IE65676B1 - Derivatized DTPA complexes pharmaceutical agents containing these compounds their use and processes for their production - Google Patents

Abstract

Compounds of the general formula <IMAGE> in which Z<1> and Z<2> each represent a hydrogen atom or the radical -(CH2)m-(C6H4)q-(O)k-(CH2)n(C6H4) l-(O)r-R, in which m and n denote the figures 0 - 20, k, l, q and r denote the figures 0 and 1 and R denotes a hydrogen atom, an unsubstituted or OR<1>-substituted C1-C6-alkyl radical or a CH2COOR<1> group where R<1> denotes a hydrogen atom, a C1-C6-alkyl radical or a benzyl group, X represents a hydrogen atom and/or a metal ion equivalent of an element of atomic number 21 - 29, 42, 44 or 57 - 83, with the proviso that at least two of the substituents X represent a metal ion equivalent in which one of the substituents Z<1> and Z<2> represents a hydrogen atom and the other does not represent a hydrogen atom, in which - if n and l each represent the figure 0 - k and r do not simultaneously each denote the figure 1, in which Z<1> or Z<2> do not represent -CH2-C6H4-O-CH2-COOCH2C6H5 or CH2-C6H4-O-(CH2)5-COOCH2C6H5 and in which -(O)r-R does not represent -OH, and their salts with inorganic and/or organic bases, amino acids or amino acid amides, are useful pharmaceutical agents.

Description

The invention relates to the subject characterised in the patent claims, that is to say to novel complexes and complex salts, to agents comprising those compounds, to their use for the preparation of agents for NMR and X-ray 5 diagnostics and radiotherapy, and to processes for the * preparation of those compounds and agents.

Metal complexes were considered as contrast agents for radiology as early as the beginning of the 1950s.

However, the compounds used at that time were so toxic that there was no question of their being used in humans. It was therefore very surprising that certain complex salts have proved to be sufficiently tolerable that routine use in humans for diagnostic purposes could be considered. As the first representative of this class of substances, the dimeglumine salt of Gd DTPA (gadolinium(III) complex of diethylenetriaminepentaacetic acid), which is described in the European patent application having the publication number 71564, has proved successful as a contrast agent for nuclear spin tomography. It has been registered worldwide under the name Magnevist(R) as the first NMR diagnostic agent.

Magnevist(R) is especially suitable for the diagnosis of pathological regions (e.g. inflammations, tumours, infarcts, etc.). After intravenous injection, the compound is distributed extracellularly and is eliminated by glomerular secretion via the kidneys. Passage through intact cell membranes and extrarenal elimination are hardly observed at all.

Contrast agents that exhibit at least only partial extrarenal elimination would be desirable especially for patients having a limited kidney function, for whom Magnevist(R) is eliminated only very slowly and in some cases can be removed from the organism only with the aid ot a dialysis unit.

There is therefore a need for NMR contrast agents whose pharmacokinetic behaviour is different from that of Magnevist(R).

Accordingly, the problem underlying the invention is to make available such compounds and agents and to provide a process for their preparation. That problem is solved by the present invention.

The compounds according to the invention exhibit the desired property: both renal elimination and excretion with the faeces.

Surprisingly, however, elimination via the gall-bladder is not the only extrarenal elimination route; in NMR studies in rats, contrast intensification of the gastro15 intestinal tract was also unexpectedly observed following intravenous administration of the compounds according to the invention. Improved contrast of*the kidneys and implanted tumours is likewise achieved.

Removal (secretion) via the stomach has the advantage 20 that it is possible to distinguish abdominal structures (e.g. the pancreas) from the gastrointestinal tract, with the contrast of pathological processes (tumours, inflammations) being intensified at the same time. Moreover, imaging of the renal system, the liver and the gall-5 bladder and bile-ducts can also be achieved. In addition to improved imaging of ulcers and gastric carcinomas, it is also possible to check the secretion of gastric juices with the aid of imaging processes.

With the provision of the compounds according to the 10 invention it is accordingly possible to help both patients with renal insufficiency and those suffering from gastrointestinal disorders (at least 10% of the population in the western industrialised countries).

Most of those patients, as well as a large number in whom such a disorder is suspected, must undergo diagnostic investigations. At present, two methods suitable for that purpose are common: endoscopy and X-ray diagnostics with the aid of barium contrast agents.

Those investigations have various disadvantages: they are accompanied by the risk of radiation exposure, they cause trauma, they are associated with unpleasantness and occasionally even with risks to the patient and may therefore cause psychological stress. They must in most cases be carried out repeatedly, they are relatively costly to perform, they require the active cooperation of the patient (e.g. the adoption of a particular posture) and often cannot be carried out on frail patients and those at risk.

Therefore, the complex compounds and agents according to the invention also solve the problem of providing novel diagnostic methods for detecting and locating gastrointestinal disorders, which methods do not possess those disadvantages.

Even without specific measures, their pharmacokinetics allows the diagnosis of numerous disorders to be improved. The complexes are for the most part eliminated again quickly and in unchanged form, so that no harmful effects are observed even at high doses, especially where relatively toxic metal ions are used.

The practical use of the novel complexes is also facilitated by their advantageous chemical stability.

The metal complexes disclosed in WO-A-88/07521 and EP-A-0 299 795 are, like Magnevist(R), extracellular contrast agents and therefore exhibit pharmacokinetic behaviour comparable with that of Kagnevist(R). In particular, in comparison with those prior-known metal complexes, the compounds according to the invention surprisingly exhibit markedly greater excretion with the faeces.

The compounds mentioned in EP-A-0 165 716 and EP-A-0 315 220, which are predominantly compounds of relatively high molecular weight, are metal complexes which - in contrast to the compounds according to the invention - are chemically bonded to an organic species, such as a protein, steroid, peptide, hydrocarbon or medicament. There is no indication in those documents that the problems underlying the present invention can be solved with those compounds.

Accordingly, the invention relates to the use of at least one physiologically tolerable compodhd of the general formula I XOOCCH z' i 2 N-CH I XOOCCH Z" CH COCX CH COOX I 2 I 2 •C H-H—CH ,—C H—N 2 2 I CH2COOX (I). in which Z1 and 22 each independently of the other represent a hydrogen atom or the radical "(CH2)a-(C6H4)q-(O)k-(CH2)n-(C6H4)1-(O)r-R, wherein m and n represent the numbers 0 to 20, k, 1, g and r represent the numbers 0 and 1, and R represents a hydrogen atom, an optionally OR1substituted Οχ-Cgalkyl radical or a group CH2COOR1 wherein R1 represents a hydrogen atom, a Cj^-Cgalkyl radical or a benzyl group, X represents a hydrogen atom and/or a metal ion equivalent of an element of atomic numbers 21-29, 42, 44 or 57-83, with the proviso that at least two of the X substituents represent a metal ion equivalent, that one of the substituents Z1 and Z2 represents a hydrogen atom and the other does not represent a hydrogen atom, that when n and 1 each represent the number 0 - k and r do not at the same time each represent the number 1, that Z1 or Z2 does not represent -CH2-C6H4-O-CH2-COOCH2C6H5 or -CH2-C6H4-O-(CH2)5-COOCH2C6H5, that -(O)r-R does not represent -OH, that Z1 does not represent -ch2-Q-oh and that the sum of q and 1 gives the number 1 or 2, and their salts with inorganic and/or organic bases, amino acids or amino acid amides, for the preparation of agents for NMR diagnostics of the gastrointestinal tract.

