WO1996026182A1 - Substituted dtpa monoamides of central carboxylic acids and metal complexes thereof, pharmaceuticals containing these complexes, diagnostic and therapeutic uses thereof and methods for preparing the complexes and pharmaceuticals - Google Patents

Abstract

The invention pertains to diethylenetriaminepentaacetic acid monoamide derivatives, their complexes and complex salts, containing an element of atomic number 12, 20-32, 39, 42-44, 49 or 57-83, pharmaceuticals containing these compounds, their use as contrast media and methods for preparing them.

Description

 Substituted DTPA monoamides of the central carboxylic acid

and their metal complexes,

pharmaceutical compositions containing these complexes,

their use in diagnostics and therapy

and processes for the preparation of the complexes and agents

The invention relates to diethylenetriaminepentaessigsäuremonoamidde vate, their complexes and complex salts, pharmaceutical compositions containing these compounds, their use as contrast agents and processes for their preparation.

Metal complexes were already considered as contrast agents for radiology in the early 1950s. However, the compounds used at that time proved to be difficult to tolerate, so that use in humans was out of the question. It was therefore very surprising that certain complex salts have proven to be sufficiently compatible so that routine use in humans could be considered.

EP 71564 B1 describes, inter alia, the meglumine salt of the gadolinium (III) complex of diethylenetriaminepentaacetic acid (DTPA) as a contrast agent for NMR tomography. A preparation containing this complex was approved worldwide as the first NMR contrast agent under the name Magnevist ^® . This contrast medium is distributed extracellularly after intravenous administration and is spread through Renal glomerular secretion excreted. A passage of intact cell membranes is practically not observed. Magnevist ^® is particularly well suited for the display of pathological areas (eg inflammation, tumors).

For the display of non-inflammatory and non-tumorous tissue areas, however, there is still a need for new contrast media that have a higher organ specificity or are excreted extrarenally.

A number of DTPA derivatives with terminal amide linkages have been proposed in EP 0263051 A1, EP 0450742 A1 and EP 0413405 A1 for use as NMR contrast media. However, these compounds have not fully met the safety and pharmacokinetic expectations associated with their manufacture.

All previously known complexes and their salts also cause problems in terms of tolerance and / or stability when used clinically. The diagnostically valuable use of heavy elements as constituents of parenteral X-ray contrast media has hitherto failed due to the insufficient tolerance of such compounds. In the paramagnetic substances previously proposed or tested for magnetic resonance imaging, the distance between the effective dose and the dose which is toxic in animal experiments is relatively narrow. They continue to have insufficient organ specificity. In many cases, their contrast-enhancing effect and their tolerance are inadequate.

There is therefore still a need for many purposes, especially for better tolerated, but also stable, readily soluble and sufficiently organ-specific complex compounds.

The invention is therefore based on the object of providing these compounds and agents and of creating a process for their preparation. This object is achieved by the objects characterized in the claims. It has been found that compounds which result from the anion of a complex-forming derivatized monoamide of the central carboxylic acid of diethylenethaminepentaacetic acid and a central ion of an element of atomic numbers 12, 20-32, 39, 42-44, 49 or 57-83 and optionally one or more cations of an organic and / or inorganic base or amino acid, are surprisingly outstandingly suitable for the production of NMR, X-ray and radio diagnostics as well as radio-therapeutic agents.

The compounds according to the invention are described by the general formula I.

wherein

X independently of one another represents a hydrogen atom or a metal ion equivalent of an element which is 12, 20-32, 39, 42-44, 49 or 57-83,

Z, E ¹ , E ² independently of one another represent a hydrogen atom, a saturated or unsaturated, branched or straight-chain Cj-Cso-alkyl chain, the chain or parts of this chain optionally being a cyclic Cs-Cg unit or a bicyclic C ^ -Cn Unit can form, the 0 to 10 oxygen and / or 0 to 2 sulfur atoms and / or 0 to 3 carbonyl, 0 to 1 thiocarbonyl, 0 to 2 imino, 0 to 2 phenylene, 0 to 1 3- Contains indole, 0 to 1 methylimidazol-4-yl and / or 0 to 3 NR ³ groups and by 0 to 2 phenyl, 0 to 2 pyridyl, 0 to 5 R ² O, 0 to 1 HS -, 0 to 4 R2QOC-, 0 to 4 RZQOC-C ^ -alkyl- and / or 0 to 1 R (H) N- Groups are substituted in which any aromatic groups present are zero to five times independently of one another by fluorine, chlorine, bromine, iodine, R ² 0 ₂ C-, 4 R ^ OC-C- alkyl-, R ² (H) N- , R ² NHOC, R ² CONH, O2N, R ² O, R ² groups may be substituted,

R ² independently of one another represents a hydrogen atom or a straight-chain or branched Ci-C ^ alkyl radical and

R3 independently of one another represents a hydrogen atom or a straight-chain or branched, saturated or unsaturated Cη -C3 _Q alkyl radical or

E ¹ and E ² together, including the nitrogen atom, stand for a five- to eight-membered saturated or unsaturated heterocycle which optionally contains one or two further nitrogen, oxygen, sulfur atoms and / or carbonyl groups,

the HO and / or H ₂ N and / or HS and or HOOC group (s) optionally present in Z, E ¹ and / or E ² can be present in protected form and in which free, for complexation carboxylic acid groups not used can also be present as salts with physiologically compatible inorganic and or organic cations or as esters or amides. The invention therefore relates to the compounds of the general formula I.

Compounds of the general formula I, in which all the radicals X which have the meaning of hydrogen are referred to below as complexing agents, compounds of the general formula I, where at least two radicals X have the meaning of a metal ion equivalent, are referred to as complexes. Salts of the complexes of the general formula I in which organic and / or inorganic bases act as counterion (s) are referred to below as complex salts. The terms terminal or central carboxylic acid are defined as follows:

Examples of groups E ¹ and E ² are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl heptyl, octyl, nonyl, decyl, undecyl, dodecyl, Tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cyclopentanone, cyclohexanol, cyclohexen 2-amino-cycloheptane, 2-hydroxyethyl, 5-oxononyl, hex-5-enyl, lcosa-19-enyl, 2-ethyl-hexyl, 2-ethoxyhexyl, phenyl, benzyl, naphthyl -, Imidazolyl, thiazolyl residues, and residues of the formulas:

Preferred groups E ¹ and E ² are straight-chain alkyl radicals with up to 20 carbon atoms, hydrogen atoms, cyclohexyl, phenyl, benzyl, naphthyl radicals and radicals of the general formula II

OH \

CH - CH; -OH

^• HC

CH OH

(II) and residues of the composition - (CH ₂ ) p- (G) _t - (CH ₂ ) _q COOH and - (CH ₂ ) _p - (G) _t - (CH ₂ ) _q NH ₂ , where G is oxygen or is sulfur, p, q independently of one another are a number between 1 and 28, t is 0 or 1, and p + t + q <30, the acid group also as a salt of an inorganic or organic base, as an ester or can be present as an amide or the amino group can also be present as an ammonium salt with a physiologically compatible anion or as an amide.

Examples of groups in which E ¹ and E ² together form a five- to eight-membered saturated or unsaturated heterocycle, including the nitrogen atom, are the imidazolyl, pyrazolyl, pyrrolyl, 3-pyrrolinyl, pyrrolidinyl, morpholinyl or the piperidinyl group.

Examples of radicals Z which may be mentioned are the hydrogen atom, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, pentyl, hexyl, cyclo-hexyl or phenyl or benzyl radicals, as well as remnants of the formulas

.CH,, O. .CH,

^' O ^'

The Z radical can also contain, for example, a 3-indole radical and / or a histidine radical.

Preferred Z radicals are alkyl and cycloalkyl radicals, such as the methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl or cyclo-hexyl radical, as well as the phenyl and the benzyl radical.

Preferred Z radicals are in particular groups which are identical to the Z ^A radicals occurring in naturally occurring amino acids of the general formula III

These are:

- H Gly

- CH ₃ Ala

- CH (CH ₃ ) ₂ val

- CH ₂ -CH (CHß) ₂ Leu CH ₂ -Ph Phl

CH ₂ OH Ser

CH (OH) -CH ₃ thr

CH ₂ SH Cys

CH ₂ -SCH ₃ Met

CH ₂ CO ₂ H Asp

CH ₂ CH ₂ -CO ₂ H Glu

- (CH ₂ ) ₄ -NH ₂ Lys

The -OH and / or -NH ₂ and / or -SH and / or -COOH group (s) optionally present in Z and or E ¹ and / or E ² may be present in protected form. Details of the syntheses with protecting groups are summarized below. Preparation of the complexes and complexing agents according to the invention

The invention also relates to the processes for producing the complex and complexing agents according to the invention.

The complexes according to the invention are prepared in the manner as has been disclosed in the patents EP 71564, EP 130934 and DE-OS 3401052 by using the metal oxide or a metal salt (for example a chloride, nitrate, acetate, carbonate or sulfate) Elements of atomic numbers 12, 20-32, 39, 42-44, 49 or 57-83 dissolve or suspend in water and / or a lower alcohol (such as methanol, ethanol or isopropanol) and with the solution or suspension of the equivalent amount the complexing agent according to the invention of general formula I and then, if desired, acidic hydrogen atoms present from acid groups substituted by cations of inorganic and / or organic bases or amino acids.

The neutralization takes place with the help of inorganic bases (e.g. hydroxides, carbonates, or bicarbonates) of e.g. Sodium, potassium or lithium and / or organic bases such as primary, secondary and tertiary amines, e.g. Ethanolamine, glucamine, N-methyl and N, N-dimethylglucamine, as well as basic amino acids, e.g. Lysine, arginine and ornithine.

To produce the neutral complex compounds, for example, the acidic complex salts in aqueous solution or suspension can be added with enough of the desired bases that the neutral point is reached. The solution obtained can then be evaporated to dryness in vacuo. It is often advantageous to neutralize the neutral salts formed by adding water-miscible solvents such as lower alcohols (methanol, ethanol, isopropanol etc.), lower ketones (acetone etc.), polar ethers (tetrahydrofuran, dioxane, 1, 2-dimethoxyethane, etc. .) to precipitate and thus to obtain crystals which are easy to isolate and easy to clean. It has proven to be particularly advantageous to add the desired base to the reaction mixture already during the complex formation and thereby to save one process step. If the acidic complexes contain several free acidic groups, it is often expedient to prepare neutral mixed salts which contain both inorganic and organic cations as counterions.

This can be done, for example, by reacting the complexing agent in aqueous suspension or solution with the oxide or salt of the desired element and half of the amount of an organic base required for neutralization, isolating the complex salt formed, purifying it if desired and then using the required amount of inorganic base added. The order of base addition can also be reversed.

Another way to get neutral complex compounds is to remove the remaining acid groups, e.g. described in EP 0450742 to convert all or part of it into esters or amides.

If the agents according to the invention are to contain radioisotopes, the complexes can be prepared from the complexing agents by the methods described in "Radiotracers for Medical Applications", Vol. I, CRC Press, Boca Raton, Florida.

The complexing agents of the general formula I according to the invention are prepared by splitting off the acid protecting groups R ¹ from compounds of the general formula IV

E ^ (IV),

wherein R ^{1 represents} an acid protecting group and Z, E ¹ and E ^{2 have} the meaning given above. Straight-chain and branched C ¹ -C 4 -alkyl and benzyl groups may be mentioned as examples of acid protecting groups R ¹ . The t-butyl and the benzyl group are preferably used. The cleavage of the protective groups takes place according to known in the art methods, for example by hydrolysis, hydrogenolysis, alkaline saponification of esters with alkali in aqueous-alcoholic solution at temperatures of 0 ° to 50 ^β C, acid saponification with mineral acids or in the case of t-butyl esters with the help of trifluoroacetic acid. The hydrogenolytic cleavage of the benzyl group and the saponification of the t-butyl group with trifluoroacetic acid are preferred.

The compounds of the general formula IV are prepared by adding compounds of the general formula V

wherein Z and R ^{1 have} the meaning given above, after activation of the free carboxylic acid group, with amines of the general formula VI

E ¹

H - N

(VI)

in organic solvents such as toluene or tetrahydrofuran at temperatures from -10 ° C to 50 ° C, preferably room temperature and below, with the addition of one or more activation reagents.

Activation can be carried out, for example, by reacting the acid with dicyclohexylcarbodiimide, N-hydroxysuccinimide / dicyclohexylcarbodiimide, carbonyldiimidazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline _l oxalic acid dichloride or chloroformic acid isobutyl ester as described in the literature: ♦ Activation of carboxylic acids. Overview in Houben-Weyl, Methods of Organic Chemistry, Volume XV / 2, Georg Thieme Verlag Stuttgart, 19.

♦ Activation with carbodiimides. R. Schwyzer u. H. Kapier, Helv. 46: 1550 (1963). ♦ E. Wünsch et al., B. 100: 173 (1967).

♦ Activation with carbodiimides / hydroxysuccinimide: J. Am. Chem. Soc. 86: 1839 (1964) and J. Org. Chem. 53: 3583 (1988). Synthesis 453 (1972).

♦ Anhydride method, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline: B. Belleau et al., J. Am. Chem. Soc, 90: 1651 (1986), H. Kunz et al., Int. J. Pept. Prot.

Res., 26: 493 (1985) and J.R. Voughn, Am. Soc. 73: 3547 (1951).

♦ Imidazolid method: B.F. Gisin, R.B. Menifield, D.C. Tosteon, Am. Soc. 91: 2691 (1969).

♦ Acid chloride methods, thionyl chloride: Helv., 42: 1653 (1959). ♦ Oxalyl chloride: J. Org. Chem., 29: 843 (1964).

Further details of the reaction procedure can be found in the examples.

With regard to the prior art, the method according to the invention is distinguished by several decisive advantages:

1) The amine of the general formula VI is linked selectively to the compounds of the general formula V on the central carboxylic acid.

2) The amine of the general formula VI is linked to the compounds of the general formula V under very mild conditions. The temperature can be kept below room temperature. This suppresses unwanted side reactions such as rearrangements, racemizations, eliminations, etc. The method is therefore ideal for coupling to very sensitive amines.

3) Due to the good solubility of all components in the solvent used, the amine of the general formula VI is linked to the acid of the general formula V in a homogeneous solution.

4) The amine of the general formula VI can be linked to the acid of the general formula V while avoiding chlorinated solvents, thereby avoiding side reactions (such as splitting off HCl from the solvent). 5) The acid protecting groups in the compounds of the general formula IV are removed in a very mild manner: existing amides are not saponified, rearrangements, eliminations and racemizations do not take place.

6) The compounds of general formula I are obtained in high yield and purity.

7) The free acid group of the compounds of the general formula V can be activated in various ways and thus reacted under optimal conditions with regard to the particular amine.

The invention therefore relates to the process for the preparation of compounds of the general formula I, which is characterized in the claims

wherein

X each represents a hydrogen atom,

Z, E ¹ , E ² independently of one another represent a hydrogen atom or a saturated or unsaturated, branched or straight-chain C1-C5 ₀ -alkyl chain, the chain or parts of this chain optionally being a cyclic C ₅ -C ₈ unit or a can form bicyclic C1 ₀ - 14 unit which contains 0 to 10 oxygen and / or 0 to 2 sulfur atoms and / or 0 to 3 carbonyl, 0 to 1 thiocarbonyl, 0 to 2 imino, 0 to 2 phenylene, 0 to 1 3-indole, 0 to 1 methyl-imidazol-4-yl and / or 0 contains up to 3 NR ³ groups and through 0 to 2 phenyl, 0 to 2 pyridyl, 0 to 5 R ² O, 0 to 1 HS, 0 to 4 R ² OOC, 0 to 4 R ^ OC- C ^ alkyl and / or 0 to 1 R ² (H) N groups is substituted, in which any aromatic groups present are zero to five times independently of one another by fluorine atoms, R ² O ₂ C, R ² OOC-C _{1 4} -alkyl-, C 1-4 -alkyl-NH-, R ² NHOC-, R ² CONH-, O ₂ N-, R ² O-, R ² -groups can be substituted,

R ² independently of one another for a hydrogen atom or a straight-chain or branched C- _| -C4 alkyl radical and

R3 independently of one another represents a hydrogen atom or a straight-chain or branched, saturated or unsaturated C 1 -C ₃₀ -alkyl radical or

E ¹ and E ² together, including the nitrogen atom, stand for a five- to eight-membered saturated or unsaturated heterocycle which optionally contains one or two further nitrogen, oxygen, sulfur atoms and / or carbonyl groups,

wherein the HO and / or H ₂ N and / or HS and / or HOOC group (s) optionally contained in E ¹ and / or E ² may be present in protected form and in which free ones for complexation purposes are not carboxylic acid groups used can also be present as salts with physiologically tolerable inorganic and / or organic cations or as esters or amides,

characterized in that a partially protected diethylene triamine pentacarboxylic acid derivative according to the general formula V,

in which R ^{1 represents} t-butyl or a benzyl group and 71 has the meaning of an optionally protected group Z, in which Z has the meaning given above, with an amine of the general formula VI

.E ¹

/

H - N

\

E ² (VI), in which E ¹ and E ^{2 have} the meaning given above, optionally with the addition of an activating reagent and by selective and mild cleavage of the group R ¹ and those which may be present in Z '

Protecting groups, then the free acid of the general formula I produces.

Numerous amines which correspond to the general formula VI

H - N

^E (VI), where n E ¹ and E ^{2 have} the meanings mentioned above, are commercially available (for example: E. Merck, Darmstadt, Fluka Chemie AG, CH-9470 Buchs) or can, as for example in Houben-Weyl, Methods of organic chemistry, nitrogen compounds II, Volume XI / 1 and XI / 2, Georg Thieme Verlag Stuttgart, 1957 described. Examples of amines of the general formula VI are ammonia, methylamine, dimethylamine, ethylamine, diethylamine, isopropylamine, diisopropylamine, cyclohexylamine, dicyclohexylamine, diisopropenylamine, cyclohexenylamine, 2-hydroxyethylamine, 5-oxononylamine and hex-5-enylamine -, 2-ethyl-hexylamine, 2-ethoxyhexylamine, aniline, benzylamine, naphthylamine, pipe din, N-ethylpiperazine, 4-hydroxymethylpiperidine, 4- (2-hydroxyethyl) piperidine, 4-piperidone, piperidine-3 -carbon- acid diethyiamide, piperidine-4-carboxylic acid dimethylamide, 2,6-dimethylpiperidine, dioctadecylamine, dihexadecylamine, aminoundecanoic acid, lysine, N-acetylpiperazine, pyrazoline, oxazolidine, imidazole or thiazole. The preferred radicals for E ¹ and E ² have already been mentioned above.

The HO, HS, HOOC or H ₂ N groups which may be present in the residues E ¹ and E ^{2 can} be present in protected form. Details of the possible protective group syntheses are described below.

Compounds of the general formula V are prepared in that an educt of the general formula VII

wherein R ¹ and Z have the meaning given above and

T is a straight-chain or branched C1-C5 alkyl group, a benzyl, trimethylsilyl, triisopropylsilyl, 2,2,2-trifluoroethoxy, trityl, 2,2,2-trichloroethoxy group, or a metal ion equivalent of an alkali or

Can be alkaline earth elements, where T is always different from R ¹ ,

is converted into the compound of the general formula V by splitting off the group T. The preferred radical T is the benzyl radical if R ^{1 represents} a t-butyl group. The protecting group T is removed from compounds of the general formula VII by the processes known to the person skilled in the art, such as, for example, by hydrolysis, hydrogenolysis, acidic or alkaline saponification of the esters in an aqueous alkaline medium, where appropriate solubilizers such as alcohols, preferably methanol, ethanol, isopropanol or ether such as tetrahydrofuran,

1, 4-dioxane, 1, 2-dimethoxyethane can be added. Alkali or alkaline earth metal hydroxides or their carbonates such as, for example, lithium hydroxide, sodium hydroxide, barium hydroxide or potassium carbonate and cesium carbonate can be used as the base. Preferred temperatures are 0 ^β C -100 ^β C, in particular 0 ^β C-50 ^β C. The subsequent isolation of the compound of the general formula V is carried out in such a way that an ammonium salt, such as NH ₄ Cl, ( NH ₄ ) SO ₄ or (NH ₄ ) ₃ PO ₄ , or the salts are converted into the free acids using an acidic ion exchanger.

The use of dilute citric acid or acidic ion exchangers has also proven effective in releasing the acid function from the alkali or alkaline earth salts.

The acidic hydrolysis is with mineral acids such as hydrochloric acid, sulfuric acid or organic acids (eg, trifluoroacetic acid) at temperatures of 0 ° C-100 ° C, preferably from 0 ^β C-50 ° C, in the case of trifluoroacetic acid between 0 ° C - 25 ° C carried out. The silyl-containing protective groups are split off using fluoride ions according to the methods familiar to the person skilled in the art.

The hydrogenolytic cleavage of benzyl derivatives takes place using the palladium catalysts known to the person skilled in the art, preferably 10% Pd on activated carbon or Pearlman catalyst Pd (OH) ₂ on carbon. Homogeneous catalysts of the Wilkinson type can also be used. The hydrogenation is carried out in alcohols such as methanol, ethanol or isopropanol, but preferably in isopropanol, at temperatures between 10 ^β C-50 ^β C, but preferably at room temperature and normal pressure. The preparation of compounds of the general formula VII takes place, for example, in that an amino acid derivative of the general formula VIII

wherein T and Z have the meaning given above, with an alkylating agent of the general formula IX

wherein

R ^{1 has} the meaning given above and Y ^{1 represents} a halogen atom such as Cl, Br or I, but preferably Cl, is converted (see also MA Williams, H. Rapoport, J. Org. Chem., 58, 1151 (1993 )).

Preferred amino acid derivatives are the esters of naturally occurring α-amino acids.

