NZ276413A

NZ276413A - 3,6,9-triaza-3,6,9-tris (carboxy methyl)-1,11-und-ecandioic acid derivatives containing halogenated (mono-, di- trisodo-benzyl) aromatic moiety

Info

Publication number: NZ276413A
Application number: NZ276413A
Authority: NZ
Inventors: Werner Krause; Franz Karl Maier; Wolf-Rudiger Press; Gabriele Schumann-Giampieri; Michael Bauer; Heribert Schmitt-Willich; Peter Mareski
Original assignee: Schering Ag
Priority date: 1993-12-03
Filing date: 1994-11-26
Publication date: 1998-04-27
Also published as: IL111817A; WO1995015306A1; HUT74389A; KR960706467A; CA2177977A1; DE4341724A1; CN1136805A; AU687477B2; ZA949604B; AU1067595A; EP0731784A1; HU9601478D0; JPH09506347A; NO962243L; NO962243D0; IL111817A0

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £76413 New Zealand No. 276413 International No. PCT/EP94/03919 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 03.12.1993; Complete Specification Filed: 26.11.1994 Classification:^) C07C229/08.76; C07C237/04.52; A61K49/00.04 Publication date: 27 April 1998 Journal No.: 1427 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: Aryl halide substituted metallic complexes, pharmaceuticals containing these complexes, their use for diagnostic purposes, and methods for preparing the complexes and pharmaceuticals Name, address and nationality of applicant(s) as in international application form: SCHERING AKTIENGESELLSCHAFT, a Federal Republic of Germany body corporate of Mullerstrasse 178, D-13353 Berlin, Federal Republic of Germany 276413 Haloaryl-Substituted Metal Complexes, Pharmaceutical Agents Containing these Complexes, Their Use in Diagnosis, as well as Process for the Production of the Complexes and Agents The invention relates to the objects characterized in the claims, i.e., new haloaryl-substituted metal complexes, pharmaceutical agents containing these complexes, their use in diagnosis as well as process for the production of the complexes and agents. Contrast media are indispensable auxiliary agents in modern diagnosis; thus, many diseases could not be diagnosed without the use of contrast media. Contrast media are used in all areas of diagnosis, such as, e.g., diagnostic radiology, radiodiagnosis or ultrasonic diagnosis 6r magnetic resonance tomography. The selection of the respectively preferred methods depends, i.a., on the diagnostic problem, but is also determined by the choice of apparatus respectively available to the physician. Thus, because of the considerable technical and associated high costs, nuclear spin tomography especially has not yet found the wide-spread use of other methods, such as, e.g., methods of diagnostic radiology. Also, the selection of the suitable contrast medium varies as a function of the respective problem. Thus, the suitability of the contrast medium for a specific object is last but not least determined by its (concentration) distribution behavior in the organism. 276413 Although great progress has been achieved with respect to equipment and contrast media, satisfactory solutions are not yet available for all problems. Thus, contrast media that are suitable for all indications do not yet exist for the various imaging processes. In CI particular, to this day, no suitable x-ray contrast medium for liver diagnosis is available. In diagnostic radiology, basically contrast media based on triiodobenzene have been able to gain acceptance, since these compounds exhibit a high x-ray opacity and a low general and local toxicity and are very readily water-soluble. Such compounds are described, e.g., in EP 0 105 725, EP 0 015 867. But the latter do not show any concentration, sufficient for imaging, in the liver. since the suitability of a compound as x-ray contrast medium, in addition to the concentration behavior in the j' respective organ, basically depends on the value of the mass attenuation coefficient of the elements that are contained in the compound, in the diagnostic radiation area, in addition to the iodine-containing compounds, metal complexes of an element with a high atomic number should also be suitable. Such compounds are widely used in the field of NMR diagnosis. In this case, there are generally metal complexes, as they are described, e.g., in EP 0 071 564. WO 93/16375 describes metal complexes, which are linked by amide bonds to iodine-substituted aromatic compounds. With only one administration of the contrast medium, these compounds are to 276413 make it possible to carry out both NMR and x-ray studies. A combination of the two imaging processes is advantageous in many cases for a differentiated visualization and a reliable determination of certain diseases. These compounds are to be suitable especially for angiography. But as the duplication of the production examples showed, the compounds show no concentration, sufficient for x-ray studies, in the area of the liver. Liver-specific NMR contrast media are described in EP 0 405 704. The latter in principle should also be suitable for diagnostic radiology because of the metal content in the complexes. A duplication of the experimental examples did not show sufficient contrasting of the liver in the x-ray picture even when a high dose was administered (conc.: 1 M/l, dose: 0.5 mmol of Gd/kg intravenously). A sufficient imaging effect in diagnostic radiology is achieved only with a dose in which the safety margin is reduced to a no longer justifiable measurement. It was therefore the object of this invention to make available very readily compatible and water-soluble contrast media, which are suitable especially for diagnostic radiology of the liver. This object is achieved by this invention. It has been found that metal complexes that contain 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 complexing ligand of 276413 formula I ■ > 1 2 2 3 2 v U RU R R V in which R1 stands for a hydrogen atom, a carboxylic acid radical, a straight-chain or branched 0,-0,5 alkyl radical, C6-C15 aryl radical, or a C7-C15 aralkyl radical, which optionally is substituted by 1-5 hydroxy groups and/or 1-2 carboxy groups and/or is interrupted by 1-4 oxygen atoms, or in which R' stands for a radical of general formula II or III, CO—NR4R5 (II) -CH2—NR6-CO-R7 (III) in which R4, R5, independently of one another, stand for a hydrogen atom, a straight-chain or branched 0,-0,5 alkyl radical, C6-C,5 aryl radical, or a 07-0,5 aralkyl radical, which optionally contains 1-5 hydroxy groups, 1-2 carboxy groups and/or 1-4 oxygen atoms, or in which RA, R5, togetheL" with incorporation of the nitrogen atom, form a 5- or 6-ring * optionally containing an oxygen atom, another acylated nitrogen atom or a sulfonyl group, optionally substituted with 1-3 hydroxy groups, 276413 R6 stands for a hydrogen atom, a straight-chain or branched 0,-0,5 alkyl radical, C6-C15 aryl radical or a C7-C,5 aralkyl radical, which optionally contains 1-4 hydroxy groups, 1-2 carboxy groups and/or 1-2 oxygen atoms, or in which R6 together with R7, with incorporation of the nitrogen atom and the carbonyl group, forms a 5- or 6-ring optionally containing an oxygen atom, another acylated nitrogen atom or a sulfonyl group, optionally substituted with 1-3 hydroxy groups, and R7 stands for a hydrogen atom, a straight-chain or branched C,-C,s alkyl radical, C6-C,5 aryl radical or a C7-C,5 aralkyl radical, which optionally contains 1 to 2 hydroxy groups or o carboxy group or in which R7 together with R6, with incorporation of the nitrogen atom and the carbonyl group, forms a 5- or 6-ring optionally containing an oxygen atom, another acylated nitrogen atom or a sulfonyl group, optionally substituted with 1-3 hydroxy groups, R2, R3, independently of one another, stand for a hydrogen atom, a C,-C,5 alkyl radical, a C6-C,5 aryl radical or a Cj-CK aralkyl radical, which optionally is substituted by 1-5 hydroxy groups and/or is interrupted by 1-4 oxygen atoms, or together form a trimethylene or tetramfethylene group, or have the meaning indicated for U1 (U2), # Z1, Z2, Z3, independently of one another, stand for a hydroxy group or a radical -NR17-U1', in which @ 276413 R17 stands for a hydrogen atom, a methyl or methoxyethyl group, and U1, U1', U2, V1, V2 and V3, respectively independently of one another, stand for a hydrogen atom or for a halogenated aromatic radical of general formula IV, (TV) in which R8, R9,, independently of one another, stand for a group -NR6-CO-R7 eind/or have the meaning indicated for R1, with the exception of a 0,-0,5 alkyl radical, C6-C,5 aryl radical or a C7-C,5 aralkyl radical, R10, R11, independently of one another, stand for a halogen atom or a hydrogen atom, X stands for a halogen atom or a bridge-type crosslink of general formula V, and Y stands for R9 or a bridge-type crosslink of general formula V (a) — (CH2) p— (C6H4) n— (L) R12— (B) (V) in which ra, n, p, independently of one another, stand for numbers 0 or 1, 276413 L stands for an oxygen atom, a sulfur atom, a C.,-C4 alkylene radical, a group >S=0, >S02 or >NR4 with R4 in the mentioned meaning, and R12 stands for a direct bond, a carbonyl, a carboxy 1, a -CO-NR18-, an -NR18-CO-, an -NH-CS- or a CS-NH group, in which R18 means a hydrogen atom, a straight-chain or branched Cj-C^ alkyl radical, C6-C15 aryl radical, or a C7-C15 aralkyl radical, which optionally contains 1-4 hydroxy groups, 1-2 carboxy groups and/or 1-2 oxygen atoms, or in which R12 stands for a straight-chain or branched C,—CA alkylene radical, which optionally contains a carbonyl group and/or an amino group, whereby position (a) is linked with the diethylenetriamine skeleton and position (6) is linked with the halogenated aromatic compound, whereby Y stands for a bridge-type crosslink of formula V, if X is equal to halogen, and Y stands for R9, if X stands for a bridge-type crosslink of formula V and at least one of radicals R2, R3, Z1, Z2, Z3, (J1, U2, V1, V2 or V3 stands for the radical of general formula IV or contains the latter, and optionally free carboxy groups, not required for complexing the metal ions of the mentioned elements, are present as salts of an inorganic and/or organic base or amino acid, with at least one of the following provisions, that R8 and/or R9 contains an aryl radical, and/or 276413 that Z1 and/or Z2 then stand for a radical of general formula IV only if at least one of substituents R2, R3, U1, U2, V1, V2 or V3 does not stand for a hydrogen atom, and/or that if Z3 contains a completely substituted aromatic compound of formula IV, Z1 and/or Z2 do not contain any fully substituted aromatic compounds of formula IV, and/or that if all substituents R2, R3, U1, U2, V1, V2 and V3 mean hydrogen, at least one of radicals R8, R9, R10 or R11 stands for a hydrogen atom, and/or R8 and/or R9 mean a radical which contains a carboxylic acid that is not directly bound, are excellently suited for the production of contrast media for NMR diagnosis and/or diagnostic radiology, preferably of contrast media for diagnostic radiology, especially for diagnostic radiology of the liver. The complexes according to the invention preferably contain as a metal ion a manganese(II) ion, iron(III) ion, iron(II) ion, praseodymium(III) ion, neodymium(III) ion, samarium(III) ion, dysprosium(III) ion, an ytterbium(III) ion or a bismuth(III) ion, especially a gadolinium(III) ion. As halogen atom(s), the complexes according to the invention contain (a) chlorine, bromine or iodine atom(s), preferably (a) bromine or iodine atom(s), but especially (an) iodine atom(s). Preferred halogenated aromatic compounds of formula IV are triiodized aromatic compounds, i.e., aromatic compounds in which X, R10 and R11 stand for iodine, and in which R8 and R9, independently of one another, stand for a hydrogen atom, for a 9 276413 group -OH, -COOH, -0~CH2-CH(0H)-CHz-OH, -0-CH3, -0-CH2-CH3, -CO-NH-CH(CH20H)-(CH0H-CH20H) , -CO-NR4-CH- (CH2OH) 2, -NR6-CO-CH2OH, -CO-NRa-CH2-CH2OH, -CO-NH2, -N(CHj) -CO-CH3, -NH-CO-CHJ, -CO-NH-CH3, -N(CH3)-C0-(CH2)2C00H, -CO-N-(C2Hs)2, -CO-N (CH3) -CH2-COOH, -CO-NH-(CH2) 10-COOH, -C0-NH-CH2-C6H4-0Et or a group -CO-N(CH3) -CH2-CH(OH) -CH2-OH, and in which Y stands for a bridge-type crosslink of formula V. Preferred bridge-type crosslinks of formula V are, if one of radicals - u stands for a halogenated aromatic radical, the groups -ch2-, -ch2-c6h4-o-ch2-, -ch2-o-ch2-, -ch2-o-, -ch2-o-co-, -ch2-nh-co-, -ch2-co-nh-, -ch2-c6h4-o-ch2-co~nh-, -ch2-o-co-nh-, -ch2-nh-c0-nh-, -nh-c0-, -nh-co-ch.,-, - Z stands for a halogenated aromatic radical, the groups -NH-CH2-C0-NH-, -NH CH2CH2-C0-NH- or -NH CH2CH2-NH-CO- and that - V stands for a halogenated aromatic radical, the groups -ch2-, -ch2-o-, -ch2-o-ch2-, -ch2-o-co-, -ch2-nh-co~, -ch2-co-nh-, -ch2-o-co-nh- or -ch2-nh-co-nh- . Especially preferred among them are the complexes in which U1 stands for the radical of general formula IV, i.e., compounds that are substituted with the halogenated aromatic compound in the ethylene bridge of the polyaminocarboxylic acid and in which Z stands for a hydroxy group. As radical R1, there are considered straight-chain or branched alkyl radicals, such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl radicals, but preferred are hydrogen, C.,-C4 alkyl and hydroxyalkyl radicals, such as, e.g., 276413 the hydroxymethyl radical as well as alkoxyalkyl radicals, such as, e.g., the methoxymethy1 radical. As radicals R2, R3, the radicals listed for R1 are considered, but hydrogen atoms are preferred. For diagnostic radiology of the liver, especially ionic complexes are preferred, in which free carboxy1 groups that are present in the molecule (i.e., carboxy1 groups that are not required for charge equalization of the metal ions of the elements of the mentioned atomic numbers) are present as free acids or as salts of an inorganic and/or organic base or amino acid. Suitable cations of inorganic bases are, for example, the lithium ion, the potassium ion, the calcium ion, the magnesium ion and especially the sodium ion. Suitable cations of organic bases are, i.a., those of the primary, secondary or tertiary amines, such as, e.g., ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethyl glucamine and especially N-methyl glucamine. Suitable cations of amino acids are, for example, those of lysine, arginine and ornithine. The production of the complexes according to the invention can be carried out in varied ways. The various processes as well as the initial compounds required for them are known in principle to one skilled in the art. Thus, the compounds generally can be produced analogously to the already known complexes or complexing agents, by reaction of a reactive species of the halogenated aromatic compounds with a reactive species of the complexing agent in a suitable solvent. The selection of the method of 276413 synthesis most suitable in each case depends on the desired linkage point between the halogenated aromatic compound(s) and the polyaminopolycarboxylic acid. Accordingly, the complexes can be divided into three groups. Thus, the halogenated aromatic compound(s) can be bound I) to the a-carbon atoms of the carboxylie acid (acetic acid) radical, II) to the alkylene (ethylene) bridges or III) to the carboxylic acid group(s) of the polyaminopolycarboxylic acid. Complexing agents or complexes of group I can be produced analogously to the processes that are described in European Patent Application EP 0 230 893. Other universally applicable possibilities of synthesis for