The compounds according to the invention are characterised by the general formula I * XOOCCH I 2 NI XOOCCH, CHI -CHCH COOX i 2 CH.COOX z -CH,—CH,—N Z Z ι (I), CHjCOOX in which Z1 and Z2 each independently of the other represent a hydrogen atom or the radical -(CH2)m-(C6H4)q-(O)k- (CH2)n-(C6H4)i-(O)r-R, wherein m and n represent the numbers 0 to 20, k, 1, q and r represent the numbers 0 and l, and R represents a hydrogen atom, an optionally OR1substituted C^-Cgalkyl radical or a group CH2COORl· wherein R1 represents a hydrogen atom, a C^-Cgalkyl radical or a benzyl group, X represents a hydrogen aton and/or a netal ion equivalent of an element of atonic numbers 21-29, 42, 44 or 57-83, with the proviso that at least two of the X substituents represent a netal ion equivalent, that one of the substituents Z1 and Z2 represents a hydrogen atom and the other does not represent a hydrogen atom, that when n and 1 each represent the number 0 - k and r do not at the sane time each represent the number 1, that Z1 or Z2 does not represent -CH2-C6H4-O-CH2-COOCH2C5H5 or -CH2-C6H4-O-(CH2)5-COOCH2C6H5/ that -(O)r-R does not represent -OH, that Z1 does not represent -CH?—ζ~^-οκ , and that the sun of q and 1 gives the number 1 or 2, and their salts with inorganic and/or organic bases, amino acids or amino acid amides.

If the agent according to the invention is intended for use in NMR diagnostics, then the central ion of the complex salt must be paramagnetic. Paramagnetic ions are especially the di- and tri-valent ions of the elements of atomic numbers 21-29, 42, 44 and 58-70. Suitable ions are, for example, the chromium(III), manganese(ll), iron(II), cobalt(II), nickel(II), copper(II), praseodym(III), neodym(III), samarium(III) and ytterbium(III) ions. The gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III) and iron(III) ions are especially preferred on account of their very strong magnetic moment.

If the agent according to the invention is intended for use in X-ray diagnostics, then the central ion must be derived from an element having a relatively high atomic number in order to achieve sufficient absorption of the X-rays. It has been found that diagnostic agents containing a physiologically tolerable complex salt having central ions of elements of atomic numbers between 21-29, 42, 44, 57-83 are suitable for that purpose; such ions are, for example, the lanthanum(III) ion and the above-mentioned ions of the lanthanide series.

The numbers represented by m and n are preferably 0 to 5.

Suitable alkyl substituents R and R1 are straight-chained or branched hydrocarbons having up to 6, preferably up to 4, carbon atoms, which, in the case of R, are optionally substituted by one or more, preferably from 1 to 3, hydroxy groups or Cj-Cgalkoxy, preferably alkoxy, groups.

There may be mentioned as optionally substituted alkyl groups, for example, the methyl, hydroxymethyl, ethyl, 2-hydroxyethyl, 2-hydroxy-l-(hydroxymethyl) -ethyl, 1-(hydroxymethyl)-ethyl, propyl, isopropyl, 2- and 3hydroxypropyl, 2,3-dihydroxypropy1, η-, sec.- and tert.butyl, 2-, 3- and 4-hydr oxy buty 1, 2- and 3-hydroxyisoX butyl, pentyl, 2-, 3- and 4-hydroxy-2-methylbutyl, 2,3,4trihydroxybutyl, 1,2,4-trihydroxybutyl, cyclopentyl, cyclohexyl and 2,3,4,5,6-pentahydroxyhexyl groups and in the case of the hydroxyalkyl groups - also their C3-C6alkyl, preferably C1-C4alkyl, derivatives.

Preferred substituents Z1 and Z2 of the compounds according to the invention are the radicals -CH2-C6H4-OCH3, -CH2-C6H5, -CH2-C6H4-O-CH2-C6H4-OCH3, -ch2-o-ch2-c6h5, -ch2-c6h4-o-ch2-cooh, -ch2-c6h4-oc2h5, -ch2-c6h4-oc4h9 , -ch2-c6h4-o-ch2-c6h5 .

An additional preferred substituent Z1 or Z2 which may be mentioned for use as agents for NMR diagnostics of the gastrointestinal tract is the radical -CH2-CgH4OH.

If not all acidic hydrogen atoms are substituted by the central atom, it is possible for one, more than one or all of the remaining hydrogen atoms to be replaced by cations of inorganic and/or organic bases or of amino acids. Suitable inorganic cations are, for example, the lithium ion, the potassium ion, the calcium ion, the magnesium ion and, especially, the sodium ion. Suitable cations of organic bases are inter alia cations of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, Ν,Ν-dimethylglucamine and, especially, Nmethylglucamine. Suitable cations of amino acids are, for example, cations of lysine, of arginine and of ornithine. Suitable cations of amino acid amides are, for example, those of lysine methylamide, glycine ethylamide and serine methylamide.

The complex compounds of the general formula I according to the invention are prepared as follows: compounds of the general fornula II R OOCCH, I R OOCCH, Z3 Z‘ CH,COOR2 I I I 2 CH-CH-N-CH*-CH* CH COOR2 I 2 N I 2 CH*COOR (II), in which R2 represents an acid-protecting group, and Z3 and Z4 each represent a hydrogen atom or the radical -(CH2)B-(CeH4)q-OH, with the proviso that one of the substituents Z3 and Z4 represents a hydrogen atom and the other represents the mentioned radical, are converted in a manner known per se into a compound containing the radical mentioned for Z1 and Z2, the acid protecting groups R2 are removed, the resulting complexing agent acids of the general formula I wherein X represents a hydrogen atom (formula I*) are reacted with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 42, 44 or 57-83, and then - if desired - acidic hydrogen atoms that are present are replaced by cations of inorganic and/or organic bases, amino acids or amino acid amides.

Suitable acid-protecting groups R2 are lower alkyl, aryl and aralkyl groups, for example the methyl, ethyl, propyl, n-butyl, tert.-butyl, phenyl, benzyl, diphenylIQ methyl, triphenylmethyl and bis(p-nitrophenyl)-methyl groups, as well as trialkylsilyl groups.

The protecting groups R2 are removed according to the processes known to the person skilled in the art [e.g.

E. Wunsch, Methoden der Org. Chemie (Houben-Weyl), Vol. XV/l, 4th edition, 1974, p. 315 ff], for example by hydrolysis, hydrogenolysis or alkaline hydrolysis of the esters with alkali in aqueous-alcoholic solution at temperatures of from 0 to 50*C. For the removal of the X tert.-butyl esters, which are especially advantageous for the present reactions, organic or inorganic acids are used: The ester compound dissolved in a suitable anhydrous organic solvent, but preferably the powdered dry substance, has added to it either hydrogen halide solution in glacial acetic acid, trifluoroacetic acid, or alternatively boron trifluoride diethyl etherate in glacial acetic acid, and is removed at temperatures of from -10'C to 60*C, preferably at room temperature.

The compounds of the general formula II used as starting materials for the preparation of the complex compounds according to the invention are known (DOS 3 710 730 and literature mentioned therein) or can be synthesised analogously to the preparation methods described therein.

For the reaction of the known aliphatic or aromatic hydroxy compounds to form the corresponding aryl alkyl ethers or dialkyl ethers there are available in the literature a number of methods known to the person skilled in the art (e.g. J. March, Advanced Organic Chemistry, third edition 1985, p. 342 ff).

For that purpose, the compounds of formula II, wherein R2 represents an acid-protecting group that is stable to alkali, are dissolved in a polar aprotic solvent, such as, for example, tetrahydrofuran, dimethoxyethane or dimethyl sulphoxide, and there is added thereto a base, such as, for example, sodium hydride, sodium hydroxide or alkali metal or alkaline earth metal carbonates, at temperatures of from -30"C to the boiling point of the solvent in question, but preferably from 0"C to 60*C.

There is added thereto a compound of the general formula III (III) wherein Y represents a nucleofugal group, such as, for example, Cl, Br, I, CH3-C5H4SO3 or CF3SO3, and the remaining symbols have the same meaning as in the general formula I.

Depending upon the steric hindrance of the radicals involved, the reaction times are from 30 minutes to 8 hours.

