BG107540A - Perfluoroalkyl-containing complexes comprising sugar residues, method for producing the same and use trhereof - Google Patents

Abstract

The invention relates to perfluoroalkyl-containing complexes comprising sugar residues of the general formula wherein R represents a mono- or oligo-saccharide residue bound in the 1-OH or 1-SH position, Rf represents a perfluorated carbon chain, K is a metal complex and Y and Z are linker groups. The inventive complexes are suitable for use in intravenous lymphography, in tumor diagnosis and for infarct and necrosis imaging. 23 claims, 2 figures

Description

Technical field

The invention relates to perfluoroalkyl-containing metal complexes with sugar residues of general formula I, to a method for their preparation and use in NMR and X-ray diagnostics, radiodiagnosis and radiotherapy, MRT lymphography, as well as to serve for imaging vascular volume (blood-pool-agents). The compounds of the invention are particularly suitable for intravenous lymphography, for tumor diagnosis and for infarct and necrosis imaging.

BACKGROUND OF THE INVENTION

In the magnetic resonance after the hydrogen element, the element fluorine is of the greatest importance.

1) fluorine has a high sensitivity of 83% of that of hydrogen.

2) fluorine has only one NMR-active isotope.

3) fluorine has a hydrogen-like resonance frequency fluorine and hydrogen can be measured with the same apparatus.

4) the fluorine is biologically inert.

5) fluorine does not occur in biological material (except in the teeth) and can therefore be used as a probe or contrast agent for a signal-free background.

These properties cause fluorine to occupy a wide space in the diagnostic patent literature that underlies magnetic nuclear resonance: fluorine-19 imaging, functional diagnosis, spectroscopy.

Thus, in U.S. Patent 4,639,664 (Mallinckrodt), trifluoromethanesulfonamides are proposed as contrast agents for fluorine-19 imaging:

CF ₃ SO ₂ NH ₂

CF ₃ SO ₂ NH-CH ₂ - (CHOH) ₄ -CH ₂ OH

Fluorine-19 imaging is also covered by German patent DE 4203254 (Max-Planck-Gesellschaft), in which the aniline derivative is proposed:

nhcoch ₂ i fluorine-19 imaging is the subject of application WO 93/07907 (Mallinckrodt), which also describes phenyl derivatives as contrast agents:

CO ₂ H

Significantly simple compounds have also been described for fluorine-19 imaging. Thus, U.S. Patent No. 4,586,521 (Children's Hospital Medical Center) mentions perfluorooctyl bromide

CF ₃ (CF ₂ ) ₇ - Br, European patent EP 307863 (Air Products) discloses perfluoro15-crown-5-ethers

and in U.S. Patent No. 4,858,279 (University of Cincinnati, Children's Hospital Research Foundation) perfluorocarbon compounds such as perfluorocyclononan or -octane, perfluorinated ethers such as tetrahydrofuran

or dieters such as perfluoro-propylene glycol-diethyl ether

Also, fluorine-19 imaging is referred to in the application WO 94/22368 (Molecular Biosystems) compounds such as

CH3 (CH2) ₇ CH = CH (CH2) ₇ CO— Ο / --- OCO (CH ₂ ) ₆ R \ - OCO (CH ₂ ) ₆ R

which have in the fluorine residue a perfluoro-1T, 1H-neopentyl group.

Another structural type of compound with advanced diagnostic application is US patent U. S. 5 362 478 (VIVORX), which uses the fluorocarbon / polymer coating combination for imaging purposes. Perfluoronanone and human serum albumin are mentioned. This combination proves to be suitable for the application of the fluorine atom as a probe for local temperature measurement and oxygen partial pressure determination.

Perfluorocarbons are also described in U. S. Patent 4 586 511 for the determination of oxygen.

German patent DE 4008179 (Schering) describes fluoro-containing benzenesulfonamides as pH probes:

F

NHSO ₂ CH ₂ CH ₂ CO ₂ H

Compounds containing iodine and fluorine atoms are also described for MRI diagnostics as contrast enhancers see. WO 94/05335 and WO / 22368 (both Molecular Biosystems):

C (CF ₃ ) ₃

C (CF ₃ ) ₃

Also, the fluorine-paramagnetic metal ion combination is considered in the fluorine-19 imaging for open-chain complexes according to WO 94/22368 (Molecular Biosystems) with e.g.

H ₂ C - HNOC

CONH-CH

C (CF ₃ ) ₃ C (CF ₃ ) ₃

C (CF ₃ ) ₃ C (CF ₃ ) ₃ and in EP 292 306 (TERUMO Kabushiki Kaisha) c for example:

R = --- CH ₂ CF ₃

C (CF ₃ ) ₃

but also for cyclic compounds as mentioned in EP

292 306 (TERUMO Kabushiki Kaisha) rf

CO ₂ '

CO ₂

The combination of a fluorine atom - a rare earth metal is also protected for NMR spectroscopic temperature measurements in DE 43177588 (Schering):

Ln: rare earth element: La, Pr, Dy, Eu

While the fluorine-iodine-containing compounds do not have a variable action between the two nuclei, the fluorine-containing compounds and the paramagnetic centers (radicals, metal ions) have an intense variable action, which is expressed in the reduction of the fluorine relaxation time. core. The magnitude of this effect depends on the number of non-pair electrons of the metal ion (Gd ³⁺ > Mn ²⁺ > Fe ³⁺ > Cu ²⁺ ) and on the distance between the paramagnetic ion and the F atom.

The more non-pin electrons of a metal are and the closer they are to the fluorine, the greater the reduction in the relaxation time of the fluorine nucleus.

The reduction in relaxation time as a function of the distance from the paramagnetic ion becomes noticeable in all nuclei with a spin spin number as well as a proton, and therefore gladolin compounds are widely used in contrast agents in nuclear spintomography (Magnevist®, Prohance®, Omniscan® , Dotarem®).

For ¹ H-MP imaging ( ¹ H-MRI), the relaxation time T ¹ or T ² of the protons is measured, that is, first of all, the protons of water, not the relaxation time of the fluorine nuclei used to obtain the picture. The quantitative measure of the reduction in relaxation time is relaxation [µ / mmol sec]. Paramagnetic ion complexes are successfully used to shorten the relaxation times. The following table gives the relaxation of some commercially available preparations:

T - relaxivity in water [L / mmol, 39 ° C, 0.47 T]. T - relaxivity in plasma [L / mmol. sec, 39 ° C, 0.47 T]. Magnevist® 3.8 4.8 Dotarem®) 3.5 4.3 Omniscan®  3.8 4.4 Prohance® 3.7 4.9

In these compounds, only actions between protons and gladolin ion occur. For these contrast agents in water, a relaxation of about 4 l / mmol / sec is observed.

Therefore, both fluorine compounds for fluorine-19 imaging can be used for MP imaging, using the shortened relaxation time of the fluorine nucleus, as well as fluorine-free compounds, which measure the relaxation time of protons of water.

When introducing perfluorocarbon-containing residues into a paramagnetic contrast medium, i. in the combination of properties that have hitherto been considered suitable only for fluorine imaging compounds, with compounds used for proton imaging, the relaxation with respect to protons of water is surprisingly increased. It reaches values of 10-50 [L / mmol / sec], compared to values between 3.5 and 3.8 [L / mmol / sec], as already shown for some commercial products in the table above.

DE 196 03 033.1 discloses perfluoroalkyl containing metal complexes. These compounds are not sufficiently applicable in all cases. Thus, there is still a need for contrast agents for the imaging of malignant tumors, lymph nodes and necrotic tissue.

Malignant tumors often metastasize to regional lymph nodes, which may involve more lymph node reservoirs. Thus, lymph node metastases are detected in about 50-69% of all patients with malignant tumors (Elke, Lymphographie, in: Frommhold, Stender, Thurn (eds), Radiologic Diagnostic im Klinik und Praxis, Band IV, Thieme Verlag Stuttgart, 7th ed., 434 - 496, 1984). The diagnosis of a metastatic spread in lymph nodes is essential in view of the treatment and prognosis of malignancies. With modern imaging (CT, US, and MRI) methods, lymphogenous C cancers can only be poorly recognized by malignancies, since in most cases only the size of the lymph node can serve as diagnostic criteria. Small metastases in a non-enlarged lymph node (<2 cm) from hyperplasia of a lymph node without a malignancy cannot be recognized (Steinkamp et al., Sonographie und Kernspintomographie: Differentialdiagnostic von reaktiver , diag., 33: 158,1992).

It would be desirable, when using specific contrast agents, to distinguish lymph nodes with metastases from hyperplastic lymph nodes.

Direct X-ray lymphography (injection of oily suspension of a contrast agent into a parboiled lymphatic vessel) is known as the only rarely used invasive method that can depict only a few lymphatic reservoirs.

Experimentally, fluorescence-labeling dextrans were used in animal experiments to monitor lymph drainage after interstitial administration. Common to all used lymphatic and lymph node imaging markers after interstitial / intracutaneous administration is that they are substances that are in the form of single particles ('particles, such as emulsions and nanocrystalline suspensions) or large polymers (see also WO 90/14846).

The formulations described so far are still insufficiently suitable for indirect lymphography due to their insufficient local and systemic tolerance as well as their low lymphatic patency, which determines their poor diagnostic performance.

Because lymph node formation is central to the early diagnosis of metastatic formation in w cancer patients, there is a great need for lymphospecific contrast formulations to diagnose relevant changes in the lymphatic system.

Possible higher contrast media loading and high stability are also desirable, as are relevant, possible even lymphatic accumulation across multiple lymphatic vessels. The load of the whole organism is less with the rapid and complete separation of the contrast medium. The rapid onset of action, within a few hours after administration of the contrast agent, is important for radiological practice. Good tolerance is also required.

Last but not least, it is desirable that lymphospecific contrast agents are available that enable one primary diagnosis and possible metastasis of the lymph nodes to be diagnosed with one diagnosis.

Another important area of medicine is the tracking, localization and monitoring of necrosis or heart attacks. Thus, myocardial infarction is not a stationary event, but a dynamic process that extends over a longer period of time (weeks to months). The disease occurs in approximately three phases that are not sharply separated from each other but overlap.

The first phase, the development of myocardial infarction, encompasses 24 hours after the infarction, in which the destruction progresses as a shock wave (wavefrontal phenomenon), progressing from the subendocardium to the myocardium. The second phase of pre-existing infarction involves stabilizing the area in which tissue formation (fibrosis) follows as a healing process. The third phase, healing heart attack, begins after all the destroyed tissue has been replaced with fibrous connective tissue. There has been a major restructuring during this period.

To date, no precise and reliable method is available to diagnose the current phase of a myocardial infarction in a living patient. It is crucial for the assessment of a myocardial infarction to know what part of the tissue is lost in a heart attack and where the loss is, since it depends on the treatment.

Heart attacks occur not only in the myocardium but also in other tissues, especially the brain.

As long as the heart attack is treatable, necrosis, locally limited tissue death, can only prevent or at least relieve the harmful effects of the rest of the body. Necrosis can be obtained in many ways: through injury, chemicals, oxygen deficiency, or radiation. As with myocardial infarction, knowing the extent and type of necrosis is important for further treatment.

Therefore, there has long been attempts to improve the localization of infarcts and necrosis by applying contrast agents in non-invasive methods such as scintigraphy or nuclear spintomography. There has been a considerable amount of effort in the literature to attempt to use porphyrins for necrosis. However, the results achieved provide a contradictory picture. Thus, Winkelman and Hoyes described in Nature, 200, 903 (1967) that manganese-5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrin (TPPS) accumulated selectively in the necrotic portion of the tumor.

In contrast, Lyon et al., (Magn. Res. Med. 4, 24 (1987)) observed that manganese-TPPS is distributed in the body and in the kidney, liver, tumor, and only a small portion of the muscle. The interesting thing is that the concentration in the tumor reaches its maximum only on day 4 and only after the authors have increased the dose from 0.12 mmol / kg to 0.2 mmol / kg. Therefore, the authors write about a non-specific uptake of TPPS in the tumor. In turn, Bockhurst et al. Reported in Acta Neurochir. 60, 347 (1994, suppl.) That MnTPPS binds selectively to tumor cells.

Foster et al., (J. Nucl. Med. 26, 756 (1985)), in turn, found that ^{111 1} n-5,10,15,20-tetrakis- (4-N-methylpyridine) porphyrin (TMPrP) it does not enrich the necrotic part, but accumulates in the living end layers. It follows that porphyrin-tissue metabolism may exist.

In Circulation Vol. 90, No. 3 4, Teil 2, Seite 1468, Abstract No. 2512 (1994) Ni et al., Report that they can depict infarcted areas with one manganese-tetraphenyl-porphyrin (Mn-TPPS) and one gladoline mesoporphyrin (Gd-MP). In International Patent Application WO 95/31219, both infarcted and necrotic imaging agents are administered. The authors Marchal and Ni described (see Example 3) that for the Gd MP compound, the metal content in the infarcted kidney was similar to that of the non-infarcted organ, but nevertheless in the myocardium in infarcted tissue (Example 1), the content was nine times higher. high. Surprisingly, the ratio of MRI signal intensities for infarct versus healthy tissue in both cases is 2.10, respectively 2.19. Other metal pyridines are described in application DE 198 35 082 (Schering AG).

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

DE 197 44 003 (Schering AG), DE 197 44 004 (Schering AG) and WO 99/17809 (EPIX) describe contrast agents for necrotic and infarct imaging that are not derived from the porphyrin skeleton. However, so far there are no compounds that can be satisfactorily applied as contrast agents in infarcted and necrotic imaging.

It is an object of the invention, therefore, to develop contrast agents that are particularly suitable for MRT lymphography, but also for tumor diagnosis and necrosis and infarction imaging.

SUMMARY OF THE INVENTION

The object of the invention is solved by perfluoroalkyl containing complexes of sugar residues of general formula I (K), - G- (Z ^ Rf) m ( ^y - ^R ) p (I) in which:

R represents a mono- or oligosaccharide moiety which is attached via the 1-OH or 1-SH-position,

R _f denotes a perfluorinated, straight or branched carbon chain of formula -C _n F _2n E in which E is at the end a fluorine, chlorine, bromine, iodine or hydrogen atom and η stands for the numbers 4 - 30,

K represents a metal complex of general formula II

wherein:

R ¹ represents hydrogen or the metal ion equivalent of the numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83;

provided that at least two R ¹ denote metal ion equivalents;

R ² and R ³ independently represent hydrogen, C 1-6 alkyl, benzyl, phenyl, -CH ₂ OH or -CH ₂ OCH ₃ and

U represents -C ₆ H ₄ -O-CH ₂ -a -, - (CH 2 -co, phenyl group, -CH ₂ NHCO-CH ₂ -CH (CH ₂ COOH) -C ₆ H ₄ -o-, -C ₆ H ₄ - (O-CH ₂ CH ₂ ) _{0. 1} -N (CH ₂ COOH) CH ₂ -O or optionally interrupted by one or more oxygen atoms, 1 to 3-NHCO-, 1 to 3 -CONH-rpynn and / or by 1 to 3- (CH _{2) 0. 5} -COOH substituted C ^^ - alkylene or C _{7. 12} -C ₆ H ₄ -O-group in which the ω means the binding site to the -CO-, or of the general formula III

COOR ¹

COOR ¹ in which R ¹ has the above meanings, R ⁴ is hydrogen or the metal ion equivalent described in R ¹ and U ¹ is -C ₆ H ₄ -O-CH ₂ ω-, where ω denotes the binding site to -CO-, or of the general formula IV

wherein R ¹ and R ² have the meanings given above or the general formula VA or VB

N

--COOR ¹

--COOR ¹ KG

ROOC

COOR ¹ (VA)

COOR ¹ -COOR ¹

COOR ¹

COOR ¹ (VB) in which R ¹ has the above meanings or of the general formula VI

R ¹ OOC

R ¹ OOC

Ν

X - COOR ¹

COOR ¹ in which R ¹ has the above meanings or of the general formula VII (VI)

R100C

R ¹ OOC

Ο

R ¹ OOC - \ /

N

R ¹ OOC

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

U ¹ means -C ₆ H ₄ -O-CH ₂ -a> -, where ω denotes the binding site to -CO-, or by the general formula VIII

-COOR1

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

G in the case where K denotes the metal complexes II to VII, it means at least three times a functionalized residue selected from the following residues a) to j):

(a) (b)

y <lmml00 Q - (CH ₂ ) 4 --- β

And so on

NH α

(c)

axis

β (e) ί

co β ΛνΛΛΜtAAAMV (f)

H

NH — CO C— (CH ₂ ) ₄ - NawwC /.

/ I H

NH (g) (h) \

/ ¹

H

H - CO ^- C - (CH ₂ ) _{4 -} N ' ^MM ^ a IH

NH

NH

NH - CO - CH ^- (CH ₂ ) ₄ - Ν <^ Λ »β / ^H

N CO — CH— <CH ₂ ) ₄ - NH ^ / I

NH \

NH-CO-CH- (CH ₂ ) ₄ —N β I h

NH

H _α - (CH ₂ ) ₄ - C — NH— C 0- C— (CH ₂ ) ₄ - N β η II h

CO., LTD

NH (i) axis

N- (CH ₂ ) 4 ~ C-CO— ν ν— ^Η L O-?

OS (j) α «μλμ | \ || - | ---- CH ---- CO -waw '/

G if Κ denotes the metal complex VIII, then at least three times a functionalized residue is selected from k) or I), (k) β - ^^ ΝΗ - (CH ₂ ) e - CH CO ^^ a

ΝΗ

Υ (I) a - CO - CH ₂ --CH - CH ₂ --CO - Y

NH β

where a denotes the binding site of G to complex K, β is the binding site of G to residue Υ and γ is the binding site of G to residue Ζ

Υ is -CH ₂ -, δ- (ΟΗ ₂ ) _η ΟΟ-β (where η = 1-5), δ-ΟΗ ₂ -ΟΗΟΗ-ϋΟ-β, or δ-ΟΗ (ΟΗΟΗ-ΟΗ ₂ ΟΗ) -ΟΗΟΗ- ΟΗΟΗ-ϋΟ-β, where δ is the location of

binding to the sugar residue R and β is the binding site to the residue G

Ζ means

B ------ S O ₂ --- ^ε

Y-COCH ₂ -N (C ₂ H ₅ ) -SO ₂ -8, Y-COCH ₂ -O- (CH ₂ ) ₂ -SO ₂ - £, ⁰ ?

Ί - N _x __ _Z N - SO ₂ - ^ε or γ - NH-CH ₂ -CH ₂ -O-CH ₂ -CH ₂ - ε in which γ is the junction point of Ζ to the residue G and ε is the point of attachment of Ζ to the perfluorinated residue R _f and

I, m independently denote integers 1 or 2 and

p is an integer from 1 to 4.

If the compound of the invention is intended for use in NMR diagnostics, then the metal ion of the signaling group must be paramagnetic. These are especially divalent or trivalent ions of the elements of numbers 21-29, 42, 44 and 58-70. Suitable ions are, for example, chromium (III) -, iron (II) -, cobalt (II) -, nickel (II ) -, copper (II) -, praseodymium (III) - neodymium (III) -, samarium (III) - and ytterbium (III). Because of their strong magnetic moment, the ions of gadolinium (III) -, terbium (III) -, dysprosium (III) -, holmium (III) -, erbium (III) -, iron (III) - and manganese (II) are particularly preferred -.

For the use of the compounds of the invention in nuclear medicine (radiodiagnosis and radiotherapy), the metal ion must be radioactive. For example, radioisotopes of the elements of order numbers 27, 29, 31- 33, 37-39, 43, 49, 62, 64, 70, 75 and 77 are suitable. Technetium, gallium, indium, rhenium and yttrium are preferred.

If the compound of the invention is intended for use in X-ray diagnostics, then the metal ion must be of a higher order element in order to obtain sufficient X-ray absorption. It has been found that physiologically tolerable metal ion complexes of 25, 26, and 39, as well as 57-83, are suitable for diagnostic agents for this purpose.

Preferred are manganese ions (II), iron (II), praseodymium (III), neodymium (III), samarium (III), gadolinium (III), ytterbium (III) or bismuth (III), especially of dysprosium (III) and of yttrium (III) -.

The hydrogen atoms present in R ¹ , i. those which are not substituted by the central ion may optionally be completely or partially replaced by cations of inorganic and / or organic bases or amino acids or amino acids amides.

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

Particularly preferred compounds of general formula I are those of macro-ring K in general formula II.

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

The alkyl groups R ² and R ³ in the macro-ring of general formula II may be straight or branched. Examples are methyl, ethyl, propyl, isopropyl, n-boogyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl. Predominantly R ² and R ³ independently of one another represent hydrogen or alkyl _b4.

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

The benzyl or phenyl group R ² or R ³ in the macro-ring K of general formula II may also be substituted in the ring.

The residue R in general formula I means a mono- or oligosaccharide moiety or a thiosaccharide V moiety linked through a 1-OH or 1-SH position, wherein according to the invention this may also be a deoxy-sugar moiety which in place of one or more OH groups contain an H atom. In a preferred embodiment of the invention, R represents a monosaccharide moiety having 5 or 6 C atoms, preferably glucose, mannose, galactose, ribose, arabinose or xylose, or a deoxy saccharide such as 5-deoxygalactose (fucose) or 6-deoxymannose (rhamnose) or thiosacchar, wherein glucose, mannose or galactose are particularly preferred.

Of the compounds of the invention of general formula I are further preferred those in which R _f is -C _n F _{2n + 1} . η stands for ^w mostly numbers 4-15. Particularly preferred are residues -C ₄ F ₉ , C ₆ Fi 3 -C ₁₂ F ₂₅ and -C ₁₄ F _29i as well as residues of the compounds described in the examples.

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

Y and Z denote, in general formula I, said linkers (linking groups), wherein independently of one another are preferred to the Z residue

Y - \ - SO ₂ - ^ε and for Υ the residue δ - CH ₂ CO - β.

Sugar-containing perfluoroalkyl metal complexes of general formula I (K), - G - (Z ^ Rf) m (Y- ^R ) _{P (|)} in which K has the meanings given to the metal complex of general formulas II through VII and G.cbc meaning of formulas a) to j), wherein Y, Z, R, R _fl m, p and I of the above are obtained in a known manner as a carboxylic acid of the general formula Pa

29, 31 - 33, 37 - 39, 42 - 44, 49 or 57 - 83 or a carboxylic protecting group and R ² , R ³ and U have the meanings mentioned above or a carboxylic acid of the general formula Illa

(Illa) in which R ⁴ , R ⁵ and U ¹ have the meanings mentioned above or a carboxylic acid of the general formula IVa

ESD ⁵

R ⁵ OOC

COOR ⁵ (IVa) wherein R ⁵ and R ² have the above meanings or a carboxylic acid of the general formula Va or Vb

COOR ⁵

COOR ⁵

COOR ⁵

CO-OH

SPE

COOR ⁵

COOR ⁵

COOR ⁵

COOR ⁵ (Va) (Vb) in which R ⁵ has the indicated meaning or a carboxylic acid of the general formula Via

R5OOC - \ \ / —is-'N ν;

R ⁵ OOC-- '--COOR ⁵ in which R ⁵ has the indicated meaning or a carboxylic acid of the general formula Vila (Via)

R5OOC

R5OOC

R ⁵ OOC (Vila) in which R ⁵ and U ¹ have the meanings already mentioned, optionally reacted with an amine of the general formula IX

Η — G- (Z-Rf) m

^(Y - ^R) P (IX) in which G has the meaning given by formulas (a) to (j) and R, R _f , Y, Z, m, and p have the meanings indicated in the coupling reaction and any subsequent cleavage of the possibly present protecting group to a metal complex of general formula I or when R ⁵ has the meaning of a protecting group, after cleavage of that protecting group in a further step, reacts by itself in a known manner with at least one metal oxide or metal salt per element with the order of 21-29, 31-33, 37-39, 42-44, 49 or 57-83 and then, if desired, any acidic hydrogen atoms, if desired. and are substituted by cations of inorganic and / or organic bases, amino acids or amino acid amides.

The compounds of the invention of general formula I with K having the meaning of a metal complex of general formula VIII and G having the meaning of formula k) or I) are prepared as a known amine of the general formula Villa

the number 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or denotes a carboxyl protecting group,

is reacted with optionally activated carboxylic acid of general formula X

HO-G-1Z-Rpm (X) in which G has the meaning given by formulas k) or I) and R, R _f , Y, Z, m, and p have these meanings in the coupling reaction and any subsequent cleavage of any a protecting group present to a metal complex of general formula I, or when R ⁵ has the meaning of a protecting group, after cleavage of that protecting group in a further step, reacts by itself in at least one metallic oxide or metal salt element with serial number 21-29, 31-33, 37-39, 42-44, 49 or 57-83 and then, if desired, any acidic hydrogen atom, if desired and are replaced by cations of inorganic and / or organic bases, amino acids or amides of amino acids.

The carboxylic acids of the general formulas Pa to Vila used are either known compounds or prepared by the methods described in the examples. Thus, the preparation of the carboxylic acid of general formula Pa is known from DE 196 52 386. The preparation of carboxylic acids of general formula Illa can be obtained analogously to example 3 of the present application. The preparation of the carboxylic acids of general formula IVa can be done according to DE 197 28 954.

A preliminary step for the compounds of general formula VA is N ³ (2,6-dioxomorpholinoethyl) -N ⁶ - (ethoxycarbonylmethyl) -3,6-diazooctanedicarboxylic acid, which is described in EP 263 059.

The compounds of general formula VB are derivatives of the isomeric diethylenetriamine-pentaacetic acid which binds via standing

at the middle N atom of acetic acid. This DTPA is described in patents DE195 07 819 and DE 195 08 058.

Compounds of general formula VI are prepared from N (carboxymethyl) -1 N- [2- (2,6-dioxo-4-morpholinyl) -ethyl] -glycine, the preparation of which is described in J. Am. Oil. Chem. Soc., (1982), 59 (2), 104 - 107.

Compounds of general formula VII are prepared from 1- (4carboxymethoxybenzyl) -ethylenediamine-tetraacetic acid, which is described in U.S. Patent 4 622 420.

The preparation of amines of general formula IX and of carboxylic acids of general formula X is described in detail in the examples of this application and can be carried out according to the methods specified therein. The amine of the general formula Villa is a known starting compound.

The perbenzylated sugar acids used as starting materials can be prepared analogously to those described by Lockhoff, Angew, Chem. 1998, 110 Nr. 24, S. 3634ff method. For example, the preparation of 1-O-acetic acid is carried out by perbenzyl glucose in 2 steps, by trichloroacetimidate and conversion with hydroxyacetic acid ethyl ester, BE _3- catalysis into tetrahydrofuran and subsequent saponification with NaOH in methanol / tetrahydrofuran.

According to one advantageous method, the perbenzylated sugars used as starting materials can also be obtained as the perbenzylated 1-OH sugar is dissolved in a water-immiscible organic solvent and reacted with an alkylating reagent of general formula XI

Nu-L-COO-Sg (XI) in which Nu stands for nucleophage, L - (CH ₂ ) - _N , (wherein η = 1-5), CH ₂ -CHOH-, -CH (CHOH-CH ₂ OH) - CHOH-CHOH- and Sg represents a protecting group, in the presence of a base and optionally a phase-transfer catalyst. Alkylating reagents of general formula XI, for example residues -Cl, -Br, -J, -OTs, OMs, -OSO ₂ CF ₃ , -OSO ₂ C ₄ Fg, or -OSO ₂ C ₃ Fi ₇ may be used as nucleophages.

The protecting group refers to the usual acid protecting group. These protecting groups are well known in the art (Protective Groups in Organic Syntheses, second edition, T. W. Green and P. G. M. Wuts, John Wiley & Sons Inc., New York 1991).

