 00 -β, 8-CH ₂ -CHOH-COβ, or δ-CH (CHOH-CH ₂ OH) -CHOH-CHOH- CO-β, where δ denotes the binding site to the sugar residue R and β denotes the binding site 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, 0 0 ^ n — SO ^ -S or γ -NHCH ₂ CH ₂ - 0 - CH ₂ CH ₂ - ε where γ is the point of attachment of Z to the remainder of G and ε is the point of attachment of Z to the perfluorinated residue R ^{F and l} , m ¹ are independently integers 1 or 2 and p is an integer from 1 to 4. • · β · ti · ti · ti · ti ··· ti · · 377 Use according to claim 30, characterized in that a compound of the formula Ic is used, wherein R is a monosaccharide radical having 5 to 6 carbon atoms or a desoxy compound thereof, preferably glucose, mannose or galactose. 32. Use according to claim 30, characterized in that it is used a compound of formula Ic where R ² and R ³ are independently hydrogen or alkyl having 1 to 4 carbon atoms and / or E in formula -C _n F _2n E is a fluorine atom. Use according to claim 30, characterized in that a compound of formula Ic is used, wherein G is a lysine residue (a) or (b). Use according to claim 30, characterized in that a compound of the formula Ic is used, wherein Z is y-n-so ₂ -e wherein γ denotes the binding site of Z to the residue G and ε denotes the binding site of Z to the perfluorinated residue R ^F and / or Y is 8CH 2 -CO-P, where δ is the binding site to the sugar moiety R and β is the binding site to the moiety G. Use according to claim 30, characterized in that a compound of the formula Ic is used, wherein U in the metal complex K is -CH ₂ - or -C ₆ H ₄ -O-CH ₂ -o), where ω is a bonding agent place to group -CO-. Use according to claim 30, characterized in that the gadolinium complex with 6-N- [1,4,7tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N is used. · · · · · · · · · · · · · · · · · · · · · 378 (Pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - 2-N- [1-O-α-Dcarbonylmethyl-mannopyranose] -L-lysine-1- [1- (4-fluorooctylsulfonyl)] piperazine] -amide. Use according to one of Claims 1 to 7, characterized in that compounds of the general formula Id (K), '- G - (ZR ^F ) _m ' are used as perfluoroalkyl metal complexes with polar residues. I (Id) (R) p ² wherein r ^f is a perfluorinated, straight or branched hydrocarbon chain of formula -C _n F _2n E, wherein 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 IId ROOC R ³ N- (Hd) where R ¹ is a hydrogen atom or a metal ion equivalent of atomic number 23 to 29, 42 to 46 or 58 to 70, R ¹ and R ³ are independently from each other 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-CH ₂ -o, - (CH ₂ ) is -ω, phenyl, -CH ₂ -NHCO-CH ₂ -CH (CH ₂ COOH) -C ₆ H ₄ -m, group 379 • · «· ·· ···· C ₆ H ₄ - (OCH ₂ CH ₂ ) o N (CH ₂ COOH) -CH _{2 -} , or an alkylene group having 1 to 12 carbon atoms or a C ₇ -C ₁₂ -C ₆ H ₄ -O- group, optionally interrupted by one or more oxygen atoms, 1 to 3 -NHCO-, 1 to 3 groups -CO-NH- and / or substituted with 1 to 3 - (CH _{2) 0-5} COOH, where ω is a binding site for -CO-, or of formula IIId ROOC ' -N N COOR ¹ ΝΛ COOR ⁴ 0 _N uJ ¹ - COOR ¹ (IIld) wherein R ¹ is as defined above, R ⁴ is hydrogen or the metal ion equivalent listed under R ¹ and U ¹ is -C ₆ H ₄ -O-CH ₂ -co-, where ω is the binding site to -C0nebo group of formula IVd (IVd) wherein R ¹ and R ² are as defined above, or formula VdA or VdB 380 ROOCT / ^{, N} ^ -COOR ¹ -N \ _n ^ -COOR ¹ ^ - COOR ¹ (VdA) • fc · fcfcfc