NL8400079A - DIAGNOSTIC MEDICINE. - Google Patents

Description

VO 5301

Diagnostic agent

The invention relates to the subject characterized in the claims.

Complexes or their salts have long been used in medicine, for example as an aid for the administration of sparingly soluble ions (eg iron) and as antidotes "(calcium or zinc complexes are preferred) for detoxification at a per Incorrectly Established Inclusion of Heavy Metals or their Radioactive Isotopes It has now been found that physiologically tolerable complex salts, from the anion of a complexing acid 10 and one or more central ions of an element having atomic numbers 21 to 29 , 42, 44 or 57 to 83 and optionally of one or more cat ions of an inorganic and / or organic base or amino acid, against which cations are physiologically free, surprisingly excellent for the preparation of diagnostic agents, which 15 are suitable for use in NMR or X-ray diagnostics or ultrasonic diagnostics.

The element with the above-mentioned atomic number, which constitutes the central ion or the central ions of the physiologically tolerable complex salt, must of course not be radioactive for the intended purpose of the diagnostic agent according to the invention.

If the agent according to the invention is intended for use in NMR diagnostics (see European patent application 71 564), then the central ion of the complex salt must be paramagnetic. These are in particular the 2 and 3-valent ions of the elements with atomic numbers 21 to 29, 42, 44 and 58 to 70. Suitable ions are, for example, the chromium (III), manganese (II) -, iron (III) -, iron (II) -, cobalt (XI) -, nickel (II) -, copper (II) -, praseodymium (III) -, neodymium (III) -, samarium (III ) and ytterbium (III) ion. Due to their very strong magnetic moment, the gadolinium (III) -30 terbium (III), dysprosium (III), holmium (III) and erbium (III) ion are particularly preferred.

If the agent according to the invention is intended for use in X-ray diagnostics, then the central ion must be derived from an element with a higher atomic number in order to achieve an adequate absorption of the X-rays. It was found that for this. target diagnostic agents containing a physiologically tolerable complex salt with central ions of elements having atomic numbers between 57 and 83; these are, for example, the lanthanum (III) ion, the above-mentioned ions of the lanthanide series, the gold (III) ion, the lead (II) ion or in particular the bismuth (III) ion.

Both the means according to the invention, which are intended for use in NMR diagnostics, as well as those intended for use in X-ray diagnostics, are suitable for use in ultrasonic diagnostics.

Suitable complexing acids are those representatives which are usually used for complexing the above-mentioned central ions. Suitable complexing acids are, for example, those which contain 3-12, preferably 3-8 methylene phosphonic acid groups, methylene carbohydroxamic acid groups, carboxyethylidene groups, or in particular carboxymethylene groups, of which one, two or three are each bound to a nitrogen atom supporting the complex formation. . if three of the azidic groups are attached to a nitrogen atom, the complexing acids underlying the complex salts of the general formula 2 according to claim 2 are present. If only one or two of the azidic groups. are bound to a nitrogen atom, the nitrogen is bound to another nitrogen atom via an optionally substituted ethylene or via up to four ethylene units separated each time by a nitrogen or oxygen or sulfur atom which supports complex formation. Preferred complexing acids of this type are those of the general formula 1 according to claim 2.

The complexing acids can be cross-linked as conjugates with biomolecules which are known to increase sharply in the organ or organ part under investigation. Such biomolecules are, for example, hormones such as insulin, prostaglandin, steroid hormones, amino sugars, peptides, proteins or lipids. Particular emphasis should be placed on conjugates with albumins, such as human serum albumin, antibodies, such as, for example, monoclonal, 8400079 * 4 3 tumor-associated antigen specific antibodies or anti-myosin. The diagnostic agents formed from this are suitable, for example, for use in tumor and infarct diagnosis. Conjugates or cage compounds with 5 liposomes are suitable for liver research, for example, which are used, for example, as unilamellar or multilamellar phosphatidylcholine cholesterol vesicles. The conjugate formation takes place either via a carboxyl group of the complexing acid, or in the case of the proteins or peptides also via a group: 10 "Vp-W-" as defined in claim 2. In the conjugate formation of the complexing acids with proteins, peptides or lipids, various acid residues can be partially bound to the macromolecular biomolecule. In this case, any complexing acid residue can carry a central ion. If the complexing acids are not bound to biomolecules, they optionally carry two central ions, in particular a central ion.

Suitable complex salts of the general formula 1 according to claim 2 are, for example, those representatives of the general formula 1a, wherein X, V, R 2, R 1 and R 2 have the meaning as defined in claim 2.

The following complexing acids are suitable for the preparation of the complex salts of the general formula la: ethylenediamine-tetra-acetic acid, ethylenediamine-tetra-acetethroxamic acid, trans-1,2-cyclohexylenediamine-tetra-acetic acid, DL-2 , 3-butylene-diamine-tetra-acetic acid, DL-i, 2-butylene-diamine-tetra-acetic acid, DL-1,2-propylene-diamine-tetra-acetic acid, 1,2-diphenylethylene-diamine-tetra-acetic acid, ethylene dinitrilo -tetrakis (methane phosphonic acid) and N- (2-hydroxyethyl) -ethylenediamine triacetic acid.

Other suitable complex salts of the general formula 1 according to claim 2 are, for example, those of the general formula 1b, wherein X, V, Z, and m have the meaning as defined in claim 2. If Z represents an oxygen atom or a sulfur atom, complex salts with m in the sense of 1 or 2 are preferred.

The following complexing acids are suitable for the preparation of the complex salts of the general formula Ib: diethylene triamine-pentaacetic acid, triethylene-tetramine-hexa-acetic acid, 8400079 * 4 tetraethylene-pentamine-hepta-acetic acid, 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-penta-aza-penta-triacontanedioic acid, 3,9-bis (1-carboxyethyl) -3, 6,9-tri-aza-undecanedioic acid, diethylenetriamine-pentakis- (methylene-phosphonic acid), 1,10-diaza-4,7-dioxadecane-1,1,10,10-tetra-acetic-5-acid and 1,1Q- diaza-4,7-dithiadecane-1,1,10,10-tetraacetic acid.

Suitable complex salts of the general formula 1 according to claim 2 are furthermore those of the general formula 1c, wherein X and w have the meaning as defined in claim 2. The following complexing acids are suitable for the preparation of complex salts of the general formula lc: 1,4,8,11-tetra-aza-cyclotetradecane-tetra-acetic acid and in particular 1,4,7, 10-tetra-aza-cyclodode-canaan-tetra-acetic acid.

Other complexing acids suitable for the preparation of the complex salts of the general formula 1 are, for example, 1,2,3-tris [bis (carboxymethyl) -amino] -propane and nitrilotris- (ethylenitrilo) hexa- acetic acid. Nitrilo-tri-acetic acid is mentioned as an example of a complexing acid for the preparation of complex salts of the general formula II.

When not all azidic hydrogen atoms of the complexing acid are substituted by the central ion or central ions, it is expedient to increase the solubility of the complex salt with the remaining hydrogen atoms by cations of inorganic and / or organic bases or amino acids, against which cations are physiologically free from substitution. Suitable inorganic cations are, for example, the lithium ion, the potassium ion or in particular the sodium ion. Suitable organic base cations include those of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine, or especially N-methylglucamine. Suitable amino acid cations are, for example, those of the lysine, arginine or ornithine.

The complexing acids required for the agents according to the invention are known or can be prepared in a manner known per se.

For example, the preparation of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-penta-aza-penta-triacontane-diacid is carried out according to the R.A. Bulman et al in Naturwissenschaften _68, (1981) 3400079 * 5 483 proposed improved form:

17.85 g (= 50 mmol) of 1,5-bis- (2,6-dioxomorpholino) -3-azapentane-3-acetic acid are suspended in 400 ml of dry dimethylformamide and the suspension after addition of 20.13 g (= 100 mmol) 11-amino-5 undecanoic acid heated at 70 ° C for 6 hours. The clear solution is concentrated under reduced pressure. The yellow oily residue is stirred with 500 ml of water at ambient temperature. An almost white bulky solid precipitates, which is filtered off and washed several times with water. The product obtained is placed in 200 ml of acetone for further purification and stirred at ambient temperature for 30 minutes. After suction and drying under reduced pressure at 50 ° C, 36.9 g (= 97% of the theory) of a white powder with a melting point of 134 - 138 ° C are obtained.

The conjugation of the complexing acids with biomolecules also takes place according to methods known per se, for example by reaction of nucleophilic groups of the biomolecule - such as, for example, amino, hydroxyl, thio or imidazole groups - with an activated derivative of the complexing acid.

As activated derivatives of the complexing acids, for example, acid chlorides, acid anhydrides, activated esters, nitrenes or isothiocyanates are suitable. Conversely. it is also possible to convert an activated biomolecule with the complexing acid.

For the conjugation with proteins, substituents with the structure of CgH 2 NBCOCH 3 halogen are also available.

The preparation of the complex salts is also partly known or can take place in a manner known per se by the metal oxide or a metal salt (for instance the nitrate, chloride or sulphate) of the element with the atomic numbers 21 to 29, 42, 44 or 57 to 83 in water and / or a low alcohol (such as methanol, ethanol or isopropanol) or to dissolve and add to the solution or suspension the equivalent amount of the complexing acid in water and / or a low add and stir alcohol, if necessary with heating or heating to boiling point, until conversion is complete. When the complex salt formed is insoluble in the solvent used, it is isolated by filtration. When it is soluble, it can be isolated by evaporating the solution to dryness, for example, by 8400079 a * 6 by spray drying.

