DD296276B5 - Derivatized DTPA complexes, pharmaceutical compositions containing these compounds, their use and methods for their preparation - 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

Field of application of the invention

The invention relates to novel complexes and complex salts, to agents containing these compounds, to their use in NMR diagnosis and to processes for the preparation of these compounds and agents.

Characteristic of the known state of the art

Metal complexes have been considered as contrast media for radiology since the early 1950s. However, the compounds used at that time were so toxic that their use in humans was out of the question. It was therefore quite surprising that certain complex salts proved to be sufficiently compatible so that routine human use for diagnostic purposes could be considered. As the first representative of this class of substance, the dimeglumine salt of Gd DTPA (gadolinium III complex of diethylenetriaminepentaacetic acid) described in European Patent Application Publication No. 71564 has proved to be very effective as a contrast agent for magnetic resonance imaging. It has been registered as the world's first NMR diagnostic device under the name Magnevist®.

Magnevist® is particularly well suited for the diagnosis of pathological areas (eg inflammation, tumors, infarcts, etc.). After intravenous injection, the compound distributes extracellularly and is eliminated by glomerular secretion via the kidneys. Passage of intact cell membranes and extrarenal secretion are virtually unnoticed. Especially for patients with impaired renal function, in which Magnevist * is excreted only very slowly and can only be removed from the organism with the help of a dialysis machine, it would be desirable to use contrast agents that show at least partial extrarenal excretion.

Object of the invention

The invention eliminates the disadvantages of the prior art.

Explanation of the essence of the invention

There is therefore a need for NMR contrast agents that exhibit a different pharmacokinetic behavior than Magnevist *. The invention is therefore based on the object to provide such compounds and means available and to provide a method for their preparation. This object is achieved by the present invention.

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

Surprisingly, however, elimination via the bile is not the only extra-renal excretory pathway; in NMR studies in rats after intravenous administration of the compounds of the invention unexpectedly also a contrast enhancement of the liver and the stomach was observed. The kidneys and implanted tumors are also better contrasted.

Such a phenomenon has hitherto not been described by any contrast agent for magnetic resonance imaging. The excretion (secretion) via the stomach has the advantage that a delineation of abdominal structures (eg pancreas) from the gastrointestinal tract with simultaneous contrast enhancement of pathological processes (tumors, inflammations) is made possible without an additional oral administration. In addition, a representation of the gallbladder and biliary tract can also be achieved. In the diagnosis of the stomach, such compounds are of great advantage, since in addition to the improved visualization of ulcioses and gastric carcinomas, it is also possible to check gastric secretion with the aid of imaging methods. By providing the compounds according to the invention it is thus possible to assist both kidney-deficient patients and those suffering from gastrointestinal diseases (at least 10% of the population in the western industrialized countries). Most of these patients, as well as a large number of patients suspected of having such a condition, must undergo diagnostic tests. At present, two suitable methods are the most common: Endoscopy and X-ray diagnostics with the aid of barium contrast agents. These studies have several disadvantages: they involve the risk of radiation exposure, trauma-causing, inconvenience, occasionally even risks to the patient, and may therefore cause psychological stress. They usually have to be performed repeatedly, are relatively time-consuming to perform, require the active cooperation of the patient (eg taking a certain posture) and are often not applicable to frail and risky patients.

The task of providing new diagnostic methods for the detection and localization of gastrointestinal diseases, which do not possess these disadvantages, is therefore also solved by the complex compounds and compositions according to the invention.

Even without specific measures, their pharmacokinetics allows them to improve the diagnosis of many diseases. For the most part, the complexes are excreted unchanged and rapidly, so that even in the case of the use of relatively toxic metal ions, no harmful effects are observed, even at high doses. The practical application of the new complexes is also facilitated by their favorable chemical stability. The compounds according to the invention are characterized by the general formula I.

XOOCCH ₂ Z ¹ Z ² CH ₂ COOX CH ₂ COOX

I I I I

N CH CH N CH ₂ -CH ₂ -N (I),

I i

XOOCCH ₂ CH ₂ COOX

wherein

Z ¹ and Z ² independently of one another represent a hydrogen atom or the radical

wherein

m and η the numbers 0-20, k, I, q and r are the numbers O and 1 and

R is a hydrogen atom, an optionally OR ¹ -substituted C _r C ₆ -alkyl radical or a CH ₂ COOR ¹ group with R ¹ meaning a hydrogen atom, a C ¹ -C ₆ -alkyl radical or a benzyl radical,

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 substituents X are a metal ion equivalent, that one of the substituents Z ¹ and Z ^{2 is} a hydrogen atom and the other is not a hydrogen atom of q and I, the number 1 or 2 shows that - if η and I are each the number O - к and r are not the same time each number 1, that Z ¹ and Z ² not for -CH ₂ -C ₆ H ₄ -O-CH ₂ -COOCH ₂ C ₆ H ₆ , -CH ₂ -C ₆ H ₄ -O- (CH ₂ ) ₅ -COOCH ₂ C ₆ H ₅ or -CH ₂ -C ₆ H ₄ -OH, and their salts with inorganic and / or bases, amino acids or amino acid amides.

If the agent according to the invention is intended for use in NMR diagnosis, the central ion of the complex salt must be paramagnetic. These are in particular the divalent and trivalent ions of the elements of atomic numbers 21-29, 42, 44 and 58-70. Examples of suitable ions are the chromium (III), manganese (II), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III ), Samarium (III) and ytterbium (III) ion. Because of their very strong magnetic moment, the gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III) and iron (III) ions are particularly preferred. 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 of a higher atomic number in order to achieve sufficient absorption of the X-rays. It has been found that for this purpose diagnostic agents containing a physiologically acceptable complex salt with central ions of elements of atomic numbers between 21-29, 42, 44, 57-83 are suitable; these are, for example, the lanthanum (III) ion and the abovementioned ions of the lanthanide series

 The numbers standing for m and η are preferably 0 to 5.

As the alkyl substituents R and R ¹ are straight-chain or branched hydrocarbons having up to 6, preferably up to 4, carbon atoms, which in the case of R optionally by one or more, preferably 1 to 3, hydroxy or C ₁ -C ₆ - preferred Ci ~ C ₄ alkoxy groups are substituted, in question.

