SK277828B6 - Complex dipa derivatives, pharmaceutical agents containing this compounds, their using and method of their production - Google Patents

Abstract

Compounds with general formula I, where Z exp.1 and Z exp.2 mean independently atom of hudrogene or surplus -(C/SUB_6H sub.4) sub.q-(O)sub.k-(CH sub.2)sub.n- -(C sub.6 H sub.4)sub.l-(O)sub.r-R, where m and n mean number 0 to 20; k,l,q and r numbers 0 and 1 and R atom of hydrogene, C sub.1 to C sub.6-alkyl surplus, incidentaly substituted OR exp.1 or group CH sub.2COOR exp.1 with R exp.1 in importance of hydrogen atom, C/SUB_1/ to C/SUB_2/- -alkyl surplus or benzyl group, X atom of hydrogen and/or equivalent of metal ion element with atom number 21 to 29, 42, 44 or 57 to 83, where at least one from substituents Z/EXP_1/ and Z/EXP_2/ is atom of hydrogen and second higher said surplus and in cause when n and l mean number 0, k and r don't mean parallely number 1 and their salts with inorganic and/or organic basis, aminoacids or amides of aminoacids. These compounds are appreciate pharmaceutical agents.

Description

Technical field

The invention relates to novel complexes and salts of the complexes, compositions containing the compounds, their use in diagnostics and therapy, as well as a process for the preparation of these compounds and compositions.

Metallic complexes as contrast media for radiology were considered in the early 1950s. However, the compounds used at that time were so toxic that their use in humans was out of the question. Therefore, it was quite surprising that certain salts of the complexes were shown to be sufficiently tolerable, so that routine use of these complex salts in humans for diagnostic purposes could be considered. The dimeglumine salt of Gd DTPA (gadolinium-II-diethylenetriamine pentaacetic acid complex) was the first representative of this class of substances to be well-suited for tomography with nuclear full-load. This was registered under the name MagnevistW worldwide as the first NMR diagnostics.

Magnevist® is particularly well suited for the diagnosis of pathological areas (e.g., inflammations, tumors, heart attacks, etc.). After intravenous injection, the compound is separated extracellularly and eliminated by glomerular secretion through the kidney. Penetration through the intact cell membrane and extrarenal secretion are practically not observed.

Especially for patients with impaired renal function in whom Magnevist® is only very slowly excreted and in part can only be removed from the body using a dialysis machine, contrast media that exhibit at least partial extrarenal excretion would be desirable.

Thus, NMR-contrast agents are required which

It is therefore an essential object of the invention to provide such compounds and compositions as well as to provide a process for their preparation. This object is accomplished by the present invention.

The compounds of the invention exhibit the desirable property of both renal excretion and excretion together with faeces.

Surprisingly, it has been shown that bile elimination is not the only extrarenal route of excretion: in NMR tests in rats, an increase in gastric-intestinal contrast was unexpectedly observed following an intravenous dose of the compounds of the invention. The kidneys as well as the implanted tumors are also more contrasted.

Secretion by the stomach has the advantage of allowing the abdominal structures (e.g., pancreas) of the gastrointestinal tract to be limited while enhancing the contrast of pathological processes (tumors, inflammations). In addition, an illustration of the renal system, liver and gall bladder and bile duct can be achieved. In addition to an improved presentation of gastric ulcer and carcinomas, secretion of gastric juices can also be examined using an imaging system.

By providing the compounds of the invention, patients with renal insufficiency as well as patients with gastrointestinal disease (at least 10% of the population of western industrialized countries) can be assisted. Most frequent patients, as well as a large number of patients suspected of having such a disease, should undergo diagnostic examinations. There are currently two suitable methods for this purpose: endoscopy and X-ray diagnostics using barium contrast contrast media.

These examinations show various shortcomings: they are exposed to the risk of radiation, are traumatic, inconvenient, occasionally even risk to the patient, and can therefore cause physiological stress. Most often they have to be performed repeatedly, they are relatively expensive to carry out, require active collaboration with patients (for example, assuming a certain posture), and are often unusable in old and at risk patients.

The task of making available new diagnostic methods for the detection and localization of gastrointestinal diseases which do not have these drawbacks is therefore also solved by the compounds of the complexes and compositions of the invention.

Even without specific measures, their pharmacokinetics will allow the diagnosis of many diseases to be improved. The complexes are largely eliminated again unchanged and rapidly, so that no harmful effects are observed even at high doses, especially when relatively toxic metal ions are used.

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

The invention therefore relates to the use of at least one physiologically tolerable compound of the formula I

XOOCCH; l ^l X * CMjCOOX CHjCOOX

II

9 - CM CTI ------- H — CH3 ---- CH j W (I},

II

Wherein Z ^1a is independently hydrogen or the radical - (CH ₂ ) _m - (C ₆ H ₄ ) _q - (O) _k - (CH ₂ ) _n - (C ₆ H ₄ ) ₁ - ( O) _r -R where m and n are 0 to 20; k, 1, q and numbers 0 and 1 a

R is a hydrogen atom, a C 1 -C 8 -alkyl radical, optionally substituted by OR ', or a CH ₂ COOR' s R * radical, a C 1 -C 8 -alkyl radical or a benzyl group,

X is a hydrogen atom and / or a metal ion equivalent of an element having atomic number 21-29, 42.44 or 5783, with at least two of X being a metal ion equivalent that one of Z * and Z ^ is hydrogen and the other is not a hydrogen atom and that when 1 is 0, it does not simultaneously represent 1;

as well as salts thereof with inorganic and / or organic bases, amino acids or amino acid amides for the manufacture of means for NMR diagnosis of the stomach intestinal tract.

