BG107541A - Complexes containing perfluoroalkyl with polar radicals, method for the production and use thereof - Google Patents

Abstract

The invention relates to complexes containing perfluoroalkyl with polar radicals of gerneral formula wherein R represents the polar radicals, Rf is a perfluorated carbon chain, K is a metal complex and Z is a linker group. The inventive complexes are suitable for intraveenous lymphography, tumour diagnosis and infarct and necrosis imaging. 21 claims

Description

Technical field

The invention relates to perfluoroalkyl-containing metal complexes with polar residues of general formula I, to a method for their preparation and use in MRI and X-ray diagnostics, radiodiagnosis and radiotherapy, MRT lymphography, and vascular imaging (blood -pool-agents). The compounds of the invention are 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) the fluorine has only one NMR-isotope.

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

4) 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 lead to the fact that fluorine has a great place in the diagnostic patent literature, which is the basis for 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:

CF ₃ CF ₃

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 (CH ₂ ) ₇ CH = CH (CH ₂ ) 7CO— o / --- OCO (CH ₂ ) gR \ - OCO (CH ₂ ) ₆ R

which have as fluorine residue a perfluoro-1H, 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:

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.

o +

Gd ³ and in EP 292 306 (TERUMO Kabushiki Kaisha) with for example:

CO ₂ ' ₃ + Gd 2 ^C <CF ₃ ) ₃

»

but also for cyclic compounds as mentioned in EP

292 306 (TERUMO Kabushiki Kaisha)

s o ₂ s O 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 ¹⁹ 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 [L / 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 ¹ - Plasma relaxation [Yummol. 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. A relaxation of about 4 L / mmol / sec is observed for these contrast agents in water.

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

When introducing perfluorocarbon-containing residues into a paramagnetic contrast medium, i. E. 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 methods (CT, US and MRI), lymphogenous scans of malignant tumors can only be poorly recognized, as 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 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 f · ^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, possibly uniform 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, possibly within a few hours of administration of the contrast agent, is important for radiological practice. Is needed ^w also well tolerated.

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. In the literature, attempts have been made to use porphyrins for 'necrotic imaging'. 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-M-methylpyridine) porphyrin (TMPurP ) enriches not the necrotic part but accumulates in the living end layers. It follows that porphyrin-tissue metabolism may exist, without necessarily.

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 therefore an object of the invention to develop contrast agents which 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 polar residue complexes of general formula I (K)! --- G --- (Z-Rf)

C. (R) P in which:

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 .COOR ¹

(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 represents -C ₆ H ₄ -O-CH ₂ -O-, - (CH ₃ -C, phenyl group, -CH ₂ NHCO-CH ₂ -CH (CH ₂ COOH) -C ₆ H ₄ - _W -, - C ₆ H ₄ - (O-CH ₂ CH ₂ ) _{0. 1} -N (CH ₂ COOH) CH ₂ or possibly interrupted by one or more oxygen atoms, 1 to 3-NHCO-, 1 to 3- CSS \ 1H-groups and / or by 1 to 3- (CH _{2) 0. 5} -COOH substituted C _H2 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

COOR ⁴ ^ (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-, where ω means the binding site to -CO-, or of the general formula IV

or the general formula VA or VB

ROOC

COOR ¹ -COOR ¹

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— \ \ / —COOR ¹

N N

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

R100C

R ¹ OOC

R ¹ OOC - \ /

N

R ¹ OOC

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

U ¹ denotes -C ₆ H ₄ -O-CH ₂ - (o-, wherein ω denotes the binding site to -CO-, 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 means at least three times a functionalized residue selected from the following residues a) to e):

(a)

(B) (C)

(d) (f)

γ

CO., LTD

OS

Η 11

N— (CH ₂ ) ₄ - C— NH — CO-C— (CH ₂ ) ₄ - N ““ 'β η II ^H

CO NH (g)

Hl · / \ lH ci Y β (h) γ — co (cn ₂ ) ₂ _ ₃ —chco - β

NH a

(i) β --- CO (CH ₂ ) ₂ _ ₃ --- CHCO --- Y

NH (h) when G represents the residue (c) or (d) and R represents a complex selected from general formulas II and V, then R must not be identical with the residue K of the general formula I when Z represents yC (O) CH ₂ -O- (CH ₂ ) ₂ -SO ₂ -8, where a denotes the binding site of G to the complex K, β is the binding site of G to the residue R and γ is the binding site of G to the residue Ζ

Ζ means

SO ₂ - ^ε γ - C (O) CH ₂ -O- (CH ₂ ) ₂ -SO ₂ -ε in which γ is the binding site of Ζ to the residue G and ε is the binding site of Ζ to the perfluorinated residue R _f

R represents a polar moiety selected from the complexes K of general formulas II through VII, in which R ¹ here represents hydrogen or the metal ion equivalent of the numbers 20-29, 31-33, 37-39, 42-44, 49 or 57-83 ;

and the residues R ² , R ³ , R ⁴ , U and U ¹ have the meanings already mentioned, where if G is the residue (c) or (d) and R represents a complex selected from the general formulas II and V, then R it must not be identical with the residue K of the general formula I when Z represents yC (O) CH ₂ -O- (CH ₂ ) ₂ -SO ₂ -s, or a folic acid residue or carbon chain which is bonded through -CO-, SO ₂ or directly linked to the G carbon chain with 2 -30 C atoms, straight or branched, saturated or unsaturated, optionally interrupted by 1 - 10 oxygen atoms, 1-5 -NHCO groups, 1-5 -CONH groups, 1-2 sulfur a Ohms, 1-5 -NH-group or 1-2 phenyl groups, which may optionally be substituted with 1-2 OH groups, 1-2 NH ₂ groups, 1 -2 -COOH groups or 1 -2 -SO ₃ H-rynyn or optionally substituted with 1-8 OH-groups, 1-5-COOH-groups or 1-2 SO ₃ H-rynyn, 1-5 NH ₂ groups, 1-5 C 1-6 -alkoxy groups, and

I, m, p independently denote an integer 1 or 2.

If the compound of the invention is intended for use in MRI 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 (H) -, 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 (1P) - 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 (P) -, iron (H) -, iron (III) -, praseodymium (III) -, neodymium (III), samarium (III), gadolinium (III) -, ytterbium (III) or bismuth (III), especially dysprosium (III) and 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, III, VB or VII.

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-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl. Preferably R ² F and R ³ independently represent hydrogen or C _1-4 alkyl.

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 in a preferred embodiment the complex K, wherein it is preferably a Gd ³⁺ or Mn ²⁺ complex, but may also be a Ca ²⁺ complex. Particularly preferred are all polar residues R of the complexes K of general formulas II, III, VA or VII. Most preferred are those with R ¹ having a C> metal ion equivalent of 20, 25 or 64.

In a particularly preferred embodiment, the polar residue R has the following meanings:

-C (O) CH ₂ CH ₂ SO ₃ H

-C (O) CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ OH

-C (O) CH ₂ OCH ₂ CH ₂ OH

-C (O) CH ₂ OH ₂ CH (OH) CH ₂ OH

-G (O) CH ₂ NH-C (O) CH ₂ COOH

-C (O) CH ₂ CH (OH) CH ₂ OH

-C (O) CH ₂ OCH ₂ COOH

-SO ₂ CH ₂ CH ₂ COOH

-C (O) -C ₆ H ₃ - (t-COOH) ₂

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

-C (O) CH ₂ O-C ₆ H ₄ - m-SO ₃ H

-C (O) CH ₂ NH-C (O) CH ₂ NH-C (O) CH ₂ OCH ₂ COOH

-C (O) CH ₂ OCH ₂ CH ₂ OCH ₂ COOH -C (O) CH ₂ OCH ₂ CH (OH) CH ₂ O- CH ₂ CH ₂ OH -C (O) CH ₂ OCH ₂ CH (OH) CH ₂ OCH ₂ -CH (OH) - CH ₂ OH -C (O) CH ₂ SO ₃ H.

-C (O) CH ₂ CH ₂ COOH

-C (O) CH (OH) CH (OH) CH ₂ OH

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

-C (O) CH ₂ O [(CH ₂ ) ₂ O] ₁ . ₉ -H

-C (O) CH ₂ OCH (CH ₂ OH) ₂

-C (O) CH ₂ OCH (CH ₂ OCH ₂ COOH) ₂

-C (O) - C ₆ H ₃ - (t-OCH ₂ COOH) ₂

-C (O) CH ₂ O- (CH ₂ ) ₂ O- (CH ₂ ) ₂ O- (CH ₂ ) ₂ O- (CH ₂ ) ₂ O-CH ₃ mainly -C (O) CH ₂ O [( CH ₂ ) ₂ O] ₄ -CH ₃ .

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

Of the compounds of the invention of general formula I, further preferred are those wherein R _f is -C _n F ₁₇ and η is preferably a number 4-15. Particularly preferred are residues -C ₄ F ₉ C ₆ F ₁₃ -C ₈ F ₁₇ and -C ₁₄ F ₂₉ as well as the compounds of the examples.

At least three times functionalized residue G in the general formula

I, which constitutes the "ticks", represents in a preferred embodiment of the invention the lysine residue (a) or (b).

Z denotes, in general formula I, the linker (linking group) at which the residue / - \

Y --- Ν. N --- SO ₂ --- ^ε is preferred.

Perfluoroalkyl containing metal complexes with polar residues of general formula I (Kh-G- (Z-Rf) (R) p (I, in which K, G, R, Z, R _f , m, p and I are as defined in the above meanings are obtained in a manner known per se by carboxylic acid of the general formula IIa

in which R ⁵ denotes a metal ion equivalent of 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or a carboxyl protecting group and R ² , R ³ and U have the meanings mentioned or a carboxyl an 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

wherein R ⁵ and R ² are as defined above or a carboxylic acid of the general formula Va or Vb

COOR ⁵

COOR ⁵

-COOR ⁵ co-on

COOR ⁵

COOR ⁵ COOR ⁵

COOR5 (Va) (Vb) in which R ⁵ has the indicated meaning or a carboxylic acid of the general formula Via

R5OOC co-on

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

R5OOC

R ⁵ OOC

R ⁵ OOCR ⁵ OOC (Vila) wherein R ⁵ h U ¹ have the meanings already mentioned, optionally reacted with an amine of general formula VIII

HG- (Z-Rf) _m ^(R) P (VIII) in which G, R, Z, R _f , m and p have the meanings indicated above, in the coupling reaction and possibly after subsequent cleavage of a possibly protecting group converted into a metal complex of the 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 in a known manner in at least one metal oxide or metal salt of an element with in sequence 21 - 29, 31 - 33, 37 - 39, 42 - 44, 49 or 57 - 83 and then, if desired, the possibly present acidic hydrogen atoms are replaced by cat. they are inorganic and / or organic bases, amino acids or amides of amino acids.