When azide groups are still present in the complex salt obtained, it is usually expedient to use the acidic complex salt by means of inorganic and / or organic bases or amino acids, which form cat-5 ions, against which physiologically there is no objection, in neutral complexes convert salts and isolate them. In many cases this is even unavoidable, since the dissociation of the complex salt is reduced by the shift of the pH value to neutral so far that this actually only allows the isolation of uniform products or at least the purification thereof. .

It is expedient to effect the preparation by means of organic base or basic amino acids. However, it may also be advantageous to carry out the neutralization by means of inorganic bases (hydroxides, carbonates or hydrogen carbonates) of sodium, potassium or lithium.

For example, to prepare the neutral salts, the acidic complex salts, dissolved or suspended in water, can be charged with enough of the desired base to reach the neutral point.

The resulting solution can then be evaporated to dryness under reduced pressure. It is often advantageous for the neutral salts formed by adding water-miscible solvents, such as, for example, low alcohols (methanol, ethanol, isopropanol, etc.), low ketones (acetone, etc.), polar ethers (tetrahydrofuran, dioxane, 1, 2-dimethoxyethane, etc.) and thus easily isolate and obtain well-purifiable crystallization products. It has been found to be particularly advantageous to add the desired base to the reaction mixture already during the complex formation and thereby to save a process step.

When the acidic complex salts contain several free azide groups, it is usually expedient to prepare neutral mixed salts containing both inorganic and organic cations, which are physiologically free, as counterions. This can be done, for example, by the complexing acid in a suspension or aqueous solution, with the oxide or salt of the element providing the central ion, and with half the amount of an organic base required for neutralization to isolate the complex salt formed, purify it if desired and then, to completely neutralize it, add the required amount of inorganic base thereto. The order of addition of the bases can also be reversed.

The preparation of the diagnostic agents according to the invention also takes place in a manner known per se by suspending or dissolving the complex salts, optionally with the addition of the additives customary in galenic pharmacy, in an aqueous medium and then the solution or suspension to sterilize. Suitable additives are, for example, buffers, against which physiologically there is no objection (such as, for example, trimethamine hydrochloride), minor additions of complexing agents (such as, for example, diethylene triamine-pentaacetic acid) or, if necessary, electrolytes (such as, for example, sodium chloride).

In principle, it is also possible to prepare the diagnostic means according to the invention without isolation of the complex salts. In any case, particular care must be taken to carry out the chelation in such a way that the salts and salt solutions according to the invention are practically free from uncomplexed, toxic acting metal ions. This can be ensured, for example, with the aid of color indicators, such as xylenol orange, by control titrations during the preparation process. The invention therefore also relates to processes for the preparation of the complex compound and its salts. The final safety remains a purification of the isolated complex salt.

When, for oral administration or other purposes, suspensions of the complex salts in water or in physiological saline are desired, a sparingly soluble complex salt with one or more auxiliary substances and / or tensides and / or flavoring substances customary in galenic pharmacy for improving the taste mixed.

The diagnostic agents of the invention preferably comprise from 1 µm to 1 mole per liter of the complex salt and are generally dosed in amounts from 0.001 to 5 mmole / kg. They are intended for oral and in particular parenteral administration.

The agents according to the invention satisfy - according to claim 4 - the multiple conditions for being suitable as a contrast agent for nuclear spin tomography. For example, they are eminently suitable for enhancing, after oral or parenteral administration, by increasing the signal intensity the image obtained with the nuclear spin tomograph in terms of its expression power. Furthermore, they exhibit the strong action necessary to load the bodies with the least possible amounts of foreign matter and the good tolerability necessary to maintain the non-invasive character of the study (the one in J. Comput. Tomography, 5, 6: 543-46 (1981), compounds indicated in Radiology, 144, 343 (1982) and Brevet Special de Medicament No. 484 M (1960) are, for example, too toxic). The good water solubility of the agents according to the invention makes it possible to prepare highly concentrated solutions, thereby keeping the volume load of the cycle within defensible limits and equalizing the dilution by the body fluid, i.e. NMR diagnostics must be 100 - 1000 are more soluble in water than the compounds for NMR spectroscopy. Furthermore, the agents of the invention exhibit not only great stability in vitro, but also surprisingly great stability in vivo, such that a release or exchange of the non-covalently bound, per se toxic ions within the complexes within the 24 hours, in which -20 as pharmacological research has shown - the new contrast agents are completely excreted again, take place only extremely slowly. The conjugates with proteins and antibodies used for tumor diagnostics, for example, already effect a surprisingly large signal amplification in such a small dose that solutions of correspondingly lower concentration can be used here.

The agents according to the invention are - according to claim 5 - eminently suitable as X-ray contrast agents, with particular emphasis being placed on the fact that no indications can be seen for the anaphylaxis-like reactions known to the iodinated contrast agents in biochemical-pharmacological research. They are particularly valuable because of their favorable absorption properties in areas of higher tube voltages for digital sub-traction techniques.

The means according to the invention are, according to claim 3, also suitable as ultrasonic diagnostics on account of their property of influencing the ultrasonic velocity.

8400079 * «9

In contrast to conventional X-ray diagnostics with shading contrast agents, NMR diagnostics with paramagnetic contrast agents have no linear dependence of the signal gain due to the applied concentration. As control studies demonstrate, an increase in the administered dose does not unconditionally lead to a signal gain, and with a large dose of paramagnetic contrast agent it may even lead to a quenching of the signal. It was surprising, therefore, that some pathological processes only after the administration of doses greater than the doses indicated in British Patent Specification 71 564 (which may be 0.001 mmol / kg to 5 mmol / kg) of a strong paramagnetic contrast agent according to the invention. For example, evidence of a defective blood-brain barrier in the area of a cranial abscess can only be obtained after administration of 0.05 - 2.5 mmol / kg, preferably 0.1 - 0.5 mmol / kg, of 15 paramagnetic complex salts such as, for example, gadolinium diethylene triamine penta acetic acid or manganese 1,2 cyclohexylenediamino tetra acetic acid are supplied in the form of their water-soluble salts.

*

For a dose of more than 0.1 mmol / kg, solutions of higher concentrations up to 1 mol / liter, preferably 0.25 - 0.75 mol / liter, are required, since only in this way the volume load is reduced and the handling of the injection solution is guaranteed.

Particularly small dosages (less than 1 mg / kg) and thus less concentrated solutions (1 µmol / liter to 5 mmol / liter) than are indicated in British patent 71.564, are for example for the organ-specific NMR diagnostics for the need to demonstrate tumors and heart attacks.

The following exemplary embodiments serve to further illustrate the invention.

Example I

30 Preparation of the gadolinium-III complex of nitrilo-N, N, N-tri-acetic acid, C-H. GdNO, 6 6 6

A suspension of 36.2 g (= 100 mmol) of gadolinium oxide ((k ^ O ^) and 38.2 g (= 200 mmol) of nitrilo-triacetic acid in 1.2 liters of water was stirred at 90 ° C to 100 ° C and stirred at this temperature for 48 hours, then the undissolved substance was filtered over activated charcoal and the filtrate evaporated to dryness The amorphous residue was pulverized.

3100079 * * 10

Yield: 60 g (87% of theory);

Melting point: 300 ° C;

Gadolinium: calculated 45.5%, found 44.9%.

The iron III complex of the nitrilo-N, N, N-tri-acetic acid was obtained using iron III chloride, FeCl 2.

Example II

Preparation of the disodium salt of the gadolinium-III complex of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-penta-aza-penta-triacontane-diacid , gGdN ^ .0 ^ ^. 2Na 10 In 400 ml of water, 15.2 g (= 20 mmol) of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,2 4-penta-aza-penta- Triacontane diacid is suspended and heated to 95 ° C. Then 7.43 g (= 20 mmol) of gadolinium III chloride hexahydrate, dissolved in 60 ml of water, were added dropwise slowly. The mixture was kept at this temperature for 2 hours, after which time 60 ml of 1 n sodium hydroxide solution was added to neutralize the hydrochloric acid formed.

After complete conversion (test with xylenol orange), the resulting precipitate was filtered and washed with free of chloride. 17.60 g (96% of theory) of a water-insoluble white powder, mp 290-292 ° C, were obtained.

Gadolinium III complex of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15, 18,21,24-penta-aza-pentatriacontane diacid.

Analysis: '(Calculated) C 47.30, H 6.84, N 7.66 Gd 17.20 25 (Found) C 47.13, H 6.83, N 7.60, Gd 17.06

14.6 g (= 16 mmol) of the gadolinium-III complex thus obtained were suspended in 200 ml of water, after which 13.4 ml of 1N sodium hydroxide solution was added dropwise. After 1 hour, a clear solution was obtained, which was filtered and then concentrated under reduced pressure. After drying under reduced pressure at 80 ° C, 13.2 g (87% of theory) of a highly water-soluble white powder, mp 279-285 ° C, were obtained.

Analysis: (Calculated) C 45.13, H 6.31, N 7.31, Gd 16.41, Na 4.80 35 (Found) C 45.20, H 6.12, N 7.28, Gd 16 , 26, After 4.75

Similarly, with N-methylglucamine in place of sodium hydroxide solution, the di-N-methyiglucamine salt of the gadolinium-III complex of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12, 15,18,21,24-penta-aza-penta-triacontane-diacid, C 3 -3 GdNjO22>.

