CS9003174A2 - Derivatives of dtpa complexes, pharmaceuticals that contain these compounds, their application and method of 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 present invention relates to novel complexes and salts of complexes, compositions containing these compounds, their use in diagnosis and therapy, as well as the method of making such compounds and compositions. Metal complexes as radiological contrast agents have been considered early in the 1950s. However, the compounds used at that time were such that their use in humans did not come into play. Therefore, it was surprising that some salts of the complexes were sufficiently tolerable, so that routine use of these complexes in humans for diagnostic purposes could be considered. As the first representative of this class of substances, dimegluroin salt Gd BTPA / has been well established for nuclear spin-mography. gadolinium-III-diethylenetriamine pentaacetic acid complex. This was registered under the name Magne -visi as the world's first NMR-diagnostics.

In particular, Magnevis is well suited for the diagnosis of pathologies (e.g., inflammations, tumors, heart attacks, etc.). After digestion, this compound is separated extracellularly and eliminated by glomerular secretion through the kidneys. Intact cell membrane penetration and extrarenal excretion are not practically observed *

In particular, contrast media which exhibit at least partial extrarenal excretion would be desirable, especially for patients with limited renal function, where Magnevis is only very slowly eliminated and can only be removed from the body by dialysis apparatus.

Accordingly, NMR-curing agents which exhibit a different pharmacokinetic behavior than Magnevis are required. It is therefore an object of the present invention to provide such compounds and compositions as well as processes for their preparation.

The compounds of the invention exhibit the desired properties: both renal excretion and excrecolysis with faeces *. Surprisingly, elimination of bile was not the only extrarenal route of excretion: In NME rat investigations, an increase in stomach-intestinal tract strength was unexpectedly observed following intravenous administration of the compounds of the invention.

The secretion / secretion / stomach has the advantage of allowing the limitation of ahaominal structures (eg, pancreas / gastrointestinal tract) while enhancing the contrast of pathological processes / tumors, inflammations. In addition, the representation of the renal system, liver and gallbladder and bile ducts can be achieved. In addition to improved ulcer representation and gastric cancers, gastric secretion can also be screened using the imaging method.

By making the compounds of the invention available, patients suffering from renal insufficiency as well as patients with gastrointestinal disease (at least 10) of western industrial populations can be assisted. The most frequent patients, as well as the large number of patients suspected of such ailments, must undergo diagnostic examinations. Two suitable methods are currently available for this purpose: endoscopy and X-ray diagnostics using barium contrast agents * - 4-

These examinations show various drawbacks: they are exposed to the risk of exposure, are traumatic, associated with inconvenience, occasionally even to patient risks and can therefore cause physiological stress. patients / for example taking a certain posture / and are often useless in decrepit and risky patients. Therefore, the role of providing new diagnostic methods for the recognition and localization of gastrointestinal diseases, which do not have these deficiencies, is also addressed by the various complexes and compositions of the invention. Even without specific measures, their pharmacokinetics will improve the diagnosis of multiple diseases. The majority of the complexes are excreted unchanged and rapidly, so that especially when relatively toxic ions are used, no harmful effects are observed even at high doses.

The irreversible use of new complexes is also facilitated by favorable chemical stability.

V V -L

Accordingly, the present invention relates to the use of one or more physiologically tolerable compounds of formula (I) XOOCCH, K-Z,

I-CH 2

I -CH- í —N-

H2C00X

CH2C00X

XOOCCH -CH, -CH,

-N

AND

CH2C00X / 1 /, where water / bu or o 1 2 * ---- 'Z and Z mean nea'w / t xcb y residue

- (CH 2) H - (C 6 H 4) (1- (O-) - CH 2 / n - (06Fyi) / O / rE where m and n are 0 to 20 k, 1q and n are Gala R hydrogen, C 1 - C 4 ') an alkyl radical optionally substituted by OIT, or a CH 2 OOR 2 -R 2 radical in the meaning of hydrogen, a C 1 -C 8 -alkyl radical or a benzyl radical, X is a hydrogen atom and / or an equivalent of a metal ion of an atomic number element 21-29,42,44 or 57-83, provided that at least two of the χ substituents are equivalent to the metal ion, that one of the 2 Z and Z substituents is hydrogen and the other is ω / water, and that - when 1 is 0, it does not simultaneously represent the number 1, ^ 1 with the inorganic salts and / or the amino and the amino acids.,, rn, iirp, or amides amines -? for the WW ° - intestinal tract.

The compounds of the invention are characterized by the general formula (I) XOCCCH, z

AND

-CE - • Gu-

CHnC00X ú.

J -N-

-CH GH,

E..COOX

I XCOCCK, c? ' cocx XI /, where i ο? #> # ι <fod / lta or j Z “and Z ^ independently of each other ^ / residue - / CH" / n- / C6H4 / </ 0 / k- / 0H £ / n- (6x'14) l- (O) r- where i is a number of C to 20 k, 1, c and r of the number 0 and 1 and atc ™ of the radical, a C 1 -C 8 -alkyl radical substituted by in the case of OK - or OHgCOOK "with K 1 in the meaning of hydrogen, C 1 -C 8 -alkyl or benzyl, the hydrogen atom and / or the metal ion equivalent is 21-29,42,44 or 57-83, s in that at least two substituents X represent a metal equivalence, that of the substituents Z1 and Z2 represents a hydrogen atom and the other does not represent a hydrogen atom, that in the case of n1 being the number 0, the n is not equal to 1 that Z or Z are not or CH-CH-O- / CEVc-o 4 g. o 3 o 4 5 CCOCH pCgH 2 and that - / 0 / r or - OH, as well as their salts with inorganic and / or organic bases, amino acids or amino acid amides.

When the composition of the invention is intended for use in NMR-diagnostics, the central ion of the solicomplex must be paramagnetic. These are, in particular, divalent and trivalent ions of atomic number elements 21-29,42,44 and 58-70. Suitable ions are, for example, trivalent ions of chromium, divalent ions of manganese, divalent ions of iron, divalent ions of cobalt, divalent ions of nickel, divalent ions of copper, trivalent ions of praseodymium, trivalent ions of ± &amp; rneodymium, trivalent ions of samarium, and trivalent ions of ions. In view of their very strong magnetic moment, the trivalent ion of gadolinium, the trivalent ion of terbium, the trivalent ion of dysprosium, the trivalent ion of ions, the trivalent ion of erbium and the trivalent of iron are particularly preferred.

If the composition of the invention is intended for diagnosis, then the central ion must be derived from a higher atomic number element to achieve sufficient X-ray absorption. It has been found that the diagnostic means contained therein are found to be useful. -require the physiologically tolerable salt of the complex with the atomic number elements of 21-29,42,44,57-83; these are, for example, the trivalent ion and the aforementioned lanthanide ions. Preferred numbers for m and n are 0 to 5.

