DE10307759B3 - Trimers of macrocyclically substituted benzene derivatives, their production and use as contrast media and pharmaceutical compositions containing them - Google Patents

Abstract

The metal complexes of the general formula I DOLLAR F1 in which Hal represents bromine or iodine and A · 1 · and A · 2 · have different meanings are suitable as contrast agents.

Description

The Invention relates to the subjects characterized in the claims: new trimeric macrocyclically substituted triiodine and tribromobenzene derivatives, their manufacture and use as contrast agents in X-ray and MRI diagnostics.

During the In the past decade, imaging diagnostics have been impressive Progress made. Imaging techniques like DAS, CT and MRI have become the normal and indispensable tools in the Developed and offer diagnostics and interventional radiology today a spatial one resolution less than 1 mm. The application possibilities of these techniques continue to be crucial through the use of contrast media elevated. This wide spread and acceptance of contrast media today in X-ray diagnostics is on the introduction of nonionic monomeric triiodoaromatics in the 80s, and the isoosmolar dimers introduced in the 1990s Iodinated aromatics. By these two classes of compounds was the frequency of contrast media-induced Side effects on 2-4% reduced (Bush W.H., Swanson D.P .: Acute reactions to intravascular contrast media: types, risk factors, recognition and specific treatment. AJR 157, 1153-1161, 1991. Rydberg J., Charles J., Aspelin P .: Frequency of late allergy-like adverse reactions following injection of intravascular non-ionic contrast media. Acta Radiológica 39, 219-222, 1998). The use of contrast media in connection with the modern Imaging techniques today range from tumor detection, for high resolution Vascular imaging, up to the quantitative determination of physiological factors like permeability or perfusion of organs. Essential for the Contrast and detection sensitivity is the concentration of the X-ray contrast agent (here the iodine atom). Despite the further development of technology, the for a medical diagnosis or the necessary concentration applying dose can not be reduced. So in a classic CT Examination 100 g or more substance injected per patient.

Although the tolerance of X-ray contrast media through the introduction of the nonionic triiodobenzenes have been improved Side effects still high. Because of the very high number of examinations of several million per year in X-ray diagnostics tens of thousands of patients affected. These contrast medium-induced Side effects range from mild reactions such as nausea, dizziness, vomiting, Urticaria to severe reactions such as bronchospasm, kidney failure to reactions like shock or even death. Fortunately, these are severe Cases very much rare and with frequency observed from only 1/200000 (Morcos S.K., Thomsen H.S .: Adverse reactions to iodinated contrast media. Eur Radiol 11, 1267-1275, 2001).

The frequency this was also observed as a pseudo-allergic contrast agent-induced Side effects are increased by a factor of 3 in atopic patients, and by a factor of 5 in patients with a history of contrast media Side effects increased. Asthma increased the risk of severe contrast-induced side effects the factor 6 for non-ionic contrast media (Thomsen H.S., Morcos S.K .: Radiographic contrast media. BJU 86 (Suppl1), 1-10, 2000. Thomsen H.S., Dorph S .: High-osmolar and low-osmolar contrast media. An update on frequency of adverse drug reactions. Acta Radiol 34, 205-209, 1993. Katayama H, Yamaguchi K., Kozuka T., Takashima T., Seez P., Matsuura K .: Adverse reactions to ionic and nonionic contrast media. Radiology 175, 621-628, 1990. Thomsen H.S., Bush Jr W.H .: Adverse effects on contrast media. incidence, prevention and management. Drug Safety 19: 313-324, 1998). In these situations the investigators use for X-ray diagnostics lately more and more non-iodine Gd chelates instead of the classic triiodoaromatics in computer tomography but also in interventional radiology and the DSA (Gierada D.S., Bae K.T .: Gadolinium as CT contrast agent: Assessment in a porcine model. Radiology 210, 829-834, 1999. Spinosa D.J., Matsumoto A.H., Hagspiel K.D., Angle J.F., Hartwell G.D .: Gadolinium-based contrast agents in angiography and interventional radiology. AJR 173; 1403-1409, 1999. Spinosa D.J., Kaufmann J.A., Hartwell G.D .: Gadolinium chelates in angiography and interventional radiology: A useful alternative to iodinated contrast media for angiography. Radiology 223, 319-325, 2002). On the one hand, this is due to the very good tolerance of those used in MRI Metal chelates justified, but also due to the well-known fact that lanthanides are also radiopaque are. Gadolinium and other lanthanides show iodine especially at higher ones X-ray voltages / energies a greater absorption as iodine, so that they are principally used as contrasting elements for X-ray diagnostics are suitable (Schmitz S., Wagner S., Schuhmann-Giampieri G., Wolf K.J .: Evaluation of gadobutrol in an rabbit model as a new lanthanide contrast agent for computer tomography. Invest. Radiol. 30 (11): 644-649, 1995).

The Gd-containing chelate compounds mentioned originally used in MRI are also readily water-soluble and are characterized by excellent compatibility. Opposite the iodhalti gen / nonionic contrast media, the rate of mild pseudoallergic reactions is greatly reduced, the rate of fatal reactions is extremely rare and is given as 1/1000000 (Runge VM: Safety of approved MR contrast media for intravenous injection. J. Magn Reson Imaging 12, 205– 213, 2000). In contrast to other side effects induced by contrast agents, such as kidney tolerance, pseudo-allergic reactions tend to be independent of the dose administered. Even the smallest doses can trigger a pseudo-allergic reaction.

Are desired Substances that take advantage of both chemically totally different Unite connection classes.

For a minor intolerance rate she speaks extraordinarily high hydrophilicity of the metal chelates. Iodine aromatics have one around Factor 100-200 higher Lipophilia (larger partition coefficient between butanol / water) as metal chelates.

Due to the low substance concentration and the low specific proportion of the imaging metal in the total molecule, the previously known metal chelates are not optimal for X-ray diagnostics (Albrecht T., Dawson P .: Gadolinium-DTPA as X-ray contrast medium in clinical studies. BJR 73, 878 -882, 2000). More recent approaches to solving this problem describe the production of metal complex conjugates in which triiodoaromatics are covalently bound to an open-chain or macrocyclic metal complex ( US 5,324,503 . US 5,403,576 , WO 93/16375, WO 00/75141, WO 97/01359, WO 00/71526, US 5,660,814 ). However, due to their low hydrophilicity and high viscosity, they cannot be applied in sufficient concentration and reasonable volumes.

aim it is to produce compounds that have sufficient hydrophilicity - comparable that of Gd chelates and additionally have a high concentration of contrasting elements. Values, which is significantly higher than about 25% (w / w) metal chelates would be desirable. At a higher one Concentration must also have a very good water solubility be given. The highly concentrated solutions must be in addition to their good pharmacological Properties also a practical viscosity and a Show low osmotic pressure.

This The object is achieved by the present invention.

worin
Hal für Brom oder Jod,
A¹ für die Reste
-CONR¹-(CH₂)_n-NR²-(CO-CHZ¹-NH)_m-CO-CHZ²-,
-CONR¹-(CH₂)_p-(CONR²CH₂)_m-CHOH-CH₂-,
-CH₂O-(CH₂)_p-CHOH-CH₂-,
-CH₂O-(CH₂)_n-NR¹-(CO-CHZ¹-NH)_m-CO-CHZ²-,
-CH₂-NR¹-CO-(CHZ¹-NH-CO)_m-CHZ²-,
A² die gleiche Bedeutung wie A¹ hat oder im Falle, dass A¹ die oben erstgenannte Bedeutung hat auch für den Rest -NR¹-CO-(NR¹)_m-(CH₂)_p-NR²-(CO-CHZ¹-NH)_m-CO-CHZ²- stehen kann,
in denen R¹ und R² unabhängig ein Wasserstoffatom, eine C₁-C₂-Alkylgruppe oder eine Monohydroxy-C₁-C₂-Alkylgruppe,
Z¹ und Z² unabhängig voneinander ein Wasserstoffatom oder eine Methylgruppe,
n die Ziffern 2–4,
m die Ziffern 0 oder 1 und
p die Ziffern 1–4 bedeuten,
K für einen Makrocyclus der Formel I_A

mit X in der Bedeutung eines Wasserstoffatoms oder eines Metallionenäquivalents der Ordnungszahlen 20–29, 39, 42, 44 oder 57–83 stehen, mit den Maßgaben, dass mindestens zwei X für Metallionenäquivalente stehen und gegebenenfalls vorhandene freie Carboxygruppen gegebenenfalls als Salze organischer und/oder anorganischer Basen oder Aminosäuren oder Aminosäureamide vorliegen, zeigen eine sehr gute Löslichkeit und einen Verteilungskoeffizienten, der mit dem von Gd-Chelaten vergleichbar ist. Weiterhin weisen die neuen Verbindungen einen hohen spezifischen Gehalt an kontrastgebenden Elementen, eine niedrige Viskosität und Osmolalität, und damit gute Toleranz/Verträglichkeit auf, so dass sie hervorragend als Kontrastmittel für die Röntgen- und MR-Bildgebung geeignet sind.The metal complexes of the general formula I according to the invention

wherein
Hal for bromine or iodine,
A ¹ for the residues
-CONR ¹ - (CH ₂ ) _n -NR ² - (CO-CHZ ¹ -NH) _m -CO-CHZ ² -,
-CONR ¹ - (CH ₂ ) _p - (CONR ² CH ₂ ) _m -CHOH-CH ₂ -,
-CH ₂ O- (CH ₂ ) _p -CHOH-CH ₂ -,
-CH ₂ O- (CH ₂ ) _n -NR ¹ - (CO-CHZ ¹ -NH) _m -CO-CHZ ² -,
-CH ₂ -NR ¹ -CO- (CHZ ¹ -NH-CO) _m -CHZ ² -,
A ^{2 has} the same meaning as A ¹ or, in the case where A ^{1 has} the first-mentioned meaning, also for the radical -NR ¹ -CO- (NR ¹ ) _m - (CH ₂ ) _p -NR ² - (CO-CHZ ¹ -NH) _m -CO-CHZ ² - can stand,
in which R ¹ and R ² independently represent a hydrogen atom, a C ₁ -C ₂ alkyl group or a monohydroxy C ₁ -C ₂ alkyl group,
Z ¹ and Z ² independently of one another are a hydrogen atom or a methyl group,
n the numbers 2-4,
m the digits 0 or 1 and
p denotes the digits 1-4,
K for a macrocycle of the formula I _A

with X in the meaning of a hydrogen atom or a metal ion equivalent of atomic numbers 20-29, 39, 42, 44 or 57-83, with the provisos that at least two X stand for metal ion equivalents and any free carboxy groups which may be present as salts of organic and / or inorganic bases or amino acids or amino acid amides are present, show a very good solubility and a distribution coefficient that is comparable to that of Gd chelates. Furthermore, the new compounds have a high specific content of contrasting elements, a low viscosity and osmolality, and thus good tolerance / tolerance, so that they are outstandingly suitable as contrast agents for X-ray and MR imaging.

Hal is preferably iodine, R ¹ and R ^{2 are} hydrogen and the methyl group, n is the number 2 and p is the number 1.

Residues A ¹ mentioned by way of example are:
-CONH (CH ₂ ) _{2; 3} NHCOCH ₂ NHCOCH (CH ₃ ) -,
-CONH (CH ₂ ) _{2; 3} NHCOCH ₂ NHCOCH ₂ -,
-CONH (CH ₂ ) _{2; 3} NHCOCH ₂ -,
-CONH (CH ₂ ) _{2; 3} NHCOCH (CH ₃ ) -,
-CONHCH ₂ CH (OH) CH ₂ -,
-CON (CH ₃ ) CH ₂ CH (OH) CH ₂ -,
-CH ₂ OCH ₂ CH (OH) CH ₂ -,
-CONHCH ₂ CONHCH ₂ CH (OH) CH ₂ -,
-CH ₂ NHCOCH ₂ -,
-CH ₂ NHCOCH (CH ₃ ) -,
-CH ₂ NHCOCH ₂ NHCOCH ₂ -,
-CH ₂ NHCOCH ₂ NHCOCH (CH ₃ ) -,
-CH ₂ O (CH ₂ ) ₂ NHCOCH ₂ -,
-CON (CH ₂ CH ₂ OH (CH ₂ ) ₂ NHCOCH ₂ -,
-CH ₂ O (CH ₂ ) ₂ N (CH ₂ CH ₂ OH) COCH ₂ -.

Residues A ² mentioned by way of example are:
-NHCOCH ₂ NHCOCH ₂ NHCOCH (CH ₃ ) -,
-NHCOCH ₂ NHCOCH ₂ NHCOCH ₂ -,
-NHCOCH ₂ NHCOCH ₂ -,
-NHCOCH ₂ NHCOCH (CH ₃ ) -,
-N (CH ₃ ) COCH ₂ NHCOCH ₂ -,
-NHCONH (CH ₂ ) ₂ NHCONH ₂ -,
-NHCOCH ₂ N (CH ₂ CH ₂ OH) COCH ₂ -,
-N (CH ₃ ) COCH ₂ N (CH ₂ CH ₂ OH) COCH ₂ -.

• a) einen Trijod- oder Tribromaromaten der allgemeinen Formel II
  
  in an sich bekannter Weise mit einem Makrocyclus der allgemeinen Formel III
  
  worin C^xO für eine -COOH- oder aktivierte Carboxylgruppe, W für eine Schutzgruppe oder eine -CH₂COOX'-gruppe mit X' in der Bedeutung von X oder einer Schutzgruppe und -Y¹-NR¹-CO-B¹- für den Rest A¹ in der Bedeutung von -CO-NR¹-(CH₂)_n-NR²-(CO-CHZ¹-NH)_m-CO-CHZ²- oder -CH₂-O-(CH₂)_n-NR¹-(CO-CHZ¹-NH)_m-CO-CHZ²- und Y²-NR¹-CO-B¹ für Y¹-NR¹-CO-B¹ oder für den Fall, dass Y¹-NR¹-CO-B¹ die oben erstgenannte Bedeutung hat auch für -NR¹-CO-(NR¹)_m(CH₂)_p-NR²-(CO-CHZ¹-NH)_m-CO-CHZ²-stehen, wobei B¹ den an die erste oder zweite (von K aus gesehene) Carbonylgruppe zwischen -CO- und K stehenden Rest bedeutet und Y¹ bzw. Y² für den um eine Iminogruppe verminderten fehlenden Rest der Linkergruppe steht, umsetzt und anschließend gegebenenfalls die Schutzgruppe W entfernt und die Reste CH₂COOX in an sich bekannter Weise einführt bzw. die für X' gegebenenfalls stehende Schutzgruppe entfernt und anschließend in an sich bekannter Weise mit einem Metalloxid oder Metallsalz eines Elements der Ordnungszahlen 20–29, 39, 42, 44 oder 57–83 umsetzt oder
• b) einen Trijod- oder Tribromaromaten der allgemeinen Formel IV
  
  in an sich bekannter Weise mit einem Makrocyclus der allgemeinen Formel V
  
  worin -C^xO und X' die oben genannte Bedeutung haben und -CO-NR¹-Y³ für den Rest A¹ in der Bedeutung -CONR¹-(CH₂)_p-(CONR²CH₂)_m-CH(OH)CH₂- und damit Y³ in der Bedeutung von -NR¹-(CH₂)_p-(CONR²CH₂)_m-CH(OH)CH₂-stehen, umsetzt und anschließend die für X' gegebenenfalls stehende Schutzgruppe entfernt und danach in an sich bekannter Weise mit einem Metalloxid oder Metallsalz eines Elements der Ordnungszahlen 20–29, 39, 42, 44 oder 57–83 umsetzt oder
• c) einen Trijod- oder Tribromaromaten der allgemeinen Formel VI
  
  worin A¹ für einen Rest
  
  steht, in an sich bekannter Weise mit einem Cyclen der allgemeinen Formel VII
  
  worin W' für ein Wasserstoffatom oder eine Schutzgruppe steht, zu (nachdem man die gegebenenfalls vorhandenen Schutzgruppen entfernt und anschließend in an sich bekannter Weise die Reste -CH₂COOX eingeführt hat) einem Metallkomplex der allgemeinen Formel I mit A in der Bedeutung des Restes -CH₂-O-(CH₂)_p-CHOH-CH₂- umsetzt oder
• d) einen Trijod- oder Tribromaromaten der allgemeinen Formel VIII
  
  worin Nucleofug für eine nucleofuge Gruppe steht, in an sich bekannter Weise mit einem Makrocyclus der allgemeinen Formel IX
  
  worin R¹ und W die oben genannte Bedeutung haben, und B² für den Rest -(CHZ¹-NHCO)_m-CHZ²- steht, umsetzt und anschließend wie unter a) angegeben weiter verfährt, so dass man Metallkomplexe der allgemeinen Formel I mit A¹ in der Bedeutung des Restes -CH₂-NR¹-CO-(CHZ¹-NHCO)_m-CHZ² erhält, wobei anschließend gegebenenfalls in den so nach a)–d) erhaltenen Metallkomplexen der allgemeinen Formel I noch vorhandene acide Wasserstoffatome durch Kationen von anorganischen oder organischen Basen, Aminosäuren oder Aminosäureamiden substituiert werden.