The compounds of the invention are characterized by formula (I)

XOOCCH, X ¹ CH 3 COOX CM 3 COOX

II

H ------- CH ----- CH ------- H ---- CHj ---- CH j --- H (I>,

II

XCOCCWj OIjCOOX where Z * and Z ^ are each independently hydrogen or a radical

- (CH 2) _m - (C ₆ H 4) - (O) k - (CH 2) n - (C ₆ H 4) 1 - (O) r R, where m and n are 0 to 20; k, 1, q and numbers 0 and 1 a

R is a hydrogen atom, a C 1 -C 8 -alkyl radical, optionally substituted by an OR 4, or a CH ₂ (C 1 -C 8) R 8 radical as a hydrogen atom, a C 1 -C 8 -alkyl radical or a benzyl group,

X is a hydrogen atom and / or a metal ion equivalent having atomic number 21-29, 42, 44 or 57-83, with at least two substituents X being the metal ion equivalent that one of Z * and 7? is a hydrogen atom and the other is not a hydrogen atom that when n and 1 are 0, k and r do not simultaneously represent 1 that Z * or are not groups

-COOCH ₂ C ₆ H _5, or CH ₂ -C ₆ H 4 -O- (CH _{2) 5} -COOCH-jCgHj, and it is not -OH, _-CH2 not -CgH4-OH and the sum of q 1 is 1 or 2; as well as their salts with inorganic and / or organic bases, amino acids or amino acid amides.

If the composition of the invention is intended for use in NMR diagnostics, the central ion of the complex salt must be paramagnetic. These are in particular divalent and trivalent ions of the elements of atomic numbers 21-29,42,44 and 5870. Suitable ions are, for example, trivalent chromium ions, divalent manganese ions, divalent iron ions, divalent cobalt ions, divalent nickel ions, divalent copper ions, trivalent prazodyme ions, neodymium trivalent, samarium trivalent ions, and yterbium trivalent ions. Due to their very strong magnetic moment, trivalent gadolinium ion, trivalent dysprosion ion, trivalent holmium ion, trivalent erbia ion and trivalent iron ion are particularly preferred.

If the device according to the invention is intended for X-ray diagnostics, then the central ion must be derived from the element with a higher atomic number in order to obtain sufficient X-ray absorption. It has been found that diagnostic means which contain a physiologically tolerable salt of the complex with the central ion of the elements of atomic numbers 21-29,42, 44, 57-83, i.e. the lanthanum trivalent ion and the above-mentioned lanthanide ions are suitable for this purpose.

Preferred numbers for m and n are 0 to 5.

Suitable substituents for the R and R * alkyls are linear or branched chain hydrocarbons having up to 6, preferably up to 4, carbon atoms, which in the case of R are optionally substituted one or more times, preferably 1 to 3, hydroxy groups or C1-C6- alkoxy, preferably C 1 -C 4 -alkoxy.

Optionally substituted alkyl groups include, for example, methyl, hydroxymethyl, ethyl, 2-hydroxyethyl, 2-hydroxy-1- (hydroxymethyl) ethyl, 1- (hydroxymethyl) ethyl, propyl, isopropyl, - 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-tri-hydroxybutyl, cyclopentyl, cyclohexyl, 2,3,4,5,6-pentahydroxyhexyl, as well as in the case of hydroxyalkyl groups, their C 1 -C 4 -alkyl derivatives, preferably C 1 -C 4 -alkyl derivatives.

Preferred substituents of "optionally 7? · Compounds of the invention are -CH ₂ -C ₆ H ₄ OH-CH ₂ -C ₆ H ₄ OCH ₃ -, -CH ₂ -C ₆ H ₅ -, _-CH2 -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 _s -, -CH ₂ - C ₆ H ₄ -OC ₄ H ₉ -. -CH ₂ -c ₆ h ₄ -o <h ₂ -c ₆ h ₅ .

In addition, the preferred substituent Z ¹ or Z ² for use as a means for NMR-diagnosis of the gastrointestinal tract is the radical -CH ₂ -C ₆ H ₄ OH.

If not all of the acidic hydrogen atoms are substituted by a central ion, one, more, or all of the remaining atoms may be replaced by inorganic or organic base or amino acid cations. Suitable inorganic cations are, for example, lithium, potassium, calcium, magnesium and especially sodium. Suitable organic base cations are, inter alia, those derived from primary, secondary or tertiary amines, such as ethanolamine, diethanolamine, morpholine, glucamine, Ν, Ν-dimethylglucamine and especially N-methylglucamine. Suitable amino acid cations are, for example, cations of lysine, arginine and omitin. Suitable amino acid amide cations are, for example, cations of lysine methyl amide, glycine amide, serine methyl amide.

Preparation of complexes of the invention the compounds of formula I, is carried out by reacting compounds of formula r'ooCCHj Π 1 '1' ¹ CHjCOM CKjCOOR ²

I

H -------- CH ------ CH -------- * ---- CH ₃ ---- CH ₃ H (II>,

I I a´ooCCHj CHjCOMÍ where it means

R ² an acid protecting group,

Z 1 and Z 4 are hydrogen or - (CH ₂ ) ™ - (C 8 H ₄ ) q -OH, with one of Z ⁴ being hydrogen and the other mentioned; converted in a known manner to a compound of the radicals mentioned for Z ^ and Z ^2, R ² groups protecting acid is cleaved, the acid thus obtained complexing agents of formula I with X in the meaning of hydrogen (formula I) are reacted with at least one metal oxide or the metal salt of the element having the atomic number 21-29, 42,44 or 57-83 and finally, if desired, the acidic hydrogen atoms present are substituted with cations of inorganic and / or organic bases, amino acids or amino acid amides.

As the group R ² protecting acids are lower alkyl groups, aryl groups or aralkyl groups, e.g., methyl, ethyl, propyl, n-butyl, t-butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl a bis (p-nitrophenyl) methyl group as well as trialkylsilyl groups.

