DE4341724A1 - Pharmaceutical compositions containing haloaryl-substituted metal complexes, their use in diagnostics, and methods for producing the complexes and compositions - Google Patents

Description

The invention relates to the objects characterized in the claims, that is new haloaryl-substituted metal complexes containing these complexes pharmaceutical agents, their use in diagnostics and methods for Production of complexes and means.

Contrast agents are indispensable aids in modern diagnostics; so would be many diseases cannot be diagnosed without the use of contrast media. Contrast agents can be found in all areas of diagnostics such as B. the X-ray, the Radio or ultrasound diagnostics or magnetic resonance tomography Use.

The choice of the preferred method depends on. a. after the diagnostic The question is also available to the doctor available apparatus options. So in particular Magnetic resonance imaging due to the considerable technical and related high cost not yet the widespread use of other methods, such as e.g. B. X-ray diagnostic methods found.

The choice of the suitable contrast medium also varies depending on the particular one Question. This is how the contrast medium is used for a specific task not least because of its (enrichment) distribution behavior in the organism certainly.

Although large both on the device technology side and on the contrast medium side Progress has not yet been made on all issues satisfactory solutions are available.

For example, there are not all indications for the various imaging methods suitable contrast medium. In particular, there is still no suitable one today X-ray contrast media are available for liver diagnosis.

In X-ray diagnostics, contrast agents based on Triiodobenzene can enforce because these compounds have a high X-ray density and  have a low general and local toxicity and are very soluble in water are.

Such connections are e.g. B. in EP 0 105 725, EP 0 015 867. However, these do not show any enrichment in the image that is sufficient for imaging Liver.

Since the usefulness of a compound as an X-ray contrast medium, in addition to Enrichment behavior in the respective organ, essentially on the size of the Mass weakening coefficients of the elements contained in the connection in the Diagnostic radiation range depends on the iodine-containing compounds metal complexes of an element with a high atomic number may also be suitable. Such Compounds are widely used in the field of NMR diagnostics. It deals are generally metal complexes such as z. B. in EP 0 071 564 to be discribed.

WO 93/16375 describes metal complexes which have amide bonds iodine-substituted aromatics are linked. These connections are supposed to be with just one Application of the contrast agent allows both NMR and X-ray To conduct investigations. A combination of the two imaging methods is in many cases for a differentiated presentation and reliable Determination of certain diseases is an advantage. These connections are said to be particularly suitable for angiography. How to rework the Production examples revealed, but the compounds show none for X-ray examinations sufficient accumulation in the area of the liver.

Liver-specific NMR contrast media are described in EP 0 405 704. Because of the metal content in the complexes, these should in principle also be suitable for X-ray diagnostics. A reworking of the experimental examples showed even with administration of a high dose (conc .: 1 M / l, dose:
0.5 mmol Gd / kg intravenously) insufficient liver contrast in the X-ray. A sufficient imaging effect in X-ray diagnostics is only achieved at a dose at which the safety margin is reduced to an unacceptable level.

The object of the present invention was therefore to be very well tolerated and to provide water-soluble contrast agents, especially for the X-ray diagnostics of the liver are suitable.  

This object is achieved by the present invention.

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

wherein
R¹ represents a hydrogen atom, a carboxylic acid residue, a straight-chain or branched C₁-C₄-alkyl residue which is optionally substituted by 1-4 hydroxyl and / or 1-2 carboxy groups and / or is interrupted by 1-2 oxygen atoms, or a residue of the general Formula II or III stands,

-CO-NR⁴R⁵ (II)

-NR⁶-CO-R⁷ (III)

wherein
R⁴, R⁵ independently of one another represent a hydrogen atom, a straight-chain or branched C₁-C₁₀ alkyl radical which may contain 1-4 hydroxyl, 1-2 carboxy groups and / or 1-2 oxygen atoms or together, including the nitrogen atom, an optionally form an oxygen, another acylated nitrogen atom or a sulfonyl group, optionally substituted with 1-3 hydroxy groups, 5 or 6 ring,
R⁶ is a hydrogen atom, a straight-chain or branched C₁-C₁₀ alkyl radical, which may contain 1-4 hydroxyl, 1-2 carboxy groups and / or 1-2 oxygen atoms, or together with R⁷, including the nitrogen atom and the carbonyl group, one optionally forms an oxygen, another acylated nitrogen atom or a sulfonyl group, optionally substituted with 1-3 hydroxyl groups, 5 or 6 ring and
R⁷ is a hydrogen atom, a straight-chain or branched C₁-C₁₀ alkyl radical, which optionally contains 1 to 2 hydroxyl groups or a carboxy group, or together with R⁶, including the nitrogen atom and the carbonyl group, one optionally an oxygen, another acylated nitrogen atom or forms a 5 or 6-ring containing a sulfonyl group, optionally substituted with 1-3 hydroxyl groups,
R², R³ independently of one another represent a hydrogen atom, a C₁-C₄ alkyl radical which is optionally substituted by 1-4 hydroxyl groups and / or interrupted by 1-2 oxygen atoms, or represent a phenyl or benzyl group or together a trimethylene or tetramethylene group form, or independently of one another have the meaning given for U¹ (U²),
Z¹, Z², Z³ independently represent a hydroxyl group or a radical -NH-U¹ and
U¹, U², V¹, V² and V³ each independently represent a hydrogen atom or a halogenated aromatic radical of the general formula IV,

wherein
R⁸, R⁹ independently of one another have the meaning given for R¹, with the exception of a C₁-C₄-alkyl radical,
R¹⁰, R¹¹ independently of one another represent a halogen or a hydrogen atom,
X represents a halogen atom or a bridge member of the general formula V and
Y represents R⁹ or a bridge member of the general formula V,

(α) - (CH₂) _p - (C₆H₄) _n - (L) _m -R¹²- (β) (V)

wherein
m, n, p independently of one another represent the digits 0 or 1,
L represents an oxygen atom, a sulfur atom, a C₁-C₄ alkylene radical, a group <S = O, <SO₂ or <NR⁴ with R⁴ in the abovementioned meaning and
R¹² for a direct bond, a carbonyl, a carboxyl, a -CO-NH, a -NH-CO-, a -NH-CS group or a straight-chain or branched C₁-C₄ alkylene radical, which is optionally a carbonyl - and / or contains an amino group, the position (α) being linked to the diethylenetriamine skeleton and the position (β) being linked to the halogenated aromatics,
where Y is a bridge member of the formula V when X is halogen and Y is R⁹ when X is a bridge member of the formula V and
at least one of the radicals R², R³, Z¹, Z², Z³, U¹, U², V¹, V² or V³ represents or contains the rest of the general formula IV and, if desired, free carboxy groups not required for complexing the metal ions of the elements mentioned, as Salt of an inorganic and / or organic base or amino acid are present,
with the proviso that Z¹, Z², Z³ only represents a radical of the general formula IV if at least one of the substituents R², R³, U¹, U², V¹, V² or V³ does not represent a hydrogen atom or if all the substituents R², R³, U¹, U², V¹, V² or V³ are hydrogen, at least one of the radicals R⁸, R⁹, R¹⁰ or R¹¹ of the formula IV represents a hydrogen atom,
excellent for the production of contrast media for NMR and / or X-ray diagnostics, preferably contrast media for X-ray diagnostics, especially for X-ray diagnostics of the liver.

The complexes according to the invention preferably contain a manganese (II) -, Iron (III) -, iron (II) -, praseodymium (III) -, neodymium (III) -, samarium (III) -, Dysprosium (III) -, a ytterbium (III) - or a bismuth (III) ion, especially a Gadolinium (III) ion.  

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

Preferred halogenated aromatics of formula IV are triiodinated aromatics, i.e. H. Aromatics in which X, R¹⁰ and R¹¹ are iodine and in which R⁸ and R⁹ independently for a hydrogen atom, for a group -OH, -COOH, -O-CH₂-CH (OH) -CH₂-OH, -O-CH₃, -O-CH₂-CH₃, -CO-NH-CH (CH₂OH) - (CHOH-CH₂OH), -CO-NR⁴-CH- (CH₂OH) ₂, -NR⁶-CO-CH₂OH, -CO-NR⁴-CH₂-CH₂OH, -CO-NH₂, -N (CH₃) -CO-CH₃, -NH-CO-CH₃, -CO-NH-CH₃, -N (CH₃) -CO- (CH₂) ₂COOH, -CO-N- (C₂H₅) ₂, -CO-N (CH₃) -CH₂-COOH, -CO-NH- (CH₂) ₁₀-COOH or a group -CO-N (CH₃) -CH₂-CH (OH) -CH₂-OH and where Y is a bridge member Formula V stands.

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

• - U stands for a halogenated aromatic radical, the groups
  -CH₂-, -CH₂-C₆H₄-O-CH₂-, -CH₂-O-CH₂-, -CH₂-O-, -CH₂-O-CO-, -CH₂-NH-CO-, -CH₂-CO-NH -, -CH₂-C₆H₄-O-CH₂-CO-NH-, -CH₂-O-CO-NH-, -CH₂-NH-CO-NH-, -NH-CO-, -NH-CO-CH₂-,
• - Z stands for a halogenated aromatic radical, the groups
  -NH-CH₂-CO-NH-, -NH CH₂CH₂-CO-NH- or -NH CH₂CH₂-NH-CO-
  and that
• V stands for a halogenated aromatic radical, the groups
  -CH₂-, -CH₂-O-, -CH₂-O-CH₂-, -CH₂-O-CO-, -CH₂-NH-CO-, -CH₂-CO-NH-, -CH₂-O-CO-NH - or -CH₂-NH-CO-NH-.

Particularly preferred are the complexes in which U¹ for the rest of the general formula IV, d. H. Compounds in the ethylene bridge of the Polyaminocarboxylic acid are substituted with the halogenated aromatic and where Z represents a hydroxy group.

As R¹ come into consideration, straight-chain or branched alkyl radicals such as Methyl, ethyl, propyl, iso-propyl, butyl and tert-butyl radicals are preferred however, hydrogen, C₁-C₄ alkyl and hydroxyalkyl radicals, such as. B. the Hydroxymethyl and alkoxyalkyl, such as. B. the methoxymethyl radical.  

The radicals R 2, R 3 are the radicals listed for R 1, are preferred however, hydrogen atoms.

Ionic complexes are particularly preferred for X-ray diagnosis of the liver those of the free carboxyl groups present in the molecule (i.e. the carboxyl groups which are not to balance the charge of the metal ions of the elements of the atomic numbers mentioned are required) as a free acid or as a salt of an inorganic and / or organic base or amino acid.

Suitable cations of inorganic bases are, for example, the lithium, the Potassium, calcium, magnesium and especially sodium ion. Suitable Cations of organic bases include those of primary, secondary or tertiary amines, such as. B. ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine and especially N-methylglucamine. Suitable cations of Amino acids are, for example, those of lysine, arginine and ornithine.

The complexes according to the invention can be prepared in a variety of ways respectively. The different processes as well as the necessary ones Starting compounds are known in principle to the person skilled in the art. So they can Compounds usually analogous to already known complexes or Complexing agents, by implementing a reactive species of the halogenated Aromatics with a reactive species of the complexing agent in a suitable Solvents. The selection of the most appropriate Synthesewes depends on the desired link between the halogenated aromatics and polyaminopolycarboxylic acid. Then you can Complexes can be divided into three groups. So the (can) halogenated aromatic (s)

• I) to the α-carbon atoms of the carboxylic acid (acetic acid) residue,
• II) to the alkylene (ethylene) bridges or
• III) to the carboxylic acid group (s)

be bound to the polyaminopolycarboxylic acid.

Complexing agents or complexes of group I can be analogous to those in the European patent application EP 0 230 893 become. Other universally applicable synthesis options for the Complexing agents are mentioned below by way of example.  