The reaction of compound (VIII) with compound (IX) is preferably carried out in a buffered alkylation reaction, an aqueous phosphate buffer solution being used as the buffer. The reaction takes place at pH values of 7-9, but preferably at pH 8. The buffer concentration can be between 0.1-2.5 M, but a 2 M phosphate buffer solution is preferably used. The temperature of the alkylation can be between 0 ^β C and 50 ° C, the preferred temperature is room temperature.

The reaction is carried out in a polar solvent, such as, for example, acetonitrile, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane. Acetonitrile is preferably used. In the case that Y ¹ in the general formula IX is a chlorine or bromine atom, an alkali iodide such as sodium iodide or potassium iodide can be added to the reaction in catalytic amounts.

The amino acid esters of the general formula VIII used in the reaction can be prepared by methods known to the person skilled in the art (for example Houben-Weyl, methods of organic chemistry, synthesis of peptides, part II, volume XV / 2, Georg Thieme Verlag Stuttgart, 1974, p. 3 ff) are prepared from the commercially available amino acids. Amino acids and derivatives, e.g. available from Fluka Chemie AG, CH-9470 Buchs or BACHEM Feinchemialen AG, CH-4416 Bubendorf.

Preferred amino acid derivatives of the general formula VIII are the amino acid benzyl esters. In the synthesis of these compounds, salts (such as hydrochlorides, hydrosulfates, sulfates, phosphates or p-toluenesulfonates) are generally obtained, which can advantageously be used directly in the reaction.

The block of the general formula IX used in the alkylation can, in the case where Y ¹ = Br, be prepared analogously to the description by Rapoport. The corresponding compound with Y ¹ = Cl in can, however, be used in the same way for the reaction described above. The chlorine compound is also inexpensive from the alcohol of the general formula X

can be produced on a large scale by reaction with thionyl chloride.

An alternative way of preparing compounds of the general formula VII is to use a compound of the general formula XI

R ^ C - ^ ^ CO ^ ¹

(XI) With

R ¹ in the meaning given above

with an alkylation agent of the general formula XII

implements whereby

T and Z have the meaning given above and where

Nu for a nucleofug, such as Cl, Br, I, p-CH ₃ C ₆ H ₄ SO ₃ -, CH ₃ SO ₃ - or

CF ₃ SO ₃ -, preferably for Br and Cl.

The reaction to the compound of general formula VII takes place in polar solvents, such as dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, formamide, dimethylacetamide, dimethyl sulfoxide, acetone and in alcohols, such as, for example, methanol, ethanol, isopropanol, preferably in acetonitrile and dimethyl formamide. In the case of the preferred bromides and chlorides, catalytic amounts of iodide can be added. To trap the acid generated during the alkylation, organic bases such as e.g. Triethylamine, Hünig base or

1, 4-diazabicyclooctane (DABCO) or metal hydrides, for example sodium hydride or alkali or alkaline earth metal hydroxides or carbonates thereof. Kaiium carbonate is preferably used. The reactions take place at 0 ° C-100 °, preferably between 20 ° C and 60 ° C. Some of the alkylating reagents described by the general formula XII are commercially available or can be prepared from the corresponding carboxylic acids or α-hydroxycarboxylic acids in a manner known from the literature (see for example: CF Ward, Soc, 121: 1164 (1922)). The compound of the general formula XI is obtained by splitting off the protective group A from the compound of the general formula XIII

obtained, wherein R ^{1 has} the meaning given above and A for a protective group, such as a benzyloxycarbonyl, t-butyloxycarbonyl (BOC), fluorenylmethoxycarbonyl (FMOC), benzyl, 4-methoxybenzyl, (CH ₃ ) ₃ Si- (CH ₂ ) ₂ -SO ₂ -, CF ₃ CO-, CCI ₃ CO-, (C ₆ H ₅ ) (t-Bu) ₂ Si- or a trityl group.

If A is the BOC residue, the cleavage takes place by treatment with trifluoroacetic acid. Silyl protective groups are with dilute mineral acid or with

Cleaved fluoride ions. If A is the (CH ₃ ) ₃ Si- (CH ₂ ) ₂ -SO group, tetrabutylammonium fluoride is used as the cleavage reagent. If A represents the benzyl or benzyloxycarbonyl radical, this is split off at room temperature by hydrogenolysis with palladium catalyst (10% Pd / C) or even more favorably with pearimane catalyst (Pd (OH) ₂ / C) in alcohols, preferably ethanol .

The compound of general formula XIII is derived from the compound of general formula XIV

where A has the meaning given above, obtained by reaction with α-haloacetic acid esters.

The chloro- or bromoacetic acid t-butyl esters and the corresponding benzyl esters are preferably used. The reaction analogous to the reaction of the compound of general formula VIII with the compound of general formula IX to the compound of general formula VII. The compound of general formula XIII, wherein A represents the benzyl radical, can also be prepared by reacting benzylamine with the alkylating reagent of general formula IX, as described above for the amino acid esters of general formula VIII.

The compound of the general formula XIV is obtained by cleaving off the protective group L, known to the person skilled in the art, from the compound of the general formula XV

wherein

A has the meaning given above and what

L represents a group -NHD, in which

D represents for example the benzyloxycarbonyl, BOC, CF ₃ CO, CCI ₃ CO or the trityl group

or L represents a phthalimido group. If D stands for the benzyloxycarbonyl group, hydrogenolysis takes place in the presence of palladium catalysts (see above).

If D is the CF ₃ CO group, saponification with alkali or alkaline earth hydroxides or their carbonates, but preferably potassium carbonate, is carried out. Aqueous ammonia solution can also be used. Mixtures of alcohols or tetrahydrofuran or 1,4-dioxane with water are preferably used as solvents. The reaction temperatures are between 0 ° C - 60 ° C, preferably at room temperature. If L is the phthalimino group, the phthalyl protective group is split off by hydrazinolysis or by treatment with alkali metal hydroxides, preferably sodium hydroxide or potassium hydroxide in aqueous alcohols, preferably n-butanol under reflux or by treatment with aqueous mineral acids, preferably concentrated hydrochloric acid, under reflux.

It has proven to be particularly advantageous to carry out the saponification with aqueous potassium carbonate solution, since it is possible in this way without isolating the Intermediate of the general formula XIV can carry out the alkylation to the tetraester of the general formula XIII.

1, 4,7-Triaza-4-benzyl-heptane can also be prepared as described in EP 0292689. The compound of general formula XV can be obtained by reacting the compound of general formula XVI

where L has the meaning given above

with the usual protecting group reagents (see e.g. Protective Groups in Organic Syntheses, second Edition, T.W. Greene and P.G.M. Wuts, John Wiley & Sons, Inc., New York, 1991).

The compound of general formula XVI are obtained by reacting an acylating reagent of general formula XVII

D-G (XVII)

with diethylenetriamine (XVIII)

received, whereby

G represents a C≡N group or an OR ³ group,

R ^{3 represents} a branched or unbranched, partially or fully fluorinated Ci-Cβ alkyl or a benzyl group,

or in the event that L represents the phthalimino group,

DG stands for phthalic anhydride. Preferred reagents DG are, in addition to the phthalic anhydride mentioned, ethyl trifluoroacetate and benzyl cyano formate.

For example, the reaction of diethylene amine (XVIII) with trifluoroacetic acid ethyl ester in ethanol at room temperature gives the already known (US 4,415,737 A (1983)) 1,7-bis-trifluoroacyl derivative (see examples) in almost quantitative yield.

The 1, 7-dibenzyloxycarbonyl compound (see examples) can be obtained by reacting diethylenetriamine (XVIII) with benzyl cyanoformate in tetrahydrofuran (Shun-Ichi Munehashi et al., Chemistry Letters, pp. 879-882 (1987)). The implementation of diethylenetriamine (XVIII) is another possibility for the production

• Dibenzyl carbonate in toluene

• Benzyloxycarbonylbenztriazol in THF with triethylamine or sodium hydroxide solution as base

• benzyloxycarbonylsuccinimide • benzyloxycarbonylpyrrole.

The phthalimido protecting group can be introduced into diethylenetriamine as described in J. Org. Chem. USSR, 23: 3302 (1987).

Protecting groups

The protection of the named groups in the radicals E ¹ , E ² and Z can be carried out in numerous ways known to the person skilled in the art. The embodiments described below serve to explain these protective group techniques without being limited to these synthetic routes.

Suitable acid protecting groups are C-Ce-alkyl, C ₆ -C ₁₀ aryl and C ₆ -C ₁ o-Ar (C ₁ -C) alkyl groups and trialkylsilyl groups. The methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl and t-butyl groups are preferred.

These acid protecting groups are split off by the processes known to the person skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline saponification of the esters with alkali in aqueous-alcoholic solution at temperatures from 0 to 50 ° C, acid saponification with mineral acids or in the case of t-butyl esters with the help of trifluoroacetic acid.

As come e.g. the benzyl, 4-methoxybenzyl, 4-nitrobenzyl, trityl, diphenylmethyl, trimethylsilyl, dimethyl-t-butylsilyl, diphenyl-t-butylsilyl groups in question.

The hydroxy groups can also e.g. as THP ether, α-alkoxyethyl ether, MEM ether or as ester with aromatic or aliphatic carboxylic acids, e.g. Acetic acid or benzoic acid. In the case of polyols, the hydroxy groups can also be in the form of ketals with e.g. Acetone, acetaldehyde, cyclohexanone or benzaldehyde must be protected.

The hydroxyl protective groups can be prepared using the literature methods known to the person skilled in the art, e.g. by hydrogenolysis, acid treatment of the ethers and ketals or alkali treatment of the esters (see e.g. Protective Groups in Organic Syntheses, second Edition, T.W. Greene and P.G.M. Wuts, John Wiley & Sons, Inc., New York, 1991).

The thiol groups can be protected as benzyl ethers, which can be cleaved with sodium in ammonia or boiling ethanol (W.L. Patterson, v. Du Vigneaud, J. Biol. Chem. 111: 393. 1993). S-t-butyl ethers can be readily cleaved with hydrogen fluoride / anisole at room temperature (S. Salzakibona et al., Bull. Chem. Soc. Japn., 40: 2164, (1967)). S-benzyloxycarbonyl derivatives can be easily cleaved by concentrated ammonia solution at room temperature (A. Berger et al., J. Am. Chem. Soc, 78: 4483. 1956). S-Benzyloxycarbonyl derivatives of trifluoroacetic acid are only split at boiling temperature (L. Zervas et al., J. Am. Chem. Soc, 85: 1337 (1963)).

The NH ₂ groups can be protected and uncovered in a variety of ways. The N-trifluoroacetyl derivative is derived from potassium or sodium carbonate in water (H. Newman, J.Org.Chem., 30: 287 (1965), MA Schwartz et al., J.Am. Chem. Soc, 95,. G12 ( 1973)) or simply cleaved by ammonia solution (M. Imazama and F. Eckstein, J.Org.Chem., 44: 2039 (1979)). The t-butyloxycarbonyl derivative is also easy to split: stirring with trifluoroacetic acid is sufficient (BF Lundt et al., J.Org.Chem., 43: 2285 (1978)). The group of NH ₂ protective groups to be split hydrogenolytically or by reduction is very large: the N-benzyl group can be split easily with hydrogen / Pd-C (WH Hardening and R. Simonoff, Org. Reactions VII, 263 (1953)), which also applies to the trityl group (L Zervas et al., J.Am. Chem. Soc, 78: 1359 (1956)) and the benzyloxycarbonyl group (M.Bergmann and L Zervas, Ber. 65: 1192 (1932) ).

Of the silyl derivatives, the easily cleavable t-butyldiphenylsilyl compounds (LE Overman et al., Tetrahedron Lett., 27: 4391 (1986)), as well as the 2- (thmethylsilyl) ethyl carbamates (L. Grehn et al., Angew. Chem. Int. Ed. Engl., 23: 296 (1983)) and the 2-trimethylsilylethanesulfonamides (RS Garigipati and SM Weinreb, J. Org. Chem., 53: 4143 (1988)), which are cleaved with fluoride ions can.

9-Fluorenylmethyl carbamate is particularly easy to cleave: Cleavage takes place with amines such as pipehdin, morpholine, 4-dimethylaminopyridine, but also with tetrabutylammonium fluoride (LA. Corpino et al., J. Org. Chem., 55: 1673 (1990) , M. Ueki and M. Amemiya, Tetrahedron Lett., 28: 6617 (1987)).

Production and use of the agents according to the invention

The pharmaceutical compositions according to the invention are prepared in a manner known per se by suspending or dissolving the complex compounds according to the invention - optionally with the addition of the additives customary in galenicals - in an aqueous medium and then optionally sterilizing the suspension or solution. Suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), small additions of complexing agents (such as DTPA or the respective compound of the general formula I with X in the meaning of hydrogen) and / or their calcium, magnesium or Zinc complexes or, if desired, electrolytes (such as sodium chloride) and antioxidants (such as ascorbic acid).

If suspensions or solutions of the agents according to the invention in water or physiological saline solution are desired for enteral administration or other purposes, they are mixed with one or more of the auxiliaries customary in galenics, such as methyl cellulose, lactose or mannitol, and / or surfactants, such as, for example, lecithins, Tween ^® or Myrj ^®, and / or flavoring substances for taste correction, such as essential oils, for example, mixed.

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

This can be ensured, for example, with the help of color indicators such as xylenol orange through control titrations during the manufacturing process. The invention therefore also relates to processes for the preparation of the complex compounds and their salts. As a last resort, cleaning of the isolated complex salt remains.

The pharmaceutical compositions according to the invention preferably contain 1 μmol / l-2 mol / l of the complex salt and are generally dosed in amounts of 0.001-20 mmol / kg body weight. They are intended for enteral and parenteral application.

The complex compounds according to the invention are used:

1. for NMR diagnostics in the form of their complexes with divalent and trivalent ions of the elements of atomic numbers 21-29, 42, 44 and 57-70. Suitable ions are, for example, chromium (III), iron (II), Cobalt (ll) -,

Nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III), and ytterbium (III) ion. Because of their very strong magnetic moment, gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), manganese (II) and iron (III) are particularly preferred. -ion.

2. for X-ray diagnostics in the form of its complexes with an element with a higher atomic number, which ensures adequate absorption of the X-rays.

It has been found that complexes according to the invention which contain elements of atomic numbers 57-83 as central atom are suitable for this application. 3. for radio diagnostics and radiotherapy in the form of their complexes with radioactive central ions. For example, radioisotopes of the elements copper, cobalt, gallium, germanium, yttrium, holmium, lutetium, scandium, iron, europium, technetium, indium, ytterbium, gadolinium, samarium and iridium are suitable.

The agents of the general formula I according to the invention satisfy, if X for one of the above-mentioned. paramagnetic metals, the diverse requirements for the suitability as a contrast agent for magnetic resonance imaging. Thus, they are excellently suited to, after oral or parenteral application by increasing the signal intensity, the image obtained with the aid of the magnetic resonance scanner in its

To improve the informative value. They also show the high effectiveness that is necessary to burden the body with the smallest possible amount of foreign substances and the good tolerance that is necessary to maintain the non-invasive character of the examinations.

In general, the agents according to the invention for use as NMR diagnostics are dosed in amounts of 0.001-5 mmol / kg body weight, preferably 0.005-0.5 mmol / kg body weight. Details of the application are, for example, in H.J. Weinmann et al., Am. J. of Roentgenology 142, 619 (1984).

Particularly low doses (below 1 mg / kg body weight) of organspecific NMR diagnostics can be used, for example, to detect tumors and heart attacks.

Furthermore, the complex compounds according to the invention can advantageously be used as susceptibility reagents and as shift reagents for in-vivo NMR spectroscopy.

The agents according to the invention are also outstandingly suitable as X-ray contrast agents, it being particularly emphasized that they do not show any signs of the anaphylaxis-like reactions known from the iodine-containing contrast agents in biochemical-pharmacological examinations. The substances according to the invention fulfill the diverse requirements that are to be placed on contrast agents in modern diagnostics. The compounds and means made from them are characterized by:

a high absorption coefficient for X-rays, good tolerability, high effectiveness, low viscosity, low osmolality, favorable excretion kinetics.

In addition to the surprisingly good tolerability of the heavy metal complexes, the compounds according to the invention have a positive effect in X-ray diagnostics in that the complex compounds according to the invention in particular also allow examinations for short-wave X-rays than is possible with conventional contrast media, which significantly reduces the radiation exposure of the patient , since it is known that soft radiation is absorbed much more strongly by tissue than hard radiation [R. Felix, "The X-ray picture"; Thieme-Verlag Stuttgart (1980)].

Because of the favorable absorption properties of the invention

Contrast agents in the field of hard X-rays are also particularly suitable for digital subtraction techniques (which work with higher tube voltages).

Details of the use of X-ray contrast media are discussed, for example, in Barke, X-ray contrast media, G. Thieme, Leipzig (1970) and P. Thurn, E. Bücheier "Introduction to X-ray diagnostics", G. Thieme, Stuttgart, New York (1977).

In general, the agents according to the invention for use as X-ray contrast agents are dosed in amounts of 0.1-20 mmol / kg body weight, preferably 0.25-5 mmol / kg body weight.

If the agents according to the invention are radioactive, because of their favorable properties and the good stability of the complex compounds they contain, they are also suitable as radio diagnostics. Details of their application and dosage are e.g. in "Radiotracers for Medical Applications", CRC-Press, Boca Raton, Florida.

Another imaging method using radioisotopes is positron emission tomography, which uses positron emitting isotopes such as ³ Sc, ⁴ Sc, ⁵² Fe, ⁵⁵ Co and ⁶⁶ Ga used [Heiss, WD; Phelps, ME; Positron Emission Tomography of Brain, Springer-Verlag Berlin, Heidelberg, New York (1983)].

The compounds according to the invention can also be used in radioimmunotherapy or radiation therapy. This differs from the corresponding diagnostics only in the amount and type of the isotope used. The goal is the destruction of tumor cells by high-energy short-wave radiation with the shortest possible range. Suitable β-emitting ions are, for example, ^ Sc, ⁴⁷ Sc, ⁴⁸ Sc, ⁷² Ga, ⁷³ Ga and ⁹⁰ Y. Suitable α-emitting ions having short half-lives are, for example, ²¹¹ Bi, ²¹² Bi, ²¹³ Bi, ²¹ Bi, where ²¹² Bi is preferred. A suitable photon and electron emitting ion is ¹⁵⁸ Gd, which can be obtained from ¹⁵⁷ Gd by neutron capture.

Is the agent according to the invention for use in the RL Mills et. al. [Nature Vol. 336, (1988), p. 787] proposed variant of the radiation therapy, the central ion must be derived from a Mössbauer isotope, such as ⁵⁷ Fe or ¹⁵¹ Eu.

Details of the use of radiotherapeutics are e.g. in R.W. Kozak et al., TIBTEC, October 1986, 262.

The aqueous X-ray and NMR contrast medium solutions can be applied enterally or parenterally, namely orally, rectally, intravenously, intraarterially, intravascularly, intracutaneously, subcutaneously (lymphography), subarachnoidally (myelography), intravenous application being preferred.

The agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that a release or an exchange of the ions which are not covalently bound in the complexes - in themselves toxic - within the time in which the new ones Contrast agents are completely excreted, not done. It has been shown in particular that the compounds according to the invention, which are complexes of DTPA amides of central acetic acid, have higher complex formation constants than comparable complexes of DTPA amides of terminal acetic acids. Due to the high concentration of compounds according to the invention with lipophilic residues (eg compound according to Example 13c) in the liver, spleen and in the lymph nodes, these compounds are particularly suitable for the diagnosis of these organs. The compounds according to the invention can also be encapsulated in liposomes using customary methods (for example WO 94/08626 and the literature cited therein). Such formulations are particularly suitable for the diagnostic imaging of the liver, spleen, bile, lymph channels and nodes and the intravascular space.

Overall, it has been possible to synthesize new complexing agents, metal complexes and metal complex salts which open up new possibilities in diagnostic and therapeutic medicine. The invention therefore relates to the compounds of the general formula I explained above, processes for their preparation, pharmaceutical compositions, processes for the preparation of these compositions and the use of these compositions in diagnosis and therapy.

Examples

The following examples serve to explain the subject of the invention in more detail without wishing to restrict it to them.

example 1

a) 1,7-bis (trifluoroacetyl) -1,4,7-triazaheptane

113.3 g (790 mmol) of ethyl trifluoroacetate are added dropwise to a solution of 41.14 g (390 mmol) of 1,4,7-triazaheptane in 350 ml of tetrahydrofuran at 0 ° C. and under nitrogen. The mixture is stirred at room temperature overnight and concentrated in vacuo. The remaining oil is crystallized from hexane.

Yield: 115 g (99.9% of theory)

Melting point: 68-70 ° C

Elemental analysis: calc .: C 32.55 H 3.76 F 38.62 N 14.24 found: C 32.63 H 3.75 F 38.38 N 14.19

b) 1,7-bis (trifluoroacetyl) -4-benzyloxycarbonyl-1,7,4-thazaheptane

14.75 g (50 mmol) of the trifluoroacetyl compound prepared in Example 1a) and 8.3 ml (60 mmol) of triethylamine are dissolved in 120 ml of dichloromethane and cooled to 0.degree. 7.5 ml (53 mmol) of benzyl chloroformate (97%), dissolved in 20 ml of dichloromethane, are then added dropwise with stirring. The mixture is stirred overnight at room temperature, the salts are extracted with distilled water, the dichloromethane solution is dried over sodium sulfate, concentrated to dryness in vacuo and the residue is crystallized from ether / hexane.