the complexing agents will be mentioned as examples below. Thus, by reaction of chloroacetic acid derivatives of general formula VI CI CO2H r° (vi) in which R13 is the desired halogenated aromatic radical of general formula IV or an optionally still unhalogenated precursor 12 276413 of this radical, with polyamines of general formula VII H,NS ^ "7T H I, (vn) first compounds of general formula VIII can be obtained, (viid which then are reacted in a way known in the art with haloacetic acid esters, preferably with bromoacetic acid esters, and then — if a precursor of the respectively desired aromatic compound is involved — are halogenated in a way known in the art and optionally present ester groups or protective groups are cleaved in a way known to one skilled in the art. Disubstitution can also be achieved with corresponding stoichiometry. An alternative process for the production of a-C-substituted polyaminopolycarboxylic acids starts from an acid-protected polyaminocarboxylic acid (e.g., from the pentamethyl ester of * diethylenetriaminepentaacetic acid). The latter is reacted with the lithium salt of a precursor of the desired aromatic compound. A corresponding lithium salt can be obtained from the benzyl 13 276413 halide (e.g., 3-nitrobenzyl chloride, 3,5-dinitrobenzyl chloride, 3-benzyloxybenzyl chloride) by reaction with lithium diisopropylamine in THF/hexane. Following the coupling, the aromatic compound is reacted to the desired halogenated aromatic compound of formula IV, e.g., by the optionally present nitro groups being reduced to amino groups, vhich are optionally reacted with acetyl chloride to the amide; benzyloxy radicals can be converted to hydroxy radicals, e.g., by catalytic hydrogenation. The iodization of the aromatic compound is also carried out in a way known in the art, e.g., by reaction with iodomonochloride solution in hydrochloric acid medium. Before the introduction of the iodine atoms, the acid protective groups of the pentaester are saponified in the basic medium. An alternative process for the production of iodine-containing polyaminopolycarboxylic acids starts from an a-amino acid derivative of general formula XXIII X (xxdd whose primary amino group optionally can also be present in protected form (e.g., as monobenzylamine). This amino group is dialkylated on a nitrogen atom with an alkylating agent of 14 276413 formula XXIV v'u' R1 u2 z'-co-l^ y~-( N Nf ruooc (XXIV) and then — after cleavage of the optionally present protective groups — with an alkylating agent of formula XXV R2 R3 V2 /i-co-z2 Nf N Vc00R'4 (XXV) whereby Nf stands for a nucleofuge, such as, e,g., chloride, bromide, iodide, methanesulfonate or toluenesulfonate, and Ru stands for an acid protective group, such as, e.g., a lower alkyl, aryl, aralkyl or trialkylsilyl group, and R1, R2, R3, U1, U2, V1, V2, V3, Z1, Z2 and Z3 have the previously indicated meaning. Synthesis for the production of an a-C-substituted polyaminopolycarboxylic acid starts from, e.g., a phenylamino acid, such as, e.g., 3-aminophenylalanine. The latter is first halogenated in a way known in the art, the acid group then protected as ester. The thus obtained intermediate product is * reacted with two equivalents of N,N-bis[(benzyloxycarbonyl)-methyl]-2-bromomethylamine. Before the cleavage of the acid 15 276413 protective groups; the substituents of the aromatic compound are optionally converted to the desired radicals. The production of the complexing agents of group II can be carried out analogously to the methods that are described in EP o 405 704 as well as DE 43 02 289 , corresponding to EP 680467. Thus, the process starts from, e.g., known compounds (DE 37 10 730, corresponding to EP 35557622 and literature cited there) of general formula IX, OH 9^ 9*2 gogr14 ooorm ooor" (ix) in which R14, R1, R2 and R3 have the indicated meanings, in which the phenolic OH group is reacted with a reactive form of the desired halogenated aromatic compound (or its precursor, e.g., 276413 benzyl halide) of formula X in which R8', R9', R10' and R11' stand for desired groups R8, R9, R10 and R11 or a precursor of the latter. If groups R8', R9', R10' and R11' stand for precursors of the desired groups, the latter are generated from those. Acid protective groups Ru are cleaved in a known way [see, e.g., E. Wiinsch, Methoden der Org. Chemie [Methods of Org. Chemistry] (Houben Weyl), Vol. XV/1, 4th Edition, 1974, p. 315 ff], for example, by hydrolysis, hydrogenolysis or alkaline saponification, generally before the halogenation of the aromatic compound. Both acidic and aqueous-alkaline reaction conditions can be selected for the cleavage of the t-butyl esters that are especially advantageous for this reaction. In the compounds of general formula IX, the aromatic radical can also be iodized, e.g., with iodomonochloride, in a way known in the art. Optionally, the phenolic -OH groups can be ♦ etherified in a way known in the art with alkyl halide/sodium hydride. The cleavage of the acid protective groups is carried out in the previously described way. 17 276413 An alternative process also starts from halogen-containing chlorinated aromatic compounds of formula X, which are reacted with a partially protected glycerol, first to the corresponding dihydroxypropyloxy compound of formula XI 9' R which then are reacted after partial protection of one hydroxy group and activation of the remaining group with sodium azide to the corresponding azido compound of general formula XII 9' R R OR (XII) in which R15 stands for a protective group, such as, e.g., a benzyl group. After cleavage of OH-protective group R15 and activation of the resulting hydroxy group, e.g., as methanesulfonic acid ester, * the reaction is first performed with the corresponding ethylenediamine and then the azide group is reduced in a way 276413 known in the art, e.g., with triphenylphosphine, to compounds of formula XIII The latter are reacted in a known way with bromoacetic acid ester to the corresponding pentaesters. After cleavage of the acid protective groups, e.g., by reaction with trifluoroacetic acid and generation of desired groups R8, R9, R10 and R11 from groups R8', R9', R10' and R11', the desired complexing agents are obtained. An alternative process for the production of complexing agents of group II starts from acid-protected polyaminocarboxylic acid derivatives of general formula XIV R R F R oh chj ch, ch, ! W I M I W OOCR ooor coor .(XIV), 19 276413 which are reacted with isocyanato compounds of general formula XV N=C~0 (xv) to the corresponding urethanes. As an alternative, the hydroxy group in the compounds of general formula XIV can also be reacted, e.g., with N-chlorosuccinimide to the corresponding chloride of formula XVI a R1 R2 r ocg—^ ^^ R \ r -ooor CH, ca, CH, coor14 am14 oooR14 (xvi). The latter is then reacted in a way known in the art with a reactive species of a desired (e.g., hydroxy-group-containing or carboxy-group-containing) halogenated aromatic compound of formula XVII (XVIt) 20 276413 in which R8, R9, R10 and R11 have the indicated meanings and Y' stands for an OH or COOH group, to the corresponding ethers or esters. The cleavage of acid protective groups Ru is carried out in the above-described way. As an alternativef the compounds of general formula XVI can be reacted with an azide (e.g., sodium azide) to the corresponding azido compound, which then is reduced in a known way to the amino compound. The latter is then a) either reacted with an isocyanato compound of formula XV to the corresponding urea derivative or b) reacted with a halobenzoyl chloride of formula XVIII (xvm) to the corresponding amide. An alternative process starts from an aminoethyl alcohol of formula XIX, R0' Rl H \ N OH R (XIX) in which R16 stands for an amino protective group, preferably a benzyloxycarbonyl group and R13' means an unhalogenated precursor 276413 of the desired aromatic compound, or a "linker," to which the desired halogenated aromatic compound is bound in a later reaction step. The aminoethyl alcohol is reacted first in a way known in the art, e.g., with methanesulfonic acid chloride, toluenesulfonic acid chloride or trifluoroacetic anhydride to the corresponding mesylate, tosylate or triflate and then it is reacted with an optionally substituted ethylenediamine. If, in the case of R13', an unhalogenated precursor of the desired aromatic compound of general formula IV is involved, it is iodized, e.g., with iodomonochloride; if, however, a "linker" is involved, the latter is brought to reaction with a reactive species of the desired aromatic compound (or its unhalogenated precursor). Finally, the amino protective groups are cleaved and reacted with haloacetic acid ester to the desired amino acids (complexing agents). The complexing agents of group III, i.e., complexing agents in which the halogenated aromatic radical is bound in the form of an amide bond to the carboxylic acid groups of the polyaminopolycarboxylic acid, can be produced analogously to the processes that are described in DE 42 32 925. Thus, the complexing agents can be produced by partial conversion of activated carboxyl groups, e.g., of the desired pentacarboxylic acid, to amide groups. For this process, all synthesis possibilities known to one skilled in the art are considered, such as, e.g., the reaction of the acid anhydrides of 22 276413 general formulas XX or XXI with halogenated aromatic compounds of general formula XXII to the amides according to the invention, CGCH (XX) OOOH Rr / R5' N. HDOC/XN/\/ ^N" J R" 0 Hoocr (XXI) (xxn) in which R8', R9', R10' and R11' stand for desired groups R8, R9, R10 and R11 or a precursor of the latter, and Q stands for the radical of a linker of general formula V. The production of the • » 276413 aromatic compounds of general formula XXII is carried out as described, e.g., in DE 25 23 567 , corresponding to US 4005188. As radical h2n-q, there can be mentioned as examples an h2n-ch2-co-nh, h2n-nh-co-nh, h2n-ch2ch2-co-nh, h2n-nh-co-ch2ch2, h2n-chgchg—nh-co group or an h2n-ch2ch2-n(co-chj) group. This reaction is carried out in liquid phase. Suitable reaction media are, for example, water, dipolar aprotic solvents, such as diethyl ether, tetrahydrofuran, dioxane, acetonitrile, N-methylpyrrolidone, dimethyIformamide, dimethylacetamide and the like or mixtures thereof. Thfe reaction temperatures are between about -80°C and 160°C, and temperatures of 20°C to 80°C are preferred. The reaction times are between 0.5 hour and 7 days, preferably between 1 hour and 36 hours. The production of acid anhydrides of general formula XX can be carried out according to known processes, e.g., according to the process with acetic anhydride in pyridine that is described in US 3,660,388 or in DE 16 95 050 , corresponding to GB 1161461. But in certain cases, it is advantageous to undertake gently the dehydration with carbodiimides in a suitable solvent, such as, e.g., dimethylformamide or dimethylacetamide. The production of the monoanhydrides of general formula XXI is described in J. Pharm. Sci., 68 (1979) 194. The halogenated aromatic compounds that are used in the various processes are known or can be generated easily from the knotr*. compounds. Thus, e.g., in German laid-open specification DE 29 28 417, corresponding to EP 22744, iodized aromatic compounds are described, which are readily 276413 reacted with, e.g., thionyl chloride, to the corresponding acid chloride group-containing avomatic compounds. Other aromatic radicals can be produced as described in M. Sovak; Radiocontrast Agents, Handbook of Experimental Pharmacology Vol. 73 (1984), Springer Verlag, Berlin -Heidelberg - New York - Tokyo or in European Patent EP 0 015 867. Corresponding chlorine or bromine compounds can be produced as described in patents EP 0 055 689 , EP 0 073 715 or EP 0 118 347 — or analogously to the compounds that are described there. Amino group-containing aromatic compounds, as they are required, e.g., for the production of acetic acid-substituted compounds of group III, can be obtained analogously to the compounds that are described in DE 25 23 567» corresponding to US 4005188. The production of the metal complexes according to the invention from the above-described complexing agents of groups I-III is carried out in the way as disclosed in patents EP 0 071 564, EP 0 130 934 and DE 34 01 052,corresponding to AU 8423559, by 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 being dissolved or suspended in water and/or a lower alcohol (such as methanol, ethanol, isopropanol and or N,N-dimethyIformamide) and reacted with the solution or suspension of the equivalent amount of the complexing agent. If desired, other acidic hydrogen atoms of acid groups can then be substituted by cations of inorganic and/or organic bases or amino acids. 276413 As bases, inorganic bases (e.g., hydroxides, carbonates or bicarbonates) of, e.g., sodium, potassium or lithium and/or organic bases, such as, i.a., primary, secondary and tertiary amines, such as, e.g., ethanolamine, morpholine, glucamine, N-methyl glucamine and N,N-dimethyl glucamine, as well as basic amino acids, such as, e.g., lysine, arginine and ornithine, are suitable. To provide neutral complex compounds, enough of the desired bases can be added, for example, to the acid complex salts in aqueous solution or suspension to ensure that the neutral point is reached. The solution obtained can then be evaporated to dryness in a vacuum. Often, it is advantageous to precipitate the neutral salts formed by adding water-miscible solvents, such as, e.g., lower alcohols (methanol, ethanol, isopropanol, etc.), lower ketones (acetone, etc.), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.) and thus to obtain easily isolated and readily purified crystallizates. It has proven especially advantageous to add the desired base as early as during the complexing of the reaction mixture and thus to save a process step. If the acid complex compounds contain several free acid groups, it is often suitable to produce neutral mixed salts, which contain both inorganic and organic cations as counterions. This can happen, for example, by the complexing acid being t reacted in aqueous suspension or solution with the oxide or salt of the element supplying the central ion and half of the amount of an organic base required for neutralization, the complex salt 276413 formed being isolated, optionally purified and then being mixed with the required amount of .inorganic base for complete neutralisation. The sequence of addition to the base can also be aother object of the invention are agents that contain at least one of the compounds according to the invention. The invention further relates to a process for the production of these agents, which is characterized in that the paramagnetic complex salt that is dissolved in water is brought into a form that is suitable for enteral or parenteral administration with the additives and stabilizers that are commonly used in galenicals, so that the complex salt is present at a concentration of 1 to 1500 mmol/1, preferably at 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 optionally sterilized. They are administered generally in a dose of 1-300 ml on the basis of the halogen content and the diagnostic problem. Suitable additives are, for example, physiologically harmless buffers (such as, e.g., tromethamine), small additions of