MXPA97003974A - Use of metal complexs as x-ray diagnostic agents for the liver and the bil vesicula - Google Patents

Abstract

Metal complexes of DTPA derivatives substituted with benzyl in position 4 or position 5 are suitable as contrast media for computer tomography of the liver and bile ducts

Description

USE OF METAL COMPLEXES AS X-RAY DIAGNOSTIC AGENTS FOR THE LIVER AND THE BILIARY VESICLE DESCRIPTION OF THE INVENTION The invention relates to the use of metal complexes in diagnostic radiology of the liver and gallbladder using X-ray radiation, especially in computed tomography. The first detection of focal liver diseases, especially liver metastases and liver tumors, is one of the most important diagnostic problems in oncology. Four processes to form the image are available for this purpose: scintigraphy, ultrasonography, computer tomography and magnetic resonance tomography. Each of these processes has specific advantages and disadvantages, none is acly carried out optimally according to the current state of the art and virly every process would benefit from the presence of compatible, specific contrast media that can be administered intravenously [Hamed, RK, Chezmar, JL, Nelson RC: Imaging of Patients with potentially Resectable Hepatic Neoplasms. AJR 159, 1191-1194 (1992)].

Scintigraphy offers inadequate spatial resolution and is limited in its use by insufficient or excessive specificity (only usable for a few types of tumors) of the radiopharmaceutical agents, so that it is not mentioned in the review article mentioned in the above . At this time, sonography is also an unreliable technique for the detection of focal, solid liver changes since the latter are often insufficiently distinguished from healthy liver tissue in their acoustic properties. Minor lesions of the liver tissue can only be detected during an operation after the liver is exposed and with the use of high frequency transducers. The magnetic resonance tomography (MRI) is able to detect the entire liver with a spatial resolution and depending on the measurement method, also with good tissue differentiation. For MRI, well tolerated effective contrast media can be administered intravenously in a clinical trial, which also improves the uses of this image formation process. The disadvantages, however, are the movement artifacts in the high-resolution measurement process, which takes several minutes and the high costs of the same hardware; These factors limit its availability. Computed tomography (CT) is currently the ideal technique for the diagnosis of the liver. With modern hardware, the entire liver can be scanned within approximately 30 seconds with excellent spatial resolution. An individual liver layer takes approximately 1 second, in such a way that the movements caused by respiration and peristalsis hardly play any role. The costs of the CT are considerably lower than those of the MRI. The disadvantage of the resolution of low density of fabric must however be compensated for by the contrast media. With the contrast media now available clinically, there are the following possibilities: 1. The contrast media are injected intravenously or rapidly given by infusion and in large doses (50-200 g). A few minutes may have, in individual cases, a difference in the contrast between the lesion and normal liver tissue, which is due to differences in perfusion, the relative blood volume of the tissue, and the extracellular space. Only with the CT scan of very high speed, mentioned in the foregoing, this period of unequal distribution of contrast media can be exploited for diagnosis. 2. 4-6 hours after I read administration of at least 120 g of the usual urogasal contrast media, the improved contrast between the healthy liver parenchyma, which absorbs the contrast medium and the focal liver lesions, which in In most cases it does not incorporate the contrast medium, it will be observed in a very small portion of patients. This technique mentioned as "delayed exploration", however, is not sufficiently reliable and informative, in such a way that it can not be used routinely. 3. In the case of arterial hepatography, a catheter must be inserted for example into mesenteric A.; then the patient is brought to the CT device and the scan is performed, while approximately 150 ml of the contrast medium is given by infusion. This technique is invasive, time consuming and expensive, but at this time it produces the most reliable data on the presence and location of liver metastases. This information is of decisive importance for the decision on the resectability of the metastasis. CT with arterial hepatography is therefore performed regularly preoperatively, despite the cost. The effect of the problems described in the above, is that the X-ray contrast media now available are basically urográfico products, which are not concentrated in the liver. However, to produce some contrast, the liver is flooded by the bloodstream with very large amounts of contrast media over a short period ("dynamic scan"), or an attempt is made to use 1-2% of the medium. contrast that is found in a portion of the patients later in the liver parenchyma ("delayed exploration"). It can be easily seen that there is a need for the improved diagnosis of focal hepatic lesions, since the existing processes are too inefficient, too expensive, or too heavy for patients. Therefore, for decades, numerous attempts have been made to develop liver-specific X-ray contrast media, which can be administered intravenously. Of the large number of preparations tested, only a few can be mentioned (see also Table 1-2): torotraste (colloidal suspensions of thorium oxide) produce excellent liver contrast, but it is not excreted. A-emitting thorium caused liver tumors decades after its administration. In 1940, Schering sold the hepatoselectan preparation, an emulsion of very fine drops of a triyoidal oil. Due to the acute side effects, it has been removed from the market. The successor products of other companies and research groups (EOE-13, AG-60-99, etc.) are given even during clinical trials due to the same problems Table 1: Emulsions Table 2: Liposomes In addition to a considerable number of pharmaceutical problems, all the individual preparations (suspensions, emulsions, liposomes) have the disadvantage, at high doses (5-20 g) used for diagnostic radiology, of causing characteristic side effects that They are difficult to avoid. In the decade of the 70s and in the early 80s, therefore, great efforts were made to find water soluble X-ray contrast media that accumulate in the liver enough for CT. Such substances were provided with up to 6 iodine atoms per molecule and to a large extent for this reason, they were very effective and well tolerated in some cases in animal experiments. Large differences in effectiveness were notable in the case of individual animal species. Until now, however, none of the water-soluble contrast media containing iodine reached a sufficiently high concentration in the liver in humans to make the development for CT look promising. A characteristic example of the many tests that failed was published by Mützel,. , Egener, O. H., Souchon, R. and Heinmann, H. - J., Water-Soluble Contrast Agents for Computed Tomography of the Liver: Experimental Studies in Dog. In Amiel (edt.): Contrast Media in Radiology, Lyon 1981, Springer Verlag Berlin Heidelberg New York 1982, p. 320-323, Table 1. Also in this case, insufficient liver contrast was found in humans, unlike what was found in many types of animals. Intravenous colposive agents, such as iotroxinate and ioglicamate, selectively accumulate in the liver. However, this process is very limited in capacity. At a concentration corresponding to 5 μg of iodine per ml of plasma, a concentration of 5 times in the liver is achieved, at a concentration of 50 μg of iodine / ml a concentration of twice as much and 500 μg of iodine / ml is rarely achieved of plasma, the concentration in the liver is considerably lower than in plasma and therefore to a large extent without diagnostic value, because the differentiation between actively accumulating tissue and perfusion alone is impossible. Computer tomography, however, reliably detects iodine only at initial concentrations of approximately 1 mg / ml (Speck, U., Mützel, W., Herz-Hübner, U., Siefert, HM Pharmakologie der Iotroxinsáure, eines neuen intravenosen Cholegraphicums I. Pharmakokinetik und Radiologie beim Tier. [Phamacology of Iotroxic Acid, a New Intravenous Cholegent Agent I. Pharmacokinetics and Radiology in Animáis] .Drug. Res. 28, 2143-2149 (1978). maintain that there is a need for specific, compatible, stable x-ray contrast media, preferably soluble in water and therefore easily characterized in pharmaceutical form, which are effective and not at doses too high and despite decades of effort Until now, no product has been sold or they are only in a stage of clinical trial promise Due to the dependence of the unpredictable species on the absorption, the Excretion and excretion through the liver by means of experimental tests on animals is difficult to find such preparations; Also, many disappointing results in the findings of experiments in animals, and humans can no longer be considered an indication of the adequacy or inadequacy of a substance or family of substances. Contrast media containing metal for magnetic resonance tomography also absorb X-rays. Therefore, an effort has been made in individual cases to use these substances for computer tomography (Schild, HH et al .: Gadolinium DTPA (Magnevist (R as Contrast Media for Arterial DSA, Fortschr. Rontgenstr. [X-Ray Radiation Research], 160, 218-221 (1994); Quinn, A. D. et al .: Gd-DTPA: An Alternative Contrast Medium for CT. J. Comput. Assis. Tomogr. 18, 634-636 (1994)). It should be taken into consideration that the previously available metal complexes bind only to one opacification metal ion per molecule, while the X-ray contrast media contains 3 or 6 iodine atoms. Despite the higher effectiveness of some metal ions compared with iodine (Zwicker, C, Langer, M., Langer, R., Keske, U. Comparison of Iodinated and Noniodinated Contrast Media in Computed Tomography., Invest. Radiol. 26, 162-164 (1991), iodine contrast media so far can not be replaced by metal chelates in any important indication.An important disadvantage of using metal chelates as X-ray contrast media is the content significantly Minor element that absorbs X-rays in molecules (iodinated X-ray contrast media: 3 or 6 iodine atoms / molecule; contrast media RM; 1 metal ion / molecule). The opacification is correspondingly weak, so that the metal complexes are used almost exclusively for experimental studies in radiology. In MRI, low concentrations of metal ions are sufficient, since the latter rapidly affect the exchange of protons in water, while in radiology the metal itself must be made visible. The object of this application for invention, therefore, is to select, from known pharmaceutical substances based on metal chelates, which are suitable for diagnosis by imaging, those substances which are suitable for the production of contrast media for diagnostic radiology, especially computer tomography of the liver and bile ducts. The object is achieved by this invention, as characterized in the claims. Therefore, the invention relates to the objects characterized in the claims. It has been found that metal complexes consisting of a metal of atomic numbers of 44-51 or 56-83 and a complexing agent are suitable for the production of contrast media for use in computed tomography enhanced by liver contrast. and the bile ducts. In this case, there are compounds of the general formula in which X, independently of another, means a hydrogen atom or an equivalent metal ion of an element of atomic numbers 44-51 or 56-83, one of the radicals R1 means a radical of the formula -CH2-CgH4- (0) r-R2, in which the aromatic ring of one of the radicals R1 can be substituted in the ortho, meta or para position and another radical R1 signifies hydrogen, R2 signifies a hydrocarbon radical consisting of 1-6 carbon atoms and -2 oxygen atoms, a phenyl radical or a benzyl radical, or R2 means hydrogen and r means the number zero or one, in which the carboxyl groups may be present as amides, together with the physiologically compatible cations that are optionally required to equalize load. As radicals R of the general formula I, substituted benzyl can be used, such as, for example, methoxybenzyl, ethoxybenzyl, propoxybenzyl, butoxybenzyl, pentoxybenzyl, benzyloxybenzyl, methylbenzyl, ethylbenzyl, propylbenzyl, butylbenzyl, pentylbenzyl and benzylbenzyl radicals. The substituents of the benzyl radicals can be in the 2-, 3- or 4- position, that is, the ortho, meta or para position. In this case, the substituents in the ortho and para position are preferred and the radicals in the para position are particularly preferred. The Rl radicals can be in the 4- or 5- position of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -undecane-dioic acid, in which the 4- position is preferred. A hydrogen atom is in the other respective position of Rx. Those oxygen-containing radicals (r = 1) are preferred. The ethoxybenzyl radical is very particularly preferred.

As radicals R2 the compounds may contain alkyl radicals of C-L to Cg, for example methyl, ethyl, propyl, butyl, pentyl or hexyl radicals. In this case, the C3 to Cg alkyl radicals may be straight or branched chain, such as, for example, isopropyl, isobutyl, tert-butyl, neopentyl or isohexyl radicals. The alkyl radicals, however, can also contain 2 oxygen atoms (in which the peroxo compounds are, of course, not considered), for example as ethoxyethyl, ((ethoxy-) ethoxy) ethyl or methoxypropyl radicals. Of the metal ions, the lanthanoids are preferred. In measurements under current conditions (see Example 8), holmium, erbium and ytterbium have more adequately provided that the elements most commonly used in MRI are gadolinium and dysprosium. Due to its high price, the thulium seems to be the least suitable from the economic point of view, but it is still adequate in principle. Other elements, however, can also be used. In particular, the chelate compounds lutetium, praseodymium, cerium, hafnium, lead and bismuth also exhibit particularly advantageous properties. The carboxyl groups may also be present as amides, for example, as alkylamides or dialkylamides, in which the alkyl groups exhibit 1-4 carbon atoms or as a morpholide group. The amide functions are not negatively charged in contrast to the carboxyl functions. Accordingly, the charge of the complex changes when a carboxyl function is converted to an amide function. Generally, a maximum of sufficient carboxyl functions are converted to amide functions, such that an electrically neutral complex results. As physiologically compatible cations, sodium "1", calcium 2"1", magnesium 2"1" and zinc 2 + can be mentioned as examples, as well as organic cations of the following organic bases: meglumine, glucosamine, arginine, ornithine, lysine, 2-amino -l, 3, 4-butanetriol and ethanolamine. The following compounds are especially suitable for use according to the invention: Gadolinium complex (III) of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) acid ) -undecandioic, ytterbium (III) complex of 3,6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid, • praseodymium complex (III) of the acid 3,6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic, Cerium (III) complex of 3,6,6-triaza-3,6 acid , 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 complex, hafnium (IV) complex of 3,6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid, complex of bismuth (III) of acid 3,6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecane-dioic acid, • Ytterbium acid complex 3.6, 9-triaza-3, 6, 9-tris (carboxymethyl) -5- (4- [2- (2-ethoxyethoxy) -ethoxy] benzyl] -undecanedioic acid, Lead complex (II) of acid 3 , 6, 9-triaza-3, 6, 9 -tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic, Ytterbium complex (III) of acid 3,6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -4- (2-ethoxy-benzyl) -undecane-dioic acid, gadolinium (III) complex of 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-butylbenzyl) -undecanedioic, Ytterbium (III) complex of 3,6,6-triaza-3,6-9-tris- (carboxymethyl) -4- (4-butyl-benzyl) -undecanedioic acid complex. praseodymium (III) of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butyl-benzyl) -undecanedioic acid, hafnium (IV) complex of acid 3,6,9 -triaza-3, 6, 9-tris- (carboxymethyl) -4- (4-butyl-benzyl) -undecanedioic, Complex of bismuth (III) of acid 3,6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- (4-butyl-benzyl) -undecanedioic, • Lutetium (III) acid complex 3,6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- (4-butyl-benzyl) -undecanedioic acid, Complex of lead (II) of acid 3,6, 9-triaza-3, 6 , 9-tris (carboxymethyl) -4- (4-butyl-benzyl) -undecandioic acid, as well as their salts and amides. The production of the compounds according to the invention is familiar to those skilled in the art. Some of these substances and their production are described in, among others EP 0 405 704 and US 4,880,008. Also in the examples of this document, the possible advance of the production is described, which one skilled in the art can modify it depending on his needs to obtain the desired compounds.

The metal complexes mentioned above are preferably used in the form of their sterile, aqueous solutions. In addition, for the metal complexes to absorb X-rays they may contain the usual pharmaceutical adjuvants, such as buffers, bases, acids, stabilizers, solubilizers, substances for coupling the osmolarity and viscosity, pharmacologically active additives and an excess of free or complex agents. its salts / complexes with weakly bound physiologically compatible ions such as, calcium2"1", magnesium2 + and zinc2 + to improve the excretion of heavy metal ions. Suitable substances and their concentration ranges are known to those skilled in the art or are found for the literature. The metal complexes are preferably used in a concentration of 0.1 mol to 1.0 mol relative to that of the opacification metal ion. Higher to lower concentrations are possible depending on the requirements and the solubility of the compounds in question. To increase the contrast in the liver, the dose is approximately 0.1-1.5 mmol / kg body weight; it is preferably in the range of 0.2-0.6 mmol / kg. The administration can be done in the usual forms in medicine. The preferred one is intravenous infusion or injection for a period of about 1 minute to 30 minutes. It is surprising that despite the considerably worse preconditions in terms of light absorption action of each molecule for the first time in humans, a level of X-ray absorption in the liver that was completely satisfactory for computed tomography was achieved with these metal chelates in this case without having to use doses that were approximately as high as in the case of iodinated x-ray contrast media, not specific. At the same time, it was shown that the accumulation in the liver is carried out quickly and sufficiently long for the computed tomographic diagnosis process. The administration can be done non-invasively (for example, intravenously). The compatibility in the dose range required (see above) is very good. In summary, it can be noted that with the family of substances described here, it has been possible for the first time to obtain a concentration of specific contrast medium in the human liver, which produces beneficial diagnostic data with the computed tomographic technique now available. This discovery is all the more surprising, as - Preparations for this purpose have been searched in vain for decades, - despite the presence of all the molecular properties although they are required and a significantly higher content of the opacification element in the molecule, the iodinated X-ray contrast media do not meet the requirements, the use according to the invention of the substances requires a dose that is greater by a factor of in the case of magnetic resonance tomography, without any loss in physiological compatibility that is detectable, - the concentrations that are reached in the human liver with the use according to the invention, is still achieved by many contrast media of iodine x-rays, standard, without it being possible therefore for these agents that are used for computed tomography, to improve the diagnosis of focal liver changes, - the discoveries of experiments in animals currently obtained with respect to the suitability of the Contrast media to increase the contrast in the computed tomography of the liver, have completely proven to be unreliable. The following examples were used to illustrate the invention without intending that the object be limited to the latter.

Axis 1 Lutetium complex (III) of the disodium salt of acid 3,6, 9-triaza-3, 6, 9-tris (carboxymethyl) -5- (4-ethoxy-benzyl) -undecanedioic acid, a) 3-, 6-, 9-triaza-3, 6, 9-tris- (tert-butoxycarbonylmethyl) -5- (4-ethoxybenzyl) -undecanedioic acid di-tert-butylester 16.7 g (21.4 mmoles) of di is dissolved 3-, 6, 9-triaza-3, 6, 9-tris- (tert-butoxycarbonylmethyl) -5- (4-ethoxybenzyl) -undecane-dioic acid ester (DOS 3710730) in 50 ml of N, N-dimethylformamide Anhydrous and it is mixed at 0 ° C under argon with 0.94 g (23.5 mmol) of a dispersion of sodium hydride (60% in mineral oil). The batch is allowed to stir for 15 minutes, then 3.74 g (24.0 mmoles) of ethyl iodide is added, the reaction temperature is allowed to rise to room temperature, and it is stirred for another four hours. For working up, the batch is extracted in toluene and stirred several times against aqueous sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated by evaporation. The oily residue is chromatographed on silica gel with hexane / diethyl ether / triethylamine, the product containing the fractions is combined and concentrated by evaporation. Yield: 16.4 g (94.8% theory) of a colorless oil Analysis (relative to the substance without solvent): Calculated: C 63.92 H 9.11 N 5.20 O 21.78 Found: C 63.77 H 9.28 N 5.13 b) Lutetium complex of acid disodium salt 3,6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -5- (4-ethoxybenzyl) -undecanedioic acid 16.1 g (20 mmol) of the compound produced according to Example a) is dissolved in 50 ml. of tetrahydrofuran and mixed with 60 ml of a 2N sodium hydroxide solution, stirred for two hours at 60 ° C, adjusted to pH 1 with concentrated hydrochloric acid, highly concentrated by evaporation in a rotary evaporator, and the residue was evaporated. purify by ion exchange chromatography (cation exchanger (H + form), eluent: a solution of ammonia-water). The eluted material is concentrated by evaporation and dried highly under high vacuum, whereby the complex free agent is obtained. The penta acid is extracted in 250 ml of water and mixed with 3.98 g (10 mmol) of lutetium oxide. The suspension is stirred for 36 hours at 100 ° C and filtered. Then it is adjusted to pH 7.3 with a 1N sodium hydroxide solution. After 1.6 g of activated carbon is added, the solution is stirred for one hour at 80 ° C and filtered. After it is lyophilized, the filtrate produces a colorless solid. Yield: 14.1 g (94.8% theory) Analysis (relative to the 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 acid 3,6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -4- (2-ethoxybenzyl) -undecane-dioic 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 it is mixed dropwise with 7.6 ml (105 mmol) of thionyl chloride. After an hour, the mixture is heated to a reflux temperature and stirred for three hours. Then, it is stirred overnight at room temperature. It is evaporated to dryness, the residue is extracted in methanol, concentrated by evaporation, and the process is repeated twice. Extract in 50 ml of water, adjust to pH 8.5 with a 1.5 molar sodium carbonate solution and add 22.1 ml (63 mmol) of benzyl chloroformate under pH control. It is stirred for four hours at room temperature, the organic phase is separated, washed with water and dried with sodium sulfate. After concentration by evaporation, the residue is chromatographed on silica gel (methylene chloride / ethyl acetate). Yield: 13.5 g (78.2% theory) of a colorless oil, which crystallizes slowly.

Analysis (relative to the substance without solvent): Calculated: C 65.64 H 5.82 N 4.25 O 24.29 Found: C 65.57 H 5.63 N 4.30 b) N-benzyloxycarbonyl-3- [2-ethoxyphenyl] -alanine methyl ester 10.2 g (31 mmol) of the ortho-phenol of Example a) is dissolved at 40 ° C in 6 ml of N, N-dimethylformamide, mixed with 9.2 g (66.5 mmoles) of potassium carbonate and 0.3 ml of water. Then 5.7 ml (43.4 mmoles) of diethyl sulfate is added dropwise and the mixture is stirred for 3.5 hours. 6.6 ml of ammonia is added and the batch is left to stand for one hour. Then, it is mixed with water and extracted with tert-butyl methyl ether. The organic phase is separated and washed with dilute sulfuric acid and water. It is dried over sodium sulfate, concentrated by evaporation after filtration and the residue is chromatographed on silica gel. Yield: 8.2 g (74% theory) of a colorless oil.

Analysis (relative to the substance without solvent): Calculated: C 67.21 H 6.49 N 3.92 O 22.38 Found: C 67.09 H 6.53 N 3.77 c) N-benzyloxycarbonyl-2- [2-ethoxybenzyl] -2-amino-ethanol 7.9 g (22 min.) of N-benzyloxycarbonyl-3- [2-ethoxyphenyl] -alanine methyl ester (Example b) is dissolved in 63 ml. of tert-butyl methyl ether and mixed with 1.1 g (30.1 mmol) of sodium borohydrate. 15 ml of methanol is added at 5 ° C and stirred for 5 hours at a constant temperature. Then add 1.5 ml of dissolved acetic acid in 5 ml of tetrahydrofuran, mix with 9 ml of water and stir for ten minutes at room temperature. The organic phase is separated, washed with water and dried with sodium sulfate. The drying agent is removed by suction, the filtrate is concentrated by evaporation and the residue is chromatographed on silica gel for purification. Yield: 7.25 g (100% theory) of a colorless oil, which crystallizes quickly and completely.

Analysis (relative to the substance without solvent): Calculated: C 69.28 H 7.04 N 4.25 O 19.43 Found: C 69.32 H 7.00 N 4.18 d) N-benzyloxycarbonyl-2- [2-ethoxybenzyl] -1,4,7-triazaheptane dihydrochloride. Dissolve 7.2 g (22 mmol) of the alcohol of the Example c) in 18 ml of tetrahydrofuran and mixed at room temperature with 4.9 ml (35 mmoles) of triethylamine. 2.54 ml (32.6 mmol) of methanesulfonic acid chloride is added, dissolved in 2 ml of tetrahydrofuran and stirred at 20 ° C for 6 hours. Then 22.2 ml (330 mmol) of ethylenediamine is added dropwise at a temperature between 30 ° C and 45 ° C. It is heated to 50 ° C and the mixture is allowed to stir for four hours. The reaction mixture is then concentrated by evaporation and the residue is extracted into ethyl acetate and washed with water. The organic phase is cooled in an ice bath and mixed with concentrated hydrochloric acid. The resulting precipitate is extracted by suction, washed with cold isopropanol and dried at 50 ° C. Yield: 7.5 g (76.7% theory) of a colorless oil.

Analysis (relative to the substance without solvent): Calculated: C 56.76 H 7.03 Cl 15.95 N 9.45 O 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 of Example d) is suspended in 72 ml of methanol, mixed with 1.08 g of palladium (10%) in activated carbon and 0.5 ml of water and hydrogenated at normal pressure, at room temperature. After the absorption of hydrogen is complete, the catalyst is filtered, and the filtrate is concentrated by evaporation. Yield: 4.9 g (97.5% theory) of a colorless solid.

Analysis (relative to substance without solvent): Calculated: C 50.33 H 8.12 Cl 22.85 N 13.54 O 5.16 Found: C 50.17 H 8.34 Cl 23.11 N 13.40 f) di-tert-butylester of acid 3, 6, 9, -triaza- 3, 6, 9-tris (tert-butoxycarbonylmethyl) -4- (2-ethoxybenzyl) -undecanedioic acid 11.2 g (81.5 mmoles) of potassium carbonate is dissolved in 11 ml of water and mixed at 35 ° C with 4.8 g (15.5 mmol) of triamine (Example e). It is added drop by drop 12. 5 ml (85.3 mmoles) of tert-butyl bromoacetic acid, and the batch is stirred for seven hours at 65 ° C. After After 18 hours of stirring at room temperature, the reaction mixture is mixed with water and stirred with ethyl acetate.

The organic phase is dried over sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel (methylene chloride / methanol). Afterwards, the product containing the fractions is concentrated by evaporation, the pentaester is obtained as a pale yellow oil. Yield: 11.9 g (95% theory) Analysis (relative to the substance without solvent): Calculated: C 63.92 H 9.11 N 5.20 O 21.78 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 the pentaester of Example f) in 86 ml of methanol is dissolved. and reacted with 4.65 g (116.3 mmol) of sodium hydroxide in 7.1 ml of water. It is stirred for four hours at 65 ° C, then the methanol is evaporated, water is added and the mixture is evaporated again. It is extracted in water and adjusted to pH 1.8 with an ion exchanger, acid. After the exchanger is filtered, the aqueous solution is largely concentrated by evaporation and the penta acid is purified by preparative CLAP (water / methanol / pH 2.5). The product containing the fractions is concentrated by evaporation, extracted again in water and lyophilized. Yield: 4.9 g (64% theory) Analysis (relative to the substance without solvent): Calculated: C 52.37 H 6.31 N 7.97 O 33.36 Found: C 52.19 H 6.46 N 7.88 h) Yttrium complex of the disodium salt of acid 3,6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -4- (2-ethoxybenzyl) -undecane dioic 3.72 g (7.05 mmoles) of the penta acid is dissolved from Example g) at 60 ° C in 19 ml of water and mixed in portions with 1.85 g (3.53 mmol) of ytterbium carbonate. Then the complex is complete, filtered, adjusted to pH 7.0, stirred with 0.2 g of activated carbon for 10 minutes at 100 ° C, filtered again and the filtrate is lyophilized. Yield: 4.6 g (88% theory) of a colorless lyophilisate Analysis (relative to the anhydrous substance): Calculated: C 37.26 H 3.81 N 5.67 O 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 salt 3,6,6-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedioic acid 2.9 g (5.5 mmoles) of acid 3,6 , 9-triaza-3, 6, 9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedioic acid (EP 0405704, Example 8b) is suspended in 20 ml of water and complexed with 1.45 g (2.75 mmol) of Ytterbium carbonate at 60 ° C. After the reaction is complete, the batch is neutralized with methylglucamine. It is filtered and the metal complex is obtained by lyophilization of the filtrate. Yield: 5.7 g (95.3% theory) of a colorless lyophilisate.

Analysis (relative to the substance without solvent): Calculated: C 40.85 H 5.93 N 6.44 O 30.88 Yb 15.90 Found: C 40.67 H 6.03 N 6.17 Yb 15.62 b) Ytterbium complex of the di- (2-amino-1,3,4-butanetriol) salt of 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-) acid ethoxybenzyl) -undecandioic The title of the compound is obtained analogously to that of Example a), if the acid complex is neutralized with 2-amino-1,3,4-butanetriol. c) 3,6,9-Triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedioic acid disodium salt complex The title compound is obtained analogously to that of Example a), if the ligands (EP 0405704, Example 8b) are reacted with cerium carbonate and neutralized with a sodium hydroxide solution. d) Yttrium complex of acid disodium salt 3,6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) -undecane dioic 2.1 g (4 mmoles) of acid 3, 6, 9-triaza-3, 6, 9 -tris- (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedioic acid (EP 0405704, Example 8b) is suspended in 15 ml of water and complexed with 1.05 g (2 mmoles) of ytterbium carbonate at 60 ° C. After the complex is complete, the batch is neutralized with a 1N sodium hydroxide solution. The solution of the complex is filtered and the title compound is obtained by lyophilization of the filtrate. Yield: 3.0 g (100% theory) of a colorless lyophilisate.

Analysis (relative to the anhydrous substance): Calculated: C 37.16 H 3.81 N 5.67 O 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 acid disodium salt 3,6,9-triaza-3,6-9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedioic acid 3.0 g (5.7 mmol) of the disodium salt of 3,6,9-triaza- 3, 6, 9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) -undecane-dioic acid (EP 0405704, Example 8b) in 15 ml of water and complexed with 1.07 g (2.7 mmoles) of lutetium oxide at 95 ° C. After the complex is complete, the batch is neutralized with a 1N sodium hydroxide solution. The solution is filtered and the title compound is obtained by lyophilization of the filtrate.

Yield: 3.9 (92% theory) of a colorless lyophilisate.

Analysis (relative to the anhydrous substance): Calculated: C 37.16 H 3.80 N 5.65 O 23.67 Lu 23.53 Na 6.18 Found: C 37.02 H 4.01 N 5.53 Lu 23.36 Na 5.87 In an analog form, the corresponding bismuth complex (consisting of bismuth oxycarbonate), the hafnium complex (consisting of hafnium hydroxide), the lead complex (consisting of lead carbonate), the lanthanum complex ( consisting of lanthanum carbonate), the dysprosium complex (consisting of dysprosium oxide), the erbium complex (consisting of erbium carbonate), the terbium complex (consisting of terbium carbonate), the complex of holmium (consisting of holmium carbonate) and the praseodymium complex (consisting of praseodymium carbonate).

Example 4 Gadolinium complex of the disodium salt of acid 3,6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -4- (2-butoxybenzyl) -undecandioic acid a) N-benzyloxycarbonyl-3- [2-butoxyphenyl] -alanine methyl ester 5.0 g (15.2 mmol) of the ortho-phenol of Example 2a) is dissolved in 4 ml of N, N-dimethylformamide at 40 ° C, mixed with 4.5 g (31.1 mmoles) of potassium carbonate and 0.2 ml of water. 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 is added and the batch is left to stand for one hour. It is then mixed with water and extracted with tert-butyl methyl ether. The organic phase is separated, washed with dilute sulfuric acid and water. It is dried over sodium sulfate, concentrated by evaporation after filtration and the residue is chromatographed on silica gel. Yield: 4.7 g (80.2% theory) of a colorless oil.

Analysis (relative to substance without solvent): Calculated: C 68.55 H 7.06 N 3.63 O 20.75 Found: C 68.42 H 7.18 N 3.59 b) N-Benzyloxycarbonyl-2- [2-butoxybenzyl] -2-amino-ethanol Dissolves 3.9 g (11 mmol) of N-benzyloxycarbonyl-3- [2-butoxyphenyl] -alanine methyl ester (Example a) in 30 ml of tert-butyl methyl ether and mixed with 0.55 g) (15 mmol) of sodium borohydride. 8 ml of methanol are added at 3 ° C and stirred for five hours at constant temperature. Then, add 0.8 ml of dissolved acetic acid in 3 ml of tetrahydrofuran, mix with 5 ml of water and stir for 10 minutes at room temperature. The organic phase is separated, washed with water and dried over sodium sulfate. The drying agent is removed by suction, the filtrate is concentrated by evaporation and the residue is chromatographed on silica gel for purification. Yield: 3.4 g (86.5% theory) of a colorless oil.

Analysis (relative to the substance without solvent): Calculated: C 70.56 H 7.61 N 3.92 O 17.90 Found: C 70.43 H 7.60 N 4.07 c) N-benzyloxycarbonyl-2- [2-butoxybenzyl] -1,4,7-triazaheptane dichloride 3.1 g (8.8 mmoles) of the alcohol of Example b) is dissolved in 8 ml of tetrahydrofuran and mixed at room temperature with 2.0 my (14 mmol) of triethylamine. 1.02 ml (13 mmol) of methanesulfonic acid chloride dissolved in 1 ml of tetrahydrofuran is added and stirred at 20 ° C for five hours. Then, 8.9 ml (132 mmol) of ethylenediamine is added dropwise at a temperature between 35 ° C and 45 ° C. It is heated to 50 ° C and the batch is allowed to stir for three hours. After the reaction mixture is concentrated by evaporationThe residue is extracted into ethyl acetate and washed with water. The organic phase is cooled in an ice bath and mixed with concentrated hydrochloric acid. The resulting precipitate is extracted by suction, washed with cold isopropanol and dried at 50 ° C. Yield: 3.8 g (91.4% theory) of a yellowish solid.

Analysis (relative to the substance without solvent): Calculated: C 58.47 H 7.47 Cl 15.01 N 8.89 O 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 of Example c) is suspended in 35 ml of methanol, mixed with 0.4 g of palladium in activated carbon (10%) and mixed with 0.3 ml of water and hydrogenated at normal pressure at room temperature. After the absorption of hydrogen is complete, the catalyst is filtered and the filtrate is concentrated by evaporation. Yield: 2.4 g (87.6% theory) of a yellowish solid.

Analysis (relative to the substance without solvent): Calculated: 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-butylester 5.3 g (38.8 mmol) of carbonate are dissolved of potassium in 5 ml of water and mixed at 35 ° C with 2.3 g (7.4 mmol) of triamine dihydrochloride (Example d). 5.9 ml (40.6 mmoles) of tert-butylester of bromoacetic acid are added dropwise and the batch is stirred for eight hours at 60 ° C. After stirring for 15 hours at room temperature, the reaction mixture is mixed with water and stirred with ethyl acetate. The organic phase is dried over sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel (ethyl acetate / acetone). After the product containing the fractions is concentrated by evaporation, the pentaester is obtained as a colorless oil. Yield: 5.3 g (85.7% theory) Analysis (relative to the substance without solvent): Calculated: C 64.64 H 9.28 N 5.03 O 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 mmoles) of the pentaester of Example e) is dissolved in 40 ml of methanol and it is reacted with 2.02 g (50.6 mmoles) of sodium hydroxide in 3.1 ml of water. It is stirred for three hours at 55 ° C, then the methanol is evaporated, water is added and it is again concentrated by evaporation. It is extracted in water and adjusted to pH 1.9 with an acidic ion exchanger. After the exchanger is filtered, the aqueous solution is largely concentrated by evaporation and the penta acid is purified by preparative CLAP (water / methanol / pH 2.8). The product containing the fractions is concentrated by evaporation, extracted again in water and lyophilized. Yield: 2.9 g (82.8% theory) of a colorless lyophilisate.

Analysis (relative to substance without solvent): Calculated: C 54.05 H 6.71 N 7.56 O 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-tris- (carboxymethyl) -4- (2-butoxy-benzyl) -undecanedioic acid 2.48 g (4.7 mmoles) of the penta acid from Example f) in 20 ml of water at 85 ° C and mixed in portions with 0.85 g (2.35 mmol) of gadolinium oxide. After the complexation is complete, it is filtered, adjusted to pH 7.2, stirred with 0.2 g of activated charcoal for ten minutes at 90 ° C, filtered again and the filtrate is lyophilized. Yield: 3.5 g (98.8% theory) of a colorless lyophilisate.

Analysis (relative to the anhydride substance): Calculated: C 39.84 H 4.28 N 5.58 O 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 acid 3,6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -5-. { 4- [2- (2-ethoxyethoxy) -ethoxy] -benzyl} -undecanodioico a) di-tert-butylester of 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- acid. { 4 - [2- (2-Ethoxyethoxy) -ethoxy] -benzyl} -undecandioic 16. 7 g (21.4 mmoles) of 3,6, 9-triaza-3, 6, 9-tris- (tert-butoxycarbonylmethyl) -5- (4-hydroxybenzyl) -undecanedioic acid di-tert-butylester ( DOS 3710730) is dissolved in 50 ml of anhydrous N, N-dimethylformamide and mixed at 0 ° C under argon with 0.94 g (23.5 mmoles) of a sodium hydride dispersion (60% in mineral oil). The batch is left to shake for 15 minutes, then 4.73 g (24.0 mmoles) of 2- (2-ethoxyethoxy) -ethyl bromide is added, the reaction temperature is allowed to rise to room temperature and is stirred for another four hours. For working up, the batch is extracted in toluene and stirred several times against aqueous sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated by evaporation. The oily residue is chromatographed on silica gel with hexane / diethyl ether / triethylamine, the product containing the fractions is combined and concentrated by evaporation. Yield: 17.7 g (92.4% theory) of a colorless oil.

Analysis (relative to the anhydrous 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 acid disodium salt 3.6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -5-. { 4- [2- (2-ethoxyethoxy) -ethoxy] -benzyl} -undecandiodic 13.4 g (15.0 mmol) of the compound produced according to a) is dissolved in 35 ml of tetrahydrofuran and mixed with 45 ml of a 2N sodium hydroxide solution, stirred for 2 hours at 60 ° C, adjusted to pH 1 with concentrated hydrochloric acid, is highly concentrated by evaporation in a rotary evaporator, and the residue is purified by ion exchange chromatography (cation exchanger (H + form), eluent: ammonia-water solution). The eluted material is concentrated by evaporation and dried highly under high vacuum, whereby the complex free agent is obtained. The penta acid is extracted in 150 ml of water and mixed with 3.94 g (7.5 mmol) of ytterbium carbonate. The suspension is stirred for 3 hours at 60 ° C and filtered. Then it is adjusted to pH 7.3 with a 1N sodium hydroxide solution. After 1.0 g of activated carbon is added, the solution is stirred for one hour at 80 ° C and filtered. After it is lyophilized, the filtrate produces a colorless solid. Yield: 11.4 g (91.6% theory) Analysis (relative to the anhydrous substance): Calculated: 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 The increase in the density of the healthy liver parenchyma 10 and 60 minutes after the infusion of a 0.25 molar solution of the gadolinium complex (III) of the disodium salt of acid 3, 6, 9-triaza-3, 6, 9- tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedioic acid (Gd-EOB-DTPA, described in Example 8c of EP 0405704) in the case of 5 patients with hepatic metastasis at a dose of 0.35 mmol / kg in units Houndsfield (UH). This dose corresponds to approximately 16 g of the complex per 70 Kg of the patient.

Table 1 In comparison, according to Mützel et al.

(Contrast Media in Radiology, Ed .: M. Amiel, Springer Verlag, Berlin, Heidelberg, 1982), SH L 433 A hexayodado (formula XI) which was specially developed for the diagnosis of the liver. at a dose corresponding to 360 mg of iodine / kg (approximately 25 g of iodine per 70 kg of patient's weight) produced an increase of only < 10 UH (monkey, dog, mouse:> 40 UH). The iotroxinate excreted by the bile ducts in approximately 90% of humans (hexayodado, 2 carboxyl groups) reaches only 15 UH in the liver in the case of the maximum compatible dose corresponding to approximately 7 g of iodine / 70 kg of patient weight (Hübner, KH: Computertomographische Densitometrie von Leber, Milz und Nieren bei intravenós vereibreichten lebergángigen Kontrastmitteln in Bolusform. [Computed tomographic densitometry of the liver, spleen and kidneys in the case of intravenously administered contrast media that pass through the liver in the form of a bolus ], Fortschr. Rontgenstr. [Research of X-ray Radiation] 129, 289-297 (1978)). In comparison, such greater absorption of x-rays in the human liver is achieved with approximately 3.5 g of gadolinium in the form of a complex, which contains only one gadolinium ion / molecule, than with 25 g of iodine of SH L 433 ( formula XI) or 7 g of iotroxinate iodine, although both of these x-ray contrast media are hexayoded compounds.

Example 7 The following solution occurs: 0. 1 mole of the complex of holmium (III) of the salt dimeglumine of acid 3, 6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -4- (4-butylbenzyl) -undecandioic acid 0.005 mole of the calcium complex (II) of the trimeglumine salt of 3, 6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -4- (4-butylbenzyl) -undecane-dioic acid in 1 liter of 5% mannitol solution, pH 7.0 The solution is administered by infusion for 30 minutes at a dose of 0.3 mmol / kg body weight. 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 The disodium salt is complexed with different metal ions that absorb x-rays and then in the case of different concentration, the density values of the samples are measured in water ghost, since approximately it corresponded in dimensions to that of the human abdomen. The operation was performed on a commercially available computerized tomograph with the commonly used voltage of 137 kV and 110 mA.

Table 4 Discoveries in units Hound.sf ie .Ld (UH ± SD) It turns out that there is a surprisingly high effectiveness of rare earths for iodine, which is supposedly attributable to the special measurement conditions that exist in abdominal CT. Among the lanthanides, erbium, ytterbium and holmium are going to be preferred over gadolinium and dysprosium, the elements that have been studied most to date.

Example 9 Conducting the Test Fifteen patients with known liver metastases were examined on liver CT at 10 minutes, 60 minutes and (N = 5) 120 minutes after intravenous infusion of 0.2, 0.35 or 0.5 mmol / kg of Gd-EOB-DTPA ( see Example 6) Gd-EOB-DTPA (0.25 mmol / L) was administered intravenously in an intravenous drip into the arm vein. The infusion time was 20 minutes for the doses of 0.2 and 0.35 mmol / kg and 30 minutes for the maximum dose of 0.5 mmol / kg. Patients had major tumors that were histologically detected (N = 9 with colorectal carcinoma, N = 2 with intestinal carcinoid, N = 1 with carcinoma of the stomach, N = 1 with leiomyosarcoma and N = 1 with adenocarcinoma of ovarian cysts) and metastasis (N = 5) had been detected by CT enhanced by contrast medium one month before the study with Gd-EOB-DTPA. Exclusion criteria for patients were: • age less than 18 years anamnesis of side effects similar to allergy or severe after administration of contrast media, • before administration of Gd-EOB-DTPA, • administration of contrast media at 24 hours before the study, • a transplanted organ, • women before menopause, • an operation or biopsy of the liver 24 hours before or after the study, and • patients with laboratory parameters that deviate greatly from the standard. The CT studies were done before and 10 minutes, 60 minutes and (N = 5) 120 minutes after the intravenous infusion of the Gd-EOB-DTPA with a Siemens-Spiral CT. The entire liver was measured 20-30 seconds after a pause in breathing. The feeding speed of the table was 8 mm / second, the collimation was 8 mm. Using a base of precontrast and postcontrast images, two independent observers evaluated the number and size of the metastasis qualitatively (excellent, good, moderate, minimal, without improvement) and quantitatively (measurement of the Houndsfield units).

The compatibility of the Gd-EOB-DTPA was determined when determining the general condition, the registration of the vital parameters and the laboratory analysis of the serum and urine parameters.

Results After intravenous infusion of Gd-EOB-DTPA, a dose-dependent increase in CT density of the healthy liver was found. Figure 1 shows the time plot of TC density (Houndsfield units, UH) in the liver of patients with primary tumors, which can be detected histologically after the start of an infusion of 0.2 (o), 0.35 (*) or 0.5 mmoles / kg of Gd-EOB-DTPA (). CT density in liver metastases is represented by the symbol *. The CT density of the metastases was unchanged. In addition, a visualization of the gallbladder and bile ducts was possible. Visualization of metastases was improved in all dose groups after the infusion of Gd-EOB-DTPA. It was excellent in two groups of higher doses. After the maximum dose, on average, two additional metastases were discovered, which were not previously known. The average size of the smallest metastasis, found, decreased correspondingly from 20.3 to 16.6 mm. In the case of a patient with a known metastasis in the right lobe of the liver, an additional lesion with a diameter of 7 mm, which had not been previously found, was detected in the left lobe of the liver after Gd-EOB-DTPA . The general compatibility of the Gd-EOB-DTPA was good. Only four mild or moderate side effects were observed. In two cases, patients reported a burning sensation at the site of the infusion or behind it, which persisted for a few seconds or minutes. Other side effects were nausea and a feeling of pressure in the epigastric region. The evaluation of laboratory parameters did not produce an accurate trend. In the case of three patients, slight increases in aspartate transferase and alamininyl transferase were found, which were probably caused, however, by liver metastasis. In summary, it is assumed that Gd-EOB-DTPA represents a contrast medium for liver or gallbladder well tolerated and effective for CT.

Claims (11)

1. The use of the chelate compounds of the general formula I (I) in which X, independently of another, means a hydrogen atom or an equivalent metal ion of an element of atomic numbers 44-51 or 56-83, one of the radicals R1 means a radical of the formula -CH2-CgH4- ( 0) r-R2, in which the aromatic ring of one of the radicals R can be substituted in the ortho, meta or para position and another radical R1 signifies hydrogen, R2 signifies a hydrocarbon radical consisting of 1-6 carbon atoms and 0-2 oxygen atoms, a phenyl radical or a benzyl radical, or R2 means hydrogen and r means the number zero or one, in which the carboxyl groups may be present as amides, together with the physiologically compatible cations which are optionally required to equalize the load, for medical diagnosis, characterized in that in the computer tomography of the liver and bile ducts are involved in the diagnosis process.

2. The use of the chelate compounds according to claim 1, characterized in that the metal complex is a lanthanoid atom.

3. The use of the chelate compounds according to claims 1 and 2, characterized in that the metal complex is cerium, praseodymium, gadolinium, dysprosium, holmium, erbium, ytterbium or lutetium.

4. The use of the chelate compounds according to claim 1, characterized in that the metal complex is hafnium, bismuth or lead.

5. The use of the chelate compounds according to claim 1, characterized in that at least one of the physiologically compatible cations is Na +, Ca2 +, Mg2 + or a cation of the organic bases of meglumine, glucosamine, arginine, ornithine, lysine, 2-amino -l, 3, 4-butanetriol or ethanolamine.

6. The use of the chelate compounds according to claim 1, characterized in that r means zero.

7. The use of the chelate compounds according to claim 1, characterized in that r means one.

8. The use of the chelate compounds according to claim 1, characterized in that R2 means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl or benzyl.

9. The use of the chelate compounds according to claim 1, characterized in that R1 is in the ortho or para position.

10. The use of the chelate compounds according to claim 1, characterized in that the chelate compound is Gadolinium complex (III) of acid 3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- (4) -ethoxy-benzyl) -undecanedioic, ytterbium (III) complex of 3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid, praseodymium complex (III) of the acid 3,6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecandioic acid, Lutetium (III) complex of acid 3,6, 9- triaza-3, 6, 9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic, Cerium (III) complex of 3,6,9-triaza-3,6, 9-tris (carboxymethyl) acid ) -4- (4-ethoxy-benzyl) -undecane dioic, hafnium complex (IV) of acid 3, 6, 9-triaza-3,6, 9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecandioic, Bismuth complex (III) of acid 3, 6, 9-triaza-3,6, 9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecandioic, Ytterbium acid complex 3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) -5-. { 4- [2- (2-ethoxyethoxy) -ethoxy] benzyl} -undecandioic, Lead complex (II) of 3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanedioic acid, Ytterbium (III) acid complex 3, 6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -4- (2-ethoxy-benzyl) -undecane-dioic acid.

11. The use of the chelate compounds according to claim 1, characterized in that the chelate compound is gadolinium complex (III) of acid 3, 6, 9-triaza-3,6, 9-tris- (carboxymethyl) -4- ( 4-butylbenzyl) -undecanedioic, Ytterbium (III) complex of 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-butyl-benzyl) -undecane-dioic acid, Praseodymium complex (III) of 3,6,9-triaza-3, 6, 9-tris (carboxymethyl) -4- (4-butyl-benzyl) undecane-dioic acid, Lutetium (III) complex of acid 3, 6, 9-triaza-3,6, 9-tris (carboxymethyl) -4- (4-butyl-benzyl) undecanedioic, hafnium complex (IV) of acid 3, 6, 9-triaza-3,6, 9- tris- (carboxymethyl) -4- (4-butyl-benzyl) -undecanedioic acid, Complex of bismuth (III) of acid 3, 6, 9-triaza-3,6, 9-tris (carboxymethyl) -4- (4- butyl-benzyl) -undecanedioic, Lead complex (II) of 3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- (4-butyl-benzyl) -undecanedioic acid.