WO1995015306A1 - Aryl halide substituted metallic complexes, pharmaceuticals containing these complexes, their use for diagnostic purposes, and methods for preparing the complexes and pharmaceuticals - Google Patents

Abstract

The invention pertains to new metallic complexes containing an ion of an element of atomic number 12, 13, 20-31, 39-42, 44-50 or 57-83 and a halogenated complexing ligand of formula (I), where R?1, R2, R3, Z1, Z2, Z3, U1, U2, V1, V2 or V3¿ have various meanings. The invention pertains as well to pharmaceuticals containing these complexes, to their use in NMR and/or X-ray diagnostics, especially in X-ray diagnosis of the liver, and to methods for preparing the complexes and pharmaceuticals.

Description

 Halogenaryl-substituted metal complexes, pharmaceutical compositions containing these complexes, their use in diagnostics, and methods for producing the complexes and compositions

The invention relates to the objects characterized in the claims, that is to say new halogenaryl-substituted metal complexes, pharmaceutical compositions containing these complexes, their use in diagnostics and methods for producing the complexes and compositions.

Contrast agents are indispensable aids in modern diagnostics; many diseases would not be diagnosed without the use of contrast agents. Contrast agents can be found in all areas of diagnostics such as X-ray, radio or ultrasound diagnostics or magnetic resonance imaging.

The choice of the preferred method depends in part on according to the diagnostic question, but is also determined by the available device options for the doctor. Magnetic resonance imaging in particular, due to the considerable technical and associated high cost, does not yet have the widespread use of other methods, e.g. X-ray diagnostic methods found.

The choice of a suitable contrast medium also varies depending on the particular question. The suitability of the contrast medium for a specific task is determined not least by its (enrichment) distribution behavior in the organism.

Although great progress has been made on both the device technology and the contrast agent side, satisfactory solutions are not yet available for all questions.

For the various imaging methods, there are not suitable contrast agents for all indications. In particular, no suitable x-ray contrast agent for liver diagnosis is available to date.

In X-ray diagnostics, contrast agents based on triiodobenzene have been able to prevail, since these compounds have a high X-ray density and have a low general and local toxicity and are very soluble in water.

Such connections are e.g. in EP 0 105 725, EP 0 015 867. However, these show no accumulation in the liver which is sufficient for imaging.

Since the usability of a compound as an X-ray contrast medium, in addition to the accumulation behavior in the respective organ, essentially depends on the size of the mass attenuation coefficient of the elements contained in the compound in the diagnostic radiation range, metal complexes of an element with a high atomic number should also be suitable in addition to the iodine-containing compounds. Such compounds are widely used in the field of NMR diagnostics. These are generally metal complexes, such as those e.g. be described in EP 0 071 564.

WO 93/16375 describes metal complexes which are linked to iodine-substituted aromatics via amide bonds. These compounds should allow both NMR and X-ray examinations to be carried out with only one application of the contrast medium. A combination of the two imaging methods is in many cases for a differentiated representation and a reliable one

Determination of certain diseases is an advantage. These compounds are said to be particularly suitable for angiography. As the reworking of the preparation examples showed, however, the compounds do not show sufficient accumulation in the area of the liver for X-ray examinations.

Liver-specific NMR contrast media are described in EP 0 405 704. Because of the metal content in the complexes, these should in principle also be suitable for X-ray diagnostics. A reworking of the experimental examples in animal experiments did not show sufficient contrast of the liver in the X-ray image even when a high dose (conc.: 1 M / 1, dose: 0.5 mmol Gd / kg intravenously) was administered. A sufficient imaging effect in the

X-ray diagnostics are only achieved at a dose at which the safety margin is reduced to an unacceptable level.

It was therefore an object of the present invention to provide very well tolerated and water-soluble contrast media which are particularly suitable for X-ray diagnosis of the liver. This object is achieved by the present invention.

It has been found that metal complexes containing at least one ion of an element of atomic numbers 12, 13, 20-31, 39-42, 44-50 or 57-83 and a 5 halogen-containing complex-forming ligand of the formula I

worm

10 R ^{1 represents} a hydrogen atom, a carboxylic acid radical, a straight-chain or branched C _r C ₁₅ alkyl, C ₆ -C ₁₅ aryl or a C ₇ -C ₁₅ aralkyl radical which is optionally substituted by 1-5 hydroxy and / or 1-2 carboxy groups and / or interrupted by 1-4 oxygen atoms, or wherein

R ^{1 represents} a radical of the general formula II or III,

15

4 5 CO - R R (Tj)

-CH -NR-CO-R ⁷

^ σπ)

20 where

R ⁴ , R ⁵ independently of one another represent a hydrogen atom, a straight-chain or branched C _r C ₁₅ alkyl, C ₆ -C ₁₅ aryl or a C ₇ -C ₁₅ aralkyl radical which may contain 1-5 hydroxy, Contains 1-2 carboxy groups and / or 1-4 oxygen atoms or wherein R ⁴ , r 25 R ⁵ together including the nitrogen atom, one. optionally form an oxygen, another acylated nitrogen atom or a sulfonyl group, optionally substituted with 1-3 hydroxyl groups, 5 or 6 ring,

30 R ⁶ for a hydrogen atom, a straight-chain or branched

CC ^ -Alky! -, C ₆ -C ₁₅ aryl or a CyC - ^ - aralkyl radical, which optionally contains 1-4 hydroxyl, 1-2 carboxy groups and / or 1-2 oxygen atoms or wherein R ⁶ together with R ⁷ , including the nitrogen atom and the carbonyl group, optionally contains an oxygen, a further acylated nitrogen atom or a sulfonyl group , optionally substituted with 1-3 hydroxy groups, 5 or 6 ring forms and

R ^{7 represents} a hydrogen atom, a straight-chain or branched C _r C ₁₅ alkyl, C ₆ -C ₁₅ aryl or a C ₇ -C ₁₅ aralkyl radical which optionally contains 1 to 2 hydroxyl groups or a carboxy group or in which R ⁷ together with R ⁶ , including the nitrogen atom and the carbonyl group, forms a 5 or 6 ring which may optionally contain an oxygen, another acylated nitrogen atom or a sulfonyl group and is optionally substituted by 1-3 hydroxyl groups,

R ² , R ³ independently of one another represent a hydrogen atom, a C _j -C ^ alkyl radical, a C ₆ -C ₁₅ aryl radical or a C ₇ -C ₁₅ aralkyl radical which is optionally substituted by 1-5 hydroxyl groups and / or through 1-4

Oxygen atoms is interrupted, stand or together form a trimethylene or tetramethylene group, or have the meaning given for U ¹ (U ² ),

Z ¹ , Z ² , Z ³ independently of one another for a hydroxyl group or a radical

-NR ^ -U ^{1 '} , where

R ^{17 represents} a hydrogen atom, a methyl or methoxyethyl group and U ¹ , U ¹ ', U ² , V ¹ , V ² and V ³ each independently

Represent hydrogen atom or a halogenated aromatic radical of the general formula IV,

wherein

R ⁸ , R ⁹ independently of one another represent a group -NR ⁶ -CO-R ⁷ and / or the meaning given for R ¹ , with the exception of a C _r C ₁₅ alkyl, C ₆ -C ₁₅ aryl or a C. Have ₇ -C ₁₅ aralkyl radicals,

R ¹⁰ , R ¹¹ independently of one another represent a halogen or a hydrogen atom,

X represents a halogen atom or a bridge member of the general formula V and

Y represents R ⁹ or a bridge member of the general formula V,

(α (CH ₂ ^ - (C ^^ CL, - R (ß)

(V)

where m, n, p independently of one another represent the digits 0 or 1,

L for an oxygen atom, a sulfur atom, a C _j -C ^

Alkylene radical, a group> S = O,> SO ₂ or> NR ⁴ with R ⁴ in the meaning given and

R ^{12 stands} for a direct bond, a carbonyl, a carboxyl, a -CO-NR ¹⁸ -, a -NR ¹⁸ -CO-, a -NH-CS-, a CS-NH- group, in which R ¹⁸ represents a hydrogen atom, a straight-chain or branched -C ^ alkyl, C ₆ -C ₁₅ aryl or a C ₇ -C ₁₅ aralkyl radical which may contain 1-4 hydroxyl, 1-2 carboxy groups and / or 1-2 Contains oxygen atoms or in which R ^{12 is} a straight-chain or branched C _r C ₄ -

Alkylene radical, which is optionally a carbonyl and / or

Contains amino group, the position (α) being linked to the diethylenetriaminepentaacetic acid skeleton and the position (β) being linked to the halogenated aromatics, where Y is a bridge member of the formula V when X is halogen and Y is R ⁹ when X is a bridge member of the formula V and at least one of the radicals R ² , R ³ , Z ¹ , Z ² , Z ³ , U ¹ , U ² , V ¹ , V ² or V ³ represents or contains the rest of the general formula IV and, if desired, free ones, not for complexing the metal ions of the above

Elements required carboxy groups are present as a salt of an inorganic and / or organic base or amino acid,

under at least one of the following provisions that R ⁸ and / or R ⁹ contains an aryl radical and / or that Z ¹ and / or Z ² only represent a radical of the general formula IV if at least one of the substituents R ² , R ³ , U ¹ , U ² , V ¹ , V ² or V ³ does not represent a hydrogen atom, and / or that if Z ^{3 contains} a fully substituted aromatic of the formula IV, Z ¹ and / or Z ² does not contain a fully substituted aromatic of the formula IV contain, and / or that if all substituents R ² , R ³ , U ¹ , U ² , V ¹ , V ² and V ^{3 are} hydrogen, at least one of the radicals R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ for a Hydrogen atom and / or R ⁸ and / or R ^{9 represent} a radical which contains a carboxylic acid which is not directly bound, excellent for the production of contrast media for NMR and / or X-ray diagnostics, preferably contrast media for X-ray diagnostics, in particular for X-ray diagnostics of the liver are suitable.

The complexes according to the invention preferably contain a manganese (II) -, iron (HI) -, iron (II) -, praseodymium (HI) -, neodymium (III) -, samarium (πi) -, dysprosium (III) - as metal ion, a ytterbium (III) or a bismuth (III) ion, in particular a gadolinium (III) ion.

The complexes according to the invention contain, as halogen atom (s), chlorine, bromine or iodine, preferably (bromine) or iodine, but especially (i) iodine atom (s).

Preferred halogenated aromatics of the formula IV are triiodinated aromatics, ie aromatics in which X, R ¹⁰ and R ^{11 are} iodine and in which R ⁸ and R ⁹ independently of one another represent a hydrogen atom, a group -OH, -COOH, -O- CH ₂ -CH (OH) -CH ₂ -OH, -O-CH3, -O-CH ₂ -CH ₃ , -CO-NH-CH (CH ₂ OH) - (CHOH-CH ₂ OH), -CO- NR4-CH- (CH ₂ OH) ₂ , -NR6-CO-CH ₂ OH, -CO-NR -CH ₂ -CH ₂ OH, -CO-NH ₂ , -N (CH ₃ ) -CO-CH ₃ , -NH-CO-CH3, -CO-NH -CH3, -N (CH ₃ ) -CO- (CH ₂ ) ₂ COOH, -CO-N- (C ₂ H ₅ ) ₂ , -CO-N (CH ₃ ) -CH ₂ -COOH, -CO-NH - (CH ₂ ) ₁₀ -COOH, -CO-NH-CH ₂ -C ₆ H ₄ -OEt or a group -CO-N (CH ₃ ) -CH -CH (OH) -CH ₂ -OH and in which Y stands for a bridge member of the formula V.

Preferred bridge members of the formula V are in the event that one of the radicals

- U stands for a halogenated aromatic radical, the groups -CH -,

-CH ₂ -C ₆ H ₄ -O-CH ₂ -, -CH ₂ -O-CH ₂ -, -CH ₂ -O-, -CH ₂ -O-CO-, -CH ₂ -NH-CO-, -CH ₂ -CO-NH-, -CH ₂ -C ₆ H ₄ -O-CH ₂ -CO-NH-, -CH ₂ -O-CO-NH-,

-CH2-NH-CO-NH-, -NH-CO-, -NH-CO-CH ₂ -,

- Z stands for a halogenated aromatic radical, the groups

-NH-CH ₂ -CO-NH-, -NH CH ₂ CH ₂ -CO-NH- or -NH CH ₂ CH ₂ -NH-CO- and that - V represents a halogenated aromatic radical, the groups -CH ₂ -, -CH ₂ -O-, -CH ₂ -O-CH ₂ -, -CH ₂ -O-CO-, -CH ₂ -NH-CO-, -CH ₂ -CO-NH-, -CH ₂ - O-CO-NH- or -CH ₂ -NH-CO-NH-.

Particularly preferred among these are the complexes in which U - * - represents the rest of the general formula IV, i.e. Compounds which are substituted in the ethylene bridge of the polyaminocarboxylic acid with the halogenated aromatic and in which Z represents a hydroxy group.

Suitable radicals R ¹ are straight-chain or branched alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl radicals, but preference is given to hydrogen, Cχ-C4-alkyl and hydroxyalkyl radicals, such as the hydroxymethyl radical and alkoxy alkyl radicals, such as the methoxymethyl radical.

Suitable radicals R 1, R 3 are the radicals listed for R *, but hydrogen atoms are preferred.

For X-ray diagnostics of the liver, ionic complexes are particularly preferred, in which free carboxyl groups present in the molecule (ie carboxyl groups which are not required for the charge balance of the metal ions of the elements of the atomic numbers mentioned) are present as free acid or as a salt of an inorganic and / or organic base or amino acid . Suitable cations of inorganic bases are, for example, the lithium, the potassium, the calcium, the magnesium and in particular the sodium ion. Suitable cations of organic bases include those of primary, secondary or tertiary amines, such as. As ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine and especially N-methylglucamine. Suitable cations of amino acids are, for example, those of lysine, arginine and ornithine.

The complexes according to the invention can be prepared in a variety of ways. The various processes and the starting compounds required therefor are known in principle to the person skilled in the art. Thus, as a rule, the compounds can be prepared analogously to already known complexes or complexing agents by reacting a reactive species of the halogenated aromatic with a reactive species of the complexing agent in a suitable solvent. The selection of the most appropriate synthetic route depends on the desired link between the halogenated aromatic (s) and the polyaminopolycarboxylic acid. The complexes can then be divided into three groups. Thus, the halogenated aromatic (s)

I) to the α-carbon atoms of the carboxylic acid (acetic acid) residue,

II) to the alkylene (ethylene) bridges or

III) to the carboxylic acid group (s)

be bound to the polyaminopolycarboxylic acid.

Complexing agents or complexes of group I can be prepared analogously to the processes described in European patent application EP 0 230 893. Further universally applicable synthesis options for the complexing agents are mentioned below by way of example.

Thus, by reacting chloroacetic acid derivatives of the general formula VI

Cl \ CC ^ H

R (VI) wherein R - * " ^{3 is} the desired halogenated aromatic radical of the general formula IV or an optionally still unhalogenated precursor of this radical, with polyamines of the general formula VII,

first compounds of the general formula VIII are obtained,

which are then reacted in a manner known per se with haloacetic acid esters, preferably with bromoacetic acid esters, and then - provided that it is a precursor of the desired aromatic compound - are halogenated in a manner known per se and any ester or protective groups present in the person skilled in the art are known Be split off. Disubstitution can also be achieved with appropriate stoichiometry.

An alternative process for the preparation of α-C-substituted polyaminopolycarboxylic acids starts from an acid-protected polyaminocarboxylic acid (for example from the pentamethyl ester of diethylenetriaminepentaacetic acid). This is reacted with the lithium salt of a precursor of the desired aromatic. A corresponding lithium salt can be obtained from benzyl halide (for example 3-nitrobenzyl chloride, 3,5-dinitrobenzyl chloride, 3-benzyloxybenzyl chloride) by reaction with lithium diisopropylamine in THF / hexane. Following the coupling, the aromatic is converted to the desired halogenated aromatic of the formula IV, for example by reducing the nitro groups which may be present to amino groups, which, if desired, are reacted with acetyl chloride to give the amide. Benzyloxy radicals can be converted into hydroxy radicals, for example by catalytic hydrogenation. The aromatics are also iodinated in a manner known per se, for example by reaction with iodine monochloride solution in the hydrochloric acid medium. Before the Introducing the iodine atoms, the acid protecting groups of the pentaester are saponified in basic.

An alternative process for the preparation of the iodine-containing polyaminopolycarboxylic acids is based on an amino acid derivative of the general formula XXIII

the primary amino group of which may also be in protected form (e.g. as a monobenzylamine). This amino group is with an alkylating agent of formula XXIV

.4 J

R OOC (XXIV)

and then - after splitting off the protective groups which may be present, using an alkylating agent of the formula XXV

(XXV)

dialkylated on the nitrogen atom, where Nf stands for a nucleofug such as chloride, bromide, iodide, methanesulfonate or toluenesulfonate and R ^{14 stands} for an acid protecting group such as a lower alkyl, aryl, aralkyl or trialkylsilyl group and R ¹ , R ² , R ³ , U ¹ , U ² , V ¹ , V ² , V ³ , Z ¹ , Z ² and Z ^{3 have} the meaning given above.

So goes a synthesis to produce a -C-substituted

Polyaminopolycarboxylic acid, for example from a phenylamino acid such as 3-aminophenylalanine. This is initially done in a manner known per se halogenated, the acid group then protected as an ester. The intermediate product thus obtained is reacted with two equivalents of N, N-bis [(benzyloxycarbonyl) methyl] - 2-bromomethylamine. If desired, the substituents on the aromatic are converted into the desired radicals before the acid protecting groups are split off.

