WO1996016678A1

WO1996016678A1 - Use of chelate compounds as diagnostic agents in the x-ray examination of liver and bile ducts

Info

Publication number: WO1996016678A1
Application number: PCT/EP1995/004547
Authority: WO
Inventors: Franz-Karl Maier; Michael Bauer; Werner Krause; Ulrich Speck; Gabriele Schuhmann-Giampieri; Andreas Mühler; Thomas Balzer; Wolf-Rüdiger Press
Original assignee: Schering Aktiengesellschaft
Priority date: 1994-11-30
Filing date: 1995-11-20
Publication date: 1996-06-06
Also published as: EP0794800A1; NO972458D0; NO972458L; HUT77553A; CA2206558A1; FI972285A0; JPH10509734A; AU4173896A; SK68897A3; CZ166797A3; PL320482A1; MX9703974A; FI972285A; CN1167443A; IL116207A0

Abstract

Described are metal complexes of DTPA derivatives substituted with a benzyl group in the 4 or 5 position, the complexes being suitable for use as contrast media in computed tomography of the liver and the bile ducts.

Description

Use of chelating compounds as liver and biliary X-ray diagnostics

The invention relates to the use of metal complexes in liver and 5-gall x-ray diagnostics by means of x-rays, in particular in computer tomography.

The early detection of focal liver diseases, in particular liver metastases and liver tumors, is one of the most important diagnostic problems in oncology. Four imaging methods are available for this: 0 scintigraphy, ultrasonography, computed tomography and magnetic resonance imaging. Each of the methods has specific advantages and disadvantages, none is optimal in its own right, and practically every method would benefit from the presence of specific, compatible, intravenously administrable contrast agents [Harned, RK, Chezmar, JL, 5 Nelson, RC: Imaging of patients with potentially resectable hepativ neoplasms. AJR 159, 1191-1194 (1992)].

Scintigraphy offers a spatial resolution that is too low and its application is limited by the insufficient or too high specificity of the radiopharmaceuticals (which can only be used for a few types of tumor), so that it is not mentioned in the above-mentioned review article. Sonography is currently also not a sufficiently reliable technique for the detection of solid focal liver changes, since these often do not differ sufficiently from the healthy liver tissue in their acoustic properties. Smaller lesions 5 in the liver tissue can only be detected intraoperatively after exposing the liver and when using high-frequency transducers. Magnetic resonance imaging (MR) is able to record the entire liver with good spatial resolution and, depending on the measurement mode, also with good tissue differentiation. For MR, intravenously administrable, well-tolerated, effective contrast agents are in clinical trials that will further improve the benefits of this imaging method. 0 disadvantages are movement artifacts in the case of the few minutes high-resolution measurement methods and the high cost of the devices themselves, which limit their availability.

Computer tomography (CT) is actually the ideal technique for liver diagnosis. With modern devices, the entire liver can be captured within about 30 seconds with excellent spatial resolution. A single liver layer takes about 1 second, so movements through breathing and peristalsis hardly play a role. The cost of CT is significantly lower than that of MR. The disadvantage of the low tissue density resolution must, however, be compensated for by contrast agents. With the contrast media clinically available today there are the following options:

1. The contrast media are injected or infused rapidly and in high doses (50-200 g) intravenously. For a few minutes there may be a difference in contrast between the lesion and normal liver tissue due to differences in perfusion, the relative blood volume of the individual

Tissue and extracellular space. This period of uneven distribution of contrast media can only be used for diagnostics with the modern, very fast CT mentioned.

2. 4-6 hours after the administration of at least 120 g of the usual urographic contrast agents, an improved contrast between the healthy liver parenchyma that absorbs the contrast agent and the mostly non-absorbing focal liver lesions is observed in a very small number of patients. However, this technique, known as a late scan, is not sufficiently reliable and meaningful, so that it is not used routinely.

3. For arterial portography, a catheter e.g. are introduced into the mesenteric artery, the patient is then brought to the CT device and the scan is carried out during the infusion of approximately 150 ml of contrast medium. This technique is invasive, time-consuming and expensive, but currently provides the safest information about the presence and location of liver metastases. This

Information is for the decision about the resectability of metastases vital. The CT with arterial portography is therefore performed regularly preoperatively despite the effort.

The problems described above arise because the X-ray contrast media available today are intrinsically urographic products that do not accumulate in the liver. In order to nevertheless generate some contrast, the liver is briefly flooded with very large amounts of contrast medium by the blood stream ("dynamic scan") or an attempt is made to use the 1 - 2% of the contrast medium which is late in some of the patients Find times in the liver parenchyma ("late scan").

It is easy to see that there is a need for improved diagnosis of focal liver lesions because the existing methods are too inefficient, too expensive or too burdensome for the patient. Therefore there have been countless attempts over the decades to develop intravenously administrable liver-specific X-ray contrast media. Only a few of the large number of preparations tested should be mentioned (see also Tab. 1-2): Thorotrast (colloidal suspensions of thorium oxide) brought about excellent liver contrast, but was not excreted. The thorium α-emitter caused liver tumors decades after application. In 1940 Schering launched the hepatoselectan preparation, an emulsion of the finest droplets of a triiodinated oil. It had to be withdrawn from the market due to acute side effects. Successor products from other companies and research groups (EOE-13, AG-60-99 etc.) were abandoned during the clinical trials because of the same problems.

Table 1: Emulsions

Oil emulsions i.v.

Name company auditor status

AG 60-99 Guerbet Lamarque 100 patients, discontinued

EOE 13 Measure several hundred

Patient, canceled

EOE 14 Abbott - preclinical only

Perfluorooctyl bromide Boehringer Bruneton clinical trial

Ingelheim canceled

Intraiodol Lunderquist clinical trial canceled

Oil emulsions in general

Lipiodol numerous without approval

user

Table 2: Liposomes

Liposomes

Name company auditor status

Amidotrizoat " ^UL - ^L - *" Rosenberg High side effect rate in humans, not approved or lotrolan approved lopromid Schering Krause animal experiment lopamidol Bracco Musu animal experiment loxaglat Guerbet Corot animal experiment In addition to a large number of pharmaceutical problems, all particulate preparations (suspensions, emulsions, liposomes) have the disadvantage of causing characteristic side effects which are difficult to avoid and which are characteristic of high doses (5-20 g) for X-ray diagnostics. In the 1970s and early 1980s, great efforts were therefore made to find water-soluble X-ray contrast media that accumulate in the liver - sufficient for CT. Such substances were provided with up to 6 iodine atoms per molecule and not least because of this in animal experiments such. T. very effective and were well tolerated. There were striking differences in the effectiveness of the individual animal species. To date, however, none of the tested iodine-containing water-soluble contrast agents in humans has reached a sufficient concentration in the liver that would make a development for CT appear promising. A characteristic example of the many failed attempts was given by Mützel, W., Wegener OH, Souchon, R. and Weinmann, H.-J., Water-soluble contrast agents for computed tomography of the liver: experimental studies in dog. In Amiel (edt.): Contrast media in radiologiy, Lyon 1981, Springer Verlag Berlin Heidelberg New York 1982, pp. 320-323, Tab. 1. In this case too, in contrast to many animal species, adequate liver contrast was not found in humans.

