CA2177977A1 - Aryl halide substituted metallic complexes, pharmaceuticals containing these complexes, their use for diagnostic purposes, and methods for preparing the complexes and pharmaceuticals - Google Patents

Abstract

The invention pertains to new metallic complexes containing an ion of an element of atomic number 12, 13, 20-31, 39-42, 44-50 or 57-83 and a halogenated complexing ligand of formula (I), where R1, R2, R3, Z1, Z2, Z3, U1, U2, V1, V2 or V3 have various meanings. The invention pertains as well to pharmaceuticals containing these complexes, to their use in NMR and/or X-ray diagnostics, especially in X-ray diagnosis of the liver, and to methods for preparing the complexes and pharmaceuticals.

Description

21779~7 lo~ryl-5ubst~tuted M~t~l Complexes, ph-rr-~ ~utical Agents Containing thes~ Complexes, ~rheir Us~ in Di~gnosis, ~8 well as Process ~or the Production o~ 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 or 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.

2177~77 Although great progress has been achieved with respect to equipment and contrast media, satisfactory solutions are not yet available for all problems.
Thu6, contrast media that are suitable for all indications do not yet exist for the various imaging processes. In 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, 6ufficient for imaging, in the liver.
Since the suitability of a ~ d as x-ray contrast medium, in addition to the concentration behavior in the respective organ, basically depends on the value of the mass attenuation coef f icient of the elements that are contained in the compound, in the diagnostic radiation area, in addition to the iodine-containing ~ n~l~, metal complexes of an element with a high atomic number should also be suitable. Such compounds are widely used in the field of N~ diagnosis. In this case, there are generally metal complexes, as they are described, e.g., in EP
o 071 564.
Wo 93/16375 descri~es 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 m~ike it pos~ible to carry out both N~ 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 e6pecially 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 NI~R 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 tconc.: 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 21~7~7 formula I

V U R U R R V

Z~ Ni--HOOC V J~ ~COOH
CO
Z
in which R1 stands for a hydrogen atom, a carboxylic acid radical, a straight-chain or branched C1-C1s alkyl radical, C6-C1s aryl radical, or a C7-C~s 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--NR4RS ( I I ) --CH2--NR6-Co--R7 ( I I I ) in which R4, Rs, indPrpl ~Pntly of one another, stand for a hydrogen atom, a straight-chain or branched C1-C15 alkyl radical, C6-C1s aryl radical, or a C7-C1s aralkyl radical, which optionally contains 1-5 hydroxy groups, 1-2 carboxy groups and/or 1-4 oxygen atoms, or in which R4, Rs, together 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, 2177~77 R6 stands for a hydrogen atom, a straight-chain or branched C~-C~5 alkyl radical, C6-C1s aryl radical or a C7-C1s 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 C1-C1s alkyl radical, C6-C1s aryl radical or a C7-C1s aralkyl radical, which optionally contains l to 2 hydroxy groups or a 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, optLonally substituted with 1-3 hydroxy groups, RZ, R3, indep~n~ently of one another, stand for a hydrogen atom, a C1-C1s alkyl radical, a C6-C1s aryl radical or a C7-C1s aralkyl radical, which optionally is substituted by 1-5 hydroxy groups and/or is interrupted by 1-4 oxygen atoms, or together ~orm a trimethylene or tetramethylene group, or have the meaning indicated for U1 (U2), Z1, ZZ, Z3, ;n~ r~nr~ntly of one another, stand for a hydroxy group or a radical -NR17-U1, in which R17 stands for a hydrogen atom, a methyl or methoxyethyl group, and U1, U1', U2, V~, VZ and V3, respectively independently of one another, stand for a hydrogen atom or for a halogenated aromatic radical of general formula IV, R

y~R
X
in which R8, R9, independently of one another, stand for a group -NR6-Co-R7 and/or have the meaning indicated for R1, with the exception of a C1-C1s alkyl radical, C6-C1s aryl radical or a C7-C15 aralkyl radical, R1C, 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)--(CHz) p--(C6H4) n--(L) ~ R (B) (V) in which m, n, p, independently of one another, ~;tand for num~ers O or l, 217~g77 L stands for an oxygen atom, a sulfur atom, a C1-C~, alkylene radical, a group ~S=O, >SOz or >NR4 with R~ in the mentioned meaning, and R1Z stands for a direct bond, a carbonyl, a carboxyl, 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 C1-C1s alkyl radical, C6-C15 aryl radical, or a C7-C1s 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 C1-C4 alkylene radical, which optionally contains a carbonyl group and/or an amino group, whereby position (~) is linked with the diethylenetriamine skeleton and position (B) 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, U1, 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 21779~7 that Z1 and/or ZZ 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 _ ~.1 of formula IV, Z1 and/or Z2 do not contain any fully substituted aromatic ~ ~oun~l~ of formula IV, and/or that if all substituents R2, R~, 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 r~n~n~e(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 2177~77 group -OH, -COOH, -o-CH2-CH(OH) -CH2-OH, -o-CH3, -o-CH2-CH3, -CO-NH-CH(CH20H)--(CHOH-CH20H), -Co-NR4-CH--(CHzoH)2~ -NR6--CO-CH20H, --Co-NR4-CH2-CH20H, -CO-NH2, --N (CH3) -CO-CH3, -NH-CO-CH3, -Co-NH-CH3, --N (CH3) -CO-(CH2)2COOH, -CO-N--(C2Hs)2, -C-N(CH3)-cH2 - cooH~ -CO-NH--(CH2)10-COOH, -CO-NH-CH2-C6H4-OEt or a group -Co-N(CH3)-CH2-CH(OH)-CH2-OH, and in which Y 6tands 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--C6H4-0-CH2--, -CH2-0-CH2--, -CH2-0-, CH2 CO , --CH2--NH-CO-, -CH2-CO-NH-, --CH2-C6H4-O-CH2-CO--NH-, --CH2-0-CO-NH--, --CH2--NH-CO-NH--, -NH--CO-, --NH-CO-CH2-, - Z stands for a halogenated aromatic radical, the groups -NH-CH2-CO-NH-, -NH CH2CH2-CO-NH- or -NH CH2CH2-NH-CO- and that - V stands for a halogenated aromatic radical, the groups --CH2--, -CH2--0-, -CH2-0-CH2-, -CH2-0-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 ~tands for the radical of general formula IV, i.e., c u~Ll,ds that are substituted with the halogenated aromatic compound in the ethylene bridge of the polyaminocarboxylic acid and in ~hich Z stands f or a hydroxy group .
A6 radical R1, there are considered straight-chain or branched aLlcyl radicals, such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl radicals, but preferred are hydrogen, C1-C4 alkyl and hydroxyalkyl radicals, such as, e.g., 2177g77 the hydL~ y ~hyl radical as well as alkoxyalkyl radicals, such as, e.g., the methoxymethyl 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 carboxyl groups that are present in the molecule ( i . e ., carboxyl 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 2177g77 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 cc~: ' (s) can be bound I) to the ~-carbon atoms of the carboxylic 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 O 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

Cl ~--CO~H
R (VI) in which R13 is the desired halogenated aromatic radical of general formula IV or an optionally still unhalogenated precursor 21~7~7 of this radical, with polyamines of general formula VII

H~N~N ~ NH.

j~ H 13 R R (VII) first compounds of general formula VIII can be obtained, 3 RyCO~H

H~N N~/NH

~ H 3 R R ~

which then are reacted in a way known in the art with haloacetic acid esters, pref erably 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 onc skilled in the art. Disubstitution can also be achieved with corresponding stoichiometry.
An alternative process for the production of ~-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 217797~
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 _ ~ull~ is reacted to the desired halogenated aromatic compound of formula IV, e.g., by the optionally present nitro groups being reduced to amino groups, which 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 io~ o~ hloride 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

H`N ~H
V3 ~ CO
Z ~
whose primary amino group optionally can also be present in protected form (e.g., as monobenzylamine). Thi6 amino group is dialkylated on a nitrogen atom with an alkylating agent of 21~7~77 formula XXIV

Vl Ul Rl UZ

N Nf Rl~O
oC (XXIV) and then -- after cleavage of the optionally present protective groups -- with an alkylating agent of formula XXV

~ ~Lco-zZ
Nf N

COOR~

whereby Nf stands for a nucleofuge, such as, e.g., chloride, bromide, iodide, methanesulfonate or toluenesulfonate, and R14 stands for an acid protective group, such as, e.g., a lower alkyl, aryl, aralkyl or trialkylsilyl group, and R1, RZ, R3, U1, UZ, V1, V2, V3, z1, Z2 and Z3 have the previously indicated meaning .
Synthesis for the production of an ~-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 int~ liAte product is reacted with two equivalents of N,N-bis[ (benzyloxycarbonyl) -methyl]-2-bromomethylamine. Before the cleavage of the acid 15 21779~7 protective groups, the substituents of the aromatic C~l r_ ' are optionally converted to the de6ired radicals.
The production of the complexing agents of group II can be carried out analogously to the method5 that are described in EP 0 405 704 as well as DE 43 02 289. Thus, the process starts from, e.g., known c __I.d6 (DE 37 10 730 and literature cited there) of general formula IX, C~
ll J
`f~ Rl R3 R3 0C~\N)~\I~)~N/--C3~R'"~R1' a~ORI4 in which R1~, 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., O 16 2177~7 benzyl halide) o~ formula X

R
~R~

~CI
10 ' R (X), in which R8', R9', R10 and R1t stand for desired groups R8, R9, R10 and Rl1 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 R14 are cleaved in a known way [see, e.g., E. Wiinsch, Methoden der Org. Chemie [Methods of Org. Chemistry] (Houben Weyl), Vol. XV/l, 4th Edition, 1974, p. 315 ff~, for example, by hydrolysis, hydrogenolysis or AlkAl inC~ saponification, generally beforc the halogenation of the aromatic compound. Both acidic and aqueous-AlkAl ine 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 io~ no~hloride, in a way known in the art. Optionally, the phenolic -OE~ groups can be etherifled in a way known in the art with alkyl ha;ide/sodium hydride. The cleavage of the acid protective groups is carried out in the previously described way.