Example III

Preparation of the disodium salt of the gadolinium-III complex of 3,9-bis (1-carboxyethyl) -6-carboxymethyl-3,6,9-triaza-undecane diacid, C16H22GdN3 ° 102Na

In 250 ml of water, 36.2 g (= 0.1 mol) of gadolinium III oxide and 84.2 g (= 0.2 mol) of 3,9-bis (1-carboxyethyl) -6-carboxymethyl-ΙΟ 3 , 6,9-triaza-undecanedioic acid suspended and refluxed for 1 hour. The small amount of undissolved substance was filtered off and the solution evaporated to dryness under reduced pressure. The residue was pulverized and dried at 60 ° C under reduced pressure. 112.8 g (= 98% of theory) of the chelate as white powder were obtained.

Analysis: C 1 H 3 GdN 3 (Calculated) C 33.39, H 4.20, Gd 27.32, N 7.30 (Found). C 33.25, H 4.49, Gd 27.42, N 7.21

57.6 g (= 0.1 mol) of the chelate were placed in a solution of 0.1 mol of sodium hydroxide in 100 ml of water. By adding an additional 20 0.1 moles of sodium hydroxide powder, the pH of the solution was adjusted to a pH of 7.5, the solution was boiled and ethanol was added to permanent cloudiness. After stirring in an ice bath for several hours, the crystallization product was filtered off, washed with ethanol and dried under reduced pressure. The disodium salt was obtained in quantitative yield as a white powder.

Analysis: (Calculated) C 31.02, H 3.58, Gd 25.38, N 6.78 (Found) C 31.10, H 3.71, Gd 25.50, N 6.61.

Example IV

Preparation of the D-morphollne salt of the gadolinium III complex of 3,9-bis (1-carboxyethyl) -6-carboxymethyl-3,6,9-triaza-undecanoic diacid, C24H42GdN5012

17.4 g (= 0.2 mol) of morpholine were dissolved in 50 ml of water. Then 42.1 g (= 0.1 mol) of 3,9-bis (1-carboxyethyl) -6-car-35 boxymethyl-3,6,9-triaza-undecane diacid and then 18.2 g (= 0, 05 mol) of gadolinium III oxide was added and refluxed until a clear solution was formed. Acetone was then added dropwise to permanent cloudiness. After stirring in an ice bath for several hours, the crystallization product was filtered off, washed with acetone and dried under reduced pressure. The dimorpholine salt was obtained in quantitative yield as a white powder.

Analysis:

Calculated C 38.44, H 5.65, Gd 20.97, N 9.34. Found C 38.31, Ξ 5.72, Gd 20.76, N 9.32.

Example V

10 Preparation of the di-N-methylglucamine salt of the gadolinium-III complex of diethylene triamine-Ν, Ν, Ν'-Ν ", N" -pentaacetic acid, C „gH ^^ GN ^ O ^ g

39.3 g (= 100 mmol) of diethyltriamine, N, N, N ', N ", N" -pentaacetic acid were suspended in 200 ml of water, after which 19.5 g (= 100 mmol) of N-methylglucamine were added. Then 18.12 g (= 50 mmol) of gadolinium III oxide, Gd2 ° 3 'were added portionwise and the resulting suspension was depleted at 95 ° C. After about 1 hour another 19.5 g (= 100 mmol) of N-methylglucamine were added and a clear solution was obtained after 2 hours of heating. After complete conversion (control with xylenol orange), the small amount of undissolved substance was filtered off and the filtrate evaporated to dryness under reduced pressure. The residue was redissolved in 100 ml of water and placed in 250 ml of ethanol with stirring.

After cooling for several hours, the crystallization product was filtered off, washed with cold ethanol and dried under reduced pressure at 60 ° C. 92.7 g (99% of theory) of a white powder with an uncharacteristic melting point were obtained.

Analysis: (Calculated) C 35.85, H 5.80, N 7.47, Gd 16.77 (Found) C 35.50, H 5.72, N 7.20, Gd 16.54.

Instead of ethanol, acetone, propanol or isopropanol could also be used to purify the complex salt.

Similarly, with dysprosium III oxide, the di-N-methylglucamine salt of the dysprosium III complex of diethylenetriamine-Ν, Ν, Ν1, N ", N" -pentaacetic acid, 35 C28H54DyN5 ° were obtained. 20; with lanthanum III oxide, La: the di-N-methylglucamine salt of the lanthanum III complex of diethylene-8400079 13 triamine-N, Ν, Ν ', N ", N" -pentacetic acid, C28H54LaN5 ° 20? with ytterbium-Ill oxide, Yr ^ O ^: the di-N-methyl-glucamine salt of the ytterbium-IIX-cplex of diethylene-5 triarain-Ν, Ν, Ν ', N ", N" -pentaacetic acid, C28H54YbN5 ° 20; with samarium III oxide, Sn 2 O 3: the di-N-methylglucamine salt of the samarium III complex of diethylene-triamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid, 10 C28HS4S "5 ° 20! With holmium III oxide, the di-N-methylglucamine salt of the holmium III complex of diethylene-triamine-Ν, Ν, Ν ', N", N "-pentaacetic acid, C28H54HoN5 ° 20; 15 with bismuth-III-oxide, Bi2 ° 3: j the di-N-methylglucamine salt of the bismuth-III complex of diethylenetriamine-N, N, N ', N ", N" -pentaacetic acid , C28H54BiN5O20; with gadolinium III oxide, GdjO2: the tri-N-methylglucamine salt of the gadolinium-III complex of triithylene tetramine-Ν, Ν, Ν ', N ", N" 1, N "' -hexa-acetic acid, C, H, GdN_Q__ 39 78 7 27

Furthermore, with holmium-III-oxide, 20ο20 ethanol and ethanolamine instead of N-methylglu-25-camine were obtained: the diethanolamine salt of the holmium-Ill complex of diethylene tetramine-Ν, Ν, Ν ', N ”, N "-pentaacetic acid, cj_gH34HoN5 ° i2; with gadolinium III oxide, Gd20g, and lysine instead of n-methylglucamine: the di-lysine salt of the gadolinium III complex of diethylene triamine--, Ν, Ν ', Ν ", Ν"' - pentaacetic acid, C2 gH ^ gGdN ^ 0 ^.

Diethanolamine gave the diethanolamine salt of the holmium III complex of diethylene triamine-8400079 J S '14 pentaacetic acid, G22H42HoN5 ° 14 *

The salts were obtained as white powders with an uncharacteristic melting point. They were very soluble in water. Example VI

5 Preparation of the disodium salt of the gadolinium III complex of diethylenetriamine-Ν, Ν, Ν1, N ", N" -pentaacetic acid, ^ "GdN ^ O ^ ^. 2 Na

18.2 g (= 0.05 mol) of gadolinium III oxide and 39.3 g (= 0.1 mol) of diethylenetriamine-pentaacetic acid were suspended in 110 ml of water, followed by refluxing for 1 hour. The clear solution was cooled and adjusted to a pH of 7.5 by adding about 80 ml of 5N sodium hydroxide solution. It was then boiled again, after which 250 ml of ethanol were added dropwise. After stirring in an ice bath for several hours, the crystallization product was filtered off, washed with ice-cold ethanol and dried under reduced pressure at 60 ° C. In quantitative yield, a white powder was obtained, which did not melt up to 300 ° C. Analysis: (Calculated) G 28.43, H 3.07, N 7.10, Gd 26.58 (Found) C 28.35, H 2.95, N.7.05, Gd 26.37

Correspondingly, with dysprosium III oxide, Dy ^ ^: the di-sodium salt of the dysprosium III complex of diethylene-triamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid C14S18DyN3 were obtained ° 10 "2 Na: with lanthanum-III-oxide: the di-sodium salt of the lanthanum-III-complex of diethylene-triamine-N, N, N ', N", N "-pentaacetic acid C14Hi8laN3 ° 10 · 2 Ha; with holmium III oxide, Ho2 O2: the di-sodium salt of the holmium III complex of diethylenetriamine-30 N, N, N ', N ", N" -pentaacetic acid G14H18HoN3 ° 10 · 2 Na with ytterbium III oxide, Yb202: the di-sodium salt of the ytterbium III complex of diethylene triamine-N, N, N1, N ", N" -pentaacetic acid 35 C14H13ibS3O10.2 Na; §4 0 0 0 7 9 15 with samarium-11-oxide, Sn 2 O 3: di-sodium salt of the samarium-III complex of diethylenetriamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid C14H18SmN3 ° 10'2 *** '' 5 erbium III oxide, Eb203: the disodium salt of the erbium III complex of this thylamine-Ν, Ν, Ν ', Ν ", N" -pentaacetic acid

ClArt ° 10 · 2 with gadolinium III oxide, Gd ^: 10 the sodium salt of the di-gadolinium III complex of tetraethylene pen-

IV IV

tamine-Ν, Ν, Ν ', N, N -hepta-acetic acid C22H30Gd2N5 ° 14 * Na'

These salts were obtained as white powders with a non-characteristic melting point and were very soluble in water.

Example VII

Preparation of the N-methylglucamine salt of the iron III complex of diethylene trramine-pentaacetic acid,

35.40 g (* 90 mmol) diethylenetriamine-pentaacetic acid was suspended in 100 ml of water, after which 24.3 g (= 90 mmol) of iron-20 IH-chloride hexahydrate (FeCl 4. 100 ml of water was added The initial dark brown suspension was heated to 95 ° C. The color changed to pale yellow for about 1 hour. To neutralize the hydrochloric acid formed, 270 ml of 1N sodium hydroxide solution was added and then Heated for 3 hours at 95 ° C. The resulting pale yellow precipitate was filtered off with suction, washed with chloride free of water and dried under reduced pressure at 60 ° C. 17.85 g (45% of theory) of a light yellow powder were obtained, whose melting point was above 300 ° C.

