LU85177A1 - DIAGNOSTIC MEANS - Google Patents

Description

I · - 12 -

description

The invention relates to the subject matter characterized in the claims.

Complex bzvi /. their salts have long been used in medicine, e.g. as an aid to the administration of poorly soluble ions (e.g. iron) and as antidotes (calcium or zinc complexes are preferred) for detoxification in the event of accidental incorporation of heavy metals or their ^ radioactive isotopes. It has now been found that physiologically-> logically compatible complex salts, from the anion of a complexing acid and one or more central ions of an element of atomic numbers 21 to 29, 42, 44 or 57 to 83 and optionally one or more physiologically acceptable cations of an inorganic and / or organic base or amino acid are surprisingly particularly suitable for the production of diagnostic agents that are suitable for use in NMR, X-ray or ultrasound diagnostics.

The element of the above-mentioned atomic number, which forms the central ion or ions of the physiologically compatible complex salt, must of course not be radioactive for the intended use 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), the central ion of the complex salt must be paramagnetic. These are in particular the divalent and trivalent ions of the elements of atomic numbers 21 to 29,

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* * - 13 - 42, 44 and 58 to 70. Suitable ions are, for example, chromium (III) -, manganese (II) -, iron (III) -, iron (II) -, cobalt (II) -, nickel ( II) -, copper (II) -, praseodymium (III) - 's

Neodymium (III), samarium (III) and ytterbium (III) ion. Because of their very strong magnetic moment, gadolinium (III), terbium (III), dysprosium (III), holmium (III) and erbium (III) ions are particularly preferred.

_ Is the agent according to the invention for use in X-ray

Diagnostics determined, so the central ion must be derived from a £ element higher atomic number in order to obtain a sufficient

To achieve absorption of the X-rays. It has been found that diagnostic agents which contain a physiologically compatible complex salt with central ions of elements of atomic numbers between 57 and 83 are suitable for this purpose; 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 agents according to the invention, which are intended for use in NMR diagnostics, and those which are intended for use in X-ray diagnostics, are suitable for use in ultrasound diagnostics.

Suitable complexing acids are those which are usually used for complexing the above-mentioned central ions. Suitable complex-forming acids are, for example, those which have 3 to 12, preferably 3 to 8

A

s «- 14 -

Contain methylenephosphonic acid groups, methylene carbohydroxamic acid groups, carboxyethylidene groups or in particular carboxymethylene groups, of which one, two ”or three are each bonded to a nitrogen atom which aids in complex formation. If three of the acidic groups are bonded to a nitrogen atom, then the complex-forming acids on which the complex salts of the general formula II are based are present. If only one or two of the acidic groups are bonded to a nitrogen atom, the nitrogen is bonded to a further nitrogen atom via an optionally substituted ethylene or via up to four ethylene units, each separated by a nitrogen or oxygen or sulfur atom which aids in the complex formation. Preferred complex-forming acids of this type are those of the general formula I according to claim 2.

The complex-forming acids can be linked as conjugates with biomolecules which are known to accumulate particularly well in the organ or organ part to be examined. Such biomolecules are, for example, hormones such as insulin, prostaglandins, steroid hormones, amino sugars, peptides, proteins or lipids. Particular mention should be made of conjugates with albumins, such as human serum albumin, antibodies, such as monoclonal antibodies or antimyosin specific for tumor-associated antigens. The diagnostic agents formed from this are suitable, for example, for use in tumor and infarct diagnostics. For

Liver examinations are suitable, for example, for conjugates or inclusion compounds with liposomes, which are used, for example, as unilamellar or multilamellar phosphatidylcholine-cholesterol vesicles. The conjugate formation takes place either via a carboxyl group of the complex-forming acid or, in the case of the proteins or peptides, also via a L · s t - 15 - (CH2VC6H4-W-

Group, «as defined in claim 2. When conjugating the complex-forming acids with proteins, peptides or lipids, several acid residues can sometimes be bound to the macromolecular biomolecule. In this case, each complex-forming acid residue can carry a central ion. If the complex-forming acids are not bound to biomolecules, they may carry two central ions, in particular one central ion.

•

Suitable complex salts of the general formula I according to claim 2 are, for example, those of the general formula Ia

X-CH_ CH ,, - X

2/1 ^ N-CHR „-CHR, -N (Ia), / Z 3 \ 7

V-CHl ^ CHR1-V

wherein X, V, R ^, R2 »and R ^ have the meaning given in claim 2.

The following complex-forming acids are suitable for the preparation of the complex salts of the general formula Ia φ: the ethyl-endiamine-tetraacetic acid, the ethylenediaminetetra-acethydroxamic acid, the trans-1,2-cyclohexylene-diamine-tetra-acetic acid, the Dl-2,3-butylene-diamine-tetra-acetic acid, the DL-1,2-butylenediamine-tetra-acetic acid the Dl-1,2-propylene-ζ diamintetraacetic acid, the 1,2-diphenylethylenediaminetetraacetic acid, the ethylenedinitrilotetrakis (methanephosphonic acid) and the N- (2-hydroxyethyl) ethylenediamine-triacetic acid.

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Further suitable complex salts of the general formula I according to claim 2 are, for example, those of the general formula Ib

x-ch2v / CH2-X

N-CH -CH, - (Z-CH_-CH_) m- N (Ib),. 2 2 2 2 m from

V-CHR1 CHR ^ V

wherein X, V, Z, R ^ and m have the meaning given in claim 2. If 2 'represents an oxygen atom or a sulfur atom, complex salts with m meaning 1 or 2 are preferred.

The following complex-forming acids are suitable for the preparation of the complex salts of the general formula Ib: the diethylenetriaminepentaacetic acid, the triethylenetetramine-hexaacetic acid, the tetraethylene-1-pentamineheptaacetic acid, the 13.23-dioxo-15.18.21-tris (carboxymethyl) -12.15.18.2isapentic acid and the pentacetic acid 3.9-bis- (1-carboxyethyl) - 3.6.9-triazaundecanedioic acid, the diethylenetriaminepentakis (methylenephosphonic acid), the 1.10-diaza-4.7-dioxadecane-1.1.-10.10-tetraacetic acid and the 1.10-diaza-4.7- dithiadecan- 1.1.10.10- tetraacetic acid.

Suitable complex salts of the general formula I according to claim 2 are also those of the general formula Ic

X-CH2 / CH2 "X

X N-CH_-CH_-N

..¾! U Z t CH2 CH2 (ÇV. (C) Vw CIc) ’

N-CH_-CH "-N

S 2 2 \

X-CH2 CH2-X

wherein X and w have the meaning given in claim 2.

, Α Λ 1 * - 17 -

The following complex-forming acids are suitable for the preparation of the complex salts of the general formula Ic: the 1,4,8.11-tetraazacyclotetradecanetetraacetic acid and in particular the 1.4.7.10-tetraazacyclododecanetetraacetic acid.

Further complex-forming acids which are suitable for the preparation of the complex salts of the general formula I are, for example: the 1.2.3-tris [bis- (carboxymethyl) amino -] - propane and the nitrilotris- (ethylene nitrilo) hexaacetic acid.

^ As an example of a complex-forming acid for the production of complex salts of the general formula II, nitrilotriacetic acid may be mentioned.

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

%

The complex-forming acids required for the agent according to the invention are known or can be prepared in a manner known per se.

For example, the production of 13.23-dioxo-15.18.21-tris (carboxymethyl) -12.15.18.21.24-pentaazapenta-triacontane-diacid takes place in an improvement of that described by R. A. Bulman et. al. in natural sciences 68., (1981) 483 proposed way: 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 after addition of 20.13 g (= 100 mmol) of 11-amino-undecanoic acid heated to 70 ° C for 6 hours. The clear solution is concentrated in vacuo. The yellow oily residue is stirred with 500 ml of water at room temperature. An almost white voluminous solid precipitates, which is filtered off with suction and washed several times with water. For further purification, the product obtained is introduced into 200 ml of acetone and stirred at room temperature for 30 minutes. After suction extraction and drying in vacuo at 50 ° C. 36.9 g (= 97¾ of theory) of a white powder with a melting point of 134-138 ° C.

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 amino, hydroxyl, thio or imidazole groups with an activated derivative of the complexing acid.

Examples of suitable derivatives of the complex-forming acids are acid chlorides, acid anhydrides, activated C esters, nitrenes or isothiocyanates. Conversely, it is also possible to react an activated 8 molecule with the Vr complexing acid.

Substituents of the structure or C ^ H ^ NHCOCH ^ halogen are also suitable for conjugation with proteins.

A.

Π f

Li - 19 -

The preparation of the complex salts is also known in some cases or can be carried out in a manner known per se by using the metal oxide or a metal salt (for example * the nitrate, chloride or sulfate) of the element of atomic numbers 21 to 29, 42, 44 or 57 to 83 dissolved or suspended in water and / or} a lower alcohol (such as methanol, ethanol or isopropanol) and mixed with the solution or suspension of the equivalent amount of the complexing acid, in water and / or a lower alcohol, and stirred, if necessary with heating or heating to the boiling point until the reaction is complete. If the complex salt formed is insoluble in the solvent ΐ used, it is isolated by filtration. If it is soluble, it can be isolated by evaporating the solution to dryness, for example by spray drying.

j <Î If acidic groups are still present in the complex salt obtained, it is often expedient to add the acidic complex salt j into neutral complex salts using inorganic and / or organic bases or amino acids which form physiologically acceptable cations transfer and isolate them, ij "In many cases this is even inevitable, since the dissociation of the complex salt is pushed back to the neutral by shifting the p ^ value j to such an extent that erst the isolation of uniform products or ij at least their cleaning is enabled.