The carboxylic acids of the general formulas Na to Vila used are either known compounds or prepared by the methods described in the examples. Thus, the preparation of the carboxylic acid of the general formula Ia is known from DE 196 52 386. The preparation of the carboxylic acids of the general formula Illa can be carried out analogously to example 4 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 stage of the compounds of general formula VA is N ³ (2,6-dioksomorfolinoetil) -1 \ 1 ⁶ - (ethoxycarbonylmethyl) -3,6-diazaoktandikarboksilna acid, which is described in EP 263 059.

The compounds of general formula VB are derivatives of the isomeric diethylenetriamine-pentaacetic acid, which is linked via the acetic acid standing at the middle N atom. This DTPA is described in patents DE195 07 819 and DE 195 08 058.

Compounds of general formula VI are derivatives of N (carboxymethyl) -N- [2- (2,6-dioxo-4-morpholinyl) -ethyl] -glycine, the synthesis 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 VIII is described in detail in the examples of this application and can be carried out analogously to the methods set forth in the examples.

It is indicated that the metal complexes according to the invention are particularly suitable for MRI and X-ray diagnostics, but also for radiodiagnosis and radiotherapy. It is therefore an object of the invention to use the perfluoro-containing metal complexes of the invention with polar residues to obtain contrast agents for use in MRI and X-ray diagnostics, especially for lymphography, for tumor diagnosis and for infarct and necrotic imaging, as well as 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 YaMRkartinnoto 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, allow to determine the volume of blood in tissues, to selectively shorten the relaxation times, respectively, the blood densities and to map 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 therapeutic control in cytostatic, antiflogistic or vasodilator therapy, early recognition of insufficiently perfused, e.g. angiography for vascular diseases and recognition and diagnosis of sterile or infectious inflammations.

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 tolerable buffers (such as tromethamine), additives of complexing agents or weak complexes (such as diethylenetriaminepentanoacetic acid) or of weak complexes or those corresponding to the metal complexes of the invention Ca-complexes) or - if necessary - addition electrolytes such as sodium chloride or, if necessary, antioxidants such as ascorbic acid.

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

In principle, it is also possible for the pharmaceutical agents of the invention to be prepared 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.

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 may 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 agents 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, by increasing the signal intensity, to improve the expressive power of the image obtained by nuclear spintomography. 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 new contrast agents are completely emitted from the body, it is performed only extremely slowly.

Generally, 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 spectra.

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, at .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.

They also differ in that they are completely eliminated from the body f and are 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 the 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 the purpose

h. Variable actions of the metals contained in the complexes (such as iron or gadolinium) with ionizing radiation (eg X-ray) or with neutron radiation 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 in radiation therapy for malignant tumors (e.g., using Moessbauer effects or in 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, ²¹¹ Bi, ²¹² Bi, ²¹³ Bi and ²¹⁴ Bi, where ²¹² Bi is preferred. One suitable photon- and electron-emitting ion is ¹⁵⁸ Gd, which can be obtained from ¹⁵⁷ Gd by electron capture.

Since 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, according to ^w 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, analogously to, for example, Meglumin Diatrizoat in a quantity 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 in the intravasal space and thus have a decisive advantage over extracellular contrast agents.

Examples of carrying out the invention

Example 1a

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

100.0 g (356.7 mmol) of 6-benzyloxycarbonyl-1-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.

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

From Example 1b

2-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 800 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 = w 20: 1).

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

Elemental analysis:

Calculated: C 36.30 H 2.83 N 6.05 F 41.01 S 3.46 Found: C 36.18 H 2.94 N5.98 F 40.87 S 3.40 Example 1c β-N-benzyloxycarbonyl-L-lysine [1- (4-fluoro-quinoxy-sulfonyl) -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 N 6.75 F 38.89 S 3.86 found: C 37.55 H 3.33 N 6.68 F 38.78 S 3.81 Example 1d ^w 6-N-benzyloxycarbonyl-2-N- (3,6,9,12,15 pentaoxachexadecanoyl) -lysine [ 1- (4-perfluorooctylsulfonyl) piperazine] -amide

To 50.0 g (60.20 mmol) of the title compound of Example 1 c), 7.10 g (70 mmol) of triethylamine dissolved in 350 ml of dichloromethane was added dropwise at 0 ° C a solution of 19.93 g (70 mmol) of 3.6.9 , 12,15 pentaoxachexadecanoyl chloride in 50 ml of dichloromethane and stirred for 3 hours at 0 ° C. 200 ml of 5% aqueous hydrochloric acid was added and stirred at room temperature for 5 min. The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo to dryness. The residue is chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1)

Yield: 53.7 g (93% of theory) as a colorless, thick oil.

Elemental analysis:

calculated: C 33.83 H 4.94 N 5.84 F 3.34 S 33.69 found: C 33.75 H 5.05 N5.78 F3.29 S 33.75 Example 1e-2-N- (3,6,9,12,15-pentaoxachexadecanoyl) -Lysine [1- (4perfluorooctylsulfonyl) -piperazine] -amide

50.0 g (52.15 mmol) of the title compound of Example 1d) was dissolved in 500 ml of ethanol and 6.0 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

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

calculated: C 27.68 H 5.01 N6.79 F 39.17 S 3.89 Found: C 27.60 H 5.13 N6.68 F 39.09 S 3.81 Example 1f

6-N- [1,4,7-Tris (carboxylatomethyl)] - 1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5w yl)] - 2- P - (3,6,9,12,15-pentaoxachexadecanoyl) -Lysine [1- (4 perfluoroctylsulfonyl) piperazine] -amide, Gd-complex

20.0 g (24.25 mmol) of the title compound of Example 1 f), 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1,4,7-tris (carboxylatomethyl) ) -10 - [(3-aza-

4-Oxo-5-methyl-pent-5-yl)] - pentanoic acid 1,4,7,10-tetraazacyclododecane, Gd complex, was dissolved under gentle warming in 200 ml of dimethyl sulfoxide. At 10 ° C, 8.25 g (40 moles) 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: 28.21 g (81.0% of theory) as a colorless solid.

Water Content: 11.0%

Elemental analysis: (calculated as anhydrous substance) calculated: C 31.78 H 4.84 N8.78 F 22.49 S 2.23 Gd 10.95 found: C 31.74 H4.98 N8.69 F 22.39 S 2.15 Gd 10.87 Example 2a

3,9-bis (tert-butoxycarbonylmethyl) -3,6,9-triazaoundecane-1,11-dicarboxylic acid 6-N- [bis (tert-butyl ester) 6-carbonylmethyl] -2N- [3,6 , 9,12,15-pentaoxachexadecanoyl) -lysine [1- (4-perfluoroctylsulfonyl) piperazine] -amide To a solution of 20 g (24.08 mmol) of the title compound of Example 1e, 14.88 g (24.08 mmol) bis (tert. 3.9bis (tert -butyloxycarbonylmethyl-3,6,9-triazaoundecane-1,11dicarboxylic acid tert-butyl ester and 2.77 g (24.08 mmol) of N-hydroxysuccinimide dissolved in 150 ml of dimethylformamide was added at 0 ° C 8.25 t (40 mmol)) N, N-dicyclohexylcarbodiimide. 3 hours at 0 ° C and then overnight at room temperature The separated urea was filtered off, the filtrate was concentrated in vacuo to dryness and chromatographed on silica gel (eluent = dichloromethane / ethanol = 20: 1).

Yield: 31.61 g (91.0% of theory) as a thick oil.

Elemental analysis:

calculated: C 40.80 H 6.71 N 6.80 F 22.39 S 2.22 found: C 40.72 H 6.82 N6.75 F 22.30 S 2.14 Example 2b

6-N- [N6-carbonylmethyl-3,9-bis (carboxylatomethyl) -3,6,9triazoundecane dicarboxylic acid-1-carboxy-11 carboxylate -] - 2N- (3,6,9,12,15-pentaoxachexadecanoyl) -Lysine [1 (4-perfluorooctylsulfonyl) piperazine] -amide, Gd-complex, sodium salt (20.8 mmol) of the title compound of Example 2a were dissolved in 300 ml of trifluoroacetic acid and stirred at room temperature for 5 hours. Concentrate to dryness, take up the residue in 300 ml of water and adjust 10% aqueous NaOH pH to 2.5. 3.77 g (10.4 mmol) of gadolinium oxide were then added and stirred for 3 hours at 60 ° C. It was allowed to cool to room temperature and adjusted to pH 7.4 with sodium hydroxide. It is concentrated to dryness and the residue is purified on silica gel RP-18, eluent: gradient from water / acetonitrile).

Yield: 19.18 g (67% of theory) as a colorless amorphous solid.

Water Content: 9.8%

Elemental analysis: (calculated as anhydrous substance) calculated: C 28.80 N 4.25 N7.12 F 23.47 S 2.33 Gd 11.48 Na 1.67 found: C 28.67 H 4.34 N7.03 F 23.38 S 2.27 Gd 11.37 Na 1.74

Example For w Lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide g (24.08 mmol) of the title compound of Example 1c was dissolved in 300 ml of ethanol and 4 g of palladium catalyst (10% Pd / C) was added. . Hydrated at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 16.77 g (quantitative) as a colorless solid.

Elemental analysis:

calculated: C 31.04 H 3.04 N 8.04 F 46.38 S 4.60 found: C 30.97 H3.15 N7.98 F 46.31 S 4.51

Example 3b ^w 2,6-P, P'-bis [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl- 5yl)] - lysine- [1- (4-perfluoroctylsulfonyl) piperazine] -amide, Gdcomplex g (14.36 mmol) of the title compound of Example 3a,

3.34 g (29 mmol) of N-hydroxysuccinimide, 2.54 g (60 mmol) of lithium chloride and 18.26 g (29 mmol) of 1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl- 5-yl) 1,4,7,10-tetraazacyclododecan-6b-complex was dissolved under gentle warming in 200 ml of dimethyl sulfoxide. At 10 ° C was added

12.38 g (60 mmol) of N, N-dicyclohexylcarbodiimide 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: 19.02 g (69% of theory) as a colorless solid.

Water Content: 11.3%

Elemental analysis: (calculated as anhydrous substance) calculated: C 35.03 H 4.04 N10.21 F 16.82 S 1.67 Gd 16.38 found: C 34.96 H4.13 N10.16 F 16.74 S 1.61 Gd 16.33 Example 4a

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

To 200 g (1.204 mol) of 4-hydroxyphenylacetic acid methyl ester, 212 g (2 mol) of sodium carbonate in 2000 ml of acetone were added

233.8 g (1.4 mol) of ethyl bromoacetic acid and refluxed for 5 hours. The precipitate was filtered off and the filtrate was concentrated in vacuo to dryness. The residue was chromatographed on silica gel (eluent: n-hexane / ethyl acetate = 15: 1).

