BG107542A - The use of perfluoralkyl-containing metallic complexes as contrast means for images in nuclear magnetic resonance and representation of plaques, tumours and necroses - Google Patents

Abstract

The invention relates to the use of perfluoralkyl-containing metallic complexes with critical concentration of mycelium-formation <10-3 mol/l, hydrodynamic diameter of the mycelium (2 Rh) >1 mm and proton relaxation in plasma (R1) >10 l/mmol.s as contrast means for images in nuclear magnetic resonance, as well as for the presentation of plaques, lymphatic nodes, infarction and necrotic tissues, as well as independent imaging of necrotized and tumour tissues. 50 claims, 17 figures

Description

USE OF HA P ERFLUORAL KIL CONTAINING METAL COMPLEXES AS CONTRAINDIC IMAGES FOR NUCLEAR - MAGNETIC RESONANCE, AND NOZZLE REPRESENTATION

Technical field

The invention relates to the use of perfluoro-containing metal complexes, which show a critical concentration for the formation of micelles <10 ~ ³ mol / l, hydrodynamic diameter of the micelles (2 Rh)> 1 nm and proton relaxation in plasma (R ¹ )> 10 I / mmol.s, as contrasts for MR - imaging of both plaques, lymph nodes, infarcted and necrotic tissues, as well as for independent imaging of necrotic tissue and tumor tissue. Perfluorine-containing metal complexes with these properties were found to be suitable for imaging plaques, tumors, and necrosis with the help of nuclear magnetic imaging and at the same time discovering the diagnostically important area for imaging infarction and necrosis images.

BACKGROUND OF THE INVENTION

Arteriosclerosis is the most important and common painful change of the arteries with hardening, thickening, loss of elasticity and reduction of the aperture. They are the most common cause of death in Western industrial communities. Changes to the walls of the vessels lead to lipid accumulation, to the enlargement of the connective tissue and calcification with uneven deposition, to destabilization of the walls, to alteration of the vessels and to the deposition of clots.

Diseases are caused by numerous external and internal poisons, respectively, such as hypertension, hyperlipidemia, hyperfibrogenemia, Diabetes mellitus, toxins, nicotine, antigen-antibody complexes, inflammation, hypoxia, mental stress, age and family burden. All of these lead to disturbances in the integrity of the inner walls of the vessels, to disturbances in the control of smooth muscle growth on the walls of the vessels, and to the degradation of other naturally occurring cell constituents. It is not possible to treat arteriosclerosis alone, the goal of medical efforts is to prevent it by reducing risk factors, for example by reducing lipid content.

Diagnosis of arteriosclerosis in clinical practice is currently being done through angiography as the best option. The limitation of all methods based on measurement of vascular cavity reduction, however, is an early stage of the disease, which is characterized by a single vessel vessel compaction at a normal vascular cavity (Glagov S, Zarins SK. Quantitating atherosclerosis. In: Bond MG , Insull W, Glagov S, Chandler AB,

Cornhill JF (eds.). Clinical Diagnosis of Atherosclerosis. Quantitative Methods of Evaluation. New York: Springer-Verlag, 1983, 11-35). Another method of diagnosing vascular walls and vascular cavities is intra-space or subcutaneous ultrasound irradiation.

Magnetic magnetic resonance imaging (MRT) is a modern, non-aggressive radiological method that is possible with a very good imaging of physiological and pathophysiological structures. The use of specific contrast agents with selective uptake in certain tissues and organs can greatly increase diagnostic capabilities. The preparations of contrast agents with selective accumulation in arteriosclerotic plaques could cover the localization and extent of the disease in an initial stage and thus make timely therapy and prophylaxis possible, and therefore the search for appropriate contrast agents is early.

For example, US Patent No. 4,677,636 describes hematoporphyrin derivatives as contrast agents for the detection of atherosclerotic plaques. Scintigraphy, X-ray, fluorescence and for paramagnetic metal porphyrins are also referred to as nuclear nuclear magnetic spectrometry. Gd, Cr, Co, Ni, Ag and Eu are mentioned as vapor - magnetic ions.

The disadvantage of these compounds is that porphyrins are deposited in the skin and cause discolourations that can persist for many weeks. As a result, they lead to photosensitivity. In addition, there is a danger of metalloporphyrin losing metal during a longer stay in vivo.

WO 95/09856 discloses metal porphyrins (plaque porphyrins) for the diagnosis and treatment of plaques. MRI is indicated as the diagnostic method. And for these porphyrins, it is true that they cause skin discoloration.

WO 95/09013 discloses conjugated compounds of specifically linked peptides and metal complexes. These compounds should bind to the plaques and thus be able to diagnose and treat them. Scintigraphy, computed tomography and MRI are indicated as diagnostic methods. Scintigraphy has been experimented with, but MRI guidelines are missing.

Patent US 5,807,536 describes labeled phycocyanins as contrast agents for imaging plaques. X-ray, computed tomography, scintigraphy, SPECT and nuclear magnetic imaging are referred to as diagnostic methods. Scintigraphy was experimentally required.

There are countless many contrast agents known in the literature for the presentation of infarction and necrosis. Attempts have been made to improve the localization of infarcts and necrosis by adding contrast agents to non-interventional methods such as scintigraphy or CT scans. Numerous experiments have been described in the literature using porphyrins for necrosis. However, some results provide a contradictory picture. For example, Winkelman and Hoyes describe in Nature, 200, 903 (1967) that manganese-5,10,15,20 tetrakis (4-sulfonatophenyl) -porphyrin (TPPS) is selectively taken up in the necrotizing portion of a tumor.

Conversely, Lyon at al. (Magn. Res. Med. 4, 24 (1987)) observed that manganese - TPPS is distributed in the body, and thus in the kidneys, lungs, tumor and only a small part in the muscles. The interesting thing here is that the concentration in the tumor reaches its maximum only on the fourth day and also, again according to the authors only, the dose is increased from 0.12 mmol / kg to 0.2 mmol / kg. Therefore, the authors also talk about a non-specific ability to receive TPPS in the tumor. Bockhurst et al. in Acta Neurochir 60, 347 (1994, Suppl.) that MnTPPS binds selectively to tumor cells.

Forster et al. (J. Nucl. Med. 26,756 (1985)), for their part, found that ¹¹¹ in-5,6,15,20 - tetrakis - (4-N-MeNnpyridine) -porphyrin (TMPur) was not accepted by the necrotic moieties , and from the living borderline. It follows that there is an exchange action between the porphin and the tissue, which is very close but not convincing.

In Circulation Vol. 90, No. 4, Part 2, Page 1468, Description No. 2512 (1994) Ni et al. reported that they could present with infarcted areas with one manganese - tetraphenyl porphyrin (Mn-TPP) and one gadolinium mesoporphyrin (Gd - MP). International Patent Application WO 95/31219 uses both substances for infarcted and necrotic imaging. The authors Marchal and Ni reported (see Example 3) that for the Gd-MP compound, the metallic content in infarcted kidneys was similar to that in the non-infarcted organ, and yet for the infarcted myocardium (Example 1) it was ninefold. Unsurprisingly, the ratio of signal intensity to nuclear-magnetic imaging for infarct tissue compared to healthy tissue in both cases at 2.10 and 2.19, respectively, is still comparable. Other metal porphyrins are described in application DE 19835082 (Schering AG).

Porphyrins tend to be deposited in the skin, leading to photosensitivity. Sensitivity can last up to weeks. This is an undesirable side effect of using porphyrins for diagnosis. In addition, the therapeutic index for porphyrins is very small, since Mn-TPPS only work at a dose of 0.2 mmol / kg and the LD50 value at 0.5 mmol / kg.

In DE 19744003 (Schering AG), DE 19744004 (Schering AG) and

WO 99/17809 (EPIX) describes non-porphyrin-containing contrast agents for necrotic and infarct imaging.

DE 19744003 describes oligomeric compounds consisting of a nucleus and linked to 1-3 metal complexes.

Application 19744004 describes lipophilic metal complexes for necrosis and infarction imaging. These compounds include metal complexes of polyaminopolycarboxylic acids, polyaminopolyphosphonic acids, porphyrins, texapyrins, saccharines, peptides.

EPIX application WO 99617809 describes the use of DTPA derivatives for necrotic imaging. The most significant compound is the gadolinium complex of a hydroxymethyl phosphodiester - DTPA (MS - 325).

Perfluoroalkyl containing metal complexes as nuclear magnetic magnetic contrast agents are also known. WO 97/26017 (Schering) and WO 99/01161 (Schering) describe the use of perfluoroalkyl containing metal complexes as lipography. WO 99601161 also describes the ability of these compounds to represent blood-pool agents.

EP 417870 A1 discloses compounds for tumor diagnosis and tumor therapy.

Heart attacks and ischemia have been reported to be depicted. However, the request does not constitute an experimental confirmation of this claim. These compounds are chelate complexes of the type N2S2 and N3S with radioisotopes. Ato diagnostic method is scintigraphy.

DE 19646762 also uses scintigraphy as a diagnostic method. The description lists metal chelates as radiosensitive for the treatment of hypoxic tumors and for the diagnosis of hypoxic conditions and necrosis. The specification specifically refers to nuclear magnetic diagnostics, X-ray diagnostics and radiodiagnosis as diagnostic methods.

German application DE 19824653 describes porphyrins as substances with affinity for necrosis for the treatment of tumors. The disclosure states that the compounds are administered in the necrotized and hypoxic regions of the tumors. The compounds can be used for diagnostic purposes in the form of their metal derivatives with paramagnetic ions and radioisotopes, respectively.

In both applications, DE 19646762 and DE 19824653, it is common ground that the presentation of necrosis and tumors does not proceed independently of one another, but that necrosis is part of the tumor.

SUMMARY OF THE INVENTION

The present invention is intended to provide nuclear magnetic imaging contrasts that are suitable for the presentation of plaques, lymph nodes, infarct and necrotic tissues as well as for the independent presentation of necrosis and tumors.

It has surprisingly been found that perfluoroalkyl containing metal complexes having a concentration limit for micelles formation <10 ^_3 mol / l, hydrodynamic diameter of the micelles (2 Rh)> 1 mm and proton relaxation in plasma (R ¹ )> 10 l / mmol.s are very suitable as contrast agents for nuclear magnetic imaging of plaques. At the same time, these compounds can be used both for the presentation of lymph nodes, infarct and necrotic tissues as well as for the independent presentation of necrotic tissues and tumor tissues.

Suitable perfluoroalkyl-containing metal complexes for use according to the invention are those which, as a non-polar moiety, have a perfluoroalkyl side chain which is optionally linked through a lipophidic unit to the whole molecule. The polar portion of the compounds according to the invention is bonded through one or more metal complexes and optionally through the other polar groups present. In aqueous systems, these aliphatic molecules exhibit properties characteristic of classical surfactants or also called surfactants (such as sodium dodecyl sulfate, SDS). In this way, they reduce the surface tension of the water. Tensiometry can be used to determine the so-called CMC (critical concentration for the formation of micelles in mol / I). This determines the surface tension depending on the concentration of the substance being measured. The CMC concentration is calculated from the characteristic of the surface tension obtained (c). The critical concentration for micelles formation of the compounds of the invention should be <10 ³ mol / l, preferably ≤ 10 ′ ⁴ mol / l.

The aliphatic compounds of the invention are associated in solution and are in the form of aggregates. The size (2 Rh) of such aggregates (such as micelles, rod cells, clouds, etc.) was determined by photon correction spectroscopy (PCS).

The second criterion is the hydrodynamic diameter of the 2 Rh micelles, which should be> 1 pg. Particularly suitable according to the invention are such perfluoroalkyl containing metal complexes whose 2Rh is> 3 nm, especially preferably> 4 nm.

Both the determination of the CMC and the photon-correlation spectroscopy are described by H.-D. Dorfler, “Grenzenflachen- und Kolloidchemie”, Weinheim, New York, Bael, Cambridge, Tokyo, VSH 1994.

The third criterion is the proton relaxation in plasma (R ¹ ) at 40 ⁰ C and a field strength of 0.47 tesla. The relaxation, which is defined in [I / mmol.s], is a quantitative measure of the shortening of the T ¹ relaxation beam of protons. For the purpose of the invention, the relaxation should be as high as possible and> 10 l / mmol.s, preferably> 13 l / mmol.s, in particular> 15 l / mmol.s.

The relaxation R ¹ [I / mmol.s] of the nuclear magnetic contrast agents according to the invention is determined by Bruker Minispec P 20. The measurements are made at a temperature of 40 ⁰ C and a field strength of 0.47 tesla. For each T1 in sequence: 180 ⁰ - TI -90 °, inversion recovery, 8 points are determined. Kraeber's bovine plasma serves as the medium. The concentrations of contrast agents [mmol /] are in the range of 0.30 to 1.16.

In one embodiment of the present invention, the compounds of general formula I according to claims 8 to 11 are used as preferred compounds. These are known compounds which are described in WO 97/26017. They can also be obtained according to the WO description provided. Surprisingly, these compounds are very suitable as contrast agents for nuclear magnetic imaging and plaque presentation. Particularly preferred compounds are metal complexes I-IV, VI and XI-XIII (cf. also Table 1).

In another embodiment of the present invention, preferred compounds are those of general formula Ia according to claims 12 to 21. These compounds are known and are described in WO 99 / -1161. However, their use as MR contrast media for plaque imaging has not yet been described. Particularly suitable for use with these compounds are metal complexes XIX (compare Table 1).

In another preferred embodiment of the invention, macrocyclic perfluoroalkyl compounds of the general formula 1b can be used

A

I _F k - N - LR (lb) in which

K means one complexing agent of general formula

II b

as

R ¹ denotes a hydrogen atom or a metal ion equivalent of ordinal number 23-29, 42-46 or 58-70,

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

U ² means the radical L ¹ , where L ¹ and U ² independently of one another may be the same or different,

A ¹ means one hydrogen atom, one straight or branched chain alkyl group of 1 to 30 carbon atoms, which is interrupted in one case by 1-15 oxygen atoms, and / or optionally substituted by 1-10 hydroxyl groups, 1 -2 COOH groups, one phenyl group, one benzyl group, and / or 1-5 OR ⁹ groups, with R ⁹ being a hydrogen atom or an alkyl radical having 1 to 7 carbon atoms, or -L ¹ -R ^F ,

L ¹ means one straight or branched chain alkylene group of 1 to 30 carbon atoms which is optionally interrupted by 1-10 oxygen atoms, 1-5 -NH-CO groups, 1-5 -CO - NH groups, from one phenylene group optionally substituted by one COOH group, 1 to 3 sulfur atoms, 1 to 2 -N (B ¹ ) - SO 2 groups, and / or 1 to 2 -SO 2 -N (B ¹ ) -rpynn as B ¹ has the meanings of a ^1, a NHCO - group, a CONH-group, a N (B ¹⁾ - SO2-group, a -SO ₂ -N (B ¹⁾ -group and / or may optionally be substituted with the radical R ^F , and

R ^f denotes one straight or branched chain perfluorinated alkyl radical of the formula C _n F _2n E, with η being the numbers 4 - 30 and

E represents one terminal fluorine atom, a chlorine atom, a bromine atom, an iodine atom or a hydrogen atom, and optionally the available acid groups may optionally be as salts of organic and / or inorganic bases or amino acids or amides of amino acids.

Because the compounds of the invention can be used in nuclear magnetic resonance diagnostics, the metal ion of the signaling groups must be paramagnetic. Such are, in particular, the divalent and trivalent ions of the elements of numbers 23 - 29, 42 - 46 and 58 70. Suitable ions are, for example, chromium (III) -, iron (II) -, cobalt (II) -, nickel ( P) -, copper (P) -, praseodymium (III) - neodymium (III) -, samarin (III) - and ytterbium (III) ion. Because of their highly polar moment, gadolinium (W) -, terbium (W) -, dysprosium (W) -, holminium (W) -, erbium (W) -, iron (W) - and manganese (H) ions are particularly suitable .

Preferred are manganese (P) -, iron (P) -, iron (1P) -, praseodymium (W) -, neodymium (W) -, samarium (W) -, gadolinium (W) -, and innerbium (1P) - ions, in particular dysprosium (1P) ions.

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

Preferred R ² , R ³ and R ⁹ are hydrogen and alkyl groups of 1 to 4 carbon atoms, in particular hydrogen and methyl.

The benzyl and phenyl groups R ² , A ¹ and B ¹ may be substituted in the phenyl ring. COOH groups are considered to be the markers.

When the compound of formula I b contains the radicals L ¹ and U ² simultaneously, then L ¹ and U ² may be different.

Alkylene groups of 1 to 30 carbon atoms U ² can be straight or branched. Examples are methylene, ethylene, propylene, isopropylene, η-butylene, 1methylpropylene, 2-methylpropylene, η-pentylene, 1 methylbutylene, 2-methylbutylene, 3-methylbutylene, 1,2dimethylpropylene.

For U ² meaning alkylene, alkylene groups of 1 to 10 carbon atoms are preferred, in particular alkylene groups of 1 to 4 carbon atoms are preferred.

Alkyl groups A ¹ may be a straight or branched chain. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3methylbutyl, 1,2-dimethylpropyl, n-hexyl.

Alkyl groups having 1 to 30 carbon atoms, A ¹ may be interrupted by 1-15 oxygen atoms, and / or be substituted by 1 - 10-hydroxy-15 alkoxy or 1-2 SOONgrupi such as C ₂ H ₄ -O-CH3, CH3-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 s 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 n ₁₄ OH, and their branched isomers,

CH (OH) CH ₂ OH,

CH (OH) CH (OH) CH ₂ OH, CH ₂ [CH (OH)] _U c and ¹ = 1-10 CH [CH ₂ (OH)] CH (OH) CH ₂ OH,

C ₂ H ₄ CH (OH) CH ₂ Ohq (CH ₂ ) _S COOH with s = 1 to 15, C ₂ H ₄ -O- (C ₂ H ₄ -O) _t -CH ₂ COOH with t = 0 to 13, C ₂ H ₄ -O- (C ₂ H ₄ -O) tC ₂ H ₄ -CnF _2n E with t = 0 to 13, η = 4 to 20 and E = one fluorine atom, hydrogen, chlorine, bromine or iodine atom.

Preferred meanings of A ¹ are each hydrogen, alkyl C1 to 10 carbon atoms,

C2H4-O-CH3, SzN ₆ -O-CH,

C ₂ H ₄ -O- (C ₂ H 4 O) _x -C ₂ H ₄ -OH, C ₂ H 4 -O- (C2H4-O) _X -S2N4-OCH _3, with x = 0 to 5,

C2H4OH, C3HeON,

CH ₂ [CH (OH)] _In CH ₂ OH, with y = 1 - 6

CH [CH ₂ (OH)] CH (OH) CH ₂ OH, (CH ₂ ) _W COOH with w = 1 to 10,

C ₂ H 4 -O- (C ₂ K4-O) _x -CH 2 COOH with x = 0 to 5, C ₂ H ₄ -fl- (C ₂ H ₄ -O) _x -C ₂ H ₄ -CnF2nE with x = 0 to 5, η = 4 to 15 and E = one fluorine atom.

When the compound of general formula 1b contains two radicals L ¹ -R ^F , then the radicals can be cracked apart.

For radical L ¹ , indicate when a for the bond with the nitrogen atom and β for the bond with the radical R ^F :

a (CH ₂ ) _s with s = 1-15 a-CH ₂ -CH ₂ - (O-CH ₂ -CH ₂ -) y- β with y = 1-6 α-ΟΗ ₂ - (0-ΟΗ ₂ -ΟΗ ₂ -) - β with y = 1-6 α-ΟΗ ₂ -ΝΗ-00-β a-CH ₂ -CH ₂ -NH-SO ₂ ^ a-CH ₂ -NH-CO-CH ₂ -N (CH ₂ COOH) -SC ^ a-CH ₂ NH-CO-CH ₂ -N (C ₂ H ₅ ) -SO ^ a-CH ₂ -NH-CO-CH ₂ -N (Ci ₀ H ₂ i) -SO ₂ ^ <a-CH2-NH-CO -CH2-N (C6H ₁₃₎ -SO2-3 a-CH2-NH- CO- (CH ₂₎ i 0-N (C ₂ H ₅₎ -SO2-P a-CH2- NH-CO-CH2-N ( -CH2-C6H ₅₎ -SO2-3 a-CH2-NH- CO-CH2-N (-CH2-CH ₂ -OH) SO2-P a-CH ₂ -NHCO- (CH ₂ ) ₁ oS-CH ₂ CH _2- RUB a-CH ₂ NHCOCH ₂ -O-CH ₂ CH2-P a-CH2-CH ₂ NHCOCH2-0-CH2CH2-P a-CH2- (CH ₂ -CH ₂ -O ) y- (CH ₂₎ 3NHCO-CH ₂ o-CH2CH ₂ -p mft y = 1-6 a-CH ₂ NHCO (CH ₂₎ i o-0-CH ₂ CH ₂ -3 a-CH ₂ CH2NHCO (CH ₂ ) iO ' ^o ' C ^H 2 ^c H2'0 a-CH ₂ -C ₆ H ₄ -O-CH ₂ CH ₂ -p as the phenylene group 1,4 or

1,3 is bonded a-CH2-O-CH2-C (CH ₂ -OCH ₂ CH ₂ -C ₆ Br 3) 2 -CH ₂ -OCH ₂ -CH ₂ -p a-CH ₂ -NHCOCH ₂ CH ₂ C0N-CH ₂ CH ₂ NHCOCH ₂ N ( C2H5) SO2C8Fi7p a-GH2-CH2NHCOCH2N (C ₂ H5) -SO2-3 a-CH2-O-CH ₂ -CH (OS ₁₀ H21) 'CH2-O-CH ₂ CH ₂ -p a- (CH ₂ NHCO) 4-CH ₂ O-CH ₂ CH ₂ ^ a- (CH ₂ SHCO) c-CH ₂ O-CH ₂ CH ₂ -p a-CH ₂ -OCH ₂ C (CH ₂ NR) ₂ -CH 2 -O-CH ₂ CH ₂ - 0

a <M2NHCOCH ₂ N (C ₆ H5) -SO2- £ a-NHCO-CH2-CH2-3 a-NHCO-CH2-O-CH ₂ CH2-P a-NH-CO-β a-NH-C0-CH2 -N (CH ₂ C00H) -SO2-3 a-NH-CO-CH2-N (C ₂ H5) -SO2- £ a-NH- € 0-CH2-N (Ci _O H ₂ 1) -SO2-₽ a-NH-CO-CH2-N (C6Hl 3) -SO ₂ -0 a-NH-CO- (CH2) io-N (C ₂ H5> SO2-p a-NH-CO-CH2-N (-CH2 -C ₆ H5) -SO2> P a-NH-CO-CH2-N (-CH ₂ -CH2-OH) SO2-RUB a-NH-C0-CH2-p a-CH2-0-C ₆ H4-O -CH2-CH2-P a-CH ₂ -C H ₄ -O-CH ₂ -CH ₂ -3 aN (C ₂ H ₅ ) -SO ₂ -p a N (C ₆ H ₅ ) -SO 2-3 a N (C ₁₀ H ₂ i) -SO 2 - P a-NfCgHisJ-SO ^ -P aN (C ₂ H4OH) -SO ₂ > P α-Ν (ΟΗ ₂ ΟΟΟΗ) -5θ2-β aN (CH2C6H5) -SO2-3 aN- [CH (CH ₂ OH) 2bSO2 -P α-Ν- (ΟΗ (ΟΗ2θΗ) ΟΗ (ΟΗ) (ΟΗ2θΗ)] - 5θ2-β

Preferred are:

a-CH2-O-CH2CH2 * ₽ a-CH2-CH2- (O-CH2-CH2-) _y -3 mit y = 1-6 a-CH2- (O-CH2-CH2 ~) y-3 mrt y = 1-6 a-CH2-CH2-NH-SO ₂ -P Bsp. 10 a-CH2NHCOCH2-O-CH2CH2- £ a-CH ₂ -CH ₂ NHCOCH ₂ -O-CH2CH2-P a-CHrCCHrCHzOJrfCH ^ sNHCO-CHz-O-CHsCHa-P mit y = 1-6 a-CH2NHCO (CH ₂ ) io-O-CH ₂ CH 2-3 a-CH ₂ CH ₂ NHCO (CH 2) iO-O-CH ₂ CH 2-3 a-CH ₂ -O-CH ₂ -CH (OC ₁ oH ₂ 1) -CH ₂ -O-CH ₂ CH _{2 -} ₽ a-CH2-O-C5H4-O-CH2-CH ₂ -P a-CH2-CbH4-O-CH ₂ -CH ₂ f

Particularly preferred according to the invention are the radicals L ¹ in the compounds of the examples of the present description.

For U ² , the above radicals for L ¹ and the preferred and especially preferred radicals, as well as those mentioned above with the meaning of alkylene and optionally, and in particular preferred radicals, are valid, provided that there are no no available a - positioned nitrogen atom and no available end - positioned (β - positioned) SO2 - or CO - groups.

Preferred B ¹ radicals are hydrogen, straight or branched chain 1 to 10 carbon atoms alkyl radicals which are optionally interrupted by 1-5 oxygen atoms and / or optionally substituted by 1 to 5 hydroxyl groups, 1 - 2 COOH groups, with one optionally COOH group substituted phenyl group, with one benzyl group and / or 1-5 -OR ⁹ groups, with R ⁹ being one hydrogen atom or one alkyl radical having 1 to 3 carbon atoms.

Preferred radicals R ^F are perfluorinated alkyl radicals having a branched or branched chain of the formula C _n F _2n E, with η being the numbers from 4 to 15 and E being the fluorine atom located at the extreme position.

Preparation of the compounds of general formula I b according to the invention k-Ν-lr ^{f A} (ib)

Wherein

K means one complexing agent or one metal complex of general formula II b

is carried out by the following method:

Method A

The carboxylic acid of formula III b contains a ready metal ion equivalent of R ¹ .

(Hlb) (IVb) (lb)

Activated optionally in situ carboxylic acid lllb in which R ¹ has znechenieto of a metal ion equivalent, is reacted with an amine IV b in terms of an addition reactive to an amide I b.

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

The coupling reaction mixture of carboxylic acids containing metal complexes of formula lb, which optionally contain available carboxylic and / or hydroxy groups in protected form, and at least one solubilizing agent up to 5, preferably 0.2 to 2 mol a carboxylic acid equivalent containing a metal complex can be obtained both in a pre-incorporated reaction step and (for example, by evaporation, freeze-drying or water spray or water-mixed component production or by precipitation with an organic solvent from the same solution) and isolated and finally in dimethylsulfoxy (DMSO) medium to react with a water-releasing reagent and optionally with an auxiliary aid can also be obtained in situ optionally by adding solubilizing agent (s) to the carboxylic acid suspension containing metal complexes in dimethyl sulfoxide, adding a water-releasing reagent and optionally one addition auxiliary.

The reaction solution obtained by this method is subjected to one pre-treatment (acid activation) for 1 to 24 hours, preferably 3 to 12 hours, at a temperature of 0 to 50 ^° C, in particular at room temperature.

Finally, an amine of the general formula IV b (IVb) is added in which the radicals R ³ , L ¹ , R ^F u A ¹ have the meanings given above, without solvent or dissolved, for example in dimethyl sulfoxide, alcohols such as methanol, ethanol, isopropanol or mixtures thereof, formamide, dimethylformamide, water or mixtures of the solvents indicated, preferably in dimethyl sulfoxide, in water or in water miscible solvents. In order to bind the amide, the resulting reaction solution is maintained at a temperature of from 0 to 70 ⁰ C, preferably from 30 to 60 ⁰ C, for 1 to 48 hours, in particular 8 to 24 hours.

In individual cases, it is advantageous to add the amine to the reaction solution as salts, such as hydrobromide or hydrochloride. A base such as triethylamine, diisopropylethylamine, N - methylmorpholine, pyridine, tripropylamine, tributylamine, lithium hydroxide, lithium carbonate, sodium hydroxide or sodium carbonate is added to release the amine. The protecting groups available in the case are eventually cleaved.

The isolation of the reaction product proceeds by methods known to those skilled in the art, preferably by precipitation with organic solvents, preferably acetone, 2-butanone, diethyl ether, acetic ester, methyl tert-butyl ester, isopropanol or mixtures thereof. Further purification may be carried out, for example, by chromatography, crystallization or ultrafiltration.

Suitable solubilizers include alkali salts, alkaline earth metal salts, trialkylammonium salts, tetraalkylammonium salts, urea, N-hydroxymides, hydroxyaryl triazoles, substituted phenols and salts of heterocyclic amines. Examples include: lithium chloride, lithium bromide, lithium iodide, sodium bromide, sodium iodide, lithium methanesulfonate, sodium methanesulfonite, lithium-p-toluenesulfonate, sodium-p-toluenesulfonate, sodium chloride, bromide, magnesium chloride, magnesium iodide, tetraethylammonium - rtoluol sulfonate, tetramethylammonium-p-toluenesulfonate, pyridinium - p-toluenesulfonate, triethylmonium - 4tololithenate, 2-trifluolate, 2 copper, N-hydroxyphthalimide, urea, tetramethylurea, N-methylpyrrolidone, formamide as well as cyclic ureas, the first five being preferred.

All reagents known to those skilled in the art are used as the reagents for separating water. For example, carbodiimides and ones reagents such as dicyclohexylcarbodiimide (DCCI), 1-ethyl-3- (3 dimethylaminopropyl) -carbodiimide-hydroxychloride (EDC), benzotriazol-1-yloxytris (dimethylamino) phosphate (dimethylamino) phosphate (ether) can be mentioned - (benzotriazol-1-yl) -1,1,3,3tetramethyluronium hexafluorophosphate (HBTU), but preferably DCCI.

The following suitable methods are described in the literature:

- Activation of carboxylic acids. Review in Houben Weyl, Methoden der Organischen Chemie, Band XV / 2, Georg Thieme Verlag Stuttgart, 1974 (und J. Chemie (S) 1996, 302).

Activation of carbodiimides. R. Schwyzer u. Kappeler, Helv. 46, 1550 (1963).

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

Activation with Carbon Diimides / 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. Belleau et al., J. Am. Chem. Soc. , 90: 1651 (1986), H. Kunz et al., Int. J. Pept. Prot. Res., 26: 493 (1985) in J. R. Voughn, Am. Soc. 73: 3547 (1951).

Imidazolid Methods: B.F. Gisin, R.B. Menifield,

D.C. Tosteon, Am. Soc. 91: 2691 (1969).

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

Oxalyl chloride: J. Oro. Chem .. 29: 843 (1964).

Used as binding auxiliaries, all those skilled in the art are known (Houben-Weyl, Methoden der Organischen Chemie, Bd. XV / 2, Georg Thieme-Verlag, Stuttgart, 1974). Examples are 4-nitrophenyl, N -hydroxysuccinimide, N-hydroxybenzothiazole, 1-hydroxy-7-aza-benzothiazole, 3.5 26 dinitrophenol and pentafluorophenyl. Preferred are 4 nitro-phenol and N-hydroxysuccinimide, in particular preferred reagents.

The cleavage of the protecting groups takes place by methods known to those skilled in the art by hydrolysis, hydrogenolysis, alkaline saponification of esters with alkalis in aqueous-alcoholic solution at temperatures from 0 ⁰ to 50 ⁰ C, acid saponification with mineral acids or in the case of, for example, trit-butyl ester using trifluoroacetic acid. [Protective Groups in Organic Synthesis, 2 ^nd Edition, TW Green and PGM Wuts, John Wiley and Sons, Inc. New York, 1991], in the case of hydrogen / palladium / charcoal benzyl ethers.

Preparation of the starting material of the compounds of formula III b

(IIIb) is known from DE 196 52 386.

The amines of general formula IV b ^Α (IVb) are commercially available (Fluorochem, ABCR) or can be obtained by the following method from compounds of general formula V b by reaction with one amine of general formula VI b and finally reduction of compounds of general formula IV b formula VII b:

For Aj> —A A A (Vb) (Vlb) (Vllb) (IVb) in which

R ^F , A ¹ , L ¹ and R ³ have the meanings given above, and L 'has the meanings of the group L ¹ which still lacks the α-CIE group, and R ⁹ denotes hydrogen or a methyl group.

According to the previously published literature method for the activation of carboxylic acids III b, the acid Vb is activated before reacting with amine Vlb. Aminolysis was carried out for R ⁹ with the meaning of one methyl group.

The compounds of general formula Vb are commercially available (Fluorochem, ABCR) or can be prepared as described in DE 196 03 033.

The compounds of formula VIb are commercially available (Fluorochem, ABCR) or can be prepared as described in Houben-Weyl, Methoden der Organischen Chemie, XI / 2 Stickstoffverbindungen, Georg Thieme Verlag Stuttgart, 1957, S.

680 Hours; J.E. Rickman and T. Atkins, Am. Chem. Soc., 96: 2268, 1974, 96: 2268; F. Chavez and A.D. Sherry, J. Org. Chem. 1989, 54: 2990:

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

Method B

Dicarboxylic acid of formula IIIx is used as the starting material as R ¹ means hydrogen - it does not yet contain the metal ion equivalent of R ¹ . The carboxyl groups are protected by methods known in the art to give one compound of the formula Illy, wherein R ⁵ is any protecting group and R ⁵ is its prior step.

As protecting carboxyl groups are meant, for example, straight or branched chain 1 to 6 carbon atoms alkyl groups, aryl and aralkyl groups such as methyl groups, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis (p-nitrophenyl) 29 methyl groups as well as trialkylsilyl groups. A tautyl group is preferred.

(Shu) (IVb)

(lx)

The interaction of the protected carboxylic acids 111 y with the amine of formula IV b and the cleavage of the protecting groups proceed as described in method A and in a further step the obtained carboxylic acid IX with still one metal oxide or metal salt of the element with the desired sequence number reacts as described above in DE 195 25 924.

When the metal complex obtained by Methods A or B still contains free COOH groups, then these groups may be in the form of salts of physiologically tolerable inorganic or organic bases.

The neutralization of any available free carboxy groups occurs by the use of inorganic bases (eg hydroxides, carbonates or bicarbonates) for example sodium, potassium, lithium, magnesium or calcium and / or organic bases such as, among others, primary, secondary and tertiary amines for example ethanolamine, morpholine, glucamine, N-methyl- and Ν, Ν-dimethylglucamine as well as amino acids, such as lysine, arginine and ornithine, or amines derived from neutral or acidic amino acids.

Particularly preferred according to the invention are metal complexes V, VII, VIII, IX and X (cf. Table 1).

These compounds of general formula I b are particularly suitable as contrast agents for imaging nuclear magnetic resonance imaging.

In another preferred embodiment of the invention can be used perfluoroalkyl containing complexes of sugar radicals of general formula I with (K) | '-G - (ZR ^F ) _m '

I (Ic) (y-R) p 'in which

R stands for a mono- or oligosaccharide radical linked by a 1-OH- or 1 -SH position,

R ^F stands for a perfluorinated, straight or branched carbon chain of formula -C _n F 2 _n E, in which E denotes a terminally fluorine, chlorine, bromine, iodine or hydrogen atom and η denotes the numbers from 4 to 30,

K means a metal complex of the general formula Ps,

(He) in which

R ¹ means one hydrogen atom or one ionic equivalent of metals of numbers 23-29, 42-46 or 58-70, provided that at least two radicals R ¹ represent an ionic equivalent of a metal

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

U represents -SbN ₄ -O-CH ₂ -NH -, - (CH ₂₎ i-5 - ω, a phenylene group, -CH2 - NHCO-CH2-CH (CH2COOH ) -C6H ₄ - ωS ₆ H ₄ - ( OCH ₂ CH ₂ ) o-1 -Ν (ΟΗ ₂ ΟΟΟΗ) -ΟΗ ₂ -ω or one optionally interrupted by one or more oxygen atoms, 1 to 3 -NHCO-, 1 to 3 -CONH-groups and / or with 1 to 3 - (CH ₂ ) o-5 COOH groups substituted with C 1 -C ₁₂ -alkylene or C ₇ -C- | ₂ - C 6 H ₄ - O -group, where ω denotes the point of attachment to -CO-, or of the general formula III with

ROOC

(IIIc) in which R ¹ has the meanings given above, R ⁴ stands for hydrogen or one designated as R ^{1 is the} ionic equivalent of a metal and U ¹ stands for -C 6 H ₆ - O-CH ₂ -ω-, where ω stands for the point of attachment to -CO or of the general formula IV c

(IVc) in which R ¹ and R ² have the meanings given above or by the general formula VcA or VcB

/ ^ -COOR ¹ ROOC ^ \ _n -COOR ' ^v ^ COOR ¹

(VcA)

II

^ -COOR ¹

COOR ¹

(VcB) in which R ¹ has the meanings given above or with the general formula VI c

ROOC - _h

R'OOC— ^χΝ

CO— • COOR '(Vic) in which R ¹ has the meanings given above or by the general formula VII with

R'OOC

R'OOC

ROOC R'OOC— ^x

(Villas) in which R ¹ has the meanings given above and

U ¹ means -C ₆ H ₄ - O-CH ₂ - ω, where ω denotes the point of attachment to -CO or of general formula VIII with

(Ville) in which R ¹ has the meanings given above and, in radical K, optionally the free acid groups available may optionally be in the form of salts of organic and / or inorganic bases or amino acids or amino acids,

G for the case when K represents the metal complex II with up to VII with, means one at least triple functional radical selected from the group of the following radicals a) to j) (a) n a ^ N-fCH ^ -C-CO 7 ^H ΝΗ β

Η γ -CO-C— (CHjlj-N ν— β ΝΗ ^Η (C)

(Φ

(f)

NH -CO-C— (CIS- ^ v-'oc NH \ h- * t $ ^ M-CO-C-CHSND-M ^ a

NH

I β

(g) β

I

NH, NH-CO-CH- (CH ₂ ) _r NH ^ 3 • _N _ _C O-CH- (CH ₂ ) _r NH- ^ a

NH

Y

NH- 'CCh-CH- (CH ₂ ) ₄ -NH- ^ O

NH

I

NH (h)

• (j) α> Μ ~ ΝΗ — CH —CO - '' W · Y β

and

G for the case where K represents a metal complex VIII c, means at least one trifunctional radical selected from k) or I), (k) p ^ -NH-CCHj ^ CH-CO- ^ a

NH 1 a ^ -CO-CHt-CH-CKr-CO ^ Y ² I ²

NH I (0 where a denotes the binding site to complex K, β denotes the binding site from G to the radical Υ and γ denotes the binding site from G to the radical Ζ

Υ stands for -CH ₂ -, δ- (0Η ₂ ) ι-500-β, b-CH ₂ -CHOH-CO-p, or b-CH (CHOH-CH ₂ OH) -CHOH-CHOH-CO-p, such as δ means the point of attachment to the saccharide radical R and β means the point of attachment to the radical G

Ζ means

Y-COCH 2 -N (C 2 H ₅ ) -SO ₂ -e,

Y-C0CH2-O- (CH2) 2-SO2-e,

or denotes y - NHCHiCHrO-CHgCHa- ε as γ denotes the binding site from Ζ to G and ε denotes the binding site from Ζ to the perfluorinated radical R ^F and

I ¹ , t ¹ independently represent integers or 2 and p ¹ denotes an integer from 1 to 4,

Since the compounds of the invention are intended to be used for the diagnosis of nuclear magnetic resonance, the metal ion of the signaling group must be paramagnetic. They can be, in particular, two- and trivalent ions of elements of order numbers 23-29, 42-46 and 58-70. Suitable ions are, for example, chromium (1P) ion, iron (II), cobalt (H) -, nickel (II), copper (II), praseodymium (III) -, neodymium (III) -, samarium (III) - and ytterbium (III) ion. Because of their highly magnetic moment, gadolinium (II) ions, terbium (III) -, dysprosinic (III) -, holmium (III) -, erbium (III) -, iron (III) - and manganese (II) are particularly suitable - ions.

Manganese (I) ions, iron (II) -, iron (III) -, praseodynia (III) -, neodymium (III) -, samarium (III) -, gadolinium (III) - and ytterbium (IP) are preferred. ions, in particular dysprosium (III) ions.

Available optionally in R ¹ acidic hydrogen atoms are called those which can not be replaced by plants ion may be added, optionally completely or partially by cations of inorganic and / or organic bases or amino acids or amino acid amides .

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

Particularly preferred compounds of general formula I c are those of macrocycle K of general formula II c.

The radical U in the metal complex preferably represents -CH ₂ - or C ₆ H ₄ -O- CH ₂ - ω, with ω denoting the binding site to -CO-.

The alkyl groups R ² and R ³ in the macrocycle of general formula II c may be straight or branched. For example, they may be methyl, ethyl, propyl, isopropyl, n-butyl, 1 methylpropyl, 2-methylpropyl, p-pentyl, 1-methylbutyl, 2 methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl. Preferably R ² and R ³ independently of one another denote hydrogen or alkyl having 1 to 4 carbon atoms. In a particularly preferred embodiment, R ² is methyl and R ³ is hydrogen. The benzyl group or the phenyl group R ² or R ³ in the macrocycle K of general formula II c may also be substituted in the ring.

The radical R in the general Formula I c denotes a mono- or oligosaccharide or thiosaccharide radical linked via the 1-OH- or 1-SH position, and according to the invention also deoxy-sugars may be considered, which instead of one or more OH- groups contains one H atom. In a preferred embodiment, R means a monosaccharide radical of 5 or 6 carbon atoms, preferably glucose, mannose, galactose, ribose, arabinose or xylose or their deoxy sugars such as 6-deoxygalactose (fucose) or

- deoxymannose (rhamnose) or their thiosaccharides, glucose, mannose and galactose being particularly preferred.

Of the compounds of general formula Ic according to the invention are preferred in which R ^{F is} C _n F _2n + i. η preferably represents the number 4-15. Especially preferred are radicals - C4F9, -C6F13, -CaFv, -C12F25 and C ₁₄ F ₂₉ as well as the radicals of the compounds of the Examples.

At least three times the functional radical G in the general formula Ic, which represents the "skeleton", in a preferred embodiment of the invention means the lysine radical (a) or (b).

Y and Z denote the linker indicated in the general formula Ic, independently of each other being Z for the radical

N-SOj-ε and the radical δ - CH ₂ CO-p is preferred for Y.

Perfluoroalkyl containing metal complexes with sugar radicals of general formula Ic (Kb'-G - (ZR ^₽ ) _m ¹ I (Ic) (YR) p 'with K are obtained, having the meaning of one metal complex of general formula No to Vile and G with the meanings of formulas (a) to (j), where Y, Z, RR ^F , m ¹ , p ¹ and I ¹ have the meanings given above 42, in a known manner a carboxylic acid of the general formula lii

COOR ⁵

(Hi) in which R ⁵ represents the ionic equivalent of metals of order number 23-29, 42-46, or 58-70 or one carboxylic protecting group, and R ² , R ³ and U have the meanings already indicated or a carboxylic acid with the general formula of Illi

COOR ⁵

OH (Illi) in which R ⁴ , R ⁵ and U ¹ have the above meanings or a carboxylic acid of the general formula I Vi

COOR ⁵

(IVi) or a carboxylic acid of the general formula Vi or Vii

nooo

(VI) (Vii) in which R ⁵ is as defined or a carboxylic acid of the general formula Vii

R ^S OOC

R ⁵ OOC

wherein R ⁵ is as defined or a carboxylic acid of the general formula Vlli

(Vlli) in which R ⁵ and U ¹ have these meanings, optionally reacted in an activated form with one amine of the general formula IXc

H - G - (ZR ^F ) _m '

I (IXc) (Y-RV in which G has the meanings of formulas a) through j) and R, R ^F , Y, Z, m ¹ and p ¹ have the meanings given above under the conditions of a coupling reaction and in optionally further cleaving the available protecting group to one metal complex of the general formula Ic or when R ⁵ means one protecting group, after cleaving this protecting group, reacts in a subsequent step in a known manner with at least one metal oxide or metal salt. element with order number 23-29, 42-46 or 58-70, and finally, if desired, in one case the available acidic hydrogen atoms are replaced atoms with cations of inorganic and / or organic bases, amino acids or amides of amino acids.

The compounds according to the invention of general formula Ic and K with the meanings of one metal complex C of the general formula Ville and G with the meanings of formulas k) or I) are prepared, in a known manner, an amine of general formula Villi

COOR ⁵

in which R ⁵ represents the ionic equivalent of a metal of serial number 23-29, 42-46 or 58-70 or a carboxylic protecting group, reacts with one, optionally activated, carboxylic acid of general formula Xc

BUT - G - ¢ -¾

I (Xc) (YR) p 'in which G has the meaning of the formulas k) or I) and R, R ^F , Y, Z, m ¹ u p ¹ have these meanings in one coupling reaction and optionally subsequent cleavage optionally present protecting group to one metal complex of general formula I with or when R ⁵ has the meaning of one protecting group, after cleavage of that protecting group in a further step, reacts in a known manner with at least one metal oxide or metal salt of an element of serial number 23-29, 42-46 or 58-70, and finally, if desired, optionally the available acidic hydrogen atoms are substantially the cation of inorganic and / or organic bases, amino acids or amino acid amides.

The carboxylic acids of the general formulas Hi to Vlli used are either known compounds or prepared as described in the examples. Thus, the preparation of carboxylic acids of general formula Hi is known from DE186 52 386. The preparation of carboxylic acids of general formula IV i is known from DE197 28 954.

A prior step of the compounds of the general formula VcA is N- (2,6-dioxy-morpholinoethyl) -N ⁶ (ethoxycarbonylmethyl) -3,6-diaza-octanedic acid, and is described in EP 263 059.

The compounds of general formula VcB are derived from the diethylenetriamine-pentacetic acid isomers, which bind acetic acid via the middle nitrogen atom. This DTPA is described in DE 195 07 819 and DE 195 08 058.

The compounds of general formula VI c are derived from N (carboxymethyl) -N- [2- (2,6-dioxy-morpholinyl) -ethyl] -glycine, the preparation of which is described in J. Am. Oil. Chem. Soc. (1982), 59, (2), 104-107.

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

The perbenzylated sugar acids used as starting materials can be obtained analogously to Lockhoff, Angew. Chem. 1998, 110 Nr 24, S. 3634ff. Thus, for example, the preparation of 1-O-acetic acid from perbenzyl glucose in two steps, through trichloroacetimide and reaction with hydroxyacetic acid ethyl ester,

BF ₃ - catalyst in tetrahydrofuran and finally closing with NaOH in MeOH / THF.

In one preferred method, the starting materials of the perbenzylated sugar acids can also be obtained, wherein the perbenzylated 1-OH-sugar is dissolved in a water-immiscible organic solvent and reacted with an alkylating reagent of general formula XI with Nu-L- COO-Sg (Xlc), in which Nu denotes one nucleofug, L stands for - (CH ₂ ) (1), CH ₂ -CHOH-, -CH (CHOHCH ₂ OH) -CHOH-CHOH-, and Sg stands for one protecting group , in the presence of a phase-transfer catalyst based, and optionally. As the nucleophage, the alkylating reagent of the general formula Xlc may contain the radicals -Cl, -Br, -J, -Ots, -Oms, -OSO2CF ₃ , -OSO2C4F9 or -OSO2C8F17.

For protecting groups, these are the usual protecting groups. These protecting groups are well known in the art (Protective Groups in Organic Syntheses, second edition, T.W. Greene and P.G.M. Wuts, John Wiley & Sons Inc., New York 1991).

The reaction according to the invention takes place at temperatures from 0 - 50 ° C, preferably from 0 ° C to room temperature. The reaction time is from 10 minutes to 24 hours, preferably from 20 minutes to 13 hours.

The base is added either in a solid form, preferably as a fine powder, or as 10-70%, preferably 30-50% 48, aqueous solution. NaOH and KOH are the preferred bases.

In the alkylation process according to the invention as organic, water-immiscible solvents, for example, toluene, benzyl, CF3-benzene, hexane, cyclohexane, diethyl ether, tetrahydrofuran, dichloromethane, MTB or mixtures thereof may be used.

In the process according to the invention, quaternary ammonium or phosphonium salts or also a crown ether such as [15] -crone-5 or [18] -crone-6 are used as phase catalysts. Preferably, quaternary ammonium salts with four identical or different hydrocarbon groups to the cation selected from methyl, ethyl, propyl, isopropyl, butyl or isobutyl are meant. The hydrocarbon groups to the cation must necessarily be large enough to allow a good solubility of the alkylating reagent in the organic solvent. According to the invention particularly preferred are N (butyl) 4 ⁺ -Cl ', N (butyl) 4 ⁺ - HSO 4 ·, but also M (methyl) 4 ⁺ - Cl'.

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

In another preferred embodiment of the invention perfluorine complexes of polar radicals of the general formula Id (K) _and '-G- (ZR ^f )''are used

I (Id) (RV in which

R ^f denotes a perfluorinated, straight or branched carbon chain of formula -CnF _2n E in which E denotes a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and η denotes an integer from 4 to 30,

K means a metal complex of general formula lid,

(lid) in which

R ¹ means one hydrogen atom or an ionic equivalent of a metal of serial number 23-29, 42-46 or 58-70, provided that at least two R ¹ radicals represent an ionic equivalent of a metal,

R ² and R ³ independently represent hydrogen, C 1 -C 4 alkyl, benzyl, phenyl, -CH ₂ OH or -CH ₂ OCH 3 and

U represents -C ₆ H ₄ -O-CH ₂ -S, - (CH ₂ ) -i-5 "W, one phenylene group, -CH ₂ -MHCO-CH ₂ -CH (CH ₂ COOH) -C ₆ H ₄ - w, -C ₆ H ₄ 50 (OCH ₂ CH ₂ ) ₀ -iN (CH ₂ COOH) -CH ₂ ^ or one optionally interrupted by one or more oxygen atoms, 1 to 3

NHCO-, 1 to 3 -CONH groups and / or 1 to 3 - (CH ₂ ) o-5COOH groups substituted with C ₁ -C ₁₂ alkylene or

C7 - Ci ₂ - C ₆ H ₄ - 0- groups, where ω denotes the binding site to -CO-, or by the general formula 11ld

COOR ¹

COOR (IIld) in which R ¹ has the meanings given above, R ⁴ is hydrogen or represents the ionic equivalents of metals indicated for R ¹ and U ¹ is -C ₆ H ₄ -O-CH ₂ -co, where ω stands for of coupling to -CO or of the general formula IVd

COOR ¹

COOP (IVd) in which R ¹ and R ² have the meanings given above or by the general formula VdA or VdB / -N \

'-COOR ¹

rooA —N / \ ^ y-COOR ¹ ^ ^Nx -COOR ¹

(VdA)

COOR ¹

COOR ¹

(VdB) in which R ¹ has the meanings given above or of the general formula Vid

ROOC

ROOC

(Vid) in which R ¹ has the meanings given above or by the general formula Vlld

ROOC

ROOC

ROOC

ROOC

(Vlld) in which R ¹ has the meanings given above and

U ¹ means -C ₆ H ₄ -O-CH ₂ -sh, with ω denoting the binding site to -CO in radical K, in which case the available free acid groups may optionally be as salts on organic and / or inorganic bases or amino acids or amides of amino acids,

G means at least three times a functionalized radical of the following radicals a) to e) (a) n

(Cl-y ₄ —C-CO — av γ ^H ΝΗ β

(b)

H γ ^ co-c-fCHjVN β

I Η ct

β

(Ο: 0 (9)

ΗΝ (h) γ -co- (cn ₂ ) _{r <>} - | Η-οο ^ β

ΝΗ

I α

β CO- {CH ₂ ) ₂ ^ -CH-CO- ^ LU

Α as α denotes the binding site of G to the complex K, β denotes the binding site of G to the radical R and γ denotes the binding site of G to the radical Ζ

Ζ means

N ~ SO ₂ -S

YC (O) CH ₂ O (CH ₂ ) _r e, where γ denotes the point of attachment of Ζ to the radical G and ε denotes the point of attachment of Ζ to the perfluorinated radical R ^F

R represents one polar radical selected from the complexes K of the general formulas lid to Vlld, with R ¹ here denoting a hydrogen atom or one ionic equivalent of a metal of serial number 20, 23-29, 42-46 or 58-70, and the radicals R ² , R ³ , R ⁴ , U and U ¹ have the meanings given above, or means a direct bond of a carbon chain of 2 to 30 carbon atoms bonded to radical G by -CO-, SO2-, which is straight or branched, saturated or unsaturated, optionally interrupted by 1 - 10 oxygen atoms, 1-5 -NHCO groups, 1-5 -CONH groups, 1-2 sulfur atoms, 1-5-групи-groups or 1-2 phenylene groups, which he gave n can be substituted by 1-2-OH-groups, 1-2 NH ₂ -pyrene, 1-2 COOH-groups, or 1-2 -SO3H-groups or optionally substituted by 1-8 OH-groups , 1-5-COOH groups, 1-2 cOH groups, 1-5 NH ₂ groups, 1-5 C 1 -C 6 alkoxy groups, and

I ¹ , t ¹ , p ² independently represent integers 1 or 2.

Because the compounds of the invention are used for nuclear magnetic resonance diagnostics, the metal ion of the signaling group must be paramagnetic. They are, in particular, di- and trivalent ions of elements of serial numbers 23-29, 42-46 and 58-70.

Suitable ions are, for example, chromium (III), iron (H) cobalt (II) -, nickel (II) - copper (H) -prasodine (1R) neodymium (III) -, samarinium (III) - and ytterbium (IR) - ions. Because of their strong magnetic moment, gadolinium (1H) -, terbium (III) -, dysprosium (III) -, holmium (III) -, erbium (III) -, iron (III) - and manganese (II) ions are particularly suitable.

Manganese (II) -, iron (II) -, iron (III) -, praseodynamic (III) -, neodymium (III) -, samarin (III), gadolinium (III) - and ytterbium (1H) ions are preferred. in particular dysprosium (III) ions.

The acid hydrogen atoms present in R ¹ , which means those which are not substituted by the central ion, can optionally be substituted in whole or in part by cations of inorganic and / or organic bases or amino acids or amides of amino acids.

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

Particularly preferred compounds of general formula Id are those of macrocycle K of general formula lid, IIld, VdB or Vlld.

The radical U in the metal complex K preferably represents -CH 2 - or C ₆ H ₄ -O-CH ₂ -co, with ω denoting the binding site to -CO-.

The alkyl groups R ² and R ³ in the macrocycle of the general formula lid may be straight or branched. For example, methyl, ethyl, propyl, isopropyl, pbutyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-butylbutyl, 2methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl may be mentioned. Preferably R ² and R ³ independently represent hydrogen or C 1 -C ₄ alkyl.

In one particularly preferred embodiment, R ² is methyl and R ³ is hydrogen.

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

The polar radical R in the general formula Id in one preferred embodiment means the complex K in which, in addition to one Gd ³⁺ - or Mn ²⁺ - complex, a Ca ²⁺ complex can also be present.

Particularly preferred as polar radicals R are the Kc complexes of the general formula lid, Hid, VdA or Vlld. Particularly preferred for R ¹ is an ionic equivalent of a metal of serial number 20, 25, 39 or 64.

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

-CfOJCHaCHaSOsH

-CCOJCHaOCHzCHzOC ^ CHzOH

-CiOJCHzOCHzCHzOH

-C (O) CH ₂ OCH ₂ CH (OH) CH 2 OH

-C (O) CH ₂ NH-C (O) CH ₂ COOH

-C (O) CH2CH (OH) CH2OH

-C (O) CH 2 O CH 2 COOH

-SO2CH2CH2COOH

-C (O) -SbNNt-COOH) g <(O) CH2O (CH2) _g C ^ NHT-COOH) ₂

-C (O) CH ₂ OC ₆ H 4 -m-SO ₃ H

-C (O) CH ₂ NHC (O) CH ₂ NHC (O) CH2OCH ₂ COOH -C ^ CH2OSNgSNgOSNgSOON -C (O) CH ₂ OCH _g CH (OH) CH ₂ O-CH ₂ CH ₂ OH -C (O) ) CH2OCH ₂ CH (OH) CH ₂ OCHrCH (OH) -CH ₂ OH

-C (O) CH ₂ SO ₃ H

-ODSNgSNgSOON

-C (O) CH (OH) CH (OH) CH ₂ OH

-C (O) CH ₂ O [(CH ₂ ) ₂ O] ₁ . ₉ -CH ₃

-C (O) CH ₂ O [(CH ₂ ) ^)] i 4rH

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

-C (O) CH ₂ OCH (CH ₂ OCH ₂ COOH) 2

-C (O) -CNHNt-OCH ₂ COOH) g

-C0-CH ₂ O- (CH ₂ ) ₂ O (CH 2) 20- (CH ₂ ) ₂ O (CH 2) 20 CH _S preferably -C (O) CH 2 O [(CH 2) 2 O] 4-CH 3.

In another preferred embodiment, the polar radical

R is a folic acid radical.

Of the compounds of the formula Id according to the invention are preferred and those in which R ^F is -C _n ^{F 2} _n + i · η is preferably numbers 4-15. Particularly preferred are the radicals - C4F9, -CeFn, -CeF2, -C12F25 and -C14F29.

At least three times the functionalized radical G in the coloring formula Id, which represents the "skeleton", in one preferred embodiment of the invention means the lysine radical (a) or (b).

Z represents the linker referred to in the general formula, preferably the radical

B — N ^ ~~ ^ N-S0 ₂ -e

Perfluoroalkyl containing polar metal radical complexes of the general formula Id (k), '- g- (z-rV

I (m)

0¾ ² in which K, G, R, Z, R ^F , I ¹ , m ¹ and p ² have the meanings given above are obtained, in a known manner, a carboxylic acid of the general formula Hk

COOR ⁵

(I 10 in which R ⁵ denotes one ionic equivalent of a metal of serial number 23-29, 42-46 or 58-70 or one carboxy group and R ² , R ³ and U have the meanings indicated or one carboxylic acid of the general formula II 1k

(IIIk) in which R ⁴ , R ⁵ and U ¹ have the meanings indicated or a carboxylic acid of the general formula IVk

COOR ⁵

(IVk) in which R ⁵ and R ² have the meanings indicated or a carboxylic acid of the general formula Vk or Vm

wherein R ⁵ is as defined (Vm) or a carboxylic acid of general formula VIk

R ^S OOC — X. / - \ / —CO-OH

R ⁵ OOC— ^Νχ —COOR ⁵ (Vlk) in which R ⁵ has the meanings given or a carboxylic acid of the general formula VI 1k

OH (Vllk) in which R ⁵ and U ¹ have the indicated meanings, and optionally the activated form is reacted with an amine of the general formula Vllld

H-G - (Z-R'W

I (Vllld) (R) p ² in which G, R, Z, R ^f , m ¹ up ² have the meanings indicated, in the conditions of the joining reaction and, in the case of the case, the subsequent cleavage of the protective groups present in one case to one metal complex of the general formula Id or when R ⁵ has the meaning of a protecting group, after cleavage of that protecting group in a further step, reacts in a known manner with at least one metal oxide or metal salt of one element of serial number 23-29, 4246 or 58-70, and finally, if desired, the acidic hydrogen present optionally substituted with non-cationic cations organic and / or organic bases, amino acids or amides of amino acids.

The carboxylic acids of general formula IIk to VIIk used are either known compounds or can be prepared as described in the examples. Thus, the preparation of carboxylic acids of the general formula Pk is known from DE 196 52 386. The preparation of carboxylic acids of general formula IVk can be found in DE 197 28 954.

A prior step for compounds of general formula VdA is N ³ - (2,6-dioxymorpholinoethyl) -N ⁶ (ethoxycarbonylmethyl) -3,6-diazo-octanedic acid, which is described in EP 263 059.

The compounds of the general formula VdB are derived from the isomers of diethylenetriamine - pentaacetic acid, which binds acetic acid via a nitrogen atom in the middle. This DTPA is described in DE 195 07 819 and DE 195 08 058.

Compounds of the general formula Vid are derived from N (carboxymethyl) -X- [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 general formula V-d are derived from 1- (4-carboxymethoxybenzyl) -ethylenediamine-tetraacetic acid, the preparation of which is described in U.S. Patent 4,622, 420.

Particularly preferred compounds of the general formula Id according to the invention are the metal complex XVI of Table 1.

In another preferred embodiment of the invention, galenic forms containing paramagnetic and diamagnetic perfluoroalkyl-containing substances may be used. Preferably the paramagnetic and diamagnetic substances are present in one aqueous solvent.

As paramagnetic perfluoro-containing compounds, any of the foregoing metal complexes of the general formulas I, Ia, Ib, Ic and / or Id can be used in the formulations according to the invention.

Diamagnetic perfluoroalkyl containing substances of general formula XX:

R ^F - L ² - B ² (XX)

In which R ^F denotes one straight or branched chain perfluoroalkyl radical of 4 to 30 carbon atoms, L ² represents one linker and B ² means one hydrophilic group. The L ² linker is one direct bond, one -SO ₂ group or one straight or branched carbon chain with up to 20 carbon atoms which can be grounded with one or more -OH, -COO, -SO ₃ - groups and / or optionally containing one or more -O-, -S-, -CO-, -CONH-, -NHCO-, CONR ⁹ , -NR ⁹ CO-, -SO2-, -PO4'-, -ΝΗ-, NR ⁹ groups, one aryl ring or one piperazine, wherein R ⁹ denotes an alkyl radical of 1 to 20 carbon atoms which may again contain one or more O atoms and / or may be substituted by -C00 'or SO ₃ - groups.

The hydrophilic group B ² is mono- or disaccharide, one or more adjacent-COO 'or SO ₃ ' groups, one dicarboxylic acid, one isophthalic acid, one picolinic acid, one benzenesulfonic acid, tetrahydropyridicarboxylic acid, one 2,6-pyridinedicarboxylic acid, one quaternary ammonium ion, one amino polycarboxylic acid, one aminodipolyethylene glycolsulfonic acid, one aminopolyethylene glycol group, one SO ₂ - (CH ₂ ) 2-OH- group, one polyhydroxyalkyl chain with at least two hydroxyl groups or one or more polyethyl glycol chains with at least two glycol units, the polyethylene glycol chains ending in one -OH or -OCH ₃ group. This type of substance has been known for a long time, in part such substances are being re-synthesized to prepare the formulations according to the invention. Known perfluoroalkyl containing substances and their preparation are described in the following publications.

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

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

M.-P. Krafft et al., Angew. Chem., 1994, Vol. 106, No. 1 10, pp. 1146-1148;

M. Lanier et al., Tetrahedron Letters, 1995, Vol. 36, No. 1 14, pp. 2491-2492;

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

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

L Clary et al., Tetrahedron, 1995, Vol. 51, No. 1 47, pp. 13073-13088;

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

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

F. Guileri et al., Angew. Chem. 1994, Vol. 106, No. 1 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, p. 285-293;

A. Milius et al., Carbohydrate Research, 1992, Vol. 229, p. 323-336;

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

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

V. Circus et al., Jounal of Fluorine Chemistry, 1997, Vol. 83, p. 151-158;

A. Odd Amanetoullah et al., Journal of Fluorine Chemistry, 1997, Vol. 84, p.

149-153;

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

L Clary et al., Tetrahedron Letters, 1995, Vol. 36, No. 1 4, pp. 539-542;

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

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

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

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

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

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

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

F. Sz6nyi et al., Journal of Fluorine Chemistry, 1991, Vol. 55, p. 85-92;

C. Santaella et al., Angew. Chem., 1991, Vol. 103, No. 1 5, pp. 584-586;

M.-P. Krafft et al., Angew. Chem., 1993, Vol. 105, No. 1 5, pp. 783-785; EP0548 096 B1.

The preparation of the new perfluoroabacid-containing substances proceeds analogously to the above methods and is described in the examples. It relates to the criteria of the invention. The physical parameters of these metal complexes I - XVI are listed in Table 2.

Like the paramagnetic compounds of general formula I, 1a, 1b, 1c and Id according to the invention to substances of general formula XXI

R ^F - X ¹ (XXI)

In which R ^f represents one straight or branched chain perfluoroalkyl radical of 4 to 30 carbon atoms and X ¹ means one radical selected from the group of the general formula (wherein η is an integer between 1 and 10):

OH

Ο

II

COO ”

ΊΟ

Preferred diagno-perfluoro-containing substances are those containing a single monosaccharide such as hydrophilic group B ² .

Particularly preferred diamagnetic perfluoroalkyl containing compounds containing one perfluoroalkyl radical Rf of 6 to 12 carbon atoms, one linker L ² which is designated one -SO ₂ group or one straight or branched carbon chain of up to 20 carbon atoms which also contains one or more - O-, -CO-, CONH-, -NHCO-, -CONR-, -NRCO-, -SO ₂ - groups or one piperazine, with R as defined above, and one monosaccharide as hydrophilic group B ² .

Other preferred diamagnetic perfluoro-containing compounds are conjugated to cyclodextrin and perfluoro-containing compounds. These conjugated compounds consist of α-, β- or y-cyclodextrin and compounds of general formula XXII

A ¹ -L ³ -R ^f (XXII) in which A ¹ stands for one adamantane, biphenyl or anthracene molecule, L ³ stands for one linker and R ^F stands for a straight or branched perfluoroalkyl radical of 4 to 30 carbon atoms. The linker L ³ is a straight or branched chain hydrocarbon having 1 to 20 carbon atoms which can be interrupted by one or more CO, SO ₂ -, CONH-, NHCO-, CONR-, NRCO-, ΝΗ-, NR- groups or one piperazine, wherein R is an alkyl radical of 1 to 5 carbon atoms.

Preferred compounds are the following compounds:

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

Preferred are mixtures of paramagnetic and diamagnetic perfluoroalkyl containing compounds wherein the perfluoroalkyl chain has a length of from 6 to 12 carbon atoms. Particularly preferred are mixtures in which both the paramagnetic and the diamagnetic perfluoroalkyl containing compounds have one perfluoroalkyl chain of 8 carbon atoms.

The preparation of the galenic forms takes place in such a way that the paramagnetic perfluoroalkyl-containing substances (component B) are in a molar ratio between 0.05 and 0.95 of components A or B and are dissolved in a suitable solvent. This solution is then added to the usual gallic additives such as buffer solution and excess Ca salt of complexing agent. The solutions were vigorously stirred at 10 to 100 ° C. Alternatively, the solutions could be treated at 10 to 100 ^° C in an ultrasonic bath. Another alternative is that the solutions are microwaved.

For substances that do not dissolve in water as separate components, it is preferable to use a solvent such as alcohol (eg methanol or ethanol) or any other miscible water, and then slowly distill off. Distillation can be carried out in vacuo. The residue was then dissolved in water and the solution filtered. It is also possible for each component to be individually dissolved in one conventional solvent, then mixed and treated further as described above. It is also advantageous to prepare a relatively highly concentrated solution (> 100 mmol) of the metal complex (component A) and then add component B in its pure state and treat the solution by stirring or ultrasound, respectively, with microwaves.

In general, the particularly preferred gadolinium complexes I - XVI listed in Table 1 can be said to meet all the criteria of the invention. The physical parameters of these metal complexes are given in Table 2.

Whereas, according to the invention, the paramagnetic compounds of the general formulas I, Ia, 1b, 1c and Id as well as according to the invention, the formulations of paramagnetic and diamagnetic perfluoroalkyl-containing substances are particularly suitable as contrast agents for nuclear magnetic resonance imaging for the presentation of plaques, tumors and necrosis .

