CZ166797A3 - Application of metal complexes as liver and gallbladder x-ray diagnostic agents - 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

Technical field

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

BACKGROUND OF THE INVENTION

At present, the recognition of focal liver diseases, especially liver metastases and liver tumors, is one of the most important diagnostic problems in oncology. There are four imaging modes available: scintigraphy, ul trasonography, computed tomography, and magnetic resonance tomography. Each of the methods has its specific advantages and disadvantages, none of which is so far optimal and virtually every method differs from the other by a specific, acceptable, intravenously applied contrast agent [Harned R.K. , Chezmar J. L., Nelson R.C. : Immagine of patients with potentially resectable hepatic neoplasms. JR 159, 1191-1194 (1922)].

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Scintigraphy provides too little spatial coverage and its use is limited by insufficient or too high (only a few tumors usable) specificity of the radiopharmaceutical, so it is not listed in the article. Ultrasonography is currently not a good technique for the detection of solid focal liver tumors, as these often differ in acoustic properties from healthy liver tissue inadequately. Only operatively after liver release and with the use of a high-frequency ultrasound head are minor lesions detectable in liver tissue. Magnetic resonance tomography (ME) is capable of spatially visualizing the entire liver with good spatial capture and, depending on the measurement mode, also with good tissue differentiation. For ME, intravenous, well-tolerated contrast agents in clinical trials that could further improve this imaging method. The disadvantage, however, is the movement artifacts which limit the several minutes of the method and the high cost of the instrument itself.

Computed tomography (CT) is actually an ideal technique for liver diagnostics. With modern instruments, the entire liver can be visualized within 30 seconds with excellent spatial imaging. The single-liver layer requires about 1 second, so the movements of respiration and peristalsis play almost no role. The cost of CT is significantly lower than the cost of ME. The disadvantage of imaging a small tissue thickness must first of all be compensated by the contrast agent. Clinically used contrast agents to date provide the following options:

1. The contrast agent is rapidly and in a high dose (50-200 g) injected or infused intravenously. Within a few minutes, there may be a contrasting difference between lesions and normal liver tissue in individual cases, based on differences in perfusion, relative blood volumes of tissue, and extracellular space. This time space of unequal contrast agent distribution can be used for diagnosis only 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 the late scout, is not sufficiently reliable and meaningful, so it is not used in routine work.

3. In arterial portography, a catheter must be inserted into, for example, A.mesenterica, the patient is then monitored on a CT-apparatus and the skeleton is infused with about 150 ml of contrast agent during infusion. This technique is invasive, time-consuming and expensive, but currently provides the most secure information about the presence and location of liver metastases. This information is critical to the decision on the resectability of metastases. CT ar s, 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 by the blood stream (dynamic scrub) or attempted to use a 1 to 2% contrast agent found later in the liver parenchyma (late scrub).

Thus, it is clear that there is a need for improved diagnosis of focal liver lesions, since the methods are poorly performing, too expensive, or burdening the patient too much. Many attempts have been made over the decades to develop an intravenously applicable liver-specific X-ray contrast agent. Only a few of the large number of preparations tested are shown (see Tables 1-2): Thorotrast (colloidal thorium oxide suspension) produces excellent liver contrast but insufficient distinguishing. α-Thorium emitter is used decades after the application of liver tumors. Schering launched • I

Table 1: Emulsions

Hepatoselectan, an emulsion of the finest droplets of three iodinated oil. It had to be withdrawn from the market for acute side effects. The following products from other companies and research groups (EOE-13, AG-60-90 etc.) have been withdrawn during clinical trials for the same problems.