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

Elemental analysis:

calculated: C 61.90 H 6.39 found: C 61.75 H 6.51

Example 4b

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

To 285 g (1.13 mol) of the title compound of Example 4a dissolved in 2000 ml of tetrachloromethane were added 201 g (1.13 mol) of bromosuccinimide and 100 mg of dibenzyl peroxide and refluxed for 8 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% of theory) as a colorless thick oil.

Elemental analysis:

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

Example 4c

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

To 603 g (3.5 mol) of 1,4,7,10-tetraazacyclododecane in 6000 ml of chloroform were added 350 g (1.57 mol) of the title compound of Example 4b was stirred overnight at room temperature. It is extracted 3 times with 3000 ml of water, the organic phase is dried over magnesium sulfate and evaporated in vacuo to dryness. The residue was used in the next step (3d) without further purification.

Yield: 448 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

Example 4d

2- [4- (3-Oxapropionic acid)] -phenyl-2 [1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecan-10-yl] acetic acid ethyl ester

445 g (1.053 mol) of the title compound of Example 4c and

496 g (5.27 mol) of chloroacetic acid were dissolved in 4000 ml of water. With 30% aqueous sodium hydroxide solution the pH was adjusted to 10. It was heated to 70 ° C and the pH was maintained by the addition of 30% aqueous sodium hydroxide solution to 10. Then the pH was adjusted to 13 and boiled. 30 minutes at reflux. The solution was cooled in an ice bath and the pH adjusted to pH 1 by the addition of concentrated hydrochloric acid. The mixture was evaporated to dryness in vacuo. The residue was taken up in 4000 ml of methanol and stirred for one hour at room temperature. The separated sodium chloride was filtered off, the filtrate was evaporated to dryness and the residue was purified on silica gel RP-18 (eluent: gradient water / ethanol / acetonitrile).

Yield: 403.2 g (69% 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

Example 4f

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

To 400 g (721.3 mmol) of the title compound of Example 4d in 2000 ml of water was added 130.73 g (360.65 mmol) of gadolin oxide and stirred for 5 hours at 80 ° C. The solution was filtered and the filtrate was freeze-dried.

Yield: 511 g (quantitative) of an amorphous solid. Water Content: 11.0%

Elemental analysis: (calculated as anhydrous substance) calculated: C 40.67 H 4.41 N7.98 Gd 22.19 found: C 40.51 H 4.52 N 8.03 Gd 22.05 Example 4f

2,6-N, N'-bis {2- [4- (3-Oxapropionyl) -phenyl] -2- [1,4,7tris (carboxymethyl) -1,4,7,10-tetraazacyclododecan-10-yl ] acetic acid} -Lysin- [4-perfluoro-octylsulfonyl) piperazine] -amide, digadoline complex, disodium salt g (14.36 mmol) of the title compound of Example 3a, 3.45 g (30 mmol) N-hydroxysuccinimide, 2.54 g (60 mmol) of lithium chloride and 21.26 g (30 mmol) of the title compound of Example 4e were dissolved under gentle warming in 250 ml of dimethyl sulfoxide. At 10 ° C, 16.51 g (80 mmol) of Ν, Ν-dicyclohexylcarbodiimide are added and then stirred overnight at room temperature. The solution was poured into 2000 ml of acetone and stirred for 10 minutes. The resulting precipitate was filtered off and then purified by chromatography (silica gel RP-18; eluent: gradient water / ethanol / acetonitrile). It is dissolved in a little water, adjusted to pH 7.4 with sodium hydroxide and freeze-dried.

Yield: 21.02 g (69% of theory) as a colorless solid.

Water Content: 11.2%

Elemental analysis: (calculated as anhydrous substance) calculated: C 37.36 H3.66 N7.92 F 15.22 S 1.51 Gd 14.82 Na 2.17 found: C 37.28 H 3.74 N8.19 F 15.14 S 1.46 Gd 14.75 Na 2.23

Example 5a

2,6-N-bis- [6-carbonylmethyl-3,9bis (tert-butyloxycarbonylmethyl) -3,6,9-triazaoundecane-1,11 dicarboxylic acid bis (tert-butyl ester) - lysine - [1- (4-perfluorooctylsulfonyl) piperazine] -amide

To a solution of 10 g (14.36 mmol) of the title compound of Example 3a, 18.53 g (30 mmol) of bis (tert -bugyl ester) of 3.9bis (tert-butyloxycarbonylmethyl) -6- (carboxymethyl-3,6, 9triazoundecane-1,11-dicarboxylic acid and 3.45 g (30 mmol) Nhydroxysuccinimide dissolved in 150 ml dimethylformamide was added at 0 ° 10.32 g (50 mmol) N, N -dicyclohexylcarbodiimide and stirred for 3 hours at 0 ° C. 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 / ether). ol = 20: 1).

Yield: 19.60 g (72% of theory) as a colorless thick oil.

calculated: C 49.41 H 6.75 N 7.39 F 17.03 S 1.69 found: C 49.35 H 6.82 N7.32 F 16.92 S 1.62 Example 5b

2,6-H, N'-bis- [6-carbonylmethyl-3,9-bis (carboxylatomethyl) -3,6,9triazoundecandicarboxylic acid -1-carboxy-11carboxylato-lysine- [1- (4-perfluorooctylsulfonyl) - piperazine ] amide, gadolin complex, sodium salt] g (7.91 mol) of the title compound of Example 5a was dissolved in 50 ml of chloroform and 200 ml of trifluoroacetic acid was added. Stirred for 10 min at room temperature. Evaporate in vacuo to dryness and dissolve the residue in 150 ml of water. 2.87 g (7.91 mmol) of gadoline oxide were added and stirred for 5 hours at 80 ° C. It was allowed to cool to room temperature and the pH was adjusted to 7.4 with 2 N NaOH. The solution was evaporated in vacuo to dryness and the residue was purified on silica gel RP-18 (eluent: gradient water / ethanol / acetonitrile).

Yield: 8.11 g (57% of theory) as a colorless amorphous solid.

Water Content: 9.6%

Elemental analysis: (calculated as anhydrous substance) calculated: C 30.70 H 3.08 N7.78 Na 2.56 S 1.78 Gd 17.48 Found: C 30.58 H3.19 N7.71 Na 2.68 S 1.72 Gd 17.42 Example 6a

4-N-Benzyloxycarbonyl-2-N- [6carboxymethyl-3,9-bis (tert-butyloxycarbonylmethyl) -3,6,9triazoundecane-1,11-dicarboxylic acid bis (tert -bugyl ester) bis-lysine- [1- (4-Fluorooctylsulfonyl) -piperazine] -amide

3,6,9-triazaoundecane-1,11-dicarboxylic acid] -Lysin- [1- (4perfluorooctylsulfonyl) -piperazine] -amide, Gd-complex r (15.43 mmol) of the title compound of Example 6b, 1.78 g (15.43 mmol) N-hydroxysuccinimide, 1.48 g (35 mmol) lithium chloride and 9.72 g (15.43 mmol) 1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) - pentanoic acid-1,4,7,10-tetraazacyclododecaneGd-complex was dissolved under gentle warming in 150 ml of dimethyl sulfoxide. At 10 ° C, 5.16 g (25 mmol) of Νdicyclohexylcarbodiimide was added and then stirred overnight at room temperature. The solution was poured into 2500 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: 22.94 g (78% of theory) as a colorless solid.

Water Content: 7.9%

Elemental analysis: (calculated as anhydrous substance) calculated: C 42.22 H 5.29 N8.82 F 16.95 S1.68 Gd 8.25 Found: C 42.15 H 5.41 N8.70 F 16.87 S 1.60 Gd 8.13 Example 6d

6-N- [1,4,7-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododecan-10 (3-aza-4-oxo-5-methyl-5-yl-pentanoyl)] - 2- N- [6-carbonylmethyl-3,9bis (carboxylatomethyl) -3,6,9-triazaoundecane dicarboxylic acid-carboxy-11-carboxylato-1] -lysine- [1- (4perfluorooctylsulfonyl) -piperazine] -amide, digadoline complex, The sodium salt d (10.49 mol) of the title compound of Example 6c was dissolved in 200 ml of trifluoroacetic acid. Stirred for 60 min at room temperature. Evaporate in vacuo to dryness and dissolve the residue in 150 ml of water. 1.90 g (5.25 mmol) of gadoline oxide was added and stirred for 5 hours at 80 ° C. It was allowed to cool to room temperature and the pH was adjusted to 7.4 with 2 N NaOH. The solution 'was evaporated in vacuo to dryness and the residue was purified on silica gel RP-18 (eluent: gradient water / ethanol / acetonitrile).

Yield: 11.89 g (61% of theory) as a colorless amorphous solid.

Water Content: 10.2%

Elemental analysis: (calculated as anhydrous substance) · Calculated: C 32.97 H 3.47 N9.05 Na 1.24 S 1.73 Gd 16.87 F 17.39 Found: C 32.90 H 3.53 N8.93 Na 1.33 S 1.67 Gd 16.87 F 17.31

Example 7a

5,6-Bis (benzyloxy) -3-oxa-hexanoic acid tert-boiling ester

100 g (376.2 mmol) of 1,2-di-O-benzyl-glycerol (prepared according to Chem. Phys. Lipidis (1987), 43 (2), 113 - 127) and 5 g of tetrabugylammonium hydrogen sulfate were dissolved in a mixture of 400 ml of toluene and 200 ml of a 50% aqueous solution of NaOH. At 0 ° C for 30 minutes, 78 g (400 mmol) of 2-bromoacetic acid tert-butyl ester were added dropwise and stirred at 0 ° C for 3 hours. The organic phase was separated, dried over magnesium sulfate and concentrated. under vacuum to dry. The residue is chromatographed on silica gel. (Eluent: n-hexane / acetone = 20: 1).

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

Elemental analysis:

calculated: C 71.48 H 7.82 found: C 71.61 H 7.92 Example 7b

5,6-bis (benzyloxy) -3-oxa-hexanoic acid

130 g (336.4 mmol) of the title compound of Example 7a were dissolved in 200 ml of dichloromethane and 100 ml of trifluoroacetic acid were added thereto at 0 ° C. It was stirred for 4 hours at room temperature and then evaporated to dryness. The residue was recrystallized from pentane / diethyl ether.