Table 1: Particularly preferred used metal complexes according to the invention

Complex Literature, Name 1 WO 97/26017, Example 33f Gadolinium complex of 10- [1-methyl-2oxo-3-aza-5-oxo- (4-perfluorooctyl-sulfonyl-piperazin-1-yl} phenyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane II WO 97/26017, Example 2c gadolinium complex of 10- [2-hydroxy-4aza-5-oxo-7-oxa-1 0.1 0.1 1.11, 12.12, 13.13, 14, 14, 15,15,16,16,17,17-Heptadecafluoroheptacellyl] -1,4,7tris (carboxymethyl) -1,4,7,7 O-Getraazacyclododecane III WO 97/26017, Example 34b gadolinium complex of 10- [2-hydroxy-4aza-5,9-0luxo-9- (4-perfluoroctyl) -piperazin-1-yl} -nonyl] -1,4,7tris (carboxymethyl ) -1, 4.7, 10- tetraazacyclododecane IV WO 97/26017, Example 1c gadolinium complex of 10- [2-hydroxy-4aza-5-oxo-7-aza-7- (perfluorooctyl-sulfonyl) -nonyl] -1,4,7,7-tris (carboxymethyl) -1,4 , 7,1-Tetraazacyclododecane

V Example 2c, the present application 1,4,7-Tris (carboxylatomethyl) -10- (3-aza-4-oxo-hexan-5-yl) acid-N- (2,3-dihydroxypropyl) -N- (1H, 1H, 2H, 2H) , 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -amide] -1, 4,7,1 0tetraazacyclododecane, gadolinium complex VI WO 97/26017, Example Zc Gadolinium complex of 10- [2-hydroxy-4-oxa-1 H, 1 H, 2H> 3H, 3H, 5H, 5H, 6H, 6H-perfluorotetradecyl] -1,4,7tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane VII Example 5f, the present application 1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5yl) acid- [N- (3,6,9,12,15-pentaox) -hexadecyl) -N - (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluorotridecyl] -amide} -1,4,7,10tetraazacyclododecane, gadolinium complex VIII Example 3c, the present application 1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) acid-N- (5-hydroxy-3-ox-pentyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl] -amide} -1,4,7,7-tetraazacyclododecane, gadolinium complex IX Example 6b, the present application 1, 4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) acid- [N-3,6,9,1 6-tetraoxa- 1 3-aza-14-oxo-C19-C ₂ 6-heptadecafluoro) hexacosyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex X Example 1 c, present application 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-hexan-5-yl] acid-1 N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl] -amide) -1,4,7,10-tetraazacyclododecane, gadolinium complex XI WO 97/26017, Example 32c gadolinium complex of 10- [2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,12,12, 13,13,14,14,15,15,16,16,17,17,18,18,19,19-henicosafluoronadecyl] -1,4,7-tris (carboxymethyl) -1,4,7, 10-Tetraazacyclododecane XII WO 97/26017, Example 38d Gadolinium complex 10- [2-hydroxy-4-aza-5-oxo-1 1-aza-1 1 (perfluorooctyl-sulfonyl) -tridecyl] -1 -4-7-tris (carboxymethyl) 1, 4,7,10 -Tetraazacyclododecane

XIII WO 97/26017, Example 35d Gadolinium complex of 10- [2-hydroxy-4-aza-5-oxo-7-aza-7 (perfluoroctyl-sulfonyl) -8-phenyl-octyl] -1 -4-7 tris (carboxymethyl) -1,4,7 , 10-Tetraazacyclododecane XIV WO 99/01 161, Example 1e 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, 4,7,1 O-Tetraazacyclododecane, Gd-KOMnneKc} -10-N-2l-1,2, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoyl] -1,4,7,1 O- tetraazacyclododecane, Gd-complex XV Example 21 f, the present application 6-N- [1, 4,7-tris (carboxylatomethyl) -1, 4,7, 1 0- tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - 2N- [1-O-a-L-carbonylmethyl-mano-pyranose] -1_-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd-complex XVI Example 54b, the present application 2,6-N, N'-6nc [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] lysine- [1- (4-perfluorooctylsulfonyl-piperazine] -amide, Gd-complex

Table 2:

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

Complex Nr. SMS (mol / l) 2Rh (nm) R ¹ plasma (l / mmol.s) 1 1.86 Ί0 ^ 4.6 35,7 II 2.30 '10' ⁵ 14 33 III 7.06 '10 ⁶ 3.2 24.9 IV 1.0-1 O ' ⁶ 31.5 29.7 V 3,9'10 ' ⁶ 4.4 19.6 VI 1.4410 ' ⁵ 3.2 27.5 VII 5.20 10 ' ⁵ 3.0 30.3

VIII 2,92'10 ' ⁵ 25 21.2 IX 2.65-1 0 ^ 6.0 13.3 X 7.90-1 0 ⁴⁵ 5.4 25.7 XI 2.88'10 ' ⁶ * 35.5 24,8 XII 1.07-10 ' ⁵ 7.4 30.5 XIII 3.25-S · ⁶ 4.3 34.0 XIV 8.90-1 0 ^liters 2.2 19.5 XV 2.50- W ⁶ 4.4 15.9 XVI 3,90-10 ' ⁵ 4.9 21.3

CMC: critical concentration for micelles formation

2Rh: hydrodynamic diameter of the micelles

R ¹ : release

Examples of carrying out the invention

Example 1

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

8.90 g (70 mmol) of oxalyl chloride were added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H - 3-oxaprofluorotridecanoic acid in 300 ml of dichloromethane and stirred for 12 hours at room temperature. temperature. Evaporate in vacuo to dryness. The residue was dissolved in 100 ml of dichloromethane at 0 ⁰ C was added dropwise to a solution of 4.51 g (60 mmol) of 2-methoxyethylamine and 6.07 g (60 mmol) of triethylamine, dissolved in dichloromethane. It was stirred for 3 hours at 0 ° C and finally for 6 hours at room temperature. Add 300 ml of 5% aqueous hydrochloric acid and stir for 15 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 = 20: 1).

Yield: 30.28 / 91% by Theor. / Elemental analysis: Calc .: C31.10 H2.44 N, 2.42 F 55.76 Gender: C, 30.87 H2.58 N2.35 F 55.51

B) Ν- (2-Μβτοκοπβτππ) -Ν- (1Η, 1H, 2H, 2H, 4H, 4H, 5H,

The 5H-3-oxa-perfluorotridecylamide g (51.79 mmol) of the title compound of Example 1a was dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borandimethyl sulfide (in tetrahydrofuran) was added. Boiled for 16 hours counterclockwise. The mixture was cooled to 0 ° C and 200 ml of methanol were added dropwise, finally evaporated in vacuo to dryness. The residue was absorbed in a mixture of 300 ml of ethanol / 50 ml of 10% aqueous hydrochloric acid and stirred for 8 hours at 40 ° C. It was evaporated in vacuo to dryness, the residue was absorbed in 300 ml of 5% - aqueous sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases were dried over magnesium sulfate, evaporated in vacuo to sufo and the residue was chromatographed on silica gel (eluent: dichloromethane / 2 propanol = 20: 1).

Yield: 26.93 g (92% of theory / colorless solid) Elemental analysis (calculated on the anhydrous substance): _Calcd; C 31.87 H2.85 N2.48 F 57.14

Gender: ^{C31> 69 H3 '10} N2.27 F 56.88

c) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohexan-5-yl) -acid-N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H) , 4H, 4H, 5H, 5H -3-oxa-perfluorotridecyl) -amide] -1,4,7,10tetraazacyclododecane, gadolinium complex / metal complex X / g (15.88 mmol) gadolinium complex of 10- [1 ( carboxymethylcarbamoyl) -ethyl] -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid and 1.35 g (31.76 tmol) lithium chloride were dissolved at 60 ° C in dimethyl sulfoxide. It was cooled to 15 ° C and 8.98 g (15.88 mmol) of the title compound of Example 1b were added. Stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitated precipitate was filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (eluent: gradient of tetrahydrofuran / acetonitrile / water).

Yield: 15.14 g / 81% by weight / colorless, amorphous powder

Water Content: 5.7%

Elemental analysis (calculated on the anhydrous substance)

Est: Gender: C, 34.70 C, 34.51 H3.77 H, 3.94 N7.14 N7.02 F 27.44 Gd 13.36 F 27.25 Gd 13.18 Example 2 a) (2H, 2H, 4H, 4H, 5H, 5H-3-oxa) - perfluorotridecane acid -N- (2,3-

dihydroxypropyl) -amide

8.90 grams (70 mmol) of oxalyl chloride were added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaprofluorotridecanoic acid and stirred for 12 hours at room temperature. It is evaporated to dryness in vacuo. The residue was dissolved in 100 ml of dichloromethane and added dropwise at 0 ° C to a solution of 5.47 g (60 mmol).

2,3-dihydroxypropylamine and 6.07 g (60 mmol) of triethylamine dissolved in 200 ml of dichloromethane. It was stirred for 3 hours at 0 ° C, finally for 6 hours at room temperature. Add 300 m 5% aqueous hydrochloric acid and stir for 15 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 / ethanol = 15: 1).

Yield: 29.70 g / 78% of theory / colorless solid

Elemental analysis: _Est; C30.32 H2.20 N2.36 F, 54.35 C, 30.12; H, 2.41; Gender: N2.18 F 54.15

b) N- (2,3-dihydroxypropyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluoro-tridecyl) -amine (48.8 mmol) of the title compound compound of Example 2a in 300 ml of tetrahydrofuran and 50 ml of 10 M borandimethylsulfide (in tetrahydrofuran) were added. Boiled for 16 hours counterclockwise. It was cooled to 0 ° C and 300 ml of methanol were added dropwise, finally evaporated in vacuo to dryness. The residue was absorbed in a mixture of 300 ml of ethanol / 50 ml of 10% aqueous hydrochloric acid and stirred for 8 hours at 60 ° C. Evaporated in vacuo to dryness, the residue was absorbed in 300 ml of 5% - aqueous sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The organic phases were dried over magnesium sulfate, evaporated in vacuo to dryness and the residue was chromatographed on silica gel (eluent: dichloromethane / methanol = 15: 1).

Yield: 24.07 g / 85% of theory / colorless solid

Elemental analysis:

_Est . C, 31.05 H2.61 N2.41 F 55.66 _gender; 031.91 H2.78 N2.33 F 55.47

c) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohexan-5-yl) acid-N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H- 3-oxa-perfluoro-tridecyl-amide] 1,4,7,1O-tetraazacyclododecane, gadolinium complex (metal complex V) g (15,88 mmol) from gadolinium complex of 10- [1 (carboxymethylcarbo-amoyl) -ethyl] -1,4,7,10 Tetraazacyclododecane-1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved at 60 ° C in 100 ml of dimethyl sulfoxide. Cool to 15 ° C and add 9.21 g (15.88 mmol) of the smoothed compound of Example 2b. Stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitated precipitate was filtered off, dissolved in a little ethanol / water mixture and chromatographed on silica gel RP-18 (eluent: tetrahydrofuran / acetonitrile / water gradients).

Yield: 16.09 g (85% of theory) colorless, amorphous powder Water content: 6.3% Elemental analysis: _Est . C, 34.26; H3.64; N7.05 F 27.10 Gd 13.19 _Paul . C 34.12 H3.83 N6.91 F, 26.88 Gd 12.93

Example 3

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa perfluorotridecanoic acid-N-hydroxy-zoxa-phenyl) -amide

8.90 g (70 mmol) of oxalyl chloride were added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H 5H-3-oxaprofluorotridecanoic acid in 300 ml of dichloromethane for 12 hours at room temperature. Evaporate in vacuo to dryness. The residue was dissolved in 100 ml of dichloromethane and at a temperature of 0 ° C was added dropwise to a solution of

6.25 g (60 mmol) of 5-hydroxy-3-pentylamine and 6.07 g (60 mmol) of triethylamine dissolved in 200 ml of dichloromethane. It was stirred for 3 hours at 0 ° C and finally for 6 hours at room temperature. Add 300 ml of 5% aqueous hydrochloric acid and stir vigorously for 15 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: 32.20 g (92% of theory) of a colorless solid. Elemental analysis:

C 31.54 H2.65 N2.30 F 53.01

C31.61 H2.84 N2.14 F 52.85

N- (5-trifluoro-3-oxa-neHTHn) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -amine

Est:

Gender:

B) g (49.24 mmol) of the title compound of Example 3 was dissolved in 300 mL of tetrahydrofuran and 31 mL of 10 M borandimethylsulfide (in tetrahydrofuran) was added. Boiled for 16 hours counterclockwise. The mixture is cooled to 0 ° C and 200 ml of methanol are added dropwise, finally evaporated to dryness in vacuo. The residue was absorbed in a mixture of 300 ml of ethanol / 50 ml of 10% aqueous hydrochloric acid and stirred for 10 hours at 50 ° C. Evaporated in vacuo to dryness, the residue was absorbed in 300 ml of 5% - aqueous sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The organic phases were dried over magnesium sulfate, evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1).

Yield: 26.09 g (89% by weight) of a colorless solid. Elemental analysis:

Calc ^{32.28 H3.05 N2.35} F 54.25 Gender ^{032.12 H3.21 N2.18 F 54.09}

c) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-hexane)

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-tetraazacycododecane, gadolinium complex (metal complex VIII) g (15, 88 mmol) of the gadolinium complex of 10- [1 (carboxymethylcarboamoyl) -ethyl] -1,4,7,1O-tetraazacyclododecane-

1,4,7-Trisacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved at 60 ° C in 100 ml of dimethyl sulfoxide. It was cooled to 15 ° C and 9.45 g (15.88 mmol) of the title compound of Example 3b was added. Stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The separated precipitate was filtered off, dissolved in a little alcohol / water mixture and chromatographed on silica gel RP-18 (Eluent: tetrahydrofuran / acetonitrile / water gradients).

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

Elemental analysis: (calculated to the anhydrous substance): C, 34.83 Est: H3.84 N, 6.96. F 26.76 Gd 13.03 C, 34.65 Gender: H3.96 N6.84 F 26.62 Gd 12.91 Example 4 a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecane

acid-N- (2-hydroxyethyl) -amide

8.90 g (70 mmol) of oxalyl chloride were added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaprofluorotridecanoic acid 300 ml of dichloromethane and stirred for 12 hours at room temperature. . In vacuo it was evaporated to dryness. The residue was dissolved in 100 ml of dichloromethane and at a temperature of 0 ° C was added dropwise to a solution of 3.66 g (60 mmol) of 2-aminoethanol and 6.07 (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It was stirred for 3 hours at 0 ° C, finally for 6 hours at room temperature. Add 300 ml of 5% aqueous hydrochloric acid and stir vigorously for 15 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 = 20: 1).

Yield: 28.90 g (89% of theory)

Elemental analysis:

C29.75 H2.14 N2.48 F 57.14

29.61 H2D9 N2.37 F 57.01

N- (2-hydroxyethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3 oxa) -perfluorotridecyl) -amine 2 (49.54 mmol) of the title compound of Example 4a was dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borandimethylsulfide (in tetrahydrofuran) are added. Boiled for 16 hours counterclockwise. Cool to 0 ° C and boil

Est:

Gender:

B) 200 ml of methanol were added dropwise, finally evaporated to dryness in vacuo. The residue was absorbed in a mixture of 300 ml of ethanol / 50 ml of 10% aqueous hydrochloric acid and stirred for 10 hours at 50 ° C. Evaporated in vacuo to dryness, the residue was absorbed in 300 ml of 5% - is extracted three times with 300 ml of dichloromethane on aqueous sodium hydroxide. The organic phases were dried over magnesium sulfate, evaporated in vacuo to dryness and the residue chromatographed on silica gel (eluent: dichloromethane / 2 propanol = 15: 1).

Yield: 25.12 g (92% of theory) colorless solid Elemental analysis (calculated on the anhydrous substance): Calcd: C 30.50 H2.56 N2.54 F 58.59 _Pol . C, 30.32; H2.71; N2.48; F, 58.43

c) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohexan-5-yl) -acid-N- (2-hydroxyethyl) -N- (1H, 1H, 2H, 2H) , 5H, 5H-oxa-perfluorotridecyl) -amine-amide] -1,4,7,10tetraazacyclododecane, gadolinium complex r (15,88 mmol) from the gadolinium complex of 1- [1 (carboxymethylcarboamoyl) -ethyl] -1, 4,7,10-tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. Cooled to 15 ° C and 8.75 g (15, 88 mmol) from the title compound of Example 4b. Stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added.

Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitated precipitate was filtered off, dissolved in a mixture of a little ethanol in water and chromatographed on silica gel RP-18 (eluent: gradients of tetrahydrofuran / acetone / water).

Yield: 16.81 g (91% of theory) colorless, amorphous powder Water content: 7.2%

Elemental analysis (calculated on the anhydrous substance):

Calc: θ ³⁴ · ⁰⁸ H3.64 N7.23 F, 27.77 Gd 13.52 Gender: ^C33 · ⁹¹ H3.82 N7.14 F, 27.58 Gd 13.41 Example 5 a) Amide of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa

perfluorotridecanoic acid

8.90 g (70 mmol) of oxalyl chloride were added to 30 g (57.45 mmol) of 2H, 2H, 4H, 2H, 5H, 5H-3-oxaprofluorotridecanoic acid in 300 ml of dichloromethane and stirred for 12 hours at room temperature. temperature. It is evaporated to dryness in vacuo. The residue was dissolved in 200 ml of dichloromethane. Then at 0 ° C ammonia gas is passed through the solution for about 2 hours. It was stirred for 4 hours at 0 ° C, then for another 2 hours at room temperature. Add 300 ml of 5% aqueous hydrochloric acid and stir vigorously for 15 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 = 20: 1).

Yield: 27.85 g (93% of theory) Elemental analysis: _Est . H, 27.66; N2.69 F61.97 0 27.49 H 1.72 Gender: N2.54 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 10 M borandidimethylsulfide (in tetrahydrofuran) was added. Boil for 16 hours counterclockwise. The mixture is cooled to 0 ° C and 200 ml of methanol are added dropwise, finally evaporated to dryness in vacuo. The residue was taken up in a mixture of 400 ml of ethanol / 100 ml of 10% aqueous hydrochloric acid and stirred for 8 hours at 60 ° C. It was evaporated in vacuo to dryness and the residue was crystallized from ethanol / diethyl ether.

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

Elemental analysis:

Est:

C 26.51 H2.04 N2.58 F 59.41 a 6.52 _Paul . C 26.37 H2.21 N2.46 F 59.25 Cl.6.38

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

To 26.5 g (48.74 mmol) of the title compound of Example 5b was added dropwise 14.8 g (146.2 mmol) of triethylamine dissolved in 300 ml of dichloromethane, added at 0 ° C 14.24 g (50 mmol) chloride of 3,6,9,12,15 pentaoxachexadecanoic acid and stirred for 3 hours at 0 ° C. 300 ml of 5% aqueous hydrochloric acid were added and stirred vigorously for 30 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 = 20: 1).

Yield 32.03 g (87% of theory)

Elemental analysis:

_Est . With 36.57 N4.00 N1,85 F 42.75 _Paul. C, 36.46; H4.12; N1.76; F, 42.53

d) N- (3,6,9,12,15-pentaoxahexadecyl) -N- (1H, 1H, 2H, 2H, 4H, 4H-3-oxa) -perfluorotridecyl) -amine d (41.03 mmol) from the title compound of Example 5c was dissolved in 300 ml of tetrahydrofuran and 25 ml of 10 M borandimethylsulfide (in tetrahydrofuran) was added. Boiled for 16 hours counterclockwise. It was cooled to 0 ° C and 200 ml of methanol were added dropwise, finally evaporated in vacuo to dryness. The residue was absorbed in a mixture of 300 ml of ethanol / 50 ml of 10% aqueous hydrochloric acid and stirred for 8 hours at 40 ° C. It was evaporated to dryness in vacuo, the residue was absorbed in 300 ml of 5% - aqueous sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases were dried over magnesium sulfate, evaporated in vacuo to dryness and the residue chromatographed on silica gel (eluent: dichloromethane / 2 propanol = 15: 1).

Yield: 27.68 g (91% of theory)

Elemental analysis:

_Est . C 37.26 H4.35 N1,89 F 43,56 _ C 37,11 H4.51 N1,73 F43.41

Gender:

e) 1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexa-

5-yl) -acid- (N-3,6,9,12,15-pentaoxa) -hexadecyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) - perfluorotridecyl] -amide} 1,4,7,10tetraazacyclododecane, 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-trioacetic acid and 1.35 g (31.76 mmol) lithium chloride were dissolved at 60 ° C in 100 ml dimethyl sulfoxide.

Cool to 15 ^° C and add 11.77 g (15.88 mmol) of the title compound of Example 5d. Stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred at room temperature for 2 hours. The precipitated precipitate was filtered off, dissolved in a mixture of ethanol / water and chromatographed on silica gel RP-18 (eluent: gradients of tetrahydrofuran / acetonitrile / water).

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

Elemental analysis (calculated on the anhydrous substance):

C 37.28 H4.47 N6.21 F 23.87 Gd 11.62

Est:

_Gender 037.11 H4.61 N6.03 F 23.64 Gd 11.42

Example 6

a) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohexan-5-yl) -acid-N- (12-amino-3,6,9-trioxidecyl) - amide] 1,4,7,10-tetraazacyclododecane, gadolinium complex g (15,88 mmol) of gadolinium complex of 10- [1 (carboxymethylcarboamoyl) -ethyl] -1,4,7,10-tetraazacyclode dressed1,4,7 -trioacetic 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 dimethyl sulfoxide at 60 ⁰ C. Cooled to 15 ⁰ C and 3.5 g (17 mmol) of Ν, 93'93 dicyclohexylcarbodiimide were added and stirred. for 5 minutes at 15 ⁰ C. The solution was filtered to remove urea. 14.66 g (60 mmol) of 1.12-diamino-3,6,9-trioxodecane and 2.02 g (20 mmol) of triethylamine were added to the filtrate and stirred for 12 hours at room temperature. The solution was poured into 1500 ml diethyl ether / 50 ml n-butanol and stirred for 30 minutes. The precipitated solid was filtered off and chromatographed on silica gel RP-18 (Eluent: gradients of tetrahydrofuran / acetonitrile / water).

Yield: 12.66 g (69% otor.) Colorless, amorphous powder Water content: 3.5%

Elemental analysis (calculated on the anhydrous substance) Calcd ^{C30.16 H4.54 N8.49 Ρ27} > 9θ Gd 13.61

^{Pol- C 30.02} H ⁴ » ⁶⁸ N8.35 F 27.81 Gd 13.45

b) 1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxohexan-5-yl) -acid- [N-3,6,9,16-tetraoxa-13-aza-14 -oxo-C- | 9C ₂ 6-hepta-decafluoro) -hexacosyl] -amide} -1,4,7,10tetraazacyclododecane, gadoline complex (metal complex IX)

11.3 g (21.64 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaprofluorotridecanoic acid, 0.85 g (20 mmol) of lithium chloride and 4.95 g (43 mmol) of N-hydroxysuccinimide dissolved at 25 ⁰ C in 150 ml of dimethyl sulfoxide. Cool to ⁰ C, add 6.19 g (30 mmol) of N, N'-dicyclohexylcarbodiimide and stir for 5 hours at 15 ° C. The solution is 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 stirred for 12 hours at room temperature. The solution was poured into 1300 ml of diethyl ether / 100 ml of acetone and stirred for 3 minutes. The precipitated solid was filtered off and chromatographed on silica gel RP-18 (Eluent: tetrahydrofuran / acetone / water gradients).

Yield: 13.01 g (90% otorr.)

Water Content: 6.7%

Elemental analysis (calculated on the anhydrous substance) _Calc . ^C36 · ^{86 Η4} · 30 N7.34 F24.17 Gd11.77

^{Floor C36.68 H4} · ^{41 N7} ' ^2S F 24.03 Gd11.55

Example 7

1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-hexan-5yl) -acid-N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3 -oxa-perfluorothridecyl) -amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex (15,88 mmol) from gadolinium complex of 10- [1 (carboxymethylcarboamyl) -ethyl] -1,4,7,10- tetraazacyclododecane 1,4,7-trioacetic acid and 1.35 g (31.76 mt) lithium chloride and

3.66 g (31.76 mmol) of N-hydroxysuccinimide were dissolved at 60 ° C in 100 ml of dimethyl sulfoxide. It was cooled to ⁰ C and 3.51 g (17 mmol) of дици'cyclohexylcarbodiimide was added and stirred for 5 hours at 15 ° C. The solution was filtered to remove the urea. 8.63 g (15.88 mmol) of the title compound of Example 5b and 5.06 g (50 mmol) of triethylamine were added to the filtrate and stirred for 12 hours at room temperature. The solution was poured into 1500 ml diethyl ether / 100 ml acetone and stirred for 30 minutes. The precipitated solid was filtered off and chromatographed on silica gel RP-18 (Eluent: gradients of tetrahydrofuran / acetonitrile / water).

Yield: 13.86 g (78% otorr.)

Water content: 9.3%

Elemental analysis: N7.51 F 28.87 N7.37 F 28.69 Gd 14.05 Gd 13.89 Calc: ^{C 33.28} Gender: ^{C 33.12} H3.42 H, 3.61 Poimeo 8 a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecane

iselin-N- (2,3,4,5,6-pentahydroxy) -hexylamide

8.90 g (70 mmol) of oxalyl chloride were added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaprofluorotridecanoic acid and stirred for 12 hours at room temperature. temperature. It is evaporated to dryness in vacuo. The residue was dissolved in 100 ml of dichloromethane and at 0 ° C was added dropwise to a solution of 10.87 g (60 mmol) of glucamine and 6.07 g (60 mmol) of triethylamine dissolved in 150 ml of dichloromethane / 150 ml of dioxane. It was stirred for 3 hours at 0 ° C, and then another 8 hours at room temperature. 400 ml of 5% aqueous hydrochloric acid were added and stirred vigorously for 15 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 / methanol = 5: 1).

Yield: 30.71 g (78% of theory)

Elemental analysis:

Calc: C31.55 H2.94 N2.04 F 47.13 _Gender; H, 31.44; N, 1.97; F, 47.01

B) N- (2,3,4,5,6-pentahydroxyhexyl) -N-1H, 1H1, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -amine g (43.77 mmol ) from the title compound of Example 8a was dissolved in 300 ml of tetrahydrofuran and 50 ml of 10 M borandimethylsulfide (in tetrahydrofuran) were added. Boiled for 48 hours counterclockwise. It was cooled to 0 ° C and 500 ml of methanol were added dropwise, then evaporated in vacuo to dryness. The residue was absorbed in a mixture of 500 ml of ethanol / 100 ml of 10% aqueous hydrochloric acid and stirred for 15 hours at 60 ° C. It was evaporated in vacuo to dryness, the residue was absorbed in 400 ml of 5% - of aqueous sodium hydroxide and extracted 5 times with 400 ml of chloroform. The organic phases were dried over magnesium sulfate, evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol = 3: 1).

Yield: 19.69 g (67%). Elemental analysis: _Est; С 32.20 НЗ, ЗО N2.09 F48.11 _Paul; C, 32.05; H, 3.43 N1.97 F, 47.93

c) 1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5yl) -acid- [N-2,3,5,6-penthydroxy) -hexyl-N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl] -amide} -1,4,7,10tetraazacyclododecane, gadolinium complex g (15,88 mmol) from gadolinium complex of 10 [ 1 (carboxymethylcarbamoyl) -ethyl] -1,4,7,10-tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved at 60 ° C in 100 ml of dimethyl sulfoxide. Cool to 15 ⁰ C and add 15.88 g (15q88 mmol) of the title compound of Example 8b. Stir for 10 minutes and then add

7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours. The precipitated precipitate was filtered off, dissolved in a mixture of ethanol / water and chromatographed on silica gel RP-18 (eluent: gradients of tetrahydrofuran / acetonitrile / water).

Yield: 16.10 g (79% of theory).

Water content: 6.3%

Elemental analysis (calculated on the anhydrous substance)

Est: C, 36.64 H, 3.93 N6.55 F 25.17 Gd 12.26 Gender: 0 34.49 H4.13 N6.48 F 25.03 Gd 12.11 Example 9 a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecane

acid-N- (2,2-dimethyl-5-hydroxy-1,3-dioxepan-6-yl) -amide

8.90 g (70 mmol) of oxalyl chloride were added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5h-3-oxaprofluorotridecanoic acid in 300 ml of dichloromethane and stirred for 12 hours at room temperature. temperature. It is evaporated to dryness in vacuo. The residue was dissolved in 100 ml of dichloromethane and at a temperature of 0 ° C a solution of 9.67 g (60 mmol) of 5-amino-2,2-dioxepan-6-ol and 6.07 g (60 mmol) was added dropwise. ) triethylamine dissolved in 200 ml of dichloromethane. It was stirred for 3 hours at 0 ° C, then for 5 hours at room temperature. 300 ml of water were added and stirred vigorously for 15 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: 27.62 g (85% of theory)

Elemental analysis:

_Est; C 34.30 NZ, OZ N2.11 F 48.54 _Gender; C 34.15 H3.19 N2.04 F 48.37

b) N- (1-hydroxymethyl-2,3-dihydroxypropyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -amine (40.58 mmol) of the title compound of Example 9a was dissolved in 300 ml of tetrahydrofuran and 26 ml of 10 M borandimethylsulfide (in tetrahydrofuran) were added. Boil for 20 hours counterclockwise. Cool to 0 ° C and add 300 ml of methanol dropwise, then evaporate to dryness in vacuo. The residue was absorbed in a mixture of 300 ml of ethanol / 100 ml of 10% aqueous strong acid and stirred for 6 hours at 60 ° C. It was evaporated to dryness in vacuo and the residue was absorbed in 400 ml of 5% - aqueous sodium hydroxide solution and extracted 5 times with 250 ml of chloroform. The organic phases were dried over magnesium sulfate, evaporated in vacuo to dryness and the residue chromatographed on silica gel (eluent: dichloromethane / methanol = 6: 1).

Yield: 20.09 g (81% of theory)

Elemental analysis:

_Est; C 31.44 H2.97 N2.29 F 52.83 _Sex: C 31.26 H3.11 N2.18 F 52.67

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

100

1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl] -amide} 1,4,7,10-tetraazacyclododecane, gadolinium complex

South (15.88 mmol) of gadolinium complex of 10- [1 (carboxymethylcarbamoyl) -ethyl] -1,4,7,10-tetraazacyclododecane-

1,4,7-Trisacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved at 60 ° C in 100 ml of dimethyl sulfoxide. Cool to 15 ° C and add 9.71 g (15.88 mmol) of the title compound of Example 9b. Stirred for 9 minutes and then 7.42 g (30 mmol) were added.

2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. Stirred for 12 hours at room temperature. The solution is then poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred at room temperature for 2 hours. The precipitate was filtered off, dissolved in a mixture of ethanol / water and chromatographed on silica gel RP-18 (eluent: gradients of tetrahydrofuran / acetonitrile / water).

Yield: 13.40 g (69%).

Water content: 9.1%

Elemental analysis (calculated on the anhydrous substance)

Calc'd: C 34.37 H3.79 N6.87 F 24.41 Gd 12.86

Sex: C 34.18 H3.95 N6.71 F 24.25 Gd 12.70

Example 10

a) Perfluorooctylsulfonic benzyloxycarbonylamino) -ethyl] -amide acid-N - [(2101 g (173.4 mmol) 1-benzyloxycarbonylamino-2aminoethane, hydrochloride, 87.1 g (173.4 mmol) perfluorooctylsulfofluoride 350 (35.4 g) 35 (35.4 g) mmol) triethylamine is heated at 80 ⁰ for 10 hours

C. Cooled to room temperature and purified by directly feeding on a silica gel column for chromatography (eluent: dichloromethane / acetone = 20: 1).

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

Elemental analysis:

Calc'd: C 31.97 H1.94 N4.14 F 47.75 S4.74

Gender: 0 31.83 H2.11 N4.03 F 47.63 S4.63

b) Perfluorooctylsulfonic acid -4'-1 - [(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 / was added). C) is hydrogenated at room temperature overnight. It was separated from the catalyst by filtration and the filtrate was evaporated in vacuo to dryness.

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

Elemental analysis7

Calc .: 022.15 H1.30 N5.17 F 59.57 _Sex: C 22.04 H1.41 N5.05 F 59.62

c) 1,4,7-Tris (carboxybatomethyl) -10 - {(3-aza-4-oxohexan-5-yl) -acid-N - [(2-perfluorooctylsulfonylamino) -

102 ethyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex r (15,88 mmol) from the gadolinium complex of 10- [1 (carboxymethylcarbamoyl) -ethyl] -1,4,7,10-tetraazacyclododecane -

1,4,7-trioacetic acid and 1.35 g (31.7 mmol) of lithium chloride and

3.66 g (31.76 mmol) of N-hydroxysuccinimide were dissolved at 60 ° C in 100 ml of diethyl sulfoxide. Cool to 15 ° C and then add 3.51 g (17 mmol) of дици'cyclohexylcarbodiimide and stir for 5 hours at 15 ° C. To remove urea, the solution is filtered. 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 stirred for 12 hours at room temperature. The solution was poured into 1500 ml of diethyl ether / 100 ml of acetone and stirred for 30 minutes. The precipitated precipitate was filtered off and chromatographed on silica gel RP-18 (eluent: gradients of tetrahydrofuran / acetonitrile / water).

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

Elemental analysis (calculated on the anhydrous substance): Calc: C 30.19 H 3.06 N 8.50 F 27.99 Gd 13.63 S2.7S Gender ^C30 '03 ^H3 ' ¹⁸ N8.41 F 27.81 Gd 13.50 S2. 61

Example 11

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

103

8.90 g (70 mmol) of oxalyl chloride were added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaprofluorotridecanoic acid and stirred for 12 hours at room temperature. temperature. It is evaporated to dryness in vacuo. The residue was dissolved in 100 ml of dichloromethane and at a temperature of 0 ° C was added dropwise to a solution of 13.84 g (60 mmol) of 1-benzyloxycarbonylamine-2amino-ethane, hydrochloride and 12.14 g (120 mmol) of triethylamine dissolved in 200 ml of dichloromethane. It was stirred for 3 hours at 0 ° C, then for 5 hours at room temperature. Add 300 ml of 5% aqueous hydrochloric acid and stir vigorously for 15 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 = 20: 1).

Yield: 33.30 g (83% of theory)

Elemental analysis:

Calc: C, 37.84; H2, 74; N, 4.01; F, 46.25 _; 0 37.67 H2.89 N3.88 F46.11

B) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid-N - [(2-amino) -ethyl] amide g (42.96 mmol) of the title compound of Example 11a was dissolved in 500 ml of methanol and 5 g of palladium catalyst (10% Pd / C) were added, hydrogenated overnight at room temperature

104 temperature. It was filtered to remove the catalyst and the filtrate was evaporated to dryness in vacuo.

Yield: 24.24 g (quantitative) colorless solid Elemental analysis: _Est . C, 29.80 H2.32 N4.96 F, 57.24 Gender: ^C29 · ^{67 H2} · ⁴ ' N4.88 F 57.15

c) 1,4,7-Tris- (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5yl) -acid-N- [3-aza-6-oxa-4-oxo- (Cd -C1b-heptadecafluoro) hexadecyl] -amide} -1,4,7,10-tetraazacycrylododecane - gadolinium complex

South (15.88 mmol) of gadolinium complex of 10 [1 (carboxymethylcarbamoyl) -ethyl] -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride and 3.66 g (31.76 mmol) of Nhydroxysuccinimide were dissolved in 100 ml of dimethyl sulfoxide at 60 ^° C. Cooled to 15 ° C and 3.51 g (17 mmol) of N, N'-dicyclohexylcarbodiimide added and stirred for 5 hours at 15 ° C. The solution is filtered to remove urea. 8.96 g (15.88 mmol) of the title compound of Example 11b and 2.02 g (20 mmol) triethylamine were added to the filtrate and stirred for 12 hours at room temperature. The solution was poured into 1500 ml diethyl ether / 100 ml acetone and stirred for 30 minutes. The precipitated solid precipitate was filtered off and chromatographed on silica gel RP-18 (eluent: gradients of tetrahydrofuran / acetone / water).

Yield: 15.31 g (82% of theory)

105

Water content: 6.3%

Elemental analysis (calculated on the anhydrous substance):

Calc'd: ^{C 33.71 H3} · ⁵¹ No. 34 ^F 2 ⁷ . ⁴³ Gd 13.37

Gender: ^{033.61 H3, S3 N8} · ^{17 F27} · ³¹ Gd 13.20

Example 12

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

8.90 g (70 mmol) of oxalyl chloride were added to 24.25 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaprofluorotridecanoic acid in 300 ml of dichloromethane and stirred for 12 hours at room temperature. It is evaporated to dryness in vacuo. The residue was dissolved in 100 ml of dichloromethane and at a temperature of 0 ° C was added dropwise to a solution of

3.66 g (60 mmol) of ethanolamine and 6.07 g (60 mmol) of triethylamine dissolved in 200 ml of dichloromethane. It was stirred for 3 hours at 0 ° C, then for 6 hours at room temperature. Add 300 ml of 5% aqueous hydrochloric acid and stir vigorously for 15 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 = 20: 1).

Yield: 24.86 g (93% of theory) of a colorless solid

Elemental analysis:

Calc: C, 30.98; H2, 60; N, 3.01; F, 53.09

106

Sex: ^{C30 71} Η2, δ1 N2.87 F 52.82

b) N- (2-hydroxyethyl) -N-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3oxa-perfluorondecyl) -amide g (51.59 mmol) of the title compound of Example 12a was dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borandimethylsulfide (in tetrahydrofuran) were added. Boil for 12 hours counterclockwise. It was cooled to 0 ° C and 200 ml of methanol were added dropwise, then evaporated in vacuo to dryness. The residue was absorbed in a mixture of 300 ml of ethanol / 50 ml of 10% aqueous hydrochloric acid and stirred for 8 hours at 40 ° C. It was evaporated to dryness in vacuo, the residue was absorbed in 300 ml of 5% - on a sodium hydroxide basis and extracted 3 times with 300 ml of dichloromethane. The organic phases were dried over magnesium sulfate, evaporated to dryness in vacuo and the residue was chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1).

Yield: 20.95 (90% of theory) Elemental analysis: _Est . H, 31.13 N3,10 F, 54.73 Gender: C, 31.71; H3.31 N3.01 F 54.58

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

107 g (15.88 mmol) of gadolinium complex of 10- [1 (carboxymethylcarbamoyl) -ethyl] -1,4,7,10-tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethyl sulfoxide at 60 ° C.

C. Cooled to 15 ° C and 8.98 g (15.88 mt) of the title compound of Example 12b was added. Stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitated precipitate was filtered off, dissolved in a mixture of ethanol / water and chromatographed on silica gel RP-18 (eluent: gradients of tetrahydrofuran / acetonitrile / water).

Yield: 14.01 g (83% otor.) Of a colorless, amorphous powder

Elemental analysis: Est: Gender: C, 35.03 C, 34.85 H, 3.98 H4.19 N7.91 N7.75 F 23.24 F, 23.05 Gd 14.79 Gd 14.58 Example 13 a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluoroundecane

acidic HHa-N- (3,6,9,12-tetraoxa-tridecyl) -amide

8.90 g (7 mmol) oxalyl chloride was added to 24.25 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaprofluoroundecanoic acid in 300 ml of dichloromethane and stirred for 12 hours at room temperature. In a vacuum

108 evaporated to dryness. The residue was dissolved in 100 ml of dichloromethane and a solution of 12.44 g (60 mmol) of 3,6,9,12-tetraoxetridecylamine and 6.07 g (60 mmol) of triethylamine was added dropwise at 0 ° C. dissolved in 200 ml of dichloromethane. It was stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid are added and stirred vigorously for 15 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.Ί).

Yield: 31.61 (90% of theory) soluble solid Elemental analysis:

_Est . C 37.33 H4.29 N2.29 F 40.40 _Gender . C 37.15 H4.41 N2.12 F 40.18

B) N- (3,6,9,12-tetraoxatridecyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorondecyl) -amine (50.7 mmol) of the title compound of Example 13a was dissolved in 300 ml of tetrahydrofuran and 32 ml of 10 M borandimethylsulfide (in tetrahydrofuran) were added. Boiled for 16 hours counterclockwise. It was cooled to 0 ° C and 200 ml of methanol were added dropwise, then evaporated in vacuo to dryness. The residue was absorbed in a mixture of 300 ml of ethanol / 50 ml of 10% aq hydrochloric acid and stirred for 8 hours at 40 ° C. In vacuo it was evaporated to dryness, the residue was absorbed in 300 ml of 5% - water

109 sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases were dried over magnesium sulfate, evaporated in vacuo to dryness, and the residue was chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1). Yield: 28.17 g (93% of theory) colorless solid elemental analysis (calculated on the anhydrous substance): _calc: C38.20 H4.72 N2.34 F41.34 sex C 38.05 H4.83 N2.40 F41.50

c) 1,4,7-Tris- (carboxylatomethyl) -10 - {(3-aza-4-oxohexan-5-yl) -acid-N - [(3,6,9,12-tetraox) -tridecyl- N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-Zox) -perfluoroundecyl] -amide} -1,4,7,10tetraazacyclododecane - gadolinium complex g (15,88 mmol) gadolinium complex on 10- [1 (carboxymethylcarbamoyl) -ethyl] -1,4,7,10-tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. Cooled to 15 ° C and 9.49 g (15.88) added. mmol) from the title compound of Example 13b. Stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred at room temperature for 2 hours. The separated precipitate was filtered off, dissolved in a mixture of ethanol / water and evaporated

110 was chromatographed on silica gel RP-18 (eluent: gradients of

tetrahydrofuran / acetonitrile / water). Yield: 16.13 g (84% of theory) F 20.43 F 20.60 Gd 13.01 Gd 13.15 Elemental analysis: _Calc; C37.75 H4.67 Sex: 0 37.91 H4.81 N6.95 N6.83 Example 14 a) 2-N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa

perfluorotridecyl) -amino-acetic acid-tetrabutyl 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 at 50 ° C were added dropwise 6.523 g (40 mmol) of bromoacetic acid - tetrabutyl ester and stirred for 3 hours at this temperature. Add 300 ml of dichloromethane, filter from the precipitated salts and evaporate 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

Elemental analysis:

Calc'd: C 34.80 H 3.24 N 2.25 F 51.98

Sex: C 34.98 H3.31 N2.20 F 52.16

Ill

b) 1,4,7-Tris- (carboxylatomethyl) -10 - {(3-aza-4-oxohexan-5-yl) -acid-N - [(tert-butyloxycarbonylmethyl) -N- (1H, 1H, 2H) , 2H, 4H, 4H, 5H, 5H-Zoxa) perfluorotridecyl] amide} 1,4,7,10-tetraazacycododecane-gadolinium complex g (15,88 mmol) gadolinium complex 10- [1 (carboxymethylcarboamoyl) -ethyl] - 1,4,7,10-tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. Cooled to 15 ° C and 9.87 g (15.88) added. mmol) from the title compound of Example 14a. Stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred at room temperature for 2 hours. The precipitated precipitate was filtered off, dissolved in a mixture of ethanol / water and chromatographed on silica gel RP-18 (eluent: gradients of tetrahydrofuran / acetonitrile / water).

Yield: 16.64 g (85% of theory) Elemental analysis: _Est . H, 36.94 N6.82 F 26.19 Gd 12.72 Gender: 0 35.92 H3.83 N6.91 F 26.29 Gd 12.84

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

112

South (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. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel RP-18 (eluent: gradients of tetrahydrofuran / acetonitrile / water). After evaporation of the product containing fractions, the residue was dissolved in water and the acidity was adjusted to pH 7.2 with 5% aqueous sodium hydroxide. The solution was filtered and the filtrate was freeze-dried.

Yield: 10.48 g (91% of theory)

Elemental analysis (calculated on the anhydrous substance):

I θ ′ 33.06 H3.28 N7.01 F 26.94 Gd 13.12 At 1.92 Gender: ^C33 · ¹⁹ NZ, 40 N7.20 F 27.14 Gd 13.25 At 2.00 Example 15 a) 2H, 2H, , 4H, 4H, 5H, 5H-3-aza-perfluorotridecane

acid-N- (2-hydroxyethyl) -amide

To 32 g of 956.61 mmol) of the title compound of Example 4a were added 2.96 g (74 mmol) of sodium hydride (60% sodium hydride in paraffin oil) in 300 ml of THF and stirred for 3 hours at room temperature. temperature in a nitrogen atmosphere. They are added dropwise

7.67 g (74 mmol) of bromoacetic acid-tetrabutyl ester dissolved in 20 ml of tetrahydrofuran and stirred for 5 hours at 50 ° C. 50 ml of methanol are added and evaporated to dryness in vacuo. The rest is

113 was chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1).

Yield: 23.46 g (61% of theory)

Elemental analysis:

Est: C, 35.36 H3.26 N2.06 F, 47.54 Gender: C, 35.52 H3.40 N2.17 F 47.40 B) N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-OKca) -N- [4-

tert-butyloxycarbonyl-3-oxa-butyl] amine

35.0 g (51.52 mmol) of the title compound of Example 15a were dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borandimethyl sulfide (in tetrahydrofuran) was added. Boiled for 16 hours counterclockwise. It was cooled to 0 ° C and 200 ml of methanol were added dropwise, then evaporated to dryness in vacuo. The residue was absorbed in a mixture of 300 ml of ethanol / 50 ml of 10% aqueous hydrochloric acid and stirred for 8 hours at 40 ° C. In vacuo it was evaporated to dryness, the residue was absorbed in 300 ml of 5% - aqueous sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases were dried over magnesium sulfate, evaporated to dryness in vacuo and the residue was chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1).

Yield: 31.88 g (93% of theory) of elemental analysis:

_calculated C 36.10 H3.64 N2.11 F 48.54 floor: 035.90 H3.75 N2.20 F48.71

114

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, 5H3oxa) perfluorotridecyl] amide} 1,4,7,10-tetraazacyclododecane, gadolinium complex g (15,88 mmol) gadolinium complex on 10- [1 (carboxymethylcarbamoyl) -ethyl] -1,4,7,1O-tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. Cooled to 15 ° C and 10.57 g (15.88) were added. mmol) from the title compound of Example 15b. Stirred for 15 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitated precipitate was filtered off, dissolved in a mixture of ethanol / water and chromatographed on silica gel RP-18 (eluent: gradients of tetrahydrofuran / acetonitrile / water).

Yield: 16.63 g (82% of theory)

Elemental analysis:

_Est . c 36.68 H4.10 N6.58 F 25.29 Gd 12.31

Gender ' ^{C 36.81} H' * · ²⁰ N6.41 F 25.40 Gd 12.19

d) 1,4,7-Tris- (carboxylatomethyl) -10 - {(3-aza-4-oxa-hexan-5yl) -acid- [N- (4-carboxy-3-oxa) -butyl) -N - (1H, 1H, 2H, 2H, 4H,

115

4H, 5H, 5H-Zoxa) perfluorotridecyl] -amide} -1,4,7,10tetraazacyclododecane, gadolinium complex g (9.40 mmol) of the title compound of Example 15c were dissolved in 50 ml of trifluoroacetic acid and stirred for 5 hours at room temperature. It was evaporated to dryness in vacuo and the residue was chromatographed on silica gel RP-18 (eluent: gradients of tetrahydrofuran / acetonitrile / water). After evaporation of the extracts containing the product, the residue was dissolved in water and the acidity was adjusted to pH 7.2 with 5% aqueous sodium hydroxide. The solution was filtered and the filtrate was freeze-dried.

Yield: 11.41 g (92% of theory)

Water Content: 5.8%

Elemental analysis:

^Est : ^{C 33.82 nz} > ⁴⁹ N6.76 F25.98 Gd 12.65 Na 1.85 ^{Floor 033.95 H3.6} ° ^{N6.88 F26 '15 Gd12} ^ Na 1.93

Example 16

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

8.90 g (70 mmol) of oxalyl chloride were added to 30 g (57.45 mmol) of 1H, 2H, 4H, 4H, 5H, 5H-3-oxaprofluorotridecanoic acid in 300 ml of dichloromethane and stirred for 12 hours at room temperature. temperature. Is evaporating

116 in vacuum to dry. The residue was dissolved in 100 ml of dichloromethane and at 0 ° C was added dropwise in a solution 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. dichloromethane. It was stirred for 3 hours at 0 ° C, then for 6 hours at room temperature. Add 300 ml of 5% aqueous hydrochloric acid and stir vigorously for 15 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: 52.87 (91% otheor.)

Elemental analysis:

Calc'd: C 28.50 H1.49 N1.38 F 63.87

Paul. 0 28.65 H1.61 N1.50 F 64.01

b) N-6nc- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -fluorotridecyl) -amine (51.42 mmol) from the title compound of Example 16a was dissolved in 500 ml. tetrahydrofuran and 31 ml of 10 M borandimethylsulfide (in tetrahydrofuran) were added. Boiled for 16 hours counterclockwise. The mixture was cooled to 0 ° C and 200 ml of methanol was added dropwise, then evaporated to dryness in vacuo. The residue was absorbed in a mixture of 400 ml of ethanol / 70 ml of 10% aqueous hydrochloric acid and stirred for 8 hours at 40 ° C. It was evaporated to dryness in vacuo and the residue was absorbed in 400 ml of 5% water.

117 aqueous sodium hydroxide solution and extracted 3 times with 400 ml of dichloromethane. The organic phases were dried over magnesium sulfate, evaporated to dryness in vacuo and the residue was chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1).

Yield: 47.18 g (92% of theory) of a colorless solid

Elemental analysis:

Calc'd: C 28.90 H1.72 N1.40 F 64.77

Sex: C 30.03 H 1.81 N1.55 F 65.00

c) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohexan-5-yl) -acid-N-bis- (1H, 1H, 2H, 2H, 4H, 4H, 5H) , 5H-3oxa-perfluorotridecyl) -amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex r (15,88 mmol) from the gadolinium complex of 10- [1 (carboxymethylcarbamoyl) -ethyl] -1,4,7 , 10-tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. Cooled to 15 ° C and 15.84 g (15.88) added. mmol) from the title compound of Example 16b. Stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitated precipitate is filtered off, dissolved in a mixture of

118 ethanol / water and chromatographed on silica gel RP-18 (eluent: tetrahydrofuran / acetonitrile / water gradients).

Yield: 20.95 g (82% of theory) Elemental analysis: _Clear .With 32.10 N2.82 N5.22 F40.14 Gd 9.77 _Gender: C, 29.87; H2.91 N5.09 F, 40.28 Gd 9.98

Example 17

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

To 32 g (52.52 mmol) of the title compound of Example 3 was added 2.80 g (70 mmol) of sodium hydride (60% sodium hydride in paraffin oil) and 300 ml of THF and stirred for 3 hours at room temperature in a nitrogen atmosphere. 9.68 g (70 mmol) of bromoacetic acid-tert-butyl ester dissolved in 20 ml of tetrahydrofuran are added dropwise and stirred for 5 hours at 50 ° C. 50 ml of methanol are added and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1). Yield: 19.31 g (59% of theory)

Elemental analysis:

Est: C, 32.76; H2.91; N2.25 F51.82 Gender: C, 32.98; H, 2.99; N, 2.36 F51,98 B) N- (3,6-dioxa-heptyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-

3-Oxa-perfluorotridecyl) -amine

119 g (51.34 mmol) of the title compound of Example 17a were dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borandimethyl sulfide (in tetrahydrofuran) was added. Boiled for 16 hours counterclockwise. It was cooled to 0 ° C and 200 ml of methanol were added dropwise, then evaporated to dryness in vacuo. The residue was absorbed in a mixture of 300 ml of ethanol / 50 ml of 10% aqueous hydrochloric acid and stirred for 8 hours at 40 ° C. It was evaporated to dryness in vacuo, the residue was absorbed in 300 ml of 5% - aqueous sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases were dried over magnesium sulfate, evaporated to dryness in vacuo and the residue was chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1).

Yield: 28.47 g (91% of theory) Elemental analysis: Calc'd: 033.51 H3.31 N2.30 F 53.01 Sex: O 33.63 H 3.41 N2.21 F 52.87

c) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxohexan-5-yl) -acid-N- (3,6-dioxa) -heptyl-N- (1H, 1H) , 2H, 2H, 4H, 2H, 5H, 5H -3-oxa-perfluorotridecyl) -amide] -1,4,7,10tetraazacyclododecane, gadolinium complex g (15,88 mmol) gadolinium complex of 10- [1 (carboxymethylcarboamyl) -ethyl] -1,4,7,10-tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride

120 was dissolved in 100 ml of dimethyl sulfoxide at 60 ^° C. Cooled to 15 ° C and 9.68 g (15.88 mmol) of the title compound of Example 17b was added. Stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred at room temperature for 2 hours. The precipitated precipitate was filtered off, dissolved in a mixture of a little ethanol / water and chromatographed on silica gel PP-18 (eluent: gradients of tetrahydrofuran / acetonitrile / water).

Yield: 16.09 g (83% of theory) Elemental analysis: _Est . 0 35.41 H3.96 N6.88 F, 26.45 Gd 12.88 _Paul . C35.57 H4.11 N6.72 F, 26.58 Gd 12.97

Example 18

a)

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

8.90 g (70 mmol) of oxalyl chloride were added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaprofluorotridecanoic acid in 300 ml of dichloromethane and stirred for 12 hours at room temperature. temperature. Evaporates to dryness in vacuo. The residue was dissolved in 100 ml of dichloromethane and at 0 ° C was added dropwise to a solution of 6.07 g (60 mmol) of n-hexylamine and 6.07 g (60 mmol) of triethylamine,

121 dissolved in 200 ml of dichloromethane. It was stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. Add 300 ml of 5% aqueous hydrochloric acid and stir vigorously for 15 minutes. The organic phase was separated and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 20: 1).

Yield: 30.95 g (89% of theory)

Elemental analysis:

Calc .: 35.72 H 3.33 Gender: ^C35 · ^{60 H3} · ⁴⁵ N2.31 N2.43 F 53.35 F, 53.63 B) N- (xeKcnn) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa perfluorotridecyl) -amine

g (51.21 mmol) of the title compound of Example 18a was dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borandimethyl sulfide (in tetrahydrofuran) was added. Boiled for 16 hours counterclockwise. It was cooled to 0 ° C and 200 ml of methanol were added dropwise, then evaporated in vacuo to dryness. The residue was absorbed in a mixture of 300 ml of ethanol / 50 ml of 10% aqueous hydrochloric acid and stirred for 8 hours at 40 ° C. It was evaporated to dryness in vacuo, the residue was absorbed in 300 ml of 5% - aqueous sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is taken up in vacuo.

122 was chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1).

Yield: 28.16 g (93% of theory)

Elemental analysis:

_Est . C, 36.56; H3.75; N2.37; F, 54.62

Gender: ^{C36> 4} ° ^{H3> 82} N2.27 F 54.81

c) 1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexane-5nn) -KhcenHHa- [N- (xeKcnn) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-oxaprofluorotridecyl) -amide]} - 1,4,7,10-tetraazacyclododecane, gadolinium complex g (15,88 mmol) gadolinium complex of 10- [1 (carboxymethylcarbamoyl) -ethyl] -1, 4,7,10-tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of diethyl sulfoxide at 60 ° C. Cooled to 15 ° C and 10.98 g (15.88 mmol) were added. ) from the title compound of Example 18b. Stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitated precipitate was filtered off, dissolved in a little alcohol / water mixture and chromatographed on silica gel RP-18 (eluent: tetrahydrofuran / acetonitrile / water gradients).

Yield: 16.29 g (84% of theory)

123

Elemental analysis:

Est: gender: C, 36.94 C, 37.18 H4.19 N6.99 H4.31 N7.18 F, 26.85 F, 26.67 Gd 13.07 Gd 13.19 Poimeo 19 a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecane

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

To a solution of 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxo-perfluorotridecanoic acid in 300 ml of dichloromethane were added 8.90 g (70 mmol) of oxalyl chloride and stirred for 12 hours at room temperature. It is evaporated to dryness in vacuo. The residue was dissolved in 100 ml of dichloromethane and at a temperature of 0 ° C was added dropwise to a solution 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. It was stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. Add 300 ml of 5% aqueous hydrochloric acid and stir vigorously for 15 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 = 20: 1).

Yield: 42.04 g (92% of theory)

Elemental analysis:

Calc'd: C 42.58 H4.76 N1.84 F 42.41

124 _Sex; C 42.74 H 4.90 N1.73 F 42.61

b) N- (10-tert-butyloxycarbonyl-decyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -amine (51.21 mmol) of the title the compound of Example 19a was dissolved in 300 ml of tetrahydrofuran and then 31 ml of 10 M borandimethylsulfide (in tetrahydrofuran) was added. Boiled for 16 hours counterclockwise. It was cooled to 0 ° C and 200 ml of methanol were added dropwise, then evaporated in vacuo to dryness. The residue was absorbed in a mixture of 400 ml of ethanol / 70 ml of 10% aqueous hydrochloric acid and stirred for 8 hours at 40 ° C. It was evaporated to dryness in vacuo and the residue was absorbed in 350 ml of 5% - and aqueous sodium hydroxide solution and extracted 3 times with 400 ml of dichloromethane. The organic phases were dried over magnesium sulfate, evaporated to dryness in vacuo, and the residue was chromatographed on silica gel (eluent 7 dichloromethane / 2 propanol = 20: 1).

Yield: 34.84 g (91% of theory)

Elemental analysis:

_Calc'd: C 43.38 H5.12 N1.87 F 43.20

Gender: 043.22 H5.23 N1.96 F 43.33

c) 1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-hexan-5-yl) acid- [N- (10-tert-butyloxycarbonyl) -decyl-N- (1H, 1H) , 2H, 2H,

125

4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl] -amide} -1,4,7,10tetraazocyclododecane, gadolinium complex g (15,88 mmol) gadolinium complex of 10- [1 (carboxymethylcarboamoyl) -ethyl] -1 , 4,7,10-tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved at 60 ° C in 100 ml of dimethyl sulfoxide. Cool to 15 ° C and add 11.87 g (15.88 mmol) of the title compound of Example 19b. Stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitated precipitate was filtered off, dissolved in a little alcohol / water mixture and chromatographed on silica gel RP-18 (eluent: tetrahydrofuran / acetonitrile / water gradients).

Yield: 17.92 g (83% of theory) Elemental analysis: _Est; H, 40.85 N6.18 F, 23.76 Gd 11.57 Gender: 040.81 H4.99 N6.32 F, 23.94 Gd 11.73

d) 1,4,7-Tris- (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5yl) -acid- {N- (10-carboxy) -decyl-N- (1H, 1H) , 2H, 2H, 4H, 4H, 5H, 5H-Zoxa) perfluorotridecyl] -amide} -1,4,7,10-tetraazocyclododecane, gadolinium complex

126 g (8.83 mmol) of the title compound of Example 19c were dissolved in 50 ml of trifluoroacetic acid and stirred for 5 hours at room temperature. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel RP18 (eluent: gradients of tetrahydrofuran / acetonitrile / water). After evaporation of the fractions containing the product, the residue was dissolved in water and the pH was adjusted to 7.2 with 5% aqueous sodium hydroxide. The solution was filtered and the filtrate was freeze-dried.

Yield: 12.48 g (92% of theory)

Water content: 6.2%

Elemental analysis:

Cal · ^{C 38.07 N4,34 N6,34} F ^24-37 Gd 11,87 Na 1,73

Gender: ^{C37 '89 H4} ' ⁴⁴ N6.22 F ²⁴ » ⁵ * Gd 12.01 Na 1.80

Example 20

a) 15-Benzyl-3,6,9,12,15-pentaoxa-hexanedecyl acid-N, 1H, 2H, 2H, 4H, 4H, 5H, 5h-3 oxa) perfluorotridecyl) -amide

8.90 g (70 mmol) of oxalyl chloride were added to 19.67 g (57.45 mmol) of 15-benzyl-3,6,9,12,15 pentaoxachexadecyl acid and stirred for 12 hours at room temperature. temperature. Evaporates to dryness in vacuo. The residue was dissolved in 100 ml of dichloromethane and at a temperature of 0 ° C was added dropwise to a solution of 32.62 g (60 mmol) of 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxafluoro127. tridecylamine, hydrochloride and 6.07 g (60 mmol) of triethylamine dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0 ° C, then -6 hours at room temperature. Add 300 ml of 5% aqueous hydrochloric acid and stir vigorously for 15 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 = 20: 1).

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

Calc'd: C 41.89 H4.12 N1.68 F 38.84 _Gender; C 42.02 H4.25 N1.83 F 39.07

b) N-15-benzyl-3,6,9,12,15-pentaoxa-hexadecyl) -N- (1H,

1H, 2H, 2H, 4H, 4H, 5H, 5H-Zoxa-perfluorotridecyl-amine (51.72 mmol) from the title compound of Example 20

a) dissolved in 400 ml of tetrahydrofuran and then 31 ml of 10 M borindimethylsulfide (in tetrahydrofuran) were added. It boils for 16 hours counterclockwise. It was cooled to 0 ° C and 200 ml of methanol were added dropwise, then evaporated in vacuo to dryness. The residue was absorbed in a mixture of 400 ml of ethanol / 50 ml of 10% aqueous hydrochloric acid and stirred for 8 hours at 40 ° C. In vacuo it was evaporated to dryness, the residue was absorbed in 350 ml of 5% aqueous sodium hydroxide. again and extracted 3 times with 400 ml of dichloromethane each. The organic phases are dried over magnesium sulphate and evaporated in vacuo

128 to dryness and the residue was chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1).

Yield: 39.32 g (93% of theory)

Elemental analysis:

Calcd: I H4.12 N1.68 F 38.84

Sex: C 42.45 H4.23 N1.57 F 38.99

c) 1,4,7-Tris- (carboxylatomethyl) -10 - {(3-aza-4-oxohexan-5-yl) -acid- [1 N- (15-benzyl-3,6,9,12,15) pentaox) hexadecyl-N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) tridecyl] amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex g (15, 88 mmol) gadolinium complex of 10 [1 (carboxymethylcarbamoyl) -ethyl] -1,4,7,10-tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved in 100 ml of dimethyl sulfoxide at 60 ^° C. Cooled to 15 ° C and 12.98 g (15.88) were added. mmol) from the title compound of Example 20 a. Stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxyquinoline were added. Stirred for 12 hours at room temperature. The solution was poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The precipitated precipitate was filtered off, dissolved in a little alcohol / water mixture and chromatographed on silica gel RP-18 (eluent: gradients of tetrahydrofuran / acetonitrile / water).

Yield: 18.84 g (83% of theory)

129

Elemental analysis:

_Calc'd: C, 40.34; H, 4.51

N5.88 F 22.60 Gd 11.00

Gender:

C, 40.50

H, 4.62

N5.76

F 22.73 Gd 11.16

d) 1,4,7-Tris- (carboxylatomethyl) -10 - {(3-aza-4-oxohexan-5-yl) -acid- [N- (14-hydroxy-3,6,9,12-tetraoxa) ) tetradecyl-N, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex g (8.40 mmol) from The title compound of Example 20 was dissolved in 150 ml of methanol and then 1.0 g of palladium catalyst (10% Pd / C) was added while hydrogenating overnight at room temperature. Filter off the catalyst and evaporate the filtrate in vacuo to dryness.

Yield: 10.13 g (95% of theory) Elemental analysis: Calcd: θ 38.80 H4.61 N1,10 F 25.45 Gd 12.39 Gender: C, 38.87; H, 4.73 N1,20 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-1-lysine were dissolved in a mixture of 1000 ml of trifluoroacetic acid ethyl ester and 500 ml of ethanol and stirred in

130 for 24 hours at room temperature. It was evaporated to dryness 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.

Elemental analysis:

_Est . C, 51.07; H5.09; N7.44; F, 15.14

D | _ol · 051.25 H5.18 N 7.58 F 15.03

a) 2-L1-Trifluoroacetyl-6-N-benzyloxycarbonyl-L-lysine [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

To 125.0 g (332.0 mmol) of the title compound of Example 21a and 188.7 g (332.0 mmol) of 1-perfluoroctylsulfonylpiperazine (prepared according to DE 19603033) in 750 ml of tetrahydrofuran are added at 0 ° C.

164.2 g (0.664 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred at room temperature overnight. It is evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / ethanol = 20: 1).

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

Elemental analysis:

^{36.30 N 2.83 N 6) 05} F 41.01 S 3.46 Gender: ^{NW 18} H 2.94

N 5.98 F 40.87 S 3.40

131

b) 6-N-benzyloxycarbonyl-E-lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

Ammonia gas was bubbled through a solution of 280.0 g (302.2 mol) of the title compound of Example 21b in 2000 ml ethanol at 0 ° C for one hour. Finally, it was stirred for 4 hours at 0 ° C. It was evaporated to dryness and the residue was washed with water. Filter the solid and dry in vacuo at 50 ° C.

Yield: 243.5 d (97 % of theory.) And colorless amorphous substance. Elemental analysis: Calc: ^S37 - ^E0 H, 3.28 N, 6.75 F 38.89 S, 3.86 Paul; ^C37 · ⁵⁵ H, 3.33 N, 6.68 F 38.78 S, 3.81

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

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-Oa-Dcarboxymethyl-2,3,4,6-tetra-O-benzyl- manopyranose and 13.86 g (120.4 mol) of N-hydroxysuccinimide dissolved in 500 ml of dimethylformamide were added at 0 ° C to 41.27 g (200.0 mmol) of N, N -dicyclohexylcarbodiimide. It was stirred for 3 hours at 0 ° C and then overnight at

132 room temperature. The precipitated urea was filtered off, the filtrate was evaporated to dryness in vacuo and chromatographed on silica gel.

(eluent: dichloromethane / ethanol = 20: 1).

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

Elemental analysis:

_Est . With 57,32 H4.8F N4,31 F 24,86 S2.47 _Paul. C 57.38 H 5.07 N4.22 F 24.78 S2.39

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

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

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

Elemental analysis:

Est:

C, 34.07

H, 3.63

N, 6.11

S, 3.50

F 35.24

Gender:

C, 33.91

H, 3.72

N, 6.04; S, 3.40

F 35.31

f) 6- N- [1,4,7-Tpnc (carboxylatomethyl)] - 1,4,7,10-tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5yl) ] -2M- [1-0-a-0-carbonylmethyl-mannopyranose] -1_-lysine [1- (4133 perfluorooctylsulfonyl) -piperazine] -amide, gadolinium complex (metal complex XV)

50.0 g (54.55 mmol) of the title compound of Example 21e, 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54 , 55 mol) 1,4,7tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methyl-pent-

5-yl) -1,4,7,10-tetraazacyclododecane, Cd-complex, was dissolved in 400 ml of dimethyl sulfoxide under gentle heating. At 10 ° C, 16.88 g (81.8 mol) of Νdicyclohexylcarbodiimide were added and 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 then purified by rhymography (RP-18 eluent: gradients of water / ethanol / acetonitrile).

Yield: 75.9 g (91.0% of theory) of a colorless solid.