Suitable alkyl substituents include straight or branched chain hydrocarbons having up to 6, preferably up to 4, carbon atoms, optionally substituted with one or more, preferably 1 to 3, or C 1 -C 8 -alkoxy groups in the case of R 1. a lot of C1-C4-alkoxy groups.

Examples of optionally substituted alkyl groups include methyl, hydroxymethyl, ethyl, 2-hydroxyethyl, 2-hydroxy-1- (hydroxymethyl) -ethyl, 1- (hydroxymethyl) -ethyl, propyl; isopropyl. - (-) - and 3-hydroxypropyl, 2,3-dihydroxypropyl, η-, sec- and target. 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-pentahydroxyhexyl and, in the case of hydroxyalkyl, C 1 -C 4 -alkyl derivatives, preferably derivatives C 1 -C 4 -alkyl. Preferred Z and Z 1 substituents are -CH 2 C 6 H 6 -OKCH 2 -C 6 H 4 "OCH 3 '» -CH 2 -C 6 E 5 "" CH 2 "C 6 H 4' °" CH 2 "C 6 H 4" OCH 3 "» -CH 2 -O-CH 2 -C 6 H 5 -, -CH 2 -C 5 H 4 -O-CH 2 -COOH, -CE 2 -C 6 H 4 -OC 2 H 5 - CE 2 -C 8 H 4 -OH 4 -, -CH 2 -GH 4 -O-CH 2 -C 8 H 4.

In addition, the preferred substituent Z 1 or o for use as a means of NMR-diagnosis of the gastrointestinal tract is the moiety -CH 2 -C 2 -HOH.

and O

If not all of the acidic hydrogen atoms are substituted by the central ion, one, more or all of the remaining hydrogen atoms may be replaced by cations of inorganic or organic bases or amino acids. Suitable inorganic cations are, for example, lithium, potassium, calcium, magnesium and especially sodium ion. Suitable cations of organic bases are, inter alia, those derived from primary, secondary or tertiary amines such as ethanol-amine, diethanolamine, morpholine, glucarine, N, K-dimethylglucarine, and in particular h-methylglucamine. Suitable cations of amino acids are, for example, lysine, arginine and ornithine cations. For example, the amide cations / amino acids are lysine-methylaraide, glycinethlamide, serine methlamide.

The process for the preparation of the compounds of the compounds of the general formula I according to the invention is carried out in such a way that the compounds of the general formula I are carried out

formula II R COCCH, N ·

I -CH- ck2cooiv

-CH 2 l

R OOCGH 2 "-cr,

GH ^ COCR I "

-N-CE, -COCR-ck is an acid-protecting group (11), -9- and is a hydrogen atom or a radical - (CHp) ffl - (C6H4) q-OH with one of the substituents T? and Z 2 is hydrogen and the other is converted in a manner known per se to the compound with the radical Z and Z, the acid protecting group R is cleaved off, the acids of the complexing agent of formula I with X are as defined above hydrogen (general formula I) are reacted with at least one metal oxide or metal salt of an element having an atomic number of 21-29, 42.44, or 57-83, and an infinite - if present, the hydrogen atoms present is doubled by inorganic and / or organic bases, amino acids or amino acid amides. O

The acid-protecting groups R6 are lower alkyl, aryl or aralkyl, for example methyl, ethyl, propyl, n-butyl, t-butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis- (p-nitrophenyl) -methyl, as well as trialkylsilyl groups.

Cleavage of the protecting groups R is carried out according to methods known to the person skilled in the art (e.g. E.W.Unsch, -10-).

Methoden der org. Chemie / Houben -Weyl /, Vol. XV / 1, 4th edition, 1974, sir. 315 ff, for example by hydrolysis, hydrogenolysis or alkaline saponification of the esters with alcohols in an aqueous alcoholic solution, at a temperature of 0 to 50 ° C. For cleavage of the t-butyl ester of the present reaction, inorganic or organic acids are used: the ester compound, dissolved in an aqueous, anhydrous organic solvent, but preferably a dry powder, is supplemented with a hydrogen halide solution in glacial acetic acid, tri. the acetic acid or boron trifluoromethyl etherate in acetic acid for the first time and is cleaved at -10 ° C to 60 ° C, preferably at room temperature.

The compounds of formula (II) used as educts for the production of complexing compounds according to the invention are known (DOS 3 710 730 and the literature cited therein) or can be synthesized analogously to the described manufacturing regulations.

For the reaction of known aliphatic or aromatic hydroxy compounds to the corresponding alkyl arylalkyl ether or dialkyl ethers, a number of metdd are available from the literature (e.g. March Organic Chemistry, third edition 1985, p. 342 ff.

For this purpose, the compounds of formula II wherein R is an acid-resistant -11-

alkali, are dissolved in a polar aprotic solvent such as tetrahydrofuran, dimethoxyethane or dimethyl dimethyl sulfoxide and made up with a base, such as, for example, diurahydride, sodium hydroxide, or alkali metal carbonates or alkaline earth carbonates, preferably between -30 ° C to the boiling point of the solvent used, but preferably between 0 ° C and 60 ° C, to which is added a compound of the formula III y - (CH 2) n - (c 6 H 4/1 - / O / r k / 111), where Y is a nucleofug, such as Cl,

Br, J, CH 2 -C 6 H 4 SO 4 or C 1-6 SO 4 and the other symbols have the same meaning as in Formula I.

The reaction times, according to the steric hindrance of the residues involved, are 30 minutes to 8 hours.

As an alternative to the reaction conditions described above, both the arylalkyl ethers and the dialkyl ether can advantageously be produced very advantageously by successive phase catalysis (Starks and Biot, Bhase Transfer Catalysis, Academic Press, B.Y.). 1978, p. 128-138.

To this end, the reaction is carried out in a biphasic mixture -12- consisting of an aqueous base, preferably 30% sodium hydroxide solution and a water-immiscible organic aprotic solvent. Phase transfer catalysts include those known to those skilled in the art, preferably the tetralkylammonium salt or the tetraalkylphosphonium salt.

If it is desired to produce compounds of general formula I with k, n, 1 and r = 0 and R, which is a hydrogen atom, then, starting from the corresponding non-substituted amino acids (e.g. phenylalanine), the synthesis can be carried out analogously to methods known in the literature.