Yield: 18.40 g (85.7% of theory)

Melting point: 131-32 ° C Elemental analysis: calc .: C 44.76 H 3.99 F 26.55 N 9.79 found: C 44.87 H 4.03 F 26.62 N 9.61

c) 3,9-bis (t-butoxycarbonylmethyl) -6-benzyloxycarbonyl-3,6,9-triazaundecanedicarboxylic acid di-t-butyl ester

4.29 g (10 mmol) of the trifluoroacetyl derivative prepared in Example 1b) are dissolved in 30 ml of ethanol, and 800 mg (20 mmol) of sodium hydroxide solution in 10 ml of distilled water are added. The mixture is stirred for 3 hours at room temperature, evaporated to dryness at 40 ° C. bath temperature, water residues are removed by azeotropic distillation with isopropanol and taken up in 30 ml of dimethylformamide. 6.9 g (50 mmol) of potassium carbonate and 9.7 g (50 mmol) of t-butyl bromoacetate are then added and the 4-benzyloxycarbonyl-1, 4,7-triazaheptane is alkylated at room temperature overnight. Then you pull that

Dimethylformamide in an oil pump vacuum, distributes the residue between water and dichloromethane, dries the organic solution over sodium sulfate, evaporates to dryness in a vacuum and purifies the residue by chromatography on silica gel. The title compound is eluted with ethyl acetate / hexane. It is preserved as a foam.

Yield: 6.49 g (93.6% of theory)

Elemental analysis: calc .: C 62.32 H 8.57 N 6.06 found: C 62.41 H 8.66 N 6.01

d) 3,9-bis (t-butoxycarbonylmethyl) -3,6,9-triazaundecanedicarboxylic acid di-t-butyl ester

3.5 g (5 mmol) of the compound prepared under Example 1c) are dissolved in 100 ml of ethanol, with 200 mg of Pearlman catalyst (Pd 20% on activated carbon) added and hydrogenated until the calculated amount of hydrogen is taken up. It is suctioned off from the catalyst and concentrated to dryness in vacuo. The title compound is obtained as a white foam.

Yield: 2.80 g (99.9% of theory)

Elemental analysis: calc .: C 60.08 H 9.54 N 7.51 found: C 60.02 H 9.62 N 7.56

e) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-methyl) -ethoxycarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.60 g (10 mmol) of the amino compound prepared in Example 1d) are dissolved in 30 ml of dimethylformamide. Then, at room temperature, 1.66 g (12 mmol) of potassium carbonate and 2.17 g (12 mmol) of 2-bromopropionate are added and the mixture is stirred overnight. It is then poured onto ice water, extracted with ethyl acetate, the organic solution is dried over sodium sulfate, concentrated to dryness in vacuo and the title compound is obtained by chromatography on silica gel. A mixture of ethyl acetate / hexane serves as the eluent.

Yield: 4.18 g (63.4% of theory)

Elemental analysis: calc .: C 60.07 H 9.32 N 6.37 found: C 60.18 H 9.40 N 6.31

f) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-methyl) -carboxymethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

6.60 g (10 mmol) of the compound prepared in Example 1e) are dissolved in 50 ml of ethanol. The solution of 400 mg (10 mmol) of sodium hydroxide in 5 ml of distilled water is then added and the mixture is stirred for 3 hours at 50 ^° C. According to the thin-layer chromatogram, the saponification is quantitative. You narrow in Vacuo to dryness to remove traces of water by codistillation with ethanol and the residue at 40 C ^β dried in vacuo. The title compound is obtained as a white powder. The remaining white residue is dissolved in 80 ml of moist ethanol (9: 1) and the solution of 535 mg (10 mmol) of ammonium chloride in 10 ml of distilled water is added with stirring. The mixture is evaporated to dryness in a vacuum, the soluble fractions are taken up in butanol and the mixture is again evaporated to dryness in a vacuum. The residue is extracted with toluene. The organic solution is evaporated to dryness in vacuo and the title compound is obtained as a foam.

Yield: 5.35 g (84.7% of theory)

Elemental analysis: calc .: C 58.93 H 9.09 N 6.65 found: C 59.01 H 9.16 N 6.60

g) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-methyl) -decylaminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.00 g (7.91 mmol) of the title compound from Example 1f) are dissolved in 25 ml of dimethylformamide and 1.00 g (8.70 mol) of N-hydroxysuccinimide is added. It is cooled to 0 ° C. and 1.795 g (8.7 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred at 0 ° C. for one hour and then at room temperature for 4 hours. The mixture is cooled to 0 ° C. and a solution of 1.25 g decylamine (7.91 mmol) in 10 ml dimethylformamide is added dropwise within 10 minutes. The mixture is stirred at 0 ^° C. for one hour, then at room temperature overnight. It is evaporated to dryness in vacuo and the residue is taken up in 100 ml of ethyl acetate. The precipitated urea is filtered off and the filtrate is washed twice with 100 ml of 5% aqu. Soda solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: n-hexane / ethyl acetate 20: 1). 5.31 g (87% of theory) of a colorless oil are obtained. Elemental analysis: calc .: C 63.86 H 10.20 N 7.27 found: C 63.95 H 10.28 N 7.18

h) 3,9-bis (carboxymethyl) -6- (2-methyl) decylaminocarbonylmethyl-3,6,9-triazaundecanedioic acid

5 g (6.48 mmol) of the title compound from Example 1g) are dissolved in 100 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 20 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.

Yield: 2.34 g (61% of theory) of a glassy solid

Water content: 7.5%

Elemental analysis (based on anhydrous substance): calc .: C 54.93 H 8.48 N 10.25 found: C 54.85 H 8.55 N 10.17

i) Gadolinium complex of 3,9-bis (carboxymethyl) -6- (2-methyl) -decylamino-carbonylmethyl-3,6,9-thazaundecanedioic acid monosodium salt

5.0 g (9.14 mmol) of the title compound from Example 1h) are dissolved in 50 ml of deionized water, and 1.665 g (4.57 mmol) of gadolinium oxide are added in portions at room temperature. After a reaction time of 3 hours at 80 ° C., the now almost clear reaction solution is cooled to room temperature and a pH of 7.2 is set with 1 N sodium hydroxide solution. After filtration, the filtrate obtained is freeze-dried. Yield: 6.48 g (98.2% of theory) of an amorphous powder

Water content: 5.62%

Elemental analysis (based on anhydrous substance): calc .: C 41.54 H 5.86 N 7.75 Gd 21.75 Na 3.18 found: C 41.48 H 5.80 N 7.69 Gd 21.68 Na 3.11

j) Iron complex of 3,9-bis (carboxymethyl) -6- (2-methyl) decylaminocarbonylmethyl-3,6,9-triazaundecanedioic acid monosodium salt

2.0 g (3.65 mmol) of the title compound from Example 1h) are dissolved in 100 ml of deionized water, and 1.29 g (3.65 mmol) of iron III-acetylacetonate are added in portions at 80 ° C. After a reaction time of 2 hours at 80 ° C., the now yellow-colored reaction solution is cooled to room temperature and extracted twice with 50 ml of methylene chloride each time. A pH of 7.2 is then set by salting the aqueous product solution with 1 N sodium hydroxide solution. After filtration, the filtrate obtained is freeze-dried.

Yield: 2.2 g (97.4% of theory) of an amorphous powder

Elemental analysis (based on anhydrous substance): calc .: C 48.32 H 6.81 N 9.02 Fe 8.99 Na 3.70 found: C 48.36 H 6.82 N 9.10 Fe 9.02 Na 3 , 74

Example 2

a) 1,7-bis (benzyloxycarbonyl) -1,4,7-triazaheptane

4.87 g (47.2 mmol) of 1,4,7-triazaheptane and 5 ml of triethylamine are dissolved in 100 ml of dichloroethane. The solution of 15.22 g (94.4 mmol) of benzyl cyanoformate in 200 ml of dichloromethane is added dropwise to this solution within 3 hours. The mixture is stirred for 2 days at room temperature, then concentrated to dryness in vacuo, taken up in diethyl ether and washed with sodium bicarbonate solution. The Ether solution is dried over sodium sulfate and evaporated to dryness in vacuo. The residue is crystallized from a little ethanol. The title compound crystallizes in white needles.

Yield: 11.46 g (65.7% of theory)

Melting point: 73-75 ^β C

Elemental analysis: calc .: C 64.67 H 6.78 N 11, 31 found: C 64.82 H 6.64 N 11, 28

b) 1,7-bis (benzyloxycarbonyl) -4-trifluoroacetyl-1,7,4-triazaheptane

Analogously to Example 1a), 37.14 g (100 mmol) of the amino compound prepared under Example 2a) are reacted with 15.63 g (110 mmol) of ethyl trifluoroacetate in 100 ml of tetrahydrofuran and worked up. The title compound is obtained as an oil.

Yield: 43.57 g (93.2% of theory)

Elemental analysis: calc .: C 56.53 H 5.18 F 12.19 N 8.99 found: C 56.60 H 5.24 F 12.14 N 9.04 ^•

c) 3,9-bis (t-butoxycarbonylmethyl) -6-trifluoroacetyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

Analogously to Example 1d), 4.675 g (10 mmol) of the trifluoroacetyl compound prepared under Example 5f) in 100 ml of ethanol with 0.5 g of Pearlman catalyst (Pd 20%, C) became 4-trifluoroacetyl-1, 4,7-triazaheptane hydrogenated and worked up. The amino compound is then in 30 ml according to Example 1 e)

Dimethylformamide with 9.7 g (50 mmol) t-butyl bromoacetate in the presence of 6.9 g (50 mmol) of potassium carbonate alkylated. The title compound is also worked up and purified analogously to 5c).

Yield: 5.88 g (89.6% of theory)

Elemental analysis: calc .: C 54.95 H 7.99 F 8.69 N 6.41 found: C 54.90 H 8.05 F 8.62 N 6.36

d) 3,9-bis (t-butoxycarbonylmethyl) -3,6,9-triazaundecanedicarboxylic acid di-t-butyl ester

Analogously to Example 1c), 6.57 g (10 mmol) of the trifluoroacetyl compound prepared in Example 2c) are dissolved in 50 ml of ethanol and saponified with 400 mg (10 mmol) of sodium hydroxide solution. The mixture is concentrated, the amino compound is taken up in warm toluene, washed with a little water, dried over sodium sulfate and concentrated to dryness in vacuo. The title compound is obtained as a foam.

Yield: 5.24 g (93.6% of theory)

Elemental analysis: (based on anhydrous substance): calc .: C 60.08 H 9.54 N 7.51 found: C 60.02 H 9.48 N 7.44

e) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-benzyl) -ethoxycarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.60 g (10 mmol) of the amino compound prepared in Example 2d) are dissolved in 30 ml of dimethylformamide. Then 1.66 g (12 mmol) of potassium carbonate and 3.0 g (12 mmol) of 2-bromophenylpropionic acid ethyl ester are added at room temperature and the mixture is stirred overnight. It is then poured onto ice water, extracted with

Ethyl acetate, the organic solution dries over sodium sulfate, evaporates to dryness in vacuo and the title compound is obtained by chromatography on silica gel. A mixture of ethyl acetate / hexane serves as the eluent. Yield: 4.30 g (58.4% of theory)

Elemental analysis: calc .: C 64.65 H 9.00 N 5.95 found: C 64.62 H 9.07 N 5.90

f) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-benzyl) carboxymethyl-3,6,9-thazaundecanedioic acid di-t-butyl ester

7.06 g (10 mmol) of the compound prepared in Example 2e) are dissolved in 50 ml of ethanol. The solution of 400 mg (10 mmol) of sodium hydroxide in 5 ml of distilled water is then added and the mixture is stirred at 50 ° C. for 3 hours. According to the thin layer chromatogram, the saponification is quantitative. It is concentrated to dryness in a vacuum, traces of water are removed by codistillation with ethanol and the residue is dried at 40 ° C. in vacuo. The title compound is obtained as a white powder. The remaining white residue is dissolved in 80 ml of moist ethanol (9: 1) and the solution of 535 mg (10 mmol) of ammonium chloride in 10 ml of distilled water is added with stirring. The mixture is evaporated to dryness in a vacuum, the soluble fractions are taken up in butanol and the mixture is again evaporated to dryness in a vacuum. The residue is extracted with toluene. The organic solution is evaporated to dryness in vacuo and the title compound is obtained as a foam.

Yield: 6.03 g (85.2% of theory)

Elemental analysis: calc .: C 63.79 H 8.77 N 6.20 found: C 63.68 H 8.83 N 6.26

g) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-benzyl) -pentylaminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.00 g (7.91 mmol) of the title compound from Example 2f) are dissolved in 25 ml of dimethyl formamide and 894 mg (7.77 mol) of N-hydroxysuccinimide are added. You cool to 0 ° C and adds 1.603 g (7.77 mmol) of dicyclohexylcarbodiimide. The mixture is stirred at 0 ° C. for one hour and then at room temperature for 4 hours. The mixture is cooled from 0 ° C. and a solution of 0.62 g of pentylamine (7.06 mmol) in 10 ml of dimethylformamide is added dropwise within 10 minutes. The mixture is stirred at 0 ^° C. for one hour, then at room temperature overnight. It is evaporated to dryness in vacuo and the residue is taken up in 100 ml of ethyl acetate. The precipitated urea is filtered off and the filtrate is washed twice with 10 ml of 5% aqu. Soda solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n-hexane / ethyl acetate 20: 1). 4.77 g (87% of theory) of a colorless oil are obtained.

Elemental analysis (based on anhydrous substance): calc .: C 64.92 H 9.34 N 7.21 found: C 64.81 H 9.28 N 7.25

h) 3,9-bis (carboxymethyl) -6- (2-benzyl) pentylaminocarbonylmethyl-3,6,9-triazaundecanedioic acid

4.50 g (5.79 mmol) of the title compound from Example 2g) are dissolved in 100 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 20 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.

Yield: 2.28 g (67% of theory) of a glassy solid

Water content: 6.1%

Elemental analysis (based on anhydrous substance): calc .: C 56.51 H 7.30 N 10.14 found: C 56.61 H 7.22 N 10.03 i) Gadolinium complex of 3,9-bis (carboxymethyl) -6- (2-benzyl) -pentylamino-carbonylmethyl-3,6,9-thazaundecanedioic acid sodium salt

Analogously to Example 1i), the reaction of 2.5 g (4.52 mmol) of the title compound from Example 2h) with 0.82 g (2.26 mmol) of gadolinium oxide after freeze drying gives 3.24 g (98.4% of theory) . Th.) Of the title compound as an amorphous powder.

Water content: 6.38%

Elemental analysis (based on anhydrous substance): calc .: C 42.85 H 4.98 N 7.69 Gd 21, 58 Na 3.15 found: C 42.78 H 4.96 N 7.68 Gd 21.52 Na 3.09

j) Dysprosium complex of 3,9-bis (carboxymethyl) -6- (2-benzyl) -pentylamino-carbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

4.0 g (7.23 mmol) of the title compound from Example 2h) are dissolved in 60 ml of deionized water, and 1.35 g (3.62 mmol) of dysprosium oxide are added in portions at room temperature. After a reaction time of 3 hours at 80 ° C., the now almost clear reaction solution is cooled to room temperature and a pH of 7.2 is set with 1 N sodium hydroxide solution. After filtration, the filtrate obtained is freeze-dried.

Yield: 5.13 g (96.8% of theory) of an amorphous powder

Water content: 7.43%

Elemental analysis (based on anhydrous substance): calc .: C 42.54 H 4.94 N 7.63 Dy 22.14 Na 3.13 found: C 42.60 H 4.98 N 7.64 Dy 22.19 Na 3.16

Example 3 a) 1,7-bis (thfluoroacetyl) -4-benzyl-1,7,4-triazaheptane

29.52 g (100 mmol) of the bis (thfluoroacetyl) compound prepared in Example 1a) are dissolved in 200 ml of dimethylformamide. Then 16.6 g (120 mmol) of potassium carbonate and 20.53 g (120 mmol) of benzyl bromide are added at room temperature and the mixture is stirred overnight. Then diluted with 500 ml

Diethyl ether, sucks off the salts, removes the ether in vacuo and then evaporates to 50 ml in an oil pump vacuum. It is diluted with 600 ml of diethyl ether, poured onto ice water and taken up in the organic solution, dried over sodium sulfate, concentrated to dryness in vacuo and the title compound is obtained by chromatography on silica gel. A mixture of ethyl acetate / hexane serves as the eluent.

Yield: 317.50 g (82.4% of theory)

Elemental analysis: calc .: C 46.76 H 4.45 F 29.58 N 10.91 found: C 46.83 H 4.51 F 29.50 N 10.87

b) 3,9-bis (t-butoxycarbonylmethyl) -6-benzyl-3,6,9-triazaundecanedicarboxylic acid di (t-butyl ester)

(300.53 g (100 mmol) of the trifluoroacetyl derivative prepared under 3a) are dissolved in 300 ml of ethanol, and 8 g (200 mmol) of sodium hydroxide solution in 100 ml of distilled water are added. The mixture is stirred for 3 hours at room temperature, concentrated to dryness at a bath temperature of 50 ° C., water residues are removed by azeotropic distillation with isopropanol and taken up in 300 ml of dimethylformamide. Then 69 g (500 mmol) of potassium carbonate and 97 g (500 mmol) of t-butyl bromoacetate are added and the 4-benzyl-1, 4,7-triazaheptane is alkylated at room temperature overnight. The dimethylformamide is then stripped off in an oil pump vacuum, the residue is partitioned between water and dichloromethane, the organic solution is dried over sodium sulfate, concentrated to dryness in vacuo and the residue is purified by chromatography on silica gel. The title compound is eluted with ethyl acetate / hexane. It is preserved as a foam.

Yield: 59.85 g (92.1% of theory) Elemental analysis: calc .: C 64.69 H 9.15 N 6.47 found: C 64.75 H 9.23 N 6.44

c) 3,9-bis (t-butoxycarbonylmethyl) -3,6,9-triazaundecanedicarboxylic acid di-t-butyl ester

6.50 g (10 mmol) of the compound prepared under 3b) are dissolved in 100 ml of ethanol, 400 mg of Pearlman catalyst (Pd 20%, C) are added and the mixture is hydrogenated until 224 ml of hydrogen have been taken up. It is suctioned off from the catalyst, washed with ethanol and concentrated to dryness in vacuo. The title compound is obtained as a white foam.

Yield: 5.58 g (99.5% of theory)

Elemental analysis: calc .: C 60.08 H 9.54 N 7.51 found: C 60.17 H 9.60 N 7.57

d) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-isopropyl) ethoxycarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.60 g (10 mmol) of the amino compound prepared under Example 3c) are dissolved in 30 ml of dimethylformamide. Then, at room temperature, 1.66 g (12 mmol) of potassium carbonate and 2.0 g (12 mmol) of 2-bromo-2-isopropyl-acetic acid ethyl ester are added and the mixture is stirred overnight. It is then poured onto ice water, extracted with ethyl acetate, the organic solution is dried over sodium sulfate, concentrated to dryness in vacuo and the title compound is obtained by chromatography on silica gel. A mixture of ethyl acetate / hexane serves as the eluent.

Yield: 4.07 g (59.2% of theory) Elemental analysis: calc .: C 61, 11 H 9.52 N 6.11 found: C 61.03 H 9.60 N 6.17

e) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-isopropyl) carboxymethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

6.88 g (10 mmol) of the compound prepared in Example 3d) are dissolved in 50 ml of ethanol. The solution of 400 mg (10 mmol) of sodium hydroxide in 5 ml of distilled water is then added and the mixture is stirred at 50 ° C. for 3 hours. According to the thin layer chromatogram, the saponification is quantitative. The mixture is concentrated in vacuo to dryness to remove traces of water by codistillation with ethanol and the residue is dried at 40 C in vacuo ^β. The title compound is obtained as a white powder. The remaining white residue is dissolved in 80 ml of moist ethanol (9: 1) and the solution of 535 mg (10 mmol) of ammonium chloride in 10 ml of distilled water is added with stirring. The mixture is evaporated to dryness in a vacuum, the soluble fractions are taken up in butanol and the mixture is again evaporated to dryness in a vacuum. The residue is extracted with toluene. The organic solution is evaporated to dryness in vacuo and the title compound is obtained from hexane.

Yield: 5.53 g (83.8% of theory)

Elemental analysis: calc .: C 60.07 H 9.32 N 6.37 found: C 60.18 H 9.41 N 6.44

f) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-isopropyl) -N-morpholinocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5 g (7.58 mmol) of the title compound from Example 3e) and 660 mg (7.58 mmol) of morpholine are dissolved in 30 ml of toluene and 2.06 g (8.34 mmol) of 2-ethoxy- 1-ethoxycarbonyl-1,2-dihydroquinoline added. The mixture is stirred at 0 ° C. for 30 minutes and then at room temperature overnight. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: hexane / ethyl acetate = 15: 1).

Yield: 5.14 g (93% of theory) of a colorless oil

Elemental analysis: calc .: C 60.96 H 9.40 N 7.69 found: C 60.87 H 9.51 N 7.60

g) 3,9-bis (t-butoxycarboxymethyl) -6- (2-isopropyl) -N-morpholinocarbonylmethyl-3,6,9-thazaundecanedioic acid

5.00 g (6.86 mmol) of the title compound from Example 3f) are dissolved in 100 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 20 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.

Yield: 2.59 g (71% of theory) of a glassy solid

Water content: 5.3%

Elemental analysis (based on anhydrous substance): calc .: C 49.99 H 7.19 N 11, 11 found: C 49.85 H 7.25 N 11.03

h) Gadolinium complex of 3,9-bis (carboxymethyl) -6- (2-isoρroρyl) -N-morpholinocarbonylmethyl-3,6,9-triazaundecanedioic acid monosodium salt Analogously to Example 1 i), the reaction of 3.0 g (5.94 mmol) of the title compound from Example 3g) with 1.07 g (2.97 mmol) of gadolinium oxide after freeze-drying gives 5.48 g (98.4% d. Th.) of the title compound as an amorphous powder.