Water content: 8.6%

Elemental analysis (calculated on the anhydrous substance):

_Est; C 35.34 H4.09 N8.24 S2.10 F 21.12 Gd 10.28

^{Floor C35.28 H4 '15 N8.19 S2} ' ^{15 F2} 1-03 Gd10.14

Example 22

a) 6-N- [1,4,7-Tris (carboxylatomethyl)] - 1,4,7,10tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5134 ππ)] -2-N- [1-0-α-D-carbonylmethyl-mannopyranose] -1_-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Cd-complex

50.0 g (54.55 mmol) of the title compound of Example 21e, 6.28 g (54.55 mmol) of N-dihydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54 , 55 mol) 1,4,7tris (carboxylatomethyl) -10- (carboxy-3-4-oxo-5-methyl-pent-

5-yl) -1,4,7,10-tetraazacyclododecane, Cd-complex, was dissolved by gentle heating in 400 ml of dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mmol) Ν, Νcyclohexylcarbodiimide were added and 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 chromatography (RP18 eluent: gradients of water / ethanol / acetonitrile).

Yield: 76.0 g (92% of theory) of a colorless solid.

Water content: 6.88%.

Elemental analysis (calculated on the anhydrous substance):

C34.90 Est: H, 3.93; N8.32 S2.12 F21,33 Gd 10.38 C, 34.81 gender: H4.02 N8.27 82.09 F 21.22 Gd 10.19 An example 23 a) methyl ester on 2- [4-3-Oxapropionic

acid ethyl ester] -phenylacetic acid

135

To 200.0 g (1204.0 mmol) of 4-hydroxyphenylacetic acid methyl ester, 212.0 g (2000p0 mmol) of sodium carbonate in 2000 ml of acetone were added 233.8 g (1400.0 mmol) of 2-bromoacetic acid ethyl ester. and boiled for 5 hours counterclockwise. The precipitated solid was evaporated to dryness in vacuo. The residue was chromatographed on silica gel. (Eluent: acetic acid n-hexane / ethyl ester = 15: 1).

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

Elemental analysis:

_Calcd. C61.90 H6.39 _Pol . C, 61.75; H6.51

B) methyl ester on

2- [4-3-Oxapropionic acid ethyl ester)] - pentyl-2-bromoacetic acid

To 285.0 g (1130.0 mmol) of the title compound of Example 23a dissolved in 201.0 g (1130.0 mmol) of N-bromosuccinimide and 100.0 mg of dibenzoyl peroxide and boiled for eight hours countercurrently. It was cooled in an ice bath, the succinimide precipitated as a precipitate was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was purified on silica gel (eluent: n-hexane / acetone = 15: 1).

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

Elemental analysis:

136

Calc: ^C47 > ²⁸ H4.57 Br 24,16 Gender: ^C47 > ¹⁹ H, 4.71 Br 24.05 c) methyl ester of 2- [4- (3-Oxapropionic)

acid-ethyl ester) -phenyl-2- [1- (1,4,7,10-tetraazacyclododecan-1-yl] -acetic acid

To 603.0 g (3500.0 mmol) of 1,4,7,10-tetraazacyclododecane, 350.0 g (1057.0 mmol) of the title compound of Example 23b were added in 6000 ml of chloroform and stirred overnight at room temperature. temperature. It is extracted 3 times, usually with 3000 ml of water, the organic phases are dried over magnesium sulfate 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 viscous oil.

Elemental analysis:

_Est . C 59.70 H8.11 N13.26 _Paul .C 59.58 H8.20 N13.18

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

445.0 g (1053.0 mmol) of the title compound of Example 23c and 496.0 g (5270.0 mmol) of chloroacetic acid were dissolved

137 in 4000 ml of water. The aqueous sodium hydroxide solution was adjusted to pH 10 with 30% aqueous solution and stirred for 8 hours at 70 ° C. The acidity of the reaction solution was then adjusted by adding 30% aqueous sodium hydroxide to pH 13 and boil for 30 minutes in countercurrent. The solution was cooled in an ice bath and the pH of the medium was brought to 1. by evaporation of concentrated hydrochloric acid. Evaporated to dryness in vacuo. The residue was absorbed in 4000 ml of methanol and stirred for 1 hour at room temperature. Filtered from the precipitated sodium salt, the filtrate was evaporated to dryness and the residue was purified on RP-18 C silica gel (eluent: gradients of water / ethanol / acetonitrile).

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

Elemental analysis (calculated on the anhydrous substance):

_Est; 051.98 H6.18 N10.10 _Gender . 051.80 H6.31 N10.01

f) 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 were added 130.73 g (360.65 mmol) of gadolinium complex and stirred for 5 hours at 80 ° C. The solution was filtered and the filtrate was freeze-dried.

Yield: 511 g (quantitative) of an amorphous solid.

138

Water content: 11.0%

Elemental analysis (calculated on the anhydrous substance):

Calc: C 40.67 N4,41 N7,98 Gd 22,19 _Paul. C, 40.51; H4.52; N8.03; Gd: 22.05

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

50.0 g (54.55 mmol) of the title compound of Example 21 is 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 were dissolved under gentle heating in 400 ml of dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mmol) of N, N-dicyclohexylcarbodiimide were added and then stirred at room temperature overnight. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was distilled off and then purified by chromatography (RP-18; eluent: gradients of water / ethanol / acetonitrile). The resulting product was dissolved in a little water and the acidity of the solution was adjusted to pH 7.4 with aqueous sodium hydroxide. Finally, the solution containing the product was freeze-dried.

Yield: 79.1 g (89% of theory) of a colorless solid.

Water content: 10.3%.

139

Elemental analysis:

_Est; C, 36.86; H3.77; N6.88

S1.97

F 19.82 Gd 9.65 _Sex _ C 36.75 H3.8 N6.80 S2.03

F 19.75 Gd9.57

Example 24

a) 6-N- [1,4,7-Tris (1-butyloxycarbonylmethyl) -10carboxymethyl-1,4,7,10-tetraazacyclododecane-10carbonylmethyl] -2-N- (1-0-a-0-carbonylmethyl- manopyranose) -1-lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

15.0 g (26.19 mmol) of 1,4,7-tris (butyloxycarbonylmethyl) 10-carboxymethyl-1,4,7,10-tetraazacyclododecane, 24.0 g (26.19 mmol) of the title compound of Example 21f and 3.01 g (26.19 mmol) of N-hydroxysuccinimide were dissolved in 150 ml of dimethylformamide and 8.25 g (40.0 mmol) of N, N-dicyclohexylcarbodiimide were added at 0 ° C. Stir overnight at room temperature. The precipitated urea was filtered off and the filtrate was evaporated to dryness in vacuo. The residue is chromatographed on silica gel. (Eluent: dichloromethane / methanol = 20: 1).

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

Elemental analysis:

_Est; 044.08 H5.69 N7.62 F21.95 S 2.18

Gender:

C44.01 H5.81

N7.53

F 21.87 S 2.03

140

b) 6-N- [1,4,7-Tpnc (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-carbonyl methyl] -2-N- [1-Fa-Dcarbonylmethyl-mannopyranose] -1_- lysine [1- (4perfluoroctylsulfonyl) -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 then 300 ml of trifluoroacetic acid were added. Stir for 10 minutes at room temperature. It was evaporated to dryness in vacuo and the residue was dissolved in 300 ml of water. 3.69 g (10.19 mmol) of gadolinium oxide are added and stirred for 5 hours at 80 ° C. The solution is evaporated to dryness in vacuo and purified on silica gel (RP-18; eluent: gradients of water (ethanol / acetonitrile).

Yield: 11.0 g (37.0% of theory) of a colorless and amorphous solid.

Water content: 11.3%.

Elemental analysis (calculated on the anhydrous basis)

substance): _Calc . C34.62 H3.87 N7.69 F 22.16 S 2.20 Gd 10.97 _Gender: C, 34.57; H3.95 N7.60 F 22.05 S 2.13 Gd 10.90 Example 25 a) 6-N- [3,6,9-Tris (carboxymethyl) 3,6,9-

triazadecandicacid-1-carboxy-11-yl] -2-N- [1-O-a-Carbonylmethyl-mannopyranose] -1_-lysine [1- (4perfluoroctylcarbonyl) -piperazine] -amide

141

To 24.0 g (26.19 mmol) of the title compound of size 21 is dissolved in 100 ml of dimethylformamide / 30 ml of pyridine, 12.10 g (30.0 mmol) of 3-N- (2,6dioxomorpholinoethyl) -6M are added. - (ethoxycarbonylmethyl) -3,6 diaza-octanedic acid and stirred for 5 hours at 50 ° C. It is evaporated to dryness in vacuo. The residue was dissolved in 200 ml of water and the pH of the resulting solution was adjusted to 13 by the addition of 20% aqueous sodium hydroxide. Stirred for 8 hours at 22 ° C and pH 13. By adding conc. the hydrochloric acid was brought to pH 7.2 and finally evaporated to dryness in vacuo. The residue was chromatographed on silica gel RP-18 (eluent: gradients of water / ethanol / acetonitrile).

Yield: 17.26 g (51.0% of theory) of a colorless solid. Water content: 9.3%

Elemental analysis (calculated on the anhydrous substance):

Calc: ^C37 »19n ⁴ & N7.59 F 25.00 S 2.48 _pol . C 37.10 H 4.30 N7.48 F 25.07 S 2.42

B) 6-N- [3,6,9-Tris (carboxylatomethyl) -3,6,9-triazoundecane diacid-1-carboxy-11-one] -2-N- [1-Oa-Dcarbonylmethyl-mannopyranose] -B- lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd-complex, sodium salt

142

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

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

Water content: 10.5%.

Elemental analysis (calculated on the anhydrous substance): _Calc . S32,72 N3,43 N6,68 S 2,18 Gd 10,71 Na 1,57 F22,00 _Paul. C32.65 Η 3.51 Ν 6.71 S 2.08 Gd 10.61 Na 1.68 F 21.87

Example 26

a) 6-N-benzyloxycarbonyl-2-N- [1,4,7tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane] -10 (pentanoyl-3-4-oxo-5-methyl-5yl)] -1_-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 , 20 mmol) 1,4,7tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10 (pentanoyl-3-aza-4-oxo-5-methyl-5-yl), Gd complex dissolved in 400 ml of dimethyl sulfoxide under low heat. At 10 ° C, 20.63 g (100.0 mmol) of Νdicyclohexylcarbodiimide were added and stirred at room temperature overnight. The solution is poured into 3000 ml of acetone and

143 was stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography (silica gel RP-18; eluent: gradients of water / ethanol / acetonitrile).

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

Water content: 10.1%

Elemental analysis (calculated on the anhydrous substance): _Calc . 037.48 H3.84 N8.74 S2.22 F 22.39 Gd 10.90 _Sex; 0 37.39 H4.02 N8.70 S2.16 F 22.29 Gd 10.75

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

70.0 g (48.53 mmol) of the title compound of Example 21 d were dissolved in 500 ml water / 100 ml ethanol, mixed with 5.0 g palladium catalyst (10% Pd / C) and at room temperature and hydrogen. the atmosphere (1 atm) is hydrogenated for a long time until any absorption of hydrogen ceases to be observed. It was then aspirated from the catalyst, washed mainly with ethanol (twice with n 75 ml) and concentrated in vacuo. The title compound is obtained as a highly viscous, colorless oil.

Yield: 63.5 g (quantitative).

Water content: 9.8%.

Elemental analysis (calculated on the anhydrous substance):

144 _Calc . C 37.48 Η 3.84 N8.74 S2.22 F 22.39 Gd 10.90

Sex: ^{C 37.39 H4.03 N8.6S S2.2} ° ^F22 > ³¹ Gd 10.78

c) 6-N- (1-O-α-O-dicarbonylmethyl-2,3,4,6, -tetra-O-benzylmani-pyranose) -2-N- [1,4,7-tris (carboxylatomethyl) -1 , 4,7,10tetraazacyclododecane, Gd - Complex-10- (pentanoyl-3-aza-4oxo-

5-methyl-5yl)] - 1-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] amide

50.0 g (38.22 mmol) of the title compound of Premir 26b, 4.40 g (38.22 mmol) of N-hydroxysuccinimide, 3.39 g (80.0 mmol) of lithium chloride and 22.88 g (38 , 22 mmol) 1-Oa-Dcarboxymethyl-2,3,4,6-tetra-O-benzyl mannopyranose was dissolved under gentle heating (30 to 40 ^° C) in 400 ml of dimethyl sulfoxide. At 10 ° C, 10.32 grams (50.0 mmol) of Ν, Ν-dicyclohexylcarbodiimide were added and 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 then purified by chromatography (silica gel PP-18 eluent: gradients of water / ethanol / acetonitrile).

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

Water content: 10.9%.

Elemental analysis (calculated on the anhydrous substance):

Est; c46.42 H4.54 N6.67 S1.70 F17.10 Gd 8.33 _Paul . 0 46.36 H4.71 N6.60 S1.61 F17.19 Gd 8.21

145

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

60.0 g (31.77 mmol) of the title compound of Example 26c were dissolved in 500 ml of methanol and mixed with 6.0 g of palladium catalyst (10% Pd / C). Hydrogen at room temperature and hydrogen atmosphere (1 atm) for as long as no more hydrogen absorption is observed. The catalyst was sucked off, washed mainly with ethanol (twice with 150 ml each) and then concentrated to dryness in vacuo. Yield: 48.55 g (quantitative) of a colorless solid.

Water content: 3.9%.

Elemental analysis (calculated on anhydrous substance): _Calc . C 35.37 H4.02 N8.25 S2.10 F 21.13 Gd 10.29

Gender: ^C35 · ^{28 H4} · ¹³ N8,17 S2.03 F21.05 Gd 10,20

Example 27

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

To 50.0 g (113.5 mmol) of 1,7-bis (benzoylcarbonyl) -

1,4,7,10-tetraazacyclododecane and 66.42 g (113.5 mmol) 2- (Ν-βτππ-

146

N-perfluoroctylsulfonyl) -aminoacetic acid (prepared according to DE 196 03 033) in 300 ml of tetrahydrofuran was added at 0 ° C to 49.46 g (200 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-ethyl ester). 1-carbonic acid) and stirred at room temperature overnight. It was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

Yield: 65.1 g (57% of theory) of a colorless solid.

Elemental analysis:

Calc'd: C 42.91 H 3.80 N 6.95 F 32.05 S3.18

Sex: ^{C 42 '85 N} 3.90 N 6.87 F 31.98 S3.15

B) 1,7-bis- (benzyloxy) -4- [2- (N-ethyl-1 N -fluorooctylsulfonyl) -amino] -acetyl-N- [1-O-α-0carbonylmethyl-2,3,4,6 -tetra-0-benzyl-mannopyranose] -1,4,7, Utetraazacycododecane

To 60.0 g (59.53 mmol) of the title compound of Example 27a and 35.64 g (59.53 mmol) of 10aD-carboxymethyl2,3,4,6, -tetra-O-benzyl mannopyranose prepared according to DE 19728954, in 300 ml of tetrahydrofuran, 24.73 g (100 mmol of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester)) were added at 0 ° C and stirred overnight at room temperature. It was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol 6 20: 1).

Yield: 76.6 g (81.0% of theory) of a colorless solid.

147

Elemental analysis: _1L C 54.44 Calc .: H, 4.70 N, 4.41 F 20.33 S2.02 _π C 54,37 Sex: H, 4.81 N, 4.35 F 20.27 S1.96

c) 1- [2- (1M-ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-7- (1-0-a-0-carbonylmethyl-mannopyranose) -1, 4,7,10tetraazcyclododecane g (44, 07 mmol) of the title compound of Example 27b was dissolved in 800 ml of ethanol and 8 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

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

Elemental analysis:

_A C 35.04 N 3.99 N 7.30 F 33.65 S3.34

Est:

C 35.15 N 4.13 N7.13 F 33.48 S3.26

Gender:

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

1,4,7,10-Tetraazacyclododecane g (20.84 mmol) of the title compound of Example 27c, 5.09 g (120 mmol) of lithium chloride and 37.78 g (60 mmol) of 1,4,7148 tris (carboxylatomethyl) ) -10-pentanoyl-3-aza-4-oxo-5-methyl-5yl) -

1,4,7,10-Tetraazacyclododecane, Gd-complex were dissolved under gentle heating in 400 ml of dimethyl sulfoxide. At 10 ° C, 29.67 g (120 mmol) of EEDQ were added and stirred at room temperature overnight. 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, eluent: gradients of water / ethanol / acetonitrile).

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

Water content: 11.8%.

Elemental analysis (calculated on the anhydrous substance):

C, 36.31 read: H4.34 N9.62 S1.47 F 14.79 Gd 14.41 gender: C ³⁶ · ²⁴ H4.27 N9.58 S, 1.51 F 14.85 Gd 14,25 An example 28

a) 1,7-bis (benzyloxycarbonyl) -4- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-10- [pentanoyl-3-aza-4-oxo-5-methyl-5yl [1,4, 7-Tpic (Acetylmethyl) -Gdomplex 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) 1,4,7tris (carboxylatomethyl) -10- (pentanoyl-3-aza-oxo-5-methyl-5-yl) -

1,4,7,10-Tetraazacyclododecane, Gd-complex are dissolved at

149 gently warming in 350 ml of dimethyl sulfoxide. At 10 ° C, 15.47 g (75 mmol) Ν, кdicyclohexylcarbodiimide were added and stirred overnight at room temperature. The solution was poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and then purified by chromatography (silica gel RP18, eluent: gradients of water / ethanol / acetonitrile).

Yield: 65.1 g (81.0% of theory) of a colorless solid.

Water content: 7.9%.

Elemental analysis (calculated on the anhydrous substance):

C40.79 H4.11 N8.65 S1.98 F19.94 Gd 9.72 _Paul . 040.71 H4.20 N8.58 S2.03 F19.87 Gd 9.68

B) 1- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl7 {(pentanoyl-3-aza-4-oxo-5-methyl-5yl) -10- [1,4,7tris (carboxylatomethyl) ) -1,4,7,10-tetrazacyclododecane, Gdcomplex]} - 1,4,7,10-tetrazacyclododecane.

60.0 g (37.05 mmol) of the title compound of Example 28a was dissolved in 600 ml of ethanol and 6.0 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

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

Water content: 3.9%.

150

Elemental analysis (calculated on the anhydrous substance): _Calc . C34.67 H4.03 N10.37 S2.37 F23.90 Gd 11.64 _Gender; C34.58 H4.15 N10.28 S2.30 F23.84 Gd 11.57

c) 1- [2- (N-βτππ -1H-perfluoroctylsulfonyl) -amino] acetyl-4,10-bis [1-O-a-O-carbonylmethyl-2,3,4,6-tetra-0-benzylmani-pyranose ] -7 - {(pentanoyl-3-aza-4-oxo-5-methyl-5-yl) - [1,4,7tris (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 1-N-αO-carboxymethyl-2, The 3,4,6-tetra-O-benzyl mannopyranose was dissolved under gentle heating in 300 ml of dimethyl sulfoxide. At 10 ° C, 24.73 g (100.0 mmol) of EEDQ was added and stirred at room temperature overnight. 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, eluent: gradients of water / ethanol / acetonitrile).

Yield: 31.98 g (43.0% of theory) of a colorless solid. Water content: 3.5%.

Elemental analysis (calculated on the anhydrous substance): _Calc . C 53.06 H5.05 N5.57 S 1.28 F 12.85 Gd 6.26 _n C 52.95 H5.19 N5.48

S1.23 F 12.77 Gd 6.14

151

d) 1- [2- (N-θτηγ-N-perfluoroctylsulfonyl) -amino] -acetyl-4, 10-bis [1-0-a-O-carbonylmethyl-2,3,4,6-tetra-O- benzylmani pyranose] -7 - {(pentanoyl-3-aza-4-oxo-5-methyl-5-yl) - [1,4,7tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-yl] Gd-complex} -1,4,7,10-tetraazacyclododecane

30.0 g (11.94 mmol) of the title compound of Example 28c was dissolved in 300 ml ethanol / 30 ml water and 4.0 g palladium catalyst (10% Pd / C) was added. It is hydrogenated at room temperature, the catalyst is filtered off and the filtrate is evaporated to dryness in vacuo.

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

Water content: 3.4%.

Elemental analysis (calculated on the anhydrous substance):

_Est . C38.87 H4.39 N7.82 S1.79 F 18.03 Gd 8.78 _POL . C 36.80 H4.50 N7.85 S1.68 F 17.91 Gd 8.70

Example 29

a) 6-N- [3,6-bis (carboxymethyl) -oxane-1,8-dicarboxylic acid 1-carboxy-8-yl] -2-N- (1-0-a-0-carboxymethylmani pyranose) -Lysine - [1- (4-perfluorooctylsulfonyl) -piperazine] amide

To 27.5 g (30.0 mmol) of the title compound of Example 21 is dissolved in 300 ml of dimethylformamide / 100 ml of pyridine, 25.62 g (100.0 mmol) of ethylenediamine,, Ν, Ν ', Ν' are added. -tetraacetic acid dianhydride and stirred in

152 for 5 hours at 50 ° C. The residue was dissolved in 300 ml of water, the pH of the solution was adjusted to 10 by the addition of 20% aqueous sodium hydroxide, and then the pH of the alkaline solution containing the product was adjusted to 3 by the addition of concentrated hydrochloric acid and evaporated in vacuo to dryness. The residue was chromatographed on silica gel (eluent: gradients of water / ethanol / acetonitrile).

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

Water content: 7.9%.

Elemental analysis (calculated to the anhydrous substance): Calc: θ 36.31 H, 3.98 N, 7.06 F, 27.12 S2.69 Gender: C, 36.23 H, 4.07 N, 6.98 F, 27.05 S2.62

B) 6-N- [3,6-bis (carboxylatomethyl) -octane-1,8-dicarboxylic acid-1-carboxylato-8-yl] -21M- (1-0-a-0-carboxymethylmanipyranose) -1_- lysine- [1- (4-perfluoroctylsulfonyl) piperazine] -amide, Mn-complex, sodium salt (8,397 mmol) of the title compound of Example 29a were dissolved in 200 ml of water. 965 mg (8,397 mmol) of manganese (II) carbonate was added and stirred for 3 hours at 60 ° C. With 5% aqueous sodium hydroxide, the pH of the solution was adjusted to 7.4, filtered and then freeze-dried.

Yield: 10.52 g (99.0% of theory) of a colorless solid.

153

Water content: 7.8%.

Elemental analysis (calculated on the anhydrous substance): _Calc . C34.16 NZ, 50 N6.64 S2.53 F25.52 Mn 4.34 Na 1.82

Gender: NW ⁴ , ⁰⁶ H 3.61 N6.58 S2.47 F 25.47 MP 4.30 Na 1.97

Example 30 a) 1,2,3,4,6-pent-O-acetyl-a, p-0-mannopyranose

Similarly described in a literary source [ML Wolfrom und A. Thompson in Methods in Catbohydrate Chemistry (RL Whistler, ML Wolfrom and JNBeMiller, Eds.), Academic Press, New York, Vol. II, 53, pp.211-215, (1963)] the reaction proceeds between 150 g (832.5 mmol) α, β-D-mannopyranose and a mixture of 1500 ml absolute pyridine and 1500 ml acetic anhydride and after further processing are obtained 315 g (96.7%) of the above title compound as a crude product as a viscous, colorless oil. The ratio of α and β anomers, which is 4: 1, is determined by ¹ H-NMR spectroscopy of the title compound thus obtained. The subsequent reaction steps for the separation of α, β-anomers may not be undertaken.

Elemental analysis:

_Est . 049.21 H5.68 _Pol . H, 49.78

154

b) 1-O-α-O- (5-ethoxycarbonyl) -phenyl-2,3,4,6-tetra-O-acetylmanipyranose

In an analogous manner described in a literature for the synthesis of aryl glycopyranosides [J. Conchie und GA Lewy in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol. II, 90, pp. 345 - 347, (1963)] the reaction proceeds between 156.2 g (400 mmol) of the title compound of Example 21a as an α, β anomeric mixture with 67 ml (400 mmol) of 6hydroxy-hexanoic acid ethyl ester and 60.8 ml ( 520 mmol) tin-IV chloride total of 600 ml of 1,2-dichloroethane after purification by column chromatography (2: 1 acetic acid ethyl ester) to give 100.05 g (51% of theory) of the above above the title compound as a colorless viscous oil. ¹ H-NMR spectroscopy revealed that the above title compound was exclusively a pure α-anomer.

Elemental analysis:

_Est . H, 52.74

Gender: C, 52.80, H6.78

c) 1-0-a-0- (5-carboxy) -phenyl-2,3,4,6-tetra-0-benzylmani-pyranose

A well stirred suspension of 141.0 g (289 mmol) of the title compound of Example 30b in 200 ml of dioxane was added.

155 were mixed in portions at room temperature while vigorously stirring with a total amount of 238.5 g (4.26 mmol) of finely divided calcium hydroxide powder. In order to increase the stirring capacity, 200 ml of dioxane were added to the reaction mixture and the suspension thus obtained was heated to reflux and at this temperature was mixed dropwise with a total of 372 ml (3.128 mol) of benzyl bromide for two hours. After a lengthening of the reaction time of 4 hours at 110 ° C followed by a lengthening of 12 hours at room temperature, the total reaction was slowly added to the reaction mixture for further processing.

2.5 liters of ice water and finally the aqueous phase is completely removed with diethyl ether. After washing the ether phase thus obtained and subsequently drying the same over sodium sulfate, it is removed from the salt by suction and the diethyl ether removed in vacuo. Finally, excess benzyl bromide was distilled quantitatively from the reaction mixture in an oil pump vacuum at an oil bath temperature of 180 ° C. The thus obtained resinous oil residue was purified on silica gel using ethyl acetate / hexane (1:10). as eluent.

Yield: 172.2 g (91% of theory) of the title compound as a colorless and viscous viscous oil.

Elemental analysis:

And zh; H, 75.68;

Paul; H, 75.79;

156

d) β-N-benzyloxycarbonyl-2-N- [1-Oa-D- (5-Kapoyl) pentyl-2,3,4,6-tetra-O-benzyl-manopyranose] -E-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

100.0 g (134.0 mmol) of the Example 3O3 carboxylic acid and 32.4 g (281.4 mmol) of N-hydroxysuccinimide were dissolved in 500 ml of dimethylformamide and mixed at 58 ° C in portions. , 0 g (281.4 mmol) Ν, дицидициcyclohexylcarbodiimide and stirred at this temperature for 3 hours. The solution of active esters thus obtained was added dropwise at 0 ° C a cooled solution of 111.3 g (134.0 mmol) of the title compound of Example 21c dissolved in 300 ml of dimethylformamide and stirred for 2 hours at 0 ° C as well as 12 hours at room temperature. The precipitated dicyclohexicarbamide was filtered for processing and the solvent was finally removed to dryness. The residue thus obtained is chromatographed on silica gel (eluent: dichloromethane / ethanol 20: 1; chromatography is carried out using a liquid gradient with a constant increase in the ethanol portion).

Yield: 132.5 g (67.4% of theory) of the title compound as a colorless, highly viscous oil.

Elemental analysis:

_Est; With 54.02 N4.88 N3.82 S2.19 F22.01 _Paul. C 53.87 H4.85 N4.02 F 22.55 S2.06

e) 2-N- [1Ο-α-O- (5-carbonyl) phenyl-mannopyranose] -1_-lysine- [1- (4-perfluoro-alkylsulfonyl) -piperazine] -amide

157

Dissolve 120.0 g (81.77 mmol) of the compound obtained in Example 30d in 800 ml of ethanol, mix with 4.5 grams of palladium catalyst (Pd 20%, C) by hydrogenation in a hydrogen atmosphere (1 atm) at room temperature for as long as it takes to stop the absorption of hydrogen (about 8 hours). It was aspirated from the catalyst, washed with ethanol (about 200 ml) and concentrated in vacuo to dryness. The title compound is obtained as a highly viscous, colorless oil.

Yield: 78.5 g (98.7% of theory).

Elemental analysis:

_Est . C 37.04 H4.25 N5.78 F 33.20 S3.30

Floor '^{C36> 96} H4.85 N5.41 F34.13 S 3.22

f) 2-N- [1-Oa-O- (5-carbonyl) phenyl-mannopyranose] -6-N- [1,4,7,7-tris- (carboxylatomethyl) -10- (3-aza-4-oxo-5 -methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -1_-lysine- [1- (4perfluoroctylsulfonyl) -piperazine] -amide, Gd-complex

99.8 g (158.4 mmol; 2.2 molar equivalents calculated from the amino component of Example 30e used) from DE 197 28 954 C1 described in patent application Example 31 h Gdcomplex of 10 - (4-carboxy-1-methyl-2- oxo-3-azabutyl) -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid and 6.7 g of anhydrous lithium chloride (158.4 mmol) were dissolved at 40 ° C in 800 ml of absolute dimethyl sulfoxide at continuous stirring. At this temperature it finally interacts with

158 total 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 dimethyl sulfoxide. After cooling to room temperature, the reaction solution was mixed with 32.7 g (158.4 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was finally mixed with excess acetone until complete precipitation of the above title compound, the precipitate was sucked off, dried, absorbed in water, filtered from insoluble dicyclohexylurea and the filtrate was desalted through one AMICON® YM 4 bar YM : 3000 Da) and is read from the low molecular weight constituents. The resulting product was freeze-dried. Yield: 93.0 g (81.6% of theory) as a colorless lyophilisate.

Water Content (Karl - Fischer): 9.53% Elemental Analysis:

_Est; C37.15 H4.39 N7.96 F 20.38 S2.02 Gd9.92 _Pol . C 36.92 H4L0 N7.68 F 19.77 S1.91 Gd 10.08

Example 31

a) 2-N- [1-0-a-0- (5-carbonyl) pentyl-mannopyranose] -6 - {{2- [4 (3-oxapropionyl) -phenyl] -2- [1,4,7 -tris- (carboxylatomethyl) 1,4,7,10-tetraazacyclododecan-10-yl] acetic acid} -1-lysine [1 (4-perfluoroctylsulfonyl) -piperazine] -amide, Gd complex, sodium salt

159

A well-stirred suspension of 5.0 g (9.06 mmol) of the title compound of Example 23e in 15 ml of absolute dimethyl sulfoxide was mixed at 0.68 g (15.9 mmol) of lithium chloride at 70 ° C. After stirring at 70 ° C for 30 minutes, the clear reaction solution was mixed in portions with a total

1.83 g (15.9 mmol) of N-hydroxysuccinimide and the reaction mixture was maintained at the same temperature for another 1 hour. After cooling to 0 ° C, it was mixed with 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide and the reaction solution was stirred for another 1 hour at 0 ° C, followed by stirring for 12 hours at 22 ° C. a reaction solution of the Nhydroxysuccinimidester of the title compound of Example 3e was mixed in portions at 22 ° C with one solution of 4.0 g (4.12 mmol) of the title compound then Example 10Ae in 15 ml of absolute dimethyl sulfoxide and stirred for an additional 12 hours at room temperature. For further processing, the reaction solution was added dropwise at 22 ° C in 900 ml of acetone, whereby the title compound was precipitated as a colorless precipitate. The precipitate was sucked off, dissolved in 200 ml of distilled water and finally the pH of this solution was adjusted to exactly 7.2 with 1 molar sodium hydroxide solution. The aqueous solution containing the product thus obtained is subjected to ultrafiltration three times through a YM3 ultrafiltration membrane (AMICON ®; cut off: 3000 Da) in order to remove salts and to separate the low molecular weight constituents

160 components. The resulting product was then freeze-dried.

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

Elemental analysis (calculated on the anhydrous substance):

And 34 'C 38.48 H4.13 N6.65 F 19.16 S 1.90 Gd 9.33 At 1.36 Gender: ^NW52 H4.12 N6.67 F 19.70 S1.89 Gd 9.30 At 1.41 An example 32 a) 3,5-bis-benzyloxycarbonylamino-benzoene acid-N-

(3-Oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide

In one solvent mixture consisting of 125 ml of anhydrous tetrahydrofuran and 125 ml of anhydrous dioxane dissolve 20 g (47.5 mmol) of 3,5-bisbenzyloxycarbonylaminobenzoic acid (Synthesis according to the following literature: Skulnick, Harvey I .; Paul D.; Aristoff, Paul A.; Morris, Joanette K.; Lovasz, Kristine D.; et al .; J. Med. Chem .; 40; 7; 1997; 1149 - 1164) as well as 4.78 g (47.5 mmol) ) triethylamine. After cooling to -15 ° C and stirring continuously, 6.56 g (48 mmol) of hydrochloric acid isobutyl ester in 30 ml of anhydrous tetrahydrofuran are slowly added dropwise, while maintaining the internal temperature below -10 ° C. After a reaction time of 15 minutes at -15 ° C, a solution of 59.6 g (47.5 mmol) of 1-amino-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H- was added dropwise. 3-oxo-perfluorine161 tridecane and 4.78 g (47.5 mmol) of triethylamine in 100 ml of anhydrous tetrahydrofuran at -20 ° C. After one hour of interaction for one hour at -15 ° C and another two hours at room temperature the reaction solution was concentrated in vacuo. The resulting residue was taken up in 300 ml of acetic acid ethyl ester and washed twice with 200 ml of saturated sodium bicarbonate solution and once with 300 ml of water. After drying the organic phases over sodium sulfate, the salt is sucked off and the acetic acid ethyl ester is removed in vacuo. The resulting oily residue was purified on silica gel using dichloromethane / hexane / 2-propanol (10: 5: 1) as eluent.

Yield: 36.2 g (82.5 g) % of theory.) a title compound such as colorless oil. Elemental analysis: _Est . H, 46.82 N4.55 F 34.97 Gender: ⁰⁴⁷ · ^{21 H3} · ³¹ N4.61 F 34.48

B) 3,5-Di-amino-benzoic acid-L- (3-oxa-1H, 1H, 2H, 2H, 4H, 4h, 5H, 5H-perfluorotridecyl) -amide

30.0 g (32.4 mmol) of the amide obtained according to Example 32a were dissolved in 300 ml of ethanol and mixed with 1.2 g of catalyst (Pd 20%, C). Hydrogenation at room temperature and under a hydrogen atmosphere (1 atm) continues for as long as necessary to no longer observe any absorption of

162 hydrogen. It was aspirated from the catalyst, washed mainly with ethanol (about 300 ml) and concentrated in vacuo to dryness. The title compound is obtained as a highly viscous, yellowish oil.

Yield: 20.12 g (94.8% of theory).

Elemental analysis:

Calc .: C 36.66 H2.77 N6.41 F 49.28 _Sex: C 36.07 H2.87 N6.23 F 49.43

c) 3-N - [- (1-O-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmani-pyranose) -5-amino-benzoic acid-N- (3-oxa-1H, 1h, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide

10.95 g (18.30 mmol) of 1-carboxymethyloxy-2,3,4-tetra-benzenyl-α-O-mannopyranoside (prepared as described in German patent DE 197 28 954 C1) was dissolved in 150 ml of dimethylformamide and mixed with a total of 2.09 g (18.3 mmol) of N hydroxysuccinimide. Cool to 0 ° C and add 3.78 g () 18.3 mmol of dicyclohexylcarbodiimide. It was stirred for 1 hour at 0 ° C and then at room temperature for 4 hours. Cool to 0 ° C and slowly add, within 3 hours, a solution of 24.0 g (36.6 mmol, 2 molar equivalents calculated from the carboxylic acid used) of the diamino compound described in Example 32b dissolved in 350 ml. dimethylformamide. Finally, it was stirred for another hour at 0 ° C and then at room temperature overnight. It is evaporated to dryness in vacuo and the residue is taken up

163 was absorbed in 300 ml of acetic acid ethyl ester. It is filtered off from the precipitated urea and the filtrate is blotted 2 times with 100 ml 5% aqueous baking soda each. The organic phase was dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: hexane / isopropanol 13: 1). 16.8 g (74.3% of theory, calculated on the carboxylic acid used) of the title compound are obtained as a colorless oil. By increasing the polarity of the eluent composition to 5: 1 hexane / isopropanol in the subsequent chromatographic steps, a total of 10.15 g of non-reacted diamino compound 32b was recovered, which, refreshed according to the above reaction step, could be reused. Elemental analysis:

_Est . C54.42 H4.40 N3.40 F 26.13 gender: C 54.32 H4.49 N3.48 F 25.94

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

Analogously to the method described for the synthesis of the title compound of Example 32b, the hydrogenolysis of 12.0 g () 9.70 mmol of the title compound of Example 32c proceeded using 0.5 g of palladium catalyst (Pd 20%, C) in one mixture of ethanol / fashion (9: 1) and after processing are obtained

164

8.08 g (967% of theory) of the title compound as a yellow colored viscous oil.

Elemental analysis:

_Est . C 37.64 Η 3 £ 8Ν 4.88 F 37.49 _Paul . C, 37.32; H3.17N4.97; F, 37.55

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

13.6 g (19.2 mmol; 2.2 molar equivalents relative to the amino component of Example 32d used) of the Gd complex described in Example 23A and 0.81 g of anhydrous lithium chloride (19.2 mmol) were dissolved at 40 ° C in 100 ml of absolute dimethyl sulfoxide was stirred at the same temperature with a total of 2.2 g (19.2 mmol) of N-hydroxysuccinimide and 7.5 g (8.7 mmol) of the title compound of Example 32dq dissolved in 50 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution was stirred with 3.96 g (19.2 mmol) of Ν'dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was finally mixed with excess acetone until complete precipitation of the title compound above, the suction was sucked off, dried, absorbed in water, filtered by insoluble

165 dicyclohexylurea and the filtrate was desalted through an AMICON® YM-3 ultrafilter membrane (cut off 3000 Da) and purified from the low molecular weight constituents. The resulting product was then freeze-dried.

Yield: 11.51 g (84.5% of theory) as a colorless lyophilisate. Aqueous CbflbpxaHne (Karl-Fischer): 6.77%.

Elemental analysis (calculated on anhydrous substance): _Calc; 040.05 H3.94 N6.29 F20.71 Gd 10.08 Na 1.47 _Gender; C39.98 H4.00 N6.31 F 20.73 Gd 10.11 Na 1.42

Example 33

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

In a solvent mixture consisting of 60 ml of anhydrous tetrahydrofuran and 70 ml of anhydrous dioxane was dissolved South (23.75 mmol of 3,5-bis-benzyloxycarbonylamino-benzoic acid (synthesis according to the following literature source: Skulnick, Harvey I .; Johnson, Paul D.; Aristoff, Paul A.; Morris, Jeanette K.; Lovasz, Kristine D.; et al .; J.Med. Chem .; 40; 7; 1997, 1149-1164) as well as 2.39 g (23 After cooling to -15 ° C, a solution of 3.28 g (24 mmol) isobutyl ester of hydrochloric acid in 20 ml of anhydrous tetrahydrofuran is slowly added dropwise with continuous stirring. -10 ° C. After a reaction time of 15 minutes at -15 ° C, a solution of

166

23.0 g (23.75 mmol) of perfluorooctylsulfonylpiperazine and 2.39 g (23.75 mmol) of triethylamine in 50 ml of anhydrous tetrahydrofuran at -20 ° C. After an hour of interaction at -15 ° C, and the reaction solution was concentrated to dryness in vacuo for two hours at room temperature. The resulting residue was taken up in 200 ml of acetic acid ethyl ester and washed twice with 100 ml of saturated sodium bicarbonate solution as well as once with 300 ml of water. After drying the organic phase over sodium sulfate, the salt is sucked off and the acetic acid ethyl ester is removed in vacuo. The resulting mass residue was purified on silica gel using dichloromethane / hexane / 2-propanol (15: 5: 1) as eluent.

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

Elemental analysis:

Calc'd: C 43.31 H2.80 N5.77 F 33.27 S 3.30 _Gender; C 43.21 H2.75 N5.61 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 obtained according to Example 33a were dissolved in 100 ml of ethanol and 0.4 g of catalyst (Pd 20%, C) was added. Hydrate for as long a time at room temperature and a hydrogen atmosphere (1 atm) as is necessary to prevent more absorption of hydrogen.

167

It was aspirated from the catalyst, washed mainly with ethanol (ca. 150 ml) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous, yellowish oil.

Yield: 6.9 g (98.2% of theory).

Elemental analysis:

_Est . C, 32.49 H2.15 N7.98

F 45.98 S 4.56

Sex: C, 32.56 H2.17

N8.09 F 45.63 S 4.61

c) 5-amino-3-1M- (1-O-a-0-carbonylmethyl-2,3,46-tetraO-benzyl-manopyranose) -benzoic acid-N- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

5.48 g (9.15 mmol of 1-carboxymethyloxy-2,3,4-tetra-benzenyl-α-0-mannopyranoside [prepared as described in German patent DE197 28 954 C1] were dissolved in 100 ml of dimethylformamide and reacted with a total of 1.04 g (9.15 mmol) of N-hydroxysuccinimide, cooled to 0 ° C and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide added, stirred for one hour at 0 ° C and then at room temperature for 4 hours After a further cooling to 0 ° C, a solution of

12.85 g (18.30 mmol, 2 molar equivalents calculated with respect to the carboxylic acid used) of the diamino compound described in Example 3b dissolved in 250 ml of dimethylformamide. It is then stirred for another hour at 0 ° C, and at room temperature overnight. Evaporates to dryness in

168 vacuum and the residue was absorbed in 100 ml of acetic acid ethyl ester. The precipitated urea was filtered off and the filtrate was washed twice with 100 ml of 5% aqueous baking soda each. The organic phase was dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: n-hexane / isopropanol 13: 1). 8.14 g (69.4% of theory, calculated on the carboxylic acid used) of the title compound are obtained as a colorless oil. By increasing the polarity of the eluent composition during chromatography to 6: 1 (n-hexane / isopropanol), a total of 4.36 g of unreacted diamino compound 3b was recovered in the following chromatographic fractions.

reimbursement as described in way up may be again used. Elemental analysis: Calcd: ^{051.49 H4} · ⁰¹ N4.37 F 25.17 S 2.50 Gender: ^C51 ′ ^{60 H4L9} N4.28 F 25.14 S, 2.44

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

Analogously to the method described for the synthesis of the title compound of Example 3b, the hydrogenolysis of 6.4 g (5.0 mmol) of the title compound of Example 3c proceeded using 0.3 g of pearl catalyst (Pd 20%, C) in one

169 ethanol / water mixture (8: 1) was obtained after further processing

4.43 g (96.2% of theory) of the title compound as a yellowish-colored viscous oil.

Elemental analysis:

Calc'd: C 35.15 H2.95 N6.07 F 35.01 S 3.48 _Gender; C 35.32 NZ, 02 N5.89 F 35.05 S 3.58

e) 3-N- (1-N-α-O-carbonylmethyl-mannopyranose) -5-N- [1,4,7tris (carboxy latomethyl) -10- (3-aza-4-oxo-5-methyl- 5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -benzoic acid-N- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide, Gd-complex

5.54 g (8.8 mmol; 2.2 molar equivalents calculated from the amino component of Example 33d used) from DE 197 28 954 C1 as described in patent application Example 31 h Gd-complex of 10- (4-carboxy-1-methyl- 2-Oxo-3-azabutyl) -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid and 0.37 g of anhydrous lithium chloride (8.8 mmol) were dissolved at 40 ° C and stirred continuously at 60 ml of absolute dimethyl sulfoxide and reacted at the same temperature with a total of 1.01 g (8.8 mmol) of Nhydroxysuccinimide and 3.7 g (4.0 mmol) of the title compound of Example 13Ad dissolved in 40 ml of absolute dim lsulfoksid. After cooling to room temperature, the reaction solution was mixed with 1.82 g (8.8 mmol) of дици'cyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was mixed

170 with acetone excess until complete precipitation of the above title compound, precipitated, dried, absorbed in water, the insoluble dicyclohexylurea was filtered and the filtrate was desalted through AMICON® YM-3 ultrafilter off ) and purified from low molecular weight compositions. The resulting product was finally freeze-dried.

Yield: 5.36 g (87.4% of wt.) Colorless lyophilisate.

Water content (Karl-Fischer): 6.77%. Elemental analysis (calculated on the anhydrous substance):

Est; s36,01 N3,61 N8,22 F21,05 Gd 10,25 S 2,09 _Paul. 035.87 Η 3.70 N8.22 F20.91 Gd 10.18 S2.16

Example 34

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

100 g (107.9 mmol) of the carboxylic acid obtained according to Example 21a and 26.1 g (226.59 mmol) of Nhydroxysuccinimide were dissolved in 500 ml of dimethylformamide and mixed at a temperature of 0 ° C with a total of 46.7 g. (226.59 mmol) N, N'-dicyclohexylcarbodiimide and stirred at this temperature for 3 hours. To the solution of active esters thus obtained was added dropwise at 0 ° C a cooled solution of 5.57 g (53.95 mmol) of diethylenetriamine dissolved in 60 ml of dimethylformamide and

171 was stirred for 2 hours at 0 ° C and then for 12 hours at room temperature. For further processing, it is filtered from the precipitated dicyclohexylurea and finally the solvent is removed to dryness. The residue thus obtained is chromatographed on silica gel (eluent: dichloromethane / ethanol 15: 1; chromatography is carried out using continuous gradients with continuous gradients.

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

Elemental analysis:

_Est . 052.74 H5.78 N11.96 F13.90 Floor _; 0 52.66 H5.89 N11.88 F 14.02

B) 1,4,7-triazaheptane-1,7-bis- (2-N-trifluoroacetyl-6-Mbenzyloxycarbonyl-L-lysine) -diamide-4- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] - acetyl

To a solution of 20.0 g (24.4 mmol) of the diamide obtained according to Example 34a dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform was added at 0 ° C and in a nitrogen atmosphere 16.18 g (27, 0 mmol) 2- [Methyl-N-perfluorooctylsulfonyl]-formic acid (prepared according to DE 196 03 033) dissolved in 50 ml of tetrahydrofuran. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinone] is then added portionwise at 0 ° C.

172 at room temperature and stirring overnight and finally concentrated in vacuo. The remaining oil was chromatographed on silica gel (eluent: n-hexane / isopropanol 15: 1). They are obtained

24.74 g (72.4% of theory, vs. sec-amine used) of

the title compound as a colorless oil. Elemental analysis: Calc: ^C42 · ⁰¹ H3.96 F31.19 N8,00 S2J29 Gender: ^{C41 '92} H4.O7 F31.22 N7.87 S2.34

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

22.0 g (15.7 mmol) of the title compound obtained according to Example 34b were dissolved in 100 ml of ethanol and ammonia gas was bubbled through the solution at 0 ° C for 40 minutes. It was then stirred for a further 4 hours at 0 ° C as well as 3 hours at room temperature and concentrated to dryness at 40 ° C in a vacuum bath. The resulting oily residue was purified on silica gel 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, highly viscous oil.

Elemental analysis:

_Est; C 44.22 H4.64 N9.38 S2.68 F 27.03

Gender: C, 44.31; H4.72; N9.30

S2.74 F 26.99

173

d) 1,7-bis- [6-N-benzyloxycarbonyl-2-N- (1-α-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-manopyranose) -1_-lysine] diamide-4- [2- (L-ethyl-N-perfluorooctylsulfonyl) -amino] -acetyl-

1,4,7-triazaheptane

5.47 g (9.15 mmol) of 1-carboxymethyloxy-2,3,4-tetra-benzyl-α-0-manopyranoside (prepared as described in German patent DE 197 28 954 C1) were dissolved in 80 ml of dimethylformamide and mixed in total with 1.05 g (9.15 mmol) of Nhydroxysuccinimide. It was cooled to 0 ° C and 1.9 g (9.15 mmol) of dicyclohexylcarbodiimide were added. It was cooled to 0 ° C and a solution of 7.6 g (9.15 mmol) of the amino compound dissolved in 50 ml of dimethylformamide was added dropwise over 3 hours. Finally, it was stirred for one hour at 0 ° C and then overnight at room temperature. It was evaporated to dryness in vacuo and the residue was taken up in 100 ml of ethyl acetate. The precipitated urea was filtered off and the filtrate washed twice with 50 ml of a 5% aqueous soda solution.

The organic phase was dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: n-hexane / isopropanol 20: 1). 17.01 g (78.9% of theory, relative to the carboxylic acid used) of the title compound are obtained as a colorless oil.

Elemental analysis:

_Est; H5.43

N4.76 F 13.71 S1.36 _Sex; H, 59.22;

N4.85

F 13.70 S1.40

174

e) 1,7-6nc- [2-N- (1-O-O-carbonylmethyl-mannopyranose) -1_-lysine] -diamide-4- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] acetyl -1,4,7-triazaheptane

Dissolve 15.0 g (6.36 mmol) of the amide obtained according to Example 34d in 150 ml of ethanol and mix with 0.5 g of pearl catalyst (Pd 20%, C). It is hydrogenated at room temperature and under a hydrogen atmosphere for as long as is necessary to avoid any further absorption of hydrogen. It was aspirated from the catalyst, washed mainly with ethanol (about 100 ml) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous, yellowish oil.

Yield: 8.54 g (97.2% of theory).

Elemental analysis:

_Est; C 39.13 H 5.04 N8.11 F 23.38 S2.32 _Pol . C 39.07 H4.98 N8.18 F 23.40 S2.30

f) 1,7-6nc- [2-N- (1-O-O-carbonylmethyl-mannopyranose) -6-N- [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4- oxo-5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -1_-lysine] -diamide-4- [2 (N-ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-1, 4,7 triazacheptane, digadolinium complex

A well-stirred suspension of 5.7 g (9.06 mmol) of the gadolinium complex of 10- (4-carboxy-1-methyl-2-oxo-3azabutyl) -1 described in patent application DE 197 28 954 b1 in Example 31 h. 4,7,10-Tetraazacyclododecane-1,4,7-trioacetic acid in 75 ml of absolute dimethyl sulfoxide are mixed

175 at 70 ° C with 0.68 g (15.9 mmol) of lithium chloride. After stirring at 70 ° C for 30 minutes, the clarified reaction solution was mixed in portions with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide and the reaction mixture was stirred for a further 1 hour at the same temperature. After cooling to 0 ° C, it is mixed with 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide and the solution is stirred for another hour at 0 ° C, followed by stirring for 12 hours at 22 ° C. The resulting LBhydroxysuccinimidester reaction solution is thus obtained. of 10- (4carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10 gadolinium complex is mixed at 22 ° C in portions with a solution of 2.84 g (2.06 mmol) of the title compound of example

34 is in 15 ml of absolute dimethyl sulfoxide and stirred for a further 12 hours at room temperature. For further processing, the reaction solution was added dropwise at 22 ° C in 500 ml of acetone, after which the title compound was precipitated as a colorless precipitate.

The precipitate was sucked off, dissolved in 200 ml of distilled water and subjected to ultrafiltration through a YM3 ultrafilter membrane (AMICON ®; cut off: 3000 Da) three times to desalinate and separate the low molecular weight components. The product thus obtained is finally freeze-dried.

Yield: 4.80 g (89.6% of theory, vs. the amino component used) as a colorless lyophilisite with an aqueous content of 8.98%.

Elemental analysis (brushed against anhydrous substance):

176 _Calc . C 38.28 Η 4.84 N9,68 F 12.40 S1.23 Gd 12,07 _Paul . 0 38.20 H 4.91 N9.77 F 12.45 S 1.19 Gd 12.10

Example 35

a) 1,7-bis (benzyloxycarbonyl) -4- {3-oxa-pentane-1,5dicarboxylic acid 1-yl-5- [1- (4-perfluoroctylsulfonyl) piperazine] -amide} -1,4,7 , 10-Tetraazacyclododecane

In a solution of 10.75 g (24.4 mmol) of 1.7bis [benzyloxycarbonyl] -1,4,7,10-tetraazacyclododecane dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform was added at 0 ° C. and under nitrogen atmosphere 16.56 g (24.4 mmol) of the title compound of Example 34e dissolved in 150 ml of tetrahydrofuran. Finally, a total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] were added portionwise at 0 ° C and allowed to stand overnight with stirring at room temperature and finally concentrated in vacuo. The remaining oil was chromatographed on silica gel (eluent: n-hexane / isopropanol 12: 1). 17.22 g (64.3% of theory, relative to the sec-amine used) of the monoamide were obtained, as well as 3.8 g (8.8% of theory) of the diamide as a by-product. The title compound is isolated as a colorless oil.

Elemental analysis:

_Calc'd C 43.41 H 3.92 F 29.18 N7.59 S2.60

Gender: ^C ^ ^{52 n 4 '07 F} 29 ^ 4 ,6 7.67 S 2.55

177

B) 1,7-bis (benzyloxycarbonyl) -4- {3-oxa-pentane-1,5-dicarboxylic acid 1-yl-5- [1- (4-perfluoroctylsulfonyl) piperazine] -amide} -10- [1- O-a-O- (5-carbonyl) -pentyl-2,3,4,6-tetra-benzyl-manopyranose] -1,4,7,10-tetraazacyclododecane

10.0 g (13.4 mmol) of the resulting 3O 3 carboxylic acid and 3.24 g (28.1 mmol) of N-hydroxysuccinimide were dissolved in 100 ml of dimethylformamide and mixed at 5 ° C in portions. , 8 g (28.1 mmol) Ν, дициΝcyclohexylcarbodiimide and stirred for 3 hours at this temperature. To this solution of active esters thus obtained was added dropwise at 0 ° C a cooled solution of 14.83 g (13.4 mmol) of the title compound of Example 35a dissolved in 100 ml of dimethylformamide and stirred for 2 hours at 0 ° C as well as 12 hours at room temperature. For further processing, the precipitated dicyclohexylurea is filtered and the solvent is finally removed to dryness. The residue thus obtained is chromatographed on silica gel (eluent: dichloromethane / ethyl acetic acid ester 20: 1; chromatography is carried out using dissolving gradients with a continuously increasing portion of acetic acid ethyl ester).

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

Elemental analysis:

_Est; H, 55.03

N4.82

F 18.52 S 1.84

178

Gender · ^C54 '87 ^H4 ' ⁸⁵ N4.92 F 18.55 S 1.86

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

Dissolve 17.0 g (9.75 mt) of the compound of Example 34b in 150 ml of ethanol, mix with 1.0 g of pearl catalyst (Pd 20%, C) and hydrogenate at room temperature and under a hydrogen atmosphere. as long as necessary to avoid observing more hydrogen absorption. It is sucked off from the catalyst, washed with ethanol (twice usually always with 75 ml) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous and colorless oil.

Yield: 10.76 g (99.0% of theory).

Elemental analysis: Calc: 0 38.78 H, 4.61 N7.54 F8.97 S2.88 Gender: 038.86 H4.65 N7.41 F 29.02 S2.92

d) 1,7-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-

Tefluorofluorofluoro-Gd-COMNeneCC-10- (neHTaHonn-3-a3a-4-oxo-5methyl) -4- [2- (N-ethyl-1 N-perfluoroctylsulfonyl) -amino] acetyl-2-oxa-acetyl] -10-acetyl] -10-acetyl [1-O-a-D-6-carbonylpentyl-mannopyranose] 1,4,7,10-tetraazacyclododecane

24.86 g (39.46 mmol; 4.4 molar equivalents relative to the amino component used in 35c) of that described in patent

179 Application DE 197 28 954 C1 in Example 31 h Gd-complex of 10- (4carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid and 1.67 g of anhydrous lithium chloride (39.46 mmol) were dissolved under stirring at 40 ° C in 200 ml of absolute dimethyl sulfoxide and mixed at this temperature with total

4.53 g (39.46 mmol) of X ± hydroxysuccinimide and 10.0 g (8.97 mmol) of the title compound of Example 34c dissolved in 100 ml of dimethyl sulfoxide. After cooling to room temperature, the reaction solution was mixed with 8.14 d (39.46 mmol) Ν, дициΝcyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was finally mixed with acetone in excess until complete precipitation of the title compound above, the precipitate was sucked off, dried, absorbed in water, the insoluble dicyclohexylcarbamod was filtered and the filtrate was purified through one AMICON®-3mbr (3 ul) cut off: 3000 Da) for desalination and purification of low molecular weight constituents. The resulting product was finally freeze-dried.

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):

_Est . C 38.01 H4.61 N9.58 F 13.81 S1.37 Gd 13.45

C, 37.92

H4.55 N9.58 F 13.77

S1.31

Gd 13.48

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

180 g (44.0 mmol) of 1-perfluorooctylsulfonylpiperazine were dissolved in 150 ml of tetrahydrofuran and mixed at room temperature with 5.1 g (44.0 mmol) of diglycolic anhydride in total, and the reaction solution thus obtained was countered for 12 hours. o'clock. After cooling to room temperature, it was concentrated to dryness and the resulting oily residue was purified on silica gel using dichloromethane / 2-propanol (16: 1) as eluent.

Yield: 27.94 g (92.8% of theory) of the title compound as a colorless and viscous oil.

Elemental analysis:

_Est . S58,52 N4D7 N1,98 S F 2,26 22,80 _Paul. C58.42 H4.41 N1.80 S2.28 F 23.02

Example 36

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

Dissolve 68.5 g (91.79 mmol) of 1-carboxy methyloxy-2,3,4-tetra-O-benzyl-a-omanopyranoside in 750 ml of anhydrous THF [the preparation is as described in German patent DE 197 28 954 Cl] and then 9.25 g (91.79 mmol) of triethylamine were added. After cooling the reaction solution to -15 ° C to -20 ° C, a solution of 12.64 g (92.5 mmol) was added slowly dropwise at the same temperature.

181 Hydrochloric acid isobutyl ester in 150 ml of anhydrous tetrahydrofuran, the drop rate being chosen so that the internal temperature of -10 ° C does not pass. After a reaction time of 15 minutes at -15 ° C, 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 was finally added dropwise. as a solution in 500 ml dry terahydrofuran - at 20 ° C. After one reaction time of one hour at -15 ° C as well as two hours at room temperature, the solution was concentrated to dryness in vacuo. The resulting residue was taken up in 450 ml of ethyl acetate and washed twice with 300 ml of saturated sodium bicarbonate solution and once with 400 ml of water. After drying the organic phase over sodium sulfate, it is sucked off from the salt and the acetic acid ethyl ester is removed in vacuo. The oily residue obtained was purified on silica gel using dichloromethane / hexane / 2-propanol (10: 20: 1) as eluent.

Yield: 130.6 g (81.6% of theory) of the title compound as a colorless and highly viscous oil.

Elemental analysis:

_Est; C 55.11 H 5.03 N4.82 F 18.52 S 1.84 _Pol . C 55.20 H 5.09 N4.91 F 18.48 S1.80

B) 1- {3-Oxa-pentane-1,5-dicarboxylic acid 1-oyl-5- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide} -7- [1-O-a

D- (5carbonyl) -pentyl-mannopyranose] -1,4,7,10-tetraazacyclododecane

182

Dissolve 110.0 g (63.08 mmol) of the compound of Example 36a in 1000 ml of ethanol, mix with 5.0 g of pearl catalyst (pd 20%, C) and hydrogenate to quantitatively absorb hydrogen. It is sucked off from the catalyst, washed with ethanol and concentrated to dryness in vacuo. The title compound is obtained as a viscous and colorless oil.

Yield: 92.61 g (99.5% of theory) Elemental analysis: _Est; C, 52.10; H, 5.12 N5,70 F21.89 S 2 17 _Gender: C, 52.20; H, 5.09 N5.71 F21.87 S2,20

c) 1,7-bis- [1,4,7-Tris (carboxylatomethyl) -10- (3-aza-4-oxo-5methyl-5-yl-pentanoyl) -4- {3-oxa-pentan-1 , 5-Dicarboxylic acid-1-yl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -N- [1-O-a-O- (5-carbonyl) -pentyl-mannopyranose] -1, 4,7,10tetraazacyclododecane, digadolinium complex

55.4 g (88.0 mmol; 4.4 molar equivalents relative to the used diamino component of Example 33d) of the gadolinium complex of 10 (4-carboxy-1-methyl-2 described in patent application DE 197 28 954 C1 in Example 31 h -oxo-3-azabutyl) -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid and 3.7 g of anhydrous lithium chloride (88.0 mmol) were dissolved at 40 ° C in 500 ml of absolute dimethyl sulfoxide with continuous stirring and at the same temperature, 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 were dissolved in 300 ml.

183 absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution was mixed with 18.2 g (88.0 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was mixed with acetone in excess until complete precipitation of the title compound above, the precipitate was sucked off, dried, absorbed in water, filtered from insoluble dicyclohexylurea and the filtrate was desalted via AMICIN® YM-3mbr cut (4m). off 3000 Da) while purifying from low molecular weight constituents. The resulting product was finally freeze-dried.

Yield: 35.96 g (76.9% of theory) as a colorless lyophilisate. Water content (Karl-Fischer): 5.98%.

Elemental analysis (calculated on the anhydrous basis): _Calc: C38.01 H4.61 N8.22 F 13.81 Gd 13.45 S 1.37 _Pol . C37.87 H4.70 N8.22 F 13.90 Gd 13.48 S 1.38

Example 37

a) 5- (ethoxycarbonyl) -2,3,4,60tetra-O-acetyl-a-Dmanopyranoside

Similarly, to the literature on the synthesis of aryl glycopyranosides [J. Conchie und GA Lewy in Methods in Carbohydrate Chemistry (R>L> Wolfrom and JNBeMiller, Ads.), Academic Press, New York, Vol.II, 90, pp. 345347, (1963)] the interaction between 156p2 g (400 mmol) of D-mannose pentacetate as α, β- (α, β-ratio = 4: 1) 184 anomeric mixture [for the synthesis of 1,2,3,4, 6-Pent-O-acetyl-a, p-Omanopyranose Compare: MLWolfrom und A.Thompson in Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol.II, 53 , pp. 211-215, (1963)] with 67 ml (400 mmol) of 6-hydroxyhexanoic acid ethyl ester and 60.8 ml (520 mmol) of tin-1H-chloride in a total of 600 ml of 1,2-dichloroethane after purification by column chromatography (eluent: hexane / ethyl acetic acid 2: 1) afforded 100.05 g (51% of theory) of the title compound as a colorless and viscous oil. By ¹ H-NMR spectroscopic examination of the title compound obtained, it was found that the title compound mentioned above was exclusively anomers.

Elemental analysis:

Calc'd: C, 52.94; H6.77

Gender: C 52.80 H 6.78

B) 5- (carboxy) pentyl-2,3,4,6, -tetra-O-benzyl-a-Dmanopyranoside

A well stirred suspension of 141.0 g (289 mmol) of the title compound of Example 37a in 200 ml of dioxane was mixed in portions at ambient temperature and stirred vigorously with a total of 238.5 g (4.26 mol) of finely powdered powder of potassium hydroxide. To increase the stirring ability, the reaction mixture is mixed with new ones

185

The 200 ml of dioxane and the suspension thus obtained was finally heated to reflux and at this temperature was mixed dropwise with a total of 372 ml (3.128 mol) of benzyl bromide for two hours. After one reaction time of 4 hours at 110 ° C followed by 12 hours at room temperature, the reaction mixture was slowly poured in order to be treated with a total of 2.5 liters of ice water and finally the aqueous phase was extracted completely with diethyl ether. After washing the ether phase thus obtained and finally drying this ether phase over sodium sulfate, the salt is sucked off and the diethyl ether extracted in vacuo. The excess benzyl bromide was finally distilled quantitatively from the reaction mixture in an oil pump vacuum at an oil bath temperature of 180 ° C. The thus obtained resinous oily residue was purified on silica gel using ethyl acetate / hexane (1:10) as eluent.

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

Elemental analysis:

_Est; With 75.68 N7,16 _Paul. H, 75.79;

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

60.0 g (91.5 mmol) of the title compound of Example 37b were dissolved in 750 ml of dimethylformamide and mixed with total

186

10.4 g (91.5 mmol) of N-hydroxysuccinimide. It was cooled to 0 ° C and 18.9 g (91.5 mmol) of dicyclohexylcarbodiimide were added. It was stirred for 1 hour at 0 ° C and then for 4 hours at room temperature. The solvent was removed in vacuo and the resulting residue was mixed with 100 ml of acetic acid ethyl ester and cooled to 0 ° C. The precipitated urea was filtered and the resulting filtrate was concentrated to dryness in vacuo. The resinous oily residue thus obtained was purified on silica gel using acetic acid / hexane ethyl ester (1:20) as eluent.

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

Elemental analysis:

_Est . C, 70.29; H, 6.57; N, 1.86

Sex: C 70.39 H 5.64 N1.91

d) 2,6-6nc _{{6-N £ -2-Na - [} - [ 1-FaD-6-Kap6oHnn-neHTHn- (2,3,4,6tetra-O-benzyl) mannopyranose} -1_-lysine} methyl ester

In a solution cooled to 0 ° C of 4.26 g (18.30 mmol; 0.5 molar equivalents relative to the carboxylic acid used) of lysine methyl ester dihydrochloride (Bachem company product) and 4.05 g (40.26 mmol) triethylamine in 100 ml of dimethylformamide was added dropwise one solution of 27.51 g (36.6 mmol) in 150 ml of dimethylformamide. After the addition is complete, it is stirred for another hour at 0 ° C and

187 then at room temperature overnight. It was evaporated to dryness in vacuo and the residue was absorbed in 3000 ml of acetic acid ethyl ester. The precipitated urea was filtered off and the filtrate was washed twice with 100 ml of 5 ml aqueous soda. The organic phase was dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: n-hexane / isopropanol 25: 1). They are obtained

39.56 g (74.4% of theory) of the title compound as a colorless oil.

Elemental analysis:

_Est; S72,88 N7.31 N1,95 _Paul. 072.90 H7.29 N2.02

f) 2,6-bis [6- [2- (2-M _a - [1-0-a-O-6-carbonyl-pentyl- (2,3,4,6-tetraO-benzyl) mannopyranose]] - 1_ -Lysine

Dissolve 30.0 g (20.92 mmol) of the compound of Example 37b 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 stirred for 3 hours at 50 ° C. After thin layer chromatography the saponification was quantified. It is concentrated in vacuo to dryness and the resulting residue is absorbed in 300 ml of acetic acid ethyl ester and the organic phase is extracted twice with 100 ml of dilute, aqueous citric acid. After drying over sodium sulfate, it is filtered and concentrated in vacuo to dryness. The residue was chromatographed on silica gel

188 (eluent: n-hexane / isopropanol 13: 1). 25.56 g of 988.5% of theory were obtained) from the title compound as a colorless oil.

Elemental analysis:

_Est; With 72.88 N7.31 N1,95 _Paul. C 72.78 H7.33 N1.98

02,5-bis [6-ME-2-M _a - [1-0-a-O-6-carbonyl-pentyl- (2,3,4,6-tetra-benzyl) -manipiranose] -1_-lysine ] -N-hydroxysuccinimidester

14.0 g (9.15 mmol) of the title compound of Example 37e were dissolved in 100 ml of dimethylformamide and mixed with a total of 1.04 g (9.15 mmol) of N-hydroxysuccinimide. Cool to 0 ° C and add 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide. It was stirred for one hour at 0 ° C and then for 4 hours at room temperature. Finally, the solvent was removed in vacuo and the resulting residue was mixed with 100 ml of acetic acid ethyl ester and cooled to 0 ° C. The precipitated urea was filtered and the resulting filtrate was concentrated to dryness in vacuo The thus obtained resinous oily residue was purified on silica. using acetic acid / n-hexane ethyl ester (1:20) as eluent.