complexing agents (such as, e.g., diethylenetriaminepentaacetic acid) or, if necessary, electrolytes, such as, e.g., sodium chloride or, if necessary, antioxidants, such as, e.g., ascorbic acid. If suspensions or solutions of the agents according to the invention in water or physiological salt solution are desired for enteral administration or other purposes, they are mixed with one 276413 or more adjuvants that are commonly used in galenicals (e.g., methyl cellulose, lactose, mannitol) and/or surfactants (e.g., lecithins, Tween(R), Myrj(R> and/or flavoring substances for taste correction (e.g., essential oils). In principle, it is also possible to produce the diagnostic agents according to the invention even without isolating the complex salts. In each case, special care must be used to undertake the chelation, so that the salts and salt solutions according to the invention are virtually free of noncomplexed metal ions that have a toxic effect. This can be ensured, for example, using color indicators, such as xylenol orange, by control titrations during the production process. The invention therefore relates also to processes for the production of complex compounds and their salts. As a final precaution, there remains purification of the isolated complex salt. Further objects of the invention are characterized by the claims. The substances according to the invention meet the varied requirements that are to be set for contrast media in modern diagnosis. The compounds and agents produced from them are distinguished by: — a high absorption coefficient for x rays, — good compatibility, which is necessary to maintain the ♦ noninvasive nature of the studies, — high effectiveness, which is necessary to burden the body with the smallest possible amounts of foreign substances, 276413 — good water-solubility (this makes it possible to produce highly concentrated solutions, as they are necessary especially for use as x-ray contrast media. Thus, the volume burden of the cycle can be kept within reasonable limits), — low viscosity, — low osmolality, — advantageous elimination kinetics. Further, the agents according to the invention exhibit not only high stability in vitro, but also surprisingly high stability in vivo, so that a release or an exchange of the ions that are not covalently bound to the complexes — toxic in themselves — is not carried out within the time in which the new contrast media are again completely excreted. In addition to the high water solubility, which it was possible to increase, surprisingly enough, in the presence of paramagnetic metal ions in a range necessary for diagnostic radiology, the compounds according to the invention have a positive effect in diagnostic radiology, in that the complex compounds according to the invention, surprisingly enough, allow for studies with more shortwave x-ray radiation than is possible with conventional contrast media, by which the radiation exposure of the patient is considerably reduced, since soft radiation, as is generally known, is a great deal more strongly absorbed by the tissue than hard radiation (R. Felix, Das RSntgenbild [The X-Ray ♦ Picture]; Thieme Stuttgart 1980). Because of the advantageous absorption properties of the contrast media according to the invention in the area of hard x- 276413 ray radiation, the media are also especially suited tor digital subtraction techniques (which operate at higher tube voltages). Especially to be emphasized is the advantageous in vivo distribution behavior of the media according to the invention. This allows for the first time for taking x-ray pictures of high diagnostic informative value in the area of the liver with a dose that is commonly used for x-ray contrast media (halogen content: 50-400 mg/ml; dose 0.1-1 ml/kg of body weight). Thus, the complexes according to the invention already produce an optimum contrast of the liver at a dose of 0.5 mmol/kg. Figure 1, upper picture, shows the liver of a rat before the contrast medium is administered. 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 produced according to Example Id). A picture taken under oth<:> wise identical conditions after 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 is administered (EP 0 405 704; Example 8c) does not show any diagnostically usable contrasting of the liver (see Fig. 2, lower picture). The upper figure shows the liver before the administration of contrast medium. In comparison, Figure 3 shows the density enhancement (which can be regarded as a measurement for the effectiveness of a contrast medium) acs a function of time, for a compound according to the invention (Example Id) and a compound of EP 0 405 704 (Example 8c). Accordingly, considerably higher density values 30 276413 are observed in the liver of the rat over the entire period of study for the compound according to the invention. Thus, the maximum values for the substance according to the invention are approximately 60 Houndsfield units (HU), but only 15 HU for the comparison substance. The studies were performed on a somatome plus VD31 (parameter of study: 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 each of the respective substance. Also, the complexes that are described in WO 93/16375 do not show any concentration in the liver that is sufficient for imaging. Thus, the isomeric gadolinium complex of l,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-pentatriazadecane (Example 17b), in Example 1 of WO 93/16375, was excreted almost completely through the kidneys. Only 1.3% of the total amount was eliminated in other ways from the body. Even assuming that this 1.3% of the complex had been completely concentrated in the liver, this amount would be far below the dose that is required for an imaging effect. These studies were performed on female rats (90-110 g of body weight) after intravenous administration of 0.27 mmol/kg of compound 17b). The iodine concentration in the blood, urine, « feces, as well as liver, kidneys, spleen, bones, was measured with x-ray fluorescence analysis. In addition, the gadolinium concentration was determined with ICP-atom emission spectroscopy. 276413 The half-life of 0.32 hour as well as the distribution volume show a distribution in the extracellular space with renal elimination by glomerular filtration through the kidneys. The agents according to the invention, which contain in the complex a paramagnetic metal ion of an element of atomic numbers 21-29, 42, 44 or 57-70, can be used, in addition to use in diagnostic radiology, also in NMR diagnosis. This dual nature opens up further fields of use. Thus, these agents according to the invention can always be used advantageously, if a combination of diagnostic radiology and NMR diagnosis is necessary for differentiated visualization and reliable determination of certain diseases. This is true, e.g., in the case of suspicion of recurrence after tumor operations or radiation therapies. In these cases, the patient is spared an additional burden resulting from double administration by using a contrast medium, which is equally suitable for both techniques. Taken overall, it has been possible to open up new possibilities in diagnostic medicine with the above-mentioned complex compounds. The following examples are used for a more detailed explanation of the object of the invention, without intending to be limited to these examples. 276413 Example 1 Gadolinium complex of the disodium salt of 3/6,9-triaza-3,6,9-tris-(carboxymethyl)-4-[4-(2,4,6-triiodobenzyloxy)-benzyl]-undeoanedioio acid a) Production 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) is suspended in 416 ml of glacial acetic acid and mixed in portions with a suspension of 6.08 g (88.1 mmol', of sodium nitrite in 40 ml of concentrated sulfuric acid while being stirred. The reaction temperature is held 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 until nitrogen generation is completed at room temperature. Then, the su,pension is cooled to 10°C, filtered, the residue is absorptively precipitated for 30 minutes with 300 ml of N,N-dimethylformamide, and the suspension is filtered. The filtrate is concentrated by evaporation in a vacuum, the residue is absorptively precipitated with water, filtered off and dried in a vacuum. 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 results. The latter is suctioned off and dried in a vacuum. Yield: 29.8 g (73.8%) of light beige solid 27 b413 Analysis (relative to solventless substance): cid: C 16.67 H 0.80 CI 7.03 I 75.50 Fnd: C 16.82 H 0.95 CI 7.14 I 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) is 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, produced according to Example la), is added to the above and 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 on Na2S04 and concentrated by evaporation. The residue is chromatographed on silica gel 60 (Merck) with hexane/methyl acetate/triethylamine, the product fractions are concentrated by evaporation and dried in a vacuum. Yield: 22.8 g (91.2% of theory) of yellowish oil Analysis (relative to solventless substance): cid: C 46.20 H 5.82 I 30.51 N 3.37 0 14.10 Fnd: C 46.37 H 5.93 I 30.44 N 3.35 276413 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 lb) is dissolved in 250 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. Then, the solution is mixed with tert-butyl methyl ether, the precipitate is suctioned off, washed with tert-butyl methyl ether and dried at 40°C in a vacuum on phosphorus pentoxide. The crude product is absorptively precipitated in water, filtered off and dried in a vacuum. Yield: 15.4 g (86.8% of theory) of light beige solid Analysis (relative to anhydrous substance): Cid: C 34.77 H 3.33 I 39.36 N 4.34 0 18.19 Fnd: C 34.63 H 3.56 I 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, produced 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 IN sodium hydroxide solution is added with a microburette and stirred for 1 more hour. Then, ♦ after 0.5 g of activated carbon is added, the solution is stirred for 2 hours at 80°C and filtered. After freeze-drying, the filtrate yields a colorless solid. 276413 Yield: 13.1 g (91.8% of theory) Analysis (relative to anhydrous substance): Old: C 28.86 H 2.34 I 32.67 N 3.61 0 15.10 Gd 13.49 Na 3.95 Fnd: C 28.66 H 2.43 I 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-triiodobenzyl chloride 42.5 g (79.7 mmol) of 3-methylamino-2,4, 6-triiodobenzyl chloride (Collection Czechoslov. Chem. Commun. [Vol. 41] 1976) is dissolved in 180 ml of N,N-dimethylacetamide and mixed drop by drop with 13.7 ml (191.3 mmol) of acetyl chloride while being cooled with ice. After 30 minutes of stirring at about 0°C, it is stirred for 12 hours at room temperature and the dark brown solution is introduced in water while being stirred. A precipitate is precipitated, which is suctioned off and dried in a vacuum. Yield: 44.6 g (99.6% of theory) of light beige solid Analysis (relative to anhydrous substance): cid: C 20.88 H 1.58 CI 6.16 I 66.17 N 2.43 O 2.78 Fnd: C 20.98 H 1.69 C1 6.04 I 66.18 N 2.52 276413 b) 3,6,9-Triaza-3,6,9-tris-(tert-butoxycarbonylmethyl)-4-[4-(N-acety 1-3-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> corresponding to EP 357622) is mixed 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, produced according to Example 2a) , is added to the above and 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 on Na2S04 and concentrated by evaporation. The residue is chromatograpiied on silica gel 60 (Merck) with hexane/methyl acetate/triethylamine, the product fractions are concentrated by evaporation and dried in a vacuum. Yield: 23.5 g (89.2% of theory) of yellowish oil Analysis (relative to solventless substance): cid: C 46.45 H 5.89 I 28.87 N 4.2^ 0 18.49 Fnd: C 46.63 H 5.96 I 28.72 N 4.18 c) 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-[4-(N-acetyl-3-methylamino-2,4, 6-triiodobenzyloxy) -benzyl]-undecanedioic acid 21.9 g (16.6 mmol) of the tert-butyl ester described in Example 2b) is dissolved in 250 ml of trifluoroacetic acid and 276413 stirred for 1 hour at room temperature. Then, the solution is mixed with diethyl ether; the precipitate is suctioned off, washed with diethyl ether and dried at 40°C in a vacuum on phosphorus pentoxide. The crude product is absorptively precipitated in water, filtered off and dried in a vacuum. Yield: 16.2 g (94.1% of theory) of light beige solid Analysis (relative to anhydrous substance): cid: C 35.86 H 3.59 I 36.67 N 5.40 0 18.49 Fnd: C 35.73 H 3.75 I 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-triiodobenzyloxy)-benzyl]-undecanedioic acid A suspension of 14.8 g (14.3 mmol) of the penta acid, produced according to Example 2c), 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. Then, 28.5 ml of IN sodium hydroxide solution is added with a microburette and stirred for one more hour. Then, after 0.8 g of activated carbon is added, the solution is stirred for two hours at 80°C and filtered. After concentration by evaporation, the filtrate yielded a colorless solid. Yield: 16.4 g (93.3% of theory) * Analysis (relative to anhydrous substance): Cid: C 30.11 H 2.61 I 30.79 N 4.53 O 15.53 Gd 12.72 Na 3.72 Fnd: C 30.00 H 2.82 I 30.58 N 4.67 Gd 12.79 Na 3.82 276413 Example 3 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-triiodobenzyloxy]-benzyl}-undecanedioic acid a) N- (5-0xa-l,4-dioxoheptyl) -3-methylamino-2,4,6-triiodobenzyl chloride 24.7 g (150 mmol) of succinic acid chloride monoethyl ester is added at room temperature to a suspension of 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, stirred with exclusion of moisture. The batch is refluxed for several hours until no more feedstock can be detected according to thin-layer chromatography; then, it is concentrated by evaporation, the residue is taken up in dichloromethane and shaken out with saturated aqueous sodium bicarbonate solution. After drying on anhydrous magnesium sulfate, the organic phase is concentrated by evaporation, and the residue is recrystallized from ethyl acetate/tert-butyl methyl ether. Yield: 58.4 g (88.3% of theory) of colorless solid Analysis (relative to solventless substance;: Cid: C 25.42 H 2.29 Cl 5.36 I 57.56 N 2.12 O 7.26 Fnd: C 25.31 H 2.49 Cl 5.43 I 57.50 N 2.17 276413 b) 3,6,9-Triaza-3,6,9-tris-(tert-butoxycarbonylmethyl)-4-{4-[N-(5-oxa-l, 4-dioxo-heptyl) -3-m®thylamino-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, corresponding to EP 357622) is mixed 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, produced according to Example 3a), is added to the above and 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 on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel 60 (Merck) with hexane/ethyl acetate/triethylamine, the product fractions are concentrated by evaporation and dried in a vacuum. Yield: 22.9 g (81.6% of theory) of yellowish oil Analysis (relative to solventless substance): Cid: C 47.02 H 5.95 I 27.10 N 3.99 0 15.94 Fnd: C 46.86 H 6.13 I 26.98 N 3.84 c) 3,6,9-Triaza—3,6,9-tris-(carboxymethyl)-{4-[N-(3-carboxypropionyl)-3-methylamino-2,4,6-triiodobenzyloxy]-benzyl}-undecanedioic acid 20.4 g (14.5 mmol) of the hexaester described in Example 3b) is dissolved in 100 ml of methanol and mixed with 87 ml of 2N 276413 sodium hydroxide solution. It is refluxed for about 2 hours, the methanol is drawn off in a vacuum and, after 100 ml of water is added, it is stirred for another 2 hours at 60°C. By adjusting to pH 1-2 with semiconcentrated hydrochloric acid, a colorless precipitate results, which is suctioned off and dried in a vacuum. Yield: 15.3 g (96.0% of theory) of colorless solid Analysis (relative to anhydrous substance): Cid: C 36.15 H 3.59 I 34.72 N 5.11 O 20.43 Fnd: C 36.23 H 3.65 I 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-triiodobenzyloxy] -benzyl}-undecanedioic acid A suspension of 14.1 g (12.9 mmol) of the hexa acid, produced 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 IN sodium hydroxide solution is added with a microburette and stirred for 1 more hour. Then, after 0.8 g of activated carbon is added, the solution is stirred at 80°C for 2 hours and filtered. After freeze-drying, the filtrate yielded a colorless solid. Yield: 16.3 g (96.4% of theory) 276 4 13 Analysis (relative to anhydrous substance): Cid: C 30.11 H 2.53 I 28.92 N 4.26 0 17.01 Gd 11.94 Na 5.24 Fnd: C 30.01 H 2.64 I 28.88 N 4.34 Gd 11.86 Na 5.02 Example 4 Gadolinium complex of 3,6,9-triaza-3,6,9-tri®-(carbcxymethyl)-4-(3,5-diiod-4-ethoxybenzyl)-undecanedioic acid, disodium salt a) 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-(4-hydroxybenzyl)-undecanedioic acid 7.8 g (10 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> corresponding to EP 357622) is dissolved in 100 ml of trifluoroacetic acid and stirred for 1.5 hours at room temperature. Then, it is diluted with diethly ether, and the precipitate is suctioned off. 