Oil emulsions i.v. ';Name firm values and tel state AG 60-90 EOE 13 Guerbet Lamarque Vermess 100 patients, interrupted several hundred patients. interrupted EOE 14 Abbott - just curse- nicky Perfluor- octyl bromide Boehringer Ingelheim Bruneton clinical trials discontinued Intraiodol - ~ Lunderqui s t clinical trials discontinued Oil emulsions i. a. Lipiodol - many users bez.registrace

Table 2: Liposomes

Company name

Amidotrizoat --- evaluator

Rosenberg stav

Iopromide Schering Krause

TS

Iopamidol Bracco Musu

Ioxaglat

Guerbet Corot, a large proportion of human side effects, unregistered animal experiments those animal experiments those 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 which accumulate in the liver, sufficient for CT. Such substances contained up to 6 iodine atoms per molecule and not only because they were partially effective in animal experiments and were well tolerated. Significant differences in efficacy were observed between species. However, to date, none of the tested iodine containing water-soluble contrast agents has been sufficient in humans

Ί liver concentration that would provide sufficient resolution for CT development. A characteristic example of many failed attempts is published in the work of which they are written

Mutzel W., Wegener O.H., Souchon R and Weinmann H.-J-, Water soluhle contrast agents for computed tomography of liver:

Experimental studies in dog. In Amiel (edt.): Contrast media in radiology, Lyon 1981, Springer Verlag Berlin Heidelberg New

York 1982, pp. 320-323, tab.l. Also in this case, unlike many animal species, no excellent liver contrast was achieved in humans.

Intravenous choleography 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 of iodine / ml only a 2-fold concentration is achieved. in plasma and therefore further diagnostically worthless since differentiation of actively enriching tissue and mere perfusion is impossible. However, computed tomography only recognizes iodine concentrations from about 1 mg / ml with sufficient confidence (Speck U., Mutzel W.

Herz-Hiibner U., Siefer H.M. Pharmacology der Iotroxinsáure, eines neuen intravenosen Cholegraficums I. Pharmacokinetik und

Radiology beim Tier. Drug. Res. 28, 2143-2149 (1978).

It remains to be noted that the need is preferably water soluble and therefore pharmaceutically well characterized

stable, acceptable, specific, and not very high doses of effective X-ray contrast agents persist and there is no such product on the market or at the clinical trial stage despite many years of effort. Such preparations are difficult to detect by animal experiments due to unpredictable species dependency in terms of their uptake, accumulation and secretion by the liver; also findings from animal experiments N1

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even after many other results in humans, the inadequacy of a substance or class of substances cannot be further considered as an indication of its suitability.

Metals containing magnetoresonance tomography contrast agents also absorb X-rays. It has therefore been attempted in individual cases to use these substances for computed tomography (Schild HH et al .; Gadolinium DTPA (Magnevist ^R ) and in Contrastmittel fur die arterielle DSA. Fortschr. Rontgenstr., 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 potency of some metal ions against iodine (Zwicker C., Langer, Langer, E., Keske, U. Comparative of iodinated and noniodinated contrast media in computed tomography. Invest Radiol. 26, 162-164 (1991), iodinated contrast agents are not hitherto used in any relevant indication as metal chelates.

A significant disadvantage of using metal chelates as an X-ray contrast agent is the substantially lower content of the X-ray absorbing element in the molecules (iodinated X-ray contrast agent: 3 or 6 iodine atoms / macromolecule; 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 MR, metal ions are reached at such low concentrations as these rapidly changing protons are influenced by water, while in X-rays the metal itself must be safely detectable.

The object of the present invention is to select from the known imaging diagnostics suitable metal chelate-based pharmaceutical substances which are suitable for the production of X-ray contrast agents, in particular for the computed tomography of the liver and bile ducts.

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 the contrast-enhanced computed tomography of the liver and bile ducts.

These are compounds of formula I

N COOX

COOX

to.

(and).

where

X is, independently of one another, a hydrogen atom or a metal ion equivalent of the element having the order number 44-51 or

56-83, one of the radicals R ¹ is of the formula -CH 2 -SCH 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 represents a hydrocarbon radical comprising 1-6 carbon atoms and 0-2 oxygen atoms, phenyl or hydrogen or benzylzbytek Ar represents zero or one, wherein the carboxyl groups may be present as amides, together sk hub compensation required or physiologically acceptable cations.

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

^Radicals R can be at position 4 or 5 3,6,9-triaza-3,6,9- tris (carboxymethyl) -undecanedioic acid ester, preferably wherein the position 4. In any other position, R ¹ each represents a hydrogen atom.

Preferred are those containing oxygen (r = 1). Especially preferred is the ethoxybenzyl radical.