Water content: 4.94%

Elemental analysis (based on anhydrous substance): calc .: C 37.05 H 4.74 N 8.23 Gd 23.10 Na 3.38 found: C 37.09 H 4.76 N 8.26 Gd 23.12 Na 3.40

i) Europium complex of 3,9-bis (carboxymethyl) -6- (2-isopropyl) -N-morpholinocarbonylmethyl-3,6,9-triazaundecanedioic acid mono-sodium salt

2.5 g (4.95 mmol) of the title compound from Example 3g) are dissolved in 50 ml of deionized water and 0.87 g (2.47 mmol) of europium oxide are added in portions at room temperature. After a reaction time of 3 hours at 80 ° C., the now almost clear reaction solution is cooled to room temperature and a pH of 7.2 is set with 1 N sodium hydroxide solution. After filtration, the filtrate obtained is freeze-dried.

Yield: 3.25 g (97.5% of theory) of an amorphous powder

Water content: 6.21%

Elemental analysis (based on anhydrous substance): calc .: C 37.34 H 4.78 N 8.29 Eu 22.50 Na 3.40 found: C 37.21 H 4.69 N 8.19 Eu 22.24 Na 3.33

Example 4

a) 1,7-bis (phthalimido) -4-benzyl-1,7,4-triazaheptane

36.34 g (100 mmol) of 1,7-bis (phthalimido) -1,4,7-triazaheptane [shown in J. Org. Chem. USSR, 23: 3302 (1987)] are dissolved in 500 ml of dimethylformamide. Then 16.6 g (120 mmol) of potassium carbonate and 20.53 g (120 mmol) are added Add benzyl bromide and stir overnight at 25 ° C. It is poured into ice water, the precipitated product is suctioned off, washed with water, taken up in 1,2-dichloroethane, dried over sodium sulfate and evaporated to the dry state in a vacuum. The title compound is obtained as a solid.

Yield: 42.76 g (94.3% of theory)

Elemental analysis: calc .: C 71.51 H 5.11 N 9.27 found: C 71, 40 H 5.18 N 9.38

b) 3,9-bis (t-butoxycarbonylmethyl) -6-benzyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

22.68 g (50 mmol) of the compound prepared under 4a) are partly added to 250 ml of hydrazine hydrate with stirring. The mixture is warmed to 60 ° C. for a further 4 hours, allowed to cool, the phthalhydrazide is filtered off, washed with hydrazine hydrate and concentrated in vacuo. The residue is freed of hydrazine residues by codistillation with isopropanol. The 4-benzyl-1, 4,7-triazaheptane is taken up in 150 ml of dimethylformamide, 34.5 g (250 mmol) of potassium carbonate are added and finally 48.5 g (250 mmol) of t-butyl bromoacetate. The alkylation is allowed to run overnight at room temperature. The dimethylformamide is then stripped off in an oil pump vacuum, the residue is partitioned between water and dichloromethane, dried over sodium sulfate, concentrated to dryness in vacuo and the residue is purified by chromatography on silica gel. The title compound is obtained as a foam.

Yield: 51.15 g (78.7% of theory)

Elemental analysis. calc .: C 64.69 H 9.15 N 6.47 found: C 64.60 H 9.20 N 6.53 c) 3,9-bis (t-butoxycarbonylmethyl) -3,6,9-triazaundecanedicarboxylic acid di-t-butyl ester

13.0 g (20 mmol) of the compound prepared under 4b) are dissolved in 200 ml of ethanol, 0.8 g of Pearlman catalyst (Pd 20%, C) are added and the mixture is hydrogenated until 448 ml of hydrogen have been taken up. It is suctioned off from the catalyst, washed with ethanol and concentrated to dryness in vacuo. The title compound is obtained as a foam.

Yield: 5.52 g (98.7% of theory)

Elemental analysis: calc .: C 60.08 H 9.54 N 7.51 found: C 60.01 H 9.62 N 7.58

d) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-phenyl) methoxycarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.60 g (10 mmol) of the amino compound prepared in Example 4c) are dissolved in 30 ml of dimethylformamide. Then, at room temperature, 1.66 g (12 mmol) of potassium carbonate and 2.22 g (12 mmol) of 2-chlorophenylacetic acid methyl ester are added and the mixture is stirred overnight. It is then poured onto ice water, extracted with ethyl acetate, the organic solution is dried over sodium sulfate, concentrated to dryness in vacuo and the title compound is obtained by chromatography on silica gel. A mixture of ethyl acetate / hexane serves as the eluent.

Yield: 4.40 g (62.1% of theory)

Elemental analysis: calc .: C 62.78 H 8.69 N 5.94 found: C 62.89 H 8.76 N 5.88

e) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-phenyl) carboxymethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

7.08 g (10 mmol) of the compound prepared in Example 4d) are dissolved in 50 ml of ethanol. The solution of 400 mg (10 mmol) of sodium hydroxide in 5 ml of distilled water is then added and the mixture is stirred at 50 ° C. for 3 hours. According to the thin layer chromatogram, the saponification is quantitative. The mixture is concentrated in vacuo to dryness to remove traces of water by codistillation with ethanol and the residue is dried at 40 C in vacuo ^β. The title compound is obtained as a white powder. The remaining white residue is dissolved in 80 ml of moist ethanol (9: 1) and the solution of 535 mg (10 mmol) of ammonium chloride in 10 ml of distilled water is added with stirring. The mixture is evaporated to dryness in a vacuum, the soluble fractions are taken up in butanol and the mixture is again evaporated to dryness in a vacuum. The residue is extracted with toluene. The organic solution is evaporated to dryness in vacuo and the title compound is obtained as a foam.

Yield: 5.99 g (86.3% of theory) Elemental analysis: calc .: C 62.32 H 8.57 N 6.06 found: C 62.40 H 8.65 N 6.02

f) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-phenyl) - (6'-hydroxyhexyl) aminocarboxymethyl-3,6,9-thazaundecanedioic acid di-t-butyl ester

5 g (7.21 mmol) of the title compound from Example 4e) and 845 mg (7.21 mmol) of 6-aminohexan-1-ol are dissolved in 30 ml of toluene and 1.96 g (7.93 mmol ) 2-Ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline added. The mixture is stirred for 30 minutes at 0 ° C., then overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: hexane / isopropanol = 20: 1). 4.52 g (79% of theory) of a colorless oil are obtained.

Elemental analysis: calc .: C 63.61 H 9.15 N 7.06 found: C 63.75 H 9.27 N 6.95

g) 3,9-bis (carboxymethyl) -6- (2-phenyl) - (6'-hydroxyhexyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

4 g (5.04 mmol) of the title compound from Example 4f) are dissolved in 100 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The

The residue is dissolved in 100 ml of water. 16 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo. Yield: 2.22 g (73% of theory) of a glassy solid

Water content: 5.8%

Elemental analysis (based on anhydrous substance): calc .: C 54.92 H 7.09 N 9.85 found: C 54.87 H 7.18 N 9.77

h) Gadolinium complex of 3,9-bis (carboxymethyl) -6- (2-phenyl) - (6'-hydroxyhexyl) aminocarbonyimethyl-3,6,9-triazaundecanedioic acid monosodium salt

Analogously to Example 1 i), the reaction of 4.2 g (7.38 mmol) of the title compound from Example 4g) with 1.33 g (3.69 mmol) of gadolinium oxide after freeze-drying gives 5.40 g (98 4% of theory) of the title compound as an amorphous powder.

Water content: 7.56%

Elemental analysis (based on anhydrous substance): calc .: C 41, 93 H 4.87 N 7.52 Gd 21, 11 Na 3.09 found: C 42.01 H 4.92 N 7.54 Gd 21, 20 Na 3, 12th

i) Manganese complex of 3,9-bis (carboxymethyl) -6- (2-phenyl) - (6'-hydroxyhexyl) - aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-sodium salt

3.0 g (5.27 mmol) of the title compound from Example 4g) are dissolved in 100 ml of deionized water, and 0.60 g (5.27 mmol) of manganese II carbonate are added in portions at room temperature. After a reaction time of 3 hours at 80 ° C., the now almost clear reaction solution is cooled to room temperature and a pH of 7.2 is set with 1 N sodium hydroxide solution. After filtration, the filtrate obtained is freeze-dried.

Yield: 3.43 g (97.8% of theory) of an amorphous powder

Water content: 5.68% Elemental analysis (based on anhydrous substance): calc .: C 46.92 H 5.45 N 8.42 Mn 8.26 Na 6.91 found: C 46.90 H 5.42 N 8.40 Mn 8.23 Na 6.87

Example 5

a) 2-Bromo-2- (4-methoxyphenyl) acetic acid methyl ester

In a mixture of 18.46 g (100 mmol) of 2- (4-methoxyphenyl) acetic acid chloride and 1.24 g (40 mmol) of red phosphorus, 27.01 g (169 mmol) of bromine are added with vigorous stirring so that the Bromine staining disappears continuously. After about half of the amount of bromine has been added, the mixture is heated

3 hours at 40 ° C. 4.49 g (140 mmol) of methanol are then added dropwise to the cooled solution, the mixture is left to stir for one hour, diluted with 100 ml of dichloromethane, the solution is dropped into ice water with vigorous stirring, the organic phase is separated off, washed with saturated sodium carbonate solution and dried over sodium sulfate and evaporated to dryness in vacuo. The residue is purified by distillation in a Kugelrohr in an oil pump vacuum.

Yield: 19.59 g (75.6% of theory)

Elemental analysis: calc .: C 46.36 H 4.28 Br 30.84 found: C 46.42 H 4.35 Br 30.78

b) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (4-methoxyphenyl)] methoxycarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.60 g (10 mmol) of the amino compound prepared in Example 1d) are dissolved in 30 ml of dimethylformamide. Then 1.66 g (12 mmol) of potassium carbonate and 3.11 g (12 mmol) of 2-bromo-2- (4-methoxyphenylacetic acid methyl ester) are added at room temperature and the mixture is stirred overnight. It is then poured onto ice water, extracted with ethyl acetate, the organic solution is dried over sodium sulfate, concentrated in Vacuum to dryness and the title compound by chromatography on Kieseigel. A mixture of ethyl acetate / hexane serves as the eluent.

Yield: 5.50 g (74.6% of theory)

Elemental analysis: calc .: C 61.85 H 8.60 N 5.69 found: C 61.78 H 8.66 N 5.75

c) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (4-methoxyphenyl)] carboxymethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

7.38 g (10 mmol) of the compound prepared in Example 5b) are dissolved in 50 ml of ethanol. The solution of 400 mg (10 mmol) of sodium hydroxide in 5 ml of distilled water is then added and the mixture is stirred at 50 ° C. for 3 hours. According to the thin layer chromatogram, the saponification is quantitative. It is evaporated to the dry state in a vacuum, traces of water are removed by codistillation with ethanol and the residue is dried at 40 ° C. in vacuo. The title compound is obtained as a white powder. The remaining white residue is dissolved in 80 ml of moist ethanol (9: 1) and the solution of 535 mg (10 mmol) of ammonium chloride in 10 ml of distilled water is added with stirring. The mixture is evaporated to dryness in a vacuum, the soluble fractions are taken up in butanol and the mixture is again evaporated to dryness in a vacuum. The residue is extracted with toluene. The organic solution is evaporated to dryness in vacuo and the title compound is obtained as a foam.

Yield: 6.39 g (88.3% of theory)

Elemental analysis: calc .: C 61.39 H 8.49 N 5.80 found: C 61.31 H 8.56 N 5.74 d) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (4-methoxyphenyl)] - aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5 g (6.91 mmol) of the title compound from Example 5c) are dissolved in 30 ml of anhydrous benzene and 1.75 g (13.82 mmol) of oxalic acid dichloride are added at 0 ° C. The mixture is stirred at 0 ° C. for 3 hours and then evaporated to dryness in vacuo. The residue is dissolved in 30 ml of benzene and again evaporated to dryness. At 0 ° C, ammonia gas is passed into the solution with vigorous stirring (30 minutes). The solution is washed twice with 50 ml of 5% aqu. Soda solution, the organic phase dries over magnesium sulfate and evaporates to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / hexane / isopropanol = 10.J 0: 1)

Yield: 3.95 g (79% of theory) of a colorless solid

Elemental analysis: calc .: C 61.47 H 8.64 N 7.75 found: C 61.58 H 8.75 N 7.61

e) 3,9-bis (carboxymethyl) -6- [2- (4-methoxyphenyl)] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

3.5 g (4.84 mmol) of the title compound from Example 5d) are dissolved in 100 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 15 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.

Yield: 1.60 g (63% of theory) of a glassy solid

Water content: 5.0% Elemental analysis (based on anhydrous substance): calc .: C 50.60 H 6.07 N 11, 24 found: C 50.70 H 6.15 N 11.13

f) Gadolinium complex of 3,9-bis (carboxymethyl) -6- [2- (4-methoxyphenyl)] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

In analogy to Example 1i), the reaction of 2.8 g (5.61 mmol) of the title compound from Example 5e) with 1.01 g (2.80 mmol) of gadolinium oxide after freeze drying gives 3.74 g (99.0% of theory) . Th.) Of the title compound as an amorphous powder.

Water content: 7.49%

Elemental analysis (based on anhydrous substance): calc .: C 37.38 H 3.88 N 8.30 Gd 23.31 Na 3.41 found: C 37.31 H 3.84 N 8.28 Gd 23.28 Na 3.39

g) Manganese complex of 3,9-bis (carboxymethyl) -6- [2- (4-methoxyphenyl)] - aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-sodium salt

Analogously to Example 4i), the reaction of 1.8 g (3.61 mmol) of the title compound from Example 5e) with 0.41 g (3.61 mmol) of manganese II carbonate after freeze-drying gives 2.09 g (97 , 6% of theory) of the title compound as an amorphous powder.

Water content: 4.72%

Elemental analysis (based on anhydrous substance): calc .: C 42.37 H 4.40 N 9.41 Mn 9.23 Na 7, .72 found: C 42.40 H 4.44 N 9.43 Mn 9, 25 Na 7.74 Example 6

a) 3- (4-Ethoxyphenyl) propionic acid

16.62 g (100 mmol) of 3- (4-hydroxyphenyl) propionic acid are dissolved in 45 ml (225.0 mmol) of 5N sodium hydroxide solution while stirring and covering with argon, and 15.73 g (100 mmol) are added dropwise. , (98%) Diethyl sulfate so quickly that the temperature does not exceed 40 ° C (water cooling). After the addition has ended, the mixture is heated to 100 ^° C. for a further 30 minutes. After cooling, the mixture is extracted with diethyl ether, then acidified to pH 4 with sulfuric acid and the compound which has precipitated is taken up in ether. After drying over sodium sulfate, the mixture is evaporated to dryness in vacuo. The title compound is obtained as a solid.

Yield: 15.21 g (78.3% of theory)

Elemental analysis: calc .: C 68.02 H 7.26 found: C 68.13 H 7.34

b) ethyl 2-bromo-3- (4-ethoxyphenyl) propionate

A drop of dimethylformamide is added to 9.71 g (50 mmol) of the acid prepared under 6a) in 50 ml of 1,2-dichloroethane. The mixture is then heated to 80 ° C. and 5.0 ml (68.6 mmol) of thionyl chloride are added dropwise. There is lively gas evolution. When the addition is complete, the mixture is boiled under reflux for one hour, then concentrated to dryness in vacuo and 0.62 g (20 mmol) of red phosphorus are added to the acid chloride. Then 13.6 g (85 mmol) of bromine are added dropwise so rapidly that the bromine coloration just disappears. When about half the amount of bromide has been added, the mixture is heated to 40 ° C. and the temperature is maintained for another three hours. The mixture is cooled to room temperature and 3.22 g (70 mmol) of ethanol in 20 ml of dichloromethane are then added dropwise. After an hour, the mixture is diluted with 200 ml of dichloromethane, poured onto ice water, the organic solution is separated off, washed with saturated sodium bicarbonate solution and concentrated to dryness in vacuo. The title compound is purified by chromatography on silica gel. A mixture of ethyl acetate and hexane serves as the eluent. The title compound is obtained as a syrup. Yield: 11.57 g (76.8% of theory)

Elemental analysis: calc .: C 51.84 H 5.69 Br 26.53 found: C 51.77 H 5.74 Br 26.59

c) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (4-ethoxybenzyl) ethoxycarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.60 g (10 mmol) of the amino compound prepared in Example 1d) are dissolved in 30 ml of dimethylformamide. Then, at room temperature, 1.66 g (12 mmol) of potassium carbonate and 3.61 g (12 mmol) of 2-bromo-2- (4-ethoxybenzyl) ethyl acetate are added and the mixture is stirred overnight. It is then poured onto ice water, extracted with ethyl acetate, the organic solution is dried over sodium sulfate, concentrated to dryness in vacuo and the title compound is obtained by chromatography on silica gel. A mixture of ethyl acetate / hexane serves as the eluent.

Yield: 4.95 g (63.4% of theory)

Elemental analysis: calc .: C 63.13 H 8.92 N 5.39 found: C 63.07 H 8.89 N 5.44

d) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (4-ethoxybenzyl) carboxymethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

7.80 g (10 mmol) of the compound prepared in Example 6c) are dissolved in 50 ml of ethanol. The solution of 400 mg (10 mmol) of sodium hydroxide in 5 ml of distilled water is then added and the mixture is stirred at 50 ° C. for 3 hours. According to the thin layer chromatogram, the saponification is quantitative. The mixture is concentrated in vacuo to dryness to remove traces of water by codistillation with ethanol and the residue is dried at 40 C in vacuo ^β. The title compound is obtained as a white powder. The remaining white residue is dissolved in 80 ml of moist ethanol (9: 1) and with stirring with the solution of 535 mg (10 mmol) ammonium chloride in 10 ml of distilled water. The mixture is evaporated to dryness in a vacuum, the soluble fractions are taken up in butanol and the mixture is again evaporated to dryness in a vacuum. The residue is extracted with toluene. The organic solution is evaporated to dryness in vacuo and the title compound is obtained as a foam.

Yield: 6.47 g (86.1% of theory)

Elemental analysis: calc .: C 62.29 H 8.71 N 5.59 found: C 62.36 H 8.77 N 5.57

e) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (4-ethoxybenzyl)] - aminocarboxymethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5 g (6.65 mmol) of the title compound from Example 6d) are dissolved in 30 ml of anhydrous benzene and 1.69 g (13.30 mmol) of oxalic acid dichloride are added at 0 ° C. The mixture is stirred at 0 ° C. for 3 hours and then evaporated to dryness in vacuo. The residue is dissolved in 30 ml of benzene and again evaporated to dryness. At 0 ° C, ammonia gas is passed into the solution with vigorous stirring (30 minutes). The solution is washed twice with 50 ml of 5% aqu. Soda solution, the organic phase dries over magnesium sulfate and evaporates to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / hexane / isopropanol = 10: 10: 1)

Yield: 4.05 g (81% of theory) of a colorless solid

Elemental analysis: calc .: C 62.38 H 8.86 N 7.46 found: C 62.45 H 8.78 N 7.35 f) 3,9-bis (carboxymethyl) -6- [2- (4-ethoxybenzyl) aminocaoxymethyl-3,6,9-triazaundecanedioic acid

4.00 g (5.32 mmol) of the title compound from Example 6e) are dissolved in 100 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 15 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.

Yield: 1.90 g (64% of theory) of a glassy solid

Water content: 5.7%

Elemental analysis (based on anhydrous substance): calc .: C 52.47 H 6.51 N 10.64 found: C 52.38 H 6.60 N 10.58

g) Gadolinium complex of 3,9-bis (carboxymethyl) -6- [2- (4-ethoxybenzyl) aminocarboxymethyl-3,6,9-triazaundecanedioic acid sodium salt

In analogy to Example 1 i), the reaction of 1.9 g (3.60 mmol) of the title compound from Example 6f) with 0.65 g (1.80 mmol) of gadolinium oxide

Freeze-drying 2.41 g (95.5% of theory) of the title compound as an amorphous powder.

Water content: 8.18%

Elemental analysis (based on anhydrous substance): calc .: C 39.31 H 4.30 N 7.97 Gd 22.98 Na 3.27 found: C 39.28 H 4.26 N 7.95 Gd 22.32 Na 3.25 h) Europium complex of 3,9-bis (carboxymethyl) -6- [2- (4-ethoxybenzyl) aminocarboxymethyl-3,6,9-triazaundecanedioic acid sodium salt

Analogously to Example 3i), the reaction of 1.2 g (2.27 mmol) of the title compound from Example 6f) with 0.40 g (1.14 mmol) of europium oxide after freeze-drying gives 1.52 g (96.6% of theory) . Th.) Of the title compound as an amorphous powder.

Water content: 7.45%

Elemental analysis (based on anhydrous substance): calc .: C 39.61 H 4.34 N 8.03 Eu 21.79 Na 3.30 found: C 39.62 H 4.32 N 7.99 Eu 21.78 Na 3, 32

Example 7

a) Ethyl 2-bromo-2- (pyrid-2-yl) -acetate

16.52 g (100 mmol) of ethyl 2-pyridylacetate are dissolved in 50 ml of carbon tetrachloride. It is cooled to 0 ° C. and then 15.98 g (100 mmol) of bromine, dissolved in 15 ml of carbon tetrachloride, are added dropwise over the course of 30 minutes. Then allowed to react for one hour at 25 ° C. The bromine color disappears. The mixture is concentrated in vacuo and the hydrobromide of the title compound is obtained. The free compound is obtained by ether extraction from the aqueous solution after adding sodium bicarbonate.

Yield: 22.80 g (93.4% of theory)

Elemental analysis: calc .: C 44.29 H 4.13 Br 32.74 N 5.74 found: C 44.22 H 4.18 Br 32.81 N 5.68

b) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (pyrid-2-yl)] ethoxycarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester 5.60 g (10 mmol) of the amino compound prepared in Example 1d) are dissolved in 30 ml of dimethylformamide. Then, at room temperature, 1.66 g (12 mmol) of potassium carbonate and 2.93 g (12 mmol) of 2-bromo-2- (pyrid-2-yl) ethyl acetate are added and the mixture is stirred overnight. It is then poured onto ice water, extracted with ethyl acetate, the organic solution is dried over sodium sulfate, concentrated to dryness in vacuo and the title compound is obtained by chromatography on silica gel. A mixture of ethyl acetate / hexane serves as the eluent.