The cleavage of the R ² protecting groups is carried out by methods known to those skilled in the art (e.g. E. Wunsch, Methoden der org. Chemie (Houben-Weyl), Vol. XV / 1, 4th edition, 1974, p. 315 ff), e.g. by hydrolysis, hydrogenolysis or alkaline saponification of the esters with alkali in an aqueous-alcoholic solution, at temperatures of 0 to 50 ° C. Inorganic or organic acids are used to cleave the t-butyl ester particularly suitable for the present reactions: the ester compound dissolved in a suitable anhydrous organic solvent, but preferably a dry powdered dry substance, is supplemented with either hydrogen halide in glacial acetic acid, trifluoroacetic acid or boron trifluorodiethyl ether in glacial acetic acid and cleaved at -10 ° C to 60 ° C, preferably at temperatures

276 rooms.

The compounds of the general formula (Π), which serve as starting materials for the production of complex-forming compounds according to the invention, are known (DOS 3,710,730 and the literature cited therein) or can be synthesized analogously to the production regulations described therein.

In the reaction of known aliphatic or aromatic hydroxyl compounds to the corresponding arylalkyl ethers or dialkyl ethers, a number of methods known to those skilled in the art are available (e.g. J. March. Advanced Organic Chemistry, third edition 1985, p. 342 ff).

For this purpose, the compounds of formula Π, where the alkali-resistant acid protecting group is, are dissolved in a polar aprotic solvent such as tetrahydrofuran, dimethoxyethane or dimethylsulfoxide and are supplemented with a base such as sodium hydride, sodium hydroxide or alkali metal carbonates at temperatures between -30 ° C and the boiling point of the solvent just used, but preferably between 0 ° C and 60 ° C. To this is added the compound of formula m.

Y- (CH ₂ ) _n - (C ₆ H ₄ ) _1- (O) _r R (HT), wherein

Y is a nucleofug, such as Cl, Br, J, CHy -CgffySOy or CF3SOy, and the other symbols have the same meaning as in Formula I.

The reaction times are, depending on the residues involved, 30 minutes to 8 hours.

As an alternative to the reaction conditions described above, both arylalkyl ethers and dialkyl ethers can be produced very advantageously by sequential phase 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 biphasic mixture consisting of an aqueous base, preferably 30% sodium hydroxide solution and a water-immiscible organic aprotic solvent. Suitable phase transfer catalysts are compounds known to those skilled in the art, but preferably a tetraalkylammonium salt or a tetraalkylphosphonium salt.

If it is desired to produce compounds of formula I, with k, n, 1 and r = 0 and R being hydrogen, it is possible, starting from the corresponding unsubstituted amino acids (e.g. phenylalanine), to perform the synthesis analogously to methods known in the literature.

If a series of analogous compounds are to be synthesized, it is recommended to produce the phenol derivatives described in DOS 3,710,730 and the reductive removal of functional phenolic groups by methods known to those skilled in the literature. Particular mention may be made of the reduction of aryldiethylphosphates by titanium, which can also be carried out very advantageously in the presence of ester groups (S.C. Melch et al., J. Org. Chem., 43,4797-99 (1978) and the literature described therein). In this case, the corresponding aryldiethyl phosphate is first formed from the phenolic starting material by reaction with diethyl phosphoric acid chloride in 70 to 100% yield, preferably using sodium hydride as the base in a polar aprotic solvent. It is then reduced from freshly made titanium metal. Preferably, to produce highly active titanium, titanium tetrachloride is reduced by magnesium or potassium in anhydrous tetrahydrofuran under an inert gas.

To this mixture is added diethyl phosphate as described above and is heated for 2 to 24 hours, preferably 6 to 16 hours under reflux. After completion of the reaction, chromatographic work-up is optionally carried out. Palladium catalyzed reduction of the corresponding aryl triflates of S. Cacchi et al. Tet. Lett. 27, 2541 -44 (1986).

The compounds of the formula (X) thus obtained with the meaning of the hydrogen atom are complexing agents. They can be isolated and purified, or converted without isolation to metal complexes of formula I with at least two substituents X in terms of metal ion equivalent.

The metal complexes according to the invention are produced as disclosed in DE 3 401 052, in which a metal oxide or a metal salt (e.g. nitrate, acetate, carbonate, chloride or sulphate) of the element with atomic number 21-29,42, 44, 58-70 dissolved or suspended in water and / or a low alcohol (e.g. methanol, ethanol or isopropanol) and reacted with a solution or suspension of an equivalent amount of a complexing acid of formula (I) with X in the meaning of a hydrogen atom, preferably at temperatures between 40 to 100 ° C and finally, if desired, the acidic hydrogen atoms present are substituted with cations of inorganic and / or organic bases, amino acids or amino acid amides.

Neutralization is carried out using inorganic bases (e.g. hydroxides, carbonates or bicarbonates), for example, derived from sodium, potassium, lithium, magnesium or calcium and / or organic bases, such as, inter alia, primary, secondary or tertiary amines such as ethanolamine, morpholine, glucamine, N-methylglucamine and Ν, Ν-dimethylglucamine as well as basic amino acids such as lysine, arginine and omitin.

For the production of neutral complex-forming compounds, for example, so many of the required bases can be added to the acid salts of the complex in aqueous solution or suspension to achieve a neutralization point. The resulting solution can then be concentrated to dryness. Often it is preferred that the formed neutral salts be precipitated by the addition of water-miscible solvents such as low alcohols (methanol, ethanol, isopropanol and others), low ketones (acetone and others), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane and others) to obtain easy-to-isolate and well-purified crystals. It has proven to be particularly advantageous to add the desired base to the reaction mixture already during complex formation, thereby saving one step of the process.

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

This can be done, for example, by reacting the complex-forming acid in an aqueous suspension or solution with the oxide or salt of the central ion-providing element and half of the amount of organic base necessary for neutralization, isolating or forming the complex formed and then The inorganic base addition may also be reversed.

The pharmaceutical compositions of the invention are also prepared in a known manner by suspending or dissolving the complex-forming compounds of the invention - optionally with the addition of conventional pharmaceutical ingredients - in an aqueous medium, and then optionally sterilizing the suspension or solution. Suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), small additives of complexing agents (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 saline are desired for enteral use or other purposes, these are mixed with one or more galenic excipients (e.g. methylcellulose, lactose, mannitol) and / or surfactant or surfactants, for example lezithin, Tween®, Myij® and / or flavoring or flavoring agents (e.g., essential oils).