17.85 g (= 40 mmole) of the obtained iron-III complex was suspended in 200 ml of water, after which 7.8 g (= 40 mmole) of N-methylglucamine were added portionwise in the solid state. Then it was heated to 50 ° C for about 3 hours to obtain an almost clear, red-brown solution, which was filtered and then evaporated to dryness under reduced pressure. The residue was dried under reduced pressure at 50 ° C. 24.3 g (95% of theory) of a red-brown powder with a melting point of 131-133 ° C were obtained.

8400079 * * 16

Analysis: (Calculated) C 39.82, H 5.89, N 8.85, Fe 8.81 (Found) C 39.70, H 6.00, N 8.65, Fe 9.01.

Using sodium hydroxide instead of the organic base, the following were obtained: the sodium salt of the iron III complex of ethylenediamine-tetraacetic acid, C 1 H 4 FeN 2 g Na; the sodium salt of the iron III complex of trans-1,2-cyclohexylene diamine tetraacetic acid, C 1 H 4 g Fe 2 Og.Na; The di-sodium salt of the iron-III complex of diethylene trinitrile penta (methanephosphonic acid), Cg ^ FeNgO ^ Pg ^ Na; the sodium salt of the iron III complex of 1,10-diaza-4,7-dioxadecane-1,1,10,10-tetra-acetic acid, C 4 H 2 QFeN 2 ° 10 Na, the sodium salt of the iron III complex of ethylenediamine-tetra-acetate-15-hydroxamic acid, C 4 H 4 FeNgOg.Na.

Similarly, with N-methylglucamine, the di-N-methylglucamine salt of the iron III complex of diethylenetriamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid, 20 C28H54FeN5 ° 20; the N-methylglucamine salt of the iron III complex of trans-1,2-cyclohexylenediamine-Ν, Ν, N ', N'-tetraacetic acid, C21H36PeN3 ° 13; the N-methylglucamine salt of the iron III complex of ethylenediamine-N, N, N ', N'-tetraacetic acid, C 1 HgQFeNgO 2; the tri-N-methyl glucamine salt of the iron III complex of triethylene-tetramine-N, N, N1, N ", N" 1, N "- hexa-acetic acid, C39H78FeN7 ° 27 '

Using diethanolamine instead of N-30 methylglue amine, the diethanolamine salt of the iron III complex of diethylenetriamine-N, N, N ", N", N "-pentaacetic acid, C22H42FeN5 ° 144 was changed 8400079 17

Example VIII

Preparation of the N-methylglucainine salt of the gadolinium-III complex of trans-1,2-cyclohexylenediamine-N, N, N ', Ν'-tetraacetic acid,

Sl3 5 20.78 g (= 60 mmol) of trans-1,2-cyclohexylenediamine-Ν, Ν, Ν ', Ν'-tetra-acetic acid was suspended in 150 ml of water. After adding 11.7 g (= 60 mmol) of N-methylglucamine, an almost clear solution was obtained, to which 10.88 g (= 30 mmol) of gadolinium oxide (Gd ^ O ^) was added. The re-obtained suspension was heated to 95 ° C for 6 hours. The small amount of undissolved substance was filtered off and the filtrate evaporated to dryness. The residue was dried under reduced pressure at 60 ° C and powdered. 38.6 g (92% of theory) of a white powder with a melting point of 258-261 ° C were obtained.

Analysis. * - 15 (Calc'd) C 36.25, H 5.22, N 6.04, Gd 22.60 (Found) C 36.40, H 5.50, N 5.98, Gd 22.52.

Likewise, with sodium hydroxide instead of N-methylglucamine, the sodium salt of the gadolinium-Ill complex of trans-1,2-cyclohexylenediamine-N, N, N ', Ν'-tetraacetic acid, C 1 H 2 gGdN ^ Og., Obtained after 20.

With freshly precipitated chromium-III-hydroxide, Cr (OH) ^, the sodium salt of the chromium-Ill complex of ethylenediamine-N, N, N ', Ν'-tetra-acetic acid, cQHH2CrN2 ° 8 * Na was obtained.

Example IX

Preparation of the di-sodium salt of the manganese II complex of trans-1,2-cyclohexylenediamine-N, N, N *, N'-tetraacetic acid, MnN 2 O 3. 2 Na

In 100 ml of water, 34.6 g (= 100 mmol) of trans-1,2-cyclo-hexylene-diamine-Ν, Ν, Ν ', Ν'-tetraacetic acid are suspended under nitrogen, after which 11.5 g (= 100mmol) mancano II carbonate, Mn CO 2, was added. Then it was heated to 95 ° C and 200 ml of 1N sodium hydroxide solution was added dropwise. The clear solution was concentrated under reduced pressure and the residue dried under reduced pressure at 60 ° C. 40.8 g (92% of theory) of a pink powder were obtained.

Analysis: 35 (Calculated) C 37.94, H 4.09, N 6.32, Mn 12.40 (Found) C 37.78, H 4.12, N 6.20, Mn 12.31.

8400079 18

In a corresponding manner: from copper II carbonate the di-sodium salt of the copper II complex of trans-1,2-cyclohexylenediamine-tetra-acetic acid, C 2 H O CuNoO 2 Na; 14 l a o from cobalt II carbonate is the disodium salt of the cobalt II complex of trans-1,2-cyclohexylenediamine-tetraacetic acid, C 1 H 2 gGN 2 Og. 2After? from nickel II carbonate the di-sodium salt of the nickel II complex of trans-1,2-cyclohexylenediamine-tetraacetic acid, C14H18NiN2Og.2 Na.

With N-methylglucamine instead of caustic soda, the di-N-methylglucamine salt of the manganese II complex of trans-1,2-cyclohexylenediamine tetraacetic acid, C28H54MnN40ig; the di-N-methylglucamine salt of the manganese II complex of DL-2,3-butylenediamine-tetraacetic acid, 26 26 ^ 52 ^ ^ 4 ^ 18; 15 the di-N-methylglucamine salt of the manganese II complex of ethylenediamine-Ν, Ν, Ν ', Ν'-tetraacetic acid, C24H48MnN4 ° ig' the di-N-methylglucamine salt of the manganese II complex of DL-1,2-butylenediamine-Ν, Ν, Ν ', Ν'-tetraacetic acid, C 2 H 22 MnN 4 ° j> Q? the di-N-methylglucamine salt of the manganese II complex of DL-1,2-20 propylenediamine-Ν, Ν, Ν ', Ν'-tetraacetic acid, CggHggMn ^ Q ^ g; the tri-N-methylglucamine salt of the manganese II complex of diethylene-triamine-pentaacetic acid, Cg; with nickel II carbonate, NiCOg the di-N-methylglucamine salt of the nickel II complex of ethylene diamine-mine--, Ν, Ν ', Ν'-tetraacetic acid, C24H48NiN4 ° iS; with cobalt II carbonate, CoCOg and ethanolamine the diethanolamine salt of the cobalt II complex of ethylenediamine-N, N, N ', Ν'-tetraacetic acid, C 4 H 28 CO 4 N 4 ° 1Q; with copper II carbonate, CuCOg and ethanolamine the diethanolamine salt of the copper II complex of ethylenediamine-N, N, N ', N' - tetraacetic acid, C 4 H 2 g C 2 O 2 g? with manganese II carbonate, MnCOg and diethanolamine 8400079 19 the tri-diethanolamine salt of the manganese II complex of diethylene triamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid, C26H54MnN6 ° 16; with manganese II carbonate, MnCO 2 and morpholine the di-morpholine salt of the manganese II complex of ethylenediamine-N, N, 5 N ", N" -tetraacetic acid, C 1 H 3 MnN 2 Q.

Example X.

N-Methylglucamine salt of the gadolinium-III complex of ethylenediamine-Ν, Ν, Ν *, Ν'-tetraacetic acid, C ^ ^ H ^ gGdNjO ^.

29.2 g (= 100 mmol) of ethylene dia-10 mine-Ν, Ν, Ν ', Ν'-tetra-acetic acid were suspended in 100 ml of water and with 18.1 g (= 50 mmol) of gadolinium-III oxide, heated at 95 eC. During heating, 19.5 g (= 100 mmol) of N-methylcrlucamine were added portionwise. After about 3 hours, a clear solution was obtained, which was filtered and evaporated to dryness under reduced pressure. The residue was dried under reduced pressure at 60 ° C. 61.3 g (95% of theory) of a white powder with an uncharacteristic melting point were obtained.