Yield: 5.11 g (69.2% of theory)

Elemental analysis: calc .: C 60.14 H 8.46 N 7.58 found: C 60.21 H 8.55 N 7.66

c) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (pyrid-2-yl)] carboxymethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

7.39 g (10 mmol) of the compound prepared in Example 7b) are dissolved in 50 ml of ethanol. The solution of 400 mg (10 mmol) of sodium hydroxide in 5 ml of distilled water is then added and the mixture is stirred at 50 ° C. for 3 hours. According to the thin layer chromatogram, the saponification is quantitative. It is concentrated to dryness in a vacuum, traces of water are removed by codistillation with ethanol and the residue is dried at 40 ° C. in vacuo. The title compound is obtained as a white powder. The remaining white residue is dissolved in 80 ml of moist ethanol (9: 1) and the solution of 535 mg (10 mmol) of ammonium chloride in 10 ml of distilled water is added with stirring. The mixture is evaporated to dryness in a vacuum, the soluble fractions are taken up in butanol and the mixture is again evaporated to dryness in a vacuum. The residue is extracted with toluene. The organic solution is evaporated to dryness in vacuo and the title compound is obtained as a foam.

Yield: 5.96 g (87.6% of theory) Elemental analysis: calc .: C 61.74 H 6.59 N 6.17 found: C 61.66 H 6.65 N 6.24

d) 3, 9-bis (t-butoxycarbonylmethyl) -6- {2- (pyridyl-2-yl)] - (4-carboxybutyl) amino-caΦonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5 g (7.34 mmol) of the title compound from Example 7c) and 0.74 g (7.34 mmol) of triethylamine are dissolved in 50 ml of methylene chloride. A solution of 1.11 g (8.1 mmol) of isobutyl chloroformate in 10 ml of methyl chloride is added dropwise at -10 ° C. in the course of 5 minutes and the mixture is stirred at -10 ° C. for 20 minutes. The solution is cooled to -15 ° C. and a solution of 0.86 g (7.34 mmol) of 5-aminopentanoic acid and 2.23 g (22.0 mmol) of triethylamine in 10 ml of methylene chloride is added dropwise over the course of 10 minutes and stirred for 30 minutes at -15 ° C, then overnight at room temperature. It is extracted 2 times with 100 ml of 10% aqu. Ammonium chloride solution, the organic phase dries over magnesium sulfate and evaporates to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / ethanol = 20: 1).

Yield: 4.60 g (79% of theory) of a colorless solid

Elemental analysis: calc .: C 60.51 H 8.50 N 8.82 found: C 60.63 H 8.60 N 8.71

e) 3,9-bis (carboxymethyl) -6- [2- (pyridyl-2-yl)] - (4-carboxybutyi) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

4.50 g (5.67 mmol) of the title compound from Example 7d) are dissolved in 100 ml

Trifluoroacetic acid dissolved. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 20 ml of acidic ion exchanger are added IR 120 (H ⁺ form) and stir for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.

Yield: 2.07 g (59% of theory) of a glassy solid

Water content: 8.1%

Elemental analysis (based on anhydrous substance): calc .: C 50.61 H 6.19 N 12.30 found: C 50.50 H 6.27 N 12.36

f) Gadolinium complex of 3,9-bis (carboxymethyl) -6- [2- (pyridyl-2-yl)] - {4-carboxybutyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid disodium salt

Analogously to Example 1 i), the reaction of 2.3 g (4.04 mmol) of the title compound from Example 7e) with 0.73 g (2.02 mmol) of gadolinium oxide after freeze-drying gives 3.05 g (98.4% d. Th.) of the title compound as an amorphous powder.

Water content: 5.54%

Elemental analysis (based on anhydrous substance): calc .: C 37.55 H 3.94 N 9.12 Gd 20.48 Na 5.99 found: C 37.51 H 3.88 N 9.10 Gd 20.46 Na 5.97

g) Iron complex of 3,9-bis (carboxymethyl) -6- [2- (pyridyl-2-yl)] - (4-carboxy-butyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid disodium salt

Analogously to Example 1j), the reaction of 1.42 g (2.49 mmol) of the title compound from Example 7e) with 0.88 g (2.49 mmol) of iron III acetylacetonate after freeze-drying gives 1.59 g (96 , 0% of theory) of the title compound as an amorphous powder.

Water content: 6.21% Elemental analysis (based on anhydrous substance): calculated: C 43.25 H 4.54 N 10.51 Fe 8.38 Na 6.90 found: C 43.25 H 4.51 N 10.48 Fe 8.36 Na 6, 88

Example 8

a) Benzyl 4,7-dioxaoctanoate

1.15 g (50.0 mmol) of sodium are dissolved in 100 ml of dried ethylene glycol monomethyl ether. Then 5.01 g (50 mmol) of freshly distilled acrylic acid ethyl ester, dissolved in 15 ml of dry diethyl ether at 0 ° C., are added dropwise with stirring and exclusion of moisture. The mixture is stirred at low temperature for 1 hour, then 5 ml of water are added and the mixture is heated at 60 ° C. for 2 hours in order to saponify the ester. The mixture is concentrated in vacuo to 30 ml, diluted with 100 ml of water, the solution is etherified and the aqueous phase is then adjusted to a pH of 4 using sulfuric acid. The excreted compound is taken up in diethyl ether, the solution is dried over sodium sulfate and concentrated to dryness in vacuo. The title compound is obtained as a syrup.

Yield: 6.11 g (82.5% of theory)

Elemental analysis: calc .: C 48.64 H 8.16 found: C 48.71 H 8.23

b) Benzyl 2-bromo-4,7-dioxaoctanoate

A drop of dimethylformamide is added to 7.41 g (50 mmol) of the acid prepared in Example 8a) in 50 ml of 1,2-dichloroethane. The mixture is then heated to 80 ° C. and 5.0 ml (68.6 mmol) of thionyl chloride are added dropwise. It is lively

Gas evolution. After the addition has ended, the mixture is boiled under reflux for one hour and then concentrated to dryness in vacuo. 0.62 g (20 mmol) of red phosphorus is added to the acid chloride, and 13.6 g (85 mmol) of bromine are then added dropwise with stirring, so that the bromine coloration just disappears. If about half Of bromine is added, it is heated to 40 ^β C and kept at this temperature for three hours. The mixture is cooled to room temperature and the mixture of 7.57 g (70 mmol) of benzyl alcohol and 7.08 g (70 mmol) of dry triethylamine in 20 ml of dichloromethane is then added dropwise. After 1 hour, the mixture is diluted with 200 ml of dichloromethane, poured onto ice water and the organic solution is separated off. It is washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated to dryness in vacuo. The title compound is purified by chromatography on silica gel. A mixture of ethyl acetate and hexane serves as the eluent. The title compound is obtained as a syrup.

Yield: 12.43 g (78.4% of theory)

Elemental analysis: calc .: C 49.23 H 5.40 Br 25.19 found: C 49.30 H 5.46 Br 25.10

c) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (2,5-dioxahexyl)] benzyloxycarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.60 g (10 mmol) of the amino compound prepared in Example 1d) are dissolved in 30 ml of dimethylformamide. Then, at room temperature, 1.66 g (12 mmol) of potassium carbonate and 3.81 g (12 mmol) of 2-bromo-4,7-dioxaoctanoic acid benzyl ester are added and the mixture is stirred overnight. It is then poured onto ice water, extracted with ethyl acetate, the organic solution is dried over sodium sulfate, concentrated to dryness in vacuo and the title compound is obtained by chromatography on silica gel. A mixture of ethyl acetate / hexane serves as the eluent.

Yield: 5.20 g (65.2% of theory)

Elemental analysis: calc .: C 61.79 H 8.85 N 5.27 found: C 61.87 H 8.92 N 5.22 d) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (2,5-dioxahexyl)] carboxymethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

7.97 g (10 mmol) of the benzyl ester prepared under 8c) are dissolved in 100 ml of ethanol, and 0.4 g of Pearlman catalyst (Pd 20%, C) are added. The mixture is hydrogenated until 224 ml of hydrogen are taken up, then the catalyst is filtered off with suction, washed well with ethanol and the solution is evaporated to the dry state in a vacuum. The product is obtained as a foam.

Yield: 6.87 g (97.3% of theory)

Elemental analysis: calc .: C 57.85 H 9.00 N 5.95 found: C 57.91 H 9.11 N 6.01

e) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (2,5-dioxahexyl)] - (2-hydroxyethyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5 g (7.08 mmol) of the title compound from Example 8d) and 476 mg (7.08 mmol) of ethanolamine are dissolved in 30 ml of toluene and 1.93 g (7.79 mmol) of 2-ethoxy-1 at 0 ° C -ethoxycarbonyl-1,2-dihydroquinoline added. The mixture is stirred at 0 ° C. for 30 minutes and then at room temperature overnight. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: hexane / ethyl acetate = 15: 1).

Yield: 4.93 g (93% of theory) of a colorless oil

Elemental analysis: calc .: C 57.73 H 9.15 N 7.48 found: C 57.61 H 9.23 N 7.35 f) 3,9-bis (carboxymethyl) -6- [2- (2,5-dioxahexyl)] - (2-hydroxyethyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

4.5 g (6.01 mmol) of the title compound from Example 8f) are dissolved in 100 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 20 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.

Yield: 2.50 g (72% of theory) of a glassy solid

Water content: 9.1%

Elemental analysis (based on anhydrous substance): calc .: C 45.80 H 6.92 N 10.68 found: C 45.93 H 6.84 N 10.75

g) Gadolinium complex of 3,9-bis (carboxymethyl) -6- [2- (2,5-dioxahexyl)] - (2-hydroxyethyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

In analogy to Example 1 i), the reaction of 3.6 g (6.86 mmol) of the title compound from Example 8f) with 1.24 g (3.43 mmol) of gadolinium oxide is provided

Freeze-drying 4.75 g (99.1% of theory) of the title compound as an amorphous powder.

Water content: 6.14%

Elemental analysis (based on anhydrous substance): calc .: C 34.28 H 4.60 N 8.00 Gd 22.44 Na 3.28 found: C 34.27 H 4.56 N 7.98 Gd 22.42 Na 3.26 h) Ytterbium complex of 3,9-bis (carboxymethyl) -6- [2- (2,5-dioxahexyl)] - (2-hydroxyethyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

1.6 g (3.05 mmol) of the title compound from Example 8f) are dissolved in 100 ml of deionized water and 0.60 g (1.52 mmol) of ytterbium oxide are added in portions at room temperature. After a reaction time of 3 hours at 80 ° C., the now almost clear reaction solution is cooled to room temperature and a pH of 7.2 is set with 1 N sodium hydroxide solution. After filtration, the filtrate obtained is freeze-dried.

Yield: 2.08 g (95.4% of theory) of an amorphous powder

Water content: 7.66%

Elemental analysis (based on anhydrous substance): calc .: C 33.53 H 4.50 N 7.82 Yb 24.15 Na 3.21 found: C 33.55 H 4.53 N 7.86 Yb 24.20 Na 3.23

Example 9

a) 3-Benzyloxy-2-bromo-propionic acid methyl ester

40.3 g (339 mmol) of potassium bromide are dissolved in 200 ml of 2.5 N sulfuric acid. 19.52 g (100 mmol) of 3-benzyloxy-serine are added, the mixture is cooled to 0 ° C. and 10.6 g (154 mmol) of sodium nitrite are added over the course of an hour, with vigorous stirring. The mixture is left to stir at 0 ° C. for one hour and another at 25 ° C. Then the mixture is extracted with ether, the solution is washed with water, dried over sodium sulfate and the carboxylic acid is esterified by adding a portion of an ethereal diazomethane solution until the end of the reaction is discernible (coloration, TLC control). The solution is concentrated in vacuo. The title compound is purified by chromatography on silica gel using a mixture of ether and hexane as the eluent. It is preserved as an oil.

Yield: 22.97 g (84.1% of theory) Elemental analysis: calc .: C 48.37 H 4.80 Br 29.26 found: C 48.30 H 4.86 Br 29.33

b) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (benzyloxymethyl)] ethoxycarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.60 g (10 mmol) of the amino compound prepared in Example 1d) are dissolved in 30 ml of dimethylformamide. Then, at room temperature, 1.66 g (12 mmol) of potassium carbonate and 3.28 g (12 mmol) of 2-bromo-3-benzyloxypropionic acid benzyl ester are added and the mixture is stirred overnight. It is then poured onto ice water, extracted with ethyl acetate, the organic solution is dried over sodium sulfate, concentrated to dryness in vacuo and the title compound is obtained by chromatography on silica gel. A mixture of ethyl acetate / hexane serves as the eluent.

Yield: 5.09 g (67.1% of theory)

Elemental analysis: calc .: C 63.39 H 7.85 N 5.54 found: C 63.51 H 7.90 M 5.59

c) 3, 9-bis (t-butoxycarbonylmethy I) -6- (2-hydroxymethy I) -carboxy methy I) -3, 6,9-triazaundecanedioic acid di-t-butyl ester

7.52 g (10 mmol) of the benzyl ether prepared under 9b) are dissolved in 100 ml of ethanol and 0.4 g of Pearlman catalyst (Pd 20%, C) are added. The mixture is hydrogenated until 224 ml of hydrogen are taken up, then it is suctioned off from the catalyst, washed well with ethanol and concentrated to dryness in vacuo. The product is obtained as a foam.

Yield: 5.71 g (88.1% of theory) Elemental analysis: calc .: C 57.48 H 8.87 N 6.49 found: C 57.60 H 8.98 N 6.59

d) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-hydroxymethyl) - (2,2-dimethyl-6-hydroxy-1,3-dioxepan-5-yl) aminocarbonylmethyl-3,6,9 -triazaundecanedioic acid di-t-butyl ester

5 g (7.72 mmol) of the title compound from Example 9c) and 781 mg (7.72 mmol) of triethylamine are dissolved in 50 ml of methylene chloride. A solution of 1.16 g (8.5 mmol) of isobutyl chloroformate in 10 ml is added dropwise at -10 ° C.

Methyl chloride within 5 minutes and stirred for 20 minutes at -10 ° C. The solution is cooled to -15 ° C. and a solution of 1.24 g (7.72 mmol) of 5-amino-2,2-dimethyl-1, 3-dioxepan-6-ol and 2.12 g ( 21 mmol) of triethylamine in 10 ml of methylene chloride within 10 minutes and stirred for 30 minutes at -15 ° C, then overnight at room temperature. It is extracted twice with 100 ml of 10% aqu. Ammonium chloride solution, the organic phase dries over magnesium sulfate and evaporates to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / ethanol = 20: 1).

Yield: 4.50 g (79% of theory) of a colorless solid

Elemental analysis: calc .: C 57.70 H 8.92 N 7.08 found: C 57.60 H 9.05 N 7.15

e) 3,9-bis (carbonylmethyl) -6- (2-hydroxymethyl) - [1- (hydroxymethyl) -2,3-dihydroxypropyl] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

4 g (5.06 mmol) of the title compound from Example 9d) are dissolved in 100 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The The residue is dissolved in 100 ml of water. 20 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.

Yield: 1.76 g (61% of theory) of a glassy solid

Water content: 7.5%

Elemental analysis (based on anhydrous substance): calc .: C 43.34 H 6.51 N 10.64 found: C 43.25 H 6.65 N 10.51

f) Gadolinium complex of 3,9-bis (carbonylmethyl) -6- (2-hydroxymethyl) - [1-

(hydroxymethyl) -2,3-dihydroxypropyl] aminocarbonylmethyl-3,6,9-triazaunde-candic acid sodium salt

Analogously to Example 1 i), the reaction of 4.10 g (7.78 mmol) of the title compound from Example 9e) with 1.41 g (3.89 mmol) of gadolinium oxide after freeze-drying gives 5.18 g (94.8% d. Th.) of the title compound as an amoφhes powder.

Water content: 9.53%

Elemental analysis (based on anhydrous substance): calc .: C 32.48 H 4.30 N 7.97 Gd 22.38 Na 3.27 found: C 32.51 H 4.32 N 7.99 Gd 22.42 Na 3.30

g) Manganese complex of 3,9-bis (carbonylmethyl) -6- (2-hydroxymethyl) - [1- (hydroxymethyl) -2,3-dihydroxypropyl] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid disodium salt

Analogously to Example 4i), the reaction of 3.30 g (6.26 mmol) of the title compound from Example 9e) with 0.72 g (6.26 mmol) of manganese II carbonate after freeze drying gives 3.71 g (95 , 3% of theory) of the title compound as an amorphous powder.

Water content: 8.83% Elemental analysis (based on anhydrous substance): calc .: C 36.61 H 4.85 N 8.99 Mn 8.81 Na 7.38 found: C 36.58 H 4.82 N 8.96 Mn 8.79 Na 7.36

Example 10

a) 3,9-Bis (t-butoxycarbonylmethyl) -6- [2- (4-bromo) butyl] ethoxycarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.60 g (10 mmol) of the amino compound prepared in Example 1d) are dissolved in 30 ml of dimethylformamide. Then, at room temperature, 1.66 g (12 mmol) of potassium carbonate and 3.62 g (12 mmol) of 2,6-dibromohexanoic acid ethyl ester are added and the mixture is stirred overnight. It is then poured onto ice water, extracted with ethyl acetate, the organic solution is dried over sodium sulfate, concentrated to dryness in vacuo and the title compound is obtained by chromatography on silica gel. A mixture of ethyl acetate / hexane serves as the eluent.

Yield: 4.90 g (62.7% of theory)

Elemental analysis: calc .: C 55.38 H 8.52 Br 10.23 N 5.38 found: C 55.48 H 8.59 Br 10.34 N 5.31

b) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (4-benzyloxycarbonylamino) butyl] carboxymethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

7.81 g (10 mmol) of the compound prepared in Example 10a) are dissolved in 50 ml of nitromethane, and 1.56 (10.4 mmol) of silver cyanate are added. The mixture is stirred at room temperature for 70 hours with the exclusion of moisture. 1.62 g (15 mmol) of benzyl alcohol are then added and the mixture is stirred for a further 3 hours at room temperature. The mixture is then diluted with 200 ml of diethyl ether, the silver salt is filtered off, the solution is concentrated in vacuo and the residue is purified by column chromatography on silica gel. A mixture of ethyl acetate and hexane serves as the eluent. The title compound is obtained as an amorphous foam. Yield: 5.84 g (68.6% of theory)

Elemental analysis: calc .: C 62.10 H 8.76 N 6.58 found: C 62.23 H 8.83 N 6.67

c) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (4-benzyloxycarbonylamino) butyl] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5 g (6.65 mmol) of the title compound from Example 10b) are dissolved in 30 ml of anhydrous benzene and 1.54 g (12.15 mmol) of oxalic acid dichloride are added at 0 ° C. The mixture is stirred at 0 ° C. for 3 hours and then evaporated to dryness in vacuo. The residue is dissolved in 30 ml of benzene and again evaporated to dryness. At 0 ° C, ammonia gas is passed into the solution with vigorous stirring (30 minutes). The solution is washed twice with 50 ml of 5% aqu. Soda solution, the organic phase dries over magnesium sulfate and evaporates to dryness in vacuo. The residue is chromatographed on silica gel (mobile phase: methylene chloride / hexane / isopropanol = 10: 10: 1)

Yield: 4.2 g (84% of theory) of a colorless solid

Elemental analysis: calc .: C 61, 37 H 8.71 N 8.52 found: C 61.25 H 8.80 N 8.43

d) 3,9-bis (t-butoxycarbonylmethyl) -6- [2- (4-amino) butyl] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

4.0 g (4.87 mmol) of the title compound from Example 10c) are dissolved in 100 ml of isopropanol and 2 g of palladium catalyst (10% Pd on carbon) are added. It is hydrogenated overnight at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / ethanol = 25: 1). Yield: 3.05 g (91% of theory) of a colorless oil

Elemental analysis: calc .: C 59.36 H 9.52 N 10.18 found: C 59.27 H 9.61 N 10.27

e) 3,9-bis (carboxymethyl) -6- [2- (4-amino) butyl] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

3.0 g (4.36 mmol) of the title compound from Example 10d) are dissolved in 100 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 20 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.

Yield: 1.23 g (57% of theory) of a glassy solid

Water content: 6.7%

Elemental analysis (based on anhydrous substance): calc .: C 46.64 H 7.18 N 15.11 found: C 46.60 H 7.09 N 15.00

f) Gadolinium complex of 3,9-bis (carboxymethyl) -6- [2- (4-amino) butyl] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

Analogously to Example 1i), the reaction of 2.7 g (5.82 mmol) of the title compound from Example 10e) with 1.05 g (2.91 mmol) of gadolinium oxide after freeze-drying gives 3.54 g (95.3% of theory) . Th.) Of the title compound as an amorphous powder.

Water content: 6.48% Elemental analysis (based on anhydrous substance): calc .: C 33.80 H 4.57 Gd 24.58 N 10.95 Na 3.59 found: C 33.78 H 4.55 Gd 24.52 N 10.93 Na 3.56

g) Iron complex of 3,9-bis (carbonylmethyl) -6- [2- (4-benzyloxycarbonylamino) butyl] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester sodium salt

Analogously to Example 1j), the reaction of 1.5 g (3.23 mmol) of the title compound from Example 10e) with 1.14 g (3.23 mmol) of iron II-acetylacetonate after freeze-drying gives 1.70 g (98 , 4% of theory) of the title compound as an amorphous powder.

