Diagnostic agent, manufacture and complex salt

(54) DIAGNOSTIC AGENT (57) Described and claimed is a diagnostic agent comprising at least one physiologically acceptable complex salt of 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 58 to 70 and optionally one or more physiologically acceptable cation (s) of an inorganic and / or organic base or amino acid, optionally with the additives customary in galenicals, dissolved or suspended in an aqueous medium, for use in NMR diagnosis. Further described and claimed is a diagnostic agent, containing at least one physiologically acceptable complex salt of the anion of a complexing acid and one or more central ion (s) of an element of atomic numbers 57 to 83 - excluding a physiologically acceptable complex salt of the anion of EthylendiCQ amintetramethylenephosphonic or Diethylenpentamethylenphosphonsäure and one or more central ion (s) one Elements of atomic numbers 72 and 73 and optionally one or more physiological harmless 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, for use in X-ray diagnostics.

AT 397 465 nressrasis

AT397 465 B

The invention relates to diagnostic agents for use in NMR and X-ray diagnostics. Complexes or their salts have long been used in medicine, such. B. as an aid to

The administration of poorly soluble ions (eg iron) and as antidotes (in which case calcium or zinc complexes are preferred) for the detoxification in the case of the accidental incorporation of heavy metals or their radioactive isotopes.

US Pat. No. 4,176,173 also discloses various hafnium and tantalum phosphonic acid complexes which are described as radiographic contrast agents exclusively for oral administration.

In contrast, the present invention aims to provide diagnostic agents intended especially for parenteral administration. In addition, it should be noted that the requirements for a contrast agent for NMR diagnosis are completely different than for an X-ray contrast medium.

The prerequisite for the suitability of a substance as an X-ray contrast agent is its ability to increase density differences between the organ to be delivered and the surrounding tissue, ie its stronger (eg, BaSO 4) or weaker (eg, air) absorption of X-rays in comparison to the body tissue. The utility of an element as an X-ray contrast agent depends essentially on the size of its mass absorption coefficient in the diagnostic radiation region (and of course its chemical-toxicological and pharmaceutical properties).

By contrast, NMR or Kemspin tomography is based on the physical effect of nuclear magnetic resonance (NMR). This diagnostic method makes it possible to obtain sectional images of the living body and insight into metabolic processes without the use of ionizing radiation, as in X-ray diagnostics. The effect of nuclear resonance is shown by atomic nuclei, which - like hydrogen, which is mainly present in the biological tissue as water - have a magnetic moment and thereby align themselves in a strong external magnetic field. By a high-frequency pulse (resonance frequency) they are brought out of their equilibrium position, in which they return at a characteristic speed again. The duration of the return to the equilibrium state, the so-called relaxation time, provides information about the degree of order of the atoms and their interaction with their environment.

The visual representation obtained by measuring the proton density or the relaxation times is of high diagnostic value and provides information about the water content and the state of the examined tissue. For example, tumor tissue exhibits longer relaxation times than healthy comparison tissue.

It has now been found that physiologically acceptable complex salts of the anion of a complex-forming acid and one or more central ion (s) of an element of atomic numbers 21 to 29,42,44 or 58 bis

70 and optionally one or more physiologically acceptable cation (s) of an inorganic and / or organic base or amino acid surprisingly excellent for the preparation of diagnostic agents for use in NMR diagnosis are suitable.

An object of the invention are thus diagnostic agents containing at least one physiologically acceptable complex salt of the anion of a complex-forming acid and one or more central ion (s) of an element of atomic numbers 21 to 29,42,44 or 58 to 70 and optionally one or more physiological harmless cation (s) of an inorganic and / or organic base or amino acid, optionally with the additives customary in galenics, dissolved or suspended in aqueous medium for use in NMR diagnosis.

The element of the abovementioned atomic number, which forms the central ion (s) of the physiologically tolerable complex salt, may be used for the intended use of the diagnostic agent according to the invention

By means of course not be radioactive.

In the agent of the present invention intended for use in NMR diagnosis (see European Patent Application 71564), 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, 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), neodymium (III), samarium (III) and ytterbium (III) ions. Because of their very strong magnetic moment, the gadolinium (III), terbium (III), dysprosium (III), holmium (m) and erbium (III) ions are particularly preferred.

Another object of the invention are diagnostic means, containing at least one physiologically acceptable complex salt of the anion of a complexing acid and one or more central ion (s) of an element of atomic numbers 57 to 83 - excluding a physiologically acceptable complex salt of the anion of ethylenediaminetetramethylphosphohydric acid or diethylpentamethylphosphonic acid and one or more central ion (s) of an element the atomic numbers 72 and 73 - and optionally one or more physiologically harmless Cation (s) of an inorganic and / or organic base or amino acid, optionally with the additives customary in galenicals, dissolved or suspended in an aqueous medium, for use in X-ray diagnostics.

In the present invention, intended for use in X-ray diagnostics means the central ion must be derived from a higher atomic number element to sufficient absorption of X-rays

-2AT397 465B. It has been found that for this purpose diagnostic agents containing a physiologically acceptable complex salt with central ions of elements of atomic numbers between 57 and 83 are suitable; these are, for example, the lanthanum (IU) ion, the abovementioned ions of the lanthanide series, the gold (m) ion, the lead (H) ion or, in particular, the bismuth (IH) ion.

Suitable complex-forming acids are those which are customarily used for complex formation of the abovementioned central ions. Suitable complex-forming acids are, for example, those containing 3 to 12, preferably 3 to 8, methylenephosphonic acid groups, methylenecarbohydroxamic acid groups, carboxyethylidene groups or, in particular, carboxymethylene groups, one of each of which , two or three are attached to a nitrogen atom supporting the complex formation. If three of the acidic groups are bonded to a nitrogen atom, then the complexing acids underlying the complex salts of the general formula Π according to claim 2 or 4 are present. If in each case only one or two of the acidic groups are bonded to one nitrogen atom, then the nitrogen is bonded to another nitrogen atom via an optionally substituted ethylene or via up to four ethylene units which are each separated by a complex forming nitrogen or oxygen or sulfur atom. Preferred complexing acids of this type are those of the general formula 1 according to claims 2 and 4, respectively.

The complexing acids can be linked from conjugates to biomolecules which are known to be particularly rich 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. Particularly noteworthy are conjugates with albumins, such as human serum albumin, antibodies, such as monoclonal for tumor-associated antigens specific antibodies or antimyosin. The diagnostic agents formed therefrom are suitable, for example, for use in tumor and infarct diagnostics. For example, conjugates or inclusion compounds with liposomes which are used, for example, as unilamellar or multilamellar phosphatidylcholine-cholesterol vesicles are suitable for liver studies. The conjugate formation takes place either via a carboxyl group of the complex-forming acid or, in the case of the proteins or peptides, via a (CH₂)_p-C₆H₄-W group, as defined in claim 2 or 4. In the conjugate formation of the complex-forming acids with proteins, peptides or lipids, in some cases several acid residues can be bound to the macromolecular biomolecule. In this case, any complex-forming acid residue can carry a central ion. If the complex-forming acids are not bound to biomolecules, they optionally carry two central ions, in particular a central ion.

Suitable complex salts of the general formula I according to claim 2 or 4 are, for example, those of the general formula

X-CH

B.C ^x A.D₀CHR, -N

3 \

CH - XZ ² (Ia)

CHR ^ -V wherein X, V, R j, R₂, and Rß have the meaning given in claim 2 or 4.

