CA2020142C - Derivatized dtpa complexes - Google Patents

Abstract

Compounds of the formula (see above formula) wherein:
one of Z1 and Z2 is H, and the other is - (CH2)m-(C6H4)q-(O)k-(CH2)n-(C6H4)l-(O)r-R, wherein m and n, independently, are each 0-20, k, l, q and r are each, independently, 0 or 1, R is H, C1-C6-alkyl, OR1-substituted C1-C6-alkyl or CH2COOR1, where R1 is H, C1-C6-alkyl or benzyl;
and X is, in each case, a hydrogen atom or a metal ion equivalent of an element of atomic number 21-29, 42, 44 or 57-83;
with the provisos that:
at least two of the substituents X represent a metal ion equivalent;
when n and 1 each are 0, then k and r are not simultaneously 1;
at least one of q and l is 1;
-(O)r-R is not OH; and Z1, and Z2 are not -CH2-C6H9-O-CH2-COOCH2C6H5 or -CH2-C6H4-O- (CH2)5-COOCH2C6H5;
as well as their salts with inorganic and/or organic bases, amino acids or amino acid amides, are valuable pharmaceutical agents, e.g., for NMR or X-ray imaging.

Description

DERIVATIZED DTPA COMPLEXES
Background of the Invention The invention relates to novel complexes and complex salts, agents containing these compounds, their use in diagnostics and therapy, as well as processes for preparing these compounds and agents.
Metallic complexes have been scrutinized as early as at the beginning of the fifties as contrast media for radiology. The compounds then employed were, however, of such toxicity that utilization on human patients could not be considered. It was, therefore, entirely surprising to find that certain complex salts exhibit adequate compatibility for considering__routine administration to human patients for diagnostic purposes.
The first representative of this class of compounds was the dimeglumine salt of Gd DTPA [gadolinium(III) complex of diethylenetriaminepentaacetic acid] described in the European Patent Application, Publication No. 71564, which proved itself very well in the form of a contrast medium for nuclear spin tomography. This compound has been registered, under the name of "Magnevist'", worldwide as the first NMR diagnostic agent.

Contrast media exhibiting an at least only partial extrarenal excretion would be desirable, in particular for patients with limited kidney function.
Consequently, there is a need for NMR contrast media exhibiting various pharmacokinetic behaviors.
Summary of the Invention The invention makes such compounds and media available, and also provides a process for their production. .-The compounds according to this invention display renal elimination as well as excretion with feces.
Surprisingly, elimination via the gallbladder, however, is not the only extrarenal path of elimination:
in NMR studies on rats, upon intravenous administration of the compounds of this invention, a contrast enhancement of the gastrointestinal tract has also been unexpectedly observed. The kidneys, as well as implanted tumors, are likewise visualized with improved contrast.
The elimination (secretion) by way of the stomach has the advantage that demarcation of abdominal structures (e. g., the pancreas) from the gastrointestinal tract is made possible, with a simultaneous contrast enhancement of pathological processes (tumors, inflammations). Imaging of the renal system, of the liver and gallbladder, and the bile ducts can moreover likewise be achieved. Besides the improved visualization of ulcers and stomach carcinomas, it is also possible ~0~~1~'~
_ 3 to perform studies regarding gastric acid secretion with the aid of imaging procedures.
Accordingly, by making the compounds of this invention available, help can be extended to patients with renal insufficiency as well as patients suffering from gastrointestinal disorders (at least 10% of the population in the Western industrial countries).
Most of these patients, as well as a large number of patients suspected of harboring such disease, must submit to diagnostic tests. At present, two methods suitable for this purpose are utilized above all: Endoscopy and X-ray diagnostics with the aid of barium contrast media.
These tests exhibit various drawbacks: they carry the risk of radiation stress, cause trauma, are :L5 connected with inconvenience, occasionally even with risk to the patient, and thus can evoke psychological stress.
In most instances, these tests must be repeated; their performance is relatively complicated, require the patient's active cooperation (e.g. assumption of a specific bodily attitude) and frequently cannot be employed in case of frail and high-risk patients.
Provision of novel diagnostic methods for the identification and localization of gastrointestinal diseases, which methods do not exhibit these drawbacks, has thus likewise been attained by tile complex compounds and agents according to this invention.
Their. pharmacokinetics permits, even without specific measures, an improvement in the diagnosis of numerous diseases. The cornplexes for the most: part are excreted again in unchanged form and rapidly so that, especial.l.y also in case of using relatively toxic metallic ions, no damaging effects are observed even at high dosage.
The practical use of the novel complexes is also facilitated by their favorable chemical stability.

The compounds of this invention are characterized by general Formula I
XOOCCHZ Z~ ZZ CHZCOOX CIiZCOOX
i CH -CH N-CH2-CHZ i ( I ) , XOOCCHZ CIiZCOOX
wherein:
one of Z1 and ZZ is H, and the other is -(CHZ)m-(C6H9)q-(0)x-(CH2)n-(CsHa)m(O)r-R.
wherein m and n, independently, are each 0-20, k, l, q and r are each, independently, 0 or 1, R is H, C1-C6-alkyl, OR1-substituted C1-C6-alkyl or CH2COOR1, where R1 is H, C1-C6-alkyl or benzyl;
and X is, in each case, a hydrogen atom or a metal ion equivalent of an element of atomic number 21-29, 42, 44 or 57-83;
with the provisos that:
at least two of the substituents X represent a metal ion equivalent;
when n and 1 each are 0, then k and r are not simultaneously 1;
at least one of q and 1 is 1;
-(O)r-R is not OH; and Z1 and ZZ are not -CHZ-C6Hq-O-CHz-COOCH2C6H5 or -CHZ-C6H4-0- (CHZ) 5-COOCHzC6H5;
or a physiologically-acceptable salt thereof with an inorganic and/or organic base, an amino acid or amino acid amide.

