FI79026C - Diagnostic agents for use ultrasound, NMR and X-ray diagnostics, process for their preparation, complex salts contained therein and their use for the production of diagnostic agents. - Google Patents

Description

1 79026

Diagnostic agents for ultrasonic, NMR and X-ray diagnostics, method for their preparation, complex salts they contain and their use for the preparation of diagnostic agents 5

The invention relates to objects defined by the features of the claims.

The complexes and their salts, respectively, have been used in medicine for a long time, thus e.g.

10 as excipients in the drug administration of sparingly soluble ions (e.g. iron) and as antidotes (here calcium or zinc complexes are preferred) in order to detoxify the heavy metals or their radioactive isotopes inaccurately incorporated. For example, FR-M-15 484 describes the iron (II) salt of the iron (III) complex of EDTA as an anti-anemic agent, FR-M-988 for copper) -EDTA and its disodium salt as agents for the treatment of rheumatism, and FR-1 111 504 The disodium and dipotassium salts of the cobalt complex of EDTA as blood-forming agents. However, there are no references in these publications to the diagnostic use of these compounds. In J. Am. Chem. Soc. may 99 (1977) 1762 discloses lanthanide-EDTA complexes containing ammonium cations for use as lanthanide shift reagents in physical studies. They also do not mention diagnostic use. DE-A-2 831 524 generally describes complex salts in which the complex-forming acid may be e.g. ethylenediaminetetra (methylenephosphonic acid), and their use in X-ray diagnosis-30 drop.

It has now been found that the complex salts of the formula I or II as defined in claim 1, which contain the anion of the complexing acid and the central ion formed by one or more elements of the order 21-29, 42, 44 or 57-83, are surprising. 79026 are particularly suitable for use in the manufacture of diagnostic agents suitable for use in NMR, X-ray or ultrasound diagnostics. The invention thus relates to diagnostic agents containing these complex salts and to the complex salts as defined in claim 8.

An element having the above-mentioned order, which forms the central ion or ions of a physiologically tolerable complex salt, must not, of course, be radioactive for the desired use of the diagnostic agent according to the invention.

If the substance 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 para-magnetic. Such are, in particular, the divalent and trivalent ions of the elements having the order numbers 21 to 29, 42, 44 and 58 to 70. Suitable are, for example, chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), praseodymium (III), neodymium (III) , the same-rium (III) and ytterbium (III) ions. Due to their very strong magnetic moment, gadolinium (III), terbium (III), dysprosium (III), holmium (III) and erbium (III) ions are particularly preferred.

If the substance according to the invention is intended for use in X-ray diagnostics, the central ion must be derived from an element of higher order in order to achieve sufficient absorption of X-rays. It was found that diagnostic agents containing a physiologically tolerable complex salt having center ions of the order of 57 to 83 are suitable for this purpose? these are, for example, lanthanum (III) ion, the above-mentioned ions of the lanthanide series, gold (III) ion, lead (II) ion or especially bismuth (III) ion.

Both the substances according to the invention which are intended for NMR diagnostics and those intended for use in X-ray diagnostics are suitable for use in ultrasound diagnostics.

Suitable complexing acids are those conventionally used to form the above-mentioned central ion complexes. Suitable complexing acids are, for example, acids containing 3 to 12, preferably 3 to 8, methylenephosphonic acid groups, methylenecarbohydroxamic acid groups, carboxyethylidene-10 groups or, in particular, carboxymethylene groups, in each case one, two or three of which are attached to the nitrogen atom supporting the complex formation. If three of the acid groups are attached to a nitrogen atom, these are the complexing acids which form the basis of the complex salts of the general formula II as defined in claim 1. If in each case only one or two of the acid groups are attached to the nitrogen atom, the nitrogen atom is attached to the other nitrogen atom via optionally substituted ethylene or at most four ethylene units separated by nitrogen or oxygen or sulfur atoms supporting the complexation in each case. These are the complex salts of the general formula I as defined in claim 1.