Analysis: (Calculated) C 31.82, H 4.71, N 6.55, Gd 24.51 (Found) C 31.65, H 4.59, N 6.52, Gd 24.56 20. : with dysprosium III oxide, Dy the N-methylglucamine salt of the dysprosium III complex of ethylenediamine-N, N, N ', Ν'-tetraacetic acid, C 1 H 3 DyNgO 3; the N-methylglucamine salt of the gadolinium-III complex of 1,10-diaza-25 4,7-dioxadecane-1,1,10,10-tetraacetic acid, CjjHggGdNgO 5, the N-methylglucamine salt of the gadolinium-III complex of 1,2-diphenyl-ethylenediamino-tetraacetic acid, C29 ^ 38N3 ^ 1 ^ Gd; with lead II oxide, PbO and sodium hydrochloride the disodium salt of the lead II complex of ethylenediamine-tetraacetic acid, C 1 H N.O Pb. 2 Na; 1U 12 2 o with freshly precipitated chromium-III-hydroxide, Cr (OH) - the sodium salt of the chromium-III complex of ethylenediamine-tetraacetic acid, CΛΗ, NCrN_O.Na; and analogously the sodium salt of the gadolinium-III complex of ethylenediamine-tetra-8400079-acetroxroxamic acid, C 1 H -GdN.0-Na; 1U lo o o the sodium salt of the gadoliniuxn-III complex of ethylenediamine-N, N, N ', N'-tetraacetic acid, C ^ gH ^ 2G <3N208'Na'

Example XI

Preparation of the sodium salt of the gadolinium-III complex of 1,4,7 / 10-tetraazacyclododecane-NyN1, N ", N" - tetraacetic acid, ^ H ^ ^ GdN ^ On.Na In 20 ml water, 4.0 g (= 10 mmol) 1,4,7,10-tetra-azacyclododecane-Ν, Ν ', N ", N"' - tetraacetic acid was suspended, and 10 ml of 1N sodium hydroxide solution was added. Then 1.8 g (= 5 mmol) of gadiolium III-oxide, Gd2O3, were added and the suspension was heated at 50 ° C for 2 hours. The clear solution was filtered and concentrated under reduced pressure. The residue was dried and powdered. 5.5 g (95% of theory) of a white powder were obtained.

Analysis: 15 (Calculated) C 33.10, H 4.17, N 9.65, Gd 27.08 (Found) C 33.01, H 4.20, N 9.57, Gd 27.16

In the same manner, the N-methylglucamine salt of the gadolinium-III complex of 1,4,7,10-tetra-aza-cyclododecane-Ν, Ν ', N ", N" -tetraacetic acid, the sodium salt of the gadolinium III complex of 1,4,8,11-tetra-aza-cyclotetradecane-Ν, Ν ', N ", N"' -tetraacetic acid, C 1 H 1 GdN 2 OG. Na.

Example XII

Preparation of the tetra-N-methylglucamine salt of the gadolinium-III complex. of ethylene dinitrile-tetrakis (methane phosphonic acid), ^ H ^ GdN ^ Q ^ 2 ~ 25 I4; .

- 9.11 g (= 20 mmol) of ethylenedini trilotetrakis (methanephosphonic acid) were suspended in 150 ml of water and the suspension adjusted to a pH value of 5 with the appropriate amount of N-methylglucamine. Then 3.6 g (= 10 mmol) of gadolinium III oxide, Gd2O2> were added and heated to 70 ° C. After about 1 hour, a clear solution was obtained to which the remaining portion of N-methylglucamine was added. A total of 15.6 g (= 80 mmol) of N-methylglucamine was consumed. The solution was evaporated to dryness under reduced pressure and the remaining gel-like residue was placed in 200 ml of acetonitrile. Then it was stirred at 30 ° C for about 20 hours and the resulting fine precipitate was filtered off.

8400079 21

After drying under reduced pressure at 40 ° C, 23.4 g (85% of theory) of a white powder with a melting point of 115-118 ° C was obtained. Analysis: (Calculated) C 29.78, H 6.25, N 6.13, p 9.04, Gd 11.47 5 (Found) C 29.85, H 6.57, N 5.98, P 8 78, Gd 11.26

In the same manner, the hepta-N-methylglucamine salt of the gadolinium-III complex of diethylenetriamine-Ν, Ν, Ν ', Ν ”, Ν" -ρβηηη (πιβί1ιη3ηίο3ίοηηηητ), C ^ H ^ GdN ^ O ^ -

V

10 and using caustic soda instead of N-methylglucamine: the disodium salt of the gadolinium-III complex of diethylene-trini-trilopenta (methane phosphonic acid), Cg ^ GdN ^ O ^ Pg ^ Na.

Example XIII

Preparation of the disodium salt of the manganese II complex of ethylene-15-dinitrilo-tetra (acethydroxamic acid), C 1 H 2 MnN 2.

In 18 ml of water, 2.30 g of manganese II carbonate and J 7.05 g of ethylene dinitrile tetra (acethydroxamic acid) were refluxed for 3 hours. Then the pH was adjusted to 7 by the addition of dilute sodium hydroxide solution and 40 ml of acetone were added dropwise. After stirring in an ice bath for several hours, the separated crystallization product was filtered off, washed with acetone and dried under reduced pressure at 50 ° C. In a quantitative yield, as a white powder, a dihydrate having a melting point above 300 ° C was obtained. Mn: (calculated) 11.30 (found) 11.12

Example XIV

Preparation of a solution of a mixed salt ("Mischsalz") of the sodium and N-methylglucamine salt of the gadolinium III complex of diethylene triamine-pentaacetic acid 30 a) Preparation of the mono-N-methylglucamine salt of the complex,

195.2 g (1 mol) of N-methylglucamine were dissolved in 7 liters of water. Thereafter, 393.3 g (1 mole) of diethylene triamine pentaacetic acid and 181.3 g (0.5 mole) of gadolinium oxide, Gd2O4, were added and refluxed for 2 hours. The filtered clear solution was spray-dried. A white crystal B / B Λ Λ -7 <v o ϋ ϋ & & & 22 22 22 22 22 22 22 lijn lijn lijn lijn lijn lijn lijn lijn lijn lijn lijn lijn lijn lijn lijn lijn lijn lijn lijn lijn lijn lijn poeder lijn poeder Ύ Ύ poeder poeder lijn Ύ Ύ dat dat dat lijn lijn dat dat,, Ύ Ύ Ύ dat, dat s, polishing sintering method at 133 ° C and melting at 190 ° C.

Gd (Calculated) 21.1.7 (Found) 21.34 5 b) Preparation of the Neutral Solution of the "Mixing Salt"

In 630 ml water p.i. (p.i. - pro injectione), 730.8 g (= 1 mole) of the salt obtained according to a) were suspended, after which 40 g (= 1 mole) of sodium hydroxide powder / was added in portions.

The neutral solution was washed with water p.i. made up to 1000 ml, bottled through a 10 pyrogen filter and sterilized by heat treatment. This 1 molar solution contained 753.8 g of the "mixing salt" per liter.

Example XV

Preparation of a solution of the di-N-methylglucamine salt of the gado-linium-III complex of diethylene triamine-pentaacetic acid

In 500 ml water p.i. 535.0 g (= 730 mmol) of the salt described in Example V were slurried and dissolved by adding 142.4 g (= 730 mmol) N-methylglucamine at a pH of 7.2. Then p.i. made up to 1000 ml, the solution is put into 20 ampoules and sterilized by heat treatment.

Example XVI

Preparation of a solution of the disodium salt of the gadolinium-III complex of diethylenetriamine-pentaacetic acid

In 500 ml water p.i. 485.1 g (= 820 mmol) of the disodium salt obtained according to example VI were slurried. Then p.i. made up to 1000 ml, placed in ampoules and sterilized by heat treatment.

Example XVII

Preparation of a solution of the disodium salt of the gadolinium-30 Ill complex of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-penta-aza-pentatriacontane diacid

In 500 ml water p.i. 392.0 g (= 400 mmol) of the salt described in Example II were slurried, and by supplementing with water p.i. dissolved to 1000 ml with gentle heating. The solution was placed in 35 bottles and heat sterilized.

8400079 23

Example XVIII

Preparation of a solution of the N-methyl glucamine salt of the crado-linium II complex of 1,4,7,10-tetra-aza-cyclododecane-tetra-acetic acid In 500 ml of water p.i. 370.9 g (= 500 mmol) of the salt mentioned in Example XI were slurried and supplemented with water p.i. dissolved to 1000 ml. The solution was placed in ampoules and heat sterilized.

Example XIX

Preparation of a solution of the di-N-methylglucamine salt of the man-10-going II complex of trans-1,2-cyclohexylenediamine-tetraacetic acid

In 500 ml water p.i. 395.9 g (= 500 mmol) of the salt mentioned in Example IX were suspended. Then 1.3 g of ascorbic acid were added and p.i. to.t 1000 ml of solution is established. The solution was filtered sterile and placed in 15 ampoules. ^

Example XX

Preparation of a solution of the tri-N-methylglucamine salt of the mangan an II complex of ethylene triamine-pentaacetic acid

In 600 ml water p.i. 514.4 g (= 500 mmol) of the salt mentioned in Example IX were suspended. Then 1.3 g of ascorbic acid were added and p.i. up to 1000 ml of solution. The sterile filtered solution was placed in ampoules.

Example XXI

Preparation of a solution of the di-N-methylglucamine salt of the iron III complex of diethylene triamine-pentaacetic acid

In 40 ml water p.i. 44.6 g (= 0.1 mol) of the iron-III complex of diethylenetriamine-pentaacetic acid obtained according to Example 7 were suspended. After the addition of 0.18 g of tromethamine-30 hydrochloride and 39.1 g (= 0.2 mol) of N-methylglucamine, the solution was neutral and the solution was added with water p.i. make up to 100 ml, ampoules and heat sterilize.

Example XXII

Preparation of a solution of the gadolinium-III complex of nitrilo-35 tri-acetic acid

In 100 ml of water p.i. 1.9 g (= 10 mmol) of nitrile-8400079 'V> 24 triacetic acid and 1.8 g (= 5 mmol) of gadolinium III oxide were dissolved under heating. The solution was placed in ampoules and heat sterilized.