As R ² radicals, the compounds may contain C 1 -C 8 -alkyl radicals, for example methyl, ethyl, propyl, butyl, pentyl or hexyl radicals. The C3-C8-alkyl radicals may be straight or branched, such as, for example, isopropyl, isobutyl, tert-butyl, neopentyl or isohexyl radicals. However, the alkyl radicals may also contain up to 2 oxygen atoms (not including peroxy compounds), e.g. as ethoxyethyl-, ((ethoxy-) ethoxy) ethyl) - or methoxypropyl radicals.

Of the metal ions, lanthanides are preferred. In practical measurements (see Example 8), holmium, erbium and ytterbium have been shown to be more suitable than the usual gadolinium and dysprosium elements in MR. Thulium appears to be less suitable in economic terms because of the high price, but in principle it is. Furthermore, the elements lutecium, praseodymium, bismuth, lead and hafnium are also suitable. Other elements may be used. In particular, the chelated compounds of lutecia, praseodymium, cerium, hafnium, lead and bismuth exhibit a particularly advantageous property i.

The carboxyl groups may also be present as amides, for example as alkyl or dialkylamide, wherein the alkyl groups have 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 much carboxyl function is converted to the amide function 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.

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

3,6.9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid,

3,6.9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid,

3,6.9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid,

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

3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid,

3,6.9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid,

3.6.9-triaza-3,6,9-tri with (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid,

3,6.9-triaza-3,6,9-tris- (carboxymethyl) -5- (4- [2- (2-ethoxyethoxy) -ethoxy] -benzyl} -undecanedicarboxylic acid,

3,6,9-thiazole-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid,

3.6.9-triaza-3,6,9-tri with (carboxymethyl) -4- (2-ethoxybenzyl) undecanedicarboxylic acid,

3.6.9-triaza-3,6,9-tri with (carboxymethyl) -4- (4-butylbenzyl) undecanedicarboxylic acid,

3,6.9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butylbenzyl) undecanedicarboxylic acid,

3,6.9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butylbenzyl) undecaridicarboxylic acid,

3,6,9-triaza-3,6,9-tris (carboxymethyl) -4,8-bis- (4-butylbenzyl) -undecanedicarboxylic acid,

3,6,9-triaza-3,6,9-tris (carboxymethyl) -4,8-bis- (4-butylbenzyl) -undecanedicarboxylic acid,

-and;

/ G

3,6,9-triazine-3,6,9-tris (carboxymethyl) -4,8-bis- (4-butylbenzyl) -undecanedicarboxylic 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 will be apparent to those skilled in the art. Some such substances and their preparation 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 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, solubilizers, osmolality and viscosity adjusting substances, pharmaceutically active ingredients and an excess of the diagnostically active metal complex) of the free complexing agent or salts / complexes thereof with weakly bound physiologically acceptable ions such as calcium ²⁺ , magnesium ² * and zinc ² * to improve the exclusion of heavy metal ions. Suitable substances and their concentration areas are known to the person skilled in the art or can be ascertained from the literature.

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

Administration can be accomplished by the usual medical procedures. 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 satisfactory X-ray absorption in the liver for humans for the first time without compromising the dosage of the X-ray. in the case of an iodinated X-ray contrast agent. At the same time, it has been shown that accumulation in the liver proceeds rapidly and lasts long enough for the diagnostic method by computed tomography. Administration may be by non-invasion outside (i.e., intravenously). Compatibility is very good in the necessary dose area (see above).

In summary, a human-specific contrast agent accumulating in the liver for the first time in the class of substances described herein has led 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 all theoretically needed properties of the molecule and a significantly higher content of the contrast-providing element in the molecule does not meet the requirements, the use of the substances according to the invention requires a 10 times higher dose than magnetoresonance tomography without impairing physiological compatibility

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- ,. *; ι; ι * ν5, · ¹ · · r ¹⁴ * '»· ;. ι- ^'τ concentrations which constituent liver are achieved in the present application' .byly: achieved even from very j '· many conventional iodinated X-ray contrast media, without this being able to slide as? be used for computer tomography to improve the diagnosis of focal liver changes,

A. The findings from animal experiments have been shown to be unsuitable for contrast enhancers to enhance contrast in computer tomography and liver tomography.