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

wherein R¹³ is the desired halogenated aromatic radical of the general formula IV or is an optionally still unhalogenated precursor of this residue, with Polyamines of the general formula VII,

first compounds of the general formula VIII are obtained,

which is then carried out in a manner known per se using haloacetic acid esters, preferably with bromoacetic acid esters, and then - if it is a precursor of the desired aromatic - in itself are halogenated in a known manner and any ester or Protecting groups are split off in a manner known to those skilled in the art. Disubstitution can also be achieved with appropriate stoichiometry.

An alternative method for the production of α-C substituted Polyaminopolycarboxylic acids starts from the acid-protected polyaminocarboxylic acid (e.g. from the pentamethyl ester of diethylenetriaminepentaacetic acid). This is with the Lithium salt of a precursor of the desired aromatics implemented. A corresponding one Lithium salt is made of benzyl halide (e.g. 3-nitrobenzyl chloride, 3,5-dinitrobenzyl chloride, 3-benzyloxybenzyl chloride) by reaction with Lithium diisopropylamine available in THF / hexane. Following the coupling  the aromatic is converted to the desired halogenated aromatic of formula IV, e.g. B. by reducing any nitro groups present to amino groups which, if desired, are reacted with acetyl chloride to give the amide, Benzyloxy radicals can e.g. B. converted into hydroxy radicals by catalytic hydrogenation become. The iodination of the aromatic also takes place in a manner known per se, for. B. by reaction with iodine monochloride solution in a hydrochloric acid medium. Before the Introduction of the iodine atoms, the acid protection groups of the pentaester in basic saponified.

An alternative method for the production of α-C substituted Polyaminopolycarboxylic acids, is from a phenylamino acid such. B. 3-aminophenylalanine. This is initially done in a manner known per se halogenated, the acid group then protected as an ester. The so obtained The intermediate is mixed with two equivalents of N, N-bis [(benzyloxycarbonyl) methyl] - Implemented 2-bromomethylamine. Before the acid protection groups are split off if desired, the substituents of the aromatic are converted into the desired radicals.

The preparation of complexing agents of group II can be analogous to that in the EP 0 405 704 and DE 43 02 289 methods described. So z. B. of known compounds (DE 37 10 730 and literature cited therein) the general formula IX,

wherein R¹⁴ is an acid protecting group, such as. B. a lower alkyl, aryl, aralkyl or Means trialkylsilyl groups and R¹, R² and R³ have the meanings given, where the phenolic OH group has a reactive form of the desired halogenated aromatics (or its precursor, e.g. benzyl halide) of the formula X is implemented

wherein R ^{8 '} , R ^9' , R ^{10 '} and R ^{11' represent} the desired groups R⁸, R⁹, R¹⁰ and R¹¹ or a precursor thereof. If the groups R ^{8 '} , R ^9' , R ^{10 '} and R ^11' stand for preliminary stages of the desired groups, these are generated from those. The acid protecting groups R¹⁴ are in a known manner [see z. BE Wünsch, Methods of Org. Chemie (Houben Weyl), Vol. XV / 1, 4 ed. 1974, S 315 ff], for example, by hydrolysis, hydrogenolysis or alkaline saponification, generally before the halogenation of the aromatic compound. Both acidic and aqueous-alkaline reaction conditions can be selected to remove the t-butyl esters which are particularly advantageous for the present reaction.

In the compounds of the general formula IX, the aromatic radical in can also known way z. B. is iodinated with iodine monochloride. If necessary, you can the phenolic -OH groups in a manner known per se Alkyl halide / sodium hydride are etherified. The spin-off of the Acid protection groups are carried out in the manner described above.

An alternative process is also based on halogenated chlorinated aromatics of the formula X, which with a partially protected glycerol, initially for corresponding dihydroxypropyloxy compound of formula XI are implemented

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

wherein R¹⁵ for a protective group such as. B. is a benzyl group. After splitting off the OH protecting group R¹⁵ and activation of the resulting Hydroxy group e.g. B. as a methanesulfonic acid ester, you first start with corresponding ethylenediamine and then reduces the azide group in known way z. B. with triphenylphosphine to compounds of formula XIII

These are reacted in a known manner with bromoacetic acid esters to give the corresponding pentaesters. After splitting off the acid protecting groups z. B. by reaction with trifluoroacetic acid and generation of the desired groups R⁸, R⁹, R¹⁰ and R¹¹ from the groups R ^{8 '} , R ^9' , R ^{10 '} and R ^11' , the desired complexing agent is obtained.

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

those with isocyanato compounds of the general formula XV

to the corresponding urethanes.

Alternatively, the hydroxy group in the compounds of the general formula XIV z. B. with N-chlorosuccinimide to the corresponding chloride of formula XVI be implemented

This is then treated in a manner known per se with a reactive species of (e.g. a hydroxy- or carboxy group-containing) desired halogenated Aromatics of the formula XVII

wherein R⁸, R⁹, R¹⁰ and R¹¹ have the meanings given and Y 'for an OH or COOH group is converted to the corresponding ethers or esters. The The acid protecting groups R¹⁴ are split off in the manner described above.  

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

• a) either with an isocyanato compound of the formula XV to the corresponding Urea derivative implemented or
• b) with a halogen-benzoyl chloride of the formula XVIII

to the corresponding amide.

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

wherein R¹⁶ for an amino protecting group, preferably a benzyloxycarbonyl group and R ^{13 'is} an unhalogenated precursor of the desired aromatic, or a "linker", to which the desired halogenated aromatic is bound in a later reaction step. The aminoethyl alcohol is first z. B. with methanesulfonic acid chloride, toluenesulfonic acid chloride or trifluoroacetic anhydride to the corresponding mesylate, tosylate or triflate and then reacted with an optionally substituted ethylenediamine. If it is in R ^{13 '} is an unhalogenated precursor of the desired aromatic of the general formula IV, z. B. iodinated with iodine monochloride, but if it is a "linker", this is reacted with a reactive species of the desired aromatic (or its unhalogenated precursor).

Finally, the amino protecting groups are split off and with Haloacetic acid esters to the desired amino acids (complexing agents) implemented.

The group III complexing agents, i.e. H. Complexing agents in which the halogenated aromatic residue in the form of an amide bond to the carboxylic acid groups of the Polyaminopolycarboxylic acid is bound, can be analogous to that in the Process described in DE 42 32 925.

The complexing agents can thus be produced by partial conversion of activated carboxyl groups e.g. B. the desired pentacarboxylic acid in amide groups. All synthetic possibilities known to the person skilled in the art are suitable for this process Consider how. B. the implementation of the acid anhydrides of the general formulas XX or XXI with halogenated aromatics of the general formula XXII to the amides according to the invention,

wherein R ^{8 '} , R ^9' , R ^{10 '} and R ^{11' represent} the desired groups R⁸, R⁹, R¹⁰ and R¹¹ or a precursor thereof and Q represents the rest of a linker of the general formula V. The aromatics of the general formula XXII are prepared as for. B. described in DE 25 23 567.

As an H₂N-Q radical, examples include an H₂N-CH₂-CO-NH-, H₂N-NH-CO-NH-, H₂N-CH₂CH₂-CO-NH-, H₂N-NH-CO-CH₂CH₂-, H₂N-CH₂CH₂-NH-CO- or an H₂N-CH₂CH₂-N (CO-CH₃) group.

This reaction is carried out in the liquid phase. Suitable reaction media are, for example, water, dipolar aprotic solvents such as diethyl ether, Tetrahydrofuran, dioxane, acetonitrile, N-methylpyrrolidone, dimethylformamide, Dimethylacetamide and the like or mixtures thereof. The reaction temperature ren are between about -80 ° C and 160 ° C, with temperatures from 20 ° C to 80 ° C are preferred. The response times are between 0.5 hours and 7 days, preferably between 1 hour and 36 hours.

The acid anhydrides of the general formula XX can be prepared according to known methods Procedures take place, e.g. B. according to US 3,660,388 or DE 16 95 050 described method with acetic anhydride in pyridine. In certain cases it is however advantageous, the elimination of water with carbodiimides in a suitable Solvents such as As dimethylformamide or dimethylacetamide, gently to make.

The preparation of the monoanhydrides of the general formula XXI is described in J. Pharm. Sci., 68 (1979) 194.

The halogenated aromatics used in the various processes are known or easily generated from known.

So z. B. in German Offenlegungsschrift DE 29 28 417 iodinated aromatics described that easily with z. B. thionyl chloride to the corresponding Aromatics containing acid chloride groups are implemented.

Other aromatic residues are as in M. Sovak; Radiocontrast Agents, Handbook of Experimental Pharmacology Vol 73 (1984), Springer Verlag, Berlin - Heidelberg - New York - Tokyo or described in European patent EP 0 015 867, producible.  

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

Aromatics containing amino groups, such as, for. B. for the production of acetic acid Substituted compounds of group III are required, are analogous to those in the DE 25 23 567 described compounds available.

The preparation of the metal complexes according to the invention from those described above Group I-III complexing agents are carried out in the manner described in the patents EP 0 071 564, EP 0 130 934 and DE 34 01 052 has been disclosed by doing this Metal oxide or a metal salt (for example the nitrate, acetate, carbonate, chloride or sulfate) of the element of atomic numbers 12, 13, 20-31, 39-42, 44-50 or 57-83 in water and / or a lower alcohol (such as methanol, ethanol, isopropanol and / or N, N-dimethylformamide) dissolves or suspended and with the solution or Suspension of the equivalent amount of the complexing agent is implemented.

If desired, further acidic hydrogen atoms of acid Groups by cations of inorganic and / or organic bases or amino acids be substituted.

Suitable bases are inorganic bases (e.g. hydroxides, carbonates or Bicarbonates) from e.g. B. sodium, potassium or lithium and / or organic bases such as including primary, secondary and tertiary amines such as. B. ethanolamine, Morpholine, glucamine, N-methyl and N, N-dimethylglucamine, as well as basic Amino acids such as B. lysine, arginine and ornithine.

To produce the neutral complex compounds, for example, the acidic complex salts in aqueous solution or suspension as much as desired Add bases so that the neutral point is reached. The solution obtained can then concentrated to dryness in vacuo. It is often an advantage that formed neutral salts by adding water-miscible solvents, such as e.g. B. lower alcohols (methanol, ethanol, isopropanol, etc.), lower ketones (Acetone etc.), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.) precipitate and thus to obtain crystals that are easy to isolate and easy to clean. It has proven to be particularly advantageous during the desired base add the complex formation of the reaction mixture and thereby one Process step to be saved.  

It is often the case that the acidic complex compounds contain several free acidic groups expedient to produce neutral mixed salts, both inorganic and contain organic cations as counterions.

This can be done, for example, by adding the complexing acid to aqueous suspension or solution with the oxide or salt of the central ion supplying element and half of the amount required for neutralization converts organic base, the complex salt formed is isolated, if desired purified and then for complete neutralization with the required amount organic base added. The order of base addition can also be reversed become.

The invention further relates to agents which comprise at least one of the Contain compounds of the invention.

The invention further relates to a method for producing these agents, which characterized in that the paramagnetic complex salt dissolved in water with the additives and stabilizers common in galenics in one for enteral or parenteral application is brought into a suitable form so that the complex salt in a concentration of 1 to 1500 mmol / l, preferably in a concentration of 10-1000 mmol / l is present. The halogen content of the solutions is usually in the range between 10-400 mg / ml. The resulting funds will then be sterilized if desired. They are dependent on the halogen content and the diagnostic problem usually applied in a dose of 1-300 ml.

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

Are suspensions or solutions for enteral administration or other purposes of the agents according to the invention in water or physiological saline solution, they are mixed with one or more auxiliary substances commonly used in galenics (e.g. Methyl cellulose, lactose, mannitol) and / or surfactants (e.g. lecithins, Tweens®, Myrj® and / or flavoring agents for flavor correction (e.g. essential oils) mixed.  