217~77 An alternative process also star~s from halogen-contalning chlorinated aromatic compounds of formula X, which are reacted with a partially protected glycerol, first to the corresponding dihyclLuxy~rv~yloxy compound of formula XI

R
. 1 10' ! l ~ R OH
t ~0 !w R OH (XI) which then are reacted after partial protection of one hydroxy group and activation of the r~ ining group with sodium azide to the corresponding azido compound of general formula XII

R
Ir 1 10' R N
~0 10' 15 R OR ~I) in which R1s stands for a protective group, such as, e.g., a benzyl group.
After cleavage cf OH-protective group R15 and activation of the resulting hydroxy group, e.g., as methanesul~onic acid ester, the reaction i6 fir6t performed with the . oLLe:,~o~lding ethylen~;;,~inf~ and then the azide group is reduced in a way 2~77977 known in the art, e.g., with triphenylphosphine, to compounds of f ormula XI II
R
Ir ¦ lo~
R~ NHl R

R ~ ~NH2 Rw R R2 (Xm) The latter are reacted in a known way with bromoacetic acid ester to the corresponding pentaesters . Af ter cleavage of the acid protective groups, e.g., by reaction with trifluoroacetic acid and generation of desired groups RB, R9, R10 and Rl~ from groups R8, R9, R10 and R11, the desired complexing agents are obta ined .
An alternative process for the production of complexing agents of group II starts from acid-protected polyaminocarboxylic acid derivatives of general formula XIV

C~

R 00~, ,~ y~,--GOOR

(~2 a~2 ~2 ~OR COOR CX)OR

which are react~d with isocyanato rolnrQ~ln~l~ of general formula XV
R
R~R
R ~\N=C=O
(XV) to the corresponding urethanes.
As an alternative, the hydroxy group in the compounds of general forr~ula XIV can also be reacted, e.g., with N-chlorosuccinimide to the corresponding chloride of formula XVI
'\ R R R3 ~2 COaR ~CR C~OR (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
l~R
R ~Y' R (XVII) in which R~, R9, R10 and R11 have the indicated r ni n~s and Y' stands for an OH or COOH group, to the corresponding ethers or esters. The cleavage of acid protective groups R14 is carried out in the above-described way.
As an alternative, the compounds of general formula XVI can be reacted with an azide (e.g., sodium azide) to the coLLe-yol,~;n~ 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

R
Il I lC
R O ~xvm) to the corr~srnn~l i n~ amide .
An alternative proces~ starts from an aminoethyl alcohol of formu1a XIX, R~

~N~
!,6 R (XIX) in which R16 stands for an amino protective group, preferably a benzyloxycarbonyl group and R13 means an unhalogenated precursor 2~ 7~77 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 f irst 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 ethylene~ mi n~ . 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 2177~77 general formulas XX or XXI wi~h halogenated aromatic compounds of general formula XXII to the amides according to the invention, R ~ R
0~ ~1 "N~ ~0 ~T~ R2 ~o O O
R ~ R
HOOC/~N~N~ /\
H~C~ R- ~0 O
R
r I RW' ~`~
R ~2 1~' R (XX~) in which R8, R9, R10 and R1~ 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 217~77 aromatic compounds of general formula XXII is carried out as described, e.g., in DE 25 23 567.
As radical H2N-Q, there can be mentioned a5 examples an H2N-CH2--CO-NH, H2N-NH--CO--NH, H2N-CH2CH2--CO-NH, H2N-NH-CO-CH2CH2, H2N-CH2CH2-NH-co group or an H2N-CH2CH2-N(C0-CH3) 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, dimethylformamide, dimethylacetamide and the like cr mixtures thereof. The reaction temperatures are between about -80C and 160C, and temperatures of 20C to 80C 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. 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 known compounds.
Thus, e.g., in German laid-open specification DE 29 28 417, iodized aromatic compound~ are described, which are readily 2177~77 reacted with, e.g., thionyl chloride, to the corr~-cpon~in~ acid chloride group-containing aromatic compounds.
Other aromatic radicals can be produced as described in M.
Sovak; ~adiocontrast Agents, E~andbook of Experimental Pharmacology Vol. 73 (1984), Springer Verlag, Berlin -h~rg - 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 or DE 10 03 743, 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.
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, by the metal oxide or a metal salt (for sxample, 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 6uspended in water and/or a lower alcohol (such as methanol, ethanol, isopropanol and/or N,N-dimethylformamide) 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.

217~7~
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 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 217~77 formed being isolated, optionally purified and then being mixed with the required amount of inorganic base for complete neutralization. The sequence of addition to the base can also be reversed .
Another 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/l, preferably at a concentration of 10-1000 mmol/l. 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 complexi~g agents (such as, e.g., diethylenetriaminepentaacetic acid) or, if necr~cs~y, electrolytes, guch as, e.g., sodium chloride or, if necessary, antioxidants, such as, e.g., ascorbic acid.
If su~pensions or solutions of the agents according to the invention in water or physiological salt solution are desired for enteral adm inistration or other purposes, they are mixed with one 2~77~77 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 cl olln~ 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 ss~allest possible amounts of oreign substances, 2~ 77977 -- 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, -- adYantageous 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 -- i8 not carried out within the time in which the new contrast media are again completely excreted.
In addition to the high water 601ubility, which it was possible to increase, surprisingly enough, in the presence of paramagnetic metal ions in a range necessary for diagnostic radiology, the ~ G.~I~ds according to the invention have a positive efect 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 Rontgenbild [The X-Ray Picture ]; rhieme Stuttgart 19 8 0 ) .
Because of the advantageous absorption properties of the contrast meaia according to the invention in the area of hard x-2177~77 ray radiation, the media are also especially suited for digitalsubtraction 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 O . 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 in~ection of 0. 5 mmol/kg of the c~ : ulld according to the invention produced according to Example ld).
A picture taken under otherwise identical conditions after the 6ame dose of the disodium salt of the gadolinium complex of (4s) 4- (4-ethoxybenzyl) -3, 6, 9-tris (carboxylatomethyl) -3, 6, 9-triazalln~An~linic acid is administered (EP O 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) as a function of time, for a compound according to the invention (Example ld) and a compound of EP O 405 704 (Example 8c). Accordingly, considerably higher density values 21~77 ~re 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 re3pective 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 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-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 ~sS~m; n~ 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 c _ul.d 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.

The half-life of o . 32 hour as well aG the distribution volume show a distribution in the extracellular space with ren21 elimination by glomerular f iltration 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 N~R diagno6is. This dual nature opens up further f ields 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 ll~lted to these ex~mple~.

21~7g~7 Exampl~ 1 Ga~olinium comelex o~ the di80dium ~lt of 3,6,9-triaz7-3,6,9-trL8-~carbo~y ~hyl~-~-[4-(2,4,6-triiodobenzyloxy)-benzyl]-nller-r - '; oic ~cid a) Production Or 2,~,6-tr~edob~n~yl chlorid~
41.6 g (80.1 mmol) of 3-amino-2,4,6-triiodobenzyl chloride tCollection Czechoslov. Chem. Commun. [Vol. 41] 1976) is s~p~n~lP~ 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 25C 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 suspension is cooled to 10C, f iltered, 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 0C, whereby a precipitate results. The latter is suctioned off and dried in a vacuum.
Yield: 29.8 g (73.8~) of light beiqe solid 33 21~977 Analy~is (relative to solventless subYtance):
Cld: C 16. 67 H 0 . 80 Cl 7 . 03 I 7S . 50 Fnd: C 16.82 H 0.95 Cl 7.14 I 75.41 b) 3,6,9-Triaz~-3,6,9-tris-(t~rt-butoxyc~rbonylm~thyl)-4-[4-(2,~,6-tri~ocl~h~n~yloYy)-benzyl]-l 'ec~ns~ioic ~cid-~i-t~rt-butyl aster 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 0C with 660 mg (22 . 0 mmol) of 80% sodium hydride suspension in mineral oil. 12 . 4 g (22 . o mmol) of the 2 , 4 , 6-triiodobenzyl chloride, produced according to Example la), i8 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 NazSO4 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 (91.296 of theory) of yellowish oil Analysis (relative to solventless substance):
Cld: 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 c) 3,6,9-~riasa-3,6,9-tris-~carboxylssthyl)-4-t4-~2,~,6-triiodobon8yloxy)-benzyl]-~ndecAne~ioic ~cid 22.8 q (18.3 mmol) of the tert-butyl ester described in Example lb) i6 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 40C 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):
Cld: C 34.77 H 3.33 I 39.36 N 4.34 o 18.19 Fnd: C 34.63 H 3.56 I 39.28 N 4.38 d) G~dolinium complex of tho disodium ~alt of 3,6,9-triaza-3,6,9-tris-~c~lrboxymothyl)-4-t~ 2,~,~-triiodobenzyloxy)-b~nzyl]-~n~ec~n~;oic 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 80C
for 2 hour6 . Then, 24 . 4 ml of lN 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 80C and filtered. After freeze-drying, the filtrate yields a colorless solid.

Yield: 13.1 g (91.89~ of theory) Analysis (relative to anhydrous substance):
Cld: C 28 . 86 H 2 . 34 I 32 . 67 N 3 . 61 O 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 ExamplQ 2 Gadol~nium complex of the -;^o~ lt of 3,6,9-triaza-3,6,9-tris-tc~LLv~ethy~ [4-(N-~cctyl-3-methylamino-2~4~6 triiodobenzyloxy)-benzyl]-unaecanedioic ~cid a) N-Ac~tyl-3-methyl~mino-2, ~, 6-triiollobenzyl 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 acelyl chloride while being cooled with ice. After 30 minutes of stirring at about 0C, 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):
Cld: C 20 . 88 H 1. 58 Cl 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 b~ 3,6,9-q!riaz~-3,6,9-tris-(tert-butoxyc~rbonylmethyl)-~-[~-tN-acetyl-3-methylamino-2, 4, 6-triiodobenzyloxy) -benzyl] -~nl~c~ngl~;oiC 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) is mixed in tetrahydrofuran at 0C 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 Na2SO4 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: 23 . 5 g (89 . 2% of theory) of yellowish oil Analysis (relative to solventless substance):
Cld: C 46 . 45 H 5 . 89 I 28 . 87 N 4 . 25 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-methyla~ino-2, ~, 6-triiodobenzyloxy) -benzyl] -unde~anedioic ~c id 21.9 g (16.6 mmol) of the tert-butyl ester described in Example 2b) is dissolved in 250 ml of trifluoroacetic acid and ~ 2177977 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 40C in a vacuum on phosphoru8 pentoxide. The crude product i5 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):
Cld: 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) G~olinium complex of the disodium sAlt of 3,6,9-triaza-3,6,9-tris-(c~rboxymethyl) -~.-t4-(N-acetyl-3-methylAmino-2,4,6-tri;odob~n~yloxy~-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 80C
for two hours. Then, 28 . 5 ml of lN sodium hydroxide solution is added with a microburette and stirred f or one more hour . Then, after 0 . 8 g of activated carbon is added, the solution is stirred for two hours at 80C and filtered. After concentration by evaporation, the ~iltrate yielded a colorless ~olid.
Yield: 16.4 g (93.3~c of theory) Analysis (relative to anhydrous substance):
Cld: C 30.11 H 2.61 I 30.79 N 4.53 0 15.53 Gd 12.72 Na 3.7a Fnd: C 30.00 H 2.82 I 30.58 N 4.67 Gd 12.79 Na 3.82 21779~7 Ex~mpl~ 3 Gadolinium compl~3x of th~ trisodium s~lt of 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -{~-[N- (3-car~oxypropionyl) -3-methylamino-2, ~, 6-triiodol~nzyloxy] -benzyl} -ll nrler~n e~ ~ oic acid a) N- (5-Oxa-1, ~-dioxoheptyl) -3-methyl~mino-2, 4, 6-triiodo~enzyl 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. tVol. 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. Af~er drying on anhydrous magnesium sulfate, th~ organic phase is concentrated }~y evaporation, and the residue is recrystallized from ethyl acetate/tert-butyl methyl ether.
Yield: 58.4 g (88.396 of theory) of colorless solid Analys~ s (relative to solventless substance):
Cld: C 25.42 H 2.29 Cl 5.36 I 57.56 N 2.12 0 7.26 Fnd: C 25.31 H 2.49 C1 5.43 I 57.50 N 2.17 b) 3~6~9-Triaz~-3~6~9-tris-~t~rt-butoxycarbonylmethy~ -{~-tN
~5-ox~ -dioxo-heptyl) -3-methyl~mino-2,~, 6-tr~odob~n~yloxy~-benzyl}-~n~ ec-ne~ ioic aci~
15 . 6 q (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~ is mixed in tetrahydrofuran at 0C 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. ~hen, 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) wit~l hexane/ethyl acetate/triethylamine, the product fractions are concentrated by evaporation and dried in a vacuum.
Yield: 22.9 g (81.6~c of theory) of yellowish oil Analy ~is (relative to solventless substance):
Cld: Y 47.02 E~ 5.95 I 27.10 N 3.99 0 15.94 Fnd: ~ 46.86 H 6.13 I 26.98 N 3.84 c) 3,6,9--~rri~z~-3,6,9-tris-~carboxymethyl)-{~-[N-~3-c~rbo~propionyl) -3-methylamino-2,4,6-triiodobenzyloxy]-benzyl~---nC~ec~n~ ioic ~cid 20.4 ~ (14.5 mmol) of the hexaester described in Example 3b) is dissolv~ in 100 ml of methanol and mixed with 87 ml of 2N