The reaction according to the invention can be carried out at temperatures from 0 - 50 ° C, preferably from 0 ° C to room temperature. Response times range from 10 minutes to 24 hours, preferably 20 minutes to 12 hours.

The base is applied either as a solid, preferably powder or as 10 -70%, preferably 30 - 50% aqueous solution. Preferred bases are NaOH and KOH.

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

Phase transfer portable catalysts include the quaternary ammonium or _r phosphonium salts, as well as a crowner, such as [15] -cron-5 or [18] crown-6, for the methods of the invention. Quaternary ammonium salts with four identical or different hydrocarbon groups in the cation selected from methyl, ethyl, propyl, isopropyl, butyl or isobutyl are preferred. The hydrocarbon groups at the cation should be large enough to provide sufficiently good solubility of the alkylating reagent in the organic solvent. Particularly preferred according to the invention are N (butyl) ₄ ⁺ -CG, N (6yn / m) 4 ⁺ -HSO4 ', HO and N (methyl) ₄ ⁺ -CG.

The metal complexes of the invention have been found to be particularly suitable for MRI and X-ray diagnostics, but also for radiodiagnosis and radiotherapy. Therefore, it is also an object of the invention to use the perfluoro-containing metal complexes of the invention with sugar residues to obtain contrast agents for use in MRI and X-ray diagnostics, in particular for lymphography, for tumor diagnosis and for infarct and necrotic imaging, and in radiodiagnosis and radiotherapy. The compounds of the invention are very suitable for use in interstitial and especially in intravenous lymphography. They can also be used to display blood-pool-agents.

Also contemplated by the invention are pharmaceutical agents which comprise at least one physiologically tolerated compound of the invention, optionally with customary petting additives.

The compounds of the invention are characterized by very good systemic tolerance and high accumulation in the lymph nodes in three consecutive lymph node reservoirs (which is particularly important for venous lymphography). This makes them particularly suitable for use in MRT lymphography.

The compounds of the invention are superbly suitable for the recognition and localization of vascular diseases, since in their application they are exclusively distributed in the intravascular (intravascular) space. The compounds of the invention make it possible, by means of nuclear spintomography, to clearly distinguish well-blooded from poorly-supplied tissues and to diagnose ischemia. Also, infarct tissue, based on its anemia, can be distinguished from healthy, healthy or ischemic tissue when the contrast agents of the invention are administered. This is especially important when, for example, it is necessary to distinguish heart attack from ischemia.

Unlike currently used macromolecular means for determining the vase volume, such as Gd-DTPA-Polylysin, the compounds of the invention show a higher ^T1 -relaksativnost and thus are distinguished by an increase of signal intensity with YaMRkartinno imaging. Since they also have a longer retention time in the bloodstream, they can be administered in relatively smaller doses (eg <50 µmol Gd / l body weight). Above all, the compounds of the invention are rapidly and largely eliminated from the body.

In addition, the compounds of the invention have been shown to concentrate in areas with increased permeability of vessels, such as tumors; they allow conclusions to be drawn regarding the permeability of tissues, make it possible to determine the volume of blood in tissues, selectively shorten the relaxation times, respectively, the blood densities, and to picture the permeability of blood vessels. Such physiological information cannot be obtained using extracellular contrast agents such as Gd-DTPA (Magnevist®). From this point of view, the areas of application in modern imaging methods such as nuclear spintomography and computed tomography are also outlined: specific diagnosis of malignant tumors, early treatment control in cytostatic, antiflogistic or vasodilator therapy, early recognition of insufficiently perfused areas, for example , vascular angiography and the recognition and diagnosis of sterile or infectious inflammation.

The preparation of the pharmaceutical agents of the invention is carried out in a manner known per se. The complex compounds of the invention - optionally with the addition of customary admixtures - are suspended in an aqueous medium or dissolved and then the suspension or solution is optionally sterilized. Suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), additives of complexing agents or weak complexes (such as diethylenetriaminpentanoacetic acid or of the metal complexes of the invention Sacomplexes) or - if necessary - the addition of electrolytes such as sodium chloride. needed - antioxidants such as ascorbic acid.

'If suspensions or solutions of the agents of the invention are desired in water or in physiological saline solution for enteral, parenteral or other purposes, then the compounds are mixed with one or more galenic auxiliaries (eg methylcellulose, lactose, mannitol). and / or surfactants (eg lecithin, Tween®, Myrj®) and / or flavoring agents (eg essential oils).

It is generally possible to obtain the pharmaceutical agents of the invention without isolating the complexes. In each case, care must be taken to ensure that the chelate formation is arranged so that the complexes of the invention are substantially free of uncomplexed, toxic metal ions.

d 'This can be ensured, for example, by color indicators such as xylene orange, by control titration during the production process. The invention therefore also relates to a process for the preparation of complex compounds and their salts. As a last resort, the purification of the isolated complex remains.

When administered in vivo, the agents of the invention can be administered with suitable carriers such as serum or sodium chloride saline and together with another protein such as human serum albumin (HSA).

The agents of the invention are generally administered parenterally, preferably intravenously. They can also be administered intravasally or intestitally / intracutaneously, depending on whether vessels or tissues of the body will be examined.

The pharmaceutical agents of the invention preferably contain 0.1 μmol - 2 mol / l of the complex and are generally dosed in amounts of 0.0001 - 5 mmol / kg.

The advantages of the invention meet the many prerequisites for the applicability of a contrast agent for nuclear spintomography. Thus, they are very suitable, after oral or parenteral administration, for enhancing signal integrity, the image obtained using a nuclear spintomograph is better. They also show the high efficacy needed to load the body with as few tolerable foreign substances as possible and to maintain the non-invasive nature of the studies.

The good aqueous solubility and low osmolality of the agent of the invention allows the preparation of highly concentrated solutions to maintain the circulatory load of the blood within tolerable limits and to equalize the dilution by body fluids. In addition, the agents according to the invention show not only good in vitro stability but also surprisingly good in vivo stability, so that the release or exchange of complex ions, which are themselves poisonous, during the time that the new contrast agents are completely emitted from the body is only extremely slow.

In general, the agents of the invention are administered as MRI diagnostics in amounts of 0.0001-5 mmol / kg, preferably 0.005-0.5 mmol / kg.

In addition, the complex compounds of the invention may find use as susceptible (sensitive) reagents and as shift reagents for in vivo MR spectroscopy.

The agents of the invention are, on the basis of their favorable radioactive properties and the good stability of the complex compounds contained therein, suitable for radiodiagnosis. Details of such administration and dosage are described, for example, in "Radiotracers for Medical Applications", CRC-Press, Boca Raton, Florida.

The compounds and agents of the invention can also be used in positron emission tomography using positronemitic isotopes such as ⁴² Sc, ⁴⁴ Sc, ⁵² Fe, ⁵⁵ Co, ⁶⁸ Ga and ⁸⁶ Y (Heiss, WD, Phelps, E. ., Positron Emission Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York 1983).

The compounds of the invention are also surprisingly suitable for the differentiation of malignant from benign tumors in non-blood-brain-barrier regions.

The contrast agents of the invention may, after intravenous administration, be used to quantify changes in capillary integrity caused by hyperoxia (including "acutic capillary holes" and the restoration of normal endothelial integrity after hyperoxide damage). Histological studies confirm regional microvascular hyperpermeability.

From here, the contrast agents of the invention can also be used to display abnormal capillary-permeability. They are also characterized in that they are completely eliminated from the body and therefore well tolerated.

Because the substances of the invention accumulate in malignant tumors (there is no diffusion in healthy tissues, but there is a high permeability of tumor vessels), they can also assist radiation therapy for malignant tumors. It differs from the corresponding diagnosis only in the amount and type of isotope used. The goal here is to destroy the tumor cells through energy-rich short-term irradiation with a possible short range. For this purpose, variable actions of the metals contained in the complexes (such as iron or gadolinium) with ionizing radiation (eg X-ray) or with neutron rays are used. This effect significantly increases the local radiation dose at the site of the metal complex (eg in tumors). In order to obtain the same dose of radiation in the malignant tissue, when such metal complexes are applied, the radiation load can be significantly reduced for healthy tissue, thus avoiding aggravating side effects for the patient. Therefore, the metal complex conjugates of the invention are also suitable as a radiosensitizing agent for radiation therapy of malignant tumors (eg use of Moessbauer effects or neutron capture therapy). Suitable β-emitting ions are, for example, ⁴² Sc, ⁴⁴ Sc, ⁴⁸ Sc, ⁷² Ga, ⁷³ Ga, and ⁹⁰ Y. With appropriate minimum half-lives, the emitting ions are, for example, Bi, Bi and Bi, with Bi being preferred. One suitable photon- and electron-emitting ion is ¹⁵⁸ Gd, which can be obtained from ¹⁵⁷ Gd by electron capture.

If the agent of the invention is intended for use in the variant variant of radiation therapy proposed by RL Mills et al. (Nature Vol. 336, (1988), S. 787), then the central ion must be removed from the Moesbauer isotope as about ⁵⁷ Fe or ¹⁵¹ Ei. In the in vivo administration of the agents of the invention, they can be used in conjunction with a suitable carrier such as serum or sodium chloride saline, and together with another protein such as human serum albumin. The dose will depend on the cellular disorder, the metal ion used and the type of imaging method used.

The agents of the invention are preferably administered parenterally, preferably intravenously. As already stated, they can also be administered intravasally or interstitially / intracutaneously, depending on whether vessels or tissues in the body will be examined.

The agents of the invention are excellent X-ray contrast agents, and it should be particularly emphasized that they are not observed in biochemical - pharmacological studies of iodine-containing contrast agents known as anaphylaxis-like reactions. They are particularly valuable because of their favorable absorption properties in areas with higher tube voltages for digital abstraction techniques.

Generally, the agents of the invention are dosed as X-ray contrast agents, analogous to the example of Meglumin Diatrizoat, in an amount of 0.1-5 mmol / kg, preferably 0.25-1 mmol / kg.

In particular, the compounds of the invention achieve higher blood concentrations than extracellular contrast agents. After intravenous administration, they are distributed only _d in the intravasal space and thus have a decisive advantage over extracellular contrast agents.

Examples of carrying out the invention

a) 2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-1-lysine

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

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

M.P. 98.5 ° C

Elemental analysis:

calculated: C 51.07 H 5.09 N7.44 F 15.14 found: C 51.25 H5.18 N7.58 F 15.03

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

To 125.0 g (332.0 mmol) of the title compound of Example 1a) and 188.7 g (332.0 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 196 03 033) in 750 ml of tetrahydrofuran was 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 was then evaporated in vacuo to dryness and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

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

M.P. 92 ° C

Elemental analysis:

calculated: C 36.30 H 2.83 N 6.05 F 41.01 S 3.46 found: C 36.18 H2.94 N5.98 F 40.87 S 3.40

c) 6- ^ Benzyloxycarbonyl-L-lysine [1- (4perfluoroctylsulfonyl) piperazine] -amide

In a solution of 280.0 g (302.2 moles) of the title compound of Example 1b) in 2000 ml of ethanol was introduced 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 stirred in water. The precipitate was filtered off and dried in vacuo at 50 ° C.

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

Elemental analysis:

calculated: C 37.60 H 3.28 N6.75 F 38.89 S 3.86 found: C 37.55 H 3.33 N 6.68 F 38.78 S 3.81

d) 6-N-benzyloxycarbonyl-2-N- [1-O-a-O-carbonylmethyl- (2,3,4,6 tetra-O-benzyl-mannopyranose] - L-lysine [1- (4-fluorooctylsulfonyl) piperazine] -amide

To a solution of 100.0 g (120.4 mmol) of the title compound of Example 1c), 72.1 g (120.4 mmol) of 1-O-α-D-carboxymethyl-

2,3,4,6-Tetra-O-benzyl mannopyranose and 13.86 g (120.4 mmol) of Nhydroxysuccinimide dissolved in 500 ml of dimethylformamide was 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 room temperature. The precipitated urea was filtered off, the filtrate was concentrated in vacuo to dryness and chromatographed on silica gel (eluent: dichloromethane / ethanol = 20: 1).

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

Elemental analysis:

calculated: C 57.32 H 4.89 N 4.31 F 24.86 S 2.47 found: C 57.38 H 5.07 N4.22 F 24.78 S 2.39

e) 2-N- [1-0-a-B-carbonylmethyl-mannopyranose] - L-lysine [(4perfluoroctylsulfonyl) piperazine] -amide

130.0 g (100.0 mmol) of the title compound of Example 1d) 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 concentrated in vacuo to dryness.

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

Elemental analysis:

calculated: C 34.07 H3.63 N6.11 F 35.24 S 3.50 found: C 33.91 H 3.72 N 6.04 F 35.31 S 3.40

f) 6-N- [1,4,7-Tris (carboxylatomethyl)] - 1,4,7,10tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] - 2- N-fl-OaD-carbonylmethyl-mannopyranose] - L-lysine [(4-perfluorooctylsulfonyl) piperazine] -amide, Gd-complex

50.0 g (54.55 mmol) of the title compound of Example 1 is (e),

6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol) of 1,4,7-tris (carboxylatomethyl) -N (carboxy-3-aza-4-oxo-5- methyl-pent-5-yl) -1,4,7,10tetraazacyclododecane, Gd-complex, was dissolved under gentle warming in 400 ml of dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mol) of Νdithohexylcarbodiimide was added and then stirred overnight at room temperature. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitate was filtered off and purified by chromatography (RP-18 eluent: gradient of water / ethanol / acetonitrile).

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

Water Content: 8.6%

Elemental analysis: (calculated as anhydrous substance) calculated: C 35.34 H 4.09 N8.24 F21.12 S 2.10 Gd 10.28 found: C 35.28 H 4.15 N8.19 F21.03 S 2.15 Gd 10.14 Example 2

a) 6-N- [1,4,7-Tris (carboxylatomethyl)] - 1,4,7,10tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5yl) -2 - N-tl-OaD-carbonylmethyl-mannopyranose] - L-lysine [1- (4perfluoroctylsulfonyl) -piperazine] -amide, Gd-complex

50.0 g (54.55 mmol) of the title compound of Example 1 is (e),

6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol) of 1,4,7-tris (carboxylatomethyl) -10 (carboxy-3-aza-4-oxo-5- methyl-pent-5-yl) -1,4,7,10tetraazacyclododecane, Gd-complex, was dissolved under gentle warming in 400 ml of dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mmol) of 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 precipitate was filtered off and purified by chromatography (RP-18 eluent: gradient of water / ethanol / acetonitrile).

Yield: 76.0 g (92.0% of theory) as a colorless solid.

Water Content: 6.88%

Elemental analysis: (calculated as anhydrous substance) calculated: C 34.90 H 3.93 N8.32 F21.33 S 2.12 Gd 10.38 found: C 34.81 H 4.02 N8.27 F21.22 S 2.09 Gd 10.19 Example 3

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

To 200.0 g (12-4.0 mmol) of 4hydroxyphenylacetic acid methyl ester, 212.0 g (2000.0 mmol) of sodium carbonate in 2000 ml of acetone were added 233.8 g (1400.0 mmol) of bromoacetic acid ethyl ester and refluxed for 5 hours. The precipitate was filtered off and the filtrate was evaporated in vacuo to dryness. The residue was chromatographed on silica gel (eluent: n-hexane / ethyl acetate = 15: 1).

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

calculated: C 61.90 H 6.39 found: C 61.75 H6.51

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

To 285.0 g (1130.0 mmol) of the title compound of Example 3) dissolved in 2000 ml of tetrachromomethane was added 201.0 g (1130.0 mmol) of N-bromosuccinimide and 100.0 mg of dibenzoyl peroxide and refluxed for eight hours. It was cooled in an ice bath, the precipitated succinimide was filtered off and the filtrate was concentrated in vacuo to dryness. The residue was purified on silica gel (eluent: n-hexane / acetone = 15: 1).

Yield: 359.2 g (96.0% of theory) as a thick oil.

Elemental analysis:

calculated: C 47.28 H 4.57 Br 24.16 found: C 47.19 H 4.71 Br 24.05

c) 2- [4- (3-Oxapropionic acid ester)] -phenyl-2- [1- (1,4,7,10-tetraazacyclododecan-1-yl] acetic acid methyl ester)

To 603.0 g (3500.0 mmol) of 1,4,7,10-tetraazacyclododecane in 6000 ml of chloroform was added 350.0 g (1057.0 mmol) of the title compound of Example 3b) and stirred overnight at room temperature. It is extracted 3 times with 3000 ml of water each, the organic phase is dried over magnesium sulfate and concentrated in vacuo to dryness. The residue was used in the next step (example 3d) without further purification.

Yield: 448.0 g (quantitative) as a thick oil.

Elemental analysis:

calculated: C 59.70 H8.11 N13.26 found: C 59.58 H 8.20 N13.18

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

445.0 g (1053.0 mmol) of the compound of Example 3c) and 496.0 g (5270.0 mmol) of chloroacetic acid were dissolved in 4000 ml of water. Adjust the pH to 10 with 30% aqueous sodium hydroxide solution and stir for 8 hours at 70 ° C. Then adjust the pH of the reaction solution with 30% aqueous sodium hydroxide solution to 13 and reflux for 30 minutes. The solution was cooled in an ice bath and by the addition of conc. the pH is adjusted to 1. In vacuo, it is concentrated to dryness. The residue was taken up in 4000 ml of methanol and stirred for 1 hour at room temperature, the separated sodium chloride was filtered, the filtrate was evaporated to dryness and the residue was purified on RP-18 C (eluent: gradient from water / ethanol / acetonitrile).

Yield: 403.0 g (69.0% of theory) as a colorless solid.

Water Content: 10.2%

Elemental analysis: (calculated as anhydrous substance) calculated: C 51.98 H6.18 N10.10 found: C 51.80 H 6.31 N10.01

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

To 400 g (721.3 mmol) of the title compound of Example 3d) in 2000 ml of water was added 130.73 g (360.65 mmol) of gladoline oxide and stirred for 5 hours at 80 ° C. The solution was filtered and the filtrate was freeze-dried.

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

Water Content: 11.0%

Elemental analysis: (calculated as anhydrous substance) calculated: C 40.67 H 4.41 N7.98 Gd 22.19 _g found: C 40.51 H 4.52 N 8.03 Gd 22.05%!

f) 6- [2- (4- (3-Oxapropionyl) -phenyl] -2- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-yl] acetic acid) -2-

N- (1-O-α-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 1 is (e),

6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 38.66 g (54.55 mmol) of the title compound of Example 3e) were dissolved under gentle warming in 400 ml of dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mmol) of N, N-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 precipitate was filtered off and purified by chromatography (RP-18 eluent: gradient of water / ethanol / acetonitrile). The resulting product was dissolved in a little water and the pH of the solution was adjusted to 7.4 with aqueous sodium hydroxide solution. The product solution was then freeze-dried.

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

Water Content: 10.3%

Elemental analysis: (calculated as anhydrous substance) calculated: C 36.86 H 3.77 N6.88 F 19.82 S 1.97 Gd 9.65 found: C 36.75 H 3.84 N6.80 F 19.75 S 2.03 Gd 9.57 Example 4

a) 6-N- [1,4,7-Tris (tert-butoxycarbonylmethyl) -1,4,7,10tetraazacyclododecane-10-carbonylmethyl] -2-N- (1-Oa-Dcarbonylmethyl-mannopyranose) -1_-lysine - [1- (4-Perfluorooctylsulfonyl) -piperazine] -amide

15.0 (26.19 mmol) 1,4,7-tris (tert-butyloxycarbonyl) -10carboxymethyl-1,4,6,10-tetraazacyclododecane (prepared according to WO91 / 05762), 24.0 g (28.19 mmol) of the title compound of Example 1e) and 3.01 g (26.19 mmol) of N-hydroxysuccinimide are dissolved in 150 ml of dimethylformamide and 8.25 g (40.0 mmol) of Νcyclohexylcarbodiimide are added at 0 ° C. It was stirred overnight at room temperature. The separated urea was filtered off and the filtrate was concentrated in vacuo to dryness. The residue was chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

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

Elemental analysis:

calculated: C 44.08 H 5.69 N7.62 F21.95 S 2.18 found: C 44.01 H 5.81 N 7.53 F 21.87 S 2.03

b) 6-N- [1,4,7-Tris (tert-butoxycarboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-carbonylmethyl] -2-N- (1-Oa-Dcarbonylmethyl-mannopyranose) -1_ -Lysine- [1- (4perfluoroctylsulfonyl) -piperazine] -amide, Gd-complex

30.0 g (20.39 mmol) of the title compound of Example 4a) were dissolved in 50 ml of chloroform and 300 ml of trifluoroacetic acid were added. Stirred for 10 min at room temperature. Evaporate in vacuo to dryness and dissolve the residue in 300 ml of water. 3.69 g (10.19 mmol) of gladoline oxide were added and stirred for 5 hours at 80 ° C. The solution was evaporated in vacuo to dryness and purified on silica gel (RP-18; eluent: gradient from water / ethanol / acetonitrile).

Yield: 11.0 g (37.0% of theory) as a colorless amorphous substance.

Water Content: 11.3%

Elemental analysis: (calculated as anhydrous substance): calculated: C 34.62 H 3.87 N7.69 F 22.16 S 1.97 Gd 10.97 found: C 34.57 H 3.95 N7.60 F 22.05 S 2.13 Gd 10.90 Example 5

a) 6-N-2- [3,6,9-Tris (carboxymethyl) -3,6,9-triazaundecandicarboxylic acid-1-carboxy-11 -onn] -2-N- (1-Oa-Dcarbonylmethyl-manopyranose) ) -1_-lysine- [1- (4perfluoroctylsulfonyl) -piperazine] -amide

To 24.0 g (26.19 mmol) of the title compound of Example 1 e) dissolved in 100 ml of dimethylformamide / 30 ml of pyridine were added 12.10 g (30.0 mmol) of 3-N- (2,6-dioxomorpholinoethyl) -6-I (ethoxycarbonylmethyl) -3,6-diazoactanedicarboxylic acid and stirred for 5 hours at 50 ° C. Concentrated in vacuo to dryness. 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 solution. It was stirred for 8 hours at 22 ° C and pH 13. By the addition of concentrated hydrochloric acid, the solution was brought to 7.2 and then evaporated to dryness in vacuo. The residue was purified on silica gel (RP-18 eluent: gradient from water / ethanol / acetonitrile).

Yield: 17.26 g (51.0% of theory) as a colorless solid.

Water Content: 9.3%

Elemental analysis: (calculated as anhydrous substance): calculated: C 37.19 H 4.21 N7.59 F 25.00 S 2.48 found: 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-triazaundecandicarboxylic acid-1-carboxy-11 -onn] -2-N- (1-O-oc-Dcarbonylmethyl-mannopyranose) ) -1_-Lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd-complex, sodium salt

To 10.0 g (7.74 mmol) of the title compound of Example 5a) in 100 ml of water were added 1.40 g (3.87 mmol) of gladoline oxide and stirred for 2 hours at 70 ° C. The solution was filtered. The filtrate was adjusted to pH 7.4 with 2 N NaOH and freeze-dried.

Yield: 11.36 g (quantitative) as a colorless amorphous substance. Water Content: 10.5%

Elemental analysis: (calculated as anhydrous substance) calculated: C 32.72 H 3.43 N6.68 F 22.00 S 2.18 Gd 10.71 Na 1.57 found: C 32.65 H 3.51 N6.71 F21.87 S 2.08 Gd 10.61 Na 1.68 Example 6

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

50.0 g (60.20 mmol) of the title compound of Example 1 c), 6.93 g (60.20 mmol) of N-hydroxysuccinimide, 5.09 g (120.0 mmol) of lithium chloride and 37.91 g (60.20 mmol) of 1,4,7-tris ( carboxymethyl) -1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl), the Gd complex was dissolved under gentle warming in 400 ml of dimethyl sulfoxide. At 10 ° C, 20.63 g (100.0 mmol) of 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 separated precipitate was filtered off and purified by chromatography (silica gel RP-18; eluent: gradient from water / ethanol / acetonitrile).

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

Water Content: 10.1%

Elemental analysis: (calculated as anhydrous substance) calculated: C 37.48 H 3.84 N8.74 F 22.39 S 2.22 Gd 10.90 found: C 37.39 H 4.02 N8.70 F 22.29 S 2.16 Gd 10.75 b) 2-N- [1,4. 7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecane] Gd-complex, 10 (pentanoyl-3-aza 4-oxo-

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

70.0 g (48.53 mmol) of the title compound of Example 1d) was dissolved in 500 ml water / 100 ml ethanol, 5.0 g palladium catalyst (10% palladium / C) was added and hydrogenated at room temperature under hydrogen atmosphere (1 atm) ) until hydrogen is withdrawn. It was then filtered off from the catalyst, washed mainly with ethanol (twice with 75 ml each) and concentrated in vacuo to dryness. The title compound is obtained as a very viscous oil.

Yield: 63.5 (quantitative).

Water Content: 9.8%

Elemental analysis: (calculated as anhydrous substance) calculated: C 37.48 H 3.84 N8.74 F 22.39 S 2.22 Gd 10.90 found: C 37.39 H 4.03 N8.65 F 22.31 S 2.20 Gd 10.78

c) 2-N- (1-O-α-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmani-pyranose) -2-N- [1,4,7-tris (carboxylatomethyl) -1, 4,7,10tetraazacyclododecane], Os1-complex-10- (pentanoyl-3-aza 4-oxo-

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

50.0 g (38.22 mmol) of the title compound of Example 6b), 4.40 g (38.22 mmol) of N-hydroxysuccinimide, 3.39 g (80.0 mmol) of lithium chloride and 22.88 g (38.22 mmol) of 1-0-a-0-carboxymethyl- 2,3,4,6-Tetra-0-benzyl mannopyranose was dissolved under gentle warming (30 to 40 ° C) in 400 ml of dimethyl sulfoxide. At 10 ° C, 10.32 g (50.0 mmol) of 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 separated precipitate was filtered off and purified by chromatography (silica gel RP-18; eluent: gradient from water / ethanol / acetonitrile).

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

Water Content: 10.9%

Elemental analysis: (calculated as anhydrous substance) calculated: C 46.42 H 4.54 N6.67 F 17.10 S 1.70 Gd 8.33 Found: C 46.36 H 4.71 N6.60 F 17.19 S 1.61 Gd 8.21

d) 2-N- (1-O-α-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmani-pyranose) -2-N- [1,4,7-tris (carboxylatomethyl) -1, 4,8,10tetraazacyclododecane], Gd-κomplecbc-10- (pentanoyl-3-aza 4-oxo-

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

60.0 g (31.77 mmol) of the title compound of Example 6c) was dissolved in 500 ml of ethanol, 6.0 g of palladium catalyst (10% palladium / C) was added and hydrogenated at room temperature under hydrogen atmosphere (1 atm) until absorption stopped. of hydrogen. It was then filtered off from the catalyst, washed mainly with ethanol (twice with 150 ml each) and concentrated in vacuo to dryness.

Yield: 48.55 (quantitative) as a colorless solid.

Water Content: 3.9%

Elemental analysis: (calculated as anhydrous substance) calculated: C 35.37 H 4.02 N8.25 F 21.13 S 2.10 Gd 10.29 found: C 35.28 H 4.13 N8.17 F21.05 S 2.03 Gd 10.20 Example 7

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

To 50.0 g (113.5 mmol) of 1,7-bis (benzyloxycarbonyl) -1,4,7,10tetraazacyclododecane and 66.42 g (113.5 mmol) of 2-ethyl-Perfluoroctylsulfonyl) -aminoacetic acid (prepared according to DE 196 03 033) in 300 ml of tetrahydrofuran was added at 0 ° C to 49.46 g (200.0 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred at room temperature overnight. It was evaporated in vacuo to dryness and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

Yield: 65.2 g (57% of theory) as a colorless solid.