Examples of optionally substituted alkyl groups are methyl, hydroxymethyl, ethyl, 2-hydroxyethyl, 2-hydroxy-1- (hydroxymethyl) ethyl, 1- (hydroxymethyl) ethyl, propyl, isopropyl, 2 and 3-hydroxypropyl, 2,3-dihydroxypropyl, n-, sec- and tert-butyl, 2-, 3-, and 4-hydroxybutyl, 2- and 3-hydroxyisobutyl, pentyl, 2-, 3- and 4-hydroxy-2-methylbutyl, 2,3,4-trihydroxybutyl, 1,2,4-trihydroxybutyl, cyclopentyl, cyclohexyl, 2,3,4,5,6- Pentahydroxyhexylgruppe and-in the case of the hydroxyalkyl groups -deren C ₁ -C ₆ -, preferably C ₁ -C ₄ -AlkVlderivate called. Preferred substituents Z ¹ and Z ^{2 of} the compounds of the invention are the CH ₂ -C ₆ H ₄ -OCH ₃ ^ -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 -, -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 -OC ₄ H ₉ -, -CH ₂ -C ₆ H ₄ -O-CH ₂ -C ₆ H ₅ - remainder.

As additional preferred substituent Z ¹ or Z ² for use as means for the NMR diagnosis of the gastrointestinal tract, the -CHz-C ₆ H ₄ OH-ReSt may be mentioned.

If not all acidic hydrogen atoms are substituted by the central ion, one, several or all of the remaining hydrogen atom (s) may be replaced by cations of inorganic and / or organic bases or amino acids. Suitable inorganic cations are, for example, the lithium ion, the potassium ion, the calcium ion, the magnesium ion and in particular the sodium ion. Suitable cations of organic bases include those of primary, secondary or tertiary amines, such as ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine and especially N-methylglucamine. Suitable cations of amino acids are, for example, those of lysine, arginine and 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 by reacting, in a manner known per se, compounds of the general formula II

R ² OOCCH ₂ Z ³ Z * CH ₂ COOR ² CH ²

N CH CH N CH ₂ CH ₂

² OOCCH CHCOOR ²

R ² OOCCH CH ₂ COOR

wherein R ²

R ^{2 for an} acid protecting group,

Z ³ and Z ⁴ each represent a hydrogen atom or the residue (CH ₂ ) _m - (C ₆ H ₄ ) _q -OH, with the proviso that one of the substituents

Z ³ and Z * represent a hydrogen atom and the other represents the stated radical,

converted into a compound with the radical indicated for Z 'and Z ² , the acid protecting groups R ² split off, the complexing acids of general formula I thus obtained with X meaning a hydrogen atom (formula I') with at least one metal oxide or metal salts Elements of atomic numbers 21-29,42,44oder 57-83 and then-if desired-existing acidic hydrogen atoms substituted by cations of inorganic and / or organic bases, amino acids or amino acid amides.

Suitable acid protecting groups R ² are lower alkyl, aryl and aralkyl groups, for example the methyl, ethyl, propyl, n-butyl, t-butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis (p Nitrophenyl) methyl group, as well as trialkylsilyl groups in question.

The cleavage of the protective groups R ² is carried out according to the methods known to the person skilled in the art (for example Wünsch, Methoden der Org. Chemie [Houben-Weyl], Bd.XV / 1.4.Aufl. 1974, p.315ff.), For example by Hydrolysis, hydrogenolysis or alkaline saponification of the esters with alkali in aqueous-alcoholic solution at temperatures of 0 to 50 ° C. For splitting off the particularly advantageous for the present reactions t-butyl ester, organic or inorganic acids are used: The dissolved in a suitable anhydrous organic solvent ester compound, but preferably the powdered dry substance, either with hydrogen halide solution in glacial acetic acid, with trifluoroacetic acid or Bortrifluoriddiethyletherat in Glacial acetic acid and at temperatures of -10 ° C to 6O ⁰ C, preferably at room temperature, cleaved. The compounds of general formula II which are used as starting materials for the preparation of the complex compounds according to the invention are known (DOS 3710730 and references cited therein) or can be synthesized analogously to the preparation instructions described therein.

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

For this purpose, the compounds of formula II, wherein R ^{2 is} an alkali-stable acid protecting group, in a polar aprotic solvent, such as. For example, tetrahydrofuran, dimethoxyethane or dimethyl sulfoxide, and dissolved with a base such. For example, sodium hydride, sodium hydroxide or alkali or alkaline earth (icarbonaten, at temperatures between -30 ° C and the boiling point of the solvent is added, but preferably between 0 ⁰ C and 60 ° C. For this purpose, a compound of general formula III

Y- (CH ₂ ) "- {C ₆ H ₄ ) HO) _f -R (III)

where Y is a nucleofuge, such as Cl, Br, I, CH ₃ -C ₆ H ₄ SO ₃ or CF ₃ SO ₃ , and the remaining indices have the same meaning as in the general formula I.

The reaction times are depending on the steric hindrance of the residues involved 30 minutes to 8 hours. As an alternative to the reaction conditions described above, both aryl-alkyl and diaryl ethers can be prepared very advantageously by phase-transfer catalysis (Starks and Liotta, Phase Transfer Catalysis, Academic Press, N.Y., 1978, pp. 128-138).

For this purpose, the reaction is carried out in a two-phase mixture of aqueous base, preferably 30% sodium hydroxide solution, and a water-immiscible organic aprotic solvent. Suitable phase-transfer catalysts are the compounds known to the person skilled in the art, but preferably tetraalkylammonium or tetraalkylphosphonium salts.

If it is desired to synthesize compounds of the general formula I with k, n, I and r = O and R in the meaning of a hydrogen atom, it is possible to carry out the synthesis analogously to the methods known from the literature from the corresponding unsubstituted amino acid (for example phenylalanine).

However, if a number of analogous compounds are to be synthesized, the preparation of the phenol derivatives described in DOS 3710730 and the reductive removal of the phenol function by the literature method known to the person skilled in the art are recommended. Above all, the reduction of aryl diethyl phosphates with titanium, which can be carried out very advantageously even in the presence of ester groups (SCWelch et al., J. Org. Chem. 43, 437-4799 (1978) and literature cited there) In this case, the corresponding aryl diethyl phosphate is first formed from the phenolic educt by reaction with phosphoric acid diethyl chloride in 70-100% yield, preferably by using sodium hydride as base in a polar aprotic solvent.

Subsequently, the reduction is carried out with freshly prepared titanium metal. Preferably, anhydrous titanium (III) chloride is reduced by magnesium or potassium in anhydrous tetrahydrofuran under inert gas to produce highly active titanium.

To such a mixture, the above-described diethyl phosphate is added and heated under reflux for 2 to 24 hours, preferably 6 to 16 hours.