Example XXIII

Preparation of a solution of the N-methylglucamine salt of the gado-linium-III complex of ethylenediamine-tetra-acetic acid

In 70 ml of water p.i. 38/62 g (= 60 mmol) of the substance described in Example X were dissolved. After addition of 0.12 g of tromethamine, water p.i. made up to 100 ml, the solution put into ampoules and heat sterilized.

Example XXIV

Preparation of a solution of the di-N-methylglucamine salt of the dys-prosium III complex of diethylenetriamine-pentaacetic acid

In 70 ml of water p.i. 35.7 g (= 60 mmol) of the dysprosium II'I complex of diethylene triamine-pentaacetic acid (8.0% water content) were suspended, and by adding 21.2 g (= 120 mmol) ) N-methylglucamine dissolved at a pH of 7.5. Then p.i. made up to 100 ml, placed in ampoules and sterilized by heat.

20 Example XXV

Preparation of a solution of the N-methylglucamine salt of the gado-linium III complex of trans-1,2-cyclohexylene-diamine-tetra-acetic acid. Of the salt described in Example VIII, 555.8 g (= 0.8 mol ) in water pi dissolved to 1000 ml with make-up. After filtration over a pyrogenic filter, the solution was placed into ampoules and heat sterilized.

Example XXVI

Preparation of a solution of the N-methylglucamine salt of the ruthenium-III complex of 1,1Q-diaza-4,7-dithiadecane-1,1,10,10-tetraacetic acid

In 50 ml water p.i. 15.6 g (= 0.03 mol) of the ruthenium-III complex of 1,10-diaza-4,7-dithiadecane-1,1,10,10-tetraacetic acid were suspended and by adding 5, 9 g (= 0.03 mol) of N-methylglucamine were dissolved at a pfi of 7.5. Then 35 with water p.i. made up to 1000 ml, the solution put into ampoules and heat sterilized.

- 3400079 25

Example XXVII

Preparation of a solution of the di-lysine salt of the gadolinium-III complex of diethylenetriamine-penta-acetic acid

In 500 ml water p.i. 273/8 g (= 0.5 mole) of the gadolinium-III complex of diethylene-triamine-penta-acetic acid was suspended. Then 292.4 g (= 1 mole) of lysine was added, after which it was gently stirred for several hours. heating was stirred and then with water pi. up to 1000 ml. The solution was bottled and heat sterilized,

Example XXVIII

Preparation of a solution of the tri-N-methylene glucamine salt of the molybdenum VI complex of diethylene triamine pentaacetic acid

In 50 ml water p.i. 18.8 g (= 0.28 mol) of the complex H ^ Mo ^ (OHJ ^ .C ^ H ^ N ^ O ^] were suspended and by addition of 16.4 g (0.84 mol) N- methylglucamine dissolved neutral Then 0.15 g of tromethamine was added, water was made up to 100 ml with water and the solution was subjected to sterile filtration and ampoules.

Example XXIX

20 Preparation of a solution of the di-sodium salt of the manganese II complex of ethylenediamine-tetra-acetic acid

In 500 ml water p.i. 343.2 g (* 1 mol) of the manganese II caraplex of ethylenediamine-tetra-acetic acid were suspended and neutral dissolved by portionwise addition of 80 g (»2 mol) of sodium hydroxide. After adding 1.5 g of tromethamine, the solution was washed with water p.i. made up to 1000 ml, bottled and heat sterilized.

Example XXX

Preparation of a solution of the sodium salt of the iron-III complex of ethylenediamine-tetra-acetic acid

In 500 ml water p.i. 345.7 g (= 1 mole) of the iron-III complex of ethylenediamine-tetra-acetic acid were suspended and dissolved neutral by portionwise addition of 40 g (= 1 mole) of sodium hydroxide. After adding 1.5 g of tromethamine, the solution was washed with water: p.i. made up to 1000 ml, bottled and heat sterilized.

8400079 9 τ 26

Example XXXI

Preparation of a solution of the di-sodium salt of the iron-III complex of diethylenetriamine-pentaacetic acid

In 500 ml water p.i. 334.6 g (= 0.75 mol) of the iron-III complex of diethylenetriamine-pentaacetic acid were suspended and neutral dissolved by portionwise addition of 60 g (= 1.5 mol) of sodium hydroxide. The solution was washed with water p.i. made up to 1000 ml, bottled and heat sterilized.

Example XXXII

Preparation of a solution of the sodium salt of the gadolinium-III complex of trans-1,2-cyclohexylenediamine-tetra-acetic acid

In water p.i. 558.6 g (= 1 mol) of the in the example. VIII said salt dissolved in addition to 1000 ml. The solution was bottled and heat sterilized.

Example XXXIII

Preparation of a solution of the N-methylglucamine salt of the gadolinium-Ill complex of 1,2-diphenylethylenediamine-tetraacetic acid

In 600 ml water p.i. 396.9 g (= 500 mmol) of the salt described in Example X were slurried and dissolved by making up to 1000 ml. The solution was placed in ampoules and heat sterilized.

Example XXXIV

Preparation of a solution of the sodium salt of the iron III complex of ethylenediamine-tetra-acetic acid 25 In 500 ml of water p.i. 183.5 g (= 500 mmol) of the salt mentioned in Example VII were slurried. Then 1.0 g of tromethamine was added, the mixture was added with. water p.i. to 1000 ml, and the solution was placed in ampoules and heat sterilized.

Example XXXV

Preparation of a solution of the -di-N-methylglucamine salt of the lanthanum-III complex of diethylenetriamine-pentaacetic acid

In 650 ml water p.i. 459.8 g (= 500 mmol) of the salt mentioned in Example V were slurried and supplemented with aqueous p.i. dissolved to 1000 ml. The solution was placed in ampoules. 35 and heat sterilized.

840 079 27

Example XXXVI

Preparation of a solution of the di-N-methylglucamine salt of the bismuth-Ill complex of diethylenetriamine-penta-azxic acid

In 600 ml water p.i. 692.8 g (= 700 mmol) of the salt mentioned in Example V were slurried and after addition of 1.8 g of thromethamine by addition with water p.i. dissolved to 1000 ml with gentle heating. The solution was placed in ampoules and heat sterilized.

Example XXXVII

Preparation of a solution of the di-N-methylglucamine salt of the holmium III coniplex of diethylene triamine pentaacetic acid

In 600 ml water p.i. 662.0 g (= 700 mmol) of the salt mentioned in Example V were slurried and after addition of 1.8 g of tromethamine by addition with water p.i. dissolved to 1000 ml with gentle heating. The solution was placed in ampoules and heat sterilized.

Example XXXVIII

Preparation of a solution of the di-N-methylglucamine salt of the ytterbium-Ill complex of diethylene triamine-pentaacetic acid 20 Xn 650 ml water p.i. 476.9 g (= 400 mmol) of the salt mentioned in Example V were slurried and after addition of 1.5 g of tromethamine by addition with water p.i. dissolved to 1000 ml. The solution was placed in ampoules and heat sterilized.

Example XXXIX

Preparation of a solution of the di-sodium salt of the lanthanum III complex of diethylenetriamine-pentaacetic acid

In 650 ml water p.i. 573.2 g (= 100 mmole) of the salt referred to in Example 6 were slurried and supplemented with water p.i. dissolved to 1000 ml. The solution was placed in ampoules and sterilized by hit-30.

Example XL

Preparation of a solution of the dl sodium salt of the dvsprosium-Ill complex of diethylenetriamine-pentaacetic acid

In 600 ml water p.i. 477.4 g (= 800 mmol) of the salt mentioned in Example 6 were slurried and by supplementing with water p.i. welded up to 1000 ml. The solution was placed into ampoules and sterilized by heat 8400079-128.

Example XLI

Preparation of a solution of the di-sodium salt of the holmium-III complex of diethylenetriamine-pentaacetic acid 5 In 500 ml of water p.i. 299.6 g (= 500 mmol) of the salt mentioned in example VI were slurried and supplemented with water p.i. dissolved to 1000 ml. The solution was placed in ampoules and heat sterilized.

Example XLII

Preparation of a solution of the di-sodium salt of the ytterbium-II complex of diethylenetriamine-penta-acetic acid

In 500 ml water p.i. 303.5 g (= 500 mmol) of the salt mentioned in Example VI were slurried and supplemented with water p.i. dissolved to 1000 ml. The solution was placed in ampoules and heat sterilized.

Example XLIII

Preparation of a solution of the tetra-N-methylglucamine salt of the gadolinium-III complex of ethylene dinitrile-tetrakis (methane phosphonic acid)

In 500 ml water p.i. 137.1 g (= 100 mmol) of the salt mentioned in example XII were slurried and after addition of 0.8 g of tromethamine by addition with water p.i. dissolved to 1000 ml. The solution was placed in ampoules and heat sterilized.

Example X3L1V

Preparation of a solution of the gadolinium-III complex of -N '- (2-25 hydroxyethyl) ethylenediamine-Ν, Ν, Ν' -tri-acetic acid

In 6 ml water p.i. 1.9 g (= 6.7 mmol) of N '- (2-hydroxyethyl) -ethylenediamine-Ν, Ν, Ν'-triacetic acid and 1.2 g (= 3.35 mol) of gadolinium III oxide dissolved under heating. The solution was placed in ampoules and heat sterilized.

