HRP20030171A2 - Complexes containing perfluoralkyl with polar radicals, method for the production and use thereof - Google Patents

Description

The invention relates to the contents indicated in the claims, namely metal perfluoroalkyl complexes with polar radicals of the general formula I, the process for their production and their use in NMR diagnostics and X-ray diagnostics, radiodiagnostics and radiotherapy, in MRT-lymphography and as agents for blood pool (blood-pool agents). The compounds according to the invention are particularly suitable for intravenous lymphography, for the diagnosis of tumors and for the visualization of infarction and necrosis.

In nuclear magnetic resonance, the element fluorine is second in importance after hydrogen.

1) Fluorine has a high sensitivity of 83% of hydrogen sensitivity.

2) Fluorine has only one NMR-active isotope.

3) Fluorine has a resonance frequency similar to that of hydrogen -- fluorine and hydrogen can be measured with the same system.

4) Fluorine is biologically inert.

5) Fluorine does not appear in biological materials (exception: teeth) and can therefore be used as a test or contrast medium for a background that is free of interfering signals.

The effect of these features is that fluorine occupies a large place in the patent literature related to diagnostics based on magnetic nuclear resonance: fluorine-19-display, functional diagnosis, spectroscopy.

US Patent 4,639,364 (Mallinckrodt) thus proposes trifluoromethanesulfonamides as a contrast medium for fluorine-19 imaging:

CF3SO2NH2

CF3SO2NH-CH2-(CHOH)4-CH2OH

German Patent DE 4203254 (Max-Planck-Gesellschaft), in which an aniline derivative is proposed:

[image]

also refers to the fluorine-19-display.

Fluorine-19-imaging is the subject of application WO 93/07907 (Mallinckrodt), in whose claims phenyl derivatives are also mentioned as contrast media:

[image]

For fluorine-19-display, compounds of significantly simpler structures are also required. Thus Patent US 4,586,511 (Children's Hospital Medical Center) mentions perfluorooctyl bromide

CF3(CF2)7-Br,

European Patent EP 307863 (Air Products) mentions perfluoro-15-crown-5-ether

[image]

and the U.S. US Patent 4,588,279 (University of Cincinnati, Children's Hospital Research Foundation) mentions perfluorocarbon compounds such as perfluorocyclononane or -octane, perfluorinated ethers such as tetrahydrofuran

[image]

or diethers such as perfluoropropylene glycol diether

[image]

Compounds mentioned in WO 94/22368 (Molecular Biosystems), e.g.,

[image] , which as

fluorine-containing radicals having a perfluoro-1H group or a 1H-neopentyl group are also used for fluorine-19-display.

LOUSE. US Patent 5,362,478 (VIVORX) suggests another structural type with extended diagnostic use, and in that patent, for illustrative purposes, a fluorocarbon/polymer shell combination is specified in the claims. Perfluorononane and human serum albumin are mentioned. This combination proves to be suitable, moreover, for the use of the fluorine atom as a probe for local temperature measurement and for determining the partial pressure of oxygen.

Perfluorocarbons are also claimed in U.S. Patent 4,586,511 for oxygen determination.

In German Patent DE 4008179 (Schering), fluorine-containing benzenesulfonamides are claimed as pH probes:

[image]

Compounds containing iodine and fluorine atoms as contrast enhancers are also claimed for NMR diagnosis in WO 94/05335 and WO 94/22368 (both molecular biosystems):

[image]

The fluorine-paramagnetic metal ion combination is also claimed for fluorine-19-display, especially for open-chain complexes in WO 94/22368 (Molecular Biosystems) with, e.g.:

[image]

and in EP 292 306 (TERUMO Kabushiki Kaisha) with, e.g.:

[image]

but also for cyclic compounds, as mentioned in EP 628 316 (TERUMO Kabushiki Kaisha)

[image]

The combination of a fluorine atom and a rare earth metal is also required for NMR-spectroscopic temperature measurements in DE 4317588 (Schering):

[image]

Ln: rare earths: La, Pr, Dy, Eu

While no interactions occur between the two nuclei in compounds containing the elements fluorine and iodine, intense interaction occurs in compounds containing fluorine and paramagnetic centers (radicals, metal ions), which are shown by shortening the relaxation time of the fluorine nucleus. The range of this effect depends on the number of unpaired electrons of the metal ion (Gd3+ > Mn2+ > Fe3+ > Cu2+) and on the migration between the paramagnetic ion and the 19F-atom.

The more unpaired electrons of the metal ion are present and the closer they are to the fluorine, the greater the shortening of the relaxation time of the fluorine nucleus.

The shortening of the relaxation time as a function of the distance from the paramagnetic ion becomes apparent in all nuclei that have unequal spin numbers, so also in the case of protons, and gadolinium compounds are therefore widely used as a contrast medium in nuclear spin tomography (Magnevist(R), Prohance(R) ), Omniscan(R), and Dotarem(R)).

In 1H-MR imaging (1H-MRI), however, the T1 or T2 relaxation time for protons is measured and used to display, i.e. mainly water protons, not the reaction time of the fluorine nucleus. The quantitative measure for shortening the relaxation time is relaxivity (L/mmol ̇s). Paramagnetic ion complexes are successfully used to shorten the relaxation time. The following table shows the relaxivity of several commercial preparations:

[image]

In these compounds, only interactions between protons and gadolinium ions were found. A relaxivity of approximately 4 [1/mmol ̇s] was observed for these contrast media in water.

Both fluorine compounds for fluorine-19-imaging, in which the shortened relaxation time of the fluorine nucleus is used, and non-fluorine compounds, in which the relaxation time of the water proton is measured, have thus been successfully used for MR imaging.

Upon introduction of a perfluorocarbon-containing radical into the paramagnetic contrast medium, i.e., in combination with a feature previously known to be suitable only for compounds used in fluorine imaging, the relaxivity related to water protons also increases rapidly, surprisingly enough, with compounds that were used in the representation using protons. It now reaches boiling points of 10-50 [1/mmol ̇s] compared to values of between 3.5 and 3.8 [1/mmol ̇s] already quoted for some commercial products in the table above.

Metal complexes containing perfluoroalkyl are already known from DE 196 03 033.1. These compounds, however, cannot be satisfactorily used for all applications. Therefore, there is still a need for a contrast medium to visualize malignant tumors, lymph nodes, and necrotic tissue.

Malignant tumors metastasize in clusters in regional lymph nodes, where sites with multiple lymph nodes may be involved. Lymph node metastases are thus found in approximately 50-60% of all patients with malignant tumors (Elke, Lymphographie (Lymphography), in: Frommhold, Stender, Thurn (eds.), Radiologische Diagnostik in Klinik und Praxis [Radiological Diagnosis in Clinical Studies and in Practice], Volume IV, Thieme Verlag Stuttgart, 7th Ed., 434-496, 1984). The diagnosis of metastatic attack of the lymph nodes is of great importance with regard to the treatment and prognosis of the malignant type of disease. With modern imaging methods (CT, US and MRI), lymphogenic evacuations of malignant tumors are established only inadequately, since in most cases only the size of the lymph node can be used as a diagnostic criterion. Thus, small metastases in non-enlarged lymph nodes (< 2 cm) cannot be clearly distinguished from lymph node hyperplasia without a malignant attack. (Steinkamp et al., Sonographie und Kernspintomographie: Differentialdagnostik von reaktivier Lymphknoten-vergrößerung und Lymphknoten-metastasen am Hals [Sonography and Nuclear Spin Tomography: Differential Diagnosis of reactive Lymph Node Enlargement and Lymph Node Metastasis on the Neck], Radiol. Diagn. 33 :158, 1992).

It would be desirable if, using specific contrast media, lymph nodes with metastatic attack could be distinguished from hyperplastic lymph nodes.

Direct x-ray lymphography (injection of a suspension of oil contrast medium into a prepared lymphatic vessel) is known as an invasive method that is used only very rarely and can provide visualization of only small units of lymphatic drainage.

Fluorescently labeled dextrans are also used experimentally in animal experiments to monitor lymphatic drainage after their interstitial administration. All commonly used markers for visualization of lymphatic channels and lymph nodes after interstitial/intracutaneous administration have in common the fact that they are substances of a particulate nature ("particulates", e.g., emulsions and nanocrystalline suspensions) or large polymers (see above, WO 90/14846) . Considering their inadequate local and systemic compatibility as well as their small lymphatic passage, which causes inadequate diagnostic efficiency, the previously described preparations have not yet been proven to be optimally suitable for immediate lymphography.

Since the visualization of lymph nodes is of central importance for the early detection of metastatic disease in cancer patients, there is a great need for lymph-specific contrast medium preparations for the diagnosis of corresponding changes in the lymphatic system.

The highest possible contrast medium concentration and high stability are just as desirable as the diagnostically relevant, most uniform possible lymphatic concentration in several lymphatic units. Harmful consequences for the entire organism should be kept low by rapid and complete excretion of the contrast medium. A quick start, if possible already within a few hours after administration of the contrast medium, is important for radiological practice. Good compatibility is essential.

For this reason, it is most desirable to have available a contrast medium specific for lymph, which in the diagnostic session allows the visualization of both the primary tumor and the possible metastases of the lymph node.

The next important area in medicine is the determination, localization and monitoring of necrosis or infarction. Thus, myocardial infarction is not a stationary process, but rather a dynamic process that extends over a long period (weeks to months). The disease unfolds in approximately three phases that overlap rather than are strictly separate from each other. The first phase, the development of myocardial infarction, covers 24 hours after the infarction, when destruction from the subendocardium progresses towards the myocardium as a shock wave (wave front phenomenon). The second phase, the already existing infarction, includes the stabilization of the area in which the formation of fibers (fibrosis) occurs, which marks the healing process. The third stage, the healed infarct, begins after all the destroyed tissue has been replaced by fibrous scar tissue. During that period, extensive reconstruction takes place.

Until now, there is no known precise and reliable procedure that allows diagnosing the current stage of myocardial infarction in a living patient. For the assessment of myocardial infarction, it is of decisive importance to know the proportion of tissue that was lost in the infarction and at what point the loss occurred, since the type of therapy depends on this knowledge.

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

While the infarction can be healed to a certain extent, in the case of necrosis, locally limited tissue death, only the dangerous consequences for the rest of the organism can be prevented or at least reduced. Necrosis can develop in many ways: due to trauma, chemicals, lack of oxygen or radiation. As with infarction, knowledge of the extent and type of necrosis is important for further medical treatment.

Research to improve the localization of infarcts and necrosis using contrast media in non-invasive procedures, such as scintigraphy or nuclear spin tomography, has therefore already taken place earlier. The literature is replete with reports of attempts to use porphyrins to visualize necrosis. The results that have been achieved, however, give a contradictory picture. Winkelman and Hoyes thus describe in Nature, 200, 903 (1967) that manganese-5,10,15,20-tetrakis(4-sulfonatophenyl)-porphyrin (TPPS) selectively accumulates in the necrotic part of the tumor.

Lyon et al. (Magn. Res. Med. 4, 24 (1987)) noted, however, that manganese TPPS is dispersed in the body, especially in the kidney, liver, tumor and only in a small part of the muscles. In this case, it is preferable that the concentration in the tumor reaches its maximum only on the fourth day and only after the authors increased the dose from 0.12 mmol/kg to 0.2 mmol/kg. The authors therefore also talk about the non-specific uptake of TPPS into the tumor. Bockhurst et al., for their part, report in Acta Neurochir 60, 347 (1994, Suppl.) that MnTPPS binds selectively to tumor cells.

Foster et al. (J. Nucl. MED. 26, 756 (1985)), for their part, found that 111In-5,10,15,20-tetrakis-(4-N-methyl-pyridinium)-porphyrin (TMPyP) does not accumulate in the necrotic part, but more in the living marginal layers. It follows from the above that the interaction between porphyrin and tissue exists and is obvious but not necessary.

In Circulation Vol. 90, No.4 Part 2, Page 1468, Abstract No. 2512 (1994), Ni et al. report that they can visualize infarct areas with manganese-tetraphenyl-porphyrin (Mn-TPP) and gadolinium-mesoporphyrin (Gd-MP). In International Patent Application WO 95/31219 both substances were used to show necrosis and infarction. The authors Marchal and Ni write (see Example 3) that for the compound Gd-MP the metal content in the infarcted kidney was high, similar to that in non-infarcted organs, but was nine times higher for the myocardium in the case of infarcted tissue ( Example 1), It was surprising that the MRI signal intensity ratio for infarcted patients was comparably high compared to healthy tissue in both cases with 2.10 or 2.19. Other metalloporphyrins were described in Application DE 19835082 (Schering AG).

Porphyrins tend to be deposited in the skin, resulting in photosensitisation. Sensitization can last for days or even weeks. This is an unwanted side effect of using porphyrins as diagnostic agents. Additionally, the therapeutic index for porphyrins is only very small, since, e.g. for Mn-TPPS, the action is only effective at a dose of 0.2 mmol/kg, but the LD50 is already approximately 0.5 mmol/kg.

Contrast media for visualization of necrosis and infarction that are not derived from a porphyrin skeleton are described in DE 19744003 (Schering AG), DE 19744004 (Schering AG) and WO 99/17809 (EPIX). Today, however, there are still no compounds that can be satisfactorily used as contrast media for the visualization of infarction and necrosis.