The compounds of the general formula I according to the invention can be prepared by processes known to the person skilled in the art, for example by

• a) a triiodo or tribromoaromatic of the general formula II
  
  in a manner known per se with a macrocycle of the general formula III
  
  wherein C ^x O for a -COOH or activated carboxyl group, W for a protective group or a -CH ₂ COOX 'group with X' in the meaning of X or a protective group and -Y ¹ -NR ¹ -CO-B ¹ - for the radical A ¹ in the meaning of -CO-NR ¹ - (CH ₂ ) _n -NR ² - (CO-CHZ ¹ -NH) _m -CO-CHZ ² - or -CH ₂ -O- (CH ₂ ) _n -NR ¹ - (CO-CHZ ¹ -NH) _m -CO-CHZ ² - and Y ² -NR ¹ -CO-B ¹ for Y ¹ -NR ¹ -CO-B ¹ or in the event that Y ¹ -NR ¹ -CO-B ^{1 also has} the meaning given above for -NR ¹ -CO- (NR ¹ ) _m (CH ₂ ) _p -NR ² - (CO-CHZ ¹ -NH) _m -CO-CHZ ² - are, where B ^{1 is} the radical on the first or second carbonyl group (seen from K) between -CO- and K and Y ¹ or Y ^{2 is} the missing radical of the linker group reduced by an imino group, and then optionally reacted the protective group W is removed and the radicals CH ₂ COOX are introduced in a manner known per se or the protective group which may be X 'is removed and then known per se with a metal oxide or metal salt of an element of atomic numbers 20-29, 39, 42, 44 or 57-83 or
• b) a triiodo or tribromoaromatic of the general formula IV
  
  in a manner known per se with a macrocycle of the general formula V
  
  where -C ^x O and X 'have the meaning given above and -CO-NR ¹ -Y ³ for the radical A ^{1 has} the meaning -CONR ¹ - (CH ₂ ) _p - (CONR ² CH ₂ ) _m -CH ( OH) CH ₂ - and thus Y ³ in the meaning of -NR ¹ - (CH ₂ ) _p - (CONR ² CH ₂ ) _m -CH (OH) CH ₂ -, and then the one for X ', if appropriate protective group removed and then reacted in a manner known per se with a metal oxide or metal salt of an element of atomic numbers 20-29, 39, 42, 44 or 57-83 or
• c) a triiodo or tribromoaromatic of the general formula VI
  
  where A ¹ for a radical
  
  stands in a manner known per se with a cycle of the general formula VII
  
  in which W 'represents a hydrogen atom or a protective group, (after removing the protective groups which may be present and then introducing the radicals -CH ₂ COOX in a manner known per se) into a metal complex of the general formula I with A in the meaning of the radical - CH ₂ -O- (CH ₂ ) _p -CHOH-CH ₂ - or
• d) a triiodo or tribromoaromatic of the general formula VIII
  
  wherein Nucleofug stands for a nucleofugic group, in a manner known per se with a macrocycle of the general formula IX
  
  wherein R ¹ and W have the meaning given above, and B ^{2 represents} the radical - (CHZ ¹ -NHCO) _m -CHZ ² -, and then proceeds as indicated under a), so that metal complexes of the general formula I are used A ¹ in the meaning of the radical -CH ₂ -NR ¹ -CO- (CHZ ¹ -NHCO) _m -CHZ ² is obtained, with acidic hydrogen atoms still present in the metal complexes of the general formula I thus obtained according to a) -d) can be substituted by cations of inorganic or organic bases, amino acids or amino acid amides.

As Amino protecting groups W are the benzyloxycarbonyl, tert-butoxycarbonyl, Trifluoroacetyl, fluorenylmethoxycarbonyl, benzyl, formyl, 4-methoxybenzyl, 2,2,2-trichloroethoxycarbonyl, Phthaloyl, 1,2-oxazoline, tosyl, dithiasuccinoyl, allyloxycabonyl, Sulfate, pent-4-encarbonyl-, 2-chloroacetoxymethyl (or -ethyl) called benzoyl, tetrachlorophthaloyl, alkyloxycarbonyl groups [Th. W. Greene, P.G.M. Wuts, Protective Groups in Organic Syntheses, 2nd ed, John Wiley and Sons (1991) pp. 30-385; E. Meinjohanns et al, J. Chem. Soc. Pekin Trans 1, 1995, 405; U. Ellensik et al, Carbohydrates Research 280, 1996, 251; R. Madsen et al, J. Org. Chem. 60, 1995, 7920; R. R. Schmidt, Tetrahedron Letters 1995, 5343].

The The protective groups are split off according to those known to the person skilled in the art Procedure (see e.g. E. Wünsch, Methods of Org. Chemie, Houben-Weyl, Vol XV / 1, 4th edition 1974, P. 315), for example by hydrolysis, hydrogenolysis, alkaline Saponification of the esters with alkali in aqueous-alcoholic solution Temperatures from 0 ° C up to 50 ° C, acidic saponification with mineral acids or in the case of Boc groups with the help of trifluoroacetic acid.

bevorzugt sind 4-Nitrophenylester und N-Hydroxysuccinimidester.Activated carboxyl groups are understood above to mean those carboxyl groups which are derivatized in such a way that they facilitate the reaction with an amine. It is known which groups can be used for activation and reference can be made, for example, to M. and A. Bodanszky, "The Practice of Peptide Synthesis", Springer Verlag 1984. Examples are adducts of carboxylic acid with carbodiimides or activated esters such as hydroxybenzotriazole esters. Acid chloride, N-hydroxysuccinimide ester,

4-nitrophenyl esters and N-hydroxysuccinimide esters are preferred.

ist möglich (Hal = Halogen).The activated esters of the compounds described above are prepared as known to those skilled in the art. Also the reaction with correspondingly derivatized esters of N-hydroxysuccinimide such as:

is possible (Hal = halogen).

In general, all customary activation methods for carboxylic acids which are known in the prior art can be used for this purpose. The carboxylic acid is activated by the usual methods. Examples of suitable activation reagents are dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) and O- (benzotriazol-1-yl) -1,1,3,3 -tetramethyluronium hexafluorophosphate (HBTU), preferably DCC. It is also possible to add O-nucleophilic catalysts, such as N-hydroxysuccinimide (NHS) or N-hydroxybenzotriazole.

The residues advantageously serve as nucleofug:
F, Cl, Br, I, -OTs, -OMs, OH,

If X 'for an acid protection group stands, come lower alkyl, aryl and aralkyl groups, for example the methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl, Triphenylmethyl, bis- (p-nitrophenyl) methyl group, and trialkylsilyl groups in question.

Prefers are the t-butyl and the benzyl group.

The protecting groups are split off by the processes known to the person skilled in the art (see, for example, E. Wünsch, Methods of Org. Chemistry, Houben-Weyl, Vol XV / 1; 4th edition 1974, p. 315), for example by hydrolysis, hydrogenolysis, alkaline saponification the ester in aqueous-alcoholic solution at temperatures of 0 ° C to 50 ° C, acid saponification with mineral acids or in the case of tert-butyl esters with the aid of trifluoroacetic acid (Protective Groups in Organic Synthesis, 2 ^nd Edition, TW Greene and PGM Wuts , John Wiley and Sons Inc., New York, 1991).

The desired metal ions can be introduced in the manner described in the patents EP 71564 . EP 130934 and DE-OS 34 01 052 has been disclosed. For this purpose, the metal oxide or a metal salt (for example a chloride, nitrate, acetate, carbonate or sulfate) of the desired element is dissolved or suspended in water and / or a lower alcohol (such as methanol, ethanol or isopropanol) and with the solution or suspension of the equivalent Amount of complexing agent implemented.

The Neutralization of any free carboxy groups still present takes place with the help of inorganic bases (e.g. hydroxides, carbonates or bicarbonates) of e.g. Sodium, potassium, lithium, magnesium or calcium and / or organic bases such as primary, secondary and tertiary Amines such as Ethanolamine, morpholine, glucamine, N-methyl and N, N-dimethylglucamine, as well as basic amino acids, such as. Lysine, arginine and ornithine or from amides original neutral or acidic amino acids.

to One can, for example, prepare the neutral complex compounds in acidic complex salts in aqueous solution or suspension as much of the desired Add base so that the neutral point is reached. The received solution can then be evaporated to dryness in vacuo. It is often an advantage that neutral salts formed by adding water-miscible solvents, such as. lower alcohols (methanol, ethanol, isopropanol and others), lower ketones (acetone and others), polar ethers (tetrahydrofuran, Dioxane, 1,2-dimethoxyethane and others) precipitate and so easy to isolate and to get easy-to-clean crystals. To be particularly advantageous it has proven to be the one you want Base already during add the complex formation of the reaction mixture and thereby to save one procedural step.

The complexes thus obtained are purified, if necessary after adjusting the pH by adding an acid or base to pH 6 to 8, preferably about 7, preferably by ultrafiltration with Membranes of suitable pore size (eg Amicon ^® YM1, Amicon ^® YM3), gel filtration on eg suitable Sephadex ^® gels or by HPLC on silica gel or reverse phase material.

A Cleaning can also be done by crystallization from solvents such as methanol, Ethanol, i-propanol, acetone or their mixtures with water.

In the case of neutral complex compounds, it is often advantageous to give the oligomeric complexes via an anion exchanger, for example IRA 67 (OH ^- form) and, if appropriate, additionally via a cation exchanger, for example IRC 50 (H ⁺ form) for the separation of ionic components

• a) Die Umsetzung von Trijod- oder Tribromaromaten der allgemeinen Formel II mit Verbindungen der allgemeinen Formel III erfolgt nach den dem Fachmann bekannten Verfahren der Amidbildung. Hierbei kann entweder eine direkte Kupplung der freien Säure von III mit dem freien Amin von II mit wasserabspaltenden Reagenzien wie Dicyclohexylcarbodiimid, Diisopropylcarbodiimid, EDC, EEDQ, TBTU, HATU in aprotischen Lösungsmitteln wie DMF, DMA, THF, Dioxan, Toluol, Chloroform oder Methylenchlorid bei Temperaturen von 0°–50°C durchgeführt werden, oder aber man aktiviert die Säuregruppe in der Verbindung der allgemeinen Formel III, indem man sie zuerst in einen Aktivester überführt (siehe Seite 11) und dann diesen Ester in einem Lösungsmittel, wie beispielsweise DMF, DMA, THF, Dioxan, Dichlormethan, i-ProOH, Toluol, gegebenenfalls unter Zusatz einer organischen oder anorganischen Base, wie NEt₃, Pyridin, DMAP, Hünigbase, Na₂CO₃, CaCO₃ bei Temperaturen von –10° bis +70° C umsetzt mit dem Amin der allgemeinen Formel II. In einigen Fallen hat es sich als vorteilhaft erwiesen, direkt die Metallkomplexe der allgemeinen Formel III herzustellen und deren endständige Carbonsäure unter den in WO 98/24775 genannten Verfahren zu kuppeln. Die Herstellung der Metallkomplexe ist in WO 98/24774 beschrieben. Die Herstellung von Verbindungen der allgemeinen Formel II erfolgt im Falle, wenn Y² für Y¹ steht durch Umsetzungen von Verbindungen der allgemeinen Formel IV
  
  mit Diaminen der allgemeinen Formel A HNR¹-(CH₂)_m-NR²H (A)worin Hal, CO*, R¹, R², m in der oben angegebenen Bedeutung stehen, nach den dem Fachmann bekannten Methoden der Amidbildung (siehe oben) in einem aprotischen Lösungsmittel wie DMF, DMA, THF, Dioxan, 1,2-Dichlorethan, Chloroform, Dichlormethan oder Toluol gegebenenfalls unter Zusatz einer organischen oder anorganischen Base wie NEt₃, Pyridin, DMAP, Hünigbase, Na₂CO₃, K₂CO₃, CaCO₃ bei Temperaturen von 0°C–100°C. In manchen Fällen hat es sich als vorteilhaft erwiesen, das Diamin selbst als Lösungsmittel zu verwenden. Manchmal kann es von Vorteil sein, eine der beiden endständigen Aminogruppen in geschützter Form einzusetzen (z.B. Mono-Boc, Mono-Z) und nach erfolgter Kupplung diese Schutzgruppe nach den em Fachmann bekannten Methoden abzuspalten (T.W. Greene, s.o.). Die Diamine bzw. monogeschützten Diamine sind literaturbekannt und käuflich zu erwerben (z.B. Aldrich, Fluka). Bevorzugt wird das Säurechlorid der Verbindung der allgemeinen Formel IV verwendet. Die Herstellung der Verbindung
  
  ist in DE 3001292 beschrieben. Die Herstellung der entsprechenden Tri-Bromverbindung erfolgt in analoger Weise aus Tribromaminoisophthalsäure durch Sandmeyer-Reaktion (Einführung von CN und anschließender Verseifung) wie in EP 0073715 beschrieben, hergestellt werden. Im Falle dass Y² ungleich Y¹ ist hat sich die folgende Vorgehensweise bewährt: Die Verbindungen der allgemeinen Formel B
  
  worin CO*, Hal in der oben genannten Bedeutung stehen, werden zuerst mit Verbindungen der allgemeinen Formel C CO*-(CHZ¹)-NH-Sg (C)worin CO*, Z¹ die oben genannte Bedeutung haben und Sg für eine Aminoschutzgruppe stellt, umgesetzt. Die Umsetzung erfolgt nach den bereits oben angegebenen Methoden der Amidbildung (Neher et al Helv. Chim. Acta, 1946, 1815.) Anschließend wird wie oben bereits beschrieben mit Verbindungen der allgemeinen Formel A umgesetzt und anschließend eventuell vorhandene Aminoschutzgruppen gespalten (s. T.W. Greene). Als vorteilhaft hat es sich erwiesen, die Säurechloride der allgemeinen Formel C einzusetzen. Im Falle wenn Sg eine Trifluoracetyl-Schutzgruppe darstellt, wird diese in einem Eintopf-Verfahren direkt mit einem Überschuss Diamin der allgemeinen Formel A abgespalten. Verbindungen der allgemeinen Formel C sind nach literaturbekannten Methoden erhältlich. Zur Herstellung von Harnstoffderivaten werden Verbindungen der allgemeinen Formel B zuerst mit Isocyanaten der allgemeinen Formel D
  
  umgesetzt und dann wie oben beschrieben mit den Diaminen der allgemeinen Formel weiter umgesetzt. Die Umsetzung der Isocyanate erfolgt in aprotischen Lösungsmitteln wie oben zur Amidbildung beschrieben. Die Reaktionstemperatur beträgt 0°C bis 100°C. Isocyanate (D) werden, wie z.B. in Guichard et al., J. Org. Chem., 1999, 8702 beschrieben, hergestellt. Verbindungen der allgemeinen Formel B sind in DE 3001292 beschrieben.
• b) Die Umsetzung von Verbindungen der allgemeinen Formel IV mit Verbindungen der allgemeinen Formel V erfolgt nach den dem Fachmann bekannten Methoden der Amid-Bildung, wie sie bereits zuvor unter a) ausführlich beschrieben wurden. Auch hier wird bevorzugt das Säurechlorid der Verbindungen IV eingesetzt. Verbindungen der allgemeinen Formel V erhält man aus Verbindungen der allgemeinen Formel E
  
  worin X' in der oben genannten Bedeutung steht, durch Umsetzung mit primären Epoxiden der allgemeinen Formel F
  
  worin R¹, Sg, p, m, R² in der oben genannten Bedeutung stehen. Die Umsetzung erfolgt in protischen oder aprotischen Lösungsmitteln wie Methanol, Ethanol, Butanol, Propanol, DMF, Toluol, CHCl₃, DMA (gegebenenfalls jeweils unter Zusatz von Wasser) bei Temperaturen von 0°C bis 15°C. In einigen Fällen hat sich der Zusatz einer Lewissäure wie LiCl, LiBr, LiJ, LiClO₄ oder Y(triflat)₃ bewährt. Verbindungen der allgemeinen Formel F sind nach literaturbekannten Methoden zugänglich (Krawiecka et al., J. Chem. Soc. Perkin Trans. 1, 2001, 1086) oder sind käuflich erwerbbar. Verbindungen der allgemeinen Formel E sind sogenannte DO3A-derivate und sind in der Literatur beschrieben (Chatal et al., Tetrahedron Lett., 1996, 7515).
• c) Die Umsetzung der Epoxide der allgemeinen Formel VI mit Verbindungen der allgemeinen Formel VII erfolgt nach den unter b) beschriebenen Methoden der Umsetzung von Epoxiden mit Aminen. In einigen Fallen hat es sich als vorteilhaft erwiesen, den in EP 0545511 beschriebenen Weg unter Verwendung der Verbindung
  
  zu benutzen. Man kann aber auch nach EP 0643705 vorgehen oder das unter WO 98/55467 beschriebene Lithiumverfahren benutzen. Die Herstellung der Verbindungen VII im Falle von W'-Schutzgruppe siehe b) ist literaturbekannt. Die TriBoc-Cyclen Verbindung ist in Kimura et al., J. Am. Chem. Soc., 1997, 3068, die Tri Z-Cyclen Verbindung in Delaney et al., J. Chem. Soc., Perkin Trans., 1991, 3329 beschrieben. Verbindungen der allgemeinen Formel VI sind durch Umsetzung von Triolen der allgemeinen Formel G
  
  mit Epoxiden der allgemeinen Formel H
  
  mit p in der oben genannten Bedeutung und worin Z für Cl, Br, I, OT_s steht, zugänglich. Die Umsetzung erfolgt nach literaturbekannten Methoden der Glycidetherbildung (p = 1) bzw. Veretherung Mouzin et al., Synthesis, 1983, 117. Verbindungen der allgemeinen Formel H sind literaturbekannt z.B. Sharpless et al., J. Org. Chem., und DE 935433 bzw. käuflich erhältlich (z.B. Epichlorhydrin, Fluka, Aldrich). Verbindungen der allgemeinen Formel G im Fall von Hal=Iod sind in US 6,310,243 beschrieben. Die Herstellung der Bromverbindung erfolgt in analoger Weise.
• d) Die Umsetzung erfolgt derart, indem man zuerst das Amid der Verbindungen der allgemeinen Formel IX nach dem den Fachmann bekannten Methoden deprotoniert, z.B. mit NaH in DMF, THF, DMA, Dioxan, Toluol (Temperaturen 0°C–100°C) oder BuLi, LDA, Li-HMDS, Na-HMDS in THf, MTB bei Temperaturen von –70° bis 0°C und anschließend mit Verbindungen der allgemeinen Formel VIII umsetzt (bevorzugte Temperaturen –70 bis 70°C). Verbindungen der allgemeinen Formel VIII erhält man aus Verbindungen der allgemeinen Formel G
  
  nach den dem Fachmann bekannten Methoden zur Umwandlung einer primären OH-Gruppe in ein Halogenid bzw. Tosylat, Triflat, etc. Verbindungen der allgemeinen Formel IX erhält man aus Verbindungen der allgemeinen Formel IXa
  
  durch Amidbildung mit Aminen der Formel R¹NH₂ (Amide der Formel sind käuflich bzw. literaturbekannt) nach den bereits unter a) erwähnten Methoden der Amidkupplung. Verbindungen der allgemeinen Formel IX a sind z.B. in WO 97/02051, WO 99/16757 beschrieben oder können nach literaturbekannten Methoden einfach aus Tri-Boc Cyclen, bzw. Tri-Z-Cyclen hergestellt werden. Die erfindungsgemäßen Verbindungen sind sowohl in der Röntgen- als auch in der MR Diagnostik einsetzbar. Die hohe Röntgendichte gepaart mit ihrer guten Wasserlöslichkeit der iodierten Röntgenkontrastmittel ist mit der ausgeprägten Hydrophilie der Metall-Chelate und der ihnen innewohnenden guten Verträglichkeit in einem Molekül vereint. Die sehr hohe Hydrophilie der neuen Verbindungen führt dazu, dass das Nebenwirkungsprofil dem der sehr gut verträglichen Gd-Verbindungen entspricht, wie sie in der MR-Bildgebung verwendet werden. Diese Eigenschaft macht sie daher besonders geeignet für den Einsatz bei Patienten mit einer nachgewiesenen Allergie gegen iodierte Verbindungen oder bei vorhandener Atopie. Besonders wird die Inzidenz der schweren Nebenwirkungen wie Bronchospasmus und Schock oder gar Tod auf das niedrige Niveau der MR-Kontrastmittel gesenkt.