Water content: 7.31%

Elemental analysis (based on anhydrous substance): calc .: C 40.16 H 5.43 N 13.01 Fe 10.37 Na 4.27 found: C 40.10 H 5.39 N 12.98 Fe 10.35 Na 4.25

Example 11

a) 3,9-bis (t-butoxycarbonylmethyl) -6-benzyloxycarbonylmethyl-3,6,9-triazaunde-candic acid di-t-butyl ester

5.60 g (10 mmol) of the amino compound prepared in Example 1d) are dissolved in 30 ml of dimethylformamide. Then, at room temperature, 1.66 g (12 mmol) of potassium carbonate and 2.58 g (12 mmol) of 2-bromoacetic acid benzyl ester are added and the mixture is stirred overnight. It is then poured onto ice water, extracted with ethyl acetate, the organic solution is dried over sodium sulfate, concentrated to dryness in vacuo and the title compound is obtained by chromatography on silica gel. A mixture of ethyl acetate / hexane serves as the eluent.

Yield: 6.32 g (89.3% of theory) Elemental analysis: calc .: C 64.65 H 9.00 N 5.95 found: C 64.62 H 9.07 N 5.90

b) 3,9-bis (t-butoxycarbonylmethyl) -6-carboxymethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

7.08 g (10 mmol) of the benzyl ester prepared under 11a) are dissolved in 100 ml of ethanol and 0.4 g of Pearlman catalyst (Pd 20%, C) are added. The mixture is hydrogenated until 224 ml of hydrogen are taken up, the catalyst is filtered off with suction, washed well with ethanol and the solution is evaporated to the dry state in a vacuum. The product is obtained as a foam which crystallizes from ether / hexane.

Yield: 6.87 g (97.3% of theory)

Melting point: 73-75 ° C

Elemental analysis: calc .: C 57.85 H 9.00 N 5.95 found: C 57.91 H 9.11 N 6.01

c) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-aminoethyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.00 g (8.09 mmol) of the title compound from Example 11b) are dissolved in 25 ml of dimethylformamide and 1.02 g (8.90 mol) of N-hydroxysuccinimide are added. The mixture is cooled to 0 ° C. and 1.84 g (8.90 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred at 0 ° C. for one hour and then at room temperature for 4 hours. The mixture is cooled to 0 ° C. and a solution of 2.67 g of 1, 2 diaminoethane (44.5 mmol) in 50 ml of dimethylformamide is added dropwise within 10 minutes. The mixture is stirred for one hour at 0 ° C., then overnight at room temperature. It is evaporated to dryness in vacuo and the residue is taken up in 100 ml of ethyl acetate. The precipitated urea is filtered off and the filtrate is washed twice with 100 ml of 5% aqu. Soda solution. The organic phase is over magnesium sulfate dried and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 15: 1). 2.83 g (53% of theory) of a completely oil are obtained.

Elemental analysis: calc .: C 58.25 H 9.32 N 10.61 found: C 58.17 H 9.25 N 10.55

d) 3,9-bis (carboxymethyl) -6- (2-aminoethyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

2.60 g (3.94 mmol) of the title compound from Example 11c) are dissolved in 100 ml

Trifluoroacetic acid dissolved. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 15 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.

Yield: 1.29 g (57% of theory) of a glassy solid

Water content: 7.9%

Elemental analysis (based on anhydrous substance): calc .: C 44.13 H 6.71 N 16.08 found: C 40.25 H 6.63 N 16.18

e) Gadolinium complex of 3,9-bis (carboxymethyl) -6- (2-aminoethyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid monosodium salt

Analogously to Example 1 i), the reaction of 1.20 g (2.75 mmol) of the title compound from Example 11d) with 0.50 g (1.37 mmol) of gadolinium oxide after freeze-drying gives 1.64 g (97.8% d. Th.) of the title compound as an amoφhes powder. Water content: 7.93%

Elemental analysis (based on anhydrous substance): calc .: C 31, 42 H 4.12 Gd 25.71 N 11.45 Na 3.76 found: C 31, 46 H 4.14 Gd 25.74 N 11, 48 Na 3.80

f) Ytterbium complex of 3,9-bis (carboxymethyl) -6- (2-aminoethyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid monosodium salt

Analogously to Example 8h), the reaction of 1.0 g (2.29 mmol) gives the

Title compound from Example 11d) with 0.45 g (1.15 mmol) ytterbium oxide after freeze-drying 1.40 g (97.5% of theory) of the title compound as an amorphous powder.

Water content: 8.06%

Elemental analysis (based on anhydrous substance): calc .: C 30.63 H 4.02 N 11, 16 Na 3.66 Yb 27.58 found: C 30.59 H 4.00 N 11, 13 Na 3.61 Yb 27.51

g) Europium complex of 3,9-bis (carboxymethyl) -6- (2-aminoethyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

Analogously to Example 3i), the reaction of 1.0 g (2.29 mmol) of the title compound from Example 11d) with 0.40 g (1.15 mmol) of europium oxide

Freeze-drying 1.36 g (98.0% of theory) of the title compound as an amorphous powder.

Water content: 8.02%

Elemental analysis (based on anhydrous substance): calc .: C 31.69 H 4.16 N 11.55 Eu 25.06 Na 3.79 found: C 31.66 H .10 N 11, 51 Eu 25.01 Na 3.72 Example 12

a) 3,9-Bis (t-butoxycarbonylmethyl) -6- (3-oxa-5-aminopentyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.00 g (8.09 mmol) of the title compound from Example 11b) are dissolved in 25 ml of dimethylformamide and 1.02 g (8.90 mol) of N-hydroxysuccinimide are added. The mixture is cooled to 0 ° C. and 1.84 g (8.90 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred at 0 ° C. for one hour and then at room temperature for 4 hours. The mixture is cooled from 0 ° C. and a solution of 2.67 g of 1.5 diamino-3-oxapentane (44.5 mmol) in 50 ml of dimethylformamide is added dropwise within 10 minutes. The mixture is stirred for one hour at 0 ° C., then overnight at room temperature. It is evaporated to dryness in vacuo and the residue is taken up in 100 ml of ethyl acetate. The precipitated urea is filtered off and the filtrate is washed twice with 100 ml of 5% aqu. Soda solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile phase: n-hexane / ethyl acetate 20: 1). 2.79 g (49% of theory) of a colorless oil are obtained.

Elemental analysis: calc .: C 58.01 H 9.31 N 9.95 found: C 57.90 H 9.41 N 9.87

b) 3,9-bis (carboxymethyl) -6- (3-oxa-5-aminopentyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

2.60 g (3.69 mmol) of the title compound from Example 1g) are dissolved in 100 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 20 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo. Yield: 1.11 g (57% of theory) of a glassy solid

Water content: 8.9%

Elemental analysis: calc .: C 45.09 H 6.94 N 14.61 found: C 45.17 H 6.86 N 14.55

c) Gadolinium complex of 3,9-bis (carboxymethyl) -6- (3-oxa-5-aminopentyl) aminocarbonyimethyl-3,6,9-triazaundecanedioic acid sodium salt

Analogously to Example 1 i), the reaction of 2.4 g (5.00 mmol) of the title compound from Example 12b) with 0.90 g (2.50 mmol) of gadolinium oxide after freeze-drying gives 3.23 g (98.6% d. Th.) of the title compound as an amorphous powder.

Water content: 6.47%

Elemental analysis (based on anhydrous substance): calc .: C 32.97 H 4.46 N 10.68 Gd 23.98 Na 3.51 found: C 32.91 H 4.44 N 10.63 Gd 23.92 Na 3.48

d) Dysprosium complex of 3,9-bis (carboxymethyl) -6- (3-oxa-5-aminopentyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

Analogously to Example 2j), the reaction of 1.8 g (3.75 mmol) of the title compound from Example 12b) with 0.70 g (1.87 mmol) of dysprosium oxide after freeze drying gives 2.40 g (96.8% of theory) . Th.) Of the title compound as an amoφhes powder.

Water content: 7.13%

Elemental analysis (based on anhydrous substance): calc .: C 32.71 H 4.42 N 10.60 Dy 24.59 Na 3.48 found: C 32.68 H 4.39 N 10.57 Dy 24.55 Na 3.41 Example 13

a) 3,9-bis (t-butoxycarbonyimethyl) -6-bis (octadecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5 g (8.09 mmol) of the title compound from Example 11 b) and 4.22 g (8.09 mmol) of bisoctadecylamine are dissolved in 30 ml of toluene and 2.20 g (8.9 mmol) of 2- Ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline added. The mixture is stirred for 30 minutes at 0 ° C., then overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: hexane / ethyl acetate = 20: 10: 1).

Yield: 7.99 g (88% of theory) of a colorless solid

Elemental analysis: calc .: C 70.67 H 11, 50 N 4.99 found: C 70.78 H 11, 60 N 4.83

b) 3,9-bis (carboxymethyl) -6-bis (octadecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

5 g (4.46 mmol) of the title compound from Example 13a) are dissolved in 100 ml of trifluoroacetic acid and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: methylene chloride / ethanol / 33% strength aqueous ammonia solution 20: 5: 0.5). The fractions containing the product are evaporated to dryness in vacuo and the residue is dissolved in a mixture of 80 ml of ethanol / 20 ml of water / 30 ml of chloroform. 20 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 30 minutes. The ion exchanger is filtered off and the filtrate is evaporated to dryness in vacuo.

Yield: 2.67 g (65% of theory) of a glass-like solid

Water content: 2.7% Elemental analysis: calc .: C 67.11 H 10.90 N 7.57 found: C 67.21 H 10.98 N 7.46

c) Gadolinium complex of 3,9-bis (carboxymethyl) -6-bis (octadecyl) -amino-carbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

2.0 g (2.22 mmol) of the title compound from Example 13b) are dissolved in 100 ml of water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and at 80 ° C. in portions with 0.40 g ( 1, 11 mmol) gadolinium oxide added. The reaction solution thus obtained is then boiled under reflux for 5 hours. After cooling to room temperature, the solvent mixture is drawn off completely in vacuo and the remaining residue is mixed with 200 ml of a water / n-butanol mixture (1: 1). With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 1.96 g (82.4% of theory) of a glass-like solid

Water content: 6.16%

Elemental analysis (based on anhydrous substance): calc .: C 55.94 H 8.64 Gd 14.65 N 5.22 Na 2.14 found: C 55.90 H 8.59 Gd 14.62 N 5.18 Na 2, 11

Solutions and suspensions of liposomal formulations of this compound show excellent relaxivities. A compilation of measured values can be found in the following table:

Relaxivity (l / mmol * s)

T1 T2

Compound after 13 c water 16.19 18.04

Plasma 21, 06, 23.28

Compound after 13 c encapsulated in liposomes water 18.80 19.17

Plasma 18.88 24.43

It has been shown in animal experiments that the compound according to Example 13 c accumulates excellently in the liver and spleen after intravenous administration. For example, 68% of the applied substance was detected in the liver and 7% in the spleen 5 hours after the injection. It is therefore particularly suitable for the diagnostic imaging of the liver and spleen.

After interstitial application, the compound according to Example 13 c shows a high concentration in the lymph nodes. The effect was already 60 min. after the injection. It was particularly noticeable that the accumulation was not only observed in the first lymph node (popliteal), but also in the second (inguinally profound) and in the third (iliac) lymph node. The concentration ratio of the compound within these lymph nodes was as 2.5: 1, 6: 1.0 after 240 min. The connection is therefore ideal for the diagnostic imaging of the lymph nodes.

d) Iron complex of 3,9-bis (carboxymethyl) -6-bis (octadecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

1.0 g (1.11 mmol) of the title compound from Example 13b) are dissolved in 75 ml of water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and at 80 ° C. in portions with 0.39 g ( 1.11 mmol) of iron III-acetylacetonate were added. The reaction solution thus obtained is then boiled under reflux for 5 hours. After cooling to room temperature, the solvent mixture is in vacuo completely removed and the remaining residue with 150 ml of a water / n-butanol mixture (1: 1). With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 0.87 g (81.0% of theory) of a glass-like solid

Water content: 5.93%

Elemental analysis (based on anhydrous substance): calc .: C 61, 78 H 9.54 N 5.76 Fe 5.74 Na 2.36 found: C 61, 82 H 9.57 N 5.81 Fe 5.76 Na 2.41

e) Dysprosium complex of 3,9-bis (carboxymethyl) -6-bis (octadecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

1.25 g (1.39 mmol) of the title compound from Example 13b) are dissolved in 75 ml

Dissolve the water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and add 0.26 g (0.69 mmol) of dysprosium oxide in portions at 80 ° C. The reaction solution thus obtained is then boiled under reflux for 5 hours. After cooling to room temperature, the solvent mixture is completely stripped off in vacuo and 150 ml of a water / n-butanol mixture (1: 1) are added to the remaining residue. With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 1.34 g (89.6% of theory) of a glass-like solid

Water content: 5.85% Elemental analysis (based on anhydrous substance): calc .: C 55.67 H 8.60 Dy 15.06 N 5.19 Na 2.13 found: C 55.61 H 8.76 Dy 15.02 N 5.16 Na 2.10

f) Manganese complex of 3,9-bis (carboxymethyl) -6-bis (octadecyl) -amino-carbonylmethyl-3,6,9-triazaundecanedioic acid disodium salt

2.0 g (2.22 mmol) of the title compound from Example 13b) are dissolved in 150 ml of water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and at 80 ° C. in portions with 0.25 g ( 2.22 mmol) manganese II carbonate added. The reaction solution thus obtained is then boiled under reflux for 5 hours. After cooling to room temperature, the solvent mixture is drawn off completely in vacuo and the remaining residue is mixed with 200 ml of a water / n-butanol mixture (1: 1). With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 1.86 g (84.2% of theory) of a glass-like solid

Water content: 5.79%

Elemental analysis (based on anhydrous substance): calc .: C 60.40 H 9.33 Mn 5.53 N 5.64 Na 4.62 found: C 60.33 H 9.29 Mn 5.51 N 5.60 Na 4.59

Example 14

a) Bis (octadecyl) amino acetic acid

30 g (57.47 mmol) bisoctadecylamine and 8.38 g (60.3 mmol) bromoacetic acid are dissolved in a mixture of 150 ml toluene / 10 ml dioxane and heated under reflux overnight. 200 ml of 5% aqu. Ammonia solution and stir 10 mins. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / ethanol = 20: 1).

Yield: 20.33 g (61% of theory) of a waxy solid

Elemental analysis: calc .: C 78.69 H 13.38 N 2.41 found: C 78.80 H 13.50 N 2.34

b) 1 - [bis (octadecyl) amino] -2-oxo-3-aza-13-aminotridecane

10 g (17.24 mmol) of the title compound from Example 14a) and 2.18 g (18.96 mmol) of N-hydroxysuccinimide are dissolved in 100 ml of dimethylformamide. The mixture is cooled to 0 ° C. and 3.91 g (18.96 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred at 0 ° C. for 1 hour, then at room temperature for 3 hours. The precipitated urea is filtered off and the filtrate is added dropwise to a solution of 9.80 g (56.88 mmol) of diaminodecane and 5.76 g (56.88 mmol) of triethylamine in 200 ml within 30 minutes

Methylene chloride. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is dissolved in 200 ml of toluene. The organic phase is washed twice with 100 ml of 5% aqu. Soda solution, dries over magnesium sulfate and evaporates to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / isopropanol / triethylamine = 50: 2: 1).

Yield: 5.19 g (41% of theory) of a waxy solid

Elemental analysis: calc .: C 78.51 H 13.59 N 5.72 found: C 78.61 H 13.68 N 5.60 c) 3,9-bis (t-butoxycarbonylmethyl) -6- [11-aza-13-bis (octadecyl) amino-12-oxotridecyl] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5 g (8.09 mmol) of the title compound from Example 11b) are dissolved in 25 ml of dimethylformamide and 1.44 g (8.9 mmol) of N.N'-carbonyldiimidazole are added. The mixture is stirred for 4 hours at room temperature. The solution is cooled to 0 ° C. and a solution of 5.94 g (8.09 mmol) of the title compound from Example 14b) and 0.82 g (8.09 mmol) of triethylamine, dissolved in 50 ml of methylene chloride, is added dropwise over the course of 30 minutes . The mixture is stirred overnight at room temperature. It is evaporated to dryness, the residue is taken up in 150 ml of toluene and extracted twice with 100 ml of 5% aqueous solution. Soda solution. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / hexane / acetone = 20: 10: 1).

Yield: 8.42 g (78% of theory) of a waxy solid

Elemental analysis: calc .: C 70.22 H 11, 48 N 6.30 found: C 70.31 H 11, 59 N 6.17

d) 3,9-bis (carboxymethyl) -6- [11-aza-13-bis (octadecyl) amino-12-oxotridecyljaminocarbonylmethyl 1-3,6, 9-triazaundecanedioic acid

5 g (3.75 mmol) of the title compound from Example 14c) are dissolved in 100 ml of trifluoroacetic acid and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: methylene chloride / ethanol / 33% strength aqueous ammonia solution 20: 5: 0.5). The fractions containing the product are evaporated to dryness in vacuo and the residue is dissolved in a mixture of 80 ml of ethanol / 20 ml of water / 30 ml of chloroform. 15 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 30 minutes. The ion exchanger is filtered off and the filtrate is evaporated to dryness in vacuo.

Yield: 3.05 g (71% of theory) of a glass-like solid Water content: 3.1%

Elemental analysis: calc .: C 67.11 H 10.90 N 7.57 found: C 67.21 H 10.98 N 7.46

e) Gadolinium complex of 3,9-bis (carboxymethyl) -6- [11-aza-13- bis (octadecyl) amino-12-oxotridecyl] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

2.5 g (2.25 mmol) of the title compound from Example 14d) are dissolved in 150 ml of water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and at 80 ° C. in portions with 0.40 g ( 1.12 mmol) gadolinium oxide added. The reaction solution thus obtained is then boiled under reflux for 5 hours. After cooling to room temperature, the solvent mixture is completely stripped off in vacuo and the remaining residue is mixed with 250 ml of a water / n-butanol mixture (1: 1). With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 2.67 g (92.4% of theory) of a glassy solid

Water content: 6.31%

Elemental analysis (based on anhydrous substance): calc .: C 57.91 H 9.09 Gd 12.23 N 6.54 Na 1, 79 found: C 57.87 H 9.02 Gd 12.20 N 6.52 Na 1, 77 f) Manganese complex of 3,9-bis (carboxymethyl) -6- [11-aza-13- bis (octadecyl) amino-12-oxotridecyl] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid disodium salt

1.5 g (1.35 mmol) of the title compound from Example 14d) are dissolved in 100 ml of water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and at 80 ° C. in portions with 0.15 g ( 1.35 mmol) manganese II carbonate added. The reaction solution thus obtained is then boiled under reflux for 5 hours. After cooling to room temperature, the solvent mixture is completely stripped off in vacuo and 150 ml of a water / n-butanol mixture (1: 1) are added to the remaining residue. With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 1.38 g (85.1% of theory) of a glass-like solid

Water content: 7.02%

Elemental analysis (based on anhydrous substance): calc .: C 61, 72 H 9.69 N 6.97 Mn 4.55 Na 3.81 found: C 61, 68 H 9.67 N 6.94 Mn 4.50 Na 3.78

Example 15

a) 3,9-Bis (t-butoxycarbonylmethyl) -6- [3-aza-4-oxo-heneicosyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5 g (7.58 mmol) of the title compound from Example 11c) and 2.30 g (22.73 mmol) of triethylamine are dissolved in 40 ml of methylene chloride. A solution of 2.53 g (8.34 mmol) of octadecanoic acid chloride in 20 ml of methylene chloride is added dropwise at 0 ° C. in the course of 20 minutes. The mixture is stirred overnight at room temperature. It is mixed with 50 ml of 5% aqu. Brine extracted, the organic phase dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / hexane / isopropanol = 20: 10: 1). Yield: 6.39 g (91% of theory) of a waxy solid

Elemental analysis. calc .: C 64.83 H 10.34 N 7.56 found: C 64.73 H 10.40 N 7.48

b) 3,9-bis (carboxymethyl) -6- [3-aza-4-oxo-heneicosyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

5 g (5.4 mmol) of the title compound from Example 15a) are dissolved in 100 ml of trifluoroacetic acid and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel

(Eluent: methylene chloride / ethanol / 33% aqueous ammonia solution 20: 5: 0.5). The fractions containing the product are evaporated to dryness in vacuo and the residue is dissolved in a mixture of 80 ml of ethanol / 20 ml of water / 30 ml of chloroform. 15 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 30 minutes. The ion exchanger is filtered off and the filtrate is evaporated to dryness in vacuo.

Yield: 2.51 g (64% of theory) of a glass-like solid

Water content: 3.5%

Elemental analysis (based on anhydrous substance): calc .: C 58.18 H 9.05 N 9.98 found: C 58.03 H 9.14 N 9.89

c) Gadolinium complex of 3,9-bis (carboxymethyl) -6- [3-aza-4-oxo-heneicosyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

2.0 g (2.85 mmol) of the title compound from Example 15b) are in 150 ml

Water / ethanol / chloroform (2: 1: 1) mixture dissolved at the boiling point and 0.51 g (1.42 mmol) of gadolinium oxide was added in portions at 80.degree. The reaction solution thus obtained is then boiled under reflux for 5 hours. After this Cooling to room temperature, the solvent mixture is drawn off completely in vacuo and the remaining residue is mixed with 250 ml of a water / π-butanol mixture (1: 1). With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 2.06 g (82.6% of theory) of a glass-like solid

Water content: 7.66%

Elemental analysis (based on anhydrous substance): calc .: C 46.51 H 6.77 Gd 17.91 N 7.98 Na 2.62 found: C 46.48 H 6.73 Gd 17.88 N 7.95 Na 2 , 59

d) Manganese complex of 3,9-bis (carboxymethyl) -6- [3-aza-4-oxo-heneicosyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid disodium salt

1.5 g (2.13 mmol) of the title compound from Example 15b) are dissolved in 100 ml of water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and at 80 ° C. in portions with 0.24 g ( 2.13 mmol) of manganese II carbonate were added. The reaction solution thus obtained is then boiled under reflux for 5 hours. After cooling to room temperature, the solvent mixture is drawn off completely in vacuo and the remaining residue is mixed with 200 ml of a water / n-butanol mixture (1: 1). With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 1.50 g (88.6% of theory) of a glass-like solid

Water content: 6.41% Elemental analysis: calc .: C 51.12 H 7.45 Mn 6.88 N 8.77 Na 5.76 found: C 51.08 H 7.40 Mn 6.84 N 8.74 Na 5.73

Example 16

a) 3,9-bis (t-butoxycarbonylmethyl) -6- (10-carboxydecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5 g (8.09 mmol) of the title compound from Example 11b) and 0.82 g (8.09 mmol) of triethylamine are dissolved in 50 ml of methylene chloride. A solution of 1.10 g (8.09 mmol) of isobutyl chloroformate in 20 ml is added dropwise at -10.degree

Methylene chloride within 5 minutes and stirred at -10 ° C for 20 minutes. The solution is cooled to -15 ° C. and a solution of 1.63 g (8.09 mmol) of 11-aminoundecanoic acid and 2.43 g (24 mmol) of triethylamine in 50 ml of methylene chloride is added dropwise over the course of 10 minutes and the mixture is stirred for 30 minutes at -15 ° C, then overnight at room temperature. It is extracted twice with 100 ml of 10% aqu.