The complexing acids can be coupled to conjugate biomolecules known to be particularly enriched in the organ or part of the organ being examined. Such biomolecules include, for example, insulin, prostaglandins, steroid hormones, amino sugars, peptides, proteins or lipids. Particular mention should be made of conjugates alubimic with, for example, human serum albumin, antibodies such as, for example, monoclonal antibodies specific for tumor-associated antigens or antimyosin. The diagnostic agents formed from these are suitable, for example, for use in tumor and infarct diag 35. Suitable for liver studies are, for example, conjugates or occlusion compounds formed with 4,79026 posomes and used, for example, as unilamellar or multilamellar phosphatidylcholine cholesterol vesicles. The formation of the conjugate takes place either via the carboxyl group of the complexing acid or, in the case of proteins or peptides, also via the group (CH2) p-c6H4-w-10 as defined in claim 1. When forming complexes of complexing acids with proteins, peptides or lipids, several acid residues may be partially associated with the macromolecular biomolecule. In this case, the complex-forming acid residue may already contain a central ion. If the complexing acids are not attached to the biomolecules, they may have two central ions, especially one central ion.

Suitable complex salts of general formula I as defined in claim 1 are, for example, salts of general formula Ia.

X-CH, CH - X

\ / NN-CHR9-CHR2-N (Ia), 2 5 S 1 J \ / \

V-CHR1 CHR1-V

wherein X, V, R 1, R 2 and R 2 are as defined in claim 1 of claim 2q.

Suitable complexes for the preparation of the complex salts of the general formula Ia include the following complexing acids: ethylenediaminetetraacetic acid, ethylenediaminetetraacetohydroxamic acid, trans-1,2-cyclo-35hexylenediaminetetraacetic acid, D1-2,3-butylene acetyl -butylenediaminetetraacetic acid, D1-1,2-propylenediaminetetraacetic acid, 1,2-diphenylethylenediaminetetraacetic acid, ethylenedinitrolotetrakis (methanephosphonic acid) and N- (2-hydroxy-5-ethyl) ethylenediamineacetic acid.

Other complex salts of general formula I as defined in claim 1 are, for example, salts of general formula Ib

10 X-CH0 CH - X

\ / N-CH - CH - (Z-CH0-CH ~) -N (Ib), λ 2. 2. λ m s.

X \

V-CHR ^ CHR1-V

Wherein X, V, Z, R 1 and m have the same meaning as in claim 1. If Z represents an oxygen atom or a sulfur atom, complex salts are preferred, in which m represents the number 1 or 2. For the formation of complex salts of the general formula Ib, e.g. the following 20 acids: diethylenetriaminepentaacetic acid, triethylene-tetramine-hexacetic acid, tetraethylenepentamine-hexta-acetic acid, 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-penta-azapentatriacontane - (1-carboxyethyl) -3,6,9-triazaundecanoic acid, diethylenetriaminepentakis (methylenephosphonic acid), 1,10-diaza-4,7-dioxadecane-1,1,10,10-tetraacetic acid and 1.10 -diatsa-4,7-ditiadekaani-l, 1,10,10-tetraacetic acid.

Suitable complex salts of general formula I as defined in claim 1 are further complex salts of general formula Ie

X-CH0 CH - X

\ / 2 n-ch9-ch ~ -n

I ^ ^ I

35? H2 fH2 (Ic), "; H2> w <? H2» w

N-CH - CH - N

X-CH2-CH2-X

6,79026 wherein X and w are as defined in claim 1.

Suitable complexes for the preparation of the complex salts of the general formula Ie are, inter alia, the following complex-forming acids: 1,4,8,11-tetraazacyclotetradecanetraacetic acid and in particular 1,4,7,10-tetraazacyclododane tetraacetic acid.

Other complexing acids suitable for the preparation of complex salts of general formula I include, for example: 1,2,3-tris / bis (carboxymethyl) amino / propane and nitrilotris / ethylenenitrile) hexaacetic acid. An example of an acid used for the preparation of complex salts of general formula II is nitrilotriacetic acid.