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

Elemental analysis:

_Est . C71.40 H7.05 N2.74

189 _Gender; C71.39 H7 / I4 N2.81

g) 2,6-N, N'-6nc [1-0-a-0- (6-carbonyl) -pentyl-2,3,4,6-tetra-0-benzyl-mannopyranose] -lysine-1,7- (1,4,7-Thiazepheptane) diamide

In a solution cooled to 0 ° C of 0.47 g (4.57 mmol) of diethylenetriamine in 25 ml of dimethylformamide is slowly added dropwise one solution of 14.0 g (9.15 mmol; 2 mole equivalents relative to the amine used) of the title compound of Example 37f in 100 ml of dimethylformamide. After the addition was complete, it was stirred for another hour at 0 ° C and then stirred at room temperature overnight. It was evaporated to dryness in vacuo and the residue was absorbed in 200 ml of ethyl acetic acid. The precipitated urea was filtered off and the filtrate washed twice with 50 ml 5% aqueous baking soda each time. The organic phase was dried over magnesium sulfate and evaporated in vacuo to dryness. The residue was chromatographed on silica gel (eluent: n-hexane / isopropanol 25: 1). They are obtained

9.53 g (71.4% of theory) of the title compound as a colorless oil.

Elemental analysis:

_Est . C, 72.79 H7.42N3.36

Sex: C 72.90 H7.39 N3.32

h) 2-N- [2- (N-Ethyn-N-perfluoroctylsulfonyl) -amino] -acetyl-6- N- (benzyloxycarbonyl) -1_-lysine-methyl ester

190

20.8 g (35.6 mmol) of 2- (N-ethyl-N-perfluoroctylsulfonyl) -aminoacetic acid as well as 3.60 g (35.6 mmol) of triethylamine were dissolved in 200 ml of dimethylformamide and then added 4 , 09 g (35.6 mmol) of Nhydroxysuccinimide. It was cooled to 0 ° C and 7.34 g (35.6 mmol) of dicyclohexylcarbodiimide were added. It is stirred for 1 hour at 0 ° C and then for 4 hours at room temperature. Cool to 0 ° C and a solution of 11.77 g (35.6 mmol) of 6-N-benzyloxycarbonyl-L-lysine-methyl ester hydrochloride and 4.0 g (40.0 mmol) was added dropwise within 10 minutes. ) triethylamine in 100 ml of dimethylformamide. It is stirred for 1 hour at 0 ° C and then at room temperature overnight. The mixture was evaporated to dryness in vacuo and the residue was taken up in 100 ml of acetic acid ethyl ester. The precipitated urea was filtered off and the filtrate washed twice with 100 ml 5% aqueous baking soda each. The organic phase was dried over magnesium sulfate and evaporated in vacuo to dryness. The residue was chromatographed on silica gel (eluent: n-hexane /

acetic acid ethyl ester 20: 1). 27.43 g are obtained (88.0% of theory.) Colorless butter. Elemental analysis: _Est; C, 38.41; H, 3.45; N, 4.80 F, 36.89 S3.66 _Paul; 038.45 H3.38 N4.88 F, 37.02 S, 3.71 ΐ) 2-Να - {[2- (Ν-βτππ- N-perfluorooctylsulfonyl] -amino-

acetyl} -6-N- (benzyloxycarbonyl) -1_-lysine

191

Dissolve 25.0 g (28.55 mmol) of the compound of Example 37h 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 stirred for 3 hours at 50 ° C. After thin layer chromatography, the saponification was carried out and quantified. It is concentrated to dryness in vacuo and the residue is absorbed in 300 ml of acetic acid ethyl ester, and the organic phase is extracted twice with 100 ml of dilute, aqueous citric acid. After drying over sodium sulfate, it is filtered and concentrated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: n-hexane / isopropanol 10: 1). 22.73 g (92.4% of theory) of the title compound as a colorless oil are obtained.

Elemental analysis:

_Est . C 37.64 H3.28 N4.88 F 37.49 S3.72 Sex: ^C 37.65 H3.38 N4.88 F 37.52 S3.73

j) 1,4,7-Tpna3axenTaH-4- {2-N- [2- (N-ethyl-N-perfluoro-cyclohexyl) -amino] -acetyl-6-N-benzyloxycarbonyl} -1_-lysine-amide-1,7-6πο { 2,6-Ν, Ν'-6πο [1-Ο-α- D (5-carbonyl) -pentyl-2,3,4,6-tetra-benzylmanganyl] -L-lindiamide}

In 250 ml of dry THF dissolved 15.33 g (17.8 mmol) of the title compound of Example 37i as well as 1.80 g (17.8 mmol) of triethylamine. After cooling the reaction solution to -15 ° C to -20 ° C at this temperature

A solution of 4.92 g (35.6 mmol) of hydrochloric acid isobutyl ester dissolved in 50 ml of dry tetrahydrofuran was slowly added to the temperature and stirring, with the drop rate determined so that an internal temperature of -15 ° C was not be crossed. After a reaction time of 15 minutes, a solution of 52.0 g (17.8 mmol) of the title compound of Example 37g and 1.80 g (17.8 mmol) of triethylamine was added dropwise at -20 ° C. 300 ml of dry tetrahydrofuran. After one reaction time of one hour at -15 ° C as well as two hours at room temperature, the reaction solution was evaporated to vacuum in vacuo. The resulting residue was taken up in 500 ml of acetic acid ethyl ester and washed twice with 200 ml of saturated sodium bicarbonate solution and once with 200 ml of water. After drying the organic phase over sodium sulfate, the salt is sucked off and the acetic acid ethyl ester is removed in vacuo. The oily residue obtained was purified on silica gel using acetic acid / n-hexane (1:20) ethyl ester as eluent.

Yield: 54.6 g (81 pb% of theory) of the title compound as a colorless and highly viscous oil.

Elemental analysis:

_Est . C 65.09 H 6.45 N3.72 F8.58 S0.85 _Sex C 65.13 H4.41 N3.69 F8.52 5 0.90

k) 1,4,7-Tetraazepheptan-4- {2-N- [2- (N-ethyl-Mperfluoroctylsulfonyl) -amino] -acetyl} -1_-lysine-amide-1,7193

6nc {2,6-N, N'-6nc [1-O-a-O- (5-carbonyl) -pentyl-monopyranose] -1-lysine-diamide}

50.0 g (13.28 mmol) of the compound obtained in Example 37j were dissolved in 500 ml of ethanol, 4.0 g of pearl catalyst (Pd 20%, C) was added and the hydrogenation was carried out for as long as necessary no more absorption of hydrogen is observed. It was aspirated from the catalyst, washed mainly with ethanol (about 400 ml) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous and colorless oil.

Yield: 26.85 g (93.0% of theory) Elemental analysis:

_Est . With 45.85 N6,35 N6,44 F 14,86 S1.47 _Paul. C, 45.76; H6.35; N6.41; F, 14.92; S1.39

1) 1,4,7-triazepheptan-4- {2-N- [2- (N-ethyl-methyl-fluorooctylsulfonyl) -amino] -acetyl-6-N- [1,4,7tris (carboxylatomethyl) -10- ( 3-aza-4-oxo-5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane} -1_-lysine-amide-1,7-bis {2,6-N, N-bis [1-O-a-O- (5-carbonyl) -pentyl-mannopyranose] -1_-lysine-diamide}, gadolinium complex

5.54 g (8.8 mmol; 2.2 molar equivalents to the amino component of Example 37k used) of the gadolinium complex of 10- (4-carboxy-1-methyl-2- described in patent application DE 197 28 954 Cl in Example 31 h oxo-3-azabutyl) -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid and 0.37 g

194 anhydrous lithium chloride (8.8 mmol) was dissolved at 40 ° C in 60 ml absolute dimethyl sulfoxide with continuous stirring, and at the same temperature was mixed with 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. After cooling to room temperature, the reaction solution was mixed with 1.82 g (8.9 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension is then treated with sufficient acetone until complete precipitation of the above title compound is achieved, the precipitate is sucked off, dried, absorbed in water, the insoluble dicyclohexylurea is filtered and the filtrate is desalted via AMICON® YM-ultra YM membrane (cut off 3000 Da) and purified from the low molecular weight components. The resulting product was finally freeze-dried.

Yield: 8.77 g (78.7% of theory) as a colorless lyophilisate. Water content (Kag1-E | 5c11g): 4.43%.

Elemental analysis (calculated on the anhydrous substance):

C, 43.98 H5.97 N7.54 F, 11.59 Gd 5.64 S 1.15 C, 43.97 H6.02 N7.62 F, 11.61 Gd 10.18 S 1.15 An example 38

a) 2-Ma-6-N-bis [1-E-a-0-carbonylmethyl-1,3,4,6-tetra-0-benzyl-manopyranose] -1-lysine] -methyl ester

195

10.95 g (18.30 mmol) of 1-carboxymethyloxy-2,3,4-tetra-benzenyl-α-0-manopyranoside [was prepared as described in patent application DE 197 28 954] was dissolved in 150 ml of dimethylformamide and were mixed with a total of 2.09 g (18.3 mmol) of Nhydroxysuccinimide. It was cooled to 0 ° C and then 3.78 g (18.3 mmol) of dicyclohexylcarbodiimide were added. Stir for at least one hour at 0 ° C and then for 4 hours at room temperature. It was cooled to 0 ° C and a solution of 2.13 g (9.15 mmol; 0.5 mole equivalents to the carboxylic acid used) of Llysinmethyl ester dihydrochloride (Bachem's commercial product) was added dropwise within one hour. 2.02 g (20.13 mmol) of triethylamine in 70 ml of dimethylformamide. Upon completion of the addition, stirring was continued for another hour at 0 ° C and stirred overnight at room temperature. It was evaporated to dryness in vacuo and the residue was taken up in 300 ml of acetic acid ethyl ester. The precipitated urea was filtered and the filtrate was washed twice with 100 ml of a 5% aqueous solution of soda each. The organic phase was dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: n-hexane / isopropanol 25: 1). 10.05 g (81.3% of theory) of the title compound are obtained as a colorless oil.

Elemental analysis:

Est:

C 71.94 H6.79 N2.10

C 71.90 H6.79 N2.09

Gender:

196

B) 2-Ma-6-N-bis [1-O-a-O-carbonylmethyl-2,3,4,6-tetra-benzyl-manopyranose] -1_-lysine

Similarly, the saponification for methyl ester of 15 g (11.23 mmol) of the title compound of Example 38a to form 13.89 g (93.6% of theory) was performed for the synthesis of the corresponding title compounds. ) from the above-mentioned title compound as a colorless and viscous oil.

Elemental analysis:

_1A C 71.80 H 6.71 N 2.12

Est:

Sex: C 71.84 H6.69 N2.15

ο) 2-Να-6-Νε-6πο- [

1-O-α-0-carbonylmethyl-2,3,4,6-tetra-0 benzyl mannopyranose] -1_-lysine-N-hydroxysuccinimide ester

12.09 g (9.15 mmol) of the title compound of Example 38b were dissolved in 100 ml of dimethylformamide and combined in total with 1.04 g (9.15 mmol) of N-hydroxysuccinimide. Cool to 0 ° C and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide are added. It was stirred for one hour at 0 ° C and then for 4 hours at room temperature. The solvent was removed in vacuo and the resulting residue was mixed with 100 ml of acetic acid ethyl ester and then cooled to 0 ° C. The precipitated urea was filtered and the resulting filtrate was concentrated to dryness in vacuo. The resin-oily residue thus obtained is purified on

197 silica gel using acetic acid ethyl ester / n-hexane (1:20) as eluent.

Yield: 12.24 g (94.4% of theory) of the title compound as a colorless and viscous oil.

Elemental analysis:

_Est . C, 70.27; H6.47; N2,96

Gender: C, 70.31; H6.44; N3.01

d) 6-N-benzyloxycarbonyl -2N - {[2,6-N, N-bis (1-N-α-Dcarbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)] - 1_ -Lysine- [1 (4-perfluoroctylsulfonyl) -piperazine] -amide

19.0 g (13.4 mmol) of the carboxylic acid-N-hydroxysuccinimidester obtained according to Example 38c was dissolved in 75 ml of dimethylformamide and mixed at 0 ° C in portions with a cooled to 0 ° C solution of 11.13 g as well. (13.4 mmol) of the title compound of Example 21c, dissolved in 50 ml of dimethylformamide, The resulting solution was stirred for a further 2 hours at 0 ° C and another 12 hours at room temperature. Filtration of the precipitated dicyclohexylurea is carried out for the treatment and the solvent is removed in vacuo to dryness. The residue thus obtained is chromatographed on silica gel [eluent: dichloromethane / ethanol 28: 1;

chromatography is performed using soluble gradients, with a continuously increasing fraction of the polar eluent component used (in this case: ethanol).

198

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

Elemental analysis:

_Est . H5.34

N3.94

F, 15.13

S1.50 _Gender . H5.35

N4.02

F 15.15

S1.56

e) 2-N - {[2,6-N, Ν'-bis (1-N-αD-carbonylmethylmanipyranose)] - 1_-lysine1_-lysine- [1- (4-perfluoroctylsulfonyl) piperazine] -amide

Dissolve 20.0 g (9.37 mmol) of the compound obtained in Example 38d in 200 ml of ethanol, mix with 1.5 g of pearl catalyst (Pd 20%, C) for a long time at room temperature under a hydrogen atmosphere ( 1 atm) until hydrogen absorption ceases to be observed. It is aspirated from the catalyst, washed mainly with ethanol (twice with about 100 ml each) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous and colorless oil.

Yield: 11.62 g (97.0% of theory).

Elemental analysis:

_Est . 038.50 H4.65 N6.57 F 25.25 S2.51 _Gender . C 38.46 H4.65 N6.51 F 25.23 S2.52

f) 6-N- [1,4,7-Tris (carboxylatomethyl) -10- (3-aza-4-oxo-5methyl-5-yl-pentanoyl) -1,4,7,10-tetraazacyclododecane) -2 - N - {[2,6N, N-bis (1-O-α-O-carbonylmethyl-mannopyranose)] -1'-lysyl} -1_-

199 Lysine [1- (4-perfluoroctylsulfonyl) -piperazine] -amide, Gd complex

9.98 g (15.84 mmol; 2.2 molar equivalents relative to the amino component of Example 38e used) of DE 197 28 954 Cl described in patent application Example 31 h Gd-complex of 10- (4-carboxy-1-methyl-2 -oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-trioacetic acid and 0.67 g (15.84 mmol) without aqueous lithium chloride were dissolved at 40 ° C in 100 ml of absolute dimethyl sulfoxide with continuous stirring and at the same temperature mixed with the total

1.82 g (15.84 mmol) of N-hydroxysuccinimide and 9.19 g (7.19 mmol) of the title compound of Example 38e were dissolved in 50 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution was mixed 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 sufficient acetone until complete precipitation of the title compound was obtained, the precipitate was sucked off, dried, absorbed in water, the insoluble dicyclohexylurea was filtered and the filtrate was desalinated through AMICON® YM-3 ultrafiltrate. of the possible, still low molecular weight components. The product is freeze-dried.

Yield: 11.85 g (87.2% of theory) as a colorless lyophilisate. Water content (Kg1-p18c1peg): 5.54%.

200

Elemental analysis (calculated from anhydrous substance):

Calc: C, 38.12 H4.64 N8.15 F 20.38 S1.70 Gd 8.32 Gender: ^{by 38.16} H4.59 N8.18 F 20.37 S1.68 Gd8,28 An example 39

a) 1,7-bis (benzyloxycarbonyl) -4- (30oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) -1,4,7,10-tetraazacyclododecane

To a solution of 1075 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 added at 0 ° C and under nitrogen atmosphere 12.74 g (24.4 mmol) of the title compound of Example 39g dissolved in 150 ml of THF. Finally, 18.0 g (36.6 mmol) of EEDQ were added in portions at 0 ° C. [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] and allowed to stand at room temperature and stirring at night and then concentrated in vacuo. The resulting oil was chromatographed on silica gel (eluent: hexane / isopropanol 16: 1). 15.89 g (69.0% of theory. Of the sec-amine used) monoamide were obtained, as well as 3.8 g (8.8% of theory) of diamide as a by-product. The title compound

is obtained as colorless oil. Elemental analysis: C, 45.77 Est: H3.95 F 34.19 N5.93 _p C 45.72 Sex: H, 4.01 F 34.22 N5.88

201

B) 1,7-bis- (benzyloxycarbonyl) -4- (3-oxa2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) -10- [1-5-a-D- (2carbonyl) -ethyl-2 , 3,4,6-Tetra-O-acetylmanipyranose] -1,4,7, Utetraazacyclododecane

7.09 g (13.4 mmol) of 3- (2,3,4,6-tetra-0-acetyl-1-thio-a-0manopyranosyl) -propionic acid-Nhydroxysuccinimidester (prepared according to J. Haensler et al ., Bioconjugate Chem. 4, 85, (1993); Chipowsky, S., and Lee, Y.C. (1973), Synthesis of 1-thio-aldosides; Carbohydrate Research 31, 339 - 346) are dissolved in 100 ml of dimethylformamide and at the temperature of 0 ° C was mixed dropwise with one solution pre-cooled to 0 ° C of 12.65 g (13.4 mmol) of the title compound of Example 39a dissolved in 100 ml of dimethylformamide. It is stirred for 2 hours at 0 ° C as well as 12 hours at room temperature. For refinement, the solvent was extracted in vacuo to dryness and the residue thus obtained was chromatographed on silica gel (eluent: dichloromethane / ethyl acetic acid 20: 1; chromatography was carried out using soluble gradients with a continuously increasing part of the ethyl ester acetic acid).

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

Elemental analysis:

Calc: ^C46 · ⁷⁰ H436 N4.11 F 23.69 S2.35 _Gender; C 46.66 H4.35 N4.12 F 23.60 S2.30

202

c) 1- (3-oxa-2H, 2H, 4H, 4H, 5H,% H-perfluorotridecanoyl) -7- [1-

5-a-O- (2-carbonyl) -ethyl-2,3,4,6-tetra-O-acetyl-mannopyranose] 1,4,7,10-tetraazacyclododecane

Dissolve 15.0 g (11.0 mmol) of the compound of Example 39b in 150 ml of ethanol, mix with 1.0 g of pearl catalyst (Pc 20%, C) and hydrogenate for so long at room temperature and in hydrogen until the absorption of hydrogen ceases to be observed. It was aspirated from the catalyst, washed with ethanol (twice with 75 ml each) and concentrated in vacuo to dryness. The title compound is obtained as a highly viscous and colorless oil.

Yield: 11.56 g (96.0% of theory).

Elemental analysis:

Calc'd: C 40.59 H4.33 N5.12 F 29.50 S2.93

Sex: C 40.63 H4.35 N5.11 F29.52 S2.92

O) 1- (3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) -7- [1-

5-a-O- (2-carbonyl) -ethyl-mannopyranose] -1,4,7, Utetraazacyclododecane

10.0 g (9.13 mmol) of the title compound of Example 39c were suspended in 100 ml absolute methanol and mixed at 5 ° C with a catalytic amount of sodium methanolate. After one reaction time of 3 hours at room temperature, control by thin layer chromatography (eluent: chloroform / methanol 4: 1) showed during the reaction one

203 quantitative interaction. For the purpose of further processing, the clear reaction solution is neutralized by reaction with Amberlite IR 120 (H ⁺ - form) cation exchange resin, washed with methanol and the methanol filtrate thus obtained is extracted in vacuo to dryness. The resulting oily residue was purified on silica gel (eluent: dichloromethane / n-hexane / ethyl acetic acid ester 15: 20: 1; chromatography was carried out using a soluble gradient with a continuous increasing portion of acetic acid ethyl ester). After ¹ H-NMR spectroscopic examination of the title compound, it is possible to _infer from the size of the coupling constant J 1 _{i 2} = 0.9 Hz that the α-configuration is available at the anomeric center of D-mannopyranose. The available α-configuration is the extremely existing configuration at the anomer center, which means the amount of possibly formed and β-configured anomers of the title compound is below the demonstrable limits of ¹ H-NMR spectroscopy. Therefore, the above title compound is only obtained as pure in the α-configuration anomers.

Yield: 8.28 g (98.0% of theory) of the title compound as a colorless and highly viscous oil.

Elemental analysis:

_Est; C 37.59 H4.24 N6.05 F 34.85 S3.46 _Sex .C 37.57 H4.28 N6.02 F 34.85 S3.44

204

e) 1- (3-oxa-2H, 2H, 4h, 4H, 5H, 5H-perfluorotridecanoyl) -7- [1-5a-O- (2-carbonyl) -ethyl-mannopyranose] -4,10-bis [ 1,4,7tris (carbosdylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl)] - 1,4,7,10-tetraazacyclododecane, digadolinium complex

Associated 1,4,7,10-tetraazacyclododecane amide with [1,7-bis [gadolinium complex of 10- (4-carboxy-1-methyl-2-oxo-3azabutyl) -1,4,7,10-tetraazacyclododecane -1,4,7-trioacetic acid]; 3- (2,3,4,6-Tetra-O-acetyl-1-thio-a-O-manopyranosyl) lropionic acid

2.48 g [(3.94 mt) m 4.4 molar equivalents relative to the used diamino component 39d] of the gadolinium complex of 10- (4-carboxy-1-methyl- described in patent application DE 197 28 954 C1 in Example 31 h) 2-Oxo-3-azabutyl) -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid and 167 mg anhydrous lithium chloride (3.94 mmol) were dissolved with continuous stirring at 40 ° C in 40 ml. absolute dimethyl sulfoxide and mixed at the same temperature with a total of 453 mg (3.94 mmol) of N-hydroxysuccinimide and 980 mg (0.885 mmol) of the title compound of Example 19Ad dissolved in 10 ml of dimethyl sulfoxide. After cooling to room temperature, it was mixed with 814 mg (3.946 mmol) of дици'cyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was finally mixed with sufficient acetone until complete precipitation of the above title compound was obtained, dried

205 is absorbed in water, the insoluble dicyclohexylcarbamide is filtered off and the filtrate is desalted through AMICON® YM-3 ultrafiltration membrane (cut off 3000 Da) and purified from the low molecular weight constituents. The product is finally freeze-dried.

Yield: 1.32 g (69.1% of theory) as a colorless lyophilisate.

Water content (Kg1-p15cIg): 7.65% Elemental analysis (calculated on the anhydrous basis):

_Est . C 37.43 H4.45 N9.12 F15.02 S1.49 Gd14.63 Sex: ^C37 · ⁴² H4.50 ^N9 > ¹⁸ F 15.07 S 1.51 Gd 14.58

() 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid-t-butyl ester

25.0 g (53.8 mmol) of 1H, 1H, 2H, 2H-perfluoro-1-decanol (commercially available by Lancaster) are dissolved in 250 ml of toluene and mixed at room temperature with a catalytic amount (about 0.75 d) Tetra-n-butyl ammonium hydrogen carbonate. A total of 7.55 g (134.6 mmol; 2.5 equivalents relative to the alcohol component used) of fine powdered potassium hydroxide powder was then added at 0 ° C, followed by 15.73 r (80.7 mmol; 1, 5 eq. Of the alcohol component used) bromoacetic acid tert-butyl ester and allowed to stand at 0 ° C for 2 hours with continuous stirring. The reaction solution thus obtained was stirred for 12 hours at room temperature and subjected to further processing.

206 is mixed with a total of 500 ml of acetic acid ethyl ester and 250 ml of water. The organic phase was separated and washed twice with water. After drying the organic phase over sodium sulfate, the salt was sucked off and the solvent removed in vacuo, the resulting oily residue was purified 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.

Elemental analysis:

_Est; C, 33.23; H2.61; F, 55.85

Sex: C 33.29 H2.61 F 55.90

e) 3-oxo-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanecarboxylic acid

20.0 g (34.58 mmol) of the title compound of Example 39f were suspended at room temperature and stirred in 200 ml of a mixture consisting of methanol and 0.5 molar sodium hydroxide in a 2: 1 ratio and then heated to 60 ° C. After one reaction time of 12 hours at 60 ° C, the clear solution was neutralized by reacting with Amberlite IR 120 (H ⁺ form) cation exchange resin, extracted from the ion exchanger and the methanol-aqueous solution thus obtained. The filtrate was removed to dryness in vacuo. The resulting amorphous oily residue was taken up

207 purified on silica gel using acetic acid / n-hexane (TH3) ethyl ester as eluent.

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

Elemental analysis:

Calcd: C27.60 H 1.35 F 61.85

Paul; C, 27.58; H, 1.36; F, 61.90

Example 40

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

To 8.0 g (24.4 mmol) of c-carbonyloxybenzyl-1-lysinemethyl ester hydrochloride (commercial product of Bachem) dissolved in a mixture of 150 ml tetrahydrofuran, 15 ml chloroform and 2.62 g (26.0 mmol) triethylamine 16.18 g (27.0 mmol) of 2 - [1 N-ethyl-N-perfluoroctylsulfonyl) -aminoacetic acid (prepared according to DE 196 03 033) dissolved in 50 were added dropwise at 0 ° C and under nitrogen atmosphere. ml of tetrahydrofuran. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] was then added in portions at 0 ° C and left overnight at room temperature. Finally, it was concentrated in vacuo and the remaining oil was chromatographed on silica gel (eluent: hexane / isopropanol 15: 1). 17.0 g (79.6% of theory versus the primary amine used) of the title compound are obtained as a colorless oil.

208

Elemental Analysis: Calc: C, 38.41 H3.45 F, 36.89 N4,80 S3.66 Gender: C, 38.42 H3.47 F, 36.92 N4.87 S3.64

B) 2- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-L-lysine-methyl ester

Dissolve 15.0 g (20.23 mmol) of the compound of Example 40a in 200 ml of ethanol, mix with 800 mg of pearl catalyst (Pd 20% on activated carbon) and hydrogenate to absorb the calculated amount of hydrogen.

It is aspirated from the catalyst, washed mainly with ethanol and concentrated to dryness in vacuo. The title compound is obtained as a colorless oil.

Yield: 14.68% (97.9% of theory)

Elemental analysis:

_Est; C, 32.40 H3.26. _Pol . C, 32.42. H3.27

F 43.56 N5.67 S4.32

F 43.60 N5.67 S4.34

c) 6- (1-O-a0-carbonylmethyl-2,3,46-tetra-0-benzyl manopyranose) 2- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] acetyl-L-lysine-methyl ester

Dissolve 21.31 g (35.6 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-a-omanopyranoside in 500 ml of dry THF (the preparation is as described in patent DE

209

197 28 954 Cl) as well as 3.60 g (35.6 mmol) of triethylamine. After cooling the reaction solution to -15 ° C to 20 ° C, a solution of 4.92 g (35.6 mmol) butyl ester of hydrochloric acid in 75 ml of dry tetrahydrofuran was added dropwise slowly at room temperature and stirring. the drip rate is determined so that the internal temperature of 10 ° C does not pass. After a reaction time of 15 minutes at -15 ° C, a solution of 26.39 g (35.6 mmol) of the title compound of Example 40b and 3.60 g (35.6 mmol) of triethylamine was added dropwise. in 100 ml of dry tetrahydrofuran at -20 ° C. After a one-hour reaction time of -15 ° C as well as two hours at room temperature, the reaction solution was concentrated to dryness in vacuo. The resulting residue was absorbed in 250 ml of acetic acid ethyl ester and washed twice with 100 ml of saturated sodium bicarbonate solution and once with 200 ml of water. After drying over sodium sulfate, the organic phase is sucked off from the salt and the acetic acid ethyl ester is removed in vacuo. The oily residue obtained was purified on silica gel using ethyl acetate / n-hexane (1:10) as eluent.

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

Elemental analysis:

Calcd. ^{0 49.92} H 3.92 N2.53 F 29.18 S2.90

210

^{Floor C 49} ' ^{H4.11 N2} ' ^{69 F} 29.22 S3.01

d) 6- (1-O-α-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmani-pyranose) 2- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] acetyl-L-lysine

Dissolve 27.65 g (20.92 mmol) of the compound of Example 40c in 250 ml of methanol. A solution of 4.0 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water is then added and stirred for 3 hours at 50 ° C. After checking the reaction process by thin layer chromatography it is visible that in methyl ester, the saponification is quantitative. It was concentrated in vacuo to dryness and the resulting stock was absorbed in 300 ml of acetic acid ethyl ester and the organic phase extracted twice with 100 ml of dilute, aqueous citric acid. After drying over sodium sulfate, it is filtered under vacuum to dryness. The resulting residue was chromatographed on silica gel (eluent: n-hexane (chloroform).

isopropanol 15: 10: 1). They receive is 24.31 g (88.9% of theory) of the title compound in the form of colorless and Original oil. Elemental analysis: Calcd: 051.46 H4.70 N3.21 F 24.71 S2.45 Gender: 051> 49 H, 4.71 N3.19 F, 24.72 S2.41

e) 6- (1-O-a-D-carbonylmethyl-mannopyranose) 2- [2 (1-ethyl-N-perfluoro-cyclo-sulfonyl) -amino] -acetyl-1-lysine

211

20.0 g (15.30 mmol) of the title compound of Example 40d were dissolved in a mixture consisting of 250 ml of 2-propanol and 25 ml of water, and mixed with 1.0 g of palladium catalyst (10% Pd on active charcoal). It is hydrogenated for 12 hours at room temperature and under one atmosphere of hydrogen pressure. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 200 ml of methanol and the reaction product was precipitated by mixing with a total of 800 ml of diethyl ether. After suction of the resulting nucil filter solid, it was dried in vacuo at 50 ° C.

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

_Est . C 35.56 H3.84 N4.44 S 3.39 F 34.15 _Gender . C 35.58 H3.81 N4.45 S 3.40 F 34.17

f) 6- (1-O-D-Carbonylmethylmanipyranose) 2- [2- (N-βτππ-Perfluoroctylsulfonyl) -amino] -acetyl-L-lysine-N- {2-hydroxyprop-3-yl - [1,4 , 7-Tris (carboxylatomethyl) -1,4,7,10 tetraazacyclododecan-10-yl]} - amide, Gd-complex

7.48 g (7.91 mmol) of the title compound of Example 40e were dissolved at 40 ° C in 50 ml of dimethyl sulfoxide and 1 g (8.70 mmol) of N-hydroxysuccinimide was added. Cool to 20 ° C and stir for 4 hours at 40 ° C. Then a solution of 4.53 g (7.91) was added dropwise at the same temperature for 10 minutes.

212 mmol) gadolinium complex of 1- (2-hydroxy-3-aminopropyl) 4,7,10-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane [to obtain compare WO 97/02051] in 20 ml dimethyl sulfoxide. It is stirred for 1 hour at 40 ° C and then left overnight at room temperature. The suspension thus obtained is mixed with sufficient acetone until complete precipitation of the above title compound, the precipitate is sucked off, dried, absorbed in water, the insoluble dicyclohexylurea is filtered and the filter is desalted via AMICON ® YM-3 ultrafil off 3000 Da) and is purified from low molecular weight constituents. The product is finally freeze-dried.

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): _Calc . C 35.16 H4.16 N7.45 F 21.48 Gd 10.46 S 2.13 _Pol . C35.17 H4.20 N7.42 F 21.49 Gd 10.48 S 2.09

Example 41

a) 6-N- [1-E-a-O- (5-carbonyl) -pentyl-2,3,4,6-tetra-O-benzylmani-pyranose] -2M- [2- (N-ethyl-N- perfluoroctylsulfonyl) -amino] acetyl-L-lysine-methyl ester

5.23 g (8.0 mmol) described in Example 30C 5 (carboxy) phenyl-2,3,4,6-tetra-0-benzyl-a-0-mannopyranoside, 1.3 g (8.0 mmol) 1-hydroxy-benzotriazole and 2.6 g (8.0 mmol) of 2- (1H213 benzotriazol-1-yl) -1,1,3,3-tetramethyl-uronium tetrafluoroborate (TBTU; Peboc Limited, UK) were dissolved in 75 ml of dimethylformamide and stirred for 15 minutes. This solution was then mixed with 5.16 ml (30 mmol) of N-ethylisopropylamine and with

5.93 g (8.0 mmol) of the amine described in Example 40b and stirred for 1.5 days at room temperature. For further processing, the solvent was removed in vacuo to dryness and the residue thus obtained was chromatographed on silica gel (eluent: dichloromethane / ethyl acetate 30: 1; chromatography was carried out using soluble gradients with a continuously increasing portion of ethyl acetate on ethyl acetate).

Yield: 9.70 g (88.0% of theory) of the title compound as a colorless and highly viscous oil.

Elemental analysis:

_Est . C 52.29 H4.97 N3.05 F 23.43 S2.33 _Gender; C52.33 H4.95 N3.12 F 23.50 S2.30

B) 6-N- [1-N-α-O- (5-carbonyl) -phenyl] -2,3,4,6-tetra-O-benzylmani-pyranose] -2N- [2- (N-ethyn-N-perfluorooctylsulfonyl) ) -amino] -acetyl-L-lysine

9.0 g (12.40 mmol) of the compound obtained in Example 41a were dissolved in 150 m lmethanol. A solution of 2.48 g (62.0 mmol) of sodium hydroxide in 15 ml of distilled water was then added and stirred for 3 hours at 50 ° C. After checking the reaction

214 by thin layer chromatography it was found that the sludge for methyl ester during the above reaction time was completely quantitative. It was concentrated to dryness in vacuo and the resulting residue was absorbed in 300 ml of acetic acid ethyl ester and the organic phase extracted twice with 100 ml of dilute, aqueous citric acid. After drying over sodium sulfate, it is filtered and concentrated in vacuo to dryness. The resulting residue was chromatographed on silica gel (eluent: n-hexane / chloroform / isopropanol 25: 10: 1). 15.88 g (93.9% of theory) of the title compound are obtained as a colorless and highly viscous oil.

Elemental analysis:

Est; C 51.95 H4.88 N3.08 F 23.67 S2.35

Sex: ^{C 51.99 H4.91 N3 '09} F 23.70 S2.33

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

13.0 g (9.52 mmol) of the title compound of Example 41 b were dissolved in a mixture consisting of 150 ml of 2-propanol and 25 ml of water and then 1 g of palladium catalyst (10 5 Pd on activated carbon) was added. . It is hydrogenated for 12 hours at a hydrogen pressure of 1 atmosphere and at room temperature. The catalyst was removed by filtration and the filtrate was evaporated to dryness in vacuo. The resulting residue was chromatographed on silica gel (eluent: n-hexane (chloroform).

215 isopropanol 15: 10: 1). 9.09 g (95.1% of theory) of the title compound are obtained as a colorless and highly viscous oil.

Elemental analysis:

_Est . C37.10 H4.22 N4.19 F 32.18 S3.10 _Gender . C37.09 H4.21 N4.19 F 32.20 S3.13

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

7.93 g (7.91 mmol) of the title compound of Example 41c were dissolved at 40 ° C in 75 ml of dimethyl sulfoxide and then mixed with 1.00 g (8.70 mol) of N-hydroxysuccinimide. Cool to room temperature and a total of 1,795 g (8.7 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred for one hour at 20 ° C and then for 4 hours at 40 ° C. To this solution of the active esters of the title compound of Example 41 s at 40 ° C is added dropwise over 10 minutes solution consisting of 4.53 g (7.91 mmol) of gadolinium complex of 10- (2hydroxy-3-aminopropyl) -4,7,10-tris (carboxymethyl) -1,4,7,10tetraazacyclododecanin [to obtain compare : WO 97/02051], in 20 ml of dimethyl sulfoxide. It is stirred for one hour at 40 ° C and at room temperature overnight. The suspension thus obtained is mixed

216 finally with sufficient amount of acetone / 2-propanol (2: 1) mixture to completely precipitate the title compound above, the suction is suctioned, washed with acetic acid ethyl ester, dried, absorbed in water, by filtration the insoluble dicyclohexyl urea was separated and the filtrate was desalted through an AMICOM ® YM-3 ultrafilter membrane (cut off 3000 Da) and purified from the low molecular weight constituents. The product is freeze-dried.

Yield: 9.71 (78.8% of theory) as a colorless lyophilisate.

Water Content (Karl-Fischer): 6.65%

Elemental analysis (calculated on the anhydrous substance):

..C 36.97 H4.52 Est: N7.19 F 20.71 Gd 10.08 S, 2.06 H, 37.02 Gender: N7.22 F 20.69 Gd 10.08 S, 2.09 Example 42

a) 6-N- {4- [2, 3-bis- (Ν, Ν-bis ((butyloxycarbovinmethyl) -amino) propyl] -phenyl} -3-oxa-propionyl-2-N- (1-α- D-carbonylmethylmanipyranose) L-lysine- [1- (4-perfluoroctylsulfonyl) piperazine] -amide

5.25 g (7.72 mmol) of Yyr-EDTAcarboxylic acid tetra-1bu-ester and 781 mg (7.72 mmol) of triethylamine were dissolved in 50 ml of methylene chloride. At a temperature of -15 ° C, a solution of 1.16 g (8.5 mmol) of hydrochloric acid isobutyl ester in 10 ml of methyl chloride was added dropwise within 5 minutes, stirring for an additional 20 minutes at -15 ° C.

217

The solution was then cooled to -25 ° C and a solution consisting of 7.07 (7.72 mmol) of the title compound of Example 30e and 2.12 g (21.0) was added dropwise within 30 minutes. mmol) triethylamine, in 70 ml of tetrahydrofuran, stirring for an additional 30 minutes at -15 ° C and finally allowed to stand at room temperature overnight. For further processing, the solvent was removed in vacuo and the oily residue obtained was absorbed in 250 ml of chloroform. It is extracted twice with 100 ml of 10% aqueous ammonium chloride solution twice, the organic phase is dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: methylene chloride / ethanol = 20: 1).

Yield: 9.60 g (79.0% of theory) of a colorless and strong viscous oil.

Elemental analysis:

_Est . C 46.39 H 5.55 N5.32 F 20.45 S 2.03

Sex: ^C 46.42 H5.51 N5.29 F 20.49 S 2.09

b) 6-N- {4- [2, 3-bis (N, N-bis (carboxymethyl) -amino) -propyl] ~ phenyl} -3-oxa-propionyl-2-N- (1-a-D -carbonylmethyl-manopranose) [_-lysine- [1- (4-perfluoroctylsulfonyl) pyrazine] -amide

9.0 g (5.70 mmol) of the compound obtained according to Example 42a was dissolved in 150 ml of methanol. A solution of 4.0 g (100.0 mmol) of sodium hydroxide in 25 was then added

218 ml of distilled water and stirred for 6 hours at 60 ° C. After checking the progress of the reaction by thin layer chromatography it was found that the saponification of tetra-1-butyl ester at the above reaction time had elapsed quantitatively. Concentrate in vacuo to dryness and the resulting residue is warmly absorbed in 50 ml of dimethyl sulfoxide and finally treated with a sufficient amount of acetic acid / ethyl ester of acetic acid (1: 1) until complete precipitation of the title compound above, followed by suction. of the resulting precipitate, washed with acetic acid ethyl ester, dried, absorbed in water, with 1 molar hydrochloric acid solution the pH of the solution containing the product was adjusted to 3.5, the available insoluble constituents were filtered as possible and filtrate This was desalted through an AMICON ® YM-3 ultrafilter membrane (cut off: 3000 Da) and purified from the low molecular weight constituents. The resulting product was freeze-dried. Yield:

6.76 g (87.6% of theory) as a colorless lyophilisate.

Water content (Karl-Fischer): 3.30%. Elemental analysis (calculated on the anhydrous substance):

_Est . C 39.89 H4.09 N6.20 F 23.84 S 2.37 _Gender; 0 39.92 H4.15 N6.22 F 23.92 S 2.29

c) 6-N- {4- [2,3-bis (N, N-bis (carboxylatomethyl) -amino) propyl] -phenyl} -3-oxa-propionyl-2-N- (1-α-D- carbonylmethyl219 manopyranose) L-lysine [1- (4-perfluoroctylsulfonyl) -piperazine] amide, Μη complex, disodium salt

30.0 g (2.22 mmol) of the title compound of Example 42b were dissolved in 150 ml of a mixture of water / ethanol (3: 1) at boiling point and at 80 DEG C. in portions mixed with 0.25 g (2.22 mmol) manganese-N-carbonate. The reaction solution thus obtained was then countered for 5 hours. After cooling to room temperature, the solvent mixture was removed in vacuo and the resulting residue was dissolved in a mixture of 200 ml of distilled water / butanol (1: 1). With vigorous stirring using 1N sodium hydroxide, the pH of the medium was adjusted to 7.2. After complete recovery of n-butane in vacuo, the remaining aqueous phase is desalted by passing through an AMICON ® YM-3 ultrafiltration membrane (cut off 3000 Da) and purified from the low molecular weight constituents. The resulting product was then freeze-dried.

Dive: 3.19 g (99.0% of theory) of a colorless lyophilisate. Water content (Karl-Fischer): 5.08%.

Elemental analysis (calculated on the anhydrous basis): _Calcd. C37.23 H 3.54 F22.25 Mn 3, 78 N5.79 Na3.17 S2.21 _Gender C 37.30 H 3.49 F 22.29 Mn 3, 81 N5, 76 At 3.19 S2.18

Example 43

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

220

A well stirred solution of 25.0 g (94.96 mmol) of 3-N (benzyloxycarbonyl) -glutaric acid-anhydride [synthesis according to Hatanaka, Minoru; Yamamoto, Yu-ichi; Nitta, Hajime, Toshiyasu; TELEAY; Tetrahedron Lett .; EN; 22; 39; 1981; 38833886;] in 150 ml of absolute tetrahydrofuran is mixed in portions with continuous stirring with a solution of 53.97 g (95.0 mmol) of 1-perfluoroctylsulfonylpiperazine in 150 ml of tetrahydrofuran, and the reaction solution thus obtained is boiled for 12 hours. After cooling to room temperature, it was concentrated to dryness in vacuo and the resulting oily residue was purified on silica gel using dichloromethane / 2-propanol (20: 1) as eluent. Yield: 75.80 g (96.0% of theory) of the title compound as a colorless viscous oil.

Elemental analysis:

_Calc'd: C 36.11 H2.67 N5.05 S3.86 F 38.84 _Gender . C 36.12 H2.61 N5.08 S 3.88 F 38.82

B) 3-amino-glutaric acid [1- (4-perfluoroctylsulfonyl) -piperazine] -monoamide

31.50 g (37.88 mmol) of the compound obtained according to Example 43b were dissolved in 300 ml of ethanol, mixed with 2.5 g of pearl catalyst (Pd 20%, C) and hydrogenated to quantitatively absorb hydrogen at a pressure of 1 atmosphere. It is sucked off from the catalyst, washed with ethanol and concentrated to

221 dry in vacuum. The title compound is obtained as an off-white, viscous oil.

Yield: 25.22 g (95.5% of theory)

Elemental analysis:

_Est; 0 29.28 H2.31 N 6.03 S 4.06 F 46.31 _Paul; C29.32 H2.29 N 6.08 S 4.08 F 46.28 c) 3-N- (1-a- 0-carbonylmethyl-2,3,4,6-tetra-0-benzyl-

manopiranose) -glutaric acid [1- (4-perfluoroctylsulfonyl) -piperazine] -monoamide

21.52 g (18.96 mmol) of 1-carbosimethoxy-2,3,4-tetra-O-benzyl-D-mannopyranoside [prepared according to German patent DE 197 28 954 C1] was dissolved in 100 ml absolute dimethylformamide at room temperature and at 0 ° C were mixed with 2.56 g (22.2 mmol) of N-hydroxysuccinimide, followed by 4.55 g (22.2 mmol) of dicyclohexylcarbodiimide. After one reaction time of 60 minutes at 0 ° C and 3 hours at 22 ° C, filtration was performed to remove the insoluble dicyclohexylurea, and the thus obtained clear solution of the active esters of the above title compound at 0 ° C was slowly added at while stirring in a solution of 13.22 g (18.96) mmol of the compound of Example 43b dissolved in 100 ml of dimethylformamide. After one reaction time of 12 hours at room temperature, the solvent was removed in vacuo and the resulting residue was absorbed in 300 ml of ethyl ester.

222 Acetic acid, the urea is filtered off and the organic filtrate is washed twice with 100 ml of saturated sodium bicarbonate solution each time and once with 100 ml of 10% aqueous citric acid solution and once with 200 ml of water. After drying the organic phase over sodium sulfate, the salt is sucked off and the acetic acid ethyl ester is removed in vacuo. The oily residue obtained was purified on silica gel using acetic acid / n-hexane ethyl ester (1:15) as eluent.

Yield: 21.39 g (88.3% of theory) of the title compound above

as colorless and highly viscous butter. Elemental analysis: _Est . H, 49.81 N3.29 F 25.27 S2.51 Gender: θ ⁴⁹ · ^{89 H4} · ¹¹ N3.32 F 25.22 S2.51

d) 3-N- (1-a-O-carbonylmethyl-mannopyranose) -glutaric acid - [1- (4-perfluoroctylsulfonyl) -piperazine] -monoamide

19.55 g (15q30 mmol) of the title compound of Example 43c was dissolved in a mixture consisting of 250 ml of 2 propanol and 25 ml of water, and mixed with 1.5 g of palladium catalyst (10% Pd on activated carbon). It is hydrogenated for 12 hours at room temperature and under one atmosphere of hydrogen pressure. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 200 ml of methanol and the reaction product was precipitated by mixing with a total of 800 ml of diethyl ether. After sucking on

223

the thus obtained solid, it was dried in vacuo at 40 ° ^C Yield: 17.49 g (97.5%). Elemental analysis: from theor.) colorless amorphous solid M, C32.73 Est: NZ, 08 N4.58 S, 3.49 F 35.20 _π 032,68 Paul: H3.15 N4.55 S, 3.50 F 35.17

e) 3-N- (1-α-O-carbonylmethyl) -glutaric acid [1- (4-perfluorooctylsulfonyl) -piperazine] -amide-5-N- {2-hydroxy-prop-

3-yl- [1,4,7-tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10-yl]} - 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 at 40 ° C in 100 ml of absolute dimethyl sulfoxide with continuous stirring and mixed at the same temperature. with a total of 1.82 g (15.84 mmol) of N-hydroxysuccinimide and one solution of 9.08 g (15.84 mmol) of gadolinium complex of 10- (2-hydroxy-3aminopropyl) -4,7,10-tris ( carboxymethyl) -1,4,7,10tetraazacycododecane [for preparation see: WO 97/02051], in 50 ml dimethylsulfoxide. After cooling to room temperature, the reaction solution was mixed with 3.27 g (15.84 mmol) of дици'cyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was treated with sufficient acetone until complete precipitation of the above

224 title compound, the precipitate is sucked off, dried, absorbed in water, the insoluble dicyclohexylurea is filtered and the filter is passed for desalting through the AM ICON ® YM-3 ultrafiltration membrane (cut off 3000 Da) and at the same time as far as possible purified from low molecular weight constituents. The resulting product was then freeze-dried.

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):

Calc'd: 034.24 H3.83 N7.61 F21.92 S2.18 Gd 10.67 _n 034.26 Gender: H3.79 N7.53 F21.87 S2.18 Gd 10.68 An example 44

a) 1,7-bis (benzyloxycarbonyl) -4- {3-oxa-pentane-1,5-dicarboxylic acid 1-yl-5- [1- (4-perfluoroctylsulfonyl) piperazine] -amide} -10- [2, 6-M, M'-bis (1-O-a-D-carbonylmethyl-

2,3,4,6-Tetra-O-benzyl mannopyranose)] - 1_-lysine-1,4,7,10tetraazacyclododecane

In a solution of 27.0 g (24.4 mmol) of the obtained in example 35a sec. Amine, in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, 33.04 g (25.0 mmol) of the title compound of Example 18c, dissolved in 250 ml of tetrahydrofuran, were added at 0 ° C and under nitrogen atmosphere. A total of 18.0 g (36.6 g) was then added portionwise at 0 ° C

225 mmol) EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] and allowed to stand overnight at room temperature. It was concentrated in vacuo to dryness and the remaining oil was chromatographed on silica gel (eluent: n-hexane / isopropanol 25: 1). 45.87 g (78.0% of theory, relative to the sec-amine used) of the title compound are obtained as a colorless oil.

Elemental analysis:

_Est . C 59.30 H5.39 F 13.40 N4.65 S1.33 _Pol . C 59.32 H5.37 F 13.37 N4.70 S1.34

b) 1- {3-Oxa-pentane-1,5-dicarboxylic acid 1-yl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -7- [2,6-M, N'-bis (1-O-a0-carbonylmethyl-mannopyranose)] -1-lysine -1,4,7,10-tetraazacyclododecane

Dissolve 24.1 g (10.0 mmol) of the title compound obtained in Example 44a in 250 ml of ethanol and add 1.4 g of pearl catalyst (Pd 20%, C). It is hydrogenated to quantitatively absorb hydrogen, aspirated from the catalyst, washed with ethanol and concentrated to dryness in vacuo. The final product is obtained as a yellowish colored and visibly viscous external oil.

Yield: 12.80 g (90.1% of theory).

Elemental analysis: ..: C 39.72 Est: H4.89 F, 22.73 N7.88 S2.26 _n C 39.72 Sex: H4.87 F, 22.77 N7.90 S2.24

226

c) 1- {3-Oxa-pentane-1,5-dicarboxylic acid-1-yl- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -7- [2,6-M, N'-bis (1 -O-α-D-carbonyl methyl-mannopyranose)] -1-lysyl-4,10-bis [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5- yl-pentanoyl)] 1,4,7,10-tetraazacyclododecane, digadolinium complex

5.54 g (8.8 mmol, 2.2 molar equivalents relative to the amino component of Example 44b used) of the gadolinium complex of 10- (4-carboxy-1-methyl-2- described in patent application DE 197 28 954 Cl of Example 31 h oxo-3-azabutyl) -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid and anhydrous lithium chloride (0.37 g, 8.8 mmol) were dissolved at 40 ° C in 60 ml of absolute dimethyl sulfoxide with continuous stirring and at the same temperature, a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 5.68 g (4.0 mmol) of the title compound of Example 44b were dissolved in absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution was mixed with 1.82 g (8.8 mmol) of дици'cyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension is then treated with sufficient acetone to completely precipitate the title compound above, the precipitate is sucked off, dried, absorbed in water, the insoluble dicyclohexylurea is filtered and the filtrate is passed through an AMICON ® ΥΜ-3-ulmbrate. (cut off 3000 Da) for desalination and purified from low molecular weight

227 constituent components. The resulting product was finally freeze-dried.

Yield: 8.52 g (80.6% of theory of diamino compound used) as a colorless lyophilisate.

Water content (Karl-Fischer): 6.09%. Elemental analysis (calculated on the anhydrous basis) 7

Calc'd ^038.61 H 4.76 N9.53 F 12.21 Gd11.89 S 1.12

Gender ^{0 38.57} Η 4.82 N9.52 F 12.21 Gd11.93 S 1.15

Example 45

a) 1,7-bis (benzyloxycarbonyl) -4- {3-oxa-pentane-1,5dicarboxylic acid 1-yl-5- [1- (4-perfluoroctylsulfonyl) piperazine] -amide} -10- {2, 6-M, N-bis (1-N-α-O- (5-carbonyl) -pentyl-

2,3,4,6-Tetra-O-benzyl mannopyranose)} - 1_-1,4,7,10tetraazacyclododecane

In a solution of 27.0 r (24.4 mmol) from the example 35a obtained. Amine, in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, 35.80 g (25.0 mmol) of the title compound of Example 37e, dissolved in 250 ml of tetrahydrofuran, were added at 0 ° C and under nitrogen atmosphere. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] was then added portionwise and stirred at room temperature overnight. Finally, it was concentrated to dryness in vacuo and the resulting oil was chromatographed on silica gel (eluent: n-hexane / isopropanol

228

20: 1). 49.48 g (8.1% of theory, relative to the sec-amine used) of the title compound are obtained as a colorless oil.

Elemental analysis:

Calc'd. ^060.47 H5.79 F 12.80 N4.44 S 1.27

Gender: ^{060.52 H5.77} F 12.77 N4.50 S1.30

b) 1- {3-Oxa-pentyl-1,5-dicarboxylic acid-1-yl-5- [1 (4-perfluorooctylsulfonyl) -piperazine] -amide} -7- [2,6-M, N'-bis ( 1-O-aO- (5-carbonyl) -pentyl-mannopyranose)] -1-lysine-1,4,7,10tetraazacyclododecane

25.2 g (10.0 mmol) of the preparation of Example 45a was dissolved in 250 ml of ethanol and mixed with 1.8 g of pearl catalyst (Pd 20%, C). It is hydrogenated to quantitatively absorb hydrogen, aspirated from the catalyst, washed well with ethanol and concentrated to dryness in vacuo. The product is obtained as a yellowish colored and highlighted viscous oil.

Yield: 14.11 g (92.5% of theory)

Elemental analysis:

Calcd: C 49.60 H7.20 F21.17 N7.34 S2.10 _Paul . C, 49.62; H.17.17; F21.20; N7.30; S2.14

c) 1- {3-Oxa-pentane-1,5-dicarboxylic acid 1-yl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -7- [2,6-N, N'-bis (1-O-a0- (5-carbonyl) -pentyl-mannopyranose)] -1-lysyl-4,10-bis [1,4,7-

229 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 relative to the amino component of Example 45b used) of the gadolinium complex of 10- (4carboxy-1-methyl-2-oxo- as described in patent application DE 197 28 954 C1 in Example 31 h) 3-Azabutyl) -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid and anhydrous lithium chloride (0.37 g, 8.8 mmol) were dissolved at 40 ° C in 60 ml of absolute dimethyl sulfoxide with continuous stirring. and at this temperature was mixed a total of 1.01 g (8.8 mmol) of Nhydroxysuccinimide and 6.10 g (4.0 mmol) of the title compound of Example 45b dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution was mixed with 1.82 g (8.8 mmol) of дици'cyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was finally treated with sufficient acetone to completely precipitate the title compound above, the precipitate was sucked off, dried, absorbed in water, the insoluble dicyclohexylurea was filtered and the filtrate was allowed to desalinate through AMICON-4mbr (cut off 3000 Da) and purified from the low molecular weight constituents. The resulting product was finally freeze-dried.

230

Yield: 9.26 g (84.0% of theory; relative to the diamino component used) as a colorless lyophilisate.

Water content (Karl-Fischer): 5.89%. Elemental analysis (calculated on the anhydrous substance): _Calc . C40.52 H5.16 N9.15 F11.72 Gd11.41 S 1.16

Gender: ^{C40 '57 H5 <2} ° ^N9 » ^{12 F11} ' ⁶⁹ ed11,43 S 1.18

Example 46

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

19.02 g (50.0 mmol) of α-N- (benzyloxycarbonyl) -e-N '- (tert-butyloxycarbonyl) -1.-lysine (commercial product of Bachem) were dissolved in 150 ml of absolute tetrahydrofuran. 8.31 g (50.0 mmol) of carbonyldiimidazole and 5.03 g (50.0 mmol) of triethylamine dissolved in 75 ml of dry tetrahydrofuran are added dropwise at 0 ° C and left for 10 minutes at this temperature. temperature and continuous stirring. Finally, a solution of 48.42 g (50q0 mmol) of perfluoroctylsulfonylpiperazine and 5.03 g (50.0 mmol) of triethylamine in 250 ml of dry tetrahydrofuran was added dropwise at 0 ° C. After stirring overnight, the tetrahydrofuran was removed in vacuo and the rest the oil was chromatographed on silica gel (eluent: n-hexane / isopropanol 15: 1). 49.48 g (80.4% of theory, relative to the sec-amine used) of the title compound as a colorless oil are obtained.

231

Elemental analysis (calculated on the anhydrous substance):

C, 40.01 H3.79 N6.02 F 34.70 S3.45 C, 40.07 H, 3.82 N6.02 F 34.67 S3.48 B) 6-M4-butyloxycarbonyl- L-lysine

perfluoroctylsulfonyl) -piperazine] -amide

30.0 g (32.2 gpto1) of the title compound of Example 46a was dissolved in 300 ml of isopropanol and mixed with 1.5 g of pearl catalyst (20% palladium hydroxide on carbon). It was hydrated for 10 hours at room temperature and the reaction was monitored by thin-layer chromatography to determine that the hydrogenolytic cleavage of the benzyloxycarbonyl protecting group was quantitative after the expiry of the above reaction time. It was filtered off from the catalyst and the filtrate was concentrated to dryness in vacuo. The resulting residue was chromatographed on silica gel.

(eluent: n-hexane / isopropanol 2571). 25.13 g (98.0% of theory) of the title compound are obtained as a colorless oil.

Elemental analysis:

_Est; C 34.68 H3.67 F 40.55 N7.03 S4.03

Sex: C34> 72 H3.70 F40.60 N7.01 S3.98

232

c) 6-1 N-Butyloxycarbonyl-2-N- [1-8-a-O- (2-carbonyl) -ethyl-

2,3,4,6-Tetra-O-acetyl-manopyranose] -L-lysine [1- (4-perfluoroalkylsulfonyl) -piperazine] -amide

Dissolve 15.53 g (35.60 mmol) of 3- (2,3,4,6-tetra-O-acetyl-1-thio-a-O-manopyranosyl) propionic acid in 300 ml of dry tetrahydrofuran (prepared according to: J. Haensler et al., Bioconjugate Chem., 4.85, (1993); Chipowsky, S., dmd Lee,

Y.C. (1973), Synthesis of 1-thio-aldosidess; Carbohydrate Research 31, 339-346) as well as 3.60 g (35.60 mmol) of triethylamine. After cooling the reaction solution to -15 ° C to -20 ° C at the same temperature, a solution of 4.92 g (35.60 mmol) isobutyl ester of hydrochloric acid in 75 ml of dry tetrahydrofuran is added slowly with continuous stirring. the dripping rate is chosen so that an internal temperature of -10 ° C does not pass. After a reaction time of 15 minutes at -15 ° C, one solution was slowly added dropwise.

28.35 g (35.60 mmol) of the title compound of Example 42b and

3.60 g (35.60 mmol) of triethylamine in 200 ml of dry tetrahydrofuran at 20 ° C. After one hour of reaction at -15 ° C and two hours at room temperature, the reaction solution is concentrated. to dry in a vacuum. The resulting residue was taken up in 250 ml of acetic acid ethyl ester and washed twice with 100 ml of saturated sodium bicarbonate solution and once with 200 ml of water. After the organic phase is dried over

233 Sodium sulphate salt is sucked off and the acetic acid ethyl ester is removed in vacuo. The resulting oily residue was purified on silica gel using acetic acid / n-hexane ethyl ester (1:25) as eluent.

Yield: 34.21 g (79.1% of theory) of the title compound as a colorless and highly viscous oil.

Elemental analysis:

^{H 039.54 H4> 23} N4.61 F 26.58 S 5.28

Gender: ^{039.49 H4 '21} N4.59 F 26.52 S5.31

d) e-N-t-butyloxycarbonyl-2-N- [1-5-a-O- (2-carbonyl) -ethylmanipyranose] -1_-lysine- [1- (4-perfluoroctylsulfonyl) piperazine] -amide

29.93 g (24.64 mmol) of the title compound of Example 46c were suspended in 400 ml of absolute methanol at 5 ° C in the presence of a catalytic amount of sodium methanolite. After one reaction time of 3 hours at room temperature, the control made by thin layer chromatography (eluent: chloroform / methanol = 9: 1) for the reaction indicates a complete quantitative reaction. For the purpose of working up, the clear reaction solution was passed for neutralization through Amberlite® IR 120 (H ⁺ - form) cation exchange resin, aspirated from the ion exchanger, and the resulting methanol filtrate was extracted to dryness in vacuo. The resulting amorphous residue was purified

234 by chromatography on silica gel using 2-propanol / ethyl acetic acid / n-hexane (1: 1: 15) as eluent.

Yield: 23.42 g (90.8% of theory) of a colorless viscous oil. Elemental analysis:

Est; C36.72 H4.14 N5.35 F 30.85 S6.13

Gender: θ ³⁶ » ⁶⁹ H4D1 N5,35 F 30,82 S6.11

e) 2-N- [1-5-a-O- (2-carbonyl) -ethyl-mannopyranose] -1_-lysine- [1 (4-perfluorooctylsulfonyl) -piperazine] -amide

20.93 g (20.0 mmol) of the title compound of Example 46d were dissolved in a mixture of 50 ml of trifluoroacetic acid and 100 ml of dichloromethane at 0 ° C with vigorous stirring and stirred at this temperature for 10 minutes. It was then evaporated to dryness in vacuo and the residue was absorbed in 150 ml of water. The pH of the resulting aqueous solution containing the product was adjusted to 9.5 by the addition of 2 molar sodium hydroxide solution dropwise. The aqueous solution containing the product was passed for desalination through an AMICON ® YM-3 ultrafiltration membrane (cut off 3000 Da) and at the same time purified from the available low molecular weight constituents as far as possible. The resulting product was finally freeze-dried.

Yield: 17.79 g (94.2% of theory) of the free amide as a colorless lyophilisate.

Elemental analysis (calculated on anhydrous substance):

235

Calc'd: ^{034.26 H3 '73 N5.92 F34} ' ¹² S6.77

Paul. ^C34 « ²⁶ Η 3.79 N5.88 F 34.07 S6.80

f) 2-N- [1-8-a-0- (2-carbonyl) -ethyl-mannopyranose] -6-1 \ 1- [1,4,7,7-tris (carboxylatomethyl) -10- (3-aza-4 -oxo-5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -1_-lysine- [1- (4perfluoroctylsulfonyl) -piperazine] -amide, gadolinium complex

5.54 g (8.8 mmol, 2.2 molar equivalents relative to the amino component of Example 46f used) of the gadolinium complex of 10- (4-carboxy-1-methyl- described in patent application DE 197 28 954 Cl in Example 31 h) 2-Oxo-3-azabutyl) -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid and 0.37 g of anhydrous lithium chloride (8.8 mmol) were dissolved under continuous stirring at 40 ° C in 60 ml of absolute dimethyl sulfoxide are mixed at the same temperature with a total of 1 -1 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 dimethyl sulfoxide. After cooling to room temperature, the reaction solution was mixed with 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension is then mixed with sufficient acetone to completely precipitate the above title compound, the precipitate is sucked off, absorbed in water, filtered from insoluble dicyclohexylurea and the filtrate is desalted by passing through an AMICON ® YM-3 ultrafilter

236

3000 Da) and is purified from the low molecular weight constituents. The resulting product was finally freeze-dried. Yield: 5.17 g (83.0% of theory) as a colorless lyophilisate.

Water content (K1g-p15spec): 4.43%.

Elemental analysis (calculated on the anhydrous substance):

Calc'd: ^35.48 H4.07 N8.09 1 = 20.72 Gd 10.09 S4.11 Gender: * C. H, 4.01 N8.12 F20.6 Acts 10:13 S4.14 An example 47

a) 6-N-benzyloxycarbonyl -2-N- (1-0-β-D-carbonylmethyl-

2,3,4,6-Tetra-O-benzylglucopyranose) -1_-lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

8.2 g (13.4 mmol) of the title compound [1carboxymethyloxy-2,3,4,6-tetra-O-benzyl-O-glucopyranoside] described in patent application DE 197 28 954 Cl in Example 46a and 3, 24 g (28.14 mmol) of N-hydroxysuccinimide were dissolved in 100 ml of dimethylformamide and mixed at a temperature of 0 ° C in portions with a total of 5.80 g (28.14 mmol) of N, N -dicyclohexylcarbodiimide. Stirred for 3 hours at this temperature. A solution of 11.13 g (13.4 mmol) of the title compound of Example 21 c, dissolved in 50 ml of dimethylformamide, was added dropwise to the solution of active esters thus obtained, stirring for 2 hours. hours at 0 ° C and then another 12 hours at room temperature. In order to finish the precipitated

237 Dicyclohexylurea was filtered and the solvent was removed to dryness in vacuo. The residue thus obtained is chromatographed on silica gel (eluent: dichloromethane / ethanol: 20: 1; chromatography is carried out using soluble gradients with a continuously increasing portion of ethanol).

Yield: 12.67 g (67.0% of theory) of the title compound as a colorless strong viscous oil.

Elemental analysis:

_Calc .: C 52.77 H4.50 N3.97 F 22.89 S2.27 _P o-- ^{C 52.75 144161 N3 '98} F 22.94 S2 ^ 6

b) 2-N- (1-N-β-O-carbonylmethyl-glucopyranose) -1_-lysine [1 (4-perfluoroctylsulfonyl) -piperazine] -amide

11.52 g (8.17 mmol) of the compound obtained according to Example 47a was dissolved in 100 ml of ethanol, mixed with 0.5 g of pearl catalyst (Pd 20%, C) and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) as long as necessary until hydrogen absorption ceases to be observed. It is sucked off from the catalyst, washed mainly with ethanol (three times with about 40 ml each) and concentrated to dryness in vacuo. The title compound is obtained as a highly viscous and colorless oil.

Yield: 7.36 g (98.4% of theory).

Elemental analysis:

_{Calcd .} : 034.07 H3.63 N8.11 F 35.24 S3.50

238 _Gender: .'C34.11 n3.59 N6.08 F 35.23 53.52

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

9.98 g (15.84 mmol; 2.2 molar equivalents of the amino component used in Example 47b) of the gadolinium complex of 10- (4-carboxy-1-methyl- as described in patent application DE 197 28 954 C1 in Example 31 h) 2-Oxo-3-azabutyl) -1,4,7,10tetraazacycododecane-1,4,7-trioacetic acid and 0.67 g (15.84 mt) anhydrous lithium chloride were dissolved at 40 ° C in 80 ml absolute. Dimethyl sulfoxide was stirred at the same temperature with a total of 1.82 g (15.84 mmol) of N-hydroxysuccinimide and 7.25 g (7.19 mmol) of the title compound of Example 47b dissolved in 30 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution was mixed with 3.27 g (15.84 mmol) of дици'cyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was mixed with sufficient acetone until complete precipitation of the above title compound, the precipitate was filtered, absorbed in water, filtered from insoluble dicyclohexylurea and the filtrate was allowed to desalinate through AMICON ® YM-3 ultrafilter cut 3000 membrane (Da) and is purified by

239 low molecular weight constituents. The resulting product was freeze-dried.

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

Water content (Karl-Fischer): 4.02%.

Elemental analysis (calculated on the anhydrous substance):

C 35.37 H 4.02 N8.25 F 21.13 S2.10 Gd 10.29 _Sex : C35.42 H4.07 N8.18 F21.09 S2.06 Gd 10.34

Example 48

a) 2-N-Trifluoroacetyl

-1_-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

10.0 g (11.46 mmol) of the compound of Example 21b were dissolved in 100 ml of ethanol, mixed with 1.0 g of pearl catalyst (Pd 20% / C) and hydrogenated to quantitatively absorb hydrogen. It is sucked off from the catalyst, washed with ethanol and concentrated to dryness in vacuo. The title compound is obtained as a viscous colorless oil. Yield: 8.85 g (97.5% of theory).

Elemental analysis:

_Est . with 30.31 H2.54 N7.07 F 47.95 S4.05 _Paul . C 30.36 H2,50 N7.11 F 47.99 S4.00

B) 2-N-Trifluoroacetyl-6-N- [1-O-α-O- (5-carbonyl) -pentyl-

2,3,4,6-Tetra-O-benzyl-mannopyranose] -1_-lysine- [1- (4-perfluoro-alkylsulfonyl) -piperazine] -amide

240

A solution of 27.51 was added dropwise to a solution of 29.0 g (36.6 mmol) of the title compound of Example 48a cooled to 0 ° C and 4.05 g (40.26 mmol) of triethylamine in 100 ml of dimethylformamide. g (36.6 mmol) of the title compound of Example 37c in 150 ml of dimethylformamide. After completion of the addition, it was stirred for an additional hour at 0 ° C and then allowed to stand at room temperature overnight. It was evaporated to dryness in vacuo and the residue was taken up in 300 ml of acetic acid ethyl ester. It is filtered off from the insoluble constituents and the filtrate is washed twice with 100 ml of a 5% aqueous solution of soda each time. The organic phase was dried over magnesium sulfate to dryness. The residue was chromatographed on silica gel (eluent: n-hexane / isopropanol 25: 1). 42.05 g (80.4% of theory) of the title compound are obtained as a colorless oil.