For the preparation of the complex salts of general formula Ia, inter alia the following complex-forming acids are suitable: ethylenediaminetetraacetic acid, ethylenediaminetetraacethydroxamic acid, trans-1,2-cyclohexylenediaminetetraacetic acid, DL-2,3-butylenediaminetetraacetic acid, DL-1,2-butylenediaminetetraacetic acid, Dl-1,2-propylenediaminetetraacetic acid, 1,2-diphenylethylenediaminetetraacetic acid, ethylenedinitrilotetrakis (methanephosphonic acid) and the N- (2-hydroxyethyl) ethylenediamine triacetic acid.

Further suitable complex salts of the general formula I according to claim 2 or 4 are, for example, those of the general formula Ib

<img file="AT397465B_D0001.tif" />

V-CHR ^

<img file="AT397465B_D0002.tif" />

CHR₁-V

Where X, V, Z, Rj and m are as defined in claims 2 and 4, respectively. If Z represents an oxygen atom or a sulfur atom, complex salts with m in the meaning of 1 or 2 are preferred

For the preparation of the complex salts of the general formula Ib are, inter alia, the following complex-forming acids; the diethylenetriaminepentaacetic acid, the triethylenetetraminehexaacetic acid, the tetraethylenepentamine heptacetic acid, the 3,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-penta-azapentatriacontanedioic acid, the 3,9-bis (l- carboxyethyl) -3,6,9-triazaundecanedioic acid, the diethylenetriaminepentakis- (methylenephosphonic acid), the l, 10-diaza-4,7-dioxadecane-1,11,10,10-tetraacetic acid and the 1,10-diaza-4,7-dithiadecan-1 , l, 10,10tetraessigsäure.

Suitable complex salts of the general formula I according to claim 2 or 4 are also those of the general formula lc

X-CH

<img file="AT397465B_D0003.tif" />

X-CH n-ch₂ch₂-n

<img file="AT397465B_D0004.tif" />

CH, ι 2

<img file="AT397465B_D0005.tif" />

N-CH, -CH, -NZ ^{2 2} \ ch₂-x (lc), wherein X and w have the meaning given in claim 2 or 4, respectively.

Inter alia, the following complex-forming acids are suitable for preparing the complex salts of the general formula Ic: 1,4,8,11-tetraazacyclotetradecane tetraacetic acid and in particular 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 1,33-tris [bis (carboxymethyl) amino] propane and the nitrilotris (ethylenenitrilo) hexaacetic acid. As an example of a complex-forming acid for the preparation of complex salts of the general formula Π may be mentioned nitrilotriacetic acid.

If not all of the acidic hydrogen atoms of the complexing acid are substituted by the central ion or central ions, it is desirable to increase the solubility of the complex salt to substitute the remaining hydrogen atoms with physiologically acceptable cations of inorganic and / or organic bases or amino acids. Suitable inorganic cations are, for example, the lithium ion, the potassium ion or, in particular, the sodium ion. Suitable cations of organic bases include those of primary, secondary or tertiary amines, such as ethanolamine, diethanolamine, morpholine, glucamine, Ν, ΝDimethylglucamin or especially 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 preparation of the 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-pentaazapentatriacontane diacid is carried out in an improvement to that of R. A. Bulman et al. in natural sciences 68,09811483 proposed way:

17.85 g (= 50 mmol) of l, 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- Aminoundecanoic 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. This precipitates an almost white voluminous solid, which is filtered off with suction and washed several times with water. The product obtained is added for further purification in 200 ml of acetone and stirred for 30 minutes at room temperature. After vacuuming and drying in vacuo at 50 ° C to obtain 36.9 g (= 97% of theory) of a white powder of melting point 134 -138 ° C.

The conjugation of complex-forming acids with biomolecules is also carried out by methods known per se, for example by reaction of nucleophilic groups of the biomolecule - such as amino, hydroxy, thio or imidazole groups with an activated derivative of the complexing acid.

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

For conjugation with proteins, there are also substituents of the structure -CgH₄N2⁺ or Cg ^ NHCOC ^ halogen.

-4AT397465B

The preparation of the complex salts is also known in part or can be done in a known manner by reacting 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 in water and / or a lower alcohol (such as methanol, Ethanol or isopropanol) is dissolved or suspended and added to 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 When the complex salt formed in the used Solvent is insoluble, it is isolated by filtration. If it is soluble, it can be isolated by evaporating the solution to dryness, for example by spray drying.

If azide groups are present in the resulting complex salt, it is often expedient to convert the acidic complex salt into neutral complex salts by means of inorganic and / or organic bases or amino acids which form physiologically acceptable cations and to isolate them. In many cases, this is even inevitable, since the dissociation of the complex salt is pushed back so far by the shift of the pH to the neutral, so that in the first instance the isolation of uniform products or at least their purification is made possible.

Conveniently, the preparation is carried out using organic bases or basic amino acids. It may also be advantageous to carry out the neutralization by means of inorganic bases (hydroxides, carbonates or bicarbonates) of sodium, potassium or lithium.

To produce the neutral salts, it is possible to add, for example, to the acidic complex salts in aqueous solution or suspension, so much of the desired base that the neutral point is reached. The resulting solution can then be concentrated to dryness in vacuo. Often it is advantageous, the neutral salts formed by the addition of water-miscible solvents, such as lower alcohols (methanol, ethanol, isopropanol, etc.), lower ketones (acetone, etc.), polar ethers (tetrahydrofuran, dioxane, 1.2-dimethoxyethane etc.) to precipitate and so easy to isolate and easy to clean crystals. It has proven 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.

If the acidic complex salts contain several free acid groups, it is often expedient 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 central ion supplying element and half of the amount required for neutralization of an organic base, isolated the complex salt formed, purifying it if desired and then to complete Neutralization with the required amount of inorganic base added The order of base addition can also be reversed.

The preparation of the diagnostic agents according to the invention is likewise carried out in a manner known per se by suspending or dissolving the complex salts, optionally with the addition of additives customary in galenicals, in an aqueous medium and then sterilizing the solution or suspension. Suitable additives are, for example, physiologically acceptable buffers (such as for example Example tromethamine hydrochloride), minor additions of complexing agents (such as Diethylenetriamine-penta-acetic acid) or, if necessary, electrolytes (such as sodium chloride).

In principle, it is also possible to prepare the diagnostic agents of the invention without isolation of the complex salts. In any case, special care must be taken to make the chelation so that the salts and salt solutions according to the invention are practically free of uncomplexed toxic metal ions. This can be ensured for example by means of color indicators such as xylenol orange by control titrations during the manufacturing process. The invention therefore also relates to processes for the preparation of the complex compound and its salts. As final security remains a purification of the isolated complex salt.

If suspensions of the complex salts in water or physiological saline are desired for oral administration or other purposes, a sparingly soluble complex salt is mixed with one or more adjuvants and / or surfactants and / or flavors customary in galenicals for taste correction.

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

The compositions of the invention meet the diverse requirements for suitability as a contrast agent for magnetic resonance imaging. Thus, they are ideally suited to improve the image obtained by means of the Kemspintomograph after oral or parenteral administration by increasing the signal intensity in its validity. Furthermore, they demonstrate the high potency needed to load the body with the least possible amounts of foreign matter and the good compatibility needed to maintain the non-invasive character of the assay (described in J. Comput. Tomography 5 , 6: 543-46 (1981), in Radiology 144, 343 (1982) and in Brevet Special de Medicament No. 484 M (1960)

-5AT397 465B, for example, too toxic). The good water solubility of the compositions according to the invention makes it possible to produce highly concentrated solutions to keep the volume load of the circuit within reasonable limits and to compensate for dilution by the body fluid, ie NMR diagnostic agents must be 100 to 1000 times better water soluble than for NMR spectroscopy , Furthermore, the compositions of the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that a release or replacement of non-covalently bound in the complexes per se toxic ions within 24 hours, in which - as pharmacological Investigations have shown that the new contrast media are completely excreted again, Only extremely slow The conjugates with proteins and antibodies used for example for tumor diagnostics cause already in such low dosage a surprisingly high signal amplification that solutions of correspondingly low concentration can be used here.