~1 77977 sodium hydroxide solution. It i8 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 60CC. 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):
Cld: C 36.15 H 3.59 I 34.72 N 5.11 0 20.43 Fnd: C 36.23 H 3.65 I 34.58 N 5.05 d) G~aolinium complex of the trisodium salt of 3,6,9-triaz~-3,C,9-tris-~c~rboxy~ethyl)-{4-[N-(3-c~rb~YyroL~ionyl1 ~3~
methylzlmino-2,~, 6-triioaobenzyloxy]-benzyl}-~n~ec~ne~ioic acia 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 80C
for 2 hours . Then, 38 . 6 ml of lN 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 80C for 2 hours and filtered. After freeze-drying, the filtrate yielded a colorless solid.
Yield: 16.3 g (96.4~6 of theory) 1-- 2~ 77977 Analysis (relative to anhydrous substance):
Cld: 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 ~
G~dolinium compleY o~ 3,6,9-tri~za-3,6,9-tris-~caLl,~,A~ ~hyl)-~-t3,5-diiod-~-ethoxybenzyl)--ln~ec-n~oic acid, di30dium s~lt a) 3,6,9-Triaza-3,6,9-tris-tcarbOXymethyl)-4-t4-hydroxybenzyl)-ioiC ~cid 7.8 g (10 mmol) of 3,6,9-triaza-3,6,9-tris-(tert-butoxycarbonylmethyl)-4-(4-hydroxybenzyl)-undecanedioic acld-di-tert-butyl ester (Example 9f of DE 3710730) is dissolved in 100 ml of trif luoroacetic acid and stirred f or 1. 5 hours at room temperature. Then, it is diluted with diethyl ether, and the precipitate is suctioned off. It is washed with diethyl ether and dried at 50C 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.

Elemen~ary analysis (taking into consideration the solvent content):
Cld: C 50.50 H 5.85 N 8.41 0 35.24 Fnd: C 50 . 68 H 5. 99 N 8 . 25 ~ 21~7977 b) 3,6,9-~riaza-3,6,9-tri8-(carboYym~thyl)-4-~3,5-aiioao-~-L~ ~L ;)nybCnZy~ -n-lecA n e~l~ QiC acid 3.2 g (6.4 mmol) of the phenol of Example 4a) is suspended in 50 ml of water and mixed with solid sodium hydroxide up to the neutral point . The batch is stirred at 50C, and 5 . 7 ml ( 14 .1 mmol) of a 40% hydrochloric acid-iodomonochloride solution is added in drops. After 20 hours at 50C, the excess iodine is reduced with sodium disulfite, the precipitate is suctioned off and washed with water.
Yield: 4.15 g (8696 of theory) of pale yellow solid Elementary analysis (taking into consideration the solvent content):
Cld: 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-~carboYymethyl)-5-(3,5-diio~o-4-ethoYybenzyl)-undecaneaioic acia 3 . 0 g (4 mmol) of the diiodophenol of Example 4b) is mixed in 25 ml of anhydrous tetrahydrofuran with 0.792 ~ (26.4 mmol) of 80~6 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 precipitate is suctioned of f and washed with water . For purification, the crude product is recrystallized from ethanol.
Yield: 2 . 35 g (7S . 4% of theory) of colorless crystals .

Elementary analysis (taking into consideration the solvent content ~:
Cld: 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) G~lolinium complex of 3,6,9-triaz~-3,6,9-tri~-(C~LLO~y -thyl)-4-~3,5-diiodo-4-ethoxy~enzyl)-~1n~ler~ ioic ~c$d 1. 75 g (2 . 2 mmol) of the pentacarboxylic acid of Example 4c) is suspended in 55 ml of water and mixed at 60C 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-mem3~rane filter (0.2 mm, Sartorius) and freeze-dried.
Yield: 1.95 g (94.996 of theory) o~ colorless lyophilizate.

Ele~nentary analysis (taking into consideration the solvent conte nt):
Cld: C 29.59 H 3.02 Gd 16.84 I 27.19 0 18.85 ~nd: C 29.64 H 3.25 Gd 16.66 I 26.93 ~ 2177'J77 e) Gadol$nl~m comploY of 3,6,9-trisz~-3,6,9-tris-~c~rboxymethyl)-4-~3,5-diiodo-4-ethoxybenzyl~ n~lec-ne~ioic ~cid, disodium salt 1.5 g (1.6 mmol) of the complex described in the above example i5 dissolved in 120 ml of water and mixed using a microburette with 3 . 2 ml of a lN sodium hydroxide 601ution .
After freeze-drying, the disodium salt is obtained as colorless lyophilizate .
Yield: 1.55 g (99% of theory) of colorless lyophilizate.

Elementary analysis (taking into consideration the solvent content ):
Cld: 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 4.4s Ex~mple 5 Gadolinium complex of the disodium salt of 4- tN-acetyl-3-methylamino-2,~,6-triiodobenzyloxymethyl)-3,6,9-triaza-3,6,9-tris- ~ c~rbo~ymethyl ) -~ ~ n eA i o ic acid a) N-Ac~tyl-N-methyl-3-[ ~2,2-dimethyl-1,3-dioxolan-4-yl)-metho~methyl ~ -2, ~, 6-triiodoani1 ine 20.0 g (36.3 mmol) of the compound produced under Example 2a), 5.8 g (43.6 mmol) of 2,3-0-isopropylidene glycerol, 0.41 g (1.8 mmol) of N-benzyl-N,N,N-triethylammoniUm chloride and 4.1 g (72.7 mmol) of ground potassium hydroxide are refluxed in 35 ml of toluene _or 6 hours. Then, the organic phase is separated, shaken out -~.ith saturated aqueous common salt solution and dried on magnQsium sulfate. After the filtrate i6 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):
Cld: 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- t (2, 3-dihydroxypropyloxy) -methyl] -2, 4, 6-triio~o~n i ~ i n~
20.2 g (30.1 mmol) 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 30C, 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, f lltered and concentrated by evaporation . The residue is chromatographed on silica gel 60 (MercX) with dichloromethane/methanol. After the product fractions are concentrated by evaporation, a colorless oil is obtained, which is dried in a vacuum.
Yield: 16.9 g (89.29~ of theory) ~ 2177977 Analysis (relative to solventless substance):
Cld: 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-Ac~tyl-N-methyl-3- [ ( 3 -b~nzoyloxy-2 -hydroxypropyloxy) -methyl~ -2, ~., 6-triio-io~ n~ 1 ~ n~
15.2 g (24.1 mmol) of the compound produced in Example Sb) is stirred in 150 ml of dichloromethane under argon and mixed first with 4.0 ml (28.9 mmol) of triethylamine, then at 0C drop by drop with 3 . 47 g (26 . 5 mmol) of benzoyl cyanide. After 12 hours of stirring at 0C, 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 chromatoqraphed on silica gel 60 (Merclc) with dichloromethane/methanol. After concentration by evaporation, the product fractions yield a colorless oil.
Yield: 13 . 9 g (78 . 4% of theory) Analy~;is (relative to solventless substance):
Cld: C 32.68 H 2.74 I 51.79 N 1.91 O 10.88 Fnd: C 32.54 H 2.88 I 51.83 N 1.74 d) N-Ac~t~l-N-mothyl-3-[ ~3-benzoyloxy-2-meth~nesul~onyl~ryLoy~loxy) methyl]-2,4,6-triiorlo~ n~1~rt 13.4 g (18.2 mmol) of the compound produced under Example 5c) is stirTed in 80 ml of dichloromethane under argon and mixed first with 3 . o ml (21. 9 mmol) of triethylamine, then at oC drop by drop with 1. 56 ml t20 .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 (~erck) 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):
Cld: C 31.02 H 2.73 I 46.82 N 1.72 o 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 -az idopropyloxy ) -methyl]-2~ 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 85CC 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 .19~ of theory) of yellowish foam Analysis (relative to 601ventless free substance):
Cld: C 31.60 H 2.52 I so.os 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-t ~2-~zido-3-hydroxypropyloxy) methyl]-2,~,6--triiodc~-ni 1 in~
9 . 58 g (12 . 6 mmol) of the compound produced according to Example 5e) is di6solved in 60 ml of methanol. After 40 ml of 2N
sodium hydroxide solution is added, it is stirred for one hour at 50C bath temperature and after the cooling, it is neutralized with 2N hydrochloric acid . The methanol is drawn of f 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 (l~erck), and the product fractions are concentrated by evaporation in a vacuum.
Yield: 7.47 g (90.396 of theory) Analysis ~relative to solventless substance):
Cld: 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-t (2-~zido-3-moth~e~ulfonyloxypropyloxy)-methyl]-2~4~6-triiollo~n;