The following examples serve to illustrate the invention without its essence 'in any way limiting: vyreJ · o'p.'d^'f.ρ' «- '* ♦. )

..... in ^: '''hýf'''íýy'ř3j.rť'i? í '"' ť, s'l '

Exemplary Embodiments ⁴ Invention Cutting »Ai.r. rný '. no · D.PG-r pr i -p «n. hididc 11 1. «βν * f ·· *“ yj, ^ ·! .ovt.

Example 1, ,,, ·,,, *, *, *, y, y, <,-, r,-,-,-,-,- * '> « ¹ ,

Complex: lutecia-double sodium salt 3) 6,9-triazine-3,6,9-trisr (carboxymethyl) -5- (4-methoxybutyl) undecanedicarboxylic acid. · - - i ·

(a) divider; Butyl lest er. *, Acid-3,6,9-tris-3 ·, 6,9-tris-**** ·. ·· *. (terc.butoxykarbonylniethyl) -5V (4-ethoxy-benzyl) - ^r. * undekand and carboxy-l H ovéth re "· it. Γ- ► '* · »- ·· *' ♦ •,. ; rt, 1bu Jj 1 ♦ · - ·! «? ' fh »say :, '« filter · :. Plť? . py ' _t . 16.7 _t g (21 '4tmmol) N-di-tert.-butyl-3,6,9-3,6,9triaza tri (tert. Bútoxykarbortýlměthyl) -5 - (4-hydroxybenzyl) -undecanedioic acid (DOS 3710730) is dissolved in 50 ml of anhydrous N, N-dimethylformamide and treated at 0 ° C under argon with ^0.94 g (23 (5 mmol)) of sodium hydride dispersion (60% in mineral oil). The batch was allowed to stir for 15 minutes, then 3.74 g (24.0 mmol) was added, and the iodide / reaction temperature was kept on silica gel with hexane / diethyl ether / triethylamine. the product was combined and evaporated.

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

Analysis (based on solvent-free substance):

calculated: 63.92% C, 9.11% H, 5.20% N, 21.78% O found: 63.77% C, 9.28% H, 5.13% N.

b) The lutecium complex with the disodium acid salt

3,6,9-triaza-3,6,9-tris- (carboxymethyl) -5- (4-ethoxybenzyl) 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 acid. o thanks o vou. ,__from. p. a r s_e__ _siln_ě__na_r o_t_ač n. í__od.R.a rce_a_ z.by_t.e.k .....

Purify by ion exchange chromatography (catheter (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 3.98 g (10 mmol) of lutecium oxide are added. 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. Thereafter, the solution was stirred at ⁰ C for 80 s after the addition of 6 g of activated carbon for one hour and filtered. The filtrate gave 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, N 5.65%, O 23.67%, 23.53%

N, 6.18%. Found: C, 37.03; H, 3.94; N, 5.51

23,38%

Lu, 5.90% Na,

Example 2

Ytterbium complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (2-ethoxybenzyl) -undecanedioic acid disodium salt

(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 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, the pH is adjusted to 8.5 L. With a sodium hydroxide solution, 22.1 ml (63 mmol) of benzyl chloroformate are added under pH control. After stirring for four hours at room temperature, 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 crystallized.

Analysis (based on solvent-free substance):

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

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

10.2 g (31 mmol) of ortho-fenolu.z Example a) is dissolved at 40 ^e C in 6 mL of Ν, Ν-dimethylformamide, treated with 9.2 g (66.5 in

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 with tert-butyl methyl ether. The organic phase was 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 (relative to solvent-free substance):

calculated: 67.21% C, 6.49% H, 3.92% N, 22.38% 0 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 is filtered off with suction, the filtrate is evaporated and the residue is chromatographed on silica gel for purification.