30 Example XLV

Preparation of a solution of the di-sodium salt of the manganese II complex of trans-1,2-cyclohexylene diamine tetra-acetic acid

Under nitrogen protection, p.i. was added in 60 ml of water.

44.3 g (- 100 mmol) of the salt mentioned in Example IX are slurried and 35 by addition with water p.i. dissolved to 100 ml. The solution was placed in ampoules and heat sterilized.

8400079 29

Example XLVI

Preparation of a solution of the sodium salt of the gadolinium-III complex of 1,8,8,11-tetra-aza-cyclotetradecane-N, N ', N ", N" - tetra-acetic acid 5 in water p.i. was dissolved with addition to 1000 ml of 552.6 g (= 1 mol) of the salt mentioned in example XI. The solution was bottled and heat sterilized.

Example XLVII

Preparation of a solution of the di-sodium salt of the bismuth-III-10 complex of diethylene triamine-pentaacetic acid

In 50 ml water p.i. 23 µg (= 50 mmol) of bismuth III oxide was suspended. After addition of 39.3 g (= 100 mmol) of diethylenetriamine-pentaacetic acid and 4.0 g (* 50 mmol) of sodium hydroxide, it was refluxed until a clear solution was obtained. The solution cooled to ambient temperature was neutralized by adding 4.0 g of sodium hydroxide and with water p.i. supplemented to 100 ml. The solution was placed in ampoules and heat sterilized.

Example XLvm 20 Preparation of a solution of the disodium salt of the samarium III complex of diethylenetriamine-pentaacetic acid

In 65 ml of water p.i. 58.5 g (= 100 mmol) of the salt mentioned in Example VI were dissolved under heating. Then p.i. made up to a total volume of 100 ml, after which the solution was filled into ampoules and heat sterilized.

Example XLIX

Preparation of a solution of the di-N-methylglucamine salt of the gado-linium-III complex of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12> 15, 18, 21,24-penta- aza-pentatriacontane-diacid 30 In 250 ml water pi 130.4 g (= 100 mmol) of the salt mentioned in Example II were slurried and dissolved under heating. Then p.i. made up to 500 ml, after which the solution was placed in ampoules and heat sterilized.

Example L

Preparation of a solution of the di-N-methylglucamine salt of the man-II complex of ethylenediamine-tetra-acetic acid

In 70 ml of water p.i. 3.68 g (= 5 mmol) of the substance described in 8400079 3 ° 5 * Example IX were dissolved and 0.4 g of sodium chloride were added to the solution. Then p.i. made up to 100 ml and the solution put into ampoules through a sterile filter. The solution is with 280 mOsm. blood isotonic.

5 Example LI

Preparation of a solution of the disodium salt of the gadolinium-III complex of diethylene trinitrile penta (methanephosphonic acid)

In 50 ml water p.i. 38.57 g (= 50 mmol) of the substance described in Example XII were slurried. The pH was adjusted to 7.2 by addition of sodium 10 hydroxide powder, followed by water p.i. was completed until. 100 ml. The solution was placed in ampoules and heat sterilized.

Example LII

Preparation of a solution of the tri-sodium salt of the manganese II-15 complex of diethylene triamine-pentaacetic acid

In 100 ml of water p.i. 39.3 g (= 100 mmol) of diethylene triamine-pentaacetic acid were suspended and 11.5 g of manganese II carbonate were added. Then it was heated to 95 ° C and 300 ml of 1N sodium hydroxide solution was added dropwise. The neutral solution was filtered sterile and placed in ampoules.

Example Dili

Composition of a powder for the preparation of a suspension 4,000 g of gadolinium-III complex of diethylenetriamine-pentaacetic acid (what content '8.0%) 25 3.895 g. sucrose 0.100 g polyoxyethylene polyoxypropylene polymer 0.005 g flavoring 8,000 g

30 Example DVI

Preparation of a solution of the gadolinium-III complex of the conjugate of diethylenetriamine-pentaacetic acid with human serum albumin. To 20 ml of a solution of 3 mg of the protein in 0.05 molar sodium hydrogen carbonate buffer (pH 7-8) was added 10 mg of 1,5-bis (2,6-dioxomorpholino) -3-aza-pentane-3-acetic acid are added. Then, it was stirred at ambient temperature for 30 minutes and then was dialyzed against a 0.3 molar sodium phosphate buffer. Then 50 mg of gal-8400079 31 dolinium-III acetate was added and gel chromatography purified on a Sephadex G 25 column. The fraction obtained was sterile filtered and placed in multivials. Freeze-drying yields a dry preparation that can be stored.

In an analogous manner, a solution of the corresponding complex conjugate was obtained with immunoglobulin.

Example LV

Preparation of a solution of the gadolinium-III complex from the conjugate of diethylene trlamine pentaacetic acid (DTPA) with a monoclonal antibody

To 20 µl of a solution of 0.3 mg of a monoclonal antibody in 0.05 molar sodium hydrogen carbonate buffer (pH 7-8) was added 1 mg of a mixed DTPA anhydride (obtained, for example, from DTPA and isobutyl chloroformate) and stirred at ambient temperature for 15 minutes. Then, dialyzed against 0.3 molar sodium phosphate buffer and 2 mg of the gadolinium-III complex of ethylenediamine-tetraacetic acid (EDTA) was added to the antibody fraction obtained. After purification by gel chromatography on Sephadex G 25, the sterile filtered solution was placed in multivials and lyophilized.

Using the mixed anhydride of trans-1,2-diaminocyclohexane-tetraacetic acid (CDTA), a solution of the corresponding gadolinium III complex of the CDTA antibody was obtained in an analogous manner.

Using the manganese II complex of ethylenediamine-tetraacetic acid, the manganese II complexes of the antibodies coupled with DTPA or CDTA were obtained in an analogous manner.

Example LVI

Preparation of a solution of the gadolinium-III complex of the conjugate of 1-phenyl-ethylene-dietin tetraacetic acid with immunoglobulin

According to the J. Med. Chem. 1974, vol. 17, p. 1307, a 2% solution of the protein in a 0.12 molar sodium hydrogen carbonate solution containing 0.01 mol of ethylenediamine tetraacetic acid was cooled to + 4 ° C and added to the egg. White equivalent amount of a freshly prepared, ice-cold diazonium salt solution of 1- (p-aminophenyl) -ethylenediamine-tetraacetic acid is added dropwise. The mixture was stirred at + 4 ° C overnight (pH 8.1) and then dialyzed against a 0.1 molar sodium citrate solution.

After dialysis was completed, an excess of gadolinium III chloride was added to the conjugate solution and the mixture was ultrafiltrated to remove ions. Finally, the sterile filtered solution was placed in multivials and freeze-dried.

Example, LVII ~

Preparation of a colloldal dispersion of a Mn-CDTA-lipid conjugate. In 50 ml of water 0.1 mmole of distearoylphosphatidylethanolamine and 0.1 mmole of bisanhydride of trans-1,2-diamino-cyclohexane-tetraacetic acid 24 stirred at ambient temperature for an hour. Then 0.1 mmol of manganese II carbonate was added and stirred for an additional 6 hours at ambient temperature. After purification on a Sephadex G 50 column 15, the sterile filtered solution was placed in multivials and freeze-dried.

In an analogous manner, a colloldal dispersion of the gadolinium-DTPA-lipid conjugate could be obtained with gadolinium III oxide.

Example LVIII

Preparation of gadolinium-PTPA-loaded liposomes

According to Proc. Natl., Acad. Sci. ü.S.A. 75, 4194, a lipid mixture of 75 mole% egg phosphatidylcholine and 25 mole% cholesterol was prepared as dry matter. Of this, 25 500 mg was dissolved in 30 ml of diethyl ether and added dropwise, in an ultrazonate bath, 3 inl of a 0.1 molar solution of the di-N-methylglucamine salt of the gadolinium-III complex of diethylene triamine-pententaacetic acid in water pi. After complete addition of the solution, the ultrasonic treatment is continued for an additional 10 minutes and then concentrated in a Rotavapor. The gel-like residue was suspended in 0.125 molar sodium chloride solution and liberated repeatedly at 0 ° C by centrifugation (20,000 g / 20 minutes) of unencapsulated contrast media. The lyposomes thus obtained were then lyophilized in multivials. The administration took place as a colloidal dispersion in a 0.9 wt.% Table salt solution.