_ 5 _ If the agent of this invention is intended for use in NMR diagnostics, then the central ion of the complex salt must be paramagnetic. These are, in particular, the divalent and trivalent ions of the elements of atomic numbers 21-29, 42, 44 and 58-70.
Suitable ions are, for example, the chxomium(III), manganese(II), iron(II), cobalt(II), nickel(II), copper(II), praseodymium(III).,neodymium(III), samarium(III) and ytterbium(III) ions. On account of p their very strong magnetic moment, the gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III) and iron(III)ions are especially preferred.
If the agent of this invention is meant for X-ray diagnostics, then the central ion must be derived ~5 from an element of a higher atomic number in order to obtain adequate absorption of the X-rays. It has been found that suitable diagnostic media for this purpose are those containing a physiologically compatible complex salt with central ions of elements of atomic 20 numbers between 21-29, 42, 44, 57-83; these are, for example, the lanthanum(III) ion and the above-cited ions of the lanthanide series.
The numbers standing for m and n are prefer-ably 0 to 5.
25 Suitable as the alkyl substituents R and Rl are straight-chain or branched hydrocarbons of up to 6, preferably up to 4 carbon atoms which, in case of R, are optionally substituted by one or several, preferably 1-3, hydroxy or C1-C6-, preferably Cl-C4-alkoxy groups.

~~~~~.4?

Examples that can be cited for optionally substituted alkyl groups are the methyl, hydroxymethyl, ethyl, 2-hydroxyethyl, 2-hydroxy-1-(hydroxymethyl)ethyl, 1-(hydroxymethyl)ethyl, propyl, isopropyl, 2- and 3-hydroxypropyl, 2,3-dihydroxypropyl, n-, sec- and tert-butyl, 2-, 3- and 4-hydroxybutyl, 2- and 3-hydroxyiso-butyl, pentyl, 2-, 3- and 4-hydroxy-2-methylbutyl, 2,3,4-trihydroxybutyl, 1,2,4-trihydroxybutyl, cyclo-pentyl, cyclohexyl, 2,3,4,5,6-pentahydroxyhexyl groups as well as -- in case of the hydroxyalkyl groups ---their C~-C6-, preferably C~-C4-alkyl derivatives, i.e., the corresponding C~_6-alkoxy groups.
Preferred substituents Z~ and ZZ are the CHZ-C6H4-OCH3, -CHZ-CaHs, -CFiz-C6H4-O-CHZ-C6H4-OCH3.
-CHZ-O-CHZ-CbHs, -CHz-C6H4-O-CHZ-COOH, -CHZ-C:6H4-OCZI-15, -CHZ-C6H4-OC4H9, -CHz-C6H4-O-CHZ-C6H5 residue:>. Thus, m preferably is l, and/or q preferably is 1, k and/or r preferably is 1, etc., and two phenyl rings are preferably separated by -O-CHz, etc.
In case not all of the acidic hydrogen atoms are substituted by the central ion, it is possible to replace one, several, or all remaining hydrogen atoms) by rations of inorganic and/or organic bases or amino acids.
Suitable inorganic rations are, for example, the lithium ion, the potassium ion, the calcium ion, the magnesium ion and, in particular, the sodium ion. Suitable rations of organic bases are, inter alia, those of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethyglucamine and, in particular, N-methylglucamine.
Suitable rations of amino acids are, for example, those of lysine, of arginine, and or ornithine. Suitable rations of amino acid amides axe lysine methyl amide, glycine ethyl amide and serine methylamide.

~~2~~.4?
The production of the complex compounds of this invention in accordance with general Formula I
takes place by converting, in a manner known per se, compounds of general Formula II
Rz00C iFiz i3 i~ iH2C00R2 'HZCOORz N C H--C H-N-C H z--C ti Z N ( I I ) , RZOOCCIIZ CHZCOORZ
wherein R2 means an acid blocking group, Z3 and Z4 each means a hydrogen atom or the residue - (CH2) m (C6H4) q-OH, with the proviso that one of the substituents Z3 and Z4 is a hydrogen atom and the other is the indicated residue, and m and q are as in formula I
into a compound with the residue indicated for Z1 and Z2, splitting off the acid blocking groups R2, reacting I5 the thus-obtained complex-forming acids of general Formula I where X' is a hydrogen atom (I: ormul.a I' ) with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 92, 49 ar 57-83, and subsequently -- if desired -- substituting any present acidic ?0 hydrogen atoms by canons of inorganic and/or organic bases, amino acids or amino acid amides.

Suitable acid blocking groups R2 are lower alkyl, aryl and aralkyl groups, e.g. the methyl, ethyl, propyl, n-butyl, tert-butyl, phenyl, benzyl, diphenyl-methyl, triphenylmethyl, bis(p-nitrophenyl)methyl groups, as well as trialkylsilyl groups.
Splitting off of the blocking groups R2 takes place according to methods known to one skilled in the art [for example, E. Wtinsch, "Methoden der Org. Chemie"
[Methods of Organic Chemistry] (Houben-Weyl), vol. XV/1, 4th ed., 1974, pp. 315 et seq.), for instance by hydrolysis, hydrogenolysis or alkaline saponification of the esters with an alkali in aqueous-alcoholic solution at temperatures of 0-50° C. Organic or inorganic acids are used for splitting off the tert-butyl esters which are especially advantageous for the present reactions: The ester compound dissolved in a suitable anhydrous organic solvent, but preferably the pulverized dry material, is combined either with a hydrogen halide solution in glacial acetic acid, with trifluoroacetic acid, or also with boron trifluoride diethyl etherate in glacial acetic acid and split off at temperatures of -10° C to 60° C, preferably at room temperature.
The compounds of general Formula II, serving as educts for the production of the complex compounds of this invention, are known or can be synthesized.
A series of literature methods known to a person skilled in the art is available for reacting the known aliphatic or aromatic hydroxy compounds to the corresponding arylalkyl or dialkyl ethers (for example, J. March, Advanced Organic Chemistry, 3rd ed., 1985, pp. 342 et seq.).

~o~o.~~~

For this purpose, the compounds of Formula II
wherein R2 stands for an alkali-stable acid blocking group are dissolved in a polar aprotic solvent, such as, for example, tetrahydrofuran, dimethoxyethane or dimethyl su~.foxide, and combined with a base, such as, for example, sodium hydride, sodium hydroxide or alkali or alkaline earth carbonates, at temperatures of between -30° C and the boiling point of the respective solvent, but preferably between 0° C and 60° C.
A compound of general Formula III is added to this mixture Y-(CHL)~-(C6H~)~-(011,-R (III) wherein Y means a nucleofugal entity, such as, for ex-ample, C1, I3r, I, CH3-C6II4S03 or CF3S03, and the remaining indices have the same meanings as in general Formula I.
The reaction periods are 30 minutes to 8 hours, depending on the steric hindrance of the residues participating in the reaction.
As an alternative to the aforedescribed re-action conditions, it is possible to produce aryl-alkyl as well as dialkyl ethers in a very advantageous way by phase transfer catalysis (Stacks and Liotta, Phase Transfer Catalysis, Academic Press, N.Y. 1978, pp. 128-138).
For this purpose, the reaction is performed in a two-phase mixture of an aqueous base, preferably 30~ sodium hydroxide solution, and a water-immiscible organic aprotic solvent. Suitable phase transfer catalysts are the compounds known to a person skilled in the art, but preferably tetraalkylamrrlonium or tetraalkylphosphonium salts.

20~~~.4~
- ,o -If it is desired to synthesize compounds of general Formula t wherein k, n, 1 and r = 0 and R means a hydrogen atom, then it is possible to conduct the synthesis in analogy to the methods known from the literature, starting with the corresponding unsubstituted amino acid (e. g. phenylalanine).
However, if a series of analogous compounds is to be synthesized, then it is recommended to prepare the phenol derivatives described in DOS 3,710,730 and to reductively remove the phenol function in accordance with literature methods known to those skilled in the art. Above all, the reduction of aryl diethyl phosphates with titanium can be cited which can be performed in a very advantageous way also in the presence of ester groups [S.C. Welch et al., J. Org. Chem. 43 . 4797-99 (1978) and literature cited therein]. In this procedure, the corresponding aryl diethyl phosphate is first formed from the phenolic educt by reaction with phos-phoric acid diethyl ester chloride in a 70-100 yield, preferably by the use of sodium hydride as the base in a polar aprotic solvent. Subsequently, the reduction is 'performed with freshly prepared titanium metal.
Preferably, anhydrous titanium(III) chloride is reduced by magnesium or potassium in anhydrous tetrahydrofuran under an inert gas for preparing highly active titanium.
The above-described diethyl phosphate is added to such a mixture and heated under reflux for 2-24 hours, preferably 6-16 hours. llfte.r the reaction is ter-rninated, the mixture is optionally worked up by chromatography. It is also possible to employ the palladium-catalyzed reduction of the corresponding aryl triflates according to S. Cacchi et al., Tetr. Lett.