Intravenous cholegraphics such as lotroxinate and loglycamat selectively accumulate in the liver. However, this process is very limited in capacity. With a concentration corresponding to 5 μg iodine / ml plasma, the 5-fold concentration in the liver is still achieved, with a concentration of 50 μg iodine / ml only barely twice the concentration, with 500 μg iodine / ml plasma the concentration in the liver is clearly lower than in plasma and therefore largely diagnostically worthless, since it is impossible to differentiate between actively enriching tissue and mere perfusion. However, computed tomography only detects iodine concentrations from approx. 1 mg / ml with sufficient certainty (Speck, U., Mützel, W., Herz-Hübner, U., Siefert, HM Pharmacology of lotroxinic acid, a new intravenous cholegraphic agent I. Pharmacokinetics and radiology in animals, Drug Res. 28, 2143-2149 (1978). It must therefore be stated that there is a need for preferably water-soluble and therefore pharmaceutically well-characterized, stable, compatible, specific and not too high dose X-ray contrast media and that despite decades of efforts, not a single product has been on the market or even in a promising stage of clinical trial there. Such preparations are difficult to find due to the unpredictable species dependence of absorption, enrichment and excretion by the liver by means of animal experiments; In addition, after many disappointing results in animal experiments, animal findings are no longer to be regarded as an indication of the suitability or inappropriateness of a substance or class of substances.

Metallic contrast agents for magnetic resonance imaging also absorb X-rays. In individual cases, attempts have therefore been made to use these substances for computed tomography (Schild, HH et al .: Gadolinium DTPA (Magnevist®) as contrast medium for arterial DSA. Progr. Röntgenstr. 160, 218-221 (1994); Quinn, AD et al .: Gd-DTPA: An alternative contrast medium for CT. J. Comput. Assist. Tomogr. 18, 634-636 (1994)). It has to be taken into account that the metal complexes available so far bind only one contrasting metal ion per molecule, while the iodinated X-ray contrast media contain 3 or 6 iodine atoms. Despite higher effectiveness of some metal ions against iodine (Zwicker, C, Langer, M., Langer, R., Keske, U. Comparision of iodinated and noniodinated contrast media in computed tomography. Invest. Radiol. 26, 162-164 (1991) the iodinated contrast agents have not been replaced by metal chelates in any relevant indication.

A major disadvantage of using metal chelates as X-ray contrast media is the significantly lower content of X-ray absorbing element in the molecules (iodinated X-ray contrast media: 3 or 6 iodine atoms / molecule; MR contrast media: 1 metal ion / molecule). The contrast is correspondingly weak, so that the metal complexes were used almost only for experimental investigations in X-rays. Low concentrations of the metal ions are sufficient in the MR because they influence the rapidly exchanging protons of the water, whereas the metal itself has to be made visible on the X-ray. The object of the present invention application is therefore to select from the known pharmaceutical substances suitable for imaging diagnostics on the basis of metal chelates those which are suitable for the production of contrast media for X-ray diagnostics, in particular computed tomography, the liver and biliary tract.

The object is achieved by the present invention as characterized in the patent claims. The invention therefore relates to the objects characterized in the claims.

It has been found that metal complexes consisting of a metal of atomic numbers 44-51 or 56-83 and a complexing agent are suitable for the production of contrast media for use in contrast-enhanced computed tomography of the liver and the biliary tract.

These are compounds of the general formula I.

wherein

X independently represents a hydrogen atom or a metal ion equivalent of an element of atomic numbers 44-

51 or 56-83, one of the radicals R ^{1 represents} a radical of the formula -CH ₂ -C ₆ H - (0) _r -R ² , in which the aromatic ring can be substituted in the ortho, meta or para position and the other radical R ^{1 is} hydrogen, R ^{2 is} a hydrocarbon radical consisting of 1-6

Carbon atoms and 0-2 oxygen atoms, a phenyl or a benzyl radical or for hydrogen and r stands for the numbers zero or one, in which carboxyl groups can also be present as amides, together with the physiologically compatible cations which may be required for charge balance.

As radicals R ¹ of the general formula I can be used substituted benzyl, such as methoxybenzyl, ethoxybenzyl, propoxybenzyl, Butoxybenzyl-, Pentoxybenzyl-, benzyloxybenzyl, methylbenzyl, ethylbenzyl, propylbenzyl, butylbenzyl, pentylbenzyl and benzylbenzyl remains. Preferred radicals R ¹ are ethoxybenzyl and butylbenzyl radicals. The substituents of the benzyl radicals can be in the 2-, 3- or 4-position, that is to say ortho, meta or para. Ortho and para substituents are preferred, para residues are very particularly preferred. The R ¹ radicals can be in the 4- or 5-position of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -undecanedioic acid, the 4-position being preferred. In the other position R ¹ there is a hydrogen atom.

Those radicals which contain oxygen (r = 1) are preferred. The ethoxybenzyl radical is very particularly preferred. The radicals R ² may contain the compounds d to C ₆ -alkyl radicals, for example methyl, ethyl, propyl, butyl, pentyl or hexyl radicals. C ₃ to C ₆ alkyl radicals can be straight-chain or branched, such as, for example, isopropyl, isobutyl, tert-butyl, neopentyl or isohexyl radicals. However, the alkyl radicals can also contain up to 2 oxygen atoms (peroxo compounds naturally not being considered), for example as ethoxyethyl, ((ethoxy) ethoxy) ethyl or methoxypropyl radicals.