In principle, it is also possible to use the diagnostic agents according to the invention without isolating the complex salts. In any case, special care must be taken be used to chelate so that the Salts and salt solutions according to the invention are practically free of non-complexed toxic metal ions.

This can be done, for example, with the help of color indicators such as xylenol orange Control titrations can be guaranteed during the manufacturing process. The The invention therefore also relates to processes for the preparation of the complex compounds and their salts. As a final security, cleaning of the isolated remains Complex salt.

Further objects of the invention are characterized by the claims.

The substances according to the invention meet the diverse requirements that are met Contrast agents have to be provided in modern diagnostics. The connections and out Means manufactured to them are characterized by:

• - a high absorption coefficient for X-rays,
• - good tolerance, which is necessary to the non-invasive character to maintain the investigations,
• - A high effectiveness, which is necessary to the body with as much as possible burden small amounts of foreign substances,
• - good solubility in water (this allows highly concentrated solutions manufacture as they are particularly suitable for use as X-ray contrast media required are. This allows the volume load of the circuit in reasonable limits are kept.),
• - a low viscosity,
• - low osmolality,
• - favorable excretion rate.

Furthermore, the agents according to the invention not only have high stability in vitro on, but also a surprisingly high stability in vivo, so that a release or an exchange of the non-covalently bound in the complexes - which are toxic in themselves - Ions within the time when the new contrast agent is fully restored are eliminated, did not take place.  

In addition to the high water solubility, which surprisingly occurs in the presence of paramagnetic metal ions into one required for X-ray diagnostics Could be increased range, the compounds of the invention act positive in X-ray diagnostics in that the inventive Surprisingly, complex compounds are investigated for short-wave ones Allow x-rays than is possible with conventional contrast media, which significantly reduces the patient's radiation exposure, since As is well known, soft radiation is absorbed much more strongly by the tissue than harte (R. Felix, Das Röntgenbild; Thieme Stuttgart 1980).

Because of the favorable absorption properties of the contrast media according to the invention in the field of hard X-rays, the means are also particularly suitable for digital ones Subtraction techniques (which work with higher tube voltages) are suitable.

The favorable in vivo distribution behavior of the agents according to the invention. This allows for the first time, with one for X-ray contrast medium usual dose (halogen content: 50-400 mg / ml; dose 0.1-1 ml / kg body weight), X-rays of high diagnostic To make meaningful statements in the area of the liver.

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

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

FIG. 3 shows in comparison the increase in density (which can be regarded as a measure of the effectiveness of a contrast agent) as a function of time, for a compound according to the invention (example 1d) and a compound of EP 0 405 704 (example 8c). Thereafter, significantly higher density values are observed in the rat liver over the entire investigation period for the compound according to the invention. For example, the maximum values for the substance according to the invention are 60 Houndsfield units (HU) for the comparison substance, but only 15 HU. The tests were carried out on a Somatom plus VD31 (test parameters: layer thickness = 2 mm, tube voltage / current = 120 kV / 290mA) on female rats (body weight = 200-280 g) after intravenous injection of 0.5 mmol / kg of the respective substance performed.

The complexes described in WO 93/16375 also show none for one Imaging sufficient accumulation in the liver.

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

These studies were carried out on female rats (90-110 g body weight) intravenous administration of 0.27 mmol / kg of compound 17b). The The iodine concentration in blood, urine, feces, as well as liver, kidney, spleen, bone was determined with the X-ray fluorescence analysis measured. In addition, the Gadolinium concentrations determined using ICP atomic emission spectroscopy. The Half-life of 0.32 hours and the volume of distribution show a distribution in the extracellular space with renal excretion through glomerular filtration over the Kidney.

The agents according to the invention which contain a paramagnetic metal ion in a complex Elements of the ordinal numbers 21-29, 42, 44 or 57-70 can contain next to the Use in X-ray diagnostics also used in NMR diagnostics become. This dual character opens up further areas of application. This is how they are agents according to the invention always to be used advantageously when differentiated representation and reliable determination of certain diseases a combination of X-ray and NMR diagnostics is required. This applies e.g. B. too for suspected recurrence after tumor surgery or radiation therapy. In these Cases are made to the patient by using a contrast agent that works for both Techniques are equally suited to an additional double burden Application saved.  

The following examples serve to explain the Subject of the invention, without wishing to restrict it to these.

example 1 Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) - 4- [4- (2,4,6-triiodobenzyloxy) benzyl] undecanedioic acid a) Preparation of 2, 4, 6-triiodobenzyl chloride

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

Yield: 29.8 g (73.8%) light beige solid.

Analysis (based on solvent-free substance):
calc .: C 16.67, H 0.80, Cl 7.03, I 75.50,
Found: 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-tri-iodobenzyloxy) benzyl] -undecanedioic acid di-tert-butyl ester

15.6 g (20.0 mmol) 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-hydroxy benzyl) -undecanedioic acid di-tert-butyl ester (Example 9f of DE 37 10 730) are in Tetrahydrofuran at 0 ° C with 660 mg (22.0 mmol) 80% sodium hydride suspension in Mineral oil added. For this purpose, 12.4 g (22.0 mmol) of that prepared according to Example 1a) 2,4,6-Triiodbenzylchlorids added and stirred for 3 hours. Then the solution comes with Water is added, tetrahydrofuran is distilled off and the aqueous emulsion is mixed with Extracted diethyl ether. The organic phase is washed with water, over Na₂SO₄ dried and concentrated.  

The residue is on silica gel 60 (Merck) with Hexane / methyl acetate / triethylamine, the product fractions are evaporated and dried in vacuo.

Yield: 22.8 g (91.2% of theory) of a yellowish oil.

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

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

22.8 g (18.3 mmol) of the tert-butyl ester described in Example 1b) are in 250 ml Trifluoroacetic acid dissolved and stirred for 1 hour at room temperature. Then will the solution is mixed with tert-butyl methyl ether, the precipitate is suctioned off, with tert.- Butyl methyl ether washed at 40 ° C in a vacuum over phosphorus pentoxide dried. The crude product is stirred in water, filtered off and dried in vacuo.

Yield: 15.4 g (86.8% of theory) of a light beige solid.

Analysis (based on anhydrous substance):
calc .: C 34.77, H 3.33, I 39.36, N 4.34, O 18.19,
Found: 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 prepared according to Example 1c) in 118 ml of water, 2.21 g (6.1 mmol) of gadolinium oxide are added and the mixture is at 80 ° C. 2 Hours stirred. Then 24.4 ml of normal sodium hydroxide solution are used with a micro burette added and stirred for 1 hour. The solution is then after at 80 ° C. Addition of 0.5 g activated carbon stirred for 2 hours and filtered. The filtrate yields Freeze-drying a colorless solid.

Yield 13.1 g (91.8% of theory).

Analysis (based on anhydrous substance):
calc .: C 28.86, H 2.34, I 32.67, N 3.61, O 15.10, Gd 13.49, Na 3.95,
Found: C 28.66, H 2.43, I 32.70, N 3.49, Gd 13.28, Na 4.16.

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

42.5 g (79.7 mmol) of 3-methylamino-2,4,6-triiodobenzyl chloride (Collection Czechoslov. Chem. Commun. [Vol. 41] 1976) are dissolved in 180 ml of N, N-dimethylacetamide and 13.7 ml (191.3 mmol) of acetyl chloride were added dropwise while cooling with ice. To 30 minutes stirring at about 0 ° C is stirred for 12 hours at room temperature and the dark brown solution in water while stirring. There is a precipitation which is suctioned off and dried in vacuo.

Yield: 44.6 g (99.6% of theory) of a light beige solid.

Analysis (based on anhydrous substance):
calc .: C 20.88, H 1.58, Cl 6.16, I 66.17, N 2.43, O 2.78,
Found: C 20.98, H 1.69, Cl 6.04, I 66.18, N 2.52.

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

15.6 g (20.0 mmol) 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) - 4- (4-hydroxybenzyl) -undecanedioic acid di-tert-butyl ester (Example 9f of DE 37 10 730) are 80% in tetrahydrofuran at 0 ° C with 660 mg (22.0 mmol) Sodium hydride suspension added to mineral oil. For this, 12.66 g (22.0 mmol) of added compound prepared according to Example 2a) and stirred for 3 hours. Then it will be water was added to the solution, tetrahydrofuran was distilled off and the aqueous emulsion extracted with diethyl ether. The organic phase is washed with water, over Na₂SO₄ dried and concentrated. The residue is on silica gel 60 (Merck) with Hexane / methyl acetate / triethylamine, the product fractions are evaporated and dried in vacuo.

Yield: 23.5 g (89.2% of theory) of a yellowish oil.

Analysis (based on solvent-free substance):
calc .: C 46.45, H 5.89, I 28.87, N 4.25, O 18.49,
Found: C 46.63, H 5.96, I 28.72, N 4.18.

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

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

Yield: 16.2 g (94.1% of theory) of a light beige solid.

Analysis (based on anhydrous substance):
calc .: C 35.86, H 3.59, I 36.67, N 5.40, O 18.49,
Found: 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- (carboxy methyl) -4- [4- (N-acetyl-3-methylamino-2,4,6-triiodobenzyloxy) benzyl] undecanedioic acid

A suspension of 14.8 g (14.3 mmol) of the penta acid prepared according to Example 2c) in 150 ml of water is mixed with 2.58 g (7.13 mmol) of gadolinium oxide and at 80 ° C. stirred for two hours. Then 28.5 ml are normal with a micro burette Sodium hydroxide solution added and stirred for an hour. Then the solution is at 80 ° C after adding 0.8 g of activated carbon, stirred for two hours and filtered. The filtrate gave after evaporation a colorless solid.

Yield: 16.4 g (93.3% of theory).

Analysis (based on anhydrous substance):
calc .: C 30.11, H 2.61, I 30.79, N 4.53, O 15.53, Gd 12.72, Na 3.72,
Found: C 30.00, H 2.82, I 30.58, N 4.67, Gd 12.79, Na 3.82.

Example 3 Gadolinium complex of the trisodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) {4- [N- (3-carboxypropionyl) -3-methylamino-2,4,6-triiodobenzyloxy] benzy-l} undecanedioic acid a) N- (5-Oxa-1,4-dioxoheptyl) -3-methylamino-2,4,6-triiodobenzyl chloride

To a suspension stirred under exclusion of moisture 53.3 g (100 mmol) 3-methylamino-2,4,6-triiodobenzyl chloride (Collection Czechoslov. Chem. Commun. [Vol. 41] 1976) in 200 ml of anhydrous dioxane, 24.7 g (150 mmol) Succinic acid chloride monoethyl ester added at room temperature. The approach is going Boiled at reflux for several hours until, according to thin layer chromatography, no starting material is more detectable; then evaporated, the residue in dichloromethane added and with saturated aqueous sodium bicarbonate solution shaken out. The organic phase is dried over anhydrous Magnesium sulfate evaporated and the residue from ethyl acetate / tert.- Crystallized butyl methyl ether.

Yield: 58.4 g (88.3% of theory) of a colorless solid.

Analysis (based on solvent-free substance):
calc .: C 25.42, H 2.29, Cl 5.36, I 57.56, N 2.12, O 7.26,
Found: C 25.31, H 2.49, Cl 5.43, I 57.50, N 2.17.

b) 3,6,9-Triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- {4- [N- (5-oxa-1,4-dioxo heptyl) -3-methylamino-2,4,6-triiodobenzyloxy] benzyl} undecanedioic acid

15.6 g (20.0 mmol) 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) - 4- (4-hydroxybenzyl) -undecanedioic acid di-tert-butyl ester (Example 9f of DE 37 10 730) are 80% in tetrahydrofuran at 0 ° C with 660 mg (22.0 mmol) Sodium hydride suspension added to mineral oil. 14.55 g (22.0 mmol) of the added compound prepared according to Example 3a) and stirred for 3 hours. Then it will be water is added to the solution. Tetrahydrofuran distilled off and the aqueous emulsion extracted with diethyl ether. The organic phase is washed over with water Dried sodium sulfate and concentrated. The residue is on silica gel 60 (Merck) chromatographed with hexane / ethyl acetate / triethylamine, the product fractions are evaporated and dried in vacuo.