The compounds of general formula I according to the invention can be prepared as indicated above:

• a) The reaction of triiodo or tribromoaromatics of the general formula II with compounds of the general formula III takes place according to the amide formation processes known to the person skilled in the art. Here, either a direct coupling of the free acid of III with the free amine of II with water-releasing reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, EDC, EEDQ, TBTU, HATU in aprotic solvents such as DMF, DMA, THF, dioxane, toluene, chloroform or methylene chloride Temperatures of 0 ° -50 ° C are carried out, or else the acid group in the compound of general formula III is activated by first converting it into an active ester (see page 11) and then this ester in a solvent such as DMF, DMA, THF, dioxane, dichloromethane, i-ProOH, toluene, optionally with the addition of an organic or inorganic base, such as NEt ₃ , pyridine, DMAP, Hunig base, Na ₂ CO ₃ , CaCO ₃ at temperatures from -10 ° to + 70 ° C reacts with the amine of the general formula II. In some cases, it has proven to be advantageous to prepare the metal complexes of the general formula III directly and their terminal ones To couple carboxylic acid under the methods mentioned in WO 98/24775. The production of the metal complexes is described in WO 98/24774. Compounds of the general formula II are prepared when Y ^{2 is} Y ¹ by reacting compounds of the general formula IV
  
  with diamines of the general formula A HNR ¹ - (CH ₂ ) _m -NR ² H (A) wherein Hal, CO *, R ¹ , R ² , m are as defined above, according to the methods of amide formation known to the person skilled in the art (see above) in an aprotic solvent such as DMF, DMA, THF, dioxane, 1,2-dichloroethane , Chloroform, dichloromethane or toluene, optionally with the addition of an organic or inorganic base such as NEt ₃ , pyridine, DMAP, Hunig base, Na ₂ CO ₃ , K ₂ CO ₃ , CaCO ₃ at temperatures of 0 ° C – 100 ° C. In some cases it has proven advantageous to use the diamine itself as a solvent. Sometimes it can be advantageous to use one of the two terminal amino groups in a protected form (eg Mono-Boc, Mono-Z) and, after coupling, to split off this protective group using the methods known to those skilled in the art (TW Greene, see above). The diamines or mono-protected diamines are known from the literature and are commercially available (eg Aldrich, Fluka). The acid chloride of the compound of the general formula IV is preferably used. Making the connection
  
  is in DE 3001292 described. The corresponding tri-bromo compound is prepared in an analogous manner from tribromoaminoisophthalic acid by Sandmeyer reaction (introduction of CN and subsequent saponification) as in EP 0073715 described, manufactured. In the event that Y ^{2 is} not equal to Y ¹ , the following procedure has proven successful: the compounds of the general formula B
  
  where CO *, Hal are as defined above, are first with compounds of the general formula C CO * - (CHZ ¹ ) -NH-Sg (C) where CO *, Z ^{1 have} the meaning given above and Sg represents an amino protecting group. The reaction takes place according to the methods of amide formation already given above (Neher et al Helv. Chim. Acta, 1946, 1815.) Then, as already described above, the reaction is carried out with compounds of the general formula A and then any amino protective groups which may be present are cleaved (see TW Greene ). It has proven to be advantageous to use the acid chlorides of the general formula C. If Sg represents a trifluoroacetyl protective group, this is split off directly in a one-pot process with an excess of diamine of the general formula A. Compounds of the general formula C can be obtained by methods known from the literature. To prepare urea derivatives, compounds of the general formula B are first reacted with isocyanates of the general formula D.
  
  implemented and then further reacted with the diamines of the general formula as described above. The isocyanates are reacted in aprotic solvents as described above for amide formation. The reaction temperature is 0 ° C to 100 ° C. Isocyanates (D) are produced as described, for example, in Guichard et al., J. Org. Chem., 1999, 8702. Compounds of the general formula B are in DE 3001292 described.
• b) The reaction of compounds of general formula IV with compounds of general formula V is carried out according to the methods of amide formation known to the person skilled in the art, as have already been described in detail under a). Here too, the acid chloride of the compounds IV is preferably used. Compounds of the general formula V are obtained from compounds of the general formula E.
  
  wherein X 'has the meaning given above, by reaction with primary epoxides of the general formula F
  
  wherein R ¹ , Sg, p, m, R ^{2 have} the meaning given above. The reaction takes place in protic or aprotic solvents such as methanol, ethanol, butanol, propanol, DMF, toluene, CHCl ₃ , DMA (optionally with the addition of water in each case) at temperatures from 0 ° C. to 15 ° C. In some cases, the addition of a Lewis acid such as LiCl, LiBr, LiJ, LiClO ₄ or Y (triflate) _{3 has} proven itself. Compounds of the general formula F are obtainable by methods known from the literature (Krawiecka et al., J. Chem. Soc. Perkin Trans. 1, 2001, 1086) or are commercially available. Compounds of the general formula E are so-called DO3A derivatives and are described in the literature (Chatal et al., Tetrahedron Lett., 1996, 7515).
• c) The epoxides of the general formula VI are reacted with compounds of the general formula VII by the methods described under b) for the reaction of epoxides with amines. In some cases, it has proven advantageous to use the in EP 0545511 way described using the connection
  
  to use. But you can also follow EP 0643705 proceed or use the lithium process described in WO 98/55467. The preparation of the compounds VII in the case of W'-protecting group see b) is known from the literature. The TriBoc-Cycles compound is described in Kimura et al., J. Am. Chem. Soc., 1997, 3068, the Tri Z-Cyclen compound in Delaney et al., J. Chem. Soc., Perkin Trans., 1991, 3329. Compounds of the general formula VI are obtained by reacting triols of the general formula G.
  
  with epoxides of the general formula H
  
  with p in the abovementioned meaning and in which Z stands for Cl, Br, I, OT _s , accessible. The reaction takes place according to methods of glycidether formation (p = 1) or etherification known from the literature Mouzin et al., Synthesis, 1983, 117. Compounds of the general formula H are known from the literature, for example Sharpless et al., J. Org. Chem., And DE 935433 or commercially available (e.g. epichlorohydrin, Fluka, Aldrich). Compounds of the general formula G in the case of Hal = iodine are in US 6,310,243 described. The bromine compound is prepared in an analogous manner.
• d) The reaction is carried out by first deprotonating the amide of the compounds of the general formula IX using methods known to those skilled in the art, for example with NaH in DMF, THF, DMA, dioxane, toluene (temperatures 0 ° C.-100 ° C.) or BuLi, LDA, Li-HMDS, Na-HMDS in THf, MTB at temperatures from -70 ° to 0 ° C and then reacted with compounds of general formula VIII (preferred temperatures -70 to 70 ° C). Compounds of the general formula VIII are obtained from compounds of the general formula G.
  
  according to the methods known to the person skilled in the art for converting a primary OH group into a halide or tosylate, triflate, etc. Compounds of the general formula IX are obtained from compounds of the general formula IXa
  
  by amide formation with amines of the formula R ¹ NH ₂ (amides of the formula are commercially available or known from the literature) according to the amide coupling methods already mentioned under a). Compounds of the general formula IX a are described, for example, in WO 97/02051, WO 99/16757 or can simply be prepared from tri-boc cycles or tri-z cycles by methods known from the literature. The compounds according to the invention can be used both in X-ray and in MR diagnostics. The high x-ray density combined with the good water solubility of the iodinated x-ray contrast media is combined with the pronounced hydrophilicity of the metal chelates and the inherent good compatibility in one molecule. The very high hydrophilicity of the new compounds means that the side effect profile corresponds to that of the very well-tolerated Gd compounds, as used in MR imaging. This property makes it particularly suitable for use in patients with a proven allergy to iodinated compounds or in the presence of atopy. In particular, the incidence of serious side effects such as bronchospasm and shock or even death is reduced to the low level of the MR contrast media.

The low osmolality the wording is an indication of a general very good tolerance of the new connections. They are therefore particularly suitable for intravascular ones (Parenteral) applications suitable.

Depending on the pharmaceutical formulation, the contrast agents can be used exclusively for X-ray diagnostics (triiod complexes with diamagnetic metals) but also for X-ray and MRI diagnostics (triiod complexes with paramagnetic atoms, preferably Gd). The compounds can be used very advantageously, for example, in urography, computer tomography, angiography, gastrography, mammography, cardiology and neuroradiology. The complexes used are also advantageous in radiation therapy. The connections are suitable for all perfusion measurements. It is possible to differentiate between areas well supplied with blood and ischemic areas after intravascular injection. In general, These compounds can be used in all indications where conventional contrast agents are used in X-ray or MR diagnostics.

diagnostic The contrast between brain attacks and Tumors of the liver or space-consuming processes in the liver as well of tumors of the abdomen (including the kidneys) and the musculoskeletal system. by virtue of the low osmotic pressure are particularly advantageous Blood vessels after intra-arterial but also intravenous injection can be shown.

is the compound of the invention intended for use in MR diagnostics, the metal ion of the signaling group be paramagnetic. These are in particular the divalent and trivalent ions of the elements of the atomic numbers 21-29, 42, 44 and 58-70. Suitable ions are, for example, chromium (III) -, iron (II) -, Cobalt (II) -, nickel (II) -, copper (II) -, praseodymium (III) -, neodymium (III) -, Samarium (III) and ytterbium (III) ion. Because of their strong magnetic Moments are preferably gadolinium (III) -, terbium (III) -, dysprosium (III) -, Holmium (III), erbium (III), iron (III) and manganese (II) ions, especially preferably gadolinium (III) and manganese (II) ions.

is the compound of the invention intended for use in X-ray diagnostics, the metal ion is preferably derived from a higher atomic number element to achieve adequate absorption of the X-rays. It has been found that for this purpose diagnostic means that a physiologically acceptable Complex salt with metal ions of elements of atomic numbers 25, 26 and 39 and 57-83 included, are suitable.

Prefers are manganese (II) -, iron (II) -, iron (III) -, praseodymium (III) -, neodymium (III) -, Samarium (III), gadolinium (III), ytterbium (III) or bismuth (III) ions, in particular Dysprosium (III) ions and yttrium (III) ions.

The Production of the pharmaceutical according to the invention Agents are carried out in a manner known per se by - if necessary, the complex compounds according to the invention with the addition of the usual in galenics Additives - in water Medium is suspended or dissolved and subsequently the suspension or solution if necessary sterilized. Suitable additives are, for example, physiologically harmless buffers (such as Example tromethamine), additives complexing agents or weak complexes (such as diethylenetriaminepentaacetic acid or to the metal complexes according to the invention corresponding Ca complexes) or - if necessary - electrolytes such as sodium chloride or, if necessary, antioxidants such as ascorbic acid.

If suspensions or solutions of the agents according to the invention in water or physiological saline solution are desired for enteral or parenteral administration or other purposes, they are mixed with one or more adjuvants (for example methyl cellulose, lactose, mannitol) and / or surfactants) [for example lecithins, Tween ^® , Myrj ^® ] and / or flavoring (s) for flavor correction [for example essential oils] mixed.

in principle is it also possible the pharmaceutical according to the invention To produce means without isolation of the complexes. In any case special care must be taken to avoid chelation make the complexes of the invention practically free are of non-complexed toxic metal ions.

This can, for example, with the help of color indicators such as xylenol orange by control titrations during of the manufacturing process become. The invention therefore also relates to methods of manufacture complex compounds and their salts. The last security remains a cleaning of the isolated complex.

at the in vivo application of the agents according to the invention can do this together with a suitable carrier such as serum or physiological saline and together with another protein such as human serum albumin (HSA) can be administered.

The agents according to the invention are common parenterally, preferably IV. They can also be intra-arterial or be applied interstitially / intracutaneously, depending on whether a vessel / organ selectively contrasted (e.g. representation of the coronary arteries after intra-arterial injection) or tissue or pathologies (e.g. Diagnosis of brain tumors after intravenous injection) shall be.

The pharmaceutical compositions according to the invention preferably contain 0.001-1 mol / l th compound and are usually dosed in amounts of 0.001-5 mmol / kg.

The agents according to the invention meet the diverse requirements for suitability as contrast agents for magnetic resonance tomography. They are ideally suited to improve the meaningfulness of the image obtained with the aid of the MR tomograph after oral or parenteral application by increasing the signal intensity. They also show the high effectiveness that is necessary to burden the body with the smallest possible amount of foreign substances and the good tolerance that is necessary to maintain the non-invasive character of the examinations. The high effectiveness (relaxivity) of the paramagnetic compounds according to the invention is of great advantage for use in magnetic resonance tomography. The relaxivity (L / mmol ^–1 · sec ^–1 of gadolinium-containing compounds is usually two to four times greater than that of conventional Gd complexes (eg Gadobutrol).

The good water solubility and low osmolality of the agents according to the invention allows highly concentrated solutions produce so that the volume load of the circuit in reasonable Keep limits and dilution through the body fluid compensate. Furthermore, the agents according to the invention not just high stability in vitro, but also a surprising one high stability in vivo, so that a release or exchange of those in the complexes bound - to become toxic - ions within the time in which the new contrast agent is fully restored are eliminated very slowly he follows.

in the general, the agents according to the invention for use as MRI diagnostic agents in amounts of 0.001-5 mmol Gd / kg, preferably 0.005-0.5 mmol Gd / kg, dosed.

The agents according to the invention are excellent as x-ray contrast media suitable, it should be emphasized that with them no signs of those known from the iodine-containing contrast media anaphylaxis-like reactions in biochemical-pharmacological studies reveal. They are special in the case of strong X-ray absorption effective in higher areas tube voltages (e.g. CT and DSA).

in the general, the agents according to the invention for use as an X-ray contrast medium in analogy to, for example, meglumine diatrizoate in amounts of 0.01-5 mmol / kg, preferably 0.02-1 mmol substance / kg, which in the case of e.g. Iodine-Dy compounds 0.06 to 6 corresponds to mmol (I + Dy) / kg.

ever formulations can be selected according to the diagnostic question, which are both in x-ray can also be used in MR diagnostics. For optimal results for both Imaging modalities To achieve this, it can be advantageous to choose formulations in where the proportion of paramagnetic ions is reduced, because for many Applications of MR diagnostics a too high proportion of paramagnetic Ions provides no further gain.

For one dual benefits Formulations are used in which the percentage of paramagnetic substances (e.g. Gd) to 0.05 to 50, preferably to 2-20% is reduced. An example is an application in cardiac diagnostics mentioned. For the A formulation consisting of the substances according to the invention is examined in a total concentration of e.g. 0.25 mol / L used. The The proportion of complexes containing Gd is 20%, the remaining 80% of the metals are e.g. Dy atoms. With an x-ray Coronary angiography after intra-arterial or intravenous administration e.g. 50 mL used, i.e. 0.18 mmol substance per kg body weight in a 70 kg patient. Shortly after the X-ray is displayed the coronary arteries an MR diagnosis of the heart connected to vital from necrotic To differentiate myocardial areas. The one previously applied for the examination Amount of about 110 μmol Gd / kg is for this optimal.

example 1

a) 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-aminoethyl) amide

A solution of 10 g (15.5 mmol) 1,3,5-triiodotrimesic acid trichloride ( DE 3001292 , Schering AG, priority: January 11, 1980) in 100 ml of tetrahydrofuran becomes 24 g (400 mmol) of ethylenediamine over 1 h at room temperature. dripped and raked for 14 h. The precipitated solid is filtered off, washed with ethanol, taken up in 100 ml of water and the resulting solution is adjusted to a pH of 8.0 with 1 M lithium hydroxide solution. After evaporation in vacuo, it is recrystallized from ethanol.
Yield: 7.8 g (70% of theory) of a colorless solid
Elemental analysis:

b) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3,6-diaza-4,7-dioxo-8-methyloctane-1,8-diyl- {10- [1,4,7 tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd-complex]}) amide

48.5 g (77.09 mmol) Gd complex of 10- [4-carboxy-1-methyl-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (WO 98 / 24775, Schering AG, (Example 1)) are suspended in 400 ml of DMSO and mixed with 9.8 g (84.8 mmol) of N-hydroxysuccinimide and 16.7 g (81 mmol) of dicyclohexylcarbodiimide and preactivated for 1 hour. 12.3 g (17.12 mmol) of 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-aminoethyl) -amide are then added and the mixture is stirred at room temperature for 3 days. stirred under nitrogen. Insoluble constituents are filtered off and the solution is poured into 2000 ml of acetone. The solid which precipitates out is filtered off and washed in portions with 1000 ml of acetone and with 500 ml of diethyl ether. The residue is taken up in 500 ml of water and stirred for 2 hours with 100 g of ion exchanger (IRA 67 OH form) and filtered off. The mixture is then stirred for 2 hours with 30 g of ion exchanger (IR 267 H form), filtered off, mixed with 2 g of activated carbon, heated to 60 ° C. for 2 hours, filtered off and the solution is concentrated to 100 ml. To remove the remaining dimethyl sulfoxide, the solution is poured into 1000 ml of acetone and the precipitate is filtered off. The residue is dissolved in 250 ml of water, the conductivity is adjusted to a value of 0.005 mS (pH = 7.0) with a little ion exchanger (H form and OH form), filtered off and evaporated in vacuo.
Yield: 33.9 g (73% of theory) of a colorless solid
Water content (Karl Fischer): 5.9
Elemental analysis (based on the anhydrous substance):