If a number of analogous compounds are to be synthesized, it is recommended to produce phenol derivatives described in DOS 3,710,730 and to reduce the functional phenolic groups by methods known to those skilled in the art. In particular, titanium redoxide may be mentioned by titanium reduction, which may also be carried out in the presence of esters of esters. Kelch et al., J. Org. Chem., 43, 4797-99 (1978) and the literature described therein. In this case, the corresponding aryl diethyl phosphate is preferably obtained from the phenolic educt, in particular by reaction with phosphoric acid diethyl ester 70 to 100, preferably using sodium hydride as a base in a polar aprotic solvent. It is then reduced with freshly produced titanium metal. Highly active titanium reduces titanium chloride by magnesium or potassium in anhydrous tetrahydrofuran under inert gas. Diethylphosphate as described above is added to such a mixture and heated for 2 to 24 hours, preferably 6 to 16 hours under reflux. If desired, chromatographic treatment is also carried out after completion of the reaction. et al.Tetr. lett. 27, 5541-44 (1986).

The compounds of formula (1’s) X obtained in this way represent complexing agents in the hydrogen radical. They can be isolated and purified or converted, without isolation, of metal complexes of the formula I with at least two substituents X in terms of metal ion equivalent. the metal complexes of the invention are produced as disclosed in BE 3 401 052, in that the metal oxide or metal salt (for example, nitrate, acetate, carbonate, chloride or sulfate / element with atomic number 21-29,42) is 44,58-70 dissolved in water and / or low alcohol (such as methanol, ethanol or isopropanol / or suspended therein and allowed to react with a solution or suspension of an equivalent amount of the complexing acid of formula 1's X as hydrogen, s) preferably at temperatures between 40 ° C and 100 ° C, and finally, if desired, the acidic hydrogen atoms present in the acid groups substitute for the cations of inorganic and / or organic bases, amino acids or amide amino acids.

Neutralization is carried out in this case by means of inorganic bases (e.g. hydroxides, carbonates, or bicarbonates), for example those derived from sodium, potassium, magnesium, or calcium and / or organic bases, such as among other primary, secondary or tertiary amines, e.g. ethanolamine, morilin, glucamine, N-methylglucamine and Ν, Ν-diethylglucamine, as well as basic amino acids such as lysine, ar -ginine and ornithine.

For example, for the production of neutral complexing compounds, as much of the desired base can be added to the acid complex salts in the aqueous solution or suspension, it reaches the neutralization point. It is often preferred that the neutral salts formed be precipitated by the addition of water-miscible solvents such as low alcohols / methanol, ethanol, isopropanol and other low ketones / acetone and others. - ether ethers / tetrahydrofuran, dioxane, 1,2-dimethoxane and others - thus obtaining readily isolating and well-cleaning crystals. As a particularly advantageous reaction, it has been found to be desirable to add the desired base to the mixture already during the formation of the complex and thus to save one step in the process.

If the acid complexing compounds contain more free acid groups, it is often convenient to produce neutral mixed salts which contain both inorganic and organic cations.

This can be done, for example, by allowing the complexing acid to react in an aqueous suspension or solution with the oxide or salt of the central ion-providing element and half the amount of organic base to neutralize, the complex formed is isolated or purified and then neutralized for perfect neutralization. the required amount of inorganic base. The base sequence can also be reversed.

The pharmaceutical compositions according to the invention are also prepared in a manner known per se by suspending the conjugate compounds of the invention - optionally with the addition of customary additives in galenic form - non-dissolution in an aqueous medium and then optionally sterilizing the non-boron suspension. physiologically acceptable puirs (such as tromethamine), small additives of complexing agents (such as diethylenetriamine pentaacetic acid) or, if necessary, electrolytes (such as sodium chloride), or in the case of antioxidants such as for example, ascorbic acid.

If they are. for enteral use or other purposes, suspensions or solutions of the compositions of the invention in water or physiological distillation of a saline are desirable, such as with one or more excipients customary in galenic (e.g. methylcellulose, lactose, mannitol) and / or surfactant or surfactants, e.g. , Tweeip, Myrj and / or flavoring or flavoring agents (for example ether oils).

In principle, it is also possible to prepare the pharmaceutical compositions according to the invention without isolating the complexing salt. In all cases, special care must be taken and the chelates or salt solutions of the present invention are practically free of non-complexing metal ions. -xy.

This can be ensured, for example, by means of control titrations during the production process using color indicators such as xylene orange. The invention therefore also relates to a process for the preparation of complexing compounds and their salts. As a last safe step, the purification of the isolated salt of the complex remains.

The pharmaceutical compositions of the invention are applied at a dose of 1 µmol / kg to 5 mmol / kg, preferably 10 µmol / kg of the salt of the complex of the invention. Intravenous injection uses aqueous formulations of 50 µmol / 1 to 2 mol / l, preferably 100 µmol / 1 to 1 mol / l. The rectal as well as oral use is preferably carried out with solutions of 0.1 mmol / l to 100 mmol / l. The volumes to be applied vary according to the intended purpose between 5 ml and 2 l.

The compositions of the present invention fulfill various presumptions as to the ability to be a contrast medium. T &amp;amp; k is well suited for enhancing the image expression response obtained with a tomograph with nuclear spin after enteral or parenteral administration by increasing its signal intensity. Further, it exhibits high efficacy that is necessary for the body to become burden with as little foreign matter as possible, which is necessary to maintain the non-invasive character of the investigation.

The good water solubility and low osmolality of the compositions of the present invention make it possible to produce highly concentrated solutions and thereby maintain the volumetric load of the circulation within acceptable limits and to balance the dilution with the body fluid. in vivo, so that the release or exchange of ions of ions - itself toxic - unbound covalent complexes, over a period of time when new contrast agents are completely eliminated again, is as slow as possible.

The compositions of the invention may be used in radiation therapy. Thus, gadolinium complexes, based on a large capture cross section, are perfectly suited to capture neutron therapy. If the composition according to the invention is intended for use in the irradiation variant proposed by R.I. Mills et al. / Nature vol. 336/1988 / p. Thus, the central ion must be derived from the MSssbauer isotope such as, for example, the ^ Eu. Although the compositions of the present invention are administered thereto, they may also be administered together with a suitable carrier such as, for example, a serum or physiological saline solution. The dosage is dependent on the nature of the cellular disorder and the properties of the metal complex to be used. Example 1 a / di-tert. butyldiester 3 > 6,9-triaza-3,6,9 &quot; -butoxycarbonylmethyl (-4- [4-methoxybenzyl] -indecanoic acid) 1.56 g (2 mmol) of di-tert-butyl diester 3,6,9 “triaza-3,6,9-tris- tert- butoxycarbonylmethyl (-4- (4-hydroxybenzyl) -undecanedioic acid (Example 9f of DOS3 710 730) is added to tetrahydrofuran at 0 ° C with 66 mg of -19- (2.2 mmol) / 80% sodium hydride. (2.2 mmol / iodomethane) and stirred for 30 minutes. The solution is then made up to volume with water, the tetrahydrofuran is distilled off and the aqueous emulsion is extracted with diethyl ether. The organic phase is washed with water, dried over sodium sulfate 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 / target. of the butyl ester described in Example 1a) was dissolved in 25 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. The solution was then made up with diethyl ether, the precipitate was filtered off, washed with ether and dried in vacuo at 40 DEG C. with phosphorus pentoxide. The crude product is dissolved in water and stirred with activated carbon. The charcoal is filtered off and lyophilized three times to remove trifluoroacetic acid residues. 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 -20- c / gadolinium 3,6,9-triaza-3,6,9-tris- / carboxymethyl 1 / 4- 4-Methylbenzylene-1-ol (51-3 mg / l-ol) complexing acid described in Example 1b) was dissolved in about 30 ml of water and 181 mg / 0 was added at 80 ° C, 5 mmol / Gd2O3. After 30 minutes the clear solution was filtered and the filtrate was freeze-dried. Yield: 649 mg (97.2%) of 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