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 freeze-dried several times to remove residual trifluoroacetic acid. Yield: 4.0 g (80.1% of theory) of colorless lyophilizate. Elementary analysis (taking into consideration the solvent content): Cid: C 50.50 H 5.85 N 8.41 O 35.24 Fnd: C 50.68 H 5.99 N 8.25 276413 b) 3/6#9-Triaza-3,6/ 9-tris-(carboxymetiiyl) -4-(3,5-diiodo-4-hydroxybenzyl)-undecanedioic acid 3.2 g (6.4 mmol) of the phenol of Example 4a) is suspended in 50 ml of watt r and mixed with solid sodium hydroxide up to the neutral point. The batch is stirred at 50°C, and 5.7 ml (14.1 mmol) of a 40% hydrochloric acid-iodomonochloride solution is added in drops. After 20 hours at 50°C, the excess iodine is reduced with sodium disulfite, the precipitate is suctioned off and washed with water. Yield: 4.15 g (86% of theory) of pale yellow solid Elementary analysis (taking into consideration the solvent content): cid: C 33.57 H 3.62 I 33.78 N 5.59 O 23.43 Fnd: C 33.71 H 3.86 I 33.41 N 5.65 c) 3,6,9-Triaza-3,6,9-tris- (carboxysiethyl) -4-(3,5-diiodo-4-ethoxybenzyl)-undecanedioic acid 3.0 g (4 mmol) of the diiodophenol of Example 4b) is mixed in 25 ml of anhydrous tetrahydrofuran with 0.792 g (26.4 mmol) of 80% sodium hydride suspension in mineral oil. 4.1 g (26.4 mmol) of ethyl iodide is added to this suspension, and the reaction mixture is stirred for 6 hours at room temperature. Then, it is mixed with 30 ml of 2N sodium hydroxide solution, evaporated to * dryness and the residue is taken up in water. The aqueous solution is acidified with concentrated hydrochloric acid, the 276413 precipitate is suctioned off and washed with water. For purification, the crude product is recrystallized from ethanol. Yield: 2.35 g (75.4% of theory) of colorless crystals. Elementary analysis (taking into consideration the solvent content): cid: C 35.45 H 4.01 I 32.57 N 5.39 0 22.58 Fnd: C 35.59 H 3.94 I 32.39 N 5.23 d) Gadolinium complex of 3,6,9-triaza-3,6,9-tris- (carboxymethyl)-4-(3,5-diiodo-4-ethoxybenzyl)-undecanedioic acid 1.75 g (2.2 mmol) of the pentacarboxylic acid of Example 4c) is suspended in 55 ml of water and mixed at 60°C with 407 mg (1.1 mmol) of gadolinium oxide. After 4 hours, the clear solution is treated with activated carbon. Then, it is polished with a cellulose-membrane filter (0.2 mm, Sartorius) and freeze-dried. Yield: 1.95 g (94.9% of theory) of colorless lyophilizate. Elementary analysis (taking into consideration the solvent content): Cid: C 29.59 H 3.02 Gd 16.84 I 27.19 O 18.85 Fnd: C 29.64 H 3.25 Gd 16.66 I 26.93 44 276413 e) Gadolinium complex of 3,6,9-triaza-3,6,9-tris- (carboxymethyl)-4-(3,5-diiodo-4-ethoxybenzyl)-undecanedioic acid, disodium salt 1.5 g (1.6 mmol) of the complex described in the above example is dissolved in 120 ml of water and mixed using a microburette with 3.2 ml of a IN sodium hydroxide solution. After freeze-drying, the disodium salt is obtained as colorless lyophilizate. Yield: 1.55 g (99% of theory) of colorless lyophilizate. Elementary analysis (tjaking into consideration the solvent content): Cid: C 28.26 H 2.68 Gd 16.09 I 25.96 N 4.30 Na 4.70 0 18.00 Fnd: C 28.03 H 2.91 Gd 15.86 I 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-l,3-dioxolan-4-yl)-methoxymethyl]-2,4,6-triiodoaniline 20.0 g (36.3 mmol) of the compound produced under Example 2a), 5.8 g (43.6 mmol) of 2,3-O-isopropylidene glycerol, 0.41 g (1.8 mmol) of N-benzyl-N,N,N-triethylammonium chloride and 4.1 g * (72.7 mmol) of ground potassium hydroxide are refluxed in 35 ml of toluene for 6 hours. Then, the organic phase is separated, shaken out with saturated aqueous common salt solution and dried • •' 276413 on magnesium sulfate. After the filtrate is filtered and concentrated by evaporation, an oily residue is obtained, which is chromatographed on silica gel with toluene/ethyl acetate. Concentration by evaporation of the product fractions yields a colorless oil, which is dried in a vacuum. Yield: 21.3 g (87.2% of theory) Analysis (relative to solventless substance): cid: C 28.64 H 3.00 I 56.73 N 2.09 0 9.54 Fnd: C 28.60 H 3.09 I 56.72 N 2.11 b) N-Acetyl-N-methyl-3-[(2,3-dihydroxypropyloxy)-methyl]-2,4,6-triiodcaniline 20.2 g (30.1 ttusol) of the compound produced according to Example 5a) is introduced in a mixture of 60 ml of ethanol and 10 ml of concentrated sulfuric acid. After 12 hours of stirring at 30°C, the batch is taken up in dichloromethane, and the organic phase is shaken out once with concentrated sodium chloride solution and twice with concentrated sodium bicarbonate solution. ^ The organic phase is dried on anhydrous magnesium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel 60 (Merck) with dirshloromethane/methanol. After the product fractions are concentrated by evaporation, a colorless oil is obtained, which ♦ is dried in a vacuum. Yield: 16.9 g (89.2% of theory) 27 6413 Analysis (relative to solventless substance): Cid: C 24.75 H 2.56 I 60.34 N 2.22 O 10.14 Fnd: C 24.86 H 2.69 I 60.12 N 2.34 c) N-Acetyl-N-methyl-3-[(3-benzoyloxy-2-hydroxypropyloxy)-methyl]-2,4,6-triiodoaniline 15.2 g (24.1 mmol) of the compound produced in Example 5b) is stirred in 150 ml of dichloromethane under argon and mixed first with 4.0 ml (28.9 mmol) of triethylamine, then at 0°C drop by drop with 3.47 g (26.5 mmol) of benzoyl cyanide. After 12 hours of stirring at 0°C, the batch is diluted with dichloromethane and shaken out against saturated sodium bicarbonate solution. The organic phase is dried on magnesium sulfate, filtered and concentrated by evaporation, and the residue is chromatographed on silica gel 60 (Merck) with dichloromethane/methanol. After concentration by evaporation, the product fractions yield a colorless oil. Yield: 13.9 g (78.4% of theory) Analysis (relative to solventless substance): Cid; C 32.68 H 2.74 I 51.79 N 1.91 0 10.88 Fnd: C 32.54 H 2.88 I 51.83 N 1.74 d) N-Acetyl-N-methyl-3-[ (3-benzoyloxy-2-methanesulfonyloxypropyloxy) methyl]-2,4,6-triiodoaniline 13.4 g (18.2 mmol) of the compound produced under Example 5c) is stirred in 80 ml of dichloromethane under argon and mixed 276413 first with 3.0 ml (21.9 mmol) of triethylamine, then at 0°c drop by drop with 1.56 ml (20.1 mmol) of methanesulfonic acid chloride. The reaction temperature is allowed to increase within 3 hours to room temperature and then shaken out against saturated sodium bicarbonate solution. The organic phase is dried on magnesium sulfate, filtered and concentrated by evaporation. The oily residue is chromatographed on silica gel 60 (Merck) with dichloromethane, the product fractions are concentrated by evaporation, and the residue is dried in a vacuum. Yield: 12.8 g (86.2% of theory) of yellowish foam Analysis (relative to solventless substance): cid: C 31.02 H 2.73 I 46.82 N 1.72 0 13.77 S 3.94 Fnd: C 31.20 H 2.89 I 46.67 N 1.83 S 4.02 e) N-Acetyl-N-methyl-3-[(3-benzoyloxy-2-azidopropyloxy)-methyl]-2,4,6-triiodoaniline 11.8 g (14.5 mmol) of the compound produced in Example 5d) is stirred in 50 ml of N,N-dimethylformamide together with 2.83 g (43.5 mmol) of sodium azide for one hour at 85°C under argon. Then, it is concentrated by evaporation in a vacuum, and the residue is shaken out with dichloromethane/saturated sodium bicarbonate solution. The organic phase is dried on magnesium sulfate, filtered and concentrated by evaporation in a vacuum. Yield: 10.2 g (92.1% of theory) of yellowish foam 276413 Analysis (relative to solventless free substance): cid: C 31.60 H 2.52 I 50.09 N 7.37 O 8.42 Fnd: C 31.59 H 2.63 I 49.87 N 7.49 f) N-Acetyl-N-methyl-3-[ (2-azido-3-hydroxypropyloxy) methyl]-2,4,6-triiodoaniline 9.58 g (12.6 mmol) of the compound produced according to Example 5e) is dissolved in 60 ml of methanol. After 40 ml of 2N sodium hydroxide solution is added, it is stirred for one hour at 50°C bath temperature and after the cooling, it is neutralized with 2N hydrochloric acid. The methanol is drawn off in a vacuum, and the residue is dispersed between dichloromethane and saturated sodium bicarbonate solution. The organic phase is dried on magnesium sulfate, filtered, concentrated by evaporation, the residue is chromatographed on silica gel 60 (Merck), and the product fractions are concentrated by evaporation in a vacuum. Yield: 7.47 g (90.3% of theory) Analysis (relative to solventless substance): cid: C 23.80 H 2.31 I 58.04 N 8.54 0 7.32 Fnd: C 23.92 H 2.50 I 57.85 N 8.6 g) N-Acetyl-N-methyl-3-[(2-azido-3- methanesulfonyloxypropyloxy)-methyl]-2,4,6-triiodoaniline 49 276413 7.22 g (11.0 mmol) of the hydroxy compound produced according to Example 5f) is reacted to the corresponding mesylate under the conditions described in Example 5d). Yield: 7.46 g (92.4% of theory) Analysis (relative to solventless substance): cid: C 22.91 H 2.33 I 51.86 N 7.63 O 10.90 S 4.37 Fnd: C 23.01 H 2.58 I 51.63 N 7.75 S 4.49 h) N-Acetyl-N-methyl-3-(6,9-diaza-4-azido-2-oxanonyl)-2,4,6-triiodoaniline, dihydrochloride 7.21 g (9.82 mmol) of the mesylate described in Example 5g) is dissolved in 50 ml of methanol, and after 150 ml of 1,2-diaminoethane is added, it is stirred for 15 hours at room temperature. Then, the batch is concentrated by evaporation and dispersed between dichloromethane and saturated sodium bicarbonate solution. The aqueous phase is extracted several times with dichloromethane, the combined organic phases are dried on sodium sulfate, filtered and concentrated by evaporation. The residue is taken up in tert-butyl methyl ether/methanol and adjusted to pH 2 with concentrated hydrochloric acid, whereby a colorless precipitate precipitates. The latter is separated and dried in a vacuum. Yield: 7.33 g (96.8% of theory) 50 276413 Analysis (relative to solventless substance): cid: C 23.37 H 3.01 I 49.38 N 10.90 0 4.15 Cl 9.20 Fnd: C 23.28 H 3.22 I 49.39 N 11.02 Cl 9.37 i) N-Acetyl-N-methyl-3-(4-amino-6,9-diaza-2-oxanonyl)-2,4,6-triiodoaniline, trihydrochloride 7.04 g (9.13 mmol) of the dihydrochloride produced under Example 5h) is taken up in 70 ml of a 4:1 mixture of dioxane/water and mixed with 12.0 g (45.7 mmol) of triphenylphosphine. The batch is allowed to stir for 3 days at room temperature under argon, the organic solvent is evaporated, and precipitate is filtered out. The precipitate is washed with 2N hydrochloric acid; the combined filtrates are concentrated by evaporation, and the residue is recrystallized from methanol/tert-butyl methyl ether. Yield: 6.12 g (85.8% of theory) Analysis (relative to solventless substance): Cid: C 23.05 H 3.35 I 48.72 N 7.17 O 4.10 Cl 13.61 Fnd: C 23.28 H 3.60 I 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 produced under Example 5i) is stirred ir. 60 ml of N,N-dimethylformamide under argon at room temperature and mixed with 10.6 g (76.5 mmol) of 276413 potassium carbonate and 7.46 g (38.3 mmol) of bromoacetic acid-tert-butyl ester. After 12 hours of stirring, it is filtered, concentrated by evaporation in a vacuum, and the residue is dispersed between ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried on sodium sulfate, filtered, concentrated by evaporation, and the residue is chromatographed on silica gel 60 (Merck) with hexane/ethyl acetate. After the product fractions are concentrated by evaporation, a yellowish oil is obtained. Yield: 8.94 g (98.5% of theory) Analysis (relative to solventless substance): cid: C 41.50 H 5.52 I 32.08 N 4.72 0 16.18 Fnd: C 41.52 H 5.73 I 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 produced under Example 5j) is converted to the corresponding penta acid under the conditions described in Example lc). Yield: 5.80 g (84.1% of theory) of light beige solid Analysis (relative to anhydrous substance): cid: C 31.20 H 3.46 I 39.56 N 5.82 O 19.95 Fnd: C 31.25 H 3.66 I 39.42 N 5.83 276413 1) Gadolinium complex of the qisodium salt of 4-(N-acetyl-3-methy lamino-2,4,6-triiodobenzyloxymethyl]"3,6,9-triaza-3,6,9-tris-(carboxymethyl)-undecanedioic acid 5.69 g (6.19 mmol) of the penta acid produced in Example 5k) is complexed with gadolinium oxide under the conditions described in Example Id) and converted to the corresponding disodium salt. Yield: 6.81 g (94.8% of theory) of colorless lyophilizate Analysis (relative to anhydrous substance): Cid: C 25.88 H 2.43 I 32.81 N 4.83 0 16.55 Gd 13.55 Na 3.96 Fnd: C 25.94 H 2.61 I 32.78 N 4.85 Gd 13.44 Na 4.00 Example 6 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, gadolinium complex, disodium salt a) 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 11.42 g (20 mmol) of 3-glycylamino-2,4,6-triiodobenzoic acid (DE 2523567) is dissolved in 60 ml of N,N-dimethylformamide while being heated. It is mixed at room temperature with 6.9 ml of triethylamine and 3.6 g (10 mmol) of N,N-bis-[2,6-dioxomorpholino)ethyl]-glycine, and the reaction mixture is t stirred for 15 hours at room temperature. Then, it is evaporated to dryness, the residue is taken up in water and acidified with concentrated hydrochloric acid. The settled precipitate is 53 276413 suctioned off and washed with water. The crude product is purified by an RP 18 chromatography on silica gel. Yield: 9.5 g (63% of theory) of colorless solid. Elementary analysis (taking into consideration the solvent content): cid: C 25.60 H 2.22 I 50.73 N 6.53 0 13.18 Fnd: C 25.53 H 2.35 I 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 of Example 6a) is suspended in 50 ml of water and mixed in portions with 1.74 g (4.8 mmol) of gadolinium oxide at 50-60°C. After the complexing is completed, the pH is adjusted to seven with IN sodium hydroxide solution, filtered, and the aqueous solution is freeze-dried. Yield: 7.6 g (93% of theory) of colorless lyophilizate. Elementary analysis (taking into consideration the solvent content): Cid: C 22.62 H 1.66 Gd 9.25 I 44.81 N 5.77 Na 2.71 O 13.18 Fnd: C 22.43 H 1.85 Gd 9.07 I 44.71 N 5.63 Na 2.49 276413 Example 7 1,19—Bis—{3—[(10-carboxydecyl)-carbamoyl]-2, A,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-triiodobenzoic acid amide 10.9 g (15 mmol) of 3-phthalimidoacetylamino-2,4,6-triiodobenzoic acid chloride (DE 2523567, corresponding to US 4005188) is dissolved in 60 ml of N,N-dimethylacetamide and reacted at 80 "C with 1.98 g (16 nmol) of 11-aminoundecanoic acid. The reaction mixture is stirred for sz hours at this temperature, and then hydrochloride is filtered out. The filtrate is evaporated to dryness, then residue is suspended in 40 ml of water and reacted with 4.5 g (90 nmol) ot hydrazine hydrate. After three hours of stirring at 65'C, the reaction mixture is allowed to cool, and the settled precipitate is suctioned off. The product is rewashed with ample water, and the solid is dried at 50* C in a vacuum. Yield: 9.8 g (87% of theory) of pale yellow crystals. Elementary analysis (taking into consideration the solvent content): Cid: C 34.73 H 4.05 I 40.77 N 6.75 O 13.71 Fnd: C 34.90 ri 3.9I: I 40.68 N 6.51 276413 b) l,19-Bis-{3-[ (10-carboxydecyl)-carbamoyl]-2,4,6- triiodophenyl}-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 of Example 7a) is reacted analogously to Example 6a) with 2.14 g (6 mmol) of N,N-bis-[2-(2,6-dioxomorpholino)ethyl]glycine and purified in a similar way by a column chromatography on RP 18. Yield: 17.4 g (80% of theory) of pale yellow solid. Elementary analysis (taking into consideration the solvent content): cid: C 34.73 H 4.05 I 40.77 N 6.75 O 13.71 rnd: C 34.90 H 3.92 I 40.68 N 6.51 c) 1,19-Bis-{3-[ (10-carboxydecyl) -carbamoyl] -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 15 g (8 mmol) of the ligand of Example 7b) is complexed according to Example 6b) with 2.9 g (8 mmol) of gadolinium oxide and converted with IN sodium hydroxide solution to the disodium salt. Yield: 15.6 g (95% of theory) of colorless lyophilizate. 