AU687477B2 - Aryl halide substituted metallic complexes, pharmaceuticals containing these complexes, their use for diagnostic purposes, and methods for preparing the complexes and pharmaceuticals - Google Patents

Description

I I Ir-- I Haloaryl-Substituted Metal Complexes, Pharmaceutical Agents Containing these Complexes, Their Use in Diagnosis, as well as Process for the Production of the Complexes and Agents The invention relates to the objects characterized in the claims, 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, diagnostic radiology, radiodiagnosis or ultrasonic diagnosis or magnetic resonance tomography.

The selection of the respectively preferred methods depends, 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, 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 (concentratiqp) distribution behavior in the organism.

L 0l -M MIL L Although great progress has been achieved with respect to equipment and contrast media, satisfactory solutions are not yet available for all problems.

Thus, contrast media that are suitable for all indications do not yet exist for the various imaging processes. In 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, in EP 0 105 725, EP 0 015 867. But the latter do not show any concentration, sufficient for imaging, in the liver.

Since the suitability of a compound as x-ray contrast medium, in addition to the concentration behavior in the respective organ, basically depends on the value of the mass attenuation coefficient of the elements that are contained in the compound, in the diagnostic radiation area, in addition to the iodine-containing compounds, metal complexes of an element with a high atomic number should also be suitable. Such compounds are widely used in the field of NMR diagnosis. In this case, there are generally metal complexes, as they are described, in EP 0 071 564.

WO 93/16375 describes metal complexes, which are linked by amide bonds to iodine-substituted aromatic compounds. With only one administration of the contrast medium, these compounds are to

I

make it possible to carry out both NMR and x-ray studies. A combinat of the two imaging processes is advantageous in many cases for a differentiated visualization and a reliable determination of certain diseases. These compounds are to be suitable especially for angiography. But as the duplication of the production examples showed, the compounds show no concentration, sufficient for x-ray studies, in the area of the liver.

Liver-specific NMR contrast media are described in EP 0 405 704. The latter in principle should also be suitable for diagnostic radiology because of the metal content in the complexes. A duplication of the experimental examples did not show sufficient contrasting of the liver in the x-ray picture even when a high dose was administered (conc.: 1 M/l, dose: 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, 44or 57-83 and a halogen-containing complexing ligand of Y r formula I I I I 2 2 3 2 V U RU R R V Z N N N Z z HOOC V 3 C COOH in which

R

1 stands for a hydrogen atom, a carboxylic acid radical, a straight-chain or branched C 1 -C15 alkyl radical, C 6 -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--NR

4

R

5

(II)

-CH

2

NR

6

-CO-R

7

(III)

in which

R

4

R

5 independently of one another, stand for a hydrogen atom, a straight-chain or branched C 1

-C

15 alkyl radical, C 6

-C

15 aryl radical, or a C 7 -Cg aralkyl radical, which optionally contains 1-5 hydroxy groups, 1-2 carboxy groups and/or 1-4 oxygen atoms, or in which R 4

R

5 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,

//N

I

R

6 stands for a hydrogen atom, a straight-chain or branched C -C 15 alkyl radical, C 6

-C,

1 aryl radical or a C7-C1 aralkyl radical, which optionally contains 1-4 hydroxy groups, 1-2 carboxy groups and/or 1-2 oxygen atoms, or in which R 6 together with R 7 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

R

7 stands for a hydrogen atom, a straight-chain or branched C -C 15 alkyl radical, C 6

-C

15 aryl radical or a C,-C1 aralkyl radical, which optionally contains 1 to 2 hydroxy groups or a carboxy group or in which R 7 together with R 6 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,

R

2

R

3 independently of one another, stand for a hydrogen atom, a Ci-C 15 alkyl radical, a C 6 -C15 aryl radical or a C,-C1 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 U 1

(U

2 Z, Z 2

Z

3 independently of one another, stand for a hydroxy group or a radical -NR'7-U', in which

R

17 stands for a hydrogen atom, a methyl or methoxyethyl group, and

U

1

U

1

U

2

V

i

V

2 and V 3 respectively independently of one another, stand for a hydrogen atom or for a halogenated aromatic radical of general formula IV, 8

R

I1 Y R x (rV) in which

R

8

R

9 independently of one another, stand for a group

-NR

6

-CO-R

7 and/or have the meaning indicated for R 1 with the exception of a C,-C 15 alkyl radical, C 6

-C

1 5 aryl radical or a

C

7

-C

15 aralkyl radical,

R

10

R

11 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 R 9 or a bridge-type crosslink of general formula V (CH2) p- (CH) n- (L)-R 12

(V)

in which m, n, p, independently of one another, stand for numbers O or 1, I I I I i4 L stands for an oxygen atom, a sulfur atom, a C -C 4 alkylene radical, a group >SO 2 or >NR 4 with R 4 in the mentioned meaning, and

R

12 stands for a direct bond, a carbonyl, a carboxyl, a -CO-NR 18 an -NR 18 an -NH-CS- or a CS-NH group, in which R 18 means a hydrogen atom, a straight-chain or branched C,-C 1 5 alkyl radical, C 6

-C

15 aryl radical, or a C,-C1 aralkyl radical, which optionally contains 1-4 hydroxy groups, 1-2 carboxy groups and/or 1-2 oxygen atoms, or in which R 12 stands for a straight-chain or branched

C

1

-C

4 alkylene radical, which optionally contains a carbonyl group and/or an amino group, whereby position is linked with the diethylenetriamine skeleton and position 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 R 9 if X stands for a bridge-type crosslink of formula V and at least one of radicals R 2

R

3

Z

2

Z

3

U

1

U

2

V

1

V

2 or

V

3 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 R 8 and/or R 9 contains an aryl radical, and/or

LI

,16C~ I I Is I LY L -rlll~mc~14 that Z 1 and/or Z 2 then stand for a radical of general formula IV only if at least one of substituents R 2

R

3

U

1

U

2

V

1

V

2 or V 3 does not stand for a hydrogen atom, and/or that if Z 3 contains a completely substituted aromatic compound of formula IV, Z 1 and/or Z 2 do not contain any fully substituted aromatic compounds of formula IV, and/or that if all substituents R 2

R

3

U

1

U

2

V

1

V

2 and V 3 mean hydrogen, at least one of radicals R 8

R

9

R

10 or R 11 stands for a hydrogen atom, and/or R 8 and/or R 9 mean a radical which contains a carboxylic acid that is not directly bound, are excellently suited for the production of contrast media for NMR diagnosis and/or diagnostic radiology, preferably of contrast media for diagnostic radiology, especially for diagnostic radiology of the liver.

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

As halogen atom(s), the complexes according to the invention contain 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, aromatic compounds in which X, R 10 and R 11 stand for iodine, and in which R 8 and R 9 independently of one another, stand for a hydrogen atom, for a II -I 1 I Il II group -OH, -COOH, -0-CH 2 -CH (OH) -CH 2 -OH, -O-CH 2

-CH

3

-CO-NH-

CH (CH 2 OH) (CHOH-CH 2 OH) -CO-NR 4 -CH- (CH.)OH 2' -NR 6

-CO-CH

2 OH, -CO-NR 4

CH

2 -CH 2 0H, -CO-NH 2 -N (CH 3

-CO-CH

3

-NH-CO-CH

3

-CO-NH-CH

3 1 -N (CH3) CO- (CH 2 2 COOH, -CO-N- (C 2

H

5 2 -CO-N (CH 3) -CII 2 COOH, -CO-NH- (CH 2 1 0 COOH, -CO-NH-CH 2

-C

6

H

4 -OEt or a group -CO-N(CH 3 -CH 2 -CH (OH) -CH 2

-GH,

and ia which Y stands for a bridge-type crosslink of formula V.

Preferred bridge-type crosslinks of formula V are, if one of radicals U stands for a halogenated aromatic radical, the groups

-CH

2 -CH 2

-C

6

H

4 -O-CH 2 -1 -CH 2 -O -CH 2

-CH

2

-CH

2

-O-CO-,I

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

-C

6

H

4

-O-CH

2 -CO-NH-, -CH 2

-O-CO-NH-,

-CH

2 -NH-CO-NH-, -NH-CO-, -NH-CO-CH 2 Z stands for a halogenated aromatic radical, the groups -NH-CH 2 -CO-NH-, -NH CH 2 CH 2 CO-NH- or -NH CH 2 CH 2 NH-CO- and that V stands for a halogenated aromatic radical, the groups -CH 2 -1 -CH 2 -CH 2 -O-CH 2 1 -CH 2 -O-CO-,I -CH 2 -NH-CO-, -CH 2

-CO-NH-,

-CH 2 -O-CO-NH- or -CH 2

-NH-CO-NH-.

Especially preferred among them are the complexes in which

U

1 stands for the radical of general formula IV, compounds that are substituted with the halogenated aromatic compound in the ethylene bridge of the polyaminocarboxylic acid and in which Z stands for a hydroxy group.

As radical R 1 there are considered straight-chain or branched alkyl radicals, such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl radicals, but preferred are hydrogen, C 1

-C

4 alkyl and hydroxyalkyl radicals, such as, e.g., the hydroxymethyl radical as well as alkoxyalkyl radicals, such as, the methoxymethyl radical.

As radicals R 2

R

3 the radicals listed for R 1 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 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, those of the primary, secondary or tertiary amines, such as, 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 uomplexing agent in a suitable solvent. The selection of the method of I I--L l I I synthesis most suitable in each case depends on the desired linkage point between the halogenated aromatic compound(s) and the polyaminopolycarboxylic acid. Accordingly, the complexes can be divided into three groups. Thus, the halogenated aromatic compound(s) can be bound I) to the a-carbon atoms of the 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 cr complexes of group I can be produced analogously to the processes that are described in European Patent Application EP 0 230 893. Other universally applicable possibilities of synthesis for the complexing agents will be mentioned as examples below.

Thus, by reaction of chloroacetic acid derivatives of general formula VI Cl

COCH

R

(VI)

in which R 13 is the desired halogenated aromatic radical of general formula IV or an optionally still unhalogenated precursor

L~

I of this radical, with polyamines of general formula VII 2

R

H, N I NI,

N

!i H I3 R R (VII) first compounds of general formula VIII can be obtained, 13 2 R CO,H

H

2 N

NNH

R R

(VIII)

which then are reacted in a way known in the art with haloacetic acid esters, preferably with bromoacetic acid esters, and then if a precursor of the respectively desired aromatic compound is involved are halogenated in a way known in the art and optionally present ester groups or protective groups are cleaved in a way known to one skilled in the art. Disubstitution can also be achieved with corresponding stoichiometry.

An alternative process for the production of a-C-substituted polyaminopolycarboxylic acids starts from an acid-protected polyaminocarboxylic acid 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 i I halide 3-nitrobenzyl chloride, 3,5-dinitrobenzyl chloride, 3-benzyloxybenzyl chloride) by reaction with lithium diisopropylamine in THF/hexane. Following the coupling, the aromatic compound is reacted to the desired halogenated aromatic compound of formula IV, 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, by catalytic hydrogenation. The iodization of the aromatic compound is also carried out in a way known in the art, by reaction with iodomonochloride solution in hydrochloric acid medium. Before the introduction of the iodine atoms, the acid protective groups of the pentaester are saponified in the basic medium.

An alternative process for the production of iodinecontaining polyaminopolycarboxylic acids starts from an a-amino acid derivative of general formula XXIII

H-N'H

V3 CO 13 z

(XXII)

whose primary amino group optionally can also be present in protected form as monobenzylamine). This amino group is dialkylated on a nitrogen atom with an alkylating agent of I Cr-l c~ I formula XXIV V U' R' U 2 Z-co N Nf R 4OOC

(XXIV)

and then after cleavage of the optionally present protective groups with an alkylating agent of formula XXV

R

2

R

3

V

2 H CO-Z2 Nf N

COOR

1 4

(XXV)

whereby Nf stands for a nucleofuge, such as, chloride, bromide, iodide, methanesulfonate or toluenesulfonate, and R 14 stands for an acid protective group, such as, a lower alkyl, aryl, aralkyl or trialkylsilyl group, and R 1

R

2

R

3

U

1

U

2

V

1

V

2

V

3

Z

I

Z

2 and Z 3 have the previously indicated meaning.

Synthesis for the production of an a-C-substituted polyaminopolycarboxylic acid starts from, a phenylamino acid, such as, 3-aminophenylalanine. The latter is first halogenated in a way known in the art, the acid group then protected as ester. The thus obtained intermediate product is reacted with two equivalents of N,N-bis[(benzyloxycarbonyl)methyl]-2-bromomethylamine. Before the cleavage of the acid *tA_ -r II rr I I protective groups, the substituents of the aromatic compound are optionally converted to the desired radicals.

The production of the complexing agents of group II can be carried out analogously to the methods that are described in EP 0 405 704 as well as DE 43 02 289. Thus, the process starts from, known compounds (DE 37 10 730 and literature cited there) ,of general formula IX,

OH

R R R in which R 14 R R and R 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., I

I_

benzyl halide) of formula X 9' 0 0.

in which R 8

R

9

R

1 0 and R 11 stand for desired groups R 8

R

9

R

10 and R 11 or a precursor of the latter. If groups R 8

R

9

R

1 0 and

R

11 stand for precursors of the desired groups, the latter are generated from those. Acid protective groups R 14 are cleaved in a known way [see, E. WUnsch, Methoden der Org. Chemie [Methods of Org. Chemistry] (Houben Weyl), Vol. XV/1, 4th Edition, 1974, p. 315 ff], for example, by hydrolysis, hydrogenolysis or alkaline saponification, generally before the halogenation of the aromatic compound. Both acidic and aqueousalkaline 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, with iodomonochloride, in a way known in the art. Optionally, the phenolic -OH groups can be etherified in a way known in the art with alkyl halide/sodium hydride. The cleavage of the acid protective groups is carried out in the previously described way.

J I I -I An alternative process also starts from halogen-containing chlorinated aromatic compounds of formula X, which are reacted with a partially protected glycerol, first to the corresponding dihydroxypropyloxy compound of formula XI 9'

R

R,R

OH

R8 I0 1 R OH (XI) which then are reacted after partial protection of one hydroxy group and activation of the remaining group with sodium azide to the corresponding azido compound of general formula XII 9'

R

Ir I o

N

3 1 R OR (XII) in which R 15 stands for a protective group, such as, a benzyl group.

After cleavage of OH-protective group R 15 and activation of the resulting hydroxy group, as methanesulfonic acid ester, the reaction is first performed with the corresponding ethylenediamine and then the azide group is reduced in a way t- I I_ L I known in the art, with triphenylphosphine, to compounds of formula XIII 9'

R

R R 1 S NH, R

H

8 0 N"N

R

R R

(XIII).

The latter are reacted in a known way with bromoacetic acid ester to the corresponding pentaesters. After cleavage of the acid protective groups, by reaction with trifluoroacetic acid and generation of desired groups R 8

R

9

R

1 0 and R 11 from groups R 8

R

9

R

10 and R 11 the desired complexing agents are obtained.

An alternative process for the production of complexing agents of group II starts from acid-protected polyaminocarboxylic acid derivatives of general formula XIV

OH

ROccR\ R RR R which are reacted with isocyanato compounds of general formula XV

R

9 R"

R'°

I i 0 C= 0 'o R R

(XV)

to the corresponding urethanes.

As an alternative, the hydroxy group in the compounds of general formula XIV can also be reacted, with Nchlorosuccinimide to the corresponding chloride of formula XVI a SR R3 4 CI c 14 R OOCX,\ O\DOR COOR COOR ODOR (XVI).

The latter is then reacted in a way known in the art with a reactive species of a desired hydroxy-group-containing or carboxy-group-containing) halogenated aromatic compound of formula XVII (Xvn) in which R 8

R

9

R

10 and R 11 have the indicated meanings and \V stands for an OH or COOH group, to the corresponding ethers or esters. The cleavage of acid protective groups R 14 is carried out in the above-described way.