1 ;

The preparation is expediently carried out with the aid of organic bases or basic amino acids. However, it can also be advantageous to neutralize using inorganic bases (Hy:

A

«Hydroxides, carbonates or bicarbonates) of sodium, potassium * or lithium.

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m V * - 20 -

To prepare the neutral salts, for example, the acidic complex salts in aqueous solution or suspension can be added to the desired base to such an extent that the neutral point is reached. The solution obtained can then be evaporated to dryness in vacuo. It is often from

Advantage, the neutral salts formed by adding water-miscible solvents, such as lower alcohols (methanol, ethanol, isopropanol etc.), lower Ä ketones (acetone etc.), polar ethers (tetrahydrofuran, ^ dioxane, 1,2-dimethoxyethane.etc ) fail and so easy. crystals to be isolated and easily cleaned. It has proven to be particularly advantageous to add the desired base already during the complex formation of the reaction mixture and thereby to save one process step.

If the acidic complex salts contain several free acidic groups, it is often advisable to prepare neutral mixed salts which contain both inorganic and organic physiologically acceptable cations as counterions. This can be done, for example, by reacting the complex-forming acid in aqueous suspension or solution with the oxide ™ or salt of the element providing the central ion and half of the amount of an organic base required for neutralization, isolating the complex salt formed and, if desired, purifying it and then mixed with the required amount of inorganic base * for complete neutralization. The order of base addition can also be reversed.

«* - 21 -

The diagnostic agents according to the invention are also prepared in a manner known per se by adding the complex salts, if appropriate with the addition of the in the »

Galenik's usual additives are suspended or dissolved in an aqueous medium and then the solution or suspension is sterilized. Suitable additives are, for example, physiologically acceptable buffers (such as tromethamine hydrochloride), small additions of complexing agents (such as e.g.

Ä diethylenetriamine-pentaacetic acid) or if necessary ^ electrolytes (such as sodium chloride).

In principle, it is also possible to produce the diagnostic agents according to the invention without isolating the complex salts. In any case, special care must be taken to carry out the chelation so that the salts and salt solutions according to the invention are practically free of non-complexed toxic metal ions. This can be ensured, for example, with the help of color indicators such as xylenol orange through control titrations during the manufacturing process. The invention therefore also relates to processes for the preparation of the complex compound and its salts. As a last resort, cleaning the isolated complex salt remains

If suspensions of the complex salts in water or physiological saline solution are desired for oral administration or other purposes, a slightly soluble complex salt * is mixed with one or more adjuvants and / or surfactants and / or flavorings customary in galenics for flavor correction.

The diagnostic agents according to the invention preferably contain ΙμΜοΙ to 1 mol per liter of the complex salt and are generally dosed in amounts of 0.001 to 5 mmol / kg. They are intended for oral and parenteral administration in particular.

ή • t - 22 -

According to claim 4-, the agents according to the invention meet the diverse requirements for their suitability as contrast agents for magnetic resonance imaging. They are% ideally suited to improve the meaningfulness of the image obtained with the aid of the magnetic resonance scanner after oral or parenteral application by increasing the signal intensity. Furthermore, they 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 the non-invasive

Maintaining the nature of the study (for example, the compounds given in 3.Comput.Tomography £, 6: 543-46 (1981), in Radiology 144, 343 (1982) and in Brevet Special de Médicament No. 484 M (1960) are too toxic ). The good water solubility of the agents according to the invention makes it possible to produce highly concentrated solutions, thus keeping the volume load of the circuit within reasonable limits and compensating for the dilution by the body fluid, i.e. NMR diagnostics must be 100 to 1000 times more water-soluble than for NMR 5 spectroscopy. Furthermore, the agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that the toxic ions which are not covalently bound in the complexes are released or exchanged within the 24 hours in which - As pharmacological examinations have shown - the new contrast agents are completely excreted erfolgt, takes place extremely slowly. The conjugates used, for example, for tumor diagnosis - with proteins and antibodies cause surprisingly high signal amplification even in such low doses that solutions of a correspondingly low concentration can be used here.

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€ 4 - 23 -

According to claim 5, the agents according to the invention are outstandingly suitable as X-ray contrast agents, it being particularly emphasized that they do not show any signs of the anaphylaxis-like reactions known from the iodine-containing contrast agents in biochemical-pharmacological studies. They are particularly valuable for digital subtraction techniques due to their favorable absorption properties in areas with higher tube voltages.

φ The agents according to the invention are - according to claim 3- due to their property to influence the ultrasound speed ς favorable also suitable as ultrasound diagnostics.

In contrast to conventional X-ray diagnostics with • shadowing X-ray contrast media, there is no linear dependence of the signal amplification on the concentration used in NMR diagnostics with paramagnetic contrast media. As control examinations show, an increase in the applied dose does not necessarily lead to a signal amplification, and with a high dose of paramagnetic contrast medium the signal can even be canceled. For this reason, it was surprising that some pathological processes only become visible after the application of a> strongly paramagnetic contrast medium according to the invention higher than the doses specified in EP 71564 (which can be from 0.001 mmol / kg to 5 mmol / kg). For example, the detection of a defective blood-brain barrier in the area of a cranial abscess '' 4 only after administration of 0.05-2.5 mmol / kg, preferably 0.1-0.5 mmol / kg of paramagnetic complex salts such as e.g. Gadolinium-diethylenetriaminepentaacetic acid or manganese-1,2-cyclohexylenediamino-tetraacetic acid in the form of their readily water-soluble salts. For a dose greater than 0.1 mmol / kg, solutions of higher concentrations up to 1 mol / 1, preferably 0.25 to 0.75 mol / 1, are required, h η - 24 - * * since only in this way the volume load is reduced and the Handling of the injection solution is guaranteed.

Particularly low doses (below 1 mg / kg) and thus lower concentrated solutions (ΙμΜοΙ / l to 5 mmol / 1) than specified in EP 71564, for organ-specific NMR diagnostics e.g. needed to detect tumors and heart attacks.

The following examples serve for further

Explanation of the invention.

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"Ä V 'f - 25 -

example 1

Preparation of the gadolinium III complex of nitrilo-Ν, Ν, Ν-triacetic acid, CgHgGdNOg - Oie suspension of 36.2 g (= 100 mmol) of gadolinium oxide (Gd2Ο3) and 38.2 g (= 200 mmol) of nitrilotriacetic acid in 1.2 liters Water is heated to 90 ° C. to 100 ° C. with stirring and stirred at this temperature for 48 hours.

The undissolved matter is then filtered off over activated carbon and the filtrate is evaporated to dryness. The amorphous residue φ is pulverized.

Yield: 60 g; (87 '% of theory)

'Mp: 300 ° C

Gadolinium: calculated 45.5%, found 44.9%.

The iron-III complex of nitrilo-N, N, N-triacetic acid is obtained with the help of iron-III-chloride, FeClj.

Example 2

Preparation of the disodium salt of the gadolinium III complex of 13,23-dioxo-15,18,21-tris (carboxymethyl) -. φ 12,15,18,21,24-pentaazapentatriacontanedioic acid, C36H60GdN5 ° 12 2 Na 15.2 g (= 20 mmol) 13,23-dioxo-15,18,21-tris (carboxy-methyl) -12.15, 18,21,24-pentaazapentatriacontanedioic acid are suspended in 400 ml of water and heated to 95 ° C.

7.43 g (= 20 mmol) of gadolinium-III-chloride hexahydrate, ~ dissolved in 60 ml of water, are slowly added dropwise. It is kept at this temperature for 2 hours and then mixed with 60 ml of 1N sodium hydroxide solution to neutralize the hydrochloric acid formed.

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* A

After the reaction is complete (test with xylenol orange), the precipitate obtained is filtered off and washed with water until free of chloride. 17.60 g (96% of theory) of a water-insoluble, white powder with a melting point of 290-292 ° C. are obtained.

b

Gadolinium III complex of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-pentaazapentatriacontanedioic acid.

Analysis: Ä (calc.) C 47.30 H 6.84 N 7.66 Gd 17.20 ^ (found) C 47.13 H 6.83 N 7.60 Gd 17.06 14.6 g (= 16 mmol) of the gadolinium-III

Complexes are suspended in 200 ml of water and 31.4 ml of 1N sodium hydroxide solution are added dropwise. After 1 hour, a clear solution is obtained, which is filtered and then concentrated in vacuo. After drying in vacuo at 80 ° C., 13.2 g (87% of theory) of a readily water-soluble, white powder with a melting point of 279-285 ° C. are obtained.

Analysis: (Calc.) C 45.13 H 6.31 N 7.31, Gd 16.41 Na 4.80 ®, (Found) C 45.20 H 6.12 N 7.28 Gd 16.26 Na '4.75

In the same way, the ΐ di-N-methylglucamine salt of the gadolinium III complex of 13,23-dioxo-15,18,21-tris (carboxymethy1) -12,15,18, ~ 21 is used with N-methylglucamine instead of sodium hydroxide solution , 24-pentaazapentatriacontanedioic acid, CsgHggGdNyOgg j obtained.