276413 Elementary analysis (taking into consideration the solvent content): cid: C 31.40 H 3.42 Gd 7.61 I 36.86 N 6.10 Na 2.23 O 12.39 Fnd: C 31.28 H 3.63 Gd 7.56 I 36.61 N 5.89 Na 1.97 Example 8 Gadolinium complex of the disodium salt of 4-(3-acetylamino-2,4,6-triiodobenzoyl-aminomethyl)-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., jS5, 377 (1956)) is stirred in 400 ml of dichloromethane and 52.5 ml (379 mmol) of triethylamine at 0°C under nitrogen and mixed drop by drop with 39.8 g (347 mmol) of methanesulfonic acid chloride. The reaction temperature is allowed to increase to room temperature within 3 hours, and the batch is shaken out with saturated sodium bicarbonate solution. The organic phase is dried on sodium sulfate, filtered and concentrated by evaporation. Yield: 58.5 g (89.4% of theory) of yellowish oil Analysis (relative to solventless substance): Cid: C 40.57 H 6.32 N 6.76 0 30.88 S 15.47 ♦ Fnd: C 40.49 H 6.48 N 6.83 S 15.30 2764 13 b) 4-(2,5-Diazapentyl)-2,4-dimethyl-2-oxazoline, dihydrochloride A solution of 36.7 g (177 mmol) of the compound, produced according to Example 8a) , in 100 ml of methanol is added drop by drop to 291 ml (4427 mmol) of 1,2-diaminoethane. The reaction mixture is stirred for 3 hours at 50°C and for another 12 hours at room temperature. Then, the batch is completely concentrated by evaporation in a vacuum. A solution of the residue in methanol is adjusted to pH 1.5 at 0°C with concentrated hydrochloric acid. Ethylenediamine-dihydrochloride precipitating in this connection is separated by filtration. By adding tert-butyl methyl ether in drops to the filtrate, a colorless precipitate results, which is suctioned off and dried in a vacuum. Yield: 38.2 g (88.4% of theory) Analysis (relative to solventless substance): Cid: C 39.35 H 7.84 N 17.21 O 6.55 Cl 29.04 Fnd: 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 produced under Example 8b) is taken up in 150 ml of ethanol. After 31 ml of concentrated hydrochloric acid is added, it is refluxed for 4 hours. After the cooling, the batch is concentrated by evaporation on a vacuum and stirred in 300 ml of isopropanol. 276413 The precipitate is suctioned off, washed with isopropanol and diethyl ether and dried in a vacuum. Yield: 29.6 g (91.4 of theory) Analysis (relative to solventless substance): Cid: C 28.08 H 7.86 N 16.38 0 6.24 Cl 41.45 Fnd: 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 produced under Example 8c) is added to a solution of 51.2 g (369 mmol) of potassium carbonate in 60 ml of water. While being stirred vigorously, 60.0 ml (369 mmol) of bromoacetic acid-tert-butyl ester, dissolved in 60 ml of tetrahydrofuran, is now added and stirred for 6 hours at 60°C. After the cooling, ethyl acetate and water are added and shaken out; the aqueous phase is extracted several times with ethyl acetate. The combined organic phases are dried on sodium sulfate, filtered, and the filtrate is concentrated by evaporation in a vacuum. Yield: 52.2 g (98.8% of theory) Analysis (relative to solventless substance): Cid: C 60.23 H 9.41 N 5.85 O 24.51 Fnd: C 60.11 H 9.62 N 5.67 59 276413 e) 4-Chloromethyl-4-methyl-3, 6,9-tris-(tert-butyloxycarbonylmethyl) -3,6,9-triazaundecanedioic acid-di-tert-butyl ester A solution of 22.3 g (31.0 mmol) of the alcohol, produced under Example 8d), in 100 ml of dichloromethane is mixed with 8.91 g (34.0 mmol) of triphenylphosphine and, after cooling to 0°C, mixed with 4.54 g (34.0 mmol) of N-chlorosuccinimide. After 2 hours of stirring at 0°C, it is stirred up with 200 ml of diethyl ether, the solid is separated and discarded. The ether phase is concentrated by evaporation, and the residue is chromatographed on silica gel 60 (Merck) with hexane/ethyl acetate (2:1). After concentration by evaporation in a vacuum, the product fractions yield a yellowish oil. Yield: 18.7 g (81.7% of theory) Analysis (relative to solventless substance): Cid: C 58.72 H 9.03 Cl 4.81 N 5.71 O 21.73 Fnd: C 58.68 H 9.23 Cl 4.98 N 5.64 f) 3,6,9-Triaza-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, produced * under Example 8e), in 70 ml of N,N-dimethylformamide is mixed with 4.92 g (75.8 mmol) of sodium azide and stirred for 6 hours at 50°C. Then, it is concentrated by evaporation in a vacuum, 60 276413 ' and the residue is dispersed between ethyl acetate and saturated sodium bicarbonate solution. After the organic phase is dried on magnesium sulfate, filtration and concentration by evaporation, a yellowish oil is obtained. Yield: 18.2 g (97.0% of theory) Analysis (relative to solventless substance): Cid: C 58.20 H 8.95 N 11.31 O 21.73 Fnd: C 58.15 H 8.72 N 11.18 g) 4-Aminomethyl-3,6,9-triaza-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, produced in Example 8f) , in 180 ml of ethanol is vigorously shaken after 0.90 g of palladium on activated carbon (10% by weight of palladium, manufacturer Degussa) is added under hydrogen atmosphere, until no more hydrogen absorption can be observed. Then, catalyst is filtered out, and the filtrate is concentrated by evaporation in a vacuum. Yield: 17.4 g (99.9% of theory) of yellowish oil Analysis (relative to solventless substance): cid: C 60.31 H 9.56 N 7.82 0 22.32 Fnd: C 60.22 H 9.78 N 8.03 276413 h) 4—(3-Acetylamino-2,4,6-triiodobenzoylaminomethyl)-3,6,9- triaza-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, produced under 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. 82, 651 (1954)), and it is stirred for 6 hours at room temperature. Then, it is concentrated by evaporation in a vacuum, the residue is dispersed between ethyl acetate and saturated sodium bicarbonate solution, and the organic phase is dried on sodium sulfate. After filtration, the filtrate is concentrated by evaporation, and the residue is chromatographed on silica gel 60 (Merck) with hexane/ethyl acetate (3:1). After the product fractions are concentrated by evaporation, a yellowish oil is obtained. Yield: 27.9 g (92.6% of theory) Analysis (relative to solventless substance): cid: C 43.04 H 5.78 I 30.32 N 5.58 O 15.29 Fnd: C 43.21 H 5.86 I 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' under Example 8h) is converted to the corresponding penta acid under the conditions described in Example lc). 276413 Yield: 19.5 g (94.4%) of light beige solid Analysis (relative to anhydrous substance): Cid: C 30.79 H 2.32 I 39.04 N 7.18 Na 3.92 O 19.69 Fnd: C 30.98 H 2.40. I 38.84 N 7.24 Na 4.04 j) Gadolinium complex of the disodium salt of 4-(3-acetylamino-2,4,6-triiodobenzoyl-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) is converted to the title compound under the conditions described in Example lc). Yield: 20.7 g (91.5% of theory) of colorless solid Analysis (relative to anhydrous substance): cid: C 25.59 H 2.32 Gd 13.50 I 32.44 N 5.97 Na 3.92 O 16.36 Fnd: C 25.64 H 2.40 Gd 13.29 I 32.27 N 6.08 Na 4.04 Example 9 Gadolinium complex of the disodium salt of 4-(3-acetylamino-2,4,6-triiodobenzoyl-oxymethyl)-3,6,9-triaza-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 276 A13 added at room temperature to a solution of 16.9 g (29.9 mmol) of the sodium salt of 3-acetylamino-2,4,6-triiodobenzoic acid (Wallingford et al., J. Am. Chem. Soc. 74, 4365 (1952)) in 50 ml of N,N-dimethylacetamide. The reaction mixture is stirred for 6 hours at 80°C, then concentrated by evaporation in a vacuum and shaken out with ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried on sodium sulfate, filtered and concentrated by evaporation, the residue is chromatographed on silica gel 60 (Merck) with hexane/ethyl acetate (3:1). After the product fractions are concentrated by evaporation, a light beige oil remains. Yield: 18.0 g (71.9% of theory) Analysis (relative to solventless substance): Cid: C 43.01 H 5.59 I 30.29 N 4.46 O 16.55 Fnd: C 43.11 H 5.84 I 30.42 N 4.48 b) 4-(3-Acetylamino-2,4,6-triiodobenzoyloxymethyl)-4-methyl-3,6,9-triaza-3,6,9-tris-(tert-butyloxy-carboxymethyl)-undecanedioic acid 17.7 g (14.1 mmol) of the pentaester described under Example 9a) is converted to the corresponding penta acid under the conditions described in Example Id). Yield: 12.7 g (92.7% of theory) of light beige solid 276413 Analysis (relative to anhydrous substance): cid: C 30.76 H 3.20 1 39.00 N 5.74 0 21.30 Fnd: 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-triiodobenzoy1-oxymethyl)-3,6,9-tri&za-3,6,9-tris-(carboxymethyl) -4-methylundecanedioic acid 9.26 g (9.48 mmol) of the penta acid described under Example 9b) is converted to the title compound analogously to the conditions described in Example Id). Yield: 9.88 (88.7% of theory) of colorless solid Analysis (relative to anhydrous substance): Cid: C 25.14 H 2.29 I 33.21 N 4.89 O 16.75 Gd 13.72 Na 4.01 Fnd: C 25.13 H 2.38 I 33.11 N 4.,93 Gd 13.67 Na 4.11 Example 10 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 a) 3,6,9-Triaza-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 according to Example 8e), in 35 ml of N,N-dimethylacetamide is added at room temperature to a solution of 16.3 g (30.8 mmol) of 3-hydroxy-2,4,6-triiodobenzoic acid- 276413 Diethylamide (P.L. 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 for 8 hours at 60°C, then concentrated by evaporation in a vacuum, and the residue is shaken out vith ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried on sodium sulfate, filtered and concentrated by evaporation, the residue is chromatographed on silica gel 60 (Rerck) with hexane/ethyl acetate (3:1). After the product fractions are concentrated by evaporation, a light beige oil remains. Yield: 21.9 g (69.4% of theory) Analysis (relative to solventless substance): cid: C 43.01 H 5.82 I 30.98 N 4.56 0 15.63 Fnd: C 43.20 H 5.97 I 30.72 N 4.60 b) 3,6,9-Triaza-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) is converted to the corresponding penta acid under the conditions described in Example lc). Yield: 13.9 g (86.3% of theory) of light beige solid 27 6 k 13 Analysis (relative to anhydrous substance): Cid: C 30.40 H 3.30 I 40.15 N 5.91 0 20.25 Fnd: C 30.64 H 3.52 I 39.94 N 6.04 c) Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris-(carboxymethyl)-4-methy1-4-(3-methylcarbamoyl-2,4,6-triiodophenyloxymethyl)-undecanedioic acid 13.2 g (13.9 mmol) of the penta acid described under Example 10b) is converted to the title compound analogously to the conditions described in Example Id). Yield: 15.0 g (94.1% of theory) of colorless lyophilizate Analysis (relative to anhydrous substance): cid: C 25.14 H 2.29 I 33.21 N 4.39 0 16.75 Gd 13.72 Na 4.01 Fnd: C 25.13 H 2.38 I 33.11 N 4.93 Gd 13.67 Na 4.11 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 is added in drops at 50°C to a mixture of 300 ml of concentrated hydrochloric acid and 240 ml of 2N potassium iodine dichloride solution in 6.0 1 of water while being stirred slowly. After another 3.5 hours, the hot clouded solution is filtered and 276413 concentrated by evaporation in a vacuum until the crystallization starts. Then, it is also well-cooled in ice, suctioned off, absorptively precipitated with water and dried on phosphorus pentoxide. Yield: 50.7 g (67.0% of theory) of light beige solid Analysis (relative to anhydrous substance): cid: C 18.19 H 1.70 I 64.06 N 4.71 O 5.38 Cl 5.97 Fnd: C 18.38 H 1.94 I 63.82 N 4.83 Cl 6.11 b) 3-Amino-2,4,6-triiodophenylalaninethylester hydrochloride 30.8 g (51.8 mmol) of the amino acid produced according to Example lla) is refluxed in a mixture of 150 ml of ethanol and 4.1 ml (57 mmol) of thionyl chloride for 10 minutes, then stirred for 12 hours at room temperature. The batch is then concentrated by evaporation, and the residue is dried in a vacuum. Yield: 32.3 g (100% of theory) of light beige solid Analysis (relative to anhydrous substance): Cid: C 21.23 H 2.27 I 61.17 N 4.50 O 5.14 Cl 5.70 Fnd: C 21.44 H 2.38 I 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-triiodophenyl&laninethylester 20.4 g (32.7 mmol) of the amine produced according to Example lib) and 31.0 g (73.7 mmol) of N,N-bis-[(benzyloxycarbonyl)-methyl]-2-bromomethylamine (M. Williams and 276413 H. Rapoport, J. Org. Chem. 58, 1151 (1993)) are introduced in 50 ml of acetonitrile and mixed with 20 ml of 2N phosphate buffer solution (pH 8.0). The batch is vigorously stirred at room temperature for 24 hours, whereby the aqueous phosphate buffer phase is exchanged after 2 and 8 hours for fresh buffer solution. Then, the organic phase is concentrated by evaporation in a vacuum, and the residue is chromatographed on silica gel with hexane/ethyl acetate/triethylamine (3:1:0.01). The product-containing fractions are concentrated by evaporation in a vacuum. Yield: 25.8 g (62.3% of theory) of yellowish oil. Analysis (relative to solventless substance): cid: C 48.43 H 4.38 I 30.10 N 4.43 O 12.65 Fnd: C 48.50 H 4.45 I 30.01 N 4.44 d) N,N-Bis-[2-[N',N'-bis-[(benzyloxycarbonyl)-methyl]-amino]-ethyl]-3-acetylamino-2,4,6-triiodophenylalaninethylester 13.7 g (10.8 mmol) of the compound described in Example 11c) is dissolved in 30 ml of N,N-dimethylacetamide, and after 1.80 ml (13.0 mmol) of triethylamine and 0.85 ml (11.9 mmol) of acetyl chloride are added, it is stirred for 12 hours at room temperature with exclusion of moisture. Then, it is concentrated by evaporation in a vacuum, and the residue is dispersed between ethyl acetate and sodium bicarbonate solution. The organic phase is dried on sodium sulfate, filtered and concentrated by evaporation. Yield: 13.8 g (97.6% of theory) of yellowish oil 276413 Analysis (relative to solventless substance): cid: C 48.71 H 4.40 I 29.13 N 4.29 0 13.47 Fnd: C 48.83 H 4.67 I 29.02 N 4.38 e) N-N-Bis-[2-[N',N'-bis-(carboxymethyl)-amino]-ethyl]-3-aoetylamino-2,4,6-triiodophenylalanine 12.8 g (9.80 mmol) of the