Elemental analysis:

Calc .: ^{C50 '42 H4} · ⁵¹ N7.96 F 26.59 S2.24 Gender: ^{050.38 H4.5} ° ^N7 ' ^{91 F26 '62} S2.20

c) 6-N- [1-0-a-0- (5-carbonyl) -pentyl-2,3,4,6-tetra-0-benzylmani-pyranose] -1_-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] - amide

Dissolve 20.0 g (14.0 mmol) of the compound of Example 48b in 150 ml of ethanol. A solution of 2.8 g (70.0 mmol) of sodium hydrochloride in 25 ml of distilled water was then added and stirred for 0.5 h at 50 ° C.

241

C. Thin layer chromatography shows the complete quantitative cleavage of the protecting groups at this point. Concentrates to dryness in vacuo and repeatedly

coding with ethanol remove follow of water. The rest is chromatograph on silica gel (eluent: p-hexyl / isopropanol 20: 1). They receive se 16.66 g (89.3%) by theor.) by the title compound In the form on colorless butter. Elemental analysis: Est: ⁰⁵² · ²⁵ H4.91 N4.20 F 24.22 S2.41 Gender: ^C52 · ³⁰ H, 4.90 N4.18 F 24.22 S2.38

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

In a 10: 1 mixture of ethanol and water, 15.0 g (11.25 mmol) of the compound obtained in Example 48c were dissolved and mixed with 1.0 g of pearl catalyst (Pd 20% / C). It is then hydrogenated at room temperature and in a hydrogen atmosphere with a hydrogen pressure, one atmosphere to quantitatively absorb hydrogen. It was aspirated from the catalyst, washed with ethanol / water (10: 1) and concentrated to dryness in vacuo. The title compound is obtained as a viscous and colorless oil.

Yield: 10.77 g (98.4% of theory).

Elemental analysis:

Calc'd: ^{C 37.04 H4.25} N5.76 F 33.20 S3.30

242

Gender: ^{0 37.06} Η 4.20 N5.81 F 33.19 S3.30

e) 6-N- [1-O-a-O- (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] -1_-lysine [1- (4perfluoroctylsulfonyl) -piperazine] -amide, Gd-complex

5.54 g (8.8 mmol, 2.2 molar equivalents relative to the used amino component of Example 48d) of the gadolinium complex of 10- (4carboxy-1-methyl-2- described in patent application DE 197 28 954 C1 in Example 31 h oxo-3-azabutyl) -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid and 0.37 g (8.8 mmol) of anhydrous lithium chloride were dissolved at 40 ° C and stirred continuously in 60 ml. absolute dimethyl sulfoxide and at the same temperature were mixed with a total of 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 dimethyl sulfoxide. After cooling to room temperature, the reaction solution was mixed with 1.82 g (8.8 mmol) of N, N-dicyclohexylcarbodiimide and stirred at room temperature for 1 hour. The resulting suspension was mixed with sufficient acetone until complete precipitation of the above title compound, the precipitate was filtered, absorbed in water, filtered from insoluble dicyclohexylurea, and the filtrate was allowed to desalinate through AMICON ® YM-3 (cut off: 3000 Da) and is purified by

243 low molecular weight constituents. The resulting product was finally freeze-dried.

Yield: 4.81 g (75.9% of theory) as a colorless lyophilisate.

Water content (Karl-Fischer): 8.98%.

Elemental analysis (calculated on anhydrous substance):

,. C, 37.15 Est: H4.39 N7.96 F 20.38 Gd 9.92 S2.02 _m from 37.27 Gender: H, 4.40 N8.02 F 20.31 Gd 10.00 S1.98 An example 49

a) 1,7-bis (benzyloxycarbonyl) -4- (1-0-p-0-carbonylmethyl-

2,3,4,6-Tetra-O-benzyl-galacturonic acid) -10- {3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5- [1- (4perfluoroctylsulfonyl) -piperazine] - amide} -1,4,7,10tetraazacyclododecane

In a solution of 27.0 g (24.4 mmol) of the resulting 35a sec. Amine, in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, was added at 0 ° C and under nitrogen atmosphere 35.80 g (25.0 mt) of the title compound of Example 37e dissolved in 250 ml of tetrahydrofuran. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] was then added portionwise at 0 ° C and allowed to stand overnight at room temperature at continuous stirring. It was then concentrated to dryness in vacuo and the remaining oil was chromatographed on silica gel (eluent: n-hexane / isopropanol 20: 1). 32.11 g (78.0%) are obtained

244% of theory, compared to the sec. amine) from the title

compound as a colorless oil. Elemental analysis _Est . C, 54.09; H, 4.72 F 19.14 N4.98 S1.90 Gender: ^C54 &lt; ¹² & gt ^; H4.77 F 19.17 N5.03 S1.90

b) 1- (1-O-p-O-carbonylmethyl-galactopyranose) -7- {3-oxapentane-1,5-dicarboxylic acid 1-oyl-5- [1- (4-perfluoroctylsulfonyl) -piperazine] - amide} -1,4,7,10tetraazcyclododecane

30.0 g (17.77 mmol) of the title compound obtained in Example 49a were dissolved in 250 ml of ethanol and mixed with 3.0 g of pearl catalyst (Pd 20%, C). Hydrogenated to quantitative absorption of hydrogen, aspirated from the catalyst, washed well with ethanol and concentrated in vacuo. The product is obtained as a yellowish-colored viscous oil.

Yield: 17.89 g (95.1% of theory).

Elemental analysis: Est: C ³⁶ · ³⁰ H4.09 F 30.50 N7.94 S3.03 Gender: ^C36 · ²⁶ H, 4.12 F, 30.46 N7.90 S3.04

c) 1- (1-O-p-O-carbonylmethyl-galactopyranose) -7- {3-oxapentan-1,5-dicarboxylic acid-1-yl-5- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide} -4,10-bis [1,4,7-tris

245 (Carbonyloxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazicyclododecane] -1,4,7,10tetraazacycododecane, gabodinium complex

5.54 g (8.8 mmol; 4.4 molar equivalents relative to the amino component of Example 49b used) of the gadolinium complex of 10- (4-carboxy-1-methyl- described in patent application DE 197 28 954 Cl in Example 31 h) 2-Oxo-3-azabutyl) -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid and 0.37 g (8.8 mmol) of anhydrous lithium chloride were dissolved at 40 ° C with continuous stirring in 60 ml of absolute dimethyl sulfoxide were mixed at the same temperature with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 2.11 g (2.0 mmol) of the title compound of Example 49b dissolved in 25 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution was mixed with 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was mixed with sufficient acetone until complete precipitation of the title compound above, the precipitate was sucked off, dried, absorbed in water, filtered from insoluble dicyclohexylurea and the desalination filtrate was passed through AMICON ® YM-3 ultrafil off: 3000 Da) and purified from the low molecular weight constituents. The resulting product was finally freeze-dried.

246

Yield: 3.29 g (72.2% of theory; relative to the amino component used) as a colorless lyophilisate.

Water content (Karl-Fischer): 5.99%. Elemental analysis (calculated on the anhydrous basis): Calcd · ^{036.84 H4.37 N9} ′ ⁸² F 14.15 Gd 19.63 S 1.40

POL ' ^{036.87 H4.4} ° ^{N9.82 F} 14.09 Gd19.59 S 1.38

Example 50

a) 3- (1-N-α-0-2,3,4,6-tetra-0-benzyl-manopyranose) -2-Mbenzyloxycarbonyl-L-serine methyl ester

21.42 g (39.61 mmol) of 2,3,4,6-tetra-0-benzyl-α-0-mannopyranose were dissolved in 500 ml of dry acetonitrile (prepared according to: F. Kong et al., J. Carbohydr Chem .; 16; 6; 1997; 877-890). After cooling the reaction solution 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 at this temperature, and then a solution of 20 was added dropwise. , 06 g (79.21 mmol) of N-benzyloxycarbonyl-Lserinmethyl ester (Bachem's commercial product) in 50 ml of acetonitrile, the drop rate being chosen so as not to exceed an internal temperature of 10 ° C. one reaction time of 15 minutes at room temperature The ionic solution was concentrated to dryness in vacuo. The resulting residue was taken up in 250 ml of ethyl ester

247 acetic acid and washed twice with 100 ml of saturated sodium bicarbonate solution and once with 200 ml of water. After drying the organic phase over sodium sulfate, it is sucked off from the salt and the ethyl acetate is removed in vacuo. The oily residue obtained was purified on silica gel 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.

Elemental analysis:

Calc: 71.21

H, 6.37

N1,81

Gender: ^C71 · ¹⁹

H, 6.41

N1.79

B) 3- (1-0-a0-2,3,4,6-tetra-0-benzyl-manopyranose) -2-benzyloxycarbonyl-L-serine

In one mixture of 20 ml of methanol, 20 ml of water and 50 ml of tetrahydrofuran dissolve 10.0 g (12.90 mmol) of the compound of Example 50a. 0.47 g (19.35 mmol) of lithium chloride dissolved in 25 ml of distilled water are added at room temperature and finally stirred for 6 hours at 60 ° C. After checking the reaction process by means of thin layer chromatography (eluent: CH2 Cl2 / MeOH 10: 1) found that the saponification for the methyl ester of Example 30a was completely quantitative. For the sake of refinement, the solution containing the product was concentrated in vacuo to dryness and the residue obtained was concentrated.

248 is absorbed warmly (about 60 ° C) in 250 ml of acetic acid ethyl ester. Finally, the ethyl ester phase of the acetic acid thus obtained is washed twice with 50 ml of a 15% aqueous hydrochloric acid solution each time, and once with 100 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: n-hexane / ethyl acetate 5: 1). 8.40 g (85.7% of theory) of the title compound are obtained as a colorless oil.

Elemental analysis:

_Est . C 70.94 H 6.22 N1.84 _Sex: C70.97 H6.30 N1.78

c) 3- (1-O-a-D -2,3,4,6-tetra-O-benzyl-manopyranose-2-N-benzyloxycarbonyl-1-serine [1- (4-perfluoroctylsulfonyl) 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 were added dropwise at 0 ° C and under a nitrogen atmosphere of 20.57 g (27 , 0 mmol) obtained according to Example 50b carboxylic acid dissolved in 50 ml of tetrahydrofuran. A total of 18.0 g (36.60 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] was then added portionwise at 0 ° C, allowing to stand at room temperature overnight and stirring. With purpose

Concentration solution was concentrated in vacuo and the remaining viscous oil was chromatographed on silica gel using n-hexane / isopropanol (15 &lt; 1 &gt;) - mixture as eluent. 17.0 g (79.6% of the theory .p relative to the secondary amine used) are obtained

the title compound as colorless viscous oil. Elemental analysis: _Est . C51.53 H4.23 N3.15 F, 25.65 S, 2.41 Gender: ^{by 51.48 H4.27} N3,10 F 25.71 S, 2.35

d) 3- (1-0-a-0-mannopyranose) -1_-serine- [1 (perfluoroctylsulfonyl) piperazine] -amide

Dissolve 15.0 g (11.41 mmol) of the compound of Example 50c in 200 ml of ethanol and mix with

1.5 g of pearl catalyst (Pd 20%, C). The reaction solution was then hydrogenated at room temperature in a hydrogen atmosphere (1 atm) for as long as hydrogen absorption ceased to be observed (about 8 hours). For further processing, the catalyst was sucked off, washed mainly with ethanol (twice with 100 ml each) and the resulting ethanoline filtrate containing the product was concentrated in vacuo to dryness. The title compound is obtained as a highly viscous and colorless oil.

Yield: 8.79 g (94.0% of theory).

Elemental analysis:

250

F, 39.41 _; C 30.78 H3 ^ O N5.13

Gender ^C30 '87 ^H3 ' ¹⁴ N5,19 F 39,50

S, 3.91

S, 3.88

e) 3- (1-O-aD-MaH0nnpaO03a) -2-N- [1,4,7 tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl-pentyl) 1,4,7,10-Tetraazacyclododecane] -1_-serine- [1- (4perfluoroctylsulfonyl) -piperazine] -amide, Gd-complex

A well stirred suspension of 5.7 g (9.06 mmol; 1.5 molar equivalents of the title compound (primary amine) of Example 50d, respectively) of the gadolinium complex described in patent application DE 197 28 954 C1 of Example 31 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid in 75 ml absolute dimethylsulfoxide was mixed at 70 ° C with 0 , 68 g (15.9 mmol) of lithium chloride. After stirring for 30 minutes at 70 ° C, the clear reaction solution was mixed in portions with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide and the reaction mixture remained for another hour at 70 ° C. 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide were added to the reaction solution at 10 ° C and the reaction solution was stirred for an additional 1 hour at 0 ° C and then for another 12 hours at a temperature of 22 ° C. The thus obtained Nhydroxysuccinimidester solution of gadolinium complex of 10- (4carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10tet aazatsiklododekan-1,4,7-triacetic acid, was added

251 portions at 22 ° C with one solution of 4.94 g (6.03 mmol) of the title compound of Example 30d, in 15 ml absolute dimethyl sulfoxide, and stirred for a further 12 hours at room temperature. For the sake of processing, the reaction solution was slowly added dropwise at 22 ° C to a solvent mixture consisting of 250 ml of acetone and 250 ml of 2-propanol, precipitating the title compound as a yellowish colored oil after 12 hours. Carefully decant the above eluent mixture and absorb the oily product in 200 ml of distilled water, which process is complete, completely, to give a slightly yellowish-colored aqueous solution of the above title compound. Finally, the aqueous solution containing the product is first filtered through a membrane filter to desalinate and separate the low molecular weight constituents, and then ultrafiltered three times through a YM3 ultrafilter membrane (AMICON ®; cut off: 3000 Da). The product thus obtained is finally freeze-dried.

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

Elemental analysis (calculated on the anhydrous substance): _Calc . S33,57 NT 80 N7,83 F22,57 Gd10,99 S 2,24 _Paul. C33.57 Η 3.76 N7.82 F 22.63 Gd 11.06 S 2.18

Example 51

252

a) 6-1H-benzyloxycarbonyl -2-N- [0-β-D-galactopyranosyl (1-> 4) -gluconosyl] -1-lysine- [1- (4-perfluoroctylsulfonyl) piperazine] -amide

Stirring to a solution of 4.98 g (6.0 mmol) of the title compound of Example 21 with 40 ml of absolute dimethyl sulfoxide and room temperature was added dropwise one solution of 13.3 g (37.2 mmol) of O- p-O-galactopyranosyl (1-> 4) -0-glucono-1,5-lactone [lactobionolactone according to:

(a) Williams, T. J.; Plessas, N. R., Goldstein, I.J. Carbohydr. Really. 1978, 67, Cl. (b) Kobayashi, K.; Sumitomo, H., Ina, Y. Polim. J. 1985, 17, 567, (c) Hiromi Kitano, Katsuko Sohda, and Ayako Kosaka, Bioconjugate Chem. 1995, 5 131-134] in 40 ml of absolute dimethyl sulfoxide. The resulting reaction solution was then stirred for 14 hours at 40 ° C. For the purpose of processing at room temperature, 500 ml of absolute 2-propanol was added and the resulting colorless precipitate was sucked off on a G4-Fritte and washed thoroughly with a total of 250 ml. absolute 2-propanol. The solid thus obtained was dissolved in 300 ml of distilled water and passed through a YM3 ultrafiltration membrane (AMICON ®; cut off: 3000 Da) for triple ultrafiltration. Threefold ultrafiltration removes both excess lactobiolactone and possibly low molecular weight constituents. The residue deposited in the ultrafiltration membrane was finally dissolved in 300 ml of distilled water and freeze-dried.

253

Yield: 6.51 g (91.7% of theory) as a colorless lyophilisate.

Water content: 10.03%.

Elemental analysis (calculated on the anhydrous substance):

_Est; C 38.98 H4.05 N4.79 F 27.58 S 2.74 _Sex; C 39.04 H4.09 N4.82 F 27.61 S 2.71

b) 2-N- [O-β-O-galactopyranosyl (1-> 4)] -1-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

In 100 ml of ethanol was dissolved 5.0 g (4.27 mmol) of the compound of Example 51a, mixed with 0.5 g of pearl catalyst (Pd 20%, C) and hydrogenated to an amount of hydrogen absorption at a pressure of hydrogen from 1 atmosphere. It is sucked off from the catalyst, washed with ethanol and concentrated to dryness in vacuo. The title compound is obtained as a colorless and viscous oil.

Yield: 4.36 g (98.5% of theory).

Elemental analysis:

_Est; C 34.76 H3.99 N5.40 F 31.51 S 3.09 _Gender; C 34.78 H4.04 N5.34 F31.51 S 3.15

c) 2-N- [O-β-O-galactopyranosyl (1-> 4) -gluconosyl] -6-N [1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo- 5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -1_-lysine [1- (4-fluoro-quinoxyl-sulfonyl) -piperazine] -amide, Gd-complex

254

5.54 g (8.8 mmol; 2.2 molar equivalents relative to the amino component of Example 51b used) of the gadolinium complex of 10- (4-carboxy-1-methyl- described in patent application DE 197 28 954 C1 in Example 31 h) 2-Oxo-3-azabutyl) -1,4,7,10 tetraazacyclododecane-1,4,7-trioacetic acid and 0.37 g (8.8 mmol) of anhydrous lithium chloride were dissolved in 60 ml of absolute dimethyl sulfoxide at 40 And stirred vigorously at the same temperature

1.01 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 dimethyl sulfoxide. After cooling to room temperature, the reaction solution was mixed with 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The resulting suspension was mixed with sufficient acetone / 2-propanol (1: 1) until complete precipitation of the above title compound and suction precipitated. The resulting precipitate was absorbed in 300 ml of water and filtered with insoluble dicyclohexylurea. The filtrate was passed through an AMICON ® YM-3 ultrafilter membrane (cut off: 3000 Da) for triple ultrafiltration. By conducting a threefiltration of the desired product, both the excess Gd complex and the possible low molecular weight constituent components are removed. The residue obtained on the ultrafiltration membrane was finally dissolved completely in 500 ml of distilled water and freeze-dried.

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

255

Water content (Karl-Fischer): 10.08%.

Elemental analysis (calculation on anhydrous substance): _Calc . 035.70 H4.22 N7.65 F19.59 Gd9.54 S1.95

Gender: ^{035.77 H4.17 N7.71} F 19, β1 Gd9.60 S1.99

Example 52

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

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

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

H / C _: C51.07 H 5.09 F 15.14 N 7.44

Gender: ^C51 · ²⁵ N 5.18 F 15.03 N 7.58

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

To 125 g (332 mmol) of the title compound of Example 52a and 188.7 g (332 mmol) of 1-perfluoctophenylsulfonyl-piperazine (prepared according to DE 19603033) in 800 ml of tetrahydrofuran were added at 0 ° C 164.2 g. (0.664 mmol) EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carbonic ethyl ester

256 acid) and stirred at room temperature overnight. It was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 286 g (93% of theory) of a colorless solid.

Elemental analysis: Calc: θ 36.30 H, 2.83 F 41.01 N, 6.05 S, 3.46 Gender: ^{C, 36.13} H, 2.94 F, 40.87 N, 5.98 S, 3.40

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

In a solution of 280 g (302.2 mmol) of the title compound of Example 52b in 2000 ml of ethanol was passed an ammonia gas at 0 ° C for one hour. It was stirred for 4 hours at 0 ° C. It was evaporated to dryness and the residue was stirred with water. The solid was filtered off and dried in vacuo (50 ° C).

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

_Est . C 37.60 H 3.28 F 38.89 N6.75 S 3.86

Gender: ^{037 '15 n} 3.33 F38.78 N6.68 S 3.81

d) 6-N-benzyloxycarbonyl -2-N- (3,6,9,12,15-pentaoxachexadecanoyl) -L isine- [1- (4-perfluorooctylsulfonyl) piperazine] -amide

257

To a solution of 50 g (60.20 mmol) of the title compound of Example 52c and 7.10 g (70 mmol) of triethylamine dissolved in 350 ml of dichloromethane was added dropwise at 0 ° C a solution of 19.93 g (70 mmol) chloride of 3,6,9,12,15 pentaoxachexadecanoic acid (obtained according to Liebigs Ann. Chem. (1980), (6), 852-62) in 50 ml of dichloromethane and stirred for 3 hours at 0 ° C. 200 ml of 5% aqueous hydrochloric acid were added and 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: 53.7 g (93% of theory) colorless, viscous oil. Elemental analysis: _Est; 0 33.83 H 4.94 F3.34 N, 5.84; S, 33.69 _Paul; 033.75 H 5.05 F3.29 N 5.78 S 33.75

e) 2-N- (3,6,9,12,15-pentaoxachexadecanoyl) -lysin- [1- (4-perfluoroctylsulfonyl) -piperazine] -amine 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. Hydrated at room temperature. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo.

Yield: 43.0 g (quantitative) of a colorless solid.

258

Elemental analysis: Calc: C, 27.68 n 5.01 F, 39.17 N, 6.79 S3.89 Gender: ^{Cr7 '60} n 5.13 F 39.09 N, 6.68 S, 3.81

f) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10- (pentanol-3-aza-4-oxo-5-methyl-5-yl)] 2-N- (3,6,9,12,15-pentaoxachehexadecanoyl) -lysine - (1- (4-perfluoroctylsulfonyl) -piperazine] -amide, Ga - complex g (24,25 mmol) of the title compound of Example 52f, 2 , 79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1,4,7tris (carboxylatomethyl) -10 - [(3-aza) -4-Oxo-5-methyl-5-yl) pentanoic acid] -1,4,7,110-tetraazacyclododecane, gadolinium complex was dissolved under gentle heating in 200 ml of dimethyl sulfoxide. 8.25 g (10 ° C) was added at 10 ° C. 40 mmol) N, N-cyclohexyl of carbonbodiimide and standing overnight at room temperature and stirring, then the solution was poured into 3000 ml of acetone and stirred for 10 minutes.The precipitated solid was filtered and finally purified by chromatography (silica gel RP-18, eluent: gradients of water / ethanol / acetonitrile) Yield: 28.21 g (81% of theory) of a colorless solid.

Water content: 11.0%.

Elemental analysis (against inorganic substance):

_Est; C31.78 H 4.84 F 22.49 N8.78 S 2 ^ 3 Gd10.95

259 _Paul . 031.74 Η 4.98 F22.39 N8.69 S 2.15 Gd10.87

Example 53

a) 6-N- [3,9-6nc (1-butyloxycarbonylmethyl) -3,6,9-triazaoundecane-1,11-dicarboxylic acid bis (1-butyl ester) -6carbonylmethyl] -2-N- [3,6,9,12 , 15-pentoxohexadecanoyl) -Lysine [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

To a solution of 20 g (24q08 mmol) of the title compound of Example 52e, 14.88 g (24.08 mmol) of 3,9bis-butyloxycarbonylmethyl-3,6,9-triazaoundecane-1,11 dicarboxylic acid-bis-butyl ester) and 2.77 g (24.08 mmol) of Nhydroxysuccinimide dissolved in 150 ml of dimethylformamide were added at 0 ° C to 8.25 g (40 mmol) of Νcyclohexylcarbodiimide. It was stirred for 3 hours at 0 ° C and then allowed to stand at room temperature overnight. The precipitated urea was filtered off, the filtrate was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: = dichloromethane / ethanol 20: 1).

Yield: 31.61 g (91% otor.) Of gin oil.

Elemental analysis:

_Est . 0 40.80 N 6.71 F 22.39 N 6.80 S2.22

Gender: 0 40.72 H 6.82 F 22.30 N 6.75 S2.14

b) 6-N- [6-carbonylmethyl-3,9-bis (carboxylatomethyl) -3,6,9-triazaundecandicarboxylic acid-1-carboxy-11-carboxylato] -2-N- (3,6,9,12 , 15-pentaoxahexadecanoyl) -Lysin- [1- (4260 perfluoroctylsulfonyl) -piperazine] -amide, gadolinium complex, sodium salt d (20.8 mmol) of the title compound of Example 53a were dissolved in 300 ml of trifluoroacetic acid and dissolved in trifluoroacetic acid. continued for 5 hours at room temperature. It is evaporated to dryness, the residue is absorbed in 300 ml of water and the pH is adjusted to 2.5 with 10% aqueous sodium hydroxide solution. Then 3.77 g (10.4 mmol) of gadolinium chloride were added and stirred for 3 hours at 60 ° C. Cooled to room temperature and adjusted to pH 7.4 with sodium hydroxide. It was evaporated to dryness and the residue was purified on RP-18 silica gel. (Eluent: gradients of water / acetonitrile).

Yield: 19.18 g (67% of theory) of a colorless, amorphous solid.

Water content: 9.8%.

Elemental analysis (calculated on the anhydrous substance): _Calc . C28.80 H 4.25 F23.47 N7.12 S 2.33 Gd 11.48 Na 1.67 _Gender; C28.67 H 4.34 F 23.38 N7.03 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) added. . Hydrated at room temperature.

261

It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo. Yield: 16.77 g (quantitative) of a colorless solid.

Elemental analysis:

Calcd. ^{031.04 H3.04 F 46.38 N8lD4 S4.6} ° _Pol . C, 30.97; H3.15; F, 46.31; N7.98; S4.51

b) 2,6-N, N'-bis [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5 -yl)] lysine- [1- (4-perfluoroctylsulfonyl-piperazine)] - amide, gadolinium complex, (metal complex XVI)

South (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- (3aza-4-oxo- The 5-methyl-5yl) 1,4,7,1O-tetraazacyclododecane-Gd-complex was dissolved under gentle heating in 200 ml of dimethyl sulfoxide. At 10 ° C, 12.38 g (60 mmol) of Ν, Ν-dicyclohexylcarbodiimide were added and stirred at room temperature overnight. The solution was added to 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified on silica gel (silica gel RP-18, eluent: gradients of water / ethanol / acetonitrile). Yield: 19.02 g (69% of theory) of a colorless solid.

Water content: 11.3%.

262

Elemental analysis (calculated on anhydrous substance):

Calcd. Θ 65.03 H, 4.04 F, 16.82 N, 10.21 S 1.67 Gd 16.38 Gender: ⁰³⁴ · ⁹⁶ H, 4.13 F, 16.74 N, 10.16 S, 1.61 Gd 16.33 An example 55

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

To 200 g (1,204 mmol) of 4hydroxyphenylacetic acid methyl ester, 212 g (2 mol) of sodium carbonate in 2000 ml of acetone were added 233.8 g (1.4 mol) of 2-bromoacetic acid-ethyl ester and boiled over 5 hours counterclockwise. The solid was filtered off and evaporated in vacuo to dryness. The residue was chromatographed on silica gel (eluent: m-hexane / ethyl acetate = 15: 1). Yield: 288.5 g (95% of theory) of a colorless oil.

Elemental analysis:

Calc'd: C 61 »90 H 6.39

Gender: ^c 61.75 H 6.51

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

To 285 g (1.13 mol) of the title compound of Example 55a dissolved in 2000 ml of tetrachloromethane were added 201 g (1.13 mol) of N-bromosuccinimide and 100 mg of dibenzyl peroxide and boiled for 8 hours countercurrently. Cool in an ice bath, filter the precipitated succinimide and filter the filtrate.

263 evaporated to dryness in vacuo. The residue was purified on silica gel (eluent: n-hexane / acetone = 15: 1).

Yield: 359.2 g (96% of theory) of a colorless, viscous oil. Elemental analysis:

Calcd. Θ 47.28

Gender: ^{from 47} · ¹⁹

Η 4,57

Η 4.71

Br 24.16

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

To 603 g ml of chloroform (3.5 mol) 1,4,7,10-tetraazacyclododecane in 6000 were added 350 g (1,057 mol) of the title Example 55b and stirred overnight at room temperature. It is then extracted three times with 3000 ml of water, the organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was used in the next reaction (3d) without further purification.

Yield: 448 g (quantitative) of viscous oil.

Elemental analysis:

Calcd: ^059.70

H, 8.11

N, 13.26

Gender: ^059.58

H, 8.20

N, 13.18

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

264

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 was adjusted to 10. With 30% aqueous sodium hydroxide, the temperature was brought to 70 ° C and the pH of the medium was maintained at 10 at the same temperature by the addition of 30% aqueous sodium hydroxide. The mixture was stirred at 70 ° C for 8 hours. Finally, the pH was adjusted to 13 and was further countenanced for 30 minutes. The solution was cooled in an ice bath and the pH was brought to 1. by evaporation of concentrated hydrochloric acid. Evaporated to dryness in vacuo. The residue was absorbed in 4000 ml of methanol and stirred for one hour at room temperature. The precipitated sodium salt was filtered off, the filtrate was evaporated to dryness and the residue was precipitated on silica gel RP-18 (eluent: gradients of water / ethanol / acetonitrile).

Water content: 10.2%

Elemental analysis (calculated on anhydrous substance):

_Est . C, 51.98; H, 6.18; N, 10.10

Sex: 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

130, 73 g (360.65 mmol) of gadolinium oxide were added to 400 g (721.3 mmol) of the title compound of example 55d in 2000 ml of water and stirred for 5 hours.

265 hours at 80 ° C. The solution was filtered and the filtrate was freeze-dried.

Yield: 511 g (quantitative) of an amorphous solid.

Water content: 11.0%

Elemental analysis (calculated on the anhydrous substance): _Calc . C, 40.67; H, 4.41; Gd, 22.19; N, 7.98 _; C, 40.51; H, 4.52; Gd; 22.05; N, 8.03

f) 2,6-N, N'-bis (2- [4- (3-oxapropionyl) -phenyl] -2- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane -10-yl] acetic acid] -Lysin- [4-perfluoro-octylsulfonyl) -piperazine] amide, digadolinium complex, disodium salt

South (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 4Dissolve under gentle warming in 250 ml of dimethyl sulfoxide. At 10 ° C, 16.51 g (80 mmol) of Ν, ди-dicyclohexylcarbodiimide were added and 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 finally purified by chromatography (silica gel RP-18, eluent: gradients of water / ethanol / acetonitrile). Dissolve in a little water, bring the pH to 7.4 with sodium hydroxide and freeze-dry.

Yield: 21.02 g (69% of theory) colorless solid Water content: 11.2%

266

Elemental analysis (calculated on the anhydrous substance):

Calc: ^{C, 37.36} H, 3.66 F 15.22 Gd 14.82 N, 7.92 At 2.17 S, 1.51 Gender: θ 37.28 H, 3.74 F 15.14 Gd 14.75 N, 8.03 At 2.23 S, 1.46 An example 56

a) 2,6-N, N'-bis [6-carbonylmethyl-3,9-bis (t-butoxycarbonylmethyl) 3,6,9-triazaoundecane-1,11-dicarboxylic acid-bis (t-butyl ester)] - lysine - [1- (4perfluoroctylsulfonyl) -piperazine] -amide

To a solution of South (14.36 mmol) the title compound of Example 54a, 18.53 g (30 mmol) of 3.9bis (1-butyloxycarbonylmethyl) -6-carboxymethyl-3,6,9triazoundecane-1,11-dicarboxylic acid bis ( 1 Butylester) and

3.45 g (30 mmol) of N-hydroxysuccinimide dissolved in 150 ml of dimethylformamide were added at 0 ° C to 10.32 g (50 mmol) of N, N-dicyclohexylcarbodiimide. It was stirred for 3 hours at 0 ° C and allowed to stand at room temperature overnight. The precipitated urea was filtered off, the filtrate was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / ethanol = 20: 1).

Yield: 19.60 g (72% of theory) of viscous oil.

Elemental analysis:

_Est . H, 6.75

Gender:

C, 49.35

H, 6.82

F17.03 N7,39

F16.92 N 7.32

S, 1.69

S, 1.62

267

b) 2,6-N, N- [6-carbonylmethyl-3,9-bis (carboxylatomethyl) 3,6,9-triazaundecandicarboxylic acid-1-carboxy-11-carboxylato-lysine- [1- (4-perfluorooctylsulfonyl) ) -piparazin] amidre 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 of trifluoroacetic acid were added. Stir for 10 minutes at room temperature. It is evaporated to dryness in vacuo and the residue is dissolved in 150 ml of water. 2.87 g (7.91 mmol) of gadolinium oxide are added and the mixture is stirred for 5 hours at 80 ° C. It is cooled to room temperature and the pH is adjusted to 7.4 with 2 N sodium hydroxide solution. The solution was evaporated to dryness in vacuo and purified on RP-18 (eluent: gradients of water / ethanol / acetonitrile).

Yield: 8.11 g (57% of theory) of a colorless amorphous solid.

Water content: 9.6%

Elemental analysis / calculated on the anhydrous substance / _Calc . 030.70 NZ, 08 Gd17.48 N7.78 Na2.56 S 1.78 _Pol . 0 30.58 Η 3.19 Gd 17.42 N7.71 At 2.68 S 1.72 «

Example 57

a) 6-N-benzyloxycarbonyl -2-N- [6-carboxymethyl-3,9bis-butyloxycarbonyl methyl) -3,6,9-triazaoundecane-1,11 dicarboxylic acid bis (t-butyl ester)] -lysine - [1- (4perfluoroctylsulfonyl) -piperazine] -amide

268

To a solution of 20 g (24.08 mmol) of the title compound of Example 52c, 14.88 g (24.08 mmol) of 3.9bis (1-butyloxycarbonylmethyl) -6-carboxymethyl-3,6,9-triazaoundecane-1,11 dicarboxylic acid bis-butyl ester) and 2.88 g (25 mol) of N-hydroxysuccinimide dissolved in 100 ml of dimethylformamide were added at 0 ° C to 8.25 g (40 mol) of N, N-dicyclohexylcarbodiimide. It was stirred for 3 hours at 0 ° C, and finally allowed to stand at room temperature overnight. The precipitated urea was filtered off, the filtrate was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / ethanol = 20: 1).

Yield: 27.21 g / 79% w / v viscous oil. Elemental analysis: Calc: θ 47.03 H, 5.64 F, 22.58 N 6.85 S 2.24 Gender: θ ⁴ ® · ⁹⁴ H, 5.58 F 22.65 N 6.84 S, 2.31

B) 2-N- [carbonylmethyl-3,9-bis (1-butyloxycarbonylmethyl) 3,6,9-triazaoundecane-1,11-dicarboxylic acid-bis (1-butyl ester) lysine [1- (4-perfluoroctylsulfonyl) -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. Hydrated at room temperature. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo.

269

Yield: 22.66 g (quantitative) of a colorless solid. Elemental analysis:

Calc'd: C 44.48 H 5.75 F 24.92 N7.56 S 2.47

Sex: C 44.59 H 5.81 F 25.03 N 7.46 S 2.52

c) 6-N- [1,4,7-Tpnc (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl5yl)] -2-N- [ 6-carbonylmethyl-3,9bis (1-butyloxycarbonylmethyl) 3,6,9-triazaoundecane-1,11- (t-butyl ester)] - lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] amide, gadolinium 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) of lithium chloride and 9.72 g (15.43 mmol) of 1.4.7- Tris (carboxylatomethyl) -10- (3-aza-4-oxo-5methyl-5-yl) -pentanoic acid-1,4,7,10-tetraazacyclododecane, gadolinium complex were dissolved under gentle warming in 150 ml of dimethyl sulfoxide. At 10 ° C, 5.16 g (25 mmol) of N, N-dicyclohexylcarbodiimide were added and stirred at room temperature overnight. The solution was poured into 2500 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by chromatography (silica gel RP-18, eluent: gradients of water / ethanol / acetonitrile).

Yield: 22.94 g (78% of theory) of a colorless solid. Water content: 7.9%.

Elemental analysis (calculated on the anhydrous substance):

270 _Calc . 42.22 Η 5.29

F16,95

Gd 8.25 Ν 8.82

S 1.68 _Gender; H, 5.41

F, 16.87

Gd 8.13 N 8.70

S, 1.60

d) 6-N- [1,4,7-Tpnc (carboxy latomethyl) -1,4,7,10-10- (3-aza-4-oxo-5-methyl-5-yltetraazacycododecane pentanoyl)] - 2 -N- [6-carbonylmethyl-3,9-bis (carboxylatomethyl) 3,6,9-triazaoundecane dicarboxylic acid carboxy-11-carboxy lato-z] -lysine perfluorooctylsulfonyl) -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. Stirred for bpm at room temperature. It is evaporated to dryness in vacuo and the residue is dissolved in 150 ml of water. 1.90 g (5.25 mmol) of gadolinium oxide were added and stirred for 5 hours at 80 ° C. Cooled to room temperature and adjusted to pH 7.4 with sodium hydroxide. The solution was evaporated to dryness in vacuo and purified on silica gel RP-18. (Eluent: gradients of water / ethanol / acetonitrile).

Yield: 11.89 g (61% of theory) of a colorless amorphous solid.

Water content: 10.2%

Elemental analysis (calculated on the anhydrous substance):

Calc: C32.97 H 3.47 F 17.39 Gd16.93 N 9.05 Na 1.24 S 1.7 ^ 1

271 _Sex: 0 32.90 Η 3.53 F 17.31 Gd 16.87 N 8.92 Na 1.33 S 1.67

Example 58

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

100 g (376.2 mmol) of 1,2-di-O-benzyl-glycerol (prepared according to Chem. Phys. Lipids (1987), 43 (2), 113 - 277) and 5 g of tetrabutylammonium hydrogensulfate were dissolved in a 400 mixture mixture. ml of toluene and 200 ml of 50% aqueous sodium hydroxide. At 0 ° C, 78 g (400 mmol) of 2-bromoacetic acid-t-butyl ester were added dropwise over 30 minutes and stirred for 3 hours at 0 ° C. The organic phase was stripped off and evaporated to dryness in vacuo. . The residue was chromatographed on silica gel (eluent: n-hexane / acetone = 20: 1).

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

Elemental analysis:

_Calc: C, 71.48; H, 7.82

Gender: C, 71.61; H, 7.92

b) 5,6-bis (benzyloxy) 030-oxa-hexanoic acid

130 g (336.4 mmol) of the title compound of Example 58a were dissolved in 200 ml of dichloromethane and mixed with 100 ml of trifluoroacetic acid at 0 ° C. Stirred for 4 hours at room temperature and finally evaporated to dryness. The residue was crystallized from pentane / diethyl ether.

272

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

Elemental analysis:

Calc: θ 69.07

H, 6.71

Paul: 69.19 ^with

H, 6.82

perfluoroctylsulfonyl) -piperazine] -amide, gadolinium complex g (60,20 mmol) of the title compound, 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 1,4,7tris (carboxylatomethyl) -1,4,7, 10-Tetraazacyclododecan-10 (pentanoyl-3-aza-4-oxo-5-methyl-5yl), gadalinium complex, were dissolved under gentle heating in 400 ml of dimethyl sulfoxide. 20.63 g (100 mmol) Ν, Νcyclohexylcarbodiimide were added at 0 ° C and stirred at room temperature overnight. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by chromatography (silica gel RP-18, eluent: gradients of water / ethanol / acetonitrile). Yield: 75.53 g (87% of theory) of a colorless solid.

Water content: 10.1%

Elemental analysis (calculated on the anhydrous substance):

273

Est: C, 37.48 H, 3.84 F 22.39 Gd 10.90 N, 8.74 S 2.22 Gender: C, 37.39 H, 4.02 F 22.29 Gd 10.75 N, 8.70 S 2.22 F. 2-Ν- [1,4,7-τρπο (carboxylatomethyl) -1,4,7,10-

tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] lysine - [1- (4-perfluoroctylsulfonyl) -piperazine] -amide, gadolinium complex g (48.53 mmol) of the title compound of Example 58c was dissolved in 500 ml water / 100 ml ethanol and 5 g palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo.

Ages: 63.5 g (quantitative) colorless solid. Water Content: 9.8%

Elemental analysis (calculated on the anhydrous basis): _Calcd. C 37.48 N 3.84 F 22.39 Gd 10.90 N 8.74 S 2.22

Sex: ^{C 37.39 H 4) 03 F} 2 ^{2 '31} Gd 10.78 N 8.65 S 2.20

e) 6-N- [5,6-6nc (benzyloxy) -3-oxahexanoyl] -2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10 (pentanoyl) -Zaza-4-oxo-5-methyl-5yl)] - lysine - [1- (4perfluoroctylsulfonyl) -piperazine] -amide, gadolinium complex g (7.64 mmol) of the title compound of Example 58d, 3.30 g ( 10 mmol) from the title compound of Example 7b,

274

0.85 g (20 mmol) of lithium chloride and 1.15 g (10 mmol) of N-hydroxysuccinimide are dissolved under gentle heating in 150 ml of dimethyl sulfoxide. At 0 ° C, 3.10 g (15 mmol) of N, N'-dicyclohexylcarbodiimide were added and stirred for 8 hours at room temperature. The reaction solution was then poured into 2000 ml of acetone and the separated precipitate was isolated. The title compound was purified on silica gel RP-18 (eluent: gradients of water / ethanol / acetonitrile).

Yield: 11.14 g (90% of theory) of a colorless, amorphous solid.

Water content: 4.3%

Elemental analysis (calculated on the anhydrous substance):

_Est . C41.51 H 4.29 F19.93 N7.78 Gd 9.70 S 1.98 _Pol . C41.45 H 4.38 F19.84 N7.70 Gd 9.58 S 1.90

f) 6-N- (5,6-dihydroxy-3-oxahexanoyl) -2-N- [1,4,7tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10pentanoyl-3-aza-4- oxo-5-methyl-5yl)] - lysine - [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, gadolinium complex g (6.17 mmol) of the title compound of Example 58e were dissolved in 200 ml of ethanol and 3 g were added palladium catalyst (10% Pd / C). Hydrated at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. Yield: 8.89 g (quantitative) of a colorless solid.

275

Water content: 3.1%

Elemental analysis (calculated on the anhydrous substance):

Calcd. Θ 35.03 H, 3.99 F, 22.42 Gd 10.92 Ν 8,75 S 2.23 Gender: ^{C34 '95} H, 4.12 F 22.30 Gd 10.78 Ν 8,71 S 2.18 An example 59

a) 6-N-benzyloxycarbonyl -2-N [-5,6-6nc (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 Nhydroxysuccinimide dissolved in 100 ml of dimethylformamide was 9.28 g (45 mmol) Ν, Νcyclohexylcarbodiimide are added at 0 ° C. It was stirred for 3 hours at 0 ° C and left at room temperature overnight. The precipitated urea was filtered off, the filtrate was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / ethanol = 20: 1).

Yield:

24.50 g (89% of theory) of viscous oil. Elemental analysis: _Calc C 47.29 H 4.14 F 28.26 N, 4.90 S, 2.81. Gender: ⁰⁴⁷ · ^{14 Η4} · 2® F 28.17 N, 4.91 S, 2.89

276

B) 2-N- (5,6-Dihydroxy-30-oxahexanoyl) -lysine- (1- (4-fluorooctylsulfonyl) -piperazine] -amide g (17.5 mmol) of the title compound of Example 52d was dissolved in 300 ml of ethanol and 5 g of palladium catalyst (10% Pd / C) were added, hydrogenated at room temperature, filtered from the catalyst and the filtrate evaporated to dryness

in a vacuum. substance. Yield: 17.65 g (quantitative) colorless solid Elemental analysis: And θ 'θ 44.05 H, 4.10 F, 32.02 N, 5.55 S, 3.18 Gender: C, 43.96 H, 4.21 F31.94 N, 5.48 S, 3.24

c) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] lysine - (1 - (4-perfluorooctylsulfonyl) -piperazine] -amide, gadolinium complex g (14.87 mmol) of the title compound of Example 59b 1.73 g (15 mmol) of N-hydroxysuccinimide, 1.27 g (30 mmol) of lithium chloride and 9.48 g (15 mmol) 1,4,7-Tris (carboxylatomethyl) -10- (3aza-4-oxo-5-methyl-5-yl) -pentanoic acid in-1,4,7,10tetraazacyclododecane, gadolinium the complex was dissolved under gentle warming in 100 ml of dimethyl sulfoxide, 5.16 g (25 mmol) Ν, Νdicyclohexylcarbodiimide were added at 0 ° C and the mixture was stirred overnight The solution was poured into 1500 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by chromatography.

277 (silica gel RP-18 eluent: gradients of 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) Calc: C 4131 H 4.29 F19.93 Gd 9.70 N7.78 S 1.98 _Gender . C 41.37 H 4.40 F 19.88 Gd 9.58 N7.67 S 1.85

Example 60

a) 6-N-benzyloxycarbonyl -2-N- [2,6-N, N-bis (benzyloxycarbonyl) -lysyl] -lysine - [1- (4-perfluoro-cyclo-sulfonyl) -piperazine] -amide g (24.08 mmol) of the title compound of Example 52c and 2.53 g (25 mmol) of triethylamine were dissolved in 200 ml of THF and 14.46 g (27 mmol) of di-N, N-Z-lysin-paranitrophenolester were added. It was stirred for 5 hours at 50 ° C. It was evaporated to dryness in vacuo and the residue was chromatographed on silica gel. Eluent: dichloromethane / methanol = 20: 1.

yield: 28.07 g (95% of theory) of a colorless solid. Elemental analysis:

_Est . C 46.99 N 4.19 F 28.32 N6.85 S 2.61 _Gender . C47.08 H 4.32 F 26.21 N6.75 S 2.54

b) 2-N (lysyl) -Lysin- [1- (4-perfluoroctylsulfonyl) piperazine] -amide, trihydrobromide

278

To 25 g (20.37 mmol) of the title compound of Example 60f was added 100 ml of hydrobromic acid in glacial acetic acid (48%) and stirred for 2 hours at 40 ° C. Cooled to 0 ° C. 1500 ml of diethyl ester are added dropwise and the precipitated solid is filtered off. Drying in vacuo (60 ° C) afforded 21.52 g (99% of theory) of a slightly yellowish colored crystalline solid.

Elemental analysis:

_Est . C27.01 H 3.40 Br.22.46 F30.26 N7.87 S 3.00 _Pol . C26.92 H 3.53 Br.22.15 F30.14 N7.69 S 2.87

c) 6-N- [1,4,7-τρπο (carboxylatomethyl) -1,4,7,10tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] 2-N- ] 2,6-N, N'-bis [1,4,7-Tris (carboxylatomethyl) 1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] lysyl] -Lysine - [1- (4-perfluoroctylsulfonyl) -piperazine] -amide, gadolinium complex

31.49 g (50 mmol) of 1,4,7-tris (carboxylatomethyl) -10- (3-aza-

4-Oxo-5-methyl- (5-yl) -pentanoic acid, gadolinium complex

6.91 g (60 mmol) of N-hydroxysuccinimide and 4.24 g (100 mmol) of lithium chloride were dissolved under gentle warming in 350 ml of dimethyl sulfoxide. At 0 ° C, 16.51 g () of 80 mmol Ν, Ν-dicyclohexylcarbodiimide were added and stirred for 5 hours at 10 ° C. To this mixture was added 10 g (9.37 mmol) of the title compound by

279 Example 60b and 3.03 g (30 mmol) of triethylamine were then stirred for 12 hours at 60 ° C. Cooled to room temperature and poured into 3000 ml of acetone. The precipitate was filtered off and purified on silica gel RP-18 (eluent: gradients of water / ethanol / acetonitrile). Yield: 16.7xg (67% of theory) a colorless solid.

Water Content: 7.9%

Elemental analysis (calculated on the anhydrous substance):

Est: C, 36.58 H, 4.43 F 12.14 Gd 17.74 N, 11.06; S, 1.14 Gender: C, 36.47 H, 4.54 F 12.03 Gd 17.65 N, 10.95; S, 1.21 Example 61 a) 1.7 bis (benzyloxycarbonyl) -4- (3,6,9,12,15-

pentaoxyhexadecanoyl) -1,4,7,10-tetraazacyclododecane

To 18.13 g (68.1 mmol) of 3,6,9,12,15 pentaoxachexadecanoic acid and 30 g (68.1 mmol) of 1,7fln-Zcyclic prepared according to Z. KoVacs and A.D. Sherry, J. Chem. Soc. Chem. Commun. (1995), 2.185, in 300 ml of tetrahydrofuran, were added at 0 ° C 24.73 g (100 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and added overnight stirred at room temperature. It was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1). Yield: 19.13 g (42% of theory) of a colorless solid.

Elemental analysis:

280

Calcd: ^061.03 Η 7.61

Gender: ^{060.92 and} 7.75

N, 8.13

N, 8.04

B) 1,7-bis (benzyloxycarbonyl) -4- (3,6,9,12,15 pentaoxyhexadecanoyl) -10- (2H, 2H, 4H, 4H, 5H5H-3-oxaprofluorotridecanoyl) -1,4,7,10 -Tetraazacyclododecane

To 18 g (26.91 mmol) of the title compound of Example 61a and 14.05 g (26.91 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaprofluorotridecanoic acid prepared according to DE 19603033, in 300 ml tetrahydrofuran, added at 0 ° C to 12.36 g (50 mmol) of EEDQ (2ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred at room temperature overnight. Evaporate to dryness in vacuo and chromatograph on silica gel (eluent: dichloromethane / methanol = 20: 1)

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

Calc'd: ^{C47.32 H 4.82} F 27.07 ^Ν4 · ⁷ °

Gender: ^{047.26 N} 5.01 F26.94 N 4.59

c) 1- (3,6,9,12,15-pentaoxahexadecanoyl) -7 (2H, 2H, 4H, 4H, 5H, 5H-3-oxaprofluorotridecanoyl) -1,4,7,10tetraazacyclododecan g (16.77 mmol) ) from the title compound of Example 52d was dissolved in 200 ml of ethanol and 2.5 g of palladium were added

281 catalyst (10% Pd / C). Hydrated at room temperature. It is filtered off from the catalyst and evaporated to dryness in vacuo. Yield: 15.5 g (quantitative) of a colorless solid.

Elemental analysis:

_Est; C, 40.27; H, 4.90; F; 34.93; N, 6.06

Gender: 040.15 N 4.99 F 34.87 N5.94

d) 1,7-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -

4- (3,6,9,12,15-pentaoxahexadecanoyl) -10- (2H, 2H, 4H, 4H, 5,5H-3oxaprofluorotridecanoyl) -1,4,7,10-tetraazacyclododecane, gadolinium complex 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 1,4,7tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) pentanoic acid, gadolinium complex was dissolved by gentle warming in 300 ml of dimethyl sulfoxide. At 10 ° C, 24.73 g (100 mmol) of EEDQ were added and finally stirred at room temperature overnight. The solution was poured into 3000 ml of acetone and stirred for 10 minutes.

The precipitated solid precipitate was filtered off and finally purified by chromatography on silica gel RP-18 (eluent: gradients of water / ethanol / acetonitrile).

Yield: 19.86 g (57% of theory) of a colorless solid Water content: 11.3%

282

Elemental analysis (calculated on the anhydrous substance alone)

Calc: C, 38.58 H, 4.74 F, 15.04 Gd 14.64 Ν 9,13 Gender: C, 38.47 H, 4.91 F 14.95 Gd 14.57 Ν 9,04 An example 62

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

To 20 g (35.2 mmol) and 8.1 g (80 mmol) of triethylamine dissolved in 200 ml of dichloromethane dropwise at 0 ° C was added a solution of 8.76 g (38 mmol) of 3,5-nitrobenzoyl chloride in 55 ml of dichloromethane and stirred for 3 hours at 0 ° C. 200 ml of 5% aqueous hydrochloric acid were added and 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.

Elemental analysis: Calcd: 029.35 H, 1.45 F 42.37 N, 7.35 S, 4.21 Gender: 0 29.28 H, 1.61 F 42.15 N, 7.25 S, 4.15

B) 3,5diaminobenzoic acid [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

283 g (26.23 mmol) of the title compound of Example 62a were dissolved in 400 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo. Yield: 18.43 g (quantitative) of an off-white solid.

Elemental analysis:

Calc: ^032.49 H 2.15 F 45.98 N 7.98 S 4.57 Gender: 32- ^{to 29} H 2.35 F 45.69 N 7.81 S 4.40

c) 3,5-N, N'-bis [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5 -yl-)] benzoic acid - [1- (4-perfluoroctylsulfonyl) -piperazine] amide, gadolinium complex

South (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- (3aza-4-oxo) -5-methyl-5-yl) -pentanoic acid, gadolinium

complex is dissolved under gentle heating in 200 ml

dimethyl sulfoxide. At 10 ° C, 10.32 g (50 mmol) of Ν, ди-dicyclohexylcarbodiimide are added and stirred at room temperature overnight. The solution was poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered and finally purified by chromatography (silica gel RP-18, eluent: gradients of water / ethanol / acetonitrile). Yield: 19.74 g (72% of theory) of a colorless solid.

284

Water content: 11.8%

Elemental analysis (calculated on the anhydrous substance):

Calc: ^C35 · ⁵⁵ H, 3.72 F, 16.77 Gd 16.33 N, 10.18 S, 1.67 Gender: ^035.48 H, 3.84 F, 16.58 Gd 16,24 N, 10.07 S, 1.58 An example 63

a) 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanecarboxylic acid 1-butyl ester

25.0 g (53.8 mmol) of 1 H, 1 H, 2 H, 2 H-perfluoro-1-decanol (commercially available by Lancaster) are dissolved in 250 ml of absolute toluene and mixed at room temperature with a catalytic amount (ca. 0.75 g) of tetra-n-butyl ammonium hydrogen sulfate. A total of 7.55 g (134.6 mmol; 2.5 equivalents relative to the alcohol component used) of a fine powder of potassium hydroxide was then added at 0 ° C, followed by the addition of 15.73 g (80.7 mmol; 1 , 5 equivalents to the alcohol component used) bromoacetic acid tert-butyl ester and stirred for 2 hours at 0 ° C. The resulting reaction solution was then stirred for a further 12 hours at room temperature and mixed with 500 ml of acetic acid ethyl ester and 250 ml of water. The organic phase was separated and washed twice with water. After drying the organic phase over sodium sulfate, it is sucked out of the salt and the solution is removed in vacuo. The oily residue obtained is purified on

285 silica gel using acetic acid / hexane ethyl ester (1:10) as eluent.

Yield: 26.3 g (84.6% of theory) of the title compound as a colorless and highly viscous oil

Elemental analysis:

_Est . With 33.23 N2,61 F 55,85 _Paul. C, 33.29; H2.61; 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 were suspended in a mixture consisting of methanol and 0.5 molar sodium hydroxide at a ratio of 2: 1 with continuous stirring and room temperature and then heated to 60 ° C. After a reaction time of 12 hours at 60 ° C, the clear reaction mixture is refined by neutralization by mixing with Amberlite® IR 120 (H ⁺ form) cation exchange resin, extracted from the ion exchanger and the methanol thus obtained - the aqueous filtrate is removed in vacuo to dryness. The resulting amorphous oily residue was purified on silica gel using acetic acid / n-hexane (1: 3) ethyl ester as eluent.

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

Elemental analysis:

Calc'd: C 27.60 H1.35 F 61.85

Gender: 027.58 H1.36 F 61.90

286

c) 1,7-bis {[1,4,7-Tris (carboxylatomethyl) -10- (3-aza-4-oxy-5methyl-5-yl-pentanoyl)] - 1,4,7,10-tetraazacyclododecane } diethylenetriamine, digadolinium complex

2.48 g [(3.94 mmol)] of 2.05 mole equivalents relative to the diethylenetriamine used] of the gadolinium complex of 10- (4carboxy-1-methyl-2-oxo described in patent application DE 197 28 954 C1 in Example 31 -3-Azabutyl) -1,4,7,10tetraazacyclododecane-1,4,7-trioacetic acid and 167 mg anhydrous lithium chloride (3.94 mmol) were dissolved under stirring at 40 ° C in absolute dimethyl sulfoxide and at the same temperature was mixed with a total of 453 mg (3.94 mmol) of N-hydroxysuccinimide. After cooling to room temperature, the resulting solution was mixed with 814 mg (3.946 mmol) of N, N-dicyclohexylcarbodiimide and stirred for 2 hours at room temperature. The resulting active ester suspension was mixed with 198.3 mg (1.92 mmol) of diethylenetriamine dissolved in 5 ml of absolute dimethyl sulfoxide and stirred for 12 hours at room temperature. For further processing, the reaction mixture is mixed with sufficient acetone until complete precipitation of the title compound above is precipitated, sucked in, dried, absorbed in water, the insoluble dicyclohexylurea is filtered and the filtrate is allowed to desalinate through AMICON ® YMON-YM ultrafilter membrane (cut off 3000 Da) and purified from low molecular weight constituents

287 components. The resulting product was finally freeze-dried.

Yield: 1.85 g (72.7% of theory) of a colorless lyophilisate. Water content (Karl-Fischer): 3.89%.

Elemental analysis (calculated on the anhydrous substance): _Calc . C 36.03 H 5.24 N 13.73 Gd 23.71

Gender: ^{037.98 H5.2} ° N13.69 Gd23.78

b) 1,7-bis {[1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-

5-methyl-5-yl-pentanoyl) 1,4,7,10-tetraazacyclododecane} -4- (3oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) diethylenetriamine, digadolinium complex

One solution of 3.23 g (2.44 mmol) of the title compound of Example 63c, in a mixture of 30 ml of dimethyl sulfoxide, was added dropwise at 50 ° C and under a nitrogen atmosphere of 1.27 g (2.44 mmol). ) from the title compound of Example 63b, dissolved in a mixture of 15 ml of tetrahydrofuran and 15 ml of dimethyl sulfoxide. A total of 1.80 g (3.66 mmol) of EEDQ [2ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] was then added portionwise at 0 ° C with continuous stirring and left overnight at room temperature and stirring. The resulting reaction solution was finally mixed with sufficient acetone until complete precipitation of the title compound above, the precipitate was sucked off, dried, absorbed in water, filtered from the insoluble constituents, and the filtrate was passed for ultrafiltration through AMICON ® YM- 3

288 ultrafilter membrane (cut off 3000 Da), achieving both complete saline release and purification of the title compound from the low molecular weight constituents. The resulting product was finally chromatographed. 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):

Calc: θ 35.43 H4.07 N, 9.95 F, 17.64 Gd 17.18 Gender: θ'35.42 H4.01 N9.89 F, 17.67 Gd 17.18 An 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 were stirred for 24 hours at room temperature. It was evaporated to dryness 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.

Elemental analysis:

_Est; C 51.07 H5.09N 7.44 F 15.14 _Gender: C 51 ^ 5 H5.18N 7.58 F 15.03

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

289

To 125.0 g (332.0 mmol) of the title compound of Example 52a and 188.7 g (332q0 mmol) of perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 750 ml of THF, were added at 0 ° C 164.2 g ( 0.664 mmol) EEDQ (2ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred at room temperature overnight. It was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane methanol = 20: 1).

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

M.p .: 92 ° C.

Elemental analysis:

_Est; C36.30 H 2.83 N6.05

F41.01

S 3.46 _Sex; 0 36.18 N 2.94 N5.98

c) 6-N-benzyloxycarbonyl

F 40.87 S 3.40

L-Lysineperfluoroctylsulfonyl) -piperazine] -amide

In a solution of 280.0 g (302.2 mmol) of the title compound of Pimer 52b in 2000 ml of ethanol, ammonia gas was bubbled at 0 ° C for one hour. The mixture was then stirred at 0 ° C for 4 hours. It is evaporated to dryness and the residue is stirred with water. The solid was filtered off and dried in vacuo at 50 ° C.

Yield: 243.5 g (97.0% of theory) of an amorphous solid. Elemental analysis:

Calc'd: C 37.60 H 3.28 N6.75 F 38.89 S 3.86

290

Sex: C 37.55 H 3.33 N6.68 F 38.78 S 3.81

d) L-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

200.0 g () 240.8 mmol of the compound obtained according to Example 64c were dissolved in 1000 ml of ethanol, 5.0 g of pearl catalyst (Pd 20%, C) were added and hydrogenated at room temperature under a hydrogen atmosphere (1 atm). ) until hydrogen absorption ceases to be observed. It is aspirated from the catalyst, washed mainly with ethanol (three times with about 100 ml each) and concentrated in vacuo to dryness. The title compound is obtained as a highly viscous and yellowish colored oil.

Yield: 162.5 g (96.9% of theory).

Elemental analysis:

Calcd. Θ31.04 NZ, 04 N8.05 F 46.38 S4.60 Gender: ^C31.11 NZ, 09 N8.08 F 46.33 S4.62

d) 6N-2N-6HC {4- [2, 3-bis- (Ν, би-bis (t-butyloxycarbonylmethyl) -amino) -propyl] -phenyl} -3-oxapropionyl-1-lysine- [1- ( 4-perfluorooctylsulfonyl) -piperazine] amide

5.25 g (7.72 mmol) of 4- [2, 3-bis (Ν, би-bis (t-butyloxycarbonylmethyl) -amino) -propyl] -phenyl} -3-oxapropionic acid and 781.0 mg (7 , 72 mmol) triethylamine was dissolved in 50 ml of methylene chloride. At -15 ° C, a solution of 1.16 g (8.5 g) was added dropwise over 5 minutes

291 mmol) isobutyl ester of hydrochloric acid in 10 ml of methylene chloride, stirring for an additional 20 minutes at -15 ° C. The 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 was added dropwise within 30 minutes at -15 ° C. g (21.0 mmol) of triethylamine in 70 ml of THF and then allowed to stand overnight at room temperature. For further processing, the solvent was removed in vacuo and the oily residue obtained was absorbed in 250 ml of chloroform. The chloroform phase is extracted twice with 100 ml of a 10% aqueous ammonium chloride solution twice, the organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: methylene chloride / ethanol = 20: 1).

Yield: 5.37 g (68.8% of theory) a colorless and very viscous oil.

Elemental analysis: _Est; C52D7 H6.43 N5.54 F, 15.97 S, 1.59 _Paul . C, 52.22; H6.51; N5.49 F 15.99 S, 1.63 f) 6N-2N-6nc- (4- [2,3-bis- (M, N-bis (carboxylatomethyl) -

amino) -propyl] -phenyl} -3-oxa-propionyl-L-lysine- [1- (4-perfluoroalkylsulfonyl) -piperazine] -amide, octa-sodium salt

5.0 g (2.47 mmol) of the title compound of Example 64e were dissolved in 60 ml of absolute dichloromethane. The mixture was then mixed at a temperature of 0 ° C with a total of 75 ml of trifluoroacetic acid. After a reaction time of 12 hours at room temperature, it was concentrated in vacuo to dryness. The resulting residue was mixed with 100 ml of water

292 sushi in vacuum. The residue thus obtained was dissolved in 200 ml of distilled water and the aqueous solution containing the product of the above title compound was extracted twice with 60 ml of diethyl ether. The resulting aqueous solution containing the product by mixing with water is brought to a total volume of 300 ml, the insoluble constituents are filtered and the filtrate is passed by ultrafiltration through AMICON ® Ym-3 ultrafilter membrane (cut off 3000 Da), which serves both for the complete removal of salts and the purification of the title compound from the low molecular weight constituents. By mixing with water, the product is brought to a total volume of 200 ml and the pH of this solution is adjusted to 10.0 using 15% sodium hydroxide solution. The resulting stock aqueous solution of the product is finally freeze-dried.

4.0 g (92.8% of thiore) of the title compound are obtained as the octa-sodium salt as amorphous lyophilisate.

Water Content: 5.37%

Elemental analysis (calculated on the anhydrous basis): _Calc; C, 38.46; N, 8 N, 6.41; F18.47; S, 1.83; Na, 10.52 _; C38.42 H3.31 N6.39 F18.51 S 1.87 Na 10.38

g) 6N-2N-6nc {4- [2, 3-bis (Ν, с-bis (carboxymethyl) -amino) propyl] -phenyl} -3-oxa-propionyl-1-lysine- [1- (4- perfluoroctylsulfonyl) -piperazine] -amide, dimangan complex, tetra-sodium salt

1.94 g (1.11 mmol) of the title compound of Example 64f were dissolved in 100 ml of distilled water and the acidity of

The resulting solution was adjusted to pH 4.0 using 1 molar aqueous hydrochloric acid. 0.25 g (2.22 mmol) of manganese-N-carbonate were added portionwise at 80 ° C. The resulting solution was then heated to reflux for 5 hours. After cooling to room temperature and vigorously stirring, the pH of the aqueous solution containing the product was adjusted to 7.2 by mixing with 1 N sodium hydroxide solution and passed for desalination through an AMICON ® YM-3 ultrafilter membrane (cut off 3000 Da) and purified from low molecular weight constituents. The resulting product was finally freeze-dried.

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): Calc: C 38.07 H3.25 F 18.28 Mn6.22 N6.34 Na 5.20 S1.81 _Gender: C38.01 H3.29 F18.29 Μη 6.21 N6.36 Na 5.26 S1.78

Example 65

a) 6-N- (benzyloxycarbonyl) -2-N - [(N-pteroyl) -1_-glutaminyl] lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide r (45.31 mmol) folic acid was dissolved in 300 ml of dimethyl sulfoxide and 9.49 g (46 mmol) of N, N-dicyclohexylcarbodiimide were added at 10 ° C. Stir overnight at room temperature. 29.1 g (35 mmol) of the title compound of Example 52c and 20 were added to this solution.

294 ml of pyridine and stirred for 3 hours at 50 ° C. Cooled to room temperature and then a mixture of 1500 ml of diethyl ether / 1500 ml of acetone was added. The precipitate was filtered off and purified on (RP-18) (eluent = gradients of water / ethanol / tetrahydrofuran).

Yield: 21.59 g (38% of theory) of a yellow solid.

Water content: 2.1%

Elemental analysis (calculated on the anhydrous substance):

Calc'd: 0 43.10 H3.54 F 25.76 N11.29 S2.56

Gender: 043.02 H3.62 F 25.68 N11.21 S2.48

B) 2-M - [(M-pteroyl) -1_-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 hydrobromic acid in glacial acetic acid (48%) and stirred for 2 hours at 40 ° C. Cooled to 0 ° C. 2000 ml of diethyl ether are added dropwise and the precipitated solid is filtered off. Drying in vacuo (60 ° C) gave 18.96 g (99% of theory) of a yellow, crystalline solid.

Elemental analysis:

Calc'd: C 37.01 H3.27

H3.42

Br 6.65 F26.90 N12.83 S2.67

Br 6.31 F 29.75 N 12.72 S 2.56

c)

6-N- [1,4,7-Tpnc (carboxylatomethyl) -1,4,7,10tetraazacyclododecane-10- (pentanoyl-3-aza-4oxo-5-methyl-5yl) 295

2-M - [(N-pteroyl] -1_-glutaminyl] -lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, gadolinium complex

0.92 g (8 mmol) of N-hydroxysuccinimide, 0.68 g (16 mmol) of lithium chloride and 5.04 g (8 mmol) of 1,4,7tris (carboxylatomethyl) -10- (3-aza-4-oxo) -5-methyl-5-yl) -1,4,7,10tetraazacyclododecane, gadolinium complex was dissolved under gentle heating in 80 ml of dimethyl sulfoxide. At 10 ° C, 2.06 g (10 mmol) Ν, Νcyclohexylcarbodiimide were added and stirred for 3 hours at room temperature. To this reaction solution was added 5 g (4.16 mmol) of the title compound of Example 65b and 10 ml of pyridine. Stays overnight at room temperature. The solution was then poured into 1000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by chromatography (silica gel RP-18, eluent: gradients of water / ethanol / acetonitrile). It is dissolved in a little water, with sodium hydroxide the pH is adjusted to 7.4. and freeze-dried.