Group II complexing agents can be prepared analogously to the methods described in EP 0 405 704 and DE 43 02 289. For example, starting from known compounds (DE 37 10 730 and literature cited therein) of the general formula IX,

OH

^

wherein R ¹⁴ , R ¹ , R ² and R ^{3 have} the meanings given, in which the phenolic OH group is reacted with a reactive form of the desired halogenated aromatic (or its precursor, for example benzyl halide) of the formula X.

wherein R ⁸ ', R ⁹ ', R ¹⁰ 'and R ¹¹ ' represent the desired groups R ⁸ , R ⁹ , R! 0 and R ¹¹ or a precursor thereof. If the groups R ⁸ ', R ⁹ ', RIO 'and R * • ** • *' stand for preliminary stages of the desired groups, these are generated from those. The acid protecting groups R14 are known in a known manner [see, for example, E. Wünsch, Methods of Org. Chemistry (Houben Weyl), Vol. XV / 1, 4 ed. 1974, p 315 ff], for example by hydrolysis, hydrogenolysis or alkaline hydrolysis the Rule before halogenation of the aromatic, split off. Both acidic and aqueous-alkaline reaction conditions can be selected for the relaxation of the t-butyl esters which are particularly advantageous for the present reaction.

In the compounds of the general formula IX the aromatic radical can also be used in a manner known per se e.g. is iodinated with iodine monochloride. If appropriate, the phenolic -OH groups can be etherified with alkyl halide / sodium hydride in a manner known per se. The acid protection groups are released in the manner described above.

An alternative process is also based on halogenated chlorinated aromatics of the formula X, which are first reacted with a partially protected glycerol to give the corresponding dihydroxypropyloxy compound of the formula XI

which are then reacted after partial protection of one hydroxyl group and activation of the remaining ones with sodium azide to give the corresponding azido compound of the general formula XII

9 ^*

R

where Rl5 stands for a protective group such as a benzyl group. After splitting off the OH protecting group R --- 5 and activating the resulting hydroxy group, for example as methanesulfonic acid ester, the reaction is first carried out with the corresponding ethylenediamine and then the azide group is reduced in a manner known per se, for example with triphenylphosphine, to give compounds of the formula XIII

These are reacted in a known manner with bromoacetic acid esters to give the corresponding pentaesters. After splitting off the acid protecting groups, for example by reaction with trifluoroacetic acid and generation of the desired groups R ⁸ , R ⁹ , R ¹⁰ and R ^{1 1} from the groups R ⁸ ', R ⁹ ', R ¹⁰ 'and R ^{1 1} ', the desired groups are obtained Complexing agent.

An alternative process for the preparation of complexing agents of group II is based on acid-protected polyammocarboxylic acid derivatives of the general formula XIV

OH

H, CH, CH.

GOOR ¹⁴ COOR ¹⁴ COOR (XIV),

those with isocyanato compounds of the general formula XV

to the corresponding urethanes.

Alternatively, the hydroxyl group in the compounds of the general formula XIV can be reacted, for example, with N-chlorosuccinimide to give the corresponding chloride of the formula XVI α

CH, C - H CH,

1

14 '14 14

OXR COOR O-OR (XVI);

This is then, in a manner known per se, with a reactive species of the desired halogenated aromatic of formula XVII (e.g. containing hydroxyl or carboxy groups)

wherein R ⁸ , R ⁹ , R ^ and R - * * - * have the meanings given and Y 'represents an OH or COOH group, converted to the corresponding ethers or esters. The acid protection groups R * 4 are released in the manner described above.

Alternatively, the compounds of general formula XVI can be reacted with an azide (e.g. sodium azide) to give the corresponding azido compound, which is subsequently reduced to the amino compound in a known manner. This is then a) either with an isocyanato compound of the formula XV to the corresponding

Urea derivative implemented or b) with a halogen-benzoyl chloride of the formula XVIII

(xvm) _{* converted} to the corresponding amide.

An alternative process is based on an aminoethyl alcohol of the formula XIX,

(XIX)

wherein R ^ for an amino protecting group, preferably a benzyloxycarbonyl group and R13 'is an unhalogenated precursor of the desired aromatic or a "linker" to which the desired halogenated aromatic is bound in a later reaction step. The aminoethyl alcohol is first reacted in a manner known per se, for example with methanesulfonyl chloride, toluenesulfonyl chloride or trifluoroacetic anhydride to give the corresponding mesylate, tosylate or triflate and then reacted with an optionally substituted ethylenediamine. If R ¹³ 'is an unhalogenated precursor of the desired aromatic of the general formula IV, iodine is used, for example, with iodine monochloride; if, on the other hand, it is a "linker", this is reacted with a reactive species of the desired aromatic (or its unhalogenated precursor) to react. Finally, the amino protecting groups are split off and with

Halogenoacetic acid ester converted to the desired amino acids (complexing agents).

The group III complexing agents, i.e. Complexing agents in which the halogenated aromatic radical in the form of an amide bond to the carboxylic acid groups of the

Polyaminopolycarbonsäure is bound, can be analogous to that in the

Process described in DE 42 32 925.

Thus the complexing agents can be prepared by partial conversion of activated carboxyl groups e.g. the desired pentacarboxylic acid in amide groups. All synthetic possibilities known to the person skilled in the art are suitable for this process

Consider how. B. the reaction of the acid anhydrides of the general formulas XX or XXI with halogenated aromatics of the general formula XXII to give the amides according to the invention,

wherein R ⁸ ', R ⁹ ', R ¹⁰ 'and R ¹¹ ' represent the desired groups R ⁸ , R ⁹ , R ¹⁰ and RH or a precursor thereof and Q represents the remainder of a linker of the general formula V. The aromatics of the general formula XXII are prepared as described, for example, in DE 25 23 567.

Examples of a H ₂ NQ radical are an H ₂ N-CH ₂ -CO-NH-, H ₂ N-NH-CO-NH-, H ₂ N-CH ₂ CH ₂ -CO-NH-, H ₂ N- NH-CO-CH ₂ CH ₂ -, H ₂ N-CH ₂ CH ₂ -NH-CO - or an H ₂ N-CH ₂ CH ₂ -N (CO-CH ₃ ) - group.

This reaction is carried out in the liquid phase. Suitable reaction media are, for example, water, dipolar aprotic solvents such as diethyl ether, tetrahydrofuran, dioxane, acetonitrile, N-methylpyrrolidone, dimethylformamide,

Dimethylacetamide and the like or mixtures thereof. The reaction temperatures are between approx. -80 ° C and 160 ° C, with temperatures from 20 ° C to 80 ° C are preferred. The reaction times are between 0.5 hours and 7 days, preferably between 1 hour and 36 hours.

The acid anhydrides of general formula XX can be prepared by known processes, e.g. by the process described in US Pat. No. 3,660,388 or in DE 16 95 050 with acetic anhydride in pyridine. In certain cases, however, it is advantageous to dehydrate with carbodiimides in a suitable solvent, e.g. Dimethylformamide or dimethylacetamide, to be carried out gently. The preparation of the monoanhydrides of the general formula XXI is described in J. Pharm. Sei., 68 (1979) 194.

The halogenated aromatics used in the various processes are known or can easily be generated from known ones. For example, described in German published patent application DE 29 28 417 iodinated aromatics, which can easily be mixed with e.g. Thionyl chloride to the corresponding

Aromatics containing acid chloride groups are implemented.

Other aromatic residues are as in M. Sovak; Radiocontrast Agents, Handbook of

Experimental Pharmacology Vol 73 (1984), Springer Verlag, Berlin - Heidelberg - New York - Tokyo or in the European patent EP 0 015 867.

Corresponding chlorine or bromine compounds can be prepared as described in the patents EP 0 055 689 or DE 10 03 743, EP 0 073 715 or EP 0 118 347 - or analogously to the compounds described there.

Aromatics containing amino groups, e.g. required for the preparation of acetic acid-substituted compounds of group III can be obtained analogously to the compounds described in DE 25 23 567.

The metal complexes according to the invention are prepared from the complexing agents of groups I-III described above in the manner as has been disclosed in the patents EP 0 071 564, EP 0 130 934 and DE 34 01 052 by using the metal oxide or a metal salt (for example the nitrate, acetate, carbonate, chloride or sulfate) of the element of atomic numbers 12, 13, 20-31, 39-42, 44-50 or 57-83 in water and / or a lower alcohol (such as methanol, ethanol, Isopropanol and / or N, N-dimethylformamide) dissolves or suspended and reacted with the solution or suspension of the equivalent amount of the complexing agent. If desired, further acidic hydrogen atoms of acid groups can then be substituted by cations of inorganic and / or organic bases or amino acids.

Suitable bases are inorganic bases (e.g. hydroxides, carbonates or bicarbonates) of e.g. B. sodium, potassium or lithium and / or organic bases such as primary, secondary and tertiary amines such as e.g. Ethanolamine, morpholine, glucamine, N-methyl and N, N-dimethylglucamine, and basic amino acids such as B. 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 formed salts by adding water-miscible solvents, such as. B. lower alcohols (methanol, ethanol, isopropanol, etc.), lower ketones (acetone, etc.), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.) to precipitate and thus to easily isolate and easy to clean crystals . It has proven to be particularly advantageous to add the desired base already during the complex formation of the reaction mixture and thereby to save one process step.

If the acidic complex compounds 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 complex-forming acid in aqueous suspension or solution with the oxide or salt of the element providing the central ion and half of the amount of an organic base required for neutralization, isolating the complex salt formed, purifying it if desired and then to complete it Neutralization with the required amount of organic base added. The order of base addition can also be reversed.

The invention further relates to agents which contain at least one of the compounds according to the invention. The invention further relates to a process for the preparation of these agents, which is characterized in that the paramagnetic complex salt dissolved in water is brought into a form suitable for enteral or parenteral administration with the additives and stabilizers customary in galenics, so that the complex salt is present in a concentration of 1 to 1500 mmol / 1, preferably in a concentration of 10 - 1000 mmol / 1. The halogen content of the solutions is usually in the range between 10-400 mg / ml. The resulting agents are then sterilized if desired. Depending on the halogen content and the diagnostic question, they are usually applied in a dose of 1-300 ml.

Suitable additives are, for example, physiologically harmless buffers (such as tromethamine), minor additions of complexing agents (such as diethylenetriaminepentaacetic acid) or, if necessary, electrolytes such as. B. sodium chloride or, if necessary, antioxidants such as. B. ascorbic acid.

If suspensions or solutions of the agents according to the invention in water or physiological saline are desired for enteral administration or other purposes, they are mixed with one or more adjuvants common in galenics (e.g. methyl cellulose, lactose, mannitol) and / or surfactants (e.g. B. lecithins, Tweens ^® , Myrj ^® and / or flavoring agents for flavor correction (z. B. essential oils) mixed.

In principle, it is also possible to produce the diagnostic agents 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. The final security is cleaning the isolated complex salt.

Further objects of the invention are characterized by the claims. 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, which is necessary to maintain the non-invasive character of the examinations, high effectiveness, which is necessary to burden the body with the smallest possible amount of foreign substances, - good water solubility (This allows to produce highly concentrated solutions, which are particularly necessary for the use as X-ray contrast media. This means that the volume of the circulatory system can be kept within reasonable limits.), low viscosity, - low osmolality, favorable excretion kinetics.

Furthermore, the agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that a release or an exchange of the ions which are not covalently bound in the complexes - in themselves toxic - within the time in which the new contrast medium are completely excreted, did not occur.

In addition to the high water solubility, which, surprisingly, in the presence of paramagnetic metal ions in one required for X-ray diagnostics

Range, the compounds according to the invention have a positive effect in X-ray diagnostics in that the complex compounds according to the invention surprisingly permit examinations with short-wave X-rays than is possible with conventional contrast agents, which significantly reduces the radiation exposure of the patient, as is known to be soft radiation from the tissue is absorbed much more strongly than hard (R. Felix, Das Röntgenbild; Thieme Stuttgart 1980).

Because of the favorable absorption properties of the contrast agents according to the invention in the area of hard X-rays, the agents are also particularly suitable for digital subtraction techniques (which work with higher tube voltages). Of particular note is the favorable in vivo distribution behavior of the agents according to the invention. For the first time, this allows x-rays of high diagnostic value to be taken in the area of the liver with a dose that is usual for x-ray contrast media (halogen content: 50 - 400 mg / ml; dose 0.1 - 1 ml / kg body weight).

The complexes according to the invention thus result in an optimal contrast of the liver even at a dose of 0.5 mmol / kg. Figure 1 top picture shows the liver of a rat before administration of the contrast agent. The lower picture shows the liver of the same rat 10 minutes after injection of 0.5 mmol / kg of the compound according to the invention prepared according to Example ld).

A picture taken under otherwise identical conditions after administration of the same dose of the disodium salt of the gadolinium complex of (4s) 4- (4-ethoxybenzyl) -3, 6, 9-tris (carboxylatomethyl) -3, 6, 9-triazaundecanedioic acid (EP 0 405 704 ; Example 8c) shows no diagnostically usable contrasting of the liver (see Fig. 2 bottom picture). The picture above shows the liver before contrast medium administration.

FIG. 3 shows in comparison the increase in density (which can be regarded as a measure of the effectiveness of a contrast agent) as a function of time, for a compound according to the invention (example Id) and a compound of EP 0 405 704 (example 8c). Thereafter, significantly higher density values are observed in the rat liver over the entire investigation period for the compound according to the invention. For example, the maximum values for the substance according to the invention are 60 Houndsfield units (HU) for the comparison substance, but only 15 HU. The tests were carried out on a Somatom plus VD31 (test parameters: layer thickness = 2 mm, tube voltage / current = 120 kV / 290mA) on female rats (body weight = 200 - 280 g) after intravenous injection of 0.5 mmol / kg of the respective substance performed.

The complexes described in WO 93/16375 also show none for one

Imaging sufficient accumulation in the liver.

Thus, the gadolinium complex of 1,13-bis- [5- (propion-3-ylamido) -2,4,6-triiodoisophthalic acid bis- (2-hydroxy-l-hydroxymethylethyl) isomeric to example 1 of WO 93/16375 was -diamide] -4,7, 10-tris- (carboxymethyl) - (2, 12-dioxo) -l, 4,7,10, 13-pentatriazadecans (Example 17 b) almost completely excreted via the kidney. Only 1.3% of the total was eliminated from the body in other ways. Even assuming that this 1.3% of the complex is complete accumulated in the liver, this amount would be far below the dose required for an imaging effect.

These investigations were carried out on female rats (90-110 g body weight) after intravenous administration of 0.27 mmol / kg of the compound 17 b). The iodine concentration in blood, urine, feces, as well as liver, kidney, spleen, bone was measured with the X-ray fluorescence analysis. In addition, the

Gadolinium concentrations determined using ICP atomic emission spectroscopy. The half-life of 0.32 hours and the volume of distribution show a distribution in the extracellular space with renal excretion through glomerular filtration through the kidney.

The agents according to the invention, which contain a paramagnetic metal ion of an element of order numbers 21-29, 42, 44 or 57-70 in the complex, can be used in NMR diagnostics as well as in X-ray diagnostics. This dual character opens up further areas of application. Thus, these agents according to the invention are always to be used with advantage when a combination of X-ray and NMR diagnostics is required for the differentiated representation and reliable determination of certain diseases. This applies e.g. too for suspected recurrence after tumor surgery or radiation therapy. In these cases, the patient is spared the additional burden of double application by using a contrast agent that is equally suitable for both techniques.

Overall, the complex compounds mentioned have opened up new possibilities in diagnostic medicine.

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

For example

Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) - 4- [4- (2, 4, 6-triiodobenzyloxy) benzyl] undecanedioic acid

a) Preparation of 2, 4, 6-triiodobenzyl chloride

41.6 g (80.1 mmol) of 3-amino-2,4,6-triiodobenzyl chloride (Collection Czechoslov. Chem. Commun. [Vol. 41] 1976) are suspended in 416 ml of glacial acetic acid and added with a suspension of 6.08 g (88.1 mmol) of sodium nitrite in 40 ml of concentrated sulfuric acid. The reaction temperature is kept at 25 ° C. by cooling. After 30 minutes, the reaction mixture is added to a suspension of 12 g of copper powder in 416 ml of methanol and stirred at room temperature until the evolution of nitrogen has ended. The suspension is then cooled to 10 ° C., filtered, the residue is stirred for 30 minutes with 300 ml of N, N-dimethylformamide and the suspension is filtered. The filtrate is evaporated in vacuo, the residue is stirred with water, filtered off and dried in vacuo. The crude product is stirred in hot acetonitrile with activated carbon, then it is filtered and the filtrate is cooled to 0 ° C., whereby a precipitate forms. This is suctioned off and dried in vacuo.