! m - 27 -

Example 3

Preparation of the disodium salt of the gadolinium III complex of 3,9-bis (1-carboxyethyl) -6-carboxymethy1-3.6.9- triazaundecanedioic acid "gH22 ^^ NgO ^ Q * 2 Na" 36.2 g (= 0 , 1 mol) of gadolinium-III-oxide and 84.2 g (= 0.2 mol) of 3.9- bis (1-carboxyethy1) -6-carboxymethyl-3,6,9-triaza-undecanedioic acid are suspended in 250 ml of water and heated to reflux for 1 hour. A little undissolved is filtered off and the solution is evaporated to dryness φ in vacuo. The residue is pulverized and dried in vacuo at 60 ° C. 112.8 g (= 98% of theory) of the chelate are obtained as a white powder.

Analysis: C ^ H ^ GdNgO'jQ

(Calc.) 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 are introduced into a solution of 0.1 mol of caustic soda in 100 ml of water. By adding a further 0.1 mol of caustic soda powder, the pH is adjusted to 7.5, the solution is heated to boiling and ethanol is added dropwise until it becomes cloudy. φ After stirring for several hours in an ice bath, mah'd aspirates the crystals, washes them with ethanol and dries them in a vacuum. The disodium salt is obtained in quantitative yield as a white powder.

Analysis: »* v (calc.) 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 / ^ \« · - 28 -

Example 4

Preparation of the di-morpholine salt of gadolinium-III- «Ml

Complex of 3,9-bis (1-carboxyethyl) -6-carboxymethy1- 3,6,9-triazaundecanedioic acid »C24H42GdN5 ° 12 17.4 g (= 0.2 mol) of morpholine are dissolved in 50 ml of water, j * One gives 42.1 g (= 0.1 mol) of 3,9-bis (1-carboxyethyl) -6- \ carboxymethy1-3,6,9-triazaundecanedioic acid and then 18.2 g (= 0.05 mol) of gadolinium-III -oxid and holds at reflux until clear solution has occurred. Then -1 φ is added dropwise until the acetone remains cloudy. After stirring for more hours in an ice bath, the crystals are suctioned off, - washed with acetone and dried in vacuo. The di-morpholine salt is obtained in quantitative yield as a white powder.

Analysis: (Calc.) C 38.44 H 5.65 Gd 20.97 N 9.34 (Found) C 38.31 H 5.72 Gd 20.76 N 9.32

Example 5 φ Preparation of the Di-N-Methylglucamine Salt of the 'Gadolinium III Complex of Diethylenetriamine-Ν, Ν, Ν', N ", ΝΊ-Penta-Acetic Acid, C28H64GdN50 20 39.3 g (= 100 mmol) of Diethylenetriamine-Ν , Ν, Ν ', N ", N" -penta- 4 5 * acetic acid are suspended in 200 ml of water and mixed with 19.5 g (= 100 mmol) of N-methylglucamine. Then 18.12 g (= 50 mmol) of gadolinium III-oxide, Gd203, was added in portions and the suspension obtained was heated to 95 ° C. After about 1 hour, a further 19.5 g (= 100 mmol) of N-methylglucamine were added and a clear solution was obtained after a further 2 hours of heating

- A

'I' - 29 - complete reaction (control with xylenol orange) · is filtered from a little undissolved and the filtrate in

Vacuum concentrated to dryness. The residue is redissolved in 100 ml of water and in 250 ml of ethanol *; stirred in. After cooling for several hours you suck it

Crystallize off, wash with cold ethanol and dry it at 60 ° C in a vacuum. 92.7 g (99% of theory) of a white powder with uncharacteristic properties are obtained

Melting point.

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

To purify the complex salt, acetone, propanol or isopropanol 'can also be used instead of ethanol.

Accordingly, the following are obtained:

With dysprosium-III-oxide, DygOg

Di-N-methylglucamine salt of the dysprosium III complex of diethylenetriamine-N, N, Ν ', N ", N" -pentaacetic acid C28H54DyN5 ° 20; with lanthanum III oxide, U203 φ di-N-methylglucamine salt of the lanthanum III complex of

Diethylenetriamine-N, N, Ν ', N ", N" -pentaacetic acid C28H54LaN5 ° 20; with ytterbium-III-oxide, Yb203 ·. Di-N-methylglucamine salt of the ytterbium III complex of

Diethylenetriamine-N, Ν, N ', N ", N" -pentaess acetic acid C28H54YbN5 ° 20 with samarium-IlI oxide, Sm203

Di-N-methylglucamine salt of the samarium III complex of diethy1entriamiπ-Ν, N, N *, N ", N" -pentaacetic acid C28H54SmN5 ° 20; - 30 - with Hclmium-11i-ox ία, Ηο20 ·,

Di-N-methy 1 g l'jcami nsa 1 z of the holmium III complex of

The eth lent ri am in-N. N, Ν ', N ", N" -pentaacetic acid, ^ 28 ^ 54 ^ ° * ^ 020 »with Î-.iSi .-. LiÎ-I I-cxid, B i 2 0 ^

Di-N-methyîglucamine salt of the bismuth III complex of diethylenetriamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid, C28H54SiN5 ° 20 ’« with gadolinium-III-oxide, Gd203

Tri-N-methylglucamine salt of the gadolinium III complex of

Triethylenetetramine-N, N, N ', N ", N'", N '"- hexaacetic acid, C3gH7gGdN7027

You also get: with holmium-III-oxide, Ho203 and ethanolamine instead of N-methylglucamine

Di-ethanolamine salt of the holmium III complex of diethylenetriamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid, C18H34HoN5 ° 12; with gadolinium-III-oxide, Gd203 and lysine instead of N-methylglucamine

Di-lysine salt of the gadolinium III complex of diethylenetriamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid, c26H486dN7 ° 14 · i

Using diethanolamine, the di-diethanolamine salt of the holmium III complex of diethylenetriamine-pentaacetic acid, C22H42HoN5014 *

The salts are obtained as white powder with an uncharacteristic melting point. They are very soluble in water.

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Example 6 s Preparation of the disodium salt of the gadolinium III complex of diethylenetriamine-Ν, Ν, Ν ', N ", N" -penta-acetic acid, gGdN ^ O ^ q - 2 Na 18.2 g (= 0 , 05 mol) of gadolinium-III-oxide and 39.3 gd «(= 0.1 mol) of diethylenetriamine-pentaacetic acid are in | Suspended 110 ml of water and heated to reflux for 1 hour. The clear solution is cooled and brought to pH 7.5 by adding about 80 ml of 5N sodium hydroxide solution. The mixture is heated to boiling again and 250 ml of ethanol are added dropwise. After stirring for several hours in an ice bath, the crystals are suctioned off, washed with ice-cold ethanol and * dried at 60 ° C. in vacuo. In quantitatively

Jj tative yield a white powder that does not melt up to 300 ° C.

* j Analysis: I (calc.) C 28.43 H 3.07 N 7.10 Gd 26.58 | (Found) C 28.35 H 2.95 N 7.05 Gd 26.37; ïï 1 In a corresponding manner, the following are obtained: ij, with dysprosium III oxide, Dy £ 03 I disodium salt of dysprosium III Complex of diethylene I * triamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid ί c14H18DyN3 ° 10 * 2 Na;

-W

I "with lanthanum 111-oxide, La2 ° 3 jy disodium salt of the lanthanum III complex of diethylene! Triamine-Ν, Ν, Ν ', N", N "-pentaacetic acid] C14H18LaN3 ° 10 * 2 Na' * / U.

- 32 - with holmium III oxide, Ho203

Disodium salt of the holmium III complex of diethylene-triamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid C14H18H0N3O10 · 2 Na; with ytterbium-III-ox'id, Yb203

Di-sodium salt of the ytterbium-III complex of diethylene-triamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid C14H18YbN3 ° 10' 2 Na 'with samarium-III-oxide, Sm203 Φ di-sodium salt of samarium- III complex of diethylene triamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid C14H18SmN3 ° 10' 2 Na '* with erbium-I I-oxide, Eb203

Disodium salt of the erbium III complex of diethylene-triamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid C14H18EbN3 ° 10 * 2 Na; with gadolinium-III-oxide, Gd203

Sodium salt of the di-gadolinium III complex of tetraethylene pentamine-N, N, N ', N ", N" ,, N' * ', N "' - heptaacetic acid •. C22H30Gd2N5 ° 14 * Na *

These salts are obtained as white powders with an uncharacteristic melting point and are very water-soluble.