pentaester described in Example lid) is dissolved in 75 ml of methanol and mixed with 49 ml of 2N sodium hydroxide solution. It is refluxed for about 2 hours, and the methanol is drawn off in a vacuum. By adjusting to pH 1-2 with semiconcentrated hydrochloric acid, a colorless precipitate results, which is suctioned off and dried in a vacuum. Yield: 7.80 g (86.7% of theory) Analysis (relative to anhydrous substance): Cid: C 30.09 H 3.18 I 41.46 N 6.10 0 19.17 Fnd: C 30.22 H 3.31 I 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-triiodophenylalanine 7.42 g (8.08 mmol) of the penta acid described in Example lie) is converted to the title compound analogously to the conditions described in Example id). Yield: 8.72 g (96.7% of theory) 276413 Analysis (relative to anhydrous substance): Cid: C 24.75 H 2.17 Gd 14.07 X 34.10 N 5.02 Na 4.12 0 15.76 Fnd: C 24.64 H 2.38 Gd 13.83 I 33.94 N 5.08 Na 3.89 Example 12 2- (3-Acetamido-2, A, 6-ti:iiodobenzyl) -3,6,9-triaza-3, 6,9-tris-(carboxymethyl)-undecanedioic acid, gadolinium complex, disodium salt a) 3,6,9 -Tr iaza-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 is introduced at 0°C and mixed drop by drop with 38.2 ml (0.524 mol) of thionyl chloride within 30 minutes. Then, the reaction mixture is stirred for 16 hours at room temperature. After the reaction is completed, it is concentrated by evaporation on a rotary avaporator, 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, and the aqueous phase is extracted three times with 100 ml each of diethyl ether. The extract is dried on potassium carbonate and evaporated to dryness after filtration. The product is dried overnight in a vacuum on phosphorus pentoxide. Yield: 19.7 g (81% of theory) of colorless oil. 276413 Elementary analysis (taking into consideration the solvent content): Cid: C 49.24 H 7.18 N 9.07 0 34.52 Fnd: C 49.37 H 7.26 N 8.85 b) 3,6,9-Triaza-3,6,9-tris-(methoxycarbonylmathyl)-2-(3-nitrobenzyl)-undecanedioic acid dimethyl ester 6.64 ml (47.3 mmol) of diisopropylamine in 200 ml of anhydrous tetrahydrofuran is introduced in a light argon stream at 0°C and mixed drop by drop with 22.2 ml (52 mmol) of butyllithium (15% in hexane) within 15 minutes. Then, it is cooled to -78°C, and 18.4 g (40 mmol) of pentaester (Example 12a) dissolved in 300 ml of anhydrous tetrahydrofuran is added in portions to it. After 30 minutes of stirring at this temperature, a solution of 8.11 g (47.3 mmol) of 3-nitrobenzyl chloride and 1.38 ml (11.44 mmol) of l,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone in 180 ml of anhydrous tetrahydrofuran is added within 30 minutes. The reaction mixture is allowed to reach room temperature overnight, ana the solution is concentrated by evaporation on a rotary evaporator. The oily residue is taken up in 150 ml of ethyl acetate and mixed with 50 ml of ice water. The organic phase is separated, and the aqueous phase is extracted three times with 75 ml of ethyl acetate each. The combined organic phases are dried on 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 pale yellow oil. 72 276413 Elementary analysis (taking into consideration the solvent content): Cid: C 52.17 H 6.40 N 9.36 0 32.07 Fnd: C 52.01 H 6.23 N 9.48 c) 2-(3-Aminobenzyl)-3,6,9-triaza-3,6,9-tris-(methoxycarbonylmethyl)-undecanedioic acid dimethyl ester A methanolic solution of 12.7 g (21.2 mmol) of the nitro compound of Example 12b) is hydrogenated at room temperature with the addition of 1.35 g of palladium on carbon (10%) at 4 bars. After 5 hours, the hydrogenation is completed, and catalyst is filtered out. The filtrate is evaporated to dryness and used in the next stage without further purification. Yield: 11.35 g (94% of theory) of colorless oil. d) 2-(3-Aminobenzyl)-3,6,9-triaza-3,6,9-tris-(carboxymethyl)-undecanedioic acid 10.8 g (19 mmol) of the pentaester of Example 12c) is saponified with 60 ml of 2N sodium hydroxide solution at 40°C. After the reaction is completed, the solution is mixed with concentrated hydrochloric acid until the acid is completely precipitated. The precipitate is suctioned off and washed neutral with water. The product ir dried overnight at 50°C in a vacuum. Yield: 9.75 g (96% of theory) of colorless solid. 276413 Elementary analysis (taking into consideration the solvent content): cid: C 47.15 H 5.84 Cl 6.63 N 10.47 O 29.91 Fnd: 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) is suspended in 50 ml of water and mixed drop by drop with 22.8 ml (56.4 mmol) of a hydrochloric acid 40% iodomonochloride solution. The reaction mixture is allowed to stir for 16 hours at 65°C, and the iodine excess is reduced with diluted sodium disulfite solution. The settled precipitate is suctioned off and rewashed with water. The dried solid is taken up in concentrated ammonia solution, filtered and precipitated with concentrated hydrochloric acid. The precipitate is washed until neutrality of the wash water is reached. The product is dried for 18 hours at 50°C in a vacuum until a constant weight is reached. Yield: 13.1 g (83% of theory) of light yellow solid. Elementary analysis (taking into consideration the solvent content): cid: C 28.79 H 3.11 I 43.45 N 6.39 0 18.26 Fnd: C 28.93 H 3.37 I 43.32 N 6.48 276413 f) 2-(3-Acetylamino-2,4,6-triiodobenzyl) -3,6,9-tris- (carboxymethyl)-3,6,9-triazaundecanedioic acid 12.7 g (14.5 mmol) of triiodoaniline of Example 12e) is dissolved in 30 ml of N,N-diraethylacetamide and mixed with 2.465 ml (34.8 mmol) of acetyl chloride while being cooled with ice. It is allowed to reach room temperature overnight, and the reaction mixture is stirred in ice water. The precipitate is suctioned off, washed with water and dried at 50°C in a vacuum. Yield: 11.55 g (87% of theory) of colorless solid. Elementary analysis (taking into consideration the solvent content): cid: C 30.09 H 3.18 I 41.46 N 6.10 0 19.17 Fnd: C 29.88 H 3.26 I 41.29 N 6.02 g) 2-(3-Acetamido-2,4,6-triiodobenzyl)-3,6,9-triaza-3,6,9-tris-(carboxymethyl)-undecanedioic acid, gadolinium complex, disodium salt 11.2 g (12.2 mmol) of complexing agent of Example 12f) is reacted according to the method of Example 4d) with gadolinium oxide at 50°C. After the complexing is completed, the intermediate product is converted to disodium salt with IN sodium hydroxide solution. The resulting solution is purified with 1.2 g of activated carbon, filtered with a 0.2 jum membrane-cellulose filter and then freeze-dried. Yield: 12.6 g (92.5% of theory) of colorless lyophilizate. 276413 Elementary analysis (taking into consideration the solvent content): cid: C 24.75 H 2.17 Gd 14.09 I 34.10 N 5.02 Na 4.12 O 15.76 Fnd: C 24.89 H 2.23 Gd 13.88 I 34.02 N 4.87 Na 4.03 Example 13 Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris-(carboxymethyl)-4-[3-[N,N'-dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-3,5-dicarbamoyl-2,4,6- triiodophenylcarbamoylmethoxy]-benzyl]-undecanedioic acid a) N,O—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., 97, 1858 (1967)) is dissolved in 3.0 1 of tetrahydrofuran and cooled to 0°C. After 72.8 ml (525 mmol) of triethylamine is added, 36.7 ml (383 mmol) of chloroformic acid ethyl ester is added in drops. 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 is added. After stirring overnight, the resulting precipitate is suctioned off, the filtrate is concentrated by evaporation and dried in a vacuum. Yield: 183.7 g (78.3% of theory) of colorless solid. 276413 Analysis (relative to solventless substance): Cid: C 67.19 H 5.64 N 6.72 O 20.46 Fnd: 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) is suspended in 1.5 1 of methanol and after 6.3 g of palladium on carbon (10% by weight of palladium, Degussa) is added, it is hydrogenated with hydrogen at normal pressure. Then, it is filtered, the filtrate is concentrated by evaporation, and the residue is absorptively precipitated in diisopropyl ether. After suctioning off and drying in a vacuum, a colorless solid is obtained. Yield: 21.4 g (95.8% of theory) Analysis (relative to solventless substance): cid: C 59.17 H 7.67 N 18.82 O 14.33 Fnd: C 59.28 H 7.73 N 18.74 c) l,5-Diamino-3-aza-2-(3-ethoxybenzyl)-pentane, trihydrochloride 20.1 g (90 mmol) of the compound described in Example 13b) is taken up in 135 ml of tetrahydrofuran and mixed drop by drop at 0°C under argon with 180 ml of 1 m boron hydride solution in tetrahydrofuran. After 30 minutes of stirring at 0°C, stirring is continued for 120 hours at 60°C. After the cooling, 100 ml of methanol is added in drops, the reaction mixture is saturated 276413 with hydrogen chloride, and the resulting acid suspension is stirred for 6 hours. Then, the precipitate is suctioned off ar.d dried at 50°C in a vacuum. Yield: 25.0 g (87.2%) of colorless solid Analysis (relative to solventless substance): cid: C 41.46 H 6.96 Cl 33.38 N 13.19 O 5.02 Fnd: C 41.40 H 7.04 Cl 33.47 N 13.08 d) 3,6,9-Triaza-4-(3-hydroxybenzy1)-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) is suspended in 500 ml of tetrahydrofuran and mixed with 25 ml of water and 34.5 g (249 mmol) of potassium carbonate. After 52.3 ml (356 mmol) of bromoacetic acid-tert-butyl ester is added in drops, it is stirred for 3 days at 60°C. After the cooling, it is filtered, concentrated by evaporation in a vacuum, and the residue is chromatographed on silica gel with diethyl ether/hexane/triethylamine (70:20:5). The product fractions are concentrated by evaporation in a vacuum. Yield: 27.2 g (73.3% of theory) of yellowish oil Analysis (relative to solventless substance): Cid: C 63.13 H 8.92 N 5.39 0 22.56 Fnd: C 63.24 H 8.88 N 5.43 78 276 A13 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'-dimethy1-N,N'-bis-(2,3-dihydroxypropyl) -diamide (DE 2928417 > corresponding to EP 22744) is introduced in 500 ml of tetrahydrofuran and mixed with 0.95 2 (5-0 nmol) of ptoluenesultonic acid monohydrate and 22.9 g (220 nmol) of 2,2- dimethoxypropane. Then, it is refluxed for 12 hours, concentrated by evaporation in a vacuum, the residue is dispersed between ethyl acetate and sodium bicarbonate solution. The organic phase is dried on magnesium sulfate and filtered, concentrated by evaporation, and the residue is absorptively precipitated with tert-butyl methyl ether. After filtering, the residue is dried in a vacuum. Yield: 79.7 g (89.6% of theory) of colorless solid Analysis (relative to solventless substance): cid: C 32.40 H 3.51 Cl 3.99 I 42.79 N 4.72 O 12.59 Fnd: C 32.38 H 3.62 Cl 4.04 I 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-1,3-dioxolan-4- ylmethyl)-3,5-dicarbamoyl-2,4,6-triiodophenyl-carbamoyl- * methoxy]-benzyl]-undecanedioic acid-di-tert-butyl ester 12.8 g (16.4 mmol) of the hydroxy compound described in Example 13d) is dissolved in 50 ml of N,N-dimethylformamide under 276413 argon and mixed with 0.59 g (19.7 mmol) of 80% sodium hydride suspension in mineral oil. After 30 minutes of stirring at room temperature, 19.0 g (21.3 mmol) of the compound described in Example 13e) is added, and the batch is ...llowed to stir for 12 hours at 50°C. Then, it is concentrated by evaporation in a vacuum, and the residue is chromatographed on silica gel 60 (Merck) with diethyl ether/hexane/triethylamine (70:20:5). The product fractions are concentrated by evaporation in a vacuum. Yield: 16.8 g (62.6% of theory) of viscous oil Analysis (relative to solventless substance): Cid: C 47.80 H 6.11 I 23.31 N 5.15 O 17.63 Fnd: C 47.63 H 6.05 I 23.24 N 5.24 g) 3,6 ,9-Triaza-3,6,9-tris- (carboxymethyl) -4-[3-[N,N'-dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-3,S-dicarbamoyl-2,4,6-triiodophenylcarbamoylmethoxy]-benzyl]-undecanedioic acid 16.1 g (9.86 mmol) of the compound described in Example 13f) is freed of all protective groups under the conditions described in Example lc) and converted to the title compound. Yield: 12.4 g (98.7% of theory) of light beige solid Analysis (relative to anhydrous substance): cid: C 36.81 H 4.04 I 29.92 N 6.60 O 22.63 Fnd: C 36.94 H 4.05 I 29.86 N 6.53 276413 h) Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris-(carboxymethyl)-4-[3-[N,N'-dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-3,5-dicarbamoyl-2,4,6-triiodophenyl-carbamoylmethoxy]-benzyl]-undecanedioic acid 11.9 g (9.35 mmol) of the penta acid described under Example 13g is converted to the title compound analogously to the conditions described in Example Id). Yield: 13.1 g (95.5% of theory) of colorless lyophilizate Analysis (relative to anhydrous substance): cid: C 31.85 H 3.15 I 25.88 N 5.71 0 19.58 Gd 10.69 Na 3.13 Fnd: C 31.92 H 3.20 I 25.76 N 5.73 Gd 10.58 Na 3.20 Example 14 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 a) 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-(3-hydroxybenzyl)-undecanedioic acid 13.2 g (16.9 mmol) of the compound described in Example 13d) is converted to the corresponding penta acid under the conditions described in Example lc). Yield: 8.20 g (97.0% of theory) « Analysis (relative to anhydrous substance): Cid: C 50.50 H 5.85 N 8.41 O 35.24 Fnd: C 50.41 H 5.93 N 8.49 • " 276413 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) .1 :! > is dissolved in 80 ml of 5N aqueous ammonia. 26.8 wl of 2N . potassium iodine dichloride solution is now slowly added in drops while being stirred, and stirring is continued for 12 hours. .It is adjusted to pH 1.5 with concentrated hydrochloric acid and sodium disulfite is added until a light suspension is present; this is stirred for 6 hours and filtered. The residue is washed with 2N hydrochloric acid and dried in a vacuum. Yield: 12.1 g (84.8% of theory) Analysis (relative to anhydrous substance): Cid: C 28.75 H 2.99 I 43.40 N 4.79 0 20.06 Fnd: C 28.81 H 2.83 I 43.43 N 4.62 c) 3,6,9-Triaza-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) is 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 is added to it and stirred for 30 minutes. Then, the solution is mixed with 60 ml of 2N sodium hydroxide solution and refluxed for 30 minutes. After the cooling, the organic solvent is drawn off in a vacuum, and the remaining aqueous solution is adjusted to pH 1.5 with 276413 concentrated hydrochloric acid. A precipitate precipitates, which is suctioned off and dried in a vacuum. Yield: 10.7 g (91.4% of theory) Analysis (relative to anhydrous substance): cid: C 29.65 H 3.17 I 42.72 N 4.72 0 19.75 Fnd: C 29.74 H 3.23 I 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) is converted to the title compound as described in Example Id). Yield: 11.7 g (94.0% of theory) of colorless lyophilizate Analysis (relative to anhydrous substance): Cid: C 24.26 H 2.13 I 34.95 N 3.86 0 16.15 Gd 14.43 Na 4.22 Fnd: C 24.30 H 2.10 I 34.91 N 3.90 Gd 14.50 Na 4.28 Example is Gadolinium complex of the disodium salt of 3,6,9-triaza-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)) is mixed under nitrogen 276413 atmosphere at room temperature with 250 ml of 2N toluenic phosgene solution. After 0.5 ml of N,N-dimethylformamide is added, the batch is allowed to stir for 5 hours at 60°C and then evaporated to dryness. Yield: 59.60 g (100.0% of theory) of yellowish solid Analysis (relative to solventless substance): Cid: C 24.18 H 1.86 I 63.88 N 4.70 0 5.37 Fnd: C 24.07 H 1.92 I 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 14.68 g (20.85 mmol) of 3,6,9-triaza-3,6,9-tris-(tert-butyloxy-carbonylmethyl)-4-hydroxymethyl-undecanedioic acid-di-ter\.