Di-sodium salt of the gadolinium complex

The complex obtained in the manner described above (500 mg, 0.75 mmol) is dissolved in ten times the amount of water and microburette is made up with 1.5 ml of 1 N sodium hydroxide solution. 533 mg of white crystals are obtained after freeze-drying. - relaxivity / 1 / mmol-sec / in water 4.54 + 0.13 in plasma 6.89 + 0.17

The β-N-methyl-D-glucamine salt of the gadolinium complex of 3.34 g (5 mmol) of gadolinium complex is made up in 40 mL of water in portions with stirring of 1.96 g (10 mmol) of N-methyl-L-glucamine. the base is freeze-dried. -21- 2 5.55 g of a colorless crystalline compound.

H 2 O / Karl-Pischer assay: 4.73 $ d / europium complex 3,6,9-triaza-3,6,9-tris // carboxy-methyl / -4- (4-methoxybenzyl) - undecanedioic acid 5.13 g (10 mmol) of the complexing acid described in Example 1b) were dissolved in about 30 ml of water and 1.76 g / 5 mmole / EuO2 of 80%. After 30 minutes, the almost clear solution was filtered and the filtrate was freeze-dried. Yield: 6.62 g

Analysis (based on anhydrous substance) : C 39.89 H 4.26 K 6.34 Eu 22.94 Found: C 39., ^ 1 H 4.38 N 6.17 Eu 22.58

Europium di-sodium salt

The complex produced as described above (497 mg, 0.75 mmol) is dissolved in ten times the amount of water and supplemented with 1.5 ml of 1N sodium hydroxide solution using a microburette. After freeze drying, 540 mg of white crystals are obtained.

The europium di-E-methyl-D-glucamine salt of 3.31 g (5 mmol) of europium complex is added in 40 ml portionwise with 1.96 g (10 mmol) of E-methyl-Dglucamine. freeze-dried. 5.63 g of a colorless crystalline compound remain. (e) 3, 6, 9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-methoxybenzyl) -undecanedioic acid ferric complex; 13 g (10 mmol) of the complexing acid described in Example 1b is dissolved in about 30 ml of water and 793 mg / 5 mmole / Pe 2 is added at 80 ° C. The clear solution was filtered for 30 minutes and the filtrate was freeze dried. Yield: 5.66 g

Analysis / drawn on anhydrous substance /: calculated: C 46.66 I 3 4.98 N 7.42 Pe 9, 86 found .: C 46.71 I 3 5.03 N 7.33 Pe 9, 81

Ferric complex di-sodium salt

The complex obtained as described above (25 mg, 0.75 mmol) is dissolved in a 10-fold amount of water and made up with 1.5 ml of 1N sodium hydroxide solution using a microburette.

After freeze-drying, 460 mg of white crystals are obtained. Iron-1-N-methylethyl-D-glucamine salt of 2.33 g (5 mmol) of ferric complex is charged with 1.96 g (10 mmol) of N-methyl-L in 40 ml. after the complete dissolution of the base, it was freeze-dried. 4.83 g of a colorless crystalline compound remain. -23-

In a similar manner, a bismuth oxide complex of the vizraut is obtained as a dinatriate salt or as a N-methyl-D-glucamine salt. Example 2 3,6,9-Triaza-3,6,9-tris- (tert -butoxycarbonylmethyl) -5- (4-methoxybenzyl) -undecanedioic acid tert-butyl ester in 3.9 g (5 mmol) / di- 3,6,9-tri-aza-3,6,9-tris-tert-butyl ester; butoxycarbonylmethyl (-5- (4-hydroxybenzyl) -undecanedioic acid (Example I7d of DOS 3 710 730) was reacted according to the formula described in Example 1 to give 3.61 g (91%) of the title compound.

Vypoč. C 63.53 K 9.01 N 5.29

Found: C 63.59 E 9.07 N 5.27 b / 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -5- (4-methoxybenzyl) undecanedioic acid 3.13 g / 4 mmole / target. The butyl ester described in Example 2a was treated with trifluoroacetic acid according to the procedure described in Example 1b and further processed to give 1.62 g (79%) of a colorless lyophilizate. K 8.18

Found: 051.34 H 6.14 N 3.11 -24 c / gadolinium 3,6,9-triaza-3,6,9-tris- / carboxymethyl / -5- (4-methoxybenzyl) -yl complex 1 -undecanedioic acid 1.03 g (2 mmol) of the complexing acid described in Example 2b) were complexed according to Example 1c). 1.32 g (99%) of a colorless lyophilizate are obtained. Vypoč. : C 39.57 H 4.23 K 6.29 Gd 23.55 Found: G 39.51 H 4.19 N 6.25 Gd 23.61 T ^ -relaxivity / 1 / mmol.sec / in water 4, Plasma 17 + 0.14 6.61 + 0.18 Example 3 3,6,9-Triaza-3,6,9-tris - (tert-butoxycarbonylmethyl) -4- / "4 - di-tert-butyl ester 4 - (4-methoxybenzyloxy) -benzyl-7-undecanedioic acid 1.56 g (2 mmol) of di-tert-butyl ester 3,6T9-tri-aza-3,6,6-tris (tert-butoxycarbonylmethyl) -4- (4) Hydroxybenzyl (undecanedioic acid) (Example of DOS 3 710 730) is added in tertrahydrofuran at 0 ° C with 66 mg (2.2 mmole / 60) of sodium hydride. 0.3 ml (2.2 mmol) of 4-methoxybenzyl chloride and stirring overnight The solution is made up with water, tetrahydrofuran.