After completion of the reaction is optionally worked up by chromatography. Also applicable is the palladium-catalyzed reduction of the corresponding aryl triflates according to S.Cacchi et al., Tetr. Lett. 27, 5541-5544 (1986). The compounds of the general formula Γ where X in the meaning of a hydrogen atom are complexing agents. They can be isolated and purified or converted without isolation into metal complexes of the general formula I with at least two of the substituents X in the meaning of a metal ion equivalent. The preparation of the metal complexes according to the invention is carried out in the manner disclosed in DE 3401052 by reacting the metal oxide or a metal salt (for example the nitrate, acetate, carbonate, chloride or sulfate) 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) is dissolved or suspended and reacted with the solution or suspension of the equivalent amount of the complex-forming acid of general formula Γ with X in the meaning of a hydrogen atom, preferably at temperatures between 40 and 100 ⁰ C, and then-if desired-existing acidic hydrogen atoms of acid groups substituted by cations of inorganic and / or organic bases, amino acids or amino acid amides. The neutralization takes place with the aid of inorganic bases (for example hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium, lithium, magnesium or calcium and / or organic bases, such as inter alia primary, secondary and tertiary amines, for example ethanolamine, Morpholine, glucamine, N-methyl and N, N-dimethylglucamine, as well as basic amino acids such as lysine, arginine and ornithine.

To prepare the neutral complex compounds, for example, the acidic complex salts in aqueous solution or suspension can be added as much of the desired bases that the neutral point is reached. The resulting solution can then be concentrated to dryness in vacuo. It is often advantageous to add the neutral salts formed by addition of water-miscible solvents, such as lower alcohols (methanol, ethanol, isopropanol and others), lower ketones (acetone and others), polar ethers (tetrahydrofran, dioxane, 1,2 -Dimethoxyethane and others) to precipitate and so easy to isolate and easy to clean crystals. It has proven to be particularly advantageous to add the desired base to the reaction mixture already during the complex formation and thereby to save a process step.

If the acidic complex compounds contain several free acidic groups, it is often useful to prepare neutral mixed salts containing both inorganic and organic cations as counterions.

This can be done, for example, by reacting the complex-forming acid in aqueous suspension or solution with the oxide or salt of the central ion-supplying element and half of the amount required for neutralization of an organic base, isolating the complex salt formed, purifying it if desired and then to complete Neutralization offset with the required amount of inorganic base. The order of base addition can also be reversed.

The preparation of the pharmaceutical compositions according to the invention is likewise carried out in a manner known per se by suspending or dissolving the complex compounds according to the invention in aqueous medium, if appropriate with the addition of additives customary in galenicals, and then optionally sterilizing the suspension or solution. Suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), minor additives of complex binders (such as diethylenetriamine pentaacetic acid) or, if necessary, electrolytes (such as sodium chloride) or, if necessary, antioxidants such as ascorbic acid.

If suspensions or solutions of the compositions of the invention in water or physiological saline are desired for enteral administration or other purposes, they will be administered with one or more adjuvants (s) (for example, methylcellulose, lactose, mannitol) and / or surfactant (s) commonly used in galenicals. For example, lecithins, tween *, myrj * and / or flavoring (s) are included for taste correction (for example, essential oils).

In principle, it is also possible to prepare the pharmaceutical compositions of the invention without isolation of the complex salts. In any case, special care must be taken to make the chelation so that the salts and salt solutions according to the invention are practically free of uncomplexed toxic metal ions.

This can be ensured for example by means of color indicators such as xylenol orange by control titrations during the manufacturing process. The invention therefore also relates to processes for the preparation of the complex compounds and their salts. As final security remains a purification of the isolated complex salt.

The pharmaceutical compositions according to the invention are applied in a dose of 1 pmol / kg to 5 mmol / kg, preferably from ΙΟμηηοΙ to 0.5 mmol / kg of the complex salt according to the invention. In an intravenous injection, aqueous formulations of concentration δΟμιηοΙ / Ι to 2mol / l, preferably lOOmmol / l to 1 mol / l, use. Rectal and oral use is preferably carried out with solutions of concentration 0.1 mmol / l to lOOmmol / l. The applied volumes are between 5 ml and 21 depending on the diagnostic question.

The compositions of the invention meet the diverse requirements for suitability as a contrast agent. Thus, they are excellently suited for improving the informative value of the image obtained with the help of the magnetic resonance tomograph after enteral or parenteral administration by increasing the signal intensity. Furthermore, they show the high potency necessary to burden the body with the least possible amounts of foreign matter and the good compatibility needed to maintain the noninvasive nature of the studies.

The good solubility in water and low osmolality of the compositions according to the invention makes it possible to produce highly concentrated solutions in order to keep the volume load of the circulation within acceptable limits and to compensate for the dilution by the body fluid. Furthermore, the agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that a release or an exchange of non-contractionally bound in the complexes - in itself toxic - ions within the time in which the new contrast agent completely excreted, only extremely slowly.

The agents according to the invention can also be used for radiation therapy. Thus, complexes of gadolinium are ideally suited for neutron capture therapy due to the large capture cross section. If the agent according to the invention is for use in the method described by RL Mills et al. (Nature Vol. 336 [1988] p. 787), the central ion must be derived from a Mössbauer isotope such as ⁶⁷ Fe or ¹⁵¹ Eu.

In the application of the compositions of the invention, these may also be used together with a suitable carrier such. As serum or saline solution and / or together with a protein such as. B. human serum albumin. The dosage depends on the nature of the cellular disorder and the properties of the metal complex used.

The following examples illustrate the invention without wishing to be limited thereto.

example 1

a) S ^^ triaza-S ^^ tris-tert-butoxycarbonylmethyD ^ -t ^ methoxybenzyD undecanedioic di-tert-butyl diester 1.56g (2mmol) 3,6,9-triaza-3,6, 9-tris- (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) -undecandisäure-di-tert-butyl diester (example 9f of DOS 3,710,730) are dissolved in tetrahydrofuran at 0 ⁰ C with 66 mg (2.2 mmol) of 80% Sodium hydride added. There are added 0.31 g (2.2 mmol) of iodomethane and stirred for 30 minutes. Then, the solution is mixed with water, distilled off tetrahydrofuran and the aqueous emulsion extracted with diethyl ether. The organic phase is washed with water, dried over Na ₂ SO ₄ and concentrated

 Yield: 1.55 g (97.6%)

Calcd .: 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 1 a) are dissolved in 25 ml of trifluoroacetic acid and stirred at room temperature for 1 hour. Subsequently, the solution is combined with diethyl ether, the precipitate is filtered off with suction, washed with ether and dried at 4OX in vacuo over phosphorus pentoxide. The crude product is dissolved in water and stirred with activated charcoal. The mixture is filtered off from the charcoal and lyophilized three times to remove residual trifluoroacetic acid. Yield: 0.62 g (75.4%)

Calc .: C 51.46 H 6.09 N8.18 Found: C 51.27 H 6.02 N8.11

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 described in Example 1 b) are dissolved in about 30 ml of water and treated at 80 ⁰ C with 181 mg (0.5 mmol) Gd ₂ O ₃ . After 30 minutes, the almost clear solution is filtered and the filtrate freeze-dried. Yield: 649 mg (97.2%), based on the anhydrous substance.