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

Analysis (based on solvent-free substance):

calculated: 69.28% C, 7.04% H, 4.25% N, 19.43% O found: 69.32% C, 7.00% H, 4.18% N.

d) Dihydrochloride

N-benzyloxycarbonyl-2- [2-ethoxybenzyl] -1,4,7-triazaheptane

7.2 g (22 mmol) of the alcohol of example c) are dissolved in 18 ml of tetrahydrofuran and treated at room temperature with 4.9 ml (35 mmol) of triethylamine. 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 22.2 ml (330 mmol) of ethylenediamine are added dropwise 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 was cooled in an ice bath and treated with concentrated hydrochloric acid. The resulting precipitate was 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,

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) are suspended in 72 ml of methanol, treated with 1.08 g of palladium (10%) on charcoal and 0.5 ml of water and under normal pressure. hydrogenates at room temperature. 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, 13.54% N,

H, 8.34; H, 23.11; N, 13.40.

f) 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (2-ethoxybenzyl) undecanedioic acid di-tert-butyl ester> 1

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 mmol) of tert-butyl bromoacetate were added and the batch was stirred at 65 ° C for seven hours. After stirring at room temperature for 18 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 (methylene chloride / methanol). Evaporation of the product containing fractions gave the pentaester as an off-yellow oil.

Yield: 11.9 g (95% of theory)

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

11.75 g (14.5 mmol) of the pentaester of example f) are dissolved in 86 ml of methanol and treated with 4.65 g (116.3 mmol) of sodium hydroxide in 7.1 ml of water. 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 an ion exchanger. After filtering off the ion exchanger, the aqueous solution was evaporated and the penta acid is purified by preparative HPLC (water / methanol / pH 2, ^l 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): Calculated: C 52.37, H 6.31, N 7.97,% 33.36 Found: C 52.19, H 6.46, 88 ÍS N.

h) Ytterbium complex with disodium acid salt

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

3.72 g (7.05 mmol) of the pentacic acid of example g) are dissolved at 60 DEG C. in 19 ml of water and treated portionwise with 1.85 g (3.53 mmol) of tan-ytterbium carbonate. After complete complexation, it is filtered, the pH is adjusted to 7.0, stirred at 100 ^° C for 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% C, 3.81% H, 5.67% N, 23.74% O, 23.34% Yb, 6.20% Na Found: % H, 4.02;% N, 5.55.

Yb, 5.87% Na.

Example 3

Ytterbium complex with dimeglumine salt of acid salt

3,6.9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid

2.9 g (5.5 mmol)

3.6.9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid (EP 0405.704, Example 8b) is suspended in ml of water and complexed with 1.45 g (2 (75 mmol) of ytterbium carbonate at 60 ° C. After completion of the reaction, the batch was neutralized with methylglucamine. Filter to obtain a 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: C 40.85%, H 5.93%, N 6.44%, O 30.88%, Y 15.90% Found: C 40.67% % 08, N 6.17%, 14.62%

Yb.

b) Ytterbium complex with di- [2-amino-1,3,4-butanetriol) acid salt

3.6.9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid

The title compound is obtained analogously to Example a) when the complex salt is neutralized

2-amino-1,3,4-butanetriol.

c) Cerium complex with a dibasic acid salt

3,6.9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) undecanoic

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) Ytterbium complex with disodium acid salt

3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-methoxybenzyl) undecanedicarboxylic acid

2.1 g (4 mmol) of acid

3.6.9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid (EP 0405704, Example 8b) is suspended in 15 ml of water and complexed with 1.05 g (2 mmol) Ytterbium carbonate at 60 ° 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 freeze-drying 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% 0, 23.34% Yb, 6.20% Na Found: 37, % H, 4.11;% N, 5.50;% 23.22.

Yb, 5.94% Na ·. .............. -

e) The lutecium complex with the disodium acid salt

3,6,9-triaza-3,6,9-tris- (carboxamethyl) -4- (4-ethoxybenzyl) udecanedioic acid

3.0 g (5.7 mmol)

3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid (EP 0405704, Example 8b) is suspended in 15 ml of water and complexed with 1.07 g (2, 7 mmol) of lutecium oxide at 95 ° C. After complete complexation, the batch was neutralized with 1 N sodium hydroxide. The solution was filtered to give the title compound by freezing the filtrate.

Yield: 3.9 g (92% of theory)

Analysis (relative to solvent-free substance): calculated: 37.16% C, 3.80% H, 5.65% N, 23.67% 0, 23.53% Lu, 6.18% Na, found: 37 H, 4.01; H, 5.53. % N, 23.36%

Lu, 5.87% Na.