In principle, it is also possible to manufacture the pharmaceutical compositions according to the invention without isolating the complexing salt. In all cases, particular care must be taken and, in the production of chelates, proceed in such a way that the salts or salt solutions according to the invention are practically free of toxic, non-complexing metal ions.

This can be ensured, for example, by 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 complex-forming compounds and their salts. As a final safety step, purification of the isolated salt of the complex remains.

The pharmaceutical compositions of the invention are administered at a dosage of 1 pmol / kg to 5 mmol / kg, preferably 10 to 0.5 mmol / kg of the salt of the complex of the invention. For intravenous injection, aqueous formulations with a concentration of 50 pmol / l to 2 mol / l, preferably 100 mmol / l to 1 mol / l are used. Rectally as well as oral use is preferably carried out with solutions ranging from 0.1 mmol / l to 100 mmol / l. Depending on the diagnostic purpose, the application volumes are between 5 ml and 2 l.

The compositions of the present invention meet various prerequisites in terms of capability as contrast media. Thus, they are excellent in enhancing the image strength of a nuclear spin tomography image after enteral or parenteral administration by increasing its signal strength. Furthermore, they exhibit the high efficacy necessary to allow the body to be burdened with as little foreign matter as possible, which is essential to maintain the non-invasive nature of the investigation.

The good water solubility and low osmolality of the compositions according to the invention make it possible to produce highly concentrated solutions, thereby keeping the circulating volume load within the defensible limits and equalizing the dilution with body fluid. Furthermore, the compositions of the invention not only exhibit high stability in vitro, but also exhibit surprising stability also in vivo, so that the release or exchange of ions, in themselves poisonous, not bound covalently in complexes during the time when new contrast agents are completely eliminated again. slowest.

The compositions of the invention may also be used for radiation therapy. Thus, the gadolinium complexes, due to the large cross-sectional area, are well suited for neutron capture therapy. If the composition of the invention is intended for use in the radiation variant proposed by R. L. Mills et al. (Nature vol. 336 (1988), p.

787), the central ion must be derived from the Mssbauer isotope, such as 57p _{e B} or _e

When the composition of the invention is administered, these may also be administered together with a suitable carrier, such as serum or saline. The dosage depends on the type of cellular disorder and the properties of the metal complex to be used.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

a) 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-methoxybenzyl) undecanoic acid, di-tert-butyl diester

1.56 g (2 mmol) of 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) undecanoic acid di-tert-butyl diester (Example 9f DOS 3,710) 730) was added in tetrahydrofuran at 0 ° C with 66 mg (2.2 mmol) of 80% sodium hydride. To this was added 0.31 g (2.2 mmol) of iodomethane and 30 min. is stirred. Then the solution is made up 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 sulphate and concentrated.

Yield: 1.55 g (97.6%) Calculated: 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) undecanoic acid

1.27 g (1.6 mmol) of the tert-butyl ester described in Example 1a) are dissolved in 25 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. The solution was made up with diethyl ether, the precipitate is suction filtered, washed with ether and dried in vacuo at 40 C over ^much pentoxide. The crude product is dissolved in water and mixed with activated carbon. The coal was filtered off and lyophilized three times to remove trifluoroacetic acid residues.

Yield: 0.62 g (75.4%) Calculated: C 51.46 H 6.09 N 8.18 Found: C 51.27 H 6.02 N 8.11

c) gadolinium 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-methoxybenzyl) undecanedioic acid complex

513 mg (1 mmol) of the complexing acid described in Example 1b) are dissolved in about 30 ml of water and at 80 ° C are added 181 mg (0.5 mmol) of Gd 2 O 3. After 30 minutes, the nearly clear solution was filtered off and the filtrate was freeze-dried.

Yield: 649 mg (97.2%) based on anhydrous material

Calculated: 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

Gadolinium di-sodium salt.

The complex obtained as described above (500 mg, 0.75 mmol) was dissolved in a 10-fold amount of water and made up with 1.5 ml of 1 N sodium hydroxide solution by microburette. After freeze-drying, 533 mg of white crystals are obtained.

Tj - relaxivity (l / mmol.sec) in water is 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 gadolinium complex are added in portions of 40 ml of water in portions with stirring 1.96 g (10 mmol) of N-methyl-D-glucamine. After complete dissolution, the base is freeze-dried.

5.55 g of a colorless crystalline compound remain. H 2 O content (Karl-Fischer assay): 4.73%.

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

5.13 g (10 mmol) of complexing acid described in Example 1b) are dissolved in about 30 ml of water and at 80 ° C 1.76 g (5 mmol) of E 2 O 3. After 30 minutes, the almost pure solution was filtered and the filtrate was freeze-dried.

Yield: 6.62 g

Analysis (based on anhydrous substance) Calculated: C 39.89 H 4.26 N 6.34 Eu 22.94 Found: C 39.71 H 4.38 N 6.17 Eu 22.58

Di-sodium salt of the Europaium complex.

The complex prepared as described above (497 mg, 0.75 nunol) was dissolved in ten times the amount of water and made up with 1.5 ml of 1 N sodium hydroxide solution by microburette. After freeze-drying, 540 mg of white crystals are obtained.

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

3.31 g (5 mmol) of the europium complex in 40 ml of water was added portionwise with stirring 1.96 g (10 mmol) of N-methyl-D-glucamine. After complete dissolution, the base is freeze-dried.

5.63 g of a colorless crystalline compound remain.

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

5.13 g (10 mmol) of the complexing acid described in Example 1b are dissolved in about 30 ml of water and 798 mg (5 mmol) Fe 2 O 3 are added at 80 ° C. After 30 minutes, the nearly clear solution was filtered and the filtrate was freeze-dried.