As an alternative to the reaction conditions described above, both aryl alkyl ethers and dialkyl ethers can be prepared very advantageously by phase transfer catalysis (Starks and Liotta, Phase Transfer Catalysis, Academic Press, N.Y. 1978, p. 128-138).

For that purpose, the reaction is carried out in a twophase mixture consisting of an agueous base, preferably 30% sodium hydroxide solution, and a water-immiscible organic aprotic solvent. There are suitable as phase transfer catalysts the compounds known to the person skilled in the art, but preferably tetraalkylammonium salts or tetraalkylphosphonium salts.

If compounds of the general formula I wherein k, η, 1 and r - 0 and R represents a hydrogen atom are to be synthe10 sised, then it is possible, starting from the corresponding unsubstituted amino acid (e.g. phenylalanine), to carry out the synthesis analogously to the methods known in the literature.

However, if a number of analogous compounds are to be synthesised, it is recommended to prepare the phenol derivatives described in DOS 3 710 730 and to remove the phenol function by reduction according to the processes in the literature known to the person Skilled in the art. There may be mentioned especially the reduction of aryl diethyl phosphates with titanium, which may also be carried out very advantageously in the presence of ester groups [S.C. Welch et al., J. Org. Chem. 43. 4797-4799 (1978) and literature mentioned therein]. In that process, first the corresponding aryl diethyl phosphate is formed from the phenolic starting material in a yield of from 70 to 100% by reaction with phosphoric acid diethyl ester chloride, preferably using sodium hydride as base in a polar aprotic solvent. Then the reduction is carried out with freshly prepared titanium metal.

Preferably, for the preparation of highly active titanium, anhydrous titanium(III) chloride is reduced by means of magnesium or potassium in anhydrous tetrahydrofuran under inert gas.

The above-described diethyl phosphate is added to such a mixture and heated under reflux for from 2 to 24 hours, preferably from 6 to 16 hours. When the reaction is complete, the mixture may be worked up by chromatography. It is also possible to use palladium-catalysed reduction of the corresponding aryl triflates according to S. Cacchi et al., Tetr. Lett. 27. 5541-5544 (1986).

The compounds of the general formula I* so obtained wherein X represents a hydrogen atom are complexing agents. They can be isolated and purified or can be converted, without being isolated, into metal complexes of the general formula I in which at least two of the X substituents represent a metal ion equivalent.

The metal complexes accordinq to the invention are prepared in the manner disclosed in Patent Specification DE 3 401 052, by dissolving or suspending the metal oxide or a metal salt (for example the nitrate, acetate, carbonate, chloride or sulphate) of the element of atomic numbers 21-29, 42, 44 or 58-70 in water and/or a lower alcohol (such as methanol, ethanol or isopropanol) and reacting it with the solution or suspension of the equivalent amount of the complex-forming acid of the general formula I* wherein X represents a hydrogen atom, preferably at temperatures of from 40 to 100*C, and then - if desired - replacing acidic hydrogen atoms of acid groups that are present with cations of inorganic and/or organic bases, amino acids or amino acid amides.

The neutralisation is carried out with the aid of inorganic bases (for example hydroxides, carbonates or hydrogen carbonates) of, for example, sodium, potassium, lithium, magnesium or calcium, and/or organic bases, such as inter alia primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N-methylglucamine and Ν,Ν-dimethylglucamine, and also basic amino acids, such as, for example, lysine, arginine and ornithine.

In order to prepare the neutral complex compounds it is possible, for example, to add to the acidic complex salts in aqueous solution or suspension such an amount of the desired bases that the neutral point is reached. The resulting solution can then be concentrated to dryness in vacuo. Frequently it is advantageous to precipitate the resulting neutral salts by the addition of water-miscible solvents, such as, for example, lower alcohols (methanol, ethanol, isopropanol, etc.), lower ketones (acetone, etc.), polar ethers (tetrahydrofuran, dioxane, 1,2dimethoxyethane, etc.) and so obtain crystals that can readily be isolated and purified. It has proved especially advantageous to add the desired base to the reaction mixture during the complex formation, thus saving one process step.

X If the acidic complex compounds contain several free acidic groups, it is often advantageous to prepare neutral mixed salts which contain both inorganic and organic cations as counter-ions.

This may be achieved, for example, by reacting the complex-forming acid in aqueous suspension or solution with the oxide or salt of the element supplying the central ion and with half the amount of an organic base required for neutralisation, isolating the resulting complex salt, purifying it, if desired, and then adding the amount of inorganic base necessary for complete neutralisation. The order in which the bases are added may also be reversed. ' 30 The preparation of the pharmaceutical agents according to the invention is also carried out in a manner known per Sfi, by suspending or dissolving the complex compounds according to the invention - optionally with the addition of additives customary in galenic pharmacy - in an aqueous medium and then optionally sterilising the suspension or solution. Suitable additives are, for example, physiologically harmless buffers (such as, for example, tromethamine), small amounts of complexing agents (such as, for example, diethylenetriaminepentaacetic acid) or, if necessary, electrolytes (such as, for example, sodium chloride) or, if necessary, antioxidants, such as, for example, ascorbic acid.

If suspensions or solutions of the agents according to the invention in water or physiological saline solution are desired for enteral administration or for other purposes, they are mixed with one or more adjuncts (for example methylcellulose, lactose, mannitol) and/or surfactants, for example lecithins, Tween(R), Kyrj(R), and/or taste-correcting flavourings ffor example ethereal oils) customary in galenic pharmacy.

In principle, it is also possible to prepare the pharmaceutical agents according to the invention without isolating the complex salts. In that case, special care must be taken to carry out the chelate formation in such a manner that the salts and salt solutions according to the invention are virtually free of non-coraplexed toxic metal ions.

That can be ensured, for example, with the aid of colour indicators such as xylenol orange by control titrations during the preparation process. The invention therefore relates also to processes for the preparation of the complex compounds and their salts. As a final safety measure there is purification of the isolated complex salt.

The pharmaceutical agents according to the invention are administered in a dose of from 1 μΜθΙ/kg to 5 mmol/kg, preferably from 10 Mmol to 0.5 mmol/kg of the complex salt according to the invention. In the case of intravenous injection, aqueous formulations having a concentration of from 50 pmol/l to 2 mol/1, preferably from 100 mmol/1 to 1 mol/1, are used. Rectal and oral administration are preferably effected using solutions having a concentration of from 0.1 mmol/1 to 100 mmol/1. The volumes administered are from 5 ml to 2 litres, depending upon the diagnostic investigation.

The agents according to the invention meet the many requirements for suitability as contrast agents. Accordingly, they are excellently suitable, following enteral or parenteral administration, for improving the meaningfulness of the image obtained by means of nuclear spin tomography by increasing the signal intensity. Moreover, they exhibit the high degree of activity which is necessary for subjecting the body to minimal amounts of foreign substances, and the good tolerability necessary for maintaining the non-invasive nature of the investigations.

Because of the good water-solubility and low osmolality of the agents according to the invention it is possible to prepare highly concentrated solutions and thus keep the volume loading of the circulation within tolerable limits and compensate for dilution by the body fluid. Furthermore, the agents according to the invention exhibit not only high stability in vitro but also a surprisingly high stability in vivo, so that the ions that are not bonded covalently in the complexes - which ions are themselves toxic - are released or exchanged only extremely slowly during the time in which the novel contrast agents are completely excreted again.

The agents according to the invention may also be used for radiotherapy. For example, complexes of gadolinium are excellently suitable for neutron capture therapy on account of the large capture cross-section. If the agent according to the invention is to be used in the variant of radiotherapy proposed by R.L. Mills et &1[Nature, Vol. 336 (1988), p. 787], then the central ion must be derived from a Mdssbauer isotope such as, for example, 57Fe or 151Eu.

The agents according to the invention may also be administered together with a suitable carrier, such as, for example, serum or physiological saline solution, and/or together with a protein, such as, for example, human serum albumin. In that case, the dosage is dependent upon the nature of the cell damage and the properties of the metal complex that ffe to be used.