27 . 5541-44 (1986).

2~~fl~4 _ 11 _ The thus-obtained compounds of general Formula I' wherein X means a hydrogen atom represent complexing agents. They can be isolated and purified or can be converted, without isolation, into metal complexes of general Formula I with at least two of the substituents X meaning a metal ion equivalent.
The metal complexes of this invention can be produced in a way disclosed in Patent DE 3,401,052, by dissolving or suspending tine metal oxide or a metal salt (e. g. the nitrate, acetate, carbonate, chloride or sulfate) of the element of atomic numbers 21-~9, 42, 44 or 58-70 in water and/or a lower alcohol (such as methanol, ethanol or isopropanol) and reacting with a solution or suspension of the equivalent amount of the complex-forming acid of general Formula I' wherein X
means a hydrogen atom, preferably at temperatures of between 40° and 100° C, and subsequently -- if desired --substituting any present acidic hydrogen atoms of acid groups by cations of inorganic and/or organic bases, amino acids or amino acid amides.
Neutralization is herein effected with the aid of inorganic bases (for example, hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium, lithium, magnesium or calcium and/or with the aid of organic bases, such as, inter alia, primary, secondary and tertiary amines, e.g. ethanolamine, morpholine, glucamine, N-methyl- and N,N-di.methyl-glucamine, as well as basic amino acids, such as, for example, lysine, arginine and ornithine.
In order to prepare the neutral. complex com-pounds, it is possible, for example, to add to the acidic complex salts in an aqueous solution or suspension such an amount of the desired bases that ~~~~~4~
_ ,Z _ the neutral point is reached. The resultant solution can subsequently be evaporated to dryness under vacuum.
It is frequently advantageous to precipitate the thus-formed neutral salts by adding water-miscible solvents, such as, for example, lower alcohols (methanol, ethanol, isopropanol, and others), lower ketones (acetone and others), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and others), and to obtain in this way crystallized products which can be readily isolated and easily purified. It proved to be especially advan-tageous to add the desired base as early as during the complexing to the reaction mixture, thereby saving a process step.
If the acidic complex compounds contain several free acidic groups, then it is frequently ex-pedient to prepare neutral mixed salts containing inorganic as well as organic cations as the counterions.
This can be done, for example, by reacting the complexing acid in an aqueous suspension or solu-tion with the oxide or salt of the element yielding the central ion and with half the amount of an organic base needed for neutralization, isolating the thus-formed complex salt, purifying same if desired, and then combining same for complete neutralization with the required amount of inorganic base. The sequence of adding the bases can also be reversed.
~L'he pharmaceuticals of i~his invention can be prepared in a likewise conventional way by suspending or dissolving the complex compounds according to the invention -- optionally adding the additives customary in galenic pharmacy -- in an aqueous medium and 'then optionally sterilizing the suspension or solution.
Suitable additives are, for example, physiologically acceptable bu:Efers (e. g. tromethamine), small additions - ~3 -of complexing agents (such as, for example, diethylene-triaminepentaacetic acid) or, if necessary, electro-lytes (such as, for example, sodium chloride) or, if necessary, antioxidants, e.g. ascorbic acid.
If, for enteral administration or other purposes, suspensions or solutions of the agents of this invention in water or a physiological saline solu-tion are desirable, they are mixed with one or several auxiliary agents) customary in galenic pharmacy (for example methylcellulose, lactose, mannitol) and/or tenside(s), e.g. lecithins, "Tween~', "Myrj"
and/or flavoring substances) for taste improvement (e. g. ethereal oils).
In principle, it is also possible to prepare the pharmaceuticals of this invention even without isolation of the complex salts. In any event, special care must be directed toward effecting the chelate formation so that the salts and salt solutions accord-ing to this invention are practically devoid of toxic-ally active metal ions that are not complexed.
This can be ensured, for example, with the aid of color indicators, such as xylenol orange, by control titrations during the manufacturing process.
Consequently, the invention also relates to processes for preparing the complex compounds and their salts.
The final safety feature resides in purification of the isolated complex salt.
The pharmaceutical agents of this invention can be administered to mammals, including humans, in a dose of 1 ~mol/kg to 5 mmol/kg, preferably 10 /~mol to 0.5 mmol/kg of the complex salt according to the invention. For intra-venous injection, aqueous formulations are utilized with a concentration of 50 ~mol/1 to 2 mol/1, preferably 100 mmol/1 to 1 mol/1. Rectal as well as oral administration is preferably performed with solutions of a concentration of 0.1 mmol/1 to 100 mmol/1. The volumes administered are between 5 ml and 2 l, depending on the diagnostic problem.
The agents according to this invention meet the variegated prerequisites for suitability as contrast media. Thus, they are excellently suited, upon enteral or parenteral administration, to improve the information content of the image obtained with the aid of the NMR
tomograph, by increasing the signal intensity. They show furthermore -the high efficacy necessary for burdening the body with minimum amounts of foreign substances, and the good compatibility required for maintaining the non-invasive character of the tests.
The high water solubility and low osmolality of the agents according to this invention permits the production of highly concentrated solutions so that the volume load on the circulation is maintained within tolerable limits and dilution by body fluids is com-pensated. Furthermore, the agents of this invention exhibit not only a high stability in vitro but also a surprisingly high stability in vivo so that release or exchange of the --actually toxic -- ions not covalently bound in the complexes takes place only extremely gradually within 'the time wherein 'the novel contrast media are aclain entirely eliminated.
The agents of this invention can also be utilized for radiation therapy. Thus, complexes of gadolinium are excellently suited due 'to the large capture cross section for neutron capture therapy.
If the agent of this invention is intended for use in the version of radiation therapy proposed by R.h. Mills et al. [Nature, 336 . 787 (1988)l, then the central ~~~~~.4 .ion must be derived from a MBssbauer isotope, such as, for example, S~Fe or 151.Eu.
When administered, the agents of this inven-tion can also be given together with a suitable carrier, such as, for example, serum or physiological saline solution andlor together with a protein, such as, for example, human serum albumin. The dosage herein is dependent on the type of cellular disorder and on the properties of the metal complex utilized.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and.in the following examples, all temperatures are set forth uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.

2~~~~ 4~

Example 7.
(a) 3,6,9-Triaza-3,6,9-tris(tert-butoxycarbonylmethyl)-4-(4-methoxybenzyl)undecanedioic Acid Di-tert-butyl Diester At 0° C, 1.56 g (2 miLlimoles) of 3,6,9-triaza-3,6,9-tris(tert-butoxycarbonylmethyl)-4-(4-hydroxybenzyl)undecanedioic acid di-tert-butyl diester (Example 9f of DOS 3,710,73U) is combined in tetra-hydrofuran with 66 mg (2.2 mmol) of 80o strength-sodium hydride. This mixtrure is combined with 0.31 g (2.2 mmol) of iodomethane and stirred for 30 minutes. Then the solution is combined with water, tetrahydrofuran is removed by distillation, and the aqueous emulsion is extracted with diethyl ether.
The organic phase is washed with water, dried over Na2S04, arid concentrated.
Yield: 1.55 g (97.60) 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)undecanedioic Acid 1.27 g (1.6 mmol.) of the tert-butyl ester described in Example 1(a) is dissolved in 25 ml of trifluoroacetic acid and stirred for one hour at room temperature. 'fhe solution is the~n combined with diethyl ether, the precipitate is suctioned off, washed with ether and dried at 40° C under vacuum over phosphorus pentoxide. 'flue crude product is dis-solved in water and combined under agitation with active carbon. The mixture is filtered off from the carbon and lyophilized three times to remove residual trifluoroacetic acid.