As an alternative, the compounds of general formula XVI can be reacted with an azide sodium azide) to the corresponding azido compound, which then is reduced in a known way to the amino compound. The latter is then a) either reacted with an isocyanpto compound of formula XV to the corresponding urea derivative or b) reacted with a halobenzoyl chloride of formula XVIII 9

R

II R ~R a o CI

R

R O (xvm) to the corresponding amide.

An alternative process starts from an aminoethyl alcohol of formula XIX, H" NOH 1 6 R

(XIX)

in which R 1 6 stands for an amino protective group, preferably a benzyloxycarbonyl group and R 13 means an unhalogenated precursor of the desired aromatic compound, or a "linker," to which the desired halogenated aromatic compound is bound in a later reaction step. The aminoethyl alcohol is reacted first in a way known in the art, with methanesulfonic acid chloride, tolueiesulfonic acid chloride or trifluoroacetic anhydride to the corresponding mesylate, tosylate or triflate and then it is reacted with an optionally substituted ethylenediamine. If, in the case of R 13 an unhalogenated precursor of the desired aromatic compound of general formula IV is involved, it is iodized, 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, 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, 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, the reaction of the acid anhydrides of -t 27."

I

~C1 -Ib sL_ 1 general formulas XX or XXI with halogenated aromatic compounds of general formula XXII to the amides according to the invention,

COOH

R

3

(XX)

HOOCX

(XXI)

(XXII)

in which R 8

R

9

R

1 0 and R 11 stand for desired groups R 8

R

9

R

10 and R 11 or a precursor of the latter, and Q stands for the radical of a linker of general formula V. The production of the '(NT H ^'c L II I I I aromatic compounds of general formula XXII is carried out as described, in DE 25 23 567.

As radical H 2 N-Q, there can be mentioned as examples an H 2

N-

CH

2 -CO-NH, H 2 N-NH-CO-NH, H 2

N-CH

2

CH

2 -CO-NH, H 2

N-NH-CO-CH

2

CH

2

H

2

N-

CH

2

CH

2 -NH-CO group or an H 2

N-CH

2

CH

2

-N(CO-CH

3 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, Nmethylpyrrolidone, dimethylformamide, dimethylacetamide and the like or mixtures thereof. The reaction temperatures are between about -80 0 C and 160 0 C, and temperatures of 20 0 C to 80 0 C are preferred. The reaction times are between 0.5 hour and 7 days, preferably between 1 hour and 36 hours.

The production of acid anhydrides of general formula XX can be carried out according to known processes, 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, in German laid-open specification DE 29 28 417, iodized aromatic compounds are described, which are readily

I

reacted with, thionyl chloride, to the corresponding acid chloride group-containing aromatic compounds.

Other aromatic radicals can be produced as described in M.

Sovak; Radiocontrast Agents, Handbook of Experimental Pharmacology Vol. 73 (1984), Springer Verlag, Berlin Heidelberg New York Tokyo or in European Patent EP 0 015 867.

Corresponding chlorine or bromine compounds can be produced as described in patents EP 0 055 689 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, 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 56'.

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 n 130 934 and DE 34 01 052, by the metal oxide or a metal salt (for example, the nitrate, acetate, carbonate, chloride or sulfate) of the element of atomic numbers 12, 13, 20-31, 39-42, 44-50 or 57-83 being dissolved or suspended in water and/or a lower alcohol (such as methanol, ethanol, isopropanol and/or N,Ndimethylformamide) 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.

R

cU

NT

a As bases, inorganic bases hydroxides, carbonates or bicarbonates) of, sodium, potassium or lithium and/or organic bases, such as, primary, secondary and tertiary amines, such as, ethanolamine, morpholine, glucamine, Nmethyl glucamine and N,N-dimethyl glucamine, as well as basic amino acids, such as, 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, 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 up^

I

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, tromethamine), small additions of complexing agents (such as, e.g., diethylenetriaminepentaacetic acid) or, if necessary, electrolytes, such as, sodium chloride or, if necessary, antioxidants, such as, ascorbic acid.

If suspensions or solutions of the agents according to the invention in water or physiological salt solution are desired for enteral administration or other purposes, they are mixed with one I I or more adjuvants that are commonly used in galenicals methyl cellulose, lactose, mannitol) and/or surfactants lecithins, Tween(R), Myrj(R) and/or flavoring substances for taste correction essential oils).

In principle, it is also possible to produce the diagnostic agents according to the invention even without isolating the complex salts. In each case, special care must be used to undertake the chelation, so that the salts and salt solutions according to the invention are virtually free of noncomplexed metal ions that have a toxic effect.

This can be ensured, for example, using color indicators, such as xylenol orange, by control titrations during the production process. The invention therefore relates also to processes for the production of complex compounds and their salts. As a final precaution, there remains purification of the isolated complex salt.

Further objects of the invention are characterized by the claims.

The substances according to the invention meet the varied requirements that are to be set for contrast media in modern diagnosis. The compounds and agents produced from them are distinguished by: a high absorption coefficient for x rays, good compatibility, which is necessary to maintain the noninvasive nature of the studies, high effectiveness, which is necessary to burden the body with the smallest possible amounts of foreign substances, good water-solubility (this makes it possible to produce highly concentrated solutions, as they are necessary especially for use as x-ray contrast media. Thus, the volume burden of the cycle can be kept within reasonable limits), low viscosity, low osmolality, advantageous elimination kinetics.

Further, the agents according to the invention exhibit not only high stability in vitro, but also surprisingly high stability in vivo, so that a release or an exchange of the ions that are not covalently bound to the complexes toxic in themselves is not carried out within the time in which the new contrast media are -4ain completely excreted.

In addition to the high water solubility, which it was possible to increase, surprisingly enough, in the presence of paramagnetic metal ions in a range necessary for diagnostic radiology, the compounds according to the invention have a positive effect in diagnostic radiology, in that the complex compounds according to the irivention, 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 Felix, Das R6ntgenbild [The X-Ray Picture]; Thieme Stuttgart 1980).

Because of the advantageous absorption properties of the contrast media according to the invention in the area of hard xj\ AAL, l I-I ray radiation, the media are also especially suited for digital subtraction techniques (which operate at higher tube voltages).

Especially to be emphasized is the advantageous in vivo distribution behavior of the media according to the invention.

This allows for the first time for taking x-ray pictures of high diagnostic informative value in the area of the liver with a dose that is commonly used for x-ray contrast media (halogen content: 50-400 mg/ml; dose 0.1 1 ml/kg of body weight).

Thus, the complexes according to the invention already produce an optimum contrast of the liver at a dose of mmol/kg. Figure 1, upper picture, shows the liver of a rat before the contrast medium is administered. The lower picture shows the liver of the same rat 10 minutes after injection of mmol/kg of the compound according to the invention produced according to Example Id).

A picture taken under otherwise identical conditions after the same dose of the disodium salt of the gadolinium complex of (4s) 4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9triazaundecanedioic acid is administered (EP 0 405 704; Example 8c) does not show any diagnostically usable contrasting of the liver (see Fig. 2, lower picture). The upper figure shows the liver before the administration of contrast medium.

In comparison, Figure 3 shows the density enhancement (which can be regarded as a measurement for the effectiveness of a contrast medium) as a function of time, for a compound according to the invention (Example Id) and a compound of EP 0 405 704 (Example 8c). Accordingly, considerably higher density values

U!

iT are observed in the liver of the rat over the entire period of stud' for the compound according to the invention. Thus, the maxiaum values for the substance according to the invention are approximately 60 Houndsfield units but only 15 HU for the comparison substance. The studies were performed on a somatome plus VD31 (parameter of study: layer thickness 2 nun, tube voltage/current 120 kV/290mA) on female rats (body weight 200-280 g) after intravenous injection of 0.5 mmol/kg each of the respective substance.

Also, the complexes that are described in WO 93/16375 do not show any concentration in the liver that is sufficient for imaging.

Thus, the isomeric gadolinium complex of 1,13-bis-[5- (propion-3-ylamido)-2,4,6-triiodoisophthalic icid-bis-(2-hydroxyl-hydroxymethylethyl)-diamide]-4,7,10-tris-(carboxymethyl)-(2,12dioxo)-1,4,7,10,13-pentatriazadecane (Example 17b), in Example 1 of WO 93/16375, was excreted almost completely through the kidneys. Only 1.3% of the total amount was eliminated in other ways from the body. Even assuming that this 1.3% of the complex had been completely concentrated in the liver, this amount would be far below the dose that is requirec Ior an imaging effect.

These studies were performed on female rats (90-110 g of body weight) after intravenous administration of 0.27 mmol/kg of compound 17b). The Ljdine 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.

I I The half-life of 0.32 hour as well as the distribution volume show a distribution in the extracellular space with renal elimination by glomerular filtration through the kidneys.

The agents according to the invention, which contain in the complex a paramagnetic metal ion of an element of atomic numbers 21-29, 42, 44 or 57-70, can be used, in addition to use in diagnostic radiology, also in NMR diagnosis. This dual nature opens up further fields of use. Thus, these agents according to the invention can always be used advantageously, if a combination of diagnostic radiology and NMR diagnosis is necessary for differentiated visualization and reliable determination of certain diseases. This is true, in the case of suspicion of recurrence after tumor operations or radiation therapies. In these cases, the patient is spared an additional burden resulting from double administration by using a contrast medium, which is equally suitable for both techniques.

Taken overall, it has been possible to open up new possibilities in diagnostic medicine with the above-mentioned complex compounds.

The following examples are used for a more detailed explanation of the object of the invention, without intending to be limited to these examples.

0 0/ ik -OMME NNE Example 1 Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9tris-(carboxymethyl)-4-[4-(2,4,6-triiodobenzyloxy)-benzyl]undecanedioic acid a) Production of 2,4,6-triiodobenzyl chloride 41.6 g (80.1 mmol) of 3-amino-2,4,6-triiodobenzyl chloride (Collection Czechoslov. Chem. Commun. [Vol. 41] 1976) is suspended in 416 ml of glacial acetic acid and mixed in portions with a suspension of 6.08 g (88.1 mmol) of sodium nitrite in ml of concentrated sulfuric acid while being stirred. The reaction temperature is held at 25 0 C by cooling. After 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 10 0 C, filtered, the residue is absorptively precipitated for 30 minutes with 300 ml of N,Ndimethylformamide, and the suspension is filtered. The filtrate is concentrated by evaporation in a vacuum, the residue is absorptively precipitated with water, filtered off and dried in a vacuum. The crude product is stirred in hot acetonitrile with activated carbon, then it is filtered, and the filtrate is cooled to 0 C, whereby a precipitate results. The latter is suctioned off and dried in a vacuum.

Yield: 29.8 g of light beige solid vT Analysis (relative to solventless substance): Cld: C 16.67 H 0.80 Cl 7.03 I 75.50 Fnd: C 16.82 H 0.95 Cl 7.14 I 75.41 b) 3,6,9-Triaza-3,6,9-tris-(tert-butoxycarbonylmethyl)-4-[4- (2,4,6-triiodobenzyloxy)-benzyl]-undecanedioic acid-di-tertbutyl ester 15.6 g (20.0 mmol) of 3,6,9-triaza-3,6,9-tris-(tertbutoxycarbonylmethyl)-4-(4-hydroxy-benzyl)-undecanedioic acid-ditert-butyl ester (Example 9f of DE 3710730) is mixed in tetrahydrofuran at 0°C with 660 mg (22.0 mmol) of 80% sodium hydride suspension in mineral oil. 12.4 g (22.0 mmol) of the 2,4,6-triiodobenzyl chloride, produced according to Example la), is added to the abov- 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 Na 2

SO

4 and concentrated by evaporation.

The residue is chromatographed on silica gel 60 (Merck) with hexane/methyl acetate/triethylamine, the product fractions are concentrated by evaporation and dried in a vacuum.

Yield: 22.8 g (91.2% of theory) of yellowish oil Analysis (relative to solventless substance): 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-Triaza-3,6,9-tris-(carboxymethyl)-4-[4-(2,4,6triiodobenzyloxy)-benzyl]-undecanedioic acid 22.8 g (18.3 mmol) of the tert-butyl ester described in Example Ib) is dissolved in 250 ml of trifluoroaceiic acid and stirred for 1 hour at room temperature. Then, the solution is mixed with tert-butyl methyl ether, the precipitate is suctioned off, washed with tert-butyl methyl ether and dried at 40 0 C in a vacuum on phosphorus pentoxide. The crude product is absorptively precipitated in water, filtered off and dried in a vacuum.

Yield: 15.4 g (86.8% of theory) of light beige solid Analysis (relative to anhydrous substance): Cld: C 34.77 H 3.33 I 39.36 N 4.34 O le,19 Fnd: C 34.63 H 3.56 I 39.28 N 4.38 d) Gadolinium complex of the disodium salt of 3,6,9-triaza- 3,6,9-tris-(carboxymethyl)-4-[4-(2,4,6-triiodobenzyloxy)benzyl]-undecanedioic acid A suspension of 11.8 g (12.2 mmol) of the penta acid, produced according to Example Ic), in 118 ml of water is mixed with 2.21 g (6.1 mmol) of gadolinium oxide and stirred at 80 0

C

for 2 hours. Then, 24.4 ml of IN sodium hydroxide solution is added with a microburette and stirred for 3 more hour. Then, after 0.5 g of activated carbon is added, the solution is stirred for 2 hours at 80 0 C and filtered. After freeze-drying, the filtrate yields a colorless solid.

A u L I Yield: 13.1 g (91.8% of theory) Analysis (relative to anhydrous substance): Cld: C 28.86 H 2.34 I 32.67 N 3.61 0 15.10 Gd 13.49 Na 3.95 Fnd: C 28.66 H 2.43 1 32.70 N 3.49 Gd 13.28 Na 4.16 Example 2 GrAolinium Complex of the disodium salt of 3,6,9-triaza-3,6,9tris-(carboxymethyl)-4-[4-(N-acetyl-3-methylamino-2,4,6triiodobenzyloxy)-benzylJ-undecanedioic acid a) N-Acetyl-3-mothylamino-2,4,6-triiodobenzyl chloride 42.5 g (79.7 mmol) of 3-methylamino-2,4,6-triodobenzyl chloride (Collection Czachoslov. Chani. Commun. [Vol. 41] 1976) is dissolvod in 180 ml of N,N-dciinthy iaicotaiimild and miixed drop by drop with 13.7 ml (191.3 mmol) of acetyl chloride while being cooled with ice. After 30 minutes of stirring at about OOC, it is stirred for 12 hours nt room temperaturo nnd the dark brown solution is introdueod in water while being ntirred. A precipitate is precipitated, which is ouctioned off and dried in a vacuum.

Yiold: 44.6 q (99.61- of theory) of litht beigo nolid Analysis (relative to anhydrous nubstance): Cid: C 20.88 II C 6.16 1 66.17 N 2.4J 0 2.1u Fnd: C 20.98 11 1.69 Ci 6.04 1 66.113 N 2.'2 'v s'~ .2P' 1. U 1~ b) 3,6,9-Triaza-3,6,9-tris-(tert-butoxycarbonylmethyl)-4-[4-(Nacetyl-3-methylamino-2,4,6-triiodobenzyloxy)-benzyl]undecanedioic acid-di-tert-butyl diester 15.6 g (20.0 mmol) of 3,6,9-triaza-3,6,9-tris-(tertbutoxycarbonylmethyl)-4-(4-hydroxybenzyl)-undecanedioic acid-ditert-butyl ester (Example 9f of DE 3710730) is mixed in tetrahydrofuran at 0 0 C with 660 mg (22.0 mmol) of 80% sodium hydride suspension in mineral oil. 12.66 g (22.0 mmol) of the compound, produced according to Example 2a), is added to the above and stirred for 3 hours. Then, the solution is mixed with water, tetrahydrofuran is distilled off, and the aqueous emulsion is extracted with diethyl ether. The organic phase is washed with water, dried on Na 2

SO

4 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-3imethylamino-2,4,6-triiodobenzyloxy)-benzyl]-undecanedioic acid 21.9 g (16.6 mmol) of the tert-butyl ester described in Example 2b) is dissolved in 250 ml of trifluoroacetic acid and A

L/

4' II stirred for 1 hour at room temperature. Then, the solution is mixed with diethyl ether; the precipitate is suctioned off, washed with diethyl ether and dried at 40 0 C in a vacuum on phosphorus pentoxide. The crude product is absorptively precipitated in water, filtered off and dried in a vacuum.