, / k ir - 33 -

Example 7

Preparation of the N-methylglucamine salt of ice - III -. Complex of diethylenetriaminepentaacetic acid, C21H37FeN4 ° 15 35.40 g (= 90 mmol) of diethylenetriaminepentaacetic acid are suspended in 100 ml of water and dissolved in 24.3 g (= 90 mmol) of iron (III) chloride hexahydrate (FeCl3 -6 H20) 100 ml water, added. The initially dark brown suspension is heated to 95 ° C. After about 1 hour, the color changes to light yellow. 270 ml of 1N sodium hydroxide solution are added to neutralize the hydrochloric acid formed and the mixture is heated at 95 ° C. for a further 3 hours. The received one. pale yellow precipitate is filtered off, washed with water to free chloride and dried in vacuo at 60 ° C. 17.85 g (45% of theory) of a light yellow powder are obtained, the melting point of which is> 300 ° C.

i | 17.85 g (= 40 mmol) of the iron III complex i obtained are suspended in 200 ml of water and mixed in portions with 7.8 g (= 40 mmol) of N-methylglucamine, solid, i. The mixture is heated to about 3 Hours at 50 ° C and. Receives an almost j clear, red-brown solution, which is filtered and then evaporated to dryness in a 1 vacuum. The residue 4 1 is dried at 50 ° C in a vacuum. 24.3 g of j are obtained. (95% of theory) of a red-brown powder from | Melting point 131-133 ° C.

| - * Analysis: * (calc.) C 39.82 H 5.89 N 8.85 Fe 8.81 J v (found) C 39.70 H 6.00 N 8.65 Fe 9.01? Ä —- \ st 5 - «»

With sodium hydroxide solution instead of the organic base, the following are obtained: i - 34 -

Sodium salt of the iron III complex of ethylenediaminetetraacetic acid, cioHi2FeN2 ° 8 -Na *

Sodium salt of the iron III complex of trans-1,2- * cyclohexylene-diaminetetraacetic acid, C ^ H ^ gFeNgOg -Na

Disodium salt of the iron III complex of diethylenetri-nitrilo-penta (methanephosphonic acid), CgHg-jFeNgO ^ gPg -2 Na ^ sodium salt of the iron III complex · 1,10-diaza-4,7-dioxadecane-1 , 1,10,10-tetraacetic acid, C ^ H2QFeN20 ^ Q -Na

Sodium salt of the iron III complex of ethylenediamine-tetraacethydroxamic acid, C ^ H ^ FeNgOg * Na.

In a corresponding manner, the following are obtained with N-methylglucamine:

Di-N-methylglucamine salt of the iron III complex of diethylenetriamine-N, N, Ν ', N ", N" -pentaacetic acid »C28H54FeN5 ° 20 •.

N-methylglucamine salt of the iron-III complex of trans-1,2-cyclohexylenediamine-N, N, N ', Ν'-tetraacetic acid, C21H36FeN3 ° 13 N-methylglucamine salt of the iron-III complex of ethylene-diamine-Ν, Ν , Ν ', Ν'-tetraacetic acid, C ^ HggFeNgOjg

Tri-N-methylglucamine salt of the iron III complex of triethylenetetramine-N, N, N ', N ", N"', N '"- hexaacetic acid, C39H78FeN7 ° 27 *

Using diethanolamine instead of N-methylglucamine, the I di-diethanolamine salt of the iron-III complex of diethylene f /. . ....................., Λ «- 35 -

Example 8

Preparation of the N-methylglucamine salt of the gadolinium-III complex of trans-1,2-cyclohexylenediamine-N, N, N ', N'-tetraacetic acid, C21H36GdN3013 * 20.78 g (= 60 mmol) of trans-1,2-cyclohexylenediamine -Ν, Ν, Ν ', Ν' -tetraacetic acid are suspended in 150 ml of water. After adding 11.7 g (= 60 mmol) of N-methylglucamine, an almost clear solution is obtained, to which 10.88 g (= 30 mmol) of gadolinium oxide (Gd203) are added. The erhaltene suspension obtained again is heated to 95 ° C. for 6 hours. A little undissolved material is filtered off and the filtrate is evaporated to dryness. The residue is dried in vacuo at 60 ° C and pulverized. 38.6 g (92% of theory) of a white powder with a melting point of 258-261 ° C. are obtained.

Analysis: (Calc.) 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

In the same way, the sodium salt of the gadolinium III complex of trans-1,2-cyclohexylenediamine-N, N, Ν ', Ν' - φ tetraacetic acid, C ^ H ^ gGdN20g -Na is obtained with sodium hydroxide solution instead of N-methylglucamine .- ·.

With freshly precipitated chromium III hydroxide, Cr (0H) 3, the sodium salt of the chromium III complex of ethylene diamine-Ν, Ν, Ν ', Ν'-tetraacetic acid, C10H12CrN20g * Na is obtained.

.. h - - 36 -

Example 9

Preparation of the disodium salt of the manganese-II complex of trans-1,2-cyclohexylenediamine-N, N, N ', N'-tetraacetic acid, C14H18MnN20g.2 Na 34.6 g (= 100 mmol) trans-1,2 -Cyclohexylenediamine-N, N, Ν ', Ν' -tetraacetic acid are suspended under nitrogen in 100 ml of water and mixed with 11.5 g (= 100 mmol) of manganese-II-carbonate MnCOg. The mixture is heated to 95 ° C. and 200 ml of 1N sodium hydroxide solution are added dropwise. The clear solution is concentrated in vacuo and the residue is dried at 60 eC in vacuo. 40.8 g (92% of theory) of a pink powder are obtained.

Analysis: (Calc.) 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

The following are obtained in a corresponding manner:

From copper (II) carbonate, the disodium salt of the copper (II) complex of trans-1,2-cyclohexylenediamine-tetraacetic acid, C14Hl8CuN208 · 2 Na; from cobalt-II-carbonate the disodium salt of the cobalt-II complex of trans-1,2-cyclohexylenediamine-tetraacetic acid, C ^ H ^ gCoNjOg · 2 Na; the disodium salt of nickel-II-i "from nickel-II-carbonate

Complex of trans-1,2-cyclohexylenediamine-tetraacetic acid, C14H18NiN208 · 2 Na.

With N-methylglucamine instead of sodium hydroxide solution, the following are obtained: - 37 -

Di-N-methylglucamine salt of the manganese-II complex of trans-1,2-cyclohexylenediamine in tetraacetic acid, C28H54MnN4 ° 18;

Di-N-methylglucamine salt of the manganese II complex of DL-2,3-butylenediamine tetraacetic acid, C26H52MnN4 ° 18;

Di-N-methylglucamine salt of the manganese-II complex of ^ ethylenediamine-Ν, Ν, Ν ', N'-tetraacetic acid, C24H48MnN4 ° l8 ’

Di-N-methylglucamine salt of the manganese-II complex of DL-1,2-butylenediamine-N, N, N ', N'-tetraacetic acid, C26H52MnN4 ° 18;

Di-N-methylglucamine salt of the manganese-II complex of DL-1,2-propylenediamine-N, N, N ', N'-tetraacetic acid, C25H50MnN4 ° 18 *

Tri-N-methylglucamine salt of the manganese-II complex of diethylenetriamine-pentaacetic acid, CggH ^ MnNgC ^ g ’with nickel-II-carbonate, Ni CO-,

Di-N-methylglucamine salt of the nickel-II complex of ethylenediamine -Ν, Ν, N ', N'-tetraacetic acid, C24H48NiN4 ° 18' with cobalt-II-carbonate, CoCOg and ethanolamine Λ di-ethanolamine salt of the cobalt-II complex the ethylenediamine-Ν, Ν, Ν ', Ν'-tetraacetic acid, ci4H28CoN4 ° 10'

Ht with copper-II-carbonate, CuC03 and ethanolamine

Di-ethanolamine salt of the copper-II-complex of ethylenediamine-Ν, Ν, Ν ', N'-tetraacetic acid, C14H28CuN4 ° 10; - 38 - with manganese II carbonate, MnCOg and diethanolamine

Tri-diethanolamine salt of the manganese-II complex of diethylene triamine in -N, N, N ', N ", N" -pentaacetic acid, C26H54MnN6 ° 16 ». with manganese II carbonate, MnC03 and morpholine

Di-morpholine salt of the manganese-II complex of ethylenediamine-Ν, Ν, Ν ", N" -tetraacetic acid, ci8H32MnN4 ° 10 *

Example 10 N-methylglucamine salt of the gadolinium III complex of ethylenediamine-Ν, Ν, Ν1, N'-tetraacetic acid, C17H30GdN3013 29.2 g (= 100 mmol) of ethylenediamine-Ν, Ν, Ν ', N'-tetraacetic acid are added 100 ml of water suspended and heated to 95 ° C. with 18.1 g (= 50 mmol) of gadolinium-111-oxide,, Gd203>, φ e 19.5 g (= 100 mmol) of N-methylglucamine are added in portions during the heating . After about 3 hours, a clear solution is obtained, which is filtered and in

Vacuum to dryness. The residue is dried in vacuo at 60 ° C. 61.3 g of I (95% of theory) of a white powder with an uncharacteristic melting point are obtained.

i j j Analysis: j (calc.) 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

: K

The following are obtained in an analogous manner: - 39 -

With dysprosium-III-oxide, DygOg N-methylglucamine salt of the dysprosium-III complex of ethylenediamine-Ν, Ν, Ν ', Ν'-tetraacetic acid, C17H30DyN3013; · # N-methylglucamine salt of the gadolinium III complex which? 1,10-diaza-4,7-dioxadecane-1,1,10,10-tetraacetic acid,; C21H38GdN3 ° 15; N-methylglucamine salt of the gadolinium III complex of φ 1,2-dipheny1ethy1endiamino-tetraacetic acid, C29H38N3 ° 13Gd; with lead II oxide, PbO and sodium hydrochloride

Disodium salt of the lead II complex of ethylenediaminetetraacetic acid, CK) Hi2N2G8Pb · 2 Na; with freshly precipitated chromium III hydroxide, Cr (0H) 3

Sodium salt of the chromium III complex of ethylenediaminetetraacetic acid, CjQH ^ CrNgOg * Na; and analog

Sodium salt of the gadolinium-III complex of ethylene diamine tetraacethydroxamic acid, C ^ H ^ GdNgOg · Na; Φ - Sodium salt of the gadolinium III complex of'-ethylenediamine-N, N, Nr, Ν'-tetraacetic acid, cioH12GdN2 ° 8. N / A.