Ammonium chloride solution, the organic phase dries over magnesium sulfate and evaporates to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / ethanol = 20: 1).

Yield: 4.41 g (68% of theory) of a colorless solid

Elemental analysis: calc .: C 61.47 H 9.56 N 6.99 found: C 61.53 H 9.48 N 6.89

b) 3,9-bis (carboxymethyl) -6- (10-carboxydecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

4 g (4.99 mmol) of the title compound from Example 16a) are dissolved in 100 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The the product containing fractions are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 16 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.

Yield: 1.95 g (63% of theory) of a glassy solid

Water content: 6.8%

Elemental analysis (based on anhydrous substance): calc .: C 52.07 H 7.69 N 9.72 found: C 52.15 H 7.60 N 9.64

c) Gadolinium complex of 3,9-bis (carboxymethyl) -6- (10-carboxydecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid disodium salt

2.0 g (3.46 mmol) of the title compound from Example 16b) are suspended in 150 ml of deionized water, and 0.62 g (1.73 mmol) of gadolinium oxide are added in portions at 80 ° C. After a reaction time of 3 hours at 80 ° C., the now almost clear reaction solution is cooled to room temperature and a pH of 7.2 is set with 1 N sodium hydroxide solution. After filtration, the filtrate obtained is freeze-dried.

Yield: 2.33 g (87.2% of theory) of an amorphous powder

Water content: 8.13%

Elemental analysis (based on anhydrous substance): calc .: C 38.75 H 5.07 Gd 20.29 N 7.23 Na 5.93 found: C 38.72 H 5.01 Gd 20.26 N 7.20 Na 5.89 d) Manganese complex of 3,9-bis (carboxymethyl) -6- (10-carboxydecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid trisodium salt

1.0 g (1.73 mmol) of the title compound from Example 16b) are suspended in 100 ml of deionized water, and 0.20 g (1.73 mmol) of manganese II carbonate are added in portions at 80.degree. After a reaction time of 3 hours at 80 ° C., the now almost clear reaction solution is cooled to room temperature and a pH of 7.2 is set with 1 N sodium hydroxide solution. After filtration, the filtrate obtained is freeze-dried.

Yield: 1.06 g (88.4% of theory) of an amorphous powder

Water content: 8.83%

Elemental analysis (based on anhydrous substance): calc .: C 43.17 H 5.65 Mn 7.90 N 8.06 Na 9.92 found: C 43.14 H 5.60 Mn 7.86 N 8.01 Na 9.88

e) Iron complex of 3,9-bis (carboxymethyl) -6- (10-carboxydecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid disodium salt

1.0 g (1.73 mmol) of the title compound from Example 16b) are suspended in 100 ml of deionized water and 0.61 g (1.73 mmol) of iron III-acetylacetonate are added in portions at 80.degree. After a reaction time of 3 hours at 80 ° C., the now almost clear reaction solution is cooled to room temperature, extracted twice with methylene chloride and a pH of 7.2 is adjusted with 1 N sodium hydroxide solution. After filtration, the filtrate obtained is freeze-dried.

Yield: 1.04 g (89.2% of theory) of an amorphous powder

Water content: 8.11%

Elemental analysis (based on anhydrous substance): calc .: C 44.59 H 5.84 Fe 8.29 N 8.32 Na 6.83 found: C 44.57 H 5.81 Fe 8.27 N 8.30 Na 6.80 Example 17

a) 1,7-bis (trifluoroacetyl) -1,4,7-triazaheptane

In a solution of 41.14 g (390 mmol) 1, 4,7-triazaheptane in 350 ml tetrahydrofuran at 113C and under nitrogen 113.3 g (790 mmol)

Trifluoroacetic acid ethyl ester added dropwise. The mixture is stirred at room temperature overnight and concentrated in vacuo. The remaining oil is crystallized from hexane.

Yield: 115 g (99.9% of theory)

Melting point: 68-70 ° C

Elemental analysis: calc .: C 32.55 H 3.76 F 38.62 N 14.24 found: C 32.63 H 3.75 F 38.38 N 14.19

b) 1,7-bis (trifluoroacetyl) -4-benzyloxycarbonyl-1,7,4-triazaheptane

14.75 g (50 mmol) of the trifluoroacetyl compound prepared in Example 17a) and 8.3 ml (60 mmol) of triethylamine are dissolved in 120 ml of dichloromethane and cooled to 0.degree. 7.5 ml (53 mmol) of benzyl chloroformate (97%), dissolved in 20 ml of dichloromethane, are then added dropwise with stirring. The mixture is stirred overnight at room temperature, the salts are extracted with distilled water, the dichloromethane solution is dried over sodium sulfate, concentrated to dryness in vacuo and the residue is crystallized from ether / hexane.

Yield: 18.40 g (85.7% of theory)

Melting point: 131-32 ° C Elemental analysis: calc .: C 44.76 H 3.99 F 26.55 N 9.79 found: C 44.87 H 4.03 F 26.62 N 9.61

c) 3,9-bis (t-butoxycarbonylmethyl) -6-benzyloxycarbonyl-3,6,9-triazaundecanedicarboxylic acid di-t-butyl ester

4.29 g (10 mmol) of the trifluoroacetyl derivative prepared in Example 17b) are dissolved in 30 ml of ethanol, and 800 mg (20 mmol) of sodium hydroxide solution in 10 ml of distilled water are added. The mixture is stirred for 3 hours at room temperature, evaporated to dryness at 40 ° C. bath temperature, water residues are removed by azeotropic distillation with isopropanol and taken up in 30 ml of dimethylformamide. 6.9 g (50 mmol) of potassium carbonate and 9.7 g (50 mmol) of t-butyl bromoacetate are then added and the 4-benzyloxycarbonyl-1, 4,7-triazaheptane is alkylated at room temperature overnight. The dimethylformamide is then stripped off in an oil pump vacuum, the residue is partitioned between water and dichloromethane, the organic solution is dried over sodium sulfate, concentrated to dryness in vacuo and the residue is purified by chromatography on silica gel. The title compound is eluted with ethyl acetate / hexane. It is preserved as a foam.

Yield: 6.49 g (93.6% of theory)

Elemental analysis: calc .: C 62.32 H 8.57 N 6.06 found: C 62.41 H 8.66 N 6.01

d) 3,9-bis (t-butoxycarbonylmethyl) -3,6,9-triazaundecanedicarboxylic acid di-t-butyl ester

3.5 g (5 mmol) of the compound prepared in Example 17c) are dissolved in 100 ml of ethanol, 200 mg of Pearlman catalyst (Pd 20% on activated carbon) are added and the mixture is hydrogenated until the calculated amount of hydrogen has been taken up. It is suctioned off from the catalyst and concentrated to dryness in vacuo. The title compound is obtained as a white foam. Yield: 2.80 g (99.9% of theory)

Elemental analysis: calc .: C 60.08 H 9.54 N 7.51 found: C 60.02 H 9.62 N 7.56

e) 3,9-bis (t-butoxycarbonylmethyl) -6-benzyloxycarbonylmethyl-3,6,9-triazaunde-candic acid di-t-butyl ester

5.60 g (10 mmol) of the amino compound prepared in Example 17d) are dissolved in 30 ml of dimethylformamide. Then, at room temperature, 1.66 g (12 mmol) of potassium carbonate and 2.58 g (12 mmol) of 2-bromoacetic acid benzyl ester are added and the mixture is stirred overnight. It is then poured onto ice water, extracted with ethyl acetate, the organic solution is dried over sodium sulfate, concentrated to dryness in vacuo and the title compound is obtained by chromatography on silica gel. A mixture of ethyl acetate / hexane serves as the eluent.

Yield: 6.32 g (89.3% of theory)

Elemental analysis: calc .: C 64.65 H 9.00 N 5.95 found: C 64.62 H 9.07 N 5.90

f) 3 ₁ 9-bis (t-butoxycarbonylmethyl) -6-carboxy-methyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

7.08 g (10 mmol) of the benzyl ester prepared under 17e) are dissolved in 100 ml of ethanol and 0.4 g of Pearlman catalyst (Pd 20%, C) are added. The mixture is hydrogenated until 224 ml of hydrogen are taken up, the catalyst is filtered off with suction, washed well with ethanol and the solution is evaporated to the dry state in a vacuum. The product is obtained as a foam which crystallized from ether / hexane.

Yield: 6.87 g (97.3% of theory) Melting point: 73-75 ° C

Elemental analysis: calc .: C 57.85 H 9.00 N 5.95 found: C 57.91 H 9.11 N 6.01

g) 3,9-bis (t-butoxycarbonylmethyl) -6- (2-aminoethyl) -aminocaΦonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.00 g (8.09 mmol) of the title compound from Example 17f) are dissolved in 25 ml of dimethylformamide and 1.02 g (8.90 mol) of N-hydroxysuccinimide are added. The mixture is cooled to 0 ° C. and 1.84 g (8.90 mmol) of dicyclohexylcarbodiimide are added. It will be one

Hour at 0 ° C and then 4 hours at room temperature. The mixture is cooled to 0 ° C. and a solution of 2.67 g of 1,2-diaminoethane (44.5 mmol) in 50 ml of dimethylformamide is added dropwise within 10 minutes. The mixture is stirred at 0 ^° C. for one hour, then at room temperature overnight. It is evaporated to dryness in vacuo and the residue is taken up in 100 ml of ethyl acetate. The precipitated urea is filtered off and the filtrate is washed twice with 100 ml of 5% aqu. Soda solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: n-hexane / isopropanol 15: 1). 2.83 g (53% of theory) of a colorless oil are obtained.

Elemental analysis: calc .: C 58.25 H 9.32 N 10.61 found: C 58.17 H 9.25 N 10.55

h) 3,9-bis (carboxymethyl) -6- (2-aminoethyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

2.60 g (3.94 mmol) of the title compound from Example 17g) are dissolved in 100 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (Mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 15 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.

Yield: 1.29 g (57% of theory) of a glassy solid

Water content: 7.9%

Elemental analysis (based on anhydrous substance): calc .: C 44.13 H 6.71 N 16.08 found: C 40.25 H 6.63 N 16.18

i) Gadolinium complex of 3,9-bis (carboxymethyl) -6- (2-aminoethyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

1.20 g (2.75 mmol) of the title compound from Example 17h) are dissolved with 15 ml of deionized water and 0.50 g (1.37 mmol) of gadolinium oxide are added in portions at room temperature. After a reaction time of 3 hours at 80 ° C., the now almost clear reaction solution is cooled to room temperature and a pH of 7.2 is set with 1 N sodium hydroxide solution. After filtration, the filtrate obtained is freeze-dried.

Yield: 1.64 g (97.8% of theory) of an amorphous powder

Water content: 7.93%

Elemental analysis (based on anhydrous substance): calc .: C 31, 42 H 4.12 Gd 25.71 N 11, 45 Na 3.76 found: C 31, 46 H 4.14 Gd 25.74 N 11, 48 Na 3.80 j) Ytterbium complex of 3,9-bis (carboxymethyl) -6- (2-aminoethyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

In analogy to Example 17i), the reaction of 1.0 g (2.29 mmol) of the title compound from Example 17h) with 0.45 g (1.15 mmol) of ytterbium oxide instead of gadolinium oxide after freeze-drying 1.40 g (97, 5% of theory) of the title compound as an amorphous powder.

Water content: 8.06%

Elemental analysis (based on anhydrous substance): calc .: C 30.63 H 4.02 N 11, 16 Na 3.66 Yb 27.58 found: C 30.59 H 4.00 N 11.13 Na 3.61 Yb 27.51

k) Europium complex of 3,9-bis (carboxymethyl) -6- (2-aminoethyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

Analogously to Example 17i), the reaction of 1.0 g (2.29 mmol) of the title compound from Example 17h) with 0.40 g (1.15 mmol) of europium oxide

Freeze-drying 1.36 g (98.0% of theory) of the title compound as an amorphous powder.

Water content: 8.02%

Elemental analysis (based on anhydrous substance): calc .: C 31, 69 H 4.16 N 11, 55 Eu 25.06 Na 3.79 found: C 31, 66 H 4.10 N 11, 51 Eu 25.01 Na 3.72

Example 18

a) 3,9-bis (t-butoxycarbonylmethyl) -6- (3-oxa-5-aminopentyl) -aminocarboπyl-methyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5.00 g (8.09 mmol) of the title compound from Example 17f) are dissolved in 25 ml of dimethylformamide and 1.02 g (8.90 mol) of N-hydroxysuccinimide are added. The mixture is cooled to 0 ° C. and 1.84 g (8.90 mmol) of dicyclohexylcarbodiimide are added. It will be one Hour at 0 ° C and then 4 hours at room temperature. It is cooled from 0 ° C. and a solution of 2.67 g of 1.5 diamino-3-oxapentane (44.5 mmol) in 50 ml of dimethylformamide is added dropwise within 10 minutes. The mixture is stirred for one hour at 0 ° C., then overnight at room temperature. It is evaporated to dryness in vacuo and the residue is taken up in 100 ml of ethyl acetate. The precipitated urea is filtered off and the filtrate is washed twice with 100 ml of 5% aqu. Soda solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile phase: n-hexane / ethyl acetate 20: 1). 2.79 g (49% of theory) of a colorless oil are obtained.

Elemental analysis: calc .: C 58.01 H 9.31 N 9.95 found: C 57.90 H 9.41 N 9.87

b) 3,9-bis (carboxymethyl) -6- (3-oxa-5-aminopentyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

2.60 g (3.69 mmol) of the title compound from Example 18a) are dissolved in 100 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 20 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.

Yield: 1.11 g (57% of theory) of a glassy solid

Water content: 8.9%

Elemental analysis: calc .: C 45.09 H 6.94 N 14.61 found: C 45.17 H 6.86 N 14.55 c) Gadolinium complex of 3,9-bis (carboxymethyl) -6- (3-oxa-5-aminopentyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

Analogously to Example 17i), the reaction of 2.4 g (5.00 mmol) of the title compound from Example 18b) with 0.90 g (2.50 mmol) of gadolinium oxide after freeze-drying gives 3.23 g (98.6% of theory) . Th.) Of the title compound as an amorphous powder.

Water content: 6.47%

Elemental analysis (based on anhydrous substance): calc .: C 32.97 H 4.46 N 10.68 Gd 23.98 Na 3.51 found: C 32.91 H 4.44 N 10.63 Gd 23.92 Na 3.48

d) Dysprosium complex of 3,9-bis (carboxymethyl) -6- (3-oxa-5-aminopentyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

Analogously to Example 17i), the reaction of 1.8 g (3.75 mmol) of the title compound from Example 18b) with 0.70 g (1.87 mmol) of dysprosium oxide instead of gadolinium oxide after freeze-drying gives 2.40 g (96. 8% of theory) of the title compound as an amorphous powder.

Water content: 7.13%

Elemental analysis (based on anhydrous substance): calc .: C 32.71 H 4.42 N 10.60 Dy 24.59 Na 3.48 found: C 32.68 H 4.39 N 10.57 Dy 24.55 Na 3.41 Example 19

a) 3,9-bis (t-butoxycarbonylmethyl) -6-bis (octadecyl) aminocart donylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5 g (8.09 mmol) of the title compound from Example 17f) and 4.22 g (8.09 mmol) of bisoctadecylamine are dissolved in 30 ml of toluene and 2.20 g (8.9 mmol) of 2-ethoxy at 0 ° C -1-ethoxycarbonyl-1,2-dihydroquinoline added. The mixture is stirred for 30 minutes at 0 ° C., then overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: hexane / ethyl acetate = 20: 10: 1).

Yield: 7.99 g (88% of theory) of a colorless solid

Elemental analysis: calc .: C 70.67 H 11, 50 N 4.99 found: C 70.78 H 11, 60 N 4.83

b) 3,9-bis (carboxymethyl) -6-bis (octadecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

5 g (4.46 mmol) of the title compound from Example 19a) are dissolved in 100 ml of trifluoroacetic acid and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: methylene chloride / ethanol / 33% strength aqueous ammonia solution 20: 5: 0.5). The fractions containing the product are evaporated to dryness in vacuo and the residue is dissolved in a mixture of 80 ml of ethanol / 20 ml of water / 30 ml of chloroform. 20 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 30 minutes. The ion exchanger is filtered off and the filtrate is evaporated to dryness in vacuo.

Yield: 2.67 g (65% of theory) of a glass-like solid

Water content: 2.7% Elemental analysis: calc .: C 67.11 H 10.90 N 7.57 found: C 67.21 H 10.98 N 7.46

c) Gadolinium complex of 3,9-bis (carboxymethyl) -6-bis (octadecyl) -amino-carbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

2.0 g (2.22 mmol) of the title compound from Example 19b) are dissolved in 100 ml of water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and at 80 ° C. in portions with 0.40 g ( 1, 11 mmol) gadolinium oxide added. The reaction solution thus obtained is then boiled under reflux for 5 hours. After cooling to room temperature, the solvent mixture is drawn off completely in vacuo and the remaining residue is mixed with 200 ml of a water / n-butanol mixture (1: 1). With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 1.96 g (82.4% of theory) of a glass-like solid

Water content: 6.16%

Elemental analysis (based on anhydrous substance): calc .: C 55.94 H 8.64 Gd 14.65 N 5.22 Na 2.14 found: C 55.90 H 8.59 Gd 14.62 N 5.18 Na 2, 11

d) Iron complex of 3,9-bis (carboxymethyl) -6-bis (octadecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

1.0 g (1.11 mmol) of the title compound from Example 19b) are dissolved in 75 ml of water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and at 80 ° C. in portions with 0.39 g ( 1.11 mmol) of iron III-acetylacetonate were added. The reaction solution thus obtained is then boiled under reflux for 5 hours. To After cooling to room temperature, the solvent mixture is completely stripped off in vacuo and 150 ml of a water / n-butanol mixture (1: 1) are added to the remaining residue. With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 0.87 g (81.0% of theory) of a glass-like solid

Water content: 5.93%

Elemental analysis (based on anhydrous substance): calc .: C 61.78 H 9.54 N 5.76 Fe 5.74 Na 2.36 found: C 61.82 H 9.57 N 5.81 Fe 5.76 Na 2.41

e) Dysprosium complex of 3,9-bis (carboxymethyl) -6-bis (octadecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

1.25 g (1.39 mmol) of the title compound from Example 19b) are dissolved in 75 ml of water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and at 80 ° C. in portions with 0.26 g ( 0.69 mmol) dysprosium oxide added. The reaction solution thus obtained is then boiled under reflux for 5 hours. After cooling to room temperature, the solvent mixture is completely stripped off in vacuo and 150 ml of a water / n-butanol mixture (1: 1) are added to the remaining residue. With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 1.34 g (89.6% of theory) of a glassy solid

Water content: 5.85% Elemental analysis (based on anhydrous substance): calc .: C 55.67 H 8.60 Dy 15.06 N 5.19 Na 2.13 found: C 55.61 H 8.76 Dy 15.02 N 5.16 Na 2.10

f) Manganese complex of 3,9-bis (carboxymethyl) -6-bis (octadecyl) -amino-carbonylmethyl-3,6,9-triazaundecanedioic acid disodium salt

2.0 g (2.22 mmol) of the title compound from Example 19b) are dissolved in 150 ml of water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and at 80 ° C. in portions with 0.25 g ( 2.22 mmol) manganese II carbonate added. The reaction solution thus obtained is then boiled under reflux for 5 hours. After cooling to room temperature, the solvent mixture is drawn off completely in vacuo and the remaining residue is mixed with 200 ml of a water / n-butanol mixture (1: 1). With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 1.86 g (84.2% of theory) of a glass-like solid

Water content: 5.79%

Elemental analysis (based on anhydrous substance): calc .: C 60.40 H 9.33 Mn 5.53 N 5.64 Na 4.62 found: C 60.33 H 9.29 Mn 5.51 N 5.60 Na 4.59

Example 20

a) Bis (octadecyl) amino acetic acid

30 g (57.47 mmol) bisoctadecylamine and 8.38 g (60.3 mmol) bromoacetic acid are dissolved in a mixture of 150 ml toluene / 10 ml dioxane and overnight heated under reflux. 200 ml of 5% aqu. Ammonia solution and stir for 10 minutes. The organic phase is separated off, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / ethanol = 20: 1).

Yield: 20.33 g (61% of theory) of a waxy solid

Elemental analysis: calc .: C 78.69 H 13.38 N 2.41 found: C 78.80 H 13.50 N 2.34

b) 1- [bis (octadecyl) amino] -2-oxo-3-aza-13-aminotridecane

10 g (17.24 mmol) of the title compound from Example 20a) and 2.18 g (18.96 mmol) of N-hydroxysuccinimide are dissolved in 100 ml of dimethylformamide. The mixture is cooled to 0 ° C. and 3.91 g (18.96 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred at 0 ° C. for 1 hour, then at room temperature for 3 hours. The precipitated urea is filtered off and the filtrate is added dropwise to a solution of 9.80 g (56.88 mmol) of diaminodecane and 5.76 g (56.88 mmol) of triethylamine in 200 ml of methylene chloride within 30 minutes. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is dissolved in 200 ml of toluene. The organic phase is washed twice with 100 ml of 5% aqu. Soda solution, dries over magnesium sulfate and evaporates to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / isopropanol / triethylamine = 50: 2: 1).