The compositions according to the invention are outstandingly suitable as X-ray contrast media, wherein it should be emphasized that no signs of the anaphylactic reactions known from the iodine-containing contrast agents can be detected in biochemical-pharmacological investigations. They are particularly valuable because of the favorable absorption properties in areas of higher tube voltages for digital subtraction techniques.

In contrast to conventional X-ray diagnostics with shadowing X-ray contrast agents, there is no linear dependence of the signal amplification on the applied concentration in the NMR diagnosis with paramagnetic contrast agents. As control studies show, an increase in the applied dose does not necessarily lead to a signal enhancement, and a high dose of paramagnetic contrast agent may even lead to an extinction of the signal. For this reason, it was surprising that some pathological processes become visible only after application of higher doses (which may be from 0.001 mmol / kg to 5 mmol / kg) than in EP 71564 of a strongly paramagnetic contrast agent of the invention. So z. B. the detection of a defective blood-brain barrier in the region of a cranial abscess after administration of 0.05 - 22 mmol / kg, preferably 0.1 - 0.5 mmol / kg of paramagnetic complex salts such. B. Gadolinium-diethylenetriaminepentaacetic acid or manganese-1,2-cyclohexy lendiamino-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, since only so the volume load is reduced and the handling of the injection solution is ensured.

Particularly low dosages (less than 1 mg / kg) and thus lower concentrated solutions (1 pmol / l to 5 mmol / Ι) than those specified in EP 71564, for the organ-specific NMR diagnosis z. As required for the detection of tumors and heart attacks The following embodiments serve to further illustrate the invention.

example 1

Preparation of the gadolinium III complex of nitrilo-N, N-triacetic acid, CgHgGdNO ^

The suspension of 36.2 g (= 100 mmol) of gadolinium oxide (0020 ^) and 38.2 g (= 200 mmol) of nitrilotriacetic acid in 12 liters of water is heated with stirring to 90 ° C to 100 ° C and stirred for 48 hours at this temperature Then it is filtered through activated carbon from the undissolved and the filtrate is evaporated to dryness. The amorphous. The residue is pulverized.

Yield: 60 g; (87% of theory)

Fp.:300°C

Gadolinium: calculated 45.5%, found 44.9%.

The iron-Iü complex of nitrilo-Ν, Ν JQ-triacetic acid is obtained with the aid of iron (III) chloride, FeCl 2.

Example 2

Preparation of the di-sodium salt of the gadolinium-HI complex of 13,23-dioxo-l 5,18,21-tris-carboxvmethvl) 12,15,18,21,24-pentaazapentatriacontan-diacid. C ^ gH ^ gGaNgO ^ * 2 Na

15.2 g (= 20 mmol) of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-pentaazapentatriacontane diacid 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 for 2 hours at this temperature and then added to neutralize the resulting hydrochloric acid with 60 ml of 1N sodium hydroxide solution

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

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

-6AT397465B

Analysis:

(Ber.) C 47.30 (Gef.) C 47.13

H6,84

H6.83

N7.66

N7,60

Gd 17.20 Gd 17.06

14.6 g (= 16 mmol) of the gadolinium III complex thus obtained are suspended in 200 ml of water and treated dropwise with 31.4 ml of 1N sodium hydroxide solution. After 1 hour, a clear solution is obtained, which is filtered and then concentrated in vacuo becomes. After drying in vacuo at 80 ° C., 13.2 g (87% of theory) of a readily water-soluble white powder of melting point 279-285 ° C. are obtained.

Analysis:

(Ber.) C 45.13 H6.31 N7.31 Gd 16.41 Na 4.80 (Gef.) C 4530 H6.12 N7.28 Gdl636 Na 4.75

Similarly, with N-methylglucamine instead of caustic soda, the di-N-methylglucamine salt of the gadolinium III complex of the 1333-dioxo-15,1831-tris (carboxymethyl) -12,15,183,134-pentaazethylenetramiccanedioic acid, C ^ QH ^ gGdNyC ^ received.

gäafeiJ

HerstellungdesDi-Natriumsa] zesdesGadolinium IH Komplexesder3.9-bis (l-cart> oxvethvl) -6-cart> oxvmethvl3.6.9-triazaundecanedioic. CigHonGdNgOjQ · 2 Na

363 g (= 0.1 mol) of gadolinium III-oxide and 84.2 g (= 0.2 mol) of 3,9-bis (1-carboxyethyl) -6-carboxymethyl-3,6,9triaza undecanedioic acid are dissolved in 250 1 ml of water and heated to reflux for 1 hour. It is filtered off from a little undissolved and the solution is concentrated to dryness in vacuo. The residue is pulverized and dried in vacuo at 60 ° C to give 112.8 g (= 98% of theory) of the chelate as a white powder.

Analysis: CjgH ^ GdNoOjQ (Ber.) C 33.39 H4.20 Gd 27.32 N7.30 (Gef.) C 3335 H4.49 Gd 27.42 N7.21

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 is adjusted in the solution to a pH 7.5, the solution is heated to boiling and added dropwise until permanent turbidity of ethanol. After several hours of stirring in an ice bath, the crystals are filtered off with suction, washed with ethanol and dried in vacuo. One receives in quantitative yield the di-

<td colspan="2">Sodium salt as a white powder.</td><td></td><td></td>

<td>Analysis: (Ber.) C 31.02</td><td>H3,58</td><td>Gd 25:38</td><td>N6,78</td>

<td>(Gef.) C 31,10</td><td>H3,71</td><td>Gd 25,50</td><td>N6,61</td>

<td>Example 4</td><td></td><td></td><td></td>

Preparation of the di-morpholine salt of the gadolinium III complex of 3,9-bis- (1-carboxvethvl) -6-carboxy-methvl-3,6,9-triazaundecanedioic acid, Co / jH ^ nGdNgOjn

17.4 g (= 03 mol) of morpholine are dissolved in 50 ml of water. 42.1 g (= 0.1 mol) of 3,9-bis (1-carboxyethyl) -6-carboxymethyl-3,6,9- triazaundecanedioic acid and thereupon 183 (= 0.05 mol) of gadolinium III-oxide and keeps refluxing until clear solution has occurred. Then it is added dropwise to the remaining turbidity acetone. After several hours of stirring in an ice bath, the crystals are filtered off with suction, 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 H5.65 Gd 20.97 N9.34 (Gef.) C 38.31 H5.72 Gd 20.76 N9.32

Example 5

Preparation of the di-N-methyl glucamine salt of the gadolinium III complex of diethylenetriamine NKN^,N¹JTpentaessigsäprc, ^ 28 ^ 54-9 ^ 5 ^ 20

393 g (= 100 mmol) of diethylenetriamine-N, Ν, Ν ', N, N-penta-acetic acid are suspended in 200 ml of water and treated with 19.5 g (= 100 mmol) of N-methylglucamine. Subsequently, 18.12 g (= 50 mmol) of gadolinium III oxide, Gd20ß, added in portions and the resulting suspension is heated to 95 'C. After about 1 hour staggered

-7AT397465B with another 19.5 g (= 100 mmol) of N-methylglucamine and obtained after a further 2 hours of heating a clear solution. After complete reaction (control with xylenol orange) is filtered from a little undissolved and the filtrate concentrated to dryness in vacuo. The residue is redissolved in 100 ml of water and stirred in 250 ml of ethanol After several hours of cooling, the crystals are filtered off with suction, washed with cold ethanol and it is dried at 60 ° C in a vacuum. This gives 92.7 g (99% of theory) of a white powder with a characteristic melting point

Analysis:

(Calc.) C 35.85 H 5.80 N 7.47 Gd 16.77 (Gef.) C 35.50 H 5.72 N 7.20 Gd 16.54

For the purification of the complex salt, acetone, propanol or isopropanol can also be used instead of ethanol. The following are obtained:

With dysprosium HI oxide, Dy₂O2

Di-N-methylglucamine salt of the dysprosium-HI complex of diethylenetriamine-N, N, N^,, N, N-pentaacetic acid, ^C28^H54^Dy^N5°20^: with lanthanum-ni-oxide, La₂O₃

Di-N-methylglucamine salt of the lanthanum-UI complex of diethylenetriamine-N, N, N^,, N, N-pentaacetic acid, ^c28^H54^LaN5°20^; with ytterbium HI oxide, Yb₂O₃

Di-N-methylglucamine salt of ytterbium III complex of diethylenetriamine-N, N, N ', N, N-pentaacetic acid, ^ 28 ^ 54 ^^ 5θ20^; with samarium-III-oxide, Sn ^ Oj

The di-N-methylglucamine salt of the samarium III complex of diethylenetriamine-N, N, J, X'-pentaacetic acid, ^ '^ ^ 54 ^^π1^ 5θ20 'with holmium oil oxide, Ho₂O₃

Di-N-methylglucamine salt of the holmium III complex of diethylenetriamine-NJSf, N ', N, N "-pentaacetic acid, C28H54HON5O2Q;

with bismuth-HI-oxide, Bi₂O₃

Di-N-methylglucamine salt of the bismuth III complex of diethylenetriamine-N, N, N ', N, N-pentaacetic acid, ^C28^H54^BiN5^O20^; with gadolinium III oxide, Gd₂O₃

Tri-N-methylglucamine salt of the gadolinium III complex of the triethylenetetramine-N, N, N^,, N, N '' N'-hexaacetic acid, Ο₃^ Ηγ8θάΝγΟ₂γ

Furthermore you get:

with holmium HI oxide, Ho₂O₃ and ethanolamine instead of N-methylglucamine

Di-ethanolamine salt of the holmium III complex of diethylenetriamine-N, N, N ', N, N-pentaacetic acid, ClgH ^ HoN ^ O ^; with gadolinium III oxide, Gd₂O₃ and lysine instead of N-methylglucamine

Di-lysine salt of the gadolinium III complex of diethylenetriamine-N, N, N ', N, N-pentaacetic acid, C ^ H ^ GdN-yO ^.

Using diethanolamine, the di-diethanolamine salt of holmium III complex of diethylenetriamine pentaacetic acid, (^ ϊ ^ ΗοΝ ^ Ο · ^.

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

Example 6

Preparation of the di-sodium salt of gadolinium-in-complex of diethylenetriamine-NNJ4^,Jⁱr'jN-pentaessigsäuie, C_HH_lgGdN₃Q₁₀ · 2 Na

183 g (= 0.05 mol) of gadolinium IÜ-oxide and 39.3 g (= 0.1 mol) of diethylenetriamine-penta-acetic acid are suspended in 110 ml of water and heated to reflux for 1 hour. The clear solution is cooled and added by adding approx 80 ml of 5 N sodium hydroxide solution brought to pH 7.5. The mixture is refluxed again and 250 ml of ethanol are added dropwise. After several hours of stirring in an ice bath, the crystals are filtered off with suction, washed with ice-cold ethanol and dried at 60 ° C in a vacuum. In quantitative yield, a white powder is obtained which does not melt to 300.degree

Analysis:

(Ber.) C 28.43 H3.07 N7.10 Gd 26.58

-8 (Gef.) C 28.35 H2.95

AT397465B N7.05 Gd 26.37

The following are obtained in a similar manner: with dysprosium-HI-oxide, Dy₂O₃

Di-sodium salt of the dysprosium III complex of diethylenetriamine-N, N, N ', N, N-pentaacetic acid; C₁₄H₁₈DyN₃O₁₀ · 2 Na;

with lanthanum-QI-oxide, La₂O₃

Di-sodium salt of the lanthanum III complex of diethylenetriamine-N, N, N ', N, N-pentaacetic acid; C j₄H jgLaNβOio · 2 Na;

with holium-III-oxide, Ηθ2θ₃

Di-sodium salt of the holmium III complex of diethylenetriamine-N, N, N^,, N, N-pentaacetic acid; cj₄HjgHoN₃OjQ · 2 Na;

with ytterbium III oxide, Yb ^

Di-sodium salt of the ytterbium-III complex of diethylenetriamine-N, N, N ', N, N-pentaacetic acid; C₁₄H,₈YbN₃O_1(|-2Na;

with samarium III oxide, Sm2O₃

Di-sodium salt of the samarium III complex of diethylenetriamine-N, N, N ', N, N-pentaacetic acid; cj₄H jgSmN₃OjQ · 2 Na;

with erbium III oxide, Er2O₃

Di-sodium salt of Erbium III complex of diethylenetriamine-N, N, N ', N, N-pentaacetic acid; cj₄H jgEbN₃O jq · 2 Na;

with gadolinium III oxide, Gd2O₃

Sodium salt of the di-gadolinium-III complex of tetraethylenepentamine-NJiJ ^^,J4^,,, N '; N, N heptaacetic acid; (^ Ηβοθί ^ Ν ^ Ο ^ · Na.

These salts occur as a white powder with an uncharacteristic melting point and are very soluble in water.

Example 7

Preparation of the N-methylglucamine salt of the iron III complex of diethylenetriaminepentaacetic acid, £₂lS₃7F ^ 4Qj5

35.40 g (= 90 mmol) of diethylenetriaminepentaacetic acid are suspended in 100 ml of water and treated with 24.3 g (= .90 mmol) of iron (III) chloride hexahydrate (FeCl₃ · 6 H2O) dissolved in 100 ml of water. The initially dark brown suspension is heated to 95 ° C After about 1 hour, the color changes to pale yellow. 270 ml of 1N sodium hydroxide solution are added to neutralize the resulting hydrochloric acid and the mixture is heated at 95.degree. C. for a further 3 hours. The resulting pale yellow precipitate is suction filtered washed with water chloride-free and dried in vacuo at 60 ° C. This gives 17.85 g (45% of theory) of a light yellow powder whose melting point is> 300 ° C.

17.85 g (= 40 mmol) of the resulting iron (III) complex are suspended in 200 ml of water and treated portionwise with 7.8 g (= 40 mmol) of N-methylglucamine, solid. The mixture is heated for about 3 hours at 50 ° C and receives an almost clear, red-brown solution, which is filtered and then concentrated in vacuo to dryness. The residue is dried at 50 ° C in vacuo to give 24.3 g (95% of theory) of a red-brown powder of melting point 131 -133 ° C.

Analysis:

(Calc.) C 39.82 H 5.89 N 8.85 Fe 8.81 (Gef.) C 39.70 H 6.00 N 8.65 Fe 9.01

With sodium hydroxide solution instead of the organic base are obtained:

Sodium salt of the iron-HI complex of ethylenediaminetetraacetic acid, C jqHΐ2 ^^ε^ 2θ8 '

Sodium salt of the iron III complex of trans-l, 2-cyclohexylenediamine tetraacetic acid,

C 14 ^ 18 ^^ 0 ^ * Na

Di-sodium salt of the iron (III) complex of diethylenetrinitrilo-penta (methanephosphonic acid), ^ 9 ^ 23 ^ * ^ ^ 3θ15 ^^>5 * N / A

Sodium salt of the iron III complex of l, 10-diaza-4,7-dioxadecane-1,11,10,10-tetraacetic acid, C j₄H2qFeN2O jq · Na

Sodium salt of the iron (III) complex of ethylenediaminetetraacethydroxamic acid, C ^ H ^ FeNgOg · Na.