Yield: 22.9 g (81.6% of theory) of a yellowish oil.

Analysis (based on solvent-free substance):
calc .: C 47.02, H 5.95, I 27.10, N 3.99, O 15.94,
Found: C 46.86, H 6.13, I 26.98, N 3.84.

c) 3,6,9- triaza-3,6,9-tris- (carboxymethyl) - {4- [N- (3-carboxypropionyl) -3- methylamino-2,4,6-triiodobenzyloxy] benzyl} undecanedioic acid

20.4 g (14.5 mmol) of the hexaester described in Example 3b) are dissolved in 100 ml Dissolved methanol and mixed with 87 ml of 2N sodium hydroxide solution. You cook for about 2 hours Reflux, the methanol is removed in vacuo and, after adding 100 ml of water, stirring another 2 hours at 60 ° C. By adjusting pH 1-2 with semi-concentrated Hydrochloric acid forms a colorless precipitate, which is filtered off and dried in vacuo becomes.

Yield: 15.3 g (96.0% of theory) of a colorless solid.

Analysis (based on anhydrous substance):
calc .: C 36.15, H 3.59, I 34.72, N 5.11, O 20.43,
Found: C 36.23, H 3.65, I 34.58, N 5.05.

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

A suspension of 14.1 g (12.9 mmol) of the hexacid prepared according to Example 3c) in 150 ml of water is added 2.33 g (6.43 mmol) of gadolinium oxide and at 80 ° C. Stirred for 2 hours. Then 38.6 ml are normal with a micro burette Sodium hydroxide solution added and stirred for 1 hour. Then the solution at 80 ° C after Add 0.8 g of activated carbon stirred for 2 hours and filtered. The filtrate yielded Freeze-drying a colorless solid.

Yield: 16.3 g (96.4% of theory).

Analysis (based on anhydrous substance):
calc .: C 30.11, H 2.53, I 28.92, N 4.26, O 17.01, Gd 11.94, Na 5.24,
Found: 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-diiodo- 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) 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) - 4- (4-hydroxybenzyl) -undecanedioic acid di-tert-butyl ester (Example 9f of DE 37 10 730) are dissolved in 100 ml of trifluoroacetic acid and 1.5 hours at room temperature touched. The mixture is then diluted with diethyl ether and the precipitate is filtered off with suction. It is washed with diethyl ether and dried at 50 ° C in a vacuum. The raw product is dissolved in water and treated with activated carbon. The filtered solution becomes several times Removal of residual trifluoroacetic acid lyophilized.

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

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

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

3.2 g (6.4 mmol) of the phenol from Example 4a) are suspended in 50 ml of water and with solid sodium hydroxide added to the neutral point. One touches the approach 50 ° C and dropwise 5.7 ml (14.1 mmol) of a 40% hydrochloric acid iodine monochloride solution to. After 20 hours at 50 ° C, the excess iodine is reduced with sodium disulfite, the precipitate is filtered off and washed with water.

Yield: 4.15 g (86% of theory) of a pale yellow solid.

Elemental analysis (taking into account the solvent content):
calc .: C 33.57, H 3.62, I 33.78, N 5.59, O 23.43,
Found: 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-diiod-4-ethoxybenzyl) - undecanedioic acid

3.0 g (4 mmol) of the diiodophenol from Example 4b) are anhydrous in 25 ml Tetrahydrofuran with 0.792 g (26.4 mmol) 80% sodium hydride suspension in Mineral oil added. 4.1 g (26.4 mmol) of ethyl iodide and the reaction mixture is stirred for 6 hours at room temperature. Then moved it is evaporated to dryness with 30 ml of 2N sodium hydroxide solution and the residue is taken in Water on. The aqueous solution is acidified with concentrated hydrochloric acid Suction filtered and washed with water. To purify it Crude product recrystallized from ethanol.

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

Elemental analysis (taking into account the solvent content):
calc .: C 35.45, H 4.01, I 32.57, N 5.39, O 22.58,
Found: C 35.59, H 3.94, I 32.39, N 3.23.

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 from Example 4c) are in 55 ml of water suspended and mixed at 60 ° C with 407 mg (1.1 mmol) of gadolinium oxide. To The clear solution is treated with activated carbon for 4 hours. Then over a Cellulose membrane filter (0.2 mm, Sartorius), finely filtered and freeze-dried.

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

Elemental analysis (taking into account the solvent content):
calc .: C 29.59, H 3.02, Gd 16.84, I 27.19, O 18.85,
Found: C 29.64, H 3.25, Gd 16.66, I 26.93.

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

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

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

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

Example 5 Gadolinium complex of the disodium salt of 4- (N-acetyl-3-methylamino 2,4,6-triiodobenzyloxymethyl) -3,6,9-triaza-3,6,9-tris (carboxymethyl) undecanedioic acid a) N-Acetyl-N-methyl-3 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxymethyl] - 2,4,6-triiodaniline

20.0 g (36.3 mmol) of the compound prepared in Example 2a), 5.8 g (43.6 mmol) 2,3-O-isopropylidene glycerol, 0.41 g (1.8 mmol) N-benzyl-N, N, N-triethylamonium chloride and 4.1 g (72.7 mmol) of ground potassium hydroxide are in 35 ml of toluene Heated under reflux for 6 hours. Then the organic phase is separated off with saturated aqueous saline solution and shaken over magnesium sulfate dried. After filtering and evaporating the filtrate, an oily product is obtained Residue, which is chromatographed on silica gel with toluene / ethyl acetate. Evaporation the product fractions result in a colorless oil which is dried in vacuo.

Yield: 21.3 g (87.2% of theory).

Analysis (based on solvent-free substance):
calc .: C 28.64, H 3.00, I 56.73, N 2.09, O 9.54,
Found: C 28.60, H 3.09, I 56.72, N 2.11.

b) N-acetyl-N-methyl-3 - [(2,3-dihydroxypropyloxy) methyl] -2,4,6-triiodaniline

20.2 g (30.1 mmol) of the compound prepared according to Example 5a) are combined in one Mixture of 60 ml of ethanol and 10 ml of concentrated sulfuric acid entered. To The mixture is taken up in dichloromethane for 12 hours at 30 ° C. and the organic phase once with concentrated sodium chloride solution and twice with  concentrated sodium hydrogen carbonate solution. The organic phase is dried over anhydrous magnesium sulfate, filtered and evaporated. Of the The residue is on silica gel 60 (Merck) with dichloromethane / methanol chromatographed. After evaporating the product fractions, a colorless oil is obtained, which is dried in a vacuum.

Yield: 16.9 g (89.2% of theory).

Analysis (based on solvent-free substance):
calc .: C 24.75, H 2.56, I 60.34, N 2.22, O 10.14,
Found: C 24.86, H 2.69, I 60.12, N 2.34.

c) N-acetyl-N-methyl-3 - [(3-benzoyloxy-2-hydroxypropyloxy) methyl] -2,4,6-- triiodaniline

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

Yield: 13.9 g (78.4% of theory).

Analysis (based on solvent-free substance):
calc .: C 32.68, H 2.74, I 51.79, N 1.91, O 10.88,
Found: C 32.54, H 2.88, I 51.83, N 1.74.

d) N-acetyl-N-methyl-3 - [(3-benzoyloxy-2-methanesulfonyloxypropyloxy) meth-yl] - 2,4,6-triiodaniline

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

Yield: 12.8 g (86.2% of theory) of yellowish foam:

Analysis (based on solvent-free substance):
calc .: C 31.02, H 2.73, I 46.82, N 1.72, O 13.77, S 3.94
Found: C 31.20, H 2.89, I 46.67, N 1.83, S 4.02.

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

11.8 g (14.5 mmol) of the compound prepared in Example 5d) are dissolved in 50 ml N, N-dimethylformamide together with 2.83 g (43.5 mmol) sodium azide for one hour Stirred at 85 ° C under argon. Then it is evaporated in vacuo and the residue with Dichloromethane / saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and in vacuo evaporated.

Yield: 10.2 g (92.1% of theory) of yellowish foam.

Analysis (based on solvent-free substance):
calc .: C 31.60, H 2.52, I 50.09, N 7.37, O 8.42,
Found: C 31.59, H 2.63, I 49.87, N 7.49.

f) N-Acetyl-N-methyl-3 - [(2-azido-3-hydroxypropyloxy) methyl] -2,4,6-triio-daniline

9.58 g (12.6 mmol) of the compound prepared according to Example 5e) are in 60 ml Dissolved methanol. After adding 40 ml of 2N sodium hydroxide solution, the mixture is stirred at 50 ° C. for one hour Bath temperature stirred and neutralized after cooling with 2N hydrochloric acid. Man strips off the methanol in vacuo and distributes the residue between dichloromethane and saturated sodium bicarbonate solution. The organic phase is over Magnesium sulfate dried, filtered, evaporated, the residue is on silica gel 60 (Merck) chromatographed and the product fractions are evaporated in vacuo.

Yield: 7.47 g (90.3 0% of theory).

Analysis (based on solvent-free substance):
calc .: C 23.80, H 2.31, I 58.04, N 8.54, O 7.32,
found: C 23.92, H 2.50, I 57.85, N 8.6.

g) N-acetyl-N-methyl-3 - [(2-azido-3-methanesulfonyloxypropyloxy) methyl] - 2,4,6-triiodaniline

7.22 g (11.0 mmol) of the hydroxy compound prepared according to Example 5f) are added implemented the conditions described in Example 5d) to the corresponding mesylate.

Yield: 7.46 g (92.4% of theory).

Analysis (based on solvent-free substance):
calc .: C 22.91, H 2.33, I 51.86, N 7.63, O 10.90, S 4.37,
Found: C 23.01, H 2.58, I 51.63, N 7.75, S 4.49.

h) N-acetyl-N-methyl-3- (6,9-diaza-4-azido-2-oxanonyl) -2,4,6-triiodanili-n, Dihydrochloride

7.21 g (9.82 mmol) of the mesylate described in Example 5 g) are in 50 ml Dissolved methanol and after adding 150 ml of 1,2-diaminoethane for 15 hours Room temperature stirred. The mixture is then evaporated and between Dichloromethane and saturated sodium bicarbonate solution. The watery Phase is extracted several times with dichloromethane, the combined organic phases are dried over sodium sulfate, filtered and evaporated. Takes the backlog one in tert-butyl methyl ether / methanol and pH 2 with concentrated hydrochloric acid a, whereby a colorless precipitate precipitates. This is separated and in a vacuum dried.

Yield: 7.33 g (96.8% of theory).

Analysis (based on solvent-free substance):
calc .: C 23.37, H 3.01, I 49.38, N 10.90, O 4.15, Cl 9.20,
Found: C 23.28, H 3.22, I 49.39, N 11.02, Cl 9.37.

i) N-acetyl-N-methyl-3- (4-amino-6,9-diaza-2-oxanonyl) -2,4,6-triiodanili-n, Trihydrochloride

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

Yield: 6.12 g (85.8% of theory).

Analysis (based on solvent-free substance):
calc .: C 23.05, H 3.35, I 48.72, N 7.17, O 4.10, Cl 13.61,
Found: 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- (t-ert.- butyloxycarbonylmethyl) -3,6,9-triazaundecanedioic acid di-tert-butyl ester

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

Yield: 8.94 g (98.5% of theory).

Analysis (based on solvent-free substance):
calc .: C 41.50, H 5.52, I 32.08, N 4.72, O 16.18,
Found: 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 shown in Example 5j) are among the in Example 1c) conditions described in the corresponding penta acid.