Calc .: C 39.47 H 4,23 N 6,29 Gd 23,55 Found: C 39,47 H 4,29 N6,21 Gd 23,19

Di-sodium salt of gadolinium complex

The complex obtained as described above (500 mg, 0.75 mmol) is dissolved in 10 times the amount of water and treated by means of a micro burette with 1.5 ml of a 1 N sodium hydroxide solution

 After freeze-drying, 533 mg of white crystals are present

 The TyRelaxivity (l / mmol · see) is

in water 4.54 ± 0.13

in plasma 6.89 ± 0.17

Di-N-methyl-D-glucamine salt of the gadolinium complex

3.34 g (5 mmol) of the gadolinium complex are added in portions in 40 ml of water with 1.96 g (10 mmol) of N-methyl-D-glucamine with stirring. After complete dissolution of the base is freeze-dried. There remains 5.55 g of a colorless crystalline compound

H ₂ O content (Karl Fischer determination): 4.73%

d) Europium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-methoxybenzyl) undecanedioic acid

5.13 g (10 mmol) of the complexing agent acid described in Example 1b are dissolved in about 30 ml of water and admixed at 80 ° C. with 1.76 g (5 mmol) of Eu ₂ O ₃ . After 30 minutes, the almost clear solution is filtered and the filtrate freeze-dried. Yield: 6.62 g

Analysis (based on anhydrous substance) Calc .: C 39.89 H 4,26 N 6,34 Eu 22,94 F .: C 39,71 H 4,38 N 6,17 Eu 22,58

Di-sodium salt of the europium complex

The complex described above (497 mg, 0.75 mmol) is dissolved in 10 times the amount of water and mixed by means of a micro burette with 1.5 ml of a 1 N sodium hydroxide solution. After freeze-drying 540 mg of white crystals are present.

Di-N-methyl-D-glucamine salt of the europium complex.

3.31 g (5 mmol) of the europium complex are added in portions in 40 ml of water with 1.96 g (10 mmol) of N-methyl-D-glucamine with stirring. After complete dissolution of the base is freeze-dried. There remain 5.63 g of a colorless crystalline compound.

e) ferric complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-methoxybenzyl) undecanoic acid

5,13g (10 mmol) of the complexing described in Example 1 b are dissolved in about 30 ml of water and treated at 80 ⁰ C with 798mg (5 mmol) of Fe ₂ O _3. After 30 minutes, the almost clear solution is filtered and the filtrate 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

Di-sodium salt of the iron-III complex

The complex obtained as described above (425 mg, 0.75 mmol) is dissolved in 10 times the amount of water and mixed by means of a micro burette with 1.5 ml of a 1N sodium hydroxide solution. After freeze-drying, 460 mg of white crystals are present.

Di-N-methyl-D-glucamine salt of the iron-III complex

2.83 g (5 mmol) of the iron-III complex are added in portions in 40 ml of water with 1.96 g (10 mmol) of N-methyl-D-glucamine with stirring. After complete dissolution of the base is freeze-dried. There remain 4.83 g of a colorless crystalline compound.

The bismuth complex is obtained in an analogous manner with bismuth oxide, Bi ₂ O ₃ , as the di-sodium salt or as the di-N-methyl-D-glucamine salt.

Example 2

a) SeS-triaza-S ^^ - tris-tert-butoxycarbonyl-methyD-Sf ^ methoxybenzyO undecanedioic acid di-tert-butyl ester S.gglSmmoDS.e ^ -Triaza-SeS-tris-tert-butoxycarbonylmethyD-St ^ hydroxybenzyD -undecandioic acid di-tert-butyl ester (Example 17 d of DOS 3710730) are reacted according to the procedure given in Example 1 a) to 3.61 g (91% of theory) 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

3.18 g (4 mmol) of the tert-butyl ester described in Example 2a) are treated with trifluoroacetic acid according to the procedure given in Example 1 b) and worked up. This gives 1.62 g (79% of theory) of colorless lyophilizate.

Calc .: C 51.46 H 6.09 N8.18 Found: C 51.34 H 6.14 N8.11

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 2 b) are complexed according to the procedure in Example 1c). This gives 1.32 g (99% of theory) of colorless lyophilisate.

Calc .: C 39.57 H 4.23 N 6.29 Gd 23.55 Found: C 39.51 H 4.19 N6.25 Gd 23.61

The TrRelaxivity (1 / mmol see) in water is 4.17 ± 0.14 in plasma, 6.61 ± 0.18

Example 3

a) 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- [4- (4-methoxybenzyloxy) -benzyl] -undecanedioic acid di-tert-butyl ester 1.56g (2 mmol) 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) -undecanedioic di-tert-butyl ester (Example 9f of DOS 3710730) in tetrahydrofuran at ⁰ ° C., 66 mg (2.2 mmol) of 80% sodium hydride are added. To this is added 0.3 ml (2.2 mmol) of 4-methoxybenzyl chloride and stirred overnight. Then the solution is mixed with water. Distilled off tetrahydrofuran and the aqueous emulsion extracted with diethyl ether, the organic phase is washed with water, dried over Na ₂ SO ₄ and concentrated. The resulting colorless oil is chromatographed on silica gel (ether / hexane 1: 1).

Yield: 1.17 g (65% of theory) of colorless oil.

Calcd .: C 65.38 H 8.62 N 4.67 Found: C 65.29 H 8.65 N 4.59

b) 3,6,9-triaza-3,6 _/ 9-tris (carboxymethyl) -4- [4- (4-methoxybenzyloxy) 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 b) and converted to 905 mg (73% of theory) of colorless, fluffy 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 S.e.S-Trlaza-S.e.S-tris-carboxymethylM - ^^ - methoxybenzyloxybenzyl-1-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 1c). 758 mg (98% of theory) are obtained.

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 Τ, -relaxivity (l / mmol see) in water is 4.23 ± 0.16 in plasma 6.99 ± 0.13

Example 4

a) diethyl phosphate des3 _/ 6,9-trlaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) undecanedioic dl-tert-butyl ester

11.2 g (14.36 mmol) of the phenol described in DOS 3710730 (Example 9f) are dissolved in 100 ml of absolute tetrahydrofuran (THF). To this is added 380 mg (15.8 mmol) of sodium hydride (prepared from 50% NaH in paraffin oil by washing three times with 10 mM HF). 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 at room temperature for 24 hours.