The furan is separated off and the aqueous emulsion is extracted with diethyl ether. The organic phase is washed with water, dried over sodium sulfate and concentrated. The colorless oil obtained is chromatographed on silica gel (ether / hexane 1: 1). Yield: 1.17 g (65%) of a colorless oil

Vypoč. : C 65.33 H 8.62 N 4.67

Found: C 65.29 H 6.65 N 4.59 b / 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- [4- (4-methoxybenzyloxy) benzyl] undecanedioic acid 1, 80 g / 2 mmoles / target. of the butyl ester described in Example 3a are treated analogously to Example 1b) with trifluoroacetic acid and reacted to 905 mg (73) of a colorless, fluffy lyophilisate.

Calc .: C 56.21 E 6.02 N 6.78

Found: U 56.10 E 5.98 N 6.82 c / gadolinium complex 3,6,9-triaza-3,6,9-tris- / carboxymethy 1 / -4 - / - 4- / 4- Methoxybenzyloxy (benzyl) undecanedioic acid The complex of 620 mg / 1mmol / complexing acid described in Example 3b) was treated (analogously to Example 1c) and further processed. 758 mg / 98 c / ° 'beo?

Vypoč. C 45.0}. H 4.43 K 5.43 Gd 20.32 Th. C 44.93 H 4.49 K 5.37 Gd. 20.18 T4 -relaxivity / l / mmol.sec./ clarified in water 4.23 + 0.16 in plasma 6.99 + 0.13 Example 4 di-tert-butyl ester diethylphosphate 3,6,9-triaza- 3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) undecanedioic acid 11.2 g (14.36 mmol) of phenol described in DOS3 710 730 (Example 9f) is dissolved in 100 ml of absolute tetrahydrofuran (THP). 380 mg (15.8 mmol) of sodium hydride (prepared from 50% NaH in paraffin oil) are then washed three times with 10 ml of THl /. After 30 minutes at room temperature, 2.60 g (15.0 mmol) of diethyl ester chloride are added. phosphorous and stirred for 24 hours at room temperature.

The solution was diluted with 500 µl ether and washed three times with 300 ml of 10% sodium hydroxide solution. After drying the organic phase over magnesium sulfate, it was concentrated in vacuo and the residue was purified by Plash chromatography / eluent / ether / hexane = 1. : 1 /. Yield: 11.97 g (91%) of a light yellow oil.

Vypoč. : C 59,00 K 8,58 Η 4,59 3? 3.38

Finding. / C 58.88 Η 3.63 Ν 4.63 1 3.30 b / di 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4-benzyl tert-butyl ester -undekandikyse - lina

A mixture consisting of 1.33 g (3.62 MW) of anhydrous titanium trichloride and 1.02 g (26.09 mmol) of finely divided potassium in 20 ml of tetrahydrofuran was refluxed under argon for 1 hour. 11.5 g (12.55 mmol) of the compound described in Example 4a / in 50 ml of tetrahydrofuran were added dropwise over 15 minutes. It is then heated for 8 hours under reflux. It is cooled in an ice bath, carefully added with 20 ml of methanol, then with 100 ml of water and extracted 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 (eluent: hexane). (ether = 2: 1) 8.9 g (93) of the title compound are obtained as a colorless oil, which when left to crystallize.

Calc .: C 64.46 H 9.40 N 5.50

Found: C 64.54 H 9.15 N 5.41 -28- c / 3,6,9-3,6,9-triaza-3,6,9-tris- / carboxymethyl] -4-benzofluoroanedioic acid 7 , 64 g / 10 mmol / target. of the butyl ester described in Example 4b) was reacted analogously to Example 1b (to 4.01 g (83%) of the title compound).

Vypoč. C 52.17 H 6.05 K 8.69 found .: C 52.23 E 5.99 E 8.73 d / gadolinium complex with 3,6,9-triaza-3,6,9-tris- / carboxymethyl (4-benzyldecanedioic acid) 2.42 g (5 mmol) of the complexing acid described in Example 4c) were reacted according to the analogous example given in Example 1c to 3.14 g (98.5%) of the title compound. colorless, flaky lyophilisate.

Calc .: C 39.55 H 4.11 N 6.59 01 24.66

Found: C 39.47 H 4.19 E 6.52 Gd 24.88 ϊ - ^ - relaxivity / 1 / mmol. sec / is: in water 4.54 + 0.13 in plasma 6.89 + 0.17 yterbium complex with 3,6,9-triaza-3,6,9-tris- / carboxymethyl / -4-benzyldecanedioic acid

Analogously to the production of the gadolinium-2 O-complex, the corresponding ytterbium complex is obtained when Yb ^ O2 is used in place of Gd2O3. -tris- / terc. -butoxycarbonylmethyl-4-benzyloxomethyl-undecane-diacid ané solidly mixed suspension consisting of 14.1 g (20 mmol) di-tert-butyl diester 4-hydroxymethyl-3,6,9-triaza-3,6,9-tris- target 7.2 ml (60 mmol) of benzyl bromide are added dropwise over 30 minutes at room temperature to 0.3 g of tetrabutylammonium hydrogen sulphate in 200 ml of dichloromethane (200 ml of 30) of sodium hydroxide solution and then stirred at room temperature. 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. After drying the combined organic phases over magnesium sulfate it is chromatographed. silica gel (ether / hexane = 1: 1). 13.0 g (82% of theory) of the title compound are obtained as a colorless oil.

Calc .: C 63.53 H 9.01 K 5.29

Balez .: C 63.42 H 9.07 K 5.21 -30- b / 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4-benzyloxymethyl-undecanedioic acid 7.94 g / 10 moles / target. The butyl ester described in Example 5a) was reacted as described in Example 133 (4.06 g) (79% theory) of the title compound.

Calc .: C 51.46 H 6.09 N 3.18

Found: C 51.51 H 6.06 N 8.12 c / gadolinium complex with 3,6,9-triaza-3,6,9-tris- / carboxymethyl / -4-benzyloxymethyl-undecanedioic acid 2.57 g / 5 mm (complexing acids described in Example 51) were reacted analogously to Example 1c to 3.30 g (93.9% of theory) of the title compound. A colorless, flaky solid is obtained.

Vypoč. : C 39.57 H 4.23 N 6.29 Gd 23.55

Found: C 39.51 E 4.26 N 6.35 Gd 23.27 T ^ -relaxivity /1/mmol.sec/ in water 4.39 + 0.12 in plasma 6.31 + 0.15 Example 6 bis- tert -butyl ester 3,6,9-triaza. 3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-carboxymethyl-xylene) -yl-undecanoic acid -31-

3,6,40 g (30 mmol) of 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-carboxymethoxybenzyl) undecanedioic acid di-tert-butyl ester 3,6,9-triaza-3,6,9-triaza-3,6,9-triaza- 2.7 g (90 mmol) of sodium hydride are added to the tetrahydrofuran at 0 ° C. To this was added dropwise 6.25 g (45 mmol) of bromoacetic acid in tetrahydrofuran, stirred at 0 ° C for 1 hour, and stirred overnight at room temperature, the solution with lower water, tetrsulfurate was distilled off and the aqueous phase was stirred. The organic phase is extracted with ethyl acetate and the organic phase is dried over sodium sulfate and concentrated.