If the central ion or central ions do not replace all acidic hydrogen atoms of the complexing acid, it is appropriate to replace the remaining hydrogen atom with physiologically harmless alkali metal or alkaline earth metal cations and / or cations of organic bases or amino acids to improve the solubility of the complex salt. Suitable inorganic cations are, for example, lithium ion, potassium ion or especially sodium ion. Suitable organic base cations include, but are not limited to, cations of primary, secondary or tertiary amines such as cations of ethanolamine, diethanolamine, morpholine, glucamine, am, Ν-dimethylglucamine or especially N-methylglucamine. Suitable amino acid cations are, for example, cations of lysine, arginine or ornithine.

The complexing acids required for the substances according to the invention are known or can be prepared in a manner known per se. Thus, for example, 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-pentaazapentatriacontanedioic acid is prepared by the improved method of R. A. Bulman et al.

Naturwissenschaften 68 (1981) 483: 7 79026 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 when 20.13 g (= 100 mmol) of 11-aminoundecanoic acid are added and the mixture is heated for 6 hours at 70 [deg.] C. The clear solution is evaporated in vacuo. The yellow oily residue is stirred at room temperature with 500 ml of water. This gives a solid white high volume solid which is filtered off with suction and washed several times with water. For further purification, the product obtained is taken up in 200 ml of acetone and stirred for 30 minutes at room temperature. After suction filtration and vacuum drying at 50 [deg.] C., 36.9 g (= 97% of theory) of a white powder with a melting point of 134-138 [deg.] C. are obtained.

Conjugation of complexing acids to biomolecules also takes place 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 the activated biomolecule with a complexing acid.

Substituents in the structure or C 8 H 2 NHCOCl 2 halogen are also available for conjugation with proteins.

The preparation of complex salts is also known in part or can be carried out in a manner known per se by dissolving or suspending a metal oxide or a metal salt of an element having the order of 21-29, 42, 44 or 57-83 (for example nitrate, chloride or or sulphate) in water and / or a lower alcohol (such as methanol, ethanol or isopropanol) and a solution or suspension of an equivalent amount of the complex-forming acid in water and / or lower alcohol is added and stirred while necessary. if required, heat or heat to boiling point until the reaction is complete. If the complex salt formed is insoluble in the solvent used, it is separated by filtration. If it is soluble, it can be isolated by evaporating the solution to dryness, for example by spray drying.

If acidic groups still remain in the complex salts obtained, it is often necessary to convert the acidic complex salt into neutral complex salts by means of inorganic and / or organic bases or amino acids which form physiologically innocuous cations and to isolate these. In many cases, this is even necessary because the transition from pH to neutral reduces the dissociation of the complex salt to such an extent that only in this way is it possible to isolate or at least purify the uniform products.

Suitably the preparation takes place by means of organic bases or basic amino acids. However, it may also be advantageous to carry out the neutralization with inorganic sodium, potassium or lithium bases (hydroxides, carbonates or bicarbonates).

To prepare neutral salts, for example, the desired base can be added to the acidic complex salts in aqueous solution or suspension in such an amount that; the neutral point is reached. The resulting solution can then be evaporated to dryness in vacuo. It is often advantageous to precipitate the formed neutral salts by adding water-miscible solvents such as lower alcohols (granular ethanol, ethanol, isopropanol, etc.), lower ketones (acetone, etc.), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.) and thus obtaining crystals which are easily isolated and well purified. It has proved particularly advantageous to add the desired base to the reaction mixture already during the complex formation and thus to reduce one process step.

9 79026

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

The invention also relates to the preparation of the above-mentioned diag-15 raising agents. This is done in a manner known per se by suspending or dissolving the complex salts in an aqueous medium, optionally with the addition of customary galenic additives, and then sterilizing the solution or suspension. Suitable excipients are, for example, physiologically innocuous buffers (such as tromethamine hydrochloride), minor additions of complexing agents (such as diethylenetriaminepentaacetic acid) or electrolytes (such as sodium chloride), if necessary.