Elemental analysis:

calculated: C 42.91 H 3.80 N6.95 F 32.05 S 3.18 found: C 42.85 H 3.90 N6.87 F31.98 S 3.15

b) 1,7-bis- (benzyloxycarbonyl) -4- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-10- [1-Oa-Dcarbonylmethyl-2,3,4,6-tetra-O -benzyl-mannopyranose) -1,4,7,10tetraazacycododecane

To 60.0 g (59.53 mmol) of the title compound of Example 7a) and 35.64 g (59.53 mmol) of 1-0-α-O-carboxymethyl-2,3,4,6-tetra-049 benzyl mannopyranose prepared according to DE 197 28 54, in 300 ml of THF were added at 0 ° C 24.73 g (100 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred at room temperature overnight. It was evaporated in vacuo to dryness and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

Yield: 76.6 g (57% of theory) as a colorless solid.

Elemental analysis:

calculated: C 54.44 H 4.70 N 4.41 F 20.33 S 2.02 Found: C 54.37 H 4.81 N4.35 F 20.27 S 1.96

c) 1- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-7- [1-O-a-O-carbonylmethyl-mannopyranose) -1,4,7,10tetraazacycododecane g (44.07 mmol) of the compound from the title of Example 7b) was dissolved in 800 ml of ethanol, 8 g of palladium catalyst (10% palladium / C) was added and hydrogenated at room temperature. It was then filtered off from the catalyst and concentrated in vacuo to dryness.

Yield: 42.3 g (quantitative) as a colorless solid. Elemental analysis:

calculated: C 35.04 H 3.99 N 7.30 F 33.65 S 3.34 Found: C 35.15 H4.13 N7.13 F 33.48 S 3.26

d) 1,7-bis- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecane-CO-complex-10- (pentanoyl-3-aza 4-oxo-

5-methyl-5-yl) -4- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] acetyl-N- [1-0-a-O-carbonylmethyl-mannopyranose) -1,4,7,10tetraazacyclododecane g (20.84 mmol) of the title compound of Example 7c), 5.09 g (120 mmol) of lithium chloride and 37.78 g (60 mmol) of 1,4,7tris (carboxylatomethyl) -10- (pentanoyl-3-aza-4-oxo- 5-methyl-5-yl) 50

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 min. The resulting precipitate was filtered off and then purified by chromatography (silica gel RP-18; eluent: gradient from water / ethanol / acetonitrile).

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

Water Content: 11.8%

Elemental analysis: (calculated as anhydrous substance) calculated: C 36.31 H 4.34 N9.62 F 14.79 S 1.47 Gd 14.41 found: C 36.24 H 4.27 N9.58 F 14.85 S 1.51 Gd 14.25 Example 8

a) 1,7-bis- (benzyloxycarbonyl) -4- [2- (N-ethyl-piperfluoroctylsulfonyl) -amino] -acetyl-10- [pentanoyl-3-aza-4-oxo-5-methyl-5-yl] - [1,4,7-Tris (carboxylatomethyl) N - complex,

1,4,7,10-Tetraazacycododecan-10-yl] -1,4,7,10 Tetraazacyclododecane

50.0 g (49.61 mmol) of the title compound of Example 7a), 5.71 g (49.61 mmol) of N-hydroxysuccinimide, 4.24 g (100.0 mmol) of lithium chloride and 31.24 g (49.61 mmol) of 1,4,7-tris (carboxylatomethyl) -10 (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) -1,4,7,10-tetraazacyclododecane, the Gd-complex was dissolved by gentle warming in 350 ml of dimethyl sulfoxide. At 10 ° C, 15.47 g (75.0 mmol) of Νdicyclohexylcarbodiimide were added and then stirred overnight at room temperature. The solution was poured into 2000 ml of acetone and stirred for 10 minutes. The separated precipitate was filtered off and purified by chromatography (silica gel RP-18; eluent: gradient from water / ethanol / acetonitrile).

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

Water Content: 7.9%

Elemental analysis: (calculated as anhydrous substance) calculated: C 40.79 H4.11 N8.65 F 19.94 S 1.98 Gd 9.72 found: C 40.71 H 4.20 N8.58 F 19.87 S 2.03 Gd 9.68

b) 1- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-

7- {pentanoyl-3-aza-4-oxo-5-methyl-5-yl- [tris (carboxylatomethyl-

1,4,7,10-tetraazacyclododecan-10-yl] - Gd-complex} -1,4,7,10tetraazocyclododecane

60.0 g (37.05 mmol) of the title compound of Example 8a) was dissolved in 600 ml of ethanol, 6.0 g of palladium catalyst (10% palladium / C) was added and hydrogenated at room temperature. The catalyst was then filtered off and concentrated in vacuo to dryness.

Yield: 50.06 g (quantitative) as a colorless solid. Water Content: 3.9%

Elemental analysis: (calculated as anhydrous substance) calculated: C 34.67 H 4.03 N10.37 F 23.90 S 2.37 Gd 11.64 found: C 34.58 H4.15 N10.28 F 23.84 S 2.30 Gd 11.57

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

40.0 g (29.60 mmol) of the title compound of Example 8b), 2.54 g (60.0 mmol) of lithium chloride and 44.9 g (75.0 mmol) of 1-Oa-Dcarboxymethyl-2,3,4,6-tetra-O-benzyl- manopiranose was dissolved under gentle warming in 300 ml of dimethyl sulfoxide. At 10 ° C, 24.73 g (100.0 mmol) of EEDQ was added and then stirred overnight at room temperature. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The separated precipitate was filtered off and purified by chromatography (silica gel RP-18; eluent: gradient from water / ethanol / acetonitrile).

Yield: 31.98 g (43.0% of theory) as a colorless solid.

Water Content: 3.5%

Elemental analysis: (calculated as anhydrous substance) calculated: C 53.06 H 5.05 N5.57 F 12.85 S 1.28 Gd 6.26 found: C 52.95 H5.19 N5.48 F 12.77 S 1.23 Gd 6.14

d) 1- [2- (1-Ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-4,10bis [1-Oa-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 8c) was dissolved in 300 ml ethanol / 30 ml water and 4.0 g palladium catalyst (10% palladium / C) was added. Hydrated at room temperature. The catalyst was then filtered off and the filtrate was concentrated in vacuo to dryness.

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

Water Content: 3.4%

Elemental analysis: (calculated as anhydrous substance) calculated: C 36.87 H 4.39 N7.82 F 18.03 S 1.79 Gd 8.78 found: C 36.80 H 4.50 N7.85 F 17.91 S 1.68 Gd 8.70 Example 9

a) 6-N- [3.6-bis (carboxymethyl) -octane-1,8-dicarboxylic acid 1-carboxy-8-yl] -2-N- (1-OaD-carboxymethyl-manopyranose) lysine [1- (4 -perfluoroctylsulfonyl) -piperazine] -amide

To 27.5 g (30.0 mmol) of the title compound of Example 1e) dissolved in 300 ml of dimethylformamide / 100 ml of pyridine were added 25.62 g (100.0 mmol) of ethylenediamine-DI, N-tetraacetic acid dianhydride and stirred for 5 hours at 50 C. Evaporates in vacuo to dryness. The residue was dissolved in 300 ml of water, adjusted to pH 10 by the addition of a 20% aqueous NaOH solution and then the alkaline solution of the product was adjusted to pH 3 by the addition of concentrated hydrochloric acid and evaporated to dryness in vacuo. The residue was chromatographed on silica gel RP-18 (eluent: gradient water / ethanol / acetonitrile).

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

Water Content: 7.9%

Elemental analysis: (calculated as anhydrous substance) calculated: C 36.31 H 3.98 N7.06 F 27.12 S 2.69 found: C 36.23 H 4.07 N 6.98 F 27.05 S 2.62 b) 6-No [3,6-bis (carboxylatomethyl) -octane -1,8-Dicarboxylic acid-1-carboxylato-8-yl] -N-complexes, sodium con] -N (1 -0-a-0-carboxymethyl-manopyranose) -1_-lysine- [1- (4perfluoroctylsulfonyl) -piperazine] -amide d (8.397 mmol) from the title compound of Example 9a) was dissolved in 200 ml of water. 965 mg (8.397 mmol) of manganese (II) carbonate were added and stirred for 3 hours at 60 ° C. The solution was adjusted with 5% aqueous sodium hydroxide solution at pH 7.4, filtered and freeze dried.

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

Water Content: 7.8%

Elemental analysis: (calculated as anhydrous substance) calculated: C 34.16 H 3.50 N6.64 F 25.52 S 2.53 Mn 4.34 Na 1.82 Found: C 34.06 H 3.61 N6.58 F 25.47 S 2.47 Mn 4.30 Na 1.97

Example 10

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

Similar to the method described in the literature [M. L. Wolfram und A. Thompson in Methods in Carbohydrate Chemistry (R. L. Whistler, M.L.

Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol, II, 53, pp. 211 - 215, (1963)] was obtained by converting 150 g (832.5 mmol) of α, βD-mannopyranose with a mixture of 1500 ml of absolute pyridine and 1500 ml of acetic anhydride after further elaboration of 315 g (96.7%) of the title compound as a crude product in the form of a viscous and colorless oil. By ¹ H-NMR spectroscopic examination of the title compound thus obtained, the ratio of α to β-anomer can be determined to be 4: 1. The separation of α, β anomers is not necessary to carry out the next step.

Elemental analysis:

calculated: C 49.21 H 5.68 found: C 49.12 H 5.78 b) 1-O-α-O- (5-ethoxycarbonyl) -pentyl-2,3,4,6-tetra-O-acetyl mannopyranose

Similarly to those described in the literature for the synthesis of aryl glycopyranosides [J. Conchie und G. A. Lewy in Methods in Carbohydrate Chemistry (R. L. Whistler, M. L. Wolfrom, and J. N. BeMiller, Eds.), Academic Press, New York, Vol, II, 90, pp. 345- 347, (1963)] converting 156.2 g (400 mmol) of the title compound of Example 10a) as an α, β-anomer mixture with 67 ml (400 mmol) of ethyl ester of

6-hydroxy-hexanoic acid and 60.8 ml (520 mmol) of tin-IV-chloride were then purified by column chromatography (eluent: hexane / ethyl acetate 2: 1) to give 100.05 g (51% of theory) of the title compound as colorless viscous oil. By ¹ NMR spectroscopic examination of the title compound thus obtained it can be determined that this compound is exclusively the pure α-anomer.

Elemental analysis:

calculated: C 52.94 H 6.77 found: C 52.80 H 6.78

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

To a suspension of 141.0 g (289 mmol) of the title compound of Example 10b) in 200 ml of dioxane was stirred vigorously at room temperature, and a total of 238.5 g (4.26 mol) of fine sprayed potassium hydroxide was added in portions. To increase the stirring ability, a further 200 ml of dioxane was added to the reaction mixture and the resulting suspension was finally refluxed and 372 ml (3.128 mol) of benzyl bromide were added dropwise at this temperature. After reacting for 4 hours at 110 ° C and 12 hours at room temperature, the reaction mixture was worked up by slowly pouring 2.5 liters of ice water and the aqueous phase was then extracted completely with diethyl ether. After washing the ether extract thus obtained and then drying over sodium sulfate, the salt is filtered off and the diethyl ether evaporated in vacuo. The excess benzyl bromide was completely distilled off with an oil pump at an oil bath temperature of 180 ° C. The resin-oil residue thus obtained was purified on silica gel using ethyl acetate / hexane (1:10) as eluent.

Yield: 172.2 g (91.0% of theory as a colorless very viscous oil.

Elemental analysis:

calculated: C 75.68 H 7.16 found: C 75.79 H 7.04

d) 6-N-benzyloxycarbonyl-2-N-flu-0-a-O- (5-carbonyl) -pentyl-

2,3,4,6-Tetra-O-benzyl-mannopyranose] -Lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

100.0 g (134.0 mmol) of the carboxylic acid obtained in Example 10c and 32.4 g (281.4 mmol) of N-hydroxysuccinimide were dissolved in 500 ml of dimethylformamide and a total of 58.0 g (281.4 mmol) of Ν were added in portions at 0 ° C. N-dicyclohexylcarbodiimide and stirred at this temperature for 3 hours. A solution of 111.3 g (134.0 mmol) of the title compound of Example 1c), dissolved in 300 ml of dimethylformamide, was added dropwise and stirred for 2 hours at 0 ° C to the thus obtained active ester solution. 12 hours at room temperature. For further development, the precipitated dicyclohexylurea is filtered off and the solvent is then distilled off to dryness. That's right

I.

The residue obtained is chromatographed on silica gel (eluent: dichloromethane / ethanol 20: 1; chromatography is carried out with gradient elution, increasing the amount of ethanol continuously).

Yield: 132.5% (67.4% of theory) as the title compound is in the form of a colorless, very viscous oil.

Elemental analysis:

calculated: C 54.02 H 4.88 N3.82 F 22.01 S 2.19 found: C 53.87 H 4.85 N 4.02 F 22.55 S 2.06

e) 2M- [1-0-a-0- (5-carbonyl) -pentyl-mannopyranose] -lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

Dissolve 120.0 g (81.77 mmol) of the compound obtained in Example 10d in 800 ml of ethanol. 4.5 g of Pearleman catalyst (Pd 20%, C) were added and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until hydrogen was withdrawn (about 8 hours). The catalyst was filtered off, washed mainly with ethanol (about 200 ml) and concentrated in vacuo to dryness. The title compound is obtained as a very viscous colorless oil.

Yield: 78.5 g (98.7% of theory)

Elemental analysis:

calculated: C 37.04 H 4.25 N 5.76 F 33.20 S 3.30 Found: C 36.96 H 4.85 N5.41 F 34.13 S 3.22

f) 2-N- [1-0-a-0- (5-carbonyl) -pentyl-mannopyranose] -6-N [1,4,7tris (carboxylatomethyl) -10- (3-aza-4-oxo- 5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] - L-lysine- [1- (4perfluoroctylsulfonyl) -piperazine] -amide, Gd complex

99.8 g (158.4 mmol; 2.2 molar equivalents with respect to the embedded amine component of Example 10f) of the Gd complex of 10- (4-carboxy-1-methyl-2oxo-3- as described in patent application DE 197 28 954Cl under Example 31 h) azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-trioacetic acid and 6.7 g of anhydrous lithium chloride (158.4 mmol) were dissolved at 40 ° C and stirred in 800 ml of absolute dimethyl sulfoxide. At this temperature, a total of 18.2 g (158.4 mmol) of N-hydroxysuccinimide and 70.0 g (71.96 mmol) of the title compound of Example 10e were then added, dissolved in 250 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 32.7 g (158.4 mmol) of N, N -dicyclohexylcarbodiimide were added to the reaction solution and stirred at room temperature for 12 hours. A sufficient amount of acetone was then added to the resulting suspension until complete precipitation of the above title compound, the precipitate was filtered off, dried, taken up in water and the insoluble dicyclohexylurea was filtered off and the filtrate was desalted on AMICON® YM-3 ultrafiltrate. : 3000 Da) and is purified from low molecular weight ingredients. What is retained on the filter is freeze-dried.

Yield: 93.0 g (81.6% of theory) as a colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 9.53% Elemental analysis: (calculated as anhydrous substance) calculated: C 37.15 H 4.39 N7.98 F 20.38 S 2.02 Gd 9.92 found: C 37.92 H 4.50 N7.68 F 19.77 S 1.91 Gd 10.08

EXAMPLES

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

To a suspension of 5Ό g (9.06 mmol) of the title compound of Example 3e) in 15 ml of absolute dimethyl sulfoxide was stirred at 70 ° C, 0.68 g (15.9 mmol) of lithium chloride was added. After stirring at 70 ° C for 30 minutes, a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide was added portionwise to the clear reaction solution and the reaction mixture was maintained at this temperature for another 1 hour. After cooling to 0 ° C, 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide were added and the solution was stirred for another hour at 0 ° C and then for 12 hours at 22 ° C. To the solution of the title compound N-hydroxysuccinimide thus obtained. Example 3e) was added dropwise at 22 ° C a solution of 4.0 g (4.12 mmol) of the title compound of Example 10e) in 15 ml of absolute dimethyl sulfoxide and stirred for a further 12 hours at room temperature. The reaction solution was then added dropwise at 22 ° C in 900 ml of acetone whereby the title compound was separated as a colorless precipitate. The precipitate was collected by filtration, dissolved in 200 ml of distilled water and the solution was adjusted to pH 7.2 exactly with 1 molar sodium hydroxide solution. The aqueous solution of the product thus obtained is ultrafiltered three times on a UMZ-ultrafiltration membrane AM ICON® (cut off: 3000 Da) to desalinate and purify from low molecular weight constituents. What is retained on the filter is freeze-dried.

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

Elemental analysis: (calculated as anhydrous substance) calculated: C 38.48 H4.13 N6.65 F19.16 S 1.90 Gd 9.33 Na1.36 found: C 39.52 H4.12 N6.67 F 19.70 S 1.89 Gd 9.30 Na 1.41

Example 12

a) 3,5-bis-benzyloxycarbonylamino-benzoic acid-N- (3-oxo-1H, 1H, 2H, 2H, 4H, 4H, _5H-1 5H perfluorotridetsil) -amide

To a mixture of solvents of 125 ml of dry tetrahydrofuran and 125 ml of dry dioxane were added 20 g (47.5 mmol) of 3,5-bisbenzyloxycarbonylamino-benzoic acid (synthesized according to the following literature source: Skulmick, 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 4.78 g (47.5 mmol) of triethylamine. After cooling to -15 ° C, a solution of 6.56 g (48 mmol) of isobutyl ester of chloroformic acid in 30 ml of dry THF was slowly added dropwise while stirring the internal temperature at -10 ° C. After 15 minutes of reaction time at -15 ° C a solution of 58.6 g (47.5 mmol) of 1-amino1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-oxa-perfluorotridecane and 4.78 g (47.5 mmol) of triethylamine in 100 ml of dry tetrahydrofuran was added dropwise at After stirring again for one hour at -15 ° C, as well as two hours at room temperature, the reaction solution was evaporated in vacuo to dryness. o. The residue was taken up in 300 ml of ethyl acetate and washed twice with 200 ml of saturated sodium bicarbonate solution and once with 300 ml of water. After drying the organic phase over sodium sulfate, the salt was filtered off and the ethyl acetate was evaporated in vacuo. The residue was oily and purified on silica gel using dichloromethane / hexane / 2-propanol (10: 5: 1) as eluent.

Yield: 36.2 g (82.5% of theory) as a colorless oil.

Elemental analysis:

calculated: C 46.82 H 3.27 N 4.55 F 34.97 found: C 47.21 H 3.31 N 4.61 F 34.48

b) 3,5-diamino-benzoic acid-N- (3-OKca-

1H, 1H, 2H, 2H, 4H, 4H ₎ 5H, 5H-perfluorotridecyl) -amide

30.0 g (32.4 mmol) of the amide obtained in Example 12a were dissolved in 300 ml of ethanol and 1.2 g of Pearlman catalyst (Pd 20%, C) was added. Hydrogen at room temperature under hydrogen atmosphere (1 atm) until hydrogen uptake ceases. The catalyst was filtered off, washed well with ethanol (about 300 ml) and concentrated in vacuo to dryness. The title compound is obtained as a very viscous yellow oil.

Yield: 20.12 g (94.8% of theory)

Elemental analysis:

calculated: C 36.66 H 2.77 N 6.41 F 49.28 found: C 36.07 H 2.87 N 6.23 F 49.43

c) 3-N- (1-O-α-O-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose) -1 \ 1- (3-oxa-1H, 1H, 2H , 2H, 4H, 4H, 5H, 5Nperfluorotridecyl) -amide

10.95 g (18.30 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-D-manopyranoside (prepared as described in DE 197 28 954 C1) was dissolved in 150 ml of dimethylformamide and 2.09 g (18.3 mmol) were added. ) Nhydroxysuccinimide. After cooling to 0 ° C, 3.78 g (18.3 mmol) of dicyclohexylcarbodiimide were added. It was stirred for one hour at 0 ° C and then for 4 hours at room temperature. It was cooled to 0 ° C and a solution of 24.0 g (36.6 mmol, 2 molar equivalents with respect to the carboxylic acid employed) of the diamino compound of Example 12b) dissolved in 350 ml of dimethylformamide was added slowly over 3 hours. It was then stirred for another hour at 0 ° C and overnight at room temperature. It was evaporated in vacuo to dryness and the residue was dissolved in 300 ml of ethyl acetate. The precipitated urea was filtered off and the filtrate washed twice with 100 ml of 5% aqueous sodium hydrogen carbonate solution twice 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 / isopropanol 13: 1). 16.8 g (74.3% of the carboxylic acid employed) of the title compound are obtained as a colorless oil. Increasing the polarity of the eluent composition to n-hexane / isopropanol 5: 1 in the following chromatographic fractions yielded a total of 10.15 g of unreacted diamino compound 12b), which can be used as a starting compound again by the above procedure.

Elemental analysis:

calculated: C 54.42 H 4.40 N3.40 F 26.13 Found: C 54.32 H 4.49 N 3.48 F 25.94

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

In a similar manner to the synthesis described for the title compound of Example 12b), hydrolysis of 12.0 g (9.70 mmol) of the title compound of Example 12c) using 0.5 g Pearlman catalyst (Pd 20%, C), in a mixture from ethanol: water (9: 1) and development afforded 8.08 g (96.7% of theory of the title compound as yellowish colored viscous oil).

Elemental analysis: calculated: C 37.64 H 3.28 N 4.88 F 37.49 found: C 37.32 H3.17 N4.97 F 37.55

e) 3-N- (1-O-a-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-OKca-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5Nperfluorotridecyl) -amide, Gd complex, sodium salt

13.6 g (19.2 mmol; 2.2 molar equivalents with respect to the inserted amino component of Example 12d) of Example G3) the Gd complex described and 0.81 g of anhydrous lithium chloride (19.2 mmol) were dissolved at 40 ° C in 100 ml of absolute dimethyl sulfoxide under stirring and at this temperature, 2.2 g (19.2 mmol) of N-hydroxysuccinimide and 7.5 g (8.7 mmol) of the title compound of Example 12d) were added to the solution dissolved in 50 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 3.96 g (19.2 mmol) of N, N'cyclohexylcarbodiimide were added to the reaction solution and stirred at room temperature for 12 hours. Acetone was then added to the resulting suspension until complete precipitation of the above title compound, the precipitate was filtered off, dried, taken up in water, the insoluble dicyclohexicarbamide was filtered off and the filtrate was ultrafiltered on UMZ-ultrafiltrate 3000 Da) to desalinate and to purify low molecular weight ingredients. What is retained on the filter is freeze-dried.

Yield: 11.51 g (84.5% of theory) as a colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 6.77%

Elemental analysis: (calculated as anhydrous substance) calculated: C 40.05 H 3.94 N6.29 F 20.71 Gd 9.92 Na 1.47 found: C 39.98 H 4.00 N6.31 F 20.73 Gd 10.11 Na 1.42 Example 13

a) 3,5-bis- (benzyloxycarbonylamino) -1- {No. [1- (4-perfluoroctylsulfonyl) -piperazine]} - benzamide

To a mixture of solvents of 60 ml of dry tetrahydrofuran and 70 ml of dry dioxane are added 10 g (23.75 mmol) of 3,5-bisbenzyloxycarbonylamino-benzoic acid (synthesized according to the following literature source: Skulmick, 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 (47.5 mmol) of triethylamine. After cooling to -15 ° C, a solution of 3.28 g (24 mmol) of hydrochloric acid isobutyl ester in 20 ml of dry THF is slowly added dropwise while stirring, the internal temperature should not exceed -10 ° C. After 15 minutes of reaction time at A solution of 23.0 g (23.75 mmol) of perfluoroctylsulfonylpiperazine and 2.39 g (23.75 mmol) of triethylamine in 50 ml of dry THF at -20 ° C was added dropwise at -15 ° C. After stirring again at -15 ° C for one hour, and for two hours at room temperature, the reaction solution was evaporated in vacuo to dryness. The residue was taken up in 200 ml of ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution each time and once with 300 ml of water. After drying the organic phase over sodium sulfate, the salt was filtered off and the ethyl acetate was evaporated in vacuo. The residue was oily and purified on silica gel using dichloromethane / hexane / 2-propanol (15: 5: 1) as eluent.

Yield: 18.35 g (79.6% of theory) as a colorless oil. Elemental analysis:

Calculated: C 43.31 H 2.80 N 5.77 F 33.27 S 3.30 Found: C 43.21 H 2.75 N 5.61 F 33.38 S 3.22

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

9.70 g (10.0 mmol) of the amide obtained in Example 13a was dissolved in 100 ml of ethanol and 0.4 g of Pearlman catalyst (Pd 20%, C) was added. Hydrogen at room temperature under hydrogen atmosphere (1 atm) until hydrogen uptake ceases. The catalyst was filtered off, washed well with ethanol (about 150 ml) and concentrated in vacuo to dryness. The title compound is obtained as a very viscous yellowish oil.

Yield: 6.9 g (98.2% of theory)

Elemental analysis:

calculated: C 32.49 H2.15 N7.98 F 45.98 S 4.56 found: C 32.56 H2.17 N8.09 F 45.63 S 4.61

c) 5-amino-3-N (1-O-α-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmani-pyranose) -benzoic acid-N-- - (4-perfluoroctylsulfonyl) -piperazine] -amide

5.48 g (9.15 mmol) of 1-carboxymethyloxy-2,3,4,6-tetra-O-benzyl-D-mannopyranoside (prepared as described in DE 197 28 954 C1) was dissolved in 100 ml of dimethylformamide and 1.04 g ( 9.15 mmol) Nhydroxysuccinimide. After cooling to 0 ° C, 1.89 g (9.15 w mmol) of dicyclohexylcarbodiimide were added. It was stirred for one hour at 0 C and then for 4 hours at room temperature. It was cooled to 0 ° C and a solution of 12.85 g (18.30 mmol, 2 molar equivalents relative to the carboxylic acid employed) of the diamino compound of Example 13b) dissolved in 250 ml of dimethylformamide was slowly added dropwise over 3 hours. It was then stirred for another hour at 0 ° C and overnight at room temperature. It was evaporated in vacuo to dryness and the residue was dissolved in 300 ml of ethyl acetate. The precipitated urea was filtered off and the filtrate washed twice with 100 ml of 5% aqueous sodium hydrogen carbonate solution twice. The organic phase was dried over magnesium sulphate 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 the carboxylic acid employed) of the title compound are obtained as a colorless oil. Increasing the polarity of the eluent composition by chromatography on 6: 1 (n-hexane / isopropanol) in the following chromatographic fractions yielded a total of 4.36 g of unreacted diamino compound 13b), which can be reused by the above procedure as starting compound.

Elemental analysis:

Calculated: C 51.49 H 4.01 N4.37 F 25.17 S 2.50 Found: C 51.60 H 4.19 N4.28 F 25.14 S 2.44

d) 5-amino-3-N- (1-0-a-0-carbonylmethyl-mannopyranose) benzoic acid-N-fl - (4-perfluoroctylsulfonyl) -piperazine] amide

Similarly as described for the synthesis of the title compound of 1bb), hydrolysis of 6.4 g (5.0 mmol) of the title compound of the example catalyst (Pd 20% further development yields 4.43 g of the title compound under

13c) C) using 0.3 g of a Pearlman ethanol / water mixture (8: 1) and following (96.2% of the theoretical form) from the above a yellow colored viscous

butter.