Yield: 29.8 g (73.8%) light beige solid

Analysis (based on solvent-free substance): calc .: C 16.67 H 0.80 Cl 7.03 1 75.50 found: C 16.82 H 0.95 Cl 7.14 1 75.41

b) 3, 6, 9-triaza-3, 6, 9-tris- (tert-butoxycarbonylmethyl) -4- [4- (2, 4, 6-triiodobenzyloxy) -benzyl] -undecanedioic acid di-tert-butyl ester

15.6 g (20.0 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-hydroxy-benzyl) -undecanedioic acid di-tert-butyl ester (Example 9f of DE 3710730) are mixed in tetrahydrofuran at 0 ° C with 660 mg (22.0 mmol) of 80% sodium hydride suspension in mineral oil. 12.4 g (22.0 mmol) of the 2,4,6-triiodobenzyl chloride prepared according to Example la) are added and the mixture is stirred for 3 hours. Then the solution is mixed with water, tetrahydrofuran is distilled off and the aqueous emulsion is extracted with diethyl ether. The organic phase is washed with water, dried over Na ₂ SÜ ₄ and concentrated. The residue is on silica gel 60 (Merck) with

Chromatograph hexane / methyl acetate / triethylamine, the product fractions are evaporated and dried in vacuo. Yield: 22.8 g (91.2% of theory) of a yellowish oil

Analysis (based on solvent-free substance): calc .: C 46.20 H 5.82 1 30.51 N 3.37 O 14.10 found: C 46.37 H 5.93 I 30.44 N 3.35

c) 3, 6, 9-Triaza-3, 6, 9-tris- (carboxymethyl) -4- [4- (2, 4, 6-triiodobenzyloxy) -benzyl] - undecanedioic acid

22.8 g (18.3 mmol) of the tert-butyl ester described in Example 1b) are dissolved in 250 ml of trifluoroacetic acid and stirred at room temperature for 1 hour. Then the solution is mixed with tert-butyl methyl ether, the precipitate is filtered off with suction, washed with tert-butyl methyl ether at 40 ° C. in vacuo and dried over phosphorus pentoxide. The crude product is stirred in water, filtered off and dried in vacuo. Yield: 15.4 g (86.8% of theory) of a light beige solid

Analysis (based on anhydrous substance): calculated: C 34.77 H 3.33 1 39.36 N 4.34 0 18.19 found: C 34.63 H 3.56 1 39.28 N 4.38

d) Gadolinium complex of the disodium salt of 3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- [4- (2,4,6-triiodobenzyloxy) benzyl] undecanedioic acid

A suspension of 11.8 g (12.2 mmol) of the penta acid prepared according to Example lc) in 118 ml of water is mixed with 2.21 g (6.1 mmol) of gadolinium oxide and stirred at 80 ° C. for 2 hours. Then 24.4 ml of normal sodium hydroxide solution are added with a microburette and the mixture is stirred for 1 hour. The solution is then stirred at 80 ° C. for 2 hours after the addition of 0.5 g of activated carbon and filtered. After freeze-drying, the filtrate gives a colorless solid. Yield 13.1 g (91.8% of theory) Analysis' (based on anhydrous substance): calc .: C 28.86 H 2.34 1 32.67 N 3.61 O 15.10 Gd 13.49 Na 3.95 found: C 28.66 H 2.43 1 32.70 N 3.49 Gd 13.28 Na 4.16

Example 2

Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) - 4- [4- (N-acetyl-3-methylamino-2,4,6-triiodobenzyloxy) benzyl] - undecanedioic acid

a) N-Acetyl-3-methylamino-2, 4, 6-trüodbenzylchloήd

42.5 g (79.7 mmol) of 3-methylamino-2,4,6-triiodobenzyl chloride (Collection Czechoslov. Chem. Commun. [Vol. 41] 1976) are dissolved in 180 ml of N, N-dimethylacetamide and added dropwise with ice cooling 13.7 ml (191.3 mmol) of acetyl chloride were added. After stirring for 30 minutes at approx. 0 ° C., the mixture is stirred at room temperature for 12 hours and the dark brown solution is introduced into water while stirring. A precipitate precipitates, which is filtered off with suction and dried in vacuo. Yield: 44.6 g (99.6% of theory) of a light beige solid

Analysis (based on anhydrous substance): calculated: C 20.88 H 1.58 Cl 6.16 1 66.17 N 2.43 0 2.78 found: C 20.98 H 1.69 Cl 6.04 1 66.18 N 2.52

b) 3, 6, 9-triaza-3, 6, 9-tris- (tert-butoxycarbonylmethyl) -4- [4- (N-acetyl-3-methylamino-2, 4, 6-triiodobenzyloxy) benzyl] -undecanedioic acid di-tert. butyl diester

15.6 g (20.0 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) - 4- (4-hydroxybenzyl) -undecanedioic acid di-tert-butyl ester ( Example 9f of DE 3710730) are mixed in tetrahydrofuran at 0 ° C with 660 mg (22.0 mmol) of 80% sodium hydride suspension in mineral oil. 12.66 g (22.0 mmol) of the compound prepared according to Example 2a) are added and the mixture is stirred for 3 hours. Then the solution is mixed with water, tetrahydrofuran is distilled off and the aqueous emulsion is extracted with diethyl ether. The organic phase is washed with water, dried over Na2S04 and concentrated. The residue is chromatographed on silica gel 60 (Merck) with hexane / methyl acetate / triethylamine, the product fractions are evaporated and dried in vacuo. Yield: 23.5 g (89.2% of theory) of a yellowish oil

Analysis (based on solvent-free substance): calculated: C 46.45 H 5.89 1 28.87 N 4.25 0 18.49 found: C 46.63 H 5.96 1 28.72 N 4.18

c) 3, 6, 9-Triaza-3, 6, 9-tris (carboxymethyl) -4- [4- (N-acetyl-3-methylamino-2, 4, 6-truodbenzyloxy) benzyl] undecanedioic acid

21.9 g (16.6 mmol) of the tert-butyl ester described in Example 2b) are dissolved in 250 ml of trifluoroacetic acid and stirred at room temperature for 1 hour. Then the solution is mixed with diethyl ether; the precipitate is filtered off, washed with diethyl ether and dried at 40 ° C in a vacuum over phosphorus pentoxide. The crude product is stirred in water, filtered off and dried in vacuo. Yield: 16.2 g (94.1% of theory) of a light beige solid

Analysis (based on anhydrous substance): calc .: C 35.86 H 3.59 1 36.67 N 5.40 0 18.49 found: C 35.73 H 3.75 1 36.81 N 5.41

d) Gadolinium complex of the disodium salt of 3, 6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -4- [4- (N-acetyl-3-methylamino-2,4,6-trüodbenzyloxy) -benzyl] - undecanedioic acid

A suspension of 14.8 g (14.3 mmol) of the penta acid prepared according to Example 2 c) in 150 ml of water is mixed with 2.58 g (7.13 mmol) of gadolinium oxide and stirred at 80 ° C. for two hours. 28.5 ml of normal sodium hydroxide solution are then added with a microburette and the mixture is stirred for one hour. The solution is then stirred at 80 ° C. for two hours after the addition of 0.8 g of activated carbon and filtered. After evaporation, the filtrate gave a colorless solid. Yield: 16.4 g (93.3% of theory)

Analysis (based on anhydrous substance): calc .: C 30.11 H 2.61 1 30.79 N 4.53 0 15.53 Gd 12.72 Na 3.72 found: C 30.00 H 2.82 1 30.58 N 4.67 Gd 12.79 Na 3.82 Example 3

Gadolinium complex of the trisodium salt of 3,6,9-tria∑a-3,6,9-tris- (carboxymethyl) - {4-jΗ- (3-carboxypropionyl) -3-methylamino-2,4,6-triiodobenzyloxy] - benzyl} - undecanedioic acid

a) N- (5-Oxa-l, 4-dioxoheptyl) -3-methylamino-2, 4, 6-triiodobenzylchloride

To a suspension stirred under exclusion of moisture, 53.3 g (100 mmol) of 3-methylamino-2,4,6-triiodobenzyl chloride (Collection Czechoslov. Chem. Commun. [Vol. 41] 1976) in 200 ml of anhydrous dioxane are added to 24.7 g (150 mmol) succinic acid monoethyl ester added at room temperature. The batch is refluxed for several hours until, according to thin layer chromatography, no educt can be detected; then it is evaporated, the residue is taken up in dichloromethane and extracted with saturated aqueous sodium bicarbonate solution. After drying over anhydrous magnesium sulfate, the organic phase is evaporated and the residue is recrystallized from ethyl acetate / tert-butyl methyl ether. Yield: 58.4 g (88.3% of theory) of a colorless solid

Analysis (based on solvent-free substance): calc .: C 25.42 H 2.29 Cl 5.36 1 57.56 N 2.12 0 7.26 found: C 25.31 H 2.49 Cl 5.43 1 57.50 N 2.17

b) 3, 6, 9-Triaza-3, 6, 9-tris- (tert-butoxycarbonylmethyl) -4- {4- [N- (5-oxa-l, 4-dioxoheptyl) -3-methylamino -2,4,6-triiodobenzyloxy] benzyl} undecanedioic acid

15.6 g (20.0 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) - 4- (4-hydroxybenzyl) -undecanedioic acid di-tert-butyl ester ( Example 9f of DE 3710730) are mixed in tetrahydrofuran at 0 ° C with 660 mg (22.0 mmol) of 80% sodium hydride suspension in mineral oil. 14.55 g (22.0 mmol) of the compound prepared according to Example 3a) are added and the mixture is stirred for 3 hours. Then water is added to the solution. Tetrahydrofuran distilled off and the aqueous emulsion extracted with diethyl ether. The organic phase is washed with water, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel 60 (Merck) with hexane / ethyl acetate / triethylamine, the product fractions are evaporated and dried in vacuo. Yield: 22.9 g (81.6% of theory) of a yellowish oil

Analysis (based on solvent-free substance): calc .: C 47.02 H 5.95 1 27.10 N 3.99 0 15.94 found: C 46.86 H 6.13 1 26.98 N 3.84

c) 3, 6, 9-Triaza-3, 6, 9-tris- (carboxymethyl) - {4- [N- (3-carboxypropionyl) -3-methylamino-2, 4, 6-trüodbenzyloxy] -ben∑yl } -undecanedioic acid

20.4 g (14.5 mmol) of the hexaester described in Example 3b) are dissolved in 100 ml of methanol and 87 ml of 2N sodium hydroxide solution are added. The mixture is boiled under reflux for about 2 hours, the methanol is stripped off in vacuo and, after addition of 100 ml of water, the mixture is stirred at 60 ° C. for a further 2 hours. By adjusting pH 1 - 2 with semi-concentrated hydrochloric acid, a colorless precipitate is formed, which is filtered off with suction and dried in vacuo. Yield: 15.3 g (96.0% of theory) of a colorless solid

Analysis (based on anhydrous substance): calc .: C 36.15 H 3.59 1 34.72 N 5, l 10 20.43 found: C 36.23 H 3.65 1 34.58 N 5.05

d) Gadolinium complex of the trisodium salt of 3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) - {4- [N- (3-carboxypropionyl) -3-methylamino-2,4,6-trüodbenzyloxyj- benzylj-undecanedioic acid

A suspension of 14.1 g (12.9 mmol) of the hexacid prepared according to Example 3c) in 150 ml of water is mixed with 2.33 g (6.43 mmol) of gadolinium oxide and stirred at 80 ° C. for 2 hours. Then 38.6 ml of normal sodium hydroxide solution are added with a microburette and the mixture is stirred for 1 hour. The solution is then stirred at 80 ° C. for 2 hours after the addition of 0.8 g of activated carbon and filtered. The filtrate, after freeze-drying, gave a colorless solid. Yield: 16.3 g (96.4% of theory)

Analysis (based on anhydrous substance): calc .: C 30.11 H 2.53 1 28.92 N 4.26 O 17.01 Gd 11.94 Na 5.24 found: C 30.01 H 2.64 1 28.88 N 4.34 Gd 11.86 Na 5.02 Example 4

Gadolinium complex of 3, 6,9-triaza-3, 6,9-tris- (carboxymethyl) -4- (3,5-diiodo-4-ethoxybenzyl) -undecanedioic acid, disodium salt

a) 3, 6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -4- (4-hydroxyben∑yl) -undecanedioic acid

7.8 g (10 mmol) of 3,6,9-tria-za-3,6,9-tris- (tert-butoxycarbonylmethyl) - 4- (4-hydroxybenzyl) -undecanedioic acid di-tert-butyl ester ( Example 9f of DE 3710730) are dissolved in 100 ml of trifluoroacetic acid and stirred for 1.5 hours at room temperature. The mixture is then diluted with diethyl ether and the precipitate is filtered off with suction. It is washed with diethyl ether and dried at 50 ° C in a vacuum. The crude product is dissolved in water and treated with activated carbon. The filtered solution is lyophilized several times to remove residual trifluoroacetic acid. Yield: 4.0 g (80.1% of theory) of colorless lyophilisate.

Elemental analysis (taking into account the solvent content): calc .: C 50.50 H 5.85 N 8.41 0 35.24 found: C 50.68 H 5.99 N 8.25

b) 3, 6, 9-Tria∑a-3, 6, 9-tris- (carboxymethyl) -4- (3, 5-diiod-4-hydroxybenzyl) - undecanedioic acid

3.2 g (6.4 mmol) of the phenol from Example 4a) are suspended in 50 ml of water and solid sodium hydroxide is added to the neutral point. The mixture is stirred at 50 ° C. and 5.7 ml (14.1 mmol) of a 40% hydrochloric acid iodine monochloride solution are added dropwise. After 20 hours at 50 ° C, the excess iodine is reduced with sodium disulfite, the precipitate is suction filtered and washed with water. Yield: 4.15 g (86% of theory) of a pale yellow solid

Elemental analysis (taking into account the solvent content): calc .: C 33.57 H 3.62 1 33.78 N 5.59 0 23.43 found: C 33.71 H 3.86 1 33.41 N 5.65 c) 3, (S, 9-Triaza-3, 6, 9-tris- (carboxymethyl) -4- (3, 5-diiod-4-ethoxybenzyl) - undecanedioic acid

3.0 g (4 mmol) of the diiodophenol from Example 4b) are mixed with 0.792 g (26.4 mmol) of 80% sodium hydride suspension in mineral oil in 25 ml of anhydrous tetrahydrofuran. 4.1 g (26.4 mmol) of ethyl iodide are added to this suspension and the reaction mixture is stirred for 6 hours at room temperature. 30 ml of 2N sodium hydroxide solution are then added, the mixture is evaporated to dryness and the residue is taken up in water. The aqueous solution is acidified with concentrated hydrochloric acid, the precipitate is filtered off with suction and washed with water. The crude product is recrystallized from ethanol for purification. Yield: 2.35 g (75.4% of theory) of colorless crystals.

Elemental analysis (taking into account the solvent content): calc .: C 35.45 H 4.01 1 32.57 N 5.39 0 22.58 found: C 35.59 H 3.94 1 32.39 N 5.23

d) Gadolinium complex of 3, 6, 9-Tria∑a-3, 6, 9-tris- (carboxymethyl) -4- (3, 5-diiodo-4-ethoxybenzyl) -undecanedioic acid

1.75 g (2.2 mmol) of the pentacarboxylic acid from Example 4c) are suspended in 55 ml of water and 407 mg (1.1 mmol) of gadolinium oxide are added at 60.degree. After 4 hours, the clear solution is treated with activated carbon. Then finely filtered through a cellulose membrane filter (0.2 mm, Sartorius) and freeze-dried. Yield: 1.95 g (94.9% of theory) of colorless lyophilisate.

Elemental analysis (taking into account the solvent content): calc .: C 29.59 H 3.02 Gd 16.84 1 27.19 0 18.85 found: C 29.64 H 3.25 Gd 16.66 1 26.93

e) Gadolinium complex of 3, 6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -4- (3, 5-diiodo-4-ethoxyben∑yl) -undecanedioic acid, disodium salt

1.5 g (1.6 mmol) of the complex described in the previous example are dissolved in 120 ml of water and 3.2 ml of a normal solution using a microburette Sodium hydroxide solution added. After freeze-drying, the disodium salt is obtained as a colorless one

Lyophilisate.

Yield: 1.55 g (99% of theory) of colorless lyophilisate.

Elemental analysis (taking into account the solvent content): calc .: C 28.26 H 2.68 Gd 16.09 1 25.96 N 4.30 Na 4.70 0 18.00 found: C 28.03 H 2.91 Gd 15.86 1 25.72 N 4.09 Na 4.45

Example 5

Gadolinium complex of the disodium salt of 4- (N-acetyl-3-methylamino

2, 4, 6-triiodobenzyloxymethyl) -3, 6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -undecanedioic acid

a) N-Acetyl-N-methyl-3 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxymethyl] - 2,4,6-triiodaniline

20.0 g (36.3 mmol) of the compound prepared in Example 2a), 5.8 g (43.6 mmol) of 2,3-0-isopropylidene glycerol, 0.41 g (1.8 mmol) of N-benzyl N, N, N-triethylamonium chloride and 4.1 g (72.7 mmol) of ground potassium hydroxide are refluxed in 35 ml of toluene for 6 hours. The organic phase is then separated off, shaken out with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After filtering and evaporating the filtrate, an oily residue is obtained which is chromatographed on silica gel using toluene / ethyl acetate. Evaporation of the product fractions gives a colorless oil, which is dried in vacuo. Yield: 21.3 g (87.2% of theory)

Analysis (based on solvent-free substance) calc .: C 28.64 H 3.00 1 56.73 N 2.09 O 9.54 found: C 28.60 H 3.09 1 56.72 N 2, l l

b) N-Acetyl-N-methyl-3 - [(2, 3-dϊhydroxypropyloxy) methyl] -2, 4, 6-truodaniline

20.2 g (30.1 mmol) of the compound prepared according to Example 5a) are combined in one

Mixture of 60 ml of ethanol and 10 ml of concentrated sulfuric acid entered. After stirring for 12 hours at 30 ° C., the mixture is taken up in dichloromethane and the organic phase is extracted once with concentrated sodium chloride solution and twice with concentrated sodium hydrogen carbonate solution. The organic phase is dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is chromatographed on silica gel 60 (Merck) with dichloromethane / methanol. After evaporating the product fractions, a colorless oil is obtained which is dried in vacuo. Yield: 16.9 g (89.2% of theory)

Analysis (based on solvent-free substance) calc .: C 24.75 H 2.56 1 60.34 N 2.22 0 10.14 found: C 24.86 H 2.69 1 60.12 N 2.34

c) N-Acetyl-N-methyl-3 - [(3-benzoyloxy-2-hydroxypropyloxy) methyl] -2, 4.6-triiodaniline

15.2 g (24.1 mmol) of the compound prepared in Example 5b) are stirred in 150 ml of dichloromethane under argon and first with 4.0 ml (28.9 mmol) of triethylamine, then at 0 ° C. dropwise with 3.47 g (26.5 mmol) of benzoyl cyanide are added. After stirring for 12 hours at 0 ° C., the mixture is diluted with dichloromethane and shaken out against saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and evaporated and the residue is chromatographed on silica gel 60 (Merck) with dichloromethane / methanol. After evaporation, the product fractions result in a colorless oil. Yield: 13.9 g (78.4% of theory)

Analysis (based on solvent-free substance) calc .: C 32.68 H 2.74 1 51.79 N 1.91 0 10.88 found: C 32.54 H 2.88 1 51.83 N 1.74

d) N-Acetyl-N-methyl-3 - [(3-benzoyloxy-2-methanesulfonyloxypropyloxy) methylj-2,4,6-triiodaniline