Yield: 5.66 g Analysis (based on anhydrous substance): Calculated: 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 ferric complex.

The complex obtained as described above (425 mg, 0.75 mmol) was dissolved in a 10-fold amount of water and made up with 1.5 ml of 1 N sodium hydroxide solution by microburette. After freeze-drying, 460 mg of white crystals are obtained.

Di-N-methyl-D-glucamine salt of ferric complex.

2.83 g (5 mmol) of ferric complex in 40 ml of water are charged with 1.96 g (10 mmol) of N-methyl-D-glucamine with stirring and portionwise. After the base is completely dissolved, it is freeze-dried. 4.83 g of a colorless crystalline compound remain.

In an analogous manner, bismuth complex is obtained with bismuth trioxide as the disodium salt or di-N-methyl-D-glucamine salt.

Example 2

a) 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- (4-methoxybenzyl) undecanedioic acid di-tert-butyl ester

3.9 g (5 mmol) of 3,6,9-triaza- di-tert-butyl ester

3,6,9-tris- (tert-butoxycarbonylmethyl) -5- (4-hydroxybenzyl) undecanoic acid (Example 17d DOS 3710730) was reacted according to the procedure given in Example 1a) to 3.61 g (91% of theory) of the title compound. compound. Calculated: 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) is treated as described in Example 1b) with trifluoroacetic acid and further processed.

1.62 g (79% of theory) of a colorless lyophilisate are obtained.

H, 6.09; N, 8.18. Found: C, 51.34; H, 6.14; N, 8.11.

c) gadolinium 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -5- (4-methoxybenzyl) undecanedioic acid complex

1.03 g (2 mmol) of the complexing acid described in Example 2b) are processed to the complex according to the procedure described in Example 1c).

1.32 g (99% of theory) of a colorless lyophilisate are obtained.

Calculated: C 39.57 H 4.23 N 6.29 Gd 23.55 Found: C 39.51 H 4.19 N 6.25 Gd 23.61 T j - relaxivity (1 / mmol.sec) is in water 4.17 ± 0.14 in plasma 6.61 ± 0.18

Example 3 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- [4- (4-methoxybenzyloxy) benzyl] iundecanedioic acid di-tert-butyl ester

1.56 g (2 mmol) of 3,6,9-triaza- di-tert-butyl ester

3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) undecanedioic acid (Example 9f DOS 3710730) was added in tetrahydrofuran at 0 ° C with 66 mg (2.2 mmol) of 60% sodium hydride. To this was added 0.3 mL (2.2 mmol) of 4-methoxybenzyl chloride and stirred overnight. Then the solution is made up 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 sulphate and concentrated. The colorless oil obtained is chromatographed on silica gel (ether / hexane 1: 1).

Yield: 1.17 g (65% of theory) of a colorless oil. Calculated: C 65.38 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 mmol) of the tert-butyl ester described in Example 3a) was treated according to an analogous procedure to that described in Example 1b) with trifluoroacetic acid and reacted to 905 mg (73% of theory) of a colorless, flaky lyophilisate. Calculated: C 56.21 H 6.02 N 6.78 Found: C 56.10 H 5.98 N 6.82

c) 3,6,9-triazine-3,6,9-tris- (carboxymethyl) -4- [4- (4-methoxybenzyloxy) benzyl] undecanoic acid gadolinium complex.

620 mg (1 mmol) of the complexing acid described in Example 3b) was processed to the complex analogously to Example 1c) and further processed.

758 mg (98% of theory) are obtained. Calculated: 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 T | - relaxivity (1 / mmol.sec) in water is 4.23 ± 0.16 in plasma 6.99 ± 0.13

Example 4 3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) un6 decanedioic acid di-tert-butyl ester diethyl phosphate.

11.2 g (14.36 mmol) of the phenol described in DOS 3710730 (Example 9f) is dissolved in 100 ml of absolute tetrahydrofuran (THF). To this was added 380 mg (15.8 mmol) of sodium hydride (made from 50% NaH in paraffin oil by washing three times with 10 mL of THF). After 30 minutes, 2.60 g (15.0 mmol) of diethyl phosphoric acid chloride was added at room temperature. and stirred for 24 hours at room temperature.

The solution is diluted with 500 ml of ether and washed three times with 300 ml of 10% sodium hydroxide solution. After drying the organic phase over magnesium sulphate, it is concentrated in vacuo and the residue is purified by flash chromatography (eluent: ether / hexane = 1: 1).

Yield: 11.97 g (91% of theory) of a pale yellow oil. Calculated: C 59.00 H 8.58 N 4.59 P 3.38 Found: C 58.88 H 8.63 N 4.63 P 3.30

b) 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4-benzyl-undecanedioic acid di-tert-butyl ester

A mixture of 1.33 g (8.62 mmol) of anhydrous titanium tetrachloride and 1.02 g (26.09 mmol) of finely cut potassium in 20 ml of tetrahydrofuran was heated under reflux for 1 hour under argon.

To this mixture was added dropwise over 15 minutes 11.5 g (12.55 mmol) of the compound described in Example 4a) in 50 mL of tetrahydrofuran. It is then heated at reflux for 8 hours. Cool in an ice bath, carefully add 20 ml of methanol, then 100 ml of water and extract 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 theory) of the title compound are obtained as a colorless oil which crystallizes when left to stand.

Calculated: C 64.46 H 9.10 N 5.50 Found: C 64.54 H 9.15 N 5.41

c) 3,6,9-3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4-benzylenedecanedioic acid.

7.64 g (10 mmol) of the tert-butyl ester described in Example 4b) was reacted analogously to Example 1b) to 4.01 g (83% of theory) of the title compound.

Calculated: C 52.17 H 6.05 N 8.69 Found: C 52.23 H 5.99 N 8.73

d) gadolinium 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4-benzylundecanoic acid complex

2.42 g (5 mmol) of the complexing acid described in Example 4c) was reacted according to the analogous procedure in Example 1c) to 3.14 g (98.5% of theory) of the title compound. The gadolinium complex is obtained as a colorless, flaky lyophilisate.