The aim of the invention was therefore to make available contrast media that can be used especially for MRT-lymphography, but also for the diagnosis of tumors and for the visualization of necrosis and infarction.

The goal of the invention was achieved by metal complexes with polar radicals containing perfluoroalkyl, general formula I

(K)1-G - (Z-Rf)m

⎢ (I)

(R) p

where

Rf represents a perfluorinated, straight-chain or branched carbon chain of the formula -CnF2nE, in which E represents a terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, and n represents the numbers 4-30,

K represents a metal complex of the general formula II

[image]

where

R1 represents a hydrogen atom or the equivalent of a metal ion of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83, whereby it is ensured that at least two R1 represent equivalents of a metal ion,

R2 and R3, independently of each other, represent hydrogen, C1-C7 alkyl, benzyl, phenyl, -CH2OH or -CH2OCH3, and

U represents -C6H4-O-CH2-ω-, -(CH2)1-5-ω, phenylene group, -CH2-NHCO-CH2-CH(CH2COOH)-C6H4-ω-, C6H4-(OCH2CH2)0-1 -, N(CH2COOH)-CH2-ω or a C1-C12 alkylene group or a C7-C12-C6H4-O group which is optionally interrupted by one or more oxygen atoms, one to three -NHCO groups or one to three -CONH groups and /or is substituted with one to three -(CH2)0-5COOH groups, where ω represents the binding site for -CO-,

or

general formula III

[image] (III)

in which R1 has the meaning mentioned above, R4 represents hydrogen or the equivalent of the metal ion mentioned under R1, and U1 represents -C6H4-O-CH2-ω-, where ω represents the site of attachment to -CO-

or general formula IV

[image]

wherein R 1 and R 2 have the meaning mentioned above

or general formulas V A or V B

[image]

wherein R 1 has the meaning mentioned above,

or general formula VI

[image] (VI)

wherein R 1 has the meaning mentioned above,

or general formula VII

[image] (VII)

wherein R 1 has the meaning mentioned above, a

U1 represents -C6H4-O-CH2-ω-, where ω represents the binding site for -CO-, and in the radical K, optionally present free acidic groups can optionally be present as salts of organic and/or inorganic bases or amino acids or amino acid amides,

G represents a radical having a reactive functional group in at least three positions and which is selected from radicals a) to g) below

[image]

[image]

[image]

[image]

(h) such that G represents the radical (c) or (d) and R represents a complex selected from the general formulas II and V, R must not be identical to the radical K of the general formula I, if Z represents δ-C(O)CH2O (CH2)2-ε,

where α represents the binding site of G to complex K, β is the binding site of G to radical R, and γ represents the binding site of G to radical Z,

Z represents

[image]

γ-C(O)CH2O(CH2)2-ξ, where γ represents the binding site of Z to the radical G, and ξ represents the binding site of Z to the perfluorinated radical Rf,

R represents a polar radical selected from the complexes K of the general formulas II to VII, where R1 here represents a hydrogen atom or the equivalent of a metal ion of atomic numbers 20-29, 31-33, 37-39, 42-44, 49 or 57-83,

and the radicals R 2 , R 3 , R 4 , U and U 1 have the meanings indicated above, where in case G represents the radical (c) or (d) and R represents a complex selected from the general formulas II and V, R must not be identical radical K of the general formula I, if Z represents δ-C(O)CH2O(CH2)2-ε,

or

folic acid radical

or

R represents a carbon chain with 2-30 C atoms that is linked via -CO- or SO2- or by a direct bond to the radical G, straight-chain or branched, saturated or unsaturated, optionally terminated with one to ten oxygen atoms, with one to five -NHCO group, with one to five -CONH groups, with one to two sulfur atoms, with one to five -NH groups or with one to two phenylene groups, which can optionally be substituted with one to two OH groups, with one to two NH2 groups , with one to two -COOH groups, or with one to two -SO3H groups,

or

optionally substituted with one to eight OH groups, with one to five -COOH groups, with one to two -SO3H groups, with one to five NH2 groups, with one to five C1-C4 alkoxy groups, and

l, m, p independently represent integers 1 or 2.

If the compound according to the invention is intended to be used for NMR diagnostics, the metal ion of the signal transmitting group must be paramagnetic. These are especially bivalent and trivalent ions of elements with atomic numbers 21-29, 42, 44, and 58-70. Suitable ions are, for example, chromium(III) ion, iron(II) ion, cobalt(II) ion, nickel(II) ion, copper(II) ion, praseodymium(III) ion, neodymium(III) ion, samarium (III) ion and ytterbium(III) ion. Due to their strong magnetic moment, gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III), iron(III) and manganese(II) ions are particularly preferred.

For the use of the compounds according to the invention in nuclear medicine (radiodiagnosis and radiotherapy), the metal ions must be radioactive. For example, radioisotopes of elements with atomic 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 according to the invention is intended to be used in X-ray diagnostics, the metal ion is preferably derived from a higher atomic number element in order to achieve sufficient X-ray absorption. Diagnostic agents comprising a physiologically compatible complex salt with metal ions of the elements of atomic numbers 25, 26 and 39 as well as 57-83 have been found to be suitable for this purpose.

Manganese(II), iron(II), iron(III), praseodymium(III), neodymium(III), samarium(III), gadolinium(III), ytterbium(III) or bismuth(III) ions, and especially dysprosium(III) ) ions and yttrium(III) ions are preferred.

Acidic hydrogen atoms optionally present in R1, i.e. those that were not substituted by the central ion, can optionally be replaced completely or partially by cations of inorganic and/or organic bases or amino acids or amino acid amides.

Suitable inorganic cations are, for example, lithium ion, potassium ion, calcium ion and especially sodium ion. Suitable organic base cations are, i.a., those of primary, secondary or tertiary amines, such as, for example, 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 amides of otherwise acidic or neutral amino acids.

Compounds of the general formula I which are particularly preferred are those with a macrocyclic compound K of the general formulas II, III, VB or VII.

Radical U in the metal complex K is preferably -CH2- or C6H4-O-CH2-ω, where ω represents the binding site for -CO-.

The alkyl groups R2 and R3 in the macrocyclic compound of the general formula II can be straight-chain or branched. For example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-methyl-propyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, and 1,2-dimethylpropyl can be mentioned. R 2 and R 3 , independently of each other, preferably represent hydrogen or C 1 -C 4 -alkyl.

In a particularly preferred aspect, R 2 represents methyl and R 3 represents hydrogen.

The benzyl group of the phenyl group R2 or R3 in the macrocyclic compound K of the general formula II can also be substituted in the ring.

The polar radical R in the general formula I represents the complex K in a preferred aspect, the latter can also be a Ca2+ complex, preferably in addition to a Gd3+ complex or a Mn2+ complex. Complexes K of the general formulas II, III, VA or VII are particularly preferred as polar radicals R. The latter, as R1, is particularly preferred, exhibiting the equivalent of a metal ion of atomic numbers 20, 25 or 64.

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

[image]

[image]

-C(O)CH2O[(CH2)2O]4-CH3 is preferred.

In another preferred aspect, the polar radical R is a folic acid radical.

Of the compounds of general formula I according to the invention, those in which Rf represents -CnF2n+1 are additionally preferred. n, preferably, represents the numbers 4-15. Particularly preferred are the radicals -C4F9, -C6F13, C8F17, C12F25 and -C14F29, as well as the radicals of the compounds mentioned in the examples.

The radical G having a reactive functional group in at least three positions in the general formula I, which represents the "skeleton", represents the lysine radical (a) or (b) in a preferred aspect of the invention.

Z represents the linker indicated in the general formula I, wherein a radical is preferred

[image]

Metal perfluoroalkyl complexes with polar radicals of the general formula I

(K)1-G - (Z-Rf)m

⎢ (I)

(R) p

in which K, G, R, Z, Rf, l, m and p have the meanings indicated above,

were produced, in a manner known in the art, by reacting a carboxylic acid of the general formula IIa

[image] (IIa)

in which R5 represents the equivalent of a metal ion of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83, or a carboxylic protecting group, and R2, R3 and U have the aforementioned meaning, or by reacting a carboxylic acids of the general formula IIIa

[image] (IIIa)

wherein R 4 , R 5 and U 1 have the above-mentioned meaning

or by reacting a carboxylic acid of the general formula IVa

[image] (IVa)

wherein R 5 and R 2 have the meaning mentioned above

or by reacting a carboxylic acid of the general formula Va or Vb

[image]

wherein R 5 has the meaning mentioned above

or by reacting a carboxylic acid of the general formula VIa

[image] (VIa)

wherein R 5 has the meaning mentioned above

or by reacting a carboxylic acid of the general formula VIIa

[image] (VIIa)

wherein R 5 and U 1 have the meanings mentioned above,

in an optionally activated form with an amine of the general formula VIII

H -G - (Z-Rf)m

⏐ (VIII)

(R) p

wherein G, R, Z, Rf, m and p are as indicated, in the coupling reaction and optionally thereafter by cleavage of optionally present protecting groups to form a metal complex of general formula I.

or

if R5 represents a protecting group, by reacting after removal of these protecting groups in a subsequent step in a manner known in the art with at least one metal oxide or metal salt of the element of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83, and then, if desired, by substitution of optionally present acidic hydrogen atoms, cations of inorganic and/or organic bases, amino acids or amino acid amides.

The carboxylic acids of the general formulas IIa to VIIa used are either known compounds or are produced according to the procedure described in the examples. Thus, the production of carboxylic acids of the general formula IIa is known from DE 196 52 386. The production of carboxylic acids of the general formula IIIa can be carried out analogously to Example 4 of this application. The production of carboxylic acids of general formula IVa can be derived from DE 197 28 954.

The precursor for compounds of the general formula V A is N3-(2,6-dioxomorpholinoethyl)-N6-(ethoxycarbonylmethyl)-3,6-diaza-octanoic acid, which is described in EP 263 059.

Compounds of the general formula V B are derived from the isomeric diethylenetriamine-pentaacetic acid, which binds through the acetic acid that is on the central N atom. That DTPA is described in Patents DE 195 07 819 and DE 195 08 058.

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

Compounds of general formula VII are derived from 1-(4-carboxymethoxybenzyl)-ethylenediamine tetraacetic acid, the production of which was described in US Patent 4,622,420.

The production of amines of the general formula VIII is described in detail in the examples of this application and can be carried out analogously to the procedures described in the examples.

It has been shown that the metal complexes according to the invention are particularly suitable for NMR diagnostics and X-ray diagnostics, but also for radiodiagnostics and radiotherapy. The object of the invention is therefore also the use of perfluoroalkyl metal complexes according to the invention with polar radicals for the production of contrast media for use in NMR diagnostics and X-ray diagnostics, in particular for lymphography, for tumor diagnosis, and for imaging infarction and imaging necrosis, as well as for radiodiagnosis and radiotherapy. The compounds according to the invention are extremely well suited for use in interstitial lymphography and especially in intravenous lymphography. Additionally, they can also be used to visualize the vascular space (blood pool reagents).

The objects of the invention are also pharmaceutical agents containing at least one physiologically compatible compound according to the invention, optionally with additives commonly used in galenic laboratories.

The compounds of this invention are determined by very good systemic compatibility and high concentration in the lymph nodes of three consecutive lymph node units (which is important especially for i.v. lymphography). They are therefore particularly well suited for use in MRT lymphography.

The compounds according to the invention are also extremely suitable for determining and localizing vascular diseases, since they spread exclusively in the latter, when administered into the intravascular space. Compounds in accordance with the invention make it possible, with the help of nuclear spin tomography, to distinguish tissue with a good blood supply from one with a poor blood supply, thus diagnosing ischemia. Because of its own anemia, infarcted tissue can also be delineated from surrounding healthy or ischemic tissue when using contrast media in accordance with the invention. This is of particular importance if the point is, e.g., to distinguish myocardial infarction from ischemia.

Compared to macromolecular compounds previously used as blood pool agents, such as, preferably, Gd-DTPA-polyzine, the compounds according to the invention also show higher T1-relaxivity and are therefore delineated by increased signal intensity in NMR imaging. Since, in addition, they have a prolonged stay in the blood space, they can also be given in relatively small doses (e.g. 7 50 μmol Gd/l of body weight). The compounds according to the invention are, however, primarily eliminated from the body quickly and as completely as possible.

It has also been shown that compounds according to the invention accumulate in areas with increased vascular permeability, such as, e.g., in tumors; they make it possible to make a statement about tissue perfusion, provide the possibility of determining the volume of blood in tissues, in order to selectively shorten relaxation times or blood density, and to graphically visualize the permeability of blood vessels. Such physiological data cannot be obtained using extracellular contrast media, such as, for example, Gd-DTPA (Magnevist(R)). These considerations also result in their use in modern imaging procedures of nuclear spin tomography and computed tomography: specific diagnosis of malignant tumors, early therapeutic containment through cytostatic, antiphlogistic or vasodilatory therapy, early detection of poorly blooded areas (e.g., in the myocardium); angiography in vascular diseases, and detection and diagnosis of sterile or infectious inflammations.