13.4 g (18.2 mmol) of the compound prepared in Example 5c) are stirred in 80 ml of dichloromethane under argon and first with 3.0 ml (21.9 mmol) of triethylamine. then 1.56 ml (20.1 mmol) of methanesulfonic acid chloride were added dropwise at 0 ° C. The reaction temperature is allowed to rise to room temperature within 3 hours and then shaken out against saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and evaporated. The oily residue is chromatographed on silica gel 60 (Merck) with dichloromethane, the product fractions are evaporated and the residue is dried in vacuo. Yield: 12.8 g (86.2% of theory) of yellowish foam

Analysis (based on solvent-free substance) calc .: C 31.02 H 2.73 1 46.82 N 1.72 0 13.77 S 3.94 found: C 31.20 H 2.89 1 46.67 N 1.83 S 4.02

e) N-Acetyl-N-methyl-3 - [(3-benzoyloxy-2-azidopropyloxy) methyl] -2, 4, 6-triiodaniline

11.8 g (14.5 mmol) of the compound prepared in Example 5d) are stirred in 50 ml of N, N-dimethylformamide together with 2.83 g (43.5 mmol) of sodium azide at 85 ° C. under argon for one hour. Then it is evaporated in vacuo and the residue is shaken out with dichloromethane / saturated sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulfate, filtered and evaporated in vacuo. Yield: 10.2 g (92.1% of theory) of yellowish foam

Analysis (based on solvent-free substance) calc .: C 31.60 H 2.52 1 50.09 N 7.37 0 8.42 found: C 31.59 H 2.63 1 49.87 N 7.49

f) N-Acetyl-N-methyl-3 - [(2-azido-3-hydroxypropyloxy) methylJ-2,4,6-triiodaniline

9.58 g (12.6 mmol) of the compound prepared according to Example 5e) are dissolved in 60 ml of methanol. After adding 40 ml of 2N sodium hydroxide solution, the mixture is stirred for one hour at a bath temperature of 50 ° C. and, after cooling, neutralized with 2N hydrochloric acid. The methanol is stripped off in vacuo and the residue is partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered, evaporated, the residue is chromatographed on silica gel 60 (Merck) and the product fractions are evaporated in vacuo. Yield: 7.47 g (90.3% of theory) Analysis' (based on solvent-free substance): calc .: C 23.80 H 2.31 1 58.04 N 8.54 0 7.32 found: C 23.92 H 2.50 1 57.85 N 8, 6

g) N-Acetyl-N-methyl-3 - [(2-azido-3-methanesulfonyloxypropyloxy) methylJ- 2,4,6-triiodaniline

7.22 g (11.0 mmol) of the hydroxy compound prepared according to Example 5f) are converted to the corresponding mesylate under the conditions described in Example 5d). Yield: 7.46 g (92.4% of theory)

Analysis (based on solvent-free substance): calc .: C 22.91 H 2.33 1 51.86 N 7.63 0 10.90 S 4.37 found: C 23.01 H 2.58 1 51.63 N 7.75 S 4.49

h) N-A cetyl-N-methyl-3- (6, 9-diaza-4-azido-2-oxanonyl) -2, 4, 6-triiodaniline, dihydrochloride

7.21 g (9.82 mmol) of the mesylate described in Example 5 g) are dissolved in 50 ml of methanol and, after addition of 150 ml of 1,2-diaminoethane, stirred for 15 hours at room temperature. The mixture is then evaporated and partitioned between dichloromethane and saturated sodium bicarbonate solution. The aqueous phase is extracted several times with dichloromethane, the combined organic phases are dried over sodium sulfate, filtered and evaporated. The residue is taken up in tert-butyl methyl ether / methanol and the pH is adjusted to 2 with concentrated hydrochloric acid, a colorless precipitate being formed. This is separated off and dried in vacuo. Yield: 7.33 g (96.8% of theory)

Analysis (based on solvent-free substance): calc .: C 23.37 H 3.01 1 49.38 N 10.90 0 4.15 Cl 9.20 found: C 23.28 H 3.22 1 49.39 N 11.02 Cl 9.37 i) N-acetyl-N-methyl-3- (4-amino-6, 9-diaza-2-oxanonyl) -2, 4, 6-triiodaniline, trihydrochloride

7.04 g (9.13 mmol) of the dihydrochloride prepared in Example 5h) are taken up in 70 ml of a 4: 1 mixture of dioxane / water and 12.0 g (45.7 mmol) of triphenylphosphine are added. The mixture is stirred for 3 days at room temperature under argon, the organic solvent is evaporated and the precipitate is filtered off. The precipitate is washed with 2N hydrochloric acid; the combined filtrates are evaporated and the residue is recrystallized from methanol / tert-butyl methyl ether.

Yield: 6.12 g (85.8% of theory)

Analysis (based on solvent-free substance): calc .: C 23.05 H 3.35 1 48.72 N 7.17 0 4.10 Cl 13.61 found: C 23.28 H 3.60 1 48.49 N 7.43 Cl 13.88

j) 4- (N-acetyl-3-methylamino-2, 4, 6-triiodobenzyloxymethyl) -3, 6, 9-tris (tert-butyloxycarbonylmethyl) -3, 6, 9-triazaundecanedioic acid di-tert. -butyl ester

5.98 g (7.65 mmol) of the trihydrochloride prepared in Example 5i) are stirred in 60 ml of N, N-dimethylformamide under argon at room temperature and mixed with 10.6 g (76.5 mmol) of potassium carbonate and 7.46 g ( 38.3 mmol) of tert-butyl bromoacetate were added. After stirring for 12 hours, the mixture is filtered, evaporated in vacuo and the residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered, evaporated and the residue is chromatographed on silica gel 60 (Merck) with hexane / ethyl acetate. After evaporating the product fractions, a yellowish oil is obtained. Yield: 8.94 g (98.5% of theory)

Analysis (based on solvent-free substance): calculated: C 41.50 H 5.52 1 32.08 N 4.72 0 16.18 found: C 41.52 H 5.73 1 31.96 N 4.68 k) 4- (N-acetyl-3-methylamino-2, 4, 6-triiodobenzyloxymethyl) -3, 6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -undecanedioic acid

8.50 g (7.16 mmol) of the pentaester shown in Example 5j) are converted into the corresponding penta acid under the conditions described in Example 1c). Yield: 5.80 g (84.1% of theory) of a light beige solid

Analysis (based on anhydrous substance): calculated: C 31.20 H 3.46 1 39.56 N 5.82 0 19.95 found: C 31.25 H 3.66 1 39.42 N 5.83

1) Gadolinium complex of the disodium salt of 4- (N-acetyl-3-methylamino-2, 4, 6-triiodobenzyloxymethyl] -3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) - undecanedioic acid

5.69 g (6.19 mmol) of the pentic acid prepared in Example 5k) are complexed with gadolinium oxide under the conditions described in Example ID) and converted into the corresponding disodium salt. Yield: 6.81 g (94.8% of theory) of colorless lyophilisate

Analysis (based on anhydrous substance): calculated: C 25.88 H 2.43 1 32.81 N 4.83 0 16.55 Gd 13.55 Na 3.96 found: C 25.94 H 2.61 1 32.78 N 4.85 Gd 13.44 Na 4.00

Example 6

1, 19-bis- (3-carboxy-2, 4, 6-trüodphenyl) -7, 10, 13-tris (carboxymethyl) - 2.5, 15, 18-tetraoxo-l, 4, 7, 10, 13, 16,19-heptaazanonadecan, gadolinium complex, disodium salt

a) 1, 19-bis (3-carboxy-2, 4, 6-triiodophenyl) - 7, 10, 13-tris (carboxymethyl) - 2, 5,15,18-tetraoxo-l, 4, 7, 10,13,16,19-heptaazanonadecane

11.42 g (20 mmol) of 3-glycylamino-2,4,6-triiodobenzoic acid (DE 2523567) are dissolved with heating in 60 ml of N, N-dimethylformamide. 6.9 ml of triethylamine and 3.6 g (10 mmol) of N, N-bis- [2,6-dioxomorpholino) ethyl] - are added at room temperature. glycine and the reaction mixture is stirred for 15 hours at room temperature. The mixture is then evaporated to dryness, the residue is taken up in water and acidified with concentrated hydrochloric acid. The precipitate is filtered off and washed with water. The crude product is purified by chromatography on RP 18 silica gel.

Yield: 9.5 g (63% of theory) of a colorless solid.

Elemental analysis (taking into account the solvent content): calc .: C 25.60 H 2.22 1 50.73 N 6.53 0 13.18 found: C 25.53 H 2.35 1 50.52 N 6.29

b) l, 19-bis (3-carboxy-2,4,6-triiodophenyl) -7,10,13-tris- (carboxymethyl) -

2,5,15, 18-tetraoxo-l, 4, 7, 10,13,16, 19-heptaazanonadecane, gadolinium complex, disodium salt

7.2 g (48 mmol) of the ligand from Example 6a) are suspended in 50 ml of water and 1.74 g (4.8 mmol) of gadolinium oxide are added in portions at 50-60 ° C. After complete complexation, the pH is adjusted to seven with sodium hydroxide solution, and the aqueous solution is filtered and freeze-dried. Yield: 7.6 g (93% of theory) of colorless lyophilisate.

Elemental analysis (taking into account the solvent content): calc .: C 22.62 H 1.66 Gd 9.25 1 44.81 N 5.77 Na 2.71 0 13.18 found: C 22.43 H 1.85 Gd 9.07 1 44.71 N 5.63 Na 2.49

Example 7

1, 19-bis- {3 - [(10-carboxydecyl) carbamoyl] -2, 4, 6-triiodophenyl} -7, 10, 13-tris (carboxymethyl) -2,5, 15, 18-tetraoxo -1,4,7,10,13,16,19-heptaazanonadecane, gadolinium complex, disodium salt

a) (3-Aminoacetylamido) -N- (10-carboxydecyl) -2, 4, 6-trüodbenzoic acid amide

10.9 g (15 mmol) 3-phthalimidoacetylamino-2,4,6-triiodobenzoic acid chloride

(DE 2523567) are dissolved in 60 ml of N, N-dimethylacetamide and at 80 ° C. with 1.98 g

(16 mmol) 11-aminoundecanoic acid reacted. The reaction mixture is stirred for 32 hours at this temperature and then filtered off from the hydrochloride. The filtrate is evaporated to dryness, the residue is suspended in 40 ml of water and reacted with 4.5 g (90 mmol) of hydrazine hydrate. After stirring at 65 ° C. for three hours, the reaction mixture is allowed to cool and the precipitate which has precipitated is filtered off with suction. The product is washed with plenty of water and the solid is dried at 50 ° C. in vacuo. Yield: 9.8 g (87% of theory) of pale yellow crystals.

Elemental analysis (taking into account the solvent content): calc .: C 34.73 H 4.05 1 40.77 N 6.75 0 13.71 found: C 34.90 H 3.92 1 40.68 N 6.51

b) l, 19-bis- {3 - [(10-carboxydecyl) carbamoyl] -2,4,6-trüodphenyl} -7,10,13-tris (carboxymethyl) -2,5, 15, 18- tetraoxo-l, 4, 7, 10, 13, 16, 19-heptaazanonadecane

8.75 g (11.6 mmol) of the amine from Example 7a) are analogous to Example 6a) with 2.14 g (6 mmol) of N, N-bis- [2- (2,6-dioxomorpholino) ethyl] implemented glycine and purified in a similar manner on a column chromatography on RP 18. Yield: 17.4 g (80% of theory) of a pale yellow solid.

Elemental analysis (taking into account the solvent content): calc.: C 34.73 H 4.05 1 40.77 N 6.75 0 13.71 found: C 34.90 H 3.92 1 40.68 N 6.51

c) 1, 19-bis- {3 - [(10-carboxydecyl) carbamoyl] -2,4,6-trüodphenyl} -7,10,13-tris (carboxymethyl) -2,5,15,18- tetraoxo-l, 4, 7,10,13,16,19-heptaazanonadecane, gadolinium complex, disodium salt

15 g (8 mmol) of the ligand from Example 7b) are made according to Example 6b) with 2.9 g

(8 mmol) gadolinium oxide complexed and converted into the disodium salt with 1N sodium hydroxide solution.

Yield: 15.6 g (95% of theory) of colorless lyophilisate. Elemental analysis (taking into account the solvent content): calc .: C 31.40 H 3.42 Gd 7.61 1 36.86 N 6.10 Na 2.23 0 12.39 found: C 31.28 H 3.63 Gd 7.56 1 36.61 N 5.89 Na 1.97

Example 8

Gadolinium complex of the disodium salt of 4- (3-acetylamino-2,4,6-triiodobenzoylaminomethyl) -3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4-methylundecanedioic acid

a) 2,4-Dimethyl-4-methanesulfonyloxymethyl-2-oxazoline

40.8 g (316 mmol) of 2,4-dimethyl-4-hydroxymethyl-2-oxazoline (J. Nys and J. Libeer, Bull. Soc. Chim. Belg., £ 5, 377 (1956)) are in 400 ml of dichloromethane and 52.5 ml (379 mmol) of triethylamine were stirred at 0 ° C. under nitrogen and 39.8 g (347 mmol) of methanesulfonic acid chloride were added dropwise. The reaction temperature is allowed to rise to room temperature within 3 hours and the batch is shaken out with saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered and evaporated. Yield: 58.5 g (89.4% of theory) of a yellowish oil

Analysis (based on solvent-free substance): calculated: C 40.57 H 6.32 N 6.76 0 30.88 S 15.47 found: C 40.49 H 6.48 N 6.83 S 15.30

b) 4- (2, 5-diazapentyl) -2, 4-dimethyl-2-oxazoline, dihydrochloride

A solution of 36.7 g (177 mmol) of the compound prepared according to Example 8a) in 100 ml of methanol is added dropwise to 291 ml (4427 mmol) of 1,2-diaminoethane.

The reaction mixture is 3 hours at 50 ° C and a further 12 hours

Room temperature stirred. Then the mixture is completely evaporated in vacuo.

A solution of the residue in methanol is adjusted to pH 1.5 at 0 ° C. with concentrated hydrochloric acid. The resulting ethylenediamine dihydrochloride is separated off by filtration. Dropwise addition of tert-butyl methyl ether to the filtrate produces a colorless precipitate which is filtered off with suction and dried in vacuo.

Yield: 38.2 g (88.4% of theory) Analysis ^* (based on solvent-free substance): calc .: C 39.35 H 7.84 N 17.21 0 6.55 Cl 29.04 found: C 39.40 H 7.78 N 17.09 Cl 29.11

c) 2-Amino-4, 7-diaza-2-methylheptan-l-ol, trihydrochloride

30.8 g (126 mmol) of the dihydrochloride shown in Example 8b) are taken up in 150 ml of ethanol. After adding 31 ml of concentrated hydrochloric acid, the mixture is boiled under reflux for 4 hours. After cooling, the mixture is concentrated in vacuo and stirred in 300 ml of isopropanol. The precipitate is filtered off, washed with isopropanol and diethyl ether and dried in vacuo. Yield: 29.6 g (91.4 th.)

Analysis (based on solvent-free substance): calculated: C 28.08 H 7.86 N 16.38 0 6.24 Cl 41.45 found: C 28.23 H 7.95 N 16.46 Cl 41.19

d) 3, 6, 9-triaza-3, 6, 9-tris- (tert-butyloxycarbonylmethyl) -4-hydroxymethyl-4-methyl-undecanedioic acid di-tert-butyl ester

18.9 g (73.7 mmol) of the trihydrochloride prepared in Example 8c) are added to a solution of 51.2 g (369 mmol) of potassium carbonate in 60 ml of water. With vigorous stirring, 60.0 ml (369 mmol) of tert-butyl bromoacetate, dissolved in 60 ml of tetrahydrofuran, are then added and the mixture is stirred at 60 ° C. for 6 hours. After cooling, ethyl acetate and water are added and the mixture is shaken out; the aqueous phase is extracted several times with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and the filtrate is evaporated in vacuo.