In principle, it is also possible to prepare the diagnostic agents according to the invention without isolating the complex salts. In any case, special care must be taken to ensure that the chelation is carried out in such a way that the salts and brines according to the invention are practically free of non-complexed toxic metal ions. This can be done, for example, by means of color indicators such as xylenol orange in control titrations during the manufacturing process. The invention therefore also relates to a process for the preparation of the complex compound and its salts. The final confirmation remains the purification of the isolated complex salt.

10 79026

If suspensions of complex salts in water or physiological saline for oral administration or other purposes are desired, the sparingly soluble complex salt will be mixed with one or more conventional galenic excipients and / or surfactants and / or flavoring agents to correct the taste.

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

The substances according to the invention meet - in accordance with claim 3 - various conditions for being suitable as a contrast agent in nuclear spin tomography. Thus, they are particularly well suited to improve the interpretability of an image obtained by nuclear spin tomography after oral or parenteral administration through an increase in signal intensity. Furthermore, they have the high power required to load the body with the least possible amount of foreign substances and the good tolerability required to maintain the harmless nature of the study (J. Comput. Tomography 5,6: 543-46 (1981), Radiology). 144, 343 (1982) and Brevet Special de Medicament No. 484M 81960) are, for example, too saturated with myr-25). The good aqueous solubility of the substances according to the invention makes it possible to prepare high-concentration solutions, whereby the volume load in the bloodstream can be kept within defensible limits and the dilution of body fluids can be smoothed, i. NMR diag-30 lifters must be 100-1000 times more water soluble than those used in NMR spectroscopy. Furthermore, the substances according to the invention have not only a high in vitro stability but also a surprisingly high in vitro stability, so that the release or exchange of non-hard-bound, inherently toxic ions 11 79026 takes place only extremely slowly during the 24 hours for which as pharmacological studies have shown, the new contrast agents are completely eliminated from the body. For example, conjugates with proteins and antibodies used in tumor diagnostics cause a surprisingly high signal amplification even at such low doses that solutions with correspondingly low concentrations can be used.

The substances according to the invention are - in accordance with claims 4 - particularly well suited as X-ray contrast agents, in which case it should be particularly emphasized that no signs of anaphylaxis-type reactions are known in biochemical pharmacological studies when used with iodinated contrast agents. They are particularly valuable due to their advantageous absorption properties in the higher tube voltage ranges used in digital subtraction techniques.

The substances according to the invention are - contrary to claim 2 - also suitable as ultrasound diagnostics due to their property that they have a beneficial effect on the speed of ultrasound.

Unlike conventional X-ray diagnostics, which use shading X-ray contrast agents, in NMR diagnostics with paramagnetic contrast agents, there is no linear dependence of the signal amplification on the concentration used. As control studies show, increasing the administered dose does not necessarily result in an amplification of the signal, and when a high dose of paramagnetic contrast agent is used, even signal loss may result. It was therefore surprising that some pathological processes can only be detected after administration of the highly para-35 magnetic contrast agent of the invention at higher doses of 12,79026 than those reported in EP 71564 (which can range from 0.001 mmol / kg to 5 mmol / kg). Thus, for example, a deficient boundary between brain and blood in the area of cranial abscess can only be demonstrated after administration of 0.05-2.5 mmol / kg, preferably 0.1-0.5 mmol / kg of paramagnetic complex salts such as gadolinium diethylene. -triaminepentaacetic acid or manganese-1,2-cyclohexylenediaminotetraacetic acid, respectively, as their highly water-soluble salts. For doses greater than 0.1 mmol / kg, more concentrated solutions are needed, at concentrations of up to 1 mol / l, preferably 0.25-0.75 mol / l, as this is the only way to reduce the volume stress and provide a solution for injection.

Particularly low doses (less than 1 mg / kg) and thus solutions with lower concentrations (1 pmol / 1-5 mmol / l) than those described in EP 71564 are used in organospecific NMR diagnostics, e.g. for the detection of tumors and myocardial infarction.

The following application examples further illustrate the invention 20.