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

Elemental analysis:

calculated: C 69.07 H 6.71 found: C 69.19 H 6.82

Example 7c

6-N-benzyloxycarbonyl-2-N- [1,4,7-tris (carboxylatomethyl) -

1,4,7,10-Tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5methyl-5-yl)] - lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] amide, Gd-complex g (60.20 mmol) of the title compound of Example 1c, 6.93 g (60.20 mmol) of N-hydroxysuccinimide, 5.09 g (120 mmol) of lithium chloride and 37.91 g (60.20 mmol) of 1,4,7-tris (carboxylatomethyl) -1, The 4,7,10tetraazacyclododecane-10-pentanoyl-3-aza-4-oxo-5-methyl-5-yl) complex was dissolved under gentle warming in 400 ml of dimethyl sulfoxide. At 10 ° C, 20.63 g (100 mmol) of N, N-dicyclohexylcarbodiimide 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: 75.53 g (87% 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 2.22 Gd 10.75 Example 7d

2-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,1048 tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5methyl-5-yl)] - lysine- [1 - (4-perfluorooctylsulfonyl) -piperazine] amide, Gd-complex g (48.53 mmol) of the title compound of Example 7c were dissolved in 500 ml water / 100 ml ethanol and 5 g palladium catalyst (10% Pd / C) was added. . Hydrates at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 63.5 g (quantitative) as a colorless solid.

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 Example 7f

6-N- [5,6-bis (benzyloxy) -3-oxahexanoyl] -2-N- [1,4,7tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10 (pentanoyl-3-aza) -4-oxo-5-methyl-5-yl)] - lysin- [1- (4-fluorooctylsulfonyl) -piperazine] -amide, Gd-complex r (7.64 mmol) of the title compound of Example 7d, 3.30 g (10 mmol) ) from the title compound of Example 7b, 0.85 g (20 mmol) of lithium chloride and 1.15 g (10 mmol) of N-hydroxysuccinimide were dissolved under gentle heating in 150 ml of dimethyl sulfoxide. At 10 ° C, 3.10 g (15 mmol) of Ν'-dicyclohexylcarbodiimide are added and then stirred for 8 hours at room temperature. The solution was poured into 2000 ml of acetone and the separated precipitate was isolated. It was purified by chromatography (silica gel RP-18; eluent: gradient from water / ethanol / acetonitrile).

Yield: 11.14 g (90% of theory) as a colorless, amorphous solid.

Water Content: 4.3%

Elemental analysis: (calculated as anhydrous substance) calculated: C 41.51 H 4.29 N7.78 F 19.93 S 1.98 Gd 9.70 found: C 41.45 H 4.38 N7.70 F 19.84 S 1.90 Gd 9.58 Example 7f

6-N- [5,6-bis (benzyloxy) -3-oxahexanoyl] -2-No [1,4,7tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10 (pentanoyl-3-aza- 4-Oxo-5-methyl-5-yl)] - lysine- [1- (4-fluorooctylsulfonyl) -piperazine] -amide, Gd-complex r (6.17 mmol) of the title compound of Example 7e were dissolved in 200 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) were added. Hydrated at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 8.89 g (quantitative) as a colorless solid.

Water Content: 3.1%

Elemental analysis: (calculated as anhydrous substance) calculated: C 35.03 H 3.99 N8.75 F 22.42 S 2.23 Gd 10.92 found: C 34.35 H4.12 N8.71 F 22.30 S 2.18 Gd 10.78 Example 8a

6-N-Benzyloxycarbonyl-2-N- [5,6-bis (benzyloxy) -3-oxahexanoyl] -lysine- [1- (4-perfluorocysulfonyl) piperazine] -amide To a solution of 20 g (24.08 mmol) of the compound from the title of Example 1 c, 9.91 g (30 mmol) of the title compound of Example 7b and 3.45 (30 mmol) N-hydroxysuccinimide dissolved in 100 ml of dimethylformamide was added at 0 ° C 9.28 g (45 mmol) Ν, Νcyclohexylcarbodiimide. 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: 24.50 g (89% of theory) as a thick oil.

Elemental analysis:

calculated: C 47.29 H4.14 N4.90 F 28.26 S 2.81 found: C 47.14 H 4.26 N4.91 F 28.17 S 2.69 Example 8b 2-No [5,6-bis (benzyloxy) -3-oxa-hexanoyl] -lysine - [1- (4perfluoroctylsulfonyl) piperazine] -amide g (17.5 mmol) of the title compound of Example 8a was dissolved in 300 ml of ethanol and 5 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 17.65 g (quantitative) as a colorless solid.

Elemental analysis:

calculated: C 44.05 H4.10 N5.55 F 32.02 S 3.18 Found: C 43.96 H 4.21 N 5.48 F 31.94 S 3.24 Example 8c

2-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] lysine- [1 - (4-perfluorooctylsulfonyl) -piperazine] -amide,

Gd-complex g (14.87 mmol) of the title compound of Example 8b, 1.73 g (15 mmol) of N-hydroxysuccinimide, 1.27 g (30 mmol) of lithium chloride and 9.48 g (15 mmol) of 1,4,7-tris (carboxylatomethyl) ) -10- (3-aza-4-oxo-5methyl-5-yl) -pentanoic acid-1,4,7,10-tetraazacyclododecane, Gdcomplex is dissolved under gentle warming in 100 ml of dimethyl sulfoxide. At 10 ° C, 5.16 g (25 mmol) of N, N-dicyclohexylcarbodiimide were added and then stirred overnight at room temperature. The solution was poured into 1500 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: 19.28 g (80% of theory) as a colorless solid.

Water Content: 10.3%

Elemental analysis: (calculated as anhydrous substance) calculated: C 41.51 H 4.29 N7.78 F 19.93 S 1.98 Gd 9.70 found: C 41.37 H 4.40 N7.67 F 19.88 S 1.85 Gd 9.58 Example 9a

6-N-benzyloxycarbonyl-2-N- [2,6-N, N'-bis (benzyloxycarbonyl) lysyl] -lysin- [1- (4-perfluorooctylsulfonyl) piperazine] -amide d (24.08 mmol) of the title compound of Example 1c and 2.53 g (25 mmol) of triethylamine were dissolved in 200 ml of tetrahydrofuran (THF) and 14.46 g (27 mmol) of di-N, N'-N-lysine-paritrophenic ester were added. The mixture was stirred for 5 hours at 50 C. The mixture was evaporated to dryness in vacuo and the residue was chromatographed on silica gel. Eluent: dichloromethane / methanol = 20: 1).

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

Elemental analysis:

calculated: C 46.99 H4.19 N6.85 F 26.32 S 2.61 found: C 47.08 H 4.32 N 6.75 F 26.21 S 2.54 Example 9b 2-N (lysyl) -Lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide , trihydrobromide

To 25 g (20.37 mmol) of the title compound of Example 9a were added 100 ml of hydrobromic acid in glacial acetic acid (48%) and stirred for 2 hours at 40 ° C. Cooled to 0 ° C, 1500 ml of diethyl was added. the ester and the precipitate separated is filtered off. Drying under vacuum (60 ° C) gave 21.52 g (99% of theory) of a pale yellow colored crystalline solid.

Elemental analysis:

calculated: C 27.01 H 3.40 N 7.87 F 30.26 S 3.00 Br 22.46 found: C 26.92 H 3.53 N7.69 F 30.14 S 2.87 Br 22.15

Example 9c

2-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] 2-N- [2,6-N, N'-6nc- [1,4,7-tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5 -yl)] lysyl] -lysine- [1- (4-perfluoroctylsulfonyl) piperazine] -amide, trigadoline complex

31.49 g (50 mmol) of 1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-

5-methyl-5-yl) -pentanoic acid, Gd-complex, 6.91 g (60 mmol) of Nhydroxysuccinimide and 4.24 g (100 ml of lithium chloride were dissolved under gentle warming in 350 ml of dimethyl sulfoxide. At 10 ° C 16.51 g ( 80 mmol) N, N-dicyclohexylcarbodiimide and stirred for 5 hours at 10 ° C. To this mixture were added 10 g (9.37 mmol) of the title compound of Example 9b and 3.03 g (30 mmol) triethylamine and stirred for 12 hours at 60 DEG C. Allow to cool to room temperature and pour the mixture into 3000 ml of acetone, filter off the precipitate and purify by chromatography (silica gel RP-18; eluent). ent: gradient of water / ethanol / acetonitrile).

Yield: 16.7 g (67% of theory) as a colorless solid.

Water Content: 7.9%

Elemental analysis: (calculated as anhydrous substance) calculated: C 36.58 H4.43 N11.06 F 12.14 S 1.14 Gd 17.74 found: C 36.47 H 4.54 N10.95 F 12.03 S 1.21 Gd 17.65 Example 10a

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

To 18.13 g (68.1 mmol) of 3,6,9,12,15-pentaoxahexadecanoic acid and 30 g (68.1 mmol) of 1,7-di-cyclene prepared according to Z. Kovacs und A. D. Sherry, J. Chem. Soc. Chem. Commun., (1995), 2, 185, in 300 ml of THF, added at 0 ° C 24.73 g (100 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and added stirred overnight at room temperature. It was concentrated in vacuo to dryness and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

Yield 19.13 g (42% of theory) as a colorless solid.

Elemental analysis: · Calculated: C 61.03 H 7.61 N 8.13 _g Found: C 60.92 H 7.75 N 8.04

Example 10b

1,7-bis (benzyloxycarbonyl) -4- (3,6,9,12,15 pentaoxachexadecanoyl) -10- (2H, 2H, 4 H, 5H, 5H-3-oxaprofluorotridecanoyl) -1,4,7,10- tetraazacyclododecane

To 18 g (26.91 mmol) of the title compound of Example 10a and 14.05 g (26.91 mmol) of 2H, 2H, 4H, 5H, 5H-3-oxaprofluorotridecanoic acid, obtained according to DE 196 03 033, was added in 300 ml of tetrahydrofuran. 0 ° C 12.36 g (50 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred at room temperature overnight. It was concentrated in vacuo to dryness and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

Yield 21.51 g (67% of theory) as a colorless solid.

Elemental analysis:

calculated: C 47.32 H 4.82 N 4.70 F 27.07 found: C 47.26 H 5.01 N 4.59 F 26.94 Example 10c

- (3,6,9,12,15-pentaoxahexadecanoyl) -7- (2H, 2H, 4H, 4H, 5H, 5H-3oxa-perfluorotridecanoyl) -1,4,7,10-tetraazacyclododecan g (16.77 mmol) from the title compound of Example 1d was dissolved in 200 ml of ethanol and 2.5 g of palladium catalyst (10% Pd / C) were added. Hydrated at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 15.5 g (quantitative) as a colorless solid.