Yield: 52.2 g (98.8% of theory)

Analysis (based on solvent-free substance): calc .: C 60.23 H 9.41 N 5.85 0 24.51 found: C 60.11 H 9.62 N 5.67 e) 4-Xlh.lormethyl-4-meth.yl-3, 6, 9-tris (tert-butyloxycarbonylmethyl) -3, 6, 9-tria∑a- undecanedioic acid di-tert-butyl ester

A solution of 22.3 g (31.0 mmol) of the alcohol prepared in Example 8d) in 100 ml of dichloromethane is mixed with 8.91 g (34.0 mmol) of triphenylphosphine and after cooling to 0 ° C. with 4.54 g ( 34.0 mmol) of N-chlorosuccinimide were added. After stirring at 0 ° C. for 2 hours, the mixture is stirred with 200 ml of diethyl ether, the solid is separated off and discarded. The ether phase is evaporated and the residue is chromatographed on silica gel 60 (Merck) with hexane / ethyl acetate (2: 1). After evaporation in vacuo, the product fractions result in a yellowish oil. Yield: 18.7 g (81.7% of theory)

Analysis (based on solvent-free substance): calculated: C 58.72 H 9.03 C1 4.81 N 5.71 0 21.73 found: C 58.68 H 9.23 Cl 4.98 N 5.64

f) 3, 6, 9-Tria∑a-4-azidomethyl-3, 6, 9-tris (tert-butyloxycarbonylmethyl) - 4-methylundecanedioic acid di-tert-butyl ester

A solution of 18.6 g (25.3 mmol) of the chloride prepared in Example 8e) in 70 ml of N, N-dimethylformamide is mixed with 4.92 g (75.8 mmol) of sodium azide and stirred at 50 ° C. for 6 hours . Then it is evaporated in vacuo and the residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. After drying the organic phase over magnesium sulfate, filtration and evaporation, a yellowish oil is obtained. Yield: 18.2 g (97.0% of theory)

Analysis (based on solvent-free substance): calculated: C 58.20 H 8.95 N 11.31 0 21.73 found: C 58.15 H 8.72 N 11.18

g) 4-Aminomethyl-3, 6, 9-tria∑a-3, 6, 9-tris- (tert-butyloxycarbonylmethyl) - 4-methylundecanedioic acid di-tert. -butyl ester

A solution of 18.0 g (24.2 mmol) of the azide prepared in Example 8f) in 180 ml of ethanol is added to 0.90 g of palladium on activated carbon (10% by weight Palladium, manufacturer Degussa) shaken vigorously under a hydrogen atmosphere until no more hydrogen absorption can be observed. The catalyst is then filtered off and the filtrate is evaporated in vacuo. Yield: 17.4 g (99.9% of theory) of a yellowish oil

Analysis (based on solvent-free substance): calc .: C 60.31 H 9.56 N 7.82 0 22.32 found: C 60.22 H 9.78 N 8.03

h) 4- (3-Acetylamino-2, 4, 6-triiodben∑oylaminomethyl) -3, 6, 9-tria∑a-3, 6, 9-tris- (tert-butyloxycarbonylmethyl) -4-methylundecanedioic acid di -tert.-butyl ester

A solution of 17.2 g (24.0 mmol) of the amine prepared in Example 8g) in 70 ml of N, N-dimethylacetamide is mixed with 3.99 ml (28.8 mmol) of triethylamine and 15.2 g

(26.4 mmol) of 3-acetylamino-2,4,6-triiodobenzoyl chloride (H. Priewe et al., Chem. Ber. _87th, 651 (1954)) and stirred for 6 hours at room temperature. Then it is evaporated in vacuo, the residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution and the organic phase is dried over the sodium sulfate. After filtration, the filtrate is evaporated and the residue is chromatographed on silica gel 60 (Merck) with hexane / ethyl acetate (3: 1). After evaporating the product fractions, a yellowish oil is obtained. Yield: 27.9 g (92.6% of theory)

Analysis (based on solvent-free substance): calculated: C 43.04 H 5.78 1 30.32 N 5.58 0 15.29 found: C 43.21 H 5.86 1 30.19 N 5.63

i) 4- (3-Acetylamino-2, 4, 6-triiodobenzoylaminomethyl) -3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4-methylundecanedioic acid

26.6 g (21.2 mmol) of the pentaester described in Example 8h) are converted into the corresponding penta acid under the conditions described in Example 1c). Yield: 19.5 g (94.4%) light beige solid Analysis ¹ (based on anhydrous substance): calc .: C 30.79 H 2.32 1 39.04 N 7.18 Na 3.92 0 19.69 found: C 30.98 H 2.40 1 38.84 N 7.24 Na 4.04

j) Gadolinium complex of the disodium salt of 4- (3-acetylamino-2, 4, 6-triiodo-ben∑oyl-aminomethyl) -3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- methyl undecanedioic acid

18.8 g (19.3 mmol) of the penta acid described in Example 8i) are converted into the title compound under the conditions described in Example 1c). Yield: 20.7 g (91.5% of theory) of a colorless solid

Analysis (based on anhydrous substance): calculated: C 25.59 H 2.32 Gd 13.50 1 32.44 N 5.97 Na 3.92 0 16.36 found: C 25.64 H 2.40 Gd 13.29 1 32.27 N 6.08 Na 4.04

Example 9

Gadolinium complex of the disodium salt of 4- (3-acetylamino-2,4,6-triiodobenzoyloxymethyl) -3, 6, 9-tήaza-3, 6, 9-tris (carboxymethyl) -4-methylundecanedioic acid

a) 4- (3-Acetylamino-2, 4, 6-triiodobenzoyloxymethyl) -4-methyl-3, 6, 9-tris- (tert-butyloxy-carboxymethyl) -3, 6, 9-triazaundecanedioic acid di-tert . -butyl ester

A solution of 14.7 g (20.0 mmol) of the chlorine compound described in Example 8e) in 30 ml of N, N-dimethylacetamide is converted to a solution of 16.9 g (29.9 mmol) of the sodium salt of the 3- Acetylamino-2,4,6-triiodobenzoic acid (Wallingford et al., J. Am. Chem. Soc. 74, 4365 (1952)) was added to 50 ml of N, N-dimethylacetamide. The reaction mixture is stirred for 6 hours at 80 ° C., then evaporated in vacuo and extracted with ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered and evaporated, the residue is chromatographed on silica gel 60 (Merck) with hexane / ethyl acetate (3: 1). After evaporation of the product fractions, a light beige oil remained. Yield: 18.0 g (71.9% of theory) Analysis ⁴ (based on solvent-free substance): calculated: C 43.01 H 5.59 1 30.29 N 4.46 0 16.55 found: C 43.11 H 5.84 1 30.42 N 4.48

b) 4- (3-Acetylamino-2, 4, 6-trüodben∑oyloxymethyl) -4-methyl-3, 6, 9-triaza-3, 6, 9-tris (tert-butyloxy-carboxylmethyl) -undecanedioic acid

17.7 g (14.1 mmol) of the pentaester described in Example 9a) are converted into the corresponding penta acid under the conditions described in Example Id). Yield: 12.7 g (92.7% of theory) of a light beige solid

Analysis (based on anhydrous substance): calculated: C 30.76 H 3.20 1 39.00 N 5.74 0 21.30 found: C 30.81 H 3.48 1 38.90 N 5.77

c) Gadolinium complex of the disodium salt of 4- (3-acetylamino

2, 4, 6-triiodobenzoyl-oxymethyl) -3, 6, 9-tria∑a-3, 6, 9-tris (carboxymethyl) - 4-methylundecanedioic acid

9.26 g (9.48 mmol) of the pentic acid described in Example 9b) are converted into the title compound analogously to the conditions described in Example Id). Yield: 9.88 (88.7% of theory) of a colorless solid

Analysis (based on anhydrous substance): calculated: C 25.14 H 2.29 1 33.21 N 4.89 0 16.75 Gd 13.72 Na 4.01 found: C 25.13 H 2.38 1 33.11 N 4.93 Gd 13.67 Na 4.1 1

Example O

Gadolinium complex of disodium salt of 3,6,9-Tria∑a-3,6,9-tris- (carboxymethyl) - 4-methyl-4- (3-methylcarbamoyl-2, 4, 6-triiodophenyloxymethyl) -undecanedioic acid

a) 3, 6, 9-Tria∑a-3, 6, 9-tris- (tert-butyloxycarbonylmethyl) -4-methyl-4- (3-methyl-carbamoyl-2, 4, 6-triiodophenyloxymethyl) -undecanedioic acid -di-tert. -butyl ester

A solution of 18.9 g (25.7 mmol) of the chlorine compound described in Example 8e) in 35 ml of N, N-dimethylacetamide becomes a solution of 16.3 g (30.8 mmol) of 3-hydroxy-2 at room temperature , 4,6-triiodobenzoic acid methylamide (PL Conturior, Ann. Chim II 10 (1938) 559) and 1.72 g (30.8 mmol) of potassium hydroxide in 30 ml of N, N-dimethylformamide. The reaction mixture is stirred at 60 ° C. for 8 hours, then evaporated in vacuo and the residue is shaken out with ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered and evaporated, the residue is chromatographed on silica gel 60 (Merck) with hexane / ethyl acetate (3: 1). After evaporation of the product fractions, a light beige oil remained. Yield: 21.9 g (69.4% of theory)

Analysis (based on solvent-free substance): calculated: C 43.01 H 5.82 1 30.98 N 4.56 0 15.63 found: C 43.20 H 5.97 1 30.72 N 4.60

b) 3, 6, 9-Tria∑a-3, 6, 9-tris- (carboxymethyl) -4-methyl-4- (3-methylcarbamoyl-2, 4, 6-triiodophenyloxymethyl) -undecanedioic acid

20.6 g (17.0 mmol) of the pentaester described in Example 10a) are converted into the corresponding penta acid under the conditions described in Example 1c). Yield: 13.9 g (86.3% of theory) of a light beige solid

Analysis (based on anhydrous substance): calculated: C 30.40 H 3.30 1 40.15 N 5.91 0 20.25 found: C 30.64 H 3.52 1 39.94 N 6.04 c) Gadolinium complex of the disodium salt of 3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4-methyl-4- (3-methylcarbamoyl-2,4,6-triiodophenyloxymethyl) undecanedioic acid

13.2 g (13.9 mmol) of the penta acid described in Example 10b) are converted into the title compound analogously to the conditions described in Example 1d). Yield: 15.0 g (94.1% of theory) of colorless lyophilisate

Analysis (based on anhydrous substance): calculated: C 25.14 H 2.29 1 33.21 N 4.89 0 16.75 Gd 13.72 Na 4.01 found: C 25.13 H 2.38 1 33.11 N 4.93 Gd 13.67 Na 4.1 1

Example 11

Gadolinium complex of the disodium salt of N, N-bis- [2- [N ', N'-bis (carboxymethyl) amino] ethyl] -3-acetylamino-2, 4, 6-triiodophenylalanine

a) 3-Amino-2,4,6-triiodophenylalanine, hydrochloride

A solution of 32.5 g (150 mmol) of 3-aminophenylalanine hydrochloride (Jennings, J. Chem. Soc. 1957, 1512) in 300 ml of water slowly becomes a mixture of 300 ml of concentrated hydrochloric acid and 240 at 50 ° C. with stirring ml of 2N potassium iodichloride solution was added dropwise in 6.0 l of water. After a further 3.5 hours, the warm, cloudy solution is filtered and concentrated in vacuo until crystallization begins. Then it is cooled well in ice, suction filtered, stirred with water and dried over phosphorus pentoxide. Yield: 50.7 g (67.0% of theory) of a light beige solid

Analysis (based on anhydrous substance): calculated: C 18.19 H 1.70 1 64.06 N 4.71 0 5.38 Cl 5.97 found: C 18.38 H 1.94 1 63.82 N 4.83 Cl 6.11

b) 3-Amino-2,4,6-trüodphenylalanine ethyl ester hydrochloride

30.8 g (51.8 mmol) of the amino acid prepared according to Example 1 la) are in a mixture of 150 ml of ethanol and 4.1 ml (57 mmol) of thionyl chloride for 10 minutes Boiled under reflux, then stirred for 12 hours at room temperature. The mixture is then evaporated and the residue is dried in vacuo. Yield: 32.3 g (100% of theory) of a light beige solid

Analysis (based on anhydrous substance): calculated: C 21.23 H 2.27 1 61.17 N 4.50 0 5.14 Cl 5.70 found: C 21.44 H 2.38 1 60.93 N 4.62 Cl 5.89

c) N N-bis- [2- [N ', N'-bis - [(benzyloxycarbonyl) methyl] amino] ethyl] -3-amino-2, 4, 6-triiodophenylalanine ethyl ester

20.4 g (32.7 mmol) of the amine prepared according to Example 1 lb) and 31.0 g (73.7 mmol) of Ν, Ν-bis - [(benzyloxycarbonyl) methyl] -2-bromomethylamine (M. Williams and H. Rapoport, J. Org. Chem. 58, 1151 (1993)) are placed in 50 ml of acetonitrile and mixed with 20 ml of 2N phosphate buffer solution (pH 8.0). The mixture is stirred vigorously at room temperature for 24 hours, the aqueous phosphate buffer phase being exchanged for fresh buffer solution after 2 and 8 hours. Then the organic phase is evaporated in vacuo and the residue is chromatographed on silica gel with hexane / ethyl acetate / triethylamine (3: 1: 0.01). The product-containing fractions are evaporated in vacuo. Yield: 25.8 g (62.3% of theory) of a yellowish oil.

Analysis (based on solvent-free substance): calc .: C 48.43 H 4.38 1 30.10 N 4.43 0 12.65 found: C 48.50 H 4.45 1 30.01 N 4.44

d) N, N-bis- [2- [N ', N'-bis - [(benzyloxycarbonyl) methyl] amino] ethyl] -3-acetylamino-2, 4, 6-triiodophenylalanine ethyl ester

13.7 g (10.8 mmol) of the compound described in Example 11c) are dissolved in 30 ml of N, N-dimethylacetamide and, after adding 1.80 ml (13.0 mmol) of triethylamine and 0.85 ml (11, 9 mmol) of acetyl chloride was stirred for 12 hours at room temperature with the exclusion of moisture. Then it is evaporated in vacuo and the residue is partitioned between ethyl acetate and sodium hydrogen carbonate solution. The organic phase is dried over sodium sulfate, filtered and evaporated. Yield: 13.8 g (97.6% of theory) of a yellowish oil Analysis (based on solvent-free substance): calculated: C 48.71 H 4.40 1 29.13 N 4.29 0 13.47 found: C 48.83 H 4.67 1 29.02 N 4.38

e) N-N-bis- [2- [N ', N'-bis (carboxymethyl) amino] ethyl] -3-acetylamino-2,4,6-triiodophenylalanine

12.8 g (9.80 mmol) of the pentaester described in Example 1d) are dissolved in 75 ml

Dissolved methanol and mixed with 49 ml of 2N sodium hydroxide solution. The mixture is boiled under reflux for about 2 hours and the methanol is removed in vacuo. By adjusting pH 1 - 2 with semi-concentrated hydrochloric acid, a colorless precipitate is formed, which is filtered off with suction and dried in vacuo. Yield: 7.80 g (86.7% of theory)

Analysis (based on anhydrous substance): calc .: C 30.09 H 3.18 1 41.46 N 6.10 0 19.17 found: C 30.22 H 3.31 1 41.39 N 6.17

f) Gadolinium complex of the disodium salt of N, N-bis- [2- [N ', N'-bis- (carboxymethyl) amino] ethyl] -3-acetylamino-2,4,6-trüodphenylalanine

7.42 g (8.08 mmol) of the pentic acid described in Example 1 le) are converted into the title compound analogously to the conditions described in Example Id). Yield: 8.72 g (96.7% of theory)

Analysis (based on anhydrous substance): calculated: C 24.75 H 2.17 Gd 14.07 1 34.10 N 5.02 Na 4.12 0 15.76 found: C 24.64 H 2.38 Gd 13.83 1 33.94 N 5.08 Na 3.89 Example 12

2- (3-Acetamido-2, 4, 6-triiodobenzyl) -3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) - undecanedioic acid, gadolinium complex, disodium salt

a) 3, 6, 9-triaza-3, 6, 9-tris- (methoxycarbonylmethyl) -undecanedioic acid methyl ester (JOC 55, 2868, 1990)

20.6 g (52.4 mmol) of diethylenetriaminepentaacetic acid in 618 ml of methanol are initially introduced at 0 ° C. and 38.2 ml (0.524 mol) of thionyl chloride are added dropwise over the course of 30 minutes. The reaction mixture is then stirred at room temperature for 16 hours. When the reaction has ended, the mixture is concentrated on a rotary evaporator and the whitish solid is suspended in 300 ml of diethyl ether. The suspension is mixed at 0 ° C. with 200 ml of saturated sodium bicarbonate solution, the organic phase is separated off and the aqueous phase is extracted three times with 100 ml each

Diethyl ether. The extract is dried over potassium carbonate and after filtration to

Evaporated to dryness. The product is dried overnight in a vacuum over phosphorus pentoxide.

Yield: 19.7 g (81% of theory) of colorless oil.

Elemental analysis (taking into account the solvent content): calc .: C 49.24 H 7.18 N 9.07 0 34.52 found: C 49.37 H 7.26 N 8.85

b) 3, 6, 9-Tria∑a-3, 6, 9-tris- (methoxycarbonylmethyl) -2- (3-nitroben∑yl) - undecanedioic acid dimethyl ester

6.64 ml (47.3 mmol) of diisopropylamine in 200 ml of anhydrous tetrahydrofuran are placed in a gentle stream of argon at 0 ° C. and 22.2 ml (52 mmol) of butyllithium (15% in hexane) are added dropwise over the course of 15 minutes. The mixture is then cooled to -78 ° C. and 18.4 g (40 mmol) of pentaester (Example 12a) dissolved in 300 ml of anhydrous tetrahydrofuran are added in portions. After stirring at this temperature for 30 minutes, a solution of 8.11 g (47.3 mmol) of 3-nitrobenzyl chloride and 1.38 ml (11.44 mmol) of 1,3-dimethyl-

3,4,5,6-tetrahydro-2 (1H) pyrimidinone in 180 ml of anhydrous tetrahydrofuran within 30 minutes. The reaction mixture is allowed to come to room temperature overnight and the solution is concentrated on a rotary evaporator. The oily residue is in 150 ml of ethyl acetate was added and 50 ml of ice water were added. The organic phase is separated off and the aqueous phase is extracted three times with 75 ml of ethyl acetate each time. The combined organic phases are dried over potassium carbonate, filtered and evaporated to dryness. To purify the crude product, the substance is chromatographed on silica gel 60 (Merck). Yield: 13.2 g (55% of theory) of a pale yellow oil.

Elemental analysis (taking into account the solvent content): calc .: C 52.17 H 6.40 N 9.36 0 32.07 found: C 52.01 H 6.23 N 9.48

c) 2- (3-Aminoben∑yl) -3, 6, 9-tria∑a-3, 6, 9-tris- (methoxycarbonylmethyl) - undecanedioic acid dimethyl ester

A methanolic solution of 12.7 g (21.2 mmol) of the nitro compound from Example 12b) is hydrogenated at room temperature with the addition of 1.35 g of palladium on carbon (10%) at 4 bar. The hydrogenation is complete after 5 hours and the catalyst is filtered off. The filtrate is evaporated to dryness and used in the next step without further purification.

Yield: 11.35 g (94% of theory) of a colorless oil.

d) 2- (3-aminoben∑yl) -3, 6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -undecanedioic acid

10.8 g (19 mmol) of the pentaester from Example 12c) are saponified with 60 ml of 2N sodium hydroxide solution at 40 ° C. After the reaction has ended, concentrated hydrochloric acid is added to the solution until the acid has completely precipitated. The precipitate is filtered off and washed neutral with water. The product is dried under vacuum at 50 ° C. overnight.