fc · · fc ···· O II vw — C '' VNr ^C00R ' -COOR ¹ wherein R ¹ is as defined above, (VdB) or of the formula Vid ROOCROOC) N n: -CO-COOR ¹ (Vid) wherein R ¹ is as defined above, or of formula Vild R ¹ OOCROOCROOCROOC: n: n (Vild) wherein R ¹ is as defined above and U ¹ is -C ₆ H ₄ -O-CH ₂ - (O-), where ω is the binding site to the group -CO-, and the acid groups optionally present in the remainder of K may be present in the form of organic and / or inorganic salts bases or amino acids or amino acid amides, β · β β β β β β β β β β β G is at least three times a functionalized moiety selected from the following moieties a) to i) and) H α - N - C - CO - γ ^H NH 4 β (b) LJ Y ^ CO-C-PAN β 1 H a (e) · «···· * · ···· 382 · · · 4 · 4 · 2 · 4 4 4 4 4 382 ····· ·· ·· F) Η H α - N - (CH ₂ ) ₄ -CN-CO-C- (CH 2 -N- ^ β Η Η | H 9 ° NH G) HN / - \ N NH Oí h) γ -co- (ch ₂ ), -ρΗ-οο-'Ύβ NH I α i) β C0- (CH ₂ ), ₃ -CH-CO ~ vay to toto toto t toto toto toto toto toto toto toto toto toto toto toto toto toto toto toto toto 383 ··· ··· ···· where a denotes binding site G to complex K, β denotes binding site G to residue R and γ denotes binding site G to residue Z Z is Y -> - SO ₂ - £ YC (O) CH ₂ O (CH ₂ ) _r e, where γ denotes the binding site Z to the residue G and ε denotes the binding site Z to the perfluorinated residue R ^F R is a polar radical selected from the complex K of the formulas IId to Vild, wherein R ¹ is a hydrogen atom or a metal ion equivalent of atomic number 20, 23 to 29, 42 to 46 or 58 to 70, and the radicals R ² , R ³ , R ⁴ , U and U ¹ have the above meanings, or a residue of folic acid or a hydrocarbon chain having 2 to 30 carbon atoms, straight or branched, saturated or unsaturated, bound to the rest of the group G by -C0-, -S0 ₂ - or a direct optionally interrupted having 1 to 10 oxygen atoms, 1 to 5 -NHCO-, 1 to 5 -CONH-, 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 OH groups, 1 to 5 2 NH ₂ groups, 1 to 2 -COOH groups or 1 to 2 -SO ₃ H groups, or optionally substituted with 1 to 8 hydroxy groups, 1 to 5 -COOH groups, 1 to 2 SO ₃ H groups, 1 to 2 5 NH ₂ groups, with 1 to 5 C 1 -C ₄ alkoxy groups, to a. l ¹ , m ¹ , p ² are independently integers 1 or 2. Use according to claim 37, characterized in that compounds of the formula Id are used, wherein K is a metal complex of the formula Idd, Illd, VdB or Vild. Use according to claim 37, characterized in that compounds of the formula Id are used, wherein the polar residue R has the meaning of the complex K, preferably the complex of the formula Idd, IIId, VdA or Vild. Use according to claim 37, characterized in that compounds of the formula Id are used, wherein the polar residue is: -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) CH 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 - (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 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 ·· 9 9 9 · · »Ι5 · · 385 • 9 • 9 • 9 9 9 9 9 9 99 -C (Ο) 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 -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) ₂ -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₎ ) ₂ O] ₄ -CH ₃ . Use according to claim 37, characterized in that compounds of the general formula (Id) are used, wherein the polar residue is folic acid. Use according to claim 37, characterized in that compounds of the general formula (Id) are used, wherein G is a lysine residue of (a) or (b). Use according