Example 1

Preparation of nitrolin-N, N, N-triacetic acid gadolinium (III) complex, CgHgGdNOg

A suspension of 36.2 g (= 100 mmol) of ga-25 dolinium oxide (Cd 2 O 2) and 38.2 g (= 200 mmol) of nitriloacetic acid in 1.2 liters of water is heated with stirring to 90-100 ° C and stirred here. at room temperature for 48 hours. The solution is then separated from the insoluble material by filtration on activated carbon and the filtrate is evaporated to dryness. The amorphous residue is ground.

Yield: 60 g (87% of theory);

M.p .: 30 ° C

Gadolinium: calculated 45.5%, implemented 44.9%.

The iron (III) complex of nitrile-N, N, N-triacetic acid 35 is obtained with ferric chloride, FeCl 3.

13 79026

Example 2 13.23-Dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-disodium salt of the gadolinium (III) complex of pentaazapentatriacontanedioic acid, 5 ^ 36 ^ 60 ^^ 5 ^ 12 * 2 Na , preparation 15.2 g (= 20 mmol) of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-pentaazazententriacontanic 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 to the suspension. Maintain this temperature for 2 hours and then add 60 ml of 1N sodium hydroxide solution to neutralize the hydrochloric acid formed.

When the reaction is complete (as determined by xylenol trans), the precipitate obtained is filtered off and washed chloride-free with water. 17.60 g (96% of theory) of a water-insoluble white powder with a melting point of 290-292 [deg.] C. are obtained.

13.23-dioxo-15,18,21-tris (carboxymethyl) -20 12,15,18,21,24-Pentaazazententriacontanedioic acid gadolinium (III) complex.

Analysis: (calculated) 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) complex thus obtained are suspended in 200 ml of water and 31.4 ml of 1-normal sodium hydroxide solution are added dropwise. After 1 hour, a clear solution is obtained which is filtered and then evaporated in vacuo. After drying in vacuo at 80 [deg.] C., 13.2 g (87% of theory) of a highly water-soluble white powder with a melting point of 279-285 [deg.] C. are obtained.

Analysis: (calculated) C 45.13 H 6.31 N 7.31 Gd 16.41 Na 4.80 35 (found) C 45.20 H 6.12 N 7.28 Gd 16.26 Na 4.75.

i4 79026

In a similar manner, using sodium N-methylglucamine instead of sodium hydroxide, 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-pentaazazentrentratriacontanedioic acid gadolinium (III) complex is obtained. -N-methylglucamine salt, ^ 50 ^ 96 ^ ^ ^ 2 * Example 3 Disodium salt of the gadolinium (II) complex of 3,9-bis (1-carboxyethyl) -6-carboxymethyl-3,6,9-triazaundecanedioic acid, ci6H22G <^ N3 ° 10 'Na, Preparation 10 36.2 g (= 0.1 mol) of gadolinium (III) oxide and 84.2 g (= 0.2 mol) of 3,9-bis (1-carboxyethyl) -6- carboxymethyl-3,6,9-triazaundecanedioic acid is suspended in 250 ml of water and heated to reflux for one hour. Separate from a small amount of insoluble material and evaporate the solution to dryness in vacuo. The residue is triturated and dried in vacuo at 60 ° C. 112.8 g (= 98% of theory) of chelate are obtained in the form of a white powder.

Analysis: C 16 H 24 G 2 O 3 N 3 O (calculated) C 33.39 H 4.20 Gd 27.32 N 7.30 20 (found) C 33.25 H 4.49 Gd 27.42 N 7.21.

57.6 g (= 0.1 mol) of chelate are introduced into a solution of 0.1 mol of sodium hydroxide solution in 100 ml of water.

By adding a further 0.1 mol of sodium hydroxide powder, the pH is adjusted to 7.5, the solution is heated to boiling and ethanol is added dropwise until a permanent turbidity is formed. After stirring for several hours in an ice bath, the crystallized material is filtered off with suction, washed with ethanol and dried in vacuo. The disodium salt is obtained in quantitative yields as a white powder.

Analysis: (calculated) C 31.02 H 3.58 Gd 25.38 N 6.78 (found): C 31.10 H 3.71 Gd 25.50 N 6.61.