Calculated: C 39.55 H 4.11 N 6.59 Gd 24.66 Found: C 39.47 H 4.19 N 6.52 Gd 24.88 T | - relaxivita (1 / mmol. sec) 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-benzylundecanoic acid.

Analogous to the production of the gadolinium complex, the corresponding yterbium complex is obtained when YbjOy is used instead of GdjOj.

Example 5

a) 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4-benzyloxymethylmethyldecanedioic acid di-tert-butyl ester To a well stirred mixture consisting of 14.1 g (20 mmol) di.ter. 4-hydroxymethyl-3,6,9-triaza butyl ester

-3,6,9-tris- (tert-butoxycarbonylmethyl) undecanoic acid and 0.3 g of tetrabutylammonium hydrogen sulfate in 200 ml of dichloromethane (200 ml of 30% sodium hydroxide solution, dropwise, over 30 minutes at room temperature, 7.2 ml (60 mmol) of benzyl bromide and then stirred for 8 hours.

To this suspension is added 400 ml of water, the organic phase is separated and the aqueous phase is extracted twice with 150 ml of dichloromethane each. After drying the combined organic phases over magnesium sulfate, it is chromatographed on silica gel (ether / hexane = 1: 1). 13.0 g (82% of theory) of the title compound are obtained as a colorless oil.

Calculated: C 63.53 H 9.01 N 5.29 Found: C 63.42 H 9.07 N 5.21

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

7.94 g (10 mmol) of the tert-butyl ester described in Example 5a) was reacted according to an analogous procedure to that described in Example 1b) to 4.06 g (79% of theory) of the title compound.

Calculated: C 51.46 H 6.09 N 8.18 Found: C 51.51 H 6.06 N 8.12

c) gadolinium complex with 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4-benzyloxymethylenedecanedioic acid

2.57 g (5 mmol) of complexing acid described in Example 5b) were reacted analogously to Example 1c) to 3.30 g (98.9% of theory) of the title compound. A colorless, flaky solid is obtained.

Calculated: 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

T j - relaxivity (1 / mmol.sec) in water is 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-carboxymethoxybenzyl) undecanedioic acid

23.40 g (30 mmol) of 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-carboxymethoxybenzyl) -undecanedioic acid di-tert-butyl ester (Example 9f DOS 3,710,730) was added in tetrahydrofuran at 0 ° C to 2.7 g (90 mmol) of 80% sodium hydride. To this was added dropwise 6.25 g (45 mmol) of bromoacetic acid in tetrahydrofuran, stirred at 0 ° C for 1 hour and then stirred at room temperature overnight.

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

The residue is chromatographed on silica gel with dioxane / methanol / triethylamine (15: 4: 1); The combined fractions were concentrated and partitioned between ethyl acetate and 1 N citric acid.

21.8 g (87% of theory) are obtained as a colorless oil.

Calculated: C 61.63 H 8.54 N 5.01 Found: C 61.62 H 8.62 N 4.95 b) 3,6,9-triaza-3,6,9-tris- (carboxymethyl) - 4- (4-carboxymethoxybenzyl) undecanedioic acid

21.0 g (25 mmol) of the tert-butyl ester described in Example 1b) was reacted to 11.0 g (78.9% of theory) of the title compound.

H, 5.60; N, 7.54

Found: C, 49.31; H, 5.51; N, 7.47

c) gadolinium 3,6,9-triaza-3 _> 6,9-tris- (carboxymethyl) -4- (carboxymethoxybenzyl) undecanedioic acid complex

5.57 g (10 mmol) of the complexing acid described in Example 6b) were reacted according to the analogous procedure in Example 1c) to 7.01 g (98.5% of theory) of the title compound.

Calculated: 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 T | - the relaxivity (l / mmol sec) in water is 5,00 ± 0,01 in plasma 7,10 ± 0,08

Example 7

Preparation of a sodium salt of the trivalent gadolinium complex with S. 6-O-triaza-5,6-tris-dicarboxymethyl-1-benzyloxymethylenedecanedioic acid.

6.68 g (10 mmol) of the gadolinium complex obtained according to Example 5c) are dissolved in 70 ml of water for injection (µl) and added dropwise with 1 N sodium hydroxide solution until pH 7.2. After addition of 0.02 g of tromethamine, make up with water p. i. per 100 ml, the solution is filled into vials and heat sterilized.

Example 8

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

5.85 g (7.5 mmol) of 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) undecanedioic acid di-tert-butyl diester (Example 9f DOS 3710) 730) in 0.30 g (10 mmol) of 80% sodium hydride in 100 ml of tetrahydrofuran was added. To this was added 1.56 g (10 mmol) of iodoethane and stirred for 3 hours. Then the solution is made up with water, the tetrahydrofuran is distilled off and the aqueous emulsion is 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: 4.0 g (66%)

Analysis (based on anhydrous substance): Calculated: 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) undecanoic acid

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

Yield: 1.2 g (50.6%)

Analysis (based on anhydrous substance): Calculated: C 52.36 H 6.31 N 7.97 Found: C 52.21 H 6.39 N 7.84

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

5.85 g (7.5 mmol) of 3,6,9-triaza-3,6,9-tris- (t-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) undecanedioic acid di-tert-butyl diester (Example 9f DOS 3710 730) was reacted in a manner analogous 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%) Analysis (based on anhydrous substance): Calculated: C 64.64 H 9.28 N 5.03