Elemental analysis:

calculated: C 40.27 H 4.90 N 6.06 F 34.93 Found: C 40.15 H 4.99 N5.94 F 34.87 Example 10d

1,7-bis [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-w tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -

4- (3,6,9,12,15-pentaoxahexadecanoyl) -10- (2H, 2H, 4H, 4H, 5H, 5H-3oxa-perfluorotridecanoyl) -1,4,7,10-tetraazacyclododecane, Gdcomplex g (16.22 mmol) of the title compound of Example 10c, 4.60 g (40 mmol) of N-hydroxysuccinimide, 3.39 g (80 mmol) of lithium chloride and 25.19 g (40 mmol) of 1,4,7-tris (carboxylatomethyl) -10- (3 -aza-4-oxo-5methyl-5-yl) -pentanoic acid, the Gd-complex is dissolved under gentle warming in 300 ml of dimethyl sulfoxide. At 10 ° C, 24.73 g (100 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 RP18; eluent: gradient from water / ethanol / acetonitrile).

Yield: 19.86 g (57% of theory) as a colorless solid.

Water Content: 11.3%

Elemental analysis: (calculated as anhydrous substance) calculated: C 38.58 H 4.74 N9.13 F 15.04 Gd 14.64 found: C 38.47 H 4.91 N9.04 F 14.95 Gd 14.57

amide, Gd-complex g (14.24 mmol) of the title compound of Example 11b, 3.45 g (30 mmol) of N-hydroxysuccinimide, 2.54 g (60 mmol) of lithium chloride and 18.89 g (30 mmol) of 1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5methyl-5-yl) -pentanoic acid, the Gd-complex was dissolved under gentle warming in 200 ml of dimethyl sulfoxide. At 10 ° C, 10.32 g (50 mmol) of Ν, Ν-dicyclohexylcarbodiimide 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: 19.74 g (72% of theory) as a colorless solid.

Water Content: 11.8%

Elemental analysis: (calculated as anhydrous substance) calculated; C 35.55 H 3.72 N10.18 F 16.77 S 1.67 Gd 16.33 Found: C 35.48 H 3.84 N10.07 F 16.58 S 1.58 Gd 16.24 Example 12a

3-Oxa-2H, 2H, 4H, 4H, 5H, 5Nperfluorotridecanecarboxylic acid tert-ether 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 a catalytic amount (about 0.75 g) of tetra- (at 0.75 g) was added to the solution at room temperature. n-boogyl-ammonium hydrogen sulfate. A total of 7.55 g (134.6 mmol; 2.5 eq. With respect to the 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 alcohol component) tert. bromoacetic acid-butyl ester and allowed to stir at 0 ° C for two more hours. The reaction solution thus obtained was stirred for 12 hours at room temperature and further worked up by adding a total of 500 ml of ethyl acetate and 250 ml of water. The organic phase was separated and washed twice with water. After drying the organic phase over sodium sulfate, the salt is filtered off and the solvents are removed in vacuo. The residual oily product 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, 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 Example 12b 3-Oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanecarboxylic acid

20.0 g (34.58 mmol) of the title compound of Example 12a were suspended in 200 ml of a mixture of methanol and 0.5 molar sodium hydroxide solution in a ratio of 2: 1 with stirring and room temperature and then heated at 60 ° C. a reaction time of 12 hours at 60 ° C, the clear reaction solution was further developed by adding Amberlit® IR 120 (H ⁺ -form) cation exchange resin to neutralize, the resin was filtered off and the methanol-aqueous filtrate thus obtained was distilled off in vacuo until dry. 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, highly viscous oil.

Elemental analysis:

calculated: C 27.60 H 1.35 F 61.85 found: C 27.58 H 1.36 F 61.90

Example 12c

1.7-bis {[1,2,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl pentanoyl)] - 1,4,7,10-tetraazacyclododecanediethylenetriamine, digadoline- complex '

2.48 g (3.94 mmol; 2.05 moleq with respect to the diethylenetriamine embedded) of the 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) Gd complex described in DE 197 28 954 Cl in Example 31 h 1,4,7,10 Tetraazacyclododecane. 1,4,7-trioacetic acid and 167 mg of anhydrous lithium chloride (3.94 mmol) were dissolved at 40 ° C in 40 ml of absolute dimethyl sulfoxide with stirring, and at this temperature 453 mg ( 3.94 mmol) of N-hydroxysuccinimide. After cooling to room temperature, 814 mg (3.946 mmol) of N, N -dicyclohexylcarbodiimide were added to the reaction solution and stirred for 2 hours at room temperature. 198.3 mg (1.92 mmol) of diethylenetriamine dissolved in 5 ml of absolute dimethyl sulfoxide were then added to the resulting suspension of the active ester and stirred for 12 hours at room temperature. The reaction mixture was further developed by adding sufficient acetone to it to give a complete precipitation of the title compound, the precipitate was filtered off, dried, taken up in water, the undissolved dicyclohexicarbamide was filtered off and the filtrate was ultrafiltrated on UMIC. (cut off: 3000 Da) to desalinate and purify low molecular weight ingredients. What is retained on the filter is freeze-dried.

Yield: 1.85 g (72.7% of theory) as a colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 3.89%

Elemental analysis: (calculated as anhydrous substance) calculated: C 38.03 H 5.24 N13.73 Gd 23.71 found: C 37.98 H 5.20 N13.69 Gd 23.78 Example 12d

1.7-bis {[1,4,7-Tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl pentanoyl)] - 1,4,7,10-tetraazacyclododecane} -4 - (3-oxa2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) -diethylenetriamine, digadoline complex

To a solution of 3.23 g (2.44 mmol) of the title compound of Example 12c, in a mixture of 30 ml of dimethyl sulfoxide and 3 ml of tetrahydrofuran, at 50 ° C and a solution of 1.27 g (2.44 mmol) was added dropwise. the title compound of Example 12b dissolved in a mixture of 15 ml of tetrahydrofuran and 15 ml of dimethyl sulfoxide. A total of 1.80 g (3.66 mmol) of EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) was then added dropwise at 0 ° C and allowed to stir at room temperature overnight. A sufficient amount of acetone was added to the resulting solution to give complete precipitation of the title compound, the precipitate was filtered off, dried, taken up in water and the insoluble particles filtered off. The filtrate is ultrafiltered on a AMZ-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: 3.54 g (79.4% of theory) as a colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 5.87%

Elemental analysis: (calculated as anhydrous substance) calculated: C 35.43 H 4.07 N9.95 F 17.64 Gd 17.18 found: C 35.42 H 4.01 N9.89 F 17.67 Gd 17.18 Example 13a 2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-1_ -Lysine 100.0 g (356.7 mmol) of 6-N-benzyloxycarbonyl-L-lysine are 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 N 7.44 F 15.14 found: C 51.25 H5.18 N 7.58 F 15.03 Example 13b 2-N-Trifluoroacetyl-6- Ebenzyloxycarbonyl-L-lysine [1- (4perfluoroctylsulfonyl) -piperazine] -amide

To 125.0 g (332.0 mmol) of the title compound of Example C 1a and 188.7 g (332.0 mmol) of 1-perfluoroctylsulfonylpiperazine (prepared according to DE 196 03 033) in 750 ml of tetrahydrofuran were 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 concentrated 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 N6.05 F 41.01 S 3.46 found: C 36.18 H 2.94 N5.98 F 40.87 S 3.40 Example 13c β-N-benzyloxycarbonyl-L-lysine [1- (4-perfluoroctylsulfonyl) piperazine] -amide

In a solution of 280.0 g (302.2 mol) of the title compound of Example 1b in 2000 ml of ethanol was bubbled 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 solid precipitate was filtered off and dried in vacuo at 50 ° C.

Yield 243.5 g (97.0% of theory) as an amorphous solid substance. Elemental analysis: f calculated: C 37.60 H 3.28 N 6.75 F 38.89 S 3.86 found: C 37.55 H 3.33 N 6.68 F 38.78 S 3.81

Example 13d

L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

200.0 g (240.8 mmol) of the compound obtained in Example 13c were dissolved in 1000 ml of ethanol, 5.0 g of the Reaitap catalyst (Pd 20%, C) were added and hydrogenated at room temperature under hydrogen (1 atm) until monitors hydrogen uptake. The catalyst was filtered off, washed well with ethanol (three times with about 100 ml each) and concentrated in vacuo to dryness. The title compound is obtained as a very viscous, yellowish-colored oil.

Yield: 162.5 g (96.9% of theory).

Elemental analysis:

calculated: C 31.04 H 3.04 N8.05 F 46.38 S 4.60 found: C 31.11 H3.09 N8.08 F 46.33 S 4.62

Example13f

6-N-2N-6hc {4- [2,3-bis- (N, N-bis- (tert -butyloxycarbonylmethyl) -amino) -propyl] -phenyl} -3-oxa-propionyl-E-lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

5.25 g (7.72 mmol) of {4- [2,3-6πο- (Ν, Ν-6πο- (τρβτ.butyloxycarbonylmethyl) -amino) -propyl] -phenyl} -3-oxa-propionic acid and 781.0 mg (7.72 mmol) triethylamine was dissolved in 50 ml of methylene chloride. A solution of 1.16 g (8.5 mmol) of hydrochloric acid isobutyl ester in 10 ml of methylene chloride was added dropwise at -15 ° C for 5 minutes and stirred at -15 ° C for another 20 minutes. The solution was then cooled to -25 °. A solution consisting of 2.68 g (3.86 mmol) of the title compound of Example 13d and 2.12 g (21.0 mmol) of triethylamine in 70 ml of THF was added dropwise over 30 minutes. It was then stirred for an additional 30 minutes at -15 ° C and overnight at room temperature. The solvent was evaporated 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 evaporate in vacuo to dryness. The residue was chromatographed on silica gel (eluent: methylene chloride / ethanol = 20: 1).

Yield: 5.37 g (68.8% of theory) as a colorless and highly viscous oil.

Elemental analysis:

calculated: C 52.27 H 6.43 N5.54 F 15.97 S 1.59 found: C 52.22 H 6.51 N5.49 F 15.99 S 1.63 Example 13f

6N-2N-6nc {4- [2,3-bis- (N, bis- (tert-butyloxycarbonylmethyl) amino) -propyl] -phenyl} -3-oxa-propionyl-1-lysine- [1 - ( 4perfluoroctylsulfonyl) -piperazine] -amide, octa-sodium salt

5.0 g (2.47 mmol) of the title compound of Example 13e were dissolved in 60 ml of absolute dichloromethane. A total of 75 ml of trifluoroacetic acid was then added dropwise at 0 ° C. After a reaction time of 12 hours at room temperature, it was evaporated in vacuo to dryness. 100 ml of water were added to the residue and evaporated to dryness in vacuo again. The residue thus obtained was dissolved in 200 ml of distilled water and the aqueous solution of the title compound above was extracted twice with 60 ml of diethyl ether. The resulting aqueous product solution is topped up with water to a total volume of 300 ml, the insoluble matter is filtered off and the filtrate is ultrafiltered on an AMICON® UMF ultrafiltration membrane (cut off: 3000 Da) to desalinate and purify from low molecular weight constituents. The filter retention was made up to 200 ml with water and the pH of the solution was adjusted to 10.0 with 15% sodium hydroxide. The aqueous, alkaline solution of the product was freeze-dried.