Yield: 3.87 g (53% of theory) yellow solid Water content: 5.8%

Elemental analysis (calculated on the anhydrous substance): _Calc . C38.36 H3.74 F18.42 Gd8.97 N12.78 No. 1.31 S1.83 _Gender . C38.28 H3.85 F18.33 Gd8.85 N12.69 Na1.42 S1.75

Example 66

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

296

8.90 g (70 mmol) of oxalyl chloride were added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 6H, 5H-oxaprofluorotridecanoic acid in 300 ml of dichloromethane and stirred for 12 hours at room temperature. Evaporate in vacuo to dryness. The residue was dissolved in 100 ml of dichloromethane and at 0 ° C was added dropwise to a solution containing 5.47 g (60 mmol) of 2,3-dihydroxypropylamine and 6.07 g (60 mmol) of triethylamine dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. Add 300 ml of 5% aqueous hydrochloric acid and stir vigorously for 15 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 / ethanol = 15: 1).

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

Calc'd: C 30.32 H2.20 N2.36 F 54.35 _Gender . WHO.12 H2.41 N2.18 F 54.15

B) N- (2,3-dihydroxypropyl) -N- (1H, 1H, 4H, 4H, 5H, 5H-3-oxaprofluorotridecyl) -amine (48.8 mmol) from the title compound of Example 66a was dissolved in 300 ml of tetrahydrofuran and 50 ml of 10 M borandimethylsulfide (in tetrahydrofuran) are added. It is varied for 16 countercurrent. It is then cooled to 0 ° C and 300 ml of methanol are added dropwise, finally evaporated in

297 vacuum to dry. The residue was taken up in a mixture of 300 ml of ethanol / 50 ml of 10% aqueous hydrochloric acid and stirred for 8 hours at 60 ° C. It was evaporated to dryness in vacuo and the residue was absorbed in 300 ml of 5% water. aqueous sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phases were dried over magnesium sulfate, evaporated to dryness in vacuo and the residue was chromatographed on silica gel (eluent: dichloromethane / methanol = 15: 1).

Yield: 24.07 g (85% of theory) of a colorless solid. Elemental analysis:

_Calc: C31.05 H2.61 N2.41 F 55.66

Sex: C 31.91 H2.78 N2.33 F 55.47

c) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-hexan-5yl) -acid-N- (2,3-dihydroxypropyl) -N- (1H, 1H, 4H) , 4H, 5H, 5H-3oxa) - (perfluorothridecyl) -amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex g (15,88 mmol) gadolinium complex of 10 [1 (carboxymethylcarboamoyl) -ethyl] -1 , 4,7,10-tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved at 60 ° C in 100 ml of dimethyl sulfoxide. Cool to 15 ° C and add 9.21 g (15.88 mmol) of the title compound of Example 66b. Stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution is then poured into a mixture

298 of 200 ml of acetone / 1300 ml of diethyl ether and stirred at room temperature for 2 hours. The precipitated precipitate was filtered off, dissolved in a little ethanol / water mixture and chromatographed on silica gel RP-18 (eluent: gradients of tetrahydrofur / acetonitrile / water).

Yield: 16.09 g (85% of theory) of a colorless, amorphous powder.

Water content: 6.3%.

Elemental analysis (calculated on the anhydrous substance):

Calc'd: C 34.26 H3.64 N7.05 F 27.10 Gd 13.19

Sex: C 34.12 H3.83 N6.91 F 26.88 Gd 12.93

Example 67

1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-hexan-5yl) -acid-N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3 -OKca- perfluorothridecyl) -amide] -1,4,7,10-tetraazacyclododecane, gadolinium complex g (15,88 mmol) gadolinium complex of 10- [1 (carboxymethylcarbamoyl) -ethyl] -1,4,7,10- tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolved in 100 ml of dimethyl sulfoxide at 60 ° C. 15 ° C and then 3.51 g (17 mmol) of дици'cyclohexylcarbodiimide are added. Stirring for 5 hours at 0 ° C. To remove urea, the solution was filtered. The filtrate was added to 8.63 g (15.88 mmol) of the title compound of Example 68b and 5.0 g (50 mmol) of triethylamine while stirring for 12 hours at room temperature.

299

The solution was poured into 1500 ml of diethyl ether / 100 ml of acetone and stirred for 30 minutes. The precipitated solid was filtered off and chromatized on silica gel RP-18 (eluent: gradients of tetrahydrofuran / acetonitrile / water).

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

Water content: 9.3%

Elemental analysis (calculated on the anhydrous basis):

_Est; 033.28 H 3.42 N7.51 F 28.87 Gd 14.05

Sex: C 33.12 H3.61 N7.37 F 28.69 Gd 13.89

Example 68

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxo-perfluorotridecanoic acid amide

8.90 g (70 mmol) of oxalyl chloride were added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaprofluorothyrdecanoic acid and stirred for 12 hours at room temperature. temperature. Evaporates to dryness in vacuo. The residue was dissolved in 200 ml of dichloromethane. Ammonia gas is then passed through the solution at 0 ° C for about 2 hours. It was stirred for 4 hours at 0 ° C and then for 2 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid were added and vigorously stirred for 15 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 = 20: 1).

Yield: 27.85 g (93% of theory)

300

Elemental analysis:

_Est . C, 27.66; H, 1.55; N, 2.69; F, 61.97 _; C27.49 H1.72 N2.54 F61.81

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 THF and 31 ml were added. 10M borandimethylsulfide (in tetrahydrofuran). Boiled for 16 hours counterclockwise. It was cooled to 0 ° C and 200 ml of methanol were added dropwise, finally evaporated to dryness in vacuo. The residue was taken up in a mixture of 400 ml of ethanol / 100 ml of 10% aqueous hydrochloric acid and stirred at 60 ° C for 8 hours. It was evaporated to dryness in vacuo and the residue was crystallized from little alcohol / diethyl ether.

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

Elemental analysis:

_Est; C 26.51 H2.04 N2.58 F 59.41 C16.52 _Pol . C 26.37 H2.21 N2.46 F 59.25 Q.6.38

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

To 26.5 g (48q74 mmol) of the title compound of Example 68b and 14.8 g (146.2 mmol) of triethylamine dissolved in 300

301 ml of dichloromethane were added dropwise at 0 ° C. 14.24 g (50 mmol) of 3,6,9,12,15-pentaoxahexadecanoic acid chloride and stirred at 0 ° C for 3 hours. Then, 300 ml of 5% aqueous hydrochloric acid were added and stirred vigorously for 30 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 = 20: 1).

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

Elemental analysis:

_Est; With 36.57 N4.00 N1,85 F 42,75 _Paul. C, 36.46; H4.12; N1.76; F, 42.53

d) N- (3,6,9,12,15-pentaoxahexadecyl) - N (1H, 1H, 2H, 2H, 4H, 4H-3-oxa) -perfluorotridecyl-amide g (41.03 mmol) of the title compound of Example 68c were dissolved in 300 ml of tetrahydrofuran and then 25 ml of 10 M borandimethylsulfide (in tetrahydrofuran) was added. Boiled for 16 hours counterclockwise. Cool to 0 DEG C. 200 ml of methanol are added dropwise, finally evaporated to dryness in vacuo. The residue was absorbed in a mixture of 300 ml of ethanol / 50 ml of 10% aqueous hydrochloric acid and stirred for 8 hours at 40 ⁰ C. It was evaporated to dryness in vacuo, the residue was absorbed in 300 ml of 5% aqueous sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and

302 the residue was chromatographed on silica gel (eluent: dichloromethane / 2 propanol = 15: 1).

Yield: 27.68 g (91% of theory)

Elemental analysis:

Calc'd: C 37.26 H 4.35 N1.89 F 43.56

Gender: C 37.11 H 4.51 N1.73 F 43.41

e) 1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5yl) -acid- [1-3,6,9,12,15-pentaox) -hexadexyl) -H (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 of 10- [1 (carboxymethylcarbamoyl) -ethyl] -1,4,7,10-tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved at 60 ° C in 100 ml of dimethyl sulfoxide. Cool to 15 ° C and add 11.77 g (15.88 mmol) of the title compound of Example 68d. Stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution was then poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred for 2 hours at room temperature. The separated precipitate was filtered off, precipitated in a mixture of a little ethanol / water and chromatographed on silica gel RP-18 (eluent: gradients of tetrahydrofuran / acetonitrile / water).

Yield: 18.05 g (84% of theory) of a colorless, amorphous powder

303

Water content: 6.2%

Elemental analysis (calculated on the anhydrous basis): _Calc; C 37.28 H 4.47 N6.21 F 23.87 Gd 11.62 _Gender; 037.11 H4.61 N6.03 F 23.64 Gd 11.42

Example 69

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

8.90 g (70 mmol) of oxalyl chloride were added to 30 g (57.45 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-oxaprofluorotridecanoic acid in 300 ml of dichloromethane and stirred for 12 hours at room temperature. Evaporates to dryness in vacuo. The residue was dissolved in 100 ml of dichloromethane and at a temperature of 0 ° C was added dropwise to a solution of 6.25 g (60 mmol) of 5-hydroxy-3-oxa-pentylamine and 6.07 g (60 mmol) of triethylamine dissolved in 200 ml of dichloromethane. It was stirred for 3 hours at 0 ° C and then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid were added and stirred vigorously for 15 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: 32.20 g (92% of theory) colorless solid Elemental analysis:

Calc'd: C 31.54 H2.65 N2.30 F 53.01

304

Gender: ^ 31.61 H2.84 N2.14 F52.85

b) N- (5-hydroxy-3-oxa-pentyl) -N (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -amine (49.24 mmol) of the title compound of Example 69a was dissolved in 300 ml of tetrahydrofuran and 31 ml of 10 M borandimethylsulfide (in tetrahydrofuran) was added. Boiled for 16 hours counterclockwise. The mixture is cooled to 0 ° C and 200 ml of methanol are added dropwise, finally evaporated to dryness in vacuo. The residue was absorbed in a mixture of 300 ml of ethanol / 50 ml of 10% aqueous hydrochloric acid and stirred for 10 hours at 50 ⁰ C. Evaporated to dryness in vacuo, the residue was absorbed in 300 ml of 5% aqueous sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane. The organic phases were dried over magnesium sulfate, evaporated to dryness in vacuo and the residue was chromatographed on silica gel (eluent: dichloromethane / 2-propanol = 20: 1).

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

_Est; C 32.28 NZ, 05 N2.35 F 54.25 Floor ^{C32 '12 H3} ' ²¹ N2.18 F 54.09

c) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-hexan-5-yl) -acid-N- (5-hydroxy-3-oxa-pentyl) -N305 ( 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) - (perfluorotridecyl) -amide] 1,4,7,10-tetraazacyclododecane, gadolinium complex g (15,88 mmol) gadillinium complex per 10 - [1 (carboxymethylcarbamoyl) -ethyl] -1,4,7,10-tetraazacyclododecane-

1,4,7-trioacetic acid and 1.35 g (31.76 mmol) of lithium chloride were dissolved at 60 ° C in 100 ml of dimethyl sulfoxide. Cool to 15 ° C and add 9.45 g (15.88 mmol) of the title compound of Example 69b. Stirred for 10 minutes and 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added. Stirred for 12 hours at room temperature. The solution was then poured into a mixture of 200 ml of acetone / 1300 ml of diethyl ether and stirred at room temperature for 2 hours. The precipitated precipitate was filtered off, dissolved in a little ethanol / water and chromatographed on silica gel RP-18 (eluent: tetrahydrofuran / acetonitrile / water gradients).

Yield: 16.10 g (84% of theory) of a colorless, amorphous powder

Water content: 5.7%

Elemental analysis (calculated from anhydrous substance):

_Est . C 34.83 H3.84 N6.96 F 26.76 Gd 13.03 _Gender . C34.65 H3.96 N6.84 F 26.62 Gd 12.91

Example 70

a) 1,2,3,4,6-pent-O-acetyl-a, p-O-mannopyranose

In an analogous manner to that described in the literature (M.L.Wofrom und A. Thompson in Methods in

306

Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Voll, 53, pp. 211 - 215, (1963)) the reaction of 150 g (832.5 mmol) of α, β-Dmanopyranose with a mixture of 1500 ml of absolute pyridine and 1500 ml of acetic acid anhydride yielded 315 g (96.7% of Theor.) from the above title compound as a crude product in the form of a viscous and colorless oil. By ¹ H-NMR spectroscopic examination of the title compound obtained, the a- to β-content of the two anomers was determined in a 4: 1 ratio. After separation of the α, β - anomers of the above title compound, the next reaction step may not take place.

Elemental analysis:

Calc'd: C, 49.21 _; H, 5.68 _; H, 49.78

B) 6- [1-O-a- (2,3,4,6-tetra-0-acetyl-O-mannopyranosyl) hexanoic acid ethyl ester]

Similarly, to the literature described for the synthesis of aryl glucopyranosides [J. Conchie und G.A. Lewy in Methods in Carbohydrate Chemisry (R.L. Wolfrom and J.N. BeMiller, Eds.), Academic Press, New York, Voll. II, 90, pp. 345-347, (1963)] reacted 156.2 g (400 mmol) of the title compound of Example 70a as an α, β-anomer mixture with 67 ml (400 mmol) of 6-hydroxy-hexanoic acid ethyl ester and 60, 8 ml (520 mmol) of tin-H-chloride in a total of 600 ml of 1,2-dichloroethane. Next

Purification by column chromatography (eluent: hexane / ethyl acetate 2: 1) gave 100.05 g (51% of theory) of the title compound as a colorless and viscous oil. By ¹ H-NMR-cTEKTpocKoncKO study of the title compound thus obtained, it was found that the above title compound was a pure α-anomer. Elemental analysis:

_Est . C 52.94 H 6.77 _Sex. H, 52.80

c) 6- [1-O-a- (2,3,4,6-tetra-0-benzyl-O-mannopyranosyl) hexanoic acid

A well-stirred suspension of 141.0 g (289 mmol) of the title compound of Example 70b in 200 ml of dioxane was mixed portionwise at room temperature while vigorously stirring with a total of 238.5 g (4.26 mmol) of fine powdered potassium hydroxide. To increase the mixing capacity of the reaction mixture, new 200 ml of dioxane was added and mixed and the resulting suspension was finally heated to reflux and at this temperature was mixed with a total of 372 ml (3.128 mmol) of benzyl bromide for a total of two hours. After one reaction time of 12 hours at room temperature, the reaction mixture was slowly added to the total

2.5 liters of ice water for refinement and finally extracted completely with diethyl ether. After washing the ether phase thus obtained and finally drying it over

308 Sodium sulphate salt is sucked off and the ethyl ether is removed in vacuo. The excess benzyl bromide was distilled from the reaction mixture quantitatively in an oil pump vacuum at an oil bath temperature of 180 ° C. The thus obtained resinous oil residue was purified on silica gel using ethyl acetate / hexane (1710) as eluent.

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

Elemental analysis:

Calculated: 075.68 H7.16

Gender: 075.79 H7.04

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

Dissolve 100 g (134 mmol) of the acid described in Example 70c in 1200 ml of dry tetrahydrofuran as well as 13.5 g (134 mmol) of triethylamine. After cooling to -15 ° C, a solution of 18.45 g (135 mmol) of hydrochloric acid isobutyl ester in 200 ml of dry THF is added dropwise with continuous stirring, without an internal temperature of -10 ° C. passes. After one reaction time of 15 minutes at -15 ° C, a solution of 165.5 g (134 mmol) of 1-amino-1H, 1H, 2H, 2H-perfluorodecane and 13.5 g (134 mmol) of triethylamine was added dropwise. 250 ml dry

309 tetrahydrofuran at -20 ° C. After one reaction time of one hour at -15 ° C and two hours at room temperature, the reaction solution was concentrated to dryness in vacuo. The resulting residue was taken up in 300 ml of acetic acid ethyl ester and washed twice with 400 ml of saturated sodium bicarbonate solution as well as once with 500 ml of water. After drying the organic phase over sodium sulphate, the salt is removed by suction and the acetic acid solvent is removed in vacuo. The oily residue obtained was purified on silica gel using dichloromethane / hexane / 2-propanol (10: 5: 1) as eluent.

Yield: 143.8 g (86.9% of theory)

Elemental analysis:

Calc'd: C 57.38 H4.98 N1.13 F 26.15

Sex: C 57.30 H5.44 N1.01 F26.25

e) 6- [1-O-α-O-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 70b were dissolved in 750 ml of 2-propanol and mixed with 2.0 g of palladium catalyst (10% Pd / C). The reaction solution was hydrogenated for 12 hours at a temperature of 22 ° C and a pressure of 1 atmosphere of hydrogen. Finally, it was filtered off from the catalyst and the filtrate was concentrated to dryness. The resulting residue was absorbed in 300 ml of dimethyl sulfoxide and thus obtained

310 solutions containing the product were obtained by mixing with a total of 1000 ml of diethyl ether and subsequent suction of the precipitated solid 21.52 g (88.0% of theory) of the above title compound as a colorless and crystalline powder at melting point at decomposition of 88.5 ° C.

Elemental analysis:

Est; C 36.01 H 5,92 N1,75 F 40,34 _Paul. C 36.07 H6.0S N1.76 F 40.66

f) Preparation of metal complex I and 6- [10-a-O-manopyranosyl) -hexanoic acid-N- (3-OKca-

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

To 35 ml of a solution of metal complex I (280 mmol / L) dissolved in 0.45% aqueous sodium chloride (pH 7.4; 0.25 mg / l CaNa ₃ DTPA) was added 3.17 g ( 4.2 mmol) of the title compound of Example 70e and supplemented with 0.9% aqueous sodium chloride solution to a total of 98 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with 2 N aqueous sodium hydroxide. Filter through a 0.2 μm filter. A solution thus obtained can be directly used for biological testing (the concentration is 100 mmol Gd / L).

Example 71

a) 1-0-a-0 - [(1-perfluoroctylsulfonylpiperazine-4carbonyl) -pentyl-5] -2,3,4,6-tetra-O-benzyl mannopyranose

311

In 800 ml of a mixture of tetrahydrofuran / acetonitrile (7: 3 ratio) dissolved 74.59 g (100 mmol) of the acid described in Example 71c as well as 10.11 g (100 mmol) of triethylamine. A solution in 500 ml of tetrahydrofuran in 58.0 g (102.0 mmol) of 1-perfluorooctylsulfonipiperazine is then added dropwise at room temperature; 10.11 g (100 mmol) of triethylamine and 16.84 g (110 mmol) of 1-hydroxybenzotriazole. The reaction solution thus obtained was stirred at -50 C with a solution of 22.7 g (110 mmol) of dicyclohexylcarbodiimide dissolved in 100 ml of THF and finally stirred at -5 ° C for another two hours. After thawing the reaction solution, it was stirred for a further 12 hours at room temperature, filtered from the precipitated dicyclohexylurea and the resulting filtrate was concentrated to dryness in vacuo. The resulting residue was absorbed in 600 ml of acetic acid and washed twice with 300 ml of saturated sodium bicarbonate solution and twice with 300 ml of water each. After drying the organic phase over sodium sulfate, the salt is sucked off and the acetic acid ethyl ester is removed in vacuo. The oily residue obtained was purified on silica gel using dichloromethane / acetone / 2-propanol (16: 2: 1) as eluent.

Yield: 113.01 g (79.8% of theory) of a colorless and viscous oil Elemental analysis:

_Est . C 58.52 H4.27 N1.98 S2.26 F 22.80 _Sex; C, 58.42; H, 4.41; N, 1.80; S, 2.28; F, 23.02

312

b) 1-OaD - [(1-perfluorooctylsulfonyl-piperazine-4-carbonyl) -pentyl-5] -manipiranose 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 activated carbon) were added. Hydrated for 12 hours at room temperature. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 200 ml of methanol and the reaction product precipitated after being mixed with a total of 800 ml of diethyl ether. After suction of the solid thus obtained, it was dried in vacuo at 50 ° C. Yield: 29.51 g (99% of theory) of an amorphous solid.

Elemental analysis: _Est; C, 34.13; H, 3.46 N3.32 S3.80 F 38.23 _Gender: C, 34.28; H, 3.81 N3.25 S3.80 F 38.01 (c) receipt of ready forms from metal complex II and 1-O-

α-O - [(1-perfluorooctylsulfonyl-piperazine-4-carbonyl) -pentyl5] -manopiranose

To 47 ml of a solution of metallic complex II (250 mmol / L) dissolved in 0.45% aqueous sodium chloride solution, 9.92 g (11.75 mmol) of the title compound of Example 71b were added and heated for 10 minutes. in the microwave. The solution was then cooled to room temperature, filtered through a 0.2 ppm filter. The solution thus obtained

313 can be used directly for biological experiments. (The concentration is 250 mmol Gd / L).

Example 72

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

To a well-stirred suspension of 20.16 g (700 mmol; 80% in methanol) sodium hydride in 150 ml of dimethyl sulfoxide was added dropwise at room temperature a total of 24.0 g (108.5 mmol) of 2-acetamido-2- deoxy-a, β-O-glucopyranose dissolved in 500 ml of absolute dimethyl sulfoxide, then stirred for an additional 120 minutes at room temperature and added dropwise

159.5 g (1.26 mol) of benzyl chloride. The reaction solution thus obtained was stirred for an additional 12 hours at room temperature. For the sake of processing, the reaction solution is slowly poured into

1.5 liters of ice water and then extracted with diethyl ether. After mixing, the diethyl ether phases are washed twice with 600 ml of saturated sodium bicarbonate solution and twice with 800 ml of water. After drying the organic phases over sodium sulfate, the salt is sucked off and the solvent is removed in vacuo. The resulting oily residue was purified on silica gel using acetic acid / hexane ethyl ester (1: 5) as eluent.

Yield: 48.68 g (73.6% of theory) of the title compound as a viscous and colorless oil.

Elemental analysis:

_Est . C, 70.92; H6.45; N6.89

Gender: ⁰⁷¹ · ⁴³ & ^{6 '44 N7} ' ° 2

314

b) 1-O-benzyl-3,4,6-tri-O-benzyl-2-amino-2-deoxy-a, p-glucopyranose

30.0 g (49.2 mmol) of the title compound of Example 72a were suspended in a mixture of 750 ml of methanol and 215 ml of water and mixed at room temperature with a total of 440 ml (49.2 mmol) of 0.112 molar aqueous solution. of perchloric acid. After the addition was added, the reaction solution was stirred for a further 10 min at room temperature and the resulting homogeneous reaction solution was concentrated in vacuo to dryness. After mixing the oily residue obtained with one mixture of equal parts hexane and dichloromethane, the residue is crystallized. The crystalline reaction product was sucked off, washed with hexane and dried in vacuo at room temperature.

Yield: 27.08 g (86% of theory) of the above title compound as its perchlorate, which is a colorless, crystalline compound.

M.P. : 180.5-181.5 ° C

Elemental analysis:

Calc: θ 63.68 H5.98 N2.19 CI 5.54

Gender: 0 63.43 H 6.04 N2.02 CI5.71

c) 1,3,4,6-Tetra-O-benzyl-2-deoxy-2- [acetyl (2-amino-N-ethyl-N-perfluoroctylsulfonyl) -amino] -1-a, β-D-glucopyranoseB 350 ml 20.8 g (35.6 mmol) of 2- [N-ethyl-N-perfluoroctylsulfonyl] 315 aminoacetic acid and 3.60 g (35.6 mmol) of triethylamine were dissolved in dry tetrahydrofuran. After cooling the reaction solution to -15 ° C to -20 ° C, a solution of 4.92 g (35.6 mmol) of butyl ester of hydrochloric acid in 75 ml of dry tetrahydrofuran was slowly added dropwise at the same temperature and stirring continuously. the dripping rate was chosen so as not to pass an internal temperature of -10 ° C. After a single reaction time of 15 minutes at -15 ° C, a solution of 22.78 g (35, 6 mmol) perchlorate (the title compound of Example 72b) and

3.60 g (35.6 mmol) of triethylamine in 100 ml of tetrahydrofuran at -20 ° C. After one reaction time of one hour at -15 ° C as well as two hours at room temperature, the reaction solution was concentrated to dry in a vacuum. The resulting residue was taken up in 250 ml of acetic acid ethyl ester and washed twice with 100 ml of saturated sodium bicarbonate solution and once with 200 ml of water. After drying the organic phases over sodium sulfate, the salt is sucked off and the acetic acid ethyl ester is removed in vacuo. The oily residue obtained was purified on silica gel using acetic acid / hexane ethyl ester (1: 5) as eluent.

Yield: 33.3 g (84.6% of theory) of the title compound as a colorless and highly viscous oil.

Elemental analysis:

_Est; C 49,92 H 3,92 N2,53 F 29,18 S2,90 _Paul. C 49.99 N 4.14 N2.69 F 29.22 S3.01

316

d) 2-deoxy-2- [acetyl- (2-amino-N-ethyl-N-perfluoroctylsulfonyl) -amino] -1-a, β-D-glucopyranose

20.0 g (18.06 mmol) of the title compound of Example 72c were dissolved in 250 ml of 2-propanol and mixed with 1.5 g of palladium catalyst (10% Pd / C). The reaction solution was hydrogenated for 2 hours at 22 ° C and a hydrogen pressure of 1 atmosphere. The catalyst was then filtered and the filtrate concentrated to dryness. The resulting residue was absorbed in 300 ml of dimethyl sulfoxide and from the solution thus obtained containing the product by reacting with 750 ml of a mixture of equal parts diethyl ether and ethyl acetic acid after suction of the precipitated solid yielded 12.65 g (93.8% of theory) .) from the above title compound as a colorless crystalline powder. The above title compound is in the form of the α- / β-anomer mixture, the ratio of the two possible anomers determined by ¹ H-NMR spectroscopy is about 1: 1.2. According to this study of the title compound, it is almost the same content of α / β-anomers in the mixture.

M.P. 7 132.5-133 ° C.

Elemental analysis:

_Est . C28.97 H2.57 N3.75 F 43.27 S4.30 _Gender . C 29.09 H 2.56 N 3.84 F 43.36 S 4.42

e) Preparation of metal complexes XIV and 2deoxy-2- [acetyl- (2-amino-N-ethyl-N-perfluoroctylsulfonyl) amino] -1-a, p-D-glucopyranose

317

A solution of 4.90 g (6 was added to 51 ml of a solution of XIV metal complex (300 mmol / L) dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNasDTPA). , 57 mmol) from the title compound of Example 3d, dissolved in 200 ml of ethanol, and stirred for 2 hours at 50 ° C. The solution was concentrated to dryness in vacuo and the residue was absorbed in distilled water to a total of 153 ml. It was stirred for 10 minutes at 40 ° C and filtered through a 0.2 μη filter. The solution thus obtained can be used directly for biological testing. (The concentration is 100 mmol Gd / L).

Example 73 A) 1,2,3,4,6-pent-O-acetyl-α-O-glucopyranose

In a similar manner to that described for the synthesis of the title compound of Example 70a, the reaction of 100 g (555.0 mmol) of α-glucopyranose with a mixture of 1000 ml of absolute pyridine and 1000 ml of acetic anhydride was obtained after further processing and crystallization from 95% aqueous ethanol yielded 190.6 g (88.0% of theory) of the above title compound as a colorless and crystalline compound. ¹ H-NMR spectroscopy showed that the title compound thus obtained contained the two possible 98: 2 anomers. Therefore, this title compound is exclusively an anomer configuration.

Mp: 110.5 ° C

318

Elemental analysis:

Calc'd: C, 49.21; H5.68

Gender: C, 49.24; H, 5.68

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

In a similar manner to that described for the synthesis of the title compound of Example 70b, the reaction of 130.0 g (332.8 mmol) of the title compound of Example 4a with 55.8 ml (332.8 mmol) of 6-hydroxy ethyl ester - hexanoic acid and

50.6 ml (520 mmol) of tin-1 H -chloride in 500 ml of 1,2-dichloroethane. After column chromatography (eluent: hexane / ethyl acetate 2: 1), 101.85 g (62.4% of theory) of the title compound was obtained as a colorless and viscous oil. After examination of the title compound by ¹ H NMR spectroscopy, the magnitude of the coupling constants can be found to be = 8.8 Hz for the β configuration to the anomeric center, which is the only configuration available to the anomeric center. It is thus established that the title compound mentioned above is in the form of only the β configuration of the anomers.

Elemental analysis:

_Est . With 52.94 N6,77 _Paul. H, 52.70

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

319

A well-mixed 100.0 g (204.96 mmol) of the title compound of Example 73b in 150 ml of dioxane was mixed at room temperature while vigorously stirring with a total of 169.14 g (3.03 mol) of fine potassium hydroxide. . In order to increase the stirring capacity of the reaction mixture, an additional 150 ml of dioxane was added and the resulting suspension was heated to reflux, stirring in portions for two hours at a total of 264 ml (2,218 mol) of benzyl bromide. After a single reaction period of 4 hours at 110 ° C, followed by 12 hours at room temperature, the reaction solution was slowly poured into a total of 2 liters of ice water for final processing and the aqueous phase was finally extracted completely with diethyl ether. After washing the ether phase thus obtained and the final drying of the organic phase over sodium sulfate, the salt is sucked off and the diethyl ether removed in vacuo. The excess benzyl bromide was distilled quantitatively from the reaction mixture in an oil pump vacuum at an oil bath temperature of 180 ° C. The oily residue thus obtained was purified 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 colorless and viscous viscous oil.

Elemental analysis:

Calc'd: C, 75.68; H, 16.16

Gender: ^{75.66 H7.23}

320

d) 2,3,4,6-Tetra-O-benzyl-1-O-p-O- [6-hexanoic acid-N (30oxa-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H- perfluorotridecyl) -amide] glucopyranose

Dissolve 68.5 g (91.79 mmol) of the acid described in Example 73c as well as 9.25 g (91.79 mmol) of triethylamine in 825 ml of dry tetrahydrofuran. After cooling the reaction solution to -15 ° C to -20 ° C, a solution of 12.64 g (92.5 mmol) of butyric acid hydrochloric acid ester in 150 ml of dry THF is added dropwise at this temperature, slowly is selected dropwise so as not to pass an internal temperature of -10 ° C. After a single reaction time of 15 minutes at -15 ° C, a solution of 46.40 g (91.79) is added slowly. mmol) 1H, 1H, 2H, 2H-heptadecafluoro-1- (2-aminoethoxy) decane and 9.25 g (91.79 mmol) of triethylamine as a solution in 200 ml of dry tetrahydrofuran pr. and -20 ° C. After one hour of reaction at -15 ° C as well as 2 hours at room temperature, the reaction solution was concentrated in vacuo. The resulting residue was absorbed in 250 ml of acetic acid ethyl ester and washed twice with 300 ml of saturated sodium bicarbonate solution as well as once with 400 ml of water. After the organic phase was dried over sodium sulfate, the salt was sucked off and the acetic acid ethyl ester was removed in vacuo. The resulting mass residue was purified on silica gel using dichloromethane / hexane / 2-propanol (10: 5: 1).

321 high viscous oil.

Yield: 104.7 g (92.4% of theory) of the title compound as a colorless,

Elemental analysis:

Calc'd: C 57.38 H4.98 N1.13

F 26.15 _Gender; C 57.27 H5.09 N1.11

F, 26.08

f) 1-O-p-O- [6-hexanoic acid N-C3-oxaH, 1H, 2H, 2H, 4H, 4H, 5H-perfluorotridecyl) -amide] -glucopyranose

40.0 g (32.38 mmol) of the title compound of Example 73d were dissolved in 750 ml of 2-propanol and mixed with 2.0 g of palladium catalyst (10% Pd / C). The reaction solution was powdered for 12 hours at 22 ° C and 1 atmosphere of hydrogen pressure. It was then filtered off from the catalyst and concentrated to dryness in vacuo. The resulting residue was absorbed in 300 ml of dimethyl sulfoxide and from the solution thus obtained containing the product by mixing with the total

1000 ml of diethyl ether and subsequent suction of the precipitated solid gave 22.05 g (90.2% of theory) of melting point upon decomposition of the title compound as a colorless and crystalline powder at 122-124 ° C.

Elemental analysis:

And _zh; C, 36.01 H5.92 N1.75 F, 40.34 Gender: C, 36.07 H, 6.08; N, 1.76 F, 40.66 f) Obtaining ready forms compound from Example 12 by WO 99/01161

(1,4,7-Tris {1,4,7 of the title

322 Tris (N-carboxylatomethyl) -10- (N-1-methyl-3-aza-2,5-dioxopentane-1,5-diyl) -1,4,7,10-tetraazacyclododecane, Gd-complex} 10- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] acetyl-1,4,7,10tetraazacyclododecane) and 1-N-β-O- [6-hexanoic acid-N- (3oxa-1H, 1H, 2H , 2H, 4H, 4H, 5H, 5H-lefluorotridecyl) -amide] glucopyranose

To 37 ml of a solution of 1,4,7-tris {1,4,7-tris (Νcarboxylatomethyl) -10- (N-1-methyl-3-aza-2,5-dioxo-pentane-1,5diyl) - 1,4,7,10-Tetraazacyclododecane, Gd-complex} -10- [2- (Nethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-1,4,7,10tetraazacycododecane (300 mmol) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / l CaIOSOTRA) was added 20.29 g (25.9 mmol) of the title compound of Example 73f and adjusted with 0.9% sodium solution. chloride up to 111 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH of the solution was adjusted to 7.4 by the addition of 2 N aqueous sodium hydroxide. Filter through a 0.2 pm filter. A solution thus obtained can be used directly for biological testing. (The concentration is 100 mmol Gd / L).

Example 74

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

The reaction of 50 g (128.09 mmol) of the title compound of Example 70a, used as a mixture with

323 4: 1 ratio to α, β - anomers, with one solution of 75.84 g (128.1 mmol) of 1-hydroxy-1H, 1H, 2H, 2H-perfluorodecane in 150 ml of 1,2-dichloroethane as a total 19.47 g (166.53 mmol) of tin-1 H -chloride, analogous to the synthesis of the title compound of Examples 1b and 4b described above, was carried out after further purification and purification by column chromatography (eluent: hexane / ethyl acetic acid ester). , 2: 1) to give 74.2 g (63.4% of theory) of the title compound as a viscous and colorless oil. By ¹ H-NMR spectroscopy of the title compound, the magnitude of the binding constant Ji _i2 - 13 Hz was determined relative to the available α configuration at the anomeric center, so it is obvious that this configuration is exclusive only, since it becomes clear that the above title compound represents only the pure form of α-configured anomers.

Elemental analysis:

_Est . 0 44.65 H2.53 F 35.32

Sex: C 44.77 H2.61 F 35.09

B) 1-O- (1H, 1H, 2H, 2H-perfluorodecyl) -α-D-mannopyranose g (27.33 mmol) of the title compound of Example 74a was quenched in 400 ml absolute methanol and at 5 ° C. smear with a catalytic amount of sodium methanolate. After one reaction time of 3 hours at room temperature, check the reaction process by thin layer chromatography (eluent: chloroform / methanol 9: 1)

324 shows quantitative interaction. For the purpose of processing, the clear reaction solution is neutralized by reaction with Amberlite IR 120 (H ⁺ - form) cation exchange resin, then extracted from the exchanger and the resulting methanol filtrate is extracted to dryness in vacuo. The resulting crystalline residue was purified by double crystallization from ethanol. By means of ¹ H-NMR spectroscopic examination of the title compound, it is possible, based on the measured magnitude of the coupling constant Ji _q2 = 1.0 Hz, to establish very clearly the presence of the α configuration at the anomer center. The available α-cotransfiguration is extremely common, which means that the amount of possible β-configuration of the title compound formed lies beyond the demonstrable limits of ¹ H-NMR spectroscopy. The title compound above is a striking form of pure α-configured anomers.

Yield: 16.2 g (94.6% of theory) of a colorless and crystalline solid.

M.p .: 172-174 ° C on decomposition

Elemental analysis:

_Est . 0 30.69 H 2,41 F51.57 _Paul. 0 30.57 H2.48 F 51.65

c) Preparation of formulations of metal complex II and 1-0- (1H, 1H, 2H, 2H-perfluorodecyl) -a-Dmanopyranose

325

A solution of 2.01 g was added to 50 ml of a solution of metallic complex II (150 mmol / L) dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / l CaNaaDTPA). (3.21 mmol) of the title compound of Example 74b dissolved in 200 ml of ethanol and stirred for 2 hours at 50 ° C. The solution was concentrated to dryness in vacuo and the residue supplemented with distilled water to a total of 75 ml. . It was stirred for 10 minutes at 40 ° C and filtered through a 0.2 µm filter. The solution thus obtained can be directly used for biological testing. (The concentration is 100 mmol Gd / L).

Example 75

a) 1-O- (1H, 1H, 2H, 2H-perfluorododecyl) -2,3,4,6-tetra-O-acetylD-a-manopyranose

The reaction of 35 g (89.66 mmol) of the title compound of Example 70a, which was used as a 4: 1 mixture of α, β-anomers with a solution of 50.60 g (89.7 mmol) of 1-hydroxy -1H, 1H, 2H, 2H-perfluorododecane in 100 ml of 1,2dichloroethane as well as with a total of 13.63 g (16.61 mmol) of tin-IV chloride proceeded analogously to the synthesis of the title compound of Examples 1b, 4b and 5b , and after treatment and purification by column chromatography (eluent: hexane / ethyl acetic acid = 2: 1), 62.49 g (68.7% of theory) of the title compound were obtained as a viscous and colorless mass. lo. By ¹ H-NMR spectroscopic examination of the title compound, it can be based on the magnitude of the

326 the coupling constant which is Ji _i2 ⁼ 1-4 Hz clearly determine the available a - configuration at the anomer center, which is actually the only available configuration at the anomer center, so that the given title compound can only represent a pure form of a configured anomers.

Elemental analysis:

_Est; 0 42.62 H2.28 F 39.32 _Gender . 0 42.55 H2.38 F 39.40

B) 1-O- (1H, 1H, 2H, 2H-perfluorodecyl) -a-D-mannopyranose g (24.64 mmol) of the title compound of Example 75a was suspended in 400 ml of absolute methanol and at 5 ° C. mixed with a catalytic amount of sodium atanolate. After one reaction time of 3 hours at room temperature, verification of the reaction process by thin layer chromatography (eluent: chloroform / methanol = 9: 1) showed a quantitative reaction. For the sake of refinement, the clear solution is neutralized by reaction with Amberlite IR 120 (H ⁺ -form) cation exchange resin, then aspirated from the ion exchanger and the methanoline filtrate thus obtained is extracted in vacuo to dryness. The resulting crystalline solid was purified by double crystallization from a mixture of 2-propanol / ethanol (1: 1). By ¹ H-NMR spectroscopy of the title compound, it is possible to base the magnitude of the coupling constant which is Ji _j2 = 0.9 Hz,

327 clearly establish the presence of the α configuration in the anomer center. The available α-configuration is the exclusive existing configuration at the anomer center, which means that the amount of the e-formed β configured anomers in the title compound is beyond the limits of their 1H-NMR spectroscopic demonstration. The above title compound is therefore a form of pure α-configuring anomers.

Yield: 16.96 g (90.8% of theory) of a colorless, crystalline solid

M.P. : 187 - 188 ° C on decomposition

Elemental analysis:

_Est . 0 29.77 H2.08 F 54.93

Gender: C 29.70 H 2.28 F 54.83

c) Preparation of Formulations of Metal Complex VI and 1-0- (1H, 1H, 2H, 2H-Perfluorododecyl) -α-O-mannopyranose

To 52 ml of a solution of metal complex VI (189 mmol / L) dissolved in 0.45% aqueous sodium chloride solution, 1.70 g (2.34 mmol) of the title compound of Example 75b was added and heated for 10 minutes. in the microwave. The solution was then cooled to room temperature, filtered through a 0.2 [mu] m filter and the filtrate filled in a package. The solution thus obtained can be used directly for biological testing. (The concentration is 180 mmol Gd / L).

Example 76

328

a) (2,3,4,6-Tetra-O-acetyl) -1-O-a- D- [3,6,9-TpnoKCa- (C-12-C19heptadecafluoro) -nonadecyl] -manopyranose

The reaction of 20 g (51.23 mmol) of the title compound of Example 70a, used as a 4: 1 mixture of α, β - anomers, with a solution of 30.54 g (51.23 mmol) of 1-hydroxy Tris (1H, 1H, 2H, 2H-O -) - 1H, 1H, 2H, 2Nperfluorodecane in 100 ml of 1,2-dichloroethane and with 5.98 g (51.23 mmol) of tin-IV chloride, proceeds similarly to the described synthesis of the title compounds of Examples 1b, 4b and 5b, and subsequent column chromatography (eluent: hexane / ethyl acetic acid = 1: 1), 34.22 g (72.1%) were formed by theor.) of the above title compound in the form of n and viscous, colorless oil. By ¹ H NMR spectroscopic examination of the title compound, based on the magnitude of the coupling constant which is J12 = 1.1 Hz, the presence of the α - configuration of the vanomer center, which is an extremely available configuration at the anomer center, can be determined, so that the above title compound is only a form of pure α-configured anomers. Elemental analysis: _Calc; C, 38.89; H, 3.81; F, 34.86 _; C, 39.02; H, 3.77; F, 34.90

b) 1-0-a-O- [3,6,9-triox- (C12-C- | 9-heptadecafluoro) nonadecyl] -manipiranose

329 g (21.58 mmol) of the title compound of Example 76a was suspended in 350 ml of absolute methanol and mixed with a catalog amount of sodium ethanolate at 5 ° C. After one reaction time of 3 hours at room temperature, checking the reaction process by thin layer chromatography (eluent: chloroform / methanol = 6: 1) showed a quantitative reaction. For further processing, the clear reaction solution is neutralized by reaction with an Amberlite IR 120 (H ⁺ - form) cation exchange resin, sucked off the ion exchanger and the methanol filtrate thus obtained is extracted to dryness in vacuo. The resulting crystalline residue was purified by twice crystallization from a mixture consisting of acetic acid / 2-propanol / ethanol ethyl ester (1: 0.5: 1). By ¹ H-NMR spectroscopic examination of the title compound, it is possible, based on the magnitude of the coupling constant, which is J ₁₂ = 1.0 Hz, to clearly establish the presence of α configurations at the anomer center. The available α configuration at the anomer center is the only available configuration, which means that the amount of possibly formed β-configured anomers is beyond the limit for their proof by ¹ H-NMR spectroscopy. Therefore, the above title compound is in the form of pure pure configured anomers only.

Yield: 15.20 g (92.9% of theory) of a colorless, crystalline solid.

M.p .: 141 ° C.

330

Elemental analysis:

_Est; C, 34.84; H, 3.59; F, 42.58

Sex: C 34.72 H3.66 F 42.67

c) Preparation of the title compound of Example 68 and 1-O-α-O- [3,6,9-trioxy- (C- | 2-C19-heptadecafluoro) nonadecyl] -manopyranose

To 38 ml of a solution of the title compound of Example 68 (300 mmol / L) dissolved in 0.45% aqueous sodium chloride (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) were added 3.71 g (4.89 mmol) of the title compound of Example 76b and supplemented with 0.9% aqueous sodium chloride solution to a total of 114 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with aqueous 2N sodium hydroxide. Filter through a 0.2 μνα filter and fill the filtrate in its finished forms. The solution thus obtained can be used directly for biological testing. (The concentration is 200 mmol Gd / L).

Example 77

a) 2,3,4,6-Tetra-O-acetyl-α- O- [3-thiopropionic acid N- (3-oxo-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) - amide] manopyranose

Dissolve 25.0 g (57.28 mmol) in 500 ml of dry THF; [receipt is according to:

Ponpipom, Mitree M.; Bugianesi, Robert L.; Robbins, James C.; Doebber, T. W.; Shen, T. Y.; J. Med. Chem .; 24; 12; 1981; 1388 331

1395] 3- (Tetra-O-acetyl-α-D-mannopyranosyl mercapto) propionic acid as well as 5.77 g (57.28 mmol) of triethylamine. After cooling the reaction solution to -15 ° C to -20 ° C, a solution of 7.82 g (57.28 mmol) of hydrochloric acid isobutyl ester in 100 ml of SAH is slowly added dropwise while stirring. so that an internal temperature of -10 ° C is not exceeded. After a reaction time of 15 minutes at -15 ° C, a solution of 29.05 g (57.28 mmol) of 1H, 1H, 2H, 2H-heptadecafluoro-1- (2-aminoethioxy) was added dropwise. - Dean and

5.77 g (57.28 mmol) of triethylamine as a solution in 200 ml of dry tetrahydrofuran at -20 ° C. After one reaction time of one hour at -15 ° C as well as two hours at room temperature, the reaction solution was concentrated to dryness in vacuo. The resulting residue was absorbed in 250 ml of acetic acid ethyl ester and washed twice with 200 ml of saturated sodium bicarbonate solution and once with 300 ml of water. After the organic phases were dried over sodium sulfate, the salt was sucked off and the acetic acid ethyl ester was removed in vacuo. The oily residue obtained was purified on silica gel 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 highly viscous oil.

Elemental analysis:

332

Est: Gender: C, 37.63; H, 3.48; N, 1.51 C, 37.77; H, 3.37; N, 1.61 S3.46 S3.57 F 34.89 F 35.21 B) 1-a-O- [3-thiopropionic acid- N- (3-OKca-

1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecyl) -amide] manopyranose g (32.41 mmol) of the title compound of Example 77a was suspended in 400 ml of absolute methanol and stirred at 5 ⁰ C with a catalytic amount of sodium methanolate. After one reaction time of 3 hours at room temperature, checking the progress of the reaction by thin layer chromatography (eluent: chloroform / methanol = 9: 1) showed a quantitative interaction. For further processing, the clear reaction solution is neutralized by reaction with Amberlite IR 120 (H ⁺ - form) cation exchange resin, suctioned from the ion exchange resin and the methanolic filtrate thus obtained is extracted to dryness in vacuo. The resulting crystalline residue was purified by recrystallization from a mixture consisting of acetic acid / methanol ethyl ester (0.5: 1). By ¹ H-NMR spectroscopic examination of the title compound, it is possible, based on the magnitude of the coupling constant, which is J 1 _{i 2} = 1.1 Hz, to clearly determine the presence of the α configuration at the anomer center. The established a - configuration is the extremely available configuration, which means that the amount of the possible

The 333 formed β-configurations in the title compound are beyond the limits for proving them by ¹ H-NMR spectroscopy. The title compound above is therefore the backbone of pure α-configured anomers.

Yield: 23.76 g (96.8% of theory) of a colorless and crystalline solid

Elemental analysis:

Est: C, 33.30 H3.19 N1.85 S4.23 F, 42.64 Gender: C33.21 H3.26 N1.96 S4.08 F, 42.77 c) Getting ready forms from the title compound

of Example 66 and 1-a-D- [3-thiopropionic acid-N- (3-OKca1H, 1H, 2h, 2H, 4H, 5H, 5H-perfluorotridecyl) -amide] -manipiranose

To a 47 ml solution of the title compound of Example 66 (330 mmol / L) dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA) was added a solution of 27.41 g (36.19 mmol) of the title compound of Example 77b, dissolved in 200 ml of ethanol, was stirred for 2 hours at 50 ° C. The solution was concentrated to dryness in vacuo and the residue was added with distilled water. to a total of 155 ml. The mixture was stirred for 10 minutes and filtered through a 0.2 μνη filter. The filter is filled in the finished forms. A solution thus obtained can be used directly for biological testing. (The concentration is 100 mmol Gd / L).

334

Example 78

a) 2,3,4,6-Tetra-O-acetyl-1-p-D- [3,6,9-Tpnocycn- (Ci2-C ₁ heptadecafluoro) -nonadecyl] -glucopyranosyluronic acid

20.2 g (50.85 mmol) of methyl (1-bromo-2,3,4-tri-O-α-0-glucopyranoside) uronate [preparation according to: Pelzer; Hoppe Seyler's Z. Physiol. Chem .; 314 Hours; 1949; 234 Hours; 237 as well as Goebel; Babers; J. Biol. Chem .; 111; 1935; 347, 350 and Bollenback et al .; J. Amer. Soc .; 77; 1955; 3310, 3313.] and 60.64 g (101.7 mmol) of 3,6,9 Tno-cycn- (Ci 2 -C 9 -heptadecafluoro) -nonadecan-1-ol were dissolved in 250 ml of anhydrous acetonitrile and mixed at room temperature with 13 , 0 g of freshly precipitated silver oxide. After a reaction time of 12 hours at room temperature, the insoluble silver salts were filtered off, the salts were washed well with dichloromethane and the filtrate thus obtained was removed to dryness in vacuo. The resulting residue was purified by column chromatography (eluent: hexane / ethyl acetic acid ester = 3: 1).

Yield: 22.99 g (53.3% of theory) of the title compound as a colorless, highly viscous oil.

Elemental analysis:

_Est . S41.05 H 3,92 F 38,06 _Paul. H, 3.76; F, 38.22;

B) 1-0-p-O- [3,6,9-triox- (C- | 2-C19-heptadecafluoro) nonadecyl] -glucopyranosyluronic acid

10.0 g (11.78 mmol) of the title compound of Example 78a were suspended with stirring and room temperature in 200 ml.

335 mixture consisting of methanol and 0.5 molar sodium hydroxide in a ratio of 2: 1. After one reaction time of 12 hours at room temperature, the clear reaction mixture was neutralized for refinement by passing through an Amberlit IR 120 (H ⁺ - form) cation exchange resin. It is then sucked off the ion exchanger and the methanol-aqueous filtrate thus obtained is extracted to dryness in vacuo. The resulting crystalline residue was purified by recrystallization from a mixture consisting of acetic acid / methanol ethyl ester (0.25: 1). By ¹ H-NMR spectroscopic examination of the title compound, it is possible to clearly demonstrate the presence of a β-configuration at the anomer center, based on the magnitude of the coupling constant, which is J _{1> 2} = 9.2 Hz. The presence of the β - configuration in the anomer center indicates the exceptional presence of this configuration, which means that the amount of possibly formed α - configured anomers in the title compound is beyond the limits of their proof by ¹ H-NMR spectroscopy. The above title compound, therefore, is in pure form only the β-configured anomers.

M.p .: 78.5 ° C

Elemental analysis:

_Est . C 34.21 H3.26 F 41.81 _Sex: C 34.38 H3.26 F 41.90

c) Preparation of metal complexes I and 1-O ^ -0- [3,6,9-trioxy- (C1 ₂ -C- | 9-heptadecafluoro) -nonadecyl] glucopyranosyluronic acid formulations

336

To 38 ml of a solution of metal complex I (280 mmol / L) dissolved in 0.45% aqueous sodium chloride (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) was added 19.18 g ( 24.83 mmol) from the title compound of Example 78b and supplemented with 0.9% aqueous sodium chloride solution to a total of 53.2 ml. It was heated for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with aqueous 2N sodium hydroxide. Filter through a 0.2 pm filter and fill the filtrate in the molds. The solution thus obtained can be directly used for biological testing. (The concentration is 200 mmol) Gd / L).

Example 79

a) 6- (2-oxa-1H, 1H, 3H, 3H, 4H, 4H-perfluorodecyl) 0 ¹ , 0 ² , 0 ³ , 0 ^4- diisopropylidene-α-0-galactopyranose

To a well-stirred suspension of 2.01 g (70.0 mmol; 80% in mineral oil), sodium hydride in 25 ml of dimethylformamide was added dropwise at room temperature a total of 12.15 g (46.66 mmol) of O ¹ , O ² , O ³ , O ⁴ diisopropylidene-α-galactopyranose [preparation according to: Levene; Meyer; J. Biol. Chem .; 64; 1925; 473 as well as McCreath; Smith; JJ Chem. Soc .; 1939; 387, 389 und Freudenberg; Hixon; Ckem. Ber .; 56; 1923; 1923, 2122] dissolved in 200 ml of absolute dimethylformamide. It was then stirred for an additional 120 minutes at room temperature and finally a total of 30.09 g (48.0 mmol) was added dropwise slowly.

337

1-bromo-1H, 1H, 2H, 2H-perfluorododecane dissolved in 140 ml of absolute dimethylformamide. The reaction solution thus obtained was stirred for a further 12 hours at room temperature. For further processing, the reaction solution was slowly added to 1 liter of ice water and finally extracted with diethyl ether. The combined organic phases are washed twice with 200 ml of saturated sodium bicarbonate solution and twice with 200 ml of water. After drying the organic phases over sodium sulfate, it is sucked out of the salt and the solvent is removed in vacuo. The oily residue obtained was purified on silica gel using acetic acid / hexane ethyl ester (1:10) as eluent.

Yield: 29.8 g (79.3% of theory) of the title compound as a viscous, colorless oil

Elemental analysis:

_Est . 035.75 H2.87 F49.47 _Sex; 035.64 H2.98 F 49.54

B) 2- (2-Oxa-1H, 1, 3H, 3H, 4H, 4H-perfluorodecyl) -a-Dgalactopyranose g (24.8 mmol) of the title compound of Example 79a was mixed with 300 ml of 1% aqueous sulfuric acid solution and stirred for 3 hours at 80 ° C

C. After cooling to room temperature, it is neutralized by reaction with an aqueous solution of barium hydroxide and finally filtered from barium sulphate and thus obtained

338 A clear solution of the aqueous solution containing the product was freeze-dried. By ¹ H-NMR spectroscopic examination of the title compound, the presence of the two possible configurations in the anomer center can be clearly established, and in the ¹ H-NMR-cneKrpocKoncKO study a ratio of α / β configurations of 1: 1 is determined , 4 (α: β) at the anomer center. Therefore, the above title compound is isolated only in the form of a 1: 1,4 (α: β) - anomer mixture, which means that no separation of the anomer mixture is necessary.

Yield: 15.28 g (98.4% of theory) of the title compound as a colorless lyophilisate

Elemental analysis (calculated on the anhydrous substance):

_Est; C, 35.75; H2.87; F, 49.47

Gender: F ^with 35.64 N2,98 49,54

c) Preparation of the title compound of Example 67 and 6- (2-oxa-1H, 1H, 3H, 3H, 4H, 4H-perfluorodecyl) -D-galactopyranose

To a 43 ml solution of the title compound of Example 67 (250 mmol / L) dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA) was added a solution of

1.68 g (2.69 mmol) of the title compound of Example 79b, dissolved in 200 ml of ethanol, and stirred for 2 hours at 50 ° C. The solution was concentrated to dryness in vacuo and the residue was added with distilled water. water to a total of 107.5 ml. It was stirred for 10 minutes at 40 ° C

339 and filtered through a 0.2 pm filter. The filter is filled into molds. A solution thus obtained can be used directly for biological testing. (The concentration is 100 mmol Gd / L).

Example 80

a) 1-0-a-O - [(1-perfluoroctylsulfonylpiperazine-4carbonyl) -methyl] -manipiranose d (52.8 mmol) 1-perfluoroctylsulfonylpiperazine (preparation described in DE 196 03 033) and 31.73 (53 mol )

2,3,4,6-Tetra-O-benzyl-α-D-carboxymethyl-manopranose (the preparation is described in DE 197 28 954) was dissolved in 300 ml of tetrahydrofuran. 24.73 g (100 mmol) of EEDQ (= 1,2-dihydro-2-ethoxyquinoline-1-carboxylic acid ethyl ester) were added at 0 ° C and stirred for 3 hours at 0 ° C, and finally 6 hours at room temperature. The solution was evaporated to dryness in vacuo and the residue purified on silica gel by flash chromatography (eluent: hexane / acetic ester = 10: 1). The product containing fractions were evaporated to dryness, the residue was dissolved in a mixture of 200 ml methanol / 150 ml dichloromethane and hydrogenated for 8 hours on palladium / charcoal (10% Pd / C2 g). It is filtered off by the hydrogenation catalyst and the filtrate is evaporated to dryness. The residue was recrystallized from acetone / diethyl ether.

Yield: 30.39 g (73% of theory) of a waxy, colorless solid

340

Elemental analysis:

_Est; 0 30.47 H2.68 F 40.96 N3.55 S4.07 _Sex; 030.61 H2.75 F 41.10 N3.46 S4.12

B) Preparation of Formulations of C metal complex and 1-0-a-0 - [(1-perfluoroctylsulfonylpiperazine-4-carbonyl) methyl] -manopyranose

To 32 ml of a solution of metal complex I (280 mmol / L) dissolved in 0.45% aqueous sodium chloride (pH 7.4; 0.25 mg / L CaNaaDTPA) were added 4.71 g (5, 97 mmol) of the title compound of Example 80a and supplemented with 0.9% aqueous sodium chloride solution to a total of 55 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with 2N sodium hydroxide solution. Filter through a 0.2 μνη filter and fill the filtrate into the molds. The solution thus obtained can be directly used for biological testing. (The concentration is 200 mmol Gd / L).

Example 81

a) 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid, sodium salt of (38,3 mmol) 3-oxa-2H, 2H, 4H, 4H, 5H, 5Nperfluorotridecanoic acid (the preparation is described in DE 196 03 033) were dissolved in 300 ml of ethanol and 7.7 ml were added

341

N aqueous sodium hydroxide. It was evaporated to dryness and the residue was dried in vacuo in an oven (8 hours at 60 ° C).

Yield: 20.85 g (quantitative) colorless, crystalline powder Elemental analysis:

_Est . C26.49 H1.11 F59.35 No. 4.22 _Sex; C 28.60 H1.19 F 59.47 Na 4.30

b) Preparation of formulations of metal complex I and 3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid, sodium salt

To 32 ml of a solution of metal complex I (280 mmol / L) dissolved in 0.46% aqueous sodium chloride (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) were added 2.09 r ( 3.84 mmol) of the title compound of Example 81a and with 0.9% aqueous sodium chloride solution was brought to a total of 90 ml. It was heated for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with aqueous 2N sodium hydroxide. Filter through a 0.2 ppm filter and the filtrate is ready to be filled into molds. The solution thus obtained can be directly used for biological testing. (The concentration is 100 mmol Gd / L).

c) Preparation of metal complexes I and 3-oxa-2H, 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 (pH 7.4;

342

0.25 mg / L CaNa ₃ DTPA) was added 1.00 g (1.84 mmol) of the title compound of Example 81a and supplemented with 0.9% aqueous sodium chloride solution to a total of 90 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with aqueous 2N sodium hydroxide. Filter through a 0.2 pm filter and the filtrate is ready for filling. The solution thus obtained can be used directly for biological testing. (The concentration is 100 mmol Gd / L).

d) Preparation of formulations of metal complex I and 3-oxa-2H, 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 (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) was added 0.54 g ( 1.0 mmol) of the title compound of Example 81a and supplemented with 0.9% aqueous sodium chloride solution to a total of 90 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with aqueous 2N sodium hydroxide. Filter through a 0.2 pm filter and the filter is ready for filling. A solution thus obtained can be used directly for biological testing. (The concentration is 100 mmol Gd / L).

Example 82

a) 1-Perfluoroctylsulfonyl-4- (3,6,9,12,15 pentaoxachexadecanoyl) -piperazine

343 g (35.2 mmol) of perfluorooctylsulfonylpiperazine (see Example 80a) were dissolved in 300 ml of dichloromethane and 5.06 g (50 mmol) of triethylamine were added. Cool to 0 ° C and 14.24 g (50 mmol) of 3,6,9,12,15-pentaoxahexanoic acid chloride are added dropwise within 20 minutes and stirred at 0 ° C for 3 hours. . 400 ml of 5% aqueous hydrochloric acid are added and stirred vigorously. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent = dichloromethane / methanol: 15: 1).

Yield: 26.44 g (92% of theory) of waxy solid.

_Calc'd: C 33.83 H3.58 N3.43 F 39.55 S3.93

Sex: C 33.96 H 3.66 N 3.50 F 39.67 S 3.82

B) Preparation of Formulations of Metal Complex I and 1-Perfluoroctylsulfonyl-4- (3,6,9,12,15pentoxyhexadecanoyl) -piperazine

To 47 ml of a solution of metal complex I (280 mmol / L) dissolved in 0.45% aqueous sodium chloride (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) were added 4.61 g ( 5.64 mmol) of the title compound of Example 82a and supplemented with 0.9% aqueous sodium chloride solution to a total of 66 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with 2N aqueous sodium hydroxide solution. Filter through

344

0.2 μπι filter and the filtrate is ready for filling. The solution thus obtained can be used directly for biological testing. (The concentration is 200 mmol Gd / L).

Example 83

a) 1H, 1H, 2H, 2H-perfluorodecyl-p-toluenesulfonic acid ester g (43.1 mmol) of 1H, 1H, 2H, 2H-perfluorodecanol was dissolved in 200 ml of pyridine and at 0 ° C added in portions. 9.53 g (50 mmol) of hydrochloric acid chloride. Stirred for 5 hours at room temperature. Pour the solution into 1000 ml of ice water and stir for 10 minutes. The resulting precipitate was filtered off, washed with plenty of water and finally crystallized from acetone.

Yield: 22.04 g (97% of theory) of a colorless, crystalline solid

Elemental analysis:

_Est; C 22.78 H0.76 F 61.26 S6.08 _Sex; C 22.89 H 0.70 F 61.39 S6.15

B) C18-C25-heptadeca-fluoro-3,6,9,12,15-pentaoxypentacosan-1-ol (37.94 mmol) from the title compound of Example 83a,

35.74 g (150 mmol) of pentaethylene glycol and 1 g of 18-crown-6 were dissolved in 300 ml of THF and 10.1 g (180) were added.

345 mmol) finely powdered potassium hydroxide. Stirred for 10 hours at room temperature. It was filtered off from the solid and the filtrate was concentrated 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. Elemental analysis:

Calc'd: C 35.10 H3.68 F 47.19 _Gender; H, 35.72; F47.10

c) Preparation of the Formulations of the Title Compound of Example 69 and C 1 -C 8 -heptadeca-fluoro3,6,9,12,15-pentaoxa-pentacosan-1-ol

To 53 ml of a solution of the title compound of Example 69 (310 mmol / L) dissolved in 0.45% aqueous sodium chloride was added 44.98 g (65.72 mmol) of the title compound of Example 83b and heated for 10 minutes in the microwave. The solution was cooled to room temperature, filtered through a 0.2 μπϊ filter and the filtrate ready for filling. A solution thus obtained can be used directly for biological testing (the concentration is 310 mmol Gd / L).

Example 84

a) N, N-bis (8-hydroxy-3,6-dioxo-octyl) perfluorooctylsulfonic acid amide

Perfluorooctylsulfonic acid amide 346 g (29.23 mmol) and 22.16 g (87.7 ml) of 9- (tetrahydropyran-2-yl) -3,6,9-trioxanonyl chloride were dissolved in 200 ml of acetonitrile. 41.46 g (300 mmol) of potassium carbonate and 1 g (6 mmol) of potassium iodide were added and boiled for 10 hours in counterweight. The solid was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 400 ml of ethanol and 30 ml of 10% aqueous hydrochloric acid were added. Stirred for 2 hours at room temperature. With sodium hydroxide the pH was adjusted to 7 and the solution was concentrated in vacuo. The residue was chromatographed on silica gel (eluent: chloromethane / methanol = 10: 1).

Yield: 11.38 g (51% of theory) of a colorless, viscous oil. Elemental analysis:

Est: H, 31.46 N1.83 F 42.30 8 4.20 Gender: H, 31.59; H, 3.50 N1.90 F 42.46 S 4.08 B) preparation of finished forms of metal complex I and amide on Ν, Ν bis (8-hydroxy-3,6-dioxo-octyl) -

perfluorooctylsulfonic acid

To 37 ml of a solution of metal complex I (280 mol / L) dissolved in 0.45% aqueous sodium chloride (pH 7.4; 0.25 mg / L CaNaaDTPA) were added 7.91 g (10, 36 mmol) of the title compound of Example 84a and supplemented with 0.9% aqueous sodium chloride solution to a total of 104 ml. It is heated for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to pH 2 with aqueous 2N sodium hydroxide solution

347

7.4. Filter through a 0.2 µm filter and the filtrate is ready for filling. A solution thus obtained may be used vaporously for biological testing. (The concentration is 100 mmol Gd / L).

Example 85

a) Ν, Ν-bis (t-butyloxycarbonylmethyl) perfluorooctylsulfonic acid amide g (38.97 mmol) of perfluorooctylsulfonic acid amide and 20.73 g (150 mol) of potassium carbonate were suspended in 200 ml of acetone and g (17.56 added) 90 mmol) bromoacetic acid tert-butyl ester. Boil for 3 hours counterclockwise. The solid was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: n-hexane / acetic ester = 10: 1).

Yield: 23.52 g (83% of theory) a colorless, waxy solid

Elemental analysis: Calc'd: ^ 33.02 H3.05 F 44.40 N1.93 S4.41 Gender: θ 33.19 H3.11 F 44.30 N1,99 S4.32 B) amide on Ν, N-6nc (carboxy methyl) -

perfluoroctylsulfonic acid, disodium salt g (31.62 mmol) of the title compound of Example 85a was dissolved in 300 ml of trifluoroacetic acid and

348 were stirred for 5 hours at room temperature. It was evaporated to dryness in vacuo and the residue was crystallized from acetone. The crystals were sucked off and dried in vacuo at 50 ° C.

Yield: 17.7 g (91% of theory) of a colorless, crystalline powder g (27.63 mmol) of the thus obtained di-acid was dissolved in 100 ml of water / 300 ml of ethanol and then 9.2 ml of 3N was added. aqueous sodium hydroxide. It was stirred for 20 minutes at room temperature and finally evaporated to dryness in vacuo. The residue was dried in vacuo (60 ° C for 8 hours). Yield: 18.2 g of a colorless, crystalline powder

Elemental analysis:

_Est . C21.87 BUT, 61 N2,12 F49.00 S4.86 Na6,98 _Sex: C 22,00 H0,70 N2,20 F 49,17 S4,93 Na 7,10

c) Preparation of Formulations of Metal Complex II and N, N-bis (Carboxymethyl) -perfluoroctylsulfonic acid amide, disodium salt

To 41 ml of a solution of metal complex II (250 mmol / L) dissolved in 0.45% aqueous sodium chloride (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) was added 2p89 g (4, 39 mmol) of the title compound of Example 85b and supplemented with 0.9% aqueous sodium chloride solution to a total of 52 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with aqueous 2N sodium hydroxide. Filter through 0.2

349 pm filter and the filtrate is ready for filling. A solution thus obtained can be used directly for biological testing. (The concentration is 200 mmol Gd / L).

Example 86

a) 1H, 1H, 2H, 2H-perfluordodecyl sulfuric acid monoester, sodium salt (17.73 mmol) of 1H, 1H, 2H, 2H-perfluordodecanol is dissolved in 300 ml of chloroform and at 0 ° C 2 , 82 g (17.73 mmol) of the sunterioxide-pyridine complex. It was stirred for one hour at 0 ° C and finally evaporated in vacuo to dryness. The residue was dissolved in 300 ml of ethanol and mixed with 17.8 ml of 1N aqueous sodium hydroxide. The solution was evaporated to dryness and the residue was dried in vacuo (60 ° C / 2 hours).