Example 2 1,3,5-Triiodotrimesic Acid-N, N, N-tris- (3,6-diaza-4,7-dioxooctane-1,8-diyl- {10- [1,4,7-tris- ( carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd-complex]}) amide

9.4 g (15.3 mmol) Gd complex of 10- [4-carboxy-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (WO 98/24775, Schering AG, (Example 11)) are suspended in 100 ml of DMSO and mixed with 1.96 g (17 mmol) of N-hydroxysuccinimide and 3.3 g (16 mmol) of dicyclohexylcarbodiimide and preactivated for 1 hour. 2.4 g (3.36 mmol) of 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-aminoethyl) -amide are then added and the mixture is stirred at room temperature for 3 days. stirred under nitrogen. Insoluble constituents are filtered off and the solution is poured into 1000 ml of acetone. The solid which precipitates out is filtered off and washed in portions with 300 ml of acetone and with 100 ml of diethyl ether. The residue is taken up in 200 ml of water and stirred for 2 hours with 30 g of ion exchanger (IRA 67 OH form) and filtered off. The mixture is then stirred for 2 hours with 10 g of ion exchanger (IR 267 H form), filtered off, mixed with 2 g of activated carbon, heated to 60 ° C. for 2 hours, filtered off and the solution is concentrated to 100 ml. To remove the remaining dimethyl sulfoxide, the solution is poured into 1000 ml of acetone and the precipitate is filtered off. The residue is dissolved in 250 ml of water, the conductivity is adjusted to a value of 0.005 mS (pH = 7.0) with a little ion exchanger (H form and OH form), filtered off and evaporated in vacuo.
Yield: 6.0 g (68% of theory) of a colorless solid
Water content (Karl Fischer): 5.4
Elemental analysis (based on the anhydrous substance):

Example 3 a) 1,4,7-tris (benzyloxycarbonyl) -10- (ethoxycarbonylmethyl) -1,4,7,10-tetrazacyclododecane

68.2 g (118.6 mmol) 1,4,7-tris- (benzyloxycarbonyl) -1,4,7,10-tetrazacyclododecane (Delaney et al., J. Chem. Soc. Perkin Trans. 1991, 3329) are dissolved in 700 ml Acetonitrile dissolved and mixed with 75.4 g (545.5 mmol) sodium carbonate. Then 39.6 g (355.5 mmol) of ethyl bromoacetate are added with vigorous stirring and the mixture is heated to 40 ° C. for 20 h. Insoluble constituents are filtered off, evaporated to dryness and chromatographed on silica gel (mobile solvent: ethyl acetate / hexane 20: 1). That contain the product the fractions are combined and evaporated.
Yield 72.3 g (92% of theory) of a colorless oil
Elemental analysis:

b) 1,4,7-tris (benzyloxycarbonyl) -10- (carboxymethyl) -1,4,7,10-tetrazacyclododecane

34 g (51.4 mmol) 1,4,7-tris- (benzyloxycarbonyl) -10- (ethoxycarbonylmethyl) -1,4,7,10-tetrazacyclododecane are dissolved in 300 ml dioxane and mixed with 144 ml 5 percent. aqueous NaOH solution added and 24 h at room temperature. touched. After neutralization with conc. HCl is evaporated to dryness. The residue is taken up in 250 ml of ethyl acetate and extracted twice with 250 ml of 1N HCl solution. The organic phase is dried over sodium sulfate and the solvent is evaporated to dryness.
Yield 27.8 g (85% of theory) of a colorless solid
Elemental analysis:

c) 1,3,5-Triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris (benzyloxycarbonyl) -1 , 4,7,10-tetrazacyclododecanyl]}) - amide

44.6 g (70.6 mmol.) Are added to a suspension of 16.8 g (23.5 mmol) of 1,3,5-triiodotrimesic acid N, N, N-tris (2-aminoethyl) amide in 446 ml of DMF ) 1,4,7-tris- (benzyloxycarbonyl) -10- (carboxymethyl) -1,4,7,10-tetrazacyclododecane, 21 ml (164 mmol) triethylamine, 14.6 g (70.5 mmol) dicyclohexylcarbodiimide and 8.1 g (70.5 mmol) of N-hydroxysuccinimide and 20 h at room temperature. gerüht. Insoluble constituents are filtered off and evaporated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water. The organic phase is dried over sodium sulfate, the solvent is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 23.3 g (39% of theory) of a colorless solid
Elemental analysis:

d) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {1- [1,4,7,10-tetrazacyclododecanyl]}) - amide

20 g (7.8 mmol) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris - (benzyloxycarbonyl) -1,4,7,10-tetrazacyclododecanyl]}) - amide, 140 ml HBr / AcOH (33%) are carefully added at 0–5 ° C and 3 h at room temp. touched. The reaction mixture is then poured into 800 ml of diethyl ether, the resulting solid is filtered off with suction and washed several times with diethyl ether. The residue is dissolved in 100 ml of water and 100 ml of dichloromethane and 32 percent is added while stirring vigorously. NaOH solution until a pH of 10 is reached. The organic phase is separated off, the aqueous phase is extracted three times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulfate and evaporated to dryness.
Yield 10.3 g (97% of theory) of a colorless solid
Elemental analysis:

e) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris (carboxymethyl) -1 , 4,7,10-tetrazacyclododecanyl]}) - amide

18.6 g (13.7 mmol) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {1- [1,4,7 , 10-tetrazacyclododecanyl]}) - amide are dissolved in 75 ml of water, 19.5 g (206.5 mmol) of chloroacetic acid are added and the pH is adjusted to 9.5 at 60 ° C. with 32% NaOH. The mixture is heated at 70 ° C. for 10 hours, the pH of the reaction mixture being continuously adjusted to 9.5. After cooling to room temp. is with conc. HCl adjusted a pH of 1 and the solution evaporated in vacuo. The residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H ⁺ form). It is then washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, the resulting solid is suction filtered, washed several times with diethyl ether and dried in vacuo.
Yield 13.8 g (54% of theory) of a colorless solid
Elemental analysis:

f) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1 , 4,7,10-tetrazacyclododecanyl, Gd-complex]}) amide

13 g (6.9 mmol) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- ( carboxymethyl) -1,4,7,10-tetrazacyclododecanyl]}) - amide are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.7 g (10.4 mmol) of gadolinium oxide are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 6.2 g (36% of theory) of a colorless solid
Water content (Karl Fischer): 6.2%
Elemental analysis (based on the anhydrous substance):

g) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1 , 4,7,10-tetrazacyclododecanyl, Dy-complex]}) amide

13 g (6.9 mmol) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- ( carboxymethyl) -1,4,7,10-tetrazacyclododecanyl]}) - amide are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.88 g (10.4 mmol) of dysprosium oxide are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 7.0 g (41% of theory) of a colorless solid
Water content (Karl Fischer): 5.9%
Elemental analysis (based on the anhydrous substance):

h) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1 , 4,7,10-tetrazacyclododecanyl, Y-complex]}) amide

13 g (6.9 mmol) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- ( carboxymethyl) -1,4,7,10-tetrazacyclododecanyl]}) - amide are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.72 g (10.4 mmol) of yttrium carbonate are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 6.5 g (42% of theory) of a colorless solid
Water content (Karl Fischer): 4.8%
Elemental analysis (based on the anhydrous substance):

Example 4

a) 1,4,7-tris (benzyloxycarbonyl) -10- (1-ethoxycarbonylethyl) -1,4,7,10-tetrazacyclododecane

50.1 g (87.0 mmol) 1,4,7-tris (benzyloxycarbonyl) -1,4,7,10-tetrazacyclododecane (Delaney et al., J. Chem. Soc. Perkin Trans. 1991, 3329) are dissolved in 500 ml Acetonitrile dissolved and mixed with 55.5 g (400 mmol) sodium carbonate. 54.3 g (300 mmol) of ethyl 1-bromopropionate are then added with vigorous stirring and the mixture is heated to 60 ° C. for 20 h. Insoluble constituents are filtered off, evaporated to dryness and chromatographed on silica gel (mobile solvent: ethyl acetate / hexane 20: 1). The fractions containing the product are combined and evaporated.
Yield 46 g (78% of theory) of a colorless oil.
Elemental analysis:

b) 1,4,7-tris (benzyloxycarbonyl) -10- (1-carboxyethyl) -1,4,7,10-tetrazacyclododecane

33.7 g (50 mmol) of 1,4,7-tris (benzyloxycarbonyl) -10- (1-ethoxycarbonylethyl) -1,4,7,10-tetrazacyclododecane, 300 ml of dioxane are dissolved and 140 ml of 5 percent. aqueous NaOH solution added and 24 h at room temperature. touched. After neutralization with conc. HCl is evaporated to dryness. The residue is taken up in 250 ml of ethyl acetate and extracted twice with 250 ml of 1N HCl solution. The organic phase is dried over sodium sulfate and the solvent is evaporated to dryness.
Yield 28.2 g (87% of theory) of a colorless solid
Elemental analysis:

c) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-1-methyl-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- ( benzyloxycarbonyl) -1,4,7,10-tetrazacyclododecanyl]}) - amide

45.6 g (70.6 mmol.) Are added to a suspension of 16.8 g (23.5 mmol) of 1,3,5-triiodotrimesic acid-N, N, N-tris (2-aminoethyl) amide in 450 ml of DMF ) 1,4,7-tris- (benzyloxycarbonyl) -10- (1-carboxyethyl) -1,4,7,10-tetrazacyclododecane, 21 ml (164 mmol) ttriethylamine, 14.6 g (70.5 mmol) dicyclohexylcarbodiimide and 8 , 1 g (70.5 mmol) of N-hydroxysuccinimide and 20 h at room temperature. gerüht. Insoluble constituents are filtered off and evaporated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water. The organic phase is dried over sodium sulfate, the solvent is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase dichloromethane / metha nol 20: 1). The fractions containing the product are combined and evaporated.
Yield 24.5 g (40% of theory) of a colorless solid
Elemental analysis:

d) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-1-methyl-4-oxopentane-1,5-diyl- {1- [1,4,7,10-tetrazacyclododecanyl ]}) - amide

23 g (8.85 mmol) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris - (benzyloxycarbonyl) -1,4,7,10-tetrazacyclododecanyl]}) - amide are carefully mixed with 140 ml HBr / AcOH (33%) at 0–5 ° C and 3 h at room temp. touched. The reaction mixture is then poured into 800 ml of diethyl ether, the resulting solid is filtered off with suction and washed several times with diethyl ether. The residue is dissolved in 100 ml of water and 100 ml of dichloromethane with vigorous stirring. NaOH solution until a pH of 10 is reached. The organic phase is separated off, the aqueous phase is extracted three times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulfate and evaporated to dryness.
Yield 11.7 g (95% of theory) of a colorless solid
Elemental analysis:

e) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-1-methyl-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- ( carboxymethyl) -1,4,7,10-tetrazacyclododecanyl]}) - amide

18.8 g (13.5 mmol) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-1-methyl-4-oxopentane-1,5-diyl- {1- [1 , 4,7,10-tetrazacyclododecanyl]}) - amide are dissolved in 75 ml of water, 19.5 g (206.5 mmol) of chloroacetic acid are added and the pH is adjusted to 9.5 at 60 ° C. with 32% NaOH. The mixture is heated at 70 ° C. for 10 hours, the pH of the reaction mixture being continuously adjusted to 9.5. After cooling to room temp. is with conc. HCl adjusted a pH of 1 and the solution evaporated in vacuo. The residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H ⁺ form). It is then washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, the resulting solid is suction filtered, washed several times with diethyl ether and dried in vacuo.
Yield 15.0 g (58% of theory) of a colorless solid
Elemental analysis:

f) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-1-methyl-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- ( carboxylatomethyl) -1,4,7,10-tetrazacyclododecanyl, Gd-complex]}) amide

13.2 g (6.9 mmol) of 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-1-methyl-4-oxopentane-1,5-diyl- {10- [1,4,7 -tris- (carboxymethyl) -1,4,7,10-tetrazacyclododecanyl]}) - amide are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.7 g (10.4 mmol) of gadolinium oxide are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 7.1 g (41% of theory) of a colorless solid
Water content (Karl Fischer): 5.6%
Elemental analysis (based on the anhydrous substance):

Example 5

a) Dibenzyloxiranylmethylamine

98.6 g (0.5 mol) of dibenzylamine and 55.5 g (0.6 mol) of epichlorohydrin are dissolved in 500 ml of methanol and heated to 80 ° C. for 6 h. The solution is evaporated to dryness and 500 ml of tert-butanol are added. A solution of 36.4 g (0.65 mol) of potassium hydroxide in 50 ml of water is then added with stirring and the mixture is heated to 80 ° C. for 2 h. After cooling to room temp. is filtered off from the potassium chloride formed, the filtrate is evaporated to dryness and chromatographed on silica gel (mobile solvent hexane / ethyl acetate 10: 1). The fractions containing the product are combined and evaporated.
Yield 126 g (99% of theory) of a colorless oil
Elemental analysis:

b) [1- (3-dibenzylamino-2-hydroxypropyl) -1,4,7,10-tetraazacyclododecane] Penta hydrochloride

100 ml (752.77 mmol) of N, N-dimethylformamide dimethyl acetal are added to 100 g (580.48 mmol) of 1,4,7,10-tetraazacyclododecane, dissolved in 700 ml of toluene, and the mixture is heated at 120 ° C. under nitrogen for 2 h. A methanol / toluene aceotroph is continuously distilled off. The reaction mixture is then concentrated at 70 ° C. in vacuo, 157 g (620 mmol) of dibenzyloxiranylmethylamine are added and the mixture is heated to 110 ° C. under nitrogen for 24 hours. After cooling to room temp. 500 ml of water are added and the mixture is extracted twice with 200 ml of ethyl acetate each time. The aqueous phase is concentrated with 250 ml. HCl are added and the mixture is then heated to 80 ° C. for 12 h. It is evaporated to dryness, mixed with 200 ml of ethanol and 200 ml of methanol and again evaporated to dryness. The residue is dissolved in 600 ml of hot heat and then slowly cooled to 0 ° C., a white solid crystallizing out. The solid is filtered off, washed with ethanol and then dried at 50 ° C. in vacuo.
Yield: 280 g (79% of theory) of a colorless solid
Elemental analysis:

c) 10- (3-Dibenzylamino-2-hydroxypropyl) -1,4,7-tris- (tert-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane

250 g (411.2 mmol) of [1- (3-dibenzylamino-2-hydroxypropyl) -1,4,7,10-tetraazacyclododecane] pentahydrochloride dissolved in 500 ml of water and 500 ml of dichloromethane are added 32 percent with vigorous stirring. NaOH solution until a pH of 10 is reached. The organic phase is separated off, the aqueous phase is extracted three times with 250 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 1200 ml of acetonitrile and 176.2 g (1,275 mol) of potassium carbonate are added. 248.7 g (1,275 mol) of tert-butyl bromoacetate are then added with vigorous stirring and the mixture is heated to 60 ° C. for 3 h. Insoluble constituents are filtered off, evaporated to dryness and chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 262 g (83% of theory) of a colorless solid
Elemental analysis:

d) 10- (3-Amino-2-hydroxypropyl) -1,4,7-tris- (tert-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane

76.8 g (100 mmol) of 10- (3-dibenzylamino-2-hydroxypropyl) -1,4,7-tris (tert-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane are dissolved in 500 ml of methanol, with 40 ml of water are added and 10 g of palladium catalyst (20 Pd / C) are added. The mixture is hydrogenated for 8 hours at 50 ° C. under normal pressure. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo.
Yield: 58.5 g (quantitative) of a colorless powder
Elemental analysis:

e) 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris (tert-butoxycarbonylmethyl) -1.4 , 7,10-tetraazacyclododecanyl]}) amide

To 12.86 g (20 mmol) 1,3,5-triiodotrimesic acid trischloride ( DE 3001292 , Schering AG, priority: January 11, 1980) dissolved in 400 ml of tetrahydrofuran are 12.2 g (120 mmol) of triethylamine and then 38.8 g (66 mmol) of 10- (3-amino-2-hydroxypropyl) -1,4,7-tris - (tert-Butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane added and 6 h at room temperature. touched. Insoluble constituents are filtered off, evaporated to dryness and chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 32.7 g (71% of theory) of a colorless solid
Elemental analysis:

f) 1,3,5-triiodotrimesic acid-N, N, N-tris (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris (carboxymethyl) -1,4,7 , 10-tetraazacyclododecanyl]}) amide

34.5 g (15 mmol) 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris- (tert-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide are dissolved in 100 ml of dichloromethane, 100 ml of trifluoroacetic acid are added at 0 ° C. and the mixture is stirred at 0 ° C. for 3 hours. The mixture is poured into 500 ml of diethyl ether, the solid which precipitates out is filtered off, rewashed three times with 100 ml of diethyl ether each time and dried in vacuo.
Yield 25.3 g (94% of theory) of a colorless solid
Elemental analysis:

g) 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1,4,7 , 10-tetraazacyclododecanyl]}, Gd-complex) amide

21.5 g (12 mmol) 1,3,5-triiodotrimesic acid-N, N, N-tris (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris (carboxymethyl) -1 , 4,7,10-tetraazacyclododecanyl]}) amide are dissolved in 250 ml of water and acidified by adding 5 ml of acetic acid. 13 g (36.2 mmol) of gadolinium oxide are added and the mixture is heated under reflux for 3 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 20/20/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield: 19.4 g (68% of theory) of a colorless solid
Water content (Karl Fischer): 5.3%
Elemental analysis (based on the anhydrous substance):

Example 6

a) 1-Benzyl-1-methyl (oxiranylmethyl) amine

60.6 g (0.5 mol) of benzylmethylamine and 55.5 g (0.6 mol) of epichlorohydrin are dissolved in 500 ml of methanol and heated to 80 ° C. for 6 h. The solution is evaporated to dryness and 500 ml of tert-butanol are added. A solution of 36.4 g (0.65 mol) of potassium hydroxide in 50 ml of water is then added with stirring and the mixture is heated to 80 ° C. for 2 h. After cooling to room temperature, the potassium chloride formed is filtered off, the filtrate is evaporated to dryness and chromatographed on silica gel (mobile solvent hexane / ethyl acetate 10: 1). The fractions containing the product are combined and evaporated.
Yield 85 g (96% of theory) of a colorless oil
Elemental analysis:

b) [1- (3-benzylmethylamino-2-hydroxypropyl) -1,4,7,10-tetraazacyclododecane] Penta hydrochloride