Lanthanoids are preferred among the metal ions. In measurements under practical conditions (see Example 8), holmium, erbium and ytterbium have proven to be more suitable than the elements gadolinium and dysprosium common in MR, thulium seems less suitable from an economic point of view because of the high price, but is also fundamentally suitable suitable. However, other elements can also be used. In particular, chelate compounds of lutetium, praseodymium, cerium, hafnium, lead and bismuth still have particularly favorable properties.

The carboxyl groups can also be present as amides, for example as alkyl or dialkyl amides - in which the alkyl groups have 1-4 carbon atoms - or as a morpholide group. In contrast to the carboxyl functions, the amide functions are not negatively charged. As a result, the charge of the complex changes when a carboxyl function is converted into an amide function. As a rule, at most so many carboxyl functions are converted into amide functions that an electrically neutral complex is formed.

Examples of physiologically compatible cations are sodium *, calcium ²⁺ , magnesium ²⁺ and zinc ²⁺ and organic cations from the following organic bases: meglumine, glucosamine, arginine, ornithine, lysine, 2-amino-1,3,4-butanetriol and ethanolamine.

The following compounds are particularly suitable for the use according to the invention:

• Gadolinium (III) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid, • Ytterbium (III) complex of 3,6,9 Triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid, Praseodymium (III) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid,

• cerium (III) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) - undecanedioic acid, • lutetium (III) complex of 3,6,9 Triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid,

Hafnium (IV) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid,

Bismuth (III) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid,

Ytterbium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -5- {4- [2- (2-ethoxyethoxy) ethoxy] benzyl} undecanedioic acid,

• lead (II) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) - undecanedioic acid, • ytterbium (III) complex of 3,6,9 Triaza-3,6,9-tris (carboxymethyl) -4- (2-ethoxy-benzyl) -undecanedioic acid,

Gadolinium (III) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butyl-benzyl) -undecanedioic acid,

Ytterbium (III) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butyl-benzyl) -undecanedioic acid,

Praseodymium (III) complex of 3,6,9-thaza-3,6,9-tris (carboxymethyl) -4- (4-butyl-benzyl) -undecanedioic acid,

• hafnium (IV) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butyl-benzyl) - undecanedioic acid, • bismuth (III) complex of 3,6,9 Triaza-3,6,9-tris (carboxymethyl) -4- (4-butyl-benzyl) undecanedioic acid,

Lutetium (III) complex of S.β.θ-Triaza-S.e.θ-tristcarboxymethylH ^ -butyl-benzyl) - undecanedioic acid,

• Lead (II) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butyl-benzyl) undecanedioic acid and its salts and amides. The skilled worker is familiar with the preparation of the compounds according to the invention. Some of these substances and their preparation are described in EP 0 405 704 and US 4,880,008, among others. Manufacturing examples are also described in the examples of this document, which the person skilled in the art can vary according to his needs in order to arrive at the desired compounds.

The metal complexes mentioned are preferably used in the form of their sterile aqueous solutions. In addition to the metal complexes which absorb the X-rays, they can contain the usual pharmaceutical auxiliaries, such as buffers, bases, acids, stabilizers, solubilizers, substances for adapting the osmolality and viscosity, pharmacologically active additives and an excess of free complexing agent or their salts / complexes with weak contain bound physiologically compatible ions such as calcium ²⁺ , magnesium ²⁺ and zinc ²⁺ to improve the excretion of heavy metal ions. Suitable substances and their concentration ranges are known to the person skilled in the art or can be found in the literature.

The metal complexes are preferably used in a concentration of 0.1 mol to 1.0 mol based on the contrasting metal ion. Higher or lower concentrations are possible depending on the requirements and the solubility of the compounds in question. The dosage for contrast enhancement in the liver is approximately 0.1-1.5 mmol / kg body weight, the range 0.2-0.6 mmol / kg being preferred.

The administration can take place in the usual ways in medicine. Intravenous infusion or injection over a period of about 1 minute to 30 minutes is preferred.

It was surprising that with these metal chelates, despite clearly poorer conditions on the part of the radiation-absorbing effect per molecule, an absorption of the X-rays in the liver which was completely satisfactory for computed tomography was achieved for the first time in humans, without the need to use doses as high as in the non-specific iodinated X-ray contrast media is the case. Showed at the same time that the accumulation in the liver takes place quickly and lasts for a sufficiently long time for the computer tomographic diagnostic method. Administration can be non-invasive (eg intravenous). The tolerance is very good in the necessary dose range (see above).

In summary, it can be stated that the substance class described here has succeeded for the first time in achieving a specific contrast medium concentration in the liver in humans, which leads to useful diagnostic information in the computer tomographic technology available today. This finding is all the more surprising than

♦ For decades, preparations for this purpose have been searched in vain,

♦ the iodinated X-ray contrast media did not meet the requirements despite the presence of all theoretically required molecular properties and a significantly higher content of contrasting element in the molecule,

♦ the use of the substances according to the invention requires a dose that is 10 times higher than in magnetic resonance imaging without

Loss of physiological tolerance would be noticeable,

♦ The concentrations which are reached in the human liver when used in accordance with the invention can already be achieved by a large number of classic iodinated X-ray contrast agents, without these agents therefore being used for computed tomography to improve the diagnosis of focal ones

Liver changes can be used

♦ Animal experiments have so far proven to be completely unreliable with regard to the suitability of contrast media for contrast enhancement in liver computer tomography.

The following examples serve to illustrate the invention without wishing to restrict the subject matter to it. example 1

Lutetium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -5- (4-ethoxybenzyl) -undecanedioic acid

a) 3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- (4-ethoxybenzyl) undecanedioic acid di-tert-butyl ester

16.7 g (21.4 mmol) 3,6,9-Tπaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- (4-hydroxybenzyl) -undecanedioic acid di-tert-butyl ester ( DOS 3710730) are dissolved in 50 ml of anhydrous N, N-dimethylformamide and 0.94 g (23.5 mmol) of sodium hydride dispersion (60% in mineral oil) are added at 0 ° C. under argon. The mixture is allowed to stir for 15 minutes, then 3.74 g (24.0 mmol) of ethyl iodide are added, the reaction temperature is allowed to rise to room temperature and the mixture is stirred for a further four hours. For working up, the mixture is taken up in toluene and shaken out several times against aqueous sodium hydrogen carbonate solution. The organic phase is separated off, dried over magnesium sulfate, filtered and evaporated. The oily residue is chromatographed on silica gel with hexane / diethyl ether / T ethylamine, the product-containing fractions are combined and evaporated. Yield: 16.4 g (94.8% of theory) of colorless oil.