In a similar manner, with N-methylglucamine are obtained:

Di-N-methylglucamine salt of the iron III complex of diethylenetriamine-N, N, N ', N, N-pentaacetic acid, ^C28^H54^FeN5°20

N-methylglucamine salt of the iron III complex of trans-1,2-cyclohexylenediamine-NJVX JT-tetraacetic acid;

-9AT397465B

C ^ ^ iHßgFeNßO

N-MethylglucaminsalzdesEisen IH KomplexesderEthylendiamin-NJsf ^ '^ JSF tetraessigsäure.Cj HßQFeNßOjß

Tri-N-MethylglucaminsalzdesEisen III KomplexesderTriethylentetramin-N, N, N ', N' ', N', N'-hexaacetic acid, ^C39^H78^FeN7 ° 27Using diethanolamine instead of N-methylglucamine, the

Di-diethanolamine salt of the iron III complex of diethylenetriamine-N, N, N, N, N^,! -pentaacetic acid, Ρ22 ^ 42 ^^ε1^ 5θ14 ^receive·

Example 8

Preparation of the N-methyllglucamine salt of the gadolinium III complex of trans-1,2-cyclohexanediaminoNKK-tetraacetic acid. C21^H36^GdN3°13

20.78 g (= 60 mmol) of trans-1, 2-cyclohexylenediamine-N, N, N ', N'-tetraacetic acid are suspended in 150 ml of water. After addition of 11.7 g (= 60 mmol) of N-methylglucamine gives an almost clear solution, to which 10.88 g (= 30 mmol) of gadolinium oxide (Gd20ß) are added. The resuspended suspension is heated to 95 ° C for 6 hours. It is filtered from a little undissolved and the filtrate is concentrated to dryness. The residue is dried in vacuo at 60 ° C. and pulverized. 38.6 g (92% of theory) of a white powder of melting point 258.degree.-261.degree. C. are obtained.

Analysis:

(Ber.) C 36.25 H5.22 N6.04 Gd 22.60 (Gef.) C 36.40 H 5.50 N 5.98 Gd 22.52

In the same way, with sodium hydroxide solution instead of N-methylglucamine, the sodium salt of the gadolinium-ΠΙ complex of trans-1,2-cyclohexylenediamine-N, N, Ν ', Ν'-tetraacetic acid, C ^ HjgGtB ^ Og · Na obtained.

With freshly precipitated chromium-III-hydroxide, Cr (OH) ß, the sodium salt of the chromium-in complex of ethylenediamine-Ν, Ν, Ν ', Ν'-tetraacetic acid, C ^ H ^ Cr ^ Og · Na obtained.

Example 9

Preparation of the di-sodium salt of the manganese-U complex of trans-1,2-cyclohexenediamine-NJNJ9'tetraacetic acid. C ^ HjoMnNoOo «2 Na

34.6 g (= 100 mmol) of trans-1,2-cyclohexylenediamine-N, N JST, Ν'-tetraacetic acid are suspended under nitrogen in 100 ml of water and with 11.5 g (= 100 mmol) of manganese-O-carbonate MnCO-j, heated to 95 ° C and added dropwise 200 ml of 1N sodium hydroxide solution. The clear solution is concentrated in vacuo and the residue dried at 60 ° C in vacuo to give 40.8 g (92% of theory) of a pink powder.

Analysis:

(Calc.) C 37.94 H 4 .09 N 6 .32 Mn 12,40 (Gef.) C 37,78 H 4,12 N 6,20 Mn 12,31

In a corresponding manner are obtained:

From copper ω-carbonate the di-sodium salt of the copper---complex of trans-1,2-cyclohexy-lendiaminetetraacetic acid, C j gCu ^ Og · 2 Na;

from cobalt-II-carbonate the di-sodium salt of the cobalt II complex of trans-12-cyclohexylenediaminetetraacetic acid, C ^ H jgCo ^ Og · 2 Na;

from nickel (II) carbonate the di-sodium salt of the nickel II complex of trans-1,2-cyclohexylenediaminetetraacetic acid, C ^ HjgNi ^ Og · 2 Na.

With N-methylglucamine instead of sodium hydroxide solution are obtained:

Di-N-methylglucamine salt of the manganese-II complex of trans-1,2-cyclohexylenediamine tetraacetic acid, ° 28^Η54^ΜηΝ4°18^;

Di-N-methylglucamine salt of the manganese II complex of DL-2,3-butylenediamine tetraacetic acid, ^ 26 ^ 52 ^^η^ 4θ8 '

Di-N-methylglucamine salt of the manganese-II complex of ethylenediamine-N, N, N ', N'-tetraacetic acid, (^ 24 ^ 48 ^^η^ 4θ8;

Di-N-methylglucamine salt of manganese II complex of DL-l, 2-butylenediamine-N, N, N¹, N¹tetraacetic acid, ^C26^{H <}52^{> MnN}4°8^;

Di-N-methylglucamine salt of the manganese II complex of DL-l, 2-propylenediamine-N, N, N ', N'-tetraacetic acid, ^C25^H50^MnN4°8^;

-10AT397465B

Tri-N-MethylglucaminsalzdesMangan II KomplexesderDiethylentriamin pentaacetic acid, C₃5H72 ^ⁿ^ 6®25 'with nickel-ot-carbonate NiCO₃

Di-N-methylglucamine salt of the nickel II complex of ethylenediamine-N, N, N ', N'-tetraacetic acid, ^c24^H48^NiN4^Ol8^; with cobalt-II-carbonate, CoCO₃ and ethanolamine

Di-EthanoIaminsalzdesCobalt II KompIexesderEthylendiamiri-NJ'iJN'Ji'-tetraessigsäure.C ^ H ^ ^ CoN jQ; with copper ü-cafbonat, CuCO₃ and ethanolamine

Di-n-EthanolammsalzdesKupfer-KomplexesderEthylendiamin-NJ ^ N'-tetraacetic acid, C₁4H2gCuN4O₁0; with manganese---carbonate, MnCO₃ and diethanolamine

Tri-diethanolamine salt of manganese II complex of diethylenetriamine-N, N, N ', N, N-pentaacetic acid, ^C26^H54^MnN6°16^; with manganese (II) carbonate, MnCO3 and morpholine

Di-morpholine salt of the manganese II complex of ethylenediamine NN> NN^,'Tetraacetic acid, C | gH₃2MnN4O | Q.

Example 10

N-Methvlglucaminsalz the gadolinium III complex of Ethvlendiamin-NNN'.N'-tetraacetic acid.

29.2 g (= 100 mmol) of ethylenediamine-NN, N ', N'-tetraacetic acid are suspended in 100 ml of water and washed with

18.1 g (= 50 mmol) of gadolinium-ÜI-oxide, Gd2O₃, heated to 95 ° C. During heating, add portions

19.5 g (= 100 mmol) of N-methylglucamine added. After about 3 hours, a clear solution is obtained, which is filtered and concentrated in vacuo to dryness. The residue is dried in vacuo at 60 ° C. 61.3 g (95% of theory) of a white powder with an uncharacteristic melting point are obtained

Analysis:

(Ber.) C 31.82 H4.71 N6.55 Gd 24.51.