Yield: 16.2 g (94.1% of theory) of light beige solid Analysis (relative to anhydrous substance): 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) Gadolinium complex of the disodium salt of 3,6,9-triaza- 3,6,9-tris-(carboxymethyl)-44-[4-(N-acetyl-3-methylamino- 2,4,6-triiodobenzyloxy)-benzyl]-undecanedioic acid A suspension of 14.8 g (14.3 mmol) of the penta acid, produced according to Example 2c), in 150 ml of water is mixed with 2.58 g (7.13 mmol) of gadolinium oxide and stirred at 80 0

C

for two hours. Then, 28.5 ml of IN sodium hydroxide solution is added with a microburette and stirred for one more hour. Then, after 0.8 g of activated carbon is added, the solution is stirred for two hours at 800C and filtered. After concentration by evaporation, the filtrate yielded a colorless solid.

Yield: 16.4 g (93.3% of theory) Analysis (relative to anhydrous substance): Cld: C 30.11 H 2.61 I 30.79 N 4.53 O 15.53 Gd 12.72 Na 3.72 Fnd: C 30.00 H 2.82 I 30.58 N 4.67 Gd 12.79 Na 3.82 I, _CCCL Example 3 Gadolinium complex of the trisodium salt of 3,6,9-triaza-3,6,9tris-(carboxymethyl)-{4-[N-(3-carboxypropionyl)-3-methylamino- 2,4,6-triiodobenzyloxy]-benzyl}-undecanedioic acid a) N-(5-Oxa-1,4-dioxoheptyl)-3-methylamino-2,4,6-triiodobenzyl chloride 24.7 g (150 mmol) of succinic acid chloride monoethyl ester is added at room temperature to a suspension of 53.3 g (100 mmol) of 3-methylamino-2,4,6-triiodobenzyl chloride (Collection Czechoslov. Chem. Commun. [Vol. 41] 1976) in 200 ml of anhydrous dioxane, stirred with exclusion of moisture. The batch is refluxed for several hours until no more feedstock can be detected according to thin-layer chromatography; then, it is concentrated by evaporation, the residue is taken up in dichloromethane and shaken out with saturated aqueous sodium bicarbonate solution. After drying on anhydrous magnesium sulfate, the organic phase is concentrated by evaporation, and the residue is recrystallized from ethyl acetate/tert-butyl methyl ether.

Yield: 58.4 g (88.3% of theory) of colorless solid Analysis (relative to solventless substance): 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 Cl 5.43 I 57.50 N 2.17 I I r' b) 3,6,9-Triaza-3,6,9-tris-(tert-butoxycarbonylmethyl)-4-{4-[N- (5-oxa-1,4-dioxo-heptyl)-3-methylamino-2,4,6triiodobenzyloxy]-benzyl}-undecanedioic acid 15.6 g (20.0 mmol) of 3,6,9-triaza-3,6,9-tris-(tertbutoxycarbonylmethyl)-4-(4-hydroxybenzyl)-undecanedioic acid-ditert-butyl ester (Example 9f of DE 3710730) is mixed in tetrahydrofuran at 0 0 C with 660 mg (22.0 mmol) of 80% sodium hydride suspension in mineral oil. 14.55 g (22.0 mmol) of the compound, produced according to Example 3a), is added to the above and stirred for 3 hours. Then, the solution is mixed with water, tetrahydrofuran is distilled off, and the aqueous emulsion is extracted with diethyl ether. The organic phase is washed with water, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel (Merck) with hexane/ethyl acetate/triethylamine, the product fractions are concentrated by evaporation and dried in a vacuum.

Yield: 22.9 g (81.6% of theory) of yellowish oil Analysis (relative to solventless substance): Cld: C 47.02 H 5.95 I 27.10 N 3.99 0 15.94 Fnd: C 46.86 H 6.13 I 26.98 N 3.84 c) 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-{4-[N-(3carboxypropionyl)-3-methylamino-2,4,6-triiodobenzyloxy]benzyl}-undecanedioic acid 20.4 g (14.5 mmol) of the hexaester described in Example 3b) is dissolved in 100 ml of methanol and mixed with 87 ml of 2N 1 11*I~ s sodium hydroxide solution. It is refluxed for about 2 hours, the methanol is drawn off in a vacuum and, after 100 ml of water is added, it is stirred for another 2 hours at 60 0 C. By adjusting to pH 1-2 with semiconcentrated hydrochloric acid, a colorless precipitate results, which is suctioned off and dried in a vacuum.

Yield: 15.3 g (96.0% of theory) of colorless solid Analysis (relative to anhydrous substance): 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) Gadolinium complex of the trisodium salt of 3,6,9-triaza- 3,6,9-tris-(carboxymethyl)-{4-[N-(3-carboxypropionyl)-3methylamino-2,4,6-triiodobenzyloxy]-benzyl}-undecanedioic acid A suspension of 14.1 g (12.9 mmol) of the hexa acid, produced according to Example 3c), in 150 ml of water is mixed with 2.33 g (6.43 mmol) of gadolinium oxide and stirred at 80 0

C

for 2 hours. Then, 38.6 ml of 1N sodium hydroxide solution is added with a microburette and stirred for 1 more hour. Then, after 0.8 g of activated carbon is added, the solution is stirred at 80 0 C for 2 hours and filtered. After freeze-drying, the filtrate yielded a colorless solid.

Yield: 16.3 g (96.4% of theory) I_ L_ T 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 4 Gadolinium complex of 3,6,9-triaza-3,6,9-tris-(carboxymethyl)-4- (3,5-diiod-4-ethoxybenzyl)-undecanedioic acid, disodium salt a) 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-(4-hydroxybenzyl)undecanedioic acid 7.8 g (10 mmol) of 3,6,9-triaza-3,6,9-tris-(tertbutoxycarbonylmethyl)-4-(4-hydroxybenzyl)-undecanedioic acid-ditert-butyl ester (Example 9f of DE 3710730) is dissolved in 100 ml of trifluoroacetic acid and stirred for 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 500C in a vacuum. The crude product is dissolved in water and treated with activated carbon. The filtered solution is freeze-dried several times to remove residual trifluoroacetic acid.

Yield: 4.0 g (80.1% of theory) of colorless lyophilizate.

Elementary analysis (taking into consideration the solvent content): Cld: C 50.50 H 5.85 N 8.41 0 35.24 Fnd: C 50.68 H 5.99 N 8.25 1 b) 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-(3,5-diiodo-4hydroxybenzyl)-undecanedioic 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 50 0 C, and 5.7 ml (14.1 mmol) of a 40% hydrochloric acid-iodomonochloride solution is added in drops. After 20 hours at 50 0 C, the excess iodine is reduced with sodium disulfite, the precipitate is suctioned off and washed with water.

Yield: 4.15 g (86% of theory) of pale yellow solid Elementary analysis (taking into consideration the solvent content): Cld: C 33.57 H 3.62 I 33.78 N 5.59 0 23.43 Fnd: C 33.71 H 3.86 I 33.41 N 5.65 c) 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-(3,5-diiodo-4ethoxybenzyl)-undecanedioic acid g (4 mmol) of the diiodophenol of Example 4b) is mixed in 25 ml of anhydrous tetrahydrofuran with 0.792 g (26.4 mmol) of 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 __r precipitate is suctioned off and washed with water. For purification, the crude product is recrystallized from ethanol.

Yield: 2.35 g (75.4% of theory) of colorless crystals.

Elementary analysis (taking into consideration the solvent content): 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) Gadolinium complex of 3,6,9-triaza-3,6,9-tris- (carboxymethyl)-4-(3,5-diiodo-4-ethoxybenzyl)-undecanedioic acid 1.75 g (2.2 mmol) of the pentacarboxylic acid of Example 4c) is suspended in 55 ml of water and mixed at 60 0 C with 407 mg (1.1 mmol) of gadolinium oxide. After 4 hours, the clear solution is treated with activated carbon. Then, it is polished with a cellulose-membrane filter (0.2 mm, Sartorius) and freeze-dried.

Yield: 1.95 g (94.9% of theory) of colorless lyophilizate.

Elementary analysis (taking into consideration the solvent content): Cld: C 29.59 H 3.02 Gd 16.84 I 27.19 0 18.85 Fnd: C 29.64 H 3.25 Gd 16.66 I 26.93 T V <d

A

r e) Gadolinium complex Of 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4-(3,5-diiodo-4-ethoxybenzyl) -undecanedioic acid, disodiui salt g (1.6 mmol) of the complex described in the above example is dissolved in 120 ml of water and mixed using a microburette with 3.2 ml of a 1N sodium hydroxide solution.

After freeze-drying, the disodium salt is obtained as colorless lyophilizate.

Yield: 1.55 g (99% of theory) of colorl.ess lyophilizate.

Elementary analysis (taking into consideration the solvent content): Cld: C 28.26 H 2.68 Gd 16.09 1 25.96 N 4.30 Na 4.70 0 18.00 Fnd: C 28.03 H 2.91 Gd 15.86 1 25.72 N 4.09 Na 4.45 Example Gadolinium complex of the disodium, salt of 4-(N-arcetyl-3methylamino-2,4,6-triiodobenzyloxymethyl) 6,9-triaza-3, 6,9tris- (carboxymethyl) -undecanedioic acid a) N-Acetyl-N-methyl-3-( (2,2-dimethyl-1,3-dioxolan-4-yl) methoxymethylJ 6-triiodoaniline 20.0 g (36.3 mmol) of the compound produced uinder Example 2a), 5.8 g (43.6 mrito1) 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 for 6 hours. Then, the organic phase is separated, shaken out with saturated aqueous common salt solution and dried on magnesium sulfate. After the filtrate is filtered and concentrated by evaporation, an oily residue is obtained, which is chromatographed on silica gel with toluene/ethyl acetate.

Concentration by evaporation of the product fractions yields a colorless oil, which is dried in a vacuum.

Yield: 21.3 g (87.2% of theory) Analysis (relative to solventless substance): 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-[(2,3-dihydroxypropyloxy)-methyl]-2,4,6triiodoaniline 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 ml of concentrated sulfuric acid. After 12 hours of stirring at 0 C, the batch is taken up in dichloromethane, and the organic phase is shaken out once with concentrated sodium chloride solution and twice with concentrated sodium bicarbonate solution.

The organic phase is dried on anhydrous magnesium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel 60 (Merck) with 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 (89.2% of theory) ^r 1 Analysis (relative to solventless substance): Cid: C 24.75 1-1 2.56 1 60.34 N 2.22 0 10.14 Fnd: C 24.86 H 2.69 1 60.12 N 2.34 c) N-Aootyl-N-mothiyl-3-( (3-bonzoyloxy-2-hydroxypropyloxy) mothyl] 4, 6-triiodoarkiline 15.2 g (24.1 mmol) of the compound produced in Example is stirred in 150 mil of dichioromethano under argon and mixed first with 4.0 nil, (28.9 mmol) of triethylarnine, then at 0 0 C drop by drop with 3.47 g (26.5 mmol) of benzoyl cyanide. After 12 hours of stirring at 0 0 C, the batch is diluted with dichloromothane and shaken out against saturated 'oodium bicarbonate solution. The organic phase is dried on magnesium sulfate, filtered and concentrated by evaporation, and the residue is chromatographod on silica qel 60 (Merck) with dichlorometlhano/imothanol. After concentration by evaporation, the product fractions yield a colorless oil.

Yield: 13.9 g (78.4% of theory) Analysis (relative to solvent less substance): Cld: C 32.68 11 2.74 I 51.79 N 1.91. 0 10.88 Fnd: C 32.54 H1 2.88 1 51.83 N 1.74 d) N-Acotyl-N-methyl-3-[ (3-benzoyloxy-2methanesulfonyloxypropyloxy) xnothyl]-2, 4, 6-trilodoarhiline 13.4 g (18.2 mmol) of the compound produced under Example is stirred in 80 mil of dichloromethane under argon and mixed II I first with 3.0 ml (21.9 mmol) of triethylamine, then at 0°C drop by drop with 1.56 ml (20.1 mmol) of methanoeulfonic 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 (Morck) with dichloromothano, the product fractions are concontrated by evaporation, and the residue is dried in a vacuum.

Yield: 12.8 g (86.2% of theory) of yellowish foam Analyols (rolativo to solvontlomsn ubntanco)): Cld: C 31.02 II 2.73 1 46.82 N 1.72 O 13.77 S 3.94 Fnd: C 31.20 11 2.89 I 46.67 N 1.81 S 4.02 o) N-Aootyl-N-mothyl-3-[(3-bonzoyloxy-2-azidopropyloxy)mothyl]-2,4,6-triiodonnilino 11.8 g (14.5 mmol) of the compound produced in Example is stirred in 50 ml of N,N-dimothylformamido together with 2.83 g (43.5 mmol) of sodium azide for one hour at 85 0 C under argon.

Then, it is concentrated by evaporation in a vacuum, and the residue is shaken out with dichloromethano/saturated sodium bicarbonate solution. The organic phase Is dried on magnesium sulfate, filtered and concentrated by evaporation in a vacuum.

Yield: 10.2 g (92.1% of theory) of yellowish foam _I I I Analysis (relative to solventless free substance): Cld: C 31.60 I1 2.52 I 50.09 N 7.37 0 8.42 Fnd: C 31.59 H 2.63 I 49.87 N 7.49 f) N-Aoatyl-N-mothyl-3-[ (2-azido-3-hydroxypropyloxy) methyl]- 2,4,6-triiodoaniline 9.58 g (12.6 mmol) of the compound produced according to Example 50) is dissolved in 60 ml of methanol. After 40 ml of 2N sodium hydroxide solution is added, it is stirred for one hour at 0 C bath temperature and after the cooling, it is neutralized with 2N hydrochloric acid. The methanol is drawn off in a vacuum, and the residue is dispersed betwooen dichloromethane and saturated sodium bicarbonate solution. The organic phaso Is dried on magnesium sulfate, filtored, concentrated by evaporation, the residue is chromatographed on silica grl (Merck), and the product fractions are concontlrated by evaporation in a vacuum.

Yield: 7.47 g (90.3% of theory) Analysis (relative to solventlens substance): Cld: C 23.80 11 2.31 I 58.04 N 8.54 0 7.32 Fnd: C 23.92 11 2.50 I 57.85 N 8.6 g) N-Acotyl-N-methyl-3-[(2-azido-3methanosulfonyloxypropyloxy)-mothyl]-2,4,6-triiodoanilino 7 i' 1 j

I

7.22 g (11.0 inmol) of the hydroxy compound produced according to Example 5f) is reacted to the corresponding mesylate under the conditions described in Example Yield: 7.46 g (92.4% of theory) Analysis (relative to soiventless substance): Old: C 22.91 11 2.33 1 51.86 N 7.63 0 10.90 S 4.37 Fnd: C 23.01 HI 2.58 1 51.63 N 7.75 S 4.49 h1) N-ctlNmty--69daa4aio2oaoy)246 trijodoaliliin: dihydrochloriio 7.21. g (9.82 mmol) of thle monylatu doe3cribod In Exampl(3 ic dissolved in 50 ml of? methanol, and after 3Th0 ml of' 1,2diaminoothane in added, It In n t irrod for 11) hourti at,* room temperature. Then,~. tile batch In concentrated by evaporation aInd disperoed betweenl Cichior1'11oinethan and1C 0a1J La Led nod I u bicarbonate solution. The aqU0eouz- pAV0 lin oxLracto d oevorn] times with dicbioromothane, thle combined organic phaser; are dried on nodium sulfate, filtered and concentratod by ovaporation. Tha residue In taken up In tort-but~yl. mwthy I (ther/net~litno I and adjisted to p~l 2 with concentra Led hydrochlio Ic aci. d, whoreby a colorless precipitate precipitates. Thel( latA-er in noparatod [And dried In a vacuum.