Yield: 9.75 g (96% of theory) of a colorless solid.

Elemental analysis (taking into account the solvent content): found: C 47.15 H 5.84 Cl 6.63 N 10.47 0 29.91 calcd .: C 47.04 H 6.12 Cl 6.35 N 10.59 e) 2- (3-Amino-2, 4, 6-triiodobenzyl) -3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) - undecanedioic acid

9.55 g (18 mmol) of pentacarboxylic acid (Example 12d) are suspended in 50 ml of water and 22.8 ml (56.4 mmol) of a hydrochloric acid 40% iodine monochloride solution are added dropwise. The reaction mixture is allowed to stir at 65 ° C. for 16 hours and the excess iodine is reduced with dilute sodium disulfite solution. The precipitate is filtered off and washed with water. The dried solid is taken up in concentrated ammonia solution, filtered and precipitated with concentrated hydrochloric acid. The precipitate is washed until the wash water is neutral. The product is dried for 18 hours at 50 ° C. in vacuo to constant weight. Yield: 13.1 g (83% of theory) of a pale yellow solid.

Elemental analysis (taking into account the solvent content): calc .: C 28.79 H 3, l l 1 43.45 N 6.39 0 18.26 found: C 28.93 H 3.37 1 43.32 N 6.48

f) 2- (3-acetylamino-2, 4, 6-triiodobenzyl) -3, 6, 9-tris (carboxymethyl) -3, 6, 9-tria traundecanedioic acid

12.7 g (14.5 mmol) of triiodaniline from Example 12e) are dissolved in 30 ml of N, N-dimethylacetamide, and 2.465 ml (34.8 mmol) of acetyl chloride are added while cooling with ice. The mixture is allowed to come to room temperature overnight and the reaction mixture is stirred into ice water. The precipitate is filtered off, washed with water and dried at 50 ° C in a vacuum. Yield: 11.55 g (87% of theory) of a colorless solid.

Elemental analysis (taking into account the solvent content): calc .: C 30.09 H 3.18 1 41.46 N 6.10 0 19.17 found: C 29.88 H 3.26 1 41.29 N 6.02 g) 2- (3-acetamido-2, 4, 6-triiodobenzyl) -3, 6, 9-tria∑a-3, 6, 9-tris- (carboxymethyl) - undecanedioic acid, gadolinium complex, disodium salt

11.2 g (12.2 mmol) of complexing agent from Example 12f) are reacted with gadolinium oxide at 50 ° C. using the method of Example 4d). After more complete

Complexation is converted into the disodium salt with sodium hydroxide solution. The resulting solution is cleaned with 1.2 g of activated carbon, filtered through a 0.2 μm membrane cellulose filter and then freeze-dried. Yield: 12.6 g (92.5% of theory) of colorless lyophilisate.

Elemental analysis (taking into account the solvent content): calc .: C 24.75 H 2.17 Gd 14.09 1 34.10 N 5.02 Na 4.12 0 15.76 found: C 24.89 H 2.23 Gd 13.88 1 34.02 N 4.87 Na 4.03

Example 13

Gadolinium complex of the disodium salt of 3,6,9-Tria∑a-3,6,9-tris- (carboxymethyl) - 4- [3- [N, N'-dimethyl-N, N'-bis- (2nd , 3-dihydroxypropyl) -3, 5-dicarbamoyl-2, 4, 6-triiodophenylcarbamoylmethoxyj-benzylj-undecanedioic acid

a) N, 0-bis (benzyloxycarbonyl) -3-hydroxyphenylalanine-N- [2- (benzyloxycarbonylamino) ethyl] amide

168.54 g (375 mmol) of N, O-bis (benzyloxycarbonyl) -3-hydroxyphenylalanine (de Castiglione, Bosisio, Gazz. Chim. Ital., S7, 1858 (1967)) are dissolved in 3.0 l of tetrahydrofuran and Chilled to 0 ° C. After the addition of 72.8 ml (525 mmol) of triethylamine, 36.7 ml (383 mmol) of ethyl chlorocarbonate are added dropwise. After 20 minutes, 75.8 g (390 mmol) of benzyloxycarbonyl- (2-aminoethyl) amide (G. Atwell, W. Denny, Synthesis, 1032-33 (1984)) in 500 ml of tetrahydrofuran are added. After stirring overnight, the resulting precipitate is filtered off, the filtrate evaporated and dried in vacuo. Yield: 183.7 g (78.3% of theory) of a colorless solid.

Analysis: (based on solvent-free substance) calc .: C 67.19 H 5.64 N 6.72 0 20.46 found: C 67.07 H 5.78 N 6.84 b) 3-Hydroxyphenylalanine (2-aminoethyl) amide

62.57 g (100 mmol) of the compound described in Example 13a) are suspended in 1.5 l of methanol and, after addition of 6.3 g of palladium on carbon (10% by weight palladium, Degussa), hydrogenated with hydrogen at atmospheric pressure. Then it is filtered, the filtrate is evaporated and the residue is stirred in diisopropyl ether. After vacuuming and drying in vacuo, a colorless solid is obtained. Yield: 21.4 g (95.8% of theory)

Analysis: (based on solvent-free substance) calc .: C 59.17 H 7.67 N 18.82 0 14.33 found: C 59.28 H 7.73 N 18.74

c) l, 5-diamino-3-a∑a-2- (3-ethoxybenzyl) pentane, trihydrochloride

20.1 g (90 mmol) of the compound described in Example 13b) are taken up in 135 ml of tetrahydrofuran and 180 ml of 1 M borohydride solution in tetrahydrofuran are added dropwise at 0 ° C. under argon. After stirring for 30 minutes at 0 ° C., stirring is continued at 60 ° C. for 120 hours. After cooling, 100 ml of methanol are added dropwise, the reaction mixture is saturated with hydrogen chloride and the resulting acid suspension is stirred for 6 hours. Then the precipitate is filtered off and dried at 50 ° C in a vacuum. Yield: 25.0 g (87.2%) colorless solid

Analysis (based on solvent-free substance): calculated: C 41.46 H 6.96 Cl 33.38 N 13.19 O 5.02 found: C 41.40 H 7.04 Cl 33.47 N 13.08

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

15.1 g (47.4 mmol) of the compound described in Example 13c) are suspended in 500 ml of tetrahydrofuran and mixed with 25 ml of water and 34.5 g (249 mmol)

Potassium carbonate added. After dropwise addition of 52.3 ml (356 mmol) of tert-butyl bromoacetate, the mixture is stirred at 60 ° C. for 3 days. After cooling, it is filtered, in vacuo concentrated and the residue chromatographed on silica gel with diethyl ether / hexane triethylamine (70: 20: 5). The product fractions are evaporated in vacuo. Yield: 27.2 g (73.3% of theory) of a yellowish oil

Analysis (based on solvent-free substance): calculated: C 63.13 H 8.92 N 5.39 0 22.56 found: C 63.24 H 8.88 N 5.43

e) 5-Chloroacetylamino-2, 4, 6-triiodoisophthalic acid- [N, N'-dimethyl-N, N'-bis- (2, 2-dimethyl-l, 3-dioxolan-4-ylmethyl)] diamide

81.0 g (100 mmol) of 5-chloroacetylamino-2,4,6-triiodoisophthalic acid-N, N'-dimethyl-N, N'-bis- (2,3-dihydroxypropyl) -diamide (DE 2928417) are used in 500 ml of tetrahydrofuran and 0.95 g (5.0 mmol) of p-toluenesulfonic acid monohydrate and 22.9 g (220 mmol) of 2,2-dimethoxypropane were added. The mixture is then refluxed for 12 hours, evaporated in vacuo and the residue is partitioned between ethyl acetate and sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulfate and filtered, evaporated and the residue is stirred with tert-butyl methyl ether. After filtering, the residue is dried in vacuo. Yield: 79.7 g (89.6% of theory) of a colorless solid

Analysis (based on solvent-free substance): calculated: C 32.40 H 3.51 Cl 3.99 1 42.79 N 4.72 0 12.59 found: C 32.38 H 3.62 Cl 4.04 1 42.70 N 4.63

f) 3,6,9-Triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- [3- [N, N'-dimethyl-N, N'-bis- (2, 2- dimethyl-l, 3-dioxolan-4-ylmethyl) -3, 5-dicarbamoyl-2, 4, 6-triiodophenyl-carbamoyl-methoxyj-benzylj-undecanedioic acid di-tert-butyl ester

12.8 g (16.4 mmol) of the hydroxy compound described in Example 13d) are dissolved in 50 ml of N, N-dimethylformamide under argon and mixed with 0.59 g (19.7 mmol) of 80% sodium hydride suspension in mineral oil. After stirring for 30 minutes at room temperature, 19.0 g (21.3 mmol) of the compound described in Example 13e) are added and the mixture is stirred at 50 ° C. for 12 hours. Then it is evaporated in vacuo and the residue on silica gel 60 (Merck) with Chromatographed diethyl ether / hexane / triethylamine (70: 20: 5). The product fractions are evaporated in vacuo. Yield: 16.8 g (62.6% of theory) of viscous oil

Analysis (based on solvent-free substance): calculated: C 47.80 H 6.1 l 1 23.31 N 5.15 0 17.63 found: C 47.63 H 6.05 1 23.24 N 5.24

g) 3, 6, 9-Tria∑a-3, 6, 9-tris- (carboxymethyl) -4- [3- [N, N'-dimethyl-N, N'-bis-

(2,3-dihydroxypropyl) -3,5-dicarbamoyl-2,4,6-triiodophenylcarbamoylmethoxy] benzylj-undecanedioic acid

16.1 g (9.86 mmol) of the compound described in Example 13f) are freed from all protective groups under the conditions described in Example 1c) and converted into the title compound. Yield: 12.4 g (98.7% of theory) of a light beige solid

Analysis (based on anhydrous substance): calculated: C 36.81 H 4.04 1 29.92 N 6.60 0 22.63 found: C 36.94 H 4.05 1 29.86 N 6.53

h) Gadolinium complex of the disodium salt of 3, 6, 9-tria∑a-3, 6, 9-tris- (carboxymethyl) -4- [3- [N, N'-dimethyl-N, N'- bis- (2,3-dihydroxypropyl) -3,5-dicarbamoyl-

2, 4, 6-triiodophenyl-carbamoylmethoxyJ-benzylJ-undecanedioic acid

11.9 g (9.35 mmol) of the penta acid described in Example 13 g are converted into the title compound analogously to the conditions described in Example Id). Yield: 13.1 g (95.5% of theory) of colorless lyophilisate

Analysis (based on anhydrous substance): calculated: C 31.85 H 3.15 1 25.88 N 5.71 0 19.58 Gd 10.69 Na 3.13 found: C 31.92 H 3.20 1 25.76 N 5.73 Gd 10.58 Na 3.20 Example i4

Gadolinium complex of the disodium salt of 3,6,9-tria∑a-3,6,9-tris- (carboxymethyl) - 4- (3-methoxy-2, 4, 6-triiodobenzyl) -undecanedioic acid

a) 3, 6, 9-Tria∑a-3, 6, 9-tris- (carboxymethyl) -4- (3-hydroxyben∑yl) -undecanedioic acid

13.2 g (16.9 mmol) of the compound described in Example 13d) are converted into the corresponding penta acid under the conditions described in Example 1c). Yield: 8.20 g (97.0% of theory)

Analysis (based on anhydrous substance): calculated: C 50.50 H 5.85 N 8.41 0 35.24 found: C 50.41 H 5.93 N 8.49

b) 3, 6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -4- (3-hydroxy-2, 4, 6-triiodobenzyl) - undecanedioic acid

8.11 g (16.2 mmol) of the compound described in Example 14a) are dissolved in 80 ml of 5N aqueous ammonia. Now, 26.8 ml of 2N potassium ioddi chloride solution are slowly added dropwise with stirring and the mixture is stirred for 12 hours. The pH is adjusted to 1.5 with concentrated hydrochloric acid and sodium disulfite is added until a light suspension is obtained; this is stirred for 6 hours and filtered. The residue is washed with 2N hydrochloric acid and dried in vacuo. Yield: 12.1 g (84.8% of theory)

Analysis (based on anhydrous substance): calculated: C 28.75 H 2.99 1 43.40, N 4.79 0 20.06 found: C 28.81 H 2.83 1 43.43 N 4.62

c) 3, 6, 9-Tria∑a-3, 6,9-tris- (carboxymethyl) -4- (3-methoxy-2,4, 6-triiodobenzyl) - undecanedioic acid

11.6 g (13.2 mmol) of the compound described in Example 14b) are mixed in 60 ml of tetrahydrofuran at 0 ° C. with 2.77 g (92.6 mmol) of 80% sodium hydride suspension in mineral oil. 13.1 g (92.6 mmol) of iodomethane are added and Stirred for 30 minutes. Then 60 ml of 2N sodium hydroxide solution are added to the solution and the mixture is refluxed for 30 minutes. After cooling, the organic solvent is removed in vacuo and the remaining aqueous solution is adjusted to pH 1.5 with concentrated hydrochloric acid. A precipitate precipitates, which is filtered off with suction and dried in vacuo. Yield: 10.7 g (91.4% of theory)

Analysis (based on anhydrous substance): calculated: C 29.65 H 3.17 1 42.72 N 4.72 0 19.75 found: C 29.74 H 3.23 1 42.65 N 4.63

d) Gadolinium complex of the disodium salt of 3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- (3-methoxy-2,4,6-triiodobenzyl) -undecanedioic acid

10.2 g (11.4 mmol) of the penta acid described in Example 14c) are converted into the title compound as described in Example 1 d). Yield: 11.7 g (94.0% of theory) of colorless lyophilisate

Analysis (based on anhydrous substance): calculated: C 24.26 H 2.13 1 34.95 N 3.86 0 16.15 Gd 14.43 Na 4.22 found: C 24.30 H 2.10 1 34.91 N 3.90 Gd 14.50 Na 4.28

Example 15

Gadolinium complex of the disodium salt of 3,6,9-tria∑a-4- (3-diethylcarbamoyl-2, 4, 6-triiodophenylcarbamoyloxymethyl) -3, 6, 9-tris- (carboxymethyl) -undecanedioic acid

a) 3-Isocyanato-2,4,6-triiodobenzoic acid diethylamide

57.00 g (100.0 mmol) of 3-amino-2,4,6-triiodobenzoic acid diethylamide (CA 54, P 20987i (i960)) are mixed with 250 ml of 2N toluene phosgene solution under a nitrogen atmosphere at room temperature. After the addition of 0.5 ml of N, N-dimethylformamide, the mixture is stirred for 5 hours at 60 ° C. and then evaporated to dryness.

Yield: 59.60 g (100.0% of theory) of a yellowish solid Analysis. (based on solvent-free substance) calcd .: C 24.18 H 1.86 1 63.88 N 4.70 0 5.37 found: C 24.07 H 1.92 1 63.80 N 4.66

b) 4- (3-Diethylcarbamoyl-2,4,6-triiodophenylcarbamoyloxymethyl) -3,6,9-tris (tert-butyloxycarbonylmethyl) -3,6,9-triazaundecanedioic acid di-tert. -butyl ester

A solution of 14.68g (20.85 mmol) 3,6,9-triaza-3,6,9-tris (tert-butyloxycarbonylmethyl) -4-hydroxymethyl-undecanedioic acid di-tert-butyl ester ( DE 3806795) in 100 ml of anhydrous pyridine is mixed with the exclusion of moisture with 12.42 g (20.85 mmol) of the isocyanate described in Example 15a) and stirred overnight at room temperature. The mixture is then evaporated completely and the residue is chromatographed on silica gel (eluent: hexane / ethyl acetate). After evaporating the fractions containing the product, a yellowish oil is obtained as a residue. Yield: 24.29 g (89.6% of theory)

Analysis (based on solvent-free substance): calculated: C 43.43 H 5.98 1 29.29 N 5.39 O 16.00 found: C 43.42 H 6, l l 1 29.25 N 5.44

c) 3, 6, 9-Triaza-4- (3-diethylcarbamoyl-2, 4, 6-trüodphenylcarbamoyloxymethyl) - 3,6, 9-tris (carboxymethyl) -undecanedioic acid

21.62 g (16.63 mmol) of the pentaester described in Example 15 b) are converted into the corresponding penta acid under the conditions described in Example 1c). Yield: 16.17 g (95.4% of theory) of a colorless solid

Analysis (based on solvent-free substance): calculated: C 31.81 H 3.56 1 37.35 N 6.87 0 20.40 found: C 31.73 H 3.64 1 37.25 N 6.72 d) Gadolinium complex of the disodium salt of 3, 6, 9-Tria∑a-4- (3-diethylcarbamoyl-2, 4, 6-triiodophenylcarbamoyloxymethyl) -3, 6, 9-tris- (carboxymethyl) - undecanedioic acid

15.52 g (15.22 mmol) of the pentic acid described in Example 15c) are converted into the title compound as described in Example Id). Yield: 17.44 g (94.1% of theory) of colorless lyophilisate

Analysis (based on anhydrous substance): calculated: C 24.26 H 2.13 1 34.95 N 3.86 0 16.15 Gd 14.43 Na 4.22 found: C 24.30 H 2.10 1 34, 91 N 3.90 Gd 14.50 Na 4.28

Example 16

Gadolinium complex of the disodium salt of 3,6,9-tria∑a-3, 6,9-tris- (carboxymethyl) -

4- (N-carboxymethyl-3-methylamino-2,4,6-triiodophenylureylene methyl) -

4-methylundecanedioic acid

a) 3-Isocyanato-2, 4, 6-triiodobenzoic acid N- (ethoxycarbonylmethyl) methyl amide

61.40 g (100.0 mmol) of 3-amino-2,4,6-triiodobenzoic acid N- (ethoxycarbonylmethyl) methylamide (CA 54 P 20987i (i960)) are mixed with 250 ml of 2N toluene phosgene solution under a nitrogen atmosphere at room temperature . After the addition of 0.5 ml of N, N-dimethylformamide, the mixture is stirred for 5 hours at 60 ° C. and then evaporated to dryness. Yield: 64.00 g (100.0% of theory) of a yellowish solid