Yield: 11.81 g (quantitative)

Elemental analysis:

Calcd. With 21.64 H0.61 F 59.89 Na 3.45 S4.81 _Paul . C21.70 H 0.72 F 60.00 Na 3.57 S4.92

b) Preparation of formulations of metal complex VI and monoester of 1H, 1H, 2H, 2H-perfluordodecyl-sulfuric acid, sodium salt

To 38 ml of a solution of metal complex VI (290 mmol / L) dissolved in 0.45% aqueous sodium chloride solution are

350 was added 4.90 g (7.35 mmol) of the title compound of Example 86a and heated for 10 minutes in a microwave. The solution was cooled to room temperature, filtered through a 0.2 µm filter and the filtrate ready for filling. A solution thus obtained can be used directly for biological testing. (The concentration is 290 mmol Gd / L).

Example 87

a) 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluoropentadecanoic acid, sodium salt (16.07 mmol) 2H, 2H, 4H, 4H, 5H, 5H-3-oxaprofluoropentadecanoic acid were dissolved in 300 ml of ethanol and mixed with 16.1 ml of 1N aqueous sodium hydroxide. The solution was evaporated to dryness and the residue was dried in vacuo (60 ° C / 2 hours).

Yield: 10.35 g (quantitative) colorless, amorphous powder Elemental analysis:

_m C 26.10 H 0.94 F 61.94 Na 3.57

Est:

_Sex: C 26.22 H1.00 F 62.05 Na 3.66

b) Preparation of the Formulations of the Title Compound of Example 66 and 2H, 2H, 4H, 4H, 5H, 5H-3-oxaprofluoropentadecanoic acid, sodium salt

To 45 ml of a solution of the title compound of Example 66 (270 mmol / L) dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNaaDTPA) was added a solution of

3.36 g (5.21 mmol) of the title compound of Example 87a,

351 dissolved in 200 ml of ethanol, stirred for 2 hours at 50 ° C. The solution was concentrated in vacuo and the residue supplemented with distilled water to a total of 122 ml. Stirred for 10 minutes at 40 ^° C and filtered through a 0.2 ppm filter. The filtrate is ready for filling. A solution thus obtained can be used directly for biological testing. (The concentration is 100 mmol Gd / L).

Example 88

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

To 30 g (117.1 mmol) of EDTA-bisanhydride suspended in 200 ml of dimethylformamide and 50 ml of pyridine were added portionwise at 50 ° C 10.14 g (20 mmol) of 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecylamine and stirred for 6 hours at 50 ° C. 10 ml of water was added, stirred for 10 minutes at 50 ° C and the residue was evaporated to dryness. The residue is absorbed in a little water and with glacial acetic acid PH is brought to 4. The insoluble precipitate is filtered off and chromatographed on RP-18 (eluent: acetonitrile / water / gradient).

Yield:

9.58 g (61% of theory) colorless solid water content: 8% elemental analysis:

_read; 033.64 N 3.59 N5.35 F 41.12

352 _sex C 33.51 N 3.69 N5.44 F41.24

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

9.0 g (11.46 mmol) of the title compound of Example 88a were suspended in 300 ml of water and 11.4 ml of 1-N aqueous sodium hydroxide was added. Finally, 1.15 g (11.46 mmol) of calcium carbonate were added and stirred for 5 hours at 50 ° C. The solution was filtered and the filtrate was freeze-dried.

Yield: 9.7 g (100% of theory) of a colorless, amorphous substance Water Content: 7.5% firmly Elemental analysis: C 4.74 Ca 4.82 Calc'd: C 31.25 H2.98 Gender: C31.40 NZ, 09 N4.97 F 38.20 At 2.72 N5.10 F 38.07 At 2.81 c) Receipt of a metallic complex I finished form and ethylenediamine-N, N-tetraacetic acid -N-

(1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) - monoamide, calcium salt, sodium salt

To 43 ml of a solution of metal complex I (280 mmol / L) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) were added 2.54 g ( 3.01 mmol) at

353 of the title compound of Example 88b and top up with 0.9% aqueous sodium chloride solution to a total of 121 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with 2 N sodium hydroxide solution. Filter through a 0.2 pm filter and the filtrate is ready for filling. A solution thus obtained can be directly used for biological testing. (The concentration is 100 mmol Gd / L).

Example 89

a) 1H, 1H, 2H, 2H-perfluorodecyl- (2,2-dimethyl-5-hydroxy-1,3-dioxepan-6-yl) -ether 2 (64.64 mmol) 1H, 1H, 2H, 2H- Perfluordecanol was dissolved in 200 ml of THF and at 1.00C at 1.68 g (70 mmol) of sodium hydride were added. It was stirred for 2 hours at room temperature and then for 4 hours at 60 ° C. The solution was placed in a metal autoclave, then 9.31 g (64.64 mmol) of 2.2dimethyl-1.3 were added. , 6-trioxabicyclo [5.1.0] octane and finally heated for 10 hours at 150 ° C. The reaction solution was poured into ice water and extracted twice with diethyl ether. The combined organic phases were evaporated to dryness and the residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 10: 1).

Yield: 16.12 g (41% of theory) of a colorless solid

Elemental analysis:

_Est . SPA, 57 H2.82 F53.10

354 _Sex; C, 33.69; H2.90; F, 53.35

b) 1H, 1H, 2H, 2H-perfluorodecyl- (1-hydroxymethyl-2,3-dihydroxypropyl) -ether (24.66 mmol) of the title compound of Example 89a was dissolved in 300 ml of ethanol and 30 ml of 10% was added - of aqueous hydrochloric acid. It is heated for 5 hours countercurrently. The pH was adjusted to 7 with sodium hydroxide, then concentrated to dryness and the residue chromatographed on RP-18 (eluent: acetonitrile / water / gradient).

Yield: 12.75 g (91% of theory) of a colorless solid. Water content: 4.5%

Elemental analysis:

_Est; With 29.59 N2.31 F 56,84 _Paul. C 29.48 H2.37 F 56.99

c) Preparation of the title compound of Example 12 of WO 99/01161 (1,4,7-Tris {1,4,7-Tris (Ncarboxylatomethyl) -10- (N-1-methyl-3-aza- 2,5-dioxo-pentane-1,5diyl) -1,4,7,10-tetraazacyclododecane, Gd-complex} -10- [2- (Nethyl-N-perfluoroctylsulfonyl) -amino] -acetyl1,4,7, 10 tetraazacyclododecane) and 1H, 1H, 2H, 2H-perfluorodecyl- (1-hydroxymethyl-2,3-dihydroxypropyl) -ether

To 37 ml of a solution of 1,4,7-tris {1,4,7-Tnc (Ncarboxylatomethyl) -10- (N-methyl-3-aza-2,5-dioxo-pentane-1,5diyl) 1,4 , 7,10-tetraazacyclododecane, 6b-complex} -10- [2- (M-ethyl355)

N-perfluoroctylsulfonyl) -amino] -acetyl-1,4,7,10tetraazacyclododecane (300 mmmol / L) dissolved in 0.45% aqueous sodium chloride (pH 7.4; 0.25 mg / L)

CaNa ₃ DTPA), 9.46 g (16.65 mmol) of the title compound of Example 89b were added and supplemented with 0.9% aqueous sodium chloride solution to a total of 111 ml. It was heated for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with 2N sodium hydroxide solution. Filter through a 0.2 µm filter and the filtrate is ready for filling. A solution thus obtained can be directly used for biological testing. (The concentration is 100 mmol Gd / L).

Example 90

a) 1H, 1H, 2H, 2H-perfluorodecyl- [1,2-bis (2,2-dimethyl-1,3dioxolan-4-yl) -2-hydroxyethyl] -ether 2 (64.64 mmol) 1H , 1H, 2H, 2H-perfluorodecanol were dissolved in 200 ml of THF and at 1.00C (1.68 g (70 mmol)) of sodium hydride were added. It was stirred for 2 hours at room temperature, then for 4 hours at 60 ° C. The solution was placed in a metal autoclave, and then 15.78 g (64.64 mmol) of 1,2-bis- (2,2dimethyl-1,3-dioxolan-4-yl) -oxidated and finally heated for 10 hours at 150 ^° C. The reaction solution was poured into ice water and extracted twice with diethyl ether. The combined organic phases are

356 was evaporated to dryness and the residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 10: 1) yield: 14.2 g (31% of theory) colorless solid elemental analysis:

_read; C, 37.30 H3.56 F 45.59 _gender; H, 37.48; H, 46.6; F, 45.71

b) 1H, 1H, 2H, 2H-perfluorodecyl- [1,2-bis (1,2-dihydroxy-ethyl) -2-hydroxyethyl] -ether 2 (19.76 mmol) of the title compound of Example 90a is was dissolved in 300 ml of ethanol and 30 ml of 10% aqueous hydrochloric acid was added. Heat for 5 hours in a rotary stream. The pH was adjusted to 7 with sodium hydroxide, then evaporated to dryness and the residue was chromatographed on RP-18 (eluent: acetonitrile / water / gradient).

Yield: 10.55 g (85% of theory) colorless solid Water content: 3.2%

Elemental analysis:

Calc: C 30.59 N2,73 F51.41 _Paul. C, 30.73; H2.81; F51.58

c) Preparation of metal complex II and

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

357

To 41 ml of a solution of metal complex II (300 mmol / L) dissolved in 0.45% aqueous sodium chloride (pH 7.4; 0.25 mg / L CaNaaDTPA) was added 11.98 g (19, 07 mmol) from the title compound of Example 90b and with 0.9% aqueous sodium chloride solution was added to a total of 64 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with 2N sodium hydroxide solution. Filter through pm filter and the filtrate is ready for filling. A solution thus obtained can be used for biological testing. (Concentration is 200 mmol Gd / L).

Example 91

a) Perfluorooctylsulfonic acid-b1, 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 were dissolved in 300 ml of chloroform and 2.82 g (17.73 mmol) of sulfur trioxide-pyridine complex were added at 0 ° C. The mixture was stirred at 0 ° C for one hour and then evaporated to dryness in vacuo. The residue was dissolved in 300 ml of ethanol and mixed with 17.8 ml of 1N aqueous sodium hydroxide. The solution was evaporated to dryness and the residue was dried in vacuo (60 ° C / 2 hours).

Yield: 17.15 g (quantitative)

Elemental analysis:

Est:

24.83 H2,50 F 33.83 N1.45 S 9.94 Na4.75

358 _Paul . C, 24.96; H2.62; F; 33.97; N, 1.53; S, 10.05;

B) Preparation of formulations of metal complex I and perfluorooctylsulfonic acid N-bis [(8-sulfuric acid monoester, sodium salt) -3,6-dioxaoctyl] -amide

Add 43.22 g to 43 ml of a solution of metal complex I (380 mol / L) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) ( 147.06 mmol) of the title compound of Example 91a and with a 0.9% sodium chloride solution was added to a total of 164 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with 2N sodium hydroxide solution. Filter through a 0.2 pm filter and the filtrate is ready for filling. A solution thus obtained can be directly used for biological testing. (The concentration is 100 mmol Gd / L).

Example 92

a) 2- (2, H, 2H, 3H, 3H, 5H, 6H, 6H-1,4dioxafluorotetradec-1-yl) -succinic acid diethyl e d (59.03 mmol) 1H, 1H, 2H, 2H, 4H, 4H , 5H, 5H-3-oxaprofluorotridecanol are dissolved in 300 ml of tetrahydrofuran and 1.68 g (70 mmol) of sodium chloride are added at 0 ° C. It is stirred for one hour at 0 ° C and then for 5 hours at 40 ° C. In this solution at 40 ° C.

359 drops of 10.25 g (80 mmol) of 2-hydrochloric acid diethyl ester were added dropwise over 10 minutes and stirred for 12 hours at the same temperature. 500 ml of ice water was added and extracted twice with 300 ml of diethyl ether. The combined organic phases were evaporated to dryness and the residue was chromatographed on silica gel (eluent: n-hexane / ethanol = 20: 1).

Yield: 12.05 g (30% of theory)

Elemental analysis:

Calc: θ 35.31 H3.11 F 47.47 _Sex: C 35.19 H 3.20 F 47.59

B) 2- (2H, 2H, 3H, 3H, 5H, 5H, 6H, 6H-1,4-dioxaprofluorotetradec-1-yl) -succinic acid, disodium salt

To 11.5 g (16.90 mmol) of the title compound of Example 92a, dissolved in 300 ml of methanol, was added 50 ml of 3-1 l-aqueous sodium hydroxide solution and refluxed for 8 hours. It is evaporated to dryness and the residue is absorbed in 300 ml of water. Extract the aqueous well twice with 300 ml of diethyl ether. The aqueous phase is acidified with conc. hydrochloric acid to pH 1 and extracted twice with 300 ml of chloroform. The combined chloroform phases were dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in 300 ml of water and the pH was adjusted to 5% with aqueous sodium hydroxide.

7.4. finally freeze dried.

Yield: 10.50 g (93% of theory) of a colorless, amorphous solid

360

Water content: 5.7%

Elemental analysis:

_Est; C 28.76 H1.66 F 48.33 Na 6.88

Paul; C 28.88 H 1.71 F 48.25 Na 6.95

c) Preparation of formulations of metal complex II and 2- (2H, 2H, 3H, 3H, 5H, 5H, 6H, 6H-1,4-dioxa-perfluorotetradec-1-yl) succinic acid, disodium salt

To 57 ml of a solution of metal complex II (300 mmol / L) dissolved in 0.45% aqueous sodium chloride (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) was added 1.14 g ( 1.71 mmol) of the title compound of Example 92b and supplemented with a total of 0.9% aqueous sodium chloride solution to a total of 154 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to pH 2 with aqueous 2N sodium hydroxide solution

7.4. Filter through a 02 μτη filter and the filtrate is ready for filling. A solution thus obtained can be directly used for biological testing. (The concentration is 100 mmol Gd / L).

Example 93

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

To 20 g (38.30 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3perfluorotridecanoic acid and 9.21 g (80 mmol) of N361 hydroxysuccinimide dissolved in 150 ml of dimethylformamide were added at 0 ° C 16.51 d (80 mmol), дици'dicyclohexylcarbodiimide and stirred for 3 hours at the same temperature. A solution of 5.10 g (38.30 mmol) of L-aspartic acid dissolved in 300 ml of 5% aqueous sodium carbonate solution was added to the thus obtained solution of the active esters and stirred for a while. at 2 ° C for 2 hours. It is then poured into 500 ml of ice water, filtered from precipitated dicyclohexylurea and conc. hydrochloric acid is brought to pH 1. It is extracted 3 times with 300 ml of chloroform. The combined organic phases were concentrated to dryness and the residue was chromatographed on RP-18 (eluent 7 acetonitrile / fashion / gradient). The resulting acid was dissolved in 400 ml of water and the pH was adjusted to 7.4 with 1N aqueous sodium hydroxide. The filtrate is filtered and then freeze-dried. Edible content: 6.3%

Yield: 21.13 g (81% of theory) of a colorless amorphous powder. Elemental analysis:

_Est . S28.21 N1,48 N2,06 F47.41 Na6,75 _Paul. C 28.30 N 1.53 N 2.11 F 47.53 Na 6.83

B) Preparation of metal complexes XIV and 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid-N (succin-2-yl) -amide

To 37 ml of solution of metal complex XIV (300 mmol / L) dissolved in 0.45% aqueous sodium chloride solution (pH 7.4;

362

0.25 mg / L CaNa ₃ DTPA), 422 mg (0.62 mmol) of the title compound of Example 93a were added and a 0.9% aqueous sodium chloride solution was added to a total of 111 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and brought to aqueous 2N sodium sulfate pH

7.4. Filter through a 0.2 μνπ filter and the filtrate is ready for filling. A solution thus obtained can be directly used for biological testing. (The concentration is 100 mmol Gd / L).

Example 94

Preparation of Formulations of the Title Compound of Example 67 and Perfluorooctanesulfonic acid, sodium salt

A solution of 43 ml of a solution of the title compound of Example 67 (250 mmol / L) dissolved in 0.45% sodium chloride solution (pH 7.4 / 0.25 mg / L CaNa ₃ DTPA) was added.

1.34 g (2.69 mmol) of perfluorooctanesulfonic acid, sodium salt, dissolved in 200 ml of ethanol and stirred for 2 hours at 50 ° C. The solution was concentrated to dryness and the residue was supplemented with distilled water to a total of 108 ml. It was stirred for 10 minutes at 40 ° C and then filtered through a 0.2 µm filter. The filter is ready for filling. The solution thus obtained can be used directly for biological testing (the concentration is 100 mmol Gd / L).

363

Example 95

Preparation of Formulations of the Title Compound of Example 68 and Perfluorodecansulfonic Acid, Sodium Salt

To 49 ml of a solution of the title compound of Example 68 (310 mmol / L) dissolved in 0.45% aqueous sodium chloride solution was added 3.03 g (5.06 mmol) of perfluorodecansulfonic acid, sodium salt and sat. heat for 10 minutes in a microwave. The solution was cooled to room temperature, filtered through a 0.2 µm filter and the filtrate ready for filling. A solution thus obtained can be directly used for biological testing. (The concentration is 310 mmol Gd / L).

Example 96

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

To 20 g (80.62 mmol) of 5-hydroxyisophthalic acid trisodium salt in 300 ml of diethylformamide are added

42.5 g (80.62 mmol) of the title compound of Example 14a and stirred for 10 hours at 60 ° C. It is then poured into 1500 ml of ice water and conc. the pH was adjusted to 1. Extracted 3 times with 300 ml of chloroform. The combined organic phases were evaporated and the residue was chromatographed on RP-18 (eluent: acetonitrile / water / gradient). The resulting acid was dissolved in 00

364 ml of water and with 1N aqueous sodium hydroxide the pH was adjusted to 7.4. It was filtered and the filtrate was freeze-dried.

Yield: 20.05 g (37% of theory) of a colorless amorphous solid

Water Content: 5.0%

Elemental analysis:

_Est; C, 32.16 H 1.05 F 48.05 Na 6.84 _Pol . C, 32.30 H 1.15 F 48.20 Na 6.95

B) Preparation of Formulations from the Title Compound of Example 12 of WO 99/01161 (1,4,7-Tris {1,4,7-Tris (Mcarboxylatomethyl) -10- (N-1-methyl-3-aza- 2,5-dioxo-pentane-1,5diyl) -1,4,7,10-tetraazacyclododecane, C 1 -complex} -10- [2- (N-ethyl N-perfluoroctylsulfonyl) -amino] -acetyl-1,4, 7,10tetraazacyclododecan) and (1H, 1H, 2H, 2H-perfluorodecyl) -5 - [(1,3dicarboxy, disodium salt) -phenyl] -ether

To a solution of 1,4,7-tris {1,4,7-tris (N-carboxylatomethyl) -10- (N-1-methyl-3-aza-2,5-dioxo-pentane-1,5-d yl) -1,4,7,10tetraazacyclododecane, Gd-complex} -10- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-1,4,710tetraazacycododecane (300 mmol / L) dissolved in 0.45 % aqueous sodium chloride solution (pH 7.4; 0.25 mg / L CaNaaDTPA), 6.86 g (10.2 mmol) of the title compound of Example 96a were added and supplemented with 0.9% aqueous sodium chloride solution to a total of 153 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution is

365 is cooled to room temperature and with aqueous 2N sodium hydroxide the pH is adjusted to 7.4. Filter through a 0.2 pm filter and the filtrate is ready for filling. A solution thus obtained can be directly used for biological testing. (The concentration is 100 mmol Gd / L).

Example 97

Preparation of Forms from Metal Complex XIV and 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-Perfluorotridecanoic Acid, Sodium Salt

To 4 ml of a solution of metal complex XIV (320 mmol / L) dissolved in 0.45% aqueous sodium chloride (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 made up with 0.9% aqueous sodium chloride solution to a total of 12.8 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with aqueous 2N sodium hydroxide. Filter through a 0.2 pm filter and the filtrate is ready for filling. A solution thus obtained can be used directly for biological testing. (The concentration is 100 mmol Gd / L).

Example 98

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

To 15.22 g (100 mmol) of 1-adamantanol in 300 ml of 50% aqueous potassium base, 200 ml of toluene were added at

366 temperature 0 ° C 29.26 g (150 mmol) of t-butyl ester of bromoacetic acid and stirred vigorously for 2 hours. It was then 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 concentrated to dryness in vacuo. The residue was chromatographed on silica gel (eluent: n-hexane / diethyl ether = 20: 1).

Yield: 21.58 g (81% of theory) of a viscous, colorless oil. Elemental analysis:

_Est; H, 72.84; 9.84

Gender: ^C72 · ^{26H9 '95}

b) (adamant-1-yl) -3-oxa-propionic acid g (75 mmol) of the title compound of Example 98a was dissolved at 0 ° C in 200 ml of trifluoroacetic acid and stirred at room temperature for 8 hours. . It was evaporated to dryness and the residue was crystallized from diisopropyl ether.

Yield: 14.68 g (93% of theory) of colorless flakes

Elemental analysis:

And 34 'C, 68.55; H, 8.63

Gender: C, 68.41; H8.74

c) 1- (perfluoroctylsulfonyl) -4 - [(adamant-1-yl) oxapropionyl] -piperazine (66.6 mmol) from the title compound of Example 98b and 37.50 g (66.6 mmol) of 1-perfluoroctylsulfonyl-piperazine se

36Ί was dissolved in 300 ml of tetrahydrofuran and at 0 ° C was mixed with 32.15 g (130 mmol) of 1,2-dihydro-2-ethoxyquinoline-1-carboxylic acid ethyl ester (= EEDQ). Stirred for 5 hours at room temperature. The solution was evaporated to dryness in vacuo and the residue was chromatographed on silica gel (eluent: dichloromethane / diethyl ether = 30: 1).

Yield: 43.05 g (85% of theory) colorless solid Elemental analysis:

_Est . C 37.90 H3.31 N3.68 S4.22 F 42.47

Sex: C 38.04 H 3.42 N3.49 S4.11 F 42.30

d) Formulations for administration of 0.5 parts metal complex I of β-cyclodextrin hydrate and 1 (perfluorooctylsulfonyl) -4 - [(adam-1-yl) -oxapropionyl] piperazine

To 32 ml of a solution of metal complex I (280 mmol / L) dissolved in 0.45% aqueous sodium chloride (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) was added 6.81 g (8, 96 mmol) of the title compound of Example 98c and 10.33 g (8.96 mmol) of β-cyclodextrin monohydrate and with 0.9% aqueous sodium chloride solution was added to a total of 98 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with aqueous 2Ν sodium hydroxide. Filter through a 0.2 pm filter and the filtrate is ready for filling. A solution thus obtained can be used directly for biological testing. (Gd concentration is 100 mmol Gd / L).

368

Example 99

a) 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid-N- (1-adamantyl) -amide

To 15.12 g (100 mmol) of 1-amino-adamantane, 52.21 g (100 mmol) of 3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoic acid and 11.51 g (100 mmol) N-hydroxysuccinimide dissolved in 300 ml of THF was added at 0 ° C to 30.95 g (150 mmol) of N, N-dicyclohexylcarbodiimide. It was stirred for 2 hours at 0 ° C and then for 6 hours at room temperature. Finally, the precipitated urea was filtered off, the filtrate was evaporated to dryness and the residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 30: 1).

Yield: 54.4 g (83% of theory) of waxy solid Elemental analysis:

_Est; C 40.32 H3.38 N2.14 F 49.28 _Sex .C 40.47 H3.49 N2.03 F 49.09

b) Formulations for administration of 0.6 parts metal complex and 0.4 parts included compound of β-cyclodextrin-hydrate and 3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorodidanoic acid -H- (1 -adamantyl) -amide

To 41 ml of a solution of metal complex II (250 mmol / L) dissolved in 0.45% aqueous sodium chloride (pH 7.4; 0.25 mg / L CaNa ₃ DTPA) were added 4.48 g (6, 83 mmol) of the title compound of Example 99a and 7.87 g (6.83 mmol) of β369 cyclodextrin monohydrate and with a 0.9% aqueous sodium chloride solution was added to a total of 103 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with 2N sodium hydroxide solution. Filter through a 0.2 pm filter and the filtrate is ready for filling. A solution thus obtained can be used directly for biological testing. (Gd concentration is 100 mmol Gd / L).

Example 100

a) 2- [N- (ethyl) -N- (perfluoroctylsulfonyl) -amino] -acetic acid N- (adamantyl) -amide

To 15.12 g (100 mmol) of 1-aminoadamantane, 58.52 g (100 mmol) of L1- (ethyl) -N- (perfluorocysulfonyl) -aminoacetic acid and 11.51 g (100 mmol) of N-hydroxysuccinimide dissolved in 300 ml of tetrahydrofuran were added at 0 ° C to 30.95 g (150 mmol) of Νcyclohexylcarbodiimide. It was stirred for 2 hours at 0 ° C and then for 6 hours at room temperature. It is filtered off from the precipitated urea, the filtrate is evaporated to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / acetonitrile = 30: 1).

Yield: 55.65 g (79% of theory) of amorphous solid Elemental analysis:

_Est; 0 37.51 H3.29 F 45.85 N1.99 S4.55

Sex: H3.41 F45.99 N2.12 S4.43

370

B) Formulations for administration of 0.6 parts metal complex I and 0.4 parts included compound β-cyclodextrin-hydrate and 2- [N- (ethyl) -N (perfluoroctylsulfonyl) -amino] -acetic acid-N- (1-adamantyl) ) -amide

To 32 ml of a solution of C metal complex (280 mmol / L) dissolved in 45% aqueous sodium chloride solution (pH 7.4; 0.25 mg / L CaNa3DTPA) were added 4.20 g (5.97 mmol) of the title compound of Example 100a and 6.88 g (5.97 mmol) of β-cyclodextrin monohydrate and with 0.9% aqueous sodium chloride solution was made up to a total of 90 ml. Heat for 2 hours at 60 ° C in an ultrasonic bath. The solution was cooled to room temperature and the pH was adjusted to 7.4 with aqueous 2Ν sodium hydroxide. Filter through a 0.2 pm filter and the filtrate is ready for filling. The solution thus obtained can be used directly for biological testing. (The concentration of gadolinium is 100 mmol Gd / L).

Example 101

a) 6-N-Benzyloxycarbonyl -2-N- (3,6,9,12 tetraoxatridecanoyl) -lysine [1- (4-perfluoroctylsulfonyl) piperazine] -amide, 50 g (60.20 mmol) of the title compound of Example 1c and 7.10 g (70 mol) of triethylamine dissolved in 350 ml of dichloromethane, a solution of 16.85 g (70 mmol) of chloride of 3,6,9,12 was added dropwise at 0 ° C.

371 tetraoxatridecanoic acid in 50 ml of dichloromethane and stirred for 3 hours at 0 ° C. 200 ml of 5% aqueous hydrochloric acid was added and stirred for 5 minutes at room temperature. 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: 30.94 g (92 5% of theory) of a colorless, viscous oil.

Elemental analysis: Calc: C, ^40.83 H, 4.19 F, 31.21 N, 5.41 S 3.10 _π C 40.75 Sex: H, 4.08 F, 31.29 N, 5.58 S, 3.25

B) 2 N- (3,6,9,12-tetraoxatridecanoyl) -lysine perfluorooctylsulfonyl) -piperazine]

53.96 g () of 52.15 mmol of the title compound of Example 101a were dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. It was filtered off from the catalyst and the filtrate was evaporated in vacuo to dryness.

Yield: 43.0 g (quantitative) of a colorless solid

Elemental analysis:

_Est . H, 36.14; 4.14

Gender: ⁰³⁶ * ^{20 H4} '*

F 35.86 N 6.22 S3.56

F 35.99 N 6.38 S3.71

c) 6-N- [1,4,7-Tpnc (tetraazacyclododecane carboxylatomethyl) -1,4,7,10-10- (pentanoyl-3-aza-4-oxo-5-methyl-5372 yl)] - 2 N- (3,6,9,12-tetraoxatridecanoyl) -lysine - [1- (4-perfluoroctylsulfonyl) -piperazine] -amide, gadolinium complex

21.84 g (24.25 mmol) of the title compound of Example 101b, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25) mmol) 1,4,7tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl) pentanoic acid] -1,4,7,10-tetraazacyclododecane, Gd-complex dissolve in 200 ml of dimethyl sulfoxide under gentle heating. At 10 ⁰ C, 8.25 g (40 mmol) Ν, Νcyclohexylcarbodiimide are added and stirred at room temperature overnight. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by chromatography (silica gel RP-18, eluent: gradient of water / ethanol / acetonitrile). Yield: 28.21 g (81% of theory) of a colorless solid.

Water content: 11.0%

Elemental analysis (calculated on the anhydrous substance):

^Est .: ^back > H, 433 F 21.36 N 834 S 2.12 Gd 10.40 Gender: ^036.64 H, 4.48 F 21.39 N, 8D9 S 2.15 G01037 An example 102

a) 6-N-benzyloxycarbonyl -2-N- (propyl-3-sulfonic acid) -lysine [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

373

To 50 g (60.20 mmol) of the title saedineie from example 1c and 7.10 g (70 mmol) of triethylamine, dissolved in 250 ml of dry tetrahydrofuran was added dropwise at a temperature of 50 ⁰ C was added a solution of 7.33 g (60 mmol) propansultone in 50 ml of tetrahydrofuran and stirred for 3 hours at 60 ° C. 200 ml of 5% aqueous hydrochloric acid was added and 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: 45.16 g (79% of theory) of a colorless, viscous oil.

Elemental analysis:

_Est . C 36.56 H 3,49 F 33,90 _Paul. C, 36.72; H, 335; F, 33.79

N, 5.88

N, 5.78

S 6.73

S, 6.75

B) 2-1M- (propyl-3-sulfonic acid) -Lysine - [1- (4-perfluoroctylsulfonyl) -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. Hydrated at room temperature. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo.

Yield: 42.69 g (quantitative) of a colorless solid.

Elemental analysis:

Est:

C, 30.81; H, 332

F, 39.46

N, 6.84

S, 7.83

374 _Sex; C 30.64 H 4.1 F 39.29 N 6.68 S 7.89

c) 6-N- [1,4,7-τρπο (carboxylatomethyl) -1,4,7,10tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] - 2-M - (propyl-3-sulfonic acid) -Lysine - [1- (4-perfluoroctylsulfonyl) -piperazine] -amide, Gd-complex

19.85 g (24.25 mmol) of the title compound of Example 102b, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25) mmol) 1,4,7tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl) pentanoic acid] -1,4,7,10-tetraazacyclododecane, gadolinium complex and slightly heated was dissolved in 200 ml of dimethyl sulfoxide. At 10 ° C, 8.25 g (40 mmol) of Ν, ди-dicyclohexylcarbodiimide are added and stirred at room temperature overnight. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by chromatography (silica gel RP-18, eluent: gradients of water / ethanol / acetonitrile). Yield: 28.13 g (81% of theory) as a colorless solid.

Water content: 11.0% Elemental analysis (calculated on the anhydrous basis):

_Est . C 33.27 H 3,70 F 2236 N 8,73 S 4,44 Gd 10,89 _Paul. C 32.41 H 3.88 F 22.49 N 8.69 S 435 Gd 10.97

Example 103

a) 6-N-benzyloxycarbonyl -2-N, N-6nc (propyl-3-sulfonic acid) -Lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

375

A solution of 14.65 g (120 mmol) was added to 50 g (60.20 mmol) of the title compound of Example 1c and 12.14 g (120 mmol) of triethylamine dissolved in 250 ml of THF. 1,3-propansulton in 100 ml of tetrahydrofuran and stirred for 3 hours at 60 ° C. 400 ml of 5% aqueous hydrochloric acid are added, stirred for 5 minutes at room temperature, mixed with sodium chloride, 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: 52.24 g (81% by weight) of a colorless, viscous oil.

Elemental analysis: _Est . C, 35.76 H, 3.66 F, 30.05 N 5D1 S, 8.95 Gender: ^{C, 35.75} H, 3.55 F 30.19 N, 5.08 S, 9.04

b) 2N, N bis (propyl-3-sulfonic acid) -lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

53.74 g (52.15 mmol) of the title compound of Example 103a was dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo.

Yield: 49.06 g (quantitative) of a colorless solid.

Elemental analysis:

_Calc'd: C 30.64 H 3.54 F 3433 N 5.96 S 10.23

376 _Sex; C, 30.69; H, 3.71; F; 34.19; N, 6.08; S, 10.38

c) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] 2N, N-6nc (propyl-3-sulfonic acid) -Lysine [1- (4-fluorooctylsulfonyl) -piperazine] -amide, gadolinium complex, disodium salt

38.76 g (24.25 mmol) of the title compound of Example 93B 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, gadolinium complex are dissolved slightly heating in 200 ml of dimethyl sulfoxide. At 10 ° C, 8.25 g (40 mmol) of Ν, ди-dicyclohexylcarbodiimide are added and stirred at room temperature overnight. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was separated and finally purified by chromatography (silica gel RP-18, eluent: gradients of water / ethanol / acetonitrile). Yield: 31.63 g (81% of theory) of a colorless solid.

Water content: 11.0%

Elemental analysis (calculated on the anhydrous substance):

Est:

C 32.07 H 3.57 F 20.06 N7.83 S 5.97 Gd9.76 Na 2.86

Gender:

C 31.94 Η 3.48 F 20.19 N7.69 S 5.85 Gd9.87 At 2.99

Example 104

a) N-Trifluoroacetyl-1-glutamic acid-5-benzyl ester

100 g (421.5 mmol) of L-glutamic acid-5-benzyl ester were dissolved in a mixture of 1000 ml of trifluoroacetic acid ethyl ester / 500 ml of ethanol and stirred at room temperature for 24 hours. It was evaporated to dryness and the residue was crystallized from diisopropyl ether. Yield:

140.47 g (96% of theory) of a colorless, crystalline powder.

Elemental analysis:

_Est; C, 50.46 _; H4.23 _; C51D5 H 4.18

F 17.10 N 4.20

F 17.03 N 4.28

B) 2-N-Trifluoroacetyl-L-glutamic acid-5-benzyl ester-N-bis (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 dimethylformamide, 8.25 g (40 mmol) of N, N -dicyclohexylcarbodiimide are added at 0 ° C. It was stirred for 3 hours at 0 ° C, and then allowed to stand with stirring overnight at room temperature. Filtered from the precipitated solid, the filtrate is filtered off

378 was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: = dichloromethane / ethanol = 20: 1).

Yield: 9.11 g (90% of theory) of viscous oil.

Elemental analysis:

Calc: C 51.43 H 5,51 F 13,56 N 6,66 _Paul. C 51.22 H 5.41 F 13.40 N 6.75

c) N-Trifluoroacetyl-L-glutamic acid-N bis (2hydroxyethyl) -monoamide

21.92 g (52.15 mmol) of the title compound of Example 104b were dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo.

Yield: 43.0 g (quantitative) of a colorless solid.

Elemental analysis:

_Est; H, 40.01; 5.19

F 17,26 N 8,48 _Paul. H, 39.13; 5.13

F 17.09 N 8.68

c) Trifluoroacetyl-L-glutamic acid-N-bis (2hydroxyethyl) -amide-5- [1- (4-perfluorooctylsulfonyl) -piperazine] amide

To 10.96 g (33.2 mmol) of the title compound of Example 104a and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 80 ml

379 tetrahydrofuran, 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) were added at 0 ° C and stirred at room temperature overnight. It was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

Yield: 30.93 g (93% of theory) of a colorless solid. Elemental analysis:

_Est . C, 39.61; H, 2.89; F; 35.66; N, 19.19; S, 3.54 _; C 39.68 N 2.74 F 35.81 N 6.13 S 3.40

e) 1-Glutamic acid-N-bis (2-hydroxyethyl) -amide-5 [1- (4-perfluoroctylsulfonyl) -piperazine] -amide in 200 ml of ethanol, boiled at 0 ° C for one hour ammonia gas. It was then stirred for 4 hours at 0 ° C. It was evaporated to dryness and the residue was mixed with water. It was filtered off from the solid and dried in vacuo (50 ° C).

Yield: 26.55 g (97% of theory) of an amorphous solid. Elemental analysis:

Est: £ H 2.89 F 35.66 N 6.19 S 3.54 _Sex C 41.15 H 2.83 F 35.78 N6 ^ 8 S 3.71

f) N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-cetyl-5-yl)] L- glutamic acid-N-bis (2-hydroxyethyl) -amide-5- [1- (4perfluoroctylsulfonyl) -piperazine] -amide, gadolinium complex

380

211.96 g (24.25 mmol) of the title compound of Example 104f, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25) mmol) 1,4,7tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl)] pentanoic acid] - 1,4,7,10-tetraazacyclododecane, gadolinium complex are dissolved by gentle heating in 200 ml of dimethyl sulfoxide. At 10 ° C, 8.25 g (40 mol) of Ν, ци-dicyclohexylcarbodiimide were added and stirred at room temperature overnight. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by chromatography (silica gel RP-18, eluent: gradients of water / ethanol / acetonitrile).

Yield: 27.43 g (81% of theory) of a colorless solid.

Water content: 11.0%

Elemental analysis (calculated on the anhydrous substance):

Calc: ^{C34 '41} H, 3.83 F 23.13 N, 9.03 S 230 Gd 11,26 Gender: ^CPF4 H, 3.98 F23,29 N, 9.19 S 2.15 Gd 11.07 An example 105

a) N-Trifluoroacetyl-L-glutamic acid-5-benzyl ester-N-dimethyl-bis (1,1-dihydroxymethyl) -amide

To a solution of 8.03 g (24.08 mmol) of the title compound of Example 104a, 3.98 g (24.08 mmol) of dimethyl-bis (1,1-dihydroxymethyl) -amine and 2.77 g (24, 08 mmol) Nhydroxysuccinimide dissolved in 150 ml of dimethylformamide,

381 were added at 0 ° C to 8.25 g (40 mmol) of Νcyclohexylcarbodiimide. It was stirred for 3 hours at 0 ° C and finally stirred at room temperature overnight. The precipitated urea was filtered off, the filtrate was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / ethanol = 20: 1).

Yield: 110.53 g (91% of theory) of a viscous oil.

Elemental analysis:

_Est; S50.00 H 5,66 F I, 86 N 7,18 _Paul. C50.17 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 were dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo.

Yield: 20.36 g (quantitative) of a colorless solid. Elemental analysis:

_Est . 40.00 N 5.42 F 14.60 N 7.18 _Gender . C 40.10 H 533 F 14.69 N 7.28 N-Trifluoroacetyl-L-glutamic acid in-N-bis (1,1d hydroxymethyl) amide-5- [1- (4perfluoroctylsulfonyl) piperazine] -amide

382

To 12.96 g (33.3 mmol) of the title compound of Example 105b and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 800 ml of THF were added at 0 ° C. 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred at room temperature overnight. It was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

Yield: 28.42 g (91% of theory) of a colorless solid.

Elemental analysis:

_Est; H, 31.00

F 40.40

N, 5.96

S 3.41 _Gender . C, 32.08; H, 2.94

F 40.57 N 5.88 S 3.31

b) 1-glutamine dihydroxymethyl)] - amidic acid - Schdimethyl bis (1,1-

5 - [(1-4-perfluorooctylsulfonyl) piperazine] -amide

In a solution of 28.41 g (30.2 mmol) of the titled compound of Example 105c in 200 ml of ethanol, an ammonia gas is passed at 0 ° C for one hour. It was then stirred for 4 hours at 0 ° C. It was evaporated to dryness in vacuo and the residue was stirred with water. It was filtered off from the solid and dried in vacuo (50 ° C).

Yield: 24.74 g (97% of theory) of an amorphous solid. Elemental analysis:

_Est . C 32.71 H 3.46 F 38.24 N 6.63 S 3.80

383 _Sex _ C 32.75 H 333 F 38.38 N 6.68 S 3.81

e) 2-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] -1-glutamine acid- N- [dimethyl-bis (1,1-dihydroxymethyl) -amide] -5- [1- (4-perfluorooctylsulfonyl) piperazine] -amide, gadolinium complex

20.48 g (24.25 mmol) of the title compound of Example 105d, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24p25 ppv) 1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl)] - pentanoic acid] - 1,4,7,10-tetraazacyclododecane, gadolinium complex dissolved under gentle heating in 200 ml of dimethyl sulfoxide. At 10 ° C, 8.25 g (40 mmol) Ν, Νcyclohexylcarbodiimide were added and stirred at room temperature overnight. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by chromatography (silica gel RP18, eluent: gradients of water / ethanol / acetonitrile).

Yield:

29.05 g (83% of theory) colorless solid water content: 11.0% elemental analysis (calculated on the anhydrous substance): _calcd . C 34.12 H 3 ^ 1 F2238 N8,73 S232 Gd 10,90 _gender. C 34.24 H3.98 F2239 N8.69 S2.15 Gd 10.87

Example 106

384

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-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 80 ml of tetrahydrofuran were added at 0 ° C. 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred at room temperature overnight. Evaporate to dryness in vacuo and chromatograph on silica gel (eluent: dichloromethane / methanol = 20: 1)

Yield: 27.28 g (93% of theory) of a colorless solid

Elemental analysis: _Est; C 3535 H 2.40 F 43.01 N 4.76 S, 3.63 _Paul . C, 35.48; H, 231 F 42.87 N 4.73 With evil B) M-Trifluoroacetyl- L is glutamic acid-5- [1- (4- perfluoroctylsulfonyl) -piperazine] -amide

21.92 g (52.15 mmol) of the title compound of Example 106a was dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Rd / C) was added. Hydrated at room temperature. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo.

Yield: 41.37 g (quantitative) colorless solid. Elemental analysis:

And _zch: C 28.76 H 1,91 F 47,89 N 530 S 4.04 _Sex. C 28.84 N 2.03 F 47.79 N 5.28 S 4.19

385

c) N-Trifluoroacetyl-L-glutamic acid-N-6nc (2-hydroxyethyl) -amide -5- [1- (4-perfluoroctylsulfonyl) -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) orejdkf.d; rk r

2.77 g (24.08 mmol) of N-hydroxysuccinimide dissolved in 150 ml of dimethylformamide were added at 0 ° C to 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide. It was stirred for 3 hours at 0 ° C, and was finally stirred overnight at room temperature. Filtered from the precipitated urea, the filter was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: = dichloromethane / ethanol = 20: 1).

Yield: 9.11 g (90% of theory) of a viscous oil.

Elemental analysis: Calc: ^{5 1} · ³⁷ H, 2.75 F 43.15 N, 6.36 S, 3.64 Gender: ^p H, 2.61 F 43.30 N 635 S, 3.81

b) 1-glutamic acid-N-bis (2-hydroxyethyl) -amide-5 [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

In a solution of 26.61 g (30.22 mmol) of the title compound of Example 106c in 200 ml of ethanol was passed an ammonia gas at 0 ° C for one hour. It was stirred for 4 hours at 0 ° C. It was evaporated to dryness in vacuo and the residue was stirred with water. It was filtered off from the solid and dried in vacuo (50 ° C).

386

Yield:

23.93 g (97% of theory) of an amorphous solid.

Elemental analysis:

_Est; C 30.89 H 3,09 F 39,56 N 6,86 S 3,93 _Paul. C 30.75 N 3.13 F 39.78 N 6.75 S 3.81

e) N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-40oxo-5-methyl-5yl)] - L-glutamic acid-N- -5- [1 (4-perfluoroctylsulfonyl) -piperazine] -amide bis (2-hydroxyethyl) -amide

16.43 g (24.25 mmol) of the title compound of Example 106d, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.2 g (50 mmol) of lithium chloride and 15.27 g (24.25) mmol) 1,4,7tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl)] - pentanoic acid] -1,4,7,10-tetraazacyclododecane, gadolinium complex dissolved under gentle heating in 200 ml of dimethyl sulfoxide. At 10 ° C, 8.25 g (40 mmol) of Ν, ди-dicyclohexylcarbodiimide are added and stirred at room temperature overnight. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by chromatography (silica gel RP-18, eluent: gradients of water / ethanol / acetonitrile). Yield: 28.10 g (83% of theory) of a colorless solid.

Water content: 11.0%

Elemental analysis (calculated on the anhydrous substance):

387

Est: C, 34.41 H, 3.83 F 23.13 N, 9.03 S 230 SI 11.26 Gender: C, 34.44 H, 4.98 F 23.19 N, 8.89 S 2.15 Gd 11.17 An example 107

a) N-Trifluoacetyl-glutamic acid-5-benzyl ester [1- (4-perfluoroctylsulfonyl) -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-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 80 ml of tetrahydrofuran are added at 0 ° C. 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred at room temperature overnight. It was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

Yield: 27.28 g (93% of theory) of a colorless solid.

Elemental analysis: S, 3.63 S, 3.40 _Est . C 3535 H 2.40 Gender: ^{C 35 '48 N} F 43.01 N 4.76 F 42.87 N 4.73 B) 1H-Trifluoroacetyl- L-glutamine acid-5- (1- (4- perfluoroctylsulfonyl) -piperazine] -amide

21.92 g (52.15 mmol) of the title compound of example

107a were dissolved in 500 ml of ethanol and 3 g of palladium were added

388 catalyst (10 Pd / C). Hydrated at room temperature.

It is filtered off from the catalyst and evaporated to dryness in vacuo.

Yield: 41.37 g (quantitative) colorless solid.

Elemental analysis: _Est . C, 28.76; H, 1.91 F, 47.89 N, 5.30 S 4.04 _Paul; H, 28.84; F, 47.79 N, 5.28 S 4.16 Example 108 a) β-Ν-benzyloxycarbonyl -2-N- (2,3,4 , 5-pentahydroxy-

hexanoyl) 1-lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] amide

To a solution of 100.0 g (120.4 mol) of the title compound of Example 21 s, a solution of 21.45 g (120.4 mol) of 5-glucolactone in dropwise at 500 C was added dropwise in 500 ml. 50 ml of tetrahydrofuran. It was stirred for 3 hours at 60 ° C and finally stirred at room temperature overnight. It is evaporated to dryness in vacuo and chromatographed on silica gel. (eluent: dichloromethane / ethanol = 20: 1).

Yield: 98.37 g (82% of theory) of viscous oil.

Elemental analysis:

and _zh; C 38.10 NZ, 70 F 32.02 N5.55 S3.18 _Gender . C, 38.22; H3.79; F; 32.02; N5.42; S3.29

B) 2-N- (2,3,4,5-pentahydroxy-hexanoyl) -1_-lysine-1- [(4-perfluoro-alkylsulfonyl) -piperazine] -amide

389

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. Hydrated for 12 hours at room temperature.

Yield: 87.46 g (quantitative) of a colorless solid

Elemental analysis: _Calc: C _32/6 H 3.57 Gender: ^{C 3251 H 3 '72} N, 6.41 N, 6.34 S 3.67 F 36.93 S 3.50 F 36.78 f) 6-Ν- [1,4,7-τρπο (carboxylatomethyl)] - 1,3,7,10- tetraazacyclododecane-10- N- (pentanoyl-3-aza-4-oxo-5-methyl-5-

yl)] - 2-N- [1-0-a-0-carbonylmethyl-mannopyranose] -1_-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, gadolinium complex

50.0 g (54.55 mmol) of the title compound of Example 21e, 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54 , 55 mmol) 1,4,7tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methyl-pent-

5-yl) -1,4,7,10-tetraazacyclododecane, a gadolinium complex, was dissolved under gentle heating in 400 ml of dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mol) Ν, Νcyclohexylcarbodiimide were added and stirred at room temperature overnight. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by chromatography (RP-18 eluent: gradients of water / ethanol / acetonitrile).

Yield: 75.9 g (91 pO% of theory) a colorless solid.

390

Water content: 8.6%.

Elemental analysis (calculated on the anhydrous substance):

_m ^{C35 '34} Calc .: H4.09 N8,24 S2.10 F 21.12 Gd 10,28 C, 35.28 Gender: H4.15 N8.19 S2.15 F 21.03 Acts 10:14 An example 109 a) 6-N-benzyloxycarbonyl -2-M- (2,3,4,5-pentahydroxy-

hexanoyl) 1-lysine - [1- (4-perfluoroctylsulfonyl) -piperazine] amide

To a solution of 100.0 g (120.4 mmol) of the title compound of Example 21c, and 12.18 g (120.4 mmol) of triethylamine in 500 ml of dry tetrahydrofuran was added dropwise at 50 ° C a solution of 21, 45 g (120.4 mol) of 5 gluconolactone in 50 ml of tetrahydrofuran. It was stirred for 3 hours at 60 ° C and finally stirred at room temperature overnight. Then 400 ml of 5% aqueous hydrochloric acid are added, stirred for 5 minutes at room temperature, mixed with sodium chloride, the organic phase is separated, dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel.

(Eluent: dichloromethane / ethanol = 20: 1).

Yield: 100.97 g (82% of theory) of viscous oil.

Elemental analysis:

_Est; With 37.58 N3,45 F 31,58 N5,48 S3,14 _Paul. C37.72 NZD9 F 31.72 N5.42 S3.29

B) 2M- (2,3,4,5-pentahydroxy-hexanoyl) -1_-lysine-1 - [(4-perfluorooctylsulfonyl) -piperazine] -amide

391

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. Hydrated for 12 hours at room temperature. It is filtered off from the catalyst and evaporated to dryness in vacuo.

Yield7 87.46 g (quantitative) colorless, solid. Elemental analysis:

H, 337

N, 6.41

S, 3.67

F, 36.93

H, 3.72

N, 6.34

S 330

F 3678

c) 6-N- [1,4,7-Tpnc (carboxylatomethyl)] - 1,4,7,10 tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] -2-L1- [1-O-a-O-carbonylmethyl-mannopyranose] -1_-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, gadolinium complex

50.0 g (54.55 mmol) of the title compound of Example 21 is 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) 1,4,7tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methyl-pent-

5-yl) -1,4,7,10-tetraazacyclododecane, a gadolinium complex, was dissolved under gentle heating in 400 ml of dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mol) Ν, Νcyclohexylcarbodiimide were added and stirred at room temperature overnight. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by chromatography (RP-18 eluent: gradients of water / ethanol / acetonitrile).

392

Yield: 75.9 g (91.0% of theory) of a colorless solid.

Water content: 8.6%.

Elemental analysis (calculated on the anhydrous substance):

_Est . C 35.34 H4.09 N8.24 S2.10 P 21.12 Gd 10.28 _Gender; C 35.28 H4.15 N8.19 S2.15 F 21.03 Gd 10.14

Example 110

a) 6- ^ benzyloxycarbonyl-2-N- [1-0-a

D-carbonylmethyl (2,3,4,6-tetra-O-benzyl-glucopyranose) -1_-lysine perfluorooctylsulfonyl) -piperazine] -amide

To a solution of 100.0 g (120.4 mol) of the title compound of Example 21c, 72.1 g (120.7 mol) of 1-Oa-Dcarboxymethyl-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 to 41.27 g (200.0 mmol) of N, N -dicyclohexylcarbodiimide. It was stirred for 3 hours at 0 ° C and finally stirred at room temperature overnight. Filtered from the precipitated urea, the filtrate was evaporated to dryness in vacuo and chromatographed on silica gel. (Eluent: dichloromethane / ethanol = 20: 1).

Yield: 131.1 g (87% of theory) of viscous oil.

Elemental analysis:

_Est . C 57.32 H4.89 N4.31 F 24.86 S2.47 _Gender . H, 57.48;

N4.20

F 24.69 S238

393

b) 2-N- [1-0-a-0-carbonylmethylglucopyranose] -1_-lysine-1 - [(4-perfluoroctylsulfonyl) -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. Hydrated for 12 hours at room temperature. It is filtered off from the catalyst and evaporated to dryness in vacuo.

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

Calc: ^{C 34.07 H 3,63 N 6,11 s 3 '50F 35,24} _Paul. C 33.92 N 3.71 N 6.02 S 3.42 F 3533

c) 6-N- [1,4,7-Tpnc (carboxylatomethyl)] - 1,4,7,10-tetraazacycododecane-10-1,1- (pentanoyl-3-aza-4-oxo-5-methyl- 5yl)] - 2-N- [1-0-a-0-carbonylmethyl-glucopyranose] -1_-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, gadolinium complex

50.0 g (54.55 mmol) of the title compound of Example 110b, 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54 , 55 mol) 1,4,7tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methyl-pent-

5-yl) -1,4,7,10-tetraazacyclododecane, a gadolinium complex, was dissolved under gentle heating in 400 ml of dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mol) Ν, Νcyclohexylcarbodiimide were added and finally stirred at room temperature overnight. The solution was then poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid

394 was filtered and finally purified by chromatography (RP-18 eluent: gradients of water / ethanol / acetonitrile).

Yield: 75.9 g (91.0% of theory) of a colorless, solid. Water content: 8.6%.

Elemental analysis (calculated on the anhydrous substance): _Calc . C 35.34 H4.09 N8.24 S2.10 F21.12 Gd 10.28 _Pol . C 35.26 H4.18 N8.14 S 2.158 F21.01 Gd 10.13

Example 111

a) 6-N-benzyloxycarbonyl -2-N- [1-O-α-D-carbonylmethyl, 4,6-tetra-O-benzyl-galactopyranose)] -1-lysine- [1- (4-perfluorooctylsulfonyl) -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-O-α-D-carboxymethyl-

2,3,4,6-O-benzyl-galactopyranose and 6.93 g (60.2 mmol) of Nhydroxysuccinimide dissolved in 500 ml of dimethylformamide are added at 0 ° C. 2064 g (100.0 mmol) . It was stirred for 3 hours at 0 ° C then overnight at room temperature. It is filtered off from the precipitated urea, the filtrate is evaporated to dryness in vacuo and chromatographed on silica gel. (Eluent: dichloromethane / ethanol = 20: 1).

Yield: 68.1 g (87% of theory) of viscous oil.

Elemental analysis:

_Est; C 57.32 H4.89 N4.31 F 24.86 S2.47

395 _Paul . C 57.47 'H5.05 N4.19 F24.72 S2.29

b) 2-N- [1-0-α-0-carbonylmethyl-galactopyranose] -1_-lysine-1 [(4-perfluoroctylsulfonyl) -piperazine] -amide

65.0 g (50.0 mmol) of the title compound of Example 111a was dissolved in 1000 ml of ethanol and 5.0 g of palladium catalyst (10% Pd / C) was added. Hydrated for 12 hours at room temperature. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo.

Yield: 45.85 g (quantitative) of a colorless solid. Elemental analysis:

_Est . C 34.07 H 3.63 N 6.11 S EVIL F 35.24 _Paul . C 33.93 N 3.74 N 6.01 S 3.39 F 35.05

c) 6-1 N- [1,4,7-Tris (carboxylatomethyl)] - 1,4,7,10-tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5yl) ] -2-N- [1-0-a-0-carbonylmethyl-galactopyranose] -1_-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, gadolinium complex

50.0 g (54.55 mmol) of the title compound of Example 111b, 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54 , 55 mol) 1,4,7-tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methyl-pent-5yl) -1,4,7,10-tetraazacyclododecane, gadolinium complex, were dissolved under gentle heating in 400 ml of dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mol) Ν, Νcyclohexylcarbodiimide are added and stirred overnight at

396 room temperature. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by chromatography (RP-18 eluent: gradients of water / ethanol / acetonitrile).

Yield: 37.95 g (91.0% of theory) a colorless, solid. Water content: 8.6%.

Elemental analysis (calculated on the anhydrous substance):

Calcd .: £ -35.34 H4.09 N8.24 S2.10 F 21.12 Gd 10,28 Gender: C, 35.22 H4.17 N8.18 S2.19 F 20.91 Gd 10,12 An example 112 a) N-Trifluoroacetyl- L-glutamine acid-mono-

benzyl ester

100 g (421.5 mmol) of L-glutamic acid monobenzyl ester were dissolved in a mixture of 1000 ml of Grifluoroacetic acid ethyl ester / 500 ml of ethanol and stirred for 24 hours at room temperature. It was evaporated to dryness and the residue was crystallized from diisopropyl ether. Yield: 140.47 g (96% of theory) of a colorless crystalline powder. Elemental analysis:

Calc: C, 50.46; H, 4H3; F, 17.10 _; N4, 20 _Sex; C, 51.35; H, 4.18; F, 17.03; N, 4.28

B) 2-N-Trifluoroacetyl-L-glutamic acid-monobenzyl ester-5- N- (methyl) -N- (2,3,4,5,6-pentahydroxyhexyl) -amide

397

To a solution of 24.9 g (24.08 mmol) of the title compound of Example 112a, 2 g (24.08 mmol) of N-methylglucamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide dissolved in 150 ml dimethylformamide, 8.25 g (40 mmol) of N, N -dicyclohexylcarbodiimide are added at 0 ° C. It was stirred for 3 hours at 0 ° C and finally at room temperature overnight. Filtered from the precipitated urea, the filtrate was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: = dichloromethane / ethanol = 20: 1).

Yield: 9 g (89% of theory) of viscous oil. Elemental analysis:

Calc'd: C 51.43 H 531 F 13.56 N. 6.66

Sex: C 5132 H 5.41 F 13.40 N 6.75

c) N-Trifluoroacetyl-L-glutamic acid-N- (Μβτππ) -Ν (2,3,4,5,6-pentahydroxyhexyl) -am and e

21.9 g (52.15 mmol) of the title compound of Example 112b were dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo.

Yield: 43.0 g (quantitative) colorless, solid. Elemental analysis:

H, 5.19

H, 5.13

F 1736

F 17.09

N, 8.48

N, 8.68

398

d) Trifluoroacetyl-1-glutamic acid-5-N- (methyl) -1H (2,3,4,5,6-pentahydroxyhexyl) -amide- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

To 10.96 g (33.2 mmol) of the title compound of Example 112c and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 80 ml of THF are added at 0 ° C. 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred overnight at room temperature. It was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

Yield: 28.67 g (92% of theory) of a colorless, solid.

Elemental analysis: C, 39.61; H, 2.89 Est: F, 35.66 N, 6.19 S, 3.54 Gender: ^{C, 39.68; N, 2.74} F, 35.81 N, 6.13 S, 3.40 e) 1-glutamine acid-5- Ν- (Μβτππ) -Ν- (2,3,4,5,6-

pentahydroxyhexyl) -amide- [1- (4-perfluorooctylsulfonyl) piperazine] -amide

In a solution of 28.36 g (30.22 mmol) of the title compound of Example 112d in 200 ml of ethanol was passed an ammonia gas at 0 ° C for one hour. It is then stirred for 4 hours at 0 ° C. It is evaporated to dryness and the residue is taken up

399 was stirred with water, the solid was filtered off and dried in vacuo (50 ° C).

Yield: 24.19 g (95% of theory) of an amorphous solid.

Elemental analysis: Calc'd: ^{by 41.12} H, 2.89 F, 35.66 N, 6.19 S 334 C, 41.15 Gender: H, 2.83 F, 35.78 N, 6.28 S, 3.71

f) N- [1,4,7-Tpnc (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] L-glutamic acid - 5-N- (Μβτππ) -N- (2,3,4,5,6 pentahydroxyhexyl) -amide-5- [1- (4-perfluorooctylsulfonyl) piperazine] -amide, gadolinium complex

20.43 g (24.25 mmol) of the title compound of Example 112e, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25) mmol) 1,4,7tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl) pentanoic acid] -1,4,7,10-tetraazacyclododecane, gadolinium complex are dissolved at gently heat in 200 ml of dimethyl sulfoxide. At 10 ° C, 8.25 g (40 mmol) of Ν, ди-dicyclohexylcarbodiimide are added and stirred at room temperature overnight. The solution was then poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and finally purified by chromatography (silica gel RP-18, eluent: gradients of water /

400 ethanol / acetonitrile). Yield: 28.45 g (79% of theory) of a colorless, solid.

Water content: 11.0%

Elemental analysis (calculated on the anhydrous substance):

Calc'd: C34, ⁴¹ H 3.83 F23.13 N9.03 S 2.30 Gd 11.26 _Pol . C 34.34 H 3.98 F 23.29 N9.19 S 2.15 Gd 11.07

Example 113

a) 6-N-benzyloxycarbonyl (2,3,4-tri-O-benzyl-glucuronic

2-N- [1-0-α-D-carbonylmethyl acid) -C-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 1-Oa-Dcarboxymethyl-2,3,4-tri-O-benzyl-glucuronic acid benzyl ester and 13.86 g (120.4 mol) of N-hydroxysuccinimide dissolved in 500 ml of dimethylformamide were added at 0 ° C to 41.27 g (200.0 mmol) of Νcyclohexylcarbodiimide. It was stirred for 3 hours at 0 ° C and finally stirred at room temperature overnight. It is filtered off from the precipitated urea, evaporated to dryness in vacuo and chromatographed on silica gel.

(Eluent: dichloromethane / ethanol = 20: 1).

Yield: 147.58 g (86% of theory) of viscous oil.

Elemental analysis:

_Est; C52D5 H4.31 N3.93 F22.66 S2.45

401

Gender: ^{05238 H4} '17 ^N4 ' ^{12 F22} ' ^7S S239

b) 2-N- [1-0-a-D-carbonylmethyl-glucuronic acid] -Lysine -1 - [(4-perfluoroctylsulfonyl) -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. Hydrated for 12 hours at room temperature. It was filtered off from the catalyst and the filtrate was evaporated to dryness in vacuo.

Yield: 93.06 g (quantitative) colorless, solids Elemental analysis:

Est: ³³³⁶ H, 336 N, 6.02 S 3.45 F 34.71 'With 3331 Gender: H, 3.42 N, 6.04 S 3.40 F 3551 c) 6-N- [1,4, 7-Tris (carboxylatomethyl)] - 1,4,7,10-

tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5ππ)] -2-N- [1-N-α-D-carbonylmethyl-glucuronic acid] -1_-lysine [1- (4-Perfluoroalkylsulfonyl) -piperazine] -amide, gadolinium 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) 1,4,7tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methyl-pent-

5-yl) -1,4,7,10-tetraazacyclododecane, a gadolinium complex, was dissolved under gentle heating in 400 ml of dimethyl sulfoxide. At

402 at 10 ° C was added 16.88 g (81.8 mol) Ν, Νcyclohexylcarbodiimide and stirred at room temperature overnight. The solution was then poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified on silica gel (RP-18 eluent: gradients of water / ethanol / acetonitrile).

Yield:

75.14% g (88.0% of theory) a colorless, solid.

Water content: 8.6%.

Elemental analysis (calculated on the anhydrous substance): Calc · ^{034 '53 113.80 N8} ' ^{05 Nal '47 S2} ' ⁰⁵ F20.63 <3 <* 1OL> 5

Sex: ^{C34 '38 H3} ' ^{95 N8 '19 Na1,63 S2} > ¹⁵ F20.83 0410,14

Example 114

a) 6-N- (benzyloxycarbonyl) -2- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-L-lysine

31.82 g (113.5 mmol) 6-1 \ 1- (benzyloxycarbonyl) -1_-lysine and 66.42 g (113q5 mmol) 2- (N-βτπρ-N-perfluoroctylsulfonyl) aminoacetic acid (prepared according to DE 196 03 033) in 300 ml of tetrahydrofuran, and to these were added at 0 ° C 49.46 g (200.0 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and added stirred at room temperature overnight. It was evaporated to dryness in vacuo and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

403

Yield: 55.79 g (58% of theory) of a colorless, solid.

Elemental analysis:

_Est . C, 36.85; H, 3.09; N, 4.96; F, 38.11; S, 3.78

Gender: C, 36.85; 3.19; N, 4.87; F, 38.28; S, 3.95

b) 6-N-benzyloxycarbonyl -2-N- [2- (N-βτππ-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-methylglucamine and 6.93 g (60.2 mol) of N-hydroxysuccinimide dissolved in 250 ml of dimethylformamide are added at 0 ° C to 20.64 g (100.0 mmol) of N, N-dicyclohexylcarbodiimide. It was stirred for 3 hours at 0 ° C and then overnight at room temperature. It is filtered off from the precipitated urea, evaporated to dryness in vacuo and chromatographed on silica gel.

(Eluent: dichloromethane / ethanol = 20: 1).

Yield: 53.05 g (86% of theory) of viscous oil.

Elemental analysis:

_Est . C 38.68 H4.03 N5.47 F31.52 S3.13 _Gender . C 38.49 H4.17 N5.32 F31.70 S3.29

c) 2-N- [2- (1 N -ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-l-lysine-N-methyl-N- (2,3,4,5,6-pentahydroxy-hexyl) -amide

404

102.48 g (100.0 mmol) of the title compound of Example 114b were dissolved in 2000 ml of ethanol and 10.0 g of palladium catalyst (10 5 Pd / C) was added. Hydrated for 12 hours at room temperature. It is filtered off from the catalyst and evaporated to dryness in vacuo.

Yield: 89.06 g (quantitative) colorless, solid.

Elemental analysis: _Est . C, 33.72; H, 3.96 N, 6.29 S, 3.60 F, 36.26 Gender: C 33 ^ 1 H 3.82 N, 6.14 S, 3.47 F 36.31 d) 6-N- [1,4,7-Tpnc (carboxylatomethyl)] - 1,4,7,10-

tetraazacyclododecane-10-M- (pentanoyl-3-aza-4-oxo-5-methyl-5ππ)] - 2-N- [2- (N-βτππ-N-perfluorooctylsulfonyl) -amino] -acetyl-Llysine-M -methyl-N- (2,3,4,5,6-pentahydroxy-hexyl) -amide, gadolinium 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) 1,4,7tris (carboxylatomethyl) -10- (carboxy-3-aza-4-oxo-5-methyl-pent-

5-yl) -1,4,7,10-tetraazacyclododecane, a gadolinium complex, was dissolved under gentle heating in 400 ml of dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mol) Ν, Νcyclohexylcarbodiimide were added and stirred at room temperature overnight. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off

405 and finally purified by chromatography (RP-18 eluent: gradients of water / ethanol / acetonitrile).

Yield: 73.27 g (89.4% of theory) of a colorless, solid.

Water content: 8.6%.

Elegant analysis (calculated on the anhydrous substance):

Calc: C, 35.18 H433 N4.23 S2.13 F 21.50 Gd 10.47 Gender: C, 35.28 H4.15 N4.19 5 2.18 F2133 Gd 10.61 An example 115 Image of arteriosclerotic nuclear plaques -

magnetic resonance after intravenous administration of metal complexes according to the invention

In rabbits with genetically induced arteriosclerosis (treated rabbits), 5-6 minutes and 24 hours and 48 hours after intravenous administration of 25 µm Gd / kg body weight of the compounds according to the invention was clearly expressed as T1 weight gain. gradients (TR 11.1 ms, TE 4.3 ms, Flipwinkel α 15 °) in arteriosclerotic plaques. The walls of the healthy vessels do not show or show to a very limited extent a contrast agent uptake, and therefore do not show any or very limited signal elevation in T1 weight absorption. Based on the split between signal-rich plaques and the signal on healthy vessel walls, it is possible to diagnose changes in arteriosclerotic changes in vessel walls.

406

The images in Figure 1 show a nuclear magnetic picture of the aorta 24 hours and 48 hours after intravenous administration of 25 μ mol Gd / kg body weight of metal complex XV in treated rabbits (genetically induced arteriosclerosis). T1 - weight representation of the gradients (1.5 T; TR: 11.1 ms; TE: 4.3 ms; 2Α: 2; matrix: 213 * 256; layer thickness: 1.0 mm) causes a strong increase in the signal in arteriosclerotic plaques. Localization of the plaques, in particular in the aortic arch as well as on the walls of the vessels, is accomplished by Sudan-3 staining.