Yield: 5.80 g (84.1% of theory) of a light beige solid.

Analysis (based on anhydrous substance):
calc .: C 31.20, H 3.46, I 39.56, N 5.82, O 19.95,
Found: C 31.25, H 3.66, I 39.42, N 5.83.

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

5.69 g (6.19 mmol) of the pentic acid prepared in Example 5k) are among the in Example 1d) complexed conditions with gadolinium oxide and in the appropriate disodium salt transferred.

Yield: 6.81 g (94.8% of theory) of colorless lyophilisate.

Analysis (based on anhydrous substance):
calc .: C 25.88, H 2.43, I 32.81, N 4.83, O 16.55, Gd 13.55, Na 3.96,
Found: C 25.94, H 2.61, I 32.78, N 4.85, Gd 13.44, Na 4.00.

Example 6 1,19-bis- (3-carboxy-2,4,6-triiodophenyl) -7,10,13-tris- (carboxymethyl) - 2,5,15,18-tetraoxo-1,4,7,10,13,16,19-heptaazanonadecane, gadolinium complex, Disodium salt a) 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; 19-heptaazanonadecane

11.42 g (20 mmol) of 3-glycylamino-2,4,6-triiodobenzoic acid (DE 25 23 567) are added Warming dissolved in 60 ml of N, N-dimethylformamide. It is added at room temperature with 6.9 ml triethylamine and 3.6 g (10 mmol) N, N-bis- [2,6-dioxomorpholino) ethyl]  glycine and the reaction mixture is stirred for 15 hours at room temperature. Subsequently it is evaporated to dryness, the residue is taken up in water and acidified concentrated hydrochloric acid. The precipitate is filtered off and with Washed water. The crude product is chromatographed on silica gel RP 18 cleaned.

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

Elemental analysis (taking into account the solvent content):
calc .: C 25.60, H 2.22, I 50.73, N 6.53, O 13.18,
Found: 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-1,4,7,10,13,16,19-heptaazanonadecane, gadolinium complex, Disodium salt

7.2 g (48 mmol) of the ligand from Example 6a) are suspended in 50 ml of water and mixed in portions with 1.74 g (4.8 mmol) of gadolinium oxide at 50-60 ° C. To complete complexation, the pH is adjusted to seven with 1N sodium hydroxide solution , filtered and freeze-dried the aqueous solution.

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

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

Example 7 1,19-bis- {3 - [(10-carboxydecyl) carbamoyl] -2,4,6-triiodophenyl} -7,10,13-tris- (carboxymethyl) -2,5,15,18-tetraoxo-1,4,7,10,13,16,19-heptaazanonadec-an, Gadolinium complex, disodium salt a) (3-Aminoacetylamido) -N- (10-carboxydecyl) -2,4,6-triiodobenzoic acid amide-

10.9 g (15 mmol) 3-phthalimidoacetylamino-2,4,6-triiodobenzoic acid chloride (DE 25 23 567) are dissolved in 60 ml of N, N-dimethylacetamide and at 80 ° C. with 1.98 g (16 mmol) 11-aminoundecanoic acid reacted. The reaction mixture is stirred for  32 hours at this temperature and then filtered off from the hydrochloride. The The filtrate is evaporated to dryness, the residue is suspended in 40 ml of water and reacted with 4.5 g (90 mmol) of hydrazine hydrate. After stirring for three hours at 65 ° C the reaction mixture is cooled and the precipitate which has precipitated is filtered off with suction. The product is washed with plenty of water and the solid is dried at 50.degree in a vacuum.

Yield: 9.8 g (87% of theory) of pale yellow crystals.

Elemental analysis (taking into account the solvent content):
calc .: C 34.73, H 4.05, I 40.77, N 6.75, O 13.71,
Found: C 34.90, H 3.92, I 40.68, N 6.51.

b) 1,19-bis- {3 - [(10-carboxydecyl) carbamoyl] -2,4,6-triiodophenyl} -7,10,13-tris- (carboxymethyl) -2,5,15,18-tetraoxo-1,4,7,10,13,16,19-heptaazanonadec-an

8.75 g (11.6 mmol) of the amine from Example 7a) are added in analogy to Example 6a) 2.14 g (6 mmol) of N, N-bis- [2- (2,6-dioxomorpholino) ethyl] glycine reacted and in similarly purified by column chromatography on RP 18.

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

Elemental analysis (taking into account the solvent content):
calc .: C 34.73, H 4.05, I 40.77, N 6.75, O 13.71,
Found: C 34.90, H 3.92, I 40.68, N 6.51.

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

15 g (8 mmol) of the ligand from Example 7b) are made according to Example 6b) with 2.9 g (8 mmol) gadolinium oxide complexed and with 1N sodium hydroxide solution in the disodium salt transferred.

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

Elemental analysis (taking into account the solvent content):
calc .: C 31.40, H 3.42, Gd 7.61, I 36.86, N 6.10, Na 2.23, O 12.39,
Found: C 31.28, H 3.63, Gd 7.56, I 36.61, N 5.89, Na 1.97.

Example 8 Gadolinium complex of the disodium salt of 4- (3-acetylamino-2,4,6-triiodobenzoyl aminomethyl) -3,6,9-triaza-3,6,9-tris (carboxymethyl-4-methylundecanedioic acid a) 2,4-Dimethyl-4-methanesulfonyloxymethyl-2-oxazoline

40.8 g (316 mmol) of 2,4-dimethyl-4-hydroxymethyl-2-oxazoline (J. Nys and J. Libeer, Bull. Soc. Chim. Belg., 65, 377 (1956)) are in 400 ml dichloromethane and 52.5 ml (379 mmol) triethylamine at 0 ° C under nitrogen and added dropwise with 39.8 g (347 mmol) methanesulfonic acid chloride added. The reaction temperature is left rise to room temperature within 3 hours and shakes the mixture saturated sodium bicarbonate solution. The organic phase is over Dried sodium sulfate, filtered and evaporated.

Yield: 58.5 g (89.4% of theory) of a yellowish oil.

Analysis (based on solvent-free substance):
calc .: C 40.57, H 6.32, N 6.76, O 30.88, S 15.47,
Found: C 40.49, H 6.48, N 6.83, S 15.30.

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

A solution of 36.7 g (177 mmol) of the compound prepared according to Example 8a) in 100 ml of methanol is added dropwise to 291 ml (4427 mmol) of 1,2-diaminoethane. The reaction mixture is 3 hours at 50 ° C and a further 12 hours Room temperature stirred. Then the mixture is completely evaporated in vacuo. A solution of the residue in methanol is at 0 ° C with concentrated hydrochloric acid pH 1.5 adjusted. Failing ethylenediamine dihydrochloride is by Filtration separated. By dropwise addition of tert-butyl methyl ether to the filtrate a colorless precipitate, which is filtered off and dried in vacuo.

Yield: 38.2 g (88.4% of theory).

Analysis (based on solvent-free substance):
calc .: C 39.35, H 7.84, N 17.21, O 6.55, Cl 29.04,
Found: C 39.40, H 7.78, N 17.09, Cl 29.11.

c) 2-Amino-4,7-diaza-2-methylheptan-1-ol, trihydrochloride

30.8 g (126 mmol) of the dihydrochloride shown in Example 8b) are in 150 ml of ethanol added. After adding 31 ml of concentrated hydrochloric acid Boiled under reflux for 4 hours. After cooling, the batch is applied in vacuo concentrated and stirred in 300 ml of isopropanol. The precipitate is suctioned off with Washed isopropanol and diethyl ether and dried in vacuo.

Yield: 29.6 g (91.4 th.).

Analysis (based on solvent-free substance):
calc .: C 28.08, H 7.86, N 16.38, O 6.24, Cl 41.45,
Found: C 28.23, H 7.95, N 16.46, Cl 41.19.

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

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

Yield: 52.2 g (98.8% of theory).

Analysis (based on solvent-free substance):
calc .: C 60.23, H 9.41, N 5.85, O 24.51,
Found: C 60.11, H 9.62, N 5.67.

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

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

After evaporation in vacuo, the product fractions result in a yellowish oil.

Yield: 18.7 g (81.7% of theory).

Analysis (based on solvent-free substance):
calc .: C 58.72, H 9.03, Cl 4.81, N 5.71, O 21.73,
Found: C 58.68, H 9.23, Cl 4.98, N 5.64.

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

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

Yield: 18.2 g (97.0% of theory).

Analysis (based on solvent-free substance):
calc .: C 58.20, H 8.95, N 11.31, O 21.73,
Found: C 58.15, H 8.72, N 11.18.

g) -aminomethyl-3,6,9-triaza-3,6,9-tris- (tert-butyloxycarbonylmethyl) - 4-methylundecanedioic acid di-tert-butyl ester

A solution of 18.0 g (24.2 mmol) of the azide prepared in Example 8f) in 180 ml After adding 0.90 g of palladium, ethanol is added to activated carbon (10% by weight  Palladium, manufacturer Degussa) shaken vigorously under a hydrogen atmosphere until no more hydrogen uptake can be observed. Then the catalyst filtered off and the filtrate evaporated in vacuo.

Yield: 17.4 g (99.9% of theory) of a yellowish oil.

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

h) 4- (3-acetylamino-2,4,6-triiodobenzoylaminomethyl) -3,6,9-triaza-3,6,9 - tris- (tert.- butyloxycarbonylmethyl) -4-methylundecanedioic acid di-tert-butyl ester

A solution of 17.2 g (24.0 mmol) of the amine produced in Example 8g) in 70 ml N, N-dimethylacetamide is mixed with 3.99 ml (28.8 mmol) triethylamine and 15.2 g (26.4 mmol) 3-acetylamino-2,4,6-triiodobenzoyl chloride (H. Priewe et al., Chem. Ber. 87, 651 (1954)) and stirred for 6 hours at room temperature. Then in a vacuum evaporated, the residue between ethyl acetate and saturated Distributed sodium bicarbonate solution and the organic phase over the Dried sodium sulfate. After filtration, the filtrate is evaporated and the Residue on silica gel 60 (Merck) with hexane / ethyl acetate (3: 1) chromatographed. After evaporating the product fractions, a yellowish color is obtained Oil.

Yield: 27.9 g (92.6% of theory).

Analysis (based on solvent-free substance):
calc .: C 43.04, H 5.78, I 30.32, N 5.58, O 15.29,
Found: C 43.21, H 5.86, I 30.19, N 5.63.

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

26.6 g (21.2 mmol) of the pentaester described in Example 8h) are among the in Example 1c) conditions converted into the corresponding penta acid.

Yield: 19.5 g (94.4%) light beige solid.

Analysis (based on anhydrous substance):
calc .: C 30.79, H 2.32, I 39.04, N 7.18, Na 3.92, O 19.69,
Found: C 30.98, H 2.40, I 38.84, N 7.24, Na 4.04.

j) Gadolinium complex of the disodium salt of 4- (3-acetylamino-2,4,6-triiod benzoyl aminomethyl) -3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4-methyl-l undecanedioic acid

18.8 g (19.3 mmol) of the penta acid described in Example 8i) are among the in Example 1c) transferred conditions described in the title compound.

Yield: 20.7 g (91.5% of theory) of a colorless solid.

Analysis (based on anhydrous substance):
calc .: C 25.59, H 2.32, Gd 13.50, I 32.44, N 5.97, Na 3.92, O 16.36,
Found: C 25.64, H 2.40, Gd 13.29, I 32.27, N 6.08, Na 4.04.