Elemental analysis:

Calculated: C 35.15 H 2.95 N6.07 Found: C 35.32 H 3.02 N 5.89

F 35.01 S

F 35.05 S

3.48

3.58

f) 3-N- (1-O-α-D-carbonylmethyl-mannopyranose) -

5-N- [1,4,7-Tris- (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl-pentanoyl) -1,4,7,10-tetraazacyclododecane] - benzoene acid-N- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide,

Gd complex

5.54 g (8.8 mmol; 2.2 molar equivalents with respect to the inserted amino component of Example 13d) of subheading DE 197 28 954 C1 Example 31 h) the described Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3azabutyl) -1,4,7,10-Tetraazacyclododecane, 1,4,7-trioacetic acid and 0.37 g of anhydrous lithium chloride (8.8 mmol) were dissolved at 40 ° C in 60 ml of absolute dimethyl sulfoxide under stirring and at this temperature were added to the solution. 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.7 g (4.0 mmol) of the title compound of Example 13d) were dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N.N'dicyclohexylcarbodiimide were added to the reaction solution and stirred at room temperature for 12 hours. Acetone was then added to the resulting suspension until complete precipitation of the above title compound, the precipitate was filtered off, dried, taken up in water, the undissolved dicyclohexicarbamide was filtered off and the filtrate was ultrafiltered on a DM3-ultrafiltrate. ) to desalinate and purify low molecular weight ingredients. What is retained on the filter is freeze-dried.

Yield: 5136 g (87.4% of theory) as a colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 6.77%

Elemental analysis: (calculated as anhydrous substance) calculated: C 36.01 H 3.61 N8.22 F21.05 Gd 10.25 S 2.09 found: C 35.87 H 3.70 N8.22 F 20.91 Gd 10.18 S 2.16 Example 14

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

100 g (107.9 mmol) of the carboxylic acid obtained in Example 1a and 26.1 g (226.59 mmol) of N-hydroxysuccinimide were dissolved in 500 ml of dimethylformamide and a total of 46.7 g (226.59 mmol) of N, N'-dicyclohexylhexyl was added at 0 ° C. in portions, stirring for 3 hours at this temperature. A solution of 5.57 g (53.95 mmol) of diethylenetriamine, dissolved in 60 ml of dimethylformamide, was added dropwise to this solution, and stirred for 2 hours at 0 ° C and for 12 hours at room temperature. The separated dicyclohexylurea is filtered off and the solvent is distilled off to dryness. The residue thus obtained is chromatographed on silica gel (eluent: dichloromethane / ethanol 15: 1; chromatography is carried out using a gradient of solvents, increasing the ethanol portion continuously). Yield: 26.0 g (58.8% of theory, in terms of amino). The title compound is obtained as a colorless, very viscous oil.

Elemental analysis:

calculated: C 52.74 H 5.78 N11.96 F 13.90 found: C 52.66 H 5.89 N11.88 F 14.02

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

To a solution of 20 g (24.4 mmol) of the diamide obtained in Example 14a) dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform, at 0 ° C, 16.18 g (27.0 mmol) of 2- [°- βππι№perfluoroctylsulfonyl) -aminoacetic acid (prepared according to DE 196 03 033) dissolved in 50 ml of tetrahydrofuran. A total of 18.0 g (36.0 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-

1,2-dihydroquinoline] in portions and allowed to stir at room temperature overnight. It is then evaporated in vacuo. The residual oil was chromatographed on silica gel (eluent: n-hexane / isopropanol 15: 1). 24.74 g (72.4% of the theoretical, with respect to the second-amine embedded) of the title compound are obtained as a colorless oil.

Elemental analysis:

calculated: C 42.01 H 3.96 N8.00 F31.19 S 2.29 'Even-numbered: C 41.92 H 4.07 N7.87 F31.22 S 2.34

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

22.0 g (15.7 mmol) of the compound obtained in Example 14b were dissolved in 100 ml of ethanol and ammonia gas was bubbled at 0 ° C for 40 minutes. It was then stirred for 4 hours at 0 ° C and for 3 hours at room temperature. Concentrate at 40 ° C under vacuum. The residue was purified on silica gel using dichloromethane / hexane / 2-propanol (20: 10: 1) as eluent.

w ·

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

Elemental analysis:

Calculated: C 44.22 H 4.64 N9.38 F 27.03 S 2.68 Found: C 44.31 H 4.72 N 9.30 F 26.99 S 2.74

d) 1,7-6nc- (6-N-benzyloxycarbonyl-2-N (1-0-a-0-carbonylmethyl-

2,3,4,6-Tetra-O-benzyl-mannopyranose) -1_-lysine] -diamide-4- [2- (Nethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-1,4,7-triazaheptane

5.47 g (9.15 mmol) of 1-carboxymethyloxy-2,3,4,6-tetra-O-benzyl-OCD-mannopyranoside (prepared as described in DE 197 28 954 C1) were dissolved in 80 ml of dimethylformamide and 1.05 g ( 9.15 mmol) Nhydroxysuccinimide. After cooling to 0 ° C, 1.9 g (9.15 mmol) of dicyclohexylcarbodiimide were added. It was stirred for one hour at 0 ° C and then for 4 hours at room temperature. It was cooled to 0 ° C and a solution of 7.65 g (9.15 mmol) of the amino compound of Example 14c) dissolved in 50 ml of dimethylformamide was slowly added dropwise over 3 hours. It was then stirred for another hour at 0 ° C and overnight at room temperature. Evaporate in vacuo to dryness and dissolve the residue in 100 ml of ethyl acetate. The precipitated urea was filtered off and the filtrate washed twice with 50 ml of 5% aqueous sodium hydrogen carbonate solution 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 20: 1). 17.01 g (78.9% of the carboxylic acid employed) of the title compound are obtained as a colorless oil.

Elemental analysis:

Calculated: C 59.13 H 5.43 N4.76 F 13.71 S 1.36 Found: C 59.22 H 5.39 N4.85 F 13.70 S 1.40

e) 1,7-bis- [2 N - (1-0-α-O-carbonylmethyl-mannopyranose) -L-lysine] -amide-4- [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-1,4,7-triazaheptane

Dissolve 15.0 g (6.36 mmol) of the amide obtained in Example 14d in 150 ml of ethanol and add 0.5 g of Pearlman catalyst (Pd 20%, C) to it. Hydrogen at room temperature under an atmosphere of hydrogen (1 atm) until hydrogen is withdrawn. The catalyst was filtered off, washed mainly with ethanol (about 100 ml) and concentrated in vacuo to dryness. The title compound is obtained as a very viscous, yellowish oil.

Yield: 8.54 g (97.2% of theory).

Elemental analysis:

calculated: C 39.13 H 5.04 N8.11 F 23.38 S 2.32 found: C 39.07 H 4.98 N8.18 F 23.40 S 2.30

f) 1,7-bis- [2-No (1-0-a-0-carbonylmethyl-mannopyranose) -6-No [1,4,7,7- (carboxylatomethyl) -10- (3-aza-4-oxo -5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -1_-lysine] -diamide-4- [2 (ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-1,4,7-triazepheptane , digadoline complex

To a suspension of 5.7 g (9.06 mmol) of patent application DE 197 28 954Cl obtained according to Example 31 h) Gd complex of 10- (4-carboxy-methyl-2-oxo-3-azabutyl) -1,4,7, 10-Tetraazacyclododecane-1,4,7triacetic acid in 70 ml of absolute dimethyl sulfoxide was added at 70 ° C and 0.68 g (15.9 mmol) of lithium chloride was stirred. After stirring at 70 ° C for 30 minutes, a total of 1.83 g (155.9 mmol) of N-hydroxysuccinimide was added portionwise to the already clear reaction solution and maintained at this temperature for another 1 hour. After cooling to 0 ° C, 4.52 g (23.85 mmol) of дици, дициΝcyclohexylcarbodiimide were added and the reaction mixture was stirred for another 1 hour at 0 ° C and 12 hours at 22 ° C. To the reaction solution of the Gd- hydroxysuccinimide ester thus obtained. the 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-trioacetic acid complex was added dropwise at 22 ° C to a solution of 2.84 g ( 2.06 mmol) of the title compound of Example 14f) in 15 ml of absolute dimethyl sulfoxide and stirred for a further 12 hours at room temperature. For further development, the reaction solution was added dropwise into 500 ml of acetone at 22 ° C, whereby the title compound was dropped as a colorless precipitate. The precipitate was filtered off, dissolved in 200 ml of distilled water and ultrafiltered three times on AM ICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalinate and purify the low molecular weight components. What is retained on the filter is freeze-dried.

Yield: 4.80 g (89.6% of theory of the incorporated amino component) as a colorless lyophilisate with a water content of 8.98%.

Elemental analysis: (calculated as anhydrous substance) calculated: C 38.28 H 4.84 N9.68 F 12.40 S 1.23 Gd 12.07 found: C 38.20 H 4.91 N9.77 F 12.45 S 1.19 Gd 12.10 Example 15

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

To a solution of 10.75 g (24.4 mmol) of 1,7-bis- [benzyloxycarbonyl] 1,4,7,10-tetraazacyclododecane dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform at 0 ° C and under nitrogen atmosphere were added. 16.56 g (24.4 mmol) of the title compound of Example 15e) dissolved in 150 ml of tetrahydrofuran. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] was then added at 0 ° C in portions and left overnight at room temperature and stirred and then concentrated in vacuo. The residual oil was chromatographed on silica gel (eluent: n-hexane / isopropanol 12: 1).

17.22 g (64.3% of theory of the secondary amine incorporated) 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:

calculated: C 43.41 H 3.92 N7.59 F 29.18 S 2.60 found: C 43.52 H 4.07 N 7.67 F 29.24 S 2.55

b) 1,7-bis (benzyloxycarbonyl) -4- {3-oxa-pentane-1,5-dicarboxylic acid 1-oyl-5- [1- (4-perfluorooctylsulfonyl) piperazine] -amide} -N- [1- 0-a-0- (5-carbonyl) -pentyl-2,3,4,6-tetraO-benzyl-manopyranose] -1,4,7,10-tetraazacyclododecane

10.0 g (13.4 mmol) of the carboxylic acid obtained in Example 10c and 3.24 g (28.1 mmol) of N-hydroxysuccinimide were dissolved in 100 ml of dimethylformamide and a total of 5.8 g (28.1 mmol) of дици, дици'cyclohexylcarbodiimide was added at 0 ° C. portions and stirred for 3 hours at this temperature. The solution obtained thus was added dropwise a solution cooled to 0 ° C of 14.83 g (13.4 mmol) of the title compound of Example 15a) dissolved in 100 ml of dimethylformamide and stirred for 2 hours at 0 ° C and 12 hours at room temperature. The separated dicyclohexylurea is filtered off and the solvent is distilled off to dryness. The residue thus obtained is chromatographed on silica gel (eluent: dichloromethane / ethyl acetate 20: 1; chromatography is carried out using a gradient of solvents, increasing the ethyl acetate portion continuously).

Yield: 18.3 g (78.2% of theory). The title compound is obtained as a colorless, very viscous oil.

Elemental analysis:

calculated: C 55.11 H 5.03 N4.82 F 18.52 S 1.84 Found: C 54.87 H 4.85 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- [1-0-a-0- (5carbonyl) -pentyl-mannopyranose] -1,4,7,10-tetraazacyclododecane

Dissolve 17.0 g (9.75 mmol) of the compound of Example 14b in 150 ml of ethanol and add 1.0 g of Pearl catalyst (Pd 20%, C) to it. Hydrogen at room temperature under an atmosphere of hydrogen (1 atm) until hydrogen is withdrawn. The catalyst was filtered off, washed mainly with ethanol (twice with 75 ml each) and concentrated in vacuo to dryness. The title compound is obtained as a very viscous colorless oil.

Yield: 10.76 g (99.0% of theory).

Elemental analysis:

Calculated: C 38.78 H 4.61 N 7.54 F 28.97 S 2.88 Found: C 38.86 H 4.65 N 7.41 F 29.02 S 2.92

d) 1,7-bis- [1,4,7-Tris- (carboxylatomethyl) -1,4,7,10tetraazacyclododecane] N-complex-10- (pentanoyl-3-aza-4-oxo-

5-methyl-5-yl) -4- (N-ethyl-N-perfluorooctylsulfonyl) -amino] acetyl-2-oxa-acetyl] -10- [1-OA-6-carbonylpentylmanipyranose] -1,4,7, 10-Tetraazacyclododecane

24.86 g (39.46 mmol); 4.4 moleq of embedded amino component 15c) of patent application DE 197 28 954Cl under Example 31 h) Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3azabutyl) -1,4,7,10- tetraazacyclododecane-1,4,7-trioacetic acid and 1.67 g of anhydrous lithium chloride (39.46 mmol) were dissolved at 40 ° C in 200 ml of absolute dimethyl sulfoxide under stirring, and a total of 4.53 g (39.46 mmol) of N-hydroxysuccinimide were added at this temperature. 10.0 g (8.97 mmol) of the title compound of Example 14c) dissolved in 100 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 8.14 g (39.46 mmol) of N, N -dicyclohexylcarbodiimide were added to the reaction solution and the reaction mixture was stirred for 12 hours at room temperature. Sufficient acetone was added to the suspension thus obtained to completely precipitate the title compound. The precipitate was filtered off, dried and taken up in water, the undissolved dicyclohexylurea was filtered off and the filtrate was ultrafiltered on AM ICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalinate and purify low constituents. What is retained on the filter is freeze-dried.

Yield: 16.37 g (79.3% of theory) as a colorless lyophilisate. H ₂ O content (Karl-Fischer): 7.65%

Elemental analysis: (calculated as anhydrous substance) calculated: C 38.01 H4.61 N9.58 F 13.81 S 1.37 Gd 13.45 found: C 38.92 H 4.55 N9.58 F 13.77 S 1.31 Gd 13.48

f) 3-Oxa-pentane-1,5-dicarboxylic acid mono- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide g (44.0 mmol) 1-herfluoroctylsulfonylpiperazine was dissolved in 150 ml of tetrahydrofuran and added at room temperature 5.1. d (44.0 g) diglycolic acid anhydride. The reaction solution thus obtained was refluxed for 12 hours. After cooling to room temperature, it was concentrated to dryness and the residual oil 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 viscous oil.

Elemental analysis:

calculated: C 58.52 H 4.27 N1.98 F 22.80 S 2.26 found: C 58.42 H4.41 N1.80 F 23.02 S 2.28 Example 16

a) 1,7-bis- (benzyloxycarbonyl) -4- {3-oxa-pentane-1,5dicarboxylic acid-1-oyl-5- [1- (4-perfluorooctylsulfonyl) piperazine] -amide} -N- [1 -0-a-0-6-carbonylpentyl-2,3,4,6-tetra-074 benzyl glucopyranose] -1,4,7,10-tetraazacyclododecane

In 750 ml of dry THF dissolved 68.5 g (91.79 mmol) of 1 carboxymethyloxy-2,3,4-tetra-0-benzyl-α-0-manopyranoside (prepared according to DE 197 28 954 C1) then 9.25 g (91.79) was added. mmol) triethylamine. After the reaction solution was cooled to -15 - -20 ° C at this temperature and a stirring solution of 12.64 g (92.5 mmol) of isobugil ester of hydrochloric acid in 150 ml of dry tetrahydrofuran was added dropwise at which point the drop rate should be chooses not to increase the internal temperature above -10 ° C. 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 15a) and 9.25 g (91.79 mmol) of triethylamine as a solution in 500 ml of dry tetrahydrofuran at -20 ° C. After stirring for one hour at -15 ° C and two hours at at room temperature, the reaction solution was evaporated in vacuo to dryness. The residue was taken up in 450 ml of ethyl acetate and washed twice with 300 ml of saturated sodium hydrogen carbonate solution twice and once with 400 ml of water. After drying the organic phase over sodium sulfate, the salt is filtered off and the ethyl acetate is evaporated in vacuo. The oily residue 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, highly viscous oil.

Elemental analysis:

calculated: C 55.11 H 5.03 N4.82 F 18.52 S 1.84 found: C 55.20 H 5.09 N4.91 F 18.48 S 1.80

B) 1- {3-Oxa-pentane-1,5-dicarboxylic acid 1-oyl-5- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide} -7- [1-0-a-0- (5carbonyl) ) -pentyl-mannopyranose] -1,4,7,10-tetraazacyclododecane In 1000 ml of ethanol dissolved 110.0 g (63.08 mmol) of the compound obtained in Example 16a) and 5.0 g of Pearlman75 catalyst (Pd 20%, C was added) ). Hydrogen at room temperature under an atmosphere of hydrogen (1 atm) until hydrogen is withdrawn. The catalyst was filtered off, washed mainly with ethanol and concentrated in vacuo to dryness. The title compound was obtained as a viscous colorless oil.

Yield: 92.61 g (99.5% of theory).

Elemental analysis:

calculated: C 52.10 H5.12 N5.70 F21.89 S 2.17 found: C 52.20 H 5.09 N 5.71 F 21.87 S 2.20

c) 1,7-bis- [1,4,7-Tris (carboxylatomethyl) -10- (3-aza-4-oxo-5methyl-5-yl-pentanoyl) -4- {3-oxa-pentan-1 , 5-Dicarboxylic acid-1-oyl-5- [1- (4-perfluoroctylsulfonyl) -piperazine] amide} -N- [1-0-a-O- (5-carbonyl) -pentyl-mannopyranose] -1, 4,7,10tetraazacyclododecane, digadoline complex

55.4 g (88.0 mmol; 4.4 moleq of the embedded diamino component of Example 13d) from patent application DE 197 28 954Cl under Example 31 h) Gd complex of 10- (4-carboxy-methyl-2-oxo-3-azabutyl) - 1,4,7,10-Tetraazacycododecane-1,4,7triacetic acid and 3.7 g of anhydrous lithium chloride (88.0 mmol) were dissolved at 40 ° C in 500 ml of absolute dimethyl sulfoxide under stirring and a total of 10.1 g (88.0) was added at this temperature. mmol) Nhydroxysuccinimide and 29.5 g (20.0 mmol) of the title compound of Example 16b) dissolved in 200 ml absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution was added

18.2 g (88.0 mmol) of Ν, Ν′-dicyclohexylcarbodiimide and the reaction mixture was stirred for 12 hours at room temperature. Sufficient acetone was added to the suspension thus obtained to completely precipitate the title compound. The precipitate was filtered off, dried and taken up in water, the undissolved dicyclohexylurea was filtered off and the filtrate was ultrafiltered on AMICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalinate and purify low constituents. What is retained on the filter is freeze-dried.

Yield: 35.96 g (76.9% of theory) as a colorless lyophilisate. H ₂ O - content (Karl-Fischer): 5.98%

Elemental analysis: (calculated as anhydrous substance) calculated: C 38.01 H 4.61 N8.22 F 13.81 S 1.37 Gd 13.45 found: C 38.87 H 4.70 N8.22 F 13.90 S 1.36 Gd 13.48 Example 17

a) 5- (ethoxycarbonyl) pentyl-2,3,4,6-tetra-O-acetyl-α-0-mannopyranoside

Analogous to the method described in the literature for the synthesis of aryl glycopyranoside [J. Conchie und GA Levy im Methods in Carbohydrate Chemistry (RL Whistler, ML Wolfrom and JN BeMiller, Eds.), Academic Press, New York, Vol. II, 90, pp. 345 -347, (1963)] conversion of 156.2 g (400 mmol) of D-mannosapentaacetate as α, β- (α, β ratio = 4: 1) -anomer mixture [for the synthesis of 1,2,3,4,6- pent-O acetyl-α, β-D-mannopyranose compared: M. L. Wolfrom and A. Thomoson 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-hydroxy-hexanoic acid ethyl ester and 60.8 ml (520 mmol) of tin-1H-chloride in a total of 600 ml of 1,2-dichloroethane after gas chromatographic purification (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 spectroscopic examination of the title compound thus obtained it can be shown that it is a pure α-anomer.

Elemental analysis:

calculated: C 52.94 H 6.77 found: C 52.80 H 6.78

b) 5- (carboxy) pentyl-2,3,4,6-tetra-O-benzyl-a-omanopyranoside

To a suspension of 141.0 g (289 mmol) of the title compound of Example 17a) in 200 ml of dioxane at room temperature and vigorously stirring was added portionwise 238.5 g (4.26 mol) of finely sprayed potassium hydroxide. To increase the agitation, 200 ml of dioxane were added to the reaction mixture and the resulting suspension was heated to reflux and a total of 372 ml (3.128 mol) of benzyl bromide was added thereto for two hours. After a reaction time of 4 hours at 110 ° C, followed by 12 hours at room temperature, the reaction mixture was slowly poured into 2.5 l of ice water and the aqueous phase extracted with diethyl ether. After washing the ether phase and then drying the ether phase over sodium sulfate, the salt is filtered off and the diethyl ether distilled off in vacuo. The excess benzyl bromide was distilled off from the reaction mixture then in an oil pump vacuum and at an oil bath temperature of 180 ° C. The resin thus obtained was purified on silica gel using ethyl acetate / hexane (1:10).

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

Elemental analysis:

calculated: C 75.68 H 7.16 found: C 75.79 H 7.04

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

60.0 g (91.5 mmol) of the title compound of Example 17b) was dissolved in 750 ml of dimethylformamide and 10.4 g (91.5 mmol) of N-hydroxysuccinimide were added. It was cooled to 0 ° C and 18.9 g (91.5 mmol) of dicyclohexylcarbodiimide were added. Stirred for one hour at 0 ° C and 4 hours at room temperature. The solvent was distilled off in vacuo and 100 ml of ethyl acetate was added to the residue and cooled to 0 ° C. The urea precipitate was filtered off and the resulting filtrate was concentrated to dryness in vacuo. The resin-oil residue thus obtained was purified on silica gel using ethyl acetate / hexane (1:20) as eluant. Yield: 61.23 g (89.0% of theory) of the title compound as a colorless viscous oil.

Elemental analysis:

calculated: C 70.29 H 6.57 N1.86 found: C 70.39 H 5.64 N 1.91

d) 2,6-bis- {6 ^ -2- N - [1-0-a-0-6-carbonylpentyl- (2,3,4,6-tetra-O-benzyl) -manipiranose methyl ester] -1_-lysine}

To a cooled to 0 ° C solution of 4.26 g (18.30 mmol; 0.5 moleq relative to the carboxylic acid employed) of L-lysine hydrochloride methyl ester (commercially available from Bachem) and 4.05 g (40.26 mmol) of triethylamine in 100 ml of dimethylformamide a solution of 27.51 g (36.6 mmol) of the title compound of Example 17c) was added dropwise into 150 ml of dimethylformamide. After the addition was complete, it was stirred for another hour at 0 ° C and then overnight at room temperature. The mixture was evaporated to dryness in vacuo and the residue was taken up in 300 ml of ethyl acetate. The separated urea was filtered off and the filtrate was washed twice with 100 ml of 5% aqueous solution of tartic hydrogen carbonate. The organic phase is dried over magnesium sulfate and concentrated in vacuo to dryness. The residue was purified on silica gel eluting with n-hexane / isopropanol 25: 1). Yield: 39.56 g (75.4% of theory) of the title compound as a colorless oil.

Elemental analysis:

Calculated: C 72.88 H 7.31 N1.95 Found: C 72.90 H 7.29 N 2.02

e) 2,6-0Μθ [6Ν _ε -2-Ν _α - [1-OaD-6-carbonylpentyl- (2,3,4,6-tetra-O-benzyl) -manipiranose]] - 1_-lysine

Dissolve 30.0 g (20.92 mmol) of the compound of Example 17d in 150 ml of ethanol. A solution of 4 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water was added to the solution and stirred for 3 hours at 50 ° C. According to the thin layer chromatogram, the saponification was quantitative. It was concentrated in vacuo to dryness and the residue was taken up in 300 ml of ethyl acetate and the organic phase was extracted twice with 100 ml of dilute aqueous citric acid. After drying over sodium sulfate, it is filtered and concentrated in vacuo to dryness. The residue was chromatographed on silica gel (eluent: n-hexane / isopropanol 13: 1). 25.56 g (88.5% of theory) of the title compound are obtained as a colorless oil.

Elemental analysis:

Calculated: C 72.88 H 7.31 N1.95 Found: C 72.78 H 7.33 N1.96

f) 2,6-6nc- [6N _e -2-N _a - [1-OaD- N-hydroxysuccinimide ester]

6-carbonyl-pentyl- (2,3,4,6-tetra-O-benzyl) -manipiranose] L-lysine]

14.0 g (8.15 mmol) of the title compound of Example 17f) were dissolved in 100 ml of dimethylformamide and 1.04 g (9.15 mmol) of N-hydroxysuccinimide were added. Cool to 0 ° C and add 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide. Stirred for one hour at 0 ° C and 4 hours at room temperature. The solvent was distilled off in vacuo and 100 ml of ethyl acetate was added to the residue and cooled to 0 ° C. The urea precipitate was filtered off and the resulting filtrate was concentrated to dryness in vacuo. The resin-oil residue thus obtained was purified on silica gel using ethyl acetate / hexane (1:20) as the eluent.

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

Elemental analysis:

calculated: C 71.40 H 7.05 N2.74 found: C 71.39 H7.14 N2.81

e) 2,6-N, N'-bis- [1-0-a-0- (6-carbonyl) -pentyl-2,3,4,6-tetra-0-benzyl-mannopyranose] -1_-lysine-1 , 7- (1,4,7-triazaheptane) diamide

To a cooled to 0 ° C solution of 0.47 g (4.57 mmol) of diethylenetriamine in 25 ml of dimethylformamide was slowly added a solution of 14.0 g (9.15 mmol; 2 moleq) of the title compound of Example 17f) in 100 ml of dimethylformamide . After the addition is complete, it is stirred for one hour at 0 ° C and overnight at room temperature. The mixture was concentrated in vacuo to dryness and the residue was taken up in 200 ml of ethyl acetate. The separated urea was filtered and the filtrate was washed twice with 50 ml of 5% aqueous sodium hydrogen carbonate solution. The organic phase was dried over magnesium sulfate, concentrated in vacuo. The residue was chromatographed on silica gel (eluent: n-hexane / isopropanol 25: 1). 9.53 g (71.4% of theory) of the title compound are obtained as a colorless oil.

Elemental analysis:

calculated: C 72.79 H 7.42 N 3.36 found: C 72.90 H 7.39 N 3.32 h) 2-N- [2- (N-ethyl-N-perfluoroctylsulfonyl) amino] -acetyl-6-N- (benzyloxycarbonyl) - 1_-lysine

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 4.09 g (35.6 mol) of N-hydroxysuccinimide were added. It is cooled to 0 ° C and 7.34 g (35.6 mmol) of dicyclohexylcarbodiimide are added. Stirred for one hour at 0 ° C and 4 hours at room temperature. It was cooled to 0 ° C and a solution of 11.77 g (35.6 mmol) of 6-N-benzyloxycarbonyl-L-lysine hydrochloride methyl ester and 4.0 g (40.0 mmol of triethylamine in 100 ml of dimethylformamide) was added dropwise over 10 minutes. 0 ° C and overnight at room temperature The solvent is distilled off in vacuo and 100 ml of ethyl acetate is added to the residue, the urea precipitate is filtered off and the filtrate is washed twice with 100 ml of 5% aqueous sodium hydrogen carbonate solution twice. dried over magnesium sulfate and evaporated in vacuo to dryness. was chromatographed on silica gel (eluent: n-hexane / ethyl acetate 20: 1).

Whose *

Yield: 27.43 g (88.0% of theory) as a colorless oil.