Analysis (based on solvent-free substance): calc .: C 63.92 H 9.11 N 5.20 0 21, 78 found: C 63.77 H 9.28 N 5.13

b) Lutetium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) - 5- (4-ethoxybenzyl) -undecanedioic acid

Of the compound prepared according to Example a) 16.1 g (20 mmol) are dissolved in 50 ml of tetrahydrofuran and 60 ml of two normal sodium hydroxide solution, the mixture is stirred for two hours at 60 ^β C, provides a concentrated hydrochloric acid pH 1, concentrated on a rotary evaporator strong and cleans the residue Ion exchange chromatography (cation exchanger (H ⁺ form), eluent: aqueous ammonia solution). The eluate is evaporated and dried under high vacuum, whereby the free complexing agent is obtained. The penta acid is taken up in 250 ml of water and mixed with 3.98 g (10 mmol) of lutetium oxide. The suspension is stirred at 100 ° C. for 36 hours and filtered. Then pH 7.3 is adjusted with a normal sodium hydroxide solution. The solution is then stirred at 80 ° C. for 1 hour after the addition of 1.6 g of activated carbon and filtered. After freeze drying, the filtrate gives a colorless solid. Yield: 14.1 g (94.8% of theory)

Analysis (based on anhydrous substance): calculated: C 37.16 H 3.80 N 5.65 0 23.67 Lu 23.53 Na 6.18 found: C 37.03 H 3.94 N 5.51 Lu 23.38 Na 5.90

Example 2

Ytterbium complex of the disodium salt of S.e.θ-Triaza-S.e.θ-tris ^ carboxymethylH- (2-ethoxybenzyl) -undecanedioic acid

a) N-Benzyloxycarbonyl-3- [2-hydroxyphenyl] alanine methyl ester

9.5 g (52.4 mmol) of o-tyrosine (2-hydroxyphenylalanine, Heraeus) are suspended in 48 ml of methanol, cooled in an ice bath, and 7.6 ml (105 mmol) of thionyl chloride are added dropwise. After one hour, the mixture is heated to reflux temperature and stirred for three hours. Then allowed to stir overnight at room temperature. The mixture is evaporated to dryness, the residue is taken up in methanol, the mixture is evaporated and the procedure is repeated twice. It is taken up in 50 ml of water, adjusted to pH 8.5 with 1.5 molar sodium carbonate solution and 22.1 ml (63 mmol) of benzyl chloroformate are added under pH control. The mixture is stirred for four hours at room temperature, the organic phase is separated off, washed with water and dried over sodium sulfate. After evaporation, the residue is chromatographed on silica gel (methylene chloride / ethyl acetate). Yield: 13.5 g (78.2% of theory) of a colorless oil which slowly crystallizes.

Analysis (based on solvent-free substance): calc .: C 65.64 H 5.82 N 4.25 0 24.29 found: C 65.57 H 5.68 N 4.30

b) N-Benzyloxycarbonyl-3- [2-ethoxyphenyl] alanine methyl ester

10.2 g (31 mmol) of the ortho-phenol from Example a) are dissolved in 6 ml of N, N-dimethylformamide at 40 ° C., 9.2 g (66.5 mmol) of potassium carbonate and 0.3 ml of water are added . 5.7 ml (43.4 mmol) of diethyl sulfate are then added dropwise and the mixture is stirred for 3.5 hours. 6.6 ml of ammonia are added and the mixture is left to stand for one hour. Then a little water is added and the mixture is extracted with tert-butyl methyl ether. The organic phase is separated off with dilute Washed sulfuric acid and water. It is dried over sodium sulfate, evaporated after filtering off and the residue is chromatographed on silica gel. Yield: 8.2 g (74% of theory) of colorless oil.

Analysis (based on solvent-free substance): calc .: C 67.21 H 6.49 N 3.92 0 22.38 found: C 67.09 H 6.53 N 3.77

c) N-Benzyloxycarbonyl-2- [2-ethoxybenzyl] -2-aminoethanol

7.9 g (22 mmol) of N-benzyloxycarbonyl-3- [2-ethoxyphenyl] alanine methyl ester (Example b) are dissolved in 63 ml of tert-butyl methyl ether, and 1.1 g (30.1 mmol) of sodium borohydride are added . 15 ml of methanol are added at 5 ° C. and the mixture is stirred at constant temperature for five hours. Then 1.5 ml of acetic acid dissolved in 5 ml of tetrahydrofuran are added, 9 ml of water are added and the mixture is stirred for ten minutes at room temperature. The organic phase is separated off, washed with water and dried over sodium sulfate. The drying agent is suctioned off, the filtrate is evaporated and the residue is chromatographed on silica gel for purification.

Yield: 7.25 g (100% of theory) of a colorless oil which crystallizes rapidly.

Analysis (based on solvent-free substance): calculated: C 69.28 H 7.04 N 4.25 0 19.43 found: C 69.32 H 7.00 N 4.18

d) N-Benzyloxycarbonyl-2- [2-ethoxybenzyl] -1, 4,7-triazaheptane, dihydrochloride

7.2 g (22 mmol) of the alcohol from Example c) are dissolved in 18 ml of tetrahydrofuran and 4.9 ml (35 mmol) of triethylamine are added at room temperature. 2.54 ml (32.6 mmol) of methanesulfonyl chloride dissolved in 2 ml of tetrahydrofuran are added and the mixture is stirred at 20 ° C. for six hours. Then 22.2 ml (330 mmol) are added dropwise Add ethylenediamine at a temperature between 30 ° C and 45 ° C. The mixture is heated to 50 ° C. and the batch is stirred for four hours. Then the reaction mixture is evaporated, the residue is taken up in ethyl acetate and washed with water. The organic phase is cooled in an ice bath and concentrated with. Hydrochloric acid added. The resulting precipitate is filtered off, washed with cold isopropanol and dried at 50 ° C. Yield: 7.5 g (76.7% of theory) of a colorless solid.

Analysis (based on solvent-free substance): calc .: C 56.76 H 7.03 Cl 15.95 N 9.45 0 10.80 found: C 56.62 H 7.11 Cl 15.80 N 9.36

e) 2- [2-ethoxybenzyl] -1, 4,7-triazaheptane, dihydrochloride

7.2 g (16.2 mmol) of the Z-protected amine from Example d) are suspended in 72 ml of methanol, 1.08 g of palladium (10%) on activated carbon and 0.5 ml of water are added, and at normal pressure, at Room temperature hydrogenated. When the uptake of hydrogen has ended, the catalyst is filtered off and the filtrate is evaporated. Yield: 4.9 g (97.5% of theory) of a colorless solid.