Analysis: (based on solvent-free substance) calc .: C 24.40 H 1.73 1 59.49 N 4.38 O 10.00 found: C 24.37 H 1.82 1 59.53 N 4.26 b) 3, 6, 9-Tria∑a-3, 6, 9-tris- (tert-butyloxycarbonylmethyl) -4- (N-ethoxycarbonylmethyl-3-methylamino-2, 4, 6-triiodophenylureylene methyl) -4-methylundecanedioic acid -di-tert. - butyl ester

A solution of 16.41 g (22.89 mmol) of the pentaester described in Example 8 g) in 100 ml of anhydrous pyridine is treated with the exclusion of moisture with 14.65 g (22.89 mmol) of the isocyanate described in Example 16 a) and over Stirred at room temperature overnight. The mixture is then evaporated completely and the residue is chromatographed on silica gel (eluent: hexane / ethyl acetate). After evaporating the fractions containing the product, a yellowish oil is obtained as a residue. Yield: 27.39 g (88.2% of theory)

Analysis (based on solvent-free substance): calculated: C 43.37 H 5.87 1 28.06 N 6.19 0 16.51 found: C 43.49 H 6.01 1 28.22 N 6.14

c) 3, 6, 9-triaza-3, 6, 9-tris (carboxymethyl) -4- (N-carboxymethyl-3-methylamino-2, 4, 6-triiodophenylureylene methyl) -4-methylundecanedioic acid

26.68 g (19.66 mmol) of the hexaester described in Example 16 b) are converted into the corresponding hexa acid under the conditions described in Example 3c). Yield: 19.19 g (93.1% of theory) of a colorless solid

Analysis (based on solvent-free substance): calc .: C 30.92 H 3.37 1 36.32 N 8.02 0 21.37 found: C 31.03 H 3.48 1 36.21 N 8.14

d) Gadolinium complex of the disodium salt of 3, 6, 9-triaza-3, 6, 9-tris

(carboxymethyl) -4- (N-carboxymethyl-3-methylamino-2,4,6-triiodophenyl-ureylene methyl) -4-methylundecanedioic acid

24.32 g (23.19 mmol) of the pentic acid described in Example 16 c) are converted into the title compound as described in Example Id). Yield: 27.84 (94.6% of theory) colorless lyophilisate Analysis (based on anhydrous substance): calculated: C 25.57 H 2.30 1 30.01 N 6.63 0 17.66 Gd 12.40 Na 5.44 found: C 25.62 H 2.34 1 29.94 N 6.58 Gd 12.35 Na 5.38

Example 17

Comparative experiment: Isomer ∑um Example 1 of WO 93/16375

1, 13-bis [5- (propion-3-ylamido] -2, 4, 6-triiodoisophthalic acid bis (2-hydroxy-l-hydroxymethylethyl) diamide] -4, 7,10-tris (carboxymethyl) -2 , 12-dioxo) -l, 4, 7,10, 13-pentaazatridecan, gadolinium complex

a) 1, 13-bis [5- (propion-3-ylamido] -2, 4, 6-triiodoisophthalic acid bis (2-hydroxy-l-hydroxymethylethyl) diamide] -4, 7,10-tris (carboxymethyl) -2, 12-dioxo) - 1, 4, 7, 10, 13-pentaazatridecane

16.5 g (21.2 mmol) of 5- (3-aminopropionamido) -2,4,6-triiodo-isophthalic acid bis (2-hydroxy-1-hydroxymethylethyl) diamide are dissolved in a bath temperature of 120 ° C. in 82.5 ml of DMF dissolved. 7.38 ml (53.25 mmol) of triethylamine are added at room temperature and then 3.8 g (10.64 mmol) of N, N'-bis [2- (2,6-dioxomorpholino) ethyl] glycerol. The reaction mixture is stirred overnight at room temperature. The solvent is evaporated off in vacuo and the residue is foamed using the oil pump. The solid is stirred with 200 ml of ethanol at room temperature for two hours, suction filtered and dried at 50 ° C. in vacuo. Then the residue is taken up in a little water and chromatographed on silica gel RP 18 (eluent: water / methanol). After evaporation of the product fractions, the title compound is obtained as a colorless solid. Yield: 17.24 g (42% of theory)

Analysis (based on anhydrous substance): calculated: C 30.19 H 3.43 1 39.88 N 8.07 0 18.43 found: C 29.88 H 3.30 1 40.21 N 7.95 b) 1, 13-bis [5- (propion-3-ylamido] -2, 4, 6-triiodoisophthalic acid bis (2-hydroxy-1-hydroxymethylethyl) diamide] -4, 7, 10-tris (carboxymethyl) -2,12-dioxo) - 1,4, 7,10, 13-pentaazatridecane, gadolinium complex

400 mg of the compound described in Example 17 a) are added in portions

17.8 ml of a 0.01 molar gadolinium acetate solution were added. The pH is shifted into the neutral range with triethylamine and the aqueous solution is stirred for one hour at room temperature with activated carbon. After filtration and freeze-drying, the gadolinium complex is obtained as a colorless solid. Yield: 145 mg (30.5% of theory)

Analysis (based on anhydrous substance): calculated: C 27.91 H 3.03 1 36.90 N 7.47 0 17.06 Gd 7.62 found: C 27.77 H 2.99 1 36.72 N 7.15 Gd 7.38

Example 18

Gadolinium complex of 3, 6,9-Tήaza-3, 6,9-tήs- (carboxymethyl) -4- (3-iodo-4-ethoxybenzyl) -undecanedioic acid, disodium salt

a) N-Ben∑yloxycarbonyl-3- (4-ethoxyphenyl) -2-aminopropanol

31.8 g (848.4 mmol) of sodium borohydride are added at room temperature to a solution of 221.41 g (605.9 mmol) of N-benzyloxycarbonyl-O-ethyltyrosine methyl ester in 1.5 l of tetrahydrofuran. For this purpose, 279 ml of methanol are added dropwise with stirring within two hours. The tetrahydrofuran is then distilled off in vacuo, the rest is taken up in 1 liter of water and extracted three times with 700 ml of ethyl acetate. The combined organic phase is washed with water, dried with sodium sulfate and concentrated. It is recrystallized from ethyl acetate / hexane. Yield: 187.0 g (93.7% of theory)

Analysis (based on solvent-free substance): calculated: C 69.28 H 7.04 N 4.25 0 19.43 found: C 69.11 H 7.20 N 4.13 b) l-acetoxy-N-benzyloxycarbonyl-3- (3-iodo-4-ethoxyphenyl) -2-aminopropane

29.4 g (89.3 mmol) of N-benzyloxycarbonyl-3- (4-ethoxyphenyl) -2-aminopropanol are dissolved in 88 ml of glacial acetic acid and with 22.2 g (134 mmol) of iodine monochloride in 35.5 ml of glacial acetic acid at room temperature added dropwise. The reaction mixture is left to stir at room temperature overnight and poured into 1.1 l of ice water for working up. The aqueous phase is extracted several times with ethyl acetate, the organic phase is washed with water, sodium hydrogen carbonate solution and sodium bisulfite solution and then dried over sodium sulfate. After evaporation of the solvent, a yellowish oil is obtained which slowly crystallizes through. Yield: 34.5 g (77.7% of theory)

Analysis (based on solvent-free substance): calc .: C 50.72 H 4.86 1 25.52 N 2.82 0 16.08 found: C 50.53 H 4.98 1 25.38 N 2.74

c) N-Benzyloxycarbonyl-3- (3-iodo-4-ethoxyphenyl) -2-aminopropanol

29.8 g (60 mmol) l-acetoxy-N-benzyloxycarbonyl-3- (3-iodo-4-ethoxyphenyl) -

2-aminopropane are suspended in 150 ml of methanol and 4.94 g (60 mmol) of anhydrous sodium acetate are added at room temperature. The mixture is stirred at 60 ° C. for 6 hours, evaporated to dryness and the residue is taken up in ethyl acetate. The precipitated salt is filtered off, washed with ethyl acetate and the filtrate evaporated. The viscous oil obtained is used in the next step without further purification. Yield: 27.3 g (100% of theory)

d) l-methanesulfonyloxy-N-benzyloxycarbonyl-3- (3-iodo-4-ethoxyphenyl) -2-aminopropane

26.5 g (58 mmol) of N-benzyloxycarbonyl-3- (3-iodo-4-ethoxyphenyl) -2-aminopropanol are dissolved in 130 ml of dichloromethane, mixed with 24.1 ml of triethylamine and at 0 ° C. with 6.78 ml (87 mmol) methanesulfonic acid chloride reacted. After 30

Minutes at room temperature, according to the DC, no longer detect any starting material. The mixture is diluted with dichloromethane, with sodium hydrogen carbonate and with water washed. After the organic phase has dried, the solvent is evaporated off and the product is obtained as a pale yellow oil. Yield: 30.4 g (98% of theory)

Analysis (based on solvent-free substance): calc .: C 45.04 H 4.54 1 23.79 N 2.63 0 18.00 S 6.01 found: C 45.13 H 4.72 1 23.58 N 2.74 S 5.88

e) N-Benzyloxycarbonyl-1- (3-iodo-4-ethoxybenzyl) -N '- (2-aminoethyl) ethylenediamine

28.2 g (53 mmol) l-methanesulfonyloxy-N-benzyloxycarbonyl-3- (3-iodo-4-ethoxyphenyl) -2-aminopropane are dissolved in 140 ml tetrahydrofuran at room temperature and with 143 ml (2.12 mol) ethylenediamine transferred. After stirring for 22 hours, the mixture is evaporated to an oil and the residue is dissolved in ethyl acetate. It is washed neutral with water and the organic phase is dried over sodium sulfate. After evaporation, a yellow oil is obtained. Yield: 25.9 g (98% of theory)

Analysis (based on solvent-free substance): calculated: C 50.71 H 5.67 1 25.51 N 8.45 0 9.65 found: C 50.87 H 5.78 1 25.40 N 8.74

f) l- (3-iodo-4-ethoxyben∑yl) -N '- (2-aminoethyl) ethylenediamine, trihydrobromide

25 g (50 mmol) of N-benzyloxycarbonyl-l- (3-iodo-4-ethoxybenzyl) -N '- (2-aminoethyl) ethylenediamine are suspended in 20 ml of glacial acetic acid at room temperature and mixed with 61.1 ml (250 mmol ) 33% hydrogen bromide added to glacial acetic acid. After 40 hours at room temperature, the starting material is completely consumed. The reaction mixture is evaporated in an oil pump vacuum and the residue is distilled three times with toluene. The solid is mixed with water and evaporated to dryness. To remove remaining traces of water, the residue is evaporated three times with dichloromethane. The crude product is recrystallized from ethanol. Yield: 24.6 (81.2% of theory) of colorless crystals. Analysis ^* (based on solvent-free substance): calc .: C 25.77 H 4.16 1 20.94 N 6.93 0 2.64 Br 39.56 found: C 25.89 H 4.41 1 20.73 N 6 , 74 Br 39.29

g) 4- (3-iodo-4-ethoxybenzyl) -3, 6, 9-tris (tert-butoxycarbonylmethyl) - 3,6,9-tria∑aundecan-l, 11-diacid, di- (tert.- butyl) esters

23.2 g (38.3 mmol) of l- (3-iodo-4-ethoxybenzyl) -N '- (2-aminoethyl) ethylenediamine, trihydrobromide are suspended in 450 ml of tetrahydrofuran and 43.6 g (316 mmol ) Potassium carbonate and 18 ml of water, and 42.13 ml (287.2 mmol) of tert-butyl bromoacetate were added dropwise. The mixture is stirred for 10 hours at 60 ° C. and then overnight at room temperature. The salt is filtered off, washed with tetrahydrofuran and the filtrate evaporated. The crude product is purified using a silica gel column (mobile phase: dichloromethane / methanol). Yield: 34.6 g (96.7% of theory)

Analysis (based on solvent-free substance): calc .: C 55.30 H 7.77 1 13.59 N 4.50 0 18.84 found: C 55.37 H 7.95 1 13.44 N 4.43

h) 4- (3-iodo-4-ethoxybenzyl) -3, 6, 9-tris (carboxylatomethyl) -3, 6, 9-tria∑aundecan- 1,11-diacid, gadolinium complex, disodium salt

17.6 g (18.8 mmol) of 4- (3-iodo-4-ethoxybenzyl) -3,6,9-tris (tert-butoxycarbonylmethyl) -3,6,9-triazaundecane-1,11-diacid, Di- (tert-butyl) esters are dissolved in 130 ml of methanol at room temperature and 6.03 g (150.4 mmol) of sodium hydroxide in 10 ml of water are added. The mixture is stirred for five days at 60 ° C., evaporated to dryness and redistilled twice with water. The residue is taken up in 180 ml of water and adjusted to pH 2.9 with an acidic ion exchanger. 3.41 g (9.4 mmol) of gadolinium oxide are added and the reaction mixture is heated to 80.degree. After complexing, the pH is adjusted to 7.2 with a cation exchanger (Na ⁺ form) and the clear solution is lyophilized. Yield: 14.75 g (92% of theory) Analysis ^* (based on anhydrous substance): calculated: C 32.44 H 3.20 1 14.90 N 4.93 0 20.67 Gd 18.46 Na 5.40 found: C 32.23 H 3.47 1 14.76 N 4.88 Gd 18.36 Na 5.17

Example 19

Gadolinium complex of 3, 6, 9-triaza-3, 6, 9-tris- (carboxymethyl) -4- (3-bromo-4-ethoxyben∑yl) -undecanedioic acid, disodium salt

a) l-acetoxy-N-benzyloxycarbonyl-3- (3-bromo-4-ethoxyphenyl) -2-aminopropane

20.0 g (61 mmol) of the title compound from Example 18a are dissolved in 200 ml of glacial acetic acid and 0.2 g of iron powder is added. After the reaction solution has cooled to 10 ° C., 12.48 g (78 mmol) of bromine are added dropwise at these temperatures. The reaction mixture is left to stir at room temperature overnight and poured into 750 ml of ice water for working up. The aqueous phase is extracted several times with ethyl acetate, the organic phase is washed with water, sodium hydrogen carbonate solution and sodium bisulfite solution and then dried over sodium sulfate. After the solvent has been evaporated off, yellowish-colored crystals are obtained. Yield: 19.50 g (71.0% of theory)

Analysis (based on solvent-free substance): calc .: C 56.01 H 5.37 Br 17.74 N 3, l l found: C 56.13 H 5.42 Br 17.84 N 3.16

b) N-benzyloxycarbonyl-3- (3-bromo-4-ethoxyphenyl) -2-aminopropanol

18.0 g (39.8 mmol) l-acetoxy-N-benzyloxycarbonyl-3- (3-bromo-4-ethoxyphenyl) -2-aminopropane are suspended in 100 ml methanol and at room temperature with 3.30 g (40 mmol ) anhydrous sodium acetate. The mixture is stirred at 60 ° C. for 6 hours, evaporated to dryness and the residue is taken up in ethyl acetate. The precipitated salt is filtered off, washed with ethyl acetate and the

The filtrate was evaporated. The viscous oil obtained is transferred to the next one without further purification

Stage used.

Yield: 16.0 g (98.2% of theory) c) l-methanesulfonyloxy-N-benzyloxycarbonyl-3- (3-bromo-4-ethoxyphenyl) -2-aminopropane

15.5 g (38 mmol) of N-benzyloxycarbonyl-3- (3-bromo-4-ethoxyphenyl) -2-aminopropanol are dissolved in 100 ml of dichloromethane, mixed with 6.3 ml (45 mmol) of triethylamine and at 0 ° C reacted with 5.04 ml (52 mmol) methanesulfonic acid chloride. After 30 minutes at room temperature, according to the DC no more starting material can be detected. The mixture is diluted with dichloromethane, washed with sodium hydrogen carbonate and with water. After the organic phase has dried, the solvent is evaporated off and the product is obtained as a pale yellow oil. Yield: 18.1 g (98% of theory)

Analysis (based on solvent-free substance): calculated: C 49.39 H 4.97 Br 16.43 N 2.88 S 6.59 found: C 49.21 H 4.92 Br 16.40 N 2.79 S 6.54

d) N-Benzyloxycarbonyl-l- (3-bromo-4-ethoxyben∑yl) -N '- (2-aminoethyl) ethylenediamine

17.0 g (34.9 mmol) of l-methanesulfonyloxy-N-benzyloxycarbonyl-3- (3-bromo-4-ethoxyphenyl) -2-aminopropane are dissolved in 100 ml of tetrahydrofuran at room temperature and mixed with 100 ml (1.48 mol ) Added ethylenediamine. After stirring for 36 hours, the mixture is evaporated to an oil and the residue is dissolved in ethyl acetate. It is washed neutral with water and the organic phase is dried over sodium sulfate. After evaporation, a yellow oil is obtained. Yield: 14.9 g (95% of theory)

Analysis (based on solvent-free substance): calculated: C 56.00 H 6.27 Br 17.74 N 9.33 found: C 56.21 H 6.32 Br 17.81 N 9.38

e) \ - (3-bromo-4-ethoxybenzyl) -N '- (2-aminoethyl) ethylenediamine, trihydrobromide

14 g (31 mmol) of N-benzyloxycarbonyl-1- (3-bromo-4-ethoxybenzyl) -N '- (2-aminoethyl) ethylenediamine are suspended in 39.1 ml (160 mmol) of glacial acetic acid at room temperature and mixed with 39.1 ml (160 mmol) of 33% hydrogen bromide in glacial acetic acid. After 24 hours at room temperature, the starting material is completely consumed. The reaction mixture is evaporated in an oil pump vacuum and the residue is distilled three times with toluene. The solid is mixed with water and evaporated to dryness. To remove remaining traces of water, the residue is evaporated three times with dichloromethane. The crude product is recrystallized from ethanol. Yield: 16.0 g (92.4% of theory) of colorless crystals

Analysis (based on solvent-free substance): calc .: C 27.93 H 4.51 Br 39.56 N 7.52 found: C 27.90 H 4.48 Br 39.29 N 7.49

f) 4- (3-bromo-4-ethoxybenzyl) -3, 6, 9-tris (tert-butoxycarbonylmethyl) - 3, 6, 9-triazaundecane-l, l 1-diacid, di- (tert-butyl ) -ester

15.0 g (26.8 mmol) of l- (3-bromo-4-ethoxybenzyl) -N '- (2-aminoethyl) ethylenediamine, trihydrobromide are suspended in 400 ml of tetrahydrofuran and with 29.6 g (215 mmol) of potassium carbonate and 15 ml of water, and 36.67 ml (250 mmol) of tert-butyl bromoacetate were added dropwise. The mixture is stirred for 12 hours at 60 ° C. and then overnight at room temperature. The salt is filtered off, washed with tetrahydrofuran and the filtrate evaporated. The crude product is purified using a silica gel column (mobile phase: dichloromethane / methanol). Yield: 22.4 g (94.2% of theory)

Analysis (based on solvent-free substance): calc .: C 58.23 H 8.18 Br 9.01 N 4.74 found: C 58.19 H 8.12 Br 8.96 N 4.70

g) 4- (3-bromo-4-ethoxyben∑yl) -3, 6, 9-tris (carboxylatomethyl) -3, 6, 9-triazaundecane-1,11-diacid

20.0 g (22.5 mmol) of 4- (3-bromo-4-ethoxybenzyl) -3,6,9-tris (tert-butoxycarbonylmethyl) -3,6,9-triazaundecane-1,11-diacid, Di (tert-butyl) esters are dissolved in a mixture of 400 ml of tetrahydrofuran and 40 ml of water and a solution of 6.4 g (160.8 mmol) of sodium hydroxide in 20 ml of water is added dropwise at room temperature. After a reaction time of 48 hours at room temperature, the Reaction mixture was concentrated in vacuo and the residue was distilled twice with water. The remaining residue is taken up in 300 ml of water and adjusted to pH 2.0 with a cation exchanger (H ⁺ form). The filtrate obtained after suction extraction from the ion exchanger supplies the pentacarboxylic acid as a colorless powder after freeze-drying.