The production of pharmaceutical agents according to the invention is carried out in a manner known in the art by suspending or dissolving complex compounds according to the invention in an aqueous medium and then optionally sterilizing the suspension or solution -- optionally with the addition of additives commonly used in galenic laboratories. Suitable additives are, for example, physiologically harmless buffers (such as, for example, tromethamine), complexing agent additives (such as, for example, diethylenetriamine-pentaacetic acid) or weak complexes or Ca-complexes corresponding to metal complexes in according to the invention or -- if necessary -- electrolytes such as, for example, sodium chloride or -- if necessary -- antioxidants, such as, for example, ascorbic acid.

If suspensions or solutions of the agents according to the invention in water or physiological saline are intended for enteral or parenteral administration or other purposes, they are mixed with one or more adjuvants commonly used in galenic laboratories [for example, methyl cellulose, lactose, mannitol] and/or surfactant(s) [for example, lecithins, Tween(R), Myrj(R)] and/or flavor enhancers [for example, essential oils].

Basically, it is also possible to produce a pharmaceutical agent according to the invention without isolating the complexes. In any case, special attention should be paid to carrying out the chelation so that the complexes according to the invention are practically free of uncomplexed metal ions that have a toxic effect.

This can be ensured, for example, with the help of a color indicator, such as xylenol orange, by control titrations during the production process. The invention therefore also relates to a process for the production of complex compounds and their salts. Purification of the isolated complex remains as a final precaution.

For in-vivo administration of the agents according to the invention, the latter can be administered together with a suitable carrier, such as, for example, serum or physiologically normal saline and together with another protein, such as, for example, human serum albumin ( HSA).

The agents according to the invention are usually administered parenterally, preferably i.v. They can also be administered intravascularly or interstitially/intracutaneously depending on whether body vessels or tissue are to be analyzed.

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

The agents according to the invention meet the requirements for suitability as contrast media for nuclear spin tomography. After oral or parenteral administration, they are therefore extremely well suited to enhance the informational value of the image obtained by nuclear spin tomography by enhancing the signal intensity. They also show high efficiency, which is necessary in order to burden the body with the smallest possible amount of foreign substances and good compatibility, which is necessary in order to maintain the non-invasive character of the analyses.

Good water solubility and low osmolarity of the agents according to the invention make it possible to produce highly concentrated solutions, in order to keep the volume load on the circulatory system within reasonable limits and to alleviate the dilution of body fluids. Additionally, the agents according to the invention show not only high stability in vitro, but also surprisingly high stability in vivo, so that the release or replacement of ions -- which are inherently toxic -- and bound to the complexes can only occur extremely slowly. within the time in which the new contrast media is completely secreted again.

In general, agents according to the invention for use as agents for NMR diagnostics are dosed in amounts of 0.001-5 mmol/kg, preferably 0.005-0.5 mmol/kg.

The complex compounds according to the invention can also advantageously be used as sensitivity reagents and as shift reagents ("shift" reagents) for in-vivo NMR spectroscopy.

Based on their advantageous radioactive properties and the good stability of the complex compounds contained therein, the agents according to the invention are also suitable as radiodiagnostic agents. Details of such use and dosage are described in, e.g., "Radiotracers for Medical Applications," CRC Press, Boca Raton, Florida.

The compounds and agents of the invention can also be used in positron emission tomography, which uses positron-emitting isotopes, such as, e.g., 43Sc, 44Sc, 52Fe, 55Co, 68Ga, and 86Y (Heiss, W. D.; Phelps, M. E.; Positron Emission Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York 1983).

The compounds according to the invention are also suitable, surprisingly enough, for distinguishing between malignant and benign tumors in areas without blood-brain barriers.

They are also unique in that they are completely eliminated from the body and are therefore well tolerated.

Since the substances according to the invention accumulate in malignant tumors (no diffusion into healthy tissue, only high permeability of tumor vessels), they can also support radiation therapy of malignant tumors. The latter is determined from the respective diagnoses only by the amount and type of isotope used. In this case, the purpose is to destroy tumor cells with high-energy short-wave radiation with the smallest possible scope of action. For this purpose, interactions of metals (such as, e.g., iron or gadolinium) that are in complexes with ionizing radiation (e.g., X rays) or with neutron rays are used. This effect significantly increases the local dose of radiation in the place where the metal complex is located (e.g., in tumors). In order to achieve the same dose of radiation in the malignant tissue, the radiation exposure of the healthy tissue can be significantly reduced when such metal complexes are used, and thus side effects that impose a burden on the patients are avoided. The metal complex conjugates according to the invention are therefore also suitable as radiosensitizing substances in radiation therapy of malignant tumors (e.g., using the Mossbauer effect or in neutron capture therapy). Suitable β-emitter ions are, for example, 46Sc, 47Sc, 48Sc, 72Ga, 73Ga and 90Y. The following α-emitter ions have suitable short half-lives, for example, 211Bi, 212Bi, 213Bi and 214Bi, with 212Bi being preferred. A suitable ion that emits photons and electrons is 158Gd which can be obtained from 157Gd by neutron capture.

If the agent according to the invention is intended to be used in a variant of radiation therapy proposed by R.L. Mills et al. (Nature Vol. 336, (1988), p. 787), the central ion must be derived from a Mossbauer isotope, such as, for example, 57Fe or 151Eu.

In the in-vivo administration of the agents according to the invention, the latter can be administered together with a suitable carrier, such as, for example, serum, or physiologically normal saline and together with another protein, such as, for example, human serum albumin . In this case, the dosage depends on the type of cellular disorder, the metal ion used and the type of imaging method.

The agents according to the invention are usually administered parenterally, preferably i.v. They can also -- as already discussed -- be administered intravascularly or interstitially/intracutaneously depending on whether body vessels or tissue are being analyzed.

The means according to the invention are extremely well suited as contrast media for X-rays, where it should be particularly emphasized that manifestations of anaphylactic-like reactions, known with iodine-containing contrast media, cannot be found during their biochemical-pharmacological tests. Because of their advantageous absorption characteristics in the high voltage regions of the electron tube, they are particularly valuable for digital subtraction techniques.

In general, agents according to the invention for use as contrast media for X-rays, analogous to the example with meglumine-diatrizoate, are dosed in amounts of 0.1-5 mmol/kg, preferably 0.25-1 mmol/kg.

In particular, higher blood concentrations are achieved with compounds according to the invention than with extracellular contrast media. They spread after i.v. given only in the intravascular space and thus have a decisive advantage compared to extracellular contrast media.

Aspects

Example 1a

2-N-trifluoroacetyl-6-N-benzyloxycarbonyl-lysine

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

Yield: 128.9 g (96% of theoretical) colorless, crystalline powder.

Elementary analysis:

Cld: C 51.07 H 5.09 F 15.14 N 7.44

Fnd. C 51.25 H 5.18 F 15.03 N 7.58

Example 1b

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

164.2 g (0.664 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) was added at 0°C to 125 g (332 mmol) of the title compound from Example la and 188.7 g (332 mmol) 1-perfluorooctylsulfonyl-piperazine, (produced according to DE 19603033) in 800 ml of tetrahydrofuran, and was stirred overnight at room temperature. It was evaporated to dryness in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20 : 1)

Yield: 286 g (93% of theoretical) colorless solid.

Elementary analysis:

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

Fnd: C 36.18 H 2.94 F 40.87 N 5.98 S 3.40

Example 1c

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

Ammonia (gas) was introduced at 0°C for one hour into a solution consisting of 280 g (302.2 mmol) of the title compound from Example 1b in 2000 ml of ethanol. It was then stirred for 4 hours at 0° C. It was evaporated to dryness, and the precipitate was absorptively precipitated from water. The solid was filtered off and dried in a vacuum (50° C).

Yield: 243.5 g (97% of theoretical) amorphous solid.

Elementary analysis:

Cld: C 37.60 H 3.28 F 38.89 N 6.75 S 3.86

Fnd: C 37.15 H 3.33 F 38.78 N 6.68 S 3.81

Example 1d

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

A solution consisting of 19.93 g (70 mmol) of 3,6,9,12,15-pentaoxahexadecanoic acid chloride in 50 ml of dichloromethane was added dropwise at 0°C to the title compound from Example 1c (50 g; 60.20 mmol) and triethylamine (7.10 g; 70 mmol), dissolved in 350 ml of dichloromethane and stirred for 3 hours at 0°C. 200 ml of a 5% aqueous solution of hydrochloric acid was added and stirred for 5 minutes at room temperature. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The precipitate was chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 15:1).

Yield: 53.7 g (93% of theory) colorless, viscous oil.

Elementary analysis:

Cld: C 33.83 H 4.94 F 3.34 N 5.84 S 33.69

Fnd: C 33.75 H 5.05 F 3.29 N 5.78 S 33.75

Example 1e

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

50 g (52.15 mmol) of the title compound from Example 1d was dissolved in 500 ml of ethanol, and 6 g of palladium catalyst (10% Pd/C) was added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum.

Yield: 43.0 g (quantitative) colorless solid.

Elementary analysis:

Cld: C 27.68 H 5.01 F 39.17 N 6.79 S 3.89

Fnd: C 27.60 H 5.13 F 39.09 N 6.68 S 3.81

Example 1f

6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)-2- N-(3,6,9,12,15-pentaoxahexadecanoyl)-lysine[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex

20 g (24.25 mmol) of the title compound from Example 1e, 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, Gd complex, was dissolved in 200 ml of dimethylsulfoxide with gentle heating. At 10°C, 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide was added and stirred overnight at room temperature. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 28.21 g (81% of theoretical) colorless solid.

Water content: 11.0%

Elemental analysis (refers to anhydrous substance)

Cld: C 31.78 H 4.84 F 22.49 N 8.78 S 2.23 Gd 10.95

Fnd: C 31.74 H 4.98 F 22.39 N 8.69 S 2.15 Gd 10.87

Example 2a

6-N-[3,9-bis(t-butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid bis(t-butylester)-6-carbonylmethyl]-2-N-[3,6 ,9,12,15-pentaoxahexadecanoyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide was added at 0°C to a solution consisting of 20 g (24.08 mmol) of the title compound from Example 1e, 14.88 g (24.08 mmol) of bis(t-butyl ester) 3,9- bis(t-butyloxycarbonylmethyl-3,6,9-triazaundecane-1,11-dicarboxylic acid and 2.77 g (24.08 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide. Stir for 3 hours at 0 C, then overnight at room temperature The precipitated urea was filtered off, the filtrate was evaporated to dryness under vacuum and chromatographed on silica gel (mobile solvent = dichloromethane/ethanol = 20 : 1).

Yield: 31.61 g (91% of theoretical) viscous oil.

Elementary analysis:

Cld: C 40.80 H 6.71 F 22.39 N 6.80 S 2.22

Fnd: C 40.72 H 6.82 F 22.30 N 6.75 S 2.14

Example 2b

6-N-[6-carbonylmethyl-3,9-bis(carboxylatomethyl)-3,6,9-triazaundecanedicarboxylic acid-1-carboxy-11-carboxylato-]-2-N-(3,6,9,12, 15-Pentaoxahexadecanoyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd-complex. Sodium salt.

30 g (20.8 mmol) of the title compound from Example 2a was dissolved in 300 ml of trifluoroacetic acid and stirred for 5 hours at room temperature. It was evaporated to dryness, the precipitate was taken up in 300 ml of water and adjusted to pH 2.5 with 10% aqueous NaOH. Then 3.77 g (10.4 mmol) of gadolinium oxide was added, and it was stirred for 3 hours at 60 C. It was allowed to reach room temperature, and the pH was adjusted to 7.4 with sodium hydroxide solution. It was evaporated to dryness and the residue was purified on silica gel RP-18. (mobile solvent : gradient consisting of water/acetonitrile).

Yield: 19.18 g (67% of theoretical) colorless amorphous solid.

Water content 9.8 %

Elemental analysis: (refers to anhydrous substance)

Cld: C 28.80 H 4.25 F 23.47 N 7.12 S 2.33 Gd ll.48 Na 1.67

Fnd: C 28.67 H 4.34 F 23.38 N 7.03 S 2.27 Gd 11.37 Na 1.74

Example 3a

Lysine-[1-(4-perfluorooctylsulfonyl-piperazine]-amide).

20 g (24.08 mmol) of the title compound from Example 1c was dissolved in 300 ml of ethanol, and 4 g of palladium catalyst (10% Pd/C) was added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum.

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

Elementary analysis:

Cld: C 31.04 H 3.04 F 46.38 N 8.04 S 4.60

Fnd: C 30.97 H 3.15 F 46.31 N 7.98 S 4.51

Example 3b

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

10 g (14.36 mmol) of the title compound from Example 3a, 3.34 g (29 mmol) of N-hydroxysuccinimide, 2.54 g (mmol) of lithium chloride and 18.26 g (29 mmol) of 1,4,7-tris(carboxylatomethyl)-10-( 3-aza-4-oxo-5-methyl-5yl) 1,4,7,10-tetraazacyclododecane-Gd-complex was dissolved with gentle heating in 200 ml of dimethylsulfoxide. At 10°C, 12.38 g (60 mmol) of N,N-dicyclohexylcarbodiimide was added and stirred overnight at room temperature. The solution was poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient: water/ethanol/acetonitrile). Yield: 19.02 g (69% of theoretical) colorless solid

Water content: 11.3%

Elemental analysis: (refers to anhydrous substance)

Cld: C 35.03 H 4.04 F 16.82 N 10.21 S 1.67 Gd 16.38

Fnd: C 34.96 H 4.13 F 16.74 N 10.16 S 1.61 Gd 16.33

Example 4a

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

233.8 g (1.4 mol) of 2-ethyl bromoacetic acid was added to 200 g (1,204 mol) of 4-methyl ester of hydroxyphenylacetic acid and 212 g (2 mol) of sodium carbonate in 2,000 ml of acetone and refluxed for 5 hours. The solid was filtered off and evaporated in vacuo to dryness. The precipitate was chromatographed on silica gel (mobile solvent: n-hexane/ethyl acetate = 15:1).