Analysis (based on solvent-free substance): calc .: C 50.33 H 8.12 Cl 22.85 N 13.54 0 5.16 found: C 50.17 H 8.34 CI 23.11 N 13.40

f) 3 ₎ 6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (2-ethoxybenzyl) undecanedioic acid di-tert-butyl ester

11.2 g (81.5 mmol) of potassium carbonate are dissolved in 11 ml of water and 4.8 g (15.5 mmol) of triamine (Example e) are added at 35 ° C. 12.5 ml (85.3 mmol) are added

Drops of tert-butyl bromoacetate are added dropwise and the mixture is stirred at 65 ° C. for seven hours. After stirring for 18 hours at room temperature, the The reaction mixture is mixed with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, evaporated and the residue is chromatographed on silica gel (methylene chloride / methanol). After evaporation of the product-containing fractions, the pentaester is obtained as a pale yellow oil. Yield: 11.9 g (95% of theory)

Analysis (based on solvent-free substance): calc .: C 63.92 H 9.11 N 5.20 021, 78 found: C 64, 05 H 9.23 N 5.07

g) 3,6,9-Triaza-3,6,9-tris (carboxymethyl) -4- (2-ethoxybenzyl) -undecanedioic acid

11.75 g (14.5 mmol) of pentaester from example f) are dissolved in 86 ml of methanol and reacted with 4.65 g (116.3 mmol) of sodium hydroxide in 7.1 ml of water. The mixture is stirred at 65 ° C. for four hours, then the methanol is evaporated, water is added and the mixture is evaporated again. It is taken up in water and adjusted to pH 1.8 with an acidic ion exchanger. After filtering off the exchanger, the aqueous solution is largely concentrated and the pentic acid is purified by preparative HPLC (water / methanol / pH 2.5). The product-containing fractions are evaporated, taken up again in water and freeze-dried. Yield: 4.9 g (64% of theory)

Analysis (based on solvent-free substance): calc .: C 52.37 H 6.31 N 7.97 0 33.36 found: C 52.19 H 6.46 N 7.88

h) Ytterbium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (2-ethoxybenzyl) -undecanedioic acid 3.72 g (7.05 mmol) pentanoic acid of Example g) is dissolved at 60 ^β C in 19 ml water and treated portionwise with 1.85 g (3.53 mmol) of ytterbium carbonate. After complexation is complete, the mixture is filtered, adjusted to pH 7.0, stirred with 0.2 g of activated carbon at 100 ° C. for ten minutes, filtered again and the filtrate is lyophilized. Yield: 4.6 g (88% of theory) of colorless lyophilisate.

Analysis (based on anhydrous substance): calculated: C 37.26 H 3.81 N 5.67 0 23.74 Yb 23.34 Na 6.20 found: C 37.13 H 4.02 N 5.55 Yb 23.18 Na 5.87

Example 3

a) Ytterbium complex of the dimeglumine salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedioic acid

2.9 g (5.5 mmol) of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid (EP 0405704, Example 8b) are in 20 ml Suspended water and complexed with 1.45 g (2.75 mmol) of ytterbium carbonate at 60 ° C. After the reaction has ended, the batch is neutralized with methylglucamine. The mixture is filtered and the metal complex is obtained by freeze-drying the filtrate. Yield: 5.7 g (95.3% of theory) of colorless lyophilisate.

Analysis (based on anhydrous substance): calculated: C 40.85 H 5.93 N 6.44 0 30.88 Yb 15.90 found: C 40.67 H 6.08 N 6.17 Yb 15.62

b) Ytterbium complex of the di (2-arnino-1, 3,4-butanetriol) salt of the 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) - undecanedioic acid

The title compound is obtained in a manner analogous to example a) if the complex acid is neutralized with 2-amino-1, 3,4-butanetriol.

c) Cerium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedioic acid

The title compound is obtained in an analogous manner to Example a) if the ligand (EP 0405704, Example 8b) is reacted with cerium carbonate and neutralized with sodium hydroxide solution. d) Ytterbium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedioic acid

2.1 g (4 mmol) of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid (EP 0405704, Example 8b) are suspended in 15 ml of water and complexed with 1.05 g (2 mmol) of ytterbium carbonate at 60 ^° C. When the complexation is complete, the batch is neutralized with 1 N sodium hydroxide solution. The complex solution is filtered and the title compound is obtained by freeze-drying the filtrate. Yield: 3.0 g (100% of theory) of colorless lyophilisate.

Analysis (based on anhydrous substance): calculated: C 37.26 H 3.81 N 5.67 0 23.74 Yb 23.34 Na 6.20 found: C 37.14 H 4.11 N 5.50 Yb 23 , 22 Na 5.94

e) Lutetium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) - 4- (4-ethoxybenzyl) -undecanedioic acid

3.0 g (5.7 mmol) of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid (EP 0405704, Example 8b) are added in 15 ml Suspended water and complexed with 1.07 g (2.7 mmol) of lutetium oxide at 95 ° C. After finished

The complexation is neutralized with 1 N sodium hydroxide solution. The solution is filtered and the title compound is obtained by freeze-drying the filtrate. Yield: 3.9 g (92% of theory) of colorless lyophilisate.

Analysis (based on anhydrous substance): calculated: C 37.16 H 3.80 N 5.65 0 23.67 Lu 23.53 Na 6.18 found: C 37.02 H 4.01 N 5.53 Lu 23.36 Na 5.87

The corresponding bismuth complex (made from bismuth oxycarbonate), the hafnium complex (made from hafnium hydroxide) and the lead complex can be used in an analogous manner (from lead carbonate), the lanthanum complex (from lanthanum carbonate), the dysprosium complex (from dysprosium oxide), the erbium complex (from erbium carbonate), the terbium complex (from terbium carbonate), the holmium complex (from holmium carbonate) and the praseodymium carbonate (obtained from praseodymium carbonate).