to claim 37, characterized in that compounds of the formula Id are used, wherein U in the metal complex K is -CH ₂ - or -C ₆ H ₄ -O-CH ₂ -G), where ω is the site of binding to the -CO- group. Use according to claims 37 to 43, characterized in that a gadolinium complex with 2,6-N, β-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane is used. -10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - lysine [1- (4-perfluorooctylsulfonylpiperazine) -amide. Use according to one of Claims 1 to 7, characterized in that a composition comprising a paramagnetic perfluoroalkyl metal complex of the general formula I, Ia, Ib, Ic is used as the galenical preparation of the perfluoroalkyl metal complex. 386 and / or Id and a diamagnetic perfluoroalkyl substance, preferably dissolved in an aqueous solvent. Use according to claim 45, characterized in that the diamagnetic perfluoroalkyl compound used 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. Use according to claim 46, characterized in that 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 with one or more -OH groups, COO-, -SO ₃ - and / or may optionally 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 O atoms and / or may be substituted with a group -COO or -S0 _third Use according to claim 46, characterized in that the hydrophilic group B ² is a mono- or disaccharide, one or more adjacent -COO 'or -SO ₃ ' - groups, dicarboxylic acid, isophthalic acid, picolinic acid, benzenesulfonic acid, tetrahydropyrandicarboxylic acid acid, 2,6-pyridinedicarboxylic acid, quaternary ammonium group, aminopolycarboxylic acid, aminodipolyethylene glycol sulfonic acid, aminopolyethylene glycol group, SO ₂ - (CH ₂ ) ₂ -0H group, 387 a polyhydroxyalkyl chain with at least two hydroxy groups or one or more polyethylene glycol chains with at least two glycol units, wherein the polyethylene glycol chain is terminated by -OH or OCH ₃ . Use according to claim 45, characterized in that the diamagnetic perfluoroalkyl substance used is a conjugate of α-, β- or γ-cyclodextrin and a compound of formula XXII: A ² -L ³ -R ^f (XXII) wherein A ² is adamantane, biphenyl or anthracene molecule, L ³ is a linker and R ^F is a straight or branched perfluoroalkyl radical having 4 to 30 carbon atoms, 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 of 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. Use according to claim 45, characterized in that the diamagnetic perfluoroalkyl compound is a compound of the formula (XXI): R ^f -X ^x (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): 388 Q h02 389 OH 390 ·· ···· γ-COO —S-N About —COO ' COO ' _C and ²⁺ N COO ' COO 391 OO ' COO 'ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti ti·· ti ····· 1/18 GIANT. 1 basic condition 24 h after application 48 h after application stained (Sudan III) Metal complex XV: 25 pmol / kg intravenously; 3D-T, -MPRage, TR / TE 11.1 / 4.3 ms, and 15 °; (Watanabe rabbits; A = aorta, H = heart, arrows = plaque vascular defects; MPR projection; histology after staining with Sudan III staining) 2/18 GIANT. 2 basic 35 minutes 60 minutes 24 h post-application post-application post-application Metal complex XV: 10 pmol / kg intravenously; 3D-T _r MPRange, TR / TE 11.1 / 4.3ms, α 15 ° · (Watanabe rabbits; A = aorta, H = heart, arrows = plaque vascular defects) sequence spino-stained echo sequence (Sudan III) MPRange Metal complex XV: 10 μιυοΐ / kg intravenously; 3 D-T, -MPRange, TR / TE 11.1 / 4.3 ms, α 15 °; (Watanabe rabbits; 24 h after application; aortic preparation; histology after staining with Sudan ΠΙ staining) post mortem MRI aorta stored in agar 3/18 GIANT. 