Elemental analysis:

Calculated: C 38.41 H 3.45 N 4.80 F 36.89 S 3.66 Found: C 38.45 H 3.38 N 4.88 F 37.02 S 3.71

B) 2 persons - {[2- (1 \ 1-ethyl-1 \ 1-perfluoroktilsulfonil] -amino-acetyl} -61 \ 1 _£; (benzyloxycarbonyl) -L-lysine

Dissolve 25.0 g (28.55 mmol) of the compound obtained in Example 17h in 150 ml of ethanol. A solution of 4 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water was added to the solution and stirred for 3 hours at 50 ° C. According to the thin layer chromatogram, the saponification was quantitative. It was concentrated in vacuo to dryness and the residue was taken up in 300 ml of ethyl acetate and the organic phase was extracted twice with 100 ml of dilute aqueous citric acid. After drying over sodium sulfate, it is filtered and concentrated in vacuo to dryness. The residue was chromatographed on silica gel (eluent: n-hexane / isopropanol 10: 1). 22.73 g (92.4% of theory) of the title compound are obtained as a colorless oil.

Elemental analysis:

calculated: C 37.64 H 3.28 N 4.88 F 37.49 S 3.72 Found: C 37.65 H 3.38 N 4.88 F 37.52 S 3.73

j) 1 A7-triazaheptane-4- {2-N- [2- (1-ethyl-N-perfluorooctylsulfonyl) -amino] -acetyl-6-1 \ 1-benzyloxycarbonyl} -E-lysine-amide-1,7-6nc {2,6-N, N'-6nc [1-OaD (5-carbonyl) -pentyl-2,3,4,6-tetra-O-benzylmani-pyranose] -L lysine-diamide}

Dissolve 15.33 g (17.8 mmol) of the title compound of Example 17i in 250 ml of dry THF as well as 1.80 g (17.8 mmol of triethylamine). After cooling the reaction solution to -15 - -20 ° C, it was slowly added dropwise at this temperature. stirring a solution of 4.92 g (35.6 mmol) of hydrochloric acid isobutyl ester dissolved in 50 ml of dry tetrahydrofuran as the rate of drip should be selected so as not to increase the internal temperature above -10 ° C. After a reaction time from 15 minutes at -15 ° C, a solution of 52.0 g (17.8 mmol) of solution was slowly added. the title compound of Example 17e) and 1.80 g (17.8 mmol) of triethylamine as a solution in 300 ml of dry tetrahydrofuran at -20 ° C. After stirring for one hour at -15 ° C and two hours at room temperature, the reaction solution was evaporated under vacuum to dry. The residue was taken up in 500 ml of ethyl acetate and washed twice with 200 ml of saturated sodium hydrogen carbonate solution and one stump with 200 ml of water. After drying the organic phase over sodium sulfate, the salt is filtered off and the ethyl acetate is evaporated in vacuo. The oily residue was purified on silica gel using ethyl acetate / n-hexane (1:20) as eluent.

Yield: 54.6 g (81.6% of theory) of the title compound as a colorless, very viscous oil.

Elemental analysis:

calculated: C 65.09 H 6.45 N 3.72 F 8.58 S 0.85 found: C 65.13 H 4.41 N3.69 F8.52 S 0.90

k) 1,4,7-Tpna3axenTaH-4- {2-N- [2- (N-ethyn-N-perfluorooctylsulfonyl) -amino] -acetyl} -1_-lysine-amide-1,783 bis {2,6 ^ K-bis [1-0-a-0- (5-carbonyl) -pentyl-mannopyranose] -1-lysine-diamide}

Dissolve 50.0 g (13.28 mmol) of the compound obtained in Example 17j in 500 ml ethanol and add 4.0 g Pearl Catalyst (Pd 20%, C). Hydrogen at room temperature under an atmosphere of hydrogen (1 atm) until hydrogen is withdrawn. The catalyst was filtered off, washed mainly with ethanol and concentrated in vacuo to dryness. The title compound is obtained as a very viscous colorless oil.

Yield: 26.85 g (93.0% of theory).

Elemental analysis:

calculated: C 45.85 H 6.35 N6.22 F 14.86 S 1.47 found: C 45.76 H 6.35 N6.41 F 14.92 S 1.39

I) 1,4,7-Tpna3axenTaH-4- {2-N- [2- (N-ethyn-N-perfluorooctylsulfonyl) -amino] -acetyl-6-No [1,4,7-tris (carboxylatomethyl) - 10 (3-aza-4-oxo-5-methyl-5-yl-pentanoyl) -1,4,7,10-tetraazacycododecane} -1_-lysine amide-1,7-6nc {2,6-N, N '-6nc [1-OaD- (5carbonyl) -pentyl-mannopyranose] -1_-lysine-diamide}, gadolin complex

5.54 g (8.80 mmol; 2.2 molar equivalents of the embedded amino component of Example 17k) of the patented DE 197 28 954Cl under 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 0.37 g of anhydrous lithium chloride (8.8 mmol) were dissolved at 40 ° C in 60 ml of absolute dimethyl sulfoxide under stirring and a total of 1.01 g was added at this temperature. (8.8 mmol) of N-hydroxysuccinimide and 1.84 g (4.0 mmol of the title compound of Example 17k) dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N -dicyclohexylcarbodiimide were added to the reaction solution and the reaction mixture was stirred for hours at room temperature. Sufficient acetone was added to the suspension thus obtained to completely precipitate the title compound. The precipitate was filtered off, dried and taken up in water, the undissolved dicyclohexylurea was filtered off and the filtrate was ultrafiltered on AM ICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalinate and purify low. What is retained on the filter is freeze-dried.

Yield: 8.77 g (78.7% of theory) as a colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 4.43%

Elemental analysis: (calculated as anhydrous substance) calculated: C 43.98 H 5.97 N7.54 F 11.59 S 1.15 Gd 5.64 found: C 43.97 H 6.02 N7.62 F 11.61 S 1.15 Gd 10.18 Example 18

a) 2- Na-6N methyl ester _is -6nc- [1-OaD-Kap6oHnnMeTnn-

2,3,4,6-Tetra-O-benzyl mannopyranose] -1_-lysine

10.95 g (18.30 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-D-mannopyranoside (prepared according to DE 197 28 954 C1) were dissolved in 150 ml of dimethylformamide and 2.09 g (18.3 mmol) of Nhydroxysuccinimide were added . Cool to 0 ° C and add 3.78 g (18.3 mmol) of dicyclohexylcarbodiimide. Stirred for 1 hour at 0 ° C and 4 hours at room temperature. It was cooled to 0 ° C and a solution of 2.13 g (9.15 mmol; 0.5 moleq relative to the carboxylic acid employed) of L-lysine hydrochloride methyl ester (commercially available from Bachem) and 2.02 g (20.13) was added dropwise over 1 hour. mmol) triethylamine in 70 ml of dimethylformamide. After the addition was complete, it was stirred for another hour at 0 ° C and then overnight at room temperature. The mixture was evaporated to dryness in vacuo and the residue was taken up in 300 ml of ethyl acetate. The separated urea was filtered off and the filtrate was washed twice with 100 ml of 5% aqueous sodium bicarbonate solution each time. The organic phase is dried over magnesium sulfate and concentrated in vacuo to dryness. The precipitate was purified on silica gel eluting with n-hexane / isopropanol 25: 1). Yield: 10.05 g (82.3% of theory) of the title compound as a colorless oil.

Elemental analysis:

Calculated: C 71.94. H 6.79 N2.10 found: C 71.90 H 6.79 N2.09

b) 2- Ma-6M _£ bis [1-O-a-0-karbonilmetil-

2,3,4,6-Tetra-O-benzyl mannopyranose] -1_-lysine

Similar to the synthesis described in Example 17f, for the title compound therein, methyl ester saponification of 15 g (11.23 mmol) of the title compound of Example 18a) resulted in the formation of 13.89 g (93.6% of theory) of the title compound below form of colorless viscous oil.

Elemental analysis:

calculated: C 71.80. H 6.71 N2.12 found: C 71.84 H 6.69 N2.15

c) 2- Na-6N-hydroxysuccinimide ester _is -6nc- [1-Oa-Dcarbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose] -1-lysine 12.09 g (9.15 mmol) of the title compound of Example 18b) was dissolved in 100 ml of dimethylformamide and 1.04 g (9.15 mmol) of N-hydroxysuccinimide were added. Cool to 0 ° C and add 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide. Stirred for one hour at 0 ° C and 4 hours at room temperature. The solvent was distilled off in vacuo and 100 ml of ethyl acetate were added to the residue and cooled to 0 ° C. The urea precipitate was filtered off and the resulting filtrate was concentrated to dryness in vacuo. The resin-oil residue thus obtained was purified on silica gel using ethyl acetate / hexane (1:20) as the eluent.

Yield: 12.24 g (94.4% of theory) of the title compound as a colorless and viscous oil.

Elemental analysis:

calculated: C 70.27 H 6.47 N 2.96 found: C 70.31 H 6.44 N 3.01

d) 6-N-benzyloxycarbonyl-2-N - {[2,6-N, N'-bis- (1-O-α-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose) ] -1_-lysyl} -1_-lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

19.0 g (13.4 mmol) of the carboxylic acid ester-N-hydroxysuccinimide obtained according to Example 18c was dissolved in 75 ml of dimethylformamide and a solution of 11.13 g (13.4 mmol) of the compound cooled to 0 ° C was added thereto. from the title of Example 1c) dissolved in 50.0 ml of dimethylformamide. The resulting solution was stirred for 2 hours at 0 ° C and then for 12 hours at room temperature. The precipitated dicyclohexylurea is filtered off, the solvent is evaporated to dryness in vacuo and the residue obtained is purified on silica gel (eluent / dichloromethane / ethanol 28: 1, the chromatography is carried out using gradient elution as part of the chromatography process embedded polar eluent (ethanol here)).

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

Elemental analysis:

Calculated: C 59.10 H 5.34 N3.94 F 15.13 S 1.50 Found: C 59.18 H 5.35 N4.02 F 15.15 S 1.56

e) 2-N- {[2,6-N, N'-bis- (1-0-α-O-carbonylmethyl-mannopyranose)] -1-lysyl} -1_-lysine- [1- (4-perfluoroctylsulfonyl) -piperazine ] -amide

Dissolve 20.0 g (9.37 mmol) of the compound obtained in Example 18d in 200 ml of ethanol and add 1.5 g of Pearl Catalyst (Pd 20%, C). Hydrogen at room temperature under an atmosphere of hydrogen (1 atm) until hydrogen is withdrawn. The catalyst was filtered off, washed mainly with ethanol (twice about 100 ml) and concentrated in vacuo to dryness. The title compound is obtained as a very viscous colorless oil.

Yield: 11.62 g (97.0% of theory).

Elemental analysis:

Calculated: C 38.50 H 4.65 N 6.57 F 25.25 S 2.51 Found: C 38.46 H 4.65 N 6.51 F 25.23 S 2.52

f) 6-N- [1,4,7-Tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl-pentanoyl) -1,4,7,10-tetraazacyclododecane) -2 - # {[2,6- N -bis [1-O-α-O-carbonyl-mannopyranose)] - 1_-lysyl} -1_-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd-complex

9.98 g (15.84 mmol; 2.2 molar equivalents of the incorporated amino component of Example 18f) from patent application DE 197 28 954Cl under Example 31 h) Gd complex of 10- (4-carboxy-1methyl-2-oxo-3-azabutyl) -1,4,7,10-Tetraazacyclododecane-1,4,7-trioacetic acid and 0.67 g of anhydrous lithium chloride (15.84 mmol) were dissolved at 40 ° C in 100 ml of absolute dimethyl sulfoxide under stirring and a total of 1.84 was added at this temperature. g (15.84 mmol) of Nhydroxysuccinimide and 9.19 g (7.19 mmol) of the title compound of Example 18f) dissolved in 50 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 3.27 g (15.84 mmol) of N, N -dicyclohexylcarbodiimide were added to the reaction solution and the reaction mixture was stirred for 12 hours at room temperature. Sufficient acetone was added to the suspension thus obtained to completely precipitate the title compound. The precipitate is filtered off, dried and taken up in water, the undissolved dicyclohexylurea is filtered off and the filtrate is ultrafiltered on AM ICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalinate and further purify from possible ingredients. What is retained on the filter is freeze-dried.

Yield: 8.77 g (78.7% of theory) as a colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 5.54%

Elemental analysis: (calculated as anhydrous substance) calculated: C 38.12 H 4.64 N8.15 F 20.38 S 1.70 Gd 8.32 found: C 38.16 H 4.59 N8.18 F 20.37 S 1.68 Gd 8.28 Example 19

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

To a solution of 10.75 g (24.4 mmol) of 1,7-bis (benzyloxycarbonyl) 1,4,7,10-tetraazacyclododecane dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform was added 12.74 g at 0 ° C. (24.4 mmol) of the title compound of Example 19g) dissolved in 150 ml of tetrahydrofuran. A total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] was then added at 0 ° C in portions and left overnight at room temperature and stirred and then concentrated in vacuo. The residual oil was chromatographed on silica gel (eluent: n-hexane / isopropanol 16: 1). 15.89 g (69.0% of theory of the secondary amine incorporated) 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:

calculated: C 45.77 H 3.95 N 5.93 F 34.19 found: C 45.72 H 4.01 N 5.88 F 34.22

b) 1,7-bis (benzyloxycarbonyl) -4- (3-oxa-2H, 2H, 4H, 4H, 5H, 5Nperfluorotridecanoyl) -10- [1-8-a-O- (2-carbonyl) -ethyl- 2,3,4,6 tetra-O-acetyl-manopyranose] -1,4,7,10-tetraazacyclododecane

To 7.09 g (13.4 mmol) of 3 (2,3,4,6, -tetra-O-acetyl-1-thio-a-O-mannopyranosyl) propionic acid N-hydroxysuccinimide ester (prepared according to J. Haensler et al. , Bioconjugate Chem. 4, 85, (1993); Chipowsky, S. and Lee, Y.C. (1973), Synthesisi of 1-thio-aldosides; Carbohydrate Research 31, 339 - 346), dissolved in 100 ml of dimethylformamide and at 0 ° A solution of 12.65 g (13.4 mmol) of the title compound of Example 19a) dissolved in 100 ml of dimethylformamide was added dropwise to C. It was stirred for two hours at 0 ° C and for 12 hours at room temperature. The solvent was then distilled off in vacuo and the residue was chromatographed on silica gel (eluent: dichloromethane / ethyl acetate 20: 1; chromatography was carried out with a gradual continuous increase in ethyl acetate).

Yield: 16.23 g (88.9% of theory) of the title compound is obtained as a colorless and very viscous oil.

Elemental analysis:

calculated: C 46.70 H 4.36 N4.11 F 23.69 S 2.35 found: C 46.66 H 4.35 N4.12 F 23.65 S 2.30

c) 1- (3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) -7- [1-in-a0- (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 obtained in Example 19b in 150 ml of ethanol and add 1.0 g of Pearlman catalyst (Pd 20%, C). Hydrogen at room temperature under an atmosphere of hydrogen (1 atm) until hydrogen is withdrawn. The catalyst was filtered off, washed mainly with ethanol (twice 75 ml) and concentrated in vacuo to dryness. The title compound is obtained as a very viscous colorless oil.

Yield: 11.56 g (96.0% of theory).

Elemental analysis:

calculated: C 40.59 H 4.33 N5.12 F 29.50 S 2.93 Found: C 40.63 H4.35 N5.11 F 29.52 S 2.92

d) 1- (3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) -7- [1-8-a0- (2-carbonyl) -ethyl-mannopyranose] -1,4,7, 10tetraazacycododecane

10.0 g (9.13 mmol) of the title compound of Example 19c) was suspended in 100 ml absolute methanol and at 5 ° C a catalytic amount of sodium methanolate was added to the suspension. After a reaction time of 3 h at room temperature, by thin layer chromatography (eluent: chloroform / methanol 4: 1), the reaction Γ θ was quantified. The clear reaction solution was neutralized by the addition of Amberlite IR 120 (4 ⁺ - form) cation exchange resin, the resin was filtered off, washed with methanol and the methanol filtrate thus obtained evaporated to dryness. The resulting oily residue was purified by column chromatography on silica gel (eluent: dichloromethane / hexane / ethyl acetate 15: 20: 1, increasing the portion of ethyl acetate by chromatography). ¹ NMR spectroscopic examination of the title compound, based on the magnitude of the coupling constant J ₁₂ = 0.9 Hz, it can be unequivocally concluded that there is only an α-configuration at the v anomer center, i.e. the amount of possibly formed and β-configured anomers of the title compound is therefore below the ¹ H-NMR spectroscopically demonstrable limit. Therefore, the above title compound is only formed in the form of configurable anomers.

Yield: 8.28 g (98.0% of theory) as a colorless and highly viscous oil.

Elemental analysis:

calculated: C 37.59 H 4.24 N 6.05 F 34.85 S 3.46 found: C 37.57 H 4.28 N 6.02 F 34.85 S 3.44

e) 1- (3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) -7- [1-8-a-

O- (2-carbonyl) -ethyl-mannopyranose] -4,10-bis (carboxylatomethyl) 10- (3-aza-4-oxo-5-methyl-5-yl-pentanoyl) -1,4,7,10tetraazacycododecane ), the digadoline complex

2.48 g (3.94 mmol; 4.4 molar equivalents of the embedded diamino component of Example 19d)) of patented DE 197 28 954Cl under Example 31 h) Gd complex of 10- (4-carboxy-methyl-2-oxo-3-azabutyl) -1,4,7,10-Tetraazacyclododecane-1,4,7triacetic acid and 167 mg of anhydrous lithium chloride (3.94 mmol) were dissolved at 40 ° C in 40 ml of absolute dimethyl sulfoxide under stirring and a total of 453 mg ( 3.94 mmol) Nhydroxysuccinimide and 980 mg (0.895 mmol) of the title compound of Example 19d) dissolved in 10 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 814 mg (3.946 mmol) Ν, дицидициcyclohexylcarbodiimide were added to the reaction solution and the reaction mixture was stirred for 12 hours at room temperature. Sufficient acetone was added to the suspension thus obtained to completely precipitate the title compound. The precipitate is filtered off, dried and taken up in water, the insoluble dicyclohexylurea is filtered off and the filtrate is ultrafiltered on AM ICON® UM-3 ultrafiltration membranes (cut off: 3000 Da) to be desalinated and purified from further purification ingredients. What is retained on the filter is freeze-dried.

Yield: 1.32 g (69.1% of theory) as a colorless lyophilisate.

H ₂ O - content (Karl-Fischer); 7.65%

Elemental analysis: (calculated as anhydrous substance) calculated: C 37.43 H 4.45 N9.12 F 15.02 S 1.49 Gd 14.63 found: C 37.42 H 4.50 N9.18 F 15.07 S 1.51 Gd 14.58

f) 3-Oxa-2H, 2H, 4H, 4H, 5H, 5Nperfluorotridecanoic acid tert-butyl ester

25.0 g (53.8 mmol) of 1H, 1H, 2H, 2H-perfluoro-1-decanol (commercially available from Lancaster) were dissolved in 250 ml of absolute toluene, and at room temperature a catalytic amount (about 0.75 g) of tetra- n-butyl ammonium hydrogen sulfate. A total of 7.55 g (134.6 mmol; 2.5 eq. With respect to the embedded alcohol component) of fine powdered potassium hydroxide was then added at 0 ° C, followed by 15.73 g (80.7 mmol; 1.5 eq. With respect to the embedded alcohol component) tert. -bugyl ester of bromoacetic acid and allowed to stir for another two hours at 0 ° C. The reaction solution thus obtained was stirred for 12 hours at room temperature and then a total of 500 ml of ethyl acetate and 250 ml of water were added thereto. The organic phase was separated and washed twice with water. After drying the organic phase over sodium sulfate, the salt is filtered off and the solvents are removed in vacuo. The 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:

calculated: C 33.23 H 2.61 F 55.85 found: C 33.29 H 2.61 F 55.90 e) 3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanecarboxylic acid

20.0 g (34.58 mmol) of the title compound of Example 19f) were suspended by stirring in 200 ml of a mixture of methanol and 0.5 molar sodium hydroxide solution in a 2: 1 ratio at room temperature and then the suspension was heated to 60 ° C. After a reaction time of 12 hours, Amberlit IR 120 (H ⁺ - form) cationic ion exchange resin was added to the clear reaction mixture to neutralize, the resin was filtered off and the resulting water-methanol filtrate was evaporated in vacuo to dryness. . The resulting amorphous-oil residue was purified on silica gel using ethyl acetate-n-hexane (1: 3) as eluent.

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

Elemental analysis:

calculated: C 27.60 H1.35 F61.85 found: C 27.58 H 1.36 F 61.90 Example 20

a) 6-Benzyloxycarbonyl-2- [2- (N-ethyl-Iperfluoroctylsulfonyl) -amino] -acetyl-1-lysine methyl ester

To 8.0 g (24.4 mmol) of β-carbonyloxybenzyl-L lysine hydrochloride methyl ester (commercially available from Bachem) dissolved in a mixture of 150 ml of tetrahydrofuran, 15 ml of chloroform and 2.62 g (26.0 mmol) of triethylamine at 0 ° C and 16.18 g (27.0 mmol) of 2- (N-ethyl-1-perfluorooctylsulfonyl) -aminoacetic acid (obtained according to DE 196 03 033) dissolved in 50 ml of tetrahydrofuran are added dropwise under nitrogen atmosphere. A total of 18.0 (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] was then added at 0 ° C in portions and allowed to stir overnight at room temperature. The mixture was evaporated to dryness in vacuo and the residue was purified on silica gel eluting with n-hexane / isopropanol 15: 1). Yield: 17.0 g (79.6% of theory of applied primary amine) of the title compound as a colorless oil.

Elemental analysis:

Calculated: C 38.41 H 3.45 N 4.80 F 36.89 S 3.66 Found: C 38.42 H 3.47 N 4.87 F 36.92 S 3.64

b) 2- [2- (l-1-ethyl-l-l-perfluorooctylsulfonyl) amino] -acetyl-l-lysine methyl ester

Dissolve 15.0 g (20.23 mmol) of the compound obtained in Example 20a in 200 ml of ethanol and add 800 mg of Pearl catalyst (Pd 20% on activated carbon) to it. Hydrate to absorb the calculated amount of hydrogen. The catalyst was filtered off, washed mainly with ethanol and concentrated in vacuo to dryness. The title compound was obtained as a colorless oil.

Yield: 14.68 g (97.9% of theory).

Elemental analysis:

Calculated: C 32.40 H 3.26 N 5.67 F 43.56 S 4.32 C Found: C 32.42 H 3.27 N 5.67 F 43.60 S 4.34

c) 6- (1-O-α-O-Carbonylmethyl-2,3,4,6-tetra-O-benzyl-manopyranose) -2- [2- (N-ethyl-1-1-perfluorooctylsulfonyl) amino ester ] -acetyl-1-lysine

21.31 g (35.6 mmol of 1 carboxymethyloxy-2,3,4-tetra-0-benzyl-α-0-mannopyranoside (prepared according to DE 197 28 954 Cl) as well as 3.60 g (35.6 mmol) of triethylamine were dissolved in 500 ml of dry tetrahydrofuran. After cooling the reaction solution to -15 ° C - -20 ° C, a solution of 4.92 g (35.6 mmol) of hydrochloric acid isobutyl ester in 75 ml of dry tetrahydrofuran is added dropwise while stirring, adding ^w that the internal temperature does not exceed -10 ° C. After a reaction time of 15 min at -15 ° C, a solution of 26.39 g (355.6 mmol) of the solution is slowly added. inenieto title product of Example 20b) and 3.60 g (35.6 mmol) of triethylamine in 100 ml dry tetrahydrofuran at -20 ° C. After one hour at -15 ° C and two hours at room temperature the reaction solution is concentrated under vacuum. The residue was taken up in 250 ml of ethyl acetate and washed twice with 100 ml of saturated sodium hydrogen carbonate solution twice and once with 200 ml of water. After drying the organic phase over sodium sulfate, the salt is filtered off and the ethyl acetate is removed in vacuo. The residual oil was purified on silica gel using ethyl acetate / hexane (1:10) as eluent.

Yield: 38.12 g (81.0% of theory) of the title compound as a colorless, highly viscous oil.

Elemental analysis:

calculated: C 49.92 H 3.92 N2.53 F 29.18 S 2.90 found: C 49.99 H4.11 N2.69 F 29.22 S 3.01

d) 6 (1-O-α-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmani-pyranose) -2- [2- (N-ethyl-N-perfluorooctylsulfonyl) -amino] acetyl-lysine

Dissolve 27.65 g (20.92 mmol) of the compound obtained in Example 20c in 250 ml of methanol. A solution of 4.0 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water was added and stirred for 3 hours at 50 ° C. After controlling the reaction by thin layer chromatography it was found that methyl ester saponification was quantitative. It was concentrated in vacuo and the residue was taken up in 300 ml of ethyl acetate. The organic phase is extracted twice with 100 ml of aqueous citric acid each. After drying over sodium sulfate and filtration, it is concentrated to dryness in vacuo. The resulting residue was chromatographed on silica gel (eluent: n-hexane / chloroform / isopropanol 15: 10: 1). 24.31 g (88.9% of theory) of the title compound are obtained as a colorless viscous oil.

Elemental analysis:

calculated: C 51.46 H 4.70 N3.21 F 24.71 S 2.45 found: C 51.49 H 4.71 N3.19 F 24.72 S 2.41

e) 6- (1-O-α-O-carbonylmethyl-mannopyranose) -2- [2- (N-ethyl-Perfluorooctylsulfonyl) -amino] -acetyl-1-lysine

20.0 g (15.30 mmol) of the compound obtained in Example 20d was dissolved in a mixture of 250 ml of 2-propanol and 25 ml of water and 1.0 g of palladium catalyst (10% Pd on activated carbon) was added. It is hydrogenated for 12 hours at room temperature and a hydrogen pressure of 1 atm. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness. The residue was dissolved in 200 ml of methanol and the reaction product was precipitated by the addition of a total of 800 ml of diethyl ether. After filtration of the solid precipitate thus obtained, it was dried in vacuo at 50 ° C.

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

Elemental analysis:

Calculated: C 35.56 H 3.84 N4.44 F 34.15 S 3.39 Found: C 35.58 H 3.81 N4.45 F 34.17 S 3.40

f) 6- (1-O-α-O-carbonylmethyl-mannopyranose) -2- [2- (N-ethyl-Iperfluoroctylsulfonyl) -amino] -acetyl-1-lysine-N- {2-hydroxyprop-3-yl- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacycododecan-10 -]} - amide, Gd complex

7.48 g (7.91 mmol) of the title compound of Example 20e) were dissolved at 40 ° C in 50 ml of dimethyl sulfoxide under stirring and a total of 1.00 g (8.70 mmol) of N-hydroxysuccinimide was added at this temperature After cooling to 20 ° C and 1.795 g (8.7 mmol) of N, N -dicyclohexylcarbodiimide were added. It was stirred for one hour at 20 ° C and then for 4 ζ hours at 40 ° C. At this temperature, a solution of 4.53 g (7.91 mmol) of gadolin complex of 10- (2hydroxy-3-aminopropyl) was added dropwise over 10 minutes. 4,7,10-Tris (carboxymethyl) -1,4,7,10tetraazacycododecanin (to obtain compare WO 97/02051) in 20 ml of dimethyl sulfoxide. It was stirred for one hour at 40 ° C and overnight at room temperature. Sufficient acetone was added to the suspension thus obtained to completely precipitate the title compound. The precipitate was filtered off, dried and taken up in water, the undissolved dicyclohexylurea was filtered off, and the filtrate was ultrafiltered on AMICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalinate and purify from residues. What is retained on the filter is freeze-dried.