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 sulfate, concentrate in vacuo and purify the residue by flash chromatography (eluent: ether / hexane = 1: 1).

Yield: 11.97 g (91% of theory) of a pale yellow oil.

Calcd .: C, 59.00, H, 8.58, N, 5.59, P3, 38 Found: C, 58.88, H, 8.63, N, 4.63, P, 3.30

b) S.e.S-Triaza-S.e.g.-tris-tert.-butoxycarbonylmethylM-benzyl undecanedioic 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 refluxed in an argon atmosphere for 1 hour.

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 this mixture over a period of 5 minutes, followed by refluxing for 8 hours The mixture is cooled in an ice bath and cautiously 20 ml of methanol are added then 100 ml of water and extracted three times with 200 ml of ether The organic phases are dried over magnesium sulfate and concentrated in vacuo The residue is chromatographed on silica gel (eluent: hexane / ether = 2: 1). 93% of theory) of the title compound as a colorless oil which crystallizes on standing.

Calcd .: C64; 54 H; 9.15; N, 5.41

c) S.e.-Triaza-S ^ S-tris-carboxymethylM-benzyl undecanedioic acid

7.64 g (10 mmol) of the tert-butyl ester described in Example 4b) are reacted analogously to the procedure given for Example 1 b) to give 4.01 (83% of theory) 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 S.e.-Triaza-S.e.S-tris-fcarboxymethylM-benzyl undecanedioic acid

2.42 g (5 mmol) of the complexing agent described in Example 4c) are reacted analogously to the procedure given in Example 1c) to give 3.14 g (98.5% of theory) of the title compound. The gadolinium complex is obtained as a colorless, fluffy lyophilisate.

Calc .: C 39.55 H 4.11 N 6.59 Gd 24.66 F .: C 39.47 H 4.19 N 6.52 Gd 24.88

The Ti relaxivity (1 / mmol · see) in water is 4.54 ± 0.13 in plasma, 6.89 ± 0.17

Ytterbium complex of Se ^ -Triaza-Se ^ -tris-fcarboxyrnethylM-benzyl-undecanedioic acid Analogous to the procedure for the preparation of the gadolinium complex, if one uses Gd ₂ O 3, the corresponding ytterbium complex is obtained.

Example 5

a) S.e ^ -Triaza-S.e.S-tris-tert-butoxycarbonylmethyll ^ -benzyloxymethyl undecanedioic di-tert-butyl ester

To a well-stirred suspension of 14.1 g (20 mmol) of described in DOS 3710730 (Example 37d) 4-hydroxymethyl-Seg-triaza-S ^ .S-tris-itert.-butoxycarbonylmethyD undecandi- acid tert-butyl diester and 0.3 g of tetrabutylammonium hydrogen sulfate in 200 ml of dichloromethane / 200 ml of 30% sodium hydroxide solution is added dropwise 7.2 ml (60 mmol) of benzyl bromide within 30 minutes at room temperature and then stirred for 8 hours.

400 ml of water are added to this 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 sulfate is chromatographed on silica gel (ether / hexane = 1: 1).

This gives 13.0 g (82% of theory) of the title compound as a colorless oil.

Calc .: C 63.53 H 9.01 N 5.29 F: C 63.42 H 9.07 N 5.21

b) 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4-benzyloxymethyl undecanediols

7.94 g (10 mmol) of the tert-butyl ester described in Example 5a) are reacted with trifluoroacetic acid to 4.06 g (79% of theory) of the title compound analogously to the procedure given for Example 1 b).

Calc .: C 51.46 H 6.09 N8.18 Found: C 51.51 H 6.06 N8.12

c) gadolinium complex of 3,6,9-Тгіа2а-3,6,94гі $ - (сагЬохутеіпуО-4-ЬепгуІохутеігіуІ-ипаесапаІ8а'иге

2.57 g (5 mmol) of the complexing agent acid described in Example 5b) are reacted analogously to the procedure given for Example 1c) to 3.30 g (98.9% of theory) of the title compound. You get a colorless, flaky solid.

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 TrRelaxivity (l / mmol / · see) in water is 4.39 ± 0.12 in plasma, 6.31 ± 0.15

Example 6

(a) Sre.S-triaza-SeS-tris-tert.-butoxycarbonylmethylM-1-carboxymethoxybenzyO undecanedioic-bis-tert-butyl-O-ester 23.40g OOmmoDS ^ Q-triaza-SAg-tris-Uert.-butoxycarbonylmethylM ^ hydroxybenzyD -undecandiäure di-tert-butyl ester (Example 9f of DOS 3710730) are added in tetrahydrofuran at 0 ° C with 2.7g OOmmol) 80% sodium hydride. For this purpose, 6.25 g (45 mmol) of bromoacetic acid in tetrahydrofuran are added dropwise, stirred for 1 hour at ⁰ ° C. and overnight at room temperature.

Then the solution is mixed with water. Distilled off tetrahydrofuran and the aqueous phase extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated.

The residue is chromatographed on silica gel in the eluent mixture dioxane / methanol / triethylamine (15: 4: 1); The combined fractions are concentrated and partitioned between ethyl acetate and 1N citric acid. The organic phase is then dried over sodium sulfate and concentrated. This gives 21.8 g (87% of theory) as a colorless oil.

Ben: 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 (carboymethyl) -4- (4-carboxymethoxybenzyl) 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 1 b) to give 11.0 g (78.9% of theory) of the title compound.

Calc .: C 49.55 H 5.60 N 7.5 Fe: C 49.31 H 5.51 N 7.47

c) Gadolinium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-carboxymethoxybenzyl) undecanedioic acid

5.57 g (10 mmol) of the complexing agent acid described in Example 6b) are reacted analogously to the procedure given for Example 1c) to give 7.01 g (98.5% of theory) 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 T, relaxivity (l / mmol · see) in water is 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 product obtained according to Example 5c) Gadoliniumkomplexes are dissolved in 70 ml of water per injection (pL) and treated dropwise with 1N sodium hydroxide solution until a pH of 7.2 is reached. After addition of 0.02 g of tromethamine with water p. filled to 100ml, the solution bottled and heat sterilized.