-217~977 7.22 g (11.0 mmol) of the hydroxy compound produced according to Example Sf ) 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):
Cld: C 22.91 H 2.33 I 51.86 N 7.63 0 10.90 S 4.37 ~nd: C 23.01 H 2.58 I 51.63 N 7.75 S 4.49 h) N-Acetyl-N-methyl-3-(6,9-diaz~-4-~zido-2-oxanonyl)-2,4,6-triiodo~ni ~ inQ, dibydrochloride 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 f or 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) so Analysis (relative to solventles6 6ubstance):
Cld: C 23 . 37 H 3 . 01 I 49 . 38 N 10. 90 0 4 . lS 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-diaz~-2-oxanonyl)-2,4,6-tri ~ oc'l~- n ~ l i ne, trihydrochlorid~
7 . 04 g (9 .13 mmol) of the dihydrochloride produced under Example 5h) is taken up in 70 ml of a 4: l mixture of dioxane/water and mixed with 12.0 g (4S.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 (8S.8% of theory) Analysis (relative to solventless substance):
Cld: C 23.05 H 3.35 I 48.72 N 7.17 0 4.10 Cl 13.61 Fnd: C 23 . 28 H 3 . 60 I 48 . 49 N 7 . 43 Cl 13 . 88 ; ) ~- (N-Acetyl-3-methyl~mino-2, ~, 6-triiodobenzylo~ymethyl) -3,6,9-tris-~tert-butyloxycarbonylmethyl~ -3,6,9-triaz~un~e~nedi oic ~cid-di-tert-butyl ester 5 . 98 g (7 . 6S mmol) of the trihydrochloride produced under Example 5i) is stirred in 60 ml of N,N-dimethylformamide under argon at room temperature and mixed with 10 . 6 g (76 . 5 mmol) Of 217797~
pOtassium earbonate and 7.46 g (38.3 mmol) of bromoacetie aeid-tert-butyl ester. After 12 hours of stirring, it is filtered, coneentrated by evaporation in a vacuum, and the residue is dispersed between ethyl acetate and saturated sodium biearbonate 601ution. The organie phase is dried on sodium sulfate, filtered, eoncentrated by evaporation, and the residue is chromatographed on siliea gel 60 (Merek) with hexane/ethyl acetate. After the product fractions are concentrated by evaporatiOn, a yellowish oil is obtained.
Yield: 8.94 g (98.5~c of theory) Analysis (relative to solventless substance):
Cld: C 41.50 H 5.52 I 32.08 N 4.72 O 16.18 Fnd: C 41.52 H 5.73 I 31.96 N 4.68 k) ~~ (N-Acetyl-3-methylamino-2, 4, 6-triiodobenzyloxymethyl) -3,C,9-~riAzA-3,6,9-tris-(c~rboxymethyl~-undec~nedioic ACid 8 . 50 g (7 .16 mmol) of the pentaester produced under Example 5; ) is eonverted to the eorreseonding penta acid under the conditions deseribed in Example lc).
Yield: 5.80 g (84.19~ of theory) of light beige solid Analys-- (relative to anhydrous substance):
Cld: e 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.~3 2t 77977 l) Gadolinium compleY of the qisodium s~lt o~ 4- (N-~c~tyl-3-methylamino-2, ~, 6-triioao~enzyloxymethyl ] -3, 6, 9-tri~z~-3, 6, 9-tris-tc~rboxymethyl) -~nde~nadioic ~cid 5.69 g (6.19 mmol) of the penta acid produced in Example 5k) ls complexed with gadolinium oxide under the conditions described in Example ld) and converted to the corresponding disodium salt.
Yield: 6.81 g (94.896 of theory) of colorless lyophilizate Analysis (relative to anhydrous substance):
Cld: 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 ~xample 6 1,19-Bis-~3-carboxy-2,4,6-triiodophenyl~ -7,10,13-tri~-(carboYymethyl) -2,5,15,18-tetraoxo-1,4,7,10,13,16,19-hepta~z~non~decane, g~dolinium complex, disodium s~lt a) 1,19-Bi~-~3-c~rboYy-2,4,6-triiodophenyl)-7,10,13-tris-(carboYym~thyl)-2,5,15,18-tetraoxo-1,4,7,10,13,16,19-hept~ no~ --lqc -ne 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 heate~. 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 stirred for 15 hours at room temperature. Then, it is evaporated to dryness, the residue is taken up in water and acidified with concentrate~ hydrochloric acid. The settled precipitate is 2177g77 suctioned of f and washed with water . The crude product is purified by an RP 18 chromatography on silica gel.
Yield: 9.~ g (63% of theory) o~ colorless solid.

Elementary analysis (taking into consideration the solvent content):
Cld: 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) 1,ls-Bis-~3-cJ~rboxy-2,~,6-triio~ophenyl)-7,10,13-tris-(c~rboxymethyl)-2,5,15,18-tetraoxo-1,4,7,10,13~16,19-hepta~ r~0n~d~c~ , gadolinium complex, disodium s~lt 7 . 2 g (48 mmol) of the ligand of Example 6a) is suspended in 50 ml of wa,er and mixed in portions with 1.74 g (4.8 mmol) of gadolinium oxide at 50-60C. After the complexing is completed, the pH is aljusted to seven with lN sodium hydroxide solution, filtered, ~d the aqueous solution is freeze-dried.
Yield: 7. 6 g (93% of theory) of colorless lyophilizate.

Elemer--ary analysis (taking into consideration the solvent content~:
Cl~: - 22.62 ~{ 1.66 Gd 9.25 I 44.81 N 5.77 Na 2.71 0 13.18 Fn~: _ 22.43 H 1.85 Gd 9.07 I 44.71 N 5.63 Na 2.49 ~ 54 217797~
Bxampl~ 7 l~lg-Bis-{3-~(lo-carboxydecyl)-~A~rh-r yl~-2,4,6-triiodophenyl}-7,10,13-tris-(carboYymethyl~ -2,5,15,18-tetraoxo-1, 4, 7, 1 0, 1 3, 1 6, 1 9 h e p ~ n ~ c ~ , g a d o 1 i n i um c o mp l e x, disodium salt a) ~ 3 _7~n i nA AcetylrAmido ) -N- ( 10 -carboYydecyl ) -2, 4, 6 -tri ;Od~AhAn70iC acid amide lO.9 g (15 mmol) of 3-phthalimidoacetylamino-2,4,6-triiodobenzoic acid chloride (DE 2523567) is dissolved in 60 ml of N,N-dimethylacetamide and reacted at 80C with 1.98 g (16 mmol) of ll-Am;nolln~ An~ic acid. The reaction mixture is stirred for 32 hours at this temperature, and then hydrochloride is filtered out. The filtrate is evaporated to dryness, the residue is suspended in 40 ml of water and reacted with 4 . 5 g (90 mmol) of hydrazine hydrate. After three hours of stirring at 65C, 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 50C in a vacuum.
Yield: 9.8 g (8796 of theory) of pale yellow crystals.

Elementary analysis (taking into consideration the solvent content):
Cld: C 34.73 H 4.05 I 40.77 N 6.75 0 13.71 Fnd: C 34 . 90 H 3 . 92 I 40 . 68 N 6 . 51 b) l,l9-Bis-{3-t(10-c_rboxydecyl)-~ArbA--yl~-2,4,6-trilodophenyl}-7~lo~l3-tris-(carboxymethyl~ -2,5,15,18-t~tr~oYo- l , ~., 7, 1 0 ,13 ,16 ,19 -heptaa zanonadecane 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-di~ ~holino)ethyl]glycine and purified in a similar way by a eolumn ehromatography on RP 18.
Yield: 17 . 4 g (809~ of theory) of pale yellow solid.

Elementary analysis (taking into consideration the solvent content):
Cld: C 34.73 H 4.05 I 40.77 N 6.75 0 13.71 Fnd: C 34.90 H 3.92 I 40.68 N 6.51 c) l,l9-Bis-{3-t(10-carboYydecyl)-carbamoyl]-2,4,6-triiodophenyl}-7~10~13-tris-(carboxymethyl)-2~5~15~18-tetr_oYo-1,~,7,10,13,16,19-heptaazanonAde~ne, gadolinium co~ples, di~odium ~alt 15 g (8 mmol) of the ligand of Example 7b) is complexed aeeording to Example 6b) with 2.9 g (8 mmol) of gadolinium oxide and eonverted with lN Godium hydroxide solution to the disodium salt .
Yield: 15.6 g (95% of theory) of colorless lyophilizate.

2177~77 Elementary analysis (talcing into consideration the solvent content):
Cld: C 31.40 H 3.42 Gd 7.61 I 36.86 N 6.10 Na 2.23 0 12.39 Fnd: C 31.28 H 3.63 Gd 7.56 I 36.61 N 5.89 Na 1.97 Exampl~ 8 ~;~dolinium complex of th~ Cisodium sAlt of 4-(3-~cetylamino-2, 4, 6-tr~; o-lol~ Qyl-aminomethyl) -3, 6, 9-triaza-3, 6, 9-tris-(CaLLOAy ~hyl)-4-mcthyluntleCanedioic ~cid a) 2, ~-Dimethyl-4-methanesulfonyloxymethyl-2-oxazo1ine 40.8 g (316 mmol) of 2,4-dimethyl-4-hydroxymethyl-2-oxazoline (J. Nys and J. Libeer, Bull. Soc. Chim. Belg., 65, 377 (1956) ) is stirred in 400 ml of dichloromethane and 52.5 ml (379 mmol) of triethylamine at oC under nitrogen and mixed drop by drop with 39.8 q (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):
Cld: 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 217797~
b) ~- (2, 5-Diazapentyl) -z, ~-~imethyl-2-oxazoline, ~ihy~rochlori~l~
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 i5 6tirred for 3 hours at 50C 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 0C with concentrated hydrochloric acid. Ethyl~n~ mi n~-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 (88.49~ of theory) Analysis (relative to solventless substance):
Cld: C 39.35 ~ 7.84 N 17.21 0 6.55 C1 29.04 Fnd: C 39.40 H 7.78 N 17.09 Cl 29.11 c) 2-Amino-~.~ 7-aiAz~-2-methylheptan-1-ol, trihy~rochlori~c 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.

~ 58 2177~77 The precipitate is suctioned of f, washed with isopropanol and diethyl ether and dried in a vacuum.
Yield: 29.6 g (91.4 of theory) Analysis (relative to solventless substance):
Cld: C 28.08 H 7.86 N 16.38 0 6.24 Cl 41.45 Fnd: C 28.23 ~ 7.95 N 16.46 Cl 41.19 d) 3,6,9-q~ri~z~-3,6,9-tris-ttcrt-butyloxyc~rbonylmethyl)-4 hydro~lymethyl-~-methyl-~ln~ec-n~ i oic ~cid-di-tert-butyl ~ster 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 60C. After the cooling, ethyl acetate and water are added and shaken out; the aqueous phase is eYtracted 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 198 . 896 of theory) Analysis (relative to solventless substance):
Cld: C 60.23 H 9.41 N 5.85 0 24.51 Fnd: C 60.11 H 9.62 N 5.67 2177g77 e) ~-Chlorom~thyl-4-methyl-3, 6, 9-tris- (tert-butyloYyc~rbonylmethyl) -3, 6, 9-tri~zaundecanedioic acid-ai-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 0C, mixed with 4.54 g (34.0 mmol) of N-chlorosuccinimide. After 2 hours of stirring at 0C, it i6 6tirred up with 200 ml of diethyl ether, the solid is separated and discarded. The ether phase is concentrated by evaporation, and the re6idue 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):
Cld: C 58.72 H 9.03 Cl 4.81 N 5.71 0 21.73 Fnd: C 58 . 68 H 9 . 23 Cl 4 . 98 N 5 . 64 f ) 3, 6, 9--~rriA za-~-~zi~omethyl-3, 6, 9 -tris- ( tert-butylcsycarbonylmethyl)-4-methylundecanedioic acid-di-tert-butyl ester A soll=tion of 18. 6 g (25 . 3 mmol) of the chloride, produced under Exa3i~le 8e), in 70 ml of N,N-dimethylformamide is mixed with 4.92 S (75.8 mmol) of sodium azide and stirred for 6 hours at 50~C. ~en, it is concentrated by evaporation in a vacuum, -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 solventles6 substance):
Cld: C 58.20 H 8.95 N 11.31 0 21.73 Fnd: C 58.15 H 8.72 N 11.18 g) ~-Aminomethyl-3, 6, 9-triaz~-3, 6, 9-tris- ~ tert-butyloxycArbonylmethyl~-4-methyllln~ec~ne~ioic Acid-di-t~rt-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 at~ ^re, 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 (99.996 of theory) of yellowish oil Analysis (relative to solventless substance):
Cld: C 60.31 H 9.56 N 7.82 0 22.32 Fnd: C 60.2Z H 9.78 N 8.03 217797~
h) ~-~3-Acetylamino-2~,6-triio~obenzoyl~m~r -thyl)-3,6,9-triilz~-3,C,9-tri~-ttert-butyloxyc~rbonylmothyl)-4-methyllln~e~ne~ioic ~cid-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. 87, 651 (1954) ), and it is stirred for 6 hours at room temperature. ~hen, it is concentrated by evaporation in a Yacuum, the residue is dispersed between ethyl acetate and 6aturated 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):
Cld: 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,~,6-triiodobenzoyl~mino~ethyl)-3,6,9-tri~zl-3,6,9-tri3-~c~ Lo..y~t;hyl)-4-methyl~ln~e~An~ioic _ci~
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).