By analogy, 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 erbia complex (from carbonate) erbium), terbium complex (from terbium carbonate), holmium complex (from holmium carbonate) and praseodymium complex (from praseodymium carbonate).

Example 4

Gadolinium disodium acid complex

3,6,9-triaza-3,6,9-tri- (carboxymethyl) -4- (2-butoxybenzyl) undecanedicarboxylic acid

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

5.0 g (15.2 mmol) of ortho-phenol from Example 2a are dissolved at 40 ° C in 4 ml of Ν, Ν-dimethylformamide, mixed with 4.5 g (31.1 mmol) of potassium carbonate and ml of water. 2.1 g (15.5 mmol) of n-butyl bromide are then added dropwise and stirred for 5 hours. 3.2 ml of ammonia were added and the batch was 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, filtered 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 stirred for five hours at constant temperature. 0.8 ml of acetic acid in 3 ml of tetrahydrofuran are then added.

_Λ mixed with 5 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 is filtered off with suction, the filtrate is 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: C 70.56, H 7.61, N 3.92, O 17.90 Found: C 70.43, H 7.60, 07% N.

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

3.1 g (8.8 mmol) of the alcohol from example b) are dissolved in 8 ml of tetrahydrofuran and mixed with 2.0 ml at room temperature | (14 mmol) of triethylamine. Was added 1.02 ml (13 mmol) methanesulfonic acid chloride, dissolved in 1 ml of tetrahydrofuran, .. and stirred at 20 C for five hours ^e. Then, 8.9 ml (132 mmol) of ethylenediamine is added dropwise at a temperature between 35 ° C and 45 ° C. Allow to ... warm to 50 ° C and stir the batch for three hours. The reaction mixture was evaporated, the residue was taken up in ethyl acetate and washed with water. The organic phase was cooled in an ice bath and treated with concentrated hydrochloric acid. The precipitate formed

I was aspirated, washed with cold isopropanol and dried at 50 ° C.

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

and

Analysis (relative to solvent-free substance);

calculated; C 58.47, H 7.47, Cl 15.01, N 8.89,

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, treated with 0.4 g of palladium (10%) on charcoal and 0.3 ml of water and hydrogenated under normal conditions. 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,

% H, 8.72;% C, 21.23;% N, 12.29.

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

5.3 g (38.8 mmol) of potassium carbonate are dissolved in 5 ml of water and 2.3 g (7.4 mmol) of triamine dihydrochloride (Example d) are mixed at 35 ° C. 5.9 ml (40.6 mmol) of tert-butyl bromoacetate are added dropwise and the batch is stirred at 60 ° C for eight hours. After stirring at room temperature for 15 hours, the reaction mixture was mixed with water and shaken with ethyl acetate. The organic phase was dried over sodium sulfate, evaporated and the residue 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, 9.28% H, 5.03% 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 of 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 is taken up in water and the pH is 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 again in water and freeze-dried.

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

Analysis (based on solvent-free substance):

H, 6.71; N, 7.56. Found: C, 53.91; H, 6.76; N, 7.39.

g) Gadolinium complex with disodium acid salt

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

The 2,4'8 g (4.7 mmol) of the pentacic acid of example f) is suspended at 85 ° C in 20 ml of water and mixed in portions with 0.85 g (2.35 mmol) of gadolinium oxide. After the complexation is complete, filter, adjust to pH 7.2, and stir at 90 for 10 minutes. ° C with 0.2 g of activated carbon, filtered again and the filtrate lyophilized.

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

Analysis (relative to solvent-free substance): calculated: 39.84% C, 4.28% H, 5.58% N, 23.35% 0, 20.86% Gd, 6.10% Na found: 73% C, 4.39% H, 5.47% N, 20.71%

Gd, 5.94 X Na.