Yield: 7,33 (1 (96.8% of- theory) Ir sb~-- Analysis (relative to solventless substance): Cld: C 23.37 H 3.01 I 49.38 N 10.90 0 4.15 Cl 9.20 Fnd: C 23.28 H 3.22 I 49.39 N 11.02 Cl 9.37 i) N-Acetyl-N-methyl-3-(4-amino-6,9-diaza-2-oxanonyl)-2,4,6triiodoaniline, trihydrochloride 7.04 g (9.13 mmol) of the dihydrochloride produced under Example 5h) is taken up in 70 ml of a 4:1 mixture of dioxane/water and mixed with 12.0 g (45.7 mmol) of triphenylphosphine. The batch is allowed to stir for 3 days at room temperature under argon, the organic solvent is evaporated, and precipitate is filtered out. The precipitate is washed with 2N hydrochloric acid; the combined filtrates are concentrated by evaporation, and the residue is recrystallized from methanol/tert-butyl methyl ether.

Yield: 6.12 g (85.8% of theory) Analysis (relative to solventless substance): 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 j) 4-(N-Acetyl-3-methylamino-2,4,6-triiodobenzyloxymethyl)- 3,6,9-tris-(tert-butyloxycarbonylmethyl)-3,6,9triazaundecanedioic acid-di-tert-butyl ester 5.98 g (7.65 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

I--I

potassium carbonate and 7.46 g (38.3 mmol) of bromoacetic acidtert-butyl ester. After 12 hours of stirring, it is filtered, concentrated by evaporation in a vacuum, and the residue is dispersed between ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried on sodium sulfate, filtered, concentrated by evaporation, and the residue is chromatographed on silica gel 60 (Merck) with hexane/ethyl acetate. After the product fractions are concentrated by evaporation, a yellowish oil is obtained.

Yield: 8.94 g (98.5% of theory) Analysis (relative to solventless substance): Cld: C 41.50 H 5.52 I 32.08 N 4.72 0 16.18 Fnd: C 41.52 H 5.73 I 31.96 N 4.68 k) 4-(N-Acetyl-3-methylamino-2,4,6-triiodobenzyloxymethyl)- 3 6,9-triaza-3,6,9-tris-(carboxymethyl)-undecanedioic acid 8.50 g (7.16 mmol) of the pentaester produced under Example is converted to the corresponding penta acid under the conditions described in Example ic).

Yield: 5.80 g (84.1% of theory) of light beige solid Analysis (relative to anhydrous substance): Cld: C 31.20 H 3.46 I 39.56 N 5.82 0 19.95 Fnd: C 31.25 H 3.66 I 39.42 N 5.83 1) Gadolinium complex of the cisodium salt of 4-(N-acetyl-3methylamino-2, 4, 6-triiodobenzyloxymethyl]J-3, 6,9 -triaza- 3,6,9-tris-(carboxymethyl) -undecanedioic acid 5.69 g (6.19 mmol) of the penta acid produced in Example is complexed with gadolinium oxide under the conditions described in Example ld) and converted to the corresponding disodium salt.

Yield: 6.81 g (94.8% of theory) of colorless lyophilizate Analysis (relative to anhydrous substance): Cld: C 25.88 H 2.43 1 32.81 N 4.83 0 16.55 Gd 13.55 Na 3.96 Fnd: C 25.94 H 2.61 1 32.78 N 4.85 Gd 13.44 Na 4.00 Example 6 1,19-Bis-(3-carboxy-2,4,6--triiodophenyl)-7,1O,13-tris- (carboxymethyl)-2,5,15,18--tetraoxo-1,4,7,10,.13,16,19heptaazanonadecaie, gadolinium complex, disodium salt a) 1,19-Bis-(3-carboxy-2,4,6-triiodophenyl)-7,1O,13-tris- (carboxymethyl)-2,5,15,18-'tetraoxo-1,4,7,10,13,1E,19,heptaazanonadecane 11.42 g (20 mmol) of 3-glycylamino-2,4,6-triiodobenzoic acid (DE 2523567) is dissolved in 60 ml of N,N-dimethylformamide while being heated. It is mixed at room temperature with 6.9 ml of triethylamine and 3.6 g (10 mmol) of N,N-bis-[2,6dioxomorpholino)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 anid acidified with concentrated hydrochloric acid. The settled precipitate is IL suctioned off and washed with water. The crude product is purified by an RP 18 chromatography on silica gel.

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

Elementary analysis (taking into consideration the solvent content): 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) 1,19-Bis-(3-carboxy-2,4,6-triiodophenyl)-7,10,13-tris- (carboxymethyl)-2,5,15,18-tetraoxo-1,4,7,10,13,16,19heptaazanonadecane, gadolinium complex, disodium salt 7.2 g (48 mmol) of the ligand of Example 6a) is suspended in ml of water and mixed in portions with 1.74 g (4.8 mmol) of gadolinium oxide at 50-60 0 C. After the complexing is completed, the pH is adjusted to seven with lN sodium hydroxide solution, filtered, and the aqueous solution is freeze-dried.

Yield: 7.6 g (93% of theory) of colorless lyophilizate.

Elementary analysis (taking into consideration the solvent content): Cld: C 22.62 H 1.66 Gd 9.25 I 44.81 N 5.77 Na 2.71 0 13.18 Fnd: C 22.43 H 1.85 Gd 9.07 I 44.71 N 5.63 Na 2.49 -I Example 7 1,19-Bis-{3-[(10-earboxydecyl)-carbamoyl]-2,4,6-triiodophenyl}- 7,10,13-tris-(carboxymethyl)-2,5,15,18-tetraoxo- 1,4,7,10,13,16,19-heptaazanonadecane, gadolinium complex, disodium salt a) (3-Aminoacetylamido)-N-(10-carboxydecyl)-2,4,6triiodobenzoic acid amide 10.9 g (15 mmol) of 3-phthalimidoacetylamino-2,4,6triiodobenzoic acid chloride (DE 2523567) is dissolved in 60 ml of N,N-dimethylacetamide and reacted at 80 0 C with 1.98 g (16 mmo.) o; 11-aminoundecanoic acid. The reaction mixture is sti::Zrd 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 mmol) of hydrazine hydrate. After three hours of stirring at 0 C, the reaction mixture is allowed to cool, and the settled precipitate is suctioned off. The product is rewashed with ample water, and the solid is dried at 50 0 C in a vacuum.

Yield: 9.8 g (87% 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 II I u I I b) 1,19-Bis-{3-[(10-carboxydecyl)-carbamoylJ-2,4,6triiodophenyl}-7, 10, 13-tris- (carboxymethyl) -2,5,15,18tetraoxo-1, 4,7, 10, 13, 16, 19-hieptaazanonadecane 8.75 g (11.6 mmol) of the amine of Example 7a) is reacted analogously to Example 6a) with 2.14 g (6 mmol) of N.N-bis-[2- (2,6-dioxomorpholino)ethyl~glycine and purified in a similar way by a column chromatogra~phy on RP 18.

Yield: 17.4 g (80% of theory) of pale yellow solid.

Elementary analysis (taking into consideration the solvent content): Cld: C 34.73 H 4.05 1 40.77 N 6.75 0 13.71 Fnd: C 34.90 H 3.92 1 40.68 N 6.51 C) 1,19-Bis-{3-[(10-carboxydecyl)-carbamoylJ-2,4,6triiodophenyl}-7,10,13-tris-(carboxymethyl)-2,5,15,18tetraoxo-1,4,7,10,13,16,19-heptaazanonadecane, gadolinium complex, disodium salt g (8 mmol) of the ligand of Example 7b) is complexed according to Example 6b) with 2.9 g (8 mmol) of gadolinium oxide and converted with IN sodium hydroxide solution to the disodium salt.

Yield: 15.6 g (95% of theory) of colorless lyophilizate.

Elementary analysis (taking 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 Example 8 Gadolinium complex of the disodium salt of 4-(3-acetylamino- 2,4,6-triiodobenzoyl-aminomethyl)-3,6,9-triaza-3,6,9-tris- (carboxymethyl)-4-methylundecanedioic acid a) 2,4-Dimethyl-4-methanesulfonyloxyethyl-2-oxazoline 40.8 g (316 mmol) of 2,4-dimethyl-4-hydroxymethyl-2oxazoline 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 0 C under nitrogen and mixed drop by drop with 39.8 g (347 mmol) of methanesulfonic acid chloride.

The reaction temperature is allowed to increase to room temperature within 3 hours, and the batch is shaken out with saturated sodium bicarbonate solution. The organic phase is dried on sodium sulfate, filtered and concentrated by evaporation.

Yield: 58.5 g (89.4% of theory) of yellowish oil Analysis (relative to solventless substance): 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

'I

K^

I

b) 4-(2,5-Diazapontyl)-2,4-dimethyl-2-oxazoline, dihydrochloride A solution of 36.7 g (177 mmol) of the compound, produced according to Example 8a), in 100 ml of methanol is added drop by drop to 291 ml (4427 mmol) of 1,2-diaminoethane. The reaction mixture is stirred for 3 hours at 50°C and for another 12 hours at room temperature. Then, the batch is completely concentrated by evaporation in a vacuum. A solution of the residue in methanol is adjusted to pH 1.5 at 0 C with concentrated hydrochloric acid. Ethylenediamine-dihydrochloride precipitating in this connection is separated by filtration. By adding tertbutyl methyl ether in drops to the filtrate, a colorless precipitate results, which is suctioned off and dried in a vacuum.

Yield: 38.2 g (88.4% of theory) Analysis (relative to solventless substance): Cld: C 39.35 H 7.84 N 17.21 0 6.55 Cl 29.04 Fnd: C 39.40 H 7.78 N 17.09 C1 29.11 c) 2-Amino-4,7-diaza-2-methylheptan-l-ol, trihydrochloride 30.8 g (126 mmol) of the dihydrochloride produced under Example 8b) is taken up in 150 ml of ethanol. After 31 ml of concentrated hydrochloric acid is added, it is refluxed for 4 hours. After the cooling, the batch is concentrated by evaporation on a vacuum and stirred in 300 ml of isopropanol.

6 i<.z i

TO

I

The precipitate is suctioned off, washed with isopropanol and diethyl ether and dried in a vacuum.

Yield: 29.6 g (91.4 of theory) Analysis (relative to solventless substance): Cld: C 28.08 H 7.86 N 16.38 0 6.24 Cl 41.45 Fnd: C 28.23 H 7.95 N 16.46 Cl 41.19 d) 3,6,9-Triaza-3,6,9-tris-(tert-butyloxycarbonylmethyl)-4hydroxymethyl-4-methyl-undecanedioic acid-di-tert-butyl ester 18.9 g (73.7 mmol) of the trihydrochloride produced under Example 8c) is added to a solution of 51.2 g (369 mmol) of potassium carbonate in 60 ml of water. While being stirred vigorously, 60.0 ml (369 mmol) of bromoacetic acid-tort-butyl ester, dissolved in 60 ml of tetrahydrofuran, is now added and stirred for 6 hours at 60 0 C. After the cooling, ethyl acetate and water are added and shaken out; the aqueous phase is extracted several times with ethyl acetate. The combined organic phases are dried on sodium sulfate, filtered, and the filtrate is concentrated by evaporation in a vacuum.

Yield: 52.2 g (98.8% of theory) Analysis (relative to solventless substance): Cld: C 60.23 H 9.41 N 5.85 0 24.51 Fnd: C 60.11 H 9.62 N 5.67 4 4 e) 4-Chloromethyl-4-methyl-3,6,9-tris-(tertbutyloxycarbonylmethyl)-3,6,9-triazaundecanedioic acid-ditert-butyl ester A solution of 22.3 g (31.0 mmol) of the alcohol, produced under Example 8d), in 100 ml of dichloromethane is mixed with 8.91 g (34.0 mmol) of triphenylphosphine and, after cooling to 0 C, mixed with 4.54 g (34.0 mmol) of N-chlorosuccinimide. After 2 hours of stirring at 0 C, it is stirred up with 700 ml of diethyl ether, the solid is separated and discardei. The ether phase is concentrated by evaporation, and the residue is chromatographed on silica gel 60 (Merck) with hexane/ethyl acetate 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-Triaza-4-azidomethyl-3,6,9-tris-(tertbutyloxycarbonylmethyl)-4-mothylundoanedioic acid-di-tortbutyl ester A solution of 18.6 g (25.3 mmol) of the chloride, produced under Example 8e), in 70 ml of N,N-dimethylformamide is mixed with 4.92 g (75.8 mmol) of sodium azide and stirred for 6 hours at 50°C. Then, it is concentrated by evaporation in a vacuum,

I

and the residue is dispersed between ethyl acetate and saturated sodium bicarbonate solution. After the organic phase is dried on magnesium sulfate, filtration and concentration by evaporation, a yellowish oil is obtained.

Yield: 18.2 g (97.0% of theory) Analysis (relative to solventless substance): Cld: C 58.20 H 8.95 N 11.31 0 21.73 Fnd: C 58.15 H 8.72 N 11.18 g) 4-Aminomothyl-3,6,9-triaza-3,6,9-tris-(tortbutyloxyoarbonylmothyl)-4-mothylundecanodioio aoid-di-tortbutyl oster A solution of 18.0 g (24.2 mmol) of the azlde, produced in Example 8f), in 180 ml of ethanol is vigorously shaken after 0.90 g of palladium on activated carbon (10% by weight of palladium, manufacturer Degussa) is added under hydrogen atmosphere, until no more hydrogen absorption can be observed.

Then, catalyst is filtered out, and the filtrate Is concentrated by evaporation in a vacuum.

Yield: 17.4 g (99.9% of theory) of yellowinh oil Analysis (relative to solventloen substance): Cld: C 60.31 H 9.56 N 7.82 0 22.32 Fnd: C 60.22 H 9.78 N 8.03

;F.

h) 4-(3-Aoetylamilo-2,4,6-triiodobnzoylaninoiuothyl)-3,s,9triaza-3,6,9-tris-(tort-butyloxycarboniylmothy1) -4mothylundeac~nodioic acid-di-tert-butyl, eater A soiution of' 17.2 g (24 .0 mmo] of tho ainn, prochiced under Example 8g) in 710 ml of N,N4-dimethylacotamido Is mixed with 3.99 ml (28.8 nrnoi) of triosthyamino arnd 1.1).2 qJ (26.4 mmol) of' 3-acootyltAnino-2, 4, 6-Lr11odobenfizoy I chloride (11. Pr lewe ot. alI., Chain, iBr. D1, 6531. (3,954) and ItL In ait irrod f'oi o heiri W lom tempera ture Then, I t In [Icoflcofra tee by ovaporatVi on In aa vacuum, the roe iduct in di oporned between othy aceta to and wa turnitod no1i urn bci -baronla t 1 (lo t1 antd th ole0(1 Iic r'l)(a a' Ita drfad oil nodilum aji fto. After fli nt Ion, the I I i1tt teIni concontra tad by evaporation, amid tHe n i dicuo in u ch omi V eqra phod on nil Ica rjoi 60 (Merck) with hoxano/et hy I a'etate Afterit the product V rncftlo nt aro voncontirat d by ovaplerat I en, at yol lowitih oil Ini obtniied.