Yield: 19.5 g (94.4%) of light beige solid Analysi6 lrelative to anhydrous substance):
Cld: C 30.79 H 2.32 I 39.04 N 7.18 Na 3.92 0 19.69 Fnd: C 30.98 H 2.40 I 38.84 N 7.24 Na 4.04 j ) Gadolinium compleY of the disodium s_lt o~ 4- (3-_cetylamino-2,~,6-triiodobenzoyl-~min~ ~thyl~-3,6,9-triAza-3,6,9-tris-(carboxymethyl)-4-methyl-1-n~l~cAn~;oic ~cid 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):
Cld: C 25.59 H 2.32 Gd 13.50 I 32.44 N 5.97 Na 3.92 0 16.36 Fnd: C 25.64 H 2.40 Gd 13.29 I 32.27 N 6.08 Na 4.04 BYampl~ 9 Gadolinium complex of the disodium salt of 4- ~3-acetyl_mino-2,~,6-triio.lob~n7oyl-oYymathyl)-3,6,9-triazA-3,6,9-tris-(c_rboyymethyl~-4-methylundec_nedioic ~cid a ) ~ - ~ 3 -~cety lam ino - 2, ~, 6 -tr i iodoben zoy loxymethy l ) - ~ -methy l -3,6,9--tris-~tert-bUtyloxy-c_rboYymethyl)-3~6~9-tri~z~undecanedioic acid-di-tert-butyl ester A solution of 14.7 g (20.0 mmol) of the chlorine c , u--d, described -~n Example 8e), i~ 30 ml of N,N-dimethylacetamide is 63 2i77g77 added at room temperature to a solution of 16.9 g (29.9 mmol) o~
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 f or 6 hours at 80C, then concentrated by cvaporation 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 ~lerck) with hexane/ethyl acetate (3:1). After the product fractions are concentrated by evaporation, a light beige oil remains.
Yield: 18.0 g t71.9% of theory~

Analysis (relative to solventless substance):
Cld: C 43.01 H 5.59 I 30.29 N 4.46 0 16.55 Fnd: C 43.11 H 5.84 I 30.42 N 4.48 b) ~-~3-Acctylamino-2,~,6-triiodooenZoyloXymethyl)-4-methyl-3,6,9-triazl~-3,6,9-tris-~tert-~utyloxy-c~lL~ I.hyl)-nl~eCIInt~(~;oiC aci~
17.7 g (14.1 mmol) o~ the pentaester described under Example ga) i8 converted to the correspondin~ penta acid under the conditions described in Example ld).
Yield: 12.7 g (92.7% of theory) of light beige solid 217~977 Analysis (relative to anhydrous substance):
Cld: C 30.76 H 3.20 I 39.00 N 5.74 0 21.30 Fnd: C 30 . 81 H 3 . 48 I 38 . 90 N 5 . 77 c) GadolLnium complex of th~ di~odium salt of 4- (3-acetylamino-2,~,6-triiodoh,~n~oyl-oxymethyl)-3,6,9-triaza-3,6,9-tris-~carboxymethyl)-~-methyl~ndec~n~d~oic 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 Exa~ple ld).
Yield: 9.88 (88.7% of theory) of colorless 601id Analysis (relative to anhydrous substance):
Cld: C 2S.14 H 2.29 I 33.21 N 4.89 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 EYampl~ 10 Gadolinium complex of the ~isod$um 8:~ lt of 3, 6, 9-triaza-3, 6, 9-tris- (carbo~yml~thyl) -4-methyl-~- (3-methylc~ h-- yl-2, 4, 6-triiodophenyloxymethyl)-l~n~ec~ne~;oic acid a) 3, 6, 9-~rriaza-3, 6, g-tris- (tert-butyloxycarbonylmethyl) -4-methyl-4-(3-m~thyl-~ yl-2,4,6-triiodophenyloxymethyl)-undQcanedioic acid-di-tcrt-butyl ester A sol~tion of 18.9 g (25.7 mmol) of the chlorine compound, described a~cording to Example 8e), in 35 ml of N,N-dimethylace~amide is added at room temperature to a solution of 16.3 g (30.3 mmol) of 3-hydroxy-2,4,6-triiodobenzoic acid-~ 2177~77 methylamide (P.L. Conturior, Ann. Chim II 10 (1938) 559) and 1.72g (30.8 mmol) of potassium hydroxide in 30 ml of N,N-dimethylformamide. The reaction mixture is stirred for 8 hours at 60C, then concentrated by evaporation in a vacuum, and the residue is shaken out with ethyl acetate and saturated sodium biearbonate golution. The organic phase is dried on sodium sulfate, filtered and concentrated by evaporation, the residue is chromatoqraphed on siliea gel 60 (Merck) with hexane/ethyl acetate (3 :1) . After the product fractions are concentrated by evaporatiOn, a light beige oil remains.
Yield: 21.9 g (69.496 of theory) Anal~-sis (relative to solventless substance):
Cld: C 43.01 H 5.82 I 30.98 N 4.56 0 15.63 Fnd: C 43.20 H 5.97 I 30.~2 N 4.60 b) 3~ 6, 9--TriAza-3~6~s-tri~-(cAr~o~yL.~l~hyl) -4-methyl-4-~3-~ethyl~rh~- yl-2,~,6-triiodophenyloxymethyl)-unaecanedloic ~ci~l 20 . 6 (17 . 0 mmol) of the pentaester described in Example lOa) is cc~verted to the corresponding penta acid under the conditions ~escribed in ~xample lc).
Yielc~: 13.9 g (86.3% of theory) of light beige solid 217~77 Analysis (relative to anhydrous substance):
Cld: C 30.40 H 3.30 I 40.15 N 5.91 o 20.25 Fnd: C 30.64 H 3.52 I 39.94 N 6.04 c) Gadolinium complex of the disodium s~lt of 3,6,9-tri~zA-3, 6, 9-tris- (carboxymothyl) -~-methyl-4- (3-methylcarb~moyl-2,~,6-triiodophenyloxymethyl)-~n-'lec~ne~ioic acid 13.2 g (13.9 mmol) of the penta acid described under Example lOb) is converted to the title compound analogously to the conditions described in Example ld).
Yield: 15 . O g (94 .196 of theory) of colorless lyophilizate Analysis (relative to anhydrous substance):
Cld: C 25.14 H 2.29 I 33.21 N 4.89 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 EYampl~ 11 Gadolinium comple~c of the disodium salt of N,N-bis-[2-[N',N'-bis-~c~L~ Lhyl)-amino~-ethyl]-3-acetylamino-2,~,6-triiodophenyl ,.1 ~n ~ ne a) 3-Amino-2,~,6-triiodophenylAl~n~n~, hydrochloride A solution of 32 . 5 g (150 mmol) of 3-aminophenylalanine hydrochloride (Jenninqs, J. Chem. Soc., 1957, 1512) in 300 ml of water is added in drops at 50C 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 217~977 concentrated by evaporation in a vacuum until the crystallizatio"
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):
Cld: 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,~,6-triiodopbenyl~lAn1nPthyle9ter 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 i5 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):
Cld: 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-Bis-[2-[N',N'-bis-[tbenzyloxycarbonyl)-methyl]- mino]-~thyl]-3-Amino-2,4,6-triiodophenylAl~ninethyle~ter 20.4 g (32.7 mmol) of the amine produced according to Example llb) and 31.0 g (73.7 mmol) of N,N-bis-[ (benzyloxycarbonyl) -methyl]-2-bromomethylamine (M. Williams and H. ~apoport, 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 re6idue 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 (62.396 of theory) of yellowish oil.

Analysis (relative to solventless substance):
Cld: C 48.43 H 4.38 I 30.10 N 4.43 0 12.65 Fnd: C 48.50 H 4.45 I 30.01 N 4.44 d) N~N-Bi!i-t2-[N~N~-bis-[t~enzyloxycnrbonyl)-methyl]-amino]-ethyl]-3-Acotyl mino-2,4,6-triiodopheny-~lAn;n~thyle:3ter 13.7 g (10.8 mmol) of the compound described in Example llc) 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 aceta~e 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 Analysis (relative to solventless substance~:
Cld: 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-Big-t2-tN',N'-bis-~eArboxymethyl)-amino]-ethyl]-3-ac~tylamino-2~6-triiodopheny~ An;nn 12 . 8 g (9 . 80 mmol) of the pentaester deseribed in Example lld) i8 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. ~3y ad~usting to pH 1-2 with semieoneentrated hydrochlorie aeid, a eolorless precipitate results, which is suctioned off and dried in a vacuum.
Yield: 7.80 g (86.796 of theory) Analysis (relative to anhydrous substance):
Cld: 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) GAdol~nium complex of the disoditlm salt o~ N,N-bis-t2-tN' ,~' -bi8- (carboxymethyl) -amino] -ethyl]-3-acetylamino-2,~, 6--triiodophenylalA~;ne 7.42 5 (8.08 mmol) of the penta acid described in Example lle) is ee~verted to the title eompound analogously to the eondition~ deseribed in Example ld).
Yiel~= 8.72 g (96.796 of theory) 217~977 Analysis (relative eO 2nhydrous substance):
Cld: C 24.75 H 2.17 Gd 14.07 I 34.10 N 5.02 Na 4.12 O 15.76 Fnd: C 24 . 64 ~ 2 . 38 Gd 13 . 83 I 33 . 94 N 5 . 08 Na 3 . 89 Exampl~ ~ 2 2-~3-Ac~tamido-2, 1,6-triiodobenzyl)-3,6,~-triaza-3,6,9-tris-(ca.Lo,~y ~hy~ nr~e~ np~ ic ACid, ga~olinium complex, ~isoaium 8~1t a) 3,6,9-Triaza-3,6,9-tris-(methoxyc~rbonylmethyl)-nl~Pc~nel-ioic aci~ methyl e~ter ~JOC 55, 2868, 1990) 20.6 g (52.4 mmol) of diethylenetriaminepentaacetic acld in 618 ml of methanol is introduCed at 0C 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 i5 concentrated by evaporation on a rotary evaporator, and the whitish solid is suspended in 300 ml of diethyl ether. The suspension is mixed at 0C with 200 ml of saturated sodium bicarbonate solution, the organic phase is separated, and the aqueou3 phase is extracted three times with 100 ml each of diethyl ether. The extract is dried on potassium carbonate and evaporated to dryness after f iltration . The product is dried overnight in a vacuum on phosphorus pentoxide.
Yield: 19.7 g (81% of theory) of colorless oil.

217~377 Elementary analysis (taking into consideration the solvent content):
Cld: 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-Tri~za-3,6,9-tris-(methoxycarbonylmethyl)-2-(3-nitrobenzyl)---n~lec~n~ oic ~cid ~imethyl ester 6. 64 ml (47. 3 mmol) of diisopropylamine in 200 ml of anhydrous tetrahydrofuran is introduced in a light argon stream at 0C and mixed drop by drop with 22.2 ml (52 mmol) of butyllithium (159~ in hexane) within 15 minutes. Then, it Ls cooled to -78C, 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 1,3-dimethyl-3,4,5,6-tetrahydro-2 (lH) -pyrimidinone in 180 ml of anhydrous tetrahydrofuran is added within 30 minutes. The reaction mixture is allowed to reach room temperature overnight, and 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 ~-ater. The organic phase is separated, and the aqueous phase is eYtracted three times with 75 ml of ethyl acetate each.
The combine~ organic phases are dried on potassium carbonate, filtered and evaporated to dryness. To purify the crude product, the substa}Ece is chromatographed on silica gel 60 (Merck).
Yield: 13.2 g (55% of theory) of pale yellow oil.