Example 9 Gadolinium complex of the disodium salt of 4- (3-acetylamino-2,4,6-triiodobenzoyl oxymethyl) -3,6,9-triaza-3,6,9-tris (carboxymethyl) -4-methylundecanedioic acid a) 4- (3-Acetylamino-2,4,6-triiodobenzoyloxymethyl) -4-methyl-3,6,9-tris - (- tert.- butyloxy-carboxymethyl) -3,6,9-triazaundecanedioic acid di-tert-butyl ester

A solution of 14.7 g (20.0 mmol) of the chlorine compound described in Example 8e) in 30 ml of N, N-dimethylacetamide at room temperature to a solution of 16.9 g (29.9 mmol) of the sodium salt of 3-acetylamino-2,4,6-triiodobenzoic acid (Wallingford et al., J. Am. Chem. Soc. 74, 4365 (1952)) in 50 ml of N, N-dimethylacetamide. The reaction mixture is stirred at 80 ° C. for 6 hours, then evaporated in vacuo and with ethyl acetate and saturated sodium hydrogen carbonate solution shaken out. The organic phase is dried over sodium sulfate, filtered and evaporated, the residue on silica gel 60 (Merck) with hexane / ethyl acetate (3: 1) chromatographed. After evaporation of the product fractions, a light beige oil remained back.

Yield: 18.0 g (71.9% of theory).

Analysis (based on solvent-free substance):
calc .: C 43.01, H 5.59, I 30.29, N 4.46, O 16.55,
Found: C 43.11, H 5.84, I 30.42, N 4.48.

b) 4- (3-acetylamino-2,4,6-triiodobenzoyloxymethyl) -4-methyl-3,6,9-triaza - 3,6,9-tris- (tert-butyloxy-carboxylmethyl) undecanedioic acid

17.7 g (14.1 mmol) of the pentaester described in Example 9a) are among the in Example 1d) conditions described in the corresponding penta acid.

Yield: 12.7 g (92.7% of theory) of a light beige solid.

Analysis (based on anhydrous substance):
calc .: C 30.76, H 3.20, I 39.00, N 5.74, O 21.30,
Found: C 30.81, H 3.48, I 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- (carboxymethy-l) - 4-methylundecanedioic acid

9.26 g (9.48 mmol) of the pentic acid described in Example 9b) are analogous to conditions described in Example 1d) converted into the title compound.

Yield: 9.88 (88.7% of theory) of a colorless solid.

Analysis (based on anhydrous substance):
calc .: C 25.14, H 2.29, I 33.21, N 4.89, O 16.75, Gd 13.72, Na 4.01,
Found: C 25.13, H 2.38, I 33.11, N 4.93, Gd 13.67, Na 4.11.

Example 10 Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) - 4-methyl-4- (3-methylcarbamoyl-2,4,6-triiodophenyloxymethyl) undecanedioic acid a) 3,6,9-Triaza-3,6,9-tris- (tert-butyloxycarbonylmethyl) -4-methyl- (3-m-ethyl carbamoyl-2,4,6-triiodophenyloxymethyl) -undecanedioic acid di-tert-butyl ester

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

Yield: 21.9 g (69.4% of theory).

Analysis (based on solvent-free substance):
calc .: C 43.01, H 5.82, I 30.98, N 4.56, O 15.63,
found: C 43.20, H 5.97, I 30.72, N 4.60.

b) 3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4-methyl-4- (3-methylcarbamoy-l- 2,4,6-triiodophenyloxymethyl) undecanedioic acid

20.6 g (17.0 mmol) of the pentaester described in Example 10a) are among the in Example 1c) conditions described in the corresponding penta acid.

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

Analysis (based on anhydrous substance):
calc .: C 30.40, H 3.30, I 40.15, N 5.91, O 20.25,
Found: 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- (carboxy methyl) -4-methyl-4- (3-methylcarbamoyl-2,4,6-triiodophenyloxymethyl) undecanedioic acid

13.2 g (13.9 mmol) of the penta acid described in Example 10b) are analogous to conditions described in Example 1d) converted into the title compound.

Yield: 15.0 g (94.1% of theory) of colorless lyophilisate.

Analysis (based on anhydrous substance):
calc .: C 25.14, H 2.29, I 33.21, N 4.89, O 16.75, Gd 13.72, Na 4.01,
Found: C 25.13, H 2.38, I 33.11, N 4.93, Gd 13.67, Na 4.11.

Example 11 Gadolinium complex of the disodium salt of N, N-bis- [2- [N ′, N′-bis- (carboxymethyl) amino] ethyl] -3-acetylamino-2,4,6-triiodophenylalanine a) 3-Amino-2,4,6-triiodophenylalanine, hydrochloride

A solution of 32.5 g (150 mmol) of 3-aminophenylalanine hydrochloride (Jennings, J. Chem. Soc., 1957, 1512) in 300 ml of water is slowly added at 50 ° C. with stirring a mixture of 300 ml of concentrated hydrochloric acid and 240 ml of 2N potassium iodine dichloride solution dropped in 6.0 l of water. After another 3.5 hours, the warm cloudy solution filtered and concentrated in vacuo until crystallization begins. Then it is cooled well in ice, suction filtered, stirred with water and poured over Dried phosphorus pentoxide.

Yield: 50.7 g (67.0% of theory) of a light beige solid.

Analysis (based on anhydrous substance):
calc .: C 18.19, H 1.70, I 64.06, N 4.71, O 5.38, Cl 5.97,
Found: C 18.38, H 1.94, I 63.82, N 4.83, Cl 6.11.

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

30.8 g (51.8 mmol) of the amino acid prepared according to Example 11a) are in one Mixture of 150 ml of ethanol and 4.1 ml (57 mmol) of thionyl chloride for 10 minutes  Boiled under reflux, then stirred for 12 hours at room temperature. The approach is going then evaporated and the residue dried in vacuo.

Yield: 32.3 g (100% of theory) of a light beige solid.

Analysis (based on anhydrous substance):
calc .: C 21.23, H 2.27, I 61.17, N 4.50, O 5.14, Cl 5.70,
Found: 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-ami-no- 2,4,6-triiodophenylalanine ethyl ester

20.4 g (32.7 mmol) of the amine prepared according to Example 11b) and 31.0 g (73.7 mmol) N, N-bis - [(benzyloxycarbonyl) methyl] -2-bromomethylamine (M. Williams and H. Rapoport, J. Org. Chem. 58, 1151 (1993)) are placed in 50 ml of acetonitrile and 20 ml of 2N phosphate buffer solution (pH 8.0) were added. The approach is at Room temperature vigorously stirred for 24 hours, the aqueous phosphate buffer phase is exchanged for fresh buffer solution after 2 and 8 hours. Then the organic phase evaporated in vacuo and the residue on silica gel Chromatographed hexane / ethyl acetate / triethylamine (3: 1: 0.01). The product-containing fractions are evaporated in vacuo.

Yield: 25.8 g (62.3% of theory) of a yellowish oil.

Analysis (based on solvent-free substance):
calc .: C 48.43, H 4.38, I 30.10, N 4.43, O 12.65,
Found: 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-ac-ethylamino- 2,4,6-triiodophenylalanine ethyl ester

13.7 g (10.8 mmol) of the compound described in Example 11c) are dissolved in 30 ml N, N-dimethylacetamide dissolved and after adding 1.80 ml (13.0 mmol) of triethylamine and 0.85 ml (11.9 mmol) of acetyl chloride at room temperature for 12 hours Exclusion of moisture stirred. Then it is evaporated in vacuo and the residue distributed between ethyl acetate and sodium hydrogen carbonate solution. The organic phase is dried over sodium sulfate, filtered and evaporated.

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

Analysis (based on solvent-free substance):
calc .: C 48.71, H 4.40, I 29.13, N 4.29, O 13.47,
Found: C 48.83, H 4.67, I 29.02, N 4.38.

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

12.8 g (9.80 mmol) of the pentaester described in Example 11d) are dissolved in 75 ml Dissolved methanol and mixed with 49 ml of 2N sodium hydroxide solution. You cook for about 2 hours Reflux and the methanol is removed in vacuo. By adjusting pH 1-2 with semi-concentrated hydrochloric acid produces a colorless precipitate, which is suctioned off and im Vacuum is dried.

Yield: 7.80 g (86.7% of theory).

Analysis (based on anhydrous substance):
calc .: C 30.09, H 3.18, I 41.46, N 6.10, O 19.17,
Found: 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 pentic acid described in Example 11e) are analogous to that in Example 1d) transferred conditions described in the title compound.

Yield: 8.72 g (96.7% of theory).

Analysis (based on anhydrous substance):
calc .: C 24.75, H 2.17, Gd 14.07, I 34.10, N 5.02, Na 4.12, O 15.76,
Found: 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- (carboxym-ethyl) undecanedioic acid, gadolinium complex, disodium salt a) 3,6,9-Triaza-3,6,9-tris- (methoxycarbonylmethyl) -undecanedioic acid methyl ester (JOC 55, 2868, 1990)

20.6 g (52.4 mmol) of diethylenetriaminepentaacetic acid in 618 ml of methanol are at 0 ° C. submitted and with 38.2 ml (0.524 mol) of thionyl chloride within 30 minutes added dropwise. The reaction mixture is then stirred in for 16 hours Room temperature. After the conversion is complete, the mixture is concentrated on a rotary evaporator and suspend the whitish solid in 300 ml of diethyl ether. You move it Suspension at 0 ° C with 200 ml saturated sodium bicarbonate solution, separates the organic phase and the aqueous phase extracted three times with 100 ml each Diethyl ether. The extract is dried over potassium carbonate and after filtration to Evaporated to dryness. The product is vacuumed over phosphorus pentoxide overnight dried.

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

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

b) 3,6,9-triaza-3,6,9-tris- (methoxycarbonylmethyl) -2- (3-nitrobenzyl) undecanedioic acid dimethyl ester

6.64 ml (47.3 mmol) of diisopropylamine in 200 ml of anhydrous tetrahydrofuran presented at 0 ° C in a gentle stream of argon and with 22.2 ml (52 mmol) Butyllithium (15% in hexane) was added dropwise within 15 minutes. The mixture is then cooled to -78 ° C. and 18.4 g (40 mmol) of pentaester (example 12a) dissolved in 300 ml of anhydrous tetrahydrofuran in portions. To Stirring at this temperature for 30 minutes, add a solution of 8.11 g (47.3 mmol) 3-nitrobenzyl chloride and 1.38 ml (11.44 mmol) 1,3-dimethyl 3,4,5,6-tetrahydro-2 (1H) -pyrimidinone in 180 ml of anhydrous tetrahydrofuran within of 30 minutes. The reaction mixture is left overnight at room temperature come and concentrate the solution on the rotary evaporator. The oily residue is in  150 ml of ethyl acetate was added and 50 ml of ice water were added. The organic phase is separated and the aqueous phase three times with 75 ml each Extracted ethyl acetate. The combined organic phases are over potassium carbonate dried, filtered and evaporated to dryness. To clean the raw product the substance is chromatographed on silica gel 60 (Merck).

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

Elemental analysis (taking into account the solvent content):
calc .: C 52.17, H 6.40, N 9.36, O 32.07,
Found: 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 from Example 12b) is added at room temperature with the addition of 1.35 g palladium on carbon (10%) 4 bar hydrogenated. After 5 hours the hydrogenation is complete and the is filtered off Catalyst off. The filtrate is evaporated to dryness and in without further purification the next stage.

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

d) 2- (3-aminobenzyl) -3,6,9-triaza-3,6,9-tris (carboxymethyl) undecanedioic acid

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

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

Elemental analysis (taking into account the solvent content):
found: C 47.15, H 5.84, Cl 6.63, N 10.47, O 29.91,
calc .: 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- (carboxymethy-l) undecanedioic acid

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

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

Elemental analysis (taking into account the solvent content):
calc .: C 28.79, H 3.11, I 43.45, N 6.39, O 18.26,
Found: C 28.93, H 3.37, I 43.32, N 6.48.

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

12.7 g (14.5 mmol) of triiodaniline from Example 12e) are dissolved in 30 ml of N, N-dimethyl dissolved acetamide and mixed with ice cooling with 2.465 ml (34.8 mmol) of acetyl chloride. The mixture is allowed to come to room temperature overnight and the reaction mixture is stirred into Ice water. The precipitate is filtered off, washed with water and at 50 ° C. dried in vacuo.