100 ml (752.77 mmol) of N, N-dimethylformamide dimethyl acetal are added to 100 g (580.48 mmol) of 1,4,7,10-tetraazacyclododecane, dissolved in 700 ml of toluene, and the mixture is heated at 120 ° C. under nitrogen for 2 h. A methanol / toluene aceotroph is continuously distilled off. The reaction mixture is then concentrated at 70 ° C. in vacuo, 110 g (620 mmol) of 1-benzyl-1-methyl (oxiranylmethyl) amine are added and the mixture is heated to 110 ° C. under nitrogen for 24 hours. After cooling to room temp. 500 ml of water are added and the mixture is extracted twice with 200 ml of ethyl acetate each time. The aqueous phase is concentrated with 250 ml. HCl are added and the mixture is then heated to 80 ° C. for 12 h. It is evaporated to dryness, mixed with 200 ml of ethanol and 200 ml of methanol and again evaporated to dryness. The residue is dissolved in 600 ml of hot heat and then slowly cooled to 0 ° C., a white solid crystallizing out. The solid is filtered off, washed with ethanol and then dried at 50 ° C. in vacuo.
Yield: 235 g (76% of theory) of a colorless solid
Elemental analysis:

c) 10- (3-Benzylmethylamino-2-hydroxypropyl) -1,4,7-tris- (tert-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane

To 212.7 g (400 mmol) of [1- (3-benzylmethylamino-2-hydroxypropyl) -1,4,7,10-tetraazacyclododecane] pentahydrochloride dissolved in 500 ml of water and 500 ml of dichloromethane are added 32 percent while stirring vigorously. NaOH solution until a pH of 10 is reached. The organic phase is separated off, the aqueous phase is extracted three times with 250 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 1200 ml of acetonitrile and 176.2 g (1,275 mol) of potassium carbonate are added. 248.7 g (1,275 mol) of tert-butyl bromoacetate are then added with vigorous stirring and the mixture is heated to 60 ° C. for 3 h. Insoluble constituents are filtered off, evaporated to dryness and chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 219 g (79% of theory) of a colorless solid
Elemental analysis:

d) 10- (3-methylamino-2-hydroxypropyl) -1,4,7-tris (tert-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane

69.2 g (100 mmol) of 10- (3-benzylmethylamino-2-hydroxypropyl) -1,4,7-tris (tert-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane are dissolved in 500 ml of methanol, with 40 ml of water and 10 g Palladium catalyst (20% Pd / C) added. The mixture is hydrogenated for 8 hours at 50 ° C. under normal pressure. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo.
Yield: 60 g (quantitative) of a colorless powder
Elemental analysis:

e) 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris (tert-butoxycarbonylmethyl) -1.4 , 7,10-tetraazacyclododecanyl]}) -methylamide

To 12.86 g (20 mmol) 1,3,5-triiodotrimesic acid trischloride ( DE 3001292 , Schering AG, priority: January 11, 1980) dissolved in 400 ml of tetrahydrofuran are 12.2 g (120 mmol) of triethylamine and then 39.7 g (66 mmol) of 10- (3-methylamino-2-hydroxypropyl) -1,4,7-tris - (tert-Butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane added and 18 h at room temperature. touched. Insoluble constituents are filtered off, evaporated to dryness and chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 31.4 g (67% of theory) of a colorless solid
Elemental analysis:

f) 1,3,5-triiodotrimesic acid-N, N, N-tris (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris (carboxymethyl) -1,4,7 , 10-tetraazacyclododecanyl]}) -methylamide

35.1 g (15 mmol) 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris- (tert-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) methylamide are dissolved in 100 ml dichloromethane, 100 ml trifluoroacetic acid are added at 0 ° C and the mixture is stirred at 0 ° C for 3 hours. The mixture is poured into 500 ml of diethyl ether, the solid which precipitates out is filtered off, rewashed three times with 100 ml of diethyl ether each time and dried in vacuo.
Yield 26.4 g (96% of theory) of a colorless solid
Elemental analysis:

g) 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1,4,7 , 10-tetraazacyclododecanyl]}, Gd-complex) methylamide

22 g (12 mmol) 1,3,5-triiodotrimesic acid-N, N, N-tris (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris (carboxymethyl) -1 , 4,7,10-tetraazacyclododecanyl]}) methylamide are dissolved in 250 ml of water and acidified by adding 5 ml of acetic acid. 13 g (36.2 mmol) of gadolinium oxide are added and the mixture is heated under reflux for 3 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 20/20/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield: 18.2 g (62% of theory) of a colorless solid
Water content (Karl Fischer): 6.1%
Elemental analysis (based on the anhydrous substance):

Example 7

a) 1,3,5-triiodo-2,4,6-tris (oxiranylmethoxymethyl) benzene

To a mixture of 11.0 g (20.1 mmol) of 1,3,5-triiodo-2,4,6-trishydroxymethylbenzene, 55.5 g (0.6 mol) of epichlorohydrin and 1.1 g (3.2 mmol) of tetrabutylammonium hydrogen sulfate, 55 ml of 32 percent. NaOH solution at room temp. added dropwise and then stirred for 12 h. 150 ml of water are added and the mixture is extracted twice with 200 ml of toluene each time. The combined organic phases are dried over sodium sulfate, the solvent is evaporated to dryness and chromatographed on silica gel (mobile solvent hexane / ethyl acetate 10: 1). The fractions containing the product are combined and evaporated.
Yield 10.5 g (73% of theory) of a colorless solid
Elemental analysis:

b) 1,3,5-Triiod- {2,4,6-tris [2-hydroxy-3- (1,4,7,10-tetraazacyclododecan-1-yl) propyloxy-methyl]} benzene

10 ml (75.28 mmol) of N, N-dimethylformamide dimethyl acetal are added to 10 g (58.05 mmol) of 1,4,7,10-tetraazacyclododecane, dissolved in 100 ml of toluene, and the mixture is heated at 120 ° C. under nitrogen for 2 h. A methanol / toluene aceotroph is continuously distilled off. The reaction mixture is then concentrated at 70 ° C. in vacuo, 13.6 g (19.1 mmol) of 1,3,5-triiodo-2,4,6-tris (oxiranylmethoxymethyl) benzene are added and the mixture is heated to 110 ° under nitrogen for 24 hours C. After cooling to room temp. 100 ml of 2N HCl are added and the mixture is then heated to 80 ° C. for 12 h. It is evaporated to dryness, mixed with 50 ml of ethanol and 50 ml of methanol and evaporated to dryness again. The residue is dissolved in 100 ml of hot ethanol and then slowly cooled to 0 ° C., during which time a white solid crystallizes out. The solid is filtered off, washed with ethanol and then dried at 50 ° C. in vacuo. The solid is dissolved in 100 ml of water and 100 ml of dichloromethane and with vigorous stirring, 32 percent. Add NaOH solution until a pH of 10 is reached. The organic phase is separated off, the aqueous phase is extracted three times with 100 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulfate and evaporated to dryness.
Yield: 19.0 g (81% of theory) of a colorless solid
Elemental analysis:

c) 1,3,5-triiodo- {2,4,6-tris [2-hydroxy-3- (1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecan-1-yl) propyloxymethyl] benzene}

16.6 g (13.5 mmol) 1,3,5-triiodo- {2,4,6-tris [2-hydroxy-3- (1,4,7,10-tetraazacyclododecan-1-yl) propyloxy-methyl] Benzene are dissolved in 75 ml of water, 19.5 g (206.5 mmol) of chloroacetic acid are added and the pH is adjusted to 9.5 at 60 ° C. using 32% NaOH. The mixture is heated at 70 ° C. for 10 hours, the pH of the reaction mixture being continuously adjusted to 9.5. After cooling to room temp. is with conc. HCl adjusted a pH of 1 and the solution evaporated in vacuo. The residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H ⁺ form). It is then washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, the resulting solid is suction filtered, washed several times with diethyl ether and dried in vacuo.
Yield 14.4 g (61% of theory) of a colorless solid
Elemental analysis:

d) 1,3,5-triiodo- {2,4,6-tris [2-hydroxy-3- (1,4,7-triscarboxylatomethyl-1,4,7,10-tetraazacyclododecan-1-yl) propyloxymethyl] benzene Gd complex}

12.1 g (6.9 mmol) 1,3,5-triiodo- {2,4,6-tris [2-hydroxy-3- (1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyc iododecan-1-yl) propyloxymethyl]} benzene are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.7 g (10.4 mmol) of gadolinium oxide are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 7.0 g (43% of theory) of a colorless solid
Water content (Karl Fischer): 5.4%
Elemental analysis (based on the anhydrous substance):

Example 8

a) 10- [4-Aza-6- (benzyloxycarbonylamino) -5-oxo-2-hydroxyhexyl] -1,4,7-tris (tert-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane

21.97 g (105 mmol) of Z-glycine are dissolved in 400 ml of DMF, 12.1 g (105 mmol) of N-hydroxysuccinimide and 21.7 g (105 mmol) of dicyclohexylcarbodiimide are added while cooling with ice and preactivated in ice for 1 hour. 58.8 g (100 mmol) of 10- (3-amino-2-hydroxypropyl) -1,4,7-tris- (tert-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane and 15.4 ml (120 mmol) are then Triethylamine added and overnight at room temp. touched. Insoluble constituents are filtered off and evaporated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water. The organic phase is dried over sodium sulfate, the solvent is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield: 63.2 g (81% of theory) of a colorless solid
Elemental analysis:

b) 10- (4-Aza-6-amino-5-oxo-2-hydroxyhexyl) -1,4,7-tris (tert-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane

60 g (77 mmol) 10- [4-aza-6- (benzyloxycarbonylamino) -5-oxo-2-hydroxyhexyl] -1,4,7-tris- (tert-butoxycarbonylmethyl) -1,4,7,10- tetraazacyclododecane are dissolved in 500 ml of methanol, 40 ml of water are added and 10 g of palladium catalyst (10% Pd / C) are added. The mixture is hydrogenated for 8 hours at 50 ° C. under normal pressure. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo.
Yield: 48.8 g (98% of theory) of a colorless solid
Elemental analysis:

c) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-2-oxo-5-hydroxyhexane-1,6-diyl- {10- [1,4,7-tris- ( tert-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide

To 12.86 g (20 mmol) 1,3,5-triiodotrimesic acid trischloride ( DE 3001292 , Schering AG, priority: 11.01.1980) dissolved in 400 ml of tetrahydrofuran, 12.2 g (120 mmol) of triethylamine and then 42.6 g (66 mmol) of 10- (4-aza-6-amino-5-oxo-2-hydroxyhexyl) -1,4,7-tris- (terf-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane added and 6 h at room temperature. touched. Insoluble constituents are filtered off, evaporated to dryness and chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 36.5 g (74% of theory) of a colorless solid
Elemental analysis:

d) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-2-oxo-5-hydroxyhexane-1,6-diyl- {10- [1,4,7-tris- ( carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide

34.6 g (14 mmol) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-2-oxo-5-hydroxyhexane-1,6-diyl- {10- (1,4,7 -tris- (tert-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide are dissolved in 100 ml dichloromethane, 100 ml trifluoroacetic acid are added at 0 ° C. and the mixture is stirred for 3 hours at 0 ° C. The mixture is stirred poured into 500 ml of diethyl ether, the solid which precipitates out is filtered off, rewashed three times with 100 ml of diethyl ether each time and dried in vacuo.
Yield 26.0 g (95% of theory) of a colorless solid
Elemental analysis:

e) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-2-oxo-5-hydroxyhexane-1,6-diyl- {10- [1,4,7-tris- ( carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl]}, Gd-complex) amide

23.6 g (12 mmol) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-2-oxo-5-hydroxyhexane-1,6-diyl- {10- [1,4,7 -tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide are dissolved in 250 ml of water and acidified by adding 5 ml of acetic acid. 13 g (36.2 mmol) of gadolinium oxide are added and the mixture is heated under reflux for 3 h. When the complexation is complete, the pH is adjusted again to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 20/20/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 6 ° C, filtered off and freeze-dried.
Yield: 20.8 g (67% of theory) of a colorless solid
Water content (Karl Fischer): 6.4%
Elemental analysis (based on the anhydrous substance):

Example 9

a) 1,3,5-triiodo-2,4,6-tris (toluenesulfonyloxy) methylbenzene

To a mixture of 50.0 g (91.4 mmol) 1,3,5-triiodo-2,4,6-trishydroxymethylbenzene and 3 g (8.7 mmol) tetrabutylammonium hydrogen sulfate in 200 ml 32%. NaOH solution and 300 ml of toluene are at room temperature. 76.3 g (400 mmol) of toluenesulfonic acid chloride were added dropwise and the mixture was then stirred for 12 h. It is mixed with 300 ml of water and extracted twice with 200 ml of toluene. The combined organic phases are dried over sodium sulfate, the solvent is evaporated to dryness and chromatographed on silica gel (mobile solvent hexane / ethyl acetate 10: 1). The fractions containing the product are combined and evaporated.
Yield 47.2 g (51% of theory) of a colorless solid
Elemental analysis:

b) 1,4,7-tris (benzyloxycarbonyl) -10- (carbamidomethyl) -1,4,7,10-tetrazacyclododecane

To a solution of 75 g (118.7 mmol) 1,4,7-tris- (benzyloxycarbonyl) -10- (carboxyme thyl) -1,4,7,10-tetrazacyclododecane and 16.9 g (130.5 mmol) diisopropylethylamine in 500 ml THF, 17.8 g (130.5 mmol) isobutyl chloroformate are added dropwise at -20 ° C. The mixture is then stirred at −20 ° C. for 1 hour and 20 ml of 25 percent aqueous ammonia solution are carefully added. The mixture is stirred at 0 ° C. for 2 h, then the solvent is distilled off in vacuo and the residue is chromatographed on silica gel (mobile phase ethyl acetate / hexane 10: 1). The fractions containing the product are combined and evaporated.
Yield 60.7 g (81% of theory) of a colorless solid
Elemental analysis:

c) 1,3,5-triiodo-2,4,6-tris (2-aza-3-oxobutane-1,4-diyl- {10- [1,4,7-tris (benzyloxycarbonyl) -1 benzene, 4,7,10-tetraazacyclododecanyl]})

44.6 g (70.6 mmol) 1,4,7-tris- (benzyloxycarbonyl) -10- (carbamidomethyl) -1,4,7,10-tetrazacyclododecane are dissolved in 500 ml THF and at 0 ° C under argon mixed with 1.71 g (71 mmol) sodium hydride and 1 h at room temperature. touched. A solution of 20.2 g (20 mmol) of 1,3,5-triiodo-2,4,6-tris (toluenesulfonyloxy) methylbenzene in 150 ml of THF is then added dropwise and the mixture is stirred under reflux for 20 h. After cooling, insoluble constituents are filtered off and evaporated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water. The organic phase is dried over sodium sulfate, the solvent is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 29.4 g (62% of theory) of a colorless solid
Elemental analysis:

d) 1,3,5-Triiod-2,4,6-tris- {2-aza-3-oxobutane-1,4-diyl- [10- (1,4,7,10-tetraazacyclododecanyl)]} benzene

20 g (8.4 mmol) 1,3,5-triiodo-2,4,6-tris (2-aza-3-oxobutane-1,4-diyl- {10- [1,4,7-tris ( benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene are carefully added at 0–5 ° C 140 ml HBr / AcOH (33%) and 3 h at room temp. touched. The reaction mixture is then poured into 800 ml of diethyl ether, the resulting solid is filtered off with suction and washed several times with diethyl ether. The residue is dissolved in 100 ml of water and 100 ml of dichloromethane with vigorous stirring. NaOH solution until a pH of 10 is reached. The organic phase is separated off, the aqueous phase is extracted three times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulfate and evaporated to dryness.
Yield 9.1 g (91% of theory) of a colorless solid
Elemental analysis:

e) 1,3,5-triiodo-2,4,6-tris (2-aza-3-oxobutane-1,4-diyl- {10- [1,4,7-tris (carboxymethyl) -1 benzene, 4,7,10-tetraazacyclododecanyl]})

17.7 g (15 mmol) 1,3,5-triiodo-2,4,6-tris- {2-aza-3-oxobutane-1,4-diyl- [10- (1,4,7,10-tetraazacyclododecanyl )]} benzene are dissolved in 75 ml of water, 19.5 g (206.5 mmol) of chloroacetic acid are added and the pH is adjusted to 9.5 at 60 ° C. with 32% NaOH. The mixture is heated at 70 ° C. for 10 hours, the pH of the reaction mixture being continuously adjusted to 9.5. After cooling to room temp. is with conc. HCl adjusted a pH of 1 and the solution evaporated in vacuo. The residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H ⁺ form). It is then washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, the resulting solid is suction filtered, washed several times with diethyl ether and dried in vacuo.
Yield 13.8 g (54% of theory) of a colorless solid
Elemental analysis:

f) 1,3,5-triiodo-2,4,6-tris (2-aza-3-oxobutane-1,4-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1 , 4,7,10-tetraazacyclododecanyl]}, Gd-complex) benzene

11.7 g (6.9 mmol) 1,3,5-triiodo-2,4,6-tris (2-aza-3-oxobutane-1,4-diyl- {10- [1,4,7-tris ( carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.7 g (10.4 mmol) of gadolinium oxide are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 8.4 g (53% of theory) of a colorless solid
Water content (Karl Fischer): 6.1%
Elemental analysis (based on the anhydrous substance):

g) 1,3,5-triiodo-2,4,6-tris- (2-aza-3-oxobutane-1,4-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1 , 4,7,10-tetraazacyclododecanyl]}, Dy complex) benzene

11.7 g (6.9 mmol) 1,3,5-triiodo- {2,4,6-tris [2- (4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecan-1-ylacetylamino) methyl ]} benzene are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.88 g (10.4 mmol) of dysprosium oxide are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 7.5 g (47% of theory) of a colorless solid
Water content (Karl Fischer): 5.9%
Elemental analysis (based on the anhydrous substance):

h) 1,3,5-triiodo-2,4,6-tris (2-aza-3-oxobutane-1,4-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1 , 4,7,10-tetraazacyclododecanyl]}, Y complex) benzene