Yield: 9.71 g (81.7% of theory) as a colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 3.97%

Elemental analysis: (calculated as anhydrous substance) calculated: C 35.16 H4.16 N7.45 F21.48 S 2.13 Gd 10.46 found: C 35.17 H 4.20 N7.42 F21.49 S 2.09 Gd 10.48 Example 21

a) 6- [1-0-a-O- (5-carbonyl) -pentyl-2,3,4,6-tetra-6eH3nn-MaHonnpaHO3a] -2N- [2- (N-ethyl-N-perfluoroctylsulfonyl) methyl ester ) -amino] -acetyl-lysine

5.23 g (8.0 mmol) of the 5- (carboxy) pentyl-

2,3,4,6-tetra-O-benzyl-α-0-mannopyranoside, 1.3 g (8.0 mmol) of hydroxybenzotriazole and 2.6 g (8.0 mmol) of 2- (1H-benzotriazol-1-yl) -

1,1,3,3-Tetramethyluronium tetrafluoroborate (TBTU; Peboc Limited, UK) was dissolved in 75 ml of dimethylformamide and stirred for 15 minutes. To this solution was then added 5.16 g (30 mmol) of N-ethyldiisopropylamine and 5.93 g (8.0 mmol) of the amine obtained in Example 20b) and stirred at room temperature for 1.5 days. For further development, the solvent is evaporated in vacuo to dryness and the residue thus obtained is chromatographed on silica gel (eluent: dichloromethane / ethyl acetate 30: 1; the chromatography is performed on gradient elution, increasing the ethyl acetate portion continuously).

Yield: 9.70 g (88.0% of theory) as the title compound is in the form of a very viscous colorless oil.

Elemental analysis:

calculated: C 51.29 H 4.97 N 3.05 F 23.43 S 2.33 found: C 52.33 H 4.95 N3.12 F23.50 S 2.30

b) 6- [1-O-O-O- (5-carbonyl) -pentyl-2,3,4,6-tetra-O-benzylmanipyranose] -2O [2- (N-ethyl-N-perfluorooctylsulfonyl) -amino ] - acetyl-lysine

Dissolve 9.0 g (12.40 mmol) of the compound of Example 21a in 150 ml of methanol. A solution of 2.48 g (62.0 mmol) of sodium hydroxide in 15 ml of distilled water was added and stirred for 3 hours at 50 ° C. Monitoring of the reaction by thin layer chromatography showed that methyl ester saponification was quantitative. It was concentrated in vacuo and the residue was taken up in 300 ml of ethyl acetate. The organic phase was extracted twice with 100 ml of dilute aqueous citric acid. After drying over sodium sulfate and filtration, it is concentrated to dryness in vacuo. The resulting residue was chromatographed on silica gel (eluent: hexane / chloroform / isopropanol 25: 10: 1). 15.88 g (93.9% of theory) of the title compound are obtained as a colorless and very viscous oil.

Elemental analysis:

calculated: C 51.95 H 4.88 N3.08 F 23.67 S 2.35 found: C 51.99 H 4.91 N3.09 F 23.70 S 2.33

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

13.0 g (9.52 mmol) of the compound obtained in Example 21b was dissolved in a mixture of 150 ml 2-propanol and 25 ml water and 1.0 g of palladium catalyst (10% Pd on activated carbon) was added. It is hydrogenated for 12 hours at room temperature and a hydrogen pressure of 1 atm. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness. The resulting residue was chromatographed on silica gel (eluent: hexane / chloroform / isopropanol 15: 10: 1). 9.09 g (95.1% of theory) of the title compound are obtained as a colorless, very viscous oil.

Elemental analysis:

calculated: C 37.10 H 4.22 N4.19 F 32.18 S 3.10 found: C 37.09 H 4.21 N4.19 F 32.20 S 3.13

d) 6-N- (1-OaD-5-Kapylinyl) -Nethyl-benzoyl-2H-2a) -2N- [2- (N-erypiperfluorooctylsulfonyl) -amino] -acetip-1-lysine-No. {2-hydroxyprop -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 21 c) were dissolved at 40 ° C in 75 ml of dimethyl sulfoxide at. stirring, and at this temperature was added 1.00 g (8.70 mmol) of N-hydroxysuccinimide. After cooling to room temperature, 1.795 g (8.7 mmol) of N.N′C dicyclohexylcarbodiimide are added. It was stirred for one hour at 20 ° C and then for 4 hours at 40 ° C. A solution of 4.53 g (7.91 mmol) was added dropwise over 10 minutes at this temperature to the solution of the active ester of the compound of Example 21 c). ) gadolin complex of 10- (2-hydroxy-3-aminopropyl) -4,7,10-tris (carboxymethyl) 1,4,7,10-tetraazacyclododecanin (to obtain cf. WO 97/02051) in 20 ml of dimethyl sulfoxide. It was stirred for one hour at 40 ° C and overnight at room temperature. A sufficient mixture of acetone / 2-propanol (2: 1) was added to the suspension thus obtained to completely precipitate the title compound. The precipitate was filtered off, washed with ** ethyl acetate, dried and taken in water, the insoluble dicyclohexylurea was filtered off and the filtrate was ultrafiltered on AMICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) and filtered off. of low molecular weight ingredients. What is retained on the filter is freeze-dried.

Yield: 9.71 g (78.8% of theory) as a colorless lyophilisate.

H ₂ O - Karl-Fischer content: 6.65%

Elemental analysis: (calculated as anhydrous substance) calculated: C 36.97 H 4.52 N7.19 F 20.71 S 2.06 Gd 10.08 found: C 37.02 H4.50 N7.22 F 20.69 S 2.09 Gd 10.08 Example 22

100

a) 6-1 \ 1- {4- [2,3-bis- (N, N-bis (tert-butyloxycarbonylmethyl) amino) -propyl] -phenyl} -3-oxa-propionyl-21 \ 1- ( 1-α-0carbonylmenyl-mannopyranose) -1_-lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

5.25 g (7.72 mmol) of 1- (4-carboxymethoxybenzyl) -EOTA tetra-tert-butyl ester (literature: US patent 4 622 420) and 781 mg (7.72 mmol) of triethylamine were dissolved in 50 ml of methylene chloride. A solution of 1.16 g (8.b mmol) isobutyl ester of hydrochloric acid in 10 ml of methylene chloride was added dropwise at -15 ° C for 5 minutes and stirred for a further 20 minutes at -15 ° C. The solution was then cooled to - 25 ° C and a solution consisting of 7.07 g (7.72 mmol) of the title compound of Example 10e) and 2.21 g (21.0 mmol) of triethylamine in 70 ml of THF were added dropwise over 30 minutes and then stirred for a further 30 minutes at -15 ° C and overnight at room temperature. For development, the solvent was removed in vacuo and the oily residue was taken up in 250 ml of chloroform. Extract the chloroform phase twice with 100 ml of 10% aqueous ammonium chloride solution twice, dry the organic phase over magnesium sulfate and concentrate in vacuo to dryness. The residue was chromatographed on silica gel (eluent: methylene chloride / ethanol = 20: 1).

Yield: 9.60 g (79.0% of theory) as a colorless, very viscous oil.

Elemental analysis:

calculated: C 46.39 H 5.55 N 5.32 F 20.45 S 2.03 found: C 46.42 H 5.51 N 5.29 F 20.49 S 2.09

b) 6-N- {4- [2,3-bis- (N, N-bis (carboxymethyl) -amino) -propyl] phenyl} -3-oxa-propionyl-2-N- (1-α-D - carbonylmenylmanipyranose) -E-lysine- [1- (4-perfluoroctylsulfonyl) piperazine] -amide

101

9.0 g (5.7 mmol) of the compound obtained in Example 22a was dissolved in 150 ml of methanol. A solution of 4.0 g (100.0 mmol) of sodium hydroxide in 25 ml of distilled water was added and stirred for 6 hours at 60 ° C. After controlling the reaction by thin layer chromatography, it appeared that the saponification of tetra-tert-butyl ester had elapsed. quantitatively for the above response time. Concentrate in vacuo and heat the residue in 50 ml of dimethyl sulfoxide. A sufficient amount of acetone / ethyl acetate (1: 1) was added until complete precipitation of the above title compound, the precipitate was filtered off, washed well with ethyl acetate, dried and taken up in water. The pH of the solution was adjusted to 3.5 using 1 molar hydrochloric acid solution, possible insoluble constituents were filtered off and the filtrate was ultrafiltered on AM ICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalinate and to settle purified from low molecular weight ingredients. What is retained on the filter is freeze-dried.

Yield: 6.76 g (87.6% of theory) as a colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 3.30%

Elemental analysis: (calculated as anhydrous substance) calculated: C 39.89 H 4.09 N 6.20 F 23.84 S 2.37 found: C 39.92 H4.15 N6.22 F 23.92 S 2.29

c) 6-N- {4- [2,3-Bis-N- (bis (carboxylatomethyl) -amino) -propyl] phenyl} -3-oxa-propionyl-2-N (1-α-D-carbonyl-monylpyranose) - Lysine- [1- (4-perfluorooctylsulfonyl) piperazine] -amide, Μη-complex, disodium salt

To 3.0 g (2.22 mmol) of the title compound of Example 22b) dissolved at boiling temperature of a mixture of 150 ml of water / ethanol (3: 1) and 0.25 g (2.22 mmol) of manganese were added in portions at 80 ° C. -P-carbonate. The reaction solution thus obtained was refluxed for 5 hours. After cooling to room temperature

102

'Whose *' the solvent mixture was evaporated in vacuo and the residue was dissolved in a mixture of 200 ml distilled water / n-butanol (1: 1). With frequent stirring, the pH was adjusted to 7.2 by the addition of 1 N NaOH. After complete evaporation of n-butanol in vacuo, the residual aqueous phase is ultrafiltered on AM ICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalinate and purify from low molecular weight constituents. What is retained on the filter is freeze-dried.

Yield: 3.19 g (99.0% of theory) as a colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 5.08%

Elemental analysis: (calculated as anhydrous substance) calculated: C 37.23 H 3.54 N5.79 F 22.25 S 2.21 Mn 3.78 Na 3.17 found: C 37.30 H 3.49 N5.76 F 22.29 S 2.18 Mn 3.18 Na 3.19

Example 23

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

To a 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; Ishimaru, Toshiyasy; TELEAY; Tetrahedron Lett .; EN; 22; 39; 1981; 3883-3886;] in 150 ml of absolute tetrahydrofuran was added dropwise while stirring 53.97 g (95.0 mmol) of 1-perfluoroctylsulfonylpiperazine in 150 ml of tetrahydrofuran and the resulting solution was refluxed for 12 hours. The room temperature was concentrated to dryness and the oily residue was chromatographed on silica gel using dichloromethane / 2-propanol (20: 1). eluent.

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

Elemental analysis:

calculated: C 36.11 H 2.67 N5.05 F 38.84 S 3.86

103 Found: C 36.12 H 2.61 N5.08 F 38.82 S 3.88

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

31.50 g (37.88 mmol) of the compound obtained in Example 23b was dissolved in 300 ml of ethanol and 2.5 g of Pearlman catalyst (Pd 20%, C) was added thereto. Hydrogen at room temperature under an atmosphere of hydrogen (1 atm) until the amount of hydrogen required has been absorbed. The catalyst was filtered off, washed with ethanol and concentrated in vacuo to dryness. The title C compound was obtained as a yellowish-white viscous oil.

Yield: 25.22 g (95.5% of theory).

Elemental analysis:

calculated: C 29.28 H 2.31 N 6.03 F 46.31 S 4.06 found: C 29.32 H 2.29 N 6.08 F 46.28 S 4.08

c) 3-N- (1-a-O-carbonylmethyl-2,3,4,6-tetra-O-benzylmanipyranose) -glutaric acid [1- (4-perfluorooctylsulfonyl) -piperazine] -monoamide

21.52 g (18.96 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-D-mannopyranoside (prepared according to DE 197 28 954 C1) were dissolved in 100 ml of absolute dimethylformamide and 2.56 g was added at 0 ° C. (22.2 mmol) N-hydroxysuccinimide followed by 4.55 g (22.2 mmol) of dicyclohexylcarbodiimide. It was stirred for 1 hour at 0 ° C and 3 hours at 22 ° C. It was filtered from undissolved dicyclohexylurea and the resulting clear solution of the active ester of the above compound was slowly added at 0 ° C and stirred to a solution of 13.22 g (18.96 mmol). from the compound of Example 23b) dissolved in 100 ml of dimethylformamide. After a reaction time of 12 hours at room temperature, the solvent was evaporated in vacuo and the residue was taken up in 300 ml of ethyl acetate, the urea was filtered off and the organic filtrate was washed twice with 100 ml of saturated sodium hydrogen carbonate solution.

104 as well as 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 filtered off and the ethyl acetate is distilled off in vacuo. The oily residue was purified by chromatography on silica gel using ethyl acetate / n-hexane (1:15) as the eluent.

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

Elemental analysis:

calculated: C 49.81 H4.10 N3.29 F 25.27 S 2.51 found: C 49.89 H4.11 N3.32 F 25.22 S 2.51

d) 3-N- (1-a-O-carbonylmethyl-mannopyranose) -glutaric acid f- (4-perfluorooctylsulfonyl) -piperazine] -monoamide

19.55 g (15.30 mmol) of the compound of Example 23c) was dissolved in a mixture of 250 ml of 2-propanol and 25 ml of water and 1.5 g of palladium catalyst (10% Pd on activated carbon) was added. It is hydrogenated for 12 hours at room temperature and a hydrogen pressure of 1 atm. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness. The resulting residue was dissolved in 200 ml of methanol and the reaction product was precipitated by the addition of a total of 800 ml of diethyl ether. After filtration of the solid thus obtained, it was dried at 40 ° C in vacuo

Yield: 17.49 g (97.5% of theory) of the title compound as an amorphous solid.

Elemental analysis:

Calculated: C 32.73 H 3.08 N 4.58 F 35.20 S 3.49 Found: C 32.68 H3.15 N4.55 F 35.17 S 3.50

e) 3-N- (1-a-O-carbonylmethyl-mannopyranose) -glutaric acid [1- (4-perfluorooctylsulfonyl) -piperazine] -amide-5-N- {2-hydroxyprop-3-yl- [1,4,7 -tris (carboxylatomethyl-1,4,7,10tetraazacyclododecan-10-yl]} - amide, Gd-complex

105

14.43 g (15.84 mmol) of the title compound of Example 23d) were dissolved at 40 ° C in 100 ml of absolute dimethyl sulfoxide under stirring and a total of 1.82 g (15.84 mmol) of Nhydroxysuccinimide and a solution of 9.08 g (15.84 mmol) were added at this temperature. gadolin complex of 10- (2-hydroxy-3-aminopropyl) -4,7,10-tris (carboxymethyl) 1,4,7,10-tetraazacyclododecanin (to obtain compare WO 97/02051) in 50 ml of dimethyl sulfoxide. After cooling to room temperature, 3.27 g (15.84 mmol) of дицидициcyclohexylcarbodiimide are added and stirred for 12 hours at room temperature. Sufficient acetone was added to the suspension thus obtained to completely precipitate the title compound. The precipitate was filtered off, washed with ethyl acetate, dried and taken in water, the undissolved dicyclohexylurea was filtered off and the filtrate was ultrafiltered on AMICON® ΥΜ-3 ultrafiltration membranes (cut off: 3000 Da) to desalinate and desalinated , still available low molecular weight ingredients. What is retained on the filter is freeze-dried.

Yield: 19.71 g (80.2% of theory) as a colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 4.87%

Elemental analysis: (calculated as anhydrous substance) calculated: C 34.24 H 3.83 N7.61 F21.92 S 2.18 Gd 10.67 found: C 34.26 H3.79 N7.58 F21.87 S 2.18 Gd 10.68 Example 24 1.7-bis ( benzyloxycarbonyl) -4- {3-oxa-pentane-1,5-dicarboxylic acid 1-oyl-5- [1- (4-perfluoroctylsulfonyl) -piperazine] amide} -N- [2,6-N, N ' bis (1-0-a-0-carbonylmethyl-2,3,4,6-tetra-0-benzyl-mannopyranose)] - 1-lysyl-1,4,7,10-tetraazacyclododecane To a solution of 27.0 g (24.4 mmol) ) of the secondary amine obtained according to Example 15a), in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform at 0 ° C and in a nitrogen atmosphere were added dropwise 22.04 g

106 (25.0 mmol) of the title compound of Example 18c) dissolved in 250 ml of tetrahydrofuran. A total of 18.0 (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] was then added at 0 ° C in portions and allowed to stir overnight at room temperature. The mixture was evaporated to dryness in vacuo and the residual oil was purified on silica gel eluting with n-hexane / isopropanol 15: 1). Yield: 45.87 g (78.0% of theory of secondary amine incorporated) of the title compound as a colorless oil.

Elemental analysis:

Calculated: C 59.30 H 5.39 N4.65 F 13.40 S 1.33 Found: C 59.32 H 5.37 N4.70 F 13.37 S 1.34

b) 1- {3-Oxa-pentane-1,5-dicarboxylic acid-1-yl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -7- [2,6- b] -O-α-D-carbonylmethyl-mannopyranose)] - 1_-lysyl-1,4,7,10tetraazacyclododecane

Dissolve 24.1 g (10.0 mmol) of the compound of Example 24a in 250 ml of ethanol and add 1.4 g of Pearl catalyst (Pd 20%, C) to it. Hydrogen at room temperature under an atmosphere of hydrogen (1 atm) until the amount of hydrogen required has been absorbed. The catalyst was filtered off, washed well with ethanol and concentrated in vacuo to dryness. The title compound is obtained as a yellowish-white very viscous oil.

Yield: (12.80 g (90.1% of theory).

Elemental analysis:

calculated: C 39.72 H 4.89 N 7.88 F 22.73 S 2.26 found: C 39.72 H 4.87 N7.90 F 22.77 S 2.24

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-α-D-carbonylmethyl-mannopyranose)] -1-lysyl-4,10-bis [1,4,7tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) -

107 pentanoyl] -1,4,7,10-tetraazacyclododecane, digadoline complex

5.54 g (8.8 mmol; 2.2 molar equivalents of the embedded amino component of Example 24b) from patent application DE 197 28 954Cl under 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 anhydrous lithium chloride (0.37 g, 8.8 mmol) were dissolved at 40 ° C in 60 ml of absolute dimethyl sulfoxide under stirring and a total of 1.01 was added at this temperature. g (8.8 mmol) of N-hydroxysuccinimide and 5.68 g (4.0 mmol) of the title compound of Example 24b) dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N-dicyclohexylcarbodiimide was added to the reaction solution and the reaction mixture was stirred for 12 hours at room temperature. Sufficient acetone was added to the suspension thus obtained to completely precipitate the title compound. The precipitate was filtered off, dried and taken up in water, the undissolved dicyclohexylurea was filtered off and the filtrate was ultrafiltered on AM ICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalinate and purify low. What is retained on the filter is freeze-dried.

Yield: 8.52 g (80.6% of theory as applied to diamino compound) as colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 6.09%

Elemental analysis: (calculated as anhydrous substance) calculated: C 38.61 H 4.76 N9.53 F 12.21 S 1.12 Gd 11.89 found: C 38.57 H 4.82 N9.52 F 12.21 S 1.15 Gd 11.93 Example 25

a) 1,7-bis (benzyloxycarbonyl) -4- {3-oxa-pentane-1,5dicarboxylic acid 1-oyl-5- [1- (4-perfluoroctylsulfonyl) 108 piperazine] -amide} -N- [2 , 6-M ₁ N-bis (1-0-a-0- (5-carbonyl) -pentyl-

2,3,4,6-Tetra-O-benzyl mannopyranose)] - 1_-lysyl-1,4,7,10tetraazacyclododecane

To a solution of 27.0 g (24.4 mmol) of the secondary amine obtained according to Example 15a) in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform at 0 ° C was added dropwise 35.80 g (25.0 mmol) of the title compound under a nitrogen atmosphere. of Example 17f) dissolved in 250 ml of tetrahydrofuran. A total of 18.0 (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] was then added at 0 ° C in portions and allowed to stir overnight at room temperature. The mixture was evaporated to dryness in vacuo and the residual oil was purified on silica gel eluting with n-hexane / isopropanol 15: 1). Yield: 49.48 g (80.4% of theory of secondary amine incorporated) of the title compound as a colorless oil.

Elemental analysis:

calculated: C 60.47 H 5.79 N4.44 F 12.80 S 1.27 found: C 60.52 H 5.77 N4.50 F 12.77 S 1.30

B) 1- {3-Oxa-pentane-1,5-dicarboxylic acid-1-yl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -7- [2,6-N-bis (1 -O-a0- (5-carbonyl) -pentyl-mannopyranose)] -1-lysyl-1,4,7,10tetraazacyclododecane

25.2 g (10.0 mmol) of the compound obtained in Example 25a was dissolved in 250 ml of ethanol and 1.8 g of Pearlman catalyst (Pd 20%, C) was added thereto. Hydrogen at room temperature under an atmosphere of hydrogen (1 atm) until the amount of hydrogen required has been absorbed. The catalyst was filtered off, washed well with ethanol and concentrated in vacuo to dryness. The title compound is obtained as a yellowish-white very viscous oil.

Yield: 14.11 g (90.1% of theory).

Elemental analysis:

109 calculated: C 49.60 H 7.20 N7.34 F21.17 S 2.10 found: C 49.62 H7.17 N7.30 F21.20 S 2.14

c) 1- {3-Oxa-pentane-1,5-dicarboxylic acid-1-yl-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide} -7- [2,6-N- bis (1 -O-a0- (5-carbonyl) -pentyl-mannopyranose)] - lysyl-4,10-bis [1,4,7tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5 -ylpentanoyl] -1,4,7,10-tetraazacyclododecane, digadoline complex

5.54 g (8.8 mmol; 2.2 moleq of the embedded amino component of Example 25b) of the patented DE 197 28 954Cl according to Example 31 h) Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) - 1,4,7,10-Tetraazacycododecane-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 under stirring and a total of 1.01 was added at this temperature. g (8.8 mmol) of N-hydroxysuccinimide and 6.10 g (4.0 mmol) of the title compound of Example 25b) dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N -dicyclohexylcarbodiimide were added to the reaction solution and the reaction mixture was stirred for 12 hours at room temperature. Sufficient acetone was added to the suspension thus obtained to completely precipitate the title compound. The precipitate is filtered off, dried and taken up in water, the undissolved dicyclohexylurea is filtered off and the filtrate is ultrafiltered on AM ICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalinate and clean up any possible debris . What is retained on the filter is freeze-dried.

Yield: 8.52 g (80.6% of theory as applied to diamino compound) as colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 5.89%

Elemental analysis: (calculated as anhydrous substance)

110 calculated: C 40.52 H5.16 N9.15 F11.72 S 1.16 Gd 11.72 found: C 40.57 H 5.20 N9.12 F 11.69 S 1.18 Gd 11.43 Example 26

a) 6-tert-Butyloxycarbonyl-2- {benzoyloxycarbonyl-1-lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

19.02 g (50.0 mmol) of α-N- (benzyloxycarbonyl) -8-N '- (tert-butyloxycarbonyl) -lysine (commercially available from Bachem) were dissolved in 150 ml of tetrahydrofuran. 8.31 g (50.0 mmol) of carbonyldiimidazole and 5.03 g (50.0 mmol) of triethylamine dissolved in dry tetrahydrofuran at 0 ° C were added dropwise and stirred at this temperature for 10 minutes. A solution of 48.42 g (50.0 mmol) of perfluorooctylsulfonylpiperazine and 5.03 g (50.0 mmol) of triethylamine in 250 ml of dry THF at 0 ° C was then added dropwise. The mixture was stirred overnight at room temperature. The mixture was evaporated to dryness in vacuo and the residual oil was purified on silica gel eluting with n-hexane / isopropanol 15: 1). Yield: 49.48 g (80.4% of theory of applied secondary amine) of the title compound as a colorless oil.

Elemental analysis: (calculated as anhydrous substance) calculated: C 40.01 H 3.79 N 6.02 F 34.70 S 3.45 Found: C 40.07 H 3.82 N 6.02 F 34.67 S 3.48

b) 6-N-tert-butyloxycarbonyl-lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

30.0 g (32.2 mmol) of the title compound of Example 26a) was dissolved in 300 ml of isopropanol and 1.5 g of Pearlman catalyst (Pd 20%, C) was added. Hydrogenation was carried out at room temperature for 10 hours, during which the control of the reaction by thin layer chromatography revealed that the hydrogenolytic cleavage of the benzyloxycarbonyl group after the above reaction time had been quantified. The catalyst was filtered off and the filtrate was filtered off

Ill concentrated in vacuo to dryness. The residue is chromatographed on silica gel. Eluent: n-hexane / isopropanol 25: 1). 25.13 g (98.0% of theory) of the title compound are obtained as a colorless oil.

Elemental analysis: calculated: C 34.68 H 3.67 N 7.03 F 40.55 S 4.03 found: C 34.72 H 3.70 N 7.01 F 40.60 S 3.98

c) 6-1 \ 1-tert-butyloxycarbonyl-2-N- [1 -8-a-0- (2-carbonyl) _-etil2> 3,4,6-tetra-O-acetyl-mannopyranose] -L -Lysine- [1- (4perfluoroctylsulfonyl) -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 THF (prepared according to J. Haensler et al., Bioconjugate Chem. 4, 85, (1993); Chipowskey, S., and Lee, Y. C. (1973), Synthesis of thio-aldosides; Carbohydrate Research 31, 339 - 346), as well as 3.60 g (35.60 mmol) triethylamine. After cooling the reaction solution to -15 to -20 ° C at which temperature was added dropwise slowly to a stirred solution of 4.92 g (35.60 mmol) of isobutyl chloroformate in 75 ml of dry tetrahydrofuran in which the speed of addition should also be ^w Choose that the internal temperature does not exceed -10 ° C. After a reaction time of 15 minutes at -15 ° C, a solution of

28.35 g (35.60 mmol) of the title compound of Example 22b) and 3.60 g (35.60 mmol) of triethylamine in 200 ml of dry tetrahydrofuran at 20 ° C. After a reaction time of one hour at -15 ° C and two hours at room temperature The reaction solution was concentrated in vacuo to dryness. The residue was taken up in 250 ml of ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution and once with 200 ml of water. After drying the organic phase over sodium sulfate, the salt is filtered off and the ethyl acetate is evaporated in vacuo. The oily

The 112 residue was purified by chromatography on silica gel using ethyl acetate / n-hexane (1:25) as eluent.

Yield: 34.21 g (79.1% of theory) as a colorless and very viscous oil.

Elemental analysis:

calculated: C 39.54 H 4.23 N 4.61 F 26.58 S 5.28 found: C 39.49 H 4.21 N 4.59 F 26.52 S 5.31

d) 6-N-tert-butyloxycarbonyl-2-1M- [1-c-a-0- (2-carbonyl) -ethyl ^: manopyranose] -1_-lysine- [1- (4-perfluoroctylsulfonyl) piperazine] - amide

29.93 g (24.64 mmol) of the title compound of Example 26c) were suspended in 400 ml of absolute methanol and catalytic amounts of sodium methanolate were added at 5 ⁵ C. After a reaction time of 3 hours at room temperature, thin layer chromatography (eluent: chloroform / methanol = 9: 1) was used to control the progress of the reaction and showed quantitative conversion. Amberlit® IR (H ⁺ - form) ion exchange resin was added to the clear reaction solution to neutralize, the resin was filtered off and the methanolic filtrate thus obtained was evaporated in vacuo to dryness. The resulting amorphous

The residue was purified by chromatography on silica gel using 2-propanol / ethyl acetate / n-hexane (1: 1: 15) as eluent.

Yield: 23.42 g (90.8% of theory) as a colorless viscous oil.

Elemental analysis:

calculated: C 36.72 H4.14 N5.35 F 30.85 S 6.13 Found: C 36.69 H4.11 N5.35 F 30.82 S 6.11

e) 2-N- [1-c-a-0- (2-carbonyl) -ethyl-mannopyranose] -1_-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

20.93 g (20.0 mmol) of the title compound of Example 26d) were dissolved in a mixture of 50 ml of trifluoroacetic acid and 100 ml.