21779~7 Elementary analysis (taking into consideration the solvent content):
Cld: C S2.17 H 6.40 N 9.36 0 32.07 Fnd: C S2.01 H 6.23 N 9.48 c) 2-13-~n~inob~n~yl)-3,6,9-triaza-3,6,9-tris-~ methoxycarbonylmethyl)-undecanedioic acid dimethyl e3ter 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-~"-inob--nsyl)-3,6,9-triaza-3,6,9-Sri~-(carboxymethyl)-undecanedioic ~cid 10.8 g (19 mmol) of the pentaester of Example 12c) is saponified ~ith 60 ml of 2N sodium hydroxide solution at 40C.
After the reaction is completed, the solution is mixed with concentrate~ hydrochloric acid until the acid is completely precipitate~ . The precipitate is suctioned of f and washed neutral wit~ water. The product is dried overnight at 50C in a vacuum .
Yield: 9.75 g (96% o~ theory) of colorless solid.

2177g77 Elementary analysis (taking into consideration the solvent content ):
Cld: 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-t3-Amiuo-2,4,6-triiodobenZyl)-3,6,9-triaZ~-3,6,9-tris-~ c~lLo,.~ -thyl)-l~n~e~ne~t~ic ~cid 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 4096 iodomonochloride solution.
The reaction mixture is allowed to stir for 16 hours at 65C, and the iodine excess is reduced with diluted sodium disulfite solution. The settled precipitate is 6uctioned off and rewashed with water The dried solid is taken up in concentrated ammonia solution, ~iltered and precipitated with concentrated hydrochloric acid. The precipitate is washed until neutrality of the wash w;~ter i8 reached. The product is dried for 18 hours at 50C in a ~cuum until a constant weight is reached, Yield: 13.1 g (8396 of theory) of light yellow solid.

Eleme~tary analysis (taking into consideration the solvent content ):
Cld: C 28.79 H 3.11 I 43.45 N 6.39 O 18.26 Fnd: C 28.93 H 3.37 I 43.32 N 6.48 217~9~7 f) 2-~3-Ac~tyl~mino-2~6-triiodo3~nnq~yl)-3~6~9-tri ~carboxymethyl)-3,6,9-triaz~undecanedioic acid 12.7 g (14.5 mmol) of triio~o~nil;ne of Example 12e) is dissolYed in 30 ml of N,N-dimethylaCetamide 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 50C in a vacuum.
Yield: 11.55 g (879~ of theory) of colorless solid.

Elementary analysis (taking into consideration the 301vent content):
Cld: C 30.09 H 3.18 I 41.46 N 6.10 O 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-~carbo~cymethyl)-undecanedioic acid, g~dolinium complex, ~isodium ~JIlt 11.2 g (12.2 mmol) of complexing agent of Example 12f) is reacted acc~rding to the method of Example 4d) with gadolinium oxide a~ 5C~c. After the complexing is completed, the intermedia--~ product is converted to disodium salt with lN sodium hydroxi~e ~lution . The resulting solution is purif ied with 1. 2 g of act~ ed carbon, filtered with a 0.2 ,um membrane-cellulose f ilter ~ hen freeze-dried.
Yi~'d: 12.6 g (92.5~ of theory) of colorless lyophilizate.

Elementary analysis (taking into consideration the solvent content ):
Cld: C 24.75 H 2.11 Gd 14.09 I 34.10 N 5.02 Na 4.12 0 15.76 Fnd: C 24.89 H 2.23 Gd 13.88 I 34.02 N 4.87 Na 4.03 Examp le~ 13 Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tri~-(carboxymQthyl~ -~-[3-[N,N'-dimethyl-N,N'-bis-(2,3-dihydr.",y~r~.pyl) -3, 5-dicarbamoyl-2, 4, 6-triiodophenylc~ ~lmethoxy~-benzyl]-unaecanedioic acid a) N,0-Bis-(benzyloxycarbonyl~-3-hydroXyphenylAlAn;ne-N-[2-(benzyloxycarbonylamino~ -ethyl~ -amide 168.54 g (375 mmol) of N,0-bis-(benzyloxycarbonyl)-3-hydroxyphenylalanine (de Castiglione, Bosisio, Gazz. Chim. Ital., 97, 1858 (1967) ) is dissolved in 3.0 l of tetrahydrofuran and cooled to 0C. 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 of f, the f iltrate is concentrated by evaporation and dried in a vacuum .
Yield: 183 . 7 g (78 . 3% of theory) of colorless solid.

2177~77 Analysis (relative to solventless substance):
Cld: C 67.19 H 5.64 N 6.72 0 20.46 Fnd: C 67.07 H 5.78 N 6.84 b) 3 -Hydroxyphenyl A 1 A n; n ~- ~ 2 -aminoethyl ) - mide 62.57 g (100 mmol) of the compound described in Example 13a~
is &llcppn~d in 1. 5 l 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 obta ined .
Yield: 21. 4 g (95 . 8% of theory) Analysis (relative to solventless substance~:
Cld: C 59 .17 H 7 . 67 N 18 . 82 0 14 . 33 Fnd: C 59.28 H 7.73 N 18.74 c) 1, 5-Diamino-3-aza-2- ~3-ethoxybenzyl) -pentane, trihy~rochloride 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 0C under argon with 180 ml o~ 1 m boron hydride solution in tetrahydrofuran. After 30 minutes of stirring at 0C, stirring is continue for 120 hours at 60C. After the cooling, 100 ml of methanol is added in drops, the reaction mixture is saturated ~ 77 ~ 2177977 with hydrogen chloride, and the resulting acid suspension is stirred for 6 hours. Then, the precipitate is suctioned off and dried at 50C in a vacuum.
Yield: 25. 0 g (87 . 2~) of colorless solid Analysis (relatiYe to solventless substance):
Cld: C 41.46 H 6.96 Cl 33.38 N 13.19 0 5.02 Fnd: C 41.40 H 7.04 Cl 33.47 N 13.08 d) 3,6,9-Tri~z~ 3-hydroxybcn~yl)-3,6,9-tris-~tert-buto~rycArbonylmethyl)-~n~ec~ne~;oic ~cid-di-tert-butyl ester 15.1 g (47.4 mmol) of the compound described in Example 13c) is s~l~pon~r-tl 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 60C. 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):
Cld: C 63 .13 H 8 . 92 N 5. 39 0 22 . 56 Fnd: C 63.2g H 8.88 N 5.43 e ) S -Chloroacetylamino-2, 4, 6 -tr i iodoi sophthal ic a¢ id- [N, N ' -dimethyl-N,N'-bi~-~2,2-dimethyl-1,3-dioxolan-4-ylmethyl) ]-diamide 81.0 g (100 mmol) of 5-chloroacetylamino-2,4,6-triiodoisophthalic acid-N,N'-dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-diamide (D~ 2928417) is introduced in 500 ml of tetrahydrofuran and mixed with 0. 95 g (5. 0 mmol) of p-tolu-~n~Qulfonic acid monohydrate and 22.9 g (220 mmol) of 2,2-dimethoxypropane. Then, it is refluxed for 12 hours, Concentrated by evaporation in a vacuum, and 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 (89.69~ of theory) of colorless solid Analysis (relative to solventless substance):
Cld: C 32.40 H 3.51 Cl 3.99 I 42.79 N 4.72 0 12.5 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-ttert-butoxycarbonylmethyl~-4-[3-[N,N'-dimethyl-N,N'-bis-~2,2-dimethyl-1,3-dioxolan-4-ylmethyl) -3, 5-dicarbamoyl-Z, ~, 6-triiodophenyl-carbamoyl-metho~]-benzyl]-~nde ~ne~oic 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 217797~
argon and mixed with 0.59 g (19.7 mmol) of 8096 sodium hydride suspension in mlneral 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 allowed to stir for 12 hours at 50C. 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):
Cld: C 47.80 H 6.11 I 23.31 N 5.15 0 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~-dimeth N,N'-bis-(2,3-dihydroxypropyl)-3,5-dicarbamoyl-2,4,6-triioaophenylcarbamoylmethoXy]-benzyl]-UndeCanedioiC ~cid 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):
Cld: C 36.81 H 4.04 I 29.92 N 6.60 0 22.63 Fnd: C 36.94 H 4.05 I 29.86 N 6.53 2~7~'17 h) G~tolinium complox of tho disod$um s~lt of 3,6,9-triaz~-3,6,9-tris-(carboxymethyl) -4-t3-[N,N'-di~ethyl-N,N'-bis-~2~3-dih~ yyroyyl)-3,5-dicarbamoyl-Z,4,6-triiodophenyl-carbamoylmethoxy]-benzyl~ n~lec~ne-~10ic ~cid 11.9 g (9.35 mmol) of the penta acid described under Example 13g i6 converted to the title compound analogously to the conditions described in Example ld).
Yield: 13 .1 g (95. 5% of theory) of colorless lyophilizate Analysis (relative to anhydrous substance):
Cld: 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 T 25.76 N 5.73 Gd 10.58 Na 3.20 Examp l e. 1~
Gadolinium complex of the disodium salt of 3,6,9-tri~za-3,6,9-tris-tcarb~"~y ~hyl)-4-~3-methoxy-2,-1,6-triiodobenzyl)-er-net~;oic ~cid a) 3~ 6, 9-Tri~z~-3, 6, 9-tris- (c~rboxymethyl) -4- (3-hydroxybenzyl) -undecanedioic acid 13.2 g (16.9 mmol) of the compound described in Example 13d) i8 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):
Cld: C 50.50 H 5.85 N 8.41 0 35.24 Fnd: C 50.41 H 5.93 N 8.49 J~ 2177~77 b) 3,6,9-Tri~z~-3,6,9-tris-tcaLLo,~y -thyl)-4-~3-hydroxy-~,4,6-tr i1odoben 7yl)_11n-~ e~ n~ iOic aci~
8 .11 g (16. 2 mmol) of the compound described in Example 14a) is dissolved in 80 ml of 5N aqueous ammonia. 26 . 8 ml 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 (84.89~ of theory) Analysis (relative to anhydrous substance):
Cld: 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-~riaza-3,6,9-tri~-(carboxymethyl)-4-~3-methoxy-2,4,6-triiodobenzyl) _lln~lec~n~A i oic acid 11. 6 g (13 . 2 mmol) of the compound described in Example 14b) is mixed in 60 ml of tetrahydrofuran at 0C 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 rF-~qin;nq a~ueous solution is adjusted to pH 1.5 with 2177~77 COncentrated hydrochloric acid. A precipitate precipitates, which i8 suctioned of f and dried in a vacuum .
Yield: 10.7 g (91.4% of theory) Analysis (relative to anhydrous substance):
Cld: C 29.65 H 3.17 I 42.72 N 4.72 O 19.75 Fnd: C 29.74 H 3.23 I 42.65 N 4.63 d) Gadoliniu_ complex of the di~odium salt o~ 3,6,9-tri~za-3, 6, 9 -tri~- ~ CA rboxymethyl ) -4 - t 3 -methoxy-2, 4, 6 -triio~ob~n7yl)--lln ~A~ec-n~A i oic 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 ld) .
Yield: 11.7 g (94.096 of theory) of colorless lyophilizate Analysis (relative to anhydrous substance):
Cld: 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 ~x~npl~ 15 GAdoliniwn complex o~ the di-20Aillm salt o~ 3,6,9-triaza-4-~3-diethylca.rbamoyl-2,~,6-triiodophenylcarbamoyloxymethyl) -3,6,9-tris- (cArboxymethyl) -llnAec~necli oic acid a) 3-IsocyAmlto-2,~,6-triiodobenzoic acid diethylamide 57.00 g (100.0 mmol) of 3-amino-2,4,6-triiodobenzoic acid diethylamide (CA 54, P 20987i (1960)) is mixed under nitrogen 83 2i77977 atmosphere at room temperature with 250 ml of 2N toluenic phosgene 601ution. After 0.5 ml of N,N-dimethylformamide is added, the batch is allowed to stir for 5 hours at 60C and then evaporated to dryness.
Yield: 59.60 g (100.0~6 of theory) of yellowish solid Analysis (relative to solventless substance):
Cld: 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) ~- (3-Diethylc-- ~' y1-2, 4, 6-triiodophenyl~rh~- yloxymethyl) -3, 6, 9-tris- (tert-butyloYycarbonylmethyl)-3,6,9-tr;~r-~n~er~ne~ioic acid-~i-tert-butyl ester A solution of 14.68 g (20.85 mmol) of 3,6,9-tria~a-3,6,9-tris- (tert-butyloxy-carbonylmethyl) -4-hydroxymethyl-undecanedioic acid-di-tert-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. ~hen, 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 residue.
Yield: 24.29 g (89.6% of theory) 217~
Analysis (relative to solventless substance):
Cld: 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,~,6-triiodophenylcarbamoyloxymethyl)-3,6,9-triS-(carboxymethyl)-un~l-?o~n~ oic ~cid 21. 62 g (16. 63 mmol) of the pentaester described in Example 15b) is converted to the corrPCp~nrl i n~ penta acid under the conditions described in Example lc).
Yield: 16.17 g t95 . 4% of theory~ of colorless solid Analysis (relative to solventless substance):
Cld: 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) G~olinium complex of the disodium SAlt of 3~6~9-tri~ZA-~.-(3-~i~thyl~ ~ yl-2, 4, 6-triiodophenyloarbamoyloxymethyl) -3, 6, 9-tri~- (calLv.5y ~ thyl) -llnd~c ~n~i oic 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 ld) .
Yield: 17.44 g ~94.196 of theory) of colorless lyophilizate Analysis (relative to anhydrous substance):
Cld: 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 21~7~77 Exampl~ 16 G~olinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris-~carboxymethyl)-4-~N-c~rboxymethyl-3-methylamino-2,~,6-triiodophenylureyl~nemethyl)-~-methyl~ ec~n~ioic acid A ) 3-I~ocyan~to-2, ~, 6-triiodobenzoic acid-N-( ethoxycarbonylmethyl ) -methylami~e 61.40 g tlO0.0 mmol) of 3-amino-2,4,6-triiodobenzoic acid-N-(ethoxycarbonylmethyl) -methylamide (CA 54 P 20987i (1960) ) 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 60C and then evaporated to dryness.
Yield: 64 . 00 g (100. 0% of theory) of yellowish solid Analysis (relative to solventless substance):
Cld: 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-~l!riaza-3,6,9-tris-ttert-butyloxycarbonylmethyl)-4-(N-cthoxycarbonylmethyl-3-methylamino-2, 4, 6-tri~o~oph~ylureylenemethyl)-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. ~hen, it is completely concentrated by 217~977 evaporation, and the residue i8 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):
Cld: 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 -TriA z~-3, 6, 9 -tris- ( c~r~oxymethyl ) -4 - ( N-carboxymethyl -3-methylilmino-2, ~, 6-triiodophenylureylenemethyl ) -~ -methylundec~ne~lioic ~cid 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 (93.19~ of theory) of colorles6 solid Analysis (relative to solventless substance):
Cld: C 30.92 H 3.37 I 36.32 N 8.02 0 21.37 Fnd: C 31.03 H 3.48 I 36.21 N 8.14 ~ 87 2177977 d) Gadolinlum complex of the di~odium ~alt of 3,6,9-triaza-3,6,9-tris-tcJ~lLv~y l.hyl)-4-~N-carboxymethyl-3-methylamino-2,~,6-triiodophenyl-ureylenemethyl) -4-methylundecanedioic acid 24.32 g (23.19 mmol) of the penta acid described in Example 16c) i6 converted to the title compound as described in Example ld) .
Yield: 27.84 (94.6~ of theory) of colorless lyophilizate Analysis (relative to anhydrous substance):
Cld: 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 tegt: igomer to Examp~e 1 of W0 93/16375 1,13-Bis[5-~propion-3-ylamido]-2,4,6-triiodoisophthalic acid-bis ~ 2 -hydroxy-l-L~ .,y,..cthylethyl) -diami~e l -4, 7 ,10 -tris(carbox-ymethyl)-2,12-dioxo)-1,~,7,10,13-pentaazatridec~ne, gadolinium complex a) 1,13-Bis[5-(propion-3-ylAmido]-2,4,6-triiodoisophthalic ~cid-bis (2-hy~roxy-1-hydroxymethylethyl) -diamide] -4, 7,10-tris~carboxymethyl)-2,12-dioxo)-1,~,7,10,13-pentaazatridecane 16.5 g (21.2 mmol) of 5-(3-aminopropionamido~-2,4,6-triiodoisophthalic acid-bis(2-hydroxy-1-hydroxymethylethyl)-diamide is dissolved at 120C bath temperature in 82 . 5 ml of DMF.
It is mixec~ at room temperature with 7 . 38 ml (53 . 25 mmol) of triethylamine and then with 3.8 g (10.64 mmol) of N,N'-bis[2-(2,6-dioxomorpholino)ethyl]glycerol. The reaction mixture is stirred overnight at room temperature. The solvent is evaporated in a vacuum, and the residue is foamed up in the oil pump. The solid is etirred with 200 ml of ethanol for two hours at room temperature, suctioned off and dried at 50C 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 (4296 of theory) Analysis (relative to anhydrous substance):
Cld: C 30.19 H 3.43 I 39.8~3 N 8.07 0 18.43 Fnd: C 29.88 H 3.30 I 40.21 N 7.95 b) 1~l3-Bl~[s-(proplon-3-ylamldo]-2~6-trilo~oi~ophth~lic acid-bis ( 2-hydroxy-1-hydroxymethylethyl ) -diamide] -~, 7, 10-tris ~ c~rboxy3lethyl ) -2 ,12 -d ioxo ) -1 , 4, 7 ,1 0 ,13 -penta~ tridec~ne, 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. I'he pH is moved with triethylamine into the neutral range, and the aqueous solution is stirred for one hour at room temperature with activated carbon. Af~er filtration and freeze-drying, the gadolinium complex is obtained as a colorless solid.