Example 8

a) 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-ethoxybenzyl) undecanedioic di-tert-butyl diester

5.85g (7.5mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) -undecanedioic acid di-tert-butyl diester (Example 9f of U.S. Pat DOS 3710730) are mixed in 100 ml of tetrahydrofuran at 0 ° C with 0.30 g (lOmmol) 80% sodium hydride. To this is added 1.56 g (10 mmol) of iodoethane and stirred for 3 hours. Then the solution is mixed with water. Distilled off tetrahydrofuran and the aqueous emulsion extracted with diethyl ether. The crude product obtained after drying over sodium sulfate and concentration of the solvent is chromatographed on silica gel (system: hexane / ether / triethylamine 70: 30: 5)

 Yield: 4.0g (66%)

Analysis (based on anhydrous substance): Calc .: C 63.91 H 9.11 N 5.20 Found: C, 63.67, H, 9.05, N, 5.28

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

3.64 g (4.5 mmol) of the tert-butyl ester described in Example 8 a are dissolved in 25 ml of trifluoroacetic acid, stirred for one hour at room temperature and worked up analogously to Example 1 b. Yield: 1.2 g (50.6%)

Analysis (based on anhydrous substance): Calc .: C 52.36 H 6.31 N 7.97 F .: C 52.21 H 6.39 N 7.84

c) Di-sodium salt of the gadolinium complex of the a.G.S-Triaza-S

528g (1 mmol) of the complexing described in the preceding example are dissolved in 40 ml of water at 80 ⁰ C with 181 mg (0.5 mmol) of Gd ₂ O complexed. ₃ It is then neutralized with 2 ml of 1N NaOH, stirred with charcoal, filtered and the filtrate is freeze-dried. Yield: 700 mg (96.5%)

Analysis (relative to anhydrous substance): Calc .: C38.06 H 3.89 Gd 21.67 N 5.79 Na 6.34 V .: C 37.91 H 3.99 Gd 21.30 N 5.69 Na 6.57

The T, relaxivity (1 / mmol see) in water is 5.33 ± 0.13 in plasma, 8.69 ± 0.53

In an analogous manner, the corresponding europium complex is obtained with europium oxide, EU2O3:

Calc .: C 38.34 H 3.92 Eu 21.09 N 5.83 Na 6.38 Found: C 38.20 H 4.01 Eu 20.87 N 5.79 Na 6.49

In an analogous manner, the corresponding iron complex is obtained with iron oxide, Fe ₂ O ₃ :

Calc .: C 44.25 H 4.52 Fe 8.95 N 6.73 Na 7.37 Found: 0 44.17 H 4.59 Fe 8.52 N 6.81 Na 7.49

Example 9

a) S ^ S-Triaza-Se ^ -tris-tert-butoxycarbonylmethylM-H-butoxybenzyl undecanedioic di-tert-butyl diester 5.85g (7.5mmol) 3,6,9-triaza-3,6,9- tris (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) undecanedioic di-tert-butyl diester (Example 9f of DOS 37107300) are reacted with 1.84 g (10 mmol) of 1-iodobutane analogously to Example 8a and described there , worked up.

Yield: 4.1 g (65.4%)

Analysis (based on anhydrous substance): Calc .: C 64.64 H 9.28 N 5.03 V: C 64.82 H 9.37 N 4.96

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

3.34 g (4 mmol) of the tert-butyl ester described in Example 9a are dissolved in 20 ml of trifluoroacetic acid, stirred for one hour at room temperature and worked up analogously to Example 1b. Yield: 1.36 g (61.0%)

Analysis (based on anhydrous substance): calc .: C 54.04 H 6.71 N7.57 F: C 53.88 H 6.63 N 7.41

c) Di-sodium salt of the gadolinium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butoxybenzyl) -undecanedioic acid

556 mg (1 mmol) of the complexing agent acid described in the above example are admixed with 40 ml of water and complexed at 80 ° C. with 181 mg (0.5 mmol) of Gd ₂ O ₃ . It is then neutralized with 2 ml of 1N NaOH, stirred with charcoal, 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 TV reliance (1 / mmol · see) in water is 5.80 ± 0.26 in plasma 14.20 + 0.98

In an analogous manner, the corresponding europium complex is obtained with europium oxide, Eu ₂ O ₃ :

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

In an analogous manner, the corresponding iron complex is obtained with iron oxide, Fe ₂ O ₃ :

Calc .: C, 45.83, H, 5.03, Fe, 8.30, N, 6.50, Na, 7.11

Example 10

a) 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-benzyloxybenzyl) undecanedioic di-tert-butyl diester 5.85g (7.5mmol) Seg. Triaza-Seg-tristertert.-butoxycarbonylmethyM ^ -hydroxybenzyD undecanedioic di-tert-butyl diester (Example 9 f of DOS 3710730) are reacted analogously to Example 8a with 1.71 g (10 mmol) of benzyl bromide and worked up as described there ,

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, stirred for one hour at room temperature and worked up in analogy to Example 1b

 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) Di-sodium salt of the gadolinium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-benzyloxybenzyl) undecanedioic acid

590 mg (1 mmol) of the complexing described in the preceding example are treated with 40 ml of water and 1 ml of 1N NaOH and stirred at 80 ⁰ C with 181 mg (0.5 mmol) of Gd ₂ O complexed. ₃ Then it is neutralized with 1 ml of NaOH, stirred with charcoal, filtered and the filtrate freeze-dried

 Yield: 703mg (89.2%)

Analysis (based on anhydrous substance):

Calcd .: 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 TVRelaxivity (l / mmol see) in water is 5.81 ± 0.11 in plasma 16.35 ± 1.01

In an analogous manner, the corresponding europium complex is obtained with europium oxide, EU2O3:

Calc .: C 42.98 H 3.86 Eu 19.42 N 5.37 Na 5.88 F .: C 43.10 H 3.91 Eu 19.13 N 5.27 Na 5.99

In an analogous manner, the corresponding iron complex is obtained with iron oxide, Fe ₂ O ₃ :

Calcd .: 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 of in vivo NMR diagnostics

example 1

Using a magnetic resonance tomograph from the company General Electric, which has been developed specifically for animal research, recordings were made at various times after application of the di-sodium salt of the gadolinium complex of Example 1 c) in rats.

With the magnetic resonance tomograph (CSI 2T), spin-echo images were taken at 2 Tesla (TR time of 400 ms and TE time of 20 ms). The layer thickness of this Ti-weighted uptake sequence was 3 mm, which was the receiving matrix

The contrast agent was administered intravenously into a tail vein of male nude rat (Lew / mole), weight 190 g, at a dose of 0.06 mmol / kg. The animal had a Brown-Pearce tumor in the thigh and was examined for examination by an i.m. Gift of Ketavet / Rompun anesthetized.

In the coronary space (baseline, No. 1) various dark structures are visible in the abdomen. Differentiation between intestinal lumen and stomach was not possible.