Yield: 4.0 g (92.8% of theory) of the title compound as an octa-sodium salt as amorphous lyophilisate.

Water Content: 5.37%

Elemental analysis: (calculated as anhydrous substance) calculated: C 38.46 H 3.28 N6.41 F 18.47 S 1.83 Na 10.52 found: C 38.42 H 3.31 N6.39 F 18.51 S 1.87 Na 10.38 Example 13e

6N-2N-6hc {4- [2,3-bis- (N, N-bis- (tert-butyloxycarbonylmethyl) amino) -propyl] -phenyl} -3-oxa-propionyl-1-lysine- [1 - (4perfluoroctylsulfonyl) -piperazine] -amide, dimangan complex, tetra-sodium salt

1.94 g (1.11 mmol) of the title compound of Example 13f were dissolved in 100 ml of distilled water and the resulting solution was adjusted to pH 4.0 using 1 molar aqueous hydrochloric acid. At 80 ° C, 0.25 g (2.22 mmol) of manganese carbonate were added in portions. The reaction solution thus obtained was refluxed for 5 hours. After cooling to room temperature, the pH of the aqueous solution of the product was adjusted to 7.2 with 1 N sodium hydroxide and vigorous stirring. Ultrafiltrate on AM ICON® YM-3 ultrafiltration membrane (cut off: 3000 Da) to desalinate and purify low molecular weight components. What is retained on the filter is freeze-dried.

Yield: 1.80 g (92.0% of theory) of the title compound as a colorless lyophilisate.

H ₂ O - content (Karl-Fischer): 7.28%

Elemental analysis: (calculated as anhydrous substance) calculated: C 38.07 H 3.25 N6.34 F 18.28 Mp 6.22 Na 5.20 S 1.81 Found: C 38.01 H 3.29 N6.36 F 18.29 Mp 6.21 Na 5.28 S 1.78

Example 14a

6-N- (Benzyloxycarbonyl) -2-N - [(N-pteroyl) -1_-glutaminyl] -lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide r (45.31 mmol) folic acid was dissolved in 300 ml of dimethyl sulfoxide and 9.49 g (46 mmol) of N, N -dicyclohexylcarbodiimide were added at 10 ° C. It was stirred overnight at room temperature. To this mixture was added 29.1 g (35 mmol) of the title compound of Example 1c and 20 ml of pyridine and stirred for 3 hours at 50 ° C. Cooled to room temperature and a mixture of 1500 ml of diethyl ether / 1500 ml of acetone was added. . The resulting precipitate was filtered off and purified on silica gel RP-18 (eluent = gradient water / ethanol / tetrahydrofuran).

Yield: 21.59 g (38% of theory) as a yellow solid.

Water Content: 2.1%

Elemental analysis: (calculated as anhydrous substance) calculated: C 43.10 H3.54 N11.29 F 25.76 S 2.56 found: C 43.02 H 3.62 N11.21 F 25.68 S 2.48 Example 14b

2-N- [(N-pteroyl) -1_-glutaminyl] -lysine [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

To 20 g (15.95 mmol) of the title compound of Example 14a were added 200 ml of hydrobromic acid in glacial acetic acid (48%) and stirred for 2 hours at 40 ° C. Cooled to 0 ° C, 2000 ml of diethyl was added. ether and the resulting precipitate is filtered off. Drying in vacuo (60 ° C) afforded 18.96 g (99% of theory) of a yellow colored solid.

Elemental analysis:

calculated: C 37.01 H 3.27 N12.83 F 26.90 S 2.67 Br 6.65 found: C 36.91 H 3.42 N12.72 F 29.75 S 2.56 Br 6.31 Example 14c

6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] 2- N - [(N-pteroyl) -1_-glutaminyl] -lysine- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide, Gd-complex

0.92 g (8 mmol) of N-hydroxysuccinimide and 0.68 g (16 mol) of lithium chloride and 5.04 g (8 mmol) of 1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-

5-methyl-5-yl) - 1,4,7,10-tetraazacyclododecane, the Gd complex was dissolved under gentle warming in 80 ml of dimethyl sulfoxide. At 10 ° C, 2.06 g (10 mmol) -N, N-dicyclohexylcarbodiimide was added and stirred for 3 hours at 10 ° C. To this mixture was added 5 g (4.16 mmol) of the title compound of Example 14b and 10 ml of pyridine. It was stirred overnight at room temperature. The mixture was poured into 1000 ml of acetone and stirred for 10 minutes. The precipitate was filtered off and purified by chromatography (silica gel RP-18; eluent: gradient from water / ethanol / acetonitrile). It is dissolved in a little water, the pH is adjusted to 7.4 with sodium hydroxide and freeze-dried.

Yield: 3.87 g (53% of theory) as a yellow solid.

Water Content: 5.8%

Elemental analysis: (calculated as anhydrous substance) calculated: C 38.36 H 3.74 N12.78 F 18.42 S 1.83 Gd 8.97 found: C 38.28 H 3.85 N12.69 F 18.33 S 1.75 Gd 8.85 Example 15a

6-N- (benzyloxycarbonyl) -2-N- (3,6,9,12-tetraoxatridecanoyl) lysine [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

50 g (60.20 mmol) of the title compound of Example 1c and 7.10 g (70 mmol) of triethylamine dissolved in 350 ml of dichloromethane were added dropwise at 0 ° C to a solution of 16.85 g (70 mmol) of 3,6,9,12 tetraoxatridecane acid chloride in 50 ml of dichloromethane and stirred for 3 hours at 0 ° C. 200 ml of 5% aqueous hydrochloric acid were added and stirred for 5 minutes at room temperature. The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo to dryness. The residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1).

Yield 30.94 g (92% of theory) as a colorless solid.

Elemental analysis:

calculated: C 40.63 H 4.19 N5.41 F31.21 S 3.10 found: C 40.75 H 4.08 N 5.58 F 31.29 S 3.25

Example 15b

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

53.96 g (52.15 mmol) of the title compound of Example 15a was dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 43.Og (quantitative) as a colorless solid.

Elemental analysis:

calculated: C 36.01 H4.14 N6.22 F 35.86 S 3.56 found: C 27.60 H5.13 N6.68 F 39.09 S 3.81

Example 15c

6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] 2- N - (3,6,9,12-tetra-xatri decanoyl) -l isole and n- [1- (4-fluoro-quinoxyl-sulfonyl) -piperazine] -amide, Gd-complex

21.84 g (24.25 mmol) of the title compound of Example

15b, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza4-oxo-5- methyl-5-yl) -pentanoic acid] -1,4,7,10-tetraazacyclododecane, the Gd-complex was dissolved under gentle warming in 200 ml of dimethyl sulfoxide. At 10 ° C, 8.25 g (40 mmol) of Ν, Ν67 ρ * 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 separated precipitate was filtered off and purified by chromatography (silica gel RP-18; eluent: gradient from water / ethanol / acetonitrile).

Yield: 28.21 g (81% of theory) as a colorless solid.

Water Content: 11.0%

Elemental analysis: (calculated as anhydrous substance) calculated: C 36.53 H 4.33 N8.34 F21.36 S 2.12 Gd 10.40 found: C 31.74 H 4.98 N8.69 F22.39 S 2.15 Gd 10.87 Example 16a

6-N- (Benzyloxycarbonyl) -2-N- (propyl-3-sulfonic acid) lysine [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

To 50 g (60.20 mmol) of the title compound of Example 1c and 7.10 g (70 mmol) of triethylamine dissolved in 250 ml of dry tetrahydrofuran was added dropwise at 50 ° C a solution of 7.33 g (60 mmol) of propansulton in 50 ml of tetrahydrofuran and was stirred for 3 hours at 60 ° C. 200 ml of 5% aqueous hydrochloric acid was added and stirred for 5 minutes at room temperature. The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo to dryness. The residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1).

Yield 45.16 g (79% of theory) as a colorless viscous oil.

Elemental analysis:

calculated: C 36.56 H 3.49 N 5.88 F 33.90 S 6.73 Found: C 36.72 H 3.35 N 5.78 F 33.79 S 6.75 Example 16b

2-N- (propyl-3-sulfonic acid) - lysine [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

49.68 g (52.15 mmol) of the title compound of Example 16a was dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 42.69g (quantitative) as a colorless solid.

Elemental analysis:

Calculated: C 30.81 H 3.32 N 6.84 F 39.46 S 7.83 Found: C 30.64 H 4.1 N 6.68 F 39.29 S 7.89 Example 16c

6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacycododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] 2-N- (propyl-3-sulfonic acid) - lysine [1- (4perfluoroctylsulfonyl) -piperazine] -amide, Gd-complex

19.85 g (24.25 mmol) of the title compound of Example 16b, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1,4,7-tris (carboxylatomethyl) - 10 - [(3-aza-

4-Oxo-5-methyl-5-yl) -pentanoic acid] -1,4,7,10-tetraazacyclododecane, the Gd-complex was dissolved under gentle warming in 200 ml of dimethyl sulfoxide. At 10 ° C, 8.25 g (40 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: 28.13 g (81% of theory) as a colorless solid.

Water Content: 11.0%

Elemental analysis: (calculated as anhydrous substance) calculated: C 33.27 H 3.70 N8.73 F 22.36 S 4.44 Gd 10.89 found: C 32.41 H 3.88 N8.69 F 22.49 S 4.35 Gd 10.97 Example 17a

6-N- (Benzyloxycarbonyl) -2-N, N-bis (propyl-3-sulfonic acid) -Lysine [1- (4-perfluoroctylsulfonyl) -piperazine] -amide 50 g (60.20 mmol) of the title compound of Example 1c and 12.14 g (120 mmol) of triethylamine dissolved in 250 ml of dry tetrahydrofuran was added dropwise at 50 ° C a solution of 14.65 g (120 mmol) of propansulton in 100 ml of tetrahydrofuran and stirred for 3 hours at 60 ° C. ml of a 5% aqueous hydrochloric acid solution, stirred for 5 minutes at room temperature, sodium chloride was added, the organic phase was separated, dried over magnesium sulfate and concentrated and under vacuum to dry. The residue was chromatographed on silica gel (eluent: dichloromethane / acetone = 15: 1).

Yield 52.24 g (81% of theory) as a colorless viscous oil.