;. k a - 40 -

Example 11

Preparation of the sodium salt of the gadolinium III complex • 1,4,7,1O-tetraazacyclododecane-N, N *, N ", N” -tetraacetic acid, ci6H246dN4 ° 8 · Na * 4.0 g (= 10 mmol ) 1,4,7,10-tetraazacyclododecane-N.N ', N ", N"' - tetraacetic acid are suspended in 20 ml of water and mixed with 10 ml of 1N sodium hydroxide solution. 1.8 g (= 5 mM gadolinium III oxide, GdgOg, was added and the suspension was heated for 2 hours at 50 ° C. The clear solution was filtered and concentrated in vacuo. The residue was dried and pulverized. 5.5 g (95% of theory) were obtained. i I, a white powder.

jj Analysis: j (calc.) C 33.10 H 4.17 N 9.65 Gd 27.08 I (found) C 33.01 H 4.20 N 9.57 Gd 27.16! ": In the same The following is obtained: N-methylglucamine salt of the gadolinium III complex of 1,4,7,10-tetra azacyclododecane-N, N ', N ", N te tr ae sigsigsäu re, -C23H42GdN5 ° 13! Sodium salt of the gadolinium III complex of 1,4,8,11-J tetraazacyclotetradecane-Ν, Ν ’, N", N "-tetraacetic acid, J ·" ί, ^ 18 ^ 28Gd ^ 4G8 * Na.

! ’H • i i i - 41 -

Example 12

Preparation of the tetra-N-methylglucamine salt of the gadolinium III complex of ethylenedinitrilotetrakis (methanephosphonic acid), £ 34 ^ 35 ^^ 6 ^ 32 ^ 4 * 9.11 g (= 20 mmol) of ethylenedinitrilotetrakis (methanephosphonic acid) are suspended in .150 ml of water and adjusted to a pH of 5 with the appropriate amount of N-methylglucamine. 3.6 g (= 10 mmol) of gadolinium-III-oxide, ^ Gd203, are added and the mixture is heated to 70.degree. After about 1 hour, a clear solution is obtained, to which the remaining portion of N-methylglucamine is added. A total of 15.6 g (= 80 mmol) of N-methylglucamine are consumed. The solution is evaporated to dryness in vacuo and the remaining gel-like residue is introduced into 200 ml of acetonitrile.

The mixture is stirred at 30 ° C for about 20 hours and the fine precipitate obtained is suction filtered. After drying in vacuo at 40 ° C., 23.4 g (85% of theory) of a white powder with a melting point of 115-118 ° C. are obtained.

Analysis: (calc.) C 29.78 H 6.25 N 6.13 P 9.04 Gd 11.47 ^ (found) C 29.85 H 6.57 N 5.98 P 8.78 Gd 11, 26

The following are obtained in the same way:

Hepta-N-methylglucamine salt of the gadolinium III complex of diethylenetriamine-N, N, N ', N ", N" -penta (methanephosphonic- ~ * acid), csaHi44GciN10050P5 ’and using sodium hydroxide solution instead of N-methylglucamine

Disodium salt of the gadolinium III complex of diethylene-trinitrilo-penta (methanephosphonic acid), CgH23GdN3015P5 * 2 Na.

- l · ^ · j - 42 -

Example 13

Preparation of the disodium salt of the manganese-II complex of ethylenedinitrilotetra {acethydroxamic acid), C10H16MnN6 ° 8 * ^ Na 12.30 g of manganese-II carbonate and 7.05 g of ethylenedinitrilotetra (acethydroxamic acid) in 18 ml of water Heated to reflux for 3 hours. The pH is then adjusted to 7 by adding dilute sodium hydroxide solution, and 40 ml of acetone are added dropwise. After stirring for several hours in an ice bath, φ is suctioned off the separated crystals and washed with them

Acetone and dry it at 50 ° C in vacuum. A dihydrate is obtained in quantitative yield as a white powder with a melting point above 300 ° C.

Mn: (calc.) 11.30 (found) 11.12

Example 14

Preparation of a mixed salt solution from the sodium and the N-methylglucamine salt of the gadolinium III complex of φ, diethylenetriamine-pentaacetic acid a) Preparation of the mono-N-methylglucamine salt of the complex, C21H37SdN4 ° 15 'c · 195.2 g (1 mol) N-methylglucamine are dissolved in 7 liters of water. Then 393.3 g (1 mol) of diethylenetriamine-pentaacetic acid and 181.3 g (0.5 mol) of gadolinium oxide, Gd20g, are added and the mixture is heated under reflux for 2 hours. The filtered clear solution is spray dried. A white crystalline powder with a water content of 2.6% is obtained, which sinters at 133 ° C. and melts at 190 ° C. with foaming.

Λ Gd: (calc.) 21.17 4 3 b) Preparation of the neutral mixed salt solution 730.8 g (= 1 mol) of the salt obtained under a) are dissolved in 630 ml of water p.i. suspended and 40 g (= 1 mol) caustic soda powder added in portions. The neutral solution is washed with water p.i. made up to 1000 ml, bottled via a pyrogen filter and heat sterilized. This Imolar solution contains 753.8 g mixed salt per liter.

Example 15

Preparation of a solution of the di-N-methylglucamine salt of the gadolinium III complex of diethylenetriamine-penta-acetic acid 535.0 g (= 730 mmol) of the salt described in Example 5 are dissolved in 500 ml of water p.i. slurried and brought into solution by adding 142.4 g (= 730 mmol) of N-methylglucamine at pH 7.2. Then p.i. made up to 1000 ml, the solution filled into ampoules and heat sterilized.

i. Example 16

Preparation of a solution of the di-sodium salt of the gadolinium-III complex of diethylenetriamine-penta-acetic acid i, - 485.1 g (= 820 mmol) of the disodium salt obtained in Example 6 are dissolved in 500 ml of water p.i. slurried. Then p.i. made up to 1000 ml, the solution filled into ampoules and heat sterilized.

'k p.i. = pro injectione - Λ - 44 -

Example 17 4

Preparation of a solution of the di-sodium salt of the gadolinium-IIl complex of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-pentaazapentatriacontano * diacid 392.0 g (= 400 mmol) of the salt described in Example 2 are dissolved in 500 ml of water slurried and p.i. dissolved in 1000 ml with gentle warming. The solution is bottled Φ and heat sterilized.

Example 18

Preparation of a solution of the N-methylglucamine salt of the gadolinium III complex of 1,4,7,10-tetraazacyclododecane tetraacetic acid 370.9 g (= 500 mmol) of the salt listed in Example 11 are dissolved in 500 ml of water p.i. slurried and p.i. dissolved in 1000 ml. The solution is ampouled and heat sterilized.

•.

Example 19

Preparation of a solution of the di-N-methylglucamine salt of the ^ manganese-II complex of trans-1,2-cyclohexylenediamine tetraacetic acid 395.9 g (= 500 mmol) of the salt listed in Example 9 are dissolved in 500 ml of water p.i. suspended. 1.3 g of ascorbic acid are added, and p.i. to 1000 ml in solution. The solution is sterile filtered and filled into ampoules.

A

- 45 -

Example 20 'r i

Preparation of a solution of the tri-N-methylglucamine salt of the manganese II complex of diethylenetriamine-penta-acetic acid 514.4 g (= 500 mmol) of the salt listed in Example 9 are dissolved in 600 ml of water p.i. suspended. 1.3 g of ascorbic acid are added and p.i. to 1000 ml. The sterile-filtered solution is filled into ampoules.

Example 21

Preparation of a solution of the di-N-methylglucamine salt of the iron III complex of diethyIentriamine-penta-acetic acid 44.6 g (= 0.1 mol) of the iron-III complex of diethylenetriamine-pentaacetic acid obtained in Example 7 are obtained in 40 ml water pi suspended. After adding 0.18 g of tromethamine hydrochloride and 39.1 g (= 0.2 mol) of N-methyl-glucamine, the solution is dissolved neutral, the solution with water p.i. φ filled up to 100 ml, filled into ampoules, and heat sterilized.

Example 22 '-y: Preparation of a solution of the gadolinium-III complex of nitrilotriacetic acid 1.9 g (= 10 mmol) of nitrilotriacetic acid and 1.8 g (= 5 mmol) of gadolinium-1II-oxide are dissolved in 100 ml of water p.i. dissolved under heating. The solution is ampouled and heat sterilized.

"/ L

, I f * t - 46 -

Example 23

Preparation of a solution of the N-methylglucamine salt of the gadolinium III complex of ethylenediamine-tetraacetic acid * 38.52 g (= 60 mmol) of the substance described in Example 10 are dissolved in 70 ml of water p.i. solved. After adding 0.12 g of tromethamine, p.i. made up to 100 ml, the solution filled into ampoules and heat sterilized.

Example 24 \ Preparation of a solution of the di-N-methylglucamine salt of the dysprosium III complex of diethylenetriamine-pentaacetic acid 35.7 g (= 60 mmol) of the dysprosium III complex of diethylenetriamine-pentaacetic acid (water content 8.0%) are in 70 ml water pi suspended and brought into solution by adding 21.2 g (= 120 mmol) of N-methylglucamine at pH 7.5. Then p.i. made up to 100 ml φ ", the solution ampouled and heat sterilized.

Example 25

Preparation of a solution of the N-methylglucamine salt of the gadolinium III complex of trans-1,2-cyclohexylene-diamine-tetraacetic acid 555.8 g (= 0.8 mol) of the salt described in Example 8 are dissolved in water p.i. dissolved in 1000 ml. After filtration through a pyrogen filter, the solution is filled into ampoules and heat-sterilized.