The residue is chromatographed on silica gel with dioxane / methanol / triethylamine (15: 4: 1); the combined fractions were concentrated and acetic acid (1 K citric acid) was separated. 21.3 g (87% of theory) was obtained as a colorless oil.

Calc .: C 61.63 N 3.54 K 5.01 Found: C 61.62 H 8.62 K 4.95 b / 3,6,9-triaza-3,6,9-tris- / carboxymethyl (-4- (4-carboxymethoxybenzyl) undecanedioic acid 21.0 g (25 mmol) of the tert-butyl ester described in Example 1b) were reacted to 11.0 g (73.9%) of the title compound. -32-

Calc .: C 49.55 H 5.60 K 7.54

H, 5.51; K, 7.47; (c) gadolinium 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (carboxymethoxybenzyl) -undecanediocyanate complex; 5.57 g (10 mmol) of the complexing acid described in Example 6b) were reacted according to an analogous example of Example IQ to 7.01 g (98.5%) of the title compound.

Calc .: 0 38.81 H 3.96 N 5.90 Gd 22.09

Found: C 38.75 H 3.89 K 5.97 Gd 21.93 T ^ -relaxivity /1/mmol.sec/ in water 5.00 + 0.01 in plasma 7.10 + 0.08 Example 7 Production of a sodium salt of a trivalent solution of 3,6-triaza-3,6,9-ris- / carboxymethyl-4-benzyloxymethyl-undecanedioic acid 6.6 g / 10 mmol / gadolinium complex obtained according to Example 5 ° Dissolve in 70 ml of water for injection (pi) and add dropwise with 1 N sodium hydroxide solution until pH 7.2. The addition of 0.02 g of tromethamine to the water was added to the p.i. per 100 ml, the solution is filled into vials -33- and heat sterilized. EXAMPLE 8 3,6,9-Triaza-3,6,9-tris- tert -butoxycarbonylmethyl [4- (4-ethoxybenzyl) -unde-candycellic acid] di-tert-butyl diester. 5.85 g (7.5 mmol) // 3, 6, 9-triaza-3,6,6-tris-tert-butoxycarbonylmethyl-4-4-hydroxybenzyl- undecandic acid (Example 9f LOS 3,710) Of 0.80 g (10 mmol) of sodium hydride in 100 ml of tetrahydrofuran at 0 DEG C. To this is added 1.56 g (10 mmol) of iodoethane and stirred for 3 hours. the water product 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 (relative to anhydrous substance): Calculated: 0 63.91 H 9, H K 5.20

Found: C 63,67 H 9,05 N 5,28 b / 3,6,9 - tr ia per - 3,6,9 -1 ri ε / carbo xyme t hy 1 / - 4- / 4-et ho xybe nzy 1 / - undekand iky sel ina. -34- 3.64 g / 4.5 mmol / target. of the butyl ester described in Example 8a) was dissolved in 25 ml of trifluoroacetic acid, stirred for one hour at room temperature and treated analogously to Example 1b (yield: 1.2 g / 50.6%).

Analysis (based on anhydrous substance): Calc .: C 52.36 H 6.31 K 7.97

Balez .: C 52.21 H 6.39 N 7.84 Example 9 di-tert. butyldiester 3,6,9-triaza-3,6,9-tris- / tert. butoxycarbonylmethyl-4- (4-butoxybenzyl) -unecandic acid in 5.85 g (7.5 mmol) of di-tert-butyl diester 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) The 4- (4-hydroxybenzyl) undecanedioic acid (Example 9f of DOS 3 710 730) was reacted analogously to Example 8a with 1.84 g (10 mmol) of 1-iodoethane and worked up as described in this example »Yield: 4.1 g / 65.4 / 7

Analysis (based on anhydrous substance): Calc .: C 64.64 K 9.28 B 5.03

Found: C 64.82 H, 9.37 K 4.96 3.6.9-Triaza-3,6,9-tris / carboxymethyl / 4- (4-butoxybenzyl) undecanedioic acid 3.34 g / 4 mrcol The tert-butyl ester of Example 0 was dissolved in 20 ml of trifluoroacetic acid, stirred for 1 hour at room temperature and worked up in analogy to Example 1b. Yield: 1.36 g (61.0).

Calc .: C 54.054 H 6.71 K 7.57

Found: C, 53.33; H, 6.63; To 7.41 (c) dinatriate, gadolinium, 3,6,9-triaza-3,6,9-tris / carboxymethyl) -4- (4-butoxybenzyl) complex. The undecanedioic acid 556 mg (1 mmol) of the complexing acid described in the above example is made up with 40 ml of water and treated at a temperature of 80 ° C to form a complex with 181 mg / 0.5 mmol / Gd 2 O 4. It is then neutralized with 2 ml of 1 N NaOH, stirred with activated carbon, filtered and the filtrate is freeze-dried. Yield: 711 mg / 94.3 //

Analysis (based on anhydrous substance):

Calc .: C 39, θ3 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 for 6.17 ΤΊ-relaxivity / 1 in water is 5.80 + 0.26 in plasma 14.20 + 0.98

An analogous method is obtained with europium oxide

The Eu.alpha. Calcd: C 40.11 H 4.31 Eu 20.30 N 5.61 Na 6, Found: C 39 * 97, H 4.39 Eu 20.02 N 5.72 Na 6, Anal. Corresponding iron complex with iron oxide Calc .: C 46.03 N: 4.94 Pe 8.56 N 6.44 to 7.05 Found: C 45.38 ΗΗ, 03 ί'è 8.30 N Example 10 6.50 3,6,9-Triaza-3,6,9-tris-tert-butoxycarbonylmethyl-4- (4-benzyloxybenzyl) undecanedioic acid 7,11 di-tert-butyl diester 5.85 g / 7, 5 mmol of [3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) -un-decanedioic acid (Example 9) NOS 3,710,730] does not react abalogically as in of Example 3a with 1.71 g (10 mmol) of benzyl bromide and treated as described in this example. Yield: 4.9 g / 75.1 / / -3Ί-

Analyzes / relative to anhydrous substance /

Calc .: C 66.25 H 8.69 N 4.33

Found: C 66.14 H 3.77 B 4.83 b / 3.6.9-triaza-3,6,9-tris / carboxymethyl / -4- / 4-benzyloxybenzylamine 1 .mu.m and 1 .mu.g / 4 mmole / target. The butyl ester described in Example 10a was dissolved in 20 mL of trifluoroacetic acid, stirred for 1 hour at room temperature and worked up analogously to Example 1b. Yield: 1.33 g (56.5)