(Gef.) C 31.65 H4.59 N6.52 Gd 24.56

In an analogous manner are obtained:

With dysprosium III oxide, Dy2O₃

N-methylglucamine salt of the dysprosium III complex of ethylenediamine-N, N, N ', N'-tetraacetic acid, ^C17^H30^DyN3°13^:

N-methylglucamine salt of the gadolinium III complex of -I, 10-diaza-4,7-dioxadecane-1,11,10,10-tetraacetic acid, iHßgGdNßO ^;

N-methylglucamine salt of the gadolinium III complex of 1,2-diphenylethylenediamino-tetraacetic acid, ^C29^H38^N3°13^Gd; with lead-O-oxide, PbO and sodium hydrochloride

Di-sodium salt of the lead II complex of ethylenediaminetetraacetic acid, CjQH ^^ OgPb · 2 Na; with fresh precipitated chromium ID hydroxide, Cr (OH)₃

Sodium salt of the chromium ÜI complex of ethylenediaminetetraacetic acid, CjQH ^ Cr ^ Og · Na; and analog

Sodium salt of the gadolinium III complex of ethylenediamine tetraacetic hydroxamic acid, CjQHjgGdNgOg • Na;

Sodium salt of the gadolinium III complex of ethylenediamine-N.NN'N'-tetraacetic acid, CjoH ^ Gd ^ Og • Na.

Example 11

Preparation of the sodium salt of the gadolinium III complex of the 1.4.7.10-tetraazacvlododecane-NN'K'N'tetraessiesäure. C₁₆H_2/1GdN₄Qg_ · Well

4.0 g (= 10 mmol) of l, 4,7,10-tetraazacyclododecane-N, N ', N, N'-tetraacetic acid are suspended in 20 ml of water and treated with 10 ml of 1N sodium hydroxide solution. There are 1.8 g (= 5 mmol) of gadolinium III oxide, Gd2O₃, and the suspension is heated at 50 ° C for 2 hours. The clear solution is filtered and concentrated in vacuo. The residue is dried and pulverized. 5.5 g (95% of theory) of a white powder are obtained.

Analysis:

(Ber.) C 33.10 H4.17 N9.65 Gd 27.08 (Gef.) C 33.01 H4.20 N9.57 Gd 27.16

In the same way is obtained:

N-methylglucamine salt of the gadolinium III complex of 1,4,7,10-tetraazacyclododecane-N, N ', N, N'-11AT397465B tetraacetic acid, C ^ I ^ GdNgOiß

Sodium salt of the gadolinium-HI complex of 1,4,8,1-tetraazacyclotetradecane-NX JST'-tetraacetic acid, C_l8H28GdN₄O₈ · N / A.

Example 12

Preparation of the Tetra-N-Methvlglucaminsalzes of Gadolinium-IH complex of Ethvlendinitrilo-tetrakis (methanephosphonic acid). C ^ ^ HggGdN OßoPj

9.11 g (= 20 mmol) of ethylenedinitrilo-tetrakis (methanephosphonic acid) are suspended in 150 ml of water and adjusted to a pH of 5 with the appropriate amount of N-methylglucamine. Add 3.6 g (= 10 mmol) of gadolinium HI oxide, Gc ^ Og, and heat to 70 ° C. After about 1 hour, a clear solution is obtained, which is treated with the remaining portion of N-methylglucamine. A total of 15.6 g (= 80 mmol) N-methylglucamine consumed The solution is concentrated in vacuo to dryness and the remaining gelatinous residue in 200 ml of acetonitrile. The mixture is stirred for about 20 hours at 30 ° C and the resulting fine precipitate is filtered off with suction After drying in vacuo at 40 ° C to obtain 23.4 g (85% of theory) of a white powder of melting point 115 -118 ° C.

Analysis:

(Calc.) C 29.78 H6.25 N6.13 P9.04 Gd 11.47 (Gef.) C 29.85 H6.57 N5.98 P8.78 Gd 11.26

In the same way we get:

Hepta-N-methylglucamine salt of the gadolinium-HI complex of diethylenetriamine-NJ4 NN-penta (methanephosphonic acid), CjgH ^ GdNjQO ^ QP ^;

and using caustic soda instead of N-methylglucamine

Di-sodium salt of the gadolinium III complex of diethylenetrinitrilo-penta (methanephosphonic acid), CqH22GdN2O | 2f * 5 * 2 Na.

Example 13

Preparation of the di-sodium salt of the manganese-n-complex of ethylenedinitrilo-tetra (acethvdroxamic acid)

QiOHjgMnN ^ j ^ Na

230 g manganese n-carbonate and 7.05 g of ethylenedinitrilotetra (acethydroxamic acid) are refluxed in 18 ml of water for 3 hours. Then, by adding dilute sodium hydroxide solution to pH 7 and added dropwise 40 ml of acetone. After several hours of stirring in an ice bath, the precipitated crystals are filtered off with suction, washed with acetone and dried at 50 ° C in a vacuum. A dihydrate is obtained in quantitative yield as a white powder having a melting point above 300 ° C.

Mn: (Ber.) 11,30 (Gef.) 11,12

Example 14

Preparation of a mixed salt solution of the sodium and the N-methvlglucamine salt of the gadolinium HIKomplexes of Diethvlentriamin pentaacetic acid

a) Preparation of the mono-N-methvlglucamine salt of the complex. CNIH ^ GdN ^ O ^

195.2 g (1 mol) of N-methylglucamine are dissolved in 71% water. Then, 393.3 g (1 mol) of diethylenetriaminepentaacetic acid and 181.3 g (0.5 mol) of gadolinium oxide, Gd20-j, are added and heated to reflux for 2 hours. The filtered clear solution is spray-dried to give a white crystalline powder having a water content of 2.6%, which sinters at 133 ° C and melts at 190 ° C with foaming

Gd: (Ber.) 21,17 (Gef.) 21,34

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 * and added portionwise 40 g (= 1 mol) of caustic soda powder. The neutral solution is made up to 1000 ml with water pi, bottled through a pyrogen filter and heat sterilized. This 1 molar solution contains 753.8 g of mixed salt per liter.

- 12AT397465B 'Example 15

Preparation of a solution of the di-N-methylglucamine salt of the gadolinium III complex of diethylenetriaminepentaacetic acid

535.0 g (= 730 mmol) of the salt described in Example 5 are slurried in 500 ml of water pi and brought into solution by adding 142.4 g (= 730 mmol) of N-methylglucamine at pH 7.2 Then with water pi to 1000 ml, the solution filled into ampoules and heat sterilized.

Example 16

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

485.1 g (= 820 mmol) of the obtained in Example 6 di-sodium salt are suspended in 500 ml of water pi. Then it is made up to 1000 ml with water pi, the solution is filled into ampoules and heat-sterilized.

* pi = per injection

Example 17

Preparation of a solution of the di-sodium salt of the gadolinium III complex of 13,23-dioxo-15,18,21-tris (carboxvmethvl ') - 12,15,18,21,24-pentaazapentatriacontanedioic acid

392.0 g (= 400 mmol) of the salt described in Example 2 are slurried in 500 ml of water pi and dissolved by filling with water pi to 1000 ml with gentle heating. The solution is bottled and heat sterilized.

Example 18

HerstellungeinerLösungdesN-MethvlglucaminsalzesdesGadolinium III Komplexesderl.4.7.10-Tetraazacvclododecantetraessigsäure

370.9 g (= 500 mmol) of the salt listed in Example 11 are slurried in 500 ml of water pi and dissolved by filling with water pi to 1000 ml The solution is ampoelled and heat sterilized

Example 19

HeistellungeinerLösungdesDi-N-MethvlglucaminsalzesdesMangan-n-Komplexesdertrans-1.2-Cvclohexvlendiamintetraessigsäure

395.9 g (= 500 mmol) of the salt listed in Example 9 are suspended in 500 ml of water pi. 1.3 g of ascorbic acid are added and the mixture is brought to 1000 ml by adding water to 1000 ml. The solution is sterile filtered and filled into ampoules.

Example 20

Preparation of a solution of the tri-N-methylglucamine salt of the manganese-H-complex of diethylenetriamine-phosphite gatire

514.4 g (= 500 mmol) of the salt listed in Example 9 are suspended in 600 ml of water pi. 1.3 g of ascorbic acid are added and the mixture is dissolved by filling with water to 1000 ml. The sterile-filtered solution is filled into ampoules.