2177~77 Yield: 145 mg (30. 5% of theory) Analysis (relative to anhydrous 6ubstance):
Cld: 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 Ga~Solinium complex of 3,6,9-triaza-3,6,9-tris-(carboxymethyl)-4-~3-io~o-~-ethoxybenzyl)-1lndec~ne~;0ic Acid, disodium ~alt a) N-Benzyloxycarbonyl-3- t4-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 l 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 o~f in a vacuum, the residue is taken up in 1 l of water and extracted three times with 700 ml of ethyl acetate.
~he combined organic phase is washed with water, dried with sodium sulfate and concentrated. It is recrystallized from ethyl acetate/hexane .
Yield: 187.0 g (93.7~6 of theory) Analys~ s (relative to solventless substance):
Cld: C 69.28 H 7.04 N 4.25 O 19.43 Fnd: C 69.11 H 7.20 N 4.13 9o 2177~7~
b) 1-Ac~toxy-N-benzyloYyc~rbonyl-3 - ( 3 - iodo-~-ethoxyphenyl ) -2 -aminopropAno 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 sodium bisulfite solution and then dried on sodium sulfate. After the solvent is evaporated, a yellowish oil is obtained, which is slowly thoroughly cry6tallized.
Yield: 34 . 5 g (77 . 7~c of theory) Analys is (relative to solventless substance):
Cld: 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-Be~yloyycarbonyl-3-(3-iodo-4-ethoYyphenyl)-2-A ~ op~ no l 2g.8 -- (60 mmol) of 1-acetoxy-N-benzyloxycarbonyl-3-(3-iodo-4-etho~.~h~yl)-2-aminopropane is suspended in 150 ml of methanol and miY~ 5t room temperature with 4.94 g (60 mmol) of anhydrous sodium a ze--~te. The batch is stirred for 6 hours at 60C, evapora-~ to dryness and the residue is taken up in ethyl acetate. ~'le precipitated salt is suctioned off, washed with ethyl acetate, and the filtrate i3 concentrated by evaporation.
The viscous oil obtained is used in the next stage without further purification.
Yield: 27.3 g (100% of theory) d) 1-MothAno~ulfonyloXy-N-bonzyloxycArbonyl-3- (3-iodo-4-othoxyphenyl) -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 0C with 6.78 ml (87 mmol) of methanesulfonic acid chloride . Af ter 3 0 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):
Cld: 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-Benzyloxycar~onyl-1- (3-iodo-4-ethoxybenzyl) -N'- (2-inoothyl) ~thy~ m; ng 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 ~- 217797~
mixed with 143 ml (2.12 mol) of ethylenediamine. After 22 hours of stirring, the batch i6 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 t98~ of theory) Analysis (relative to solventless substance):
Cld: 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-~thoxybenzyl) -N' - (2-aminoethyl) ethyl~ne~ i~m; ne, 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. ~he 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.

2177~77 Analy3ig ~relative to solventless substance):
Cld: 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) ~- ~ 3 -Iodo-~-ethoxybenzyl ) -3, 6, 9 -trLs ~ tert-butoxyc~rbonylmethyl)-3,6,9-tri~ ln~lec~nR-l,ll-dioic aci~l, di- (tert-butyl~ -~ster 23.2 g (38.3 mmol) of 1-(3-iodo-4-ethoxybenzyl)-N'-(2-aminoethyl)ethyl~nF~fl;Am;ne~ 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 60C and then overnight at room temperature. The salt is suctLoned off, washed with tetrahydrofuran, and the filtrate is concentrated by evaporation.
The crude product i5 purified using a silica gel column (mobile solvent: dichloromethane/methanol).
Yield: 34 . 6 g (96 . 7g~ of theory) Analys is (relative to solventless substance):
Cld: 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 217797~
h) ~- ~ 3-Iodo-~-~thv~y~ yl ) -3, 6, 9 -tris ( c~rboxyl~tomethyl ~ -3,6,9-triA~al~n~e~n~-l,ll-~ioic acid, ga~lolinium complex, Ciso~ium salt 17.6 g (18.8 mmol) of 4-(3-iodo-4-ethoxybenzyl)-3,6,9-tris (tert-butoxycarbonylmethyl) -3, 6, g-triazal~nd~r In~-l ,11-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 60C, evaporated to dryness and subsequently distilled twice with water. The residue is taken up in 180 ml of water and ad~usted 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 80C. 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):
Cld: C 32.44 H 3.20 I 14.90 N 4.93 0 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 2177~77 ~x~pl- lg Gadolinium complex of 3, 6, 9 -tri~z~ -3, 6, 9 -tris- ~ c~rboxymethyl ) -4 -~3-bromo-,1-othoxybenzyl)-1lnde~ne~oic ~c:id, di30dium salt a) l-Acstoxy-N-benzyloxyc~rbonyl-3- (3-bromo-4-ethoxyphenyl) -2-~minoprop~ ne 20.0 g (61 mmol) of the title compound of Example 18a isdissolved in 200 ml of glacial acetic acid and mixed with 0 . 2 g of iron powder. After the reaction solution is cooled to 10C, 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):
Cld: 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-BsnzyloxycJ~rbonyl-3- ~3-bromo-4-ethoxyphenyl) -2-minoprop~nol 18.0 g (39.8 mmol) of 1-acetoxy-N-benzyloxycarbonyl-3-(3-bromo-4-ethoyyphenyl)-2-aminopropane is suspended in 100 ml of methanol and mixed at room temperature wi~h 3.30 g (40 mmol) of ,~