8400079

Claims (52)

A diagnostic agent comprising at least one physiologically tolerable complex salt of the anion of a complexing acid and one or more central ions of an element having atomic numbers 21 to 29, 42, 44 or 57 to 83 and optionally contains one or more cations of an inorganic and / or organic base or amino acid, against which cations are physiologically free, with additives customary in galenic pharmacy, dissolved or suspended in an aqueous medium. The diagnostic agent according to claim 1, which contains at least 10 a physiologically tolerated complex salt of the general formula 1 or 2, in which formulas the symbols X represent the residues -COOY, -PO2 HY or -CONBOY with Y in the meaning of a hydrogen atom, a metal ion equivalent and / or a cation of an inorganic or organic base or amino acid, against which cation physiologically does not object, and wherein A means the group with the partial formula -CHE ^ -CHR ^ -, the partial formula - CH_-CH _- (ZCH_-CH_) -, 2 2 2 2 m represents the partial formula 3 or the partial formula 4, in which partial formulas 3 and 4 the symbols X have the above-mentioned meaning, in which general formula 1: the symbols hydrogen atoms or methyl groups, in which former partial formula: the symbols R 1 and R 2 together represent a trimethylene group or a tetramethylene group or separately represent hydrogen atoms, lower alkyl groups, phenyl groups or benzyl groups, or a hydrogen atom and R 1 a growth group p - (CH_) -C, .EL-W protein 2 p 6 4 with p meaning 0 or 1, W meaning -NN-, -NHCQC-or -NHCS and protein in the represent the meaning of a protein residue and in which the above-mentioned second partial formula m represents one of the numbers 1, 2 or 3 and Z represents an oxygen atom or a sulfur atom or the group NCH-X or NCH_CH_0R. 8400079 2 2 2 4 with X in the above meaning and R ^ in the meaning of a lower alkyl group, and in which general formula 1: V has the same meaning as X or one of the groups 5 -CH-OH, -CÖNH (CH_). X, or -COB i 2 n with X in the above-indicated meaning, B in the sense of a protein or lipid residue and n in the meaning of numbers 1 - 12, represents whether, if and are hydrogen atoms, the two symbols are V in the general formula 1 together represent the group of the partial formula 5 with X in the meaning indicated above and w in the sense of the numbers 1, 2 or 3, provided that at least two of the substituents Y are metal ions. equivalents of an element with the atomic numbers 21 15 to 29, 42, 44 or 57 to 83. Diagnostic agent according to claim 1 or 2, for use in ultrasonic diagnostics. Diagnostic agent according to claim 1 or 2, which agent contains an element with atomic numbers 21 to 29, 42, 44 or 58 to 20 and 70, for use in the NMR diagnostics. Diagnostic agent according to claim 1 or 2, which contains an element with atomic numbers 57 to 83, for use in - X-ray diagnostics. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-N-methylglucamine salt of the manganese (II) complex of ethylenediamine-tetraacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it is the di-N-methylglucamine salt of the gadolinium (III). complex of diethylenetriamine-pentaacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-N-methylglucamine salt of the dysprosium (III) complex of diethylene triamine-pentaacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the mono-sodium / mono-N-methylglucamine mixed salt 35 ("Mischsalz") of the gadolinium (III) complex of diethylene triamine-pentaacetic acid . Diagnostic agent according to claim 1 or 2, characterized in 8400079, that it contains the di-lysine salt of the gadolinium (III) complex of diethylene triamine-pentaacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-sodium salt of the gadolinium (III) complex of diethylenetriamine-pentaacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-N-methylglucamine salt of the iron (III) complex of diethylene triamine-pentaacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-sodium salt of the iron (III) complex of diethylene triamine-pentaacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-sodium salt of the manganese (II) complex of diethylenefriamine-pentaacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-N-methylglucamine salt of the holmium (III) complex of diethylene triamine-pentaacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-sodium salt of the manganese (II) complex of ethylenediamine-tetraacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-N-methylglucamine salt of the bismuth (III) complex of diethylene triamine-pentaacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-N-methylglucamine salt of the manganese (II) complex of trans-1,2-cyclohexylenediamine-tetraacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-sodium salt of the ytterbium (III) complex of diethylene triamine-pentaacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the N-methylglucamine salt of the gadolinium (III) complex of 1,4,7,10-tetra-aza-cyclododecane-tetra-acetic acid. 21. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-sodium salt of the manganese (II) complex of trans-1,2-cyclohexylene-diamine-tetra-acetic acid. Diagnostic agent according to claim 1 or 2, characterized in 8400079, that it contains the di-sodium salt of the bismuth (III) complex of diethylene triamine-pentaacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it is the di-N-methylglucamine salt of the gadolinium (III) -5 complex of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12 , 15,18,21,24-penta-aza-penta-triacontane-diacid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the sodium salt of the gadolinium (III) complex of 1,4,7,10-tetra-aza-cyclododecane-tetra-acetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the gadolinium (III) complex of the conjugate of diethylene triamine-pentaacetic acid with immunoglobulin. 26. A diagnostic agent according to claim 1 or 2, characterized in that it contains the gadolinium (III) complex of the conjugate of diethylenetriamine-pentaacetic acid with human serum albumin. Diagnostic agent according to claim 1 or 2, characterized in that it contains the gadolinium (III) complex of the conjugate of diethylenetriamina-pentaacetic acid with a monoclonal antibody. 28. A diagnostic agent according to claim 1 or 2, characterized in that it contains the manganese (II) complex of the conjugate of trans-1,2-cyclohexylenediamine-tetraacetic acid with a monoclonal antibody. 29. A diagnostic agent according to claim 1 or 2, characterized in that it contains the manganese (II) complex of the lipid conjugate of trans-1,2-cyclohexylenediamine-tetraacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains liposomes loaded with the gadolinium (III) complex of diethylene triamine-pentaacetic acid. 31. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-sodium salt of the holnium (III) complex of diethylene triamine-pentaacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-sodium salt of the lanthanum (III) complex of diethylene triamine-pentaacetic acid. 33. A diagnostic agent according to claim 1 or 2, characterized in that it contains the di-N-methylglucamine salt of the ytterbium (III) - 84 0 0 0 7 9 'complex of diethylene triamine-pentaacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it contains the di-sodium salt of the samarium (III) complex of diethylenetriamine-pentaacetic acid. Diagnostic agent according to claim 1 or 2, characterized in that it is the disodium salt of the gadolinium (III) complex of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15, Contains 18,21,24-penta-aza-penta-triacontane diacid. 36. Diagnostic agent according to claims 1-36, characterized in that it contains 1 µmole to 1 mole complex salt per liter. 37. A method for the preparation of the diagnostic agent according to any one of claims 1-36, characterized in that the complex salt dissolved or suspended in water or a physiological saline solution with the additives customary in galenic pharmacy in an intravascular or oral administration is brought in appropriate form. 38. Complex salts of the general formula 1, wherein X, A, V and Rj have the meaning defined in claim 2, provided that they contain 3 to 12 substituents Y, of which at least 2 have a metal ion equivalent of an element with the atomic numbers 20 21 - 29, 42, 44, or 57 - 83 and in addition at least one of the substituents Y is a cation of an organic base or amino acid, against which cation there is no physiological objection, where any substituents Y represent hydrogen atoms or cations of an inorganic base. 39. N-Methylglucamine salt of the gadolinium (III) complex of ethylenediamine-tetraacetic acid. 40. Di-N-methylglucamine salt of the gadolinium (III) complex of diethylene-triamine-pentaacetic acid. 41. Di-N-methylglucamine salt of the iron (III) complex of diethylenetriamine-pentaacetic acid. 42. Di-N-methylglucamine salt of the manganese (II) complex of ethylenediamine-tetraacetic acid. 43. Di-sodium salt of the gadolinium (III) complex of diethylenetriamine-pentaacetic acid. 44. Tri-N-methylglucamine salt of the manganese (II) complex of diethylenetriamine-pentaacetic acid. 8400079 i κ Δ Λ 45. N-Methylglucamine salt of the dysprosium (III) complex of ethylenediamine-tetraacetic acid. 46. Di-N-methylglucamine salt of the holmium (III) complex of diethylenetriamine-pentaacetic acid. 47. Di-lysine salt of the gadolinium (III) complex of diethylenetriamine-pentaacetic acid. 48. Di-N-methylglucamine salt of the manganese (II) complex of trans-1,2-cyclohexylene-tetraacetic acid. 49. Di-N-methylglucamine salt of the bismuth (III) complex 10 of diethylene triamine pentaacetic acid. 50. Di-sodium salt of the ytterbium (III) complex of diethyltriamine-pentaacetic acid. 51. N-methylglucamine salt of the gadolinium (III) complex of 1,4,7,10-tetra-aza-cyclododecane-tetra-acetic acid. 52. N-Methylglucamine sodium mixed salt ("Mischsalz") of the gadolinium (III) complex of diethylenetriamine-pentaacetic acid. 53. A diagnostic agent comprising at least one physiologically tolerated complex salt of the general formula. 1 according to claim 2, with the exception of the agents intended for use in the NMR diagnostics, containing 5 - 250 mmol per liter of a neutral N-methyl glucamine salt of the manganese (II) complex, nickel (II) complex, gadolinium (III) complex, dysprosium (III) complex or holmium (III) complex of ethylenediamine tetraacetic acid or diethylene triamine pentaacetic acid or of a neutral lysine salt of the gadolinium (III) complex of diethylenetriamine pentaacetic acid, or of a neutral sodium or morpholine salt of the manganese (II) complex of ethylenediamine tetraacetic acid, or of a neutral diethanolamine salt of the copper (II) complex or cobalt (II) complex of ethylenediamine-tetraacetic acid. 8400079 -s- 1 2. 3 X-CH ^ na ^ CH2-X NCCH2x) 3 Vc "i * h V-CHR, CHR.-V 2 3 -CH7-CH-CH7- L. 1 * L k 5 ch2-ch2-ncch2x) 2 ch2x ch2x -ch2-ch2-n-ch2-ch2- - (ch2) wn-ch2-ch2-n- (ch2) w- Ια X-CH2 / CH2'X ^ N-CHR, -CHR, -N ^ 2 3 \ U-CHR1 CHR L - \ / 1b X'CH2V CH2-X N-CH7-CH7- (Z-CH.-CH ") - n V-CHR ^ XCHR1-V 1c X-CH2 / CH2" X nn -ch7-ch7-n I 2 2 \ CH _ CH7 \ 1 I 2 (CH _) (CM.) I 2 w / 2 w N-CH „-CH - N / 2 2 \ X-CH2 CH2-X 340007S Schering Aktiengesellschaft