Example 4

Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) - 4- (2-butoxy benzyl) -undecanedioic acid

a) N-Benzyloxycarbonyl-3- [2-butoxyphenyl] alanine methyl ester

5.0 g (15.2 mmol) of the ortho-phenol from Example 2a) are dissolved in 4 ml of N, N-dimethylformamide at 40 ° C., with 4.5 g (31.1 mmol) of potassium carbonate and 0.2 ml Water added. Then 2.1 g (15.5 mmol) of n-butyl bromide are added dropwise and the mixture is stirred for 5 hours. 3.2 ml of ammonia are added and the mixture is left to stand for one hour. Then a little water is added and the mixture is extracted with tert-butyl methyl ether. The organic phase is separated off, washed with dilute sulfuric acid and water. It is dried over sodium sulfate, evaporated after filtering off and the residue is chromatographed on silica gel. Yield: 4.7 g (80.2% of theory) of colorless oil.

Analysis (based on solvent-free substance): calc .: C 68.55 H 7.06 N 3.63 0 20.75 found: C 68.42 H 7.18 N 3.59

b) N-Benzyloxycarbonyl-2- [2-butoxybenzyl] -2-aminoethanol

3.9 g (11 mmol) of N-benzyloxycarbonyl-3- [2-butoxyphenyl] alanine methyl ester

(Example a) are dissolved in 30 ml of tert-butyl methyl ether and mixed with 0.55 g (15 mmol) of sodium borohydride. At 3 ° C 8 ml of methanol are added and the mixture is stirred for five hours at constant temperature. Then 0.8 ml of acetic acid dissolved in 3 ml of tetrahydrofuran is added, 5 ml of water are added and the mixture is stirred at room temperature for ten minutes. The organic phase is separated off, washed with water and dried over sodium sulfate. The drying agent is suctioned off, the filtrate is evaporated and the residue is chromatographed on silica gel for purification. Yield: 3.4 g (86.5% of theory) of colorless oil. Analysis (based on solvent-free substance): calc .: C 70.56 H 7.61 N 3.92 0 17.90 found: C 70.43 H 7.60 N 4.07

c) N-Benzyloxycarbonyl-2- [2-butoxybenzyl] -1, 4,7-triazaheptane, dihydrochloride

3.1 g (8.8 mmol) of the alcohol from Example b) are dissolved in 8 ml of tetrahydrofuran, and 2.0 ml (14 mmol) of triethylamine are added at room temperature. 1.02 ml (13 mmol) of methanesulfonic acid chloride are added, dissolved in 1 ml of tetrahydrofuran, and the mixture is stirred at 20 ^° C. for five hours. 8.9 ml (132 mmol) of ethylenediamine are then added dropwise at a temperature between 35 ° C. and 45 ° C. The mixture is heated to 50 ° C. and the batch is stirred for three hours. Then the reaction mixture is evaporated, the residue is taken up in ethyl acetate and washed with water. The organic phase is cooled in an ice bath and concentrated with. Hydrochloric acid added. The resulting precipitate is filtered off, washed with cold isopropanol and dried at 50 ° C. Yield: 3.8 g (91.4% of theory) of a yellowish solid.

Analysis (based on solvent-free substance): calculated: C 58.47 H 7.47 Cl 15.01 N 8.89 0 10.16 found: C 58.28 H 7.24 Cl 14.93 N 8.73

d) 2- [2-butoxybenzyl] -1, 4,7-triazaheptane, dihydrochloride

3.6 g (8.1 mmol) of the Z-protected amine from Example c) are suspended in 35 ml of methanol, 0.4 g of palladium (10%) on activated carbon and 0.3 ml of water are added and at normal pressure Room temperature hydrogenated. When the uptake of hydrogen has ended, the catalyst is filtered off and the filtrate is evaporated. Yield: 2.4 g (87.6% of theory) of a yellowish solid. Analysis (based on solvent-free substance): calc .: C 53.25 H 8.64 Cl 20.96 N 12.42 0 4.73 found: C 53.08 H 8.72 Cl 21.23 N 12.29

e) 3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (2-butoxybenzyl) undecanedioic acid di-tert-butyl ester

5.3 g (38.8 mmol) of potassium carbonate are dissolved in 5 ml of water and 2.3 g (7.4 mmol) of triamine dihydrochloride (Example d) are added at 35 ° C. 5.9 ml (40.6 mmol) of tert-butyl bromoacetate are added dropwise and the mixture is stirred at 60 ° C. for eight hours. After stirring for 15 hours at room temperature, the reaction mixture is mixed with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, evaporated and the residue is chromatographed on silica gel (ethyl acetate / acetone). After evaporation of the product-containing fractions, the pentaester is obtained as a colorless oil. Yield: 5.3 g (85.7% of theory)

Analysis (based on solvent-free substance): calc .: C 64.64 H 9.28 N 5.03 0 21.05 found: C 64.77 H 9.34 N 4.88

f) 3,6,9-Triaza-3,6,9-tris (carboxymethyl) -4- (2-butoxybenzyl) -undecanedioic acid

5.11 g (6.3 mmol) of pentaester from example e) are dissolved in 40 ml of methanol and reacted with 2.02 g (50.6 mmol) of sodium hydroxide in 3.1 ml of water. The mixture is stirred at 55 ° C. for three hours, then the methanol is evaporated off, water is added and the mixture is evaporated again. It is taken up in water and adjusted to pH 1.9 with an acidic ion exchanger. After filtering off the exchanger, the aqueous solution is largely concentrated and the pentic acid by preparative HPLC (Water / methanol / pH 2.8). The product-containing fractions are evaporated, taken up again in water and freeze-dried. Yield: 2.9 g (82.8% of theory) of colorless lyophilisate.

Analysis (based on solvent-free substance): calc .: C 54.05 H 6.71 N 7.56 0 31, 68 found: C 53.91 H 6.76 N 7.39

g) Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (2-butoxybenzyl) -undecanedioic acid

2.48 g (4.7 mmol) of pentic acid from Example f) are suspended in 20 ml of water at 85 ° C. and 0.85 g (2.35 mmol) of gadolinium oxide are added in portions. When the complexation is complete, the mixture is filtered, adjusted to pH 7.2, with 0.2 g

Activated carbon stirred for ten minutes at 90 ° C, filtered again and the filtrate lyophilized. Yield: 3.5 g (98.8% of theory) of colorless lyophilisate.