Elemental analysis:

calculated: C 35.76 H 3.66 N 5.21 F 30.05 S 8.95 found: C 35.75 H 3.55 N5.08 F 30.19 S 9.04 Example 17b 2-N, N-bis (propyl-3-sulfonic acid) lysine [1- (4- perfluoroctylsulfonyl) -piperazine] -amide 53.74 g (52.15 mmol) of the title compound of Example 17a was dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 49.06g (quantitative) as a colorless solid.

Elemental analysis:

calculated: C 30.64 H 3.54 N5.96 F 34.33 S 10.23 found: C 30.69 H 3.71 N6.08 F 34.19 S 10.38 Example 17c

6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] ΊΟ

2-N, N-6nc (propyl-3-sulfonic acid) - lysine [1- (4perfluoroctylsulfonyl) -piperazine] -amide, Gd-complex, disodium salt

38.76 g (24.25 mmol) of the title compound of Example 17b, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1,4,7-tris (carboxylatomethyl) - 10 - [(3-aza-

4-Oxo-5-methyl-5-yl) -pentanoic acid] -1,4,7,10-tetraazacyclododecane, the Gd-complex was dissolved by gentle warming in 200 ml of dimethyl sulfoxide. At 10 ° C, 8.25 g (40 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: 31.63 g (81% of theory) as a colorless solid.

Water Content: 11.0%

Elemental analysis: (calculated as anhydrous substance) calculated: C 32.07 H 3.57 N 7.83 F 20.06 S 5.97 Gd 9.76 Na 2.86 found: C 32.94 H 3.48 N7.69 F 20.19 S 5.85 Gd 9.87 Na 2.99

Example 18a

N-Trifluoroacetyl-L-glutamic acid 5-benzyl ester

100 g (421.5 mmol) of 5-benzyl ester of L-glutamic acid were dissolved in a mixture of 1000 ml of trifluoroacetic acid ethyl ester / 500 ml of ethanol and stirred at room temperature for 24 hours. It was evaporated to dryness and the residue was crystallized from diisopropyl ether.

Yield 140.47 g (96% of theory) as a colorless crystalline powder.

Elemental analysis:

calculated: C 50.46 H 4.23 N4.20 F 17.10 found: C 51.35 H 4.18 N4.28 F 17.03

Example 18b

N-Trifluoroacetyl-E-glutamic acid 5-benzyl ester N-bis (2-hydroxyethyl) -amide

To a solution of 24.9 g (24.08 mmol) of the title compound of Example 18a, 2.53 g (24.08 mmol) of diethanolamine 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) Ν, Ν-dicyclohexylcarbodiimide. Stirred for 3 hours at 0 ° C and overnight at room temperature. The precipitated _r urea was filtered off, the filtrate was concentrated in vacuo to dryness and chromatographed on silica gel (eluent: dichloromethane / ethanol = 20: 1).

Yield 9.11 g (90% of theory) as a viscous 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 Example 18c

N-Trifluoroacetyl-E-glutamic acid-N-bis (2-hydroxyethyl) -monoamide

21.92 g (52.15 mmol) of the title compound of Example 18b were dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) was added. 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 Example 18d

N-Trifluoroacetyl-E-glutamic acid-N-bis (2hydroxyethyl) -amide-5- [1- (4-perfluoroctylsulfonyl) -piperazine] 72 amide

To 10.96 g (33.2 mmol) of the title compound of Example 18a and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (prepared according to DE 196 03 033) in 80 ml of tetrahydrofuran was added at 0 ° C.

16.42 g (66.42 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred at room temperature overnight. It was concentrated in vacuo to dryness and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

Yield: 30.93g (93% 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

Example 18f

L-glugamic acid-N-bis (2-hydroxyethyl) -amide-5- [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

In a solution of 30.24 g (30.22 mmol) of the title compound of Example 18b in 200 ml of ethanol was passed 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 solid precipitate was filtered off and dried in vacuo at 50 ° C.

Yield 26.55 g (97% 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

H2.83 N6.28 F 35.78

S 3.71

Example 18f

N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] L-glutamic acid-I -bis (2-hydroxyethyl) -amide-5- [1- (473 perfluoroctylsulfonyl) -piperazine] -amide, Gd-complex

211.96 g (24.25 mmol) of the title compound of Example 18e, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1,4,7-tris (carboxylatomethyl) - 10 - [(3-aza-

4-Oxo-5-methyl-5-yl) -pentanoic acid] -1,4,7,10-tetraazacyclic-dodecane, the Gd-complex was dissolved under gentle warming in 200 ml of dimethyl sulfoxide. At 10 ° C, 8.25 g (40 mmol) of ΝΝcyclohexylcarbodiimide 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: 27.43 g (81% of theory) as a colorless solid.

Water 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 N9.19 F 23.29 S 2.15 Gd 11.07

Example 19a

N-Trifluoroacetyl-1-glutamic acid 5-benzyl ester N-dimethyl-bis (1,1-dihydroxymethyl) -amide

To a solution of 8.03 g (24.08 mmol) of the title compound of Example 18a, 3.98 g (24.08 mmol) of dimethyl bis (1,1-dihydroxymethyl) amine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide dissolved in 150 ml of dimethylformamide 8.25 g (40 mmol) of Νcyclohexylcarbodiimide were added at 0 ° C. Stirred for 3 hours at 0 ° C and 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 110.53 g (91% of theory) as a viscous oil.

Elemental analysis:

calculated: C 50.00 H 5.66 N7.18 F 11.86 found: C 50.17 H 5.82 N7.15 F 11.80 Example 19b

N-Trifluoroacetyl-1-glutamic acid 5-benzyl ester [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

25.05 g (52.15 mmol) of the title compound of Example 19a were dissolved in 500 ml of ethanol and 6 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 20.36 g (quantitative) as a colorless solid.

Elemental analysis:

calculated: C 40.00 H 5.42 N7.18 F 14.60 found: C 40.10 H 5.53 N7.28 F 14.69 Example 19c

N-Trifluoroacetyl-L-glutamic acid-N-dimethyl-bis (1,1-dihydroxymethyl) -amide-5- [1- (4-perfluorooctylsulfonyl) piperazinamide

To 12.96 g (33.2 mmol) of the title compound of Example 19b and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (prepared according to DE 196 03 033) in 80 ml of tetrahydrofuran was added at 0 ° C.

16.42 g (66.42 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred at room temperature overnight. It was concentrated in vacuo to dryness and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

Yield: 28.42 g (91% of theory) as a colorless solid.

Elemental analysis:

calculated: C 31.93 H 3.00 N 5.96 F 40.40 S 3.41 Found: C 32.08 H 2.94 N 5.88 F 40.57 S 3.31

Example 19d

L-glutamic acid N- [dimethyl-bis (1,1-dihydroxymethyl) amide-5- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

In a solution of 28.41 g (30.2 mmol) of the title compound of Example 19c in 200 ml of ethanol was passed 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 solid precipitate was filtered off and dried in vacuo at 50 ° C.

Yield 24.74 g (97% of theory) as an amorphous solid. Elemental analysis:

calculated: C 32.71 H 3.46 N 6.63 F 38.24 S 3.80 Found: C 32.75 H 3.33 N 6.68 F 38.38 S 3.81 Example 19f

2-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] L-glutamic acid -I-bis (2-hydroxyethyl) -amide-L-glutamic acid-N- [dimethyl-bis (1,1-dihydroxymethyl) amide-5- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide, Gdcomplex

20.48 g (24.25 mmol) of the title compound of Example 19d, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1,4,7-tris (carboxylatomethyl) - 10 - [(3-aza-

4-Oxo-5-methyl-5-yl) -pentanoic acid] -1,4,7,10-tetraazacyclic-dodecane, the Gd-complex was dissolved under gentle warming in 200 ml of dimethyl sulfoxide. At 10 ° C, 8.25 g (40 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: 29.05 g (83% of theory) as a colorless solid.

Water Content: 11.0%

Elemental analysis: (calculated as anhydrous substance) calculated: C 34.12 H 3.91 N8.73 F 22.38 S 2.22 Gd 10.90 found: C 34.24 H 3.98 N8.69 F 22.39 S 2.15 Gd 10.87

Example 20a

N-Trifluoromethylacetyl-1-glutamic acid 5-benzyl ester- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

To a solution of 11.06 g (33.2 mmol) of the title compound of Example 18a and 18.87 g (33.2 mmol) of 1-perfluoroctylsulfonylpiperazine (prepared according to DE 196 03 033) in 80 ml of tetrahydrofuran was added at 0 ° C 16.42 g (66.42 mmol) ) EEDQ (2-ethoxy- ethyl ester-

1,2-dihydroquinoline-1-carboxylic acid) and stirred at room temperature overnight. It was concentrated in vacuo to dryness and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

Yield: 27.28 g (93% of theory) as a colorless solid.

Elemental analysis:

calculated: C 35.35 H 2.40 N 4.76 F 43.01 S 3.63 Found: C 35.48 H 2.51 N 4.73 F 42.87 S 3.50 Example 20b

N-Trifluoroacetyl-E-glutamic acid-5- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

21.92 g (52.15 mmol) of the title compound of Example 18a was dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 41.37 g (quantitative) as a colorless solid.

Elemental analysis:

calculated: C 28.76 H 1.91 N 5.30 F 47.89 S 4.04 Found: C 28.84 H2.03 N5.28 F 47.79 S 4.19 Example 20c

N-Trifluoroacetyl N-glutamic acid N-6nc (2-hydroxyethyl) -amide-5- [1- (4-perfluoroctylsulfonyl) -piperazine] amide

To a solution of 24.9 g (24.08 mmol) of the title compound of Example 18a, 2.53 g 3.98 g (24.08 mmol) of diethanolamine 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) N, N-dicyclohexylcarbodiimide. Stirred for 3 hours at 0 ° C and 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 9.11 g (90% of theory) as a viscous oil.

Elemental analysis:

calculated: C 31.37 H 2.75 N6.36 F 43.15 S 3.64 found: C 31.22 H 2.61 N6.25 F 43.30 S 3.81 Example 20d

L-glutamic acid-N-bis (2-hydroxyethyl) -amide-5 [1- (4-perfluorooctylsulfonyl) -piperazine] -amide

In a solution of 26.61 g (30.22 mmol) of the title compound of Example 18c in 200 ml of ethanol was passed 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 solid precipitate was filtered off and dried in vacuo at 50 ° C.

Yield 23.93 g (97% of theory) as an amorphous solid.