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

Elementary analysis:

Cld: C 61.90 H 6.39

Fnd: C 61.75 H 6.51

Example 4b

2-[4-(3-Ethyl ester of oxapropionic acid)]-phenyl-2-methyl ester of bromoacetic acid

201 g (1.13 mol) of N-bromosuccinimide and 100 mg of dibenzyl peroxide were added to 285 g (1.13 mol) of the title compound from Example 4a, dissolved in 2000 ml of carbon tetrachloride, and refluxed for 8 hours. It was cooled in an ice bath, the precipitated succinimide was filtered off, and the filtrate was evaporated to dryness under vacuum. The precipitate was purified with silica gel (mobile solvent: n-hexane/acetone = 15:1).

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

Elementary analysis:

Cld: C 47.28 H 4.57 Br 24.16

Fnd: C 47.19 H 4.71 Br 24.05

Example 4c

2-[4-(3-ethyl ester of oxapropionic acid)]-phenyl-2-[1-(1,4,7,10-tetraazacyclododecan-7-yl] acetic acid methyl ester

350 g (1.057 mol) of the title compound from Example 4b was added to 603 g (3.5 mol) of 1,4,7,10-tetraazacyclododecane in 6000 ml of chloroform and stirred overnight at room temperature. It was extracted 3 times with 3000 ml of water, the organic phase was dried over magnesium sulfate and evaporated in a vacuum to dryness. The precipitate was used in the next reaction (3d) without further purification.

Yield: 448 g (quantitative) of viscous oil.

Elementary analysis:

Cld: C 59.70 H 8.11 N 13.26

Fnd: C 59.58 H 8.20 N 13.18

Example 4d

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

445 g (1.053 mol) of the title compound from Example 4c and 496 g (5.27 mol) of chloroacetic acid were dissolved in 4000 ml of water. Using a 30% aqueous sodium hydroxide solution, the pH was adjusted to 10. It was heated to 70°C, and the pH was maintained at 10 by adding a 30% aqueous sodium hydroxide solution. It was mixed for 8 hours at 70°C. Then the pH was adjusted to 13 and the solution was refluxed for 30 minutes. The solution was cooled in an ice bath, and the pH was adjusted to 1 by adding concentrated hydrochloric acid. It was evaporated to dryness under vacuum. The precipitate was taken in 4000 ml of methanol and absorptively precipitated for one hour at room temperature. The precipitated common salt was filtered off, the filtrate was evaporated to dryness, and the precipitate was purified on silica gel RP-18 (mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 403 g (69% of theoretical) colorless solid.

Water content: 10.2%

Elemental analysis: (refers to anhydrous substance)

Cld: C 51.98 H 6.18 N 10.10

Fnd: C 51.80 H 6.31 N 10.01

Example 4e

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

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

Yield: 511 g (quantitative) of amorphous solid.

Water content: 11.0%

Elemental analysis: (refers to anhydrous substance)

Cld: C 40.67 H 4.41 Gd 22.19 N 7.98

Fnd: C 40.51 H 4.52 Gd 22.05 N 8.03

Example 4f

2,6-N,N'-bis{2-[4-(3-oxapropionyl)-phenyl]-2-[1,4,7-tris (carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10 -yl]-acetic acid]-lysine-[4-perfluorooctylsulfonyl)-piperazine]-amide, digadolinium complex, disodium salt

10 g (14.36 mmol) of the title compound from Example 3a, 3.45 g (30 mmol) of N-hydroxysuccinimide, 2.54 g (60 mmol) of lithium chloride and 21.26 g (30 mmol) of the title compound from Example 4e were dissolved with gentle heating in 250 ml dimethylsulfoxide. At 10°C, 16.51 g (80 mmol) of N,N-dicyclohexylcarbodiimide were added, and the mixture was stirred overnight at room temperature. The solution was poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography (silica gel RP-18, mobile solvent: gradient consisting of: water/ethanol/acetonitrile). It was dissolved in a little water, the pH was adjusted to 7.4 using a sodium hydroxide solution, and it was freeze-dried.

Yield: 21.02 g (69% of theoretical) colorless solid.

Water content: 11.2%

Elemental analysis: (refers to anhydrous substance)

Cld: C 37.36 H 3.66 F 15.22 Gd 14.82 N 7.92 Na 2.17 S 1.51

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

Example 5a

2,6-N,N'-bis[6-carbonylmethyl-3,9-bis(t-butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid-bis(t-butylester)]-lysine -[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

A solution consisting of 10 g (14.36 mmol) of the title compound from Example 3a, 18.53 g (30 mmol) of 3,9-bis(t-butyloxycarbonylmethyl)-6-carboxymethyl-3,6,9-triazaundecane-1,11- dicarboxylic acid-bis(t-butyl ester) and 3.45 g (30 mol) of N-hexoxysuccinimide, dissolved in 150 ml of dimethylformamide, 10.32 g (50 mmol) of N,N-dicyclohexylcarbodiimide were added at 0°C. It was mixed for 3 hours at 0°C, then overnight at room temperature. The precipitated urea was filtered off, the filtrate was evaporated to dryness in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 19.60 g (72% of theoretical) viscous oil.

Elementary analysis:

Cld: C 49.41 H 6.75 F 17.03 N 7.39 S 1.69

Fnd: C 49.35 H 6.82 F 16.92 N 7.32 S 1.62

Example 5b

2,6-N,N-bis[6-carbonylmethyl-3,9-bis(carboxylatomethyl)-3,6,9-triazaundecanedicarboxylic acid-1-carboxy-11-carboxylato-lysine-[1-(4-perfluorooctylsulfonyl) -piperazine]-amide, Gd-complex, sodium salt]

15 g (7.91 mol) of the title compound from Example 5a was dissolved in 50 ml of chloroform, and 200 ml of trifluoroacetic acid was added. It was mixed for 10 minutes at room temperature. It was evaporated to dryness in a vacuum, and the precipitate was dissolved in 150 ml of water. 2.87 g (7.91 mmol) of gadolinium oxide was added and stirred for 5 hours at 80°C. It was allowed to cool at room temperature and the Ph was adjusted to 7.4 using 2N sodium hydroxide solution. The solution was evaporated to dryness in vacuo and purified on RP-18 (mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 8.11 g (57% of theoretical) colorless, amorphous solid.

Water content: 9.6%

Elemental analysis: (refers to anhydrous substance)

Cld: C 30.70 H 3.08 Gd 17.48 N 7.78 Na 2.56 S 1.78

Fnd: C 30.58 H 3.19 Gd 17.42 N 7.71 Na 2.68 S 1.72

Example 6a

6-N-benzyloxycarbonyl-2-N-[6-carboxylmethyl-3,9-bis(t-butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid-bis(t-butylester)]-lysine -[1(4-perfluorooctylsulfonyl)-piperazine]-amide

A solution consisting of 20 g (24.08 mmol) of the title compound from Example 1c, 14.88 g (24.08 mmol) of 3,9-[bis(t-butyloxycarbonylmethyl)-6-carboxymethyl-3,6,9-triazaundecane-1,11 -dicarboxylic acid-bis(t-butyl ester) and 2.88 g (25 mol) of N-hydroxysuccinimide, dissolved in 100 ml of dimethylformamide, 8.25 g (40 mol) of N,N-dicyclohexylcarbodiimide were added at 0°C. It was mixed for 3 hours at 0°C, then overnight at room temperature. The precipitated urea was filtered off, the filtrate was evaporated to dryness in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 27.21 g (79% of theoretical) viscous oil.

Elementary analysis:

Cld: C 47.03 H 5.64 F 22.58 N 6.85 S 2.24

Fnd: C 49.64 H 5.58 F 22.65 N 6.84 S 2.31

Example 6b

2-N[carbonylmethyl-3,9-bis(t-butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid-bis(t-butylester)-lysine-[1-(4-perfluorooctylsulfonyl)- piperazine]-amide]

25 g (17.48 mmol) of the title compound from Example 6a was dissolved in 350 ml of ethanol, and 5 g of palladium catalyst (10% Pd/C) was added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum.

Yield: 22.66 g (quantitative) of colorless solid.

Elementary analysis:

Cld: C 44.48 H 5.75 F 24.92 N 7.56 S 2.47

Fnd: C 44.59 H 5.81 F 25.03 N 7.46 S 2.52

Example 6c

6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5yl)]-2-N -[6-carbonylmethyl-3,9,bis(t-butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid-bis(t-butyl ester)]-lysine-[1-(4-perfluorooctylsulfonyl) -piperazine-]-amide, Gd complex

20 g (15.43 mmol) of the title compound from Example 6b, 1.78 g (15.43 mmol) of N-hydroxysuccinimide, 1.48 g (35 mmol) of lithium chloride and 9.72 g (15.43 mmol) of 1,4,7-tris(carboxylatomethyl)-10- (3-aza-4-oxo-5-methyl-5yl)-pentanoic acid-1,4,7,10-tetraazacyclododecane, Gd complex were dissolved with gentle heating in 150 ml of dimethyl sulfoxide. At 10°C, 5.16 g (25 mmol) of N,N-dicyclohexylcarbodiimide was added and stirred overnight at room temperature. The solution was poured into 2500 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 22.94 g (78% of theoretical) colorless solid

Water content: 7.9%

Elemental analysis: (refers to anhydrous substance)

Cld: C 42.22 H 5.29 F 16.95 Gd 8.25 N 8.82 S 1.68

Fnd: C 42.15 H 5.41 F 16.87 Gd 8.13 N 8.70 S 1.60

Example 6d

6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(3-aza-4-oxo-5-methyl-5-yl)pentanoyl]-2- N-[carbonylmethyl-3,9-bis(carboxylatomethyl)-3,6,9-triazaundecanedicarboxylic acid-carboxy-11-carboxylato-2]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, digadolinium complex , sodium salt

20 g (10.49 mmol) of the title compound from Example 6c was dissolved in 200 ml of trifluoroacetic acid. It was mixed for 60 minutes at room temperature. It was evaporated to dryness in a vacuum, and the precipitate was dissolved in 150 ml of water. 1.90 g (5.25 mmol) of gadolinium 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 using sodium hydroxide solution. The solution was evaporated to dryness in vacuo and purified on silica gel RP-18 (mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 11.89 g (61% of theoretical) colorless, amorphous solid

Water content: 10.2%

Elemental analysis: (refers to anhydrous substance)

Cld: C 32.97 H 3.47 F 17.39 Gd 16.93 N 9.05 Na 1.24 S 1.73

Fnd: C 32.90 H 3.53 F 17.31 Gd 16.87 N 8.92 Na 1.33 S 1.67

Example 7a

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

100 g (376.2 mmol) of 1,2-di-O-benzyl-glycerol [produced according to Chem. Phys. Lipids (1987), 43(2), 113-27] and 5 g of tetrabutyl ammonia hydrogen sulfate was dissolved in a mixture consisting of 400 ml of toluene and 200 ml of a 50% aqueous solution of sodium hydroxide. At 0°C, 78 g of t-butyl ester of 2-bromoacetic acid was added dropwise over 30 minutes, and then stirred for 3 hours at 0°C. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The precipitate was chromatographed on silica gel (mobile solvent: n-hexane/acetone = 20:1).

Yield: 133.4 g (94% theoretical) colorless oil.

Elementary analysis:

Cld: C 71.48 H 7.82

Fnd: 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 from Example 7a was dissolved in 200 ml of dichloromethane, and 100 ml of trifluoroacetic acid was added at 0°. It was stirred for 4 hours at room temperature and then evaporated in a vacuum to dryness. The precipitate was crystallized from pentane/diethyl ether.

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

Elementary analysis:

Cld: C 69.07 H 6.71

Fnd: C 69.19 H 6.82

Example 7c

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

50 g (60.20 mmol) of the title compound from 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, 4,7,10-tetraazacyclododecane-10-pentanoyl-3-aza-4-oxo-5-methyl-5yl), Gd complex, were dissolved with gentle heating 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 precipitated solid was filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 75.53 g (87% of theoretical) colorless solid

Water content: 10.1%

Elemental analysis: (refers to anhydrous substance)

Cld: C 37.48 H 3.84 F 22.39 Gd 10.90 N 8.74 S 2.22

Fnd: C 37.39 H 4.02 F 22.29 Gd 10.75 N 8.70 S 2.22

Example 7d

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

70 g (48.53 mmol) of the title compound from Example 7c was dissolved in 500 ml of water/100 ml of ethanol, and 5 g of palladium catalyst (10% Pd/C) were added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum.