* ¥

Preparation of a solution of the N-methylglucamine salt of

Ruthenium III complex of 1,10-diaza-4,7-dithiadecane-1,1,10,10-tetraacetic acid - 47 -

Example 26 15.6 g (= 0.03 mol) of the ruthenium III complex of 1,10- * diaza-4,7-dithiadecane-1,1,10,10-tetraacetic acid are dissolved in 50 ml of water p.i. suspended and brought into solution by adding 5.9 g (= 0.03 mol) of N-methylglucamine at pH 7.5. Make up to 1000 ml with water p.i., fill the solution with ampoules and heat sterilize it.

Example 27

Preparation of a solution of the di-lysine salt of the gadolinium-III complex of diethylenetriamine-pentaacetic acid 273.8 g (= 0.5 mol) of the gadolinium-III complex of diethylenetriamine-pentaacetic acid are dissolved in 500 ml of water p.i. suspended. 292.4 g (= 1 mol) of lysine are added, the mixture is stirred for several hours with gentle heating and then filled with water p.i. ad 1000 ml. The solution φ is filled into bottles and heat-treated.

Example 28

Preparation of a solution of the tri-N-methylglucamine salt of the molybdenum VI complex of diethylenetriamine-penta-acetic acid 18.8 g (= 0.28 mol) of the complex Η2 [Μθ202 (° Η) 4 · 0 ^ 4Η23Η3010] are in 50 ml water pi suspended and dissolved neutral by adding 16.4 g (= 0.84 mol) of N-methylglucamine.

0.15 g of tromethamine is added, and the mixture is filled with water p.i. to _ 100 ml, subject the solution to sterile filtration / 7 and fill it into ampoules.

t »

Preparation of a solution of the disodium salt of the manganese II complex of ethylenediamine-tetraacetic acid - 48 -

Example 29 343.2 g (= 1 mol) of the manganese-II complex of ethylenediamine-tetraacetic acid are dissolved in 500 ml of water p.i. suspended and dissolved neutral by adding 80 g (= 2 mol) caustic soda in portions. After adding 1.5 g of tromethamine, the solution is washed with water p.i. filled up to 1000 ml, bottled and heat-φ sterilized.

'4

Example 30

Preparation of a solution of the sodium salt of the iron III complex of ethylenediamine tetraacetic acid 345.7 g (= 1 mol) of the iron III complex of ethylenediamine tetraacetic acid are dissolved in 500 ml of water p.i. j suspended and by adding 40 g in portions! (= 1 mol) caustic soda dissolved neutral. After adding; 1.5 g tromethamine, the solution with water p.i. ad, φ, 1000 ml filled up, bottled and heat-sterilized.

Example 31 - '* »*

Preparation of a solution of the disodium salt of the iron III complex of diethylenetriamine-pentaacetic acid, äl 334.6 g (= 0.75 mol) of the iron III complex of diethylene-triamine-pentaacetic acid are dissolved in 500 ml of water p.i. suspended and dissolved neutral by portionwise addition of 60 g (= 1.5 mol) caustic soda. The solution is p.i.

- λ ad filled up to 1000 ml, bottled and heat // sterilized.

Preparation of a solution of the sodium salt of the gadolinium III complex of trans-1,2-cyclohexylenediamine-tetraacetic acid »ψ - 49 -

Example 32 558.6 (= 1 mol) of the salt mentioned in Example 8 are dissolved in water p.i. dissolved to 1000 ml. The solution is filled into bottles and heat sterilized.

φ Example 33

Preparation of a solution of the N-methylglucamine salt of the gadolinium III complex of 1,2-diphenylethylenediamine-tetraacetic acid 396.9 g (s 500 mmol) of the salt described in Example 10 are dissolved in 600 ml of water p.i. slurried and dissolved by filling to 1000 ml. The solution is filled into ampoules and heat sterilized.

Example 34 •. -

Preparation of a solution of the sodium salt of the iron (III) complex of ethylenediamine-tetraacetic acid 183.5 g (= 500 mmol) of the salt mentioned in Example 7 are dissolved in 500 ml of water p.i. slurried. One puts 1.0 g

Tromethamine, fill with water p.i. to 1000 ml, v fill the solution into ampoules and heat sterilize.

i -4, y - 50 -

Example 35 i i

Preparation of a solution of the di-N-methylglucamine salt of the lanthanum III complex of diethylenetriamine-penta-acetic acid 459.8 g (= 500 mmol) of the salt listed in Example 5 are dissolved in 650 ml of water p.i. slurried and brought to 1000 ml in solution by filling with water p.i.

The solution is filled into ampoules and heat sterilized.

^ Example 36 j ’

Preparation of a solution of the di-N-methylglucamine salt of the bismuth III complex of diethylenetriamine-penta-acetic acid! 692.8 g (= 700 mmol) of the salt listed in Example 5 are p.i. in 600 ml of water. slurried and after adding 1.8 g tromethamine by filling with water p.i. dissolved in 1000 ml with gentle warming. The solution is filled into ampoules and heat sterilized.

! φ! Example 37

Preparation of a solution of the di-N-methylglucamine salt of the holmium III complex of diethylenetriamine-penta-acetic acid 662.0 g (= 700 mmol) of the salt listed in Example 5 are dissolved in 600 ml of water p.i. slurried and after adding 1.8 g tromethamine by filling with water p.i. dissolved in 1000 ml with gentle warming. The solution is filled into ampoules and heat sterilized.

/ *; Example 38 - 51 -

Preparation of a solution of the di-N-methylglucamine salt of the ytterbium-III complex of diethylenetriamine-pentaacetic acid 476.9 g (= 500 mmol) of the salt listed in Example 5 are dissolved in 650 ml of water p.i. slurried and after adding 1.5 g tromethamine by filling with water p.i. dissolved in 1000 ml. The solution is filled into ampoules and heat sterilized.

Example 39

Preparation of a solution of the disodium salt of the lanthanum III complex of diethylenetriamine-pentaacetic acid. 573.2 g (= 1000 mmol) of the salt listed in Example 6 are dissolved in 650 ml of water p.i. slurried and p.i. dissolved in 1000 ml. The solution is filled into ampoules and heat sterilized.

Example 40

Preparation of a solution of the -di-sodium salt of the dysprosium- * III complex of diethylenetriamine-pentaacetic acid 477.4 g (= 800 mmol) of the salt '* listed in Example 6 are dissolved in 600 ml of water p.i. slurried and by filling up with water p.i. dissolved in 1000 ml. The solution is filled into ampoules and heat sterilized.

t

Example 41

Preparation of a solution of the di-sodium salt of the holmium III complex of diethylenetriamine-pentaacetic acid 5 2 299.6 g (= 500 mmol) of the salt listed in Example 6 are dissolved in 500 ml of water p.i. slurried and p.i. dissolved in 1000 ml. The solution is filled into ampoules and heat sterilized.

Example 42 4 --r ... - -

Preparation of a solution of the disodium salt of the ytterbium III complex of diethylenetriamine-pentaacetic acid 303.5 g (= 500 mmol) of the salt listed in Example 6 are dissolved in 500 ml of water p.i. slurried and p.i. dissolved in 1000 ml. The solution is filled into ampoules and heat sterilized.

] Example 43

Preparation of a solution of the tetra-N-methylglucamine salt of the gadolinium III complex of ethylenedinitrilotetrakis (methanephosphonic acid) 137.1 g (= 100 mmol) of the salt ^ H listed in Example 12 are dissolved in 500 ml of water p.i. slurried and after adding 0.8 g tromethamine by filling with water p.i. dissolved in v 1000 ml. The solution is filled into ampoules and heat-esterified.

H

- 53 -

Example 44

Preparation of a solution of the gadolinium-III complex of N1 - (2-hydroxyethyl) ethylenediamine-N, N, N'-triacetic acid 1.9 g (= 6.7 mmol) N '- (2-hydroxyethyl) ethylenediamine-N, N, Ν'-Triacetic acid and 1.2 g (= 3.35 mol) of gadolinium - III-oxide are dissolved in 6 ml of water pi with heating.

The solution is ampouled and heat sterilized.

φ Example 45 ï Preparation of a solution of the disodium salt of manganese II

Complex of trans-1,2-cyclohexylenediamine-tetraacetic acid 44.3 g (= 100 mmol) of the salt listed in Example 9 are p.i. under nitrogen protection in 60 ml of water. slurried and p.i. brought to 100 ml in solution. The solution is ampouled and heat sterilized.

Example 46

Preparation of a solution of the sodium salt of the gadolinium III complex of 1,4,8,11-tetraazacyclotetradecane-NN ', N ", N"' - tetraacetic acid • 552.6 g (= 1 mol) of the salt mentioned in Example 11 in water pi dissolved in 1000 ml. The solution ^ is filled into bottles and heat sterilized.

«Ψ η - 54 -

Example 47

Preparation of a solution of bismuth disodium salt. III complex of diethylenetriamine-pentaacetic acid j ..........

23.4 g (= 50 mmol) of bismuth III oxide are dissolved in 50 ml of water p.i. suspended - after adding 39.3 g (= 100 mmol)

Diethylenetriamine-pentaacetic acid and 4.0 g (= 50 mmol) caustic soda are heated to reflux until the solution is clear.