3 Metallic complex XV: 100 μηιοΐ / kg intravenously; SE, TR / TE 400/6 ms; arrow = myocardial infarction 4/18 GIANT. 4 24 h post-mortem application, coronary 24 h after in vivo application, axial 24 h post-mortem, axial Metal complex I; 100 gmol / kg intravenously; SE, TR / TE 400/6 ms; arrow = myocardial infarction 5/18 GIANT. 5 basic 5 min 30 min 60 min 24 h Post-application post-application Post-application post-application Metal complex XV: 200 pmol / kg intravenously; 3D T _r MPRange, TR / TE 11.1 / 4.3 ms, α 15 °; (arrow = metastasis; T = tumor) baseline 30 minutes 60 minutes 24 h post-post administration post-post administration Metallic complex XV: 200 μιηοΐ / kg intravenously; TR / TE 11.1 / 4.3 ms, α 15 °; primary tumor TV MOl --- W 6/18 GIANT. 6 Metal complex I: 100 pmol / kg intravenously; 3D-Ij-MPRange, TR / TE 11.1 / 4.3 ms, and 15 ° (solid arrow = lymph nodes; T = tumor; arrow = later increase) TV & oe 2 7/18 GIANT. 7 6 h after application 6 h after application 6 h after in vivo application, axial post mortem, axial post mortem, coronary Metal complex X: 100 pmol / kg intravenously; SE, TR / TE 400/12ms; arrow = myocardial infarction -ÝIZ Z. 8/18 GIANT. 8 base 15 minutes 60 minutes after application ^status after application Metal complex X: 100 pmol / kg intravenously; 3D-T _r MPRange, TR / TE 11.1 / 4.3ms, and 15 ° (arrow - popial lymph node) 9/18 GIANT. 9 Metal complex X: 200 pmol / kg intravenously; 3D-T _r MPRange, TR / TE 11.1 / 4.3 ms, and 15 ° (arrows, M = metastasis, T = tumor) TV to> 3 10/18 GIANT. 10 Metal complex V: 100 pmol / kg intravenously; SE, TR / TE 400/12 ms, arrow = myocardial infarction pv 11/18 GIANT. 11 basic 15 minutes 60 min after application Metal complex III: 200 gmol / kg intravenously; 3D-Tj-MPRange, TR / TE 11.1 / 4.3 ms, and 15 (arrow = popliteal Iymph Node) TV fsog, ' 12/18 GIANT. 12 colored basic condition 15 minutes after application 60 minutes after application (H / E) Metal complex V: 200 pmol / kg intravenously; 3D-1j-MPRange, TR / TE 11.1 / 4.3 ms, and 15 (arrows, M = metastasis, T = tumor) pV Zoř! -37Z, 13/18 GIANT. 13 3 h after administration 3 h after administration 3 h after in vivo administration, axial post mortem, axial post mortem, coronary arrow = myocardial infarction 14/18 GIANT. 14 Metal complex XIV: 200 pmol / kg intravenously; flash outhphase, TR / TE 10/5 ms, α 40 ° arrows = inguinal and iliac lymph nodes 15/18 GIANT. 15 basic 10min 30 min 23 h stained post-application post-application (H / E) Metal complex XIV: 200 pmol / kg intravenously; MPRange, TR / TE 11.1 / 4.3 ms, α 15 ° · 80 rabbit sections with VX2 tumor; arrows = metastases TV 16/18 GIANT. 16 22 h after application 22 h after application 22 h after in vivo application, axial post mortem, axial post mortem, coronary Metallic complex III: i00 μιηοΐ / kg intravenously; SE, TR / TE 400/12ms; arrow = myocardial infarction TV 17/18 GIANT. 17 basic 15 minutes 60 min after application Metal complex V: 200 gmol / kg intravenously; 3D-T, -MPRange, TR / TE 11.1 / 4.3 ms, α 15 ° (arrow = popliteal lymph node) -fy SLe> » 18/18 GIANT. 18 Metal complex III: 200 μιυοΐ / kg intravenously; 3D-T | -MPRange, TR / TE 11.1 / 4.3 ms, and 15 ° (arrows, M = metastasis, T = tumor)