~~~~~.4~

Yield: 0.62 g (75.40) Calculated: C 51.46 H 6.09 N 8.18 Found: C 51,27 H 6.02 N 8.11 (c) Gadolinium Complex of 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-(4-methoxybenzyl)undecanedioic Acid 513 mg (1 mmol) of the complexing acid described in Example 1(b) is dissolved in about 30 ml of water and combined at 80° C with 181 mg (0.5 mmol) of Gd203. After 30 minutes, the almost clear solution is filtered and the filtrate freeze-dried.
Yield: 649 mg (97.20 based on the anhydrous material Calculated: C 39.57 I-1 4.23 N 6.29 Gd 23.55 Found: C 39.47 Ii 4.29 N 6.21 Gd 23.19 Disodium Salt of the Gadolinium Complex The complex (500 mg, 0.75 mmol) obtained as described above is dissolved in 10 times the amount o.f water and combined by means of a microburette with 1.5 ml of a 1N sodium hydroxide solution.
After freeze-drying, 533 mg of white crystals is obtained.
'f1 relaxation (1/mmol~sec) is in water 4.54 ~ U.13 in plasma 6.89 v 0.17 Di-N-methyl-D-glucamine Salt of the Gadolinium Complex 3.34 g (5 mmo1) of the gadolinium complex is combined in 40 ml of water in portions with 1.96 g (10 mmol) of N-methyl-D-glucamine under agitation.
After the base has been completely dissolved, the product is freeze-dried. There remains 5.55 g of a colorless crystalline compound.
H20 content (Karl Fischer determination):

4.73%
(d) Europium Complex of 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-(4-methoxybenzyl)undecanedioic Acid 5.13 g (10 mmol) of the complexing acid described in Example 1(b) is dissolved in about 30 ml of water and combined at 80° C with 1.76 g (5 mmol) of Eu203. After 30 minutes,the almost clear solution is filtered and the filtrate freeze-dried.
Yield: 6.62 g Analysis (based on anhydrous substance) Calculated: C 39.89 I-I 4.26 N 6.34 Eu 22.94 Found: C 39.71 II 4.38 N 6.17 Eu 22.58 D:isodirzm Salt of the Europium Complex The complex described above (497 mg, 0.75 mmol) is dissolved i.n lU times the quantity of water and combined by means of a microburette with 1.5 ml of a 1N
sodium hydroxide solution. After freeze-drying, 540 mg of white crystals is obtained.

~fl~~~.4?

Di-N-methyl-D-glucamine Salt of the Europium Complex 3.31 g (5 mmol) of the europium complex is mixed in 40 ml of water in portions with 1.96 g (10 mmol) of N-methyl-D-glucamine under agitation.
After the base has been completely dissolved, the mixture is freeze-dried. There remains 5.63 g of a colorless, crystalline compound.
(e) Iron(III) Complex of 3,6,9-Triaza-3,6,9-tris-1C (carboxymethyl)-4-(4-methoxybenzyl)undecanedioic Acid 5.13 g (10 mmol) of the complexing acid dis-closed in Example 1(b) is dissolved in about 30 ml of water and combined at 80° C with 798 mg (5 mmol) of Fe203. After 30 minutes, the almost clear solution is filtered and the filtrate freeze-dried.
Yield: 5.66 g Analysis (based on anhydrous substance):
Calculated: C 46.66 II 4.98 N 7.42 Fe 9.86 Found: C 46.71 II 5.03 N 7.38 Fe 9.81 Disodium Salt of the Irorr(III) Complex 'i'he complex obtained as described above (425 mg, 0.15 mmol) is dissolved in 10 times the amount of water and combined by means of a microburette with 1.5 ml of a 1N sodium hydroxide solution. After freeze-drying, 460 mg of white crystals is obtained.

Di-N-methyl-D-glucamine Salt of the Iron(III) Complex 2.83 g (5 mmol) of the iron(III) complex is combined in 40 ml of water in portions with 1.96 g (10 mmol) of N-methyl-D-glucamine under agitation.
After the base has been completely dissolved, the solution is freeze-dried. There remains 4.83 g of a colorless, crystalline compound.
Analogously, with bismuth oxide, Bi203' the bismuth complex is obtained as the disodium salt and, respectively, as the di-N-methyl-D-glucamine salt.
Example 2 (a) 3,6,9-Triaza-3,6,9-tris(tert-butoxycarbonyl methyl)-5-(4-methoxybenzyl)undecanedioic Acid Di-tert-butyl Ester In accordance with the directions given in Example 1(a), 3.9 g (5 mmol) of 3,6,9-triaza-3,6,9-tris(tert-butoxycarbonylmethyl)-5-(4-hydroxybenzyl)-undecanedioic acid di-tert-butyl ester (Example 17d in DOS 3,710,73U) is reacted to 3.61 g (91~ of theory) of the title compound.
Calculated: C 63.53 I-I 9.01 N 5.29 Found: C 63.59 II 9.07 N 5.27 (b) 3,6,9-'1'riaza-3,6,9-tris(carboxymethyl)-5 (4-methoxybenzyl)undecanedioic Acid 3.18 g (4 mmol) of the tert-butyl ester described in Example 2(a) is treated in accordance with the directions set forth in Example 1(b) with trifluoroacetic acid and worked up, thus obtaining 1.62 g (79% of theory) of a colorless lyophilized product.
Calculated: C 51.46 HI 6.09 N 8.18 Found: C 51.34 H 6.14 N 8.11 (c) Gadolinium Complex of 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-5-(4-methoxybenzyl)undecanedioic Acid According to the directions in Example 1(c), 1.03 g (2 mmol) of the complex-forming acid described in Example 2(b) is complexed with Gd203, yielding 1.32 g (99~ of theory) of a colorless lyophilized product.
Calculated: C 39.5'7 H 4.23 N 6.29 Gd 23.55 Found: C 39.51 H 4.19 N 6.25 Gd 23.61 The T~ relaxation ( 1/rmnol ~ sec ) is in water 4.17 r 0.14 in plasma 6.61 -1~ 0.18 ~~~'0~ 4~

Example 3 (a) 3,6,9-Triaza-3,6,9-tris(tart-butoxycarbonylmethyl)-4-[4-(4-methoxybenzyloxy)benzyl)undecanedioic Acid Di-tart-butyl Ester At 0° C, 1.56 g (2 mmol) of 3,6,9-triaza-3,6,9-tris(tart-butoxycarbonylmethyl)-4-(4-hydroxybenzyl)-undecanedioic acid di-tart-butyl ester (Example 9f of DOS 3,710,730) is combined in tetrahydrofuran with 66 mg (2.2 mmol) of 80~ strength sodium hydride.-To this mixture is added 0.3 ml (2.2 mmol) of 4-methoxybenzyl chloride and the mixture is stirred overnight. 'fhe solution is then combined with water, tetrahydrofuran is removed by distillation, and the aqueous emulsion is extracted with diethyl ether.
The organic phase is washed with water, dried over Na2S0~, and concentrated. The resultant colorless oil 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 8.65 N 4.59 (b) 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-[4-(4-methoxybenzyloxy)benzyl]undecanedioic Acid 1.80 g (2 mmol) of the tart-butyl ester set forth in Example 3(a) is treated analogously to the directions given in Example 1(b) with trifluoroacetic acid and reacted to 905 mg (73$ of theory) of colorless, flaky lyophilized product.
Calculated: C 56.21 II 6.02 N 6.78 Found: C 56.10 Ii 5.98 N 6.82 ~~~~1~~