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

Elemental analysis (taking into account the solvent content):
calc .: C 30.09, H 3.18, I 41.46, N 6.10, O 19.17,
Found: C 29.88, H 3.26, I 41.29, N 6.02.

g) 2- (3-acetamido-2,4,6-triiodobenzyl) -3,6,9-triaza-3,6,9-tris (carboxym-ethyl) undecanedioic acid, gadolinium complex, disodium salt

11.2 g (12.2 mmol) of complexing agent from Example 12f) are obtained using the method of Example 4d) implemented with gadolinium oxide at 50 ° C. After more complete The intermediate is complexed with 1N sodium hydroxide solution in the disodium salt transferred. The resulting solution is cleaned with 1.2 g of activated carbon, over a Filtered 0.2 µm membrane cellulose filter and then freeze-dried.

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

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

Example 13 Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) - 4- [3- [N, N'-dimethyl-N, N'-bis- (2,3-dihydroxypropyl) -3,5-dicarbamoyl-2-, 4,6- triiodophenylcarbamoylmethoxy] benzyl] undecanedioic acid a) N, O-Bis (benzyloxycarbonyl) -3-hydroxyphenylalanine-N- [2- (benzyloxy carbonylamino) ethyl] amide

168.54 g (375 mmol) of N, O-bis (benzyloxycarbonyl) -3-hydroxyphenylalanine (de Castiglione, Bosisio, Gazz. Chim. Ital., 97 1858 (1967)) are in 3.0 l Dissolved tetrahydrofuran and cooled to 0 ° C. After adding 72.8 ml (525 mmol) 36.7 ml (383 mmol) of chlorocarbonic acid ethyl ester are added dropwise to triethylamine. To 75.8 g (390 mmol) of benzyloxycarbonyl- (2-aminoethyl) are added over 20 minutes. amide (G. Atwell, W. Denny, Synthesis, 1032-33 (1984)) in 500 ml of tetrahydrofuran. After stirring overnight, the resulting precipitate is filtered off, the filtrate evaporated and dried in vacuo.

Yield: 183.7 g (78.3% of theory) of a colorless solid.

Analysis: (based on solvent-free substance):
calc .: C 67.19, H 5.64, N 6.72, O 20.46,
Found: C 67.07, H 5.78, N 6.84.

b) 3-Hydroxyphenylalanine (2-aminoethyl) amide

62.57 g (100 mmol) of the compound described in Example 13a) are dissolved in 1.5 l Suspended in methanol and after adding 6.3 g palladium on carbon (10% Weight percent palladium, Degussa) hydrogenated with hydrogen at normal pressure. Then is filtered, the filtrate evaporated and the residue stirred in diisopropyl ether. After vacuuming and drying in vacuo, a colorless solid is obtained.

Yield: 21.4 g (95.8% of theory).

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

c) 1,5-diamino-3-aza-2- (3-ethoxybenzyl) pentane, trihydrochloride

20.1 g (90 mmol) of the compound described in Example 13b) are dissolved in 135 ml Tetrahydrofuran added and dropwise at 0 ° C under argon with 180 ml of 1 m Borohydride solution in tetrahydrofuran added. After stirring for 30 minutes at 0 ° C Stirred for 120 hours at 60 ° C. After cooling, 100 ml of methanol are added dropwise the reaction mixture is saturated with hydrogen chloride and the resulting acid is stirred Suspension 6 hours. Then the precipitate is filtered off and at 50 ° C in a vacuum dried.

Yield: 25.0 g (87.2%) colorless solid.

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

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

15.1 g (47.4 mmol) of the compound described in Example 13c) are dissolved in 500 ml Tetrahydrofuran suspended and with 25 ml of water and 34.5 g (249 mmol) Potassium carbonate added. After dropping 52.3 ml (356 mmol) of bromoacetic acid tert.- butyl ester is stirred at 60 ° C for 3 days. After cooling, it is filtered, in vacuo  concentrated and the residue on silica gel with diethyl ether / hexane / triethylamine (70: 20: 5) chromatographed. The product fractions are evaporated in vacuo.

Yield: 27.2 g (73.3% of theory) of a yellowish oil.

Analysis (based on solvent-free substance):
calc .: C 63.13, H 8.92, N 5.39, O 22.56,
Found: C 63.24, H 8.88, N 5.43.

e) 5-chloroacetylamino-2,4,6-triiodoisophthalic acid- [N, N'-dimethyl-N, N'-bi-s- (2,2-dimethyl-1,3-dioxolan-4-ylmethyl)] diamide

81.0 g (100 mmol) 5-chloroacetylamino-2,4,6-triodisophthalic acid-N, N'-dimethyl- N, N'-bis (2,3-dihydroxypropyl) diamide (DE 29 28 417) are in 500 ml Tetrahydrofuran submitted and with 0.95 g (5.0 mmol) of p-toluenesulfonic acid monohydrate and 22.9 g (220 mmol) of 2,2-dimethoxypropane were added. Then it will be 12 hours refluxed, evaporated in vacuo and the residue between Distributed ethyl acetate and sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulfate and filtered, evaporated and the residue with tert-Butyl methyl ether stirred. After filtering, the residue is removed in vacuo dried.

Yield: 79.7 g (89.6% of theory) of a colorless solid.

Analysis (based on solvent-free substance):
calc .: C 32.40, H 3.51, Cl 3.99, I 42.79, N 4.72, O 12.59,
Found: C 32.38, H 3.62, Cl 4.04, I 42.70, N 4.63.

f) 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- [3- [N, N'-dimethyl-N, N'-bis- (2,2-dimethyl-1,3-dioxolan-4-ylmethyl) -3,5-dicarbamoyl-2,4,6-triiodophenyl carbamoyl-methoxy] -benzyl] -undecanedioic acid di-tert-butyl ester

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

Yield: 16.8 g (62.6% of theory) of viscous oil.

Analysis (based on solvent-free substance):
calc .: C 47.80, H 6.11, I 23.31, N 5.15, O 17.63,
Found: 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-2,4,6-triiodophenylcarbamoylmet-hoxy] benzyl] undecanedioic acid

16.1 g (9.86 mmol) of the compound described in Example 13f) are among the in Example 1c) freed conditions from all protective groups and in transferred the title compound.

Yield: 12.4 g (98.7% of theory) of a light beige solid.

Analysis (based on anhydrous substance):
calc .: C 36.81, H 4.04, I 29.92, N 6.60, O 22.63,
Found: C 36.94, H 4.05, I 29.86, N 6.53.

h) Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris- (carboxy methyl) -4- [3- [N, N'-dimethyl-N, N'-bis- (2,3-dihydroxypropyl) -3,5-dicar-bamoyl- 2,4,6-triiodophenyl-carbamoylmethoxy] benzyl] undecanedioic acid

11.9 g (9.35 mmol) of the penta acid described in Example 13 g are analogous to conditions described in Example 1d) converted into the title compound.

Yield: 13.1 g (95.5% of theory) of colorless lyophilisate.

Analysis (based on anhydrous substance):
calc .: C 31.85, H 3.15, I 25.88, N 5.71, O 19.58, Gd 10.69, Na 3.13,
Found: C 31.92, H 3.20, I 25.76, N 5.73, Gd 10.58, Na 3.20.

Example 14 Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) - 4- (3-methoxy-2,4,6-triiodobenzyl) undecanedioic acid a) 3,6,9-Triaza-3,6,9-tris (carboxymethyl) -4- (3-hydroxybenzyl) -undecanedioic acid

13.2 g (16.9 mmol) of the compound described in Example 13d) are among the in Example 1c) conditions described in the corresponding penta acid.

Yield: 8.20 g (97.0% of theory).

Analysis (based on anhydrous substance):
calc .: C 50.50, H 5.85, N 8.41, O 35.24,
Found: C 50.41, H 5.93, N 8.49.

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

8.11 g (16.2 mmol) of the compound described in Example 14a) are dissolved in 80 ml of 5N aqueous ammonia dissolved. Now 26.8 ml of 2 n Potassium iododichloride solution was added dropwise and the mixture was stirred for 12 hours. You put up with concentrated hydrochloric acid pH 1.5 and adds sodium disulfite until a light suspension is present; this is stirred for 6 hours and filtered. The residue is mixed with 2N hydrochloric acid washed and dried in vacuo.

Yield: 12.1 g (84.8% of theory).

Analysis (based on anhydrous substance):
calc .: C 28.75, H 2.99, I 43.40, N 4.79, O 20.06,
Found: C 28.81, H 2.83, I 43.43, N 4.62.

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

11.6 g (13.2 mmol) of the compound described in Example 14b) are dissolved in 60 ml Tetrahydrofuran at 0 ° C with 2.77 g (92.6 mmol) 80% sodium hydride suspension in Mineral oil added. 13.1 g (92.6 mmol) of iodomethane are added and  Stirred for 30 minutes. Then the solution is mixed with 60 ml of 2N sodium hydroxide solution and Boiled under reflux for 30 minutes. After cooling, the organic Stripped solvent in vacuo and the remaining aqueous solution with concentrated hydrochloric acid adjusted to pH 1.5. There is a precipitation that suction filtered and dried in vacuo.

Yield: 10.7 g (91.4% of theory).

Analysis (based on anhydrous substance):
calc .: C 29.65, H 3.17, I 42.72, N 4.72, O 19.75,
Found: C 29.74, H 3.23, I 42.65, N 4.63.

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

10.2 g (11.4 mmol) of the pentic acid described in Example 14c) are as in Example 1d) converted into the title compound.

Yield: 11.7 g (94.0% of theory) of colorless lyophilisate.

Analysis (based on anhydrous substance):
calc .: C 24.26, H 2.13, I 34.95, N 3.86, O 16.15, Gd 14.43, Na 4.22,
Found: C 24.30, H 2.10, I 34.91, N 3.90, Gd 14.50, Na 4.28.

Example 15 Gadolinium complex of the disodium salt of 3,6,9-triaza-4- (3-diethylcarbamoyl- 2,4,6-triiodophenylcarbamoyloxymethyl) -3,6,9-tris (carboxymethyl) -and-ecanedioic acid a) 3-Isocyanato-2,4,6-triiodobenzoic acid diethylamide

57.00 g (100.0 mmol) 3-amino-2,4,6-triiodobenzoic acid diethylamide (CA 54, P 20987i (1960)) are treated with 250 ml of 2N under a nitrogen atmosphere at room temperature toluene phosgene solution added. The mixture is left after adding 0.5 ml Stir N, N-dimethylformamide at 60 ° C for 5 hours and then evaporate to Dry it up.

Yield: 59.60 g (100.0% of theory) of a yellowish solid.

Analysis: (based on solvent-free substance):
calc .: C 24.18, H 1.86, I 63.88, N 4.70, O 5.37,
Found: C 24.07, H 1.92, I 63.80, N 4.66.

b) 4- (3-diethylcarbamoyl-2,4,6-triiodophenylcarbamoyloxymethyl) -3,6,9-tr-is- (tert.- butyloxycarbonylmethyl) -3,6,9-triazaundecanedioic acid di-tert-butyl ester

A solution of 14.68 g (20.85 mmol) of 3,6,9-triaza-3,6,9-tris- (tert-butyloxy carbonylmethyl) -4-hydroxymethyl-undecanedioic acid di-tert-butyl ester (DE 38 06 795) in 100 ml of anhydrous pyridine is excluded from moisture with 12.42 g (20.85 mmol) of the isocyanate described in Example 15a) and added overnight Room temperature stirred. Then you evaporate completely and chromatograph the residue on silica gel (eluent: hexane / ethyl acetate). Evaporation of the fractions containing the product gives a yellowish oil as a backlog.

Yield: 24.29 g (89.6% of theory).