The following Examples illustrate the invention without limiting it thereto.

Example 1 a) 3,6,9-triaza-3,6,9-tris (tert. -butoxycarbonylmethyl) 4-(4-methoxybenzyl)-undecanedioic acid di-tert.-butyl diester mg (2.2 mmol) of 80% sodium hydride are added to 1.56 g (2 mmol) of 3,6,9-triaza-3,6,9-tris(tert.-butoxycar bony lmethy 1 ) -4- (4-hydroxybenzyl) -undecanedioic acid di-tert.-butyl diester (Example 9f of DOS 3 710 730) in tetrahydrofuran at 0aC. 0.31 g (2.2 mmol) of iodomethane is added thereto and the mixture is stirred for minutes. Then water is added to the solution, tetrahydrofuran is distilled off and the aqueous emulsion is extracted with diethyl ether. The organic phase is washed with water, dried over Ifa2SO4 and concentrated. Yield: 1.55 g (97.6%) calc.: C 63.53 H 9.01 N 5.29 found: C 63.37 H 8.96 N 5.32 b) 3,6,9-triaza-3,6,9-tris ( carboxymethyl) -4- ( 4-methoxybenzyl )-undecanedioic acid 1.27 g (1.6 mmol) of the tert.-butyl ester described in Example la) are dissolved in 25 ml of trifluoroacetlc acid and the solution is stirred for one hour at room temperature. Then diethyl ether is added to the solution and the precipitate is filtered off with suction, washed with ether and dried at 40 c in vacuo over phosphorus pentoxide. The crude product is dissolved in water and stirred with activated car Eon. The carbon is filtered off and the product is lyophilised three times in order to remove residual trifluoroacetlc acid.

Yield: 0.62 g (75.4%) calc.: C 51.46 H 6.09 N 8.18 found: C 51.27 H 6.02 N 8.11 c) Gadolinium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl ) -4- (4-methoxybenzyl) -undecanedioic acid 513 mg (1 mmol) of the complexing agent acid described in Example lb) are dissolved in approximately 30 ml of water, and 181 mg (0.5 mmol) of Gd2O3 are added thereto at 80*C. After 30 minutes, the almost clear solution is filtered and the filtrate is freeze-dried.

Yield: 649 mg (97.2%), based on the anhydrous substance. calc.: C 39.57 H 4.23 N 6.29 Gd 23.55 found: C 39.47 H 4.29 N 6.21 Gd 23.19 Disodium salt of the gadolinium complex The complex obtained as described above (500 mg, 0.75 mmol) is dissolved in 10 times the amount of water, and 1.5 ml of a IN sodium hydroxide solution are added thereto by means of a microburette. Freeze-drying yields 533 mg of white crystals. io The Τχ-relaxivity (1/mmol.sec) is in water 4.54 ± 0.13 in plasma 6.89 ± 0.17.

Di-N-methyl-D-glucamine salt of the gadolinium complex 1.96 g (10 mmol) of N-methyl-D-glucamine are added in portions, with stirring, to 3.34 g (5 mmol) of the gadolinium complex in 40 ml of water. When the base has dissolved completely, freeze-drying is carried out. .55 g of a colourless crystalline compound remain.

H2O content (Karl-Fischer determination): 4.73% d) Europium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl )-4-( 4-methoxybenzyl) -undecanedioic acid .13 g (10 mmol) of the complexing agent acid described in Example lb) are dissolved in approximately 30 ml of water, and 1.76 g (5 mmol) of Eu2O3 are added thereto at 80*C. After 30 minutes, the almost clear solution is filtered and the filtrate is freeze-dried.

Yield: 6.62 g Analysis (based on anhydrous substance): calc.: C 39.89 H 4.26 N 6.34 Eu 22.94 found: C 39.71 H 4.38 N 6.17 Eu 22.58 Disodium salt of the europium complex The complex as described above (497 ng, 0.75 mmol) is dissolved in 10 times the amount of water, and 1.5 ml of a IN sodium hydroxide solution are added thereto by means of a microburette. Freeze-drying yields 540 mg of white crystals.

Di-N-methyl-D-glucaaine salt of the europium complex 1.96 g (10 mmol) of N-methyl-D-glucamine are added in portions, with stirring, to 3.31 g (5 mmol) of the europium complex in 40 ml of water. When the base has dissolved completely, freeze-drying is carried out. .63 g of a colourless crystalline compound remain. e) Iron(III) complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl )-4-(4-methoxybenzyl)-undecanedioic acid .13 g (10 mmol) of the complexing agent acid described in Example lb) are dissolved in approximately 30 ml of water, and 798 mg (5 mmol) of Fe2O3 are added thereto at 80*C. After 30 minutes, the almost clear solution is filtered and the filtrate is freeze-dried.

Yield: 5.66 g Analysis (based on anhydrous substance): calc.: C 46.66 H 4.98 N 7.42 Fe 9.86 found: C 46.71 H 5.03 N 7.38 Fe 9.81 Disodium salt of the iron(lll) complex The complex obtained as described above (425 mg, 0.75 mmol) is dissolved in 10 times the amount of water, and 1.5 al of a IN sodium hydroxide solution are added thereto by means of a microburette. Freeze-drying yields 460 mg of white crystals.

Di-N-methyl-D-glucaaine salt of the iron (III) complex 1.96 g (10 mmol) of N-aethyl-D-glucamine are added in portions, with stirring, to 2.83 g (5 mmol) of the iron (III) complex in 40 ml of water. When the base has dissolved completely, freeze-drying is carried out. 4.83 g of a colourless crystalline compound remain.

In an analogous manner, the bismuth complex is obtained in the fora of the disodium salt and in the form of the di-N-methyl-D-glucamine salt using bismuth oxide, BX2O3.

Example 2 a) 3,6,9-triaza-3,6,9-tris(tert.-butoxycarbonylmethyl)5-(4-methoxybenzyl)-undecanedioic acid di-tert.-butyl ester 3.9 g (5 mmol) of 3,6,9-triaza-3,6,9-tris(tert.-butoxycarbonylmethyl) -5- (4-hydroxybenzy 1) -undecanedioic acid di-tert.-butyl ester (Example I7d of DOS 3 710 730) are reacted in accordance with the procedure given in Example la) to yield 3.61 g (91% of the theoretical yield) of the title compound. calc.: C 63.53 H 9.01 N 5.29 found: C 63.59 H 9.07 N 5.27 b) 3,6,9-triaza-3,6,9-tris (carboxymethyl) -5-( 4-methoxybenzyl )-undecanedioic acid In accordance with the procedure given in Example lb), 3.18 g (4 mmol) of the tert.-butyl ester described in 5 Example 2a) are treated with trifluoroacetic acid and worked up. 1.62 g (79% of the theoretical yield) of a colourless lyophilisate are obtained. calc.: C 51.46 H 6.09 N 8.18 found: C 51.34 H 6.14 N 8.11 c) Gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl )-5-( 4-methoxybenzyl) -undecanedioic acid • 1.03 g (2 mmol) of the complexing agent acid described in Example 2b) are complexed with Gd2O3 in accordance with the procedure given in Example lc). 1.32 g (99% of the theoretical yield) of a colourless lyophilisate are obtained. calc.: C 39.57 H 4.23 N 6.29 Gd 23.55 found: C 39.51 H 4.19 N 6.25 Gd 23.61 The Τχ-relaxivity (1/mmol.sec) is in water 4.17 ± 0.14 in plasma 6.61 ± 0.18.