One minute after application (No. 2), the first enhancement in the urinary bladder is already visible. A strong contrast increase is in the stomach 45 minutes p.i. visible (# 3). 60 minutes p.i. (No. 4) is a good representation of the tumor (at the level of the reference tube), the bladder and the stomach to observe. In addition, a contrast of the intestine is also recognizable. This differentiation of intestinal loops, fat and lymph nodes (lymphoma) is possible. Striking is also the contrast of the renal pelvis, the 65 minutes p. i. can be better represented in a slightly different layer (# 5). In the picture No. 6,180 minutes p. i. Contrast enhancement is also clearly visible in an axial image in the liver. This allows a differentiation of the stomach, liver, duodenum and pancreas.

Example 2

The experimental animals were female rats of the strain Lew / mole with a weight of 160-180 g. Before imaging, the animals were anesthetized (Rompun · + Ketavet ·) and fitted with a catheter in the tail vein for the application of the contrast agent. The imaging took place in an MRI experimental device of the company General Electric (field strength 2 Tesla). First the images (7,9,11) without contrast medium were created with a Τ, -weighted spin-echo sequence (TR = 400 msec, TE = 20 msec, acial section plane, layer thickness 3 mm). The liver appears with the normal signal intensity; the stomach tends to be darker than the liver. In the case of Tier 1, the stomach sometimes has a fairly high signal intensity. This is due to residues of feed containing manganese in relatively high concentrations (the

Animals had not received any food for 6 hours at the time of the examination). Tier 3 was implanted an osteogenic sarcoma 3 weeks previously; this is on the blank photo isodens and indistinguishable. The contrast agent was administered through the venous catheter at a dose of 0.1 mmol Gd / kg (conc of the solutions 0.05 mmol Gd / ml in 0.9% NaCl) for all 3 substances. For all 3 substances after 90 minutes [Fig. 8, Example 8c)] or 60 minutes p.a. [Fig. 10, example 9c)]; [Fig. 12, Example 10c)] marked a marked enhancement of the liver, which is due to the uptake by the hepatocytes and is not observed at this time after application to the only currently available on the market contrast agent for magnetic resonance imaging, Magnevist *. In the case of Tier 3 [Fig. 12, Example 10c)] now also clearly recognizes the tumor, which has not taken up the contrast agent or to a lesser extent. Furthermore, in all substances - most strongly in Example 10c), least in Example 8c) - shows a strong enhancement of the stomach. This offers additional diagnostic possibilities with regard to a better delimitation of liver and stomach.

Claims (9)