~ 217~g7~
anhydrous sodium acetate. The batch is ~tirred for 6 hours at 60C, evaporated to dryness, and the residue is taken up in ethyl acetate . The precipitated salt is suctioned of f, 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-~feth~ne~ul~onyloxy-~-benzyloXyc~ rbonyl-3 - ( 3 -bromo-4 -~thoxyphenyl ) -2 -Yminopropane 15. 5 g (38 mmol) of N-benzyloxycarbonyl-3- (3-bromo-4-ethoxyphenyl)-2-aminopropanol is dissolved in 100 ml of dichloromethane, mixed with 6. 3 ml (45 mmol) of triethylamine and brought to reaction at oDC 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 yello~ oil.
Yield: 18.1 g (98% of theory) Analysis (relative to solventless substance):
Cld: 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 ~ 21~7977 d) N-B~nzyloxycarbonyl-l-t3-bromo-4-etboxybenzyl)-N'-(2-am~ no~tbyl) ethylen~ j Am; nf~
17.0 g (34.9 mmol) of 1-methanesulfonyloxy-N-benzyloxycarbonyl-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 ethyl~nP~;~min~. 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):
Cld: 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-~-ethoxybenzyl)-N'-~2-~minoethyl)ethylenetl;t~mine, trihyC~robromide 14 g (31 mmol) of N-benzyloxycarbonyl-1-(3-bromo-4-ethoxybenzyl)-N~-(2-aminoethyl)ethyl~nP~ m~n~ 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 33% 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 i5 subsequently distilled three times with toluene. The Bolid i8 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 . O g (92 . 496 of theory) of colorless crystals Analysis (relative to solventless substance):
Cld: 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-tr i8 ( tert-butoxycarbonylmethyl) -3, 6, 9-triazaundecane-1, 11-dioic ~cid, ~i- (tert-butyl) -e~ter 15.0 g (26.8 mmol) of 1-(3-bromo-4-ethoxyben~yl)-N'-(2-aminoethyl)ethylener~i~mi~R~ 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 60C and then overnight at room temperature . The salt is suctioned of f, washed with tetrahydrofuran, and the filtrate is concentrated by evaporation.
l'he crude product is purified using a silica gel column (mobile solvent: dichloromethane/methanol).
Yield: 22.4 g (94.2% of theory) 217~977 Analysis (rel~tive to solventles3 substance):
Cld: C 58.23 H 8.18 Br 9.01 N 4.74 Fnd: C 58.19 E 8.12 Br 8.96 N 4.70 g) ~-t3-Elromo-~-ethoxybenzyl)-3,6,9-tri~(carboxylatomethyl)-3, 6, 9-tr~ r~ o-llnAqc-n~ ioic ~cid 20. 0 g (22 . 5 mmol) of 4- (3-bromo-4-ethoxybenzyl) -3, 6, 9-tris (tert-butoxycarbonylmethyl) -3, 6, 9-triazaundecane-1, 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 r~ i n; n~ residue is taken up in 300 ml of water and adjusted to pH 2 . 0 wi~h cation exchanger (E~
form) . After freeze-drying, the f iltrate obtained after the suctioning-off from the ion exchanger yields the pentacarboxylic acid as colorless powder.
Yield: 11.3 g (83~6 of theory) Analysis (relative to anhydrous substance):
Cld: C 45.55 H 5.31 Br 13.17 N 6.93 Fnd: C 45.62 E 5.38 Br 13.41 N 7.02 217797~
h) ~-~3-Bromo-~-~thoYybenzyl~-3,6,9-tri~carboxylatomethyl)-3,6,9-tr~Az~l~n~ec~ne-l,ll-dioic acid, gadolinium compleY, disodium salt 10.0 g (16.5 mmol) of 4-(3-bromo-4-ethoxybenzyl)-3,6,9-tris (carboxylatomethyl) -3, 6, 9-triazaundecane-1, ll-dioic acid is dissolved in 200 ml of water and mixed at 80C with 3 . 0 g (8 . 25 mmol) of gadolinium oxide. After a reaction time of 1 hour at 80C, 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 i8 freeze-dried after f iltration.
Yield: 12.7 g (9696 of theory~

Analysis (relative to anhydrous substance):
Cld: 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 compleY of the disodium salt of N,N-bis-t2-[N',N'-bis-~carboyymethyl) -amino] -ethyl]-p-iodophenylAlAnine a ) p-IodophenylA l ~ n ~ n ~ ~opropylester, hydrochloride 50 ml of isopropanol is stirred at 0C under argon and mixed drop by drc~p 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 portionc, stirred for one hour at room temperature, and the batch is t~en allowed to reflux for two hours. After the coolinq to room tem~perature, the batch is allowed to stand overnight at ~ 2177977 0C, and then the precipitated, colorless precipitate is suctioned of f .
Yield: 12.4 g (97.896 of theory) Analy6is:
Cld: C 38.99 H 4.64 I 34.33 N 3.79 O 8.66 Cl 9.S9 Fnd: C 38.85 H 4.70 I 34.29 N 3.78 Cl 9.66 b) N,N-Bis-[2-tN'tN'-bis-[ (tert-butyloxyc~rbonyl)-methyl]-amino] -ethyl] -p-iodophenyl al ~Ini n; sopropyle~ter 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, llS1 (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 . O1) . The product-containing fractions are concentrated by evaporation in a vacuum.
Yield: 17.9 g (62.3~6 of theory) of yellowish oil.

Analysis (relative to solventless substance):
Cld: C s4.85 H 7.60 I 14.49 N 4.80 O 18.28 Fnd: C 54.80 H 7.65 I 14.41 N 4.74 ~ 2177~77 c) N,N~ 2-[N',N'-bis--(carboxymQthyl)-amino]-ethyl~-p-iodophenyl ~1 ~n ~ n~
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 i6 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):
Cld: C 41.39 H 4.63 I 20.82 N 6.90 0 26.26 Fnd: C 41.33 11 4.56 I 2~.78 N 6.93 d) G~dolinium complex of the disodium salt of N,N-bis-[2-tN' ,N' -bi5- ~c~rboxymethyl) -amino] -ethyl] -p-iodophenylA 1 Ani nR
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 oxide and stirred at 80C
for 2 hours. Then, 24.4 ml of lN sodium hydroxide solution is added with a microburette and stirred for 1 more hour. Then, after O.S g of activated carbon is added, the solution is stirred at 80C for 2 hours and filtered. After freeze-drying, the filtrate yields a colorless solid.
Yield: 9.12 g (92.6% of theory) Analysis (rel~tive to anhydrous 6ubstance):
Cld: C 31.23 H 2.87 I 15.72 N 5.20 O 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 2 1 ~dolinil~m compl~x of the monosodium salt of N,N-bi3-[2-[N',N'-bi~-tca.~ y~ hyl)- mino]-ethyl]-glycine-N''-[3,5-bis-(N'''-~2-hy~ yethyl)-c~ ~yl)-2~4~6-triiodophenyl-c~rbamoylmethyl]
a~nide a) N,N-Bi3-[2-[N',N'-bis-[ ~tert-butyloxyc~rbonyl) -methyl]-amino]-ethyl]-glycine-N''-[3,5-bi3-(N'''-(2-hy~roxyethyl)-c~rb moyl) -Z, ~, 6-triiodophenylc~rh~-~ylmethyl] -amide 22.1 g (31.5 mmol) of 5-aminoacetylamino-2,4,6-triiodoisophthalic acid-N,N'-bis-(2-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 i5 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. ~hen, the organic phase is concentrated by evaporation in a vacuum, and the residue is chromatographed on silica gel with dichloromethane/methanol (95:S). The product-containing fractions are concentrated by evaporation in a vacuum.
Yield: 21.9 g (55.8% of theory) of yellowish oil.

217~977 Analy6is (relative to solventless substance):
Cld: 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-tc~rboxymethyl)-amino]-ethyl]-glycine-N~-[3~5-bis-~N~-(2-hy~L~ y~:thyl)-carb~moyl)-2~4~6-triio~ophenylc~rbamoylnethyl] -amide 20.8 g (16.7 mmol) of the tert-butyl ester described in Example 21a) i8 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:
Cld: 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) G~dolinium complex of the nono~odit~ salt of N,N-bis-[2-[N',N'-bis-~c~rboxymethyl) -~nino]-ethyl]-glycine-N' '-[3,5-bis- (N~ ~ ~ - (2-hy~roxyethyl~ -c~rbamoyl) -2, 4, 6-triiodophenylc-- -ylmethyl] -~mide A suspension of 16.9 g (16.6 mmol) of the penta acid, produced according to Example 21b), in 130 ml of water is mixed with 3.00 g (8.28 mmol) of gadolinium oxide and stirred at 80C
for 2- hours. Then, 16.6 ml of lN 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 8~C for 2 hours and filtered. After freeze-dryin~, the filtrate yields a colorless solid.
Yield: 18.4 g (93.0% of theory) Analysis (relative to anhydrous substance):
Cld: C 26.10 H 2.61 I 31.82 N 7.02 0 17.38 Gd 13.14 Na 1.92 Fnd: C 26.11 ~ 2.74 I 31.84 N 7.06 Gd 13.10 Na 1.93

Claims (11)

Claims

1. Metal complexes that consist of 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 I

(I) in which R1 stands for a hydrogen atom, a carboxylic acid radical, a straight-chain or branched C1-C15 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 C1-C15 alkyl radical, C6-C15 aryl radical, or a C7-C15 aralkyl radical, which optionally contains 1-5 hydroxy groups, 1-2 carboxy groups and/or 1-4 oxygen atoms, or in which R4, R5, together 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, R6 stands for a hydrogen atom, a straight-chain or branched C1-C15 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 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 C1-C15 alkyl radical, C6-C15 aryl radical or a C7-C15 aralkyl radical, which optionally contains 1 to 2 hydroxy groups or a 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 C1-C15 alkyl radical, a C6-C15 aryl radical or a C7-C15 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 tetramethylene 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 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, (IV) in which R8, R9, independently of one another, stand for a group -NR6-CO-R7 and/or have the meaning indicated for R1, with the exception of a C1-C15 alkyl radical, C6-C15 aryl radical or a C7-C15 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
(.alpha.) ? (CH2)p ? (C6H4)n ? (L)m ? R12 ? (.beta.) (V) in which m, n, p, independently of one another, stand for numbers 0 or 1, L stands for an oxygen atom, a sulfur atom, a C1-C4 alkylene radical, a group >S=O, >SO2 or >NR4 with R4 in the mentioned meaning, and R12 stands for a direct bond, a carbonyl, a carboxyl, 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 C1-C15 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 C1-C4 alkylene radical, which optionally contains a carbonyl group and/or an amino group, whereby position (.alpha.) is linked with the diethylenetriaminepentaacetic acid skeleton and position (.beta.) 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, U1, 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 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.

2. Halogen-containing metal complexes according to claim 1, 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

(VI)

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.