Exanple 3 a) 3,6,9-triaza-3,6,9-tris (tert. -butoxycarbonylmethy 1) 4-(4-( 4-me thoxy benzy loxy ) -benzyl ] -undecanedioic acid di-tert.-butyl ester ng (2.2 mmol) of 801 sodiun hydride are added to 1.56 g (2 mmol) of 3,6,9-triaza-3,6,9-tris(tert.-butoxycarbonylmethy 1 )-4-( 4-hydroxybenzyl) -undecanedioic acid di-tert.-butyl ester (Example 9f of DOS 3 710 730) in tetrahydrofuran at 0’C. 0.3 ml (2.2 mmol) of 4-me thoxybenzyl chloride is added thereto and the mixture is stirred overnight. Then water is added to the solution, tetrahydrofuran is distilled off and the aqueous emulsion is extracted with diethyl ether. The organic phase is washed with water, dried over Na2SO4 and concentrated.

The resulting colourless oil is chromatographed on silica gel (ether/hexane 1:1).

Yield: 1.17 g (651 of the theoretical yield) of a colourless oil. calc.: C 65.38 H 8.62 N 4.67 found: C 65.29 H 8.65 N 4.59 b ) 3,6,9-tr iaza-3, 6 ,9-tris ( carboxymethyl )-4-(4-(4methoxybenzyloxy ) -benzyl ] -undecanedioic acid 1.80 g (2 mmol) of the tert.-butyl ester described in Example 3a) are treated with trifluoroacetic acid analogously to the procedure given for Example lb) and reacted to yield 905 mg (731 of the theoretical yield) of a colourless, flocculent lyophilisate. calc.: C 56.21 H 6.02 N 6.78 found: C 56.10 H 5.98 N 6.82 c) Gadolinium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl )-4-(4-( 4-methoxybenzyloxy) -benzyl ] -undecanedioic acid 620 mg (1 mmol) of the complexing agent acid described in Example 3b) are complexed and worked up analogously to the procedure given for Example lc), yielding 758 mg (98% of the theoretical yield). calc.: C 45.01 H 4.43 N 5.43 Gd 20.32 found: C 44.93 H 4.49 N 5.37 Gd 20.18 The Τχ-relaxivity (1/mmol.sec) is in water 4.23 ± 0.16 in plasma 6.99 ± 0.13.

Example 4 a) Diethyl phosphate of 3,6,9-triaza-3,6f 9-tris (tert.butoxycarbony lmethyl) -4-( 4-hydroxybenzyl) -undecanedioic acid di-tert.-butyl ester 11.2 g (14.36 mmol) of the phenol described in DOS 3 710 730 (Example 9f) are dissolved in 100 ml of absolute tetrahydrofuran (THF). 380 mg (15.8 mmol) of sodium hydride (prepared from 50% NaH in paraffin oil by washing three times with 10 ml of THF) are added thereto. After 30 minutes at room temperature, 2.60 g (15.0 mmol) of phosphoric acid diethyl ester chloride are added and the mixture is stirred for 24 hours at room temperature.

The solution is diluted with 500 ml of ether and washed three times with 300 ml of 10% sodium hydroxide solution. After drying the organic phase over magnesium sulphate, concentration is carried out in vacuo and the residue is 2* purified by flash chromatography (eluant: ether/hexane l:l).

Yield: 11.97 g (91% of the theoretical yield) of a pale yellow oil. calc.: C 59.00 H 8.58 N 4.59 P 3.38 found: C 58.88 H 8.63 N 4.63 P 3.30 b) 3,6,9-triaza-3,6,9-tris(tert.-butoxycarbonylmethyl)4-benzyl-undecanedioic acid di-tert.-butyl ester A mixture of 1.33 g (8.62 mmol) of anhydrous titanium(III) chloride and 1.02 g (26.09 mmol) of finely cut potassium in 20 ml of tetrahydrofuran is heated under reflux for one hour under an argon atmosphere.

A solution of 11.5 g (12.55 mmol) of the compound described in Example 4a) in 50 ml of tetrahydrofuran is added dropwise to that mixture over a period of 15 minutes. Then the mixture is heated under reflux for 8 hours. The mixture is cooled in an ice-bath, 20 ml of methanol and then 100 ml of water are added carefully, and extraction is carried out three times with 200 ml of ether. The organic phases are dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel (eluant: hexane/ether 2:1). 8.9 g (93% of the theoretical yield) of the title compound are obtained in the form of a colourless oil which crystallises when left to stand. calc.: C 64.46 H 9.10 N 5.50 found: C 64.54 H 9.15 N 5.41 c) 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-benzy1undecanedioic acid 7.64 g (10 mmol) of the tert.-butyl ester described in Example 4b) are reacted analogously to the procedure given for Example lb) to yield 4.01 g (83% of the theoretical yield) of the title compound. calc.: C 52.17 H 6.05 N 8.69 found: C 52.23 H 5.99 N 8.73 d) Gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl )-4-benzy1-undecanedioic acid 2.42 g (5 mmol) of the complexing agent acid described in Example 4c) are reacted analogously to the procedure given in Example lc) to yield 3.14 g (98.5% of the theoretical yield) of the title compound. The gadolinium complex is obtained in the form of a colourless, flocculent lyophilisate. calc.: C 39.55 H 4.11 N 6.59 Gd 24.66 found: C 39.47 H 4.19 N 6.52 Gd 24.88 The Τχ-relaxivity (1/mmol.sec) is in water 4.54 ± 0.13 in plasma 6.89 ± 0.17.

Ytterbium complex of 3,6,9-tr iaza-3,6,9-tris (carboxymethyl )-4-benzyl-undecanedioic acid Analogously to the procedure for preparing the gadolinium complex, the corresponding ytterbium complex is obtained when Yb2O3 is used instead of Gd2O3.

Example 5 a) 3,6,9-triaza-3,6,9-tr is (tert. -butoxycarbony Imethy 1) 4-benzyloxymethyl-undecanedioic acid di-tert.-butyl ester 7.2 ml (60 mmol) of benzyl bromide are added dropwise at room temperature, over a period of 30 minutes, to a thoroughly stirred suspension of 14.1 g (20 mmol) of the 4-hydroxymethyl-3,6,9-triaza-3,6,9-tr is (tert. -butoxycarbony Imethy 1)-undecanedioic acid tert.-butyl diester described in DOS 3 710 730 (Example 37d) and 0.3 g of tetrabutylammonium hydrogen sulphate in 200 ml of dichloromethane/200 ml of 30% sodium hydroxide solution. The mixture is then stirred for 8 hours. 400 ml of water are added to the suspension, the organic phase is separated off and the aqueous phase is extracted twice with 150 ml of dichloromethane each time. After drying the combined organic phases over magnesium sulphate, the product is chromatographed on silica gel (ether/hexane 1:1). 13.0 g (82% of the theoretical yield) of the title compound are obtained in the form of a colourless oil. calc.: C 63.53 H 9.01 N 5.29 found: C 63.42 H 9.07 N 5.21 b) 3,6,9-triaza-3,6,9-tris(carboxymethyl) -4-benzyloxyethyl-undecanedioic acid 7.94 g (10 mmol) of the tert.-butyl ester described in Example 5a) are reacted with trifluoroacetic acid analogously to the procedure given for Example lb) to yield 4.06 g (79% of the theoretical yield) of the title compound. calc.: C 51.46 H 6.09 N 8.18 found: C 51.51 H 6.06 N 8.12 c) Gadolinium complex of 3,6,9-tr iaza-3,6,9-tr is (carboxymethyl )-4-benzyloxymethyl-undecanedioic acid 2.57 g (5 mmol) of the complexing agent acid described in Example 5b) are reacted analogously to the procedure given for Example lc) to yield 3.30 g (98.9% of the theoretical yield) of the title compound. A colourless, flocculent solid is obtained. calc.: C 39.57 H 4.23 N 6.29 Gd 23.55 found: C 39.51 H 4.26 N 6.35 Gd 23.27 The Tj-relaxivity (1/mmol.sec) is in water 4.39 ± 0.12 in plasma 6.31 ± 0.15.