Yield: 63.5 g (quantitative) colorless solid.

Water content 9.8%

Elemental analysis: (refers to anhydrous substance)

Cld: C 37.48 H 3.84 F 22.39 Gd 10.90 N 8.74 S 2.22

Fnd: C 37.39 H 4.03 F 22.31 Gd 10.78 N 8.65 S 2.20

Example 7e

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

10 g (7.64 mmol) of the title compound from Example 7d, 3.30 g (10 mmol) of the title compound from Example 7b, 0.85 g (20 mmol) of lithium chloride and 1.15 g (10 mmol) of N-hydroxysuccinimide were dissolved in 150 ml of dimethyl sulfoxide. At 10°C, 3.10 g (15 mmol) of N,N'dicyclohexylcarbodiimide was added and stirred for 8 hours at room temperature. The reaction solution was poured into 2000 ml of acetone, and the settled precipitate was isolated. It was purified on silica gel RP-18 (mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 11.14 g (90% of theoretical) colorless, amorphous solid

Water content: 4.3%

Elemental analysis: (refers to anhydrous substance)

Cld: C 41.51 H 4.29 F 19.93 N 7.78 Gd 9.70 S 1.98

Fnd: C 41.45 H 4.38 F 19.84 N 7.70 Gd 9.58 S 1.90

Example 7f

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

10 g (6.17 mmol) of the title compound from Example 7e were dissolved in 200 ml of ethanol, and 3 g of palladium catalyst (10% Pd/C) were added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum. Yield: 8.89 g (quantitative) of a colorless solid.

Water content 3.1%

Elemental analysis: (refers to anhydrous substance)

Cld: C 35.03 H 3.99 F 22.42 Gd 10.92 N 8.75 S 2.23

Fnd: C 34.94 H 4.12 F 22.30 Gd 10.78 N 8.71 S 2.18

Example 8a

6-N-benzyloxycarbonyl-2-N-[5,6-bis(benzyloxy)-3-oxa-hexanoyl]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

To a solution consisting of 20 g (24.08 mmol) of the title compound from Example 1c, 9.91 g (30 mmol) of the title compound from Example 7b and 3.45 g (30 mmol) of N-hydroxysuccinimide, dissolved in 100 ml of dimethylformamide, was added 9.28 g ( 45 mol) of N,N-dicyclohexylcarbodiimide at 0°C. It was mixed for 3 hours at 0°C, then overnight at room temperature. The precipitated urea was filtered off, the filtrate was evaporated to dryness in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/ethanol = 20:1). Yield: 24.50 g (89% of theoretical) viscous oil.

Elementary analysis:

Cld: C 47.29 H 4.14 F 28.26 N 4.90 S 2.81

Fnd: C 47.14 H 4.26 F 28.17 N 4.91 S 2.69

Example 8b

2-N-(5,6-dihydroxy-3-oxahexanoyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

20 g (17.5 mmol) of the title compound from Example 8a was dissolved in 300 ml of ethanol, and 5 g of palladium catalyst (10% Pd/C) was added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum.

Yield: 17.65 g (quantitative) colorless solid.

Elementary analysis:

Cld: C 44.05 H 4.10 F 32.02 N 5.55 S 3.18

Fnd: C 43.96 H 4.21 F 31.94 N 5.48 S 3.24

Example 8c

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

15 g (14.87 mmol) of the title compound from 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-5-methyl-5-yl)-pentanoic acid-1,4,7,10-tetraazacyclododecane, Gd complex were dissolved with gentle heating in 100 ml of dimethyl sulfoxide. At 10°C, 5.16 g (25 mmol) of N,N-dicyclohexylcarbodiimide was added and stirred overnight at room temperature. The solution was poured into 1500 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 19.28 g (80% of theoretical) colorless solid

Water content: 10.3%

Elemental analysis: (refers to anhydrous substance)

Cld: C 41.51 H 4.29 F 19.93 Gd 9.70 N 7.78 S 1.98

Fnd: C 41.37 H 4.40 F 19.88 Gd 9.58 N 7.67 S 1.85

Example 9a

6-N-benzyloxycarbonyl-2-N-[2,6-N,N'-bis(benzyloxycarbonyl)-lysyl]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

20 g (24.08 mmol) of the title compound from 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'-Z-lysine paranitrophenol ester were added. . It was mixed for 5 hours at 50°C. It was evaporated to dryness under vacuum, and the residue was chromatographed on silica gel.

Mobile solvent: dichloromethane/methanol = 20 : 1).

Yield: 28.07 g (95% of theoretical) colorless solid

Elementary analysis:

Cld: C 46.99 H 4.19 F 26.32 S 2.61

Fnd: C 47.08 H 4.32 F 26.21 S 2.54

Example 9b

2-N-(lysyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, trihydrobromide

100 ml of hydrobromic acid in glacial acetic acid (48%) was added to 25 g (20.37 mmol) of the title compound from Example 9a, and it was stirred for 2 hours at 40°C. It was cooled to 0°C, 1500 ml of diethyl ester was added dropwise, and the precipitated solid was filtered off. After drying in vacuum (60°C), 21.52 g (99% of theory) of slightly yellowish crystalline solid was obtained.

Elementary analysis:

Cld: C 27.01 H 3.40 Br 22.46 F 30.26 N 7.87 S 3.00

Fnd: C 26.92 H 3.53 Br 22.15 F 30.14 N 7.69 S 2.87

Example 9c

6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5yl)]-2-N -[2,6-N,N'-bis-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5- methyl-5-yl)]lysyl]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, trigadolinium complex

31.49 g (50 mmol) 1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl) pentanoic acid, gd complex 6.91 g (60 mmol) N-hydroxysuccinimide and 4.24 g (100 mmol) of lithium chloride were dissolved in 350 ml of dimethyl sulfoxide with gentle heating. At 10°C, 16.51 g (80 mmol) of N,N-dicyclohexylcarbodiimide were added and the mixture was stirred for 5 hours at 10°C. 10 g (9.37 mmol) of the title compound from Example 9b and 3.03 g (30 mmol) of triethylamine were added to that mixture, and it was stirred for 12 hours at 60°C. The solution was poured into 1500 ml of acetone and stirred for 10 minutes. It was allowed to cool to room temperature and the mixture was poured into 3000 ml of acetone. The settled precipitate was filtered off, purified on silica gel RP-18 (mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 16.7 g (67% of theoretical) colorless solid

Water content: 7.9%

Elemental analysis: (refers to anhydrous substance)

Cld: C 36.58 H 4.43 F 12.14 Gd 17.74 N 11.06 S 1.14

Fnd: C 36.47 H 4.54 F 12.03 Gd 17.65 N 10.95 S 1.21

Example 10a

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

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

Yield: 19.13 g (42% of theoretical) colorless solid.

Elementary analysis:

Cld: C 61.03 H 7.61 N 8.13

Fnd: C 60.92 H 7.75 N 8.04

Example 10b

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

12.36 g (50 mmol) of EEDQ (ethyl ester of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) was added at 0°C to a mixture of 18 g (26.91 mmol) of the title compound from Example 10a and 14.05 g (26.91 mmol) 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid, produced in accordance with DE 19603033, in 300 ml of tetrahydrofuran, and was stirred overnight at room temperature. It was evaporated to dryness in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

Yield: 21.51 g (67% of theoretical) colorless solid.

Elementary analysis:

Cld: C 47.32 H 4.82 F 27.07 N 4.70

Fnd: C 47.26 H 5.01 F 26.94 N 4.59

Example 10c

1-(3,6,9,12,15-pentaoxahexadecanoyl)-7-(2H,2H,4H,4H,5H,5H-3-oxaperfluorotridecanoyl)-1,4,7,10-tetraazacyclododecane

20 g (16.77 mmol) of the title compound from Example 1d were dissolved in 200 ml of ethanol, and 2.5 g of palladium catalyst (10% Pd/C) were added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum.

Yield: 15.5 g (quantitative) colorless solid.

Elementary analysis:

Cld: C 40.27 H 4.90 F 34.93 N 6.06

Fnd: C 40.15 H 4.99 F 34.87 N 5.94

Example 10d

1,7-bis(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]- 4-(3,6,9,12,15-pentaoxahexadecanoyl)-10-(2H,2H,4H,4h,5H,5H-3-oxaperfluorotridecanoyl)-1,4,7,10-tetraazacyclododecane, Gd complex

15 g (16.22 mmol) of the title compound from 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-5-methyl-5-yl)-pentanoic acid, Gd complex, was dissolved with gentle heating in 300 ml of dimethyl sulfoxide. At 10°C, 24.73 g (100 mmol) of EEDQ was added and stirred overnight at room temperature. The solution was poured into 3000 ml of acetone and stirred for 10 minutes.

The precipitated solid was filtered off and then purified by chromatography (silica gel RP-18) (mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 19.86 g (57% of theoretical) colorless solid

Water content: 11.3%

Elemental analysis: (refers to anhydrous substance)

Cld: C 38.58 H 4.74 F 15.04 Gd 14.64 N 9.13

Fnd: C 38.47 H 4.91 F 14.95 Gd 14.57 N 9.04

Example 11a

3,5-dinitrobenzoic acid-1-[(4-perfluorooctylsulfonyl)-piperazine]-amide

A solution consisting of 8.76 g (38 mmol) of 3,5-dinitrobenzoyl chloride in 55 ml of dichloromethane was added dropwise at 0°C to a mixture of 20 g (35.2 mmol) of perfluorooctylsulfonyl-piperazine and 8.1 g (80 mmol) of triethylamine, dissolved in 200 ml of dichloromethane and stirred for 3 hours at 0°C. 200 ml of a 5% aqueous solution of hydrochloric acid was added and stirred for 5 minutes at room temperature. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The precipitate was chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 15:1).

Yield: 24.96 g (93% of theoretical) colorless solid.

Elementary analysis:

Cld: C 29.35 H 1.45 F 42.37 N 7.35 S 4.21

Fnd: C 29.28 H 1.61 F 42.15 N 7.25 S 4.15

Example 11b

3,5-diaminobenzoic acid-1-[(4-perfluorooctylsulfonyl)-piperazine]-amide

20 g (26.23 mmol) of the title compound from Example 11a was dissolved in 400 ml of ethanol, and 6 g of palladium catalyst (10% Pd/C) were added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum.

Yield: 18.43 g (quantitative) of a cream-colored solid.

Elementary analysis:

Cld: C 32.49 H 2.15 F 45.98 N 7.98 S 4.57

Fnd: C 32.29 H 2.35 F 45.69 N 7.81 S 4.40

Example 11c

3,5-N,N'-bis-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl- 5-yl)]-benzoic acid-[1-(4-perfluorooctyl-sulfonyl)-piperazine]-amide, Gd complex

10 g (14.24 mmol) of the title compound from 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-5-methyl-5-yl)-pentanoic acid, Gd complex, were dissolved in 200 ml of dimethylsulfoxide with gentle heating. At 10°C, 10.32 g (50 mmol) of N,N-dicyclohexylcarbodiimide was added and stirred overnight at room temperature. The solution was poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 19.74 g (72% of theoretical) colorless solid.

Water content: 11.8%

Elemental analysis (refers to anhydrous substance)

Cld: C 35.55 H 3.72 F 16.77 Gd 16.33 N 10.18 S 1.67

Fnd: C 35.48 H 3.84 F 16.58 Gd 16.24 N 10.07 S 1.58

Example 12

a) t-butyl ester of 3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanecarboxylic acid

25.0 g (53.8 mmol) of 1H,1H,2H,2H-perfluoro-1-decanol [commercially available from Lancaster Company] was dissolved in 250 ml of absolute toluene and mixed at room temperature with a catalytic amount (approximately 0.75 g) of tetra-n- butyl ammonia hydrogen sulfate. A total of 7.55 g (134.6 mmol; 2.5 equivalents relative to the alcohol component used) of finely powdered potassium hydroxide powder was then added at 0°C, followed by 15.73 g (80.7 mmol; 1.5 equivalents relative to the alcohol component used) of tert -butyl ester of hydrobromic acid, and was allowed to stir for the next 2 hours at 0°C. The reaction mixture thus obtained was stirred for another 12 hours at room temperature, then mixed with a total of 500 ml of ethyl acetate and 250 ml of water for the purpose of working up. The organic phase was separated and washed twice with water. After the organic phase was dried over sodium sulfate, the salt was sucked off, and the solvent was extracted under vacuum. The remaining oily residue was purified as eluent on silica gel using ethyl acetate/hexane (1:10) as eluent.

Yield: 26.3 g (84.6% of theory) of the above-mentioned title compound as a colorless highly viscous oil.

Elemental analysis (refers to anhydrous substance)

Cld: C 33.23 H 2.61 F 55.85

Fnd: C 33.29 H 2.61 F 55.90

b) 3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanecarboxylic acid

20 g (34.58 mmol) of the title compound from Example 12a) was suspended in 200 ml of a mixture consisting of methanol and 0.5 molar sodium hydroxide solution in a 2:1 ratio while stirring at room temperature, and then heated to 60°C. After a reaction time of 12 hours at 60°C, the now clear reaction mixture was neutralized for processing by mixing with Amberlite(R) IR 120 (H-form)-resin cation exchanger, the exchanger was suctioned off, and the methanol-water filtrate thus obtained was extracted in vacuum until a dry state is reached. The obtained amorphous-oil precipitate was purified as an eluent on silica gel using ethyl acetate/n-hexane (1:3).