Analysis (based on anhydrous substance): calculated: C 39.84 H 4.28 N 5.58 0 23.35 Gd 20.86 Na 6.10 found: C 39.73 H 4.39 N 5.47 Gd 20.71 Na 5.94

Example 5

Ytterbium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -5- {4- [2- (2-ethoxyethoxy) ethoxy] benzyl} undecanedioic acid

a) 3,6,9-Triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- {4- [2- (2-ethoxyethoxy) -ethoxy] -benzyl} -undecanedioic acid di-tert .-butyl ester

16.7 g (21.4 mmol) 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- (4-hydroxybenzyl) -undecanedioic acid di-tert-butyl ester ( DOS 3710730) are dissolved in 50 ml of anhydrous N, N-dimethylformamide and 0.94 g (23.5 mmol) of sodium hydride dispersion (60% in mineral oil) are added at 0 ° C. under argon. The mixture is allowed to stir for 15 minutes, then 4.73 g (24.0 mmol) of 2- (2-ethoxyethoxy) ethyl bromide are added, the reaction temperature is allowed to rise to room temperature and the mixture is stirred for a further four hours. For working up, the mixture is taken up in toluene and shaken out several times against aqueous sodium hydrogen carbonate solution. The organic phase is separated off, dried over magnesium sulfate, filtered and evaporated. The oily residue is chromatographed on silica gel with hexane / diethyl ether / triethylamine, the product-containing fractions are combined and evaporated. Yield: 17.7 g (92.4% of theory) of colorless oil.

Analysis (based on solvent-free substance): calculated: C 62.99 H 9.11 N 4.69 O 23.21 found: C 63.07 H 9.27 N 4.75

b) Ytterbium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -5- {4- [2- (2-ethoxyethoxy) ethoxy] benzyl} undecanedioic acid

13.4 g (15.0 mmol) of the compound prepared according to a) are in 35 ml

Dissolved tetrahydrofuran and mixed with 45 ml of two normal sodium hydroxide solution, stirred for two hours at 60 ° C, adjusted to pH 1 with concentrated hydrochloric acid, concentrated vigorously on a rotary evaporator and cleaned the residue through Ion exchange chromatography (cation exchanger (H ⁺ form), eluent: aqueous ammonia solution). The eluate is evaporated and dried under high vacuum, whereby the free complexing agent is obtained. The penta acid is taken up in 150 ml of water and mixed with 3.94 g (7.5 mmol) of ytterbium carbonate. The suspension is stirred at 60 ° C for 3 hours and filtered. Then pH 7.3 is adjusted with a normal sodium hydroxide solution. The solution is then stirred at 80 ° C. for 1 hour after the addition of 1.0 g of activated carbon and filtered. After freeze drying, the filtrate gives a colorless solid. Yield 11.4 g (91.6% of theory)

Analysis (based on anhydrous substance): calc .: C 39.09 H 4.37 N 5.07 O 25.07 Yb 20.86 Na 5.54 found: C 38.84 H 4.45 N 5.02 Yb 20.69 Na 5.30

Example 6

Density increase of the healthy liver parenchyma 10 and 60 minutes after infusion of a 0.25 molar solution of the gadolinium III complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedioic acid Disodium salt (Gd-EOB-DTPA, described in Example 8c of EP 0405704) in 5 patients with liver metastases in a dose of 0.35 mmol / kg in Houndsfield units (HU). This dose corresponds to approximately 16 g of the complex per 70 kg patient.

Table 3

10 min. P. Inf. 60 min. P Inf. HU HU

Patient 1 19 26

Patient 2 12 25

Patient 3 10 17

Patient 4 18 32

Patient 5 15 32

In comparison, according to Mützel et al. (Contrast Media in Radiology, Ed .: M. Amiel, Springer Verlag, Berlin, Heidelberg, 1982) the hexajodized SH L 433 A (formula XI) specially developed for liver diagnostics

CH,

(XI) at a dose corresponding to 360 mg iodine / kg (approx. 25 g iodine per 70 kg patient) only an enhancement of <10 HU (monkey, dog, mouse:> 40 HU). The approximately 90% excreted bilroxinate in humans (hexajodated, 2 carboxyl groups) only reaches 15 HU in the liver at the maximum tolerated dose corresponding to approx. 7 g iodine / 70 kg patient (Hübner, KH: computed tomographic densitometry of the liver, spleen and kidneys in intravenous bolus contrast agents administered intravenously, Progr. Röntgenstr. 129, 289-297 (1978)).

In comparison, about 3.5 g of gadolinium in the form of a complex containing only one gadolinium ion / molecule achieves a much higher X-ray absorption in the human liver than with 25 g of iodine from SH L 433 A (formula XI) or 7 g iodine of lotroxinate, although both X-ray contrast media are hexajodated compounds. Example 7

The following solution is produced:

0.1 mol of the holmium (III) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butylbenzyl) -uπdecanedioic acid, dimeglumin salt,

0.005 mol of the calcium (II) complex of the 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4-

(4-butylbenzyl) -undecanedioic acid, trimeglumine salt in 1 liter of 5% mannitol solution, pH 7.0.

The solution is infused at a dose of 0.3 mmol / kg body weight over 30 minutes. CT scans are performed before the start of the infusion, at the end of the infusion and 30 minutes after the end of the infusion in the usual way.

Example 8

3,6,9-Triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedioic acid disodium salt was complexed with different X-ray absorbing metal ions and then at different concentrations the density values of the samples in a water phantom measured, as the dimensions corresponded approximately to the abdomen of a person. It was worked on a commercially available computer tomograph with the usual voltage of 137 kV and 110 mA.

Table 4

Findings in Hounsfieldunits (HU ± SD)

Element concentration HU ± SD (mmol / L)

H ₂ 0 - 14 23

Gd 50 218 23 500 1680 33

Tb 50 228 25 500 1760 45

Dy 50 226 23 500 1840 42

Ho 50 221 29 500 1890 40

He 50 254 24 500 1955 57

Yb 50 252 18 500 1980 42

J 50 110 25 500 914 27 A surprisingly high effectiveness of the rare earths against iodine turns out, which is presumably due to the special measuring conditions existing in abdominal CT. Within the lanthanides, erbium, ytterbium and holmium are preferable to the elements gadolinium and dysprosium, which have so far been the most studied.

Example 9

Test execution

Fifteen patients with known liver metastases were examined in liver CT 10 min, 60 min and (N = 5) 120 min after intravenous infusion of 0.2, 0.35 and 0.5 mmol / kg Gd-EOB-DTPA (see Example 6) examined.