Example 6 a) 3,6,9-triaza-3,6,9-tris (tert. -butoxycarbonylmethyl) 4-(4-carboxyaethoxybenzy1) -undecanedioic acid bis(tert.-butyl) ester 2.7 g (90 mmol) of 80% sodium hydride are added to 20 23.40 g (30 mmol) of 3,6,9-triaza-3,6,9-tris(tert.butoxycarbony lmethyl) -4- (4-hydroxybenzyl) -undecanedioic acid di-tert.-butyl ester (Example 9f of DOS 3 710 730) in tetrahydrofuran at 0’C. 6.25 g (45 mmol) of bromoacetic acid in tetrahydrofuran are added dropwise thereto and the mixture is stirred for one hour at O’c and overnight at room temperature.

Then water is added to the solution, tetrahydrofuran is distilled off and the aqueous phase is extracted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated.

The residue is chromatographed on silica gel using the eluant mixture dioxane/methanol/triethylamine (15:4:1); the combined fractions are concentrated and partitioned between ethyl acetate and IN citric acid. The organic phase is then dried over sodium sulphate and concentra1q ted, yielding 21.8 g (87% of the theoretical yield) in the form of a colourless oil. calc.: C 61.63 H 8.54 N 5.01 found: C 61.62 H 8.62 N 4.95 b) 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- ( 4-carboxy15 methoxybenzyl)-undecanedioic acid 21.0 g (25 mmol) of the tert.-butyl ester described in Example 6a) are reacted analogously to the procedure given for Example lb) to yield 11.0 g (78.9% of the theoretical yield) of the title compound. calc.: C 49.55 H 5.60 N 7.54 found: C 49.31 H 5.51 N 7.47 c) Gadolinium complex of 3,6,9-triaza-3,6,9-tris (carboxy methyl) -4- ( 4-carboxymethoxybenzy 1)-undecanedioic acid .57 g (10 mmol) of the complexing agent acid described in Example 6b) are reacted analogously to the procedure given for Example lc) to yield 7.01 g (98.5% of the theoretical yield) of the title compound. calc.: C 38.81 H 3.96 N 5.90 Gd 22.09 found: C 38.75 H 3.89 N 5.97 Gd 21.93 The Τχ-relaxivity (1/mmol.sec) is in water 5.00 ± 0.01 in plasma 7.10 ± 0.08.

Example 7 Preparation of a solution of the sodium salt of the gadolinium(III) complex of 3,6,9-triaza-3,6,9-tris( carboxymethyl) -4-benzyloxymethyl-undecanedioic acid 6.68 g (10 mmol) of the gadolinium complex obtained according to Example 5c) are dissolved in 70 ml of water pro injectione (p.i.), and IN sodium hydroxide solution is added dropwise until a pH of 7.2 is reached. After the addition of 0.02 g of tromethamine, the solution is 1^ made up to 100 ml with water p.i., introduced into bottles and heat-sterilised.

Example 8 a ) 3,6,9-triaza-3,6,9-tris (tert. -butoxycarbonylmethyl) 4—(4—ethoxybenzyl)—undecanedioic acid di-tert.-butyl diester 0.30 g (10 mmol) of 80% sodium hydride is added to 5.85 g (7.5 mmol) of 3,6,9-tr iaza-3,6,9-tr is (tert.-butoxycarbony lmethyl ) -4- (4-hydroxybenzyl) -undecanedioic acid di-tert.-butyl diester (Example 9f of DOS 3 710 730) in 100 ml of tetrahydrofuran at O'C. 1.56 g (10 mmol) of iodoethane are added thereto and the mixture is stirred for 3 hours. Then water is added to the solution, tetrahydrofuran is distilled off and the aqueous emulsion is extracted with diethyl ether. The crude product obtained after drying over sodium sulphate and concentrating the solvent is chromatographed on silica gel (system: hexane/ether/triethylamine 70:30:5).

Yield: 4.0 g (66%) Analysis (based on anhydrous substance): calc.: C 63.91 H 9.11 N 5.20 found: C 63.67 H 9.05 K 5.28 b) 3,6,9-triaza-3,6,9-tris (carboxymethyl)-4-( 4-ethoxybenzy 1) -undecanedioic acid 3.64 g (4.5 mmol) of the tert.-butyl ester described in Example 8a) are dissolved in 25 ml of trifluoroacetlc acid, the solution is stirred at room temperature for one hour and working up is carried out analogously to Example lb).

Yield: 1.2 g (50.6%) χ Analysis (based on anhydrous substance): calc.: C 52.36 H 6.31 N 7.97 found: C 52.21 H 6.39 N 7.84 c) Disodium salt of the gadolinium complex of 3,6,9triaza-3,6,9-tris ( carboxymethyl) -4- ( 4-ethoxybenzy 1) undecanedioic acid 528 mg (1 mmol) of the complexing agent acid described in the preceding Example are dissolved in 40 ml of water and complexed at 80*C with 181 mg (0.5 mmol) of Gd2O3. Then the mixture is neutralised with 2 ml of IN NaOH, stirred with activated carbon and filtered, and the filtrate is freeze-dried.

Yield: 700 mg (96.5%) i Analysis (based on anhydrous substance): calc.: c 38.06 H 3.89 Gd 21.67 N 5.79 Na 6.34 found: C 37.91 H 3.99 Gd 21.30 N 5.69 Na 6.57 The Tj-relaxivity (1/nmol.sec) is 5 in water 5.33 ± 0.13 in plasma 8.69 ± 0.53.

The corresponding europium complex is obtained in an analogous manner using europium oxide, Eu2O3: calc.: C 38.34 H 3.92 Eu 21.09 N 5.83 Na 6.38 10 found: C 38.20 H 4.01 EU 20.87 N 5.79 Na 6.49 The corresponding iron complex is obtained in an analogous manner using iron oxide, Fe2O3: calc.: C 44.25 H 4.52 Fe 8.95 N 6.73 Na 7.37 found: C 44.17 H 4.59 Fe 8.52 N 6.81 Na 7.49 Example 9 a) 3,6,9-triaza-3,6,9-tris (tert. -butoxycarbonyImethy 1) 4-(4-butoxybenzyl)-undecanedioic acid di-tert.-butyl diester .85 g (7.5 mmol) of 3,6,9-triaza-3,6,9-tris(tert.2 0 butoxycarbony lmethyl) -4- (4-hydroxybenzyl) -undecanedioic acid di-tert.-butyl diester (Example 9f of DOS 3 710 730) are reacted analogously to Exaaple 8a) with 1.84 g (10 mmol) of 1-iodobutane and worked up as described in that Example.

Yield: 4.1 g (65.4%) Analysis (based on anhydrous substance): calc.: C 64.64 H 9.28 N 5.03 found: C 64.82 H 9.37 N 4.96 b) 3,6,9-tr iaza-3,6,9-tris (carboxymethyl )-4-( 4-butoxybenzyl) -undecanedioic acid 3.34 g (4 araol) of the tert.-butyl ester described in Exanple 9a) are dissolved in 20 ml of trifluoroacetic acid, the solution is stirred for one hour at room temperature and working up is carried out analogously to Example lb).

Yield: 1.36 g (61.0%) Analysis (based on anhydrous substance): calc.: C 54.04 H 6.71 N 7.57 found: C 53.88 H 6.63 N 7.41 c) Disodiua salt of the gadolinium complex of 3,6,9triaza-3,6,9-tris ( carboxymethyl )-4-( 4-butoxybenzyl) undecanedioic acid ml of water are added to 556 mg (1 mmol) of the complexing agent acid described in the preceding Example, and the mixture is complexed at 80 c with 181 mg (0.5 mmol) of Gd2O3. Then the mixture is neutralised with 2 ml of IN NaOH, stirred with activated carbon and filtered, and the filtrate is freeze-dried.

Yield: 711 mg (94.3%) Analysis (based on anhydrous substance): calc.: C 39.83 H 4.28 Gd 20.86 N 5.58 Na 6.10 found: C 39.61 H 4.35 Gd 20.51 N 5.49 Na 6.17 The Tj^-relaxivity (1/nmol.s) is in water 5.80 ± 0.26 in plasma 14.20 ± 0.98.