11.7 g (6.9 mmol) 1,3,5-triiodo- {2,4,6-tris [2- (4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecan-1-ylacetylamino) methyl ]} benzene are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.72 g (10.4 mmol) of yttrium carbonate are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 8.7 g (61% of theory) of a colorless solid
Water content (Karl Fischer): 5.4%
Elemental analysis (based on the anhydrous substance):

Example 10

a) 1,4,7-Tris- (benzyloxycarbonyl) -10- (1-carbamidoethyl) -1,4,7,10-tetrazacyclododecane

To a solution of 76.8 g (118.7 mmol) 1,4,7-tris- (benzyloxycarbonyl) -10- (1-carboxyethyl) -1,4,7,10-tetrazacyclododecane and 16.9 g (130.5 mmol) diisopropylethylamine in 500 ml 17.8 g (130.5 mmol) of isobutyl chloroformate are added dropwise to THF at −20 ° C. The mixture is then stirred at −20 ° C. for 1 hour and 20 ml of 25 percent aqueous ammonia solution are carefully added. The mixture is stirred at 0 ° C. for 2 h, then the solvent is distilled off in vacuo and the residue is chromatographed on silica gel (mobile phase ethyl acetate / hexane 10: 1). The fractions containing the product are combined and evaporated.
Yield 59.8 g (78% of theory) of a colorless solid
Elemental analysis:

b) 1,3,5-triiodo-2,4,6-tris (2-aza-4-methyl-3-oxobutane-1,4-diyl- {10- [1,4,7-tris ( benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene

45.6 g (70.6 mmol) 1,4,7-tris- (benzyloxycarbonyl) -10- (1-carbamidoethyl) -1,4,7,10-tetrazacyclododecane are dissolved in 500 ml THF and at 0 ° C 1.71 g (71 mmol) of sodium hydride are added under argon and 1 h at room temperature. touched. A solution of 20.2 g (20 mmol) of 1,3,5-triiodo-2,4,6-tris (toluenesulfonyloxy) methylbenzene in 150 ml of THF is then added dropwise and the mixture is stirred under reflux for 20 h. After cooling, insoluble constituents are filtered off and evaporated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water. The organic phase is dried over sodium sulfate, the solvent is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 27.7 g (57% of theory) of a colorless solid
Elemental analysis:

c) 1,3,5-Triiod-2,4,6-tris- {2-aza-4-methyl-3-oxobutane-1,4-diyl- [10- (1,4,7,10-tetraazacyclododecanyl )]} benzen

25 g (10.3 mmol) 1,3,5-triiodo-2,4,6-tris- (2-aza-4-methyl-3-oxobutane-1,4-diyl- {10- [1,4,7 -tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene, 150 ml HBr / AcOH (33%) are carefully added at 0–5 ° C and 3 h at room temp. touched. The reaction mixture is then poured into 800 ml of diethyl ether, the resulting solid is filtered off with suction and washed several times with diethyl ether. The residue is dissolved in 100 ml of water and 100 ml of dichloromethane with vigorous stirring. NaOH solution until a pH of 10 is reached. The organic phase is separated off, the aqueous phase is extracted three times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulfate and evaporated to dryness.
Yield 11.4 g (90% of theory) of a colorless solid
Elemental analysis:

d) 1,3,5-triiodo-2,4,6-tris (2-aza-4-methyl-3-oxobutane-1,4-diyl- {10- [1,4,7-tris ( carboxymethyl) -1,4,7,10-tetraazacyclododecanyl)}) benzene

18.3 g (15 mmol) 1,3,5-triiodo-2,4,6-tris- {2-aza-4-methyl-3-oxobutane-1,4-diyl- [10- (1,4,7 , 10-tetraazacyclododecanyl)]} benzene are dissolved in 75 ml of water, 19.5 g (206.5 mmol) of chloroacetic acid are added and the pH is adjusted to 9.5 at 60 ° C. using 32% NaOH. The mixture is heated at 70 ° C. for 10 hours, the pH of the reaction mixture being continuously adjusted to 9.5. After cooling to room temp. will with conc. HCl adjusted a pH of 1 and the solution evaporated in vacuo. The residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H ⁺ form). It is then washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, the resulting solid is suction filtered, washed several times with diethyl ether and dried in vacuo.
Yield 15.5 g (59% of theory) of a colorless solid
Elemental analysis:

e) 1,3,5-triiodo-2,4,6-tris (2-aza-4-methyl-3-oxobutane-1,4-diyl- {10- [1,4,7-tris ( carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl]}, Gd-complex) benzene

12.0 g (6.9 mmol) 1,3,5-triiodo-2,4,6-tris- (2-aza-4-methyl-3-oxobutane-1,4-diyl- {10- [1,4,7 tris (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.7 g (10.4 mmol) of gadolinium oxide are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 7.6 g (47% of theory) of a colorless solid
Water content (Karl Fischer): 5.2%
Elemental analysis (based on the anhydrous substance):

Example 11

a) 10- [4-Carbamido-1-methyl-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tert-butyl ester

To a solution of 76.5 g (118.7 mmol) of 10- [4-carboxy-1-methyl-2-oxo-3-azabutyl] 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tert-butyl ester ( DE 19549286 A1 , Schering AG, (Example 2d)) and 16.9 g (130.5 mmol) of diisopropylethylamine in 500 ml of THF are added dropwise at -20 ° C. 17.8 g (130.5 mmol) of isobutyl chloroformate. The mixture is then stirred for 1 hour at -20 ° C and carefully with 20 ml 25 percent. aqueous ammonia solution added. The mixture is stirred at 0 ° C. for 2 h, then the solvent is distilled off in vacuo and the residue is chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 61.1 g (80% of theory) of a colorless solid
Elemental analysis:

b) 1,3,5-triiodo-2,4,6-tris (2,5-diaza-3,6-dioxo-7-methylheptane-1,7-diyl- {10- [1,4,7 tris (tert-butyloxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene

44.6 g (70.6 mmol) of 10- [4-carbamido-1-methyl-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tert- Butyl esters are dissolved in 500 ml of THF and 1.71 g (71 mmol) of sodium hydride are added at 0 ° C. under argon and 1 h at room temperature. touched. A solution of 20.2 g (20 mmol) of 1,3,5-triiodo-2,4,6-tris (toluenesulfonyloxy) methylbenzene in 150 ml of THF is then added dropwise and the mixture is stirred under reflux for 20 h. After cooling, insoluble constituents are filtered off and evaporated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water. The organi phase is dried over sodium sulfate, the solvent is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 15.1 g (31% of theory) of a colorless solid
Elemental analysis:

c) 1,3,5-triiodo-2,4,6-tris (2,5-diaza-3,6-dioxo-7-methylheptane-1,7-diyl- {10- [1,4,7 tris (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene

18.2 g (7.5 mmol) 1,3,5-triiodo-2,4,6-tris (2,5-diaza-3,6-dioxo-7-methylheptane-1,7-diyl- {10- [1 , 4,7-tris- (tert-butyloxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene are dissolved in 75 ml dichloromethane, mixed with 75 ml trifluoroacetic acid at 0 ° C and stirred for 3 hours at 0 ° C , The mixture is poured into 500 ml of diethyl ether, the solid which precipitates out is filtered off, rewashed three times with 100 ml of diethyl ether each time and dried in vacuo.
Yield 14.1 g (98% of theory) of a colorless solid
Elemental analysis:

d) 1,3,5-triiodo-2,4,6-tris (2,5-diaza-3,6-dioxo-7-methylheptane-1,7-diyl- {10- [1,4,7 tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl]}, Gd-complex) benzene

13.2 g (6.9 mmol) 1,3,5-triiodo-2,4,6-tris- (2,5-diaza-3,6-dioxo-7-methylheptane-1,7-diyl- {10- [1 , 4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.7 g (10.4 mmol) of gadolinium oxide are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 10.2 g (58% of theory) of a colorless solid
Water content (Karl Fischer): 6.2%
Elemental analysis (based on the anhydrous substance):

Example 12

a) 10- (4-Carbamido-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tert-butyl ester

To a solution of 74.8 g (118.7 mmol) of 10- (4-carboxy-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tert-butyl ester ( DE 19549286 A1 , Schering AG, (Example 1i)) and 16.9 g (130.5 mmol) of diisopropylethylamine in 500 ml of THF are added dropwise at -20 ° C. 17.8 g (130.5 mmol) of isobutyl chloroformate. The mixture is then stirred at −20 ° C. for 1 hour and 20 ml of 25 percent aqueous ammonia solution are carefully added. The mixture is stirred at 0 ° C. for 2 h, then the solvent is distilled off in vacuo and the residue is chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 55.9 g (75% of theory) of a colorless solid
Elemental analysis:

b) 1,3,5-triiodo-2,4,6-tris (2,5-diaza-3,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris ( tert-butyloxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene

44.4 g (70.6 mmol) of 10- (4-carbamido-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tert-butyl ester are added in 500 ml Dissolved THF and added 1.71 g (71 mmol) sodium hydride at 0 ° C under argon and 1 h at room temperature. touched. A solution of 20.2 g (20 mmol) of 1,3,5-triiodo-2,4,6-tris (toluenesulfonyloxy) methylbenzene in 150 ml of THF is then added dropwise and the mixture is stirred under reflux for 20 h. After cooling, insoluble constituents are filtered off and evaporated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water. The organic phase is dried over sodium sulfate, the solvent is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 16.2 g (34% of theory) of a colorless solid
Elemental analysis:

c) 1,3,5-triiodo-2,4,6-tris (2,5-diaza-3,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris ( carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene

17.9 g (7.5 mmol) 1,3,5-triiodo-2,4,6-tris (2,5-diaza-3,6-dioxoheptane-1,7-diyl- {10- [1,4,7 -tris- (tert-butyloxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene are dissolved in 75 ml dichloromethane, 75 ml trifluoroacetic acid are added at 0 ° C and the mixture is stirred at 0 ° C for 3 hours. The mixture is poured into 500 ml of diethyl ether, the solid which precipitates out is filtered off, rewashed three times with 100 ml of diethyl ether each time and dried in vacuo.
Yield 13.5 g (96% of theory) of a colorless solid
Elemental analysis:

d) 1,3,5-triiodo-2,4,6-tris (2,5-diaza-3,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris ( carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl]}, Gd-complex) benzene

12.9 g (6.9 mmol) 1,3,5-triiodo-2,4,6-tris (2,5-diaza-3,6-dioxoheptane-1,7-diyl- {10- [1,4,7 tris (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.7 g (10.4 mmol) of gadolinium oxide are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 10.6 g (61% of theory) of a colorless solid
Water content (Karl Fischer): 6.5%
Elemental analysis (based on the anhydrous substance):

Example 13

a) 2,4,6-Triiod-1,3,5-tris- (2-tert-butoxycarbonylaminoethoxymethyl) benzene

To a mixture of 50.0 g (91.4 mmol) 1,3,5-triiodo-2,4,6-trishydroxymethylbenzene and 3 g (8.7 mmol) tetrabutylammonium hydrogen sulfate in 200 ml 32%. NaOH solution and 300 ml of toluene are at room temperature. 142 g (450 mmol) of 2-tert-butoxycarbonylaminoethyl toluenesulfonate (Canne et al., Tetrahedron Letters, 38, 1997, 3361) dissolved in 250 ml of toluene were added dropwise and the mixture was then stirred for 12 h. It is mixed with 300 ml of water and extracted twice with 300 ml of toluene. The combined organic phases are dried over sodium sulfate, the solvent is evaporated to dryness and chromatographed on silica gel (mobile solvent hexane / ethyl acetate 10: 1). The fractions containing the product are combined and evaporated.
Yield 28.6 g (32% of theory) of a colorless solid
Elemental analysis:

b) 2,4,6-triiodo-1,3,5-tris (aminoethoxymethyl) benzene

24.4 g (25 mmol) of 2,4,6-triiodo-1,3,5-tris (2-tert-butoxycarbonylaminoethoxymethyl) benzene are dissolved in 100 ml of dichloromethane, 100 ml of trifluoroacetic acid are added at 0 ° C. and the mixture is stirred for 3 hours 0 ° C stirred. The mixture is poured into 500 ml of diethyl ether, the resulting solid is filtered off with suction and washed several times with diethyl ether. The residue is dissolved in 100 ml of water and 100 ml of dichloromethane with vigorous stirring. NaOH solution until a pH of 10 is reached. The organic phase is separated off, the aqueous phase is extracted three times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulfate and evaporated to dryness.
Yield 14.7 g (87% of theory) of a colorless solid
Elemental analysis:

c) 2,4,6-Triiod-1,3,5-tris- {10- [1,4,7-tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl] aminoethoxymethyl} benzene

44.6 g (70.6 mmol) of 1.4 become a solution of 15.9 g (23.5 mmol) of 2,4,6-triiodo-1,3,5-tris (aminoethoxymethyl) benzene in 400 ml of DMF , 7-tris- (benzyloxycarbonyl) -10- (carboxymethyl) -1,4,7,10-tetrazacyclododecane, 21 ml (164 mmol) triethylamine, 14.6 g (70.5 mmol) dicyclohexylcarbodiimide and 8.1 g (70, 5 mmol) N-hydroxysuccinimide and 20 h at room temperature. gerüht. Insoluble constituents are filtered off and evaporated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water. The organic phase is dried over sodium sulfate, the solvent is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 29 g (49% of theory) of a colorless solid
Elemental analysis:

d) 2,4,6-triiodo-1,3,5-tris [10- (1,4,7,10-tetraazacyclododecanyl) aminoethoxymethyl] benzene

20 g (7.9 mmol) 2,4,6-triiodo-1,3,5-tris- {10- [1,4,7-tris (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl] aminoethoxymethyl} benzene are carefully mixed with 140 ml HBr / AcOH (33%) at 0–5 ° C and 3 h at room temp. touched. The reaction mixture is then poured into 800 ml of diethyl ether, the resulting solid is filtered off with suction and washed several times with diethyl ether. The residue is dissolved in 100 ml of water and 100 ml of dichloromethane with vigorous stirring. NaOH solution until a pH of 10 is reached. The organic phase is separated off, the aqueous phase is extracted three times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulfate and evaporated to dryness.
Yield 10.1 g (97% of theory) of a colorless solid
Elemental analysis:

e) 2,4,6-Triiod-1,3,5-tris {10- [1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl] aminoethoxymethyl} benzene

17.7 g (13.5 mmol) of 2,4,6-triiodo-1,3,5-tris- [10- (1,4,7,10-tetraazacyclododecanyl) aminoethoxymethyl] benzene are dissolved in 75 ml of water, 19.5 g (206.5 mmol) chloroacetic acid are added and the pH is adjusted to 9.5 at 60 ° C. using 32% NaOH. The mixture is heated at 70 ° C. for 10 hours, the pH of the reaction mixture being continuously adjusted to 9.5. After cooling to room temp. is with conc. HCl adjusted a pH of 1 and the solution evaporated in vacuo. The residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H ⁺ form). It is then washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, the resulting solid is suction filtered, washed several times with diethyl ether and dried in vacuo.
Yield 14.4 g (58% of theory) of a colorless solid
Elemental analysis:

f) 2,4,6-triiodo-1,3,5-tris- {10- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd-complex]} benzene aminoethoxymethyl

12.7 g (6.9 mmol) 2,4,6-triiodo-1,3,5-tris- {10- [1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl] aminoethoxymethyl} benzene are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.7 g (10.4 mmol) of gadolinium oxide are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 7.4 g (44% of theory) of a colorless solid
Water content (Karl Fischer): 5.9%
Elemental analysis (based on the anhydrous substance):

Example 14

a) 2,4,6-Triiod-5- [2- (2,2,2-trifluoroacetylamino) acetylamino] isophthalic acid dichloride

14.5 ml (200 mmol) of thionyl chloride are added dropwise at 0 ° C. to a solution of 34.2 g (200 mmol) of glycine trifluoroacetate in 200 ml of dimethylacetamide within 1 hour. Then 23.8 g (40 mmol) of 5-amino-2,4,6-triodisophthalic acid dichloride ( DE 2943777 , Schering AG, (priority: 10/26/79)) and stirs for 4 days at room temp. The reaction mixture is poured into 5 liters of ice water and the precipitated solid is filtered off. For further purification, the filter residue is dissolved in 1000 ml of ethyl acetate, shaken twice with saturated sodium hydrogen carbonate solution, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuo.
Yield: 29.3 g (97% of theory) of a colorless solid
Elemental analysis:

b) 5- (2-Aminoacetylamino) -N, N-bis- (2-aminoethyl) -2,4,6-triiodoisophthalic acid amide

A solution of 10 g (13.3 mmol) of 2,4,6-triiodo-5- [2- (2,2,2-trifluoroacetylamino) acetylamino] isophthalic acid dichloride in 100 ml of tetrahydrofuran is converted to 26.7 ml (399 mmol) of ethylenediamine 1 h at room temp. dripped and stirred for 14 h. The precipitated solid is filtered off, washed with ethanol, taken up in 100 ml of water and adjusted to a pH of 8.0 with 1 M lithium hydroxide solution. After evaporation in vacuo, it is recrystallized from ethanol.
Yield: 6.4 g (68% of theory) of a colorless solid
Elemental analysis:

c) 2,4,6-Triiod-5- (3,6-diaza-1,4,7-trioxo-8-methyloctane-1,8-diyl- {10- [1,4,7-tris- ( carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex]}) aminoisophthalic acid-N, N-bis- (3,6-diaza-4,7-dioxo-8-methyloctane-1,8-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd-complex]}) amide