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

Elemental analysis (refers to anhydrous substance)

Cld: C 27.60 H 1.35 F 61.85

Fnd: C 27.58 H 1.36 F 61.90

c) 1,7-bis{[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)]-1,4,7,10 -tetraazacyclododecane}-diethylenetriamine, digadolinium complex

2.48 g [(3.94 mmol); 2.05 molar equivalents in relation to the diethylene triamine used] of the Gd complex, described in Patent Application DE 197 28 954 C1 under example 31h), 10-(carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7 ,10-tetraazacyclododecane-1,4,7-triacetic 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 mixed with a total of 453 mg (3.94 mmol) of N of hydroxysuccinimide at that temperature. After cooling to room temperature, the reaction solution thus obtained was mixed with 814 mg (3,946 mmol) of N,N'-dicyclohexylcarbodiimide and stirred for 2 hours at room temperature. The active ester suspension that was obtained was then mixed with 198.3 mg (1.92 mmol) of diethylenetriamine, dissolved in 5 ml of absolute dimethyl sulfoxide, mixed and stirred for 12 hours at room temperature. For workup purposes, the reaction mixture was mixed with sufficient acetone until complete precipitation of the above-mentioned title compound was achieved, the precipitate was filtered off with suction, dried, taken up in water, the insoluble dicyclohexyl urea was filtered off, and the filtrate was desalinated on AMICON(R) YM-3 ultrafiltration membrane (cut-off, 3000 Da), and low-molecular components were removed. The retentate is then freeze-dried.

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

H2O content (Karl-Fischer): 3.89%

Elemental analysis (refers to anhydrous substance)

Cld: C 38.03 H 5.24 N 13.73 Gd 23.71

Fnd: C 37.98 H 5.20 N 13.69 Gd 23.78

d) 1,7-bis{[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)]-1,4,7,10 -tetraazacyclododecane}-4-(3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)-diethylenetriamine, digadolinium complex

1.27 g (2.44 mmol) of the title compound from Example 12b), dissolved in a mixture consisting of 15 ml of tetrahydrofuran and 15 ml of dimethyl sulfoxide, was added dropwise to a solution of 3.23 g (2.44 mmol) of the title compound from Example 12 c) in the mixture which consists of 30 ml of dimethyl sulfoxide and 3 ml of tetrahydrofuran, at 50°C and under a nitrogen atmosphere. Then a total of 1.80 g (3.66 mmol) of EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) was added in portions at 0°C and allowed to stir overnight at room temperature. The resulting reaction solution was then mixed with sufficient acetone until complete precipitation of the above-mentioned title compound was achieved, the precipitate was filtered off with suction, dried, taken up in water, the insoluble components were filtered off, and the filtrate was ultrafiltered on an AMICON(R) YM-3 ultrafiltration membrane (cut-off, 3000 Da), which was used both for complete desalination and for the purification of the title compound from low molecular components. The retentate is then freeze-dried.

Yield: 3.54 g (79.4% of theory) as a colorless lyophilisate.

H2O content (Karl-Fischer): 5.87%

Elemental analysis (refers to anhydrous substance)

Cld: C 35.43 H 4.07 N 9.95 F 17.64 Gd 17.18

Fnd: C 35.42 H 4.01 N 9.89 F 17.67 Gd 17.18

Example 13

a) 2-N-trifluoroacetyl-6-N-benzocarbonyl-1-lysine

100.0 g (356.7 mmol) of 6-N-benzyloxycarbonyl-1-lysine was dissolved in a mixture consisting of 1000 ml of trifluoroacetic acid ethyl ester and 500 ml of ethanol, and was stirred for 24 hours at room temperature. It was evaporated to dryness and the precipitate was crystallized from diisopropyl ether.

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

Melting point: 98.5°C

Elementary analysis

Cld: C 51.07 H 5.09 N 7.44 F 15.14

Fnd: C 51.25 H 5.18 N 7.58 F 15.03

b) 2-N-trifluoroacetyl-6-N-benzocarbonyl-1-lysine[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

164.2 g (0.664 mmol) of EEDQ (ethyl ester of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) was added at 0°C to a mixture of 125.0 g (332.0 mmol) of the title compound from Example 1a and 188.7 g (332.0 mmol) of 1-perfluorooctylsulfonylpiperazine (produced according to DE 196 03033) in 750 ml of tetrahydrofuran, and stirred overnight at room temperature. It was evaporated to dryness in a vacuum, and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

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

Melting point: 92°C

Elementary analysis

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

Fnd: C 36.18 H 2.94 N 5.98 F 40.87 S 3.40

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

Ammonia gas was introduced at 0°C for one hour into a solution consisting of 280.0 g (302.2 mmol) of the title compound from Example 1b in 2000 ml of ethanol. It was then stirred for 4 hours at 0°C. It was evaporated to dryness, and the precipitate was absorptively precipitated from water. The solid was filtered off and dried in a vacuum at 50°C.

Yield: 243.5 g (97.0% of theory) of amorphous solid.

Elementary analysis

Cld: C 37.60 H 3.28 N 6.75 F 38.89 S 3.86

Fnd: C 37.55 H 3.33 N 6.68 F 38.78 S 3.81

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

200.0 g (240.8 mmol) of the compound produced under 13c was dissolved in 1000 ml of ethanol, mixed with 5.0 g of Pearlman's catalyst (Pd 20%, C) and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until it could no longer be observed hydrogen intake. The catalyst was suctioned off, washed again completely with ethanol (three times, with approximately 100 ml each time) and evaporated to dryness under vacuum. The title compound was obtained as a highly viscous and yellow colored oil.

Yield: 162.5 g (96.9% of theory).

Elementary analysis

Cld: C 31.04 H 3.04 N 8.05 F 46.38 S 4.60

Fnd: C 31.11 H 3.09 N 8.08 F 46.33 S 4.62

e) 6N-2N-bis-{4-[2,3-bis-(N,N-bis(t-butyloxycarbonylmethyl)-amino)-propyl]-phenyl}-3-oxa-propionyl-1-lysine-[ 1-(4-Perfluorooctylsulfonyl)-piperazine]-amide

5.25 g (7.72 mmol) of 4-[2,3-bis-(N,N-bis(t-butyloxycarbonylmethyl)-amino)-propyl]-phenyl}-3-oxa-propionic acid and 781.0 mg (7.72 mmol) of triethylamine was dissolved in 50 ml of methylene chloride. At -15°C, a solution consisting of 1.16 g (8.5 mmol) of isobutyl chloroformate was added dropwise to 10 ml of methylene chloride within 5 minutes, and was stirred for the next 20 minutes at -15°C. Then the solution was cooled to -25°C, and a solution consisting of 2.68 g (3.86 mmol) of the title compound from Example 13d) and 2.12 g (21.0 mmol) of triethylamine in 70 ml of tetrahydrofuran was added dropwise within 30 minutes and then mixed for 30 minutes at -15°C, and then the mixing was continued overnight at room temperature. For work-up, the solvent was taken in vacuum, and the remaining oily precipitate was taken in 250 ml of chloroform. The chloroform phase was extracted twice, each time with 100 ml of a 10% aqueous solution of ammonium chloride, the organic phase was dried over magnesium sulfate and evaporated to dryness under vacuum. The precipitate was chromatographed on silica gel (mobile solvent: methylene chloride/ethanol = 20:1)

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

Elementary analysis

Cld: C 52.27 H 6.43 N 5.54 F 15.97 S 1.59

Fnd: C 52.22 H 6.51 N 5.49 F 15.99 S 1.63

f) 6N-2N-bis-{4-[2,3-bis-(N,N-bis(carboxylatomethyl)-amino)-propyl]-phenyl}-3-oxa-propionyl-1-lysine-[1- (4-Perfluorooctylsulfonyl)-piperazine]-amide, octa-sodium salt

5.0 g (2.47 mmol) of the title compound from Example 13e) was dissolved in 60 ml of absolute dichloromethane. It was then mixed drop by drop at 0°C with a total of 75 ml of trifluoroacetic acid. After a reaction time of 12 hours at room temperature, it was evaporated to dryness under vacuum. The remaining precipitate was mixed with 100 ml of water and extracted again under vacuum until the material was dry. The precipitate thus obtained was dissolved in 200 ml of distilled water, and the aqueous product solution of the above-mentioned title compound was extracted twice with 60 ml of diethyl ether each time. The resulting aqueous solution of the product was made by mixing with water to a total volume of 300 ml, the insoluble components were filtered off, and the filtrate was ultrafiltered on an AMICON(R) YM-3 ultrafiltration membrane (cut-off, 3000 Da), which was also used for complete desalination and for the purification of the title compound from low molecular components. The retentate was diluted to a total volume of 200 ml by mixing with water, and the pH of this solution was then adjusted to 10.0 using a 15% sodium hydroxide solution. The basic, aqueous solution of the product is then freeze-dried.

4.0 g (92.8% of theory) of the title compound was obtained in the form of the octa-sodium salt as an amorphous lyophilisate.

Water content: 5.37%

Elemental analysis (refers to anhydrous substance)

Cld: C 38.46 H 3.28 N 6.41 F 18.47 S 1.83 Na 10.52

Fnd: C 38.42 H 3.31 N 6.39 F 18.51 S 1.87 Na 10.38

g) 6N-2N-bis-{4-[2,3-bis-(N,N-bis(carboxymethyl)-amino)-propyl]-phenyl}-3-oxa-propionyl-1-lysine-[1- (4-perfluorooctylsulfonyl)-piperazine]-amide, di-manganese complex, tetrasodium salt

1.94 g (1.11 mmol) of the title compound from Example 13f) was dissolved in 100 ml of distilled water, and the resulting solution was brought to pH 4.0 by mixing with 1 molar aqueous solution of hydrochloric acid. At 80°C, it was now mixed in portions with 0.25 g (2.22 mmol) of manganese(II) carbonate. The resulting reaction solution was then refluxed for 5 hours. After cooling to room temperature, the pH of the aqueous solution of the product was adjusted to 7.2 by mixing with 1N sodium hydroxide solution under vigorous stirring and was desalinated using an AMICON(R) YM-3 ultrafiltration membrane (cut-off, 3000 Da), and the low molecular weight components were removed. The retentate is then freeze-dried.

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

H2O content (Karl-Fischer): 7.28%

Elemental analysis (refers to anhydrous substance)

Cld: C 38.07 H 3.25 F 18.28 Mn 6.22 N 6.34 Na 5.20 S 1.81

Fnd: C 38.01 H 3.29 F 18.29 Mn 6.21 N 6.36 Na 5.28 S 1.78

Example 14

a) 6N-(benzyloxycarbonyl)-2-N-[(N-pteroyl)-1-glutaminyl]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

20 g (45.31 mmol) of folic acid was dissolved in 300 ml of dimethyl sulfoxide, and 9.49 g (46 mmol) of N,N-dicyclohexylcarbodiimide was added at 10°C. It was mixed overnight at room temperature. 29.1 g (35 mmol) of the title compound from Example 1c and 20 ml of pyridine were added to this mixture and it was stirred for 3 hours at 50°C. It was cooled to room temperature and a mixture consisting of 1500 ml of diethyl ether/1500 ml of acetone was added to it. The settled precipitate was filtered off and purified (RP-18) (mobile solvent = gradient consisting of: water/ethanol/tetrahydrofuran).

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

Water content: 2.1%

Elemental analysis (refers to anhydrous substance)

Cld: C 43.10 H 3.54 F 25.76 N 11.29 S 2.56

Fnd: C 43.02 H 3.62 F 25.68 N 11.21 S 2.48

b) 2-N-[(N-pteroyl)-1-glutaminyl]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

200 ml of hydrobromic acid in glacial acetic acid (48%) was added to 20 g (15.95 mmol) of the title compound from Example 14a and stirred for 2 hours at 40°C. It was cooled to 0°C, 2000 ml of diethyl ether was added dropwise, and the solid precipitate was filtered off. After drying in vacuum (60°C), 18.96 g (99% of theory) of a yellow-colored, crystalline solid was obtained.

Elementary analysis

Cld: C 37.01 H 3.27 Br 6.65 F 26.90 N 12.83 S 2.67

Fnd: C 36.91 H 3.42 Br 6.31 F 29.75 N 12.72 S 2.56

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

0.92 g (8 mmol) of N-hydroxysuccinimide, 0.68 g (16 mol) of lithium chloride and 5.04 g (8 mmol) of 1,4,7-tris(carboxylatomethyl-10-(3-aza-4-oxo-5-methyl- 5-yl)-1,4,7,10-tetraazacyclododecane, Gd complex, was dissolved in 80 ml of dimethyl sulfoxide with gentle heating. At 10 °C, 2.06 g (10 mol) of N,N-dicyclohexylcarbodiimide was added and then stirred 3 hours at room temperature. 5 g (4.16 mmol) of the title compound from Example 14b and 10 ml of pyridine were added to the reaction mixture and stirred overnight at room temperature. The solution was poured into 1000 ml of acetone and stirred for 10 minutes. A precipitated solid was filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: a gradient consisting of: water/ethanol/acetonitrile).It was dissolved in some water, the pH was adjusted to 7.4 using sodium hydroxide solution and freeze-dried dried/.