The corresponding europium complex is obtained in an analogous manner using europium oxide, EU2O3: calc.: C 40.11 H 4.31 Eu 20.30 N 5.61 Na 6.14 found: C 39.97 H 4.39 Eu 20.02 N 5.72 Na 6.25 The corresponding iron complex is obtained in an analogous manner using iron oxide, Fe2O3: calc.: C 46.03 H 4.94 Fe 8.56 N 6.44 Na 7.05 found: C 45.88 H 5.03 Fe 8.30 N 6.50 Na 7.11 Example 10 a) 3,6,9-triaza-3,6,9-tris(tert.-butoxycarbony lmethyl)4-( 4-benzy loxybenzyl) -undecanedioic acid di-tert.butyl diester .85 g (7.5 nmol) of 3,6,9-triaza-3,6,9-tris(tert.butoxycarbony lmethy 1 )-4-( 4-hydroxybenzyl) -undecanedioic acid di-tert.-butyl diester (Example 9f of DOS 3 710 730) are reacted analogously to Example 8a) with 1.71 g (10 mmol) of benzyl bromide and worked up as described in that Example.

Yield: 4.9 g (75.1%) Analysis (based on anhydrous substance): calc.: C 66.25 H 8.69 N 4.83 found: C 66.14 H 8.77 N 4.83 b) 3,6,9-triaza-3,6,9-tris ( carboxymethyl )-4-( 4-benzyloxybenzyl)-undecanedioic acid 3.48 g (4 mmol) of the tert.-butyl ester described in Example 10a) are dissolved in 20 ml of trifluoroacetic acid, the solution is stirred for one hour at room temperature and working up is carried out analogously to Example lb).

Yield: 1.33 g (56.5%) Analysis (based on anhydrous substance): calc.: C 57.04 H 5.98 N 7.13 found: C 56.89 H 6.03 N 7.21 c) Disodium salt of the gadolinium complex of 3,6,9triaza-3,6,9-tris ( carboxymethyl )-4-( 4-benzyloxybenzyl)-undecanedioic acid ml of water and 1 ml of IN NaOH are added to 590 mg (1 mmol) of the complexing agent acid described in the preceding Example, and the mixture is* complexed at 80"C with 181 mg (0.5 mmol) of Gd2O3. Then the mixture is neutralised with a further 1 ml of IN NaOH, stirred with activated carbon and filtered, and the filtrate is freeze-dried.

Yield: 703 mg (89.2%) Analysis (based on anhydrous substance): calc.: C 42.69 H 3.84 Gd 19.96 N 5.33 Na 5.84 found: C 42.63 H 3.91 Gd 19.57 N 5.26 Na 5.99 The Τχ-relaxivity (1/mmol.sec) is in water 5.81 ± 0.11 in plasma 16.35 ± 1.01.

The corresponding europium complex is obtained in an analogous manner using europium oxide, EU2O3: calc.: C 42.98 H 3.86 Eu 19.42 N 5.37 Na 5.88 found: C 43.10 H 3.91 Eu 19.13 N 5.27 Na 5.99 The corresponding iron complex is obtained in an analogous manner using iron oxide, Fe2O3: calc.: C 48.99 H 4.41 Fe 8.14 N 6.12 Na 6.70 found: C 48.73 H 4.57 Fe 8.29 N 6.03 Na 6.85 Examples for in vivo NMR diagnostics With the aid of a nuclear spin tomograph from General Electric, which had been developed specifically for animal research, images were recorded at various times following administration to rats of the disodium salt of the gadolinium complex of Example lc)? Using the nuclear spin tomograph (CSI 2 T), spin-echo images were recorded at 2 tesla (Tr time of 400 ms and Te time of 20 ms). The layer thickness of the T3-weighted image sequence was 3 mm, and the image matrix was 128 x 128.

The contrast agent was administered intravenously into a tail vein of a naked male rat (Lew/Mol), weight 190 g, at a dose of 0.06 mmol/kg. The animal had a Brown-Pearce tumour in the upper thigh and was narcotised for the purposes of the investigation by the i.m. administration of Ketavet/Rompun.

In the coronary blank exposure (baseline, No. 1), various dark structures are visible in the abdomen. It was not possible to distinguish between the intestinal lumen and the stomach.

One minute after administration (No. 2), the first enhancement is already visible in the bladder. A pronounced increase in contrast is visible in the stomach 45 minutes p.i. (No. 3). 60 minutes p.i. (No. 4), a good image of the tumour (at the level of the reference tube), of the bladder and of the stomach can be observed. Moreover, contrasting of the intestine can also be seen. As a result, it is possible to distinguish between the intestinal loop, fat and lymph nodes (lymphomas). The contrasting of the pelvis of the kidney is also noticeable, and that can be seen even more clearly 65 minutes p.i. in a slightly different layer (No. 5). In Figure No. 6, 180 minutes p.i., the contrast enhancement is clearly visible also in an axial image in the region of the liver. This enables the stomach, liver, duodenum and pancreas to be distinguished.

Example-2.

The test animals were female rats of the Lew/Mol strain weighing from 160 to 180 g. Before the imaging, the animals were narcotised (Rompun(R) + Ketavet(R)) and provided with a catheter in the tail vein for administration of the contrast agent. The imaging was carried out in an MRI experimental apparatus from General Electric (field strength 2 tesla). Firstly, the images (7, 9, 11) without contrast agent were produced with a T3-weighted spin-echo sequence (Tr = 400 msec, Te = 20 msec, axial plane of section, layer thickness 3 mm). The liver appears in each case with the normal signal intensity; the stomach is naturally darker than the liver. In the case of animal 1, parts of the stomach have a very high - 37 signal intensity. This is due to remains of food containing relatively high concentrations of manganese (at the time of the study the animals had not received any food for 6 hours). An osteogenic sarcoma had been implanted into animal 3 three weeks previously; the baseline image shows the sarcoma having the same density and being not distinguishable. The contrast agent was administered via the vein catheter at a dose of 0.1 mmol of Gd/kg (cone, of the solutions 0.05 mmol of Gd/ml in 0.9% NaCl) for all 3 substances.

For all 3 substances, a marked enhancement of the liver is to be noted after 90 minutes [Fig. 8, Example 8c)] or 60 minutes p.a. [Fig. 10, Example 9c); Fig. 12, Example 10c) ], which enhancement is attributable to absorption by the hepatocytes and cannot be observed at this time after administration with the only contrast agent hitherto available commercially for nuclear spin tomography, Magnevist(R). In the case of animal 3 [Fig. 12, Example 10c)], the tumour, which has not absorbed the contrast agent or has absorbed it to a' lesser extent, is also clearly visible at that time.

Furthermore, a pronounced enhancement of the stomach is observed with all substances - most clearly in the case of Example 10c) and least clearly in the case of Example 8c). This provides additional diagnostic possibilities with regard to improved distinction between the liver and the stomach.

Claims (15)

1. Compounds of the general formula I XOOCCHg ch 2 coox (I) XOOCCHjj CHjCOOX in which Z 1 and Z 2 each independently of the other represent a hydrogen atom or the radical wherein m and n represent the numbers 0 to 20, k, 1, q and r represent the numbers 0 and 1, and R represents a hydrogen atom, an optionally OR 1 substituted Cj-Chalky1 radical or a group CHjCOOR 1 wherein R 1 represents a hydrogen atom, a C 2 -Cgalkyl radical or a benzyl group, and X represents a hydrogen atoa and/or a metal ion equivalent of an element of atomic numbers 21-29, 42, 44 or 57-83, with the proviso that at least two of the X substituents represent a metal ion equivalent, that one of the substituents Z 1 and Z 2 represents a hydrogen atom and the other does not represent a hydrogen atom, that when n and 1 each represent the number 0 - k and r do not at the same time each represent the number 1, that Z 1 or Z 2 does not represent -CH 2 -C 6 H 4 -O-CH 2 -COOCH 2 CgH5 or -ch 2 -c 6 h 4 -o-(ch 2 )5-cooch 2 c 6 h 5 , that -(O) r -R does not represent -OH, that Z 1 does not represent •H and that the sum of q and 1 gives the number 1 or 2, and their salts with inorganic and/or organic bases, amino acids or amino acid amides.