9.6 g (15.2 mmol) of Gd complex of 10- [4-carboxy-2-oxo-3-aza-1-methylbutyl] 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (WO 98 / 24775, Schering AG, (Example 1)) are suspended in 100 ml of DMSO and mixed with 1.96 g (17 mmol) of N-hydroxysuccinimide and 3.3 g (16 mmol) of dicyclohexylcarbodiimide and preactivated for 1 hour. Then 2.4 g (3.4 mmol) of 5- (2-aminoacetylamino) -N, N-bis- (2-aminoethyl) -2,4,6-triiodisophthalic acid amide are added and the mixture is left at room temperature for 3 days. stirred under nitrogen. Insoluble constituents are filtered off and the solution is poured into 1000 ml of acetone. The solid which precipitates out is filtered off and washed in portions with 300 ml of acetone and with 100 ml of diethyl ether. The residue is taken up in 200 ml of water and stirred for 2 hours with 30 g of ion exchanger (IRA 67 OH form) and filtered off. The mixture is then stirred for 2 hours with 10 g of ion exchanger (IR 267 H form), filtered off, mixed with 2 g of activated carbon, heated to 60 ° C. for 2 hours, filtered off and the solution is concentrated to 100 ml. To remove the remaining dimethyl sulfoxide, the solution is poured into 1000 ml of acetone and the precipitate is filtered off. The residue is dissolved in 250 ml of water, the conductivity is adjusted to a value of 0.005 mS (pH = 7.0) with a little ion exchanger (H form and OH form), filtered off and evaporated in vacuo.
Yield: 5.7 g (62% of theory) of a colorless solid
Water content (Karl Fischer): 5.7%
Elemental analysis (based on the anhydrous substance):

Example 15

a) 2,4,6-Triiod-5- (3,6-diaza-1,4,7-trioxooctane-1,8-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1 , 4,7,10-tetraazacyclododecanyl, Gd complex]}) aminoisophthalic acid-N, N-bis- (3,6-diaza-4,7-dioxooctane-1,8-diyl- {10- [1,4, 7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd-complex]}) amide

9.4 g (15.2 mmol) of Gd complex of 10- [4-carboxy-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (WO 98/24775, Schering AG, (Example 11)) are suspended in 100 ml of DMSO and mixed with 1.96 g (17 mmol) of N-hydroxysuccinimide and 3.3 g (16 mmol) of dicyclohexylcarbodiimide and preactivated for 1 hour. Then 2.4 g (3.4 mmol) of 5- (2-aminoacetylamino) -N, N-bis- (2-aminoethyl) -2,4,6-triiodisophthalic acid amide are added and the mixture is left at room temperature for 3 days. stirred under nitrogen. Insoluble constituents are filtered off and the solution is poured into 1000 ml of acetone. The solid which precipitates out is filtered off and washed in portions with 300 ml of acetone and with 100 ml of diethyl ether. The residue is taken up in 200 ml of water and stirred for 2 hours with 30 g of ion exchanger (IRA 67 OH form) and filtered off. The mixture is then stirred for 2 hours with 10 g of ion exchanger (IR 267 H form), filtered off, mixed with 2 g of activated carbon, heated to 60 ° C. for 2 hours, filtered off and the solution is concentrated to 100 ml. To remove the remaining dimethyl sulfoxide, the solution is poured into 1000 ml of acetone and the precipitate is filtered off. The residue is dissolved in 250 ml of water, the conductivity is adjusted to a value of 0.005 mS (pH = 7.0) with a little ion exchanger (N-form and OH-form), filtered off and evaporated in vacuo.
Yield: 6.1 g (67% of theory) of a colorless solid
Water content (Karl Fischer): 6.4%
Elemental analysis (based on the anhydrous substance):

Example 16

a) 2,4,6-Triiod-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris (benzyloxycarbonyl) -1,4,7 , 10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl) -1,4, 7,10-tetraazacyclododecanyl]}) amide

44.6 g are added to a suspension of 16.5 g (23.5 mmol) of 5- (2-aminoacetylamino) -N, N-bis- (2-aminoethyl) -2,4,6-triiodisophthalic acid amide in 446 ml of DMF (70.6 mmol) 1,4,7-tris (benzyloxycarbonyl) -10- (carboxymethyl) -1,4,7,10-tetrazacyclododecane, 21 ml (164 mmol) triethylamine, 14.6 g (70.5 mmol) Dicyclohexylcarbodiimide and 8.1 g (70.5 mmol) of N-hydroxysuccinimide added and 20 h at room temperature. gerüht. Insoluble constituents are filtered off and evaporated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water. The organic phase is dried over sodium sulfate, the solvent is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 30.5 g (51% of theory) of a colorless solid
Elemental analysis:

b) 2,4,6-Triiod-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N bis (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]}) amide

20 g (7.9 mmol) 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid- N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris (benzyloxycarbonyl ) -1,4,7,10-tetraazacyclododecanyl]}) amide, 140 ml HBr / AcOH (33%) are carefully added at 0–5 ° C and 3 h at room temp. touched. The reaction mixture is then poured into 800 ml of diethyl ether, the resulting solid is filtered off with suction and washed several times with diethyl ether. The residue is dissolved in 100 ml of water and 100 ml of dichloromethane with vigorous stirring. NaOH solution until a pH of 10 is reached. The organic phase is separated off, the aqueous phase is extracted three times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulfate and evaporated to dryness.
Yield 10.1 g (96% of theory) of a colorless solid
Elemental analysis:

c) 2,4,6-Triiod-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris (carboxymethyl) -1,4,7 , 10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4, 7,10-tetraazacyclododecanyl]}) amide

18.0 g (13.5 mmol) 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl ]}) aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]}) amide are dissolved in 75 ml of water, 19.5 g (206.5 mmol) of chloroacetic acid were added and the pH was adjusted to 9.5 at 60 ° C. using 32% NaOH. The mixture is heated at 70 ° C. for 10 hours, the pH of the reaction mixture being continuously adjusted to 9.5. After cooling to room temp. is with conc. HCl adjusted a pH of 1 and the solution evaporated in vacuo. The residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H ⁺ form). It is then washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, the resulting solid is suction filtered, washed several times with diethyl ether and dried in vacuo.
Yield 15.3 g (61% of theory) of a colorless solid
Elemental analysis:

d) 2,4,6-Triiod-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1,4,7 , 10-tetraazacyclododecanyl, Gd complex]}) aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris (carboxylatomethyl) - 1,4,7,10-tetraazacyclododecanyl, Gd-complex]}) amide

12.8 g (6.9 mmol) 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris (carboxymethyl) -1 , 4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) - 1,4,7,10-tetraazacyclododecanyl]}) amide are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.7 g (10.4 mmol) of gadolinium oxide are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 8.3 g (48% of theory) of a colorless solid
Water content (Karl Fischer): 6.9%
Elemental analysis (based on the anhydrous substance):

Example 17

a) 2,4,6-Triiod-5- (3-aza-1,4-dioxo-5-methylpentane-1,5-diyl- {10- [1,4,7-tris (benzyloxycarbonyl) -1 , 4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-5-methyl-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl)}) amide

To a suspension of 16.5 g (23.5 mmol) of 5- (2-aminoacetylamino) -N, N-bis- (2-aminoethyl) -2,4,6-triiodisophthalic acid amide in 446 ml DMF are added 45.7 g (70 , 6 mmol) 1,4,7-tris- (benzyloxycarbonyl) -10- (1-carboxyethyl) -1,4,7,10-tetrazacyclododecane, 21 ml (164 mmol) ttriethylamine, 14.6 g (70.5 mmol) Dicyclohexylcarbodiimide and 8.1 g (70.5 mmol) of N-hydroxysuccinimide added and 20 h at room temperature. gerüht. Insoluble constituents are filtered off and evaporated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water. The organic phases are dried over sodium sulfate, the solvent is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 28.6 g (47% of theory) of a colorless solid
Elemental analysis:

b) 2,4,6-Triiod-5- (3-aza-1,4-dioxo-5-methylpentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid -N, N-bis- (3-aza-5-methyl-4-oxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]}) amide

20 g (7.7 mmol) 2,4,6-triiodo-5- (3-aza-1,4-dioxo-5-methyl-pentan-1,5-diyl {10- [1,4,7-tris- (benzyloxycarbonyl) -1,4 , 7,10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-5-methyl-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl ) -1,4,7,10-tetraazacyclododecanyl]}) amide, 140 ml HBr / AcOH (33%) are carefully added at 0–5 ° C and 3 h at room temp. touched. The reaction mixture is then poured into 800 ml of diethyl ether, the resulting solid is filtered off with suction and washed several times with diethyl ether. The residue is dissolved in 100 ml of water and 100 ml of dichloromethane with vigorous stirring. NaOH solution until a pH of 10 is reached. The organic phase is separated off, the aqueous phase is extracted three times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulfate and evaporated to dryness.
Yield 10.2 g (96% of theory) of a colorless solid
Elemental analysis:

c) 2,4,6-Triiod-5- (3-aza-1,4-dioxo-5-methylpentane-1,5-diyl- {10- [1,4,7-tris (carboxymethyl) -1 , 4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-5-methyl-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide

18.6 g (13.5 mmol) 2,4,6-triiodo-5- (3-aza-1,4-dioxo-5-methylpentane-1,5-diyl- {10- [1,4,7 , 10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-5-methyl-4-oxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]}) amide are dissolved in 75 ml of water, 19.5 g (206.5 mmol) of chloroacetic acid are added and the pH is adjusted to 9.5 at 60 ° C. using 32% NaOH. The mixture is heated at 70 ° C. for 10 hours, the pH of the reaction mixture being continuously adjusted to 9.5. After cooling to room temp. is with conc. HCl adjusted a pH of 1 and the solution evaporated in vacuo. The residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H ⁺ form). It is then washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, the resulting solid is suction filtered, washed several times with diethyl ether and dried in vacuo.
Yield 14.1 g (55% of theory) of a colorless solid
Elemental analysis:

d) 2,4,6-Triiod-5- (3-aza-1,4-dioxo-5-methylpentane-1,5-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1 , 4,7,10-tetraazacyclododecanyl, Gd complex]}) aminoisophthalic acid-N, N-bis- (3-aza-5-methyl-4-oxopentane-1,5-diyl- {10- [1,4, 7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd-complex]}) amide

13.1 g (6.9 mmol) 2,4,6-triiodo-5- (3-aza-1,4-dioxo-5-methylpentane-1,5-diyl- {10- [1,4,7-tris- ( carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-5-methyl-4-oxopentane-1,5-diyl- {10- [1,4, 7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.7 g (10.4 mmol) of gadolinium oxide are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 7.6 g (44% of theory) of a colorless solid
Water content (Karl Fischer): 5.3%
Elemental analysis (based on the anhydrous substance):

Example 18

a) 2,4,6-Triiod-5- {methyl [2- (2,2,2-trifluoroacetylamino) acetyl] amino} isophthalic acid dichloride

14.5 ml (200 mmol) of thionyl chloride are added dropwise at 0 ° C. to a solution of 34.2 g (200 mmol) of glycine trifluoroacetate in 200 ml of dimethylacetamide within 1 hour. Then 24.4 g (40 mmol) of 5-amino-2,4,6-triodisophthalic acid dichloride ( EP 0033426 , Sovak, 1/80 US) and stir for 4 days at room temp. The reaction mixture is poured into 5 liters of ice water and the precipitated solid is filtered off. For further purification, the filter residue is dissolved in 1000 ml of ethyl acetate, shaken twice with saturated sodium hydrogen carbonate solution, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuo.
Yield: 28.7 g (94% of theory) of a colorless solid
Elemental analysis:

b) 5 - [(2-Aminoacetyl) methylamino] -N, N-bis- (2-aminoethyl) -2,4,6-triiodoisophthalic acid amide

A solution of 10 g (13.1 mmol) of 2,4,6-triiodo-5- {methyl- [2- (2,2,2-trifluoroacetylamino) acetyl] amino} isophthalic acid dichloride in 100 ml of tetrahydrofuran becomes 26.7 ml (399 mmol) ethylenediamine for 1 h at room temperature. dripped and stirred for 14 h. The precipitated solid is filtered off, washed with ethanol, taken up in 100 ml of water and adjusted to a pH of 8.0 with 1 M lithium hydroxide solution. After evaporation in vacuo, it is recrystallized from ethanol.
Yield: 7.3 g (78% of theory) of a colorless solid
Elemental analysis:

c) 2,4,6-Triiod-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris (benzyloxycarbonyl) -1,4,7 , 10-tetraazacyclododecanyl]}) - methylaminoisophthalsäure-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl) -1,4 , 7.10-tetraazacyclododecanyl]}) - amide

To a suspension of 16.8 g (23.5 mmol) of 5 - [(2-aminoacetyl) methylamino] -N, N-bis- (2-aminoethyl) -2,4,6-triiodisophthalic acid amide in 446 ml of DMF 44.6 g (70.6 mmol) 1,4,7-tris (benzyloxycarbonyl) -10- (carboxymethyl) -1,4,7,10-tetrazacyclododecane, 21 ml (164 mmol) triethylamine, 14.6 g (70 , 5 mmol) of dicyclohexylcarbodiimide and 8.1 g (70.5 mmol) of N-hydroxysuccinimide and 20 h at room temperature. gerüht. Insoluble constituents are filtered off and evaporated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water. The organic phase is dried over sodium sulfate, the solvent is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 34.9 g (58% of theory) of a colorless solid
Elemental analysis:

d) 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]}) - methylaminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]}) - amide

20 g (7.8 mmol) 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]}) methylaminoisophthalsäure-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl ) -1,4,7,10-tetraazacyclododecanyl]}) - amide, 140 ml HBr / AcOH (33%) are carefully added at 0–5 ° C and 3 h at room temp. touched. The reaction mixture is then poured into 800 ml of diethyl ether, the resulting solid is filtered off with suction and washed several times with diethyl ether. The residue is in 100 ml Water and 100 ml of dichloromethane dissolved with vigorous stirring are given as long as 32 percent. NaOH solution until a pH of 10 is reached. The organic phase is separated off, the aqueous phase is extracted three times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulfate and evaporated to dryness.
Yield 10.0 g (95% of theory) of a colorless solid
Elemental analysis:

e) 2,4,6-Triiod-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris (carboxymethyl) -1,4,7 , 10-tetraazacyclododecanyl]}) - methylaminoisophthalsäure-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4 , 7.10-tetraazacyclododecanyl]}) - amide

18.2 g (13.5 mmol) 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl ]}) - methylaminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]}) - amide in 75 ml of water dissolved, 19.5 g (206.5 mmol) of chloroacetic acid were added and the pH was adjusted to 9.5 at 60 ° C. using 32% NaOH. The mixture is heated at 70 ° C. for 10 hours, the pH of the reaction mixture being continuously adjusted to 9.5. After cooling to room temp. is with conc. HCl adjusted a pH of 1 and the solution evaporated in vacuo. The residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H ⁺ form). It is then washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, the resulting solid is suction filtered, washed several times with diethyl ether and dried in vacuo.
Yield 15.0 g (59% of theory) of a colorless solid
Elemental analysis:

f) 2,4,6-Triiod-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1,4,7 , 10-tetraazacyclododecanyl, Gd complex]}) - methylaminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd-complex]}) - amide

12.9 g (6.9 mmol) 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris (carboxymethyl) -1 , 4,7,10-tetraazacyclododecanyl]}) - methylaminoisophthalsäure-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) - amide are dissolved in 100 ml of water and acidified by adding 3 ml of acetic acid. 3.7 g (10.4 mmol) of gadolinium oxide are added and the mixture is heated under reflux for 6 h. When the complexation is complete, the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 8.7 g (51% of theory) of a colorless solid
Water content (Karl Fischer): 5.8%
Elemental analysis (based on the anhydrous substance):

Example 19

a) 5- [3- (2-Aminoethyl) -ureido] -N, N-bis- (2-aminoethyl) -2,4,6-triiodoisophthalic acid amide

To a solution of 29.8 g (50 mmol) of 5-amino-2,4,6-triodisophthalic acid dichloride ( DE 2943777 , Sche ring AG, (priority: 10/26/79) in 250 ml dioxane, 100 ml of a 2 M solution of phosgene in toluene are carefully added and heated to 60 ° C. for 24 h. Then the solution is evaporated in vacuo at 80 ° C, the gases by a 20 percent. aqueous NaOH solution are passed. The residue is dissolved in 200 ml of tetrahydrofuran and 66.9 ml (1.0 mol) of ethylenediamine over 1 h at room temperature. dripped and stirred for 24 h. The precipitated solid is filtered off, washed with ethanol, taken up in 200 ml of water and adjusted to a pH of 8.0 with 1 M lithium hydroxide solution. After evaporation in vacuo, it is recrystallized from ethanol.
Yield: 19.4 g (53% of theory) of a colorless solid
Elemental analysis:

b) 2,4,6-Triiod-5- (2,5-diaza-1,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris (benzyloxycarbonyl) -1.4 , 7,10-tetraazacyclododecanyl]}) - aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl) -1 , 4,7,10-tetraazacyclododecanyl]}) - amide

To a suspension of 17.1 g (23.5 mmol) of 5- [3- (2-aminoethyl) -ureido] -N, N-bis- (2-aminoethyl) -2,4,6-triiodoisophthalic acid amide in 446 ml DMF becomes 44.6 g (70.6 mmol) 1,4,7-tris (benzyloxycarbonyl) -10- (carboxymethyl) -1,4,7,10-tetrazacyclododecane, 21 ml (164 mmol) triethylamine, 14.6 g (70.5 mmol) dicyclohexylcarbodiimide and 8.1 g (70.5 mmol) N-hydroxysuccinimide and 20 h at room temperature. gerüht. Insoluble constituents are filtered off and evaporated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water. The organic phase is dried over sodium sulfate, the solvent is evaporated to dryness and the residue is chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
Yield 32.7 g (54% of theory) of a colorless solid
Elemental analysis:

c) 2,4,6-triiodo-5- (2,5-diaza-1,6-dioxoheptane-1,7-diyl- {10- [1,4,7,10-tetraazacyclododecanyl)}) - aminoisophthalic acid- N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl)}) - amide

25.7 g (10 mmol) 2,4,6-triiodo-5- (2,5-diaza-1,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris (benzyloxycarbonyl) 1,4,7,10-tetraazacyclododecanyl)}) - aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- ( benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]}) - amide, 140 ml HBr / AcOH (33%) are carefully added at 0-5 ° C and 3 h at room temp. touched. The reaction mixture is then poured into 800 ml of diethyl ether, the resulting solid is filtered off with suction and washed several times with diethyl ether. The residue is dissolved in 100 ml of water and 100 ml of dichloromethane with vigorous stirring. NaOH solution until a pH of 10 is reached. The organic phase is separated off, the aqueous phase is extracted three times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulfate and evaporated to dryness.
Yield 12.8 g (94% of theory) of a colorless solid
Elemental analysis:

d) 2,4,6-Triiod-5- (2,5-diaza-1,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris (carboxymethyl) -1.4 , 7,10-tetraazacyclododecanyl]}) - aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1 , 4,7,10-tetraazacyclododecanyl)}) - amide

18.4 g (13.5 mmol) 2,4,6-triiodo-5- (2,5-diaza-1,6-dioxoheptane-1,7-diyl- {10- [1,4,7,10 -tetraazacyclododecanyl]}) - aminoisophthalsäu re-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]}) - amide are dissolved in 75 ml of water, 19.5 g (206.5 mmol) chloroacetic acid are added and the pH is adjusted to 9.5 at 60 ° C. using 32% NaOH. The mixture is heated at 70 ° C. for 10 hours, the pH of the reaction mixture being continuously adjusted to 9.5. After cooling to room temp. is with conc. HCl adjusted a pH of 1 and the solution evaporated in vacuo. The residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H ⁺ form). It is then washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, the resulting solid is suction filtered, washed several times with diethyl ether and dried in vacuo.
Yield 14.3 g (56% of theory) of a colorless solid
Elemental analysis:

e) 2,4,6-Triiod-5- (2,5-diaza-1,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris (carboxylatomethyl) -1.4 , 7,10-tetraazacyclododecanyl, Gd complex]}) - aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- ( carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd-complex]}) - amide

13.0 g (6.9 mmol) 2,4,6-triiodo-5- (2,5-diaza-1,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris (carboxymethyl) - 1,4,7,10-tetraazacyclododecanyl]}) - aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl ) -1,4,7,10-tetraazacyclododecanyl]}) - amide are dissolved in 100 ml of water and by adding 3 ml of acetic acid acidified. 3.7 g (10.4 mmol) of gadolinium oxide are added and 6 h on Heated to reflux. After complexation is adjusted to pH 7.4 with ammonia and chromatographed on silica gel (mobile phase: dichloromethane / methanol / ammonia: 10/10/1).

The fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
Yield 7.1 g (41% of theory) of a colorless solid
Water content (Karl Fischer): 6.3%
Elemental analysis (based on the anhydrous substance):

Pharmacological examples

CT examinations with Example 1B

The The suitability of the described connection class was exemplified on Example 1B was investigated in rats using computer tomography (CT). For the A Siemens Somatom CR was available for CT examinations. The 5 second recordings were made with a layer thickness of 2 mm and a tube tension of 125 kV. Substance 1B was dissolved as an aqueous solution in a concentration of 0.17 mol / L (corresponds to 145 mg (I + Gd) / mL formulated.

Male Wistar rats (400 g body weight) were previously ( 1a ) and after intravenous injection ( 1 ) of IB at a dose of 0.15 mmol / kg (corresponds to 127 mg (I + Gd) / kg scanned.

Despite the small size of the examination animal, a very clear contrast of the blood-carrying vessels (A) and the renal cortex (N) was observed even with the low dose of 127 mg (I + Gd). This early phase reflects blood perfusion in the renal cortex. The renal pelvis was already contrasted 15 minutes later in the parenchyma phase, which is due to rapid renal excretion of the substance ( 2 ).

MRI examinations with Example 1B

The same substance (IB) was created using magnetic resonance Tomography (MRI) examined as a contrast medium.

The MRI examinations were carried out on a 1.5 T device (Siemens Symphony with 40 mT / m gradient). Wistar rats weighing 400 g were examined with T1-weighted recording sequences (angiography TR 2.54 ms, TE 1.12 ms and α = 40 ° or organ representation TR 54 ms, TE 4.8 ms and α = 40 °). Angiography (MRA, 3 ) was pi from 0–60 sec and the organ display ( 4a and b ) Made 15 min after the injection. Substance 1B was formulated as an aqueous solution in a concentration of 0.17 mol / L (corresponds to 0.5 mol Gd / L) and injected intravenously in a dose of 0.03 mmol substance or 0.1 mmol Gd / kg.

The MRA excellently represents the large arteries (aorta, a. Femoralis) as well as the heart.

In the whole body shot ( 4b ) there is a clear contrast between the liver (L) and the kidneys (renal pelvis = N). The urethers (U) could also be shown, which also underlines the rapid renal excretion of the substance.

This combined CT and MR examination demonstrates the dual benefit this new connection class. Excellent contrast enhancement was demonstrated in CT as well as in MR. It is conceivable for Example of the clinical use of these compounds in a high-resolution MultiSlice CT (imaging of the coronary arteries). This is followed by to assess vitality a delayed MRI of the heart muscle is performed. There is no second for this A contrast medium must be injected.

Phantom studies with an example 3F compared to Gadovist and Iopromid

The relative X-ray attenuation of Example 3F was determined at concentrations of 0.05, 0.1 and 0.2 mol / L of the substance, equivalent to 0.3, 0.6 and 1.2 mol / L contrasting elements (Gd + iodine), compared to equimolar concentrations of iopromide and gadobutrol. A phantom was used for this, in the dilutions of the initial formulations (Example 3F - 0.27M, Ultravist ^® 300 mg l / ml equivalent to 0.788 mol / L iopromide and Gadobutrol 1 mol / L) was pipetted into distilled water in well plates (Eastern 3524). One milliliter of each dilution was pipetted into a well plate, which corresponded to a height of 0.5 cm. The pipetted corrugated plate was placed on the horizontal patient table of the C-arm X-ray device (Stenoskop D6, General Electrics) in the beam path and a plastic container with a water column of 17 cm was placed on top of the corrugated plate to absorb soft tissue and harden the radiation of the X-rays as in the to simulate the vivo situation.

The radiographs were in the "High Pulse "modality with the DSA x-ray stenoscope D6 (General Electrics) with a cesium filter / iodine intensifier of 16 cm and 2 mm aluminum filters at different voltages the X-ray anode added.

All Images were taken after manual selection of the x-ray tube and anode voltage Variation of the mA added to the image contrast at the respective Optimize anode voltage.

The Images of the Stenoskop D6 were then in an image analysis device (Quantimet 500+, Leica) and displayed on a scale of 256 gray values. For quantitative Determination of gray value was a circular ROI (Region Of Interest) for each Well analyzed and the background at the respective anode voltage subtracted.

The measured gray values of the example 3F, iopromide and gabobutrol plotted against the respective concentration and a linear Region analysis performed. The slope of the best-fit line was calculated and that relationship the straight line between the different contrast media.

Representative x-rays of the phantom described above are shown in 5 shown.

Abbildung 5: Vergleich der Röntgenabsorption von Beispiel 3F, Gadobutrol und Iopromid. Röntgenbilder des Phantoms bei 60 und 110 kV Anodenspannung aufgenommen mit dem C-Arm Gerät Stenoskop D6 (General Electrics).

Figure 5: Comparison of the X-ray absorption of Example 3F, Gadobutrol and Iopromid. X-ray images of the phantom at 60 and 110 kV anode voltage taken with the C-arm device Stenoscope D6 (General Electrics).

The relationship between the concentrations of Example 3F, iopromide and gabobutrol was linear in all cases. The evaluation showed a significantly higher X-ray absorption of Example 3F than iopromide and gadobutrol at equimolar concentrations ( 5 ).

Abbildung 6: Relative Röntgenabsorption von Beispiel 3F im Vergleich mit Gadobutrol und Iopromid bei verschiedenen Anodenspannungen der Röntgenröhre (Stenoskop D6, General Electrics).

Figure 6: Relative X-ray absorption of Example 3F in comparison with Gadobutrol and Iopromid at different anode voltages of the X-ray tube (Stenoskop D6, General Electrics).

In the evaluation of the X-ray images showed one at 110 kV and equimolar concentrations of Example 3F 3.08 times higher X-ray absorption than iopromide and 3.77 times higher as Gadobutrol. Even higher X-ray absorption differences of Example 3F are for higher Anode voltages, as used in modern X-ray CT procedures (helicoidal and multi-line CT) are expected to be applied. Additionally occurring Strahlungaufhärtung in the in vivo situation, elements such as e.g. Gd, Dy, Yb or Bi.

The Phantom studies prove that example 3F excellent X-ray absorption has and for the application in modern DSA and CT, especially multi-line CT suitable is.

Verteilungskoeffzient

The Distribution coefficient of example 3F was compared to Gadovist, Iopromide and Iotrolan in 1-butanol and Tris-HCl buffer at pH 7.6 certainly. The contrast media were in the buffer with a final concentration dissolved from 0.1 mmol Gd / L, The iodine-containing contrast media were at an initial concentration of 1 mg l / mL is used.

Table 1: Distribution coefficient of Example 3F compared to commercially available MR and X-ray contrast media

The Data in Table 1 show that the Example 3F a very hydrophilic substance with a low partition coefficient Butanol / water is and even better values than the very well tolerated MR contrast medium Gadovist has. In comparison, the commercially available iodine contains Compound iopromide has a much lower hydrophilicity with one to to 255 times higher Partition coefficient of butanol / water (0.051 vs. 0.0002).

IC-50 / LD-50 correlation

For the determination the IC-50 became the neutral red test in the epithelial cells of the distal renal tubule used. This test is also very good helpful to get the LD-50 values of new synthesized compounds to predict with high accuracy.

Epithelial cell line MDCK from renal distal kidney tubule of the dog kidney (ECACC No. 85011435) were from 10,000 cells / well in Alpha MEM Eagle (10% fetal bovine serum) at 37 ° C and 5% CO ₂ , 95% humidity for 20 h with various examples 1B, 3F and 5F incubated. Neutral red was used as an indicator of cell viability and to measure lysosomal integrity and was used to determine the contrast medium concentration at which a 50% reduction in cell viability (IC-50) occurred after 24 h.

Four independent Replicas were made for tested every concentration of contrast media. The results are summarized in Table 2. Compared to the reference connection for MR contrast media Gadovist showed a sharp increase in tolerance. The latter is a reference compound in the clinic and a contrast agent with proven excellent tolerance. The highest tolerance was for Example 3F with 1170 μmol leq / mL found.

Table 2: Comparison of the IC ₅₀ values of various examples according to the invention with gadobutrol and the expected LD ₅₀ value in mice

Claims (13)

Metal complexes of the general formula I

wherein Hal for bromine or iodine, A ¹ for the residues -CONR ¹ - (CH ₂ ) _n -NR ² - (CO-CHZ ¹ -NH) _m -CO-CHZ ² -, -CONR ¹ - (CH ₂ ) _p - (CONR ² CH ₂ ) _m -CHOH-CH ₂ -K, -CH ₂ O- (CH ₂ ) _p -CHOH-CH ₂ -K, -CH ₂ -O- (CH ₂ ) _n -NR ¹ - ( CO-CHZ ¹ -NH) _m -CO-CHZ ² -K, -CH ₂ -NR ¹ -CO- (CHZ ¹ -NH-CO) _m -CHZ ² -, A ^{2 has} the same meaning as A ¹ or in If A ^{1 has} the meaning given above for the radical -NR ¹ -CO- (NR ¹ ) _m - (CH ₂ ) _p -NR ² - (CO-CHZ ¹ -NH) _m -CO-CHZ ² - can stand in which R ¹ and R ² independently represent a hydrogen atom, a C ₁ -C ₂ alkyl group or a monohydroxy C ₁ -C ₂ alkyl group, Z ¹ and Z ² independently of one another a hydrogen atom or a methyl group, n the numbers 2-4, m denotes the digits 0 or 1 and p denotes the digits 1-4, K for a macrocycle of the formula I _A

with X in the meaning of a hydrogen atom or a metal ion equivalent of atomic numbers 20-29, 39, 42, 44 or 57-83, with the provisos that at least two X stand for metal ion equivalents and any free carboxy groups which may be present as salts of organic and / or inorganic bases or amino acids or amino acid amides. Metal complexes according to claim 1, characterized in that A ^{1 represents} a group. -CONH (CH ₂ ) _{2; 3} NHCOCH ₂ NHCOCH (CH ₃ ) -, -CONH (CH ₂ ) _{2; 3} NHCOCH ₂ NHCOCH ₂ -, -CONH (CH ₂ ) _{2; 3} NHCOCH ₂ -, -CONH (CH ₂ ) _{2; 3} NHCOCH (CH ₃ ) -, -CONHCH ₂ CH (OH) CH ₂ -, -CON (CH ₃ ) CH ₂ CH (OH) CH ₂ -, --CH ₂ OCH ₂ CH (OH) CH ₂ -, -CONHCH ₂ CONHCH ₂ CH (OH) CH ₂ -, -CH ₂ NHCOCH ₂ -, -CH ₂ NHCOCH (CH ₃ ) -, -CH ₂ NHCOCH ₂ NHCOCH ₂ -, -CH ₂ NHCOCH ₂ NHCOCH (CH ₃ ) -, -CH ₂ O (CH ₂ ) ₂ NHCOCH ₂ -, -CON (CH ₂ CH ₂ OH (CH ₂ ) ₂ NHCOCH ₂ -, -CH ₂ O (CH ₂ ) ₂ N (CH ₂ CH ₂ OH) COCH ₂ -. Metal complexes according to claim 1, characterized in that A ² for a -NHCOCH ₂ NHCOCH ₂ NHCOCH (CH ₃ ) -, -NHCOCH ₂ NHCOCH ₂ NHCOCH ₂ -, -NHCOCH ₂ NHCOCH ₂ -, -NHCOCH ₂ NHCOCH (CH ₃ ) - , -N (CH ₃ ) COCH ₂ NHCOCH ₂ -, -NHCONH (CH ₂ ) ₂ NHCONH ₂ -, -NHCOCH ₂ N (CH ₂ CH ₂ OH) COCH ₂ -, -N (CH ₃ ) COCH ₂ N (CH ₂ CH ₂ OH) COCH ₂ -. Metal complexes according to claim 1, characterized in that X for a metal ion equivalent atomic numbers 21-29, 42, 44, 58-70 stands. Metal complexes according to claim 4, characterized in that that X for a metal ion equivalent the ions gadolinium (III), dysprosium (III), europium (III), iron (III) or manganese (II). Pharmaceutical compositions containing at least one Metal complex of the general formula I according to claim 1, if appropriate with those common in galenics Additives. Use of at least one metal complex after Claim 1 for the production of funds for the X-ray diagnostics. Use of at least one metal complex after Claim 4 for the production of funds for the MRI diagnostics. Pharmaceutical compositions each containing a metal complex according to claims 1 and 4 in a molar ratio of 2000: 1 to 1: 1, preferably 49: 1 to 4: 1. Pharmaceutical composition according to claim 6, characterized characterized in that the or the dissolved in water or physiological saline or suspended metal complexes) in a concentration of 0.001 up to 1 mol / l is / are present. Use of at least one metal complex after Claim 1 for the production of funds for the Roentgen- and MR diagnostics of brain infarctions and tumors of the liver or space-consuming processes in the liver and tumors of the abdomen (including the kidneys) and the musculoskeletal system and especially can be advantageous the connections for the visualization of blood vessels intra-arterial but also intravenous injection can be used A process for the preparation of the metal complexes of the general formula I according to claim 1, characterized in that a) a triiodo or tribromoaromatic of the general formula II

in a manner known per se with a macrocycle of the general formula III

wherein C ^x O for a -COOH or activated carboxyl group, W for a protective group or a -CH ₂ COOX 'group with X' in the meaning of X or a protective group and -Y ¹ -NR ¹ -CO-B ¹ - for the radical A ¹ in the meaning of -CO-NR ¹ - (CH ₂ ) _n -NR ² - (CO-CHZ ¹ -NH) _m -CO-CHZ ² - or -CH ₂ -O- (CH ₂ ) _n -NR ¹ - (CO-CHZ ¹ -NH) _m -CO-CHZ ² - and Y ² -NR ¹ -CO-B ¹ for Y ¹ -NR ¹ -CO-B ¹ or in the event that Y ¹ -NR ¹ -CO-B ^{1 also has} the meaning given above for -NR ¹ -CO- (NR ¹ ) _m (CH ₂ ) _p -NR ² - (CO-CHZ ¹ -NH) _m -CO-CHZ ² - are, where B ^{1 is} the radical on the first or second carbonyl group (seen from K) between -CO- and K and Y ¹ or Y ^{2 is} the missing radical of the linker group reduced by an imino group, and then optionally reacted the protective group W is removed and the radicals CH ₂ COOX are introduced in a manner known per se or the protective group which may be X 'is removed and then in itself reacted with a metal oxide or metal salt of an element of atomic numbers 20-29, 39, 42, 44 or 57-83 or b) a triiodo or tribromoaromatic of the general formula IV

in a manner known per se with a macrocycle of the general formula V

where -C ^x O and X 'have the meaning given above and -CO-NR ¹ -Y ³ for the radical A ^{1 has} the meaning -CONR ¹ - (CH ₂ ) _p - (CONR ² CH ₂ ) _m -CH ( OH) CH ₂ - and thus Y ³ in the meaning of -NR ¹ - (CH ₂ ) _p - (CONR ² CH ₂ ) _m -CH (OH) CH ₂ -, and then the protective group optionally representing X ' removed and then reacted in a manner known per se with a metal oxide or metal salt of an element of atomic numbers 20-29, 39, 42, 44 or 57-83 or c) a triiodo or tribromoaromatic of the general formula VI

where A ¹ for a radical

stands in a manner known per se with a cycle of the general formula VII

where W 'represents a hydrogen atom or a protective group, to - after removing the protective groups which may be present and then introducing the radicals -CH ₂ COOX in a manner known per se - a metal complex of the general formula I with A ¹ in the meaning of the radical -CH ₂ -O- (CH ₂ ) _p -CHOH-CH ₂ - or d) a triiodo or tribromoaromatic of the general formula VIII

wherein Nucleofug stands for a nucleofugic group, in a manner known per se with a macrocycle of the general formula IX

wherein R ¹ and W have the meaning given above, and B ^{2 represents} the radical - (CHZ ¹ -NHCO) _m -CHZ ² -, and then proceeding as indicated under a), so that metal complexes of the general formula I with A ¹ in the meaning of the radical -CH ₂ -NR ¹ -CO- (CHZ ¹ -NHCO) _m -CHZ ² , which then optionally also in the metal complexes of general formula I obtained according to a) -d) still present acidic Hydrogen atoms can be substituted by cations of inorganic or organic bases, amino acids or amino acid amides. Process for the preparation of pharmaceutical compositions according to claim 6, characterized in that one is in water or physiological saline solution dissolved or suspended complex compound, optionally with those in the Galenics usual additives in one for the enteral or parenteral application brings a suitable form.