Yield: 11.3 g (83% of theory)

Analysis (based on anhydrous substance): calc .: C 45.55 H 5.31 Br 13.17 N 6.93 found: C 45.62 H 5.38 Br 13.41 N 7.02

h) 4- (3-bromo-4-ethoxybenzyl) -3, 6, 9-tris (carboxylatomethyl) -3, 6, 9-triazaundecane-1,11-diacid, gadolinium complex, disodium salt

10.0 g (16.5 mmol) of 4- (3-bromo-4-ethoxybenzyl) -3,6,9-tris (carboxylatomethyl) - 3,6,9-triazaundecane-l, l 1-diacid are dissolved in 200 ml of water are dissolved and 3.0 g (8.25 mmol) of gadolinium oxide are added at 80 ° C. After a reaction time of 1 hour at 80 ° C., the now almost clear reaction solution is brought to room temperature and a pH of 7.2 is established by dropwise addition with 0.2 molar sodium hydroxide solution. After filtration, the reaction mixture is lyophilized. Yield: 12.7 g (96% of theory)

Analysis (based on anhydrous substance): calculated: C 34.33 H 3.38 Br 9.93 N 5.22 Gd 19.54 Na 5.71 found: C 34.26 H 3.34 Br 9.90 N 5.21 Gd 19.50 Na 5.68

Example 20

Gadolinium complex of the disodium salt of N, N-bis- [2- [N ', N'-bis- (carboxymethyl) aminoj-ethylj-p-iodophenylalanine

a) p-iodophenylalanine isopropyl ester, hydrochloride

50 ml of isopropanol are stirred at 0 ° C. under argon and 3.12 ml (41.6 mmol) of thionyl chloride are added dropwise. 30 minutes later, 10.0 g (34.4 mmol) of p-iodophenylalanine are added in portions, the mixture is stirred for one hour at room temperature and allowed to Then cook the mixture for two hours under reflux. After cooling to room temperature, the mixture is left to stand at 0 ° C. overnight and then the precipitated, colorless precipitate is filtered off with suction. Yield: 12.4 g (97.8% of theory)

Analysis: calculated: C 38.99 H 4.64 1 34.33 N 3.79 0 8.66 Cl 9.59 found: C 38.85 H 4.70 1 34.29 N3.78 Cl 9.66

b) N, N-bis- [2- [N ', N'-bis - [(tert-butyloxycarbonyl) methyl] amino] ethyl] -p-iodophenylalanine isopropyl ester

12.1 g (32.7 mmol) of the amine prepared according to Example 20a) and 25.4 g (72.0 mmol) of N, N-bis - [(tert-butyloxycarbonyl) methyl] -2-bromethylamine (M. Williams and

H. Rapoport, J. Org. Chem. 58, 1151 (1993)) are placed in 50 ml of acetonitrile and mixed with 20 ml of 2N phosphate buffer solution (pH 8.0). The mixture is stirred vigorously at room temperature for 24 hours, the aqueous phosphate buffer phase being exchanged for fresh buffer solution after 2 and 8 hours. Then the organic phase is evaporated in vacuo and the residue is chromatographed on silica gel with hexane / ethyl acetate / triethylamine (3: 1: 0.01). The product-containing fractions are evaporated in vacuo. Yield: 17.9 g (62.3% of theory) of a yellowish oil.

Analysis (based on solvent-free substance): calc .: C 54.85 H 7.60 1 14.49 N 4.80 0 18.28 found: C 54.80 H 7.65 1 14.41 N 4.74

c) N, N-bis- [2- [N ', N'-bis (carboxymethyl) amino] ethyl] p-iodophenylalanine

17.1 g (19.5 mmol) of the tert-butyl ester described in Example 20b) are dissolved in 250 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. The solution is then evaporated, the residue is stirred in water, filtered off and dried in vacuo.

Yield: 11.5 g (96.8% of theory) of a light beige solid

Analysis (based on anhydrous substance): calc .: C 41.39 H 4.63 I 20.82 N 6.90 O 26.26 found: C 41.33 H 4.56 I 20.78 N 6.93

d) Gadolinium complex of the disodium salt of N, N-bis- [2- [N ', N'-bis (carboxymethyl) amino] ethyl] -p-iodophenylalanine

A suspension of 7.43 g (12.2 mmol) of the penta acid prepared according to Example 20c) in 118 ml of water is mixed with 2.21 g (6.1 mmol) of gadolinium oxide and stirred at 80 ° C. for 2 hours. Then 24.4 ml of normal sodium hydroxide solution are added with a microburette and the mixture is stirred for 1 hour. The solution is then stirred at 80 ° C. for 2 hours after the addition of 0.5 g of activated carbon and filtered. After freeze-drying, the filtrate gives a colorless solid. Yield 9.12 g (92.6% of theory)

Analysis (based on anhydrous substance): calculated: C 31.23 H 2.87 1 15.72 N 5.20 0 19.81 Gd 19.47 Na 5.69 found: C 31.26 H 2.95 1 15.70 N 5.13 Gd 19.36 Na 5.74

Example 21

Gadolinium complex of the monosodium salt of N, N-bis- [2- [N ', N'-bis- (carboxymethyl) - amino] -ethyl] -glycine-N "- [3, 5-bis- (N'" - (2-Hydroxyethyl) carbamoyl) -2, 4, 6-triiodophenylcarbamoylmethyl] amide

a) N, N-bis- [2- [N ', N'-bis - [(tert-butyloxycarbonyl) methyl] amino] ethyl] -glycine-N "- [3,5-bis- ( N '"- (2-hydroxyethyl) carbamoyl) -2, 4, 6-triiodophenylcarbamoylmethyl] amide

22.1 g (31.5 mmol) 5-aminoacetylamino-2,4,6-triiodoisophthalic acid-N, N'-bis (2-hydroxyethyl) -diamide and 24.4 g (69.3 mmol) N, N -Bis - [(tert-butyloxycarbonyl) methyl] -2-bromethylamine (M. Williams and H. Rapoport, J. Org. Chem. 58, 1151 (1993)) are placed in 50 ml of acetonitrile and mixed with 20 ml of 2nd n Phosphate buffer solution (pH 8.0) added. The mixture is stirred vigorously at room temperature for 24 hours, the aqueous phosphate buffer phase being exchanged for fresh buffer solution after 2 and 8 hours. Then the organic phase in vacuo evaporated and the residue chromatographed on silica gel with dichloromethane / methanol (95: 5). The product-containing fractions are evaporated in vacuo. Yield: 21.9 g (55.8% of theory) of a yellowish oil.

Analysis (based on solvent-free substance): calculated: C 40.53 H 5.43 1 30.59 N 6.75 0 16.71 found: C 40.50 H 5.44 I 30.52 N 6.79

b) N, N-bis- [2- [N ', N'-bis- (carboxymethyl) amino] ethyl] -glycine-N "- [3,5-bis-

(N "'- (2-hydroxyethyl) carbamoyl) -2,4,6-triiodophenylcarbamoylmethyl] amide

20.8 g (16.7 mmol) of the tert-butyl ester described in Example 21a) are dissolved in 250 ml of trifluoroacetic acid and stirred at room temperature for 1 hour. Then the solution is mixed with tert-butyl methyl ether, the precipitate is separated off, washed with tert-butyl methyl ether and dried in vacuo. Yield: 16.9 g (98.9% of theory)

Analysis: calc .: C 30.61 H 3.46 1 37.31 N 8.24 0 20.38 found: C 30.77 H 3.58 I 37.25 N 8.28

c) Gadolinium complex of the monosodium salt of N, N-bis- [2- [N ', N'-bis (carboxymethyl) amino] ethyl] -glycine-N "- [3,5-bis- (N "'- (2-hydroxyethyl) carbamoyl) -2,4, 6-triiodophenylcarbamoylmethyl] amide

A suspension of 16.9 g (16.6 mmol) of the penta acid prepared according to Example 21b) in 130 ml of water is mixed with 3.00 g (8.28 mmol) of gadolinium oxide and stirred at 80 ° C. for 2 hours. Then 16.6 ml of normal sodium hydroxide solution are added with a microburette and the mixture is stirred for 1 hour. The solution is then stirred at 80 ° C. for 2 hours after the addition of 0.5 g of activated carbon and filtered. After freeze-drying, the filtrate gives a colorless solid. Yield 18.4 g (93.0% of theory)

Analysis (based on anhydrous substance): calculated: C 26.10 H 2.61 1 31.82 N 7.02 0 17.38 Gd 13.14 Na 1.92 found: C 26.11 H 2.74 1 31.84 N 7.06 Gd 13.10 Na 1.93

Claims

Patent claims

1. Metal complexes containing at least one ion of an element of atomic numbers 12, 13, 20-31, 39-42, 44-50 or 57-83 and a halogen-containing complex-forming ligand of the formula I.

ι

'3

Z (I)

wherein

R ^{1 represents} a hydrogen atom, a carboxylic acid residue, a straight-chain or branched

C ₆ -C ₁₅ aryl or a C ₇ -C ₁₅ aralkyl radical which is optionally substituted by 1-5 hydroxyl and / or 1-2 carboxy groups and / or is interrupted by 1-4 oxygen atoms, or in which R ^{1 is} represents a radical of the general formula II or UI,

4 5

-CO— NR R (II)

-CH ^ NR-CO-R ⁷

(III)

wherein

R ⁴ , R ⁵ independently of one another for a hydrogen atom, a straight-chain or branched

C ₆ -C ₁₅ aryl or a C ₇ -Ci ₅ aralkyl radical which optionally contains 1-5 hydroxyl, 1-2 carboxy groups and / or 1-4 oxygen atoms or in which R ⁴ , R ⁵ together including the Nitrogen atom, optionally containing an oxygen, a further acylated nitrogen atom or a sulfonyl group, optionally substituted with 1-3 hydroxyl groups, 5 or 6 ring,

R ^{6 represents} a hydrogen atom, a straight-chain or branched C _j -C - ^ - alkyl, C ₆ -C ₁₅ aryl or a C ₇ -C ₁₅ aralkyl radical, which optionally contains 1-4 hydroxyl, 1-2 carboxy groups and / or 1-2 oxygen atoms or wherein R ⁶ together with R ⁷ , including the nitrogen atom and the carbonyl group, optionally contains an oxygen, another acylated nitrogen atom or a sulfonyl group , optionally substituted with 1-3 hydroxy groups, 5 or 6 ring and

R ^{7 represents} a hydrogen atom, a straight-chain or branched C _r C ₁₅ alkyl, C ₆ -C ₁₅ aryl or a C ₇ -C ₁₅ aralkyl radical which optionally contains 1 to 2 hydroxyl groups or a carboxy group or in which R ⁷ together with R ⁶ , including the nitrogen atom and the carbonyl group, forms a 5 or 6 ring which may optionally contain an oxygen, another acylated nitrogen atom or a sulfonyl group and is optionally substituted by 1-3 hydroxyl groups,

R ² , R ³ independently of one another represent a hydrogen atom, a C _j -C ^ alkyl radical, a C ₆ -C ₁₅ aryl radical or a C ₇ -C ₁₅ aralkyl radical which is optionally substituted by 1-5 hydroxyl groups and / or by 1-4

Oxygen atoms is interrupted, stand or together form a trimethylene or tetramethylene group, or have the conditions specified for U ¹ (U ² ),

Z ¹ , Z ² , Z ³ independently of one another for a hydroxyl group or a radical

-NR ^ -U ^{1 '} , where

R ^{17 represents} a hydrogen atom, a methyl or methoxyethyl group and U ¹ , U ¹ ', U ² , V ¹ , V ² and V ³ each independently

Represent hydrogen atom or a halogenated aromatic radical of the general formula IV,

wherein

R ⁸ , R ⁹ independently of one another represent a group -NR ⁶ -CO-R ⁷ and / or the meaning given for R ¹ , with the exception of a C ₁ -C ₁₅ alkyl, C ₆ -C ₁₅ aryl or one Have C ₇ -C ₁₅ aralkyl radical,

R ¹⁰ , R ¹¹ independently of one another represent a halogen or a hydrogen atom,

10

X represents a halogen atom or a bridge member of the general formula V and

represents R ⁹ or a bridge member of the general formula V,

15

() ₍ CH ₂ ) _r - (C ₆ H ₄ ) _{! R} - (L1— R- (ß)

(V)

where m, n, p independently of one another represent the digits 0 or 1,

20 L for an oxygen atom, a sulfur atom, a C _r C ₄ -

Alkylene radical, a group> S = O,> SO ₂ or> NR ⁴ with R ⁴ in the meaning given and

R ¹² for a direct bond, a carbonyl, a carboxyl, a-CO-NR ¹⁸ -, a -NR ¹⁸ -CO-, a -NH-CS-, a CS-NH- group

25, in which R ^{18 represents} a hydrogen atom, a straight-chain or branched C _r C ₁₅ alkyl, C ₆ -C ₁₅ aryl or a C ₇ -C ₁₅ aralkyl radical which may be 1-4 hydroxy, 1-2 Contains carboxy groups and / or 1-2 oxygen atoms or wherein R ¹² for a straight-chain or branched C _r C -

30 alkylene radical, optionally a carbonyl and / or

Contains amino group, the position (α) being linked to the diylenediaminopentaacetic acid skeleton and the position (β) being linked to the halogenated aromatics, where Y is a bridge member of the formula V when X is halogen and Y is R ⁹ when X is a bridge member of the formula V and at least one of the radicals R ² , R ³ , Z ¹ , Z ² , Z ³ , U ¹ , U ² , V *, V ² or V ³ represents or contains the radical of the general formula IV and, if desired, free ones, not for complexing the metal ions of the abovementioned ones

Elements required carboxy groups are present as a salt of an inorganic and / or organic base or amino acid,

under at least one of the following provisions that R ⁸ and / or R ⁹ contains an aryl radical and / or that Z ¹ and / or Z ² only represent a radical of the general formula IV if at least one of the substituents R ² , R ³ , U ¹ , U ² , V ¹ , V ² or V ³ not for one

Is hydrogen atom, and / or that if Z ^{3 contains} a fully substituted aromatic of the formula IV Z ¹ and / or Z ² does not contain a fully substituted aromatic of the formula IV, and / or that if all substituents R ² , R ³ , U ¹ , U ² , Vl, V ² and V ^{3 represent} hydrogen, at least one of the radicals R ⁸ , R ⁹ , R ¹⁰ or R ^{11 represents} a hydrogen atom and / or R ⁸ and / or R ^{9 represent} a radical which is not directly bound

Contains carboxylic acid.

2. Halogen-containing metal complexes according to claim 1, characterized in that the radicals Z ¹ , Z ² , Z ^{3 represent} a hydroxyl group.

3. Halogen-containing metal complexes according to claim 1 and 2, characterized in that at least one of the radicals R ⁸ , R ⁹ , R ¹⁰ or R ^{11 represents} a hydrogen atom.

4. Halogen-containing metal complexes according to claim 1, 2 and 3, characterized in that U- ^ for a radical of formula VI

(VI) stands.

5. Halogen-containing metal complexes according to claims 1-4 containing a gadolinium ion as metal ion.

6. Halogen-containing metal complexes according to claims 1-4 containing iodine as halogen atom (s).

7. A compound according to claim 1, namely the gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- [4- (2,4,6-triiodobenzyloxy) benzyl] -undecanedioic acid.

8. Diagnostic agent containing at least one complex compound according to claim 1, optionally with additives customary in galenics.

9. Use of at least one metal complex for the production of agents for NMR and / or X-ray diagnostics.

10. Use of at least one metal complex for the production of agents for X-ray diagnosis of the liver.

11. A process for the preparation of the agents according to claims 1 to 6, characterized in that the complex salt dissolved in water is brought into a form suitable for enteral or parenteral administration with the additives or stabilizers customary in galenics, so that the complex salt is present in a concentration of 1 to 1500 mmol / 1.