Found: 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 pollutants described in Example 9a) are dissolved in 20 ml of trifluoroacetic acid, stirred for 1 hour at room temperature and worked up further in analogy to Example 1b. Yield: 1.36 g (61.0%) Calculated: C 54.04 H 6.71 N 7.57 Found: C 53.88 H 6.63 N 7.41

c) di-sodium salt of gadolinium complex with 3,6,9-triaza-

3.6.9- Tris- (carboxymethyl) -4- (4-butoxybenzyl) undecanedioic acid

556 mg (1 mmol) of the complexing acid described in the above example are made up to 40 ml of water and worked up at 80 ° C to a complex with 181 mg (0.5 mmol) of GdOOy Then neutralized with 2 ml of 1 N NaOH, mixed with active charcoal, filtered and the filtrate freeze-dried. Yield: 711 mg (94, 3%) Analysis (based on anhydrous substance): Calculated: 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 T] -relaxivity (l / mmol.sec) in water is 5.80 ± 0.26 in plasma 14.20 ± 0 98

In an analogous manner, the corresponding Europeium complex is obtained with EuO 3. H, 4.31; Eu, 20.30; N, 5.61

6.14

Found: C, 39.97; H, 4.39; Eu; 20.02; N, 5.72; 6.25. The corresponding iron complex is obtained in an analogous manner with ferric oxide.

Calculated: C 46.03 H 4.94 Fe 8.56 N 6.44 Na 7.05 Found: C 45.88 H 5.03 Fe 8.30 N 6.50 Na 7.11

Example 10 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-benzyloxybenzyl) undecanedioic acid di-tert-butyl diester.

5.85 g (7.5 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) undecanoic acid (Example 9f DOS 3710730) was reacted analogously as in Example 8a) with 1.71 g (10 mmol) of benzyl bromide and worked up as described in this Example. Yield: 4.9 g (75.1%)

Analysis (based on anhydrous substance): Calculated: 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-benzoyloxybenzyl) 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 1 hour at room temperature and worked up analogously to Example 1b). Yield: 1.33 g (56.5%) Analysis (based on anhydrous substance): Calculated: C 57.04 H 5.98 N 7.13 Found: C 56.89 H 6.03 N 7.21

c) di-sodium salt of gadolinium complex with 3,6,9-triaza-

3.6.9- tris- (carboxymethyl) -4- (4-benzoyloxybenzyl) undecanodic acid.

590 mg (1 mmol) of the complexing acid described in the above example are charged with 40 ml of water and 1 ml of 1 N NaOH and treated at 80 ° C.

With 181 mg (0.5 mmol) of Gd ₂ O per complex. It is then neutralized with 1 ml of 1 N NaOH, stirred with activated carbon, filtered and the filtrate freeze-dried. Yield: 703 mg (89.2%)

Analysis (based on anhydrous substance): Calculated: C 42.69 H 3.84 Gd 19.96 N 5.33 Na 5.84 Found: C 42.83 H 3.91 Gd 19.57 N 5.26 Na 5 99 Tj - relaxivity (1 / mmol.sec) in water is 5,81 ± 0,11 in plasma 16,35 ± 1,01

Analogously was obtained európiumitým oxide Eu ₂ Oj corresponding europium complex.

Calculated: C 42.98 H 3.86 Eu 19.42 N 5.37 Na 5.88 Found: C 43.10 H 3.91 Eu 19.13 N 5.27 Na 5.99 In an analogous manner it is obtained with an oxide Fe ₂ O 3 corresponding to the iron complex.

Calculated: C 48.99 H 4.41 Fe 8.14 N 6.12 Na 6.70 Found: C 48.73 H 4.57 Fe 8.29 N 6.03 Na 6.85 Examples for in vivo NMR diagnostics .

Example 1

Using a nuclear spin tomograph from General Electric, which was specially developed for experimental animal research, images were taken at various times after application of the gadolinium complex disodium salt of Example 1c) in rats.

Using a nuclear spin tomograph (CST 2 T), spin echo images were taken at 2 tests (TR 400 ms and ΊΈ 20 ms). The layer thickness of this Tj-mass image sequence was 3 mm, the image matrices were 128 x 128.

The contrast agent was injected intravenously into the tail vein of a male shaved rat (Lew / mol), weight 190 g, at a dose of 0.06 mmol / kg. The animal had a Brown-Pearce tumor in the thigh and was anesthetized i. m. dose of Ketavet / Rompun.

In the coronary blank image, various dark abdominal structures are visible. Differentiation between intestinal lumen and stomach was not possible.

One minute after application, the first enlargement is already visible in the bladder. A large increase in stomach contrast is evident 45 minutes after injection. 60 minutes p.i. a good representation of the tumor (at the height of the reference tube) of the bladder and stomach can be observed. In addition, intestinal distinction is evident. This makes it possible to differentiate intestinal loops, fat as well as lymph nodes. The contrast of the renal pelvis is also noticeable, which is even more clearly shown 65 minutes after injection in a slightly different layer. 180 minutes p.i. the contrast increase is clearly visible also in the axial image in the liver region. This will differentiate the stomach, liver, duodenum and pancreas.

Example 2

The experimental animals were female Lew / mol rats weighing 160-180 g. Prior to imaging, the animals were anesthetized (RompunW + Ketave t ( ^R )) and a catheter was inserted into the tail vein to apply the contrast agent. Imaging was performed in a General Electric MRI-experimental apparatus (field strength of 2 tesles). First, the images were created without contrast medium with the Tj - spin echo weight sequence (TR = 400 msec, TE = 20 msec, axial section plane, 3 mm layer thickness). The liver now shows at normal signal strength; The stomach tends to appear darker than the liver.

In the case of animal 1, the stomach has in part a really high signal intensity. This can be attributed to the remainder of the food that is contained in the stomach at a relatively high concentration (no food was received 6 hours prior to inspection). Animal 3 was implanted with osteogenic sarcoma 3 weeks prior to the experiment; this is isodent and unlimited in the blind image. Dosing of the contrast medium was performed using a tail vein catheter, at a dose of 0.1 mmol Gd / kg (concentration of 0.05 mmol Gd / ml in 0.9% NaCl) for all three agents.