Analysis (based on solvent-free substance):
calc .: C 43.43, H 5.98, I 29.29, N 5.39, O 16.00,
Found: C 43.42, H 6.11, I 29.25, N 5.44.

c) 3,6,9-triaza-4- (3-diethylcarbamoyl-2,4,6-triiodophenylcarbamoyloxymethyl) - 3,6,9-tris (carboxymethyl) undecanedioic acid

21.62 g (16.63 mmol) of the pentaester described in Example 15b) are among the conditions described in Example 1c) into the corresponding penta acid converted.

Yield: 16.17 g (95.4% of theory) of a colorless solid.

Analysis (based on solvent-free substance):
calc .: C 31.81, H 3.56, I 37.35, N 6.87, O 20.40,
Found: 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 pentic acid described in Example 15c) are converted into the title compound as described in Example 1d).
Yield: 17.44 g (94.1% of theory) of colorless lyophilisate.
Analysis (based on anhydrous substance):
calc .: C 24.26, H 2.13, I 34.95, N 3.86, O 16.15, Gd 14.43, Na 4.22,
Found: C 24.30, H 2.10, I 34.91, N 3.90, Gd 14.50, Na 4.28.

Example 16 Gadolinium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) - 4- (N-carboxymethyl-3-methylamino-2,4,6-triiodophenylureylene methyl) - 4-methylundecanedioic acid a) 3-Isocyanato-2,4,6-triiodobenzoic acid N- (ethoxycarbonylmethyl) methyl amide

61.40 g (100.0 mmol) 3-amino-2,4,6-triiodobenzoic acid N- (ethoxycarbonylmethyl) methylamide (CA 54 P 20987i (1960)) are added under a nitrogen atmosphere 250 ml of 2N toluene phosgene solution are added at room temperature. You leave that After adding 0.5 ml of N, N-dimethylformamide, stir for 5 hours at 60 ° C. and then evaporate to dryness.

Yield: 64.00 g (100.0% of theory) of a yellowish solid.

Analysis: (based on solvent-free substance):
calc .: C 24.40, H 1.73, I 59.49, N 4.38, O 10.00,
Found: C 24.37, H 1.82, I 59.53, N 4.26.

b) 3,6,9-triaza-3,6,9-tris- (tert-butyloxycarbonylmethyl) -4- (N-ethoxyca-rbonylmethyl- 3-methylamino-2,4,6-triiodophenylureylene methyl) -4-methylundecanedioic acid-e-di-tert.- butyl ester

A solution of 16.41 g (22.89 mmol) of the pentaester described in Example 8g) in 100 ml of anhydrous pyridine is excluded from moisture with 14.65 g (22.89 mmol) of the isocyanate described in Example 16a) were added and the mixture was left overnight Room temperature stirred. Then you evaporate completely and chromatograph the residue on silica gel (eluent: hexane / ethyl acetate). Evaporation of the fractions containing the product gives a yellowish oil as a backlog.

Yield: 27.39 g (88.2% of theory)

Analysis (based on solvent-free substance):
calc .: C 43.37, H 5.87, I 28.06, N 6.19, O 16.51,
Found: 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-methyl-mino- 2,4,6-triiodophenylureylene methyl) -4-methylundecanedioic acid

26.68 g (19.66 mmol) of the hexaester described in Example 16b) are among the conditions described in Example 3c) into the corresponding hexa acid converted.

Yield: 19.19 g (93.1% of theory) of a colorless solid.

Analysis (based on solvent-free substance):
calc .: C 30.92, H 3.37, I 36.32, N 8.02, O 21.37,
Found: 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) -4- (N-carboxymethyl-3-methylamino-2,4,6-triiodophenyl ureylenemethyl) -4-methylundecanedioic acid

24.32 g (23.19 mmol) of the pentic acid described in Example 16c) are as in Example 1d) converted into the title compound.

Yield: 27.84 (94.6% of theory) colorless lyophilisate.

Analysis (based on anhydrous substance):
calc .: C 25.57, H 2.30, I 30.01, N 6.63, O 17.66, Gd 12.40, Na 5.44,
Found: C 25.62, H 2.34, I 29.94, N 6.58, Gd 12.35, Na 5.38.

Example 17 Comparative experiment: isomer, for example 1 of WO 93/16375 1,13-bis [5- (propion-3-ylamido] -2,4,6-triiodoisophthalic acid bis (2-hydro-xy- 1-hydroxymethylethyl) diamide] -4,7,10-tris (carboxymethyl) -2,12-dioxo) - 1,4,7,10,13- pentaazatridecan, gadolinium complex a) 1,13-bis [5- (propion-3-ylamido] -2,4,6-triiodoisophthalic acid bis (2-hydro-xy- 1-hydroxymethylethyl) diamide] -4,7,10-tris (carboxymethyl) -2,12-dioxo) - 1,4,7,10,13-pentaazatridecane

16.5 g (21.2 mmol) of 5- (3-aminopropionamido) -2,4,6-triiodo-isophthalic acid bis (2-hydroxy- 1-hydroxymethylethyl) -diamide are at 120 ° C bath temperature in 82.5 ml DMF solved. 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. You steam it Solvent in a vacuum and foams the residue on the oil pump. Of the Solid is stirred with 200 ml of ethanol at room temperature for two hours, filtered off with suction and dried at 50 ° C in a vacuum. Then you take the residue in a little Water up and chromatographed on silica gel RP 18 (eluent: water / methanol). To evaporation of the product fractions gives the title compound as a colorless Solid.

Yield: 17.24 g (42% of theory).

Analysis (based on anhydrous substance):
calc .: C 30.19, H 3.43, I 39.88, N 8.07, O 18.43,
Found: 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-hydro-xy- 1-hydroxymethylethyl) diamide] -4,7,10-tris (carboxymethyl) -2,12-dioxo) - 1,4,7,10,13-pentaazatridecane, gadolinium complex

400 mg of the compound described in Example 17a) are added in portions with 17.8 ml of a 0.01 molar gadolinium acetate solution are added. The pH is shifted into the neutral range with triethylamine and the aqueous solution is stirred for one hour Room temperature with activated carbon. After filtration and freeze drying, the Gadolinium complex as a colorless solid.

Yield: 145 mg (30.5% of theory).

Analysis (based on anhydrous substance):
calc .: C 27.91, H 3.03, I 36.90, N 7.47, O 17.06, Gd 7.62,
Found: C 27.77, H 2.99, I 36.72, N 7.15, Gd 7.38.

Claims (11)

1. Metal complexes containing at least one ion of an element of atomic numbers 12, 13, 20-31, 39-42, 44-50 or 57-83 and a halogen-containing complex-forming ligand of the formula I. wherein
R¹ represents a hydrogen atom, a carboxylic acid residue, a straight-chain or branched C₁-C₄-alkyl residue which is optionally substituted by 1-4 hydroxyl and / or 1-2 carboxy groups and / or is interrupted by 1-2 oxygen atoms, or a residue of the general Formula II or III is CO-NR⁴R⁵ (II) -NR⁶-CO-R⁷ (III) wherein
R⁴, R⁵ independently of one another represent a hydrogen atom, a straight-chain or branched C₁-C₁₀ alkyl radical which may contain 1-4 hydroxyl, 1-2 carboxy groups and / or 1-2 oxygen atoms or together, including the nitrogen atom, an optionally form an oxygen, another acylated nitrogen atom or a sulfonyl group, optionally substituted with 1-3 hydroxy groups, 5 or 6 ring,
R⁶ is a hydrogen atom, a straight-chain or branched C₁-C₁₀ alkyl radical, which may contain 1-4 hydroxyl, 1-2 carboxy groups and / or 1-2 oxygen atoms, or together with R⁷, including the nitrogen atom and the carbonyl group, one optionally forms an oxygen, another acylated nitrogen atom or a sulfonyl group, optionally substituted with 1-3 hydroxyl groups, 5 or 6 ring and
R⁷ is a hydrogen atom, a straight-chain or branched C₁-C₁₀ alkyl radical, which optionally contains 1 to 2 hydroxyl groups or a carboxy group, or together with R⁶, including the nitrogen atom and the carbonyl group, one optionally an oxygen, another acylated nitrogen atom or forms a sulfonyl group containing 5 or 6 rings, optionally substituted with 1-3 hydroxy groups,
R², R³ independently of one another represent a hydrogen atom, a C₁-C₄ alkyl radical which is optionally substituted by 1-4 hydroxyl groups and / or interrupted by 1-2 oxygen atoms, or represent a phenyl or benzyl group or together a trimethylene or tetramethylene group form, or independently of one another have the meaning given for U¹ (U²),
Z¹, Z², Z³ independently represent a hydroxyl group or a radical -NH-U¹ and
U¹, U², V¹, V² and V³ each independently represent a hydrogen atom or a halogenated aromatic radical of the general formula IV, wherein
R⁸, R⁹ independently of one another have the meaning given for R¹, with the exception of a C₁-C₄-alkyl radical,
R¹⁰, R¹¹ independently of one another represent a halogen or a hydrogen atom,
X represents a halogen atom or a bridge member of the general formula V and
Y represents R⁹ or a bridge member of the general formula V, (α) - (CH₂) _p - (C₆H₄) _n - (L) _m -R¹²- (β) (V) wherein
m, n, p independently of one another represent the digits 0 or 1
L represents an oxygen atom, a sulfur atom, a C₁-C₄ alkylene radical, a group <S = O, <SO₂ or <NR⁴ with R⁴ in the abovementioned meaning and
R¹² for a direct bond, a carbonyl, a carboxyl, a -CO-NH, a -NH-CO-, a -NH-CS group or a straight-chain or branched C₁-C₄ alkylene radical, which is optionally a carbonyl - and / or contains an amino group, the position (α) being linked to the diethylenetriamine skeleton and the position (β) being linked to the halogenated aromatics,
where Y is a bridge member of the formula V when X is halogen and Y is R⁹ when X is a bridge member of the formula V and
at least one of the radicals R², R³, Z¹, Z², Z³, U¹, U², V¹, V² or V³ represents or contains the rest of the general formula IV and, if desired, free carboxy groups not required for complexing the metal ions of the elements mentioned, as Salt of an inorganic and / or organic base or amino acid are present,
with the proviso that Z¹, Z², Z³ only represents a radical of the general formula IV if at least one of the substituents R², R³, U¹, U², V¹, V² or V³ does not represent a hydrogen atom or if all of the substituents R², R³, U¹, U², V¹, V² or V³ are hydrogen, at least one of the radicals R⁸, R⁹, R¹⁰ or R¹¹ of formula IV represents a hydrogen atom. 2. Halogen-containing metal complexes according to claim 1, characterized in that the radicals Z¹, Z², Z³ represent a hydroxyl group. 3. Halogen-containing metal complexes according to claim 1 and 2, characterized characterized in that at least one of R Res, R⁹, R¹⁰ or R¹¹ is a Hydrogen atom.   4. Halogen-containing metal complexes according to claim 1, 2 and 3, characterized in that U¹ for a radical of formula VI stands. 5. Halogen-containing metal complexes according to claims 1-4 containing a gadolinium ion as metal ion. 6. Halogen-containing metal complexes according to claims 1-4 containing as Halogen atom (s) iodine. 7. A compound according to claim 1, namely the gadolinium complex of Disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- [4- (2,4,6- triiodobenzyloxy) benzyl] undecanedioic acid. 8. Diagnostic agents containing at least one complex compound after Claim 1, optionally with additives customary in galenics. 9. Use of at least one metal complex for the production of Agents for NMR and / or X-ray diagnostics. 10. Use of at least one metal complex for the production of X-ray diagnostic agents for the liver. 11. A process for the preparation of the agents according to claims 1 to 6, characterized characterized in that the complex salt dissolved in water with those in galenics usual additives or stabilizers in one for enteral or parenteral Application appropriate form is brought so that the complex salt in a Concentration from 1 to 1500 mmol / l is present.