113

dichloromethane at 0 ° C with vigorous stirring and stirring at this temperature for 10 minutes. It was then evaporated to dryness in vacuo, the residue taken up in 150 ml of water and the pH of the aqueous solution adjusted to 9.5 by the dropwise addition of 2 molar aqueous sodium hydroxide solution. The aqueous solution was ultrafiltered on AMICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalinate and purify from other available low molecular weight ingredients. What is retained on the filter is freeze-dried.

Yield: 17.79 g (94.2% of theory) of the free amine as a colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 3.09%

Elemental analysis: (calculated as anhydrous substance) calculated: C 34.26 H 3.73 N5.92 F 34.12 S 6.77 found: C 34.26 H 3.79 N 5.88 F 34.07 S 6.80

f) 2-N- [1-8-a-0- (2-carbonyl) -ethyl-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, gadolin complex

5.54 g (8.8 mmol; 2.2 moleq of the embedded amino component of Example 26f) of the patented application DE 197 28 954Cl under 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 anhydrous lithium chloride (0.37 g, 8.8 mmol) were dissolved at 40 ° C in 60 ml of absolute dimethyl sulfoxide under stirring and a total of 1.01 was added at this temperature. g (8.8 mmol) of N-hydroxysuccinimide and 3.78 g (4.0 mmol) of the title compound of Example 26f) dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N -dicyclohexylcarbodiimide was added to the reaction solution and the reaction mixture was stirred for 12 hours at room temperature. To the suspension thus obtained is

114 added enough acetone to completely precipitate the title compound. The precipitate is filtered off and taken up in water, the undissolved dicyclohexylurea is filtered off and the filtrate is ultrafiltered on AM ICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalt and purify from low molecular weight components. What is retained on the filter is freeze-dried.

Yield: 5.17 g (83.0% of theory) as a colorless lyophilisate. H ₂ O - content (Karl-Fischer): 4.43%

Elemental analysis: (calculated as anhydrous substance) calculated: C 35.45 H 4.07 N8.09 F 20.72 S 4.11 Gd 10.09 found: C 35.50 H 4.01 N8.12 F 20.68 S 4.14 Gd 10.13 Example 27

a) 6-N-benzyloxycarbonyl-2-N- (1-O-p-O-carbonylmethyl-2,3,4,6 tetra-O-benzylglucopyranose) -1_-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] - amide

8.02 g (13.4 mmol) of the title described in Example 46a) of I patent application DE 197 28 954 C1 [1carboxymethyloxy-2,3,4,6-tetra-benzyl-p-O-glucopyranoside] and 3.24 g (28.14 mmol) The N-hydroxysuccinimide was dissolved in 100 ml of dimethylformamide and a total of 5.80 g (28.14 mmol) of Ν'cyclohexylcarbodiimide was added portionwise at 0 ° C., Stirred for 3 hours at this temperature. dropwise at 0 ° C a cooled solution of 11.13 g (13.4 mmol) of the title compound of Example 1 c) dissolved in 50 ml of dimethylformamide and stirred for 2 hours nd 0 ° C and 12 hours at room temperature. The separated dicyclohexylurea is filtered off, the solvent is evaporated to dryness. The residue thus obtained is chromatographed on silica gel (eluent: dichloromethane / ethanol, 20: 1;

115

chromatography is carried out at constant gradient elution, increasing the ethanol fraction).

Yield: 12.67 g (67.0% of theory) as a colorless, very viscous oil.

Elemental analysis:

Calculated: C 52.77 H 4.50 N 3.97 F 22.89 S 2.27 Found: C 52.75 H 4.61 N 3.98 F 22.94 S 2.26

b) 2- N- (1-O-p-O-carbonylmethyl-glucopyranose) -1_-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

Dissolve 11.52 g (8.17 mmol) of the compound obtained in Example 27a in 100 ml of ethanol and add 0.5 g of Pearl catalyst (Pd 20%, C) to it. Hydrogen at room temperature under an atmosphere of hydrogen (1 atm) until the amount of hydrogen required has been absorbed. The catalyst was filtered off, washed well with ethanol (three times with about 40 ml each) and concentrated in vacuo to dryness. The title compound is obtained as a highly viscous colorless oil.

Yield: 7.36 g (98.4% of theory).

Elemental analysis:

calculated: C 34.07 H 3.63 N6.11 F 35.24 S 3.50 found: C 34.11 H 3.59 N6.08 F 35.23 S 3.52

c) 2-No (1-0-p-O-carbonylmethyl-glucopyranose) - 6-N- [1,4,7tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5- ilpentanoyl] -1,4,7,10-tetraazacyclododecane, L-lysine- [1- (4perfluoroctylsulfonyl) -piperazine] -amide, Gd-complex

9.98 g (15.84 mmol; 2.2 moleq of the embedded amino component of Example 27b) of the patented DE 197 28 954C1 Example 31 h) Gd complex of 10- (4-carboxy-1methyl-2-oxo-3-azabugyl) - 1,4,7,10-Tetraazacyclododecane-1,4,7-trioacetic acid and anhydrous lithium chloride (0.67 g, 15.84 mmol) were dissolved at

116

40 ° C in 80 ml of absolute dimethyl sulfoxide while stirring and a total of 1.82 g (15.84 mmol) of Nhydroxysuccinimide and 7.25 g (7.19 mmol) of the title compound of Example 27b) dissolved in 30 ml of absolute dimethyl sulfoxide were added at this temperature. After cooling to room temperature, 3.27 g (15.84) Ν, Ν′-dicyclohexylcarbodiimide were added to the reaction solution and the reaction mixture was stirred for 12 hours at room temperature. Sufficient acetone was added to the suspension thus obtained to completely precipitate the title compound. The precipitate is filtered off, taken up in water, the undissolved dicyclohexylurea is filtered off and the filtrate is ultrafiltered on AMICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalinate and purify from the available low molecular weight. What is retained on the filter is freeze-dried.

Yield: 9.11 g (83.0% of theory) as a colorless lyophilisate. H ₂ O - content (Karl-Fischer): 4.02%

Elemental analysis: (calculated as anhydrous substance) calculated: C 35.37 H 4.02 N8.25 F 21.13 S 2.10 Gd 10.29 found: C 35.42 H 4.07 N8.18 F21.09 S 2.06 Gd 10.34 Example 28

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

Dissolve 10.0 g (11.46 mmol) of the compound obtained in Example 1b in 100 ml of ethanol and add 1.0 g Pearl Catalyst (Pd 20%, C). Hydrogen at room temperature under an atmosphere of hydrogen (1 atm) until the amount of hydrogen required has been absorbed. The catalyst was filtered off, washed with ethanol and concentrated in vacuo to dryness. The title compound was obtained as a viscous colorless oil.

Yield: 8.85 g (97.5% of theory).

117

Elemental analysis:

calculated: C 30.31 H 2.54 N 7.07 F 47.95 S 4.05 found: C 30.36 H 2.50 N7.11 F 47.99 S 4.00

b) 2-N-Trifluoroacetyl-6- (1-O-p-O- (5-carbonyl) -pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose) -1_-lysine- [1- ( 4perfluoroctylsulfonyl) -piperazine] -amide

A solution of 27.51 g (36.6 mmol) of the title compound of example 17c was added to a solution cooled to 0 ° C of 29.0 g (36.6 mmol) of the title compound of Example 28a) and 4.05 (40.26 mmol) of triethylamine in 100 ml of dimethylformamide. ) in 150 ml of dimethylformamide. After the addition was complete, stirred for another hour at 0 ° C and overnight at room temperature. The mixture was evaporated to dryness in vacuo and the residue was taken up in 300 ml of ethyl acetate. it is filtered from the insoluble ingredients and the filtrate is washed twice with 100 ml of 5% aqueous sodium hydrogen carbonate solution twice. The organic phase was dried over magnesium sulfate and concentrated in vacuo 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:

Calculated: C 50.42 H 4.51 N 7.96 F 26.59 S 2.24 Found: C 50.38 H 4.50 N 7.91 F 26.62 S 2.20

c) 6-N- (1-O-p-O- (5-carbonyl) -pentyl-2,3,4,6-tetra-O-benzylmani-pyranose) -1_-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] -amide

Dissolve 20.0 g (14.0 mmol) of the compound of Example 28b in 150 ml of ethanol. A solution of 2.8 g (7.0 mmol) of sodium hydroxide in 25 ml of distilled water was then added to this solution and stirred for 0.5 hours at 50 ° C. According to the thin layer chromatogram, at this time the cleavage of the protecting group had elapsed

118 quantitatively. Concentrate in vacuo to dryness and remove traces of water by repeated ethanol distillation. The residue was chromatographed on silica gel (eluent: n-hexane / isopropanol 20: 1). 16.66 g (89.3% of theory) of the title compound are obtained as a colorless oil.

Elemental analysis:

Calculated: C 52.25 H 4.91 N 4.20 F 24.22 S 2.41 Found: C 52.30 H 4.90 N4.18 F 24.22 S 2.38

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

Dissolve 15.0 g (11.25 mmol) of the compound obtained in Example 28c in 150 ml of ethanol and add 1.0 g of Pearl catalyst (Pd 20%, C) to it. Hydrogen at room temperature under an atmosphere of hydrogen (1 atm) until the amount of hydrogen required has been absorbed. The catalyst was filtered off, washed with ethanol / water (10: 1) and concentrated in vacuo to dryness. The title compound was obtained as a viscous colorless oil.

Yield: 10.77 g (98.4% of theory).

Elemental analysis:

calculated: C 37.04 H 4.25 N 5.76 F 33.20 S 3.30 Found: C 37.06 H 4.20 N5.81 F 33.19 S 3.30

e) 6-N- (1-0-p-O- (5-carbonyl) -pentyl-mannopyranose) -2-N- [1,4,7,7tris (carboxylatomethyl) -10- (3-aza-4-oxo- 5-methyl-5-ylpentanoyl] -1,4,7,10-tetraazacycododecane, 1-lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide, Gd-complex

5.54 g (8.8 mmol; 2.2 molar equivalents of the incorporated amino component of Example 28d) of the patented DE 197 28 954Cl under 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 anhydrous lithium chloride (0.37 g, 8.8 mmol) were dissolved at

119

40 ° C in 60 ml of absolute dimethyl sulfoxide while stirring, and a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.89 g (4.0 mmol) of the title compound of Example 28d) dissolved in 60 ml of absolute dimethyl sulfoxide were added at this temperature. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N -dicyclohexylcarbodiimide was added to the reaction solution and the reaction mixture was stirred for 12 hours at room temperature. Sufficient acetone was added to the suspension thus obtained to completely precipitate the title compound. The precipitate is filtered off, taken up in water, ¢ - the undissolved dicyclohexylurea is filtered off and the filtrate is ultrafiltered on AM ICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalt and purify from low molecular weight. What is retained on the filter is freeze-dried.

Yield: 4.81 g (75.9% of theory) as a colorless lyophilisate. H ₂ O - content (Karl-Fischer): 8.98%

Elemental analysis: (calculated as anhydrous substance) calculated: C 37.15 H 4.39 N7.96 F 20.38 S 2.012 Gd 9.92 found: C 37.25 H 4.40 N8.02 F 20.31 S 1.98 Gd 10.00 Z Example 29

a) 1,7-bis (benzyloxycarbonyl) -4- (1-O-p-O-carbonylmethyl-2,3,4,6 tetra-O-benzyl-galactopyranose) -10- {3-aza-pentane-1, 5 Dicarboxylic acid 1-oyl-5- [1- (4-perfluoroctylsulfonyl) piperazine] -amide} -1,4,7,10-tetraazacycododecane

To a solution of 27.0 g (24.4 mmol) of the secondary amine obtained according to Example 15a) in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform at 0 ° C was added dropwise 35.80 g (25.0 mmol) of the title compound under a nitrogen atmosphere. of Example 17f) dissolved in 250 ml of tetrahydrofuran. A total of 18.0 (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] was then added at 0 ° C in portions and

120 allowed to stir overnight at room temperature. The mixture was evaporated to dryness in vacuo and the residual oil was purified on silica gel eluting with n-hexane / isopropanol 20: 1). Yield: 32.11 g (78.0% of theory of secondary amine incorporated) of the title compound as a colorless oil.

Elemental analysis:

calculated: C 54.09 H 4.72 N4.98 F 19.14 S 1.90 found: C 54.12 H 4.77 N5.03 F 19.17 S 1.90

b) 1- (1-O-p-O-carbonylmethyl-galactopyranose) -7- {3-oxa-pentane-

1,5-Dicarboxylic acid-1-oyl-5- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide} -1,4,7,10tetraazacyclododecane

Dissolve 30.0 g (17.77 mmol) of the compound of Example 29a in 250 ml of ethanol and add 3.0 g of Pearl catalyst (Pd 20%, C) to it. Hydrogen at room temperature under an atmosphere of hydrogen (1 atm) until the amount of hydrogen required has been absorbed. The catalyst was filtered off, washed well with ethanol and concentrated in vacuo to dryness. The title compound is obtained as a yellowish very viscous oil.

Yield: 17.89 g (95.1% of theory).

Elemental analysis:

Calculated: C 36.30 H 4.09 N 7.94 F 30.50 S 3.03 Found: C 36.26 H4.12 N7.90 F 30.46 S 3.04

c) 1- (1-O-p-O-carbonylmethyl-galactopyranose) -7- {3-oxa-pentane-

1,5-dicarboxylic acid-1-yl-5- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide} -4,10-bis [1,4,7tris (carboxylatomethyl) -10- (3-aza- 4-oxo-5-methyl-5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -1,4,7,10 tetraazacyclododecane, digadoline complex

121

5.54 g (8.8 mmol; 4.4 moleq of the embedded amino component of Example 29b) from patent application DE 197 28 954Cl under 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 anhydrous lithium chloride (0.37 g, 8.8 mmol) were dissolved at 40 ° C in 60 ml of absolute dimethyl sulfoxide under stirring and a total of 1.01 was added at this temperature. g (8.8 mmol) of N-hydroxysuccinimide and 2.11 g (2.0 mmol) of the title compound of Example 29b) dissolved in 25 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N -dicyclohexylcarbodiimide were added to the reaction solution and the reaction mixture was stirred for 12 hours at room temperature. Sufficient acetone was added to the suspension thus obtained to completely precipitate the title compound. The precipitate was filtered off, taken up in water, the undissolved dicyclohexylurea was filtered off and the filtrate was ultrafiltered on AM ICON® YM-3 ultrafiltration membranes (cut off: 3000 Da) to desalinate and purify from low molecular weight. What is retained on the filter is freeze-dried.

Yield: 3.29 g (72.2% of theory of incorporated amino acid) as colorless lyophilisate.

H ₂ O content (Karl-Fischer): 5.99%

Elemental analysis: (calculated as anhydrous substance) calculated: C 36.84 H 4.37 N9.82 F 14.15 S 1.40 Gd 19.63 found: C 36.87 H 4.40 N9.82 F 14.09 S 1.38 Gd 19.59 Example 30

a) 3- (1-0-a-0-2,3,4,6-tetra-0-benzylmani-pyranose) -2-N-benzyloxycarbonyl-1-serine methyl ester

21.42 g (39.61 mmol) was dissolved in 500 ml of dry acetonitrile.

2,3,4,6-Tetra-0-benzyl-α-0-mannopyranose (prepared according to: F. Kong et

122 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, followed by a solution of 20.06 g (79.21 mmol) of methyl ester ethoxy ester is added dropwise at this temperature. -L- Serine (commercially available from Bachem) in 50 ml of acetonitrile, at which point the drip rate should be selected so that the internal temperature does not exceed 10 ° C. After a reaction time of 15 hours at room temperature, the solution is concentrated under vacuum to dry. The residue was taken up in ethyl acetate and washed twice with 100 ml of saturated sodium bicarbonate solution each time and 200 ml of water each time. After the organic phase was dried over sodium sulfate, the salt was filtered off and the ethyl acetate was removed in vacuo. The resulting oily residue 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:

calculated: C 71.21 H 6.37 N 1.81 found: C 71.19 H 6.41 N1.79

b) 3- (1-O-a-0-2,3,4,6-tetra-O-benzyl-mannopyranose) -2-N-benzyloxycarbonyl-E-serine

In a mixture of 20 ml methanol, 20 ml water and 50 ml tetrahydrofuran dissolve 10.0 g (12.90 mmol) of the compound obtained according to Example 30a). 0.47 g (19.35 mmol) of lithium hydroxide dissolved in 25 ml of distilled water at room temperature are added and stirred for 6 hours at 60 ° C. The reaction is monitored by thin layer chromatography (eluent: methylene chloride / methanol 10: 1). found that saponification of the methyl ester of Example 30a) was

123 was quantified. The solution was then concentrated in vacuo to dryness and the residue was warmed up in 250 ethyl acetate (about 60 ° C). The ethyl acetate phase thus obtained is washed twice with 50 ml of 15% aqueous hydrochloric acid each time, once with 100 ml of distilled water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to dryness. 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:

calculated: C 70.94 H 6.22 N 1.84 found: C 70.97 H 6.30 N1.78

c) 3- (1-O-a-0-2,3,4,6-tetra-O-benzyl-manopyranose-2-benzyloxycarbonyl-1-serine [1- (4-perfluorooctylsulfonyl) piperazine] -amide

To 13.86 g (24.40 mmol) of 1-perfluoroctylsulfonylpiperazine (prepared according to DE 196 03 033) dissolved in a mixture of 150 ml of tetrahydrofuran and 15 ml of chloroform at 0 ° C and 20.57 g (27.0 mmol) were added dropwise under nitrogen. of the carboxylic acid obtained in Example 30b) dissolved in 50 ml of tetrahydrofuran. A total of 18.0 (36.60 mmol) of EEDQ [2ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] was then added in portions at 0 ° C and allowed to stir overnight at room temperature. The mixture was evaporated to dryness in vacuo and the residual oil was purified on silica gel eluting with a n: hexane / isopropanol mixture 15: 1). Yield: 17.0 g (79.6% of theory of applied primary amine) of the title compound as a colorless viscous oil.

Elemental analysis:

calculated: C 51.53 H 4.23 N3.15 F 25.65 S 2.41 found: C 51.48 H 4.27 N3.10 F 25.71 S 2.35

124

d) 3- (1-O-α-O-mannopyranose-1-serine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

Dissolve 15.0 g (11.41 mmol) of the compound obtained in Example 30C in 200 ml of ethanol and add 1.5 g of Pearl catalyst (Pd 20%, C) to it. Hydrogenate at room temperature under an atmosphere of hydrogen (1 atm) until the amount of hydrogen required is absorbed (about 8 hours). The catalyst was filtered off, washed well with ethanol and concentrated in vacuo to dryness. The title compound was obtained as a very viscous colorless C oil.

Yield: 8.79 g (94.0% of theory).

Elemental analysis:

calculated: C 30.78 H 3.20 N5.13 F 39.41 S 3.91 found: C 30.87 H3.14 N5.19 F 39.50 S 3.88

e) 3- (1-0-p-O-mannopyranose) -2-N- [1,4,7-tris (carboxylatomethyl) 10- (3-aza-4-oxo-5-methyl-5-yl- pentanoyl) -1,4,7,10tetraazacyclododecane] -1_-serine- [1- (4-perfluorooctylsulfonyl) piperazine] -amide, Gd complex

To a suspension of 5.7 g (9.06 mmol; corresponding to 1.5 molar equivalents with respect to the embedded title compound (primary amine) of Example 30d) of the described Gd-complexes of 10- (4carboxy-1-methyl-2-oxo-3-azabutyl ) -1,4,7,10-Tetraazacyclododecane 1,4,4-trioacetic acid in 75 ml absolute dimethyl sulfoxide was added at 70 ° C 0.68 g (15.9 mmol) of lithium chloride. With stirring at 70 ° C for 30 minutes, a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide was added to the already clear solution of the parts, and the reaction mixture was maintained at 70 ° C for another 1 hour. After cooling the mixture to 10 ° C, 4.52 g was added. (23.85 mmol) of N, N'-dicyclohexylcarbodiimide and the reaction mixture was stirred for another 1 hour at 0 ° C and 12 hours at 22 ° C. The thus obtained N-hydroxysuccinimide ester of the 10- (4125 carboxy-1 - methyl-2-oxo-3-azabugyl) -1,4,7,10-tetraazacycododecane 1,4,4-trioacetic acid was added dropwise at 22 ° C.

4.94 g (6.03 mmol) of the title compound of Example 30d) in 15 ml of dimethyl sulfoxide, and stirred for a further 12 hours at room temperature. For further development, a mixture of solvents consisting of 250 ml of acetone and 250 ml of 2-propanol is slowly added to the reaction solution, whereby the title compound is completely precipitated as a pale yellow colored oil after 12 hours at 10 ° C. The above eluent mixture was carefully decanted and the oily product was taken up in 200 ml of distilled water, completely dissolving it to give a pale yellowish solution in water of the above title compound. Finally, the aqueous solution of the product is filtered first on a membrane filter and then, three times on AMICON® YM-3 ultrafiltration membranes (cut off: 3000 Da), in order to desalinate and separate the low molecular weight components. What is retained on the filter is freeze-dried.

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

Elemental analysis: (calculated as anhydrous substance) calculated: C 33.57 H 3.80 N7.83 F 22.57 S 2.24 Gd 10.99 found: C 33.57 H 3.76 N7.82 F 22.63 S 2.18 Gd 11.06 Example 31

a) 6-N-benzyloxycarbonyl-2-N- [O-p-O-galactopyranosyl (1-4) gluconosyl] -1-lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] amide

To a solution of 4.98 g (6.0 mmol) of the title compound of Example 1c) in 40 ml of absolute dimethyl sulfoxide at room temperature and stirring was added dropwise a solution of 13.3 g (37.2 mmol) of 0-p-O-galactopyranosyl- (1- 4) -0-gluco-1,5-lactone

126 [lactobionolactone; obtained according to: (a) Williams, T. J.; Plessas, N. R., Goldstein, I. J., Carbohydr. Really. 1978, 67, Cl (b) Kobayashi, K ,; Sumitomo, H.; Ina, Y. Polym. J. 1985, 17, 567, (c) Hiromi Kitano, Katsuko Sohda, and Ayako Kosaka, Bioconjugate Chem., 1995, 6 131 - 134] in 40 ml of absolute dimethyl sulfoxide. The reaction solution thus obtained was stirred for 14 hours at 40 ° C. For further development, 500 ml of absolute 2-propanol was added at room temperature, and the resulting colorless precipitate was filtered on O4-frit and washed with a total of 250 ml of absolute propanol. The solid thus obtained was dissolved in 300 ml of distilled water and filtered to desalinate and separate low molecular weight constituents three times on AMICON® YM-3 ultrafiltration membranes (cut off: 3000 Da). By triple ultrafiltration, both excess lactobionolactone and possible low molecular weight constituents of the desired product are separated. What was retained on the membrane was completely dissolved in 300 ml of distilled water and freeze-dried.

Yield: 6.51 g (92.7% of theory) as a colorless lyophilisate.

H ₂ O - content: 10.03%

Elemental analysis: (calculated as anhydrous substance) calculated: C 38.98 H 4.05 N 4.79 F 27.58 S 2.74 Found: C 39.04 H 4.09 N 4.82 F 27.61 S 2.71

B) 2-N- [O-p-O-galactopyranosyl (1- »4) -gluconosyl] -1_-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

In 100 ml of ethanol was dissolved 5.0 g (4.27 mmol) of the compound obtained in Example 31a) and 0.5 g of Pearlman catalyst (Pd 20%, C) was added thereto. Hydrogen at room temperature under an atmosphere of hydrogen (1 atm) until the amount of hydrogen required has been absorbed. The catalyst was filtered off, washed with ethanol and concentrated in vacuo to dryness. The title compound is obtained as a colorless viscous oil.

127

Yield: 4.36 g (98.5% of theory).

Elemental analysis:

calculated: C 34.76 H 3.99 N5.40 F31.51 S 3.09 found: C 34.78 H 4.04 N5.34 F31.51 S 3.15

c) 2- [0-p-O-galactopyranosyl (1-> 4) -gluconosyl] -6-N- [1,4,7tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl) -5-ylpentanoyl) -1,4,7,10-tetraazacyclododecane] -1-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd complex

5.54 g (8.8 mmol; 2.2 molar equivalents of the embedded amino component of Example 31b) of the patented DE 197 28 954Cl under 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 anhydrous lithium chloride (0.37 g, 8.8 mmol) were dissolved at 40 ° C in 60 ml of absolute dimethyl sulfoxide under stirring and a total of 1.01 was added at this temperature. g (8.8 mmol) of N-hydroxysuccinimide and 3.85 g (4.0 mmol) of the title compound of Example 31b) dissolved in 60 ml of absolute dimethyl sulfoxide. After cooling to room temperature, 1.82 g (8.8 mmol) of N, N'-dicyclohexylcarbodiimide was added to the reaction solution and the reaction mixture was stirred for 12 hours at room temperature. Sufficient acetone / 2-propanol (1: 1) was added to the suspension thus obtained to completely precipitate the title compound. The precipitate was filtered off, taken up in 300 ml of water, the undissolved dicyclohexylurea was filtered off and the filtrate was ultrafiltered three times on AMICON® YM-3 ultrafiltration membranes (cut off: 3000 Da). In triple ultrafiltration, both the excess Gd complex and possible low molecular weight constituents are separated from the desired product. What was retained on the membrane was completely dissolved in 300 ml of distilled water and freeze-dried.

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

128

H ₂ 0 - Karl-Fischer content: 10.08%

Elemental analysis: (calculated as anhydrous substance) calculated: C 35.70 H 4.22 N7.65 F 19.59 S 1.95 Gd 9.54 found: C 35.77 H 4.17 N7.71 F 19.61 S 1.99 Gd 9.60 Example 32

a) 6- {Benzyloxycarbonyl-2-N- (2,3,4,5-pentahydroxyhexanoyl) -1_-lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] amide

A solution of 21.45 g (120.4 mol) of 5-gluconolactone in 50 ml of tetrahydrofuran was added dropwise to a solution of 100.0 g (120.4 mol) of the title compound of Example 1c) in 500 ml of dry THF. It was stirred for 3 hours at 60 ° C and then overnight at room temperature. It was concentrated in vacuo to dryness and the residue was chromatographed on silica gel. Eluent: dichloromethane / ethanol = 20: 1).

Yield: 98.37 g (82% of theory) as a thick oil.

Elemental analysis:

calculated: C 38.10 H 3.70 N5.55 F 32.02 S 3.18 found: C 38.22 H 3.79 N 5.42 F 32.02 S 3.29

b) 2-N- (2,3,4,5-pentahydroxy-hexanoyl) -1_-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

Dissolve 100.9 g (100.0 mmol) of the compound obtained in Example 32a in 2000 ml of ethanol and add 10.0 g of palladium catalyst (10% Pd / C). Hydrated for 12 hours at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 87.46 g (quantitative) as a colorless solid.

Elemental analysis:

calculated: C 32.96 H 3.57 N 6.41 F 36.93 S 3.67 found: C 32.91 H 3.72 N 6.34 F 36.78 S 3.50

c) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-

129 Tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] -2-N- [1-0-a-0-carbonylmethyl-mannopyranose] - lysine- [1- ( 4perfluoroctylsulfonyl) -piperazine] -amide, Gd complex

50.0 g (54.55 mmol) of the title compound of Example 1 is (e),

6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54.55 mmol) of 1,4,5-tris (carboxylatomethyl) -10 (carboxy-3-aza-4-oxo-5- methyl-pent-5-yl) -1,4,7,10-tetraazacyclododecane, Gd complex, under gentle warming, was dissolved in 400 ml of dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 moles) of Νdicyclohexylcarbodiimide were added and the reaction mixture was stirred for 12 hours at room temperature. To this suspension was added 3000 ml of acetone and stirred for 10 minutes. The resulting precipitate was filtered off and then purified by chromatography (RP-18 eluent: gradient with water / ethanol / acetonitrile).