claims: 1. Compounds of the general formula
XOOCCH ₂ Z ¹ Z ² CH ₂ COOX N- -CH CH- -N- XOOCCH ₂ wherein
Z ¹ and Z ² CH ₂ COOX -N CH ₂ COOX (D, independently of one another for a hydrogen atom or the radical - (CH ₂ ) _m - (C ₆ H ₄ ) _q - (O) _k - (CH ₂ ) _n - (C ₆ H ₄ ), - (O) _r - R where m and η are the numbers 0-20, k, I, q and r are the numbers O and 1 and R is a hydrogen atom, an optionally OR ¹ -substituted C ¹ -C 4 or a CH ₂ COOR ¹ group with R ¹ meaning a hydrogen atom, a C ¹ -C 6 -alkyl 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, provided that at least two of the substituents X are a metal ion equivalent, that one of the substituents Z ¹ and Z ^{2 is} a hydrogen atom and the other is not a hydrogen atom in that the sum of q and I gives the number 1 or 2 that - if η and I respectively stand for the number O - к and r do not simultaneously denote the number 1 that Z ¹ or Z ² does not represent - CH ₂ C ₆ H ₄ O-CH ₂ COOCH ₂ C ₆ H ₅ , - CH ₂ - C ₆ H ₄ - O - (CH ₂ ) ₅ - COOCH ₂ C ₆ H ₅ or - CH ₂ - C ₆ H ₄ - OH, and their salts with inorganic and / or organic bases, amino acids or amino acid amides , 2. Compounds according to claim 1, characterized in that Z ^{1 is} a hydrogen atom and Z ^{2 is} the radical - (CH ₂ ) _m - (C ₆ H ₄ ) _q - (0) _k - (CH ₂ ) _n - (C ₆ H ₄ ), - (0) _r - R stands. 3. Compounds according to claim 1, characterized in that Z ^{2 is} a hydrogen atom and Z ^{1 is} the radical - (CH ₂ ) _m - (C ₆ H ₄ ) _g - (0) _k - (CH ₂ ) _n - (C ₆ H ₄ ), - (0) _r - R stands. 4. Compounds according to claim 1, characterized in that Z ¹ or Z ² for the radicals - CH ₂ - C ₆ H ₄ - OCH ₃ , - 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 , - 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. Compounds according to claims 1 to 4: Gadolinium complex of 3, 6, 9-triaza-3,6,9-tris (carboxymethyl) -4- (4-methoxybenzyl) - undecanedioic; Europium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-methoxybenzyl) - undecanedioic; Iron III complex of 3, 6, 9-triaza-3,6,9-tris (carboxymethyl) -4- (4-methoxybenzyl) - undecanedioic; Bismuth complex of 3, 6, 9-triaza-3,6,9-tris (carboxymethyl) -4- (4-methoxybenzyl) - undecanedioic; Gadolinium complex of 3, 6, 9-triaza-3,6,9-tris (carboxymethyl) -5- (4-methoxybenzyl) - undecanedioic; Gadolinium complex of 3, 6, 9-triaza-3, 6,9-tris (carboxymethyl) -4- [4- (4-methoxybenzyloxy) - benzylj-undecanedioic acid; Gadolinium complex of 3, 6,9-triaza-3, 6,9-tris (carboxymethyl) -4-benzyl undecanedioic acid; Ytterbium complex of 3, 6, 9-triaza-3,6,9-tris (carboxymethyl) -4-benzyl undecanedioic acid; Gadolinium complex of 3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4-benzyloxymethyl undecanedioic; Gadolinium complex of 3, 6, 9-triaza-3, 6, S-trisicarboxymethylM - ^ - 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-triaza-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-triaza-3,6,9-tris (carboxymethyl) -4- (4-benzyloxybenzyl) undecanedioic acid; 6. Pharmaceutical agents containing at least one physiologically acceptable compound according to claim 1 to 5, optionally with the usual additives in galenicals. 7. Use of at least one physiologically acceptable compound according to claim 1 for the preparation of agents for NMR and X-ray diagnosis and radiation therapy. 8. Use of at least one physiologically acceptable compound of general formula I. Z ² CH ₂ COOX-CH N CH, CH ₂ COOX-N XOOCCH ₂ Z ¹ N CH CH N CH ₂ CH ₂ N (I), XOOCCH ₂ CH ₂ COOX wherein Z ¹ and Z ² independently of one another represent a hydrogen atom or the radical - (CH ₂ ) _m - (C ₆ H ₄ ) _q (O) _k - (CH ₂ J _n - (C ₆ H ₄ ), - (O) -R, wherein m and η are the numbers 0-20, k, I, q and r are the numbers O and 1 and R is a hydrogen atom, an optionally OR ^ substituted C ₁ -C ₆ -alkyl radical or a CH ₂ COOR ¹ group with R ¹ meaning a hydrogen atom, a C 1 -C 6 -alkyl radical or a benzyl group, X is a hydrogen atom and / or a metal ion equivalent of an element of Atomic numbers 21-29, 42, 44 or 57-83, provided that at least two of the substituents X are a metal ion equivalent, that one of the substituents Z ¹ and Z ^{2 is} a hydrogen atom and the other is not a water Substance atom is that the sum of q and I is the number 1 or 2 and that -if η and I are each the number O - к and r are not the same time each number 1, and their salts with inorganic and / or organic bases, amino acids or amino acid amides for the preparation of means for the NMR diagnosis of the renal and hepatobiliary system. 9. Use of at least one physiologically compatible compound of the general formula I. XOOCCH ₂ Z ¹ Z ² CH ₂ COOX CH ₂ COOX N CH CH-N CH ₂ CH ₂ -N (I), I XOOCCH ₂ CH ₂ COOX wherein Z ¹ and Z ² independently of one another represent a hydrogen atom or the radical - (CH ₂ ) _m - (C ₆ H ₄ ) _q (O) _k - (CH ₂ J _n - (C ₆ H ₄ ), - (O) -R,
wherein m and η are the numbers 0-20,
k, I, q and r are the numbers O and 1 and R is a hydrogen atom, an optionally OR ¹ -substituted C ₁ -C ₆ -AlkYlTeSt or a CH ₂ COOR ¹ group with R ¹ meaning a hydrogen atom, a C ^ Cg-alkyl 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, provided that at least two of the substituents X are a metal ion equivalent, that one of the substituents Z ¹ and Z ^{2 is} a hydrogen atom and the other is not a hydrogen atom , that the Sum of q and I gives the number 1 or 2 and that - if η and I are each the numeral O - к and r do not simultaneously denote the numeral 1, and their salts with inorganic and / or organic bases, amino acids or amino acid amides for the preparation of means for NMR diagnosis of the gastrointestinal tract.
10. A process for the preparation of compounds of general formula I. XOOCCH ₂ Z ¹ Z ² CH ₂ COOX CH ₂ COOX N CH CH-N CH ₂ CH ₂ -N (I), I XOOCCH ₂ CH ₂ COOX wherein Z ¹ and Z ² independently of one another represent a hydrogen atom or the radical - (CH ₂ ) _m - (C ₆ H ₄ ) _q (O) _k - (CH ₂ J _n - (C ₆ H ₄ ), - (O) -R,
wherein m and η are the numbers 0-20,
k, I, q and r are the numbers O and 1 and R is a hydrogen atom, an optionally OR ¹ -substituted C ¹ -C 6 -alkyl radical or a C ¹ -COROR group with R ¹ meaning a hydrogen atom, a C ¹ -C 6 -alkyl radical or a benzyl group, X is a hydrogen atom and / or a metal ion equivalent of an element of Atomic numbers 21-29, 42, 44 or 57-83, provided that at least two of the substituents X are a metal ion equivalent, that one of the substituents Z ¹ and Z ^{2 is} a hydrogen atom and the other is not a hydrogen atom, that the sum of q and I gives the number 1 or 2, that - if η and I are each the number O - к and r do not simultaneously denote the number 1 that Z ¹ or Z ^{2 is} not for - CH ₂ - C ₆ H ₄ - O - CH ₂ - COOCH ₂ C ₆ H ₅ , - CH ₂ - C ₆ H ₄ - O - (CH ₂ ) ₅ - COOCH ₂ C ₆ H ₅ or - CH ₂ - C ₆ H ₄ - OH, and their salts with inorganic and / or organic bases, amino acids or amino acid amides characterized in that in a conventional manner a compound of general formula II R ² OOCCH ₂ Z ³ Z ⁴ CH ₂ COOR ² H CH- -N- CH ₂ COOR ² -N CH ₂ COOR ² worm Z ³ and Z ⁴ for an acid protection group, each represents a hydrogen atom or the radical - (CH ₂ ) _m - (C ₆ H ₄ ) ₁ - OH, with the proviso that one of the substituents Z ³ and Z ^{4 represents} a hydrogen atom and the others stand for the rest indicated, stand, converted into a compound with the radical indicated for Z ¹ and Z ² , the acid protecting groups R ² split off, the resulting complexing acids of the general formula Γ with X in the meaning of a hydrogen atom 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 - existing acidic hydrogen atoms substituted by cations of inorganic and / or organic bases, amino acids or amino acid amides. Process for the preparation of the pharmaceutical compositions according to Claim 6, characterized in that the complex compound dissolved or suspended in water, physiological salt or protein solution, if appropriate with the additives customary in galenicals, is brought into a form suitable for enteral or parenteral administration. The invention therefore relates to the use of at least one physiologically tolerable compound of general formula I. XOOCCH ₂ Z ¹ N-XOOCCH- Z ² CH ₂ COOX CH ₂ COOX : н ₂ -ν CH ₂ COOX wherein
Z ¹ and Z ² independently of one another for a hydrogen atom or the radical - (CH ₂ ) _m - (C ₆ H ₄ ) _q - (O) _k - (CH ₂ ) _n - (C ₆ H ₄ ), - (O) _r - R where m and η the numbers 0-20, k, I, q and r are the numbers O and 1 and R represents a hydrogen atom, an optionally OR ¹ -substituted СтСе-alkyl radical or a CH ^ OOR ^ group with R ¹ meaning a hydrogen atom, a C ^ Cg-alkyl radical or a benzyl group, for a hydrogen atom and / or a metal ion equivalent of an element of ordinal numbers 21-29, 42, 44 or 57-83, provided that at least two of the substituents X are a metal ion equivalent, that one of the substituents Z ¹ and Z ^{2 is} a hydrogen atom and the other is not a hydrogen atom in that the sum of q and I gives the number 1 or 2 and that - if η and I are each the number O - к and r do not simultaneously each denote the number 1, and their salts with inorganic and / or organic bases, Amino acids or amino acid amides for the preparation of means for the NMR diagnosis of the gastrointestinal tract. For this 6 pages drawings