(c) Gadolinium Complex of 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-[4-(4-methoxybenzyloxy)benzyl]-undecanedioic Acid Analogously to the directions given for Example 1(c), 620 mg (1 mmolj of the complexing acid described in Example 3(b) is complexed and worked up, yielding 758 mg (980 of theory).
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 The T1 relaxation (1/mmol~sec) amounts to in water 4.23 ~ 0.16 in plasma 6.99 t 0.13 Example 4 (a) Diethyl Phosphate of 3,6,9-Triaza-3,6,9-tris-(tert-butoxycarbonylmethyl)-4-(4-hydroxybenzyl) undecanedioic Acid Di-tent-butyl Ester 11.2 g (14.36 mmol) of the phenol disclosed in DOS 3,710,730 (Example 9f) is dissolved in 100 ml of absolute tetrahydrofuran (THF). To this mixture is added 380 mg (15.8 mmol) of sodium hydride (prepared from 50'~ NaI-I in paraffin oil by washing three times with 10 ml of 'fI-IF) . After 30 minutes at room tempera-ture, 2.60 g (15.0 mmol) of phosphoric acid diethyl ester chloride is added and the mixture 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 sulfate, the product is concentrated under vacuum and the residue purified by flash chromatography (eluent: ether/hexane = 1:1).

~~~4?

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-butoxycarbonyl-methyl)-4-benzylundeeanedioic Acid Di-tert-butyl Ester A mixture of 1.33 g (8.62 mmol) of anhydrous titanium(III) chloride and 1.02 g (26.09 mmol) of finely chopped potassium in 20 ml of tetrahydrofuran is heated under reflux in an argon atmosphere for one hour.
Within 15 minutes, a solution of 11.5 g (12.55 mmol) of the compound described in Example 4(a) in 50 ml of tetrahydrofuran is added dropwise to this mixture. Then the mixture is heated under reflux for 8 hours, cooled in an ice bath, 20 ml of methanol is gently added, then 100 ml of water is added, and the mixture is extracted three times with 200 ml of ether.
The organic phases are dried over magnesium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel (eluent: hexane/ether - 2:1), thus obtaining 8.9 g (93~ of theory) of the title compound as a colorless oil which crystallizes upon standing.
Calculated: C 64.46 II 9.10 N 5.50 hound: C 64.54 II 9.15 N 5.41 ~fl~~~~~
- 2.6 -{c) 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-benzylundecanedioic Acid Analogously to the directions set forth in Example 1(b), 7.64 g (10 mmo1) of the tert-butyl ester described in Example 4(b) is reacted to 4.01 g (83% of theory) of the title compound.
Calculated: C 52.17 II 6.05 N 8.69 Found: C 52.23 II 5.99 N 8.73 (d) Gadolinium Complex of 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-benzylundecanedioic Acid 2.42 g (5 mmol) of the complex-forming acid described in Example 4(c) is reacted analogously to the directions given in Example 1(c) to 3.14 g (98.5 of theory) of the title compound, obtaining the gadolinium complex as a colorless, flaky lyophilized product.
Calculated: C 39.55 II 4.11 N 6.59 Gd 24.66 Found: C 39.47 Ii 4.19 N 6.52 Gd 24.88 The T1 relaxation (1/rnmol.~sec) is in water. 4.54 ~ 0.13 in plasma 6.89 ~1~ 0.17 Ytterbium Complex of 3,6,9-Triaza-3,6,9-tr:is(carboxymethyl)-4-benzylundecanedioic Acid Analogously to the directions for preparing the gadolinium complex, the corresponding ytterbium complex is obtained by using Yb203 in place of Cd203.