Vi101(i 27.9 q)i (92.6 of 0 t hrity) AmAlyin (rel ativo to tiol Voit Immn imbit ime) Cici I C 43). 04 11 '1 il N 'M 0 '1) Pnd: C 43.*21 11 1).06 1 M0. l19 14 6)I I) 4-(3-Aootylitniflo-2,4,6-tri1odoboti~oyItifhiointothlyl)-3,6,9-= trita-3, 6, 9-tri- (arboxymthy) 4-11Lly tndu od 10 10i ehoiu 26.*6 g (21 .2 iniol of the pontactter- (enu'r Ibd' under, HxamlelI alh) la converted to the corronpond i q pent 1 avid 1(1ina(r t 111 cond it ionri donrri bed In a xamplIo 1v).

Yield: 19.5 g of light beicge solid Analysia (relative to anhydrous substance): C]IA: C 30.79 If 2.32 1 39.04 N 71.18 Na ).92 0 19.69 Fnd: C 30.98 11 2.40 1 38.84 N 7.24 Na 4.04 j) Gadolinium complox of tho dinodium nalt of 4-(3-acotylamino- 2,4, 6-triiodobonzoyl-amiflnomothyl) 9-triaza-3, 6, 9-triB- (oiarboxcyinothyi.)-4-miothy-ufldoaodi~oic acid g (1.9 .3 mmoi) of tho penLtt ac:id doncr I lid In Examp 1 1.1) Ina convor tad to tho H.it. 1 a compound m ide r tbc' cond iti Inil doocribed in Example0 1c).

Yield: 20.7 q of theory) of color-lons ,ol Id Ann I ynla ro Iat'lIVO to ctnhyd)'otin iubrit iwn): CIA C: V'.1)9 11 2.*12 Cd 13.1 '0 1 12.44 N Na' I o, 10. 16 Fnd: C 25.64 11 2.40 Gd 11.29 1 12.27 N 0.011 Na 4.04 11xa18p1 9 aadolinium complax of thm dinodium nalt of 4-(3-acotylamino- 2,4,6-triiodobontoyl-oxyotlityl3,6,9-trita-"3,6,9'Lr1[J- (carboxymo thyl) -4 -mo Llty IUndoonnod io io acid A) 4-3Aoyanlo246ti-dbnolxnoly)4ii~il 3,6,9-triEI-(tort-butyoxy-Oarboicyliotlyl)-3,6,9triazundocanodioia acid-di-tort-butyl enter A rio) tiVon or 14.7 q (20).0 mmuo I) of tho ch ima In, comipound, derwr Ibod in H.Xmfiplo fa) In 1(3 111 of 11,11 dl ;ttt y1 ilm d I 1'ill added at room temperature to a solution of' 16.9 cg (29.9 mmol) or the nodlium nai1.t of 3 -acoty Iam Ino-2, 4,6- t r IIodohon zo Ic ac I d (Wallnglord at al. J. Am. Cham. S1oc. 74, 416b (19532) in 50 nil of N, N-dimot thyl aI ectfLi do. rp)o roat. toil Ofl 1x LU ri In ttit Iirod tUoi hourni at OOOC L thn concolntrltod by Ovapor.iIon 11 n o vecuum findJ tohakon out with ethyl. acetate arid raturitod nodium blcarbonnto violIuti on. Tho orrqan in phnn In drIod on trod iuuu n fal~te, U ilbtrod atnd oncilon&Weitd by ovnipo rat .ion tho u ioun(1uo I a chcurnns- qsupled on nli m jot 60 (Marck) withi hoxnnci/dthy i attt Ari Ltt) pr'odiuct f'rnutIoino ni- c'onvont rott( hl 1 W riorupI t- Ion, 41 I I qil boeq 1(0oil P0111(11 ll.

vildi 1: l.0 (I j (11.91 W' t inity) Ann yrlr 6,("tv ioi'n't Ivo It) nIolv(olil t y oihuyoilyotr IiyI CI I I C J 4 1.0 11 r, n i l) 1t 10e ,i "1 11 4 1 (1 1u (1 'Vs UIII I')IIH)I 11,1 1d C 0 1) .l i 'I I if 11i .1I it I0 ,4.1IitI) 4 1; 11i1 qd (1 .1 q 1 o P I o n 1 "U 1 (10"C Iu Inidt "llIJ liii I Analysis (relative to anhydrous substance): Cid: C 30.76 H1 3.20 1 39.00 N 5.74 0 21.30 Fnd: C 30.81 H 3.48 1 38.90 N 5.77 c) Gadolinium complex of the disodium salt of 4-(3-acetylamino- 2,4,6-triiodobenzoyl-oxymethyl)-3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4-methylundecanedioic acid 9.26 g (9.48 mmol) of the penta acid described under Example 9b) is converted to the title compound analogously to the conditions described in Example Id).

Yield: 9.88 (88.7% of theory) of colorless solid Analysis (relative to anhydrous substance): Old: C 25.14 H 2.29 1 33.21 N 4.89 0 16.75 Gd 13.72 Na 4.01 Fnd: C 25.13 H 2.38 1 33.11 N 4.93 Gd 13.67 Na 4.1.1 Example Gadolinium complex of tlbe disodium salt of 3,6,9-triaza-3,6,9tris- (carboxymethyl) -4-methyl-4- (3-methylcarbamoyl-2, 4, 6triiodophenyloxynethyl) -undecanedicic acid a) 3,6,9-Triaza-3,6,9-tris-(tert-butyloxycarbonylmethyl)-4methyl-4- (3-methyl-carbamoyl-2, 4, 6-triiodophenyloxymethyl) undeoanedioic acid-di-tert-butyl ester A solution of 18.9 g (25.7 mmol) of the chlorine compound, described according to Example 8e), in 35 ml N,Ndimethylacetamide is added at room temperature to a solution of 16.3 g (30.8 mmol) of 3-hydroxy-2,4,6-triiodobenzoic acid-

I

methylamide Conturior, Ann. Chim II 10 (1938) 559) and 1 72 g (30.8 mmol) of potassium hydroxide in 30 ml of N,Ndimethylformamide. The reaction mixture is stirred for 8 hours at 60 0 C, then concentrated by evaporation in a vacuum, and the residue is shaken out with ethyl acetate and saturated sodium bicarbonate solution. The organic phase is dried on sodium sulfate, filtered and concentrated by evaporation, the residue is chromatographed on silica gel 60 (Merck) with hexane/ethyl acetate After the product fractions are concentrated by evaporation, a light beige oil remains.

Yield: 21.9 g (69.4% of theory) Analysis (relative to solventless substance): Cld: C 43.01 H 5.82 I 30.98 N 4.56 0 15.63 Fnd: C 43.20 H 5.97 I 30.72 N 4.60 b) 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-methyl-4-(3mothylcarbamoyl-2,4,6-triiodophenyloxymethyl)-undecanedioic acid 20.6 g (17.0 mmol) of the pentaester described in Example is converted to the corresponding penta acid under the conditions described in Example Ic).

Yield: 13.9 g (86.3% of theory) of light beige solid

I

Analysis (relative to anhydrous substance): Cld: C 30.40 H 3.30 I 40.15 N 5.91 0 20.25 Fnd: C 30.64 H 3.52 I 39.94 N 6.04 c) Gadolinium complex of the disodium salt of 3,6,9-triaza- 3,6,9-tris-(oarboxymethyl)-4-methyl-4-(3-methyloarbamoyl- 2,4,6-triiodophenyloxymethyl)-undecanedioic acid 13.2 g (13.9 mmol) of the penta acid described under Example is converted to the title compound analogously to the conditions described in Example Id).

Yield: 15.0 g (94.1% of theory) of colorless lyophilizate Analysis (relative to anhydrous substance): 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 Example 11 Gadolinium complex of the disodium salt of N,N-bis-[2-[N',N'-bis- (carboxymethyl)-amino]-ethyl]-3-acetylamino-2,4,6triiodophenylalanine a) 3-Amino-2,4,6-triiodophenylalanine, hydrochloride A solution of 32.5 g (150 mmol) of 3-aminophenylalanine hydrochloride (Jennings, J. Chem. Soc., 1957, 1512) in 300 ml of water is added in drops at 50 0 C to a mixture of 300 ml of concentrated hydrochloric acid and 240 ml of 2N potassium iodine dichloride solution in 6.0 1 of water while being stirred slowly.

After another 3.5 hours, the hot clouded solution is filtered and (7 concentrated by evaporation in a vacuum until the crystallization starts. Then, it is also well-cooled in ice, suctioned off, absorptively precipitated with water and dried on phosphorus pentoxide.

Yield: 50.7 g (67.0% of theory) of light beige solid Analysis (relative to anhydrous substance): Cld: C 18.19 H 1.70 I 64.06 N 4.71 0 5.38 Cl 5.97 Fnd: C 18.38 H 1.94 I 63.82 N 4.83 C1 6.11 b) 3-Amino-2,4,6-triiodophenylalaninethylester hydrochloride 30.8 g (51.8 mmol) of the amino acid produced according to Example lla) is refluxed in a mixture of 150 ml of ethanol and 4.1 ml (57 mmol) of thionyl chloride for 10 minutes, then stirred for 12 hours at room temperature. The batch is then concentrated by evaporation, and the residue is dried in a vacuum.

Yield: 32.3 g (100% of theory) of light beige solid Analysis (relative to anhydrous substance): Cld: C 21.23 H 2.27 I 61.17 N 4.50 0 5.14 Cl 5.70 Fnd: C 21.44 H 2.38 I 60.93 N 4.62 Cl 5.89 c) N,N-Bis-[2-[N',N'-bis-[(benzyloxycarbonyl)-methyl]-amino]ethyl]-3-amino-2,4,6-triiodophenylalaninethylester 20.4 g (32.7 mmol) of the amine produced according to Example 11b) and 31.0 g (73.7 mmol) of N,N-bis- [(benzyloxycarbonyl)-methyl]-2-bromomethylamine Williams and I H. Rapoport, J. Org. Chem. 58, 1151 (1993)) are introduced in ml of acetonitrile and mixed with 20 ml of 2N phosphate buffer solution (pH 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 The productcontaining fractions are concentrated by evaporation in a vacuum.

Yield: 25.8 g (62.3% 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-Bis-[2-[N',N'-bis-[(benzyloxycarbonyl)-methyl]-amino]ethyl]-3-acetylamino-2,4,6-triiodophenylalaninethylester 13.7 g (10.8 mmol) of the compound described in Example llc) is dissolved in 30 ml of N,N-dimethylacetamide, and after 1.80 ml (13.0 mmol) of triethylamine zu.: 0.85 ml (11.9 mmol) of acetyl chloride are added, it is stirred for 12 hours at room temperature with exclusion of moisture. Then, it is concentrated by evaporation in a vacuum, and the residue is dispersed between ethyl acetate and sodium bicarbonate solution. The organic phase is dried on sodium sulfate, filtered and concentrated by evaporation.

Yield: 13.8 g (97.6% of theory) of yellowish oil v i.

I

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-Bis-[2-[N',N'-bis-(carboxymethyl)-amino]-ethyl]-3acetylamino-2,4,6-triiodophenylalanine 12.8 g (9.80 mmol) of the pentaester described in Example lid) is dissolved in 75 ml of methanol and mixed with 49 ml of 2N sodium hydroxide solution. It is refluxed for about 2 hours, and the methanol is drawn off in a vacuum. By adjusting to pH 1-2 with semiconcentrated hydrochloric acid, a colorless precipitate results, which is suctioned off and dried in a vacuum.

Yield: 7.80 g (86.7% of theory) Analysis (relative to anhydrous substance): 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) Gadolinium complex of the disodium salt of N,N-bis-[2- [N',N'-bis-(carboxymethyl)-amino]-ethyl]-3-acetylamino- 2,4,6-triiodophenylalanine 7.42 g (8.08 mmol) of the penta acid described in Example lie) is converted to the title compound analogously to the conditions described in Example id).

Yield: 8.72 g (96.7% of theory)

M

Analysis (relative to anhydrous substance): Cld: C 24.75 H 2.17 Gd 14.07 I 34.10 N 5.02 Na 4.12 0 15.76 Fnd: C 24.64 H 2.38 Gd 13.83 I 33.94 N 5.08 Na 3.89 Example 12 2-(3-Acetamido-2,4,6-triiodobenzyl)-3,6,9-triaza-3,6,9-tris- (carboxymethyl)-undecanedioic acid, gadolinium complex, disodium salt a) 3,6,9-Triaza-3,6,9-tris-(methoxycarbonylmethyl)undecanedioic acid methyl ester (JOC 55, 2868, 1990) 20.6 g (52.4 mmol) of diethylenetriaminepentaacetic acid in 618 ml of methanol is introduced at 0 C and mixed drop by drop with 38.2 ml (0.524 mol) of thionyl chloride within 30 minutes.

Then, the reaction mixture is stirred for 16 hours at room temperature. After the reaction is completed, it is concentrated by evaporation on a rotary evaporator, and the whitish solid is suspended in 300 ml of diethyl ether. The suspension is mixed at 0 C with 200 ml of saturated sodium bicarbonate solution, the organic phase is separated, and the aqueous phase is extracted three times with 100 ml each of diethyl ether. The extract is dried on potassium carbonate and evaporated to dryness after filtration. The product is dried overnight in a vacuum on phosphorus pentoxide.

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

I L fti j^ 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-Triaza-3,6,9-tris-(methoxycarbonylmethyl)-2-(3nitrobenzyl)-undecanedioic acid dimethyl ester 6.64 ml (47.3 mmol) of diisopropylamine in 200 ml of anhydrous tetrahydrofuran is introduced in a light argon stream at 0 C and mixed drop by drop with 22.2 ml (52 mmol) of butyllithium (15% in hexane) within 15 minutes. Then, it is cooled to -78 0 C, and 18.4 g (40 mmol) of pentaester (Example 12a) dissolved in 300 ml of anhydrous tetrahydrofuran is added in portions to it. After 30 minutes of stirring at this temperature, a solution of 8.11 g (47.3 mmol) of 3-nitrobenzyl chloride and 1.38 ml (11.44 mmol) of 1,3-dimethyl-3,4,5,6tetrahydro-2(1H)-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 ml of ice water. The organic phase is separated, and the aqueous phase is extracted three times with 75 ml of ethyl acetate each.

The combined organic phases are dried on potassium carbonate, filtered and evaporated to dryness. To purify the crude product, the substance is chromatographed on silica gel 60 (Merck).

Yield: 13.2 g (55% of theory) of pale yellow oil.

*T<

^e Y C: Elementary analysis (taking into consideration the solvent content): Cld: C 52.37 H 6.40 N 9.36 0 32.07 Fnd: C 52.01 H 6.23 N 9.48 c) 2-(3-Aminobenzyl)-3,6,9-triaza-3,6,9-tris- (methoxycarbonylmethyl)-undecanedioic acid dimethyl ester A methanolic solution of 12.7 g (21.2 mmol) of the nitro compound of Example 12b) is hydrogenated at room temperature with the addition of 1.35 g of palladium on carbon 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-Aminobonzyl)-3,6,9-triaza-3,6,9-tria-(carboxymothyl)undecanedioic acid 10.8 g (19 mmol) of the pentaester of Example 12c) is saponified with 60 ml of 2N sodium hydroxide solution at 40 0

C.

After the reaction is completed, the solution is mixed with concentrated hydrochloric acid until the acid is completely precipitated. The precipitate is suctioned off and washed neutral with water. The product is dried overnight at 50 0 C in a vacuum.