-butyl ester (DE 3806795) in 100 ml of anhydrous pyridine is mixed with exclusion of moisture with 12.42 g (20.85 mmol) of the isocyanate described in Example 15a), and it is stirred overnight at room temperature. Then, it is completely concentrated by evaporation, and the residue is chromatographed on silica gel (eluant: hexane/ethyl acetate). After the fractions containing the product are concentrated by evaporation, a yellowish oil is obtained as residur. Yield: 24.29 g (89.6% of theory) 276413 Analysis (relative to solventless substance): Cid: C 43.43 H 5.98 I 29.29 N 5.39 0 16.00 Fnd: C 43.42 H 6.11 I 29.25 N 5.44 c) 3,6,9-Triaza-4- (3-diethylcarbamoyl-2,4,6-triiodophenyloarbamoyloxymethyl) -3,6,9-tris- (carboxymethyl) -undecanedioic acid 21.62 g (16.63 mmol) of the pentaester described in Example 15b) is converted to the corresponding penta acid under the conditions described in Example lc). Yield: 16.17 g (95.4% of theory) of colorless solid Analysis (relative to solventless substance): cid: C 31.81 H 3.56 I 37.35 N 6.87 0 20.40 Fnd: C 31.73 H 3.64 I 37.25 N 6.72 d) Gadolinium complex of the disodium salt of 3,6,9-triaza-4-(3-diethylcarbamoyl-2,4,6-triiodophenylcarbamoyloxymethyl)-3,6,9-tris-(carboxymethyl)-undecanedioic acid 15.52 g (15.22 mmol) of the penta acid described in Example 15c) is converted to the title compound as described in Example Id) . Yield: 17.44 g (94.1% of theory) of colorless lyophilizate Analysis (relative to anhydrous substance): Cid: C 24.26 H 2.13 I 34.95 N 3.86 O 16.15 Gd 14.43 Na 4.22 Fnd: C 24.30 H 2.10 I 34.91 N 3.90 Gd 14.50 Na 4.28 27 6413 Example 16 Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris-(carboxymethyl)-4-(N-carboxymethy1-3-methylamino-2,4,6-triiodophenylureylenemethyl)-4-methylundecanedioic acid a) 3-Xsocyanato-2,4,6-triiodobenzoic acid-N-(ethoxycarbonylmethyl)-methylamide 61.40 g (100.0 mmol) of 3-amino-2,4,6-triiodobenzoic acid-N-(ethoxycarbonylmethyl)-methylamide (CA 54 P 20987i (I960)) is mixed under nitrogen atmosphere at room temperature with 250 ml of 2N toluenic phosgene solution. After 0.5 ml of N,N-dimethylformamide is added, the batch is allowed to stir for 5 hours at 60°C and then evaporated to dryness. Yield: 64.00 g (100.0% of theory) of yellowish solid Analysis (relative to solventless substance): cid: C 24.40 H 1.73 I 59.49 N 4.38 0 10.00 Fnd: C 24.37 H 1.82 I 59.53 N 4.26 b) 3,6,9-Triaza-3,6,9-tris-(tert-butyloxycarbonylmethyl)-4-(N-ethoxycarbonylmethyl-3-methylamino-2,4,6- triiodophenylureylenemethyl)-4-methylundecanedioic acid-di-tert-butyl ester A solution of 16.41 g (22.89 mmol) of the pentaester, described in Example 8g), in 100 ml of anhydrous pyridine is mixed with exclusion of moisture with 14.65 g (22.89 mmol) of the isocyanate described in Example 16a) and stirred overnight at room temperature. Then, it is completely concentrated by 276413 evaporation, and the residue is chromatographed on silica gel (eluant: hexane/ethyl acetate). After the fractions containing the product are concentrated by evaporation, a yellowish oil is obtained as residue. Yield: 27.39 g (88.2% of theory) Analysis (relative to solventless substance): Cid: C 43.37 H 5.87 I 28.06 N 6.19 0 16.51 Fnd: C 43.49 H 6.01 I 28.22 N 6.14 c) 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-(N-carboxymethy1-3-methylamino-2,4,6-triiodophenylureylenemethyl)-4-methylundecanedioic acid 26.68 g (19.66 mmol) of the hexaester described in Example 16b) is converted to the corresponding hexa acid under the conditions described in Example 3c). Yield: 19.19 g (93.1% of theory) of colorless solid Analysis (relative to cid: C 30.92 H 3.37 Fnd: C 31.03 H 3.48 solventless substance): I 36.32 N 8.02 0 21.37 I 36.21 N 8.14 276413 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-ureylenemethyl)-4-methylundecanedioic acid 24.32 g (23.19 mmol) of the penta acid described in Example 16c) is converted to the title compound as described in Example Id) . Yield: 27.84 (94.6% of theory) of colorless lyophilizate Analysis (relative to anhydrous substance): Cid: C 25.57 H 2.30 I 30.01 N 6.63 0 17.66 Gd 12.40 Na 5.44 Fnd: C 25.62 H 2.34 I 29.94 N 6.58 Gd 12.35 Na 5.38 Example 17 Comparison test: isomer to Example l of wo 93/16375 1,13-Bis[5-(propion-3-ylamido]-2,4,6-triiodoisophthalic acid- bis(2-hydroxy-l-hydroxymethylethyl)-diamide]-4,7,l0- tris(carboxymethyl)-2,12-dioxo)-l,4,7,10,13-pentaazatridecane, 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-triiodoisophthalic acid-bis(2-hydroxy-l-hydroxymethylethyl)-diamide is dissolved at 120°C bath temperature in 82.5 ml of DMF. It is mixed at room temperature with 7.38 ml (53.25 mmol) of 276413 triethylamine and then with 3.8 g (10.64 mmol) of N,N{-bis[2~ (2,6-dioxomorphoIino)ethyl]glycerol. The reaction mixture is stirred overnight at room temperature. The solvent is evaporated in a vacuum, and the residue is foamed up in the oil pump. The solid is stirred with 200 ml of ethanol for two hours at room temperature, suctioned off and dried at 50°C in a vacuum. Then, the residue is taken up in a little water and chromatographed on silica gel RP 18 (eluant: water/methanol). After the product fractions are concentrated by evaporation, the title compound is obtained as a colorless solid. Yield: 17.24 g (42% of theory) Analysis (relative to anhydrous substance): Cid: C 30.19 H 3.43 X 39.88 N 8.07 0 18.43 Fnd: C 29.88 H 3.30 I 40.21 N 7.95 b) I*13-Bis[5-(propion-3-ylamido]-2,4,6-triiodoisophthalic acid-bis(2-hydroxy-l-hydroxymuthylethyl)-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 17a) is mixed in portions with 17.8 ml of a 0.01 molar gadolinium acetate solution. The pH is moved with triethylamine into the neutral range, 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. 276413 Yield: 145 mg (30.5% of theory) Analysis (relative to anhydrous substance): cid: C 27.91 H 3.03 I 36.90 N 7.47 O 17.06 Gd 7.62 Fnd: C 27.77 H 2.99 I 36.72 N 7.15 Gd 7.38 Example 18 Gadolinium complex of 3,6,9-triaza-3,6,9-tris-(carboxymethyl)-4-(3-iodo-4-ethoxybenzyl)-undecanedioic acid, disodium salt a) N-Benzyloxycarbonyl-3-(4-ethoxyphenyl)-2-aminopropanol 31.8 g (848.4 mmol) of sodium borohydride is added to a solution of 221.41 g (605.9 mmol) of N-benzyloxycarbonyl-O-ethyltyrosine methyl ester in 1.5 1 of tetrahydrofuran at room temperature. 279 ml of methanol is added to it in drops within two hours while being stirred. Then, the tetrahydrofuran is distilled off in a vacuum, the residue is taken up in 1 1 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 (relative to solventless substance): cid: C 69.28 H 7.04 N 4.25 0 19.43 Fnd: C 69.11 H 7.20 N 4.13 276413 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 is dissolved in 88 ml of glacial acetic acid and mixed drop by drop with 22.2 g (134 mmol) of iodomonochloride in 35.5 ml of glacial acetic acid at room temperature. The reaction mixture is allowed to stir overnight at room temperature and poured in 1.1 1 of ice water for working-up. The aqueous phase is extracted several times with ethyl acetate, the organic phase is washed with water, sodium bicarbonate solution and sodixim bisulfite solution and then dried on sodixim sulfate. After the solvent is evaporated, a yellowish oil is obtained, which is slowly thoroughly crystallized. Yield: 34.5 g (77.7% of theory) Analysis (relative to solventless substance): cid: C 50.72 H 4.86 I 25.52 N 2.82 0 16.08 Fnd: C 50.53 H 4.98 I 25.38 N 2.74 c) N-Benzyloxycarbonyl-3-(3-iodo-4-ethoxyphenyl)-2-aminopropanol 29.8 g (60 mmol) of l-acetoxy-N-benzyloxycarbonyl-3-(3-iodo-4-ethoxyphenyl)-2-aminopropane is suspended in 150 ml of methanol and mixed at room temperature with 4.94 g (60 mmol) of anhydrous » sodium acetate. The batch is stirred for 6 hours at 60°C, evaporated to dryness and the residue is taken up in ethyl acetate. The precipitated salt is suctioned off, washed with 91 276413 ethyl acetate, and the filtrate is concentrated by evaporation. The viscous oil obtained is used in the next stage 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 is dissolved in 130 ml of dichloromethane, mixed with 24.1 ml of triethylamine and brought to reaction at 0°C with 6.78 ml (87 mmol) of methanesulfonic acid chloride. After 30 minutes at room temperature, no more initial material can be detected according to TLC. The batch is diluted with dichloromethane and washed with sodium bicarbonate and with water. After the organic phase is dried, the solvent is evaporated, and the product is obtained as pale yellow oil. Yield: 30.4 g (98% of theory) Analysis (relative to solventless substance): Cid: C 45.04 H 4.54 I 23.79 N 2.63 0 18.00 S 6.01 Fnd: C 45.13 H 4.72 I 23.58 N 2.74 S 5.88 e) N-Benzyloxycarbonyl-l-(3-iodo-4-ethoxybenzyl)-N'-(2-aminoethyl)ethylenediamine 28.2 g (53 mmol) of 1-methanesulfonyloxy-N-benzyloxycarbonyl-3-(3-iodo-4-ethoxyphenyl)-2-aminopropane is dissolved at room temperature in 140 ml of tetrahydrofuran and 276413 mixed with 143 ml (2.12 mol) of ethylenediamine. After 22 hours of stirring, the batch is concentrated by evaporation to an oil, and the residue is dissolved in ethyl acetate. It is washed neutral with water and the organic phase is dried on sodium sulfate. After concentration by evaporation, a yellow oil is obtained. Yield: 25.9 g (98% of theory) Analysis (relative to solventless substance): cid: C 50.71 H 5.67 I 25.51 N 8.45 0 9.65 Fnd: C 50.87 H 5.78 I 25.40 N 8.74 f) 1-(3-Iodo-4-ethoxybenzy1)-N'-(2-aminoethyl)ethylenediamine, trihydrobromide 25 g (50 mmol) of N-benzyloxycarbonyl-1-(3-iodo-4-ethoxybenzyl)-N'-(2-aminoethyl)-ethylenediamine is suspended at room temperature in 20 ml of glacial acetic acid and mixed with 61.1 ml (250 mmol) of 33% hydrobromic acid in glacial acetic acid. After 40 hours at room temperature, the feedstock is completely consumed. The reaction mixture is concentrated by evaporation in an oil pump vacuum, and the residue is subsequently distilled three times with toluene. The solid is mixed with water and evaporated to dryness. To remove residual traces of water, the residue is concentrated by evaporation three times with dichloromethane. The crude product is recrystallized from ethanol. Yield: 24.6 (81.2% of theory) of colorless crystals. 276413 Analysis (relative to solventless substance): cid: C 25.77 H 4.16 I 20.94 N 6.93 0 2.64 Br 39.56 Fnd: C 25.89 H 4.41 I 20.73 N 6.74 Br 39.29 g) 4-(3-Iodo-4-ethoxybenzyl)-3,6,9-tris(tert- butoxycarbonylmethyl) -3,6,9-triazaundecane-l,ll-dioic acid, di-(tert-butyl)-ester 23.2 g (38.3 mmol) of l-(3-iodo-4-ethoxybenzyl)-N'-(2-aminoethyl)ethylenediamine, trihydrobromide is suspended in 450 ml of tetrahydrofuran and mixed drop by drop with 43.6 g (316 mmol) of potassium carbonate and 18 ml of water, as well as with 42.13 ml (287.2 mmol) of bromoacetic acid-tert-butyl ester. It is stirred for 10 hours at 60°C and then overnight at room temperature. The salt is suctioned off, washed with tetrahydrofuran, and the filtrate is concentrated by evaporation. The crude product is purified using a silica gel column (mobile solvent: dichloromethane/methanol). Yield: 34.6 g (96.7% of theory) Analysis (relative to solventless substance): Cid: C 55.30 H 7.77 I 13.59 N 4.50 0 18.84 Fnd: C 55.37 H 7.95 I 13.44 N 4.43 • •• 2764 13 h) 4-(3-lodo-4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecane-l,ll-dioic acid, 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-l,ll-dioic acid, di-(tert-butyl)-ester is dissolved in 130 ml of methanol at room temperature and mixed with 6.03 g (150.4 mmol) of sodium hydroxide in 10 ml of water. The batch is stirred for five days at 60°C, evaporated to dryness and subsequently distilled twice with water. The residue is taken up in 180 ml of water and adjusted to pH 2.9 with acid ion exchanger. 3.41 g (9.4 mmol) of gadolinium oxide is added, and the reaction mixture is heated to 80°C. After the complexing is completed, it is adjusted to pH 7.2 with cation exchanger (Na+ form), and the clear solution is freeze-dried. Yield: 14.75 g (92% of theory) Analysis (relative to anhydrous substance): Cid: C 32.44 H 3.20 I 14.90 N 4.93 O 20.67 Gd 18.46 Na 5.40 Fnd: C 32.23 H 3.47 I 14.76 N 4.88 Gd 18.36 Na 5.17 95 2/6413 Example 19 Gadolinium complex of 3,6,9-triaza-3,6,9-tris-(carboxymethyl)-4- (3-bromo-4-ethoxybenzyl)-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 of Example 18a is dissolved in 200 ml of glacial acetic acid and mixed with 0.2 g of iron powder. After the reaction solution is cooled to 10°C, it is mixed at this temperature drop by drop with 12.48 g (78 mmol) of bromine. The reaction mixture is allowed to stir overnight at room temperature, and it is 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 bicarbonate solution and sodium bisulfite solution and then dried on sodium sulfate. After the solvent is evaporated, yellowish-colored crystals are obtained. Yield: 19.50 g (71.0% of theory) Analysis (relative to solventless substance): Cid: C 56.01 H 5.37 Br 17.74 N 3.11 Fnd: 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) of l-acetoxy-N-benzyloxycarbonyl-3-(3-bromo-4-ethoxyphenyl)-2-aminopropane is suspended in 100 ml of methanol and mixed at room temperature with 3.30 g (40 mmol) of 27 6 A13 anhydrous sodium acetate. The batch is stirred for 6 hours at 60°C, evaporated to dryness, and the residue is taken up in ethyl acetate. The precipitated salt is suctioned off, washed with ethyl acetate, and the filtrate is concentrated by evaporation. The viscous oil obtained is used in the next stage without further purification. Yield: 16.0 g (98.2% of theory) c) l-Methanesulfonyloxy-N-benayloxycarbonyl-3-(3-bromo-4-ethoxyphenyl)-2-aminopropane 15.5 g (38 mmol) of N-benzyloxycarbonyl-3-(3-bromo-4-ethoxyphenylj-2-aminopropanol is dissolved in 100 ml of dichloromethane, mixed with 6.3 ml (45 mmol) of triethylamine and brought to reaction at 0°C with 5.04 ml (52 mmol) of methanesulfonic acid chloride. After 30 minutes at room temperature, no more initial material can be detected according to TLC. The batch is diluted with dichloromethane, washed with sodium bicarbonate and with water. After the organic phase is dried, the solvent is evaporated, and the product is obtained as pale yellow oil. Yield: 18.1 g (98% of theory) Analysis (relative to solventless substance): cid: C 49.39 H 4.97 Br 16.43 N 2.88 S 6.59 Fnd: C 49.21 H 4.92 Br 16.40 N 2.79 S 6.54 276413 d) N-Benzyloxycarbonyl-1-(3-bromo-4-ethoxybenzyl)-N'-(2- aminoethyl)ethylenediamine 17.0 g (34.9 mmol) of 1-methanesulfonyloxy-N-benzyloxycarbon^l-3-(3-bromo-4-ethoxyphenyl)-2-aminopropane is dissolved at room temperature in 100 ml of tetrahydrofuran and mixed with 100 ml (1.48 mol) of ethylenediamine. After 36 hours of stirring, the batch is concentrated by evaporation to an oil, and the residue is dissolved in ethyl acetate. It is washed neutral with water, and the organic phase is dried on sodium sulfate. After concentration by evaporation, a yellow oil is obtained. Yield: 14.9 g (95% of theory) Analysis (relative to solventless substance): cid: C 56.00 H 6.27 Br 17.74 N 9.33 Fnd: C 56.21 H 6.32 Br 17.81 N 9.38 e) 1-(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 is suspended at room temperature in 39.1 ml (160 mmol) of glacial acetic acid, and it is mixed with 39.1 ml (160 mmol) of 3 3% hydrobromic acid in glacial acetic acid. After 24 hours at room temperature, the feedstock is completely consumed. The reaction mixture is concentrated by evaporation in an oil pump vacuum, and the residue is subsequently distilled three times with