Example 21

Preparation of a solution of the di-N-methvlglucamine salt of the iron III complex of diethvlentriamine pentaacetic acid

44.6 g (= 0.1 mol) of the obtained in Example 7 iron III complex of diethylenetriamine pentaacetic acid are dissolved in 40 ml of water. i. suspended. After addition of 0.18 g Tromethamm hydrochloride and 39.1 g (= 03 mol) of N-methylglucamine is dissolved neutral, the solution with water pi made up to 100 ml, filled into vials and heat sterilized.

Example 22

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 III oxide are dissolved in 100 ml of water

pi dissolved under heating. The solution is ampullated and heat sterilized

Example 23

Preparation of a solution of the N-methvlglucamine salt of the gadolinium III complex of ethylenediaminetetraacetic acid

-13AT397 465B

38.52 g (= 60 mmol) of the substance described in Example 10 are dissolved in 70 ml of water pi After addition of 0.12 g of tromethamine is made up to 100 ml with water pi, the solution filled into ampoules and heat sterilized.

Example 24

Preparation of a solution of the di-N-methyl glucamine salt of the dvsprosium III complex of diethylenetriaminepentaacetic acid

35.7 g (= 60 mmol) of the dysprosium III complex of diethylenetriamine pentaacetic acid (water content 8.0%) are suspended in 70 ml of water pi and by addition of 21.2 g (= 120 mmol) of N-methylglucamine at pH 7.5 brought into solution. Then it is made up to 100 ml with water pi, the solution is ampoelled and heat-sterilized.

Example 25

Preparation of a solution of the N-methvlglucamine salt of the gadolinium III complex of trans-1,2-cyclohexenediaminetetraacetic acid

555.8 g (= 0.8 mol) of the salt described in Example 8 are dissolved in water pi to 1000 ml. After filtration through a pyrogen filter, the solution is filled into ampoules and heat sterilized.

Example 26

Preparation of a solution of the N-methvlglucamine salt of the ruthenium III complex of 1.10-diaza-4.7dithiadecane-1.1.10.10-tetraacetic acid

15.6 g (= 0.03 mol) of the ruthenium III complex of l, 10-diaza-4,7-dithiadecan-l, l, 10,10-tetraacetic acid are suspended in 50 ml of water pi and by addition of 5, 9 g (= 0.03 mol) of N-methylglucamine are brought into solution at pH 7.5. Make up to 1000 ml with water pi, fill the solution in ampoules and heat sterilize it.

Example 27

Preparation of a solution of the di-lvsine 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 suspended in 500 ml of water pi. 292.4 g (= 1 mol) of lysine are added, the mixture is allowed to stir for a few hours with slight warming and then filled with water pi ad 1000 ml. The solution is bottled and heat sterilized

Example 28

Preparation of a solution of the tri-N-methylglucamine salt of the molybdenum VI complex of diethylenetriaminepentaacetic acid

18.8 g (= 0.28 mol) of the complex Hßllv ^ C ^ iOH ^ · C 14 ^^ 23 ^ 0 ^] are dissolved in 50 ml of water. i. Suspended and neutralized by addition of 16.4 g (= 0.84 mol) of N-methylglucamine is added 0.15 g of tromethamine, filled with water to pi to 100 ml, the solution is subjected to sterile filtration and filled into ampoules ,

Example 29

Preparation of a solution of the di-sodium salt of manganese-II complex of ethylenediamine-tetraacetic acid c

343.2 g (= 1 mol) of the manganese-II complex of ethylenediaminetetraacetic acid are dissolved in 500 ml of water. i. suspended and dissolved by portionwise addition of 80 g (= 2 mol) of sodium hydroxide neutral. After addition of 1.5 g of tromethamine, the solution is filled with water pi ad 1000 ml, bottled and heat sterilized

Example 30

Preparation of a solution of the sodium salt of the iron (III) complex of ethylenediaminetetraacetic acid

345.7 g (= 1 mol) of the iron-III complex of ethylenediaminetetraacetic acid are suspended in 500 ml of water pi and neutralized by adding portions of 40 g (= 1 mol) of caustic soda. After addition of 1.5 g of tromethamine, the solution is filled with water pi ad 1000 ml, bottled and heat sterilized.

Example 31

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

334.6 g (= 0.75 mol) of the iron (III) complex of diethylenetriamine pentaacetic acid are suspended in 500 ml of water pi and neutralized by adding in portions 60 g (= 1.5 mol) of caustic soda. The solution is mixed with water 1000 ml filled up, bottled and heat-sterilized.

Example 32

Preparation of a solution of the sodium salt of the gadolinium III complex of trans-1,2-Cyclohexvlendiamintetraessi gsäure

-14AT397 465B

558.6 (= 1 mol) of the salt mentioned in Example 8 are dissolved in water pi ad 1000 ml. The solution is bottled and heat sterilized

Example 33

Preparation of a solution of the N-methyl glucamine salt of the gadolinium III complex of 1,2-diphenvlethvienediaminetetraacetic acid

396.9 g (= 500 mmol) of the salt described in Example 10 are dissolved in 600 ml of water. 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 slurried in 500 ml of water pi. Add 1.0 g of tromethamine, make up to 1000 ml with water, fill the solution in ampoules and heat sterilize.

Example 35

Preparation of a solution of the di-N-methvlglucamine salt of the lanthanum III complex of diethvlentriaminepentaacetic acid

459.8 g (= 500 mmol) of the salt listed in Example 5 are slurried in 650 ml of water pi and brought by filling with water pi to 1000 ml in solution. The solution is poured into ampoules and heat sterilized.

Example 36

Preparation of a solution of the di-N-methvlglucamine salt of the bismuth III complex of diethvlentriamine pentaacetic acid

692.8 g (= 700 mmol) of the salt listed in Example 5 are slurried in 600 ml of water pi and dissolved after addition of 1.8 g of tromethamine by filling with water pi to 1000 ml with gentle heating. The solution is filled into ampoules and heat sterilized.

Example 37

Preparation of a solution of the di-N-methvlglucamine salt of the holmium III complex of diethvlentriamine pentaacetic acid

662.0 g (700 mmol) of the salt listed in Example 5 are slurried in 600 ml of water pi and dissolved after addition of 1.8 g of tromethamine by filling with water pi to 1000 ml with gentle heating. The solution is filled into ampoules and heat-sterilized.

Example 38

Preparation of a solution of the di-N-methvlglucamine salt of the ytterbium III complex of diethvlentriaminepentaacetic acid

476.9 g (= 500 mmol) of the salt listed in Example 5 are slurried in 650 ml of water pi and dissolved after addition of 13 g of tromethamine by filling with water pi to 1000 ml. The solution is filled into ampoules and heat sterilized

Example 39

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

573.2 g (= 1000 mmol) of the salt listed in Example 6 are slurried in 650 ml of water pi and dissolved by filling with water pi to 1000 ml The solution is filled into ampoules and heat sterilized.

Example 40

Preparation of a solution of the di-sodium salt of the dvsprosium III complex of diethvlentriamine pentaSSgigSlW

477.4 g (= 800 mmol) of the salt listed in Example 6 are slurried in 600 ml of water pi and dissolved by filling with water pi to 1000 ml The solution is filled into ampoules and heat sterilized.