~~~~~ 4) - 27 __ Example 5 (a) 3,6,9-Triaza-3,6,9-tris(tert-butoxycarbonyl-methyl)-4-benzyloxymethylundecanedioic Acid Di-tert-butyl Ester Within 30 minutes, 7.2 ml (60 mmol) of benzyl bromide is added dropwise at room temperature to a thoroughly stirred suspension of 14.1 g (20 mmol) of 4-hydroxymethy 1- 3,6,9-triaza-3,6,9-tris(tort-butoxycarbonylmethyl)-undecanedioic di-tert-butyl diester described in i)OS
3,710,730 (Example 37d) and 0.3 g of tetrabutylammonium hydrogen sulfate in 200 ml of dichloromethane/200 ml of 30$ strength sodium hydroxide solution, and the mix-ture is then agitated for 8 hours.
400 ml of water is added to this suspension;
the organic phase is separated and the aqueous phase extracted twice with respectively 150 ml of dichloro-methane. After drying the combined organic phases over magnesium sulfate, the product is chromatographed on silica gel (ether/hexane = 1:1), thus obtaining 13.0 g (82~ of. theory) of the title compound as a colorless oil.
Calculated: C 63.53 fI 9.01 N 5.29 Found: C 63.42 I-I 9.07 N 5.21 (b) 3,6,9-~'riaza-3,6,9-tris(carboxymethyl)-4-benzyloxymethylundecanedioic Acid Analogously to the directions given for Ex-ample 1.(b), 7.94 g (10 mmol) of the tort-butyl ester set forth in Example 5(a) is reacted with trifluoro-acetic acid to 4.06 g (79'L of theory) oL 'the title compound.

~~~~~ 4?
_ 28 _ Calculated: C 51.46 H 6.09 N 8.18 Found: C 51.51 H 6.06 N 8.12 (c) Gadolinium Complex of 3,6,9-Triaza-3,6,9-tris (carboxymethyl.)-4-benzyloxymethylundecanedioic Acid In analogy to the directions in Example 1(c), 2.57 g (5 mmol) of the complexing acid described in Example 5(b) is reacted to 3.30 g (98.9 of theory) of the title compound, yielding a colorless, flaky solid.
Calculated: C 39.57 H 4.23 N 6.29 Gd 23.55 Found: C 39.51 Ii 4.26 N 6.35 Gd 23.27 The 'f1 relaxation (1/mmol~sec) is in water 4.39 ~ 0.12 in plasma 6.31 ~ 0.15 Example 6 (a) 3,6,9-Triaza-3,6,9-tris(tert-butoxycarbonyl-methyl)-4-(4-carboxymethoxybenzyl)undecanedioic Acid Bis(tert-butyl) Ester At 0° C, 2:3.40 g (30 mtnol) of 3,6,9-triaza-3,6,9-tris(tort-butoxycarbonylmethyl)-4-(4-hydroxy-benzyl)undecanedioic acid di-tert-butyl ester (Ex-ample 9f of UOS 3,710,730) i.s combined in tetrahydro-furan with 2.7 cJ (90 mmol) of 8U'k strength sodium hydride. 'fo this mixture is dropped 6.25 g (45 mmol) of bromoacetic acid in tetrahydrofuran, and the mixture is stirred for one hour at 0° C and overnight at room temperature.
The solution is then combined with water, tetrahydrofuran is removed by distillation, and the 2~~~~.4?
_. 2 g _ aqueous phase is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and con-centrated.
The residue is chromatographed on silica gel in an eluent mixture of dioxane/methanol/tri.ethylamine (15:4:1); the combined fractions are concentrated and divided between ethyl acetate and 1N citric acid.
The organic phase is then dried over sodium sulfate and concentrated, thus obtaining 21.8 g (87~ of theory) 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 Analogously to the directions given for Ex-ample 1(b), 21.0 g (25 mmol) of the tert-butyl ester described in Example 6(a) is reacted to 11.0 g (78.9 of theory) of the title compound.
Calculated: C 49.55 H 5.60 N 7.54 Found: C 49.31 II 5.51 N 7.47 (c) Gadolinium Complex of 3,6,9-'Priaza-3,6,9-tris-(carboxymethyl)-4-(4-carboxymethoxybenzyl)-undecanedioic Acid 5.57 g (10 mmo:L) of the complex-forming acid described in Example 6(b) is .reacted analogously to the dire ctions set forth in Example 1(c) to yield 7.01 g (98.5' of theory) o.f the title compound.
Calculated: C 38.87. Ii 3.96 N 5.90 Gd 22.09 Found: C 38.75 II 3.89 N 5.97 Gd 21.93 The T1 relaxation (1/mmol~sec) is in water 5.00 ~ 0.01 in plasma 7.10 ~ 0.08 Example 7 Preparation of a Solution of the Sodium Salt of the Gadolinium(III) Complex of 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-benzyloxymethylundecanedioic Acid 6.68 g (10 mmol) of the gadolinium complex obtained according to Example 5(c) is dissolved in 70 ml of water pro injectione (p.i.) and combined dropwise with 1N sodium hydroxide solution until a pH of 7.2 has been reached. After adding 0.02 g of tromethamine, the mixture is filled up to 100 ml with water p.i.; the solution is dispensed into bottles and heat-sterilized.
Example 8 (a) 3,6,9-T.riaza-3,6,9-tris(tert-butoxycarbonyl-methyl)-4-(4-ethoxybenzyl)undecanedioic Acid Di-tert-butyl Diester At U° C, 5.85 g (7.5 mmol) of 3,6,9-triaza-3,6,9-tris(tart-butoxycarbonylmethyl)-4-(4-hydroxy-benzyl)undecanedioic acid di-tart-butyl diester (Example 9f of DOS 3,710,730) is combined in 100 ml of tetrahydrofuran with 0.30 g (10 mmol) of 80~
strength sodium hydride. 'fo this mixture is added 1.56 g (10 mmol) of iodoethane and the mixture is stirred for 3 hours. 'Then the solution is combined with water, 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 chromato-graphed on silica gel (system: hexane/ether/triethyl-amine 70:30:5).
Yield: 4.0 g (660) Analysis (based on anhydrous material):
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)undecanedioic Acid 3.64 g (4.5 mmol) of the tert-butyl ester disclosed in Example 8(a) is dissolved in 25 ml of trifluoroacetic acid, stirred for one hour at room temperature, and worked up analogously to Example 1(b).
Yield: 1.2 g (50.60 Analysis (based on anhydrous substance)-Calculated: C 52.36 H 6.13 N 7.97 Found: C 52.21 H 6.39 N 7.84 (c) Disodium Salt of the Gadolinium Complex of 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic Acid 528 mg (1 mmol) of the complex-farming acid described in t1e preceding example is dissolved in 40 ml of water and complexed at 80° C with 181 mg (0.5 mmol) of Gd203. 'then the mixture is neutralized with 2 ml of 1N Na0Il, stirred with activated carbon, filtered, and the filtrate is freeze-dried.
Yield: 700 mg (96.5$) ~0~~~.~?

Analysis (based on anhydrous mater_ial):
Calculated: C 38.06 II 3.89 Gd 21.67 N 5.79 Na 6.34 Found: C 37.91 H 3.99 Gd 21.30 N 5.69 Na 6.57 The Tl relaxation (1/mmol~sec) is in water 5.33 ~ 0.13 in plasma 8.69 ~ 0.53 Analogously, the corresponding europium complex is obtained with europium oxide, Eu203.
Calculated: C 38.34 H 3.92 Eu 21.09 N 5.83 Na 6.38 Found: C 38.20 H 4.01 Eu 20.87 N 5.79 Na 6.49 With iron oxide, Fe203, 'the corresponding iron complex is obtained analogously:
Calculated: C 44.25 H 4.52 Fe 8.95 N 6.73 Na 7.37 Found: C 44.17 H 4.59 Fe 8.52 N 6.81 Na 7.49 Example 9 (a) 3,6,9-Triaza-3,6,9-tris(tert-butoxycarbonyl-methyl)-4-(4-butoxybenzyl)undecanedioic Acid Di-tert-butyl Diester Analog ousl.y to Example 8(a), 5.85 g (7.5 mmol) of 3,6,9-triaza-3,6,9-tris(tert-butoxy-carbonylmethyl)-4-(4-hydroxyberxzyl)undecanedioic acid di-tert-butyl diester (Example 9f of DOS 3,710,730) is reacted with :1.84 g (:LO nut~ol) of 1-iodobutane and worked up as described therein.
Yield: 4.1 g (65.40 Analysis (based on anhydrous compound):
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 teat-butyl ester described in Example 9(a) is dissolved in 20 ml of trifluoroacetic acid, stirred for one hour at room temperature, and worked up analogously to Example 1(b).
Yield: 1.36 g (6l.Oo) Analysis (based on anhydrous material):
Calculated: C 54.04 I-I 6.71 N 7.57 Found: C 53.88 I-I 6.63 N 7.41 (c) Disodium Salt of the Gadolinium Complex of 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-butoxybenzyl)undecanedioic Acid 556 mg (1 mmol) of the complexing acid described in the preceding example is combined with 40 ml of water and complexed at 80° C with 181 mg (0.5 mmol) of Gd203. The mixture is then neutralized with 2 ml of 1N NaOH, stirred with activated carbon, filtered, and 'the filtrate freeze-dried.
Yield: 711. mg (94.30 Analysis (based on anhydrous material):
Calculated: C 39.83 II 4.28 Gd 20.86 N 5.58 Na 6.10 Found: C 39.61 I-I 4.35 Gd 20.51 N 5.49 Na 6.17 ~~.~r~