The solution, cooled to room temperature, is neutralized by adding 4.0 g of caustic soda and p.i. with water. made up to 100 ml. The solution is ampouled and heat-φ sterilized.

Example 48

Preparation of a solution of the disodium salt of the samarium III complex of diethylenetriamine-pentaacetic acid 58.5 g (= 100 mmol) of the salt listed in Example 6 are dissolved in 55 ml of water p.i. dissolved under heating. You fill with water p.i. to 100 ml total volume, ampouled and heat sterilized.

•.

Example 49 -

Preparation of a solution of the di-N-methylglucamine salt of the gadolinium III complex of 13,23-dioxo-15,18,21-tris' v (carboxymethyl) -12,15,18,21,24-pentaazapentatriacontanoic acid - v 130.4 g (= 100 mmol) of the salt listed in Example 2 are pi in 250 ml of water slurried and dissolved with warming. You fill with water p.i. to 500 ml, fill the solution into ampoules and heat sterilize.

- / U

τ- * - 55 -

Example 50

Preparation of a solution of the di-N-methylglucamine salt of the manganese-II complex of ethylenediamine-tetraacetic acid 3.68 g (= 5 mmol) of the substance described in Example 9 are dissolved in 70 ml of water p.i. dissolved and the solution with 0.4 g of sodium chloride. Then: 100 ml with water p.i. filled up and the solution filled through a sterile filter into ampoules. The solution is with 280 mOsm. blood isotonic.

Example 51

Preparation of a solution of the disodium salt of the gadolinium-III complex of diethylenetrinitrilopenta (methanephosphonic acid) 38.57 g (= 50 mmol) of the substance described in Example 12 are dissolved in 50 ml of water p.i. slurried. The pH is adjusted to 7.2 by adding caustic soda and the mixture is filled with water p.i. to 100 ml. The solution is ampouled and heat sterilized.

•; . Example 52

Preparation of a solution of the trisodium salt of manganese-II, complex of diethylenetriamine-pentaacetic acid. 39.3 g (= 100 mmol) of diethylenetriamine-pentaacetic acid are dissolved under nitrogen in 100 ml of water p.i. suspended and mixed with 11.5 g of manganese II carbonate. The mixture is heated to 95 ° C. and 300 ml of 1N sodium hydroxide solution are added dropwise. The neutral solution is sterile filtered and filled into ampoules.

/ ^ ---- / *> - 56 -

Example 53, Composition of a powder for the preparation of a

Suspension - 4,000 g of gadolinium III complex of diethylenetriaminepentaacetic acid (water content 8.0%) * 3.895 g of sucrose 0.100 g of polyoxyethylene polyoxypropylene polymer 0.005 g of flavorings from 8.000 g example 54

Preparation of a solution of the gadolinium III complex I from the conjugate of diethylenetriamine-pentaacetic acid with j human serum albumin ^ 10 mg 1.5 become 20 ml of a solution of 3 mg of the protein in 0.05 ^ * molar sodium bicarbonate buffer (pH 7-8) -Bis (2,6-dioxomorpholino) -3-azapentane-3-acetic acid - added. The mixture is stirred for 30 minutes at room temperature and then dialyzed against a 0.3 molar sodium phosphate buffer. Then you put 50 mg of gadolinium; » III-acetate and purifies by gel chromatography on a Sephadex G25 column. The fraction obtained is sterile filtered and filled into multivials.

A storable dry preparation is obtained by freeze-drying.

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

- U.

-s - 57 -

Example 55

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

To 20 μl of a solution of 0.3 mg of monoclonal antibody in 0.05 molar sodium bicarbonate buffer (pH 7-8), 1 mg of a mixed DTPA anhydride (obtained e.g. from DTPA and isobutyl chloroformate) are added and the mixture is stirred at room temperature for 30 minutes. The mixture is dialyzed against 0.3 φ molar sodium phosphate buffer and the resulting mixture is added

Antibody fraction with 2 mg of the gadolinium III complex w of ethylenediamine tetraacetic acid (EDTA). After purification by gel chromatography on Sephadex G25, the sterile-filtered solution is filled into multivials and freeze-dried.

Using the mixed anhydride of trans-1,2-diaminocyclohexane tetraacetic acid (CDTA), a solution of the corresponding gadolinium III complex of the CDTA antibody is 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 are obtained analogously.

%

Example 56 ^ Preparation of a solution of the Gadolinium III complex from

Conjugate of 1-phenyl-ethylenediamine-tetraacetic acid with immunoglobulin

According to the procedure described in J. Med. Chem. 1974, Vol. 17, p. 1307, a 2% solution of the protein in a 0.12 molar sodium bicarbonate solution, the

'/ L

- 58 - contains 0.01 mol of ethylenediamine-tetraacetic acid, cooled to +4 ° C and added dropwise with the protein-equivalent portion of a freshly prepared ice-cold diazonium salt solution of 1- (p-aminophenyl) -ethylenediamine-tetra-acetic acid. The mixture is stirred overnight at +4 ° C. (pH 8.1) and then dialyzed against a 0.1 molar sodium citrate solution. After completion * of the dialysis, the solution of the conjugate is mixed with an excess of gadolinium-III chloride and ultrafiltered to remove ions. Finally, the sterile-filtered solution is filled into multivials and φ freeze-dried.

Example 57

Preparation of a colloidal dispersion of a Mn-CDTA-lipid conjugate 0.1 mmol distearoylphosphatidylethanolamine and 0.1 mmol bisanhydride of trans-1,2-diaminocyciohexane tetraacetic acid are stirred in 50 ml water for 24 hours at room temperature. 0.1 mmol of manganese-II-carbonate are added and the mixture is stirred again at room temperature for 6 hours. After φ "cleaning on a Sephadex G50 column, the sterile-filtered solution is filled into multivials and freeze-dried.

Analogously, a colloidal 1-dispersion of the gadolinium-DTPA-lipid conjugate can be obtained with gadolinium-III-oxide.

• / K

V ’Τ '

Example 58 - 59 -

Preparation of liposomes loaded with gadolinium DTPA

According to the in Proc. Natl. Acad. Be. U.S.A. 75, 4194-4, a lipid mixture is prepared from 75 mole% egg phosphatidylcholine and 25 mole% cholesterol * as dry matter. 500 mg of this are dissolved in 30 ml of diethyl ether and added dropwise in an ultrasonic bath with 3 ml of a 0.1 molar solution of the di-N-methylglucamine salt of the gadolinium III complex φ of diethylenetriamine-pentaacetic acid in water p.i.

transferred. After the solution has been added completely, the sonication is continued for 10 minutes and then concentrated in a rotavapor. The gel-like residue is suspended in 0.125 molar sodium chloride solution and freed from non-encapsulated contrast agent portions repeatedly at 0 ° C. by centrifugation (20,000 g / 20 minutes). Finally, the liposomes thus obtained are freeze-dried in a multivial. The application takes place as a colloidal dispersion in 0.9 weight percent saline.

• ^

* ** 'S

X

Claims (53)