Example 41

Preparation of a solution of the di-sodium salt of holmium IH complex of diethylenetriamine pentaacetic acid

299.6 g (= 500 mmol) of the salt listed in Example 6 are slurried in 500 ml of water pi and dissolved by filling with water pi to 1000 ml The solution is filled into ampoules and heat sterilized

-15AT 397 465 B

Example 42

Preparation of a solution of the di-sodium salt of the ytterbium-III complex of diethylenetriaminepentaacetic acid

303.5 g (= 500 mmol) of the salt listed in Example 6 are slurried in 500 ml of water pi and dissolved by filling with water pi to 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 c)

137.1 g (= 100 mmol) of the salt listed in Example 12 are slurried in 500 ml of water pi and dissolved after addition of 0.8 g of tromethamine by filling with water pi to 1000 ml. The solution is filled into ampoules and heat sterilized.

Example 44

Preparation of a solution of the gadolinium III complex of N'-f2-hydroxvethvl ') ethlenediamine-N, N-triacetic acid

1.9 g (= 6.7 mmol) of N- (2-hydroxyethyl) ethylenediamine-N N -triacetic acid and 1.2 g (= 3.35 mol) of gadolinium ΙΠ oxide are dissolved in 6 ml of water under heating pi Solution is ampullated and heat sterilized.

Example 45

Preparation of a solution of the di-sodium salt of the manganese-II complex of trans-1,2-Cvclohexvlendiamintetraessigsäure

44.3 g (= 100 mmol) of the salt mentioned in Example 9 are slurried under nitrogen protection in 60 ml of water pi and filled with Wasserp. i. brought to 100 ml in solution. The solution is ampullated and heat sterilized.

Example 46

Preparation of a solution of the sodium salt of the gadolinium III complex of the .4.8.11 tetraazacycletradecaneNNNN-tetraacetic acid

552.6 g (= 1 mol) of the salt mentioned in Example 11 are dissolved in water. i. dissolved to 1000 ml. The solution is bottled and heat sterilized.

Example 47

Preparation of a solution of the di-sodium salt of the bismuth-UI complex of diethylenetriamine pentaacetic acid

23.4 g (= 50 mmol) of bismuth III oxide are suspended in 50 ml of water pi. After addition of 39.3 g (= 100 mmol) of diethylenetriamine pentaacetic acid and 4.0 g (= 50 mmol) of caustic soda, the mixture is heated to clear solution until refluxing. The cooled to room temperature solution is neutralized by adding 4.0 g of caustic soda and made up to 100 ml with water pi. The solution is ampullated and heat sterilized.

Example 48

Preparation of a solution of the di-sodium 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 65 ml of water pi with heating. It is filled up with water pi to a total volume of 100 ml, ampoules and heat sterilized.

Example 49

Preparation of a solution of the di-N-methvlglucamine salt of the gadolinium III complex of 13,23-dioxo15,18,21-tris (carboxvmethvl ') - 12,15,18,21,24-pentaazapentatriacontanedioic acid

130.4 g (= 100 mmol) of the salt listed in Example 2 are slurried in 250 ml of water and dissolved by heating. The mixture is made up to 500 ml with water, poured into ampoules and heat-sterilized.

Example 50

Preparation of a solution of the di-N-methvlglucamine salt of the manganese II complex of ethylenediaminetetraacetic acid

3.68 g (= 5 mmol) of the substance described in Example 9 are dissolved in 70 ml of water and the solution is combined with 0.4 g of sodium chloride. It is then made up to 100 ml with water pi and the solution is filled through a sterile filter into ampoules The solution is 280 mOsm. isotonic with blood.

-16AT397465B

Example 51

Preparation of a solution of the di-sodium salt of the gadolinium III complex of diethylenetrinitrilopentafmethanephosphonic acid ')

38.57 g (= 50 mmol) of the substance described in Example 12 are dissolved in 50 ml of water. i. slurried. It is adjusted by the addition of caustic soda powder to pH 7.2 and filled with water to pi to 100 ml. The solution is ampullated and heat sterilized.

BgigpielS?

HerstellungeinerLösungvomTri-NatriumsalzdesMangan II KomplexesderDiethvlentriamin pentaacetic acid

39.3 g (= 100 mmol) of diethylenetriamine-penta-acetic acid are added under nitrogen in 100 ml of water. i. and 11.5 g of manganese (II) carbonate are added. 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

Example 53

Composition of a powder for the preparation of a suspension

4,000 g of diethylenetriamine-pentaacetic acid gadolinium III complex (water content 8.0%)

3.895 g of sucrose

0.100 g of polyoxyethylene-polyoxypropylene polymer

0.005 g of flavorings

8,000 g

Example 54

Preparation of a solution of the gadolinium III complex from 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 M sodium bicarbonate buffer (pH 7-8) is added 10 mg of l, 5-bis (2,6-dioxomorpholino) -3-azapentan-3-acetic acid. The mixture is stirred for 30 minutes at room temperature and then dialyzed against a 0.3 molar sodium phosphate buffer. Then 50 mg gadolinium III acetate is added and purified by gel chromatography on a Sephadex G25 column. The resulting fraction is sterile filtered and filled into multivials. Freeze-drying gives a shelf-stable dry preparation.

The solution of the corresponding complex conjugate is obtained in an analogous manner with immunoglobulin.

Example 55

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

To 20 μΐ of a solution of 0.3 mg monoclonal antibody in 0.05 M sodium bicarbonate buffer (pH 7-8) is added 1 mg of a mixed DTPA anhydride (obtained, for example, from DIPA and fcobutyl chloroformate) and stirred for 30 minutes at room temperature , It is dialyzed against 0.3 molar sodium phosphate buffer and the resulting antibody fraction is mixed with 2 mg of the gadolinium III complex of ethylenediaminetetraacetic acid (EDTA). After purification by gel chromatography over 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.

Analogously, using the manganese II complex of ethylenediamine tetraacetic acid, the mangan II complexes of DTPA or CDTA coupled antibodies are obtained.

Example 56

Preparation of a solution of the gadolinium III complex from Koniugatderl-phenvl-ethvlendiamin-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 containing 0.01 mol of ethylenediaminetetraacetic acid is brought to + 4 ° Cab cooled and added to the protein equivalent portion of a freshly prepared ice-cold diazonium salt solution of 1- (p-aminophenyl) ethylenediaminetetraacetic acid dropwise. It is allowed to stir overnight at 14 ° 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 treated with an excess of gadolinium-III chloride and ultrafiltered to remove ions. Finally, the sterile-filtered solution is filled into multivials and freeze-dried.

-17AT397465B

Example 57

Preparation of a colloidal dispersion of an Mn-CDTA-lipid conjugate

0.1 mmol of distearoylphosphatidylethanolamine and 0.1 mmol of bisanhydride of trans-l, 2-diaminocyclohexanetetraacetic acid are stirred in 50 ml of water for 24 hours at room temperature. 0.1 mmol of manganese bicarbonate is added and the mixture is stirred again for 6 hours at room temperature. After purification on a Sephadex G50 column, the sterile-filtered solution is filled into multivials and freeze-dried

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

Example 58

Preparation of gadolinium DTPA-loaded liposomes

After in Proc. NatL Acad. Be. Method 75,4194 described a lipid mixture of 75 mol% egg phosphatidylcholine and 25 mol% cholesterol is prepared as a dry substance of which 500 mg are dissolved in 30 ml of diethyl ether and in the ultrasonic bath dropwise with 3 ml of a 0.1 molar solution of the diN-methylglucamine salt of the gadolinium III complex of diethylenetriamine pentaacetic acid in water pi. After complete addition of the solution, the sonication is continued after 10 minutes and then concentrated in a Rotavapor. The gelatinous residue is suspended in 0.125 molar sodium chloride solution and repeatedly freed from non-encapsulated contrast agent fractions by centrifugation (20000 g / 20 minutes). Finally, the liposomes thus obtained are freeze-dried in multivia. The application is carried out as a colloidal dispersion in 0.9% by weight saline.