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

Water content: 5.8%

Elemental analysis (refers to anhydrous substance)

Cld: C 38.36 H 3.74 F 18.42 Gd 8.97 N 12.78 Na 1.31 S 1.83

Fnd: C 38.28 H 3.85 F 18.33 Gd 8.85 N 12.69 Na 1.42 S 1.75

Example 15

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

A solution consisting of 16.85 g (70 mmol) of 3,6,9,12-tetraoxatridecanoic acid chloride in 50 ml of dichloromethane was added dropwise at 0°C to a mixture of 50 g (60.20 mmol) of the title compound from Example 1c and 7.10 g ( 70 mmol) of triethylamine, dissolved in 350 ml of dichloromethane and stirred for 3 hours at 0°C. 200 ml of a 5% aqueous solution of hydrochloric acid was added and stirred for 5 minutes at room temperature. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The precipitate was chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 15:1).

Yield: 30.94 g (92% of theory) colorless, viscous oil.

Elementary analysis:

Cld: C 40.63 H 4.19 F 31.21 N 5.41 S 3.10

Fnd: C 40.75 H 4.08 F 31.29 N 5.58 S 3.25

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

53.96 g (52.15 mmol) of the title compound from Example 15a was dissolved in 500 ml of ethanol, and 6 g of palladium catalyst (10% Pd/C) were added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum.

Yield: 43.0 g (quantitative) colorless solid.

Elementary analysis:

Cld: C 36.01 H 4.14 F 35.86 N 6.22 S 3.56

Fnd: C 27.60 H 5.13 F 39.09 N 6.68 S 3.81

c) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl]- 2-N-(3,6,9,12-tetraoxatridecanoyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex

21.84 g (24.25 mmol) of the title compound from 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-aza-4-oxo-5-methyl-5-yl)]-pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd complex, was dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10°C, 8.25 g (40 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 precipitated solid was filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 28.21 g (81% of theoretical) colorless solid.

Water content: 11.0%

Elemental analysis (refers to anhydrous substance)

Cld: C 36.53 H 4.33 F 21.36 N 8.34 S 2.12 Gd 10.40

Fnd: C 31.74 H 4.98 F 22.39 N 8.69 S 2.15 Gd 10.87

Example 16

a) 6-N-benzyloxycarbonyl-2-N-(propyl-3-sulfonic acid)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

A solution consisting of 7.33 g (60 mol) of propanesultone in 50 ml of tetrahydrofuran was added dropwise at 50°C to 50 g (60.20 mmol) of the title compound from Example 1c and 7.10 g (70 mmol) of triethylamine, dissolved in 750 ml of tetrahydrofuran and stirred for 3 hours at 60°C. 200 ml of a 5% aqueous solution of hydrochloric acid was added and stirred for 5 minutes at room temperature. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The precipitate was chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 15:1).

Yield: 45.16 g (79% of theory) colorless, viscous oil.

Elementary analysis

Cld: C 36.56 H 3.49 F 33.90 N 5.88 S 6.73

Fnd: C 36.72 H 3.35 F 33.79 N 5.78 S 6.75

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

49.68 g (52.15 mmol) of the title compound from Example 16a was dissolved in 500 ml of ethanol, and 6 g of palladium catalyst (10% Pd/C) were added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum.

Yield: 42.69 g (quantitative) of colorless solid.

Elementary analysis:

Cld: C 30.81 H 3.32 F 39.46 N 6.84 S 7.83

Fnd: C 30.64 H 4.1 F 39.29 N 6.68 S 7.89

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

19.85 g (24.25 mmol) of the title compound from 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, Gd complex, was dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10°C, 8.25 g (40 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 precipitated solid was filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 28.13 g (81% of theoretical) colorless solid.

Water content: 11.0%

Elemental analysis (refers to anhydrous substance)

Cld: C 33.27 H 3.70 F 22.36 N 8.73 S 4.44 Gd 10.89

Fnd: C 32.41 H 3.88 F 22.49 N 8.69 S 4.35 Gd 10.97

Example 17

a) 6-N-benzyloxycarbonyl-2-N,N-bis(propyl-3-sulfonic acid)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

A solution consisting of 14.65 g (120 mmol) of 1,3-propanesultone in 100 ml of tetrahydrofuran was added dropwise at 50°C to 50 g (60.20 mmol) of the title compound from Example 1c and 12.14 g (120 mmol) of triethylamine, dissolved was added to 250 ml of dry tetrahydrofuran and stirred for 3 hours at 60°C. 400 ml of 5% aqueous solution of hydrochloric acid was added and stirred for 5 minutes at room temperature, mixed with sodium chloride, the organic phase was separated, dried over magnesium sulfate and evaporated to dryness under vacuum. The precipitate was chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 15:1).

Yield: 51.24 g (81% of theory) colorless, viscous oil.

Elementary analysis:

Cld: C 35.76 H 3.66 F 30.05 N 5.21 S 8.95

Fnd: C 35.75 H 3.55 F 30.19 N 5.08 S 9.04

b) 2-N,N bis(propyl-3-sulfonic acid)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

53.74 g (52.15 mmol) of the title compound from Example 17a was dissolved in 500 ml of ethanol, and 6 g of palladium catalyst (10% Pd/C) were added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum.

Yield: 49.06 g (quantitative) of colorless solid.

Elementary analysis:

Cld: C 30.64 H 3.54 F 34.33 N 5.96 S 10.23

Fnd: C 30.69 H 3.71 F 34.19 N 6.08 S 10.38

c) 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl]- 2-N,N bis(propyl-3-sulfonic acid)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex, disodium salt

38.76 g (24.25 mmol) of the title compound from 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, Gd complex, was dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10°C, 8.25 g (40 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 precipitated solid was filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 31.63 g (81% of theoretical) colorless solid.

Water content: 11.0%

Elemental analysis (refers to anhydrous substance)

Cld: C 32.07 H 3.57 F 20.06 N 7.83 S 5.97 Gd 9.76 Na 2.86

Fnd: C 31.94 H 3.48 F 20.19 N 7.69 S 5.85 Gd 9.87 Na 2.99

Example 18

a) 5-benzyl ester of N-trifluoroacetyl-1-glutamic acid

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

Yield: 140.47 g (96% of theoretical) colorless, crystalline powder.

Elementary analysis

Cld: C 50.46 H 4.23 F 17.10 N 4.20

Fnd: C 51.35 H 4.18 F 17.03 N 4.28

b) 5-benzyl ester of 2-N-trifluoroacetyl-1-glutamic acid-N-bis(2-hydroxyethyl)-amide

To a solution consisting of 24.9 g (24.08 mmol) of the title compound from 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 8.25 g (40 mmol) of N ,N-dicyclohexylcarbodiimide at 0°C. It was mixed for 3 hours at 0°C, then overnight at room temperature. The precipitated urea was filtered off, the filtrate was evaporated to dryness in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 9.11 g (90% of theoretical) viscous oil.

Elementary analysis:

Cld: C 51.43 H 5.51 F 13.56 N 6.66

Fnd: C 51.22 H 5.41 F 13.40 N 6.75

c) N-trifluoroacetyl-1-glutamic acid-N bis(2-hydroxyethyl)-monoamide

21.92 g (52.15 mmol) of the title compound from Example 18b was dissolved in 500 ml of ethanol, and 3 g of palladium catalyst (10% Pd/C) were added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum.

Yield: 43.0 g (quantitative) colorless solid.

Elementary analysis:

Cld: C 40.01 H 5.19 F 17.26 N 8.48

Fnd: C 39.84 H 5.13 F 17.09 N 8.68

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

16.42 g (66.4 mmol) of EEDQ (ethyl ester of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) was added at 0°C to a mixture of 10.96 g (33.2 mmol) of the title compound from Example 18a and 18.87 g (33.2 mmol) 1-perfluorooctylsulfonyl-piperazine (produced according to DE 19603033) in 80 ml of tetrahydrofuran, and was stirred overnight at room temperature. It was evaporated to dryness in a vacuum, and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

Yield: 30.93 g (93% of theory) of a colorless solid.

Elementary analysis

Cld: C 39.61 H 2.89 F 35.66 N 6.19 S 3.54

Fnd: C 39.68 H 2.74 F 35.81 N 6.13 S 3.40

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

Ammonia gas was introduced at 0°C for one hour into a solution consisting of 30.24 g (30.22 mmol) of the title compound from Example 18b in 200 ml of ethanol. It was then stirred for 4 hours at 0°C. It was evaporated to dryness, and the precipitate was absorptively precipitated from water. The solid was filtered off and dried in a vacuum (50°C).

Yield: 26.55 g (97.0% of theory) of amorphous solid.

Elementary analysis

Cld: C 41.12 H 2.89 F 35.66 N 6.19 S 3.54

Fnd: C 41.15 H 2.83 F 35.78 N 6.28 S 3.71

f) N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl]-1- glutamic acid-N-bis(2-hydroxyethyl)-amide-5-[1-4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex

211.96 g (24.25 mmol) of the title compound from 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-tetraazacyclododecane, Gd complex, was dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10°C, 8.25 g (40 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 precipitated solid was filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 27.43 g (81% of theoretical) colorless solid.

Water content: 11.0%

Elemental analysis (refers to anhydrous substance)

Cld: C 34.41 H 3.83 F 23.31 N 9.03 S 2.30 Gd 11.26

Fnd: C 34.34 H 3.98 F 23.29 N 9.19 S 2.15 Gd 11.07

Example 19

a) 5-benzyl ester of N-trifluoroacetyl-1-glutamic acid-N-dimethyl-bis(1,1-dihydroxymethyl)-amide

A solution consisting of 8.03 g (24.08 mmol) of the title compound from 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 N,N-dicyclohexylcarbodiimide were added at 0°C. It was mixed for 3 hours at 0°C, then overnight at room temperature. The precipitated urea was filtered off, the filtrate was evaporated to dryness in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 110.53 g (91% of theory) of viscous oil.

Elementary analysis:

Cld: C 50.00 H 5.66 F 11.86 N 7.18

Fnd: C 50.17 H 5.82 F 11.80 N 7.15

b) 5-benzyl ester of N-trifluoroacetyl-1-glutamic acid-[1-4-perfluorooctylsulfonyl)-piperazine]-amide

25.05 g (52.15 mmol) of the title compound from Example 19a was dissolved in 500 ml of ethanol, and 6 g of palladium catalyst (10% Pd/C) were added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum.

Yield: 20.36 g (quantitative) of colorless solid.

Elementary analysis:

Cld: C 40.00 H 5.42 F 14.60 N 7.18

Fnd: C 40.10 H 5.53 F 14.69 N 7.28

c) N-trifluoroacetyl-1-glutamic acid-N-dimethyl-bis(1,1-dihydroxymethyl)-amide-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

16.42 g (66.4 mmol) of EEDQ (ethyl ester of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) was added at 0°C to a mixture of 12.96 g (33.2 mmol) of the title compound from Example 19b and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (produced according to DE 19603033) in 800 ml of tetrahydrofuran, and was stirred overnight at room temperature. It was evaporated to dryness in a vacuum, and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

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

Elementary analysis

Cld: C 31.93 H 3.00 F 40.40 N 5.96 S 3.41

Fnd: C 32.08 H 2.94 F 40.57 N 5.88 S 3.31

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

Ammonia gas was introduced at 0°C for one hour into a solution consisting of 28.41 g (30.2 mmol) of the title compound from Example 19c in 200 ml of ethanol. It was then stirred for 4 hours at 0°C. It was evaporated to dryness, and the precipitate was absorptively precipitated from water. The solid was filtered off and dried in a vacuum (50°C).

Yield: 24.74 g (97% of theory) of amorphous solid.

Elementary analysis

Cld: C 32.71 H 3.46 F 38.24 N 6.63 S 3.80

Fnd: C 32.75 H 3.33 F 38.38 N 6.68 S 3.81

e) 2-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -1-glutamic acid-N-[dimethyl-bis(1,1-dihydroxymethyl)-amide]-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex

20.48 g (24.25 mmol) of the title compound from 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-tetraazacyclododecane, Gd complex, was dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10°C, 8.25 g (40 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 precipitated solid was filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 29.05 g (83% of theoretical) colorless solid.

Water content: 11.0%

Elemental analysis (refers to anhydrous substance)

Cld: C 34.12 H 3.91 F 22.38 N 8.73 S 2.22 Gd 10.90

Fnd: C 34.24 H 3.98 F 22.39 N 8.69 S 2.15 Gd 10.87

Example 20

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

16.42 g (66.4 mmol) of EEDQ (ethyl ester of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) was added at 0°C to a mixture of 11.06 g (33.2 mmol) of the title compound from Example 18a and 18.87 g (33.2 mmol) 1-perfluorooctylsulfonyl-piperazine (produced according to DE 19603033) in 80 ml of tetrahydrofuran, and was stirred overnight at room temperature. It was evaporated to dryness in a vacuum, and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

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

Elementary analysis

Cld: C 35.35 H 2.40 F 43.01 N 4.76 S 3.63

Fnd: C 35.48 H 2.51 F 42.87 N 4.73 S 3.50

b) N-trifluoroacetyl-1-glutamic acid-5-[1-[4-perfluorooctylsulfonyl)-piperazine]-amide

21.92 g (52.15 mmol) of the title compound from Example 18a was dissolved in 500 ml of ethanol, and 3 g of palladium catalyst (10% Pd/C) were added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum.