2. Compounds according to claim 1, characterised in that Z 1 represents a hydrogen atom and Z 2 represents the radical -(CH 2 ) m -(C 6 H 4 ) q -(O) k -(CH 2 ) n -(C 6 H 4 ) 1 -(O) r -R.

3. Compounds according to claim 1, characterised in that *5 Z 2 represents a hydrogen atom and Z 1 represents the radical -(CH 2 ) B -(C 6 H 4 ) q -(O) k -(CH 2 ) n -(C 6 H 4 ) r (O) r -R.

4. Compounds according to claim 1, characterised in that Z 1 or Z 2 represents the radicals -CH 2 -C 6 H 4 -OCH3, -ch 2 -c 6 h 5 , -ch 2 -c 6 h 4 -o-ch 2 -c 6 h 4 -och 3 , -ch 2 -o-ch 2 -c 6 h 5 , io -ch 2 -c 6 h 4 -o-ch 2 -cooh, -ch 2 -c 6 h 4 -oc 2 h 5 , -ch 2 -c 6 h 4 -oc 4 h 9 , -ch 2 -c 6 h 4 -o-ch 2 -c 6 h 5 .

5. The compounds according to claim 1: gadolinium complex of 3,6,9-tr iaza-3,6,9-tr is (carboxymethyl )-4-(4-methoxybenzyl)-undecanedioic acid; 15 europium complex of 3,6,9-tr iaza-3,6,9-tr is (carboxymethyl ) -4- (4-methoxybenzyl) -undecanedioic acid; iron (III) complex of 3,6,9-tr iaza-3,6,9-tris (carboxymethyl )-4-( 4-methoxybenzyl) -undecanedioic acid; bismuth complex of 3,6,9-tr iaza-3,6,9-tr is (car boxy20 methyl)-4-(4-methoxybenzyl)-undecanedioic acid; gadolinium complex of 3,6,9-tr iaza-3,6,9-tris (carboxymethyl )-5-( 4-methoxybenzyl) -undecanedioic acid; gadolinium complex of 3,6,9-tr iaza-3,6,9-tr is (carboxymethyl ) -4- [4-( 4-methoxybenzyloxy)-benzyl ]-undecanedioic 25 acid; gadolinium complex of 3,6,9-triaza-3,6,9-tr is ( carboxymethyl )-4-benzyl-undecanedioic acid; ytterbium complex of 3,6,9-tr iaza-3,6,9-tr is (carboxymethyl )-4-benzyl-undecanedioic acid; - 30 gadolinium complex of 3,6,9-tr iaza-3,6,9-tr is (carboxymethyl )-4-benzyloxymethy 1-undecanedioic acid; gadolinium complex of 3,6,9-tr iaza-3,6,9-tris (carboxymethyl ) -4- (4-carboxymethoxybenzyl) -undecanedioic acid; gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl )-4-(4-ethoxybenzyl)-undecanedioic acid; europium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl )-4-( 4-ethoxybenzyl )-undecanedioic acid; iron complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4(4-ethoxybenzyl)-undecanedioic acid; gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl ) -4- (4-butoxybenzyl) -undecanedioic acid; europium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl )-4-( 4-butoxybenzyl) -undecanedioic acid; iron complex of 3,6,9-tr iaza-3,6,9-tris (carboxymethyl )-4( 4-butoxybenzyl) -undecanedioic acid; gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl )-4-( 4-benzyloxybenzyl) -undecanedioic acid; europium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl )-4-(4-benzyloxybenzyl)-undecanedioic acid; iron complex of 3,6,9-tr iaza-3,6,9-tr is (carboxymethyl )-4( 4-benzyloxybenzyl) -undecanedioic acid.

6. Pharmaceutical agents comprising at least one physioX logically tolerable compound according to claims 1 to 5, optionally together with additives customary in galenic pharmacy.

7. Use of at least one physiologically tolerable compound according to claim 1 for the preparation of agents for NMR and X-ray diagnostics and radiotherapy.

8. Use of at least one physiologically tolerable compound according to claims 1 to 5 for the preparation of agents for NMR diagnostics of the renal and hepatobiliary system.

9. Use of at least one physiologically tolerable compound according to claim 1 for the preparation of agents for NMR diagnostics of the gastrointestinal tract. 4 1

10. Process for the preparation of compounds of the general formula I XOOCCH z’ Z Z CM COOX CM,COOX I 2 I I I 2 I 2 N-CM-CH-N-CH -CH ,-N I 2 2 I XOOCCH, CM,coox z *· in which 5 Z 1 and Z 2 each independently of the other represent a hydrogen atom or the radical -(CHjin-iCeH^q-iOJfc-iCHain-iCeH^x-iOJr-R, wherein m and n represent the numbers 0 to 20, 10 k, 1, q and r represent the numbers 0 and 1, and R represents a hydrogen atom, an optionally OR 1 substituted C^-Cgalkyl radical or a group CHjCOOR 1 wherein R 1 represents a hydrogen atom, a C^-Cgalkyl radical or a benzyl group, 15 and X represents a hydrogen atom and/or a metal ion equivalent of an element of atomic numbers 21-29, 42, 44 or 57-83, with the proviso that at least two of the X substituents 2o represent a metal ion equivalent, that one of the substituents Z 1 and Z 2 represents a hydrogen atom and the other does not represent a hydrogen atom, that when n and 1 each represent the number 0 - k and r do not at the same time each represent the number 1, that Z 1 25 or Z 2 does not represent -CH 2 -CeH 4 -O-CH 2 -COOCH2CgH5 or -CH 2 -C 6 H 4 -O-(CH 2 ) 5 -COOCH 2 C 6 H 5 , that -(0) r -R does_ not represent -OH, that Z 1 does not represent -C-S—» and that the sum of q and 1 gives the number 1 or 2, and their salts with inorganic and/or organic bases, 30 amino acids or amino acid amides. - 42 characterised in formula II that a compound of the general a 2 oocc.H, Z J Crt,cooe 2 CH ? C00e 1 rt- 2 1 S^OOCCH, 1 1 1 1 C rt-C rt-N-C rt 7 --C H - -N 1 Crt^cooi (II), in which R 2 represents an acid-protecting group, and Z 3 and Z 4 each represent a hydrogen atom or the radical -(CH 2 )m“( c 6 H 4)q-OH, with the proviso that one of the substituents Z 3 and Z 4 represents a hydrogen atom and the other represents the mentioned radical, is converted in a manner known Efir Sfi into a compound containing the radical mentioned for Z 1 and Z 2 , the acidprotecting groups R 2 are removed, the resulting complexing agent acids of the general formula I* wherein X represents a hydrogen atom are reacted with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 42, 44 or 57-83, and then - if desired - acidic hydrogen atoms that are present are replaced by cations of inorganic and/or organic bases, amino acids or amino acid amides.

11. Process for the preparation of the pharmaceutical agents according to claim 6, characterised in that the complex compound dissolved or suspended in water, physiological saline solution or physiological protein solution, optionally together with additives customary in galenic pharmacy, is brought into a form suitable for enteral or parenteral administration.

12. A compound substantially as hereinbefore described with reference to the examples and drawings.

13. A pharmaceutical agent substantially as hereinbefore described with reference to the examples and drawings. 5

14. A use substantially as hereinbefore described with reference to the examples and drawings.

15. A process substantially as hereinbefore described with reference to the examples and drawings.