toluene. The 98 2/6413 solid is mixed with water and evaporated to dryness. To remove residual traces of water, the residue is concentrated by evaporation three times with dichloromethane. The crude product is recrystallized from ethanol. Yield: 16.0 g (92.4% of theory) of colorless crystals Analysis (relative to solventless substance): Cid: C 27.93 H 4.51 Br 39.56 N 7.52 Fnd: 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,ll-dioic acid, di-(tert-butyl)-ester 15.0 g (26.8 mmol) of 1-(3-bromo-4-ethoxybenzyl)-N'-(2-aminoethyl)ethylenediamine, trihydrobromide is suspended in 400 ml of tetrahydrofuran, and it is mixed drop by drop with 29.6 g (215 mmol) of potassium carbonate and 15 ml of water, as well as with 36.67 ml (250 mmol) of bromoacetic acid-tert-butyl ester. It is stirred for 12 hours at 60°C and then overnight at room temperature. The salt is suctioned off, washed with tetrahydrofuran, and the filtrate is concentrated by evaporation. The crude product is purified using a silica gel column (mobile solvent: dichloromethane/methanol). Yield: 22.4 g (94.2% of theory) 276413 Analysis (relative to solventless substance): Cid: C 58.23 H 8.18 Br 9.01 N 4.74 Fnd: C 58.19 H 8.12 Br 8.96 N 4.70 g) 4-(3-Bromo-4-ethoxybenzyl)-3,6,9-tris(carboxylatomethy1)-3,6,9-triazaundecane-l,ll-dioic acid 20.0 g (22.5 mmol) of 4-(3-bromo-4-ethoxybenzyl)-3,6,9-tris(tert-butoxycarbonylmethyl)-3,6,9-triazaundecane-l,ll-dioic acid, di-(tert-butyl)-ester is dissolved in a mixture of 400 ml of tetrahydrofuran and 40 ml of water, and it is mixed drop by drop at room temperature with a solution of 6.4 g (160.8 mmol) of sodium hydroxide in 20 ml of water. After a reaction time of 48 hours at room temperature, the reaction mixture is concentrated by evaporation in a vacuum, and the residue is subsequently distilled twice with water. The remaining residue is taken up in 300 ml of water and adjusted to pH 2.0 with cation exchanger (H* form). After freeze-drying, the filtrate obtained after the suctioning-off from the ion exchanger yields the pentacarboxylic acid as colorless powder. Yield: 11.3 g (83% of theory) Analysis (relative to anhydrous tvubstance) : Cid: C 45.55 H 5.31 Br 13.17 N 6.93 Fnd: C 45.62 H 5.38 Br 13.41 N 7.02 276413 h) 4—(3—Bromo—4-ethoxybenzyl)-3,6,9-tris(carboxylatomethy1)- 3,6,9-triazaundecane-l#ll-dioic acid, gadolinium complex, disodium salt 10.0 g (16.5 mmol) of 4-(3-bromo-4-ethoxybenzyl)-3,6,9-tris(c&rboxylatomethyl)-3,6,9-triazaundecane-l,ll-dioic acid is dissolved in 200 ml of water and mixed at 80°C with 3.0 g (8.25 mmol) of gadolinium oxide. After a reaction time of 1 hour at 80°C, the now almost clear reaction solution is brought to room temperature and adjusted to pH 7.2 by mixing drop by drop with 0.2 molar sodium hydroxide solution. The reaction mixture is freeze-dried after filtration. Yield: 12.7 g (96% of theory) Analysis (relative to anhydrous substance): Cid: C 34.33 H 3.38 Br 9.93 N 5.22 Gd 19.54 Na 5.71 Fnd: 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)-amino]-ethyl]-p-iodophenylalanine a) p-Iodophenylalaninisopropylester, hydrochloride 50 ml of isopropanol is stirred at 0°C under argon and mixed drop by drop with 3.12 ml (41.6 mmol) of thionyl chloride. 30 minutes later, 10.0 g (34.4 mmol) of p-iodophenylalanine is added in portions, stirred for one hour at room temperature, and the batch is then allowed to reflux for two hours. After the cooling to room temperature, the batch is allowed to stand overnight at 276413 0°C, and then the precipitated, colorless precipitate is suctioned off. Yield: 12.4 g (97.8% of theory) Analysis: Cid: C 38.99 H 4.64 I 34.33 N 3.79 0 8.66 Cl 9.59 Fnd: C 38.85 H 4.70 I 34.29 N 3.78 Cl 9.66 b) N/N-Bis-[2-[N',N'-bis-[(tert-butyloxycarbonyl)-methyl]-amino]-ethyl]-p-iodophenylalaninisopropylester 12.1 g (32.7 mmol) of the amine produced according to Example 20a) and 25.4 g (72.0 mmol) of N,N-bis-[(tert-butyloxycarbonyl) -methyl]-2-bromoethylamine (M. Williams and H. Rapoport, J. Org. Chem. 58, 1151 (1993)) are introduced in 50 ml of acetonitrile and mixed with 2 0 ml of 2N phosphate buffer solution (pH 8.0). The batch is vigorously stirred at room temperature for 24 hours, whereby the aqueous phosphate buffer phase is exchanged after 2 and 8 hours for fresh buffer solution Then, the organic phase is concentrated by evaporation in a vacuum, and the residue is chromatographed on silica gel with hexane/ethyl acetate/triethylamine (3:1:0.01). The product-containing fractions are concentrated by evaporation in a vacuum Yield: 17.9 g (62.3% of *'ieory) of yellowish oil. « Analysis (relative to solventless substance): Cid: C 54.85 H 7.60 I 14.49 N 4.80 0 18.28 Fnd: C 54.80 H 7.65 I 14.41 N 4.74 276413 c) N,N-Bis-t2-[N',N'-bis-(carboxymethyl)-amino]-ethyl]-p- iodophenylalanine 17.1 g (19.5 mmol) of the tert-butyl ester described in Example 20b) is dissolved in 250 ml of trifluoroacetic acid, and it is stirred for 1 hour at room temperature. Then, the solution is concentrated by evaporation, the residue is absorptively precipitated in water, filtered off and dried in a vacuum. Yield: 11.5 g (96.8% of theory) of light beige solid Analysis (relative to anhydrous substance): cid: C 41.39 H 4.63 I 20.82 N 6.90 O ?«.26 Fnd: 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, produced according to Example 20c), in 118 ml of water is mixed with 2.21 g (6.1 mmol) of gadolinium c<cide and stirred at 80°C for 2 hours. Then, 24.4 ml of IN sodium hydroxide solution is added with a microburette and stirred for 1 more hour. Then, after 0.5 g of activated carbon is added, the solution is stirred at 80°C for 2 hours and filtered. After freeze-drying, the filtrate yields a colorless solid. Yield: 9.12 g (92.6% of theory) 2/6413 Analysis (relative to anhydrous substance): cid: C 31.23 H 2.87 I 15.72 N 5.20 0 19.81 Gd 19.47 Na 5.69 Fnd: C 31.26 H 2.95 I 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-triiodophenyl-carbamoylmethyl] -amide a) N/N-Bis-[2-[N'/N'-bis-[ (tert-butyloxfcarbonyl) -methyl]- amino]-ethyl]-glycine-N"-[3,5-bis- (N'''- (2-hydroxyethyl) -carbamoyl) -2,4,6-triiodophenylcarbamoylmethyl] -amide 22.1 g (31.5 mmol) of 5-aminoacetylamino-2,4,6-triiodoisophthalic acid-N,N' -bis- (?-hydroxyethyl) -diamide and 24.4 g (69.3 mmol) of N,N-bis-[ (tert-butyloxycarbonyl)-methyl]-2-bromoethylamine (M. Williams and H. Rapoport, J. Org. Chem. 58, 1151 (1993)) are introduced in 50 ml of acetonitrile and mixed with 20 ml of 2N phosphate buffer solution (pH 8.0). The batch is vigorously stirred at room temperature for 24 hours, and the aqueous phosphate buffer phase is exchanged after 2 and 8 hours for fresh buffer solution. Then, the organic phase is concentrated by evaporation in a vacuum, and the residue is chromatographed on silica gel with dichloromethane/methanol (95:5). The product-containing fractions are concentrated by « evaporation in a vacuum. Yield? 21.9 g (55.8% of theory) of yellowish oil. 276413 Analysis (relative to solventless substance): Cid: C 40.53 H 5.43 I 30.59 N 6.75 O 16.71 Fnd: 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-hydroxyfithyl) -carbamoy1)-2,4,6-triiodophenylcarbamoylmethyl]-amide 20.8 g (16.7 mmol) of the tert-butyl ester described in Example 21a) is dissolved in 250 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. Then, the solution is mixed with tert-butyl methyl ether, the precipitate is separated, washed with tert-butyl methyl ether and dried in a vacuum. Yield: 16.9 g (98.9% of theory) Analysis: cid: C 30.61 H 3.46 I 37.31 N 8.24 O 20.38 Fnd: 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, produced according to Example 2lb), in 13 0 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 IN sodium hydroxide solution is added with a microburette and stirred for 1 more hour. Then </div>

Claims

<div class="application article clearfix printTableText" id="claims"> + 105 11 6 4 1 3 after 0.5 g of activated carbon is added, the solution is stirred at 80°C for 2 hours and filtered. After freeze-drying, the filtrate yields a colorless solid. Yield: 18.4 g (93.0% of theory) Analysis (relative to anhydrous substance): Cid: C 26.10 H 2.61 I 31.82 N 7.02 O 17.38 Gd 13.14 Na 1.92 Fnd: C 26.11 H 2.74 I 31.84 N 7.06 Gd 13.10 Na 1.93 106 276413 Claims l. A metal complex 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 complexing ligand of formula 1 V1 ul Rl U2 R2 R3 V2 CO-ly /■ ^ J CO 7/ N N N V (I) / v3 co coon HOOC v I Z3 wherein R1 is a hydrogen atom, a carboxylic acid radical, a straight-chain or branched C,-C13 alkyl radical, a C6-C15 aryl radical, or a CVC,5 aralkyl radical, which optionally is substituted by i-5 hydroxy groups ot, 1-2 carboxy groups. is interrupted by 1-4 oxygen atoms, or a combination thereof, or wherein R' is a radical of formula II or ID, -CO-NR4R5 (II) -CHj-NR6-CO-R7 (IE) wherein R4, R5, independently of one another, arc a hydrogen atom, a straight-chain or branched Ct-C13 alkyl radical, a Q-Cl5 aryl radical, or ~ * FEB M8 °f New Zealand 107 * 2 7 6 4 1 3 " a Ct-CI5 aralkyl radical, which optionally contains 1-5 hydroxy groups, 1-2 carboxy groups., 1-4 oxygen atoms or a combination thereof, or in which R4, RJ, together with incorporation of the nitrogen atom, form a 5- or 6-member tin®, optionally containing an oxygen atom, an additional acylated nitrogen atom or a sulfonyl group, optionally substituted with 1-3 hydroxy groups, R6 is a hydrogen atom, a straight-chain or branched Q-C, 5 alkyl radical, C6-Cjj aryl radical or a CrC15 aralkyl radical, which optionally contains 1-4 hydroxy groups, 1-2 carboxy groups, 1-2 oxygen atoms, or a combination thereof, or in which R6 together with R7, with incorporation of the nitrogen atom and the carbonyl group, forms a 5- or 6-ring optionally containing an oxygen atom, an additional acylated nitrogen atom or a sulfonyl group, optionally substituted with 1-3 hydroxy groups, and R7 is a hydrogen atom, a straight-chain or branched C,-C15 alkyl radical, C6-C15 aryl radical or a CrC15 aralkyl radical, which optionally contains 1 to 2 hydroxy groups or a carboxy group or R7 together with R6, with incorporation of the nitrogen atom and the carbonyl group, forms a 5- or 6-member ring optionally containing an oxygen atom, an additional acylated nitrogen atom or a sulfonyl group, optionally substituted with 1-3 hydroxy groups, r2, R3, independently of one another, are a hydrogen atom, a C,-C15 alkyl radical, a C6-Cl5 aryl radical or a C,-Cl5 aralkyl radical, which optionally is substituted by 1-5 hydroxy groups is interrupted by 1-4 oxygen atoms or a combination thereof, or together form a trimethylene or tetramethylene group, or have the meaning indicated for U\ Z\ Z2, Z\ independently of one another, are a hydroxy group or a radical -NRl7-U1', RECEIVED Intellectual Property Office FEB 1998 of New Zealand 108 2 7 6413 wherein R17 is a h/drogen atom, a methyl or methoxyethyl group, and U\ U1, u-s p Q-M, vl, V® and V, respectively independently of one another, are a hydrogen atom or a halogenated aromatic radical of formula IV, (IV) in which X R*, R9, independently of one another, are a group -NR?-CO-R7 or have the meaning indicated for Rl, with the exception of a 0,-0,5 alkyl radical, Q-C,5 aryl radical or a 0,-0,5 aralkyl radical, R10, R'\ independently of one another, are a halogen atom or a hydrogen atom, X is a halogen atom or a bridge crosslink of formula V, and Y is R9 or a bridge crosslink of formula V (a)-(CH2)p-(C6H<)n-(L)m-R,2-(p) (V) in which m, n, p, independently of one another, are numbers 0 or 1. L is an oxygen atom, a sulfur atom, a Cj-C4 alkylene radical, a group [>S=0, >S02 or >NR4J, I I I S=0, 0=S=0, or N-R4 and • I I I R" is a direct bond, a carbonyl, a carboxyl, a -CO-NR18-, an -NRu-CO-, an -NH-CS- or a CS-NH group, in which R" is a hydrogen atom, a straight-chain or branched C,-Cl5 alkyl radical, C6-Ci5 aryl radical or a C,-C15 aralkyl received ''itellectual Property Office ~ n FEB 1998 of Zealand 109 2764 13 radical, which optionally contains 1-4 hydroxy groups, 1-2 carboxy groups* 1-2 oxygen atoms or a combination thereof, or R12 is a straight-chain or branched Cj-C4 alkylene radical, which optionally contains a carbonyl group* an amino group or a combination thereof, whereby position (a) is linked with the dicthylenetriamine skeleton and position (p) is linked with the halogenated aromatic compound, whereby Y stands for a bridge crosslink of formula V, if X is equal to halogen, and Y stands for R', if X stands for a bridge crosslink of formula V and at least one of radicals R2, R\ Z\ Z2, Z3, U1, U2, V1, V1 or V3 contains a halogenated group of formula IV, and optionally free carboxy groups, not required for complexing the metal ions of the mentioned elements, are present as salts of an inorganic base, an organic base, an amino acid or a combination thereof, with at least one of the following provisions, that R8 and/or R9 contains an aryl radical, that Z1 and/or Z? are a radical of general formula IV only if at least one of substituents R2, R\ U\ U1, V1, V1 oi V3 is not a hydrogen atom, that if Z3 contains a completely substituted aromatic compound of formula IV, Z1 and/or Z2 do not contain any fully substituted aromatic compounds of formula IV, or that if all substituents R2, R3, U1, U2, V1, V2 and V3 mean hydrogen, at least one of radicals R®, R9, R10 or Ru is a hydrogen atom, and/or R' and/or R9 mean a radical which contains a carboxylic acid that is not directly bound. received Intellectual Property Office - * FEB 1998 of New Zealand 110 2 7 64 1 3
2. Halogen-containing metal complexes according to claim l, characterized in that radicals Z1, Z2, Z3 stand for a hydroxy group
3. Halogen-containing metal complexes according to claims 1 and 2, wherein at least one of radicals R8, R9, R10 or R11 stands for a hydrogen atom.
4. Halogen-containing metal complexes according to claims 1, 2 and 3, wherein U1 stands for a radical of formula VI 8 R R (VI) 'ntellectuaj Prop,^ ^ '''FEB I998 i2£S £'v £ D 276413
5. Halogen-containing metal complexes according to claims 1-4 that contain a gadolinium ion as metal ion.
6. Halogen-containing metal complexes according to claims 1-4 that contain iodine as halogen atom(s).
7. 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 agents that contain at least one complex compound according to claim 1, optionally with additives that are commonly used in galenicals.
9. Use of at least one metal complex for the production of agents for NMR diagnosis and/or diagnostic radiology.
10. Use of at least one metal complex for the production of agents for diagnostic radiology of the liver.
11. Process for the production of the agents according to claims 1 to 6, wherein the complex salt that is dissolved in water is brought into a form that is suitable for enteral or parenteral administration with the additives or stabilizers that are commonly used in galenicals, so that the complex salt is present at a concentration of 1 to 1500 mmol/1.
12. Halogen-containing metal complexes according to claim 1 substantially as herein described or exemplified.
13. A diagnostic agent according to claim 8 substantially as herein described or exemplified.
14. Use according to claim 9 or 10 substantially as herein described or exemplified. 112 o 7 6 A ^
15. A process according to claim 1] substantially £» nerein described or exemplified. END OF C»A!MS RECEIVED Intellectual Property Office 1 * nrq 1998 of New Zealand </div>