Example 5

Ytterbium complex with disodium acid salt

3,6.9-triaza-3,6,9-tris- (carboxymethyl) -5- {4- [2- (2-ethoxy] benzyl} -undecanedicarboxylic acid

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

16.7 g (21.4 mmol) of di-tert-butyl acid ester

3.6.9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- (4-hydroxybenzyl) -undecanedicarboxylic acid (DOS 3710730) is dissolved in 50 ml of anhydrous N, N-dimethylformamide and at 0 ° C under argon. admixed with 0.94 g (23.5 mmol) of sodium hydride dispersion (60% in mineral oil). The batch 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 against 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 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% Found: C 63.07, H 9.27, 4.75 % N.

b) Ytterbium complex with disodium acid salt

3,6,9-triaza-3,6,9-tris- (carboxymethyl) -5- {4- [2- (2-ethoxyethoxy) -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, stirred for two hours at 60 ° C, adjusted to pH 1 with concentrated hydrochloric acid, Evaporate vigorously on a rotary evaporator and purify the residue 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 ytterbium carbonate. The suspension was stirred at 60 ^° C for 3 hours and filtered. The pH is then adjusted to 7.3 with 1 N sodium hydroxide. The solution was stirred at 80 ° C for one hour after addition of 1.0 g of charcoal and filtered. The filtrate gave a colorless solid after freeze-drying.

Yield: 11.4 g (91.6% of theory)

Analysis (based on solvent-free substance): Calculated: 39.09% C, 4.37% H, 5.07% N, 25.07% O, 20.86% Yb, 5.54% Na Found: 38, 84% C, 4.45% H, 5.02% N, 20.69%

Yb, 5.30% Na.

Example 6

Increase in depth of healthy liver parenchyma 10 and 60 minutes after infusion of 0.25 molar solution of gadolinium II-complex with double acid salt

3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) undecanecarboxylic (Gd-EOB-DTPA, described in Example 8c EP 0405704) in 5 patients with hepatic metasase at dose 0.35 mmol / kg in Houndsfield units (HU). This dose corresponds to about 16 g of complex per 70 kg of patient.

Table 3 min after inf HU min after inf. HU patient 1 patient 2 patient 3 patient 4 patient 5 .32

1982, specially for

SH L 433 (Formula XI)

For comparison, Mtitzel et al., A liver diagnosis developed by hexaodinated, was tested

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). About 90% of human biliary excretion of Iotroxinate (hexa iodinated, 2 carboxyl groups) accumulates in the liver at a maximum tolerable dose, corresponding to about 7 g iodine / 7'0 kg patient only 15 HU (Hiibner KH: Computertomographische Densitometry von Leber, Milz und Nieren bei intravenos verabreichten Lebergangigen Kontrastmitteln in Bolusform, Fortschr.

For comparison, also about 3.5 g of gadolinium in the form of a complex containing only one gadolinium ion / molecule is a multiple of X-ray absorption in human liver more than 25 g of iodine from SH L 433 (Formula XI), respectively. 7 g of iotroxinate iodine, although both x-ray contrast agents are hexaodinated compounds.

Example 7

The following solution was produced:

0.1 mol holmium (III) -dimeglumine acid salt complex

3.6.9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-butylbenzyl) undecanedicarboxylic acid,

0.005 mol of calcium (II) -trimeglumine salt complex

3.6.9-triaza-3,6,9-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 on. at the end of the infusion and 30 minutes after the end of the infusion as usual.

Example 8

Disodium acid salt

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 in the aqueous phantom is measured at different concentrations because roughly corresponds to the human abdomain. Work is carried out on a commercially available computer tomograph at operating voltages of 137 kV and 110 mA.

Values in Hounsfield units (HU + SD)

Table 4

Element concentration (mmo1 / 2) HU ± SD H ₂ 0 - 14 23 Gd 50 218 23 500 1680 33 Tb 50 228 ' 25 500 1760 45 Dy 50 226 23 500 1840 42 Him 50 221 29 500 1890 40 Er 50 254 24 500 1955 57 Yb 50 252 18 500 1980 42 J 50 110 25 500 914 27 Mar:

There is a surprisingly high efficiency of rare earths against iodine, which is undoubtedly reflected back on special conditions. Abdominal CT measurements. Of the lanthanide, erbium, ytterbium and holmium are preferred over the most experienced elements so far, gadolinium and dysprosium.

Example 9

Perform the experiment

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

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

Patients had histologically established 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 were demonstrated with a contrast enhancing agent within one month prior to the Gd-EOB-DTPA study. Exclusion criteria for patients were:

administration of contrast agent, parameters.