The T1 relaxation (1./mmol~sec) is in water 5.80 ~ 0.26 in plasma 14.20 ~ 0.98 Analogously, with the use of europium oxide, Eu203, the corresponding europium complex is obtained:
Calculated: C 40.11 H 4.31 Eu 20.30 N 5.61 Na 6.14 Found: C 39.97 H 4.39 Eu 20.02 N 5.72 Na 6.25 With iron oxide, Fe203, the corresponding iron complex is analogously obtained:
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 (a) 3,6,9-Triaza-3,6,9-tris(tert-butoxycarbonyl-methyl)-4-(4-benzyloxybenzyl)undecanedioic Acid Di-tert-butyl Diester Analogously to Example 8(a), 5.85 g (7.5 mmol) of 3,6,9-triaza-3,6,9-tris(tert-butoxy-carbonylmethyl)-4-(4-hydroxybenzyl)undecaned.ioic acid di-tert-butyl diester (Example 9f of DOS
3,710,730) is reacted with 1.71 g (10 mmol) of benzyl bromide and worked up as described therein.
Yield: 4.9 g (75.10 Analysis (based on anhydrous substance):
Calculated: C 66.25 HI 8.69 N 4.83 E'ound: C 66.14 II 8.77 N 4.83 (b) 3,6,9-Triaza-3,G,9-tris(carboxymethyl)-4 (4-benzyloxybenzyl)undecanedioic Acid 3.48 g (4 mmol) of the tert-butyl ester disclosed in Example 10(a) is dissolved in 20 ml of trifluoroacetic acid, stirred for one hour at room temperature, and worked up analogously to Example 1(b).
Yield: 1.33 g (56.50) nnalysis (based on anhydrous material):
Calculated: C 57.04 H 5.98 N 7.13 Found: C 56.89 H 6.03 N 7.21 (c) Disodium Salt of the Gadolinium Complex of 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-benzyloxybenzyl)undecanedioic Acid 590 mg (1 mmol) of the complexing acid described in the preceding example is combined with 40 ml of water and 1 ml of 1N NaOH and complexed at 80° C with 181 mg 40.5 mmol) of Gd203. Then the mixture is neutralized furthermore with 1 ml of 1N
NaOH, stirred with active carbon, filtered, and the filtrate freeze-dried.
Yield: 703 mg (89.20 Analysis (based on anhydrous material):
Calculated: C 42.69 I-I 3.84 Gd 19.96 N 5.33 Na 5.84 Found: C 42.63 Ii 3.91 Gd 19.57 N 5.26 Na 5.99 The T1 .relaxation (1/mmol~sec) is in water 5.81 ~ 0.11 in plasma 16.35 ~ 1.01 ~~~~3~.4~

the corresponding europium complex is obtained analogously with europium oxide, Eu203:
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 With iron oxide, Fe203, the corresponding iron complex is obtained analogously:
Calculated: C 48.99 H 4.41 Fe 8.14 N 6.12 Na 6.70 Found: C 48.73 II 4.57 i'e 8.29 N 6.03 Na 6.85 Examples for in vivo NMR Diagnostics Example 1 Images were obtained at various times after administration of the disodium salt of the gadolinium complex of Example 1(c) to rats with the aid of an NMR tomograph by General Electric, specifically developed for animal experimental research.
Spin echo scans were made with the NMR
tomograph (CSI 2 T) at 2 tesla (TR time of 400 ms and TE time of 20 ms). The layer thickness of this Tl-weighted imaging sequence was 3 mm; the image matrix was 128 x 128.
The contrast medium was administered intra-venously into a caudal vein of a male hairless rat (Lew/Mol) weighing 190 g, in a dose of 0.06 mmol/kg.
The animal had a Brown Pearce tumor in the thigh and was anesthetized for the study by means of an intra-muscular administration of "Ketavet"/"Rompun".
Various dark structures are visible in the abdomen in the coronary blank scan (baseline, No. 1).
No differentiation was possible between.intestinal lumen and stomach.
One minute after administration (No. 2), the first enhancement is already apparent in the urinary bladder. A strong increase in contrast is visible in the stomach 45 minutes after injection (No. 3). A
good visualization of the tumor (at the level of the reference tube), of the urinary bladder, and of the stomach can be observed 60 minutes after injection (No. 4). Moreover, contrasting of the intestine can likewise be observed. This makes it possible to distinguish among intestinal loops, fat, as well as lymphatic nodes (lymphomas). Contrasting of the renal pelvis is also striking; this image can be even more improved 65 minutes after injection in a somewhat different layer (No. 5). In Figure 6, 180 minutes after injection, the contrast enhancement is likewise clearly recognizable in an axial scan in the zone of the liver. This makes it possible to differentiate among the stomach, the liver, the duodenum, and the pancreas.
Example 2 The test animals were female rats of the strain Lew/Mol weighing 160-180 g. Prior to imaging, the animals were anesthetized ("Rompun' + "Ketavet~') and provided with a catheter in the caudal vein to administer the contrast medium. Imaging took place in an MRI experimental device by General Electric (field strength 2 tesla). First of all, the images (7, 9, 11) were made without contrast medium with a Tl-weighted spin echo sequence (TR = 400 msec, TE =
msec, axial section plane, layer thickness 3 mm).
20 The liver appears in each case with the normal signal intensity; the stomach is darker in tendency than the liver. In case of animal 1, the stomach exhibits, in part, a rather high signal intensity. This is due to feed residues, the feed containing manganese in relatively high concentrations (at the time of the test, the animals had been fasting for 6 hours). Ani-mal 3 had been implanted with an osteogenic sarcoma three weeks previously; this sarcoma was of equal contrast in the blank image and could not be defined.
The administration of contrast medium took place via the venous catheter with a dose of 0.1 mmol Gd/kg (concentration of the solutions 0.05 mmol Gd/ml in 0.9o NaCl) for all 3 compounds.

2~~~~ 4j A marked enhancement of the liver can be found for all 3 compounds after 90 minutes [Figure 8, Example 8(c)] and, respectively, after 60 minutes have elapsed upon administration [Figure 10, Example 9(c);
Figure 12, Example 10(c)]; this is due to uptake by the hepatocytes and cannot be observed at this point in time after administration with the contrast medium for NMR tomography, "Magnevist", heretofore the sole contrast medium available on the market. In case of animal 3 [Figure 12, Example 10(c)], the tumor is now additionally clearly visible, which has not absorbed the contrast medium at all, or only to a lesser propor-tion.
Furthermore, all compounds -- most strongly in case of Example 10(c), least in case of Example 8(c) --show great enhancement of the stomch. This offers additional diagnostic possibilities in view of an improved distinction of liver and stomach.

Claims (42)

1. A compound of the formula wherein:
one of Z1 and Z2 is H, and the other is -(CH2)m-(C6H4)q-(O)k-(CH2)n-(C6H4)l-(O)r-R, wherein m and n, independently, are each 0-20, k, l, q and r are each, independently, 0 or 1, R is H, C1-C6-alkyl, OR1-substituted C1-C6-alkyl or CH2COOR1, where R1 is H, C1-C6-alkyl or benzyl;
and X is, in each case, a hydrogen atom or a metal ion equivalent of an element of atomic number 21-29, 42, 44 or 57-83;
with the provisos that:
at least two of the substituents X represent a metal ion equivalent;
when n and l each are 0, then k and r are not simultaneously l;
at least one of q and l is 1;
-(O)r-R is not OH; and Z1 and Z2 are not -CH2-C6H4-O-CH2-COOCH2C6H5 or -CH2-C6H4-O- (CH2)5-COOCH2C6H5;
or a physiologically-acceptable salt thereof with an inorganic and/or organic base, an amino acid or amino acid amide.

2. A compound of claim 1, in which Z1 and Z2 are not -CH2C6H5 or -CH2-C6H4-OCH3, and Z1 is not phenyl when Z2 is H.

3. A compound of claim 1 or 2, wherein Z1 is hydrogen and Z2 i s - (CH2)m-(C6H4)q- (O)k-(CH2)n-(C6H4)l-(O)r-R.

4. A compound of claim 1 or 2, wherein Z2 is hydrogen and Z1 is - (CH2)m-(C6H4)q-(O)k-(CH2)n-(C6H4)l-(O)r-R.

5. A compound of claim 1 or 2, wherein Z1 is -CH2-C6H4-O-CH2-C6H4-OCH3, -CH2-O-CH2-C6H5, -CH2-C6H4-O-CH2-COOH, -CH2-C6H4-OC2H5, -CH2-C6H4-OC4H9 or -CH2-C6H4-O-CH2-C6H5.

6. A compound of claim 1 or 2, wherein Z2 is -CH2-C6H4-O-CH2-C6H4-OCH3, -CH2-O-CH2-C6H5, -CH2-C6H4-O-CH2-COOH, -CH2-C6H4-OC2H5, -CH2-C6H4-OC4H9 or -CH2-C6H4-O-CH2-C6H5.