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

K Elementary analysis (taking into consideration the solvent content): Cld: C 47.15 H 5.84 Cl 6.63 N 10.47 0 29.91 Fnd: C 47.04 H 6.12 Cl 6.35 N 10.59 e) 2-(3-Amino-2,4,6-triiodobenzyl)-3,6,9-triaza-3,6,9-tris- (carboxymethyl)-undecanedioic acid 9.55 g (18 mmol) of pentacarboxylic acid (Example 12d) is suspended in 50 ml of water and mixed drop by drop with 22.8 ml (56.4 mmol) of a hydrochloric acid 40% iodomonochloride solution.

The reaction mixture is allowed to stir for 16 hours at 65 0 C, and the iodine excess is reduced with diluted sodium disulfite solution. The settled precipitate is suctioned off and rewashed with water. The dried solid is taken up in concentrated ammonia solution, filtered and precipitated with concentrated hydrochloric acid. The precipitate is washed until neutrality of the wash water is reached. The product is dried for 18 hours at 0 C in a vacuum until a constant weight is reached.

Yield: 13.1 g (83% of theory) of light yellow solid.

Elementary analysis (taking into consideration the solvent content): Cld: C 28.79 H 3.11 I 43.45 N 6.39 0 18.26 Fnd: C 28.93 H 3.37 I 43.32 N 6.48 f) 2-(3-Acotylamino-2,4,6-triiodobonzyl)-3,6,9-tria- (carboxyinmthyl)-3,6,9-triazaundecanedioic acid 12.7 g (14.5 mmol) of triiodoaniline of Example 12e) is dissolved 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 auctioned off, washed with water and dried at 50"C in a vacuum.

Yield: 11.55 g (87% of theory) of colorless solid.

Elementary analysis (taking into consideration the solvent content): Cld: C 30.09 11 3.18 1 41.46 0. 10 0 19. 1 End: C 29.88 II 3.26 1 41.29 N 6.02 g) 2-(3-Aootamido-2,4,6-triiodobonzyl)-3,6,9-triaza-3,6,9-tria- (oarboxymothyl)-undocanodioio acid, gadolinium complox, disodium salt 11.2 g (12.2 mmol) of complexing aqent of Example 12f) is reacted according to the method of Example 4d) wiltl cjadol nium oxide at 50 0 C. After the comploxing is completed, Lth intermediate product is converted to disodlum salt with IN sodium hydroxide solution. The resulting solution is purified with 1.2 g of activated carbon, filtered with a 0.2 sim membrane-cellulose filter and then freeze-dried.

Yield: 12.6 g (92.5% of theory) of colorless lyophilizate.

I Elementary analysis (takingj int~o consideration the solvent content): Cid: C 24.75 H 2.17 Gd 14.09 1 34.10 N b.02 Na 4.12 0 15.76 Fnd C 24.89 If 2.23 Gd 13.881 1 34.02 N 4.117 Na 4.01 Example 13 Gadolinium complex of tho disodium salt of 3,6,9-triaza-3,6,9dihiydroxypropyl) 5-dioarbarnoyl-2, 4, 6triiodophonylonrbaniioylmothioxy] -boiwyi) -undocanodioic acid a) N,O-fin-(bonzyloxyoarbonyl)-3-hiydroxyphionylalanino-N-[2- (bon?.yloxyoarbonylainino) -othiyl -ainiido 1.60.54 q (375 mmol of N,O--hbIi- (hty Ioxy('diil)ofil 1 hydroxyphnny i a an ino do CtAtt iqli onrl, lmion n (a i.('Im.1.1 97, IWO) (1967)) Ili dl rinol vod Ini 1. 1 of Itit valayct oif titfian and 00010(1 Lo 00C. Af't- ml.8 an anaol ofl tj lot by in lnt, fIn aiddod, 36.7 111 (M)8111111l ot oh11o, of ol nab no orl btyl i ni ol its added In drops After 20 ml nuo e, 71). 8 q ('190 mmo I) of bonzyloxycarbonyl.- (2-am.i noot iy 1) -a i do(] (G AtwolII, W. Dvnny, Hyntheal ,12-13J (1984)) In lii wl of a aihydi ol-tioan ill adl(It' Aftor at irr'I nq ovott n Iht, t.ho r-ono It ill pa o ip It aIo ints a' wiloaird off, the 1711t rato ina convont rat on by ovapoirat Ion and] dliv 1inl a vacuum.

Yield: 183.7 q (.1%of thoory) of colorloonn nol Id.

Analysis (relative to solventless substance): Cid: C 67.19 H1 5.64 N 6.72 0 20.46 End: C 67.07 It 5.78 N 6.84 b) 3-llydroxyphonylalanina- (2-aminoothyl) -amide 62.57 g (100 mmol) of tile compound described in Example 13a) is suspended in 1.5 1 of methanol and after 6.3 q of palladium on carbon 10% by weight of palladi um, I)eg(uina.i) In added, it Ina hyd rogena ted w it h hyd roqo fiat normal p et im roe. Then it I a flItered tile iltra to in1 concent rated by ('vaporaic .1oi, iAnd Lhe residue In aboorptivlyeIy proc ip1 tat ed Ina dl intopropyl I ivr AfItoer riuctioni nc off andi dry i n In 41 Variuum, I en Ior otI. noaitO In I~ obtained.

Y bid 21 .4 q(1~.3 of I henry) Ati Iya Iii (io' i II e o n I m vidi Iw i m. rillf-l ,ii r' Pnd: C ).211 If 7.11 N 111.14 v) 1, 5-Diainino-3-LV/.-2- (3-oiiioxybonzyl )-pont ano, trihydroohiori do 1 q (90 mmol of the comim)ufld dvlir I bed in Exaiup eI 11b)) In taken up In 13b ml of tetrahlydrofuran anid mixed drop) by drop at 0 0 C under argon with 1810 ml of 1 in boron hydrido nolution in tetrahlydrofuran. After 30 minutes of stirring at O'c, stirring is continued for 120 hours at 60 0 C. After the cooling, 100 ml of methanol in added in drops, thle reaction mixture is aturated with hydrogen chloride, and the resulting acid suspension is stirred for 6 hours. Then, the precipitate is suctioned off and dried at 50 0 C in a vacuum.

Yield: 25.0 g of colorless solid Analysis (relative 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-Triaza-4-(3-hydroxybenzyl)-3,6,9-tris-(tertbutoxycarbonylmethyl)-undecanedioic acid-di-tert-butyl ester 15.1 g (47.4 mmol) of the compound described in Example 13c) is suspended in 500 ml of tetrahydrofuran and mixed with 25 ml of water and 34.5 g (249 mmol) of potassium carbonate. After 52.3 ml (356 mmol) of bromoacetic acid-tert-butyl ester is added in drops, it is stirred for 3 days at 60 0 C. After the cooling, it is filtered, concentrated by evaporation in a vacuum, and the residue is chromatographed on silica gel with diethyl ether/hexane/triethylamine (70:20:5). The product fractions are concentrated by evaporation in a vacuum.

Yield: 27.2 g (73.3% of theory) of yellowish oil Analysis (relative to solventless substance): Cld: C 63.13 H P.92 N 5.39 0 22.56 Fnd: C 63.24 H 8.8P N 5.43 jsr s.

^Irz ipFi^C e) 5-Chloroacetylamino-2,4,6-triiodoisophthalic acid-[N,N'dimethyl-N,N'-bis-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)

J-

diamide 81.0 g (100 mmcl) of 5-chloroacetylamino-2,4,6triiodoisophthalic acid-N,N'-dimethyl-N,N'-bis-(2,3dihydroxypropyl)-diamide (DE 2928417) is introduced in 500 ml of tetrahydrofuran and mixed with 0.95 g (5.0 mmol) of ptoluenesulfonic acid monohydrate and 22.9 g (220 mmol) of 2,2dimethoxypropane. Then, it is ref luxed for 12 hours, concentrated by evaporation in a vacuum, and the residue is dispersed between ethyl acetate and soCi bicarbonate solution.

The organic phase is dried on magnesium tuifate and filtered, concentrated by evaporation, and the residue is absorptively pre-ipitated with tert-butyl methyl ether. After filtering, the residue is dried in a vacuum.

Yield: 79.7 g (89.6% of theory) of colorless solid Analysis (relative to solventless substance): Cld: C 32.40 11 3.51 Cl 3.99 1 42.79 N 4.72 0 12.59 Fnd: C 32.38 H 3.62 Cl 4.04 1 42.70 N 4.63 f) 3,6,9-Triaza-3,6,9-tris-(tertL--butoxycarbofylmethyl)4[3- [N,Nf-dimethyl-N;N'-bis-(2,2-dimethyl-1,3-dioxola'4ylmethyl) 5-dicarbamoyl-2, 4, 6-triiodophenyl-carbamoylmethoxy] -benzyl] -undecanedioic acid-di-tert-butyl ester 12.8 g (16.4 mmrol) of the hydroxy co~mpound described in Example 13d) is dissolved in 50 ml cof N,N-dimethylformamide under argon and mixed with 0.59 g (19.7 mmol) of 80% sodium hydride suspension in mineral oil. After 30 minutes of stirring at room temperature, 19.0 g mmol) of the compound described in Example 13e) is added, and the batch is allowed to stir for 12 hours at 500C. Then, it is concentrated by evaporation in a vacuum, and the residue is chromatographed on silica gel (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'-dimethyl- N,N'-bis-(2,3-dihydroxypropyl)-3,5-dicarbamoyl-2,4,6triiodophenylcarbamoylmethoxy]-benzyl]-undecanedioic acid 16.1 g (9.86 mmol) of the compound described in Example 13f) is freed of all protective groups under the conditions described in Example Ic) 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 1 JA

U

^TO

h) Gadolinium complex of the disodium salt of 3,6,9-triaza- 3,6,9-tris-(carboxymethyl)-4-[3-[N,N'-dimethyl-N,N'-bis- (2,3-dihydroxypropyl)-3,5-dicarbamoyl-2,4,6-triiodophenylcarbamoylmethoxy]-benzyl]-undecanedioic acid 11.9 g (9.35 mmol) of the penta acid described under Example 13g is converted to the title compound analogously to the conditions described in Example Id).

Yield: 13.1 g (95.5% of theory) of colorless lyophilizate Analysis (relative to anhydrous substance): 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 I 25.76 N 5.73 Gd 10.58 Na 3.20 Example 14 Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9tris-(carboxymethyl)-4-(3-methoxy-2,4,6-triiodobenzyl)undecanedioic acid a) 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-(3-hydroxybenzyl)undecanedioic acid 13.2 g (16.9 mmol) of the compound described in Example 13d) is converted to the corresponding penta acid under the conditions described in Example 1c).

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 9.

b) 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-(3-hydroxy-2,4,6triiodobenzyl)-undecanedioic acid 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 (84.8% 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-Triaza-3,6,9-tris-(carboxymethyl)-4-(3-methoxy-2,4,6triiodobenzyl)-undecanedioic acid 11.6 g (13.2 mmol) of the compound described in Example 14b) is mixed in 60 ml of tetrahydrofuran at 0 C with 2.77 g (92.6 mmol) of 80% sodium hydride suspension in mineral oil. 13.1 g (92.6 mmol) of iodomethane is added to it and stirred for minutes. Then, the solution is mixed with 60 ml of 2N sodium hydroxide solution and refluxed for 30 minutes. After the cooling, the organic solvent is drawn off in a vacuum, and the remaining aqueous solution is adjusted to pH 1.5 with k ^^jei ^A y I I- concentrated hydrochloric acid. A precipitate precipitates, which is suctioned off and dried in a vacuum.

Yield: 10.7 g (91.4% of theory) Analysis (relative to anhydrous substance): Cld: C 29.65 H 3.17 I 42.72 N 4.72 0 19.75 Fnd: C 29.74 H 3.23 I 42.65 N 4.63 d) Gadolinium complex of the disodium salt of 3,6,9-triaza- 3,6,9-tris-(carboxymethyl)-4-(3-methoxy-2,4,6triiodobenzyl)-undecanedioic acid 10.2 g (11.4 mmol) of the penta acid described in Example 14c) is converted to the title compound as described in Example Id).

Yield: 11.7 g (94.0% of theory) of colorless lyophilizate Analysis (relative to anhydrous substance): 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 Example Gadolinium complex of the disodium salt of 3,6,9-triaza-4-(3diethylcarbamoyl-2,4,6-triiodophenylcarbamoyloxymethyl)-3,6,9tris-(carboxymethyl)-undecanedioic acid a) 3-Isocyanato-2,4,6-triiodobenzoic acid diethylamide 57.00 g (100.0 mmol) of 3-amino-2,4,6-triiodobenzoic acid diethylamide (CA 54, P 20987i (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 60 0 C and then evaporated to dryness.

Yield: 59.60 g (100.0% 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) 4-(3-Diethylcarbamoyl-2,4,6triiodophenylcarbamoyloxymethyl)-3,6,9-tris-(tertbutyloxycarbonylmethyl)-3,6,9-triazaundecanedioic acid-ditert-butyl ester A solution of 14.68 g (20.85 mmol) of 3,6,9-triaza-3,6,9tris-(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. Then, it is completely concentrated by evaporation, and the residue is chromatographed on silica gel (eluant: hexane/ethyl acetate). After the fractions containing the product are concentrated by evaporation, a yellowish oil is obtained as residue.

Yield: 24.29 g (89.6% of theory) s L II 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-2,4,6triiodophenylcarbamoyloxymethyl)-3,6,9-tris-(carboxymethyl)undecanedioic acid 21.62 g (16.63 mmol) of the pentaester described in Example is converted to the corresponding penta acid under the conditions described in Example Ic).

Yield: 16.17 g (95.4% 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) Gadolinium complex of the disodium salt of 3,6,9-triaza-4- (3-diethylcarbamoyl-2,4,6-triiodophenylcarbamoyloxymethyl)- 3,6,9-tris-(carboxymethyl)-undecanedioic acid 15.52 g (15.22 mmol) of the penta acid described in Example is converted to the title compound as described in Example Id).

Yield: 17.44 g (94.1% of theory) of colorless lyophilizate Analysis (relative to anhydrous substance): 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 r 111 Example 16 Gadolinium complex of the disodium salt o~f 3,6,9-tria2za-3,6,9tris- (carboxymethyl) (N-carboxymethyl-3-methylamino-2, 4, 6triiodophenylureylenemethyl) -4-methylundecanedioic acid a) 3-Isocyanato-2, 4, 6-triiodobenzoic acid-N- (ethoxycarbonylmethyl) -methylamide 61.40 g (100.0 mmol) of~ 3-amino-2,4,6-triiodobenzoic acid-N- (ethoxycarbonylmethyl)-methylamide (CA 54 P 20987i (1960)) is mixed under nitrogen atmosphere at room temperature with 250 ml of 2N toluenic phosgene solution. After 0.5 ml of N,Ndimethylformamide is added, the batch is allowed to stir for hours at 60 0 C 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 1 59.49 N 4.38 0 10.00 Fnd: C 24.37 H 1.82 1 59.53 N 4.26 b) 3,6,9-Triaza-3,6,9-tris-(tert-butyloxycarbonylmethyl)-4-(Nethoxycarbonylmethyl-3-methylamino-2, 4, 6triiodophenylureylenemethyl) -4-methylundecanedioic acid-ditert-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 mmcd) of the isocyanate described in Example 16a) and stirred overnight at room temperature. Then, it is completely concentrated by 'Ad 0 evaporation, and the residue is chromatographed on silica gel (eluant hexane/ethyl acetate). After the fractions containing the product are concentrated by evaporation, a yellowish oil is obtained as residue.

Yield: 27.39 g (88.2% of theory) Analysis (relative to solventless substance): 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-Triaza-3,6,9-tris-(carboxymethyl)-4-(N-carboxymethyl- 3-methylamino-2,4,6-triiodophenylureylenemethyl)-4methylundecanedioic acid 26.68 g (19.66 mmol) of the hexaester described in Example 16b) is converted to the corresponding hexa acid under the conditions described in Example 3c).