Yield: 75.94 g (91.0% of theory) as a colorless solid.

H ₂ O - content: 8.6%

Elemental analysis: (calculated as anhydrous substance) calculated: C 35.34 H 4.09 N8.24 F 21.12 S 2.10 Gd 10.28 Found: C 35.28 H4.15 N8.19 F21.03 S 2.15 Gd 10.14

Example 33

a) 6-N-benzyloxycarbonyl-2-N- (2,3,4,5-pentahydroxyhexanoyl) -1-lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] amide

To a solution of 100.0 g (120.4 mmol) of the title compound of Example 1c) and 12.18 g (120.4 mmol) of triethylamine in 500 ml of dry tetrahydrofuran were added dropwise at 50 ° C a solution of 21.45 g (120.4 mol)

5-gluconolactone in 50 ml tetrahydrofuran. It was stirred for 3 hours at 60 ° C and then overnight at room temperature. Then add 400 ml of 5% aqueous hydrochloric acid, stir for 5 minutes

130 at room temperature, sodium chloride was added, the organic phase was separated, dried over magnesium sulfate, concentrated in vacuo to dryness and the residue chromatographed on silica gel. Eluent: dichloromethane / ethanol = 20: 1).

Yield: 100.97 g (82% of theory) as a thick oil.

Elemental analysis:

calculated: C 37.58 H 3.45 N5.48 F31.58 S 3.14 found: C 37.72 H 3.59 N5.42 F31.72 S 3.29

B) 2-N- (2,3,4,5-pentahydroxy-hexanoyl) -1_-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

Dissolve 100.9 g (100.0 mmol) of the compound obtained in Example 32a in 2000 ml of ethanol and add 10.0 g of palladium catalyst (10% Pd / C). Hydrated for 12 hours at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 87.46 g (quantitative) as a colorless solid.

Elemental analysis:

calculated: C 32.96 H 3.57 N 6.41 F 36.93 S 3.67 found: C 32.91 H 3.72 N 6.34 F 36.78 S 3.50 ^; C) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10-No (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] - 2 -No [1-0-a-0-carbonylmethyl-mannopyranose] -1-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide, Gd complex

50.0 g (54.55 mmol) of the title compound of Example 1 is (e),

6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54.55 mmol) of 1,4,5-tris (carboxylatomethyl) -10 (carboxy-3-aza-4-oxo-5- methyl-pent-5-yl) -1,4,7,10tetraazacyclododecane, Gd complex, under gentle warming, was dissolved in 400 ml of dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mol) Ν, Νcyclohexylcarbodiimide were added and the reaction mixture was stirred for 12 hours at

131 room temperature. To this suspension was added 3000 ml of acetone and stirred for 10 minutes. The resulting precipitate was filtered off and then purified by chromatography (RP-18 eluent: gradient with water / ethanol / acetonitrile).

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

H ₂ O - content: 8.6%

Elemental analysis: (calculated as anhydrous substance) calculated: C 35.34 H 4.09 N8.24 F 21.12 S 2.10 Gd 10.28 found: C 35.28 H 4.15 N8.19 F21.03 S 2.15 Gd 10.14 Glucose is used instead of mannose. , respectively galactose.

Example 34

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

To a solution of 100.0 g (120.4 mol) of the title compound of Example 1 c), 72.1 g (120.4 mol) of 1-0-α-O-carbonylmethyl-2,3,4,6-tetra-0-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. Stirred for 3 hours at 0 ° C and overnight at room temperature. The urea precipitate was filtered off, the filtrate was concentrated in vacuo to dryness and chromatographed on silica gel (eluent: dichloromethane / ethanol = 20: 1).

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

Elemental analysis:

calculated: C 57.32 H 4.89 N 4.31 F 24.86 S 2.47 found: C 57.48 H 5.04 N 4.20 F 24.69 S 2.38

b) 2-N- [1-0-a-0-carbonylmethylglucopyranose] -1-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

132

Dissolve 130.0 g (100.0 mmol) of the title compound of Example 34a in 2000 ml of ethanol and add 10.0 g of palladium catalyst (10% Pd / C). Hydrated for 12 hours at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

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

Elemental analysis:

Calculated: C 34.07 H 3.63 N6.11 F 35.24 S 3.50 Found: C 33.92 H 3.71 N 6.02 F 35.33 S 3.42

c) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10-No (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] - 2- N- [1-OaD-carbonylmethyl-glucopyranose] - L-lysine- [1- (4perfluoroctylsulfonyl) -piperazine] -amide, Gd complex

50.0 g (54.55 mmol) of the title compound of Example 34b),

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) of 1,4,5-tris (carboxylatomethyl) -10 (carboxy-3-aza-4-oxo-5- methyl-pent-5-yl) -1,4,7,10tetraazacyclododecane, Gd complex, under gentle warming, was dissolved in 400 ml of dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mol) Ν, Νcyclohexylcarbodiimide were added and the reaction mixture was stirred for 12 hours at room temperature. To this suspension was added 3000 ml of acetone and stirred for 10 minutes. The resulting precipitate was filtered off and then purified by chromatography (RP-18 eluent: gradient with water / ethanol / acetonitrile).

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

H ₂ O - content: 8.6%

Elemental analysis: (calculated as anhydrous substance) calculated: C 35.34 H 4.09 N8.24 F21.12 S 2.10 Gd 10.28 found: C 35.26 H4.18 N8.14 F21.01 S 2.158 Gd 10.13

133

Example 35

a) 6-N-6eH3nnoKCHKap6oHHr-2-N- [1 -0-a-0-carbonylmethyl- (2,3,4,6 tetra-O-benzyl galactopyranose] -1-lysine- [1- (4perfluoroctylsulfonyl) -piperazine ] -amide

To a solution of 50.0 g (60.2 mol) of the title compound of Example 1c), 36.05 g (60.2 mol) of 1-0-α-O-carbonylmethyl-2,3,4,6-tetra-0-benzyl galactopyranose and 6.93 g ( 60.2 mol) of N-hydroxysuccinimide dissolved in 500 ml of dimethylformamide were added at 0 ° C 20.64 g (100.0 mmol) of N, N-dicyclohexylcarbodiimide. Stirred for 3 hours at 0 ° C and overnight at room temperature. The urea precipitate was filtered off, the filtrate was concentrated in vacuo to dryness and chromatographed on silica gel (eluent: dichloromethane / ethanol = 20: 1).

Yield: 68.1 g (87% of theory) as a thick oil.

Elemental analysis:

calculated: C 57.32 H 4.89 N 4.31 F 24.86 S 2.47 found: C 57.47 H 5.05 N4.19 F 24.72 S 2.29

b) 2-N- [1-0-a-0-carbonylmethyl-galactopyranose] -1-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

65.0 g (50.0 mmol) of the title compound of Example 35a were dissolved in 1000 ml of ethanol and 5.0 g of palladium catalyst (10% Pd / C) was added thereto. Hydrated for 12 hours at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 45.85 g (quantitative) as a colorless solid.

Elemental analysis:

Calculated: C 34.07 H 3.63 N6.11 F 35.24 S 3.50 Found: C 33.93 H 3.74 N 6.01 F 35.05 S 3.39

c) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10-No (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] - 2- N- [1-OaD-carbonylmethyl-galactopyranose] - 1_-lysine- [1- (4-

157

R500C - \ / \ / - CO-OH n;

R ⁵ OOC-- '--COOR ⁵ in which R ⁵ is as defined, (Via) or a carboxylic acid of the general formula Vila

R5OOCR5QOC

R ⁵ OOC-

R ⁵ OOC (Vila) in which R ⁵ and U ¹ have the meanings already mentioned, optionally reacted with an amine of the general formula IX

H-G- (Z-Rf) m (IX) in which G, R, R _f , Y, Z, m, and p have the meanings given in the claim, in the coupling reaction and any subsequent cleavage of the possibly present protecting groups is converted in a metal complex of general formula I or when R ⁵ has the meaning of a protecting group, after cleavage of these protecting groups in a further step, by itself in a known manner, reacts with at least one metal oxide or metal salt of an element in turn numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83 and then optionally present acidic hydrogen atoms instead of empowered by cations of inorganic and / or organic bases, amino acids or amino acid amides.

135 Found: C 51.35 H4.18 N4.28 F 17.03

b) L-glutamic acid 2-N-trifluoroacetyl-mono-benzyl ester-5 '- (methyl) -N- (2,3,4,5,6-pentahydroxyhexyl) -amide

To a solution of 24.9 g (24.08 mmol) of the title compound of Example 36a, 2x g (24.08 mmol) of N-methylglucamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide dissolved in 150 ml of dimethylformamide was added at 0 ° C 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide. Stirred for 3 hours at 0 ° C and overnight at room temperature. The urea precipitate was filtered off, the filtrate was concentrated in vacuo to dryness and chromatographed on silica gel (eluent: dichloromethane / ethanol = 20: 1).

Yield: 109.40 g (89% of theory) as a thick oil.

Elemental analysis:

calculated: C 51.43 H 5.51 N6.66 F 13.56 found: C 51.22 H 5.41 N6.75 F 13.40

c) N-Trifluoroacetyl-L-glutamic acid-N- (μθτηπ) -Ν (2,3,4,5,6-pentahydroxyhexyl) -amide

77.33 g (15.15 mmol) of the title compound of Example 36b were dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) was added thereto. Hydrated at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 43.0 g (quantitative) as a colorless solid.

Elemental analysis:

calculated: C 40.01 H5.19 N8.48 F 17.26 found: C 39.84 H5.13 N8.68 F 17.09

d) N-Trifluoroacetyl-1-glutamic acid-N- (μθτμι) -Ν- (2,3,4,5,6-pentahydroxyhexyl) -amide - [1- (4perfluorooctylsulfonyl) -amidpiperazine] -amide

136

To 10.96 g (33.2 mmol) of the title compound of Example 36c) and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (prepared according to DE 196 03 033) in 80 ml of tetrahydrofuran were added at 0 ° C 16.42 g (66.4 mmol) EEDQ [2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester] and allowed to stir overnight at room temperature. The mixture was evaporated to dryness in vacuo and the residual oil was purified on silica gel eluting with a dichloromethane / methanol = 20: 1 mixture).

Yield: 28.67 g (92% of theory) as a colorless solid.

Elemental analysis:

calculated: C 39.61 H 2.89 N6.19 F 35.66 S 3.54 found: C 39.68 H 2.74 N6.13 F 35.81 S 3.40

e) L-glutamic acid-5-N (methyl) -N (2,3,4,5,6 pentahydroxyhexyl) -amide - [1- (4-perfluoroctylsulfonyl) piperazine] -amide

In a solution of 28.36 g (30.22 mmol) of the title compound of Example 36d) in 200 ml of ethanol was introduced at 0 ° C for one hour ammonia gas. It was then stirred for 4 hours at 0 ° C. It was concentrated to dryness and the residue was stirred in water. The precipitate was filtered off and dried in vacuo (50 ° C).

Yield: 24.19 g (95% of theory) as an amorphous solid.

Elemental analysis:

calculated: C 41.12 H 2.89 N6.19 F 35.66 S 3.54 found: C 41.15 H 2.83 N6.28 F 35.78 S 3.71

f) No. [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecane] -10- (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] - L-glutamic acid- 5-N (methyl) -N (2,3,4,5,6 pentahydroxyhexyl) -amide-5- [1- (4-perfluorooctylsulfonyl) -

137 piperazine] -amide, Gd complex

20.43 g (24.25 mmol) of the title compound of Example 36f, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50.0 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1,4,5-tris (carboxylatomethyl) -10 [(3-aza-4-oxo-5-methyl-pent-5-yl) -pentanoic acid] -1,4,7,10tetraazacyclododecane, Gd complex, was dissolved in 200 ml of dimethyl sulfoxide under gentle warming. At 10 ° C, 8.25 g (40 mmol) Ν, Νcyclohexylcarbodiimide were added and the reaction mixture was stirred for 12 hours at room temperature. To this suspension was added 3000 ml of acetone and stirred for 10 minutes. The resulting precipitate was filtered off and then purified by chromatography (RP-18 eluent: gradient with water / ethanol / acetonitrile).

Yield: 28.45 g (79% of theory) as a colorless solid.

H ₂ O - content: 11.0%

Elemental analysis: (calculated as anhydrous substance) calculated: C 34.41 H 3.83 N9.03 F 23.13 S 2.30 Gd 11.26 found: C 34.34 H 3.98 N 9.19 F23.29 S 2.15 Gd 11.07 Example 37

a) 6-N-Benzyloxycarbonyl-2-N [1-Oa-Dcarbonylmethyl- (2,3,4-tri-O-benzyl glucuronic acid) benzyl ester] - Lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] - amide

To a solution of 100.0 g (120.4 mol) of the title compound of Example 1c), 73.77 g (120.4 mol) of 1-Oa-Dcarbonylmethyl-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 N, N-dicyclohexylcarbodiimide. Stirred for 3 hours at 0 ° C and overnight at room temperature. The urea precipitate was filtered off, the filtrate was concentrated in vacuo to

138 was dried and chromatographed on silica gel (eluent: dichloromethane / ethanol = 20: 1).

Yield: 147.58 g (86% of theory) as a thick oil.

Elemental analysis:

calculated: C 52.25 H 4.31 N 3.93 F 22.66 S 2.45 found: C 52.38 H4.17 N4.12 F 22.78 S 2.39

b) 2-N- [1-0-a-0-carbonylmethyl-glucuronic acid] - L-lysine [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

143.52 g (100.0 mmol) of the Q compound of the title of Example 37a was dissolved in 2000 ml of ethanol and 10.0 g of palladium catalyst (10% Pd / C) was added thereto. Hydrated for 12 hours at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 93.06 g (quantitative) as a colorless solid. Elemental analysis:

Calculated: C 33.56 H 3.36 N 6.02 F 34.71 S 3.45 Found: C 33.31 H 3.42 N 6.04 F 35.51 S 3.40

c) No. [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacycododecane] -10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-

Cyl)] - N, N - [1-O-a-O-carbonylmethyl-glucuronic acid] -Lysine [1- (4-perfluoroctylsulfonyl) -piperazine] -amide, Gd complex, sodium salt

50.76 g (54.55 mmol) of the title compound of Example 37b), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mmol) of 1,4,5-tris (carboxylatomethyl) -10 [carboxy-3-aza-4-oxo-5-methyl-pent-5-yl) -1,4,7,10-tetraazacyclododecane, Gd complex was dissolved in 200 ml of dimethyl sulfoxide under gentle warming. At 10 ° C, 16.88 g (81.8 mmol) Ν, Νcyclohexylcarbodiimide were added and the reaction mixture was stirred for 12 hours at room temperature. To this suspension was added 3000 ml

139 acetone and stirred for 10 minutes. The resulting precipitate was filtered off and then purified by chromatography (RP-18 eluent: gradient with water / ethanol / acetonitrile).

Yield: 14.9 g (88% of theory) as a colorless solid.

H ₂ O - content: 8.6%

Elemental analysis: (calculated as anhydrous substance) calculated: C 34.53 H 3.80 N8.05 F 20.63 S 2.05 Gd 10.05 Na 1.47 found: C 34.38 H 3.95 N8.19 F 20.83 S 2.15 Gd 10.14 Na 1.63 Example 38

w. ·

a) 6-N-Benzyloxycarbonyl-2-N- [2- (1-ethyl-Perfluorooctylsulfonyl) -amino] -acetyl-1-lysine

To 82.0 g (113.5 mmol) of 6-N-benzyloxycarbonyl-L-lysine and 66.42 g (113.5 mmol) of 2- (N-ethyl-1-perfluoroctylsulfonyl) -aminoacetic acid (prepared according to DE 196 03 033) in 300 ml of tetrahydrofuran, 49.46 g (200.0 mmol) of EEDQ [ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester] were added at 0 ° C and allowed to stir overnight at room temperature. The mixture was evaporated to dryness in vacuo and the residual oil was purified on silica gel eluting with a dichloromethane / methanol = 20: 1 mixture).

Yield: 55.79 g (58% of theory) as a colorless solid.

Elemental analysis:

calculated: C 36.85 H 3.09 N4.96 F 38.11 S 3.78 Found: C 36.85 H3.19 N4.87 F 38.28 S 3.95

b) 6-N-Benzyloxycarbonyl-2-N [2- (N-ethyl-N-perfluoroctylsulfonyl) -amino] -acetyl-1-lysine-N-Menw-N (2,3,4,5,6-pentahydroxyhexyl) -amide

To a solution of 51.02 g (60.2 mol) of the title compound of Example 38a), 11.75 g (60.2 mol) of N-methyl-glucamine and 6.93 g (60.2 mol)

140

N-hydroxysuccinimide dissolved in 250 ml of dimethylformamide was added at 0 ° C 20.64 g (100.0 mmol) of N, N-dicyclohexylcarbodiimide. Stirred for 3 hours at 0 ° C and overnight at room temperature. The precipitated urea was filtered off, the filtrate was evaporated in vacuo to dryness and the residue was chromatographed on silica gel (eluent: dichloromethane / ethanol = 20: 1).

Yield: 53.05 g (86% of theory) as a viscous oil.

Elemental analysis:

calculated: C 38.68 H 4.03 N5.47 F 31.52 S 3.13 found: C 38.49 H 4.17 N5.32 F31.70 S 3.29

c) 2-A [2- (4-ethyl-Aperfluoroctylsulfonyl) -amino] -acetyl-1-lysineAmethylA (2,3,4,5,6-pentahydroxyhexyl) -amide

In 2000 ml of ethanol was dissolved 102.48 g (100.0 mmol) of the title compound of Example 38b) and 10.0 g of palladium catalyst (10% Pd / C) was added thereto. Hydrated for 12 hours at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 89.06 g (quantitative) as a colorless solid.

Elemental analysis:

calculated: C 33.72 H 3.96 N 6.29 F 36.26 S 3.60 found: C 33.91 H3.82 N6.14 F 36.31 S 3.47

d) No. [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecane] -10A (pentanoyl-3-aza-4-oxo-5-methyl-5yl)] - 2A [2-aethyl- N-perfluoroctylsulfonyl) -amino] -acetyl-1-lysineAmethylA (2,3,4,5,6-pentahydroxyhexyl) -amide, Gd complex

48.58 g (54.55 mmol) of the title compound of Example 38c), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54.55 mol) of 1,4,5-tris (carboxylatomethyl) -10 (carboxy-3-aza-4-oxo-5-methyl-pent-5-yl) -1,4,7,10-tetraazacyclo141 dodecane, Gd complex was dissolved under gentle warming in 400 ml of dimethyl sulfoxide. At 10 ° C, 16.88 g (81.8 mol) Ν, Νcyclohexylcarbodiimide were added and the reaction mixture was stirred for 12 hours at room temperature. The solution thus obtained was poured into 3000 ml of acetone and stirred for 10 minutes. The resulting precipitate was filtered off and then purified by chromatography (RP-18 eluent: gradient with water / ethanol / acetonitrile).

Yield: 73.27 g (89.4% of theory) as a colorless solid.

H ₂ O - content: 8.6%

Elemental analysis: (calculated as anhydrous substance) calculated: C 35.18 H 4.23 N4.23 F21.50 S 2.13 Gd 10.47 found: C 35.28 H 4.15 N4.19 F21.33 S 2.18 Gd 10.61 Example 39

Organ distribution (including accumulation in tumors and lymph nodes) after intravenous administration of the contrast agent of the invention of Example 1 in rats with prostate cancer

After intravenous administration of 225 μmol total gadolinium / kg body weight of the compound of the title of Example 1 in rats (CoryInzucht, on which 12 days pre-implanted muscle prostate carcinoma Dunning R3327 MAT-Lu) was determined 10 minutes, 1 and 24 hours after administration metal content in different organs, in the tumor as well as in the lymph nodes (collected as mesenteric and peripheral lymph nodes) (MW ± SD, n = 3).

Table

the title compound of Example 1 Gd concentration (μmol / l) 5 doses of total tissue 10 min 1 hour 24 hours 10 min 1 hour 24 hours black 387 ± 26 368 ± 8 746 ± 34 5.46 ± 5.81 ± 11.65 ±

142

the title compound of Example 1 Gd concentration (μmol / l) 5 doses of total tissue 10 min 1 hour 24 hours 10 min 1 hour 24 hours fraction 0.16 0.16 0.97 springs 548 ± 22 487 ± 25 645 ± 27 0.39 ± 0.39 ± 0.39 ± 0.03 0.02 0.03 pancre- 229 ± 27 199 ± 30 150 ± 13 0.26 ± 0.21 ± 0.17 ± as 0.05 0.05 0.02 kidney 208 ± 537 883 ± 94 1178 ± 5.02 ± 2.15 ± 2.97 ± 139 1.29 0.23 0.21 lung 837 ± 32 658 ± 29 370 ± 34 1.69 ± 1.38 ± 0.73 ± 0.06 0.08 0.04 heart 438 ± 29 289 ± 24 131 ± 9 0.46 ± 0.31 ± 0.14 ± 0.01 0.03 0.02 brain 47 ± 13 26 ± 5 14 ± 2 0.15 ± 0.08 ± 0.04 ± 0.03 0.02 0.00 muscle 99 ± 5 78 ± 1 36 ± 1 0.11 ± 0.09 ± 0.04 ** 0.03 0.03 ± 0.00 tumor 185 ± 36 184 ± 13 199 ± 19 0.28 ± 0.21 ± 0.31 ± 0.10 0.10 0.01 thigh 184 ± 4 127 ± 9 87 ± 6 0.65 ± 0.46 ± 0.31 ± 0.01 0.03 0.03 mes.lim. 359 ± 72 697 ± 42 854 ± 135 0.11 ± 0.24 ± 0.32 ± nodes 0.04 0.02 0.04 peripheral 229 ± 15 436 ± 44 373 ± 24 0.10 ± 0.20 ± 0.18 nodes 0.01 0.03 ± 0.01 stomach 231 ± 10 219 ± 46 138 ± 9 0.57 ± 0.54 ± 0.37 ± (blank) 0.04 0.12 0.06

143

the title compound of Example 1 Gd concentration (μmol / l) 5 doses of total tissue 10 min 1 hour 24 hours 10 min 1 hour 24 hours gut (empty) 342 ± 16 409 ± 67 243 ± 22 2.91 ± 0.18 3.41 ± 1.02 2.14 ± 0.14 blood 166 ± 110.5 825 ± 67 214 ± 9 42.95 ± 2.59 21.47 ± 1.78 1.78 ± 0.03 remain. bodies 225 ± 31 30.83 ± 4.05 urine 0-24 hrs 94 ± 20 20.20 ± 4.41 faeces 0-24 hrs 3128 ± 204 21.85 ± 1.46

* 58 ml of blood / kg body weight ** only tissue aliquots from the right calf *** sum of organs 10 and 60 minutes after implantation

With no solids ****, residual bodies also contain residual blood

Example 40

Imaging of lymph nodes (MRT) after intravenous administration of contrast agent of the invention of Example 1 in rabbits bearing VX-2 tumors

1 shows the MR images of iliac lymph nodes contrasted and up to 24 hours after intravenous administration of 200 μmol Gd / kg body weight of the title compound of Example 1 in rabbits with an intramuscularly implanted VX-2 tumor. T _g weighted gradient echo (1.5 T; sequence:

144

MPRange; TR 11.1 ms, TE 4.3 ms, a 15 °) explain the strong signal increase in healthy lymph node tissue. Areas without signal enhancement inside the lymph node are diagnosed as metastases and confirmed histologically (H / E - lymphatic staining). Later (24 h) after contrast application, in contrast, signal reversal can surprisingly be observed. Signal enhancement in healthy lymphatic tissue decreases, while metastasis shows a clear increase in signal.

Surprisingly, immediate enhancement of the primary tumor (especially in the periphery) can be clearly observed immediately after administration. At a later time (24 hours after administration), this Enhancement also extends toward the tumor center.

Example 41

Infarction imaging (MRT) after intravenous administration of the contrast agent of the invention of Example 1 in rats

The images in Figure 2 show MR images of the heart (in vivo and post mortem) 24 hours after intravenous administration of 100 μmol Gd / kg body weight of the compound of the title of Example 1 in rabbits with induced heart attack. T _g aggravated Spin-ehosnimki (1.5 T; TR: 400 ms, TE 6 ms; ΝΑ: 4; Matrix: 128 * 128; layer thickness: 2.5 mm) showed a strong increase of the signal in the area of infarct. Successful induction of acute myocardial infarction is confirmed by NBT staining.

Claims (1)

1. Perfluoroalkylated complexes with sugar residues of general formula I (K), - G - (Z ^ m (Y-R) p in which: R represents a mono- or oligosaccharide moiety which is attached via the 1-OH or 1-SH-position, R _f denotes a perfluorinated, straight or branched carbon chain of formula -C _n F _2n E in which E is at the end a fluorine, chlorine, bromine, iodine or hydrogen atom and η stands for the numbers 4 - 30, K means a metal complex of general formula II in which: R ¹ represents hydrogen or the metal ion equivalent of the numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83; provided that at least two R ¹ denote metal ion equivalents; R ² and R ³ independently represent hydrogen, C 1-6 alkyl, benzyl, phenyl, -CH ₂ OH or -CH ₂ OCH ₃ and U means -Ο ₆ Η ₄ -Ο-ϋΗ ₂ -ω-, - (ΟΗ ₂ ) μ ₅ -ω, phenyl group, -CH ₂ NHCO-CH ₂ -CH (CH ₂ COOH) -C ₆ H ₄ -co -, -C ₆ H ₄ - (O-CH ₂ CH 2) o <N (CH ₂ COOH) 146 CH ₂ -co or optionally interrupted by one or more oxygen atoms, 1 to 3-NHCO-, 1 to 3-CONH-rpynn and / or by 1 to 3- (CH _{2) 0. 5-} COOH substituted C 1-6 alkylene or C ₇ . ₁₂ -C ₆ H ₄ -O-group, wherein ω denotes the binding site to -CO-, or of the general formula III> COOR ¹ COOR ⁴ n R ¹ OOC ^Z \ / ^Ν ^ \ Χ ^C00R1 (III) in which R ¹ has the above meanings, R ⁴ is hydrogen or the metal ion equivalent described in R ¹ and U ¹ is -C ₆ H ₄ -O-CH ₂ ω-, wherein ω denotes the point of attachment to -CO-, or of the general formula IV in which R ¹ and R ² have the above meanings or the general formula VA or VB 147 ROOC COOR ¹ -COOR ¹ ^ YaAAJUUL * COOR ¹ (VA) COOR ¹ -COOR ¹ COOR ¹ COOR ¹ (VB) in which R ¹ has the above meanings or of the general formula VI ROOC COOR ¹ N R ¹ OOC-- ^/ N. COOR ¹ (VI) in which R ¹ has the above meanings or of the general formula VII ROOC R ¹ OOC R ¹ OOC (VII) in which R ¹ has the meanings given above and U ¹ means -C ₆ H ₄ -O-CH ₂ -a> -, where ω denotes the binding site to -CO-, or by the general formula VIII 148 COOR ¹ COOR ¹ AWAV H (VIII) in which R ¹ has the above meanings and in the remainder K optionally available free acid groups may optionally be as salts of organic and / or inorganic bases or amino acids or amides of amino acids, G in the case where K denotes the metal complexes II to VII, it means at least three times a functionalized residue selected from the following residues a) to j):