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 20-30 seconds at rest. The displacement of the table was 8 mm / s, the collision was 8 mm.

The number and size of metastases were evaluated by qualitative (excellent, good, massive, minimal, no improvement) and quantitative (Hounsfield units measurements) on the basis of pre- and post-contrast images.

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

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 CT-density (Hounsfield units, HU) in the liver of patients with histologically established primary tumors after the start of infusion of 0.2 ()) -, 0.35 (♦), respectively. 0.5 mmol / kg Gd-EOB-DTPA (4). CT density in liver metastases is indicated by *.

CT-metastasis density was unchanged. In addition, the gallbladder and biliary tract were displayed.

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, an additional 7 mm diameter lesion was found in the left liver lobe after administration of Gd-EOB-DTPA and was not found previously.

The general compatibility of Gd-EOB-DTPA was good. Only four moderate or moderate levels were observed. massive side effects. In two cases, patients experienced burning at or from the infusion site, which lasted only a few seconds or more. minutes. Other side effects were nausea and epigastral pressure.

The evaluation of 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 metastasis.

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

* i atívotót

S $ Q SU PRAGUE 2, KE & WS 0

PATENTOVÉ

1. Use of chelated

compounds

Ν 'COOX

to.

'COOX

Claims

Claims (11)

X each independently represents a hydrogen atom or a metal ion equivalent of an element of atomic numbers 44-51 or 56-83, one of the radicals E ¹ has the formula -CH 2 ^_ C6H4- (O) R ^2, wherein said aromatic ring may be substituted in the ortho position -, meta- or para- and the other radical E ¹ represents hydrogen, E ² represents a hydrocarbon radical having 1 to 6 carbon atoms and 0 to 2 oxygen atoms, a phenyl or benzyl radical or hydrogen, r being zero or one, the carboxyl groups may also be present as amides, together with a charge equalization optionally necessary physiologically acceptable cations for medical diagnostics, for the production of contrast agents 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 chelated compounds according to claim 1 or 2, characterized in that the complexed metal is cerium, praseodymium, gadolinium, dysprosium, holmium, erbium, ytterbium or lutecium. Use of chelate compounds according to claim 1, characterized in that the complexed metal is hafnium, bismuth or lead. Use of the chelate compounds according to claim 1, characterized in that at least one of the physiologically acceptable cations is Na ⁺ , Ca ⁺ , Mg ⁺ or the organic cations 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 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) -acid complex 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid, ytterbium (in) acid complex 3,6.9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid, praseodymium (III) acid complex 3,6.9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid, lutecium (III) acid complex 3.6.9- triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid cerium (III) complex 3,6.9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid hafnium (IV) complex 3,6.9-triaza-3,6,9-tri with (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid bismuth (III) complex 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanecarboxylic acid, ytterbium-acid complex 3,6.9-triaza-3,6,9-tris- (carboxymethyl) -5- (4- [2- (2-ethoxy} ethoxy) -ethoxy] -benzyl} -undecanedicarboxylic acid, lead (II) -acid complex 3,6.9-triaza-3,6,9-tri with (carboxymethyl) -4- (4-ethoxybenzyl) undecanedicarboxylic acid or ytterbium (III) acid complex 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (2-ethoxybenzyl) undecanedicarboxylic acid. Use of the chelate compounds according to claim 1, characterized in that the chelate compound is a gadolinium (III) -acid complex 3,6.9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butylbenzyl) undecanedicarboxylic acid ytterbium (III) -acid complex 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butylbenzyl) undecanedicarboxylic acid, praseodymium (III) acid complex 3.6.9- triaza-3,6,9-tris (carboxymethyl) -4- (4-butylbenzyl) undecanedicarboxylic acid, lutecium (III) acid complex 3 / 6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butylbenzyl) undecanedicarboxylic acid hafnium (IV) complex 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4,8-bis- (4-butylbenzyl) -undecanedicarboxylic acid, bismuth (III) complex with acid 3,6,9-Triaza-3,6,9-tris (carboxymethyl) -4,8-bis- (4-butylbenzyl) -undecanedicarboxylic acid or lead (II) -acid complex 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butylbenzyl) undecanedicarboxylic acid.