Analysis (based on anhydrous substance):

Calc .: C 57.04 H 5.98 K 7.13

Found: C, 56.89; H, 6.03; N, 7.21c. Gadolinium-3,6,9-tri-aza-3,6,9-tris / carboxymethyl) -4- (4-benzoyloxybenzyl) -disodium salt. -undecanedioic acid 590 mg / l of mcol / complex-forming acid described above is supplemented with 40 ml of 1N NaCH water and treated with 181 mg / 0.5 mmol / Gd2O to 80 ° C. ml of 1N NaOH, mixed with activated carbon, filtered and freeze-dried. Yield: 703 mg / 89.2 / / -33-

Analysis (based on anhydrous substance):

Calc .: C 42.69 H 3.34 Gd 19.96 K 5.33 to 5.8 &amp; Found: C 42.33 H 3.91 Gd 19-57 N 5.26 to 5.99T ^ -relaxation In water: 5.81 + 0.31 in plasma: 16.35 + 1.01

The corresponding europium complex is obtained in an analogous manner with europium oxide

Vypoč. C 42.98 H 3.86 Eu 19.42 N 5.37 Na 5.88No: C 43.10 H 3.91 Eu 19.13 N 5.27 to 5.99

The corresponding iron complex is obtained in an analogous manner with the iron (III) oxide:

Calc .: C 48.99 K 4.41 to 8.14 N 6.12 to 6.70 Found: C 48.73 H 4.57 Pe 8.29 N 6.03 to 6.85 Examples for NMR Diagnostics in vivo

Using a GeneralElectric nuclear spin tomograph, specially developed for animal experimental research, images were taken at various times after the administration of the gadolinium disodium salt of Example 1c / in rats.

Spin echo images were performed with a nuclear spin tomograph (CST 2 T) at 2 seals / TR time of 400 ms and a TE time of 20 ms /. were 128 x 128.

The contrast medium was applied intravenously to the tail vein of a male shaved rat (lew / mol), weighing 190 g, at a dose of 0.06 mmol / kg. The animal had a Brown-iearce tumor in the thigh and i.m. dose of Ketavet / Rompun. Different dark structures in the abdomen are visible in the coronary blank (baseline).

One minute after application, the first enlargement is already visible in the urinary bladder. A large increase in stomach contrast is apparent 45 minutes after injection.60 mi-nut p.i. a good representation of the tumor (s) of the reference tube / bladder and stomach can be observed. In addition, the differentiation of the intestine is evident, thereby facilitating the differentiation of the intestinal loops, fat as well as lymph nodes. Also, the contrast of ice-pans is striking, these being even better illustrated after 65 minutes after injection in a somewhat different layer. 180minut p.i. is an increase in contrast clearly visible even in the axial frame of the liver. This makes it possible to differentiate the stomach, liver, and duodenum apancreas. Example 2 TJ experimental animals were female rats / Mol rats weighing 160-130 g. The animals were anesthetized prior to imaging. The illustration was performed in a General Electric MRI-experimental instrument (field strength 2 tesla). First, the images were created without a contrast medium with a T - ^ - spin sequence mass / Tf = 400 msec, TE = 20msec, axial sectional plane, layer thickness 3mm /. The liver is now showing in normal signal intensity; the stomach tends to appear darker than the liver. In the case of animal 1, the stomach exhibits a significant amount of signal intensity, although it is attributable to the rest of the food that is contained in the stomach at a relatively high concentration / animals did not receive any food 6 hours prior to inspection. 3 weeks before the experiment, osteogenic sarcoma; this is an isodent and unboundable blank. The contrast medium was dosed using a catheter-inserted vein, at a dose of 0.1 mmol Gd / kg / solution concentration of 0.05 mmol Gd / ml at 0.90 NaCl. / for all three substances. All 3 substances can be recorded after 90 minutes for 60 minutes p.i. a distinct liver enlargement attributable to the image via the hepaocytes and in this period was not observed after the application of the hitherto single-on-the-scattered tomography contrast medium Magnevistuz. In addition, in the case of animal 3, a tumor that is not accepted by the contrast agent is now clearly recognized and received in a very low proportion. Furthermore, for all substances, the most pronounced example is 10c /, at least for example 8c), a large stomach enlargement. In addition, this offers additional diagnostic-modalities with regard to better liver-to-calf boundaries.

Claims (11)