Example 116:

Imaging of arteriosclerotic plaques at nuclear magnetic resonance after intravenous administration of metal complex XV in rats, as well as correlation of post mortem imaging with Sudan III staining

The images in Figure 2 show a nuclear magnetic representation of the aorta after 35, 60 minutes and 24 hours after intravenous administration of 10 pmol Gd / kg body weight for gadolinium metal complex XV in treated rabbits (genetically induced arteriosclerosis). T1 weight gradient representation (MPRage; 1.5 T; TR: 11.1 ms, TE:

4.3 ms; ΝΑ: 2; matrix 213 * 256; layer thickness: 1.0 mm) clearly indicates a signal increase in arteriosclerotic plaques. Localization of the plaques, in particular in the aortic arch as well as on the walls of the vessels, is achieved by Sudan staining -3. Finally, it is tested nuclear

407 the magnetic image of a preparation refreshed in agar having a T1-weighted echo gradient sequence (MPRage; 1.5 T; TR 11.1 ms; TE 4.3 ms; Flipwinkel α 15 °; ΝΑ: 2; matrix: 213 * 256) as well as spin - echo sequence that is (1.5 T; TR: 400 ms; TE: 15 ms; ΝΑ: 16; matrix 256 * 256) (post mortem image). In this case, there is a pronounced correlation of aortic regions with strongly elevated signal and stained plaques showing uptake of the compounds of the invention in arteriosclerotic plaques.

Example 117:

Imaging of nuclear magnetic resonance infarction after intravenous administration of metal complex XV in rats

The images in Fig. 3 show MR imaging of the heart (in vivo and post mortem) 24 hours after intravenous administration of 100 prnol Gd / kg body weight of metal complex XV in rats with acutely induced heart attack. T1 - weight spin-echo image (1.5 T; TR: 400 ms; TE: 6 ms; NA: 4; matrix: 128 * 128; layer thickness 2.5 mm) clearly shows a strong increase in the infarcted area. Successful induction of an acute myocardial infarction was determined by NBT staining.

Metal complex XV, 100 μ mol / kg i.v .; T1-SE, TR / TE 400/6 ms; diagnosis: myocardial infarction.

Example 118

408

Imaging of nuclear magnetic resonance infarction after intravenous administration of metal complex I in rats

The images in Figure 4 show an MR image of the heart (in vivo and postmortem) 24 hours after administration of 100 μ mol Gd / kg body weight of metal complex I in rats acutely induced by heart attack. T1-weight spin echo (1.5 T; TR: 400 ms; TE: 6 ms; NA: 4; matrix: 128 * 128; layer thickness: 2.5 mm) clearly shows a strong increase in the infarct area. Successful induction of acute myocardial infarction is determined by NBT staining.

Example 119:

Imaging of lymph nodes at nuclear magnetic resonance after intravenous administration of metal complex XV in rabbits with VX2 tumor

The images in Figure 5 show MR images of contrast lymph nodes up to 24 hours after intravenous administration of 200 μ mol Gd / kg body weight from metal complex XV of rabbits with implanted VX2 tumor. The T1 weight gradient image (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15 °) clearly shows a strongly elevated signal in the healthy lymph node tissue. Areas without signal within the lymph node are diagnosed as metastases and histologically determined (N / E - staining of the sectors then the lymph nodes). At a later point (24 hours) after

409 contrast contrast administration may have a surprising turn in the signal. The signal in healthy lymph node tissue is reduced, while metastases show a pronounced signal gain.

Surprisingly, an increase in the primary tumor (especially in the periphery) was observed immediately after administration. Later (24 hours after injection) this increase expands toward the tumor center.

Example 120:

Imaging of nuclear magnetic resonance tumors after administration of metal complex I in rabbits with VX2 tumors

The images of FIG. 6 shows contrast MR images of iliac lymph nodes of primary tumors (i.m. implanted VX2 tumors) 60 minutes and 20 hours after intravenous administration of 100 μ mol Gd / kg body weight of metal complex I in rabbits. T1 weight gradient image (1.5 T; sequence: MPRange; TR 11.1 ms, TE

4.3 ms, α 15 °) shows a clearly strong signal in the healthy tissues of the lymph nodes.

At an earlier time after admission (60 min p.i) an increase in the primary tumor (especially in the periphery) was clearly observed. At a later point, the signal also extends to the central part of the tumor.

Particularly significant is the growth of a pathologic structure (eg, secondary tumor or necrosis) on

410 the contralateral side, which becomes secure only in later photographs ("late growth").

Metal Complex X

Example 121:

Imaging of nuclear magnetic resonance infarction after intravenous administration of contrast agent in rats

The images of FIG. 7 show an MR image of the heart (in vivo and post mortem) 6 hours after intravenous administration of 100 μ mol Gd / kg body weight of a polar Gd chelate with perfluorinated side chain (metal complex X) in rats with acutely induced heart attack . The T1-weighted, ECG - retrigger spin-echo image (1.5 T; TR (effective): 400 ms; TE: 12 ms; ΝΑ: 4; matrix: 128 * 128; layer thickness: 2.5 mm) clearly shows a strong infarction signal. Successful induction of acute myocardial infarction is determined by ΝΒΤ-staining.

Example 122:

Organ distribution (including concentration in lymph nodes) after intravenous administration of contrast agent in rats

After intravenous administration of 100 μ mol total gadolinium / kg body weight of one polar gadolinium chelate with perfluorinated side chain (metal complex X) from rats 24 hours after administration, the metal content was determined in different organs as well as in lymph nodes (

411 united as mesenteric and peripheral lymph nodes) (MW, η = 2).

Organ pmol Gd / L % dose liver 104 2.34 femur 3 0.01 kidneys 150 0.65 brain 1 0.01 corpse 192 34.01 blood 1 0.01 stomach 49 0.18 The gut 65 1.22 springs 54 0.07 pancreas 6 0.02 heart 3 0.01 lung 18 0.05 muscle 1 0.00 Mesenteric lymph nodes 19 0.01 Peripheral lymph nodes 11 0.01 total 38.58

Example 123:

Imaging of lymph nodes at nuclear magnetic resonance imaging (MRT) after intravenous administration of contrast agent in rats

412

The images of FIG. 8 shows, for example, an MR image of contrast or iliac lymph nodes up to 60 minutes after intravenous administration of 100 μ mol Gd / kg body weight of metal complex X in rats. The T1 weight gradient echo (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15 °) shows clearly a strong signal in the lymph node healthy tissue, very soon after injection. Thus, an increase of 263% over a time of 15 minutes p.i. and 254% for a time of 60 minutes p.i ..

Example 124:

Imaging of lymph nodes at nuclear magnetic resonance after intravenous administration of contrast agent in rabbits with VX2 - tumor

The images of FIG. 9 show, for example, an MR image of contrast or iliac lymph nodes up to 60 minutes after intravenous administration of 200 μ mol Gd / kg body weight metal complex X from rabbits with i.m. implanted VX2 tumor. The T1 weight gradient echo (1.5 T; sequence: MPRange; TR11.1 ms, TE 4.3 ms, α 15 °) clearly shows a strong signal in the healthy tissue of the lymph nodes. Growth in healthy lymph node tissue was 382% over 15 minutes p.i. and 419% for a time of 60 minutes p.i. The areas without signal within the lymph nodes are diagnosed as metastases and histologically determined (N / E staining of lymph node sections). The ratio of healthy lymph node tissue to metastases was 3.0 over a period of 15 minutes p.i. and 3.4 for a time of 60 minutes p.i.

413

Surprisingly, a clear increase in not only the lymph nodes but also the primary tumor (especially in the periphery) was found immediately after administration (15 minutes p.i.: 277%). Later on (up to 24 hours p.i.), this increase also expanded toward the center of the tumor (24 hours p.i.: 217%).

Metal Complex V

Example 125:

Imaging of nuclear magnetic resonance imaging (MRT) after intravenous administration of contrast agent in rats

The images in Fig. 10 show MR images of the heart (in vivo and post mortem) 24 hours after intravenous administration of 100 μ mol Gd / kg body weight Gd chelate with perfluorinated side chain (metal complex V) in rats with acutely induced heart attack . T1 weight spin-echo image (1.5 T; TR (effective): 400 ms, TE: 12 ms; ΝΑ: 4; matrix: 128 * 128; layer thickness: 2.5 mm) clearly shows a strong signal in the infarcted area . Successful induction of acute myocardial infarction is confirmed by ΝΒΤ staining.

Example 126:

Organ distribution (including concentration in lymph nodes) after intravenous administration of contrast agent in rats

414

After intravenous administration of 200 μ mol total gadolinium / kg body weight, polar Gd-chelate with perfluorinated side chain (metal complex V) from rats was determined 24 h after its administration, the metallic content in different organs as well as in lymph nodes (summarized as mesenteric and peripheral lymph nodes) (LMS, η = 2).

Organ μ mol Gd / L % dose Liver 344 6.34 femur 13 0.05 kidneys 436 1.77 brain 4 0.02 corpse 268 37.93 blood 15 0.18 stomach 28 0.08 gut 113 1.56 springs 116 0.17 pancreas 30 0.05 heart 14 0.02 Lung 62 0.17 muscle 9 0.02 Mesenteric lymph nodes 70 0.05 Peripheral lymph nodes 44 0.02 total 48.43

415

Example 127:

Imaging of lymph nodes (MRT) after intravenous administration of contrast agent in rats

The images in Figure 11 show an MR image of contrast or iliac lymph nodes up to 60 minutes after intravenous administration of 200 μ mol Gd / kg body weight metal complex V in rats. The T1 weight gradient echo (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15 °) showed a strong signal in the healthy lymph node tissue at a very early point after injection. The increase is 147% over a time of 15 minutes p.i. and 230% for a time of 60 minutes p.i ..

Example 128:

Imaging of lymph nodes (MRT) after intravenous contrast administration to rabbits with VX2 - tumor

The images of FIG. 12 shows, for example, MR images of contrasting iliac lymph nodes up to 60 minutes after intravenous administration of 200 μ mol Gd / kg body weight metal complex V in rabbits with implanted VX2 tumor. T1 weight gradient echo (1.5 T;

sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15 °) clearly shows a strong signal in the healthy lymph node tissue. Growth in healthy lymph node tissue was 246% over 15 minutes p.i. and 282% for a time of 60 minutes p.i. (after injection). Areas without signal within the lymph nodes are diagnosed as metastases and confirmed

416 histologic (Η / E-staining of lymph node sections). The ratio of signal intensity from healthy lymph node tissue to metastasis is 2.5 over a period of 15 minutes p.i. to 1.7 within 60 minutes after injection (p.i.). Surprisingly shortly after admission, there was a marked increase in not only the lymph nodes but also the primary tumor (especially in the periphery) (15 minutes p.i .: 350%). At a later point (up to 24 hours p.i.), this increase expands toward the tumor center (24 hours p.i.:106%).

Metal complex XIV

Example 129:

Infarct imaging (MRT) after intravenous contrast administration to rats

The images of FIG. 13 show MR images of the heart (in vivo and post mortem) Hours after intravenous administration of 100 μ mol Gd / kg body weight polar perfused side chain Gd chelate (metal complex XIV) in rats with acutely induced heart attack. T1 weight, ECG-recorded spin-echo image (1.5 T; TR (effective): 400 feather TE: 12 ms; ΝΑ: 4; matrix: 128 * 128; layer thickness: 2.5 mm) clearly shows a strong signal in the infarcted area . Successful induction of acute myocardial infarction is demonstrated by ΝΒΤ staining.

Example 130:

417

Distribution in the organs (including concentration in the tumor and lymph nodes) after intravenous administration of contrast agent in rats with prostate cancer

After intravenous administration of 200 μ mol total gadolinium / kg body weight polar Gd-chelate with perfluorinated side chain (metal complex XIV) in ducts (Cop-lnzucht, with Dunning R3327 MAT - Lu implanted 12 days ago) after 10 minutes , 1 hour and 24 hours after receiving the chelate, the metal content in the various organs, in the tumor and in the lymph nodes (summarized as mesenteric and peripheral lymph nodes) was determined (MW ± SD, η = 3).

ORGA N Ts Metal complex XIV 10min p.i. Gd-complex 1h p.i. and r / Anol / l] 24h p.i. 10min p.i. % dose 1h p.i. 24h p.i. Liver spleen pancreas kidney lungs heart brain muscle **** Tumor tumor meso lymph nodes (lv) periphery. lv stomach (empty) intestine (empty ^ 192 ± 12 200 ± 13 191 ± 14 761 ± 60 603 ± 30 320 ± 8 38 ± 6 93 ± 5 246 ± 25 115 ± 3 291 ± 29 284 ± 19 244 ± 17 242 ± 15 147 ± 7 123 ± 10 139 ± 26 1181 ± 232 415 ± 39 190 ± 15 22 ± 2 56 ± 3 266 ± 87 81 ± 10 179 ± 16 254 ± 14 165 ± 21 201 ± 32 64 ± 4 69 ± 5 25 ± 1 338 ± 49 44 ± 4 19 ± 0 4 ± 4 8 ± 1 56 ± 4 9 ± 1 50 ± 6 51 ± 5 19 ± 2 36 ± 5 2.62 ± 0.11 0.13 ± 0.01 0.35 ± 0.02 1.76 ± 0.14 1.04 ± 0.02 0.32 ± 0.01 0.10 ± 0.03 0.06 ± 0.02 0.25 ± 0.05 0.39 ± 0.02 0.08 ± 0.01 0.13 ± 0.00 0.56 ± 0.07 1.55 ± 0.09 2.04 ± 0.15 0.08 ± 0.01 021 ± 0.05 2.84 ± 0.61 0.80 ± 0.06 0.19 ± 0.01 0.06 ± 0.00 0.04 ± 0.00 0.37 ± 0.14 0.28 ± 0.03 0.05 ± 0.01 0.14 ± 0.02 0.40 ± 0.05 1.16 ± 0.22 0.96 ± 0.0 5 0.06 ± 0.00 0.03 ± 0.01 0.81 ± 0.09 0.09 ± 0.01 0.02 ± 0.00 0.01 ± 0.01 0.00 ± 0.00 0.04 ± 0.01 0.03 ± 0.00 0.02 ± 0.00 0.02 ± 0.00 0.05 ± 0.00 026 ± 0.04

418

blood Other authorities * 957 ± 38 419 + 27 575 ± 56 392 ± 25 22 ± 1 42 ± 0 26.73 ± 0.84 70.71 ± 2.74 16.13 ± 1.77 64.27 ± 5.50 0.61 ± 0.03 6.81 + 0.16 urine 0-24 h Faeces 0-24 h 619 ± 19 781 ± 611 79.86 ± 3.13 6.00 ± 4.91 Sum of bodies *** 80.06 ± 2.84 72.94 ± 5.83 9.21 ± 0.27 Balance *** 95.07 n - 2.41

Legend:

* blood samples from other parts of the body ** 58 ml of blood / kg per kilogram body weight *** balance without blood values as they are contained in other parts of the body **** only tissue quota

Example 131:

Imaging of lymph nodes (MRT) after intravenous administration of contrast agent in guinea pigs

The images of FIG. 14 shows exemplary MR images of contrast iliac and inguinal lymph nodes up to 24 hours after intravenous administration of 200 μ mol Gd / kg body weight metal complex XIV in guinea pig stimulated lymph nodes (Freund Adjuvant). T1 - weight gradient echo images (2.0 T; TR 10 ms, TE 5 ms, and 40 °) clearly show a strong signal in the healthy tissue of the lymph nodes at very short time after injection. The increase was 127% during the 60 minutes after injection.

Example 132:

Imaging of lymph nodes (MRT) after intravenous contrast administration to rabbits with VX2-1 tumor

419

The images in Figure 15 show exemplary MR images of contrast or iliac lymph nodes up to 23 hours after intravenous administration of 200 μ mol Gd / kg body weight metal complex XIV in rabbits with i.m. implanted VX2 tumor. T1 - weight gradient echo (1.5 T; sequence: MPRdnge; TR 11.1 ms, TE 4.3 ms, α 15 °) clearly shows a strong signal in the healthy tissue of the lymph nodes. The growth in healthy lymph node tissue was 297% at 10 minutes after injection and 269% at 60 minutes after injection. Areas without signal within the lymph nodes are diagnosed as metastases and proven histologically (N / E - lymphatic staining). The ratio of signal intensity from healthy lymph node tissue to metastasis was 5.1 at 10 minutes after injection and 1.0 at 60 minutes after injection.

Surprisingly, a clear increase in not only the lymph nodes but also the adrenal tumor (especially in the periphery) was observed immediately after injection (15 minutes after injection: 594%). At one later point (up to 24 hours after injection), this increase expands toward the tumor center (120 minutes after injection: 162%).

Metal Complex III

Example 133:

Infarct imaging (MRT) after intravenous contrast administration to rats

420

The images of FIG. 16 shows MR images of the heart (in vivo and post mortem) 22 hours after intravenous administration of 100 μ mol Gd / kg live weight polar gadolinium chelate with perfluorinated side chain (metal complex III) in rats with acutely induced heart attack. T1 signal, ENG spin-echo image (1.5 T; TR (effective): 400 ms, TE: 12 ms, ΝΑ: 4; matrix: 128 * 128; layer thickness: 2.5 mm) clearly shows a strong signal in the infarcted area . Successful induction of an acute myocardial infarction is demonstrated by ΝΒΤ staining.

Example 134:

Organ distribution (including concentration in lymph nodes) after intravenous administration of contrast agent in rats

After intravenous administration of 200 μ mol total gadolinium / kg body weight polar perfluorinated side-chain Gd-chelate (metal complex III) at rat 24 hours after administration, the metal content of the various organs as well as in the lymph nodes (summarized as mesenteric and peripheral lymph nodes) (MW, η = 2).

Organ μ mol Gd / L % dose Liver 1222 26.28 femur 76 0.32 kidneys 489 1.97 brain 10 0.05

421

corpse 242 36.30 blood 83 1.15 stomach 165 0.57 gut 230 3.56 springs 464 0.89 pancreas 203 0.48 heart 82 0.13 lungs 338 0.96 muscle 28 0.04 Mesenteric lymph nodes 455 0.33 Peripheral lymph nodes 279 0.18 total 73.20

Example 135:

Imaging of lymph nodes (MRT) after intravenous administration of contrast agent in rats

The images of FIG. 17 shows exemplary MR images of contrast or iliac lymph nodes 60 minutes after intravenous administration of 200 μ mol Gd / kg body weight metal complex III in rats. The T1 weight gradient echo (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15 °) clearly shows a strong signal in the healthy lymph node tissue at a very early point after injection. The increase is 320% in one time from 15

422 after injection and 401% during the 60 minutes after injection.

Example 136:

Imaging of lymph nodes (MRT) after intravenous administration of contrast agent in rabbits with \ / X2-tumor

The images of FIG. 18 shows exemplary MR images of contrast iliac lymph nodes up to 60 minutes after intravenous administration of 200 μ mol Gd / kg body weight metal complex III in rabbits with implanted \ / X2-tumor. The T1 weight gradient echo (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, α 15 °) clearly shows a strong signal in the healthy lymph node tissue. The increase in healthy lymph node tissue was 195% at the time of 15 minutes after injection and 233% at the time of 60 minutes after injection. Areas without signal within the lymph nodes are diagnosed as metastases and proven histologically (N / E - staining of the lymph sections). The ratio of signal intensity from healthy lymph node tissue to metastases is 1.9 for the time 15 minutes after injection and 1.8 for the time 60 minutes after injection.

Surprisingly, immediately after admission, there was a marked increase in not only the lymph nodes but also the primary tumor (especially in the periphery) (15 minutes after injection: 232%).

Claims (50)

Patent Claims 1. Use of perfluoroalkyl containing metal complexes having a critical concentration for the formation of micelles <10 ' ³ mol / I, hydrodynamic diameter of the micelles (2Rh)> 1 nm and proton relaxation in plasma (R ¹ )> 10 I / mmol.s , as a contrast medium for nuclear magnetic resonance imaging and plaque presentation. Use according to claim 1, characterized in that the metal complexes are used as contrast agents in nuclear magnetic resonance imaging for lymph nodes. Use according to claim 1 or 2, characterized in that the metal complexes are used as contrast agents in nuclear magnetic resonance imaging for infarcted and necrotized tissues. Use according to one of Claims 1 to 3, characterized in that the metal complexes are used as contrast agents in nuclear magnetic resonance for the independent imaging of necrosis and tumors. Use according to claim 1, characterized in that 424 used metal complexes whose concentration for the formation of micelles is <10 ' ⁴ . Use according to claim 1, characterized in that metal complexes are used whose hydrodynamic diameter of the micelles is> nm, preferably> 4 nm. Use according to claim 1, characterized in that metal complexes are used which have proton relaxation in plasma> 13 l / mmol.s, preferably> 15 l / mmol.s. Use according to one of Claims 1 to 7, characterized in that compounds of general formula I are used as perfluoroalkyl containing metal complexes. R ^f -LK I in which R ^f means a straight-chain or branched-chain perfluorinated carbon of formula -C _n F2 _n E in which E means the fluorine, chlorine, bromine, iodine or hydrogen atom located in the extreme position and η means the numbers 4 - 30, L means one direct bond, one -NHCO-pyrene, one group 425 —pCHjF-NHCOCHa — iCH ^ pj— _R d IN— S0 ₂ “as p denotes the numbers 0 to 10, q and u independently of one another denote the numbers 0 to 1 and R ^a represents a hydrogen atom, one methyl group, one CH ₂ -OH- group, one -CH ₂ CO ₂ H-group or one C 2 -C 4-chain which can optionally be interrupted by 1 to 3 sulfur atoms , 1 to 2> CO groups, or optionally substituted aryl groups and / or substituted with 1 to 4 hydroxyl groups, 1 to 2 C 1 -C 6 alkoxy groups, 1 to 2 carboxy groups, one group -SO 3 H-, or one straight, branched, saturated or unsaturated C ₂ -C 3 carbon chain, which optionally contains 1 to 10 oxygen atoms, 1 to 3 -NR ^a groups, 1 to 2 sulfur atoms, one piperazine, one -CONR ³ group, one -NR ^a CO-rpyna, unit of the -SO2- group, one -NR ^a CO2-rpyna, 1 to 2 -CO-groups, one group CO-N - T - N (R ^a ) - SO ₂ - R ^f or 1 to 2 optionally substituted aryls and / or is interrupted by this group and / or optionally substituted by 1 to 3 -OR ^a - groups, 1 to 2 oxo groups, 1 to 2 -NH-COR ^a - groups, 1 to 2 -CONHR ^a -rpynn, 1 to 2 - (CH ₂ ) _P -CO ₂ H - groups, 1 to 2 groups - (CH ₂ ) p- (O) _q -CH ₂ CH ₂ -R ^F , such R ^a , R ^f and p and q have the meanings given above and T represents a C ₂ -C 10-chain which is optionally interrupted by 1 to 2 oxygen atoms or 1 to 2 -NHCO groups, K represents a complexing agent or a metal complex or their salts with organic and / or inorganic bases or 426 amino acids or amino acids of amino acids, and means a complexing agent or complex of general formula II ^ 006 (II) in which R ^c , R ¹ and B are independent of each other and R ^c is R ^a or - (CH 2) mL R ^F , with m being 0, 1 or 2 and L and R ^F have the meanings given above, R ¹ independently of one another denotes one hydrogen atom or one ionic equivalent of a metal having the order number 22 -29,42-46 or 58-70, B represents -OR ¹ or -N ch ₂ ch ₂ -lr ^f Oder such as R ¹ , L, R ^f and R ^c have the meanings given above, or means a complexing agent or complex of the general formula 427 in which R ^c and R ¹ have the meanings given above, and R ^b has the meaning of R ^a or means one complexing agent or complex of general formula IV (IV) in which R ¹ has the meanings given above or means one complexing agent or complex of general formula V 428 in which R ¹ the above meaning and o and q denote the numbers 0 or 1 and the sum o + q = 1, or denote a complexing agent or complex with common VI β'Ο, Ο-'Χ / - \ / CO , R ¹ in which R ¹ has the meaning given above or denotes a complexing agent or complex of general formula VII (VII) 429 in which R ¹ and B have the meanings given above or mean one complexing agent or complex of general formula VIII (VIII) in which R ^c u R ¹ have the meanings given above and R ^b have the meaning of R ^a , or one complexing agent or complex of general formula IX in which R ^c u R ¹ have the meanings given above, or means one complexing agent or complex of general formula X 430 in which R ^c and R ¹ have the meanings given above, or means a complexing agent or complex of the general formula XI (XI) -COlq-N | X / * 3θ ₂ --- vww in which R ¹ , p and q have the meanings given above and R ^b has the meanings of R ^a , or denotes a complexing agent or complex with a common XII 431 (XI) in which L, R ^f and R ⁴ have the meanings given above, or means a complexing agent or complex of general formula XIII Use according to claim 8, characterized in that compounds of general formula I are used in which L is a-CH ₂ f a-CH ₂ CH ₂ - $ 432 a- (CH ₂ ) sP s = 3-15 α-0Η ₂ -Ο-0Η ₂ 0Η2-β a-CH2- (O-CH ₂ -CH ₂ -H 1 = 2-6 a-CH ₂ -NH -CO-3 a-CH ₂ -NH-CO-CH ₂ -N (CH ₂ COOH) -SO2-p a-CH ₂ -NH-CO-CH ₂ -N (C ₂ H ₅ FSO ₂ -3 a- CH2-NH-CO-CH2-N (Ci ₀ H ₂₁ ) -S0 _2- ruble a-cng-in-co-cng-mssen-] ₃ ) -so2-p a-CH2-NH-CO- (CH ₂ ) ₁₀ -N (C ₂ H5) -SO2-₽ a-CH2-NH-CO-CH ₂ 'N (-CH ₂ -C ₆ H5) -SO2 ^ a-CH2-NH-CO-CH2-N (- CH ₂ -CH ₂ -OH) SO ₂ - £ a-CH 2 -NHCO- (CH ₂ ) and oS-CH ₂ CH ₂ -p a-CH ₂ NHCOCH ₂ -O * CH ₂ CH ₂ -fl a-CH ₂ NHCO ( CH2) io-O-CH ₂ CH2-3 a-CH ₂ -C ₆ H 4 -O-CH ₂ CH ₂ N a-CH ₂ -O-CH ₂ -C (CH ₂ -OCH ₂ CH ₂ -C ₆ F ₁ 3) ₂ - CH ₂ -OCH ₂ -CH2a-CH ₂ -NHCOCH ₂ CH ₂ CON-CH2CH2NHCOCH ₂ N (C2H5) SO2C8Fi ₇ \ CH ₂ -CH ₂ NHCOCH ₂ N (C ₂ H ₅ ) -SO ₂ ^ a-CH ₂ -O-CH ₂ -CH (OC ₁₀ H2l) -CH 2 -O-CH ₂ CH ₂ -3 a- (CH ₂ NHCO) 4-CH ₂ O-CH ₂ CH ₂ -3 a- (CH ₂ NHCO) 3-CH ₂ O-CH ₂ CH ₂ -P a-CH 2 -OCH ₂ C (CH ₂ OH) 2-CH ₂ - O-CH ₂ CH ₂ -p a-CH ₂ -OOH ₂ -C (CH 2 <^ H ₂ CH ₂ -CgF-j 3) ₂ -ΟΗ ₂ -ΟΟΗ ₂ -ΟΗ ₂ -β a-CH2-NHCOCH ₂ CH2CON -CH2CH2NHCOCH2N (C2H5) SO2C3F-j7 I CH ₂ -CH ₂ NHCOCH ₂ N (C ₂ H ₅ ) -SO ₂ ^ a-CH ₂ -OH ₂ -CH (OS ₁₀ H ₂₁ ) -CH 2 -O-CH ₂ CH ₂ F a- (CH ₂ NHCO) 4-CH ₂ O-CH ₂ CH ₂ -p a- (CH ₂ NHCO) 3-CH2O-CH ₂ CH2- £ a-CH ₂ -OCH ₂ C (CH2OH) ₂ -CH2-O-CH2CH ₂ -p 433 COOH a-NH-CO-β a-NH-CO-CH2-N (CH2COOH) -SO2-0 a-NH-CO-CH2-N (C ₂ H ₅ ) -SO2-P a-NH-CO-CH2 -N (CioH ₂ i) -SC> 2-p a-NH-CO-CH 2 -N (C ₆ H- | 3) -SO ₂ -ff a-NH-CO- (CH 2) and o N (C ₂ H ₅ ) -SO2-ff a-NH-CO-CH2-N (-CH2-C6H5) -SO2-3 a-NH-CO-CH2-N (-CH2-CH2-OH) S09-B a-NH-CO-CH ₂ -p a-CH2-OC ₆ H4-O-CH2-CH2-3 a-CH2 ~ CgH4 * O * CH2'CH ₂ -P aN (C ₂ H ₅ ) -SO ₂ -3 aN (C ₆ H ₅ ) -SO2-p α-Ν (Ο ₁₀ Η2ΐ) -δθ2-β aN (C6Hi ₃ ) -SQ2-p α-Ν (0 ₂ Η40Η) -502-β aN (CH ₂ COOH) -SO ₂ £ aN ( CH ₂ C ₆ H ₅ ) -SO 2-3 aN- [CH (CH ₂ OH) 2] -SO 2 -p aN- [CH (CH ₂ OH) CH (CH ₂ OH)] - SO 2 - 3 and where a represents the location of the complexing agent or metal complex the point of attachment to the fluorine radical. Use according to claims 8 and 9. characterized in that compounds of general formula I are used, the formula -C _n F _2n E means the numbers 4-15 formula means a fluorine atom. Use according to claims 8 to 10, coupling with α β means in which η in and / or E in this 434, characterized in that the following compounds are used: -Gadolinium complex of 10- [1-methyl-2-oxo-3-aza-5-oxo {4-perfluoroctylsulfonyl-piperazin-1-yl} -pentyl] -1,4,7-tris (carboxymethyl) -1, 4,7,110-tetraazacyclododecane, -Gadolinium complex of 10- [2-hydroxy-4-aza-5-oxo-7-oxa10,10,11,11,12,12,13,13,14,14,15,15,16,16,17 , 17heptadecafluoroheptaselyl] -1,4,7-tris (carboxymethyl) -1,4,7,10tetraazacyclododecane, -Gadolinium complex of 10- {2-hydroxy-4-aza-5,9-dioxo-9 {4-perfluoroctyl) -piperazin-1-yl} -nonyl] -1,4,7tris (carboxymethyl) -1,4 , 7,10-tetraazacyclododecane, -Gadolinium complex of 10- [2-hydroxy-4-aza-5-oxo-7-aza- 7- (perfluoroctyl-sulfonyl) -nonyl] -1,4,7-tris (carboxymethyl) 1,4,7,10-tetraazacyclododecane, -Gadolinium complex of 10- [2-hydroxy-4-oxaH, 1H, 2H, 2H, 3H, 3H, 5H, 5H, 6H, 6H-perfluoro-tetradecyl] -1,4,7tris (carboxymethyl) -1, 4,7,10-tetraazacyclododecane, -Gadolinium complex of 10- [2-hydroxy-4-aza-5-oxo-7-oxa10,10,11,11,12,12,13,13,14,14,15,15,16,16,17 , 17,18,18,19,19 henicosafluoro-nonadecyl] -1,4,7-tris (carboxymethyl) -1,4,7,10tetraazacyclododecane, -Gadolinium complex of 10 [2-hydroxy-4-aza-5-oxo-11-aza 11- (perfluoroctylsulfonyl) -tridecyl] -2,4,7-tris (carboxymethyl) 1,4,7,10-tetraazacyclododecane, 435 -Gadolinium complex of 1- [2-hydroxy-4-aza-5-oxo-7-aza-7 (perfluorooctylsulfonyl) -8-phenyl-octyl] -1-4-7-tris (carboxymethyl) -1,4, 7,10-tetraazacyclododecane. Use according to claims 1-7, characterized in that compounds of the general formula Ia are used as perfluorinated metal complex. A - R ^f (la) in which -A means a molecular moiety containing 2 to 6 metal complexes that are bonded directly or via a linker to the nitrogen atom of a ring structure chain and -R ^F means a perfluorinated, straight or branched carbon chain of formula -C _n F _2n E in which E represents fluorine, chlorine, bromine, iodine or hydrogen atom and N stands for the numbers 4 - 30, with molecular part A having the following structure: By I V I K-V-N N-G-X- I K in which -q stands for a number 0, 1,2 or 3, 436 -K means a complexing agent or metal complex or salts thereof with organic and / or inorganic bases or amino acids or amides of amino acids, -X means a direct bond to the perfluoroalkyl group, one phenylene group or one C 1 -C 10 alkylene chain, which optionally contains 1-15 oxygen atoms, 1-5 sulfur atoms, 1 10 carbonyl groups, 1-10 (NR ^d ) -group, 1-2 NR ^d SO2-rpyna, 1-10 CONR ^d -rpyna, one piperidine group, 1 - 3 SO2 group, 1 - 2 phenylene groups, or optionally substituted by 1-3 radicals R ^F , as R ^d means one hydrogen atom, one phenyl group, a benzyl or C1-C15 alkyl group which optionally contains 1 - 2 NHCO-, 1 - 2 CO groups, 1-5 oxygen atoms and may optionally be substituted with 1 - 5 chi droxy-, 1-5 methoxy-, 1-3 carboxy-, 1-3 R ^F - radicals, -V stands for one direct bond or one chain of the general formula Pa or Illa: ', And VV- (CHJ _m -C-α (Ha) 437 -R ^e denotes one hydrogen atom, one phenyl group, one benzyl group or one C 1 -C 7 alkyl group which is optionally substituted by one carboxy group, one methoxy or one hydroxy group, -W means one direct bond, one polyglycol ether group of up to 5 glycol units, or means one molecular moiety of the general formula IVa - CH (R ^h ) - (IVa) in which R ^h denotes one C 1 -C 7 -carboxylic acid, one phenyl group, one benzyl group or one - (CH ₂ ) i-5 -NH-K-pyrene, -a means the bond to the nitrogen atom of the main chain, β means the bond to the complexing agent or the metal complex K, - and in which kit means numbers between 0 and 10 and I means 0 or 1, such as D stands for one CO- or GOD group. Use according to claim 12, 438, characterized in that compounds of general formula Ia are used in which q is the number 1. Use according to claim 12, characterized in that compounds of the general formula Ia are used in which the molecular moiety X represents an alkylene chain containing 1-10 CH2CH2O- or 1-5 CHOCHIN-groups, one direct bond or one of the following structures Y-C ^ -O-CCH ^ -g, γ -CH ₂ -N-SO ₂ - δ, ? ? ^aHS γ- (ΟΗ ₂ ) ₁₀ -Ν-Ο -ch ₂ -n-so c ₂ h ₅ Η Y - (0 ^ -0- (0 ^ - _δ i θΑ Y-CH ₂ -N-SO ₂ ~ s, γ- ^ Ύ-ΟΗ, -Ν-δΟ, - -δ. y-ch ₂ -n-so ₂ -s Y-CF ^ -N-SO ₂ - δ - that associate γ with D and δ c R ^F. Use according to claim 12, characterized in that 439 uses compounds of general formula Ia, in which V denotes a molecular moiety of the following structure aC-CH ₂ -NH-p, aC-CH ₂ -Np CH ₂ Coon C-pH-NH-β CH (CH ₃ ) _{2 about} CH ₂ soon α-ΟΟΗ, -ΟΗ-ΝΗ-β, About UNC ΪΙ And aC-CH ₂ -CH-NH- β Use according to claim 12, characterized in that compounds of general formula Ia are used in which K represents a complex of general formulas Va, Via, Vila or Villa (Va) 440 (Via) (Villa) r ⁴ ooc — I N R ⁴ 00C — I? N N II — COOR ⁴ XoOR ⁴ (Villa) in which -R ¹ independently of one another denotes a hydrogen atom or an ionic equivalent of a metal of serial number 23-29, 42-46 or 58-70, -R ⁸ means one hydrogen atom or one straight, branched, saturated or unsaturated C 1 -C 3 -alkyl chain, 441 which is optionally substituted by 1 to 5 hydroxy groups, 1-3 carboxy or 1 phenyl group (s) and / or optionally interrupted by 1-10 oxygen atoms, 1 phenylene or 1 phenyleneoxy group -R ⁶ means one hydrogen atom, one straight or branched chain C 1 -C 7 alkyl radical, one phenyl or benzyl radical, -R ⁷ means one hydrogen atom, one methyl or ethyl group, which is optionally substituted by one hydroxy or carboxy group, -U ³ means 1-5 imino-, 1-3 phenylene group, 1-3 phenyleneoxy-, 1-3 phenyleneimino-, 1-5 amide groups, 1-2 hydroside, 1-5 carbonyl, 1-5 ethyleneoxy groups containing 1 carbamide group, 1 thiourea group, 1-2 carboxyalkylamino-, 1 -2 ester groups, 1 -10 oxygen atoms, 1-5 sulfur atoms and / or 1-5 nitrogen atoms and / or optionally substituted by 1-5 hydroxy-, 1- 2 mercapto-, 1-5 oxo-, 1-5 thioxy-, 1-3 carboxy-, 1-5 carboxyalkyl-, 1-5 ester and / or 1-3 amino groups, means one with straight, branched chain, saturated or unsaturated C 1 -C 20 alkylene group, such as Tea containing phenylene groups can be substituted by 1-2 carboxy, 1-2 sulfonic or 1-2 hydroxy groups -T ¹ means one -CO-β or -NHCS ^ -rpyna, with β denoting the V-binding site. Use according to claim 16, characterized in that 442 for U ³ importance Ci - C ₂₀ alkylene chain contains groups -CH2NHCO-, -NHCOCH ₂ O-, -NHCOCH2OC6H4-, -N (CH ₂ CO ₂ H) -, -CH ₂ OCH ₂ -, -NHCOCH ₂ C ₆ H ₄ -, -NHCSNHCgH ₄ -, -CH ₂ OC ₆ H ₄ -, -CH ₂ CH ₂ Oi / or is substituted by -COOH, -CH ₂ COOH. Use according to claim 16, characterized in that U ³ means one -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -C ₆ H ₄ ; -CN ₁₀ -, -CH ₂ C ₆ H ₄ -, -CH ₂ NHCOCH2CH (CH2CO ₂ H) -C ₆ H ₄ -, -CH2NHCOCH2OCH2-, -CH ₂ NHCOCH ₂ C ₆ H ₄ - group. Use according to claim 12, characterized in that compounds of the general formula Ia are used, in which K represents one of the following structures: 443 Use according to any one of claims 12 to 19, characterized in that compounds of the general formula Ia are used in which the perfluoroalkyl chain R ^F is -CgF _13i -CgFv, -C10F21 or C12F25. Use according to one of claims 12 to 20, characterized in that a gadolinium complex of 1,4,7-tris {1,4,7tris (M- (carboxylatomethyl) -10- [M-1- is used) methyl-3,6-diaza-2,5,8trioxooctane-1,8-diyl)] - 1,4,7,10-tetraazacyclododecane, Gdcomplex} -10- [M-2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoyl] -1,4,7,10-tetraazacyclododecane. 444 Use according to any one of claims 1 to 7, characterized in that compounds of the general formula I b (1b) are used as the perfluoroalkyl containing metal complex in which K denotes a complexing agent or metal complex of general formula II b ^ coor 'coor ¹ COOR (lib) as R ¹ denotes a hydrogen atom or an ionic equivalent of a metal of 23-29, 42-46 or 58-70 R ² and R ³ denote one hydrogen atom, one C 1 -C 7 alkyl group, one benzyl group, one phenyl group, -CH ₂ OH, or -CH ₂ -O-CH ₃ , U ² means the radical L ¹ , however, L ¹ and U ^{2 may} independently or independently be identical, A ¹ means one hydrogen atom, one straight or branched chain C 1 -C ₃ o-alkyl group which is optionally interrupted by 1-15 oxygen atoms, and / or 445 substituted with 1 - 10 hydroxy groups, 1-2 COOH groups, one phenyl group, one benzyl group and / or 1 -5 - OR ⁹ groups, R ⁹ being one hydrogen atom or one C 1 -C 7 alkyl radical, or -L ¹ -R ^F , L ¹ means a straight or branched chain C 1 -C 30 alkylene group which is optionally interrupted by 1 - 10 oxygen atomic, 1 -5 NH-CO groups, 1-5 -CO-NH groups, from one phenylene group given case substituted with a COOH group, 1-3 sulfur atoms, 1-2 -N (B ¹ ) -SO 2 groups, and / or 1-2 -SO ₂ -N (B ¹ ) groups such as B ¹ has the meaning of A ¹ , one NHCO group, one CONH group, one N (B ¹ ) -SO2- group, or one -SO2-N (B ¹ ) group / or optionally substituted by one radical R ^F , and R ^f means one straight or branched chain perfluorinated alkyl radical of formula C _n F ₂ nE in which η is the numbers 4-30 and E means an end-positioned fluorine atom, a chlorine atom, a bromine atom, an iodine atom or a hydrogen atom, and optionally the available acid groups may optionally be in the form of salts with organic and / or inorganic bases or amino acids or amides of amino acids. Use according to claim 22, characterized in that compounds of the general formula I b are used in which R ² , R ³ and R ⁹ independently represent hydrogen or a C 1 -C ₄ alkyl group. Use according to claim 22, 446, characterized in that compounds of general formula I b are used in which A ¹ is hydrogen, a C ₁ -C 15 -alkyl radical, the radicals СННЮ-СН3, СзНб-О-СН3, C ₂ H ₄ -O- (C2H4-O) tC ₂ H4-OH, C ₂ H 4 -O- (C ₂ H 4 -O) gC 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 Hi ₄ OH, CH (OH) CH ₂ OH, CH (OH) CH (OH) CH ₂ OH) CH ₂ [CH (OH)] and ¹ CH 2 OH> CH [CH ₂ (OH)] CH (OH) CH ₂ OH, C ₂ H ₄ CH (OH) CH ₂ OH, (CH ₂ ) sCOOH, C ₂ H 4 -O- (C ₂ H 4 O) 1SN ₂ COOH C ₂ H ₄ -0- (C ₂ H ₄ -0) _t C ₂ H ₄ -C _n F _2n E as s is an integer from 1 to 15 , t means integers 0 to 13, and ¹ means integers 1 to 10, η means integers 4 to 20, and E represents a hydrogen, fluorine, chlorine, bromine or iodine atom and, if possible, their branched isomers. Use according to claim 22, characterized in that compounds of the general formula Ib are used in which A ¹ is hydrogen, C 1 -C 10 alkyl, C ₂ H 4 -O-CH ₃ C ₃ H 4 O-CH 3 C2H4-O- (C ₂ H4-O) x-C2H4-OH, C ₂ H4-O- (C ₂ H4-O) x-C2H4-OCH ₃ , C ₂ H ₄ OH, C 3HeOH, CH ₂ [CH (OH)] in CH ₂ OH, CH [CH ₂ (OH)] CH (OH) CH ₂ OH, (CH ₂ ) wCOOH, C ₂ H ₄ -O- (C ₂ H ₄ -O) x-CH ₂ COOH, C2H4-O-fC2H4-O) x-C2H4-C _and F2nE as 447 x means integers 0 to 5, y means integers 1 to 6, w means integers 1 to 10, η means 4 to 15, and E represents a fluorine atom and, if possible, their branched isomers. Use according to claim 22, characterized in that compounds of the general formula 1b are used in which L ¹ means α- (ΟΗ ₂ ) _δ -β a-CH 2 -CH ₂ - (O-CH ₂ -CH ₂ - ) y-3 axis-CH ₂ "(0-CH ₂ CH ₂ ~) y ~ P _> a-CH ^ NH-CO-P α-ΟΗ2-ΟΗ2-ΝΗ-5θ2-β a-CH2-NH-CO- CH 2 -N (CH ₂ COOH) -SO ₂ -p a-CH ₂ -NH-CX> CH 2 -N (C ₂ H ₅ ) -SO ₂ -P a-CH ^ NH-CO-CH ^ NiCi ₀ H ₂ - | ) -δΟ ₂ -β a-CH2-NHOO-CH ₂ -N (C ₆ H ₁₃ ) -SO2 ^ a-CH ₂ -NH-CO- (CH ₂ ) ₁ QN (C ₂ H5) -SO ₂ -p a-CH ₂ -NH-CO-CH ₂ -N (-CH ₂ -C ₆ H ₅ ) -SO 2-3 a-CH ₂ -NH-CO-CH ₂ -N (-CH ₂ -CH ₂ -OH) SO ₂ - 3 a-CH ₂ -NHCO- (CH2) iQ-S- CH ₂ CH ₂ - $ Cj-CH ₂ NHCOCH2-O-CH2CH ₂ -p a-CH ₂ -CH ₂ NHCOCH ₂ -O-CH ₂ CH ₂ - p a-CH ₂ - (CH ₂ -CH2-O) r (CH ₂₎ 3NHCO-CH ₂ -O-CH ₂ CH ₂ -₽ a ^ H ₂ NHCO (CH2ho-0-CH ₂ CH2-p _ a- CH ₂ CH ₂ NHCO (CH 2) j ο-0-ΟΗ ₂ ΟΗ ₂ -β a-CH 2 -C 6 H 4 -O-CH 2 CH 2 ^ having the phenylene group attached at the 1,4 or 1,3 position 448 a-CH2-O-CH2-C (CH2-OCH2CH ₂ -C ₆ Fi3) 2-C ^H 2-OC ^H 2'C ^K 2-? a-CH2-NHCOCH ₂ CH2CON-CH ₂ CH2NHCOCH2N (C2H5) SO2C ₈ Fi73 a-CHrCHaNHCOCHzNiCgHsFSOrp a-CH2-O-CH2-CH (OCi oH ₂ 1 bCH ₂ -O-CH ₂ CH2-RUB a- (CH ₂ NH ₂ ) ₄ -CH ₂ O-CH ₂ CH 2-3 a- (CH ₂ NHCO) 3-CH ₂ O-CH ₂ CH ₂ -p a-CH ₂ -OCH 2 C (CH ₂ OH) 2-CH 2 -O-CH ₂ CH 2 ^ COOH a-CH ₂ NHCOCH2N (C ₆ H5) -SO _2- RUB a-NHCO-CH ₂ -CH2-p a-NHCO-CH ₂ -O-CH ₂ CH ₂ -3 a-NH-CO-β a- NH-CO-CH ₂ -N (CH ₂ COOH) -SO2- £ α-ΝΗ-0Ο-0Η ₂ -Ν (02Η ₅ ) -8θ2-β α-ΝΗ-0Ο-0Η2-Ν (0 ₁₀ Η ₂ ι α-ΝΗ-ΌΟ-ΟΗ2 ”Ν (ϋθΗ j 3> 5Ο ₂ -β a-NH-CC4CH2) l0-N (C ₂ H5) -SO2-₽ a-NH-CO-CH ₂ -N (-CH ₂ -C ₆ H5) -SO ₂ -3 a-NH-CO-CH 2 -N (-CH 2 -CH 2 -OH) SO ₂ ^ α-ΝΗ-0Ο-ΌΗ ₂ -β a-CH ₂ -OC ₆ H4-O -CH ₂ -CH _2- RUB a-CH2-C ₆ H4-O-CH2-CH2-3 aN (C2H5) -SO2- $ aN (C6H ₅ ) -SO2-p aN (Ci 0H21) -SO2-α α -Ν (ΟθΗ- | ₃ ) -δΟ ₂ -β aN (C ₂ H4OH) -SO2-3 aN (CH ₂ COOH) -SO2-p 449 aN (CH ₂ C ₆ H ₅ ) -SO2-B aN- [CH (CH ₂ OH) 2J-SO2-B aN- [CH (CH ₂ OH) CH (OH) (CH ₂ OH)] - SO2- B as s denotes integers 1 to 15 and y denotes integers 1 to 6. Use according to claim 22, characterized in that compounds of the general formula Ib are used, in which L ¹ means a-CH ₂ -O-CH ₂ CH ₂ -B, c-CH 2 -CH 2 - (O-CH 2 - CH ₂ -) y-B, a-CH ₂ - (O-CH ₂ -CH ₂ -) _y -Bja-CH ₂ -CH ₂ -NH-SO 2 -B, Example 10 a-CH ₂ NHCOCH ₂ -O-CH ₂ CH ₂ -B, a-CH ₂ -CH ₂ NHCOCH ₂ -O-CH ₂ CH ₂ -B, a-CH ₂ - (CH ₂ -CH ₂ -O) y- (CH ₂ ) ₃ NHCO-CH 2 -O-CH ₂ CH ₂ -B, a-CH ₂ NHCO (CH ₂ ) ₁₀ -0-CH ₂ CH ₂ -B, a-CH ₂ CH ₂ NHCO (CH 2) io-O-CH ₂ CH ₂ -B, a-CH ₂ -O- CH2-CH (OCOH ₂ L) -CH2-O-CH2CH ₂ -B, a-CH ₂ -O-C6H4-O-CH ₂ -CH ₂ -B a-CH ₂ -C6H4-0-CH2-CH ₂ - B as y means integers 1 to 6. Use according to claim 22, characterized in that compounds of the general formula 1b are used in which R ^F denotes a straight or branched chain perfluorinated alkyl radical of the formula C _n F 2 _n E in which η represents the numbers 4 to 15 and E denote one end-positioned fluorine atom. Use according to one of Claims 22 to 28, characterized in that the following compounds are used: -1,4,7-Tris (carboxylatomethyl) -10- (3-aza-4-oxo-hexan-5-yl) acid-N- (2,3-dihydroxypropyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H450 3-Oxa-Perfluorotridecyl) -amide] -1,4,7, -10tetraazacyclododecane, gadolinium complex -1,4,7-tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexane-5- yl) acid-N- (3,6,9,12,15-pentaoxa) -hexadecyl) (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa) -perfluorotridecyl] -amide} 1 , 4,7,10-tetraazacyclododecane, gadalinium complex -1,4,7-Tris (carboxylatomethyl) -10 - {(3-aza-4-oxo-hexan-5-yl) acid-L1-5-hydroxy-3-oxa-pentyl) -N (1H, 1H , 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl] -amide} 1,4,7,10-tetraazacyclododecane, gadolinium complex -1,4,7-Tris (carboxylatomethyl) -10 {(3-aza-4-oxo-hexan-5-yl) acid - [N-3,6,9,15-tetraox-12-aza-15- oxo-C- | 7-C2b decafluoro) hexacosyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex -1,4,7-Tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-hexan-5-yl) acid-N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H) , 4H, 4H, 5H, 5H-3-oxa) perfluorotridecyl] -amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex. Use according to any one of claims 1 to 7, characterized in that compounds of the general formula Ic (Y-RV) are used as the perfluoroalkyl containing metal complex. 451 R represents a mono or oligosaccharide radical linked to the 1 - OH or 1-SH position, R ^F stands for a perfluorinated, straight or branched carbon chain of formula C _n F _2n E, in which E denotes a fluorine, chlorine, bromine, iodine or hydrogen atom located at the end position and η stands for numbers 4 - 30, K denotes a metal complex of the general formula Ps, (H in which R ¹ means one hydrogen atom or one ionic metal equivalent of the order of 23-29, 42-46 or 58-70, provided that at least two R ¹ denote the ionic equivalent of a metal R ² and R ³ independently represent hydrogen, C 1 -C 4 alkyl, benzyl, phenyl, -CH ₂ OH or -CH ₂ OCH ₃ and U represents -CH _{6 - 4 -} O - CH ₂ - 1 -, - (ΟΗ ₂ ) ι - 5.ω, one phenylene group, - CH _{2 -} MHCO - CH _{2 -} CH (CH ₂ COOH) - C ₆ H ₄ - w-, -C ₆ H ₄ (OCH ₂ CH ₂ ) o N (CH ₂ COOH) -CH ₂ -u) or one optionally interrupted by one or more oxygen atoms, 1 to 3 -NHCO-, 1 to 3 - CONH-groups and / or 1 to 3 - (CH ₂ ) _O- 5-COOH-groups substituted C 2 C- | _2- alkylene or C 7 -C _{1 2} -C ₆ H ₄ -O-group, 452 as ω denotes the point of attachment to -CO- or the general formula IIIc (IIc) in which R ¹ has the meanings given above, R ⁴ represents hydrogen or one ionic equivalent of a metal specified for R ¹ and U ¹ means - CbH ₄ -O-CH ₂ -ω-, where ω denotes the binding site with -CO or of the general formula IVc R'OOC (IVc) in which R ¹ and R ² have the meanings given above or by the general formula VcA or VcB 453 Oh II • w «~ - c ROOC / '-COOR ¹ • COOR ¹ COOR ¹ \ (VcA) (VcB) in which R ¹ has the meanings given above or by the general formula Vic ROOC ROOC COOR ¹ (Vic) in which R ¹ has the meanings given above or by the general formula Vile ROOC ROOC ROOC ROOC (Villas) in which R ¹ has the meanings given above and U ¹ stands for -C 6 NH 4 -O-CH 2 -n -, with ω denotes the point of attachment with -CO454 or the general formula Ville COOR ¹ R ¹ OOC OH COOR ¹ (Ville) in which R ¹ has the meanings given above and in the radical K optionally the available free acid groups may optionally be as salts with organic and / or inorganic bases or amino acids or amides of amino acids, G, for the case where K is a metal complex Ps to Vile, means one at least three-functional radical selected from the following radicals a) to j) (a) NH β (b) a 455 (C) (θ) 456 (Ο (g)) Η NH-CO-C - ^^ N ^ a ΝΗ N-CO-CHCHi ^ Nv-a ΝΗ ι β β I ΝΗ, NH-CO-CH- (CH ₂ ) ₄ -NH - ^ & ⁴ ι / N-CO-CH- (CH,) ₄ -NH ^ a I ΝΗ Υ ΝΗ-ΟΟ-ΟΗ- (ΟΗ ₂ ) _Γ ΝΗ ^ β ΝΗ 1 β 457 (i) (i) <χ · Λ ^ · Μ4 — CH —CO— ^ Y β and G, in the case where K denotes the Ville metal complex, means at least a trifunctional radical selected from k) to I), (k) p ^ NH- (CH ₂ ) _r CH-CO- ^ a ΝΗ I V (1) a ^ -CO-CH _r CH-CH5CO- ^ Y ² I ² ΝΗ 4 β 458 as a denotes the point of attachment of G to the complex K, β denotes the point of attachment of G to the radical Υ and γ denotes the point of attachment of G to the radical Ζ Υ stands for -CH ₂ -, δ- (0Η ₂ ) ₍₁ .5) 0Ο-β, δ-ΟΗ ₂ ΟΗΟΗ-ΟΗ-β, or b-CH (CHOH-CH ₂ OH) -CHOH-CHOH-CO ^, where δ means the point of attachment to the saccharide radical R and β means the point of attachment to the radical G Ζ means N-SOj-ε rCOCH2-N (C ₂ H ₅ ) -SO 2 -E, Y-COCHz-O-fCI-tyrSOz-e, N-so ^ -ε or γ - NHCH2CH2-O-CH2CH2 - ε as γ denotes the point of attachment of Ζ to the radical G and ε denotes the point of attachment of Ζ to the perfluorinated radical R ^F and I ¹ , t ¹ independently denote integers 1 or 2 and p denotes integers 1 to 4. Use according to claim 30, characterized in that 459 uses compounds of general formula Ic, in which R represents a monosaccharide radical of 5 to 6 carbon atoms or their deoxy compounds, preferably glucose, mannose or galactose. Use according to claim 30, characterized in that compounds of the general formula Ic are used in which R ² and R ³ independently represent hydrogen or C 1 -C 4 alkyl and / or E in the formula -C _n F _2n E stands for one fluorine atom. Use according to claim 30, characterized in that compounds of the general formula Ic are used in which G denotes a lysine radical (a) or (b). Use according to claim 30, characterized in that compounds of general formula I are used in which Z is Y - ^ N-SO ₂ -E as γ denotes the point of attachment of Z to the radical G and ε denotes the point of attachment of Ζ to the perfluorinated radical R ^F and / or Y means b-CH ₂ CO-p, with δ denoting for binding to the saccharide radical R and β means the point of attachment to the radical G. Use according to claim 30, characterized in that 460 compounds of general formula Ic are used in which U in the metal complex K represents -CH ₂ - or -C ₆ H ₄ -O-CH ₂ - (x), where ω denotes the binding site with -CO-. Use according to claim 30, characterized in that the gadolinium complex of 6-N- [1,4,7-Tpnc (carboxylsatomethyl) -1,4,7,10-tetraazacycododecane-10-N (pentanoyl- 3-aza-4-oxo-5-methyl-5-yl) -2-N- [1-0-a-0carbonylmethyl-mannopyranose] -1-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide. Use according to any one of claims 1 to 7, characterized in that compounds of the polar radical of general formula Id (K), '- G- (ZR ^F ) _m ' are used as perfluoroalkyl containing metal complex. I (I) (R) p ² Wherein R ^F denotes a perfluorinated, straight or branched carbon chain of formula C _n F 2 _n E, in which E denotes a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and η denotes the integer 4 - 30, K stands for a metal complex of general formula lid 461 ROOC (lid) in which R ¹ means one hydrogen atom or one ionic metal equivalent of the order of 23-29, 42-46 or 58-70, provided that at least two R ¹ radicals represent an ionic metal equivalent R ² and R ³ independently represent hydrogen, C 1 -C 4 alkyl, benzyl, phenyl, -CH ₂ OH or -CH ₂ OCH ₃ and U represents -SbN ₄ -O-CH ₂ -NH, - (ΟΗ ₂₎ ι-5-ω, a phenylene group, -CH ₂ NHCO-CH ₂ -CH (CH ₂ COOH) -C ₆ H ₄ -u) , -C ₆ H ₄ (OCH ₂ CH 2) o N (CH ₂ COOH) -CH ₂ -co or optionally interrupted by one or more oxygen atoms, 1 to 3 NHCO-, 1 to 3 -CONH-groups and / or by 1 to 3 - (CH ₂ ) 5 COOH - groups substituted C1-C- _{A 2-} alkylene or C 1 -C 6 -C 6 N 6 -group, where ω denotes the point of attachment with -CO- or the general formula 11ld 462 COOR ¹ COOR ¹ in which R ¹ has the meanings given above, R ⁴ stands for hydrogen or one ionic metal equivalent for R ¹ and U ¹ stands for -C 6 H 6 -O-CH 6 -n, where ω stands for the bonding point with -CO or common formula IVd COOR ¹ li ^ XR ² COOR (IVd) in which R ¹ and R ² have the meanings given above or by the general formula VdA or VdB (VdA) 463 χ-COOR ¹ '''-CO OR ¹ ^ -COOR ¹ ' -COOR ¹ (VdB) in which R ¹ has the meanings given above or by the general formula Vid ROOC— \ \ χ — CO — Jr. JM NL ROOC— 'COOR ¹ (Vid) in which R ¹ has the meanings given above or by the general formula Vlld ROOC ROOC ROOC ROOC (Vlld) in which R ¹ has the meanings given above and U ¹ means -C ₆ H ₄ -O-CH ₂ -sh, with ω denoting the binding site with -CO 1 in radical K, optionally the acid groups present may optionally be as salts with organic and / or inorganic bases, or amino acids or amides of amino acids, G means at least three times a functional radical selected from the following radicals a) to i) 464 (a) (b) y ^ -CO-CHC ^ -N ^ P I H NH a 465 (θ) 9 (ί) (8) (h) > Y -CO (CH ₂ ) ₂ - ₃ -CH-CO- ^ P; (i) β-α »CO-fCHg ^ -g- ^ H-CO — Μγ 1 ΝΗ ΝΗ I I α α as α denotes the point of attachment of G to the complex K, β denotes the point of attachment of G to the radical R and γ denotes the point of attachment of G to the radical Ζ 466 Z means Y-CiOJCHaCXCHiOre, where γ denotes the point of attachment of Ζ to the radical G and ε denotes the point of attachment of Ζ to the perfluorinated radical Rf R represents one polar radical selected from the complexes K of the general formula lid to Vlld, where R ¹ denotes one hydrogen atom or one ion equivalent of sequence number 20, 23-29,42-46 or 58-70, and the radicals R ² , R ³ , R ⁴ , II and U ¹ have the meanings given above or a folic acid radical or means one bonded directly or through a -CO-, BO _2- bond to the radical G of a carbon chain of 2-30 carbon atoms, straight or branched, unsaturated or unsaturated, optionally interrupted by 1 -10 oxygen atoms, 1-5 -NHCO-groups, 1-5CONH- groups, 1- 2 sulfur atoms, 1-5 -NH-groups or 1 -2 phenylene your groups which may optionally be substituted with 1-2 OH groups, 1 -2 NH ₂ - groups, 1 - 2 -SOONgrupi or 1 - 2 -BOzN groups or optionally substituted with 1- 8 OH groups, 1-5 COOH groups, 1-2 BOZH groups, 1-5 NH ₂ -pynn, 1-5 Ci-C ₄ alkoxy groups, and I ¹ , m ¹ , p ² independently represent the integers 1 or 2. 467 Use according to claim 37, characterized in that compounds of the general formula Id are used, in which K denotes a metal complex of the general formulas lid, IIld, VdB or Vlld. Use according to claim 37, characterized in that compounds of the general formula Id are used in which the polar radical R has the meanings of complex K, preferably complex K of general formulas lid, 11ld, VdA or Vlld. Use according to claim 37, characterized in that compounds of the general formula Id are used in which the polar radical R has the following meanings: -C (O) CH ₂ CH ₂ SO _a H -OPSNgOSNgSNgOSNgSNgON -adSNgOSNgSNgON -C (O) CH ₂ OH ₂ CH (OH) CH ₂ OH -C (O) CH ₂ NH-C (O) CH ₂ C0OH -C (O) CH ₂ CH (OH) CH ₂ OH -C (O) CH ₂ OCH ₂ COOH -VogSNgSNgSOON 'C (O) -SbN3- (t-COOH) ₂ -C (O) CH ₂ O (CH ₂ ) dZD ₂ (t-COOH) 2 -C (O) CH2 O-CeH4-m-SO3H -C (O) CH ₂ NHC (O) CH ₂ NHC (O) CH ₂ OCH ₂ C0OH -C (O) CH ₂ OCH _g CH ₂ OCH ₂ COOH -C (O) CH ₂ OCH ₂ CH (OH) CH ₂ O-CH ₂ CH ₂ OH -C (0) CH ₂ OCH ₂ CH (OH) CH ₂ OCH ₂ -CH (OH) -CH ₂ OH 468 -C (O) CH ₂ SO ₃ H -C (O) CH ₂ CH ₂ COOH -C (O) CH (OH) CH (OH) CH ₂ OH -C (O) CH ₂ O {(CH ₂ ) ₂ O] - - CH ₃ -C (O) LED (CH ₂ ) ₂ OM-H -C (O) CH ₂ OH (CH ₂ OH) ₂ -C (O) CH ₂ OCH (CH ₂ OCH ₂ COOH) ₂ -C (O) -CNH3- (t-OCH ₂ COOH) ₂ -CO-CH ₂ O- (CH ₂ ) ₂ O (CH ₂ ) ₂ O- (CH ₂ ) ₂ O (CH ₂ ) ₂ OCH ₃ preferably -C (O) CH 2 O [(CH 2) 2 O] 4-CH ₃ . Use according to claim 37, characterized in that compounds of the general formula Id are used in which the polar radical R is a folic acid radical. Use according to claim 37, characterized in that compounds of the general formula Id are used in which G denotes a lysine radical (a) or (b). Use according to claim 37, characterized in that compounds of the general formula Id are used in which U in the metal complex K represents the group -CH 2 - or -C 6 H 6 -O-CH 2ω, where ω denotes the binding site with -CO -. Use according to one of claims 37-43, characterized in that a gadolinium complex of 2,6-N, N'-6nc [1,4,7-Tpnc (carboxylatomethyl) -1,4,7 is used, 10-Tetraazacyclododecan-10 (pentanonyl-3-aza-4-oxo-5-methyl-5-yl)] - lysine - [1- (4perfluoroctylsulfonyl) -piperazine] -amide. 469 Use according to any one of claims 1-7, characterized in that galenic formulations containing paramagnetic perfluoroalkyl containing metal complexes of the general formulas I, Ia, 1b, Ic and diamagnetic perfluoroalkyl containing substances are used as perfluoroalkyl containing metal complexes. dissolved in aqueous solvent. Use according to claim 45, characterized in that those having the general formula XX are used as diamagnetic perfluoroalkyl-containing substances: R ^F - L ² - B ² (XX) in which R ^F denotes a straight or branched chain perfluoroalkyl radical of 4 to 30 carbon atoms, L ² denotes one linker and B ² denotes one hydrophilic group. Use according to claim 46, characterized in that the linker L ² means one direct bond, one -SO 2 group or one straight or branched carbon chain with up to 20 carbon atoms which are substituted by one or more He, -COO '. SO3 groups and / or optionally contains one or more -O-, -S-, -CO-, -CONH-, -NHCO-, -CONR ⁹ -, -NR ⁹ CO-, -SO2, -PO4 ' , -NH-, NR ⁹ - groups, wherein R ⁹ denotes a C 1 to C 20 alkyl radical which may also contain one or more oxygen atoms and / or may be substituted by -C00 'or SO 3 groups. 470 Use according to claim 46, characterized in that the hydrophilic group B ² means one mono- or disaccharide, one or more adjacent-COO 'or SO ₃ ' -groups, one dicarboxylic acid, one isophthalic acid, one picolic acid, benzenesulfonic acid, one tetrahydropyranic acid, one 2,6-pyridinedicarboxylic acid, one quaternary ammonium ion, one aminopolycarboxylic acid, one aminodipolylethylglycolsulfonic acid, one aminopolyethylene glycol group, one SO2- (hydroxy) 2-hydroxy 2-hydroxy, 2-hydroxy, 2-hydroxy, 2-hydroxy, at least two hydroxyl groups or one or more polyethylene glycol chains with at least two glycol units, the polyethylene glycol chains ending with one -OH or -OCH3 group. Use according to claim 45, characterized in that neat compounds of α-, β- or γ cyclodextrins and compounds of general formula XXII are used as diamagnetic perfluoroalkyl-containing substances: A ² -L ³ -R ^f (XXII) in which A ² denotes one adamantane, biphenyl or anthrasene molecule, L ³ denotes one linker and R ^F denotes one straight or branched chain perfluoroalkyl radical of 4 to 30 carbon atoms; wherein the linker L ³ means a straight hydrocarbon chain having 1 to 20 carbon atoms which may be interrupted by one or 471 more oxygen atoms, esn or more CO-, SO ₂ -, CONH-, NHCO-, CONR ¹⁰ -, NR ¹⁰ CO-, ΝΗ-, NR ¹⁰ - groups or one piperazine, with R ¹⁰ being one C1-C5 - an alkyl radical. Use according to claim 45, characterized in that diamagnetic perfluoroalkyl containing substances are those of general formula XXI: R ^F - X ¹ (XXI) in which R ^F denotes one straight or branched chain perfluoroalkyl radical of 4 to 30 carbon atoms and X ¹ means one radical selected from the group of radicals below (n means an integer between 1 and 10 ):