7. A compound of claim 5, wherein Z1 is -CH2-C6H4-O-CH2-C6H4-OCH3, -CH2-O-CH2-C6H5 or -CH2-C6H4-O-CH2-COOH.

8. A compound of claim 6, wherein Z2 is -CH2-C6H4-O-CH2-C6H4-OCH3, -CH2-O-CH2-C6H5 or -CH2-C6H4-O-CH2-COOH.

9. A compound according to claim 1 or 2, wherein Z2 is -C6H4-OC2H5 or -C2H4-C6H4-OC2H5.

10. A compound according to claim 9, wherein Z2 is -C6H4-OC2H5.

11. A compound according to claim 1 or 2, wherein Z1 is -C6H4-OC2H5 or -C2H4-C6H5OC2H5.

12. A compound according to claim 1 or 2, wherein one of Z1 and Z2 is -CH2-C6H4-O- (CH2)n-(C6H4)l-(O)r-R.

13. A compound according to claim 1 or 2, wherein one of Z1 and Z2 is - (CH2)m-C6H4-O-CH2-C6H4-(O)r-R.

14. A compound according to any one of claims 1 to 13, wherein R is C1-6-alkyl or C1-6-alkyl substituted by - OR1.

15. A compound according to any one of claims 1 to 14, wherein at least two of the X groups represent a metal ion of atomic number 21-29, 42, 44 or 58-70.

16. A compound according to any one of claims 1 to 14, wherein two of the X groups represent manganese(II), iron(II), cobalt(II) or copper(II); or three of the X
groups represent chromium(III), praseodymium(III), neodymium(III), samarium(III), ytterbium(III), gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III) or iron(III).

17. A compound according to any one of claims 1 to 16, wherein the X groups which do not represent a metal ion equivalent of atomic number 21-29, 42, 44 or 57-83 are individually lithium, potassium or sodium, or two such X
groups are calcium or magnesium.

18. A compound according to any one of claims 1 to 17, wherein the groups which are not a metal ion equivalent of an element of atomic number 21-29, 42, 44 or 57-83 represent a salt with ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine, N-methylglucamine, lysine, arginine, ornithine, lysine methylamide, glycine ethylamide or serine methylamide.

19. A compound of any one of claims 1 to 18, wherein at least one X is Gd.

20. A compound of any one of claims 1 to 18, wherein at least three X groups represent a Gd ion.

21. A compound according to claim 1, wherein said compound is a complex of 3,6,9-triaza-3,6,9-tris(carboxy -methyl)-4-(4-ethoxyphenylethyl)undecanedioic acid and a metal ion of atomic number 21-29, 42, 44 or 57-83, or a physiologically-acceptable salt thereof.

22. A compound of claim 1, wherein said compound is:
gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxy -methyl)-4-(4-methoxybenzyl)-undecanedioic acid, or a physiologically-acceptable salt thereof;
europium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl) -4-(4-methoxybenzyl)undecanedioic acid, or a physiologically-acceptable salt thereof;
iron(III) complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl) -4-(4-methoxybenzyl)undecanedioic acid, or a physiologically-acceptable salt thereof;
bismuth complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl) -4-(4-methoxybenzyl)undecanedioic acid, or a physiologically-acceptable salt thereof;
gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxy -methyl)-4-(4-methoxybenzyl)undecanedioic acid or a physiologically-acceptable salt thereof;
gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxy -methyl)-4-[4-(4-methoxybenzyloxy)benzyl]undecadenioic acid, or a physiologically-acceptable salt thereof;
gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxy -methyl)-4-benzylundecanedioic acid, or a physiologically-acceptable salt thereof;

ytterbium complex of 3,6,9-triaza-3,6,9-tris(carboxy -methyl)-4-benzylundecanedioic acid, or a physiologically-acceptable salt thereof;
gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxy -methyl)-4-benzyloxymethylundecanedioic acid, or a physiologically-acceptable salt thereof;
gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxy -methyl)-4-(4-carboxymethoxybenzyl)undecanedioic acid, or a physiologically-acceptable salt thereof;
gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxy -methyl)-4-(4-ethoxybenzyl)undecanedioic acid, or a physiologically-acceptable salt thereof;
europium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl) -4-(4-ethoxybenzyl)undecanedioic acid, or a physiologically-acceptable salt thereof;
iron complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic acid, or a physiologically-acceptable salt thereof;
gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxy -methyl)-4-(4-butoxybenzyl)undecanedioic acid, or a physiologically-acceptable salt thereof;

europium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-butoxybenzyl)undecanedioic acid, or a physiologically-acceptable salt thereof;
iron complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-butoxybenzyl)undecanedioic acid, or a physiologically-acceptable salt thereof;
gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxy-methyl)-4-(4-benzyloxybenzyl)undecanedioic acid, or a physiologically-acceptable salt thereof;
europium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-benzyloxybenzyl)undecanedioic acid, or a physiologically-acceptable salt thereof;
iron complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-benzyloxybenzyl)undecanedioic acid, or a physiologically-acceptable salt thereof; or gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxy-methyl)-4-(4-ethoxyphenyl)undecanedioic acid, or a physiologically-acceptable salt thereof.

23. A pharmaceutical composition comprising a compound of any one of claims 1 to 22, and a pharmaceutically-acceptable carrier.

24. A composition according to claim 23, wherein the amount of said compound in the composition is 50 µmol/1 - 2 mol/1.

25. A composition according to claim 23, wherein the amount of said compound in the composition is 100 mmol/1 - 1 mol/1.

26. A composition according to claim 23, 24 or 25, wherein said composition further comprises a physio-logically-acceptable buffer, a complexing agent, an electrolyte and/or an antioxidant.

27. A composition according to any one of claims 23 to 26, wherein said carrier is an aqueous medium.

28. A method of enhancing an NMR image, comprising administering to a patient an NMR-contrast agent comprising a compound of any one of claims 1 to 22, wherein at least one X is of atomic number 21-29, 42, 44 or 58-70.

29. A method according to claim 28, wherein said NMR-contrast agent is administered intravenously.

30. A method according to claim 28 or 29, wherein said NMR-contrast agent is administered in a dose of 1 µmol/kg - 5 mmol/kg.

31. A method according to claim 30, wherein said NMR-contrast agent is administered in a dose of µmol/kg - 0.5 mmol/kg.

32. A method according to any one of claims 28 to 31, wherein the renal system or the hepatobiliary system is imaged.

33. A method of enhancing an X-ray image comprising administering to a patient a compound of any one of claims 1 to 22.

34. A method of claim 33, wherein at least one of k and r is 1.

35. A method according to claim 33 or 34, wherein R1 is H or C1-C6-alkyl.

36. A method according to claim 33, 34 or 35, wherein the GI tract of a patient is imaged.

37. A method according to claim 33, 34 or 35, wherein the hepatobiliary system is imaged.

38. A method according to claim 33, 34 or 35, wherein the renal system is imaged.

39. A method of any one of claims 33 to 38, wherein said compound is administered intravenously.

40. A method according to any one of claims 33 to 39, wherein said compound is administered in a pharmaceutical composition comprising said compound and a pharmaceutically-acceptable carrier.

41. A method according to any one of claims 33 to 40, wherein said compound is administered in a dose of 1 µmole/kg - 5 mmole/kg.

42. Use of a radioactive metal ion in the form of a compound as defined in any one of claims 1 to 22, for administering a radioactive metal ion to a patient undergoing radiation therapy.