1 group y 1. Diagnostic agent containing at least one] physiologically compatible complex salt from the anion of a complexing acid and one or more central ion (s) of an element of atomic numbers 21 to 29, 42, 44 or 57 to 83 and optionally also one or more physiologically acceptable ^ Cation (s) of an inorganic and / or organic base or amino acid, optionally with the additives customary in galenics, dissolved or suspended in an aqueous medium. 2. Diagnostic agent according to claim 1 containing at least one physiologically compatible complex salt of the general formula I or II X-CH9v xCH -XZ NAN Z (I), V-CHR ^ CHf ^ -V φ or N (CH2X) 3 (II), wherein: * X is the radicals -C00Y, -ΡΟ, ^ ΗΥ or -C0NH0Y with Y in the meaning of a hydrogen atom, a metal ion equivalent and / or a physiologically acceptable cation of an inorganic or organic base or amino acid and in which A is the group h - 2 - -CHR0-CHR, ~, -CH „-CH9- (ZCH9-CH,) m-, 2 3 2 2/2 m N (CH„ X) 9 ÇH7-CH_-NCCH_X) _, I 2 2 | Z 2 2 2 -CH2-CH-CH2- or -CH2-CH2-N-CH2-CH2-3, in which 3. has the meaning given above, represent hydrogen atoms or methyl groups, J R2 and Rj together represent a trimethylene group or jj represent a tetramethylene group represent or hydrogen] 'atoms, lower alkyl groups, phenyl groups, benzyl- ^ "groups R2 a hydrogen atom and R ^ a group« - (CH2) p-C6H4-W protein (with p meaning 0 or 1, W in the meaning of -NN-, -NHC0CH2- or -NHCS- and -protein in the meaning of a protein residue and m are the numbers 1, 2 or 3, Z is an oxygen atom or a sulfur atom or the group 1 -! ^ NCH2X, or NCH2CH20R4 Ί with X in the meaning given above and R ^ in “J is the meaning of a lower alkyl group 9 * * H and in which ί V has the same meaning as X, or 3. Diagnostic agent according to claim 1 and 2 for use in ultrasound diagnostics. 3 -CH2OH, -C0NH (CH2) nX, or -COB \ / u. - 3 - with X in the meaning given above, B in the meaning of a protein or lipid residue and n in the meaning of the numbers 1 to 12, * or if R ^, R2 unc1 ^ 3 hydrogen atoms both V together represent the group « CH2X CH2X with X in the meaning given above and w in the meaning of the numbers 1, 2 or 3, J means with the proviso that at least two of the substituents Y Æ metal ion equivalents of an element of the order numbers 21 to 29, 42, 44 or 57 to 83. 4. Diagnostic agent according to claim 1 and 2 containing an element of atomic numbers 21 to] 1 29, 42, 44 or 58 to 70 for use in NMR- j diagnostics. i ί i i 5. Diagnostic agent according to claim 1 and 2 jj ^ containing an element of atomic numbers 57 to 83 for use in X-ray diagnostics. 6. Diagnostic agent according to claim 1 and 2>; characterized by a content of di-N-methyl- * glucamine salt of the manganese (II) complex of ethylenediaminetetraacetic acid. L · i I - 4 - 7. Diagnostic agent according to claim 1 and 2, characterized by a content of di-N-methyl-glucamine salt of the gadolinium (III) complex of diethylenetriamine-pentaacetic acid. « 8. Diagnostic agent according to claim 1 and 2, characterized by a content of di-N-methylgluca- _minsalz des Dysprosium (III) complex of Diethylen- ™ triamin-pentaacetic acid. 9. Diagnostic agent according to claim 1 and 2, characterized by a content of mono-sodium / mono-N-methylglucamine mixed salt of the gadolinium (III) complex of diethylenetriamine-pentaacetic acid. 10. Diagnostic agent according to claim 1 and 2, characterized by a content of di-lysine salt of the gadolinium (III) complex of diethylenetriamine-pentaacetic acid, • 'h- - Λ I <- 5 - 11. Diagnostic agent according to claim 1 and 2, characterized by a content of disodium salt t of the gadolinium (III) complex of diethylenetriamine-pentaacetic acid. 12. Diagnostic agent according to claim 1 and 2, characterized by a content of di-N-methyl-glucamine salt of the iron (III) complex of diethylene-triamine-pentaacetic acid. "Y 13. Diagnostic agent according to claim 1 and 2, characterized by a content of disodium salt of the iron (III) complex of diethylenetriamine-penta-acetic acid. 14. Diagnostic agent according to claim 1 and 2, characterized by a content of disodium salt of the manganese (II) complex of diethylenetriamine-penta-acetic acid. • · 15. Diagnostic agent according to claim 1 and 2, characterized by a content of di-N-methylglucamine salt of the holmium (III) complex of diethylene-triamine-pentaacetic acid. - 6 - 16. Diagnostic agent according to claim 1 and 2, I characterized by a content of disodium salt j j of the manganese (II) complex of ethylenediamine-tetra! acetic acid. « 17. Diagnostic agent according to claim 1 and 2, characterized by a content of di-N-methyl-a glucamine salt of bismuth (III) complex of diethylene-triamine-pentaacetic acid. V 18. Diagnostic agent according to claim 1 and 2, characterized by a content of di-N-methylglucamine salt of the manganese (II) complex of trans-1,2-cyclo-hexylenediamine tetraacetic acid. 19. Diagnostic agent according to claim 1 and 2, characterized by a content of disodium salt of the ytterbium (III) complex of diethylenetriamine-pentaacetic acid. • 20. Diagnostic agent according to claim 1 and 2, characterized by a content of N-methylglucamine salt of the gadolinium (III) complex of 1.4.7.10- ^ * tetraazacyclododecane tetraacetic acid. 21. Diagnostic agent according to claim 1 and 2, characterized by a content of disodium salt of the manganese (II) complex of trans-1,2-cyclohexylene-diamint etraess acetic acid. , / U. »* - 7 - 22. Diagnostic agent according to claims 1 and 2, characterized by a content of disodium salt of bismuth (III) complex of diethylenetriamine-pentaacetic acid * 23. Diagnostic agent according to claims 1 and 2, characterized by a content of di-N-methyl-glucamine salt of the gadolinium (III) complex of the 13.23-dioxo-15.18.21-tris- (carboxymethy1) -12.15.18.21.24- ^ pentaazapentatriacontanedioic acid. 24. Diagnostic agent according to claims 1 and 2,. » characterized by a content of sodium salt - the gadolinium (III) complex of 1.4.7.10-tetra-azacyclododecane-tetraacetic acid. 25. Diagnostic agent according to claim 1 and 2, characterized by a content of gadolinium (III) complex of the conjugate of diethylenetriamine-penta-acetic acid with immunoglobulin. 26. Diagnostic agent according to claim 1 and f 2, characterized by a content of gadolinium (III) - complex of the conjugate of diethylenetriamine-penta- j 'acetic acid with human serum albumin. 27. Diagnostic agent according to claims 1 and 2, | characterized by a content of gadolinium (III) - ^ complex of the conjugate of diethylenetriamine-penta- i-4-acetic acid with monoclonal antibody. 28. Diagnostic. Agent according to claims 1 and 2, characterized by a content of manganese (II) - | Complex of the conjugate of trans-1.2-cyclohexylene diamine tetraacetic acid with monoclonal antibody. ./d Λ I - 8 - 29. Diagnostic agent according to claim 1 and 2, characterized by a content of manganese (II) t complex of the lipid conjugate of trans-1,2-cyclo-hexy1endiamine-tetraacetic acid. < 30. Diagnostic agent according to claim 1 and 2, characterized by a content of liposomes loaded with the gado-linium (III) complex of diethylenetriamine-pentaacetic acid. 31. Diagnostic agent according to claim 1 and 2, characterized by a content of di-sodium salt of the holmium (III) complex of diethylenetriamine-pentaacetic acid. 32. Diagnostic agent according to claims 1 and 2, characterized by a content of disodium salt of the lanthanum (III) complex of diethylenetriamine-pentacetic acid. 33. Diagnostic agent according to claims 1 and 2, characterized by a content of di-N-methyl- ™ 'glucamine salt of the ytterbium (III) complex of diethylene-triamine-pentaacetic acid. 34. Diagnostic agent according to claims 1 and 2, characterized by a content of disodium salt w of the samarium (111) -Kompl ex es of diethylenetriamine-pentaacetic acid. 35. Diagnostic agent according to claims 1 and 2, characterized by a content of disodium salt of the gadolinium (III) complex of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18, 21,24-pentaazapentatriacontanedioic acid. / L - 9 - 36. Diagnostic agent according to claim 1 to 35, characterized in that it contains 1 μΜοΙ to 1 mole of complex salt per liter. £ t i 37. Method of making the diagnostic agent! according to claims 1 to 36, characterized in that the complex salt, dissolved or suspended in water or physiological salt solution, is brought into a form suitable for intravascular or oral application with the additives customary in galenics. i! 4; 38. complex salts of the general formula I l X-CH_ CH_-X V-CHR ^ ^ CHR1-V wherein X, A, V and R ^ have the meaning given in claim 2, with the proviso that they have 3 to 12 1 substituents Y contain, of which at least J - two a metal ion equivalent of an element of! * Atomic numbers 21 to 29, 42, 44 or 57 to 83 ^ and in addition at least one of the substituents Y] _ is the physiologically acceptable cation of an organic base or amino acid, the optionally remaining substituents Y being hydrogen atoms or cations of an inorganic base represent. \ 39. N-methylglucamine salt of the gadolinium (III) complex> of ethylenediamine-tetraacetic acid. « 40. Di-N-methylglucamine salt of the gadolinium (III) complex "" complex of diethylenetriamine-pentaacetic acid. - 10 - 3 '41. Di-N-methylglucamine salt of the iron (III) complex of diethylenetriaminepentaacetic acid. $ j t 42. Di-N-methylglucamine salt of the manganese (II) complex | of ethylenediamine tetraacetic acid. 3 -i 43. Disodium salt of the gadolinium (III) complex of diethylenetriamine-pentaacetic acid. ^ 44. Tri-N-methylglucamine salt of the manganese (II) complex & diethylenetriamine-pentaacetic acid. k i i I 45. N-methylglucamine salt of the dysprosium (III) complex g j of ethylenediamine-tetraacetic acid. i 3 î Ά % ^ 46. Di-N-methylglucamine salt of the holmium (III) complex ÿ of diethylenetriamine-pentaacetic acid. ** - 3 * tyi? -3 * 47. Di-lysine salt of the gadolinium (III) complex of -Vl | j diethylenetriamine-pentaacetic acid. • J 4 rs 48. Di-N-methylglucamine salt of the manganese (II) complex j of trans-1,2-cyclohexylene tetraacetic acid. Ί 3 49. Di-N-methylglucamine salt of the bismuth (III) complex of diethylenetriaminepentaacetic acid. - A - 11 - 50. Disodium salt of the ytterbium (III) complex of diethylenetrianiin-pentaacetic acid. # J «51. N-Methylglucamine salt of the gadolinium (III) complex of 1.4.7.10-tetraazacyclododecane-tetraacetic acid. 52. N-methylglucamine-sodium mixed salt of the gadolinium (III) complex of diethylenetriaminepentaacetic acid. 53. Diagnostic agent containing at least one physiologically compatible complex salt of the general formula I according to claim 2, with the exception of agents intended for use in NMR diagnostics, which contain 5 to 250 mmol per liter of a neutral N-methylglucamine 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 a neutral lysine * salt of gadolinium (III) complex of diethylene- «triamine-pentaacetic acid, or a neutral sodium or morpholine salt of the manganese (II) complex of ethylenediaminetetraacetic acid, or a neutral diethanolamine salt of the copper (II) complex or • vt. L cobalt (II) complex of ethylenediamine-tetraacetic. contain acid. wjjjo. »