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

Elementary analysis:

Cld: C 28.76 H 1.91 F 47.89 N 5.30 S 4.04

Fnd: C 28.84 H 2.03 F 47.79 N 5.28 S 4.19

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

To a solution consisting of 24.9 g (24.08 mmol) of the title compound from 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 8.25 g (40 mmol) of N ,N-dicyclohexylcarbodiimide at 0°C. It was mixed for 3 hours at 0°C, then overnight at room temperature. The precipitated urea was filtered off, the filtrate was evaporated to dryness in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 9.11 g (90% of theoretical) viscous oil.

Elementary analysis:

Cld: C 31.37 H 2.75 F 43.15 N 6.36 S 3.64

Fnd: C 31.22 H 2.61 F 43.30 N 6.25 S 3.81

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

Ammonia gas was introduced at 0°C for one hour into a solution consisting of 26.61 g (30.22 mmol) of the title compound from Example 18c in 200 ml of ethanol. It was then stirred for 4 hours at 0°C. It was evaporated to dryness, and the precipitate was absorptively precipitated from water. The solid was filtered off and dried in a vacuum (50°C).

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

Elementary analysis

Cld: C 30.89 H 3.09 F 39.56 N 6.86 S 3.93

Fnd: C 30.75 H 3.13 F 39.78 N 6.75 S 3.81

e) N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-1 -glutamic acid-N-bis(2-hydroxyethyl)-amide-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex

16.43 g (24.25 mmol) of the title compound from Example 20d, 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, Gd complex, was dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10°C, 8.25 g (40 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 precipitated solid was filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient consisting of: water/ethanol/acetonitrile).

Yield: 28.10 g (83% of theoretical) colorless solid.

Water content: 11.0%

Elemental analysis (refers to anhydrous substance)

Cld: C 34.41 H 3.83 F 23.13 N 9.03 S 2.30 Gd 11.26

Fnd: C 34.44 H 4.98 F 23.19 N 8.89 S 2.15 Gd 11.17

Example 21

a) benzyl ester of N-trifluoroacetyl-glutamic acid-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

16.42 g (66.4 mmol) of EEDQ (ethyl ester of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid) was added at 0°C to a mixture of 11.06 g (33.2 mmol) of the title compound from Example 18a and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (produced according to DE 19603033) in 80 ml of tetrahydrofuran, and was stirred overnight at room temperature. It was evaporated to dryness in a vacuum, and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

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

Elementary analysis

Cld: C 35.35 H 2.40 F 43.01 N 4.76 S 3.63

Fnd: C 35.48 H 2.54 F 42.87 N 4.73 S 3.40

b) N-trifluoroacetyl-1-glutamic acid-5-[1-[4-perfluorooctylsulfonyl)-piperazine]-amide

21.92 g (52.15 mmol) of the title compound from Example 21a was dissolved in 500 ml of ethanol, and 3 g of palladium catalyst (10% Pd/C) were added. It is hydrogenated at room temperature. The catalyst was filtered off, and the filtrate was evaporated to dryness under vacuum.

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

Elementary analysis:

Cld: C 28.76 H 1.91 F 47.89 N 5.30 S 4.04

Fnd: C 28.84 H 1.81 F 47.79 N 5.28 S 4.16

Example 22

Organ distribution (including concentration in tumor and lymph node) after intravenous administration of contrast medium according to the invention of Example 3 in rats with prostate cancer.

After intravenous administration of a total of 100 μmol gadolinium/kg body weight of the title compound from Example 3 in rats (Cop-inbreeding Dunning R3327 MAT-Lu prostate cancer i.m. - implanted 12 days earlier), the metal content in various organs, in tumors and in lymph nodes (grouped as mesenteric and peripheral lymph nodes) was determined 10 minutes, 1 and 24 hours after (MW)SD administration, n = 3).

Title compound from Example 3

[image]

Key to the table:

Gd-Konzentration [μmol/l] = concentration of Gd [μmol/l]

% Dosis pro Gesamtgewebe = % dose per total tissue

Leber = liver

Milz = spleen

Niere = kidney

Lunge = lungs

Herz = heart

Gehirn = brain

Muskel** = muscle**

Mes. LK = mesenteric lymph nodes

Periph. LK = peripheral lymph nodes

Magen (entleert) = stomach (emptied)

Darm (entleert) = intestines (emptied)

Blut* = blood*

Restkörper = remaining part of the body

Harn 0-24 h = urine 0-24 h

Faeces 0-24 h = feces 0-24 h

Summe der organe = total sum of all the organs

Balance = balance

*58 ml Blut/kg KGW = 58 ml blood/kg body weight

**nur Gewebealiquot v. rechten Unterschenkelmuskel = just a tissue sample from the muscle of the right hind leg

***Summe Organe 10 und 60 min p.i. ohne Restkörper = total sum of all organs 10 and 60 minutes p.i. without the rest of the body

Claims (21)

1. Perfluoroalkyl complexes with polar radicals, general formula I (K)1-G - (Z-Rf)m ⎢ (I) (R) p and which are indicated by the fact that Rf represents a perfluorinated, straight-chain or branched carbon chain of the formula -CnF2nE, in which E represents a terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, and n represents the numbers 4-30, K represents a metal complex of the general formula II [image] where R1 represents a hydrogen atom or the equivalent of a metal ion of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83, whereby it is ensured that at least two R1 represent equivalents of a metal ion, R2 and R3, independently of each other, represent hydrogen, C1-C7-alkyl, benzyl, phenyl, -CH2OH or -CH2OCH3, and U represents -C6H4-O-CH2-ω-, -(CH2)1-5-ω, phenylene group, -CH2-NHCO-CH2-CH(CH2COOH)-C6H4-ω-, -C6H4-(OCH2CH2)0- 1-, N(CH2COOH)-CH2-ω or C1-C12-alkylene group or C7-C12-C6H4-O group which is optionally interrupted by one or more oxygen atoms, one to three -NHCO groups or one to three -CONH groups and/or is substituted with one to three -(CH2)0-5COOH groups, where ω represents the binding site for -CO-, or general formula III [image] (III) in which R1 has the meaning mentioned above, R4 represents hydrogen or the equivalent of the metal ion mentioned under R1, and U1 represents -C6H4-O-CH2-ω-, where ω represents the site of attachment to -CO- or general formula IV [image] wherein R 1 and R 2 have the meaning mentioned above or general formulas V A or V B [image] wherein R 1 has the meaning mentioned above, or general formula VI [image] (YOU) wherein R 1 has the meaning mentioned above, or general formula VII [image] (VII) wherein R 1 has the meaning mentioned above, a U1 represents -C6H4-O-CH2-ω-, where ω represents the binding site for -CO-, and in the radical K, optionally present free acidic groups can optionally be present as salts of organic and/or inorganic bases or amino acids or amino acid amides, G represents a radical having a reactive functional group in at least three positions and which is selected from radicals a) to g) below [image] [image] [image] [image] where α represents the binding site of G to complex K, β is the binding site of G to radical R, and γ represents the binding site of G to radical Z, Z represents [image] γ-C(O)CH2O(CH2)2-ξ, where γ represents the binding site of Z to the radical G, and ξ represents the binding site of Z to the perfluorinated radical Rf, R represents a polar radical selected from the complexes K of the general formulas II to VII, where R1 here represents a hydrogen atom or the equivalent of a metal ion of atomic numbers 20-29, 31-33, 37-39, 42-44, 49 or 57-83, and the radicals R 2 , R 3 , R 4 , U and U 1 have the meanings indicated above, where in case G represents radical (c) or (d) and R represents a complex selected from the general formulas II and V, R must not be identical radical K of the general formula I, if Z represents δ-C(O)CH2O(CH2)2-ε, or folic acid radical or R represents a carbon chain with 2-30 C atoms that is linked via -CO- or SO2- or by a direct bond to the radical G, straight-chain or branched, saturated or unsaturated, optionally terminated with one to ten oxygen atoms, with one to five -NHCO group, with one to five -CONH groups, with one to two sulfur atoms, with one to five -NH groups or with one to two phenylene groups, which can optionally be substituted with one to two OH groups, with one to two NH2 groups , with one to two -COOH groups, or with one to two -SO3H groups, or optionally substituted with one to eight OH groups, with one to five -COOH groups, with one to two -SO3H groups, with one to five NH2 groups, with one to five C1-C4 alkoxy groups, and l, m, p independently represent integers 1 or 2. 2. Metal complexes according to claim 1, which are characterized by the fact that the equivalent of the metal ion R1 in the K radical is an element with atomic numbers 21-29, 39, 42, 44 or 57-83. 3. Metal complexes in accordance with claim 1, which are indicated by the fact that the equivalent of the metal ion R1 in the K radical is an element with atomic numbers 27, 29, 31-33, 37-39, 43, 49, 62, 64, 70, 75 and 77. 4. Metal complexes according to one of claims 1 to 3, which are indicated by the fact that K represents a metal complex of the general formula II, III, VB or VII. 5. Metal complexes in accordance with one of the claims 1 to 4, which are indicated by the fact that the polar radical R is a complex K. 6. Metal complexes according to claim 5, which are indicated by the fact that the complexes K of the general formulas II, III, VA or VII are present as the polarine radical R. 7. Metal complexes according to claim 5 or 6, which are indicated by the fact that R1 represents the equivalent of a metal ion of atomic numbers 20, 25 or 64. 8. Metal complexes according to one of claims 1 to 4, which are characterized by the fact that the polar radical R has the following meanings: [image] [image] -C(O)CH2O[(CH2)2O]4-CH3 is preferred. 9. Metal complexes according to one of the claims 1 to 4, which are indicated by the fact that the polar radical R is a folic acid radical. 10. Metal complexes according to one of claims 1 to 9, which are indicated by the fact that G in the general formula I represents a lysine radical (a) or (b). 11. Metal complexes according to one of claims 1 to 10, which are characterized by the fact that U in the metal complex K represents the group -CH2- or -C6H4-O-CH2-ω, where ω represents the binding site for -CO- . 12. The use of metal complexes according to claim 2, which is indicated by the fact that they are used for the production of contrast media for use in NMR diagnostics and X-ray diagnostics. 13. The use of metal complexes according to claim 12, which is indicated by the fact that they are used for the production of contrast media for the visualization of infarction and necrosis. 14. The use of metal complexes according to claim 3, which is indicated by the fact that they are used for the production of contrast media for use in radiodiagnosis and radiotherapy. 15. The use of metal complexes according to claim 2, which is indicated by the fact that they are used for the production of contrast media for use in lymphography in the diagnosis of changes in the lymphatic system. 16. The use of metal complexes according to claim 2, characterized in that they are used for the production of contrast media for use in indirect lymphography. 17. The use of metal complexes according to claim 2, characterized in that they are used for the production of contrast media for use in intravenous lymphography. 18. The use of metal complexes according to claim 2, which is indicated by the fact that they are used for the production of contrast media for visualization of the vascular space. 19. The use of metal complexes according to claim 2, characterized in that they are used for the production of contrast media for use in tumor imaging. 20. A pharmaceutical agent which is indicated to contain at least one physiologically compatible compound according to claims 1 to 11, optionally with additives commonly used in galenic laboratories. 21. A process indicated for the production of metal complexes with polar radicals containing perfluoroalkyl, general formula I (K)1-G - (Z-Rf)m ⎢ (I) (R) p wherein K, G, R, Z, Rf, l, m and p have the meaning indicated in claim 1, whereby, in a manner known in the art, the carboxylic acid of the general formula IIa [image] (IIa) in which R5 represents the equivalent of a metal ion of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83, or a carboxyl protecting group, and R2, R3 and U have the meaning mentioned above, or carboxylic acid of general formula IIIa [image] (IIIa) wherein R 4 , R 5 and U 1 have the above-mentioned meaning or a carboxylic acid of general formula IVa [image] (IVa) wherein R 5 and R 2 have the meaning mentioned above or a carboxylic acid of the general formula Va or Vb [image] wherein R 5 has the meaning mentioned above or a carboxylic acid of the general formula VIa [image] (VIa) wherein R 5 has the meaning mentioned above or a carboxylic acid of the general formula VIIa [image] (VIIa) wherein R 5 and U 1 have the meanings mentioned above, reacts in an optionally activated form with an amine of general formula VIII H -G - (Z-Rf)m ⏐ (VIII) (R) p wherein G, R, Z, Rf, m and p have the aforementioned meaning, in the coupling reaction and optionally thereafter by cleavage of optionally present protecting groups to form a metal complex of the general formula I. or if R5 represents a protecting group, it is reacted after removal of these protecting groups in a subsequent step in a manner known in the art with at least one metal oxide or metal salt of the element of atomic numbers 21-29, 31-33, 37-39, 42-44 , 49 or 57-83, and then, if desired, optionally present acidic hydrogen atoms are substituted with cations of inorganic and/or organic bases, amino acids or amino acid amides.