Elemental analysis:

calculated: C 30.89 H 3.09 N 6.86 F 39.56 S 3.93 found: C 30.75 H3.13 N6.75 F 39.78 S 3.81 Example 20f

N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10tetraazacyclododecan-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] L-glutamic acid-I -bis (2-hydroxyethyl) -amide-5- (1- (4-perfluoroctylsulfonyl) -piperazine] -amide, Gd-complex

16.43 g (24.25 mmol) of the title compound of Example 20d, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium F chloride and 15.27 g (24.25 mmol) of 1,4,7-tris (carboxylatomethyl) -10 - ((3-aza-

4-Oxo-5-methyl-5-yl) -pentanoic acid] -1,4,7,10-tetraazacyclic-dodecane, the Gd-complex was dissolved under gentle warming in 200 ml of dimethyl sulfoxide. At 10 ° C, 8.25 g (40 mmol) of Νdicyclohexylcarbodiimide were added and then stirred overnight at room temperature. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The separated precipitate was filtered off and purified by chromatography (silica gel RP-18; eluent: gradient from water / ethanol / acetonitrile).

Yield: 28.10 g (83% of theory) as a colorless solid.

Water 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 34.44 H 4.98 N8.89 F 23.19 S 2.15 Gd 11.17

Example 21a

N-Trifluoroacetyl-1-glutamic acid 5-benzyl ester- (1- (4-perfluoroctylsulfonyl) -piperazine] -amide

To a solution of 11.06 g (33.2 mmol) of the title compound of Example 18a and 18.87 g (33.2 mmol) of 1-perfluoroctylsulfonylpiperazine (prepared according to DE 196 03 033) in 80 ml of tetrahydrofuran was added at 0 ° C 16.42 g (66.42 mmol) EEDQ (2-ethoxy ethyl ester79

1,2-dihydroquinoline-1-carboxylic acid) and stirred at room temperature overnight. It was concentrated in vacuo to dryness and chromatographed on silica gel (eluent: dichloromethane / methanol = 20: 1).

Yield: 27.28 g (93% of theory) as a colorless solid.

Elemental analysis:

Calculated: C 35.35 H 2.40 N 4.76 F 43.01 S 3.63 Found: C 35.48 H 2.54 N 4.73 F 42.87 S 3.40

Example 21 b

N-Trifluoroacetyl-L-glugamic acid-5- [1- (4-perfluoroctylsulfonyl) -piperazine] -amide

21.92 g (52.15 mmol) of the title compound of Example 21a was dissolved in 500 ml of ethanol and 3 g of palladium catalyst (10% Pd / C) was added. Hydrated at room temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo to dryness.

Yield: 41.37 g (quantitative) as a colorless solid.

Elemental analysis:

Calculated: C 28.76 H 1.91 N 5.30 F 47.89 S 4.04 Found: C 28.84 H1.81 N5.28 F 47.79 S 4.16

Example 22

Organ distribution (including accumulation in tumors and lymph nodes) after intravenous administration of the contrast agent of the invention of Example 3 in rats with prostate cancer

After intravenous administration of 100 μmol total gadolinium / kg body weight of the title compound of Example 3 in rats (CoryInzucht, on which 12 days prior prostate carcinoma Dunning R3327 MAT-Lu was implanted), was determined 10 minutes, 1 and 24 hours after administration. metal content in various 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 3 Gd concentration (μmol / l) % dose in total tissue 10 min 1 hour 24 hours 10 min 1 hour 24 hours liver 137 ± 39 136 ± 1 172 + 6 3.79 ± 0.12 3.93 ± 0.20 5.37 ± 0.63 springs 184 ± 58 161 ± 3 161 ± 19 0.25 ± 0.07 0.23 ± 0.01 0.25 ± 0.01 pancre- as 99 ± 26 95 ± 15 55 ± 7 0.25 ± 0.08 0.23 ± 0.07 0.18 ± 0.01 kidney 359 ± 88 394 ± 41 292 ± 18 1.70 ± 0.39 2.00 ± 0.21 1.38 ± 0.07 lung 344 ± 95 321 ± 16 146 ± 19 1.30 ± 0.33 1.27 ± 0.05 0.56 ± 0.03 heart 177 ± 46 151 ± 7 65 ± 12 0.40 ± 0.11 0.33 ± 0.01 0.15 ± 0.03 brain 16 ± 5 16 ± 3 5 ± 0 0.09 ± 0.02 0.10 ± 0.02 0.03 ± 0.00 muscle ★ w 41 ± 12 40 ± 4 13 ± 2 0.12 ± 0.04 0.08 ± 0.01 0.03 ± 0.01 tumor 82 ± 32 126 ± 10 100 ± 6 0.20 ± 0.07 0.40 ± 0.12 0.46 ± 0.41 thigh 61 ± 10 64 ± 5 33 ± 1 0.50 ± 0.06 0.50 ± 0.02 0.26 ± 0.01 mes.lim. nodes 155 ± 40 160 ± 5 127 ± 7 0.11 ± 0.04 0.10 ± 0.01 0.09 ± 0.01

the title compound of Example 3 Gd concentration (μmol / l) % dose in total tissue 10 min 1 hour 24 hours 10 min 1 hour 24 hours peripheral nodes 115 ± 27 186 ± 6 108 ± 6 0.13 ± 0.03 0.19 ± 0.03 0.11 ± 0.02 stomach (blank) 90 ± 26 93 ± 3 48 ± 8 0.47 ± 0.16 0.50 ± 0.06 0.27 ± 0.03 gut (empty) 146 ± 37 130 ± 7 101 ± 12 2.48 ± 0.56 1.85 ± 0.27 1.63 ± 0.15 blood 621 ± 137 534 ± 12 169 ± 16 35.18 ± 7.43 30.63 ± 1.05 9.58 ± 1.02 remain. solid bodies 103 ± 7 31.05 ± 4.60 urine 0-24 hrs 60 ± 19 36.38 ± 2.36 faeces 0-24 hrs 5618 ± 28 8.91 ± 2.29

amount of bodies *** 46.35 ± 9.98 41.79 ± 1.79 50.9 ± 4.52 balance 96.24 ± 3.47

ml blood / kg body weight only tissue aliquots from the right lumbar *** sum of organs 10 and 60 minutes after implantation without residual body

Claims (6)

1. Perfluoroalkyl-containing polar residue complexes of general formula I (K) m-G- (Z-Rf) _r ^{(R) P} (I) in which: 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 represents -C ₆ H ₄ -O-CH ₂ -co-, - (CH 2 -co, phenyl group, -CH ₂ NHCO-CH ₂ -CH (CH ₂ COOH) -C ₆ H ₄ - _W -, - CeH ^ iO-CH ^ H ^ o-pNiCH ^ OOH) 83 ΟΗ ₂ -ω or optionally interrupted by one or more oxygen atoms, with 1 to 3-NHCO-, with 1 to 3-CONH-pynn and / or with 1 to 3- (CH ₂ ) ₀ . _5- COOH substituted with _H2- alkylene or C ₇ . ₁₂ -C ₆ H ₄ -O-group, wherein ω denotes the site of attachment to -CO-, or of the general formula III R ¹ OO (III) in which R ¹ has the above meanings, R ⁴ represents hydrogen or the metal ion equivalent described in R ¹ and U ¹ means -C ₆ H ₄ -O-CH ₂ ω-, where ω means the binding site to -CO-, either of general formula IV or of general formula VA or VB --COOR ¹ / COOR ROOC \ / ^N \ ^vx COOR (VA) / COOR Ο (/ ⁴ COOR II _x COOR mlnm.N ^V COOR (VB) in which R ¹ has the above meanings or with the general formula VI R ¹ OOC \ L. R ¹ OOC / —coo R ¹ N \ COOR (VI) in which R ¹ has the above meanings or of the general formula VII R ¹ OOC - \ N R ¹ OOC-- ^/ In ¹ 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-, wherein ω denotes the site of attachment to -CO-, 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 means at least three times a functionalized residue selected from the following residues a) to e): Ws * '· (a) (b) (c) (θ) Υ co (f) - (CH ₂ ) ₄ —C— _NH - _C Q_ c— (CH ₂ ) ₄ - NH II ^H CO NH (g) / \ ⁷ \ HN M NH α Υβ (h) Y --- CO (CH ₂ ) ₂ _ ₃ --- CHCOβ NH (i) β --- CO (CH ₂ ) ₂ _ ₃ CHCOγ NH where a denotes the binding site of G to complex K, β is the binding site of G to residue R, and γ is the binding site of G to residue Ζ Ζ means YC (O) CH ₂ -O- (CH ₂ ) ₂ -SO ₂ -e, where y is the binding site of Z to the residue G and ε is the binding site of Ζ to the perfluorinated residue R _f R represents a polar moiety selected from complex K of general formulas II through VII, in which R ¹ here represents hydrogen or the metal ion equivalent of the numbers 20-29, 31-33, 37-39, 42-44, 49 or 57-83 ; and the residues R ² , R ³ , R ⁴ , U and U ¹ have the meanings already mentioned, where if G is the residue (c) or (d) and R represents a complex selected from the general formulas II and V, then R must not be identical with the residue K of the general formula I when Z represents YC (O) CH ₂ -O- (CH ₂ ) ₂ -SO ₂ - _£ , or a folic acid residue or carbon chain which is bonded through -CO-, SO ₂ or by a direct connection to G carbon chain with 2 - 30 C-atoms, straight or branched, saturated or unsaturated, optionally interrupted by 1 - 10 oxygen atoms, 1-5 -NHCO groups, 1-5 -CONH groups, 1-2 sulfur atoms, 1-5 -ΝΗ- groups or 1-2 phenyl groups which may be optionally substituted by 1-2 OH groups, 1-2 NH ₂ groups, 1-2 -COOH-groups or 1-2 -SO ₃ H-pyrene or optionally substituted by 1 -8 OH groups, 1-5-COOH groups or 1-2 SO ₃ H-pyrene, 1-5 NH ₂ groups, 1-5 C 1-4 alkoxy groups, and ' 1. m, p independently denote an integer 1 or 2. Metal complexes according to claim 1, characterized in that the metal ion equivalent of R ¹ in the residue K represents a metal ion equivalent of the numbers 21-29, 39, 42, 44 or 57-83. Metal complexes according to claim 1, characterized in that the metal ion equivalent R ¹ in the residue K represents a metal ion equivalent with the numbers 27, 29, 31 - 33, 37 - 39, 43, 49, 62, 64, 70 , 75 and 77. 4. Metal complexes according to claims 1 to 3, characterized with that K can to represent metallic complex of general formula II, III, VB or VII. 5. Metal complexes according to claims 1 to 4, characterized in that the polar residue R has the meanings of complex K. Metal complexes according to claim 5, characterized in that the polar residues R are the complexes K of general formula II, III, VA or VII. 7. Metal complexes according to claim 5 or 6, characterized in that R ¹ represents a metal ion equivalent of 20, 25 or 64 in sequence. Metal complexes according to claims 1 to 4, characterized in that the polar residue R has the following meanings: