SK68897A3 - Use of chelate compounds as diagnostic agents in the x-ray examination of liver and bile ducts - Google Patents

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

The invention relates to a method and use of metal complexes in liver and gallbladder diagnostics by means of X-ray radiation, in particular in computed tomography.

BACKGROUND OF THE INVENTION

Recently, the recognition of focal liver diseases, especially liver metastases and liver tumors, is one of the most important diagnostic problems in oncology. Four imaging modes are available: scintigraphy, ultrasonography, computed tomography and magnetic resonance tomography. Each method has its own advantages and disadvantages, none are so far optimal and virtually every method differs from another by a specific, acceptable, intravenously applied contrast agent [Harned RK, Chezmar JL, Nelson RC: Imaging of patients with potentially resectable hepative neoplasms] , JR 159, 1191-1194 (1922)].

Scintigraphy provides too little spatial coverage and its use is limited by insufficient or too high (only usable for few tumors) specificity of the radiopharmaceutical, so it is not mentioned in the article. Sonography is currently not a good technique for demonstrating solid focal liver tumors, as these often differ in acoustic properties from healthy liver tissue. Only after the liver is operatively loosened and a high-frequency ultrasound head is used, smaller lesions in the liver tissue are detectable. Magnetic resonance tomography (MR) is capable of spatially visualizing the entire liver with good spatial capture and, depending on the measurement mode, also with good tissue differentiation. For MR, in contrast, well-tolerated contrast agents are intravenously applicable, which could further improve this imaging method. The disadvantage, however, is the movement artifacts, which limit the several-minute method of determination and the high cost of the apparatus itself.

Computed tomography (CT) is actually an ideal technique for liver diagnostics. With modern instruments, the entire liver can be displayed in about 30 seconds with excellent spatial display. The individual liver layer requires about 1 second, so the movements of breathing and peristalsis play almost no role. The cost of CT is significantly lower than the cost of MR. The disadvantage of displaying a small tissue thickness must be compensated in particular by the contrast agent. The contrast agents used hitherto provide the following possibilities:

1. The contrast agent is rapidly and in a high dose (5% to 200g) injected or infused intravenously. Within a few minutes, there may be a contrasting difference between lesions and normal liver tissue, based on differences in perfusion, relative blood volumes of tissue, and extracellular space. This time space of unequal contrast agent distribution can only be used for diagnosis with these very fast CTs.

2. An improved contrast between a contrast agent receiving a healthy parenchyma and a majority of non-receiving focal lesions is observed 4-6 hours after administration of at least 120 g of available urographic contrast agent. However, this technique, referred to as late scan, is not sufficiently reliable and meaningful, so it is not used in routine work.

3. In arterial portography, a catheter, e.g. into A. mesenterica, the patient is then monitored on a CT-apparatus and scanned for about 150 ml of contrast agent during infusion. This technique is invasive, time consuming and expensive, but currently provides the most confident information about the presence and location of liver metastases. This information is crucial for the decision on the resectability of metastases. CT with arterial portography is regularly performed preoperatively despite the cost of performing it.

The above problems arise from the currently available X-ray contrast agents being urographic products that do not accumulate in the liver. However, in order to achieve some contrast, the liver is briefly flooded with very high amounts of contrast agent in the blood stream (dynamic scan) or attempted to use a 1 to 2% contrast agent that is not later in the liver parenchyma ("late scan") .

It is clear from the above that there is a need for improved diagnosis of focal liver lesions because the methods are poorly performing, too expensive, or too burdensome for the patient. Many attempts have been made over the decade to develop an intravenously applicable liver-specific X-ray contrast agent. Of the large number of specimens tested, only a few are listed (see Tables 1-2): Thorotrast (colloidal thorium oxide suspension) produces excellent liver contrast but is not sufficiently distinctive; the thorium α-emitter is used decades after liver tumors have been applied. Schering launched Hepatoscioctan, an emulsion of the finest droplets of triiodized oil. For acute side effects had to be withdrawn from the market. The following products from other companies and research groups (EOE-13, AG-6O-9O etc.). have been withdrawn during clinical trials for the same problems.

Table 1: Emulsions

Oil emulsions i.v. Title company assessor condition AG 60-90 Guerbet Lamarque 100 patients, suspended EOE 13 Vermess several hundred patients pľeiušené EOE 14 Abbott just preclinically Perfluóroctyl- Boehringer Bruneton clinical trials bromide Ingelheim suspended Intraiodol Lunderguist clinical trials suspended Oil emulsions i.a. Lipidiol many users without registration

Table 2: Liposomes

Title company assessor condition amidotrizoate Rosenberg large proportion of human side effects, unregistered iopromide Schering Krause animal experiments Iopamidol Bracco Musu animal experiments loxaglat Guerbet Corot animal experiments

In addition to many pharmaceutical problems, all particulate formulations (suspensions, emulsions, liposomes) have the disadvantage that, in X-ray diagnostics, high dosages (5 to 20 g) give rise to characteristic side effects which are difficult to avoid. Therefore, efforts have been made in the 1970s and early 1980s to find water-soluble X-ray contrast agents that accumulate in the liver sufficiently for CT. Such substances contained up to 6 iodine atoms per molecule and were not only very effective and well tolerated in animal experiments. Significant differences in efficacy were noticeable in the individual species. However, to date, none of the tested iodine-containing and water-soluble contrast agents have achieved a sufficient concentration in the human liver to provide sufficient resolution for CT development. A characteristic example of many failed experiments is published by MOtzel W., Wegener O.H., Souchon R and Weinmann H.J., Water soluble contrast agents for computed tomography of liver: experimental studies in dog. V. Amiel (edt.): Contrast media in radiology, Lyon 1981, Springer Verlag Berlin Heidelberg New York 1982, p. 320-323, tab.

Also in this case, unlike many animal species, no excellent liver contrast was achieved in humans.

Intravenous choleographs such as iotroxinate and ioglycamate selectively accumulate in the liver. This previous step is very limited in capacity. At a concentration corresponding to 5 µg of iodine / ml plasma a 5-fold concentration in the liver is still achieved, at a concentration of 50 µg iodine / ml only a 2-fold concentration is achieved, at 500 µg iodine / ml plasma the liver concentration is significantly lower than in plasma. further, it is diagnostically worthless, since differentiation of the actively enriching tissue and mere perfusion is impossible. Computed tomography, however, recognizes with sufficient certainty only iodine concentrations of about 1mg / ml (Speck U., Mutzel W., Herz-Hubner U., Siefer HM, Pharmacology der Lotroxinsäure, eines neuen intravenous Cholegraficums I. Pharmacokinetics and Radiology Beim Tier. Drug. Res., 28, 2143-2149 (1978).

It remains to be noted that there remains a need for advantageous water-soluble and therefore pharmaceutically well-characterized, stable, acceptable, specific and not very high doses of effective X-ray contrast agents and that no such product is present on the market or in clinical trials despite long-term efforts. Such preparations are difficult to detect by animal experiments due to unpredictable species dependence in terms of their uptake, accumulation and hepatic excretion; also, findings from animal experiments after many other results on humans cannot be considered further as an indication of the suitability or unsuitability of a substance or class of substances.

Metals containing magnetic resonance tomography contrast agents also absorb X-rays. Therefore, the use of these substances for computed tomography has been tested in individual cases (Schild HH et al.: Gadolinium DTPA (Magnevist ^R ) als Contrastmittel für die arterielle DSA. Fortschr. Röngenstr., 160: 218-221 (1994); Quinn AD et al. : Gd-DTPA: An alternative contrast medium for CT, J. Comput. Assist Tomogr. 18, 634-636 (1994)). Remarkably, the metal complexes hitherto used contain only one contrast providing the metal ion in each molecule, while the iodinated X-ray contrast agent contains 3 or 6 iodine atoms. Despite the high efficiency of some metal ions against 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) are not iodinated. contrast agents have hitherto been replaced in any relevant indication by metal chelates.

A significant disadvantage of using metal chelates as the X-ray contrast agent is the substantially lower X-ray absorbing element content in the molecules (iodinated X-ray contrast agent: 3 or 6 iodine atoms / molecule; MR-contrast agent: 1 metal ion / molecule). This corresponds to providing a slight contrast, so that metal complexes are currently used only for experimental X-ray research. In the MR, very low concentrations of metal ions are sufficient, as these affect the rapidly changing water protons, while in X-rays the metal itself must be safely detectable.

The object of the present invention is to select from the known imaging diagnosis suitable pharmaceutical chelating agents based on metal chelates which are suitable for the production of contrast agents for X-ray diagnostics, in particular for computed tomography of the liver and stomach pathways.

SUMMARY OF THE INVENTION

This object is achieved according to the present invention as indicated in the claims. The invention thus consists essentially of the claims.

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

These are compounds of formula I

(J.

where

X independently represents a hydrogen atom or a metal ion equivalent having the sequence number 44-51 or 56-83, one of the radicals R ¹ having the formula -CH 2 -C 6 H ₄ - (O) _r -R ² . wherein the aromatic ring may be substituted in the ortho, meta or para- position and the other radical R ¹ is hydrogen,

R ² is a hydrocarbon radical comprising 1 to 6 carbon atoms and 0 to 2 oxygen atoms, phenyl or hydrogen, or benzylzvyšok ar is zero or one, wherein the carboxyl group may be present as amides, together with a physiologically acceptable cation optionally required to charge alignment.

Benzyl radicals such as methoxybenzyl-, ethoxybenzyl-, propoxybenzyl-, butoxybenzyl-, pentoxybenzyl-, benzyloxybenxyl-, methylbenzyl-, ethylbenzyl-, propylbenzyl-, butylbenzyl-, pentylbenzyl- and benzylbenzyl may be used as the R ¹ radicals of the formula I. Preferred radicals ^R1 are ethoxybenzyl and butylbenzylzvyšok. The benzyl residue substituents may be in the 2-, 3-, or 4-position, i.e., ortho, meta, or paraposition. Ortho-para-substituents are preferred, radicals in the para position being particularly preferred.

Radicals R ¹ may be in the 4 or 5 3,6,9-triaza-3,6,9tris (carboxymethyl) -undekánkarboxylovej acid, the preferred location is in the fourth position of every other R ¹ each represents a hydrogen atom.

Oxygen-containing radicals (r = 1) are preferred. An ethoxybenzyl radical is particularly preferred.

As the R ² radicals, the compounds may contain C 1 -C 6 -alkyl radicals, for example methyl, ethyl, propyl, butyl, pentyl, or hexyl radicals. The C ₃ -C ₆ alkyl radicals may be straight or branched, such as isopropyl, isobutyl, tert, butyl, neopentyl or isohexyl. However, the alkyl radicals may also contain up to 2 oxygen atoms (not including peroxy compounds), e.g. such as ethoxyethyl-, ((ethoxy-) ethoxyethyl) - or methoxypropyl residues.

Of the metal ions, lanthanides are preferred. In practical measurements (see Example 8), gadolinium and dysprosium have been found to be more suitable than those used in MRI for holmium, erbium, yterbium. Due to the high price, thallium appears to be less suitable from an economic point of view, but in principle it is appropriate. Also suitable are the elements lutium, prazodymium, bismuth, lead and hafnium. Other elements may be used. In particular, the chelate compounds of lutium, prazeodyme, cerium, hafnium, lead and bismuth exhibit particularly advantageous properties.

The carboxyl groups may also be present as amides, for example as alkyl or dialkylamide, the alkyl groups having 1 to 4 carbon atoms or as the morpholide group. Unlike carboxyl functions, amide functions are not negatively charged. As a result, the charge of the complex changes by changing the carboxyl function to the amide function. Usually, at most so many carboxyl functions are converted to amide functions that a neutral complex is formed.

Physiologically acceptable cations include sodium *, calcium ² *. magnesium ² * and zinc ² * as well as organic cations of the following bases: meglumine, glucosamine, arginine, ornithine, lysine, 2-amino-1,3,4-butanetriol and ethanolamine.

The following compounds are particularly suitable for use in the present invention:

gadolinium (III) complex with 3,6,940823-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid, yterbium (III) complex with 3,6 _L 9-triaza-3 ₁ 6 ₁ 9-tris (carboxymethyl) -4- (4etoxybenzyl) -undecanedioic acid, the praseodymium (III) complex of _{3,6,9-triaza-1} 3 6 9 _I-tris (carboxymethyl) -4- (4etoxybenzyl) -undecanedioic acid, cerium complex with 3,6 _L 9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid, lutium complex with 3,6,9-triaza-3,6 _L 9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid, hafnium (IV) complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid, bismuth-acid complex 3 _L 6,9-triaza-3,6 _L 9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid, yterbium-acid complex 3 _L 6,9-triaza-3,6,9-tris- (carboxymethyl) -5- {4- [2- (2-ethoxyethoxy) -ethoxy] -benzyl} -undecanedicarboxylic acid lead (II) complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- ( 4eto xybenzyl) -undecanedicarboxylic acid, yterbium (III) complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (2-ethoxybenzyl) -undecanedicarboxylic acid, gadolinium (III) complex with 3,6, 9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butylbenzyl) -undecanedicarboxylic acid yterbium (III) complex with 3 ₁ 6,9-triaza-3,6,9-tris (carboxymethyl) -4 - (4-butylbenzyl) undecanedicarboxylic acid, prazodyme (III) complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butylbenzyl) undecanedicarboxylic acid, hafnium (IV) complex with Seg-triaza- N-Trisicarboxymethyl-.beta.-bis- (butylbenzyl) -undecanedicarboxylic acid, bismuth (III) complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4,8-bis (4-butylbenzyl) ) -undecanedicarboxylic acid, lutium (III) complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4,8-bis- (4-butylbenzyl) -undecanedicarboxylic acid complex of lead (II) with acid 3 6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butylbenzyl) -undecanedicarboxylic acid and their salts and amides.

The preparation of the compounds of the invention is obvious to the skilled person. Some such substances and their manufacture are described, inter alia, in EP 0405704 and US 4880008. Also in the examples of this document, production possibilities are described which one skilled in the art can vary based on his / her knowledge to obtain the desired compounds.

Said metal complexes are suitable for use in the form of their sterile solutions. They may contain, in addition to conventional X-ray absorbing metal complexes, conventional pharmaceutical excipients such as buffers, bases, acids, stabilizers, dissolution aids, substances for adjusting osmolality and viscosity, pharmaceutical active ingredients and excess (based on the diagnostically active metal complex) free complexing agent. agents or salts / complexes with weakly bound physiologically acceptable ions such as calcium ²⁺ , magnesium ^2+, and zinc ² * to improve the elimination of heavy metal ions. Suitable substances and their concentration areas are known to the person skilled in the art or can be found in the literature.

The metal complexes are preferably in a concentration of 0.1 mol to 1.0 mol relative to the metal ion contrast. Higher or lower concentrations are possible according to the requirements and solubility of the respective compounds. The dosage is about 0.1 to 1.5 mmol / kg body weight for enhancing liver contrast, preferably the range is 0.2 to 0.6 mmol / kg.

Administration can be carried out by the usual procedure in medicine. Intravenous infusion or injection over a time period of from about 1 minute to 30 minutes is preferred.

It is surprising that these metal chelates, despite poor predictions about the radiation absorption efficiency of each molecule, have been able to achieve fully human X-ray absorption in the liver for the first time in humans without the need to use as high a dosage as in in the case of an iodinated X-ray contrast agent. At the same time, however, it has been shown that accumulation in the liver proceeds rapidly and lasts long enough for the diagnostic method by computer tomography. Administration may be non-invasive (e.g., intravenous). Tolerance is very good in the necessary dose area (see above).

In summary, a human-specific contrast agent accumulating in the liver was first produced by the class of substances described herein, which leads to the necessary diagnostic information in the computer tomography technique used today. Therefore, this finding is so surprising that, for years, a preparation for this purpose has been sought, an iodinated X-ray contrast agent despite the calculation of all theoretically necessary properties of the molecule and a substantially higher element content in the molecule does not meet the requirements. by magnetoresonance tomography, without prejudice to physiological compatibility, the concentrations achieved in the human liver when used according to the invention have already been achieved by a number of classical iodinated X-ray contrast media, without the device being used for computed tomography to improve the diagnosis of focal liver changes, the findings from animal experiments have been shown to be totally inappropriate in terms of the suitability of contrast agents for enhancing contrast in computed liver tomography.

The following examples are intended to illustrate the invention without, however, limiting it in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Lutic complex with disodium salt of 3,6,9-triaza-3,6,9tris (carboxymethyl) -5- (4-ethoxybenzyl) -undecanedicarboxylic acid

a) di-tert. Butyl 3,6,9-triaza-3,6,9-tris (carboxymethyl) -5- (4-ethoxybenzyl) -undecanedicarboxylic acid butyl ester

16.7 g (21.4 mmol) of di-tert. Butyl 3,6,9-triaza-3,6,9tris (tert-butoxycarbonylmethyl) -5- (4-ethoxybenzyl) -undecanedicarboxylic acid (DOS 3710730) is dissolved in 50 ml of anhydrous Ν, Ν-dimethylformamide at 0 ° C 0.94 g (23.5 mmol) of sodium hydride dispersion (60% in mineral oil) was added under argon. The mixture is stirred for 15 minutes, then 3.74 g (24.0 mmol) of ethyl iodide are added, the reaction temperature is allowed to return to room temperature and stirred for a further 4 hours. The batch is dissolved in toluene and shaken several times in sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate, filtered and evaporated. The oily residue is chromatographed on silica gel with hexane / diethyl ether / triethylamine. Product containing fractions were combined and evaporated.

Yield: 16.4 g (94.8% of theory) of a colorless oil.

Analysis (based on solvent-free substance):

calculated: % C, 63.92;% H, 9.11; 5.20% N, 21.78% O found: % C, 63.77;% H, 9.28; 5.13% N. b) complex of lutium with disodium salt acids δ, δ, θ-ίΓίβζβ-δ, δ, θ-

tris (carboxymethyl) -5- (4-ethoxy-benzyl) -undecanedioic acid

16.1 g (20 mmol) of the compound prepared according to example a) are dissolved in 50 ml of tetrahydrofuran and mixed with 60 ml of 2 N sodium hydroxide, stirred for two hours at 60 ° C, adjusted to pH 1 with concentrated hydrochloric acid, evaporated The residue is purified by rotary evaporation and the residue is purified by ion exchange chromatography (cation exchange resin (H ⁺ -form), eluent: aqueous ammonia solution). The eluate was evaporated and heavily dried under high vacuum. A free complexing agent is obtained.

The pentacid is taken up in 250 ml of water and mixed with 3.98 g (10 mmol) of lutium oxide. The suspension was stirred at 100 ° C for 36 hours and filtered. The pH is then adjusted to pH 7.3 with 1 N sodium hydroxide. The solution was then stirred at 80 ° C for one hour after the addition of 1.6 g of activated carbon and filtered. The filtrate affords a colorless solid after freeze-drying.

Yield: 14.1 g (96.8% of theory) of a colorless oil.

Analysis (based on solvent-free substance):

calculated: 37.16% C, 3.80% H, 5.65% N, 23.67% O, 23.53% Lu, 6.18% Found: 37.03% C, 3.94% H N, 5.51%, Lu 23.38%, Lu 5.90%, Na 5.90%

Example 2

Ytterium complex with the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (2-ethoxybenzyl) -undecanedicarboxylic acid

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

9.5 g (52.4 mmol) of o-tyrosine (2-hydroxyphenylalanine, Heraus) are suspended in 48 ml of methanol, cooled in an ice bath and treated dropwise with 7.6 ml (105 mmol) of thionyl chloride. After one hour, heat to reflux and stir for three hours. It is then allowed to stir overnight at room temperature. Evaporate to dryness, take up the residue in methanol, evaporate and repeat the procedure twice. It is taken up in 50 ml of water and the pH is adjusted to pH

8.5 with 1.5 molar sodium hydroxide solution and under pH control is added

22.1 ml (63 mmol) of benzyl chloroformate. After stirring at room temperature for four hours, the organic phase is separated, washed with water and dried over sodium sulphate. 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):

H, 5.82; N, 4.25; O, 24.29. Found: C, 65.57; H, 5.68; N, 4.30.

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

10.2 g (31 mmol) of ortho-phenol from example a) are dissolved at 40 ° C in 6 ml of Ν, Ν-dimethylformamide, mixed with 9.2 g (66.5 mmol) of potassium carbonate and 0.3 ml of water . Then 5.7 ml (43.4 mmol) of diethyl sulfate was added dropwise and stirred for 3.5 hours. 6.6 ml of ammonia are added and the batch is allowed to stand for one hour. It is then mixed with a small amount of water and extracted. tert -butyl methyl ether. The organic phase is separated, washed with dilute sulfuric acid and water. It is dried over sodium sulphate, evaporated after filtration and the residue is chromatographed on silica gel.

Yield: 8.2 g (74% of theory) of a colorless oil.

Analysis (based on solvent-free substance):

calculated: 67.21% C, 6.49% H, 3.92% N, 22.38% O, found: 67.09% C, 6.53% H, 3.77% N.

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 treated with 1.1 g (30.1 mmol) of sodium borohydride. Methanol (15 ml) was added at 5 ° C and stirred at constant temperature for five hours. Then 1.5 ml of acetic acid dissolved in 5 ml of tetrahydrofuran is added, mixed with 9 ml of water and stirred for 10 minutes at room temperature. The organic phase was separated, washed with water and dried over sodium sulfate. The desiccant was filtered off with suction, the filtrate was evaporated and the residue chromatographed on silica gel for purification.

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

Analysis (based on solvent-free substance):

H, 7.04; N, 4.25. O, 19.43. Found: C, 69.32; H, 7.00; N, 4.18.

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

7.2 g (22 mmol) of the alcohol of example c) are dissolved in 18 ml of tetrahydrofuran and treated with 4.9 ml (35 mmol) of triethylamine at room temperature. Add 2.54 mL (32.6 mmol) of methanesulfonic acid chloride in 2 mL of tetrahydrofuran and stir at 20 ° C for six hours. Then it is added dropwise

22.2 ml (330 mmol) of ethylenediamine at a temperature between 30 ° C and 45 ° C. Heat to 50 ° C and stir for four hours. The reaction mixture was evaporated, the residue was taken up in ethyl acetate and washed with water. The organic phase is cooled in an ice bath and treated with concentrated hydrochloric acid. The precipitate formed is filtered off with suction, 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):

calculated: 56.76% C, 7.03% H, 15.95% Cl, 9.45% N, 10.80% O, found: 56.62% C, 7.11% H, 15.80% Cl, 9.36% N.

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

7.2 g (16.2 mmol) of the Z-protected amine of Example d) are suspended in 72 ml of ethanol, treated with 1.08 palladium (10%) on charcoal and 0.5 ml of water and hydrogenated at normal pressure at a temperature of rooms. After the hydrogen uptake is complete, 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):

calculated: 50.33% C, 8.12% H, 22.85% Cl, 13.64% N, 5.16% O, found: 50.17% C, 8.34% H, 23.11% Cl, 13.40% N.

f) di-tert. Butyl ester of Ο, δ, θ-Ιπθζβ-Ο, δ, θ-Ιηβ- ^ βΓΟ. -butoxycarbonylmethyl) -

4- (2-Ethoxy-benzyl) -undekánkarboxylovej

11.2 g (81.5 mmol) of potassium carbonate are dissolved in 11 ml of water and treated at 35 ° C with 4.8 g (15.5 mmol) of triamine (Example e). 12.5 ml (85.3 tert. Butyl bromoacetate) are added and the batch is stirred for 7 hours at 65 [deg.] C. After stirring at room temperature for 18 hours, the reaction mixture is mixed with water, shaken and ethyl acetate. The residue was chromatographed on silica gel (methylene chloride / methanol) to give the pentaester as an off-yellow oil after evaporation of the product-containing fractions.

Yield: 11.9 g (95% of theory) of a colorless solid.

Analysis (based on solvent-free substance):

calculated: 63.92% C, 9.11% H, 5.20% N, 21.78% O, found: 64.05% C, 9.23% H, 5.07% N.

(g) 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (2-ethoxybenzyl) -undecanedicarboxylic acid

The pentaester 11.75 (14.5 mmol) from Example f) was dissolved with methanol (86 ml) and treated with sodium hydroxide (4.65 g, 116.3 mmol) in water (7.1 ml). After stirring at 65 ° C for four hours, the methanol was evaporated, water was added and evaporated again. It is taken up in water and the pH is adjusted to 1.8 with the ion exchanger. After the ion exchanger was filtered off, the aqueous solution was evaporated and the pentacid was purified by preparative HPLC (water / methanol / pH 2.5). The fractions containing the product were evaporated, taken up in water and freeze-dried.

Yield: 4.9 g (64% of theory).

Analysis (based on solvent-free substance):

H, 6.31; N, 7.97; O, 33.36. Found: C, 52.19; H, 6.46; N, 7.88.

(h) Yterbium-3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (2-ethoxybenzyl) -undecanedicarboxylic acid disodium salt

3.72 g (7.05 mmol) of the pentacid from example g) are dissolved at 60 ° C in 19 ml of water and treated portionwise with 1.85 g (3.53 mmol) of yterbium carbonate. When the complexation is filtered, adjusted to pH 7.0, stirred at 100 C ^much ten minutes, filtered again and the filtrate is lyophilized.

Yield: 4.6 g (88% of theory).

Analysis (based on solvent-free substance):

calculated: 37.26%, 3.81% H, 5.67% N, 23.74% O, 23.34% Yb, 6.20% Found: 37.13% C, 4.02% H N, 5.55%, Y.18.18%, Na 5.87%

Example 3

Yterbium complex with dimeglumine salt of 3,6,94π3Ζ8-3,6,9-βπ8 (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid

2.9 g (5.5 mmol) of 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid (EP 0405704, Example 8b), are suspended in 20 g of the product. ml of water and complexed with 1.45 mmol yterbium carbonate at 60 ° C. After completion of the reaction, the batch is neutralized with methylglucamine. Filter and obtain the metal complex by freeze-drying the filtrate.

Yield: 5.7 g (95.3% of theory) of a colorless lyophilisate.

Analysis (based on solvent-free substance):

calculated: 40.85% C, 5.93% H, 6.44% N, 30.88% O, 15.90% Yb, found: 40.67% C, 6.08% H, 6.17% N, 14.62% Yb.

b) Yterbium complex with di- [2-amino-1,3,4-butanetriol) salt] 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) - undecane

The title compound is obtained analogously to Example a) when the complex salt is neutralized with 2-amino-1,3,4-butanetriol.

(c) Cerium complex with disodium 3,6,94Γ3,3-3-3,6,94π8 (carboxymethyl) -4- (4-ethoxybenzyl) -undecanoic acid

The title compound is obtained analogously to Example a) when the ligands (EP 0405704, Example 8b) are reacted with cerium carbonate and neutralized with sodium hydroxide.

d) Yterbium complex with the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid

2,1 g (4 mmol) of 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid (EP 0405704, Example 8b) are suspended in 15 ml of water and complexed with 1.05 g (2 mmol) of yterbium carbonate at 60 [deg.] C. After completion of the complexation, the batch was neutralized with 1N sodium hydroxide, and the complexing solution was filtered to give the title compound by freezing the filtrate.

Yield: 3.0 g (100% of theory)

Analysis (based on solvent-free substance):

calculated: 37.26% C, 3.81% H, 5.67% N, 23.74% O, 23.34% Yb, 6.20% Found: C 37.14%, 4.11% H N, 5.50%, Y.22.22%, Na 5.94%.

(e) Lutic complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid disodium salt

3.0 g (5.7 mmol) of 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid (EP 0405704, Example 8b) are suspended in 15 g. ml of water and complexed with 1.07 g (2.7 mmol) of yterbium oxide at 95 ° C. After completion of the complexation, the batch was neutralized with 1N sodium hydroxide. The complexing solution was filtered to give the title compound by freezing the filtrate.

Yield: 3.9 g (92% of theory)

Analysis (based on solvent-free substance):

calculated: 37.16%, H 3.80, N 5.65, O 23.67, Lu 23.53, 6.18% Found: C 37.02, H 4.01 N, 5.53%, Lu 23.53%, Na 5.87%.

In an analogous manner, the corresponding bismuth complex (from bismuth oxycarbonate), the hafnium complex (from hafnium hydroxide), the lead complex (from lead carbonate), the lanthanum complex (from lanthanum carbonate), the dysprosium complex (from dysprosium oxide), the erbium complex (from carbonate) erbia), yterbium complex (from yterbium carbonate), holmium complex (from holmium carbonate) and prazeodymium complex (from prazeodyme carbonate).

Example 4

3,6,9-Triaza-3,6,9-tris (carboxymethyl) -4- (2-butoxybenzyl) -undecanedicarboxylic acid gadolinium complex

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

5.0 g (15.2 mmol) of the ortho-phenol of Example 2a are dissolved in 4 ml at 40 ° C

N. N, dimethylformamide, mixed with 4.5 g (31.1 mmol) of potassium carbonate a

0.2 ml of water. Then 2.1 g (15.5 mmol) of n-butyl bromide are added dropwise and stirred for 5 hours. 3.2 ml of ammonia are added and the batch is allowed to stand for one hour. It is then mixed with a small amount of 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 sulphate, evaporated, and the residue is chromatographed on silica gel.

Yield: 4.7 g (80.2% of theory)

Analysis (based on solvent-free substance):

calculated: 68.55% C, 7.06% H, 3.63% N, 20.75% O found: 68.42% C, 7.18% H, 3.59% N.

b) N-Benzyloxycarbonyl-2- [2-butoxybenzyl] -2-aminoethanol 3.9 g (11 mmol) of methyl ester

N-benzyloxycarbonyl-3- [2-butoxyphenyl] -alanine (Example a) was dissolved in 30 ml of tert-butyl methyl ether and treated with 0.55 g (15 mmol) of sodium borohydride.

At 3 ° C, 8 ml of methanol are added and the mixture is stirred at constant temperature for five hours. 0.8 ml of acetic acid in 3 ml of tetrahydrofuran is then added, mixed with 5 ml of water and stirred for 10 minutes at room temperature. The organic phase is separated, washed with water and evaporated and the residue is chromatographed for purification on silica gel.

Yield: 3.4 g (86.5% of theory) of a colorless oil.

Analysis (based on solvent-free substance):

calculated: 70.56% C, 7.61% H, 3.92% N, 17.90% O found: 70.43% C, 7.60% H, 4.07% N.

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

3.1 g (8.8 mmol) of the alcohol of example b) are dissolved in 8 ml of tetrahydrofuran and treated at room temperature with 2.0 ml (14 mmol) of triethylamine. Add 1.02 mL (13 mmol) of methanesulfonic acid chloride dissolved in 1 mL of tetrahydrofuran and stir at 20 ° C for five hours. Then, 8.9 ml (123 mmol) of ethylenediamine is added dropwise at a temperature between 35 ° C and 45 ° C. It is allowed to warm to 50 ° C and the batch is stirred for three hours. The reaction mixture was evaporated, the residue was taken up in ethyl acetate and washed with water. The organic phase is cooled in an ice bath and treated with concentrated hydrochloric acid. The precipitate formed is filtered off with suction, washed with cold isopropanol and dried at 50 ° C.

Yield: 3.8g (91.4% of theory) of a yellowish solid.

Analysis (based on solvent-free substance):

calculated: 58.47% C, 7.47% H, 15.01% Cl, 8.89% N, 10.06% O found: 58.28% C, 7.47% H, 14.93% Cl, 8 , 73% N.

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

3.6 g (8.1 mmol) of the Z-protected amine of Example c) are suspended in 35 ml of methanol, mixed with 0.4 g of palladium (10%) on charcoal and 0.3 ml of water, and hydrogenated under stirring. normal pressure at room temperature. After the hydrogen uptake is complete, 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):

calculated: 53.25% C, 8.64% H, 20.96% Cl, 12.42% N, 4.73% O found: 53.08% C, 8.72% H, 21.23% Cl , 12.29% N.

e) di-tert. Butyl 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -

4- (2-butoxybenzyl) -undecanedioic acid

5.3 g (38.8 mmol) of potassium carbonate are dissolved in 5 ml of water and treated at 35 ° C with 2.3 g (7.4 mmol) of triamine dihydrochloride (Example d). Add

5.9 ml (40.6 mmol) of tert-butyl bromoacetate were added dropwise and the mixture was stirred at 60 ° C for eight hours. After stirring at room temperature for 15 hours, the reaction mixture was treated with water and shaken with ethyl acetate. The organic phase is dried over sodium sulphate, 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):

calculated: 64.64% C, 8.28% H, 5.03 N, 21.05% N, 21.05% O found: 64.77% C, 9.34% H, 4.88% N.

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

5.11 g (6.3 mmol) of the pentaester from example e) are dissolved in 40 ml of methanol and treated with 2.02 g (50.6 mmol) of sodium hydroxide in 3.1 ml of water. After stirring at 55 ° C for three hours, the methanol was evaporated, water was added and evaporated again. It was taken up in water and the pH adjusted to 1.9 with an ion exchanger. After filtering the ion exchanger, the aqueous solution was evaporated and the pentacid was purified by preparative HPLC (water / methanol / pH 2). The fractions containing the product were evaporated, taken up once more in water and freeze-dried.

Yield: 2.9 g (82.8% of theory) of a colorless lyophilisate.

Analysis (based on solvent-free substance):

calculated: 54.05% C, 6.71% H, 7.56 N, 31.6% O found: 53.91% C, 6.76% H, 7.39% N.

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

2.48 (4.7 mmol) of the pentacid of example f) is suspended at 85 ° C in 20 ml of water and treated portionwise with 0.85 g (2.35 mmol) of gadolinium oxide. After completion of the complexation, it is filtered, the pH is adjusted to 7.2, stirred for 10 minutes at 90 ° C with 0.2 g of activated carbon, filtered again and the filtrate is lyophilized.

Yield: 3.5 g (98.8% of theory) of a colorless lyophilisate.

Analysis (based on solvent-free substance):

calculated: 39.84% C, 4.28% H, 5.58 N, 23.35% O, 20.86 Gd, 6.10% Found: 39.73% C, 4.39% H, 5 .47 N, 20.71% Gd, 5.94% Na

Example 5

Yterbium complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -5- {4- [2- (2-ethoxy] benzyl} -undecanedicarboxylic acid disodium salt

a) di-tert. butyl ester of S.e.g-triaza-S.e.g-tris-Gerc. butoxykarboxymetyl) -

5- {4- [2- (2-ethoxyethoxy) -ethoxy] -benzyl} -undecanedioic acid

16.7 g (21.4 mmol) of di-tert. of butyl 3,6,9-triaza-3,6,9-tris (tert-butoxycarboxymethyl) -5- (4-hydroxybenzyl) -undecanedicarboxylic acid (DOS 3710730) is dissolved in 50 ml of anhydrous Ν, Ν-dimethylformamide at 0 ° C under argon was mixed with 0.94 g (23.5 mmol) of sodium hydride dispersion (60% in mineral oil). 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 temperature of the reaction mixture is allowed to rise to room temperature and stirred for another four hours. For working-up, the batch is taken up in toluene and shaken several times in aqueous sodium bicarbonate solution. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated. The oily residue is chromatographed on silica gel with hexane / diethyl ether / triethylamine, the fractions containing the product are combined and evaporated.

Yield: 17.7 g (92.4% of theory) of a colorless oil.

Analysis (based on solvent-free substance): Calculated: C 62.99, H 9.11, N 4.69, 23.21% O Found: C 63.07, H 9.27, 4.75 % N.

b) Yterbium complex with disodium salt of S.e.-triaza-S.e.-tris (carboxymethyl) -5- {4- [2- (2-ethoxy-ethoxy) -ethoxy] benzyl} -undecanedicarboxylic acid

13.4 g (15.0 mmol) of the compound produced according to a) are dissolved in 35 ml of tetrahydrofuran and mixed with 45 ml of 2 N sodium hydroxide solution. The residue is purified by rotary evaporation and the residue is purified by ion exchange chromatography (cation exchange resin (H ⁺ -form), eluent: aqueous ammonia solution). The eluate was evaporated and heavily dried under high vacuum to give the free complexing agent. The pentacid is taken up in 150 ml of water and mixed with 3.94 g (7.5 mmol) of yterbium carbonate. The suspension was stirred at 60 ° C for 3 hours and filtered. The pH is then adjusted to 7.3 with mono-sodium hydroxide. The solution was then stirred at 80 ° C for one hour after the addition of 1.0 g of activated carbon and filtered. The filtrate affords a colorless solid after freeze-drying.

Yield: 11.4 g (91.6% of theory) of a colorless oil.

Analysis (based on solvent-free substance):

calculated: 39.09% C, 4.37% H, 5.07 N, 25.07% O, 20.86% Yb, 5.54% Found: 38.84% C, 4.45% H, 5.02% N, 20.69% Yb, 5.30% Na.

Example 6

Increase the depth of healthy liver parenchyma 10 and 60 minutes after infusion of a 0.25 molar solution of gadolinium III complex with 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) acid double salt } -undecanedicarboxylic acid (Gd-EOB-DTPA, described in Example 8c of EP 0405704) in 5 patients with hepatic metastases at a dose of 0.35 mmol / kg in Hounsfield units (HU) corresponding to about 16 g of complex per 70 kg of patient.

Table 3

10 min after inf. HU 60 min after inf patient 1 19 26 patient 2 12 25 patient 3 10 17 patient 4 18 32 patient 5 15 32

For comparison, a hexaodinated SH L 433 (Formula XI) was developed by Miitzel et al., 1982, specifically for liver diagnostics.

at a dose corresponding to 360 mg iodine / kg (about 25 g iodine per 70 kg patient) and achieved an increase of only <10 HU (monkey, dog, mouse:> 40 HU). 90% in humans biliary excreted lotroxinate (hexa iodinated, 2 carboxyl groups) accumulates in the liver at a maximum tolerable dose corresponding to about 7 g iodine / 70 kg patient only 15 HU (HObner KH: Computertomographische Densitometry von Leber, Milz und Nieren bei intravenos) verabreichten lebergängigen Contrastmitteln in Bolusform, Fortschr. Röngenstr., 129, 289-297 (1978)).

For comparison, also 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 human liver than with 25 g of iodine from SH L 433 (Formula XI), respectively. 7 g of lotroxinate iodine, although both x-ray contrast agents are hexaodinated compounds.

Example 7

The following solution was produced:

0.1 mol of holmium (III) -dimeglumine salt complex of S.e.g-triaza-S.e.Otris- (carboxymethyl) -4- (4-butylbenzyl) -undecanedicarboxylic acid,

0.005 mol of calcium (II) -trimeglumine salt complex of δ, β, θ-ΓΐΓΐθΖθ-δ, β, β-tris (carboxymethyl) -4- (4-butylbenzyl) -undecanedicarboxylic acid in 1 liter of 5% mannitol solution, pH 7.0 .

The solution is infused at 0.3 mmol / kg body weight for 30 minutes. CT scans are performed at the beginning of the infusion, at the end of the infusion, and 30 minutes after the end of the infusion as usual.

Example 8

The disodium salt of 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid is complexed with various metal ion-absorbing X-rays and then the depth value of the samples is measured at different concentrations. water phantom because it approximately corresponds to the human abdomain when measured. We work on a commercially available computer tomograph at operating voltages of 137 kV and 110 mA.

Table 4

Values in Hounsfield units (HU ± SD)

element concentration (mmol / l) HU ± SD H ₂ O - 14 23 Gd 50 218 23 500 1680 33 Tb 50 228 25 500 1760 45 Dy 50 226 23 500 1840 42 him 50 221 29 500 1890 40 Er 50 254 24 500 1955 57th yb 50 252 18 500 1980 42 J 50 110 25 500 914 27

There is a surprisingly high efficiency of rare earths against iodine, which is undoubtedly reflected back on special measurement conditions at abdominal CT. Of the lanthanides, erbia, yterbia and holmium are preferred over the most tried and tested elements of gadolinium and dysprosis.

Example 9

Realization of the experiment

Fifty 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, respectively (see Example 6). ).

Gd-EOB-DTPA (0.25 mmol / l) is administered by intravenous drip infusion into the vessel on the hand. The infusion duration is 20 min for dosages 0.2 and 0.35 mmol / kg and 30 min for the highest dose of 0.5 mmol / kg.

Patients had histological primary tumors (N = 9 with colorectal cancer, N = 2 with intestinal carcinoid, N = 1 with stomach cancer, N = 1 with leiomyosarcoma and N = 1 with ovarian cysradenocarcinoma) and metastases (N <5) CT with contrast enhancing agent during one month prior to Gd-EOB-DTPA study.

The exclusion criteria for patients were:

age under 18 history of severe or allergic side effects after administration of a contrast agent previous dose of Gd-EOB-DTPA administration of a contrast agent within 24 hours before the study transplanted organ of a woman before menopause surgery or liver biopsy before or after study patients with laboratory parameters strongly deviating from the norm

CT experiments were performed before and 10 min, 60 min and (N = 5) 120 min after intravenous infusion of Gd-EOB-DTPA with Siemens-Spiral-CT. Whole liver was measured for 20 to 30 seconds in breathing rest. The displacement of the table was 8 mm / s, the collision was 8 mm.

On the basis of the pre- and post-contrast picture, the number and size of metastases were evaluated by two independent observers qualitatively (excellent, good, massive, minimal, no improvement) and quantitative (measurement of Hounsfield units).

Compatibility of Gd-EOb-DTPA was determined by determining the overall findings, recording vital parameters and laboratory analysis of serum and urine parameters.

The results

After intravenous infusion of Gd-EOB-DTPA, dose-dependent uptake of healthy liver CT-density was found. Figure 1 shows the time course of CThustota (Hounsfield units, HU) in the liver of patients with histologically established primary tumors after the start of infusion of 0.2 (o), 0.35 () and 0.5 mmol / kg Gd-EOB-DTPA (), respectively. CT density in liver metastases is indicated by *.

CT metastasis density was unchanged. In addition, the gallbladder and bile ducts were imaged.

Visualization of metastases was improved after Gd-EOB-DTPA infusion in all dose groups. It was excellent in both dose groups. On average, two metastases were found after the highest dose. The mean size of the smallest metastases found decreased from 20.3 to 16.6 mm. In patients with known metastases in the right liver lobe, a further 7 mm lesion in diameter, which had not previously been discovered, appeared in the left liver lobe following Gd-EOBDTPA administration.

The general tolerance of Gd-EOB-DTPA was good. Only four moderate, resp. massive side effects. In two cases, patients experienced burning at or from the infusion site for only a few seconds or minutes. Other side effects were nausea and epigastral pressure. The evaluation of the laboratory parameters did not show any significant trend. In three patients a slight increase in aspartate and alanine aminotransferases was found, but this was probably due to liver metastases.

It can be concluded that Gd-EOB-DTPA is a well-tolerated and effective liver or liver. gallbladder contrast agent for computed tomography.

Claims (10)

PATENT CLAIMS Use of chelated compounds of formula I coox N, COOX (1). TV 6 · Ρ <Τ-ΊΫhere X independently represents a hydrogen atom or a metal ion equivalent having the sequence number 44-51 or 56-83, one of the radicals R ¹ having the formula -CH ₂ -C ⁶ H ^{4 -} (O) _r R ² . wherein the aromatic ring may be substituted in the ortho, meta or para- position and the other radical R ¹ is hydrogen, R ² is a hydrocarbon radical comprising 1 to 6 carbon atoms and 0 to 2 oxygen atoms, phenyl or hydrogen, or benzylzvyšok ar is zero or one, wherein the carboxyl group may be present as amides, together PA hub alignment or a physiologically required acceptable cations for medical diagnostics, for the preparation of diagnostic means for computed tomography of the liver and biliary tract. Use of the chelate compounds according to claim 1, characterized in that the complexed metal is a lanthanide atom. Use of the chelate compounds according to claim 1 or 2, characterized in that the complexed metal is cerium, prazodymium, gadolinium, dysprosium, holmium, erbium, yterbium or lutium. Use of chelate compounds according to claim 1, characterized in that the complexed metal is hafnium, bismuth or lead. Use of chelated compounds according to claim 1, characterized in that at least one of the physiologically acceptable cations is Na ⁺ , Ca ²⁺ , Mg ²⁺ or the organic base cation of meglumine, glucosamine, arginine, ornithine, lysine, 2 amino-1,3 , 4-butanetriol or ethanolamine. Use of the chelate compounds according to claim 1, characterized in that r is zero. Use of chelate compounds according to claim 1, characterized in that r is one. Use of the chelate compounds according to claim 1, characterized in that R ² represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl or benzyl. Use of the chelate compounds according to claim 1, characterized in that R ¹ is in the ortho or para position. Use of the chelate compounds according to claim 1, characterized in that the chelate compound is a gadolinium (III) complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid yterbium (III) complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid, prazyme (III) complex with 3,6,9-triaza- 3 ₁ 6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid, lutium (III) complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid cerium (III) complex with 3.6 _L 9-triaza-3 ₁ 6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid hafnium (IV) complex with 3 _L 6 _L 9- triaza-3,6 _L 9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid, bismuth (III) complex with 3 _L 6,9-triaza-3,6,9-tris (carboxymethyl) -4- ( 4-ethoxybenzyl) -undecanedicarboxylic acid, yterbium-SeO-triaza-SeO-trisicarboxymethyl-O-S-β-β-ethoxy-ethoxy y) -ethoxy] -benzyl} -undecanedicarboxylic acid, lead (II) complex with 3 ₁ 6,9-triaza-3 ₁ 6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedicarboxylic acid yterbium (III) with Seg-triaza-SeO-trisicarboxymethyl-4- (ethoxybenzyl) -undecanedicarboxylic acid. 11. Use of chelate compounds according to claim 1, characterized in that the chelate compound is a complex of gadolinium (III) with 3 _{I, 6,9-triazol-3-I,} 6,9-tris (carboxymethyl) -4- (4butylbenzyl) -undecanedioic acid ytterbium (III) complex with Seg-triaza-SAg-trisicarboxymethylH- (butylbenzyl) -undecanedicarboxylic acid, prazyme (III) complex with Seg-triaza-Seg-trisCarboxymethylH (4-butylbenzyl) -undecanedicarboxylic acid, lutium (III) complex 3,6,9-βπ3-3-3,6,94π5 (3-β-β-γ-α) -4- (4-butylbenzyl) -undecanedicarboxylic acid, hafnium (IV) complex with 3,6,9-triaza-3,6,9-tris acid (carboxymethyl) -4,8-bis- (4-butylbenzyl) -undecanedicarboxylic acid, bismuth (III) complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4,8-bis (4- butylbenzyl) -undecanedicarboxylic acid or lead (II) complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butylbenzyl) -undecanedicarboxylic acid.