Yield: 5.19 g (41% of theory) of a waxy solid

Elemental analysis: calc .: C 78.51 H 13.59 N 5.72 found: C 78.61 H 13.68 N 5.60 c) 3,9-bis (t-butoxycarbonylmethyl) -6- [11-aza-13-bis (octadecyl) amino-12-oxotridecyl] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5 g (8.09 mmol) of the title compound from Example 17f) are dissolved in 25 ml of dimethylformamide and 1.44 g (8.9 mmol) of N, N'-carbonyldiimidazole are added. The mixture is stirred for 4 hours at room temperature. The solution is cooled to 0 ° C. and a solution of 5.94 g (8.09 mmol) of the title compound from Example 20b) and 0.82 g (8.09 mmol) of triethylamine, dissolved in 50 ml of methylene chloride, is added dropwise over the course of 30 minutes . The mixture is stirred overnight at room temperature. It is evaporated to dryness, the residue is taken up in 150 ml of toluene and extracted twice with 100 ml of 5% aqueous solution. Soda solution. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / hexane / acetone = 20: 10: 1).

Yield: 8.42 g (78% of theory) of a waxy solid

Elemental analysis: calc .: C 70.22 H 11.48 N 6.30 found: C 70.31 H 11.59 N 6.17

d) 3,9-bis (carboxymethyl) -6- [11-aza-13-bis (octadecyl) amino-12-oxotridecyl] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

5 g (3.75 mmol) of the title compound from Example 20c) are dissolved in 100 ml of trifluoroacetic acid and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: methylene chloride / ethanol / 33% strength aqueous ammonia solution 20: 5: 0.5). The fractions containing the product are evaporated to dryness in vacuo and the residue is dissolved in a mixture of 80 ml of ethanol / 20 ml of water / 30 ml of chloroform. 15 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 30 minutes. The ion exchanger is filtered off and the filtrate is evaporated to dryness in vacuo.

Yield: 3.05 g (71% of theory) of a glass-like solid Water content: 3.1%

Elemental analysis: calc .: C 67.11 H 10.90 N 7.57 found: C 67.21 H 10.98 N 7.46

e) Gadolinium complex of 3,9-bis (carboxymethyl) -6- [11-aza-13- bis (octadecyl) amino-12-oxotridecyl] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

2.5 g (2.25 mmol) of the title compound from Example 20d) are dissolved in 150 ml of water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and at 80 ° C. in portions with 0.40 g ( 1.12 mmol) gadolinium oxide added. The reaction solution thus obtained is then boiled under reflux for 5 hours. After cooling to room temperature, the solvent mixture is completely stripped off in vacuo and the remaining residue is mixed with 250 ml of a water / n-butanol mixture (1: 1). With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 2.67 g (92.4% of theory) of a glassy solid

Water content: 6.31%

Elemental analysis (based on anhydrous substance): calc .: C 57.91 H 9.09 Gd 12.23 N 6.54 Na 1.79 found: C 57.87 H 9.02 Gd 12.20 N 6.52 Na 1, 77 f) Manganese complex of 3,9-bis (caΦoxymethyl) -6- [11-aza-13- bis (octadecyl) amino-12-oxotridecyl] aminocarbonylmethyl-3,6,9-triazaundecanedioic acid disodium salt

1.5 g (1.35 mmol) of the title compound from Example 20d) are dissolved in 100 ml of water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and at 80 ° C. in portions with 0.15 g ( 1.35 mmol) manganese II carbonate added. The reaction solution thus obtained is then boiled under reflux for 5 hours. After cooling to room temperature, the solvent mixture is completely stripped off in vacuo and 150 ml of a water / n-butanol mixture (1: 1) are added to the remaining residue. With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 1.38 g (85.1% of theory) of a glass-like solid

Water content: 7.02%

Elemental analysis (based on anhydrous substance): calc .: C 61, 72 H 9.69 N 6.97 Mn 4.55 Na 3.81 found: C 61, 68 H 9.67 N 6.94 Mn 4.50 Na 3.78

Example 21

a) 3,9-Bis (t-butoxycarbonylmethyl) -6- [3-aza-4-oxo-heneicosyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5 g (7.58 mmol) of the title compound from Example 17g) and 2.30 g (22.73 mmol) of triethylamine are dissolved in 40 ml of methylene chloride. A solution of 2.53 g (8.34 mmol) of octadecanoic acid chloride in 20 ml of methylene chloride is added dropwise at 0 ° C. in the course of 20 minutes. The mixture is stirred overnight at room temperature. It is extracted with 50 ml of 5% aq. Saline solution, the organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel (mobile phase: methylene chloride / hexane / isopropanol = 20: 10: 1). Yield: 6.39 g (91% of theory) of a waxy solid

Elemental analysis: calc .: C 64.83 H 10.34 N 7.56 found: C 64.73 H 10.40 N 7.48

b) 3,9-bis (carboxymethyl) -6- [3-aza-4-oxo-heneicosyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

5 g (5.4 mmol) of the title compound from Example 20a) are dissolved in 100 ml of trifluoroacetic acid and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel

(Eluent: methylene chloride ethanol / 33% aqueous ammonia solution 20: 5: 0.5). The fractions containing the product are evaporated to dryness in vacuo and the residue is dissolved in a mixture of 80 ml of ethanol / 20 ml of water / 30 ml of chloroform. 15 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 30 minutes. The ion exchanger is filtered off and the filtrate is evaporated to dryness in vacuo.

Yield: 2.51 g (64% of theory) of a glass-like solid

Water content: 3.5%

Elemental analysis (based on anhydrous substance): calc .: C 58.18 H 9.05 N 9.98 found: C 58.03 H 9.14 N 9.89

c) Gadolinium complex of 3,9-bis (carboxymethyl) -6- [3-aza-4-oxo-heneicosyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid sodium salt

2.0 g (2.85 mmol) of the title compound from Example 20b) are in 150 ml

Dissolve the water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and add 0.51 g (1.42 mmol) of gadolinium oxide in portions at 80 ° C. The reaction solution thus obtained is then boiled under reflux for 5 hours. After this Cooling to room temperature, the solvent mixture is drawn off completely in vacuo and the remaining residue is mixed with 250 ml of a water / n-butanol mixture (1: 1). With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 2.06 g (82.6% of theory) of a glass-like solid

Water content: 7.66%

Elemental analysis (based on anhydrous substance): calc .: C 46.51 H 6.77 Gd 17.91 N 7.98 Na 2.62 found: C 46.48 H 6.73 Gd 17.88 N 7.95 Na 2.59

d) Manganese complex of 3,9-bis (carboxymethyl) -6- [3-aza-4-oxo-heneicosyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid disodium salt

1.5 g (2.13 mmol) of the title compound from Example 21b) are dissolved in 100 ml of water / ethanol / chloroform (2: 1: 1) mixture at the boiling point and at 80 ° C. in portions with 0.24 g ( 2.13 mmol) of manganese II carbonate were added. The reaction solution thus obtained is then boiled under reflux for 5 hours. After cooling to room temperature, the solvent mixture is drawn off completely in vacuo and 200 ml of a water / n-butanol mixture (1: 1) are added to the remaining residue. With vigorous stirring, a pH of 7.2 is set by adding 1N sodium hydroxide solution. After the butanol phase has been separated off, the remaining aqueous phase is completely extracted with n-butanol. The combined organic phases are then evaporated to dryness in vacuo.

Yield: 1.50 g (88.6% of theory) of a glass-like solid

Water content: 6.41% Elemental analysis: calc .: C 51.12 H 7.45 Mn 6.88 N 8.77 Na 5.76 found: C 51.08 H 7.40 Mn 6.84 N 8.74 Na 5.73

Example 22

a) 3,9-bis (t-butoxycarbonylmethyl) -6- (10-carboxydecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid di-t-butyl ester

5 g (8.09 mmol) of the title compound from Example 17f) and 0.82 g (8.09 mmol) of triethylamine are dissolved in 50 ml of methylene chloride. A solution of 1.10 g (8.09 mmol) of isobutyl chloroformate in 20 ml is added dropwise at -10.degree

Methylene chloride within 5 minutes and stirred at -10 ° C for 20 minutes. The solution is cooled to -15 ° C. and a solution of 1.63 g (8.09 mmol) of 11-amino undecanoic acid and 2.43 g (24 mmol) of triethylamine in 50 ml of methylene chloride is added dropwise within 10 minutes and the mixture is stirred 30 minutes at -15 ° C, then overnight at room temperature. It is extracted twice with 100 ml of 10% aqu.

Ammonium chloride solution, the organic phase dries over magnesium sulfate and evaporates to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / ethanol = 20: 1).

Yield: 4.41 g (68% of theory) of a colorless solid

Elemental analysis: calc .: C 61, 47 H 9.56 N 6.99 found: C 61, 53 H 9.48 N 6.89

b) 3,9-bis (carboxymethyl) -6- (10-carboxydecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid

4 g (4.99 mmol) of the title compound from Example 22a) are dissolved in 100 ml of trifluoroacetic acid. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The the product containing fractions are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 16 ml of acidic ion exchanger IR 120 (H ⁺ form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.

Yield: 1.95 g (63% of theory) of a glassy solid

Water content: 6.8%

Elemental analysis (based on anhydrous substance): calc .: C 52.07 H 7.69 N 9.72 found: C 52.15 H 7.60 N 9.64

c) Gadolinium complex of 3,9-bis (carboxymethyl) -6- (10-carboxydecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid disodium salt

2.0 g (3.46 mmol) of the title compound from Example 22b) are suspended in 150 ml of deionized water and 0.62 g (1.73 mmol) of gadolinium oxide are added in portions at 80 ° C. After a reaction time of 3 hours at 80 ° C., the now almost clear reaction solution is cooled to room temperature and a pH of 7.2 is set with 1 N sodium hydroxide solution. After filtration, the filtrate obtained is freeze-dried.

Yield: 2.33 g (87.2% of theory) of an amorphous powder

Water content: 8.13%

Elemental analysis (based on anhydrous substance): calc .: C 38.75 H 5.07 Gd 20.29 N 7.23 Na 5.93 found: C 38.72 H 5.01 Gd 20.26 N 7.20 Na 5.89 d) Manganese complex of 3,9-bis (carboxymethyl) -6- (10-carboxydecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid trisodium salt

1.0 g (1.73 mmol) of the title compound from Example 22b) are suspended in 100 ml of deionized water and 0.20 g (1.73 mmol) of manganese-II-caΦonate are added in portions at 80 ° C. After a reaction time of 3 hours at 80 ° C., the now almost clear reaction solution is cooled to room temperature and a pH of 7.2 is set with 1 N sodium hydroxide solution. After filtration, the filtrate obtained is freeze-dried.

Yield: 1.06 g (88.4% of theory) of an amorphous powder

Water content: 8.83%

Elemental analysis (based on anhydrous substance): calc .: C 43.17 H 5.65 Mn 7.90 N 8.06 Na 9.92 found: C 43.14 H 5.60 Mn 7.86 N 8.01 Na 9.88

e) Iron complex of 3, 9-bis (carboxymethyl) -6- (10-carboxydecyl) aminocarbonylmethyl-3,6,9-triazaundecanedioic acid disodium salt

1.0 g (1.73 mmol) of the title compound from Example 22b) are suspended in 100 ml of deionized water, and 0.61 g (1.73 mmol) of iron III-acetylacetonate are added in portions at 80.degree. After a reaction time of 3 hours at 80 ° C., the now almost clear reaction solution is cooled to room temperature, extracted twice with methylene chloride and a pH of 7.2 is adjusted with 1 N sodium hydroxide solution. After filtration, the filtrate obtained is freeze-dried.

Yield: 1.04 g (89.2% of theory) of an amorphous powder

Water content: 8.11%

Elemental analysis (based on anhydrous substance): calc .: C 44.59 H 5.84 Fe 8.29 N 8.32 Na 6.83 found: C 44.57 H 5.81 Fe 8.27 N 8.30 Na 6.80

Claims

Claims

1) Compounds of the general formula I.

wherein

X independently of one another represents a hydrogen atom or a metal ion equivalent of an element of atomic numbers 12, 20 - 32, 39, 42 - 44, 49 or 57 - 83,

Z, E ¹ , E ² independently of one another represent a hydrogen atom, a saturated or unsaturated, branched or straight-chain Ci-Cso-alkyl chain, the chain or parts of this chain optionally being a cyclic C ₅ -C8 unit or a bicyclic Cio-C - ^ - Unit can form, the 0 to 10 oxygen and or 0 to 2 sulfur atoms and / or 0 to 3 carbonyl, 0 to 1 thiocarbonyl, 0 to 2 imino, 0 to 2 phenylene, 0 to 1 3 contains -ndol-, 0 to 1 methyl-imidazol-4-yl and / or 0 to 3 NR ³ groups and by 0 to 2 phenyl, 0 to 2 pyridyi, 0 to 5 R O-, 0 to 1 HS -, 0 to 4 R ² OOC, 0 to 4 R OC-C ^ alkyl and / or 0 to 1 R ² (H) N groups in which any aromatic groups are present zero to five times independently by fluorine atoms, R ² O C-, R ² OOC-C ₁ ^ -alkyl-, C ^ -alkyl-NH-, R NHOC-, R ² CONH-, O ₂ N-, R ² 0-, R ² - Groups can be substituted, R ² independently of one another represents a hydrogen atom or a straight-chain or branched C- | -C ₄ -alkyl radical and

R3 independently of one another for a hydrogen atom or a straight-chain or branched, saturated or unsaturated C- _| -C ₃ o-alkyl radical and

E ¹ and E ² together with the nitrogen atom also represent a five- to eight-membered saturated or unsaturated heterocycle which may contain one or two further nitrogen, oxygen, sulfur atoms and / or carbonyl groups,

wherein the HO- and / or contained in Z, E ¹ and / or E ² optionally

H ₂ N and / or HS and / or HOOC group (s) can be in protected form and in which free carboxylic acid groups which are not used for complexation can also be present as salts with physiologically tolerable inorganic and or organic cations or as esters or amides .

2) Complex according to claim 1, characterized in that the central atom is an element of atomic numbers 12, 20 - 32, 39, 42 - 44, 49 or 57 - 83.

3) Compounds according to claim 1, characterized in that all of the radicals denoted by X stand for a hydrogen atom.

4) Complexes according to claim 1, characterized in that that

Central atom is a radioisotope of an element of atomic numbers 21, 26, 27, 29, 31, 32, 39, 43, 49, 62 - 64, 66, 70, 75, 77 or 83.

5) Compounds according to claim 1, characterized in that at least one of the radicals E ¹ and E ² for hydrogen or a methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl or n-lcosyl radical or that E ¹ and E ² together with the connecting nitrogen atom stand for a Moφholinrest. 6) Compounds according to claim 1, characterized in that at least one of the radicals E ¹ and E ^{2 represents} a radical - (CH ₂ ) _p - (G) _r (CH ₂ ) _q COOH, where G represents oxygen or sulfur, p, q independently of one another stand for a number between 1 and 28, t stands for 0 or 1, where p + t + q <30 and the acid group can also be present as a salt of an inorganic or organic base, as an ester or as an amide.

7) Compounds according to claim 1, characterized in that at least one of the radicals E ¹ and E ² for a radical

- (CH ₂ ) _p - (G) _t - (CH ₂ ) _q NH ₂ , where

G stands for oxygen or sulfur, p, q independently of one another stand for a number between 1 and 28, t stands for 0 or 1, p + t + q ≤ 30 and the amino group also as an ammonium salt with a physiologically compatible anion of an inorganic or organic

Acid may be present.

8) Compounds according to claim 1, characterized in that Z for a

Is hydrogen atom or the methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, or cyclo-hexyl radical.

9) Compounds according to claim 1, characterized in that Z represents a phenyl or benzyl radical which is zero to five times independently of one another by fluorine, chlorine, bromine, iodine, R ² O ₂ C-, 4 R ^ OC-C ^ -Alkyl-, C ^ -alkyl-NH-,

R ² NHOC-, R ² CONH-, O ₂ N-, R O-, R ² -groups is substituted, wherein R ^{2 stands} for a hydrogen atom or a branched or unbranched C- | -C -alkyl radical. 10) Compounds according to claim 1, characterized in that Z is identical to the radical Z ^{A of} a naturally occurring α-amino acid of the general formula III

11) Compounds according to claim 10, characterized in that the amino acid is glycine, alanine, valine, leucine, phenylalanine, tyrosine, serine, threonine, cysteine, methionine, tryptophan, aspartic acid, glutamic acid, arginine, lysine or histidine.

12) Pharmaceutical compositions containing at least one physiologically compatible compound according to claim 1, optionally with the additives customary in galenics.

13) Use of at least one physiologically compatible compound according to claim 1 for the preparation of agents for NMR or X-ray diagnosis.

14) Use of at least one physiologically tolerable compound according to claim 1 for the preparation of agents for radio diagnosis or therapy.

15) Process for the preparation of diethylenetriaminepentacarboxylic acid monoamides of the general formula (I)

wherein

X each represents a hydrogen atom,

Z, E ¹ , E2 independently of one another represent a hydrogen atom or a saturated or unsaturated, branched or straight-chain C1-C5 ₀ -alkyl chain, the chain or parts of this chain optionally being a cyclic C ₅ -C ₈ unit or a bicyclic one C ₁₀ -C ₁₄ unit can form, the 0 to 10 oxygen and / or 0 to 2 sulfur atoms and / or 0 to 3 carbonyl, 0 to 1 thiocarbonyl, 0 to 2 imino, 0 to 2 phenylene, 0 to 1 3-indole, 0 to 1 methyl-imidazol-4-yl and / or 0 to 3 NR ³ groups and by 0 to 2 phenyl, 0 to 2 pyridyl, 0 to 5 R ² O- , 0 to 1 HS, 0 to 4 R ² OOC, 0 to 4 R ^ OC-C ^ alkyl and / or 0 to 1 R ² (H) N groups, in which aromatic groups which may be present zero to five times independently of one another by fluorine atoms, R ² O ₂ C-, R ^ OC-C ^ -alkyl-, C ^ -alkyl-NH-, R ² NHOC-, R CONH-, O ₂ N-,

R O, R ² groups can be substituted,

R ² independently of one another for a hydrogen atom or a straight-chain or branched C- _| -C ₄ alkyl and R3 independently of one another represents a hydrogen atom or a straight-chain or branched, saturated or unsaturated C ₁ -C ₃ -alkyl radical or

E ¹ and E ² together, including the nitrogen atom, stand for a five- to eight-membered saturated or unsaturated heterocycle which optionally contains one or two further nitrogen, oxygen, sulfur atoms and or carbonyl groups,

the HO and / or H N and / or HS and / or HOOC group (s) optionally contained in E ¹ and / or E ² may be present in protected form and in which free complexes which are not used for complexation may be present Carboxylic acid groups can also be present as salts with physiologically compatible inorganic and / or organic cations or as esters or amides,

characterized in that a partially protected diethylene triamine pentacarboxylic acid derivative according to the general formula V,

in which R ^{1 represents} t-butyl or a benzyl group and Z has the meaning of an optionally protected group Z, in which Z has the meaning given above, with an amine of the general formula VI

H - N

^E (VI), in which E ¹ and E ^{2 have} the meaning given above, optionally with the addition of an activating reagent and then by selective and mild cleavage of the group R ¹ and the protective groups optionally present in Z, then the free acid of the general formula I is prepared.

16) Process according to claim 15, characterized in that at least one of the radicals E ¹ and E ² for hydrogen or a methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl or n-lcosyl radical.

17) Process according to claim 15, characterized in that at least one of the radicals E ¹ and E ^{2 represents} a radical - (CH ₂ ) _p - (G) _t - (CH ₂ ) _q COOH, wherein

G stands for oxygen or sulfur, p, q independently of one another stand for a number between 1 and 18, t stands for 0 or 1, where p + t + q <20 and the acid group also as a salt of an inorganic or organic base, as Ester or as an amide.

18) Process according to claim 15, characterized in that at least one of the radicals E ¹ and E ^{2 represents} a radical - (CH ₂ ) _p - (G) _t - (CH ₂ ) _q NH ₂ , G being oxygen or sulfur is, p, q independently of one another are a number between 1 and 18, t is 0 or 1, where p + t + q <20 and the amino group can also be present as an ammonium salt with a physiologically acceptable anion or as an amide. 19) Method according to claim 15, characterized in that Z is hydrogen or the methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, or cyclo-hexyl radical.

20) The method according to claim 15, characterized in that Z represents a phenyl or benzyl radical, which optionally one or more independently of one another by F-, Cl-, Br-, I-, HO-, R ² 0-, R ² -, H ₂ N, R ² OCNH, R NHCO, O ₂ N, HOOC and / or R OOC groups is substituted, wherein R ^{2 represents} a branched or unbranched C 1 -C ₄ alkyl radical.

21) Method according to claim 15, characterized in that Z is identical to the residue Z ^{A of} a naturally occurring α-amino acid, which is represented by the general formula

can be described.

22) Method according to claim 21, characterized in that the amino acid glycine, alanine, valine, leucine, phenylalanine, tyrosine, serine, threonine, cysteine,

Methionine, tryptophan, aspartic acid, glutamic acid, arginine, lysine or histidine.

23) Process according to claim 15, characterized in that R ^{1 stands} for a benzyl group and the splitting off of this group R ¹ takes place by hydrogenolysis.

24) Process according to claim 15, characterized in that R ^{1 stands} for a t-butyl group and the splitting off of this group R ¹ takes place by saponification with trifluoroacetic acid.