Gd-EOB-DTPA (0.25 mmol / L) was administered intravenously in a drip infusion into the arm vein. The infusion time was 20 min for the doses 0.2 and 0.35 mmol / kg and 30 min for the highest dose of 0.5 mmol / kg. The patients had histologically proven primary tumors (N = 9 with colorectal carcinoma, N = 2 with intestinal carcinoid, N = 1 with gastric carcinoma, N = 1 with leiomyosarcoma and N = 1 with ovarian cystadenocarcinoma) and the metastases (N <5) were complete contrast-enhanced CT was detected within one month prior to the Gd-EOB-DTPA study. Exclusion criteria for the patients were:

• age under 18 years,

History of severe or allergy-like side effects after contrast agent administration,

• prior administration of Gd-EOB-DTPA, • contrast agent administration within 24 hours before the study,

• a transplanted organ,

Pre-menopausal women

• surgery or liver biopsy 24 hours before or after the study and

• Patients with laboratory parameters that deviate greatly from the norm.

CT examinations were performed before and 10 min, 60 min and (N = 5) 120 min after intravenous infusion of Gd-EOB-DTPA with a Siemens spiral CT. The entire liver was measured within 20-30 seconds with the breath stopped. The table feed was 8 mm / sec, the collimation 8 mm.

Based on the pre- and post-contrast images, the number and size of the metastases were qualitatively assessed by two independent observers (excellent, good, moderate, minimal, no improvement) and quantitatively (measurement of the Hounsfield units) evaluated.

The tolerance of Gd-EOB-DTPA was determined by determining the general condition, the recording of vital parameters and a laboratory analysis of serum and urine parameters.

Results

After intravenous infusion of Gd-EOB-DTPA, a dose-dependent increase in the CT density of the healthy liver was found. Figure 1 shows the time course of the CT density (Hounsfield units, HU) in the liver of patients with histologically proven primary tumor after the start of an infusion of 0.2 (o), 0.35 (♦) or 0.5 mmol / kg Gd-EOB-DTPA (Λ). The CT density in the liver metastases is shown with the symbol *.

The CT density of the metastases was unchanged. The gallbladder and bile ducts were also visualized. Visualization of the metastases was improved in all dose groups after infusion of Gd-EOB-DTPA. It was excellent in the two upper dose groups. After the highest dose, an average of two additional metastases were discovered that were previously unknown. The mean size of the smallest metastases found decreased accordingly from 20.3 to 16.6 mm. In a patient with a known metastasis in the right lobe of the liver, an additional lesion of 7 mm in diameter was found after Gd-EOB-DTPA in the left lobe of the liver, which had not previously been found.

The general tolerability of Gd-EOB-DTPA was good. Only four mild or moderate side effects were observed. In two cases, patients reported burning at the infusion site or retrograde that persisted for a few seconds or minutes. Other side effects included nausea and epigastric pressure. The evaluation of the laboratory parameters showed no clear trend. Slight increases in aspartate and alanine aminotransferase were found in three patients, but were probably due to liver metastases. In summary, it follows that Gd-EOB-DTPA is a well-tolerated and effective liver or bile contrast agent for CT.

Claims

Claims:

1) Use of chelate compounds of the general formula I

where n, X independently represent a hydrogen atom or a

Metal ion equivalent of an element of atomic numbers 44-51 or 56-83, one of the radicals R ^{1 represents} a radical of the formula -CH ₂ -C ₆ H ₄ - (0) _r -R ² , in which the aromatic ring is the ortho-, can be substituted with meta or para and the other R ^{1 is} hydrogen,

R ² for a hydrocarbon radical consisting of 1 -6

Carbon atoms and 0-2 oxygen atoms, a phenyl or a benzyl radical or for hydrogen, r stands for the numbers zero or one, in which carboxyl groups can also be present as amides, together with the physiologically compatible cations which may be required for charge balancing, for medical diagnosis , characterized in that the diagnostic method is computer tomography of the liver and biliary tract.

2) Use of chelate compounds according to claim 1, characterized in that the complexed metal is a lanthanoid atom.

3) Use of chelate compounds according to claim 1 and 2, characterized in that the complexed metal is cerium, praseodymium, gadolinium, dysprosium, holmium, erbium, ytterbium or lutetium. 4) Use of chelate compounds according to claim 1, characterized in that the complexed metal is hafnium, bismuth or lead.

5) Use of chelate compounds according to claim 1, characterized in that at least one of the physiologically compatible cations Na ⁺ , Ca ^{2 *} , Mg ^{2 *} or a cation of the organic bases meglumine, glucosamine, arginine, ornithine, lysine, 2-amino-1 , 3,4-butanetriol or ethanolamine.

6) Use of chelate compounds according to claim 1, characterized in that r stands for zero.

7) Use of chelate compounds according to claim 1, characterized in that r stands for one.

8) Use of chelate compounds according to claim 1, characterized in that R ² for methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert. ^' Butyl, phenyl or benzyl is.

9) Use of chelate compounds according to claim 1, characterized in that R is in the ortho or para position.

10) Use of chelate compounds according to claim 1, characterized in that the chelate compound of the gadolinium (III) complex of the 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid, the ytterbium (III) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid, the praseodymium (III) complex of 3, 6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid, the lutetium (III) complex of 3,6,9-triaza-3,6,9- tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid, the cerium (III) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethpxy- benzyl) - undecanedioic acid, the hafnium (IV) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid, the bismuth (III) complex of 3,6,9 -Triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid, the ytterbium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -5 - {4- [2- (2-ethoxyethoxy) ethoxy] benzyl} undecanedioic acid of lead (II) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4th -ethoxy-benzyl) - undecanedioic acid or the ytterbium (III) complex which is 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (2-ethoxy-benzyl) -undecanedioic acid.

11) Use of chelate compounds according to claim 1, characterized in that the chelate compound of the gadolinium (III) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butyl-benzyl) -undecanedioic acid, the ytterbium (III) complex of 3,6,9-triaza-3,6,9-ths (carboxymethyl) -4- (4-butyl-benzyl) -undecanedioic acid, the praseodymium (III) complex of 3, 6,9-triaza-3,6,9-ths (carboxymethyl) -4- (4-butyl-benzyl) -undecanedioic acid, the lutetium (III) complex of 3,6,9-triaza-3,6,9- tris (carboxymethyl) -4- (4-butyl-benzyl) -undecanedioic acid, the hafnium (IV) complex of the 3 ₁ 6,9-triaza-3,6,9-ths (carboxymethyl) -4- (4-butyl- benzyl) -undecanedioic acid, the bismuth (III) complex of 3,6,9-thaza-3,6,9-tris (carboxymethyl) -4- (4-butyl-benzyl) undecanedioic acid or the lead (II) complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butyl-benzyl) undecanedioic acid.