Yield: 19.19 g (93.1% of theory) of colorless solid Analysis (relative to 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 d) Gadolinium complex of the disodium salt of 3,6,9-triaza- 3,6, 9-tris- (carboxymethyl) (N-carboxymethyl-3-methylamilo- 2,4, 6-triiodophenyl-ureylenemethyl) -4-methylundecanedioic acid 24.32 g (23.19 mmol) of the penta acid described in Example 16c) is converted to the title compound as described in Example id) Yield: 27.84 (94.6% of theory) of colorless lyophilizate Analysis (relative to anhydrous substance): Cld: C 25.57 H 2.30 1 30.01 N 6.63 0 17.66 Gd 12.40 Na 5.44 Fnd: C 25.62 H 2.34 1 29.94 N 6.58 Gd 12.35 Na 5.38 Example 17 comparison test: isomer to Example 1 of WO 93/16375 1,13-Bis[5-(propion-3-ylamidoJ-2,4,6-triiodoisophthalic acidbis (2-hydroxy-l-hydroxymethylethyl) -diamide] -4,7,10tris(carboxymethyl)-2,12-dioxo)-1,4,7,10,13-petaazatridcane, gadolinium complex a) 1,13-Bis[5-(propion-3-yla1UidoJ-2,4,6-triiodoisophthalic acid-bis(2-hydroxy-l-hydroxymethylethyl) -diamide]-4,7, tris(carboxymethyl)-2,12-dioxo)-1,4,7,1O,1 3 pentaazatridecane 16.5 g (21.2 mniol) of 5-(3-aminopropionamido)-2,4,6triiodoisophthalic acid-bis(2-hydroxy-l-hydroxymhethylethyl) diamide is dissolved at 120 0 C bath temperature in 82.5 ml of DM7.

It is mixed 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 stirred with 200 ml of ethanol for two hours at room temperature, suctioned off and dried at 50 0 C in a vacuum. Then, the residue is taken up in a little water and chromatographed on silica gGl RP 18 (eluant: water/methanol). After the product fractions are concentrated by evaporation, the title compound is obtained as a colorless solid.

Yield: 17.24 g (42% of theory) Analysis (relative to anhydrous substance): Cld: C 30.19 H 3.43 I 39.88 N 8.07 0 18.43 Fnd: C 29.88 H 3.30 I 40.21 N 7.95 b) 1,13-Bis[5-(propion-3-ylamido]-2,4,6-triiodoisophthalic acid-bis(2-hydroxy-l-hydroxymethylethyl)-diamide]-4,7,10tris(carboxymethyl)-2,12-dioxo)-1,4, 7 ,10, 13 pentaazatridecane, gadolinium complex 400 mg of the compound described in Example 17a) is mixed in portions with 17.8 ml of a 0.01 molar gadolinium acetate solution. The pH is moved with triethylamine into the neutral range, and the aqueous solution is stirred for one hour at room temperature with activated carbon. After filtration and freezedrying, the gadolinium complex is obtained as a colorless solid.

-I

Yield: 145 mg (30.5% of theory) Analysis (relative to anhydrous substance): Cld: C 27.91 H 3.03 I 36.90 N 7.47 0 17.06 Gd 7.62 Fnd: C 27.77 H 2.99 I 36.72 N 7.15 Gd 7.38 Example 18 Gadolinium complex of 3,6,9-triaza-3,6,9-tris-(carboxymethyl)-4- (3-iodo-4-ethoxybenzyl)-undecanedioic acid, disodium salt a) N-Benzyloxycarbonyl-3-(4-ethoxyphenyl)-2-aminopropanol 31.8 g (84'.4 mmol) of sodium borohydride is added to a solution of 221.41 g (605.9 mmol) of N-benzyloxycarbonyl-0ethyltyrosine methyl ester in 1.5 1 of tetrahydrofuran at room temperature. 279 ml of methanol is added to it in drops within two hours while being stirred. Then, the tetrahydrofuran is distilled off in a vacuum, the residue is taken up in 1 1 of water and extracted three times with 700 ml of ethyl acetate.

The combined organic phase is washed with water, dried with sodium sulfate and concentrated. It is recrystallized from ethyl acetate/hexane.

Yield: 187.0 g (93.7% of theory) Analysis (relative to solventless substance): Cld: C 69.28 H 7.04 N 4.25 0 19.43 Fnd: C 69.11 H 7.20 N 4.13 i b) 1-Acetoxy-N-benzyloxycarbonyl-3-(3-iodo-4-ethoxyphenyl)-2aminopropane 29.4 g (89.3 mmol) of N-benzyloxycarbonyl-3-(4ethoxyphenyl)-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 workingup. 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 crystallized.

Yield: 34.5 g (77.7% of theory) Analysis (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-Benzyloxycarbonyl-3-(3-iodo-4-ethoxyphenyl)-2aminopropanol 29.8 g (60 mmol) of l-acetoxy-N-benzyloxycarbonyl-3-(3-iodo- 4-ethoxyphenyl)-2-aminopropane is suspended in 150 ml of methanol and mixed at room temperature with 4.94 g (60 mmol) of anhydrous sodium acetate. The batch is stirred for 6 hours at evaporated to dryness and the residue is taken up in ethyl acetate. The precipitated salt is suctioned off, washed with ll\ I' A v \v"n ,c I_ I ethyl acetate, and the filtrate is concentrated by evaporation.

The viscous oil obtained is used in the next stage without further purific 'tion.

Yield: 27.3 g (100% of theory) d) 1-Methanesulfonyloxy-N-benzyloxycarbonyl-3-(3-iodo-4ethoxyphenyl)-2-aminopropane 26.5 g (58 mmol) of N-benzyloxycarbonyl-3-(3-iodo-4ethoxyphenyl)-2-aminopropanol is dissolved in 130 ml of dichloromethane, mixed with 24.1 ml of triethylamine and brought to reactionr at 0 0 C with 6.78 ml (87 mmol) of methanesulfonic acid chloride. After 30 minutes at room temperature, no more initial material can be detected according to TLC. The batch is diluted with dichloromethane and washed with sodium bicarbonate and with water. After the organic phase is dried, the solvent is evaporated, and the product is obtained as pale yellow oil.

Yield: 30.. 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-Benzyloxycarbonyl-1-(3-iodo-4-ethoxybenzyl)-N'-(2aminoethyl)ethylenediamine 28.2 g (53 mmol) of l-methanesulfonyloxy-Nbenzyloxycarbonyl-3-(3-iodo-4-ethoxyphenyl)-2-aminopropane is dissolved at room temperature in 140 ml of tetrahydrofuran and Tel F4il 7- 0Z V TO mixed with 143 ml (2.12 mol) of ethylenediamine. After 22 hours of stirring, the batch is concentrated by evaporation to an oil, and the residue is dissolved in ethyl acetate. It is washed neutral with water and the organic phase is dried on sodium sulfate. After concentration by evaporation, a yellow oil is obtained.

Yield: 25.9 g (98% of theory) Analysis (relative to solventless substance): 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-ethoxybenzyl)-N'-(2-aminoethyl)ethylenediamine, trihydrobromide g (50 mmol) of N-benzyloxycarbonyl-1-(3-iodo-4ethoxybenzyl)-N'-(2-aminoethyl)-ethylenediamine is suspended at room temperature in 20 ml of glacial acetic acid and mixed with 61.1 ml (250 mmol) of 33% hydrobromic acid in glacial acetic acid. After 40 hours at room temperature, the feedstock is completely consumed. The reaction mixture is concentrated by evaporation in an oil pump vacuum, and the residue is subsequently distilled three times with toluene. The solid is mixed with water and evaporated to dryness. To remove residual traces of water, the residue is concentrated by evaporation three times with dichloromethane. The crude product is recrystallized from ethanol.

Yield: 24.6 (81.2% of theory) of colorless crystals.

I

Analysis (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) 4-(3-Iodo-4-ethoxybenzyl)-3,6,9-tris(tertbutoxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dioic acid, di-(tert-butyl)-ester 23.2 g (38.3 mmol) of l-(3-iodo-4-ethoxybenzyl)-N'-(2aminoethyl)ethylenediamine, trihydrobromide is suspended in 450 ml of tetrahydrofuran and mixed drop by drop with 43.6 g (316 mmol) of potassium carbonate and 18 ml of water, as well as with 42.13 ml (287.2 mmol) of bromoacetic acid-tert-butyl ester. It is stirred for 10 hours at 60 0 C and then overnight at room temperature. The salt is suctioned off, washed with tetrahydrofuran, and the filtrate is concentrated by evaporation.

The crude product is purified using a silica gel column (mobile solvent: dichloromethane/methanol).

Yield: 34.6 g (96.7% of theory) Analysis (relative to solventless substance): 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 II I h) 4-(3-Iodo-4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)- 3,6,9-triazaundecane-l,ll-dioic acid, gadolinium complex, disodium salt 17.6 g (18.8 mmol) of 4-(3-iodo-4-ethoxybenzyl)-3,6,9tris(tert-butoxycarbonylmethyl)-3,6,9-triazaundecane-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 60 0 C, evaporated to dryness and subsequently distilled twice with water. The residue is taken up in 180 ml of water and adjusted to pH 2.9 with acid ion exchanger. 3.41 g (9.4 mmol) of gadolinium oxide is added, and the reaction mixture is heated to 0 C. After the complexing is completed, it is adjusted to pH 7.2 with cation exchanger (Na* form), and the clear solution is freeze-dried.

Yield: 14.75 g (92% of theory) Analysis (relative to anhydrous substance): 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 I' c- Example 19 Gadolinium complex of 3,6,9-triaza-3,6,9-tris-(carboxymethyl)-4- (3-bromo-4-ethoxybenzyl)-undecanedioic acid, disodium salt a) l-Acetoxy-N-benzyloxycarbonyl-3-(3-bromo-4-ethoxyphenyl)-2aminopropane 20.0 g (61 mmol) of the title compound of Example 18a is dissolved in 200 ml of glacial acetic acid and mixed with 0.2 g of iron powder. After the reaction solution is cooled to 10 0

C,

it is mixed at this temperature drop by drop with 12.48 g (78 mmol) of bromine. The reaction mixture is allowed to stir overnight at room temperature, and it is poured into 750 ml of ice water for working-up. The aqueous phase is extracted several times with ethyl acetate, the organic phase is washed with water, sodium bicarbonate solution and sodium bisulfite solution and then dried on sodium sulfate. After the solvent is evaporated, yellowish-colored crystals are obtained.

Yield: 19.50 g (71.0% of theory) Analysis (relative to solventless substance): 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-Benzyloxycarbonyl-3-(3-bromo-4-ethoxyphenyl)-2aminopropanol 18.0 g (39.8 mmol) of 1-acetoxy-N-benzyloxycarbonyl-3-(3bromo-4-ethoxyphenyl)-2-aminopropane is suspended in 100 ml of methanol and mixed at room temperature with 3.30 g (40 mmol) of

-M

anhydrous sodium acetate. The batch is stirred for 6 hours at 0 C, evaporated to dryness, and the residue is taken up in ethyl acetate. The precipitated salt is suctioned off, washed with ethyl acetate, and the filtrate is concentrated by evaporation.

The viscous oil obtained is used in the next stage without further purification.

Yield: 16.0 g (98.2% of theory) c) l-Methanesulfonyloxy-N-benzyloxycarbonyl-3-(3-bromo-4ethoxyphenyl)-2-amiiopropane 15.5 g (38 mmol) of N-benzyloxycarbonyl-3-(3-bromo-4ethoxyphenyl)-2-aminopropanol is dissolved in 100 ml of dichloromethane, mixed with 6.3 ml (45 mmol) of triethylamine and brought to reaction at 0 C with 5.04 ml (52 mmol) of methanesulfonic acid chloride. After 30 minutes at room temperature, no more initial material can be detected according to TLC. The batch is diluted with dichloromethane, washed with sodium bicarbonate and with water. After the organic phase is dried, the solvent is evaporated, and the product is obtained as pale yellow oil.

Yield: 18.1 g (98% of theory) Analysis (relative to solventless substance): 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 d) N-Benzyloxycarbonyl-1-(3-bromo-4-ethoxybenzyl)-N'-(2aminoethyl)ethylenediamine 17.0 g (34.9 mmol) of l-methanesulfonyloxy-Nbenzyloxycarbonyl-3-(3-bromo-4-ethoxyphenyl)-2-aminopropane is dissolved at room temperature in 100 ml of tetrahydrofuran and mixed with 100 ml (1.48 mol) of ethylenediamine. After 36 hours of stirring, the batch is concentrated by evaporation to an oil, and the residue is dissolved in ethyl acetate. It is washed neutral with water, and the organic phase is dried on sodium sulfate. After concentration by evaporation, a yellow oil is obtained.

Yield: 14.9 g (95% of theory) Analysis (relative to solventless substance): 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) l-(3-Bromo-4-ethoxybenzyl)-N'-(2-aminoethyl)ethylenediamine, trihydrobromide 14 g (31 mmol) of N-benzyloxycarbonyl-l-(3-bromo-4ethoxybenzyl)-N'-(2-aminoethyl)ethylenediamine is suspended at room temperature in 39.1 ml (160 mmol) of glacial acetic acid, and it is mixed with 39.1 ml (160 mmol) of 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 is subsequently distilled three times with toluene. The I -I solid is mixed with water and evaporated to dryness. To remove residual traces of water, the residue is concentrated by evaporation three times with dichloromethane. The crude product is recrystallized from ethanol.

Yield: 16.0 g (92.4% of theory) of colorless crystals Analysis (relative to solventless substance): 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-tris(tertbutoxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dioic acid, di-(tert-butyl)-ester 15.0 g (26.8 mmol) of l-(3-bromo-4-ethoxybenzyl)-N'-(2aminoethyl)ethylenediamine, trihydrobromid is suspended in 400 ml of tetrahydrofuran, and it is mixed drop by drop with 29.6 g (215 mmol) of potassium carbonate and 15 ml of water, as well as with 36.67 ml (250 mmol) of bromoacetic acid-tert-butyl ester.

It is stirred for 12 hours at 60 0 C and then overnight at room temperature. The salt is suctioned off, washed with tetrahydrofuran, and the filtrate is concentrated by evaporation.

The crude product is purified using a silica gel column (mobile solvent: dichloromethane/methanol).

Yield: 22.4 g (94.2% of theory) I I Analysis (relative to solventless substance): Cld: C 58.23 H 8.18 Br 9.01 N 4.74 Fnd: C 58.19 H 8.12 Br 8.96 N 4.70 g) 4-(3-Bromo-4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)- 3,6,9-triazaundecane-l,11-dioic acid 20.0 g (22.5 mmol) of 4-(3-bromo-4-ethoxybenzyl)-3,6,9tris(tert-butoxycarbonylmethyl)-3,6,9-triazaundecane-l,ll-dioic acid, di-(tert-butyl)-ester is dissolved in a mixture of 400 ml of tetrahydrofuran and 40 ml of water, and it is mixed drop by drop at room temperature with a solution of 6.4 g (160.8 mmol) of sodium hydroxide in 20 ml of water. After a reaction time of 48 hours at room temperature, the reaction mixture is concentrated by evaporation in a vacuum, and the residue is subsequently distilled twice with water. The remaining residue is taken up in 300 ml of water and adjusted to pH 2.0 with cation exchanger (H' form). After freeze-drying, the filtrate obtained after the suctioning-off from the ion exchanger yields the pentacarboxylic acid as colorless powder.