For all 3 substances it is possible to record after 90 minutes or 60 minutes p. i., a marked increase in liver contrast attributable to the image via hepatocytes, and at this time they could not be observed after application of the only commercially available contrast agent for nuclear spin tomography, MagnevistW, was observed. In addition, in the case of animal 3, a tumor which is not received by the contrast medium or only in a very low proportion is now clearly known.

Furthermore, for all substances, the most significant increase in gastric contrast is shown in Example 10c), at least in Example 3c). This also offers additional diagnostic options for better liver and stomach delimitation.

Claims (10)

PATENT CLAIMS Compounds of formula I XOOCCKj X ¹ X * C « ₂ COOX CHjCOOX II H -------- ca CM -------- B CH J ----- CH _and H (I}, II XOOCCH3 CH _: COOX where Z * and ΊΊ · are independently hydrogen or - ( ^CH 2) m - ( ^c 6 ^H 4) q - ( ^o ) k - ( ^CH 2) n - ( ^c 6 ^H 4) | - ( ^o ) r - ^R · where man is 0 to 20; k, 1, q and numbers 0 and 1 a R is a hydrogen atom, a C 1 -C 8 -alkyl radical optionally substituted by OR *, or a CHiCOOR * group with R * as a hydrogen atom of a C 1 -C 8 -alkyl radical or a benzyl group, X is a hydrogen atom and / or the metal ion equivalent of an atomic element 21 to 29, 42, 44 or 57 to 83, with at least two of the substituents X is a metal ion equivalent, where one of Z * a is hydrogen and the other is not hydrogen, and when 1 is 0, k is not 1 and Z * or *- are not -C 1-6. C ^ H ^ O-CH-COOCH ₂ C ₆ H _5, or CH ₂ -C ₆ H ₄ -O- (CH 2) ₅ -COOCH ₂ C ₆ H _5, and - (Ojj.-R is OH, Z * is not -CH 2 Cl 2 -OH and the sum of q and 1 is 1 or 2; as well as their salts with inorganic and / or organic bases, amino acids or amino acid amides. 2. A compound according to claim 1, characterized in characterized in that Z ¹ is H and the residue 7½ ^ 2 ^ - (0? 4) - (^ O ^ CHjVC), - (O) _r - ^R. Compounds according to claim 1, characterized in that Z ² represents a hydrogen atom and Z * a residue (CH ₂ ) _m - (C ₆ H 4) _q (O) _k (CH ₂ ) _n . (CGTY ^ O), - 4. A compound according to claim 1, characterized in characterized in that Z 'or Z ² radicals represent -CH ₂ -C ₆ H ₅ -OCH _3, -CHNO-C ^ Hj-, -CH 2 C ₆ H 4 OCH _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> -CH2-C ₆ h 4 -O-CH ₂ -C ₆ h _fifth Compounds according to claim 1, characterized in that they are a gadolinium complex with 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-methoxybenzyl) undecanedioic acid; europium complex with 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-methoxybenzyl) undecanedioic acid; iron (III) complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-methoxybenzyl) undecanedioic acid; bismuth complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-methoxybenzyl) undecanedioic acid; gadolinium complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -5- (4-methoxybenzyl) undecanedioic acid; gadolinium complex with 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- [4- (4-methoxybenzyloxy) benzyl] undecanedioic acid; gadolinium complex with 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4-benzylundecanedioic acid, yteibium complex with 3,6,9-triaza-3,6,9-tris- (carboxy- naphthyl) -4-benzylundekándikyselinou; gadolinium complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4-benzyloxymethyl imdecanedioic acid; gadolinium complex with 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-carboxymethoxybenzyl) iundecanedioic acid; gadolinium complex with 3,6,9-triaza-3,6,9-tris- ( carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid, europium complex with 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid, iron complex with 3,6 9-triaza-3,6,9-tris- (carboxymethyl) 4- (4-ethoxybenzyl) undecanedioic acid, gadolinium 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 with 3,6,9-triaza-3,6,9-tris- (carboxymethyl) - 4- (4-butoxybenzyl) undecanedioic acid, gadolinium complex with 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- (4-benzyloxybenzyl) undecanedioic acid, europium complex with 3,6,9- triaza-3,6,9- tris- (carboxymethyl) -4- (4-benzyloxy-benzyl) undecanedioic acid, complexes of iron with _3> 6,9-triaza-3,6,9- tris- (carboxymethyl) -4- (4 -benzyloxybenzyljundekándikyselinou; A process for the preparation of compounds of formula I according to claim 1, characterized by a compound of the general formula Π is that r'oocch. i 1 1 CHjCOOR ¹ CH _and CO0 · ² 1 1 1 I I --- " 1 ₂ ---- N (II), I 1 R ² OOCCK 1 CHCOO » ¹ where it means R ² an acid protecting group, Z represents a hydrogen atom or a - (C 8 H ₄ ) _q -OH radical, with one of the substituents 7? and Z ⁴ * is a hydrogen atom and the other radical mentioned; converted to a compound with the remainder indicated for Z ¹ and Z ² , the acid protecting group R ² is cleaved off, the complex-forming acids of the general formula 1 ° with X in the meaning of hydrogen thus reacted with at least one metal oxide or metal salt of the atomic number element 21 to 29, 42, 44, or 57 to 83, and optionally, the acidic hydrogen atoms present are substituted with cations of inorganic and / or organic bases, amino acids or amino acid amides. The use of at least one physiologically tolerable compound according to claims 1 to 5, optionally with additives customary in galenics, for the manufacture of a pharmaceutical composition. A process for the production of pharmaceutical compositions according to claim 7, characterized in that the water, saline or protein solution dissolved or suspended, optionally with additives customary in galenics, is converted into a form suitable for enteral or parenteral administration. Use of at least one physiologically acceptable compound according to claim 1 for the manufacture of compositions for NMR diagnostics, X-ray diagnostics and radiation therapy. Use of at least one physiologically tolerable compound according to claims 1 to 5 for the manufacture of means for NMR diagnostics of the renal and hepatobiliary systems and of the gastrointestinal tract.