-42- LAW PGKALW Row WP5 04 ί-ΑΛί'Λ b Z4 · .'43 X '> O o <C-.CD' 7? rc PATENT CLAIMS Compounds of general formula I X00CCH, L-N- (2-I-CH-Z). -CH- CHoCOOX i 2 -N- -C 1 -C 2 -CH, GH "GC0X1 -NX00CCH, ch2coox Λ /, where Z1 and targeted at odik ^ t / it / jff) Z? the remainder - / CH2 / m- / C6Vq - / ° 4 'Wn - / C6H4 / r / 0 / rB where man denotes the numbers 0 to 20, k, lq and the numbers from 0 to 1 and R the hydrogen atom, The C1 -C6 -alkyl radical substituted with OR6 or a CH2COOR7 radical having the meaning of a hydrogen atom of a C1-C6-alkyl radical or a benzyl radical, -43- X denotes a hydrogen atom and / or the equivalent of the metal ion of the atomic element number. 21-29,42, 44 or 57-33, with the proviso that at least two of the substituents X represent the equivalent of a metal ion, one of the substituents a2 Z being a hydrogen atom and the other not a hydrogen atom and in the case where 1 is 0, does not mean kar at the same time the numbers o and z or z do not mean -Chg-CgH ^ -C-CB .. “COOCH2C6E5 or -CE? -C6H4-0- / CH2 / ^ - COOCE ^ Cgl · ^ and - / 0 / rE is not - OH, as well as their salts with inorganic and / or organic bases, and amino acid amides. 2. Compounds according to claim 1, characterized in that Z @ 1 is a hydrogen atom and Z @ 2 is a radical - (-) - (CH2) - (C6H4) - (-) - (CH2) - (O) - /re. 3. Compounds according to claim 1, characterized in that Z2 represents a hydrogen atom and Z1 represents a radical - (CH2) n- / CgH4 / - / O / k- 4. Compounds according to claim 1, characterized in that, Z @ 1 and Z @ 2 respectively represent radicals -CH2-C6h4-oc3, -ch2-c6h5, -oh2-c6e4-o-ch2-c5h4-och3, -CE9-C-. CU2-C6E5, -CH2-C6H4-C-CK2-COOE, -CE2-C6R4-OC2H3, -CH2-C6H4-OC4E9'-CH2-C6E4-O-CH2-C6H5 ' 5. Gadolinium-3,6,9-triaza-3,6,9-44-tris / carboxymethyl / -4- (4-metboxybenzyl) undecanedioic acid complex; europium complex with 3,6,9-triaza-3,6,9-tris / carboxymethyl [4- (4-methoxybenzyl) undecanedioic acid; 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-methoxybenzyl) undecanedioic acid trivalent iron complex; 3,6,9-triaza-3,6,9-tris / carboxymethyl / 4- (4-methylbenzyl) -benzamide bismuth complex; 3 gadolinium 3,6,9-t'isia-3,6,9-tris / carboxymethyl / -5- (4-methoxybenzyl) -undecanedioic acid complex gadiinium / 3,6,9-triaza-3,6 complex 9-tris / carboxymethyl-4- (4- (4-methoxybenzyloxy) benzyl-7-undecanedioic acid; gadolinium complex with 3,6,9-triaza-3,6,9-tris / carboxymethyl) -4-benzyldecanedioic acid ; 3,6,9-triaza-3,6,9-tris / carboxymethyl) -4-benzyldecanedioic acid, yterbium complex; a gadolinium complex with 3,6,9-triaza-3,6,9-tris / cabboxymethyl) -4-benzyloxymethyl-undecanedioic acid; a gadolinium complex with 3,6,9-triaza-3,6,9, -tris / carboxymethyl) -4- (4-carboxymethoxybenzyl) undecanedioic acid; a 3,6,9-triaza-3,6,9-tris / carboxymethyl / -4- (4-ethoxybenzyl) undecanedioic acid complex of gadolinium; europium complex with 3,6,9-triaza-3,6,9-tris / carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid; -45- an iron complex with 3-6,9-triaza-3,6,9-tris / carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid; a gadolinium complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butoxybenzyl) undecanedioic acid; europium complex with 3,6,9-triaza-3,6,9-tris / carboxymethyl) -4- (4-butoxybenzyl) undecanedioic acid; 3,6,9-triaza-3,6,9-tris / carboxymethyl) -4- (4-butoxybenzyl) undecanedioic acid iron complex, gadolinium complex with 3,6,9-triaza-3,6, 9-tris / carboxymethyl) -4- (4-benzyloxybenzyl) imidanedioic acid; europium complex with 3, 9, 9-triaza-3, 6,9-tris / carboxymethyl-4- (4-benzyloxy) ene-1-unanecaniline; an iron complex with 6 6,9-triaza-3,6,9-tris / carboxymethyl) -4- (4-benzyloxybenzyl) undecanedioic acid; 6. A pharmaceutical composition comprising at least one physiologically tolerable compound according to items 1 to 5, optionally with additives customary in galenic form. 7. The use of one or more physiologically acceptable compounds according to the clauses for the preparation of diagnosti-diagnosis, x-ray diagnostics and radiation therapy. 8. Use of at least one physiologically tolerable compound according to items 1 to 5 for the preparation of compositions for NKR-diagnosis. and systemic system. -46- 9. Use of at least one physiologically tolerable compound of the formula I XCOCCH 1 1 Z 1 Z 2 CO 2 COX 2 CH 2 COOX 1 in 1 XO 2 CCH 2 - CE-- -CH-- -E-CIL · - -CH 2 - --- p 1 CH 2 CH 2 OX where Z 1 and Z independently represent a hydrogen atom or a radical - (CH 2) n - (6 H 4 / q - / 0 / k - / CH 2 / n - / C 6 H 4 / i - / O / r E where the numbers are man numbers) 0 - 20 k, l. , oar numbers 0 and 1 and R represents a hydrogen atom, a C1-C6-alkyl radical optionally substituted by OE ^ or by a group □ Ηζ-, ΟΟΟΒ1 with R “in the case of hydrogen, C1-C6-alkyl or benzyl- the groups, the hydrogen atom and / or the metal ion equivalent of the first atom by atomic numbers 21-29,42,44 or 57-83, with at least two of the substituents X being the equivalent of a metal ion, one of the substituents and the atom being in fact, the other is not hydrogen, and when 1 is 0, the carbons are not simultaneously the number 1, as well as their salts and inorganic and / or organic bases, amino acids, or amino acid amides for production of gastric-intestinal tract conjugation agents. XOCCC1 I 10. A process for the preparation of compounds of formula I2 CH3 GCCX1. CIE-CCOX, cZ -CH- --- p. -CH 2 -CH, XCOCCH 2 -CH 2 -CH 2 O-CH 2 -CH 2 -CH, XCOCCH 2 -CH 2 O-CH 2 O-CH 2 O-CH 2 O-CH 2 O-CH 2 O-CH 2 O- 0 / k- / 0R2 / n- / C6E4 / I- / 0 / r- B where n is an integer from 0 to 20 k, l, qar of numbers 0 and 1 and E is hydrogen, C -, - ω-alkyl a moiety optionally substituted by O- or CH-, COOR 'with E, in a hydrogen atom, a C, -C8 -alkyl or a benzyl group, X a hydrogen atom and / or a metal ion equivalent with an atomic number 21-29,42,44 or 57-33, with no less than two of the substituents X being the equivalents of the OV 1 2 metal ion, one of the substituents Z and Z denoting a hydrogen atom and the other not being a hydrogen atom in the case of at 1 denote the number 0, kar not- Ί?, known a and at the same time the number l, that Z or Z does not mean -CH 2 -C 6 H 4 -O-CH 2 -COCK 2 C 6 H 5 or -CE 2 - C 6 E 4 -O / CE 2/5-CCOC E 4 C 2 -C 8 -L a and / Q / -E is not -OH, as well as their salts No. O-X with inorganic and / or organic bases, amino acids or amino acid derivatives, wherein the compound of formula II is R-OOCCH2. CH 2 COOk -CB, -CH 2 C 6 COCR 1 '-E / 11 /, kccoccee CrhCOOH where the acid protecting group is 7p and Z 4 is a hydrogen atom or a radical - (CIL) / - CrH, /OE with the proviso that one of the substituents Z @ 4 and Z @ 4 is a hydrogen atom and the other is allowed to be converted in the known manner into the moiety of the moiety Z &quot;, and Z, the acid protecting group R is cleaved off, thus obtaining of the formula I ' with a hydrogen atom, are reacted with at least one metal oxide or metal salt of the atomic number 21-29,42,44 or 57-33, and finally if if desired, the present hydrogen atoms are substituted for the cations of inorganic and / or organic bases, amino acids or aminoscelin amides. 11. A process for the preparation of pharmaceutical compositions according to item 6, characterized in that the complex compound dissolved or suspended in water, physiological saline solution or protein solution, optionally with additives customary in galena, is formulated for enteral or parenteral administration. . f Atjvokéinf Π5 G4 PR '3 YSgTĚČKA Counseling Center IDJ> Žitná 25