Yield: 11.3 g (83% of theory) Analysis (relative to anhydrous substance): Cld: C 45.55 H 5.31 Br 13.17 N 6.93 Fnd: C 45.62 H 5.38 Br 13.41 N 7.02 100 h) 4-(3-Bromo-4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)- 3,6,9-triazaundecane-l,ll-dioic acid, gadolinium complex, disodium salt 10.0 g (16.5 mmol) of 4-(3-bromo-4-ethoxybenzyl)-3,6,9tris(carboxylatomethyl)-3,6,9-triazaundecane-l,11-dioic acid is dissolved in 200 ml of water and mixed at 80 0 C with 3.0 g (8.25 mmol) of gadolinium oxide. After a reaction time of 1 hour at 0 C, the now almost clear reaction solution is brought to room temperature and adjusted to pH 7.2 by mixing drop by drop with 0.2 molar sodium hydroxide solution. The reaction mixture is freeze-dried after filtration.

Yield: 12.7 g (96% of theory) Analysis (relative to anhydrous substance): 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 Gadolinium complex of the disodium salt of (carboxymethyl)-amino]-ethyl]-p-iodophenylalanine a) p-Iodophenylalaninisopropylester, hydrochloride ml of isopropanol is stirred at o0C under argon and mixed drop by drop with 3.12 ml (41.6 mmol) of thionyl chloride. minutes later, 10.0 g (34.4 mmol) of p-iodophenylalanine is added in portions, stirred for one hour at room temperature, and the batch is then allowed to reflux for two hours. After the cooling tp. room temperature, the batch is allowed to stand overnight at c 0°C, and then the precipitated, colorless precipitate is suctioned off.

Yield: 12.4 g (97.8% of theory) Analysis: Cld: C 38.99 H 4.64 I 34.33 N 3.79 0 8.66 Cl 9.59 Fnd: C 38.85 H 4.70 I 34.29 N 3.78 Cl 9.66 b) N,N-Bis-[2-[N',N'-bis-[(tert-butyloxycarbonyl)-methyl]amino]-ethyl]-p-iodophenylalaninisopropylester 12.1 g (32.7 mmol) of the amine produced according to Example 20a) and 25.4 g (72.0 mmol) of N,N-bis-[(tertbutyloxycarbonyl)-methyl]-2-bromoethylamine 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 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 The productcontaining fractions are concentrated by evaporation in a vacuum.

Yield: 17.9 g (62.3% of theory) of yellowish oil.

Analysis (relative to solventless substance): Cld: C 54.85 H 7.60 I 14.49 N 1.80 0 18.28 Fnd: C 54.80 H 7.65 I 14.41 N 4.74 ooy f/T eT ^lNr 102 c) N,N-Bis-[2-[N',N'-bis-(carboxymethyl)-amino]-ethyl]-piodophenylalanine 17.1 g (19.5 mmol) of the tert-butyl ester described in Example 20b) is dissolved in 250 ml of trifluoroacetic acid, and it is stirred for 1 hour at room temperature. Then, the solution is concentrated by evaporation, the residue is absorptively precipitated in water, filtered oti 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 H 4.56 I 20.78 N 6.93 d) Gadolinium complex of the disodium salt of N,N-bis-[2- [N',N'-bis-(carboxymethyl)-amino]-ethyl]-p-iodophenylalanine A suspension of 7.43 g (12.2 mmol) of the penta acid, produced according to Example 20c), in 118 ml of water is mixed with 2.21 g (6.1 mmol) of gadolinium oxide and stirred at 80 0

C

for 2 hours. Then, 24.4 ml of 1N sodium hydroxide solution is added with a microburette and stirred for 1 more hour. Then, after 0.5 g of activated carbon is added, the solution is stirred at 80 0 C for 2 hours and filtered. After freeze-drying, the filtrate yields a colorless solid.

Yield: 9.12 g (92.6% of theory) 103 Analysis (relative to anhydrous substance): Cid: C 31.23 11 2.87 1 15.72 N 5.20 0 19.81 Gd 19.47 Na 5.69 Fnd: C 31.26 H 2.95 1 15.70 N 5.13 Gd 19.36 Na 5.74 Example 21 Gadolinium, complex of the monosodium salt of N,N-bis-[2-[N',Nlhydroxyethyl) -cai~bamoyl) 6-triiodophenyl-carbamoylmethyl] amide a) NN-Bis-[2-[N',N'-bis-[ (tert-butyloxycarbonyl)-methylJamino]-ethylJ-glycinie-N''-[3,5-bis-(N'''-(2-hydroxyethyl)carbamoyl) 6-triiodophenylcarbamoylmethylJ -amide 22.1 g (31.5 mmol) of 5-aminoacetylamino-2,4,6triiodoisophthalic acid-N,N'-bis-(2-hydroxyethyl)-diamide and 24.4 g (69.3 mmol) of N,N-bis-((tert-butyloxycarbonyl)-methyl]-2bromoethylamine Williams and Ii. 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 The batch is vi~gorously stirred at room temperature for 24 hours, and the aqueous phosphate buffsr phase is exchanged after 2 and 8 hours for fresh biaffer solution. Then, the organic phase is concentrated by evaporation in a vacuum, and the residue is chromatographed on silica gel with dichloromethane/methanol The product-containing fractions are concentrated by evaporation in a vacuum.

Yield: 21.9 g (55.8% of theory) of yellowish oil.

__71 104 Analysis (rel.ative to solventless substance): Cid: C 40.53 H 5.43 1 30.59 N 6.75 0 16.71 Fnd: C 40.50 H 5.44 1 30.52 N 6.79 b) k,N-Iis-2-[N,N-bis-(carboxymethyl)-aminoj-ethyl]-glycine- N''-[3,5-bis-(NI''-(2-hydroxyethyl)-carbamioyl)-2,4,6triiodophenylcarbamoylmethylj -amide 20.8 g (16.7 mmol) of the tert-butyl ester described in Example 21a) is dissolved in 250 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. Then, the solution is mixed with tert-butyl methyl ether, the precipitate is separated, washed with tert-butyl methyl ether and dried in d vacuum.

Yield: 16.9 g (98.9% of theory) Analysis: Cld: C 30.61 H 3.46 1 37.31 N 8.24 0 20.38 Fnd: C 30.77 H 3.58 1 37.25 N 8.28 c) Gadolinium complex of the monosodium salt of N,N-bis-[2- [N',N'-bis-(carboxymethyl)-aminoJ-ethyl]-glycine-N bis-(N'''-(2-hydroxyethyl)-carbamoyl)-2,4,6triiodophenylcarbamoylmethyl] -amide 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 80 0

C

for 2 hours. Then, 16.6 ml of IN sodium hydroxide solution is added with a microburette and stirred for 1 more hour. Then, 4i s I 105 after 0.5 g of activated carbon is added, the solution is stirred at 80°C for 2 hours and filtered. After freeze-drying, the filtrate yields a colorless solid.

Yield: 18.4 g (93.0% of theory) Analysis (relative to anhydrous substance): 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 H 2.74 I 31.84 N 7.06 Gd 13.10 Na 1.93 Throughout this specification and the appended claims, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

S

0

Claims (9)

1. 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 formula I V U RU R R V Z N N N \2 HOOC V CO 'COOH 13 z(I) in which R 1 stands for a hydrogen atom, a carboxylic acid radical, a straight-chain or branched C 1 -C 1 5 alkyl radical, C 6 -C 15 aryl radical, or a C 7 -C 15 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--TRR 5 (II) -CH 2 -NR 6 -CO-R 7 (III) in which R 4 R 5 independently of one another, stand for a hydrogen atom, a straight-chain or branched C,-C 1 5 alkyl radical, C 6 -C 1 5 aryl radical, or a C 7 -C 1 5 aralkyl radical, which optionally contains 1-5 hydroxy groups, 1-2 carboxy groups and/or 1-4 oxygen atoms, or in which R 4 R 5 together with incorporation of the nitrogen atom, form a 5- or 6-ring M I I optionally containing an oxygen atom, another acylated nitrogen atom or a sulfonyl group, optionally substituted with 1-3 hydroxy groups, R 6 stands for a hydrogen atom, a straight-chain or branched C 1 -C 1 5 alkyl radical, C 6 -C 1 5 aryl radical or a aralkyl radical, which optionally contains 1-4 hydroxy groups, 1-2 carboxy groups and/or 1-2 oxygen atoms, or in which R 6 together with R 7 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 R 7 stands for a hydrogen atom, a straight-chain or branched C -C 15 alkyl radical, C 6 -C 15 ar;,l radical or a C -C, aralkyl radical, which optionally contains 1 to 2 hydroxy groups or a carboxy group or in which R 7 together with R 6 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, R 2 R 3 independently of one another, stand for a hydrogen atom, a C 1 -C 15 alkyl radical, a C 6 -C, 1 aryl radical or a C,-C1s 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 U 1 (U 2 I l (ftjtP, C I 1 C1 L I 108 Z 1 Z 2 Z 3 independently of one another, stand for a hydroxy group or a radical -NR 17 in which R 1 7 stands for a hydrogen atom, a methyl or methoxyethyl group, and U 1 U 1 U 2 V 1 V 2 and V 3 respectively independently of one another, stand for a hydrogen atom or for a halogenated aromatic radical of general formula IV, R I 1 R R Y 'R x (IV) in which R 8 R 9 independently of one another, stand for a group -NR 6 -CO-R 7 and/or have the meaning indicated for with the exception of a C 1 -C 15 alkyl radical, C 6 -C 15 aryl radical or a C 7 -C 15 aralkyl radical, R 10 R 11 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 R 9 or a bridge-type crosslink of general formula V p- (C6H4)- (L)m--R 1 2 (V) I I 'I 109 in which m, n, p, independently of one another, stand for numbers O or 1, L stands for an oxygen atom, a sulfur atom, a Cl-C, alkylene radical, a group >SO 2 or >NR 4 with R 4 in the mentioned meaning, and R 12 stands for a direct bond, a carbonyl, a carboxyl, a -CO-NR 18 an -NR 18 an -NH-CS- or a CS-NH group, in which R 18 means a hydrogen atom, a straight-chain or branched C -C 15 alkyl radical, C 6 -C 15 aryl radical, or a C7-C1 aralkyl radical, which optionally contains 1-4 hydroxy groups, 1-2 carboxy groups and/or 1-2 oxygen atoms, or in which R 12 stands for a straight-chain or branched C 1 -C 4 alkylene radical, which optionally contains a carbonyl group and/or an amino group, whereby position is linked with the diethylenetriamine skeleton and position 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 R 9 if X stands for a bridge-type crosslink of formula V and at least one of radicals R 2 R 3 Z 2 Z 3 U 2 V 1 V 2 or V 3 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, I 110 that R 8 and/or R 9 contains an aryl radical, and/or that Z 1 and/or Z 2 then stand for a radical of general formula IV only if at least one of substituents R 2 R 3 U 1 U 2 V 1 V 2 or V 3 does not stand for a hydrogen atom, and/or that if Z 3 contains a completely substituted aromatic compound of formula IV, Z' and/or Z 2 do not contain any fully substituted aromatic compounds of formula IV, and/or that if all substituents R 2 R 3 U 1 U 2 V 1 V 2 and V 3 mean hydrogen, at least one of radicals R 8 R 9 R 1 0 or R 1 stands for a hydrogen atom, and/or R 8 and/or R 9 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 Z 1 Z 2 Z 3 stand for a hydroxy group.

3. Halogen-containing metal complexes according to claims 1 and 2, wherein at least one of radicals R 8 9, Ri0 or R 1 stands for a hydrogen atom.

4. Halogen-containing metal complexes according to claims 1, 2 and 3, wherein U 1 stands for a radical of formula VI I R8 CH2O CH 2 I R (VI) 'v II I V \^ovS P- g 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) 2,4,6-triiodobenzyloxy) -benzyl] undecanedioic acid.

8. Diagnostic agents that contain at least one complex compound according to claim I, in association with additives that are commonly used in galenicals.

9. A method of NMR diagnosis and/or diagnostic radiology which comprises administration to a patient in need of such diagnosis at least one metal complex as claimed in claim I and then carrying out said NMt .,Iid/or diagnostic radiology The method of claim 9 wherein said diagnostic radiology is 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 S 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/l. I i I 112 Abstract The invention relates to new 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 formula I I I 1 2 2 3 2 V U RU R R V Z N N N Z HOOC V 3 'CO COOH OI z 0) in which R 1 R 2 R 3 Z1, Z 2 Z 3 U 1 U 2 V 1 V 2 or V 3 have different meanings, pharmaceutical agents that contain these complexes, their use in NMR diagnosis and/or diagnostic radiology, especially in diagnostic radiology of the liver, as well as processes for the production of the complexes and agents. W INTERNATIONAL SPIiAC1 REPTORT F-n. -A Application No IPCT/EP 94/03919 A CL.ASSIFICATION 01: SUIIJEC'I'MAIT11IR IPC 6 C07C229/16 A61K49/00 C07C233/25 C07C237/12 C07C237/46 C07C235/46 C07C229/36 According to International [latent Classification (IPC) or to both national classification and PIC Dl. FIILf WAIICIIIID Minirrmum Zumentain searched tiication system followed by clas-sification symbols) IPC 6 C07C A61K Docurnrtaton icarchcd oitier than minimum documentation to thc extent that such documents arc Pincluded in the fields searched Electroric data base cortsulted during thc international search (name of data base and, where practical, search terms wsed) C. I)OCUM ENTS CONSIDEREDlil TOC B11 RELE VA Category ]Citation ol' documcnt, with indication, wl~crc appropriate, of the relevant passages 3 Relevant to claim No. A WO,A,93 16375 (MALLINCKRODT MEDICAL INC) 1-11 19 August 1993 cited in the application see claims; examples A EP,A,0 405 704 (SCHERING 1-li AKTIENGESELLSCHAFT) 2 January 1991 cited in the application see claims Further document% arc listed in thc continuation of box C. MV] Ptt t. famiuly members are listed in annex. *Special categories of citcd document,: 7* later documrent published after the international filing date docuentdefnrngthegenralstat oftheart hic isnotor priority date and not in conflict with the application hut W doumet deinig th geera %lae o theartwhic isnotcited to understand the principle or theory underlying the considered to he of particular relevance invention Tl' earlier document hut published on tir after the international X document Of particular relevance; the claimed invention filing date cannot he considered iiovel or cannot he considered to W document which may throw doubts on pnont. .in(s) or involve aii inveistive step when the document is taken alone which is cited to establish the publication date ot another document of particular relevance; the claimed invention citation or other special reason (as specified) cannoit he considered to involve an inventive step when the document refern'ng to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means menits, such comination being obvious to a person silled TP document published poior to the International filing date hut in Lh,, art. later than the. prornty date claimed document member of the same patent family Date of the actual completion or the international search Date of mailing of thc International search report 13 April 1995 Name and mailing address of the ISA Authjinzcd officer lhuropean Patent Office, 1P.11. 581 S Patentlaan 2 Nt. 2280 1 IV Rtilswik Tel. 1i31.70) 340-2040. 31 651 epo nl,S nhe G rca J.M 14r. 1 3170) 3403016 Sn hzG r i ,J M Form PCTIISA1iO Isecon1 sheet) (Juliy 1992) I NTERN'ATI ONAL. SfE.ARCI I REPORT In tii Applicaion No i n f r n i t t o r o n p a c n f A I I M b r XP C T E P 9 4 0 3 9 1 9 Paternt document ublicato Patent famnily Publication cited in search report d ate member(s) date WO-A-931'6375 19-08-93 US-A- 5324503 28-06-94 AU-B- 3602293 03-09-93 EP-A- 0625263 23-11-94 US-A- 5403576 04-04-95 EP-A-405704 02-01-91 DE-A- 3922005 10-01-91 AT-T- 115546 15-12-94 AU-B- 637111 20-05-93 AU-A- 5802490 03-01-91 CA-A- 2020142 31-12-90 DE-D- 59007987 02-02-95 ES-T- 2066113 01-03-95 HU-B- 210208 28-02-95 JP-A- 3215457 20-09-91 I r-orm PCT/ISA/2ID (patent famikly anneal (July 1992)