15 79026

Example 4 Preparation of 3-bis (1-carboxyethyl) -6-carboxymethyl-3,6,9-triazaundecanedioic acid gadolinium (III) complex dimorpholine salt, C24H42GdN5 O2, 5 Dissolve 17.4 g (= 0.2 mol) of morpholine in 50 ml of: aan water. 42.1 g (= 0.1 mol) of 3,9-bis (1-carboxyethyl) -6-carboxymethyl-3,6,9-triazaundecanoic acid are added, followed by 18.2 g (= 0.5 mol) of gadolinium ( III) oxy-10 dia and kept at reflux temperature until a clear solution is formed. Acetone is then added dropwise until permanent turbidity is formed. After stirring for several hours in an ice bath, the crystallized product is separated by suction filtration, washed with acetone and dried in vacuo. The di-morpholine salt is obtained in quantitative yields as a white powder.

Analysis: (calculated) 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.

20 Example 5

Preparation of the di-N-methylglucamine salt of diethylenetriamine-Ν, Ν,, ', N ", N" -pentaacetic acid gadolinium (III) complex, C28H54GdN5 ° 20, 39.3 g (= 100 mmol) of diethylenetriamine-Ν, Ν ', N ", 25 N" pentaacetic acid is suspended in 200 ml of water and 19.5 g (= 100 mmol) of N-methylglucamine are added. 18.12 g (= 50 mmol) of gadolinium (III) oxide, Gd 2 Og, are then added portionwise and the resulting suspension is heated to 95 ° C. After about one hour, a further 19.5 g (= 100 mmol) of N-methylglucamine are added and, after heating for a further 2 hours, a clear solution is obtained. When the reaction is complete (check with xylenol orange), a small amount of insoluble matter is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is redissolved in 35 ml of water and added with stirring to 250 ml of ethanol. After cooling for several hours, the crystallized product is filtered off with suction, washed with cold ethanol and dried at 60 [deg.] C. in vacuo. 92.7 g (99% of theory) of a white powder without 5 characteristic melting points are obtained.

Analysis: (calculated) C 35.85 H 5.80 N 7.47 Gd 16.77 (found) C 35.50 H 5.72 N 7.20 Gd 16.54.

Acetone, propanol or isopropanol can also be used instead of ethanol 10 to purify the complex salt.

Correspondingly, the following is obtained: di-N-methylglucamine salt of dysprosium (III) complex of diethylenetriamine, Ν, Ν, Ν ', N ", N" -pentaacetic acid with dysprosium (III) oxide, DY2 ° 3', C28H54DyN5 ° 20; with lanthanum (III) oxide, I ^ Oj, diethylenetriamine-Ν, Ν, Ν ', N ”, N” -pentaacetic acid lanthanum (III) complex di-N-methylglucamine salt, 2 ° C28H54LaN502 (,; ytterbium (III) oxide, Yb 2 O 2, with diethylenetriamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid ytterbium (III) complex di-N-glucamine salt, C28H54YbN5 ° 20; with samarium (III) oxide, Sm2O2, with diethylenetriamine-Ν, Ν, Di, N ", N" -pentaacetic acid samarium) complex di-N-methylglucamine salt, C28H54SmN5 ° 20; holmium (III) oxide, Ho 2 O 2, diethylenetriamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid holmium (III) complex di-N-methylglucamine salt, C28H54HoN5 ° 20; Bismuth (III) oxide, B 2 O 2: diethylenetriamine--, Ν, Ν ', N ", N" -pentaacetic acid bismuth (III) complex di-N-methylglucamine salt, 17 79026 C28H54B1N5 ° 20; gadolinium (III) oxide, with triethylenetetramine-Ν, Ν, Ν ', N ", N"', N '"- hexacetic acid gadolinium (III) complex tri-N-methylglucamine salt, 5 C39H78GdN7 ° 27'

Further obtained: with holmium (III) oxide and using ethanolamine instead of N-methylglucamine diethylenetriamine-N, N, N ', N ", N" -pentaacetic acid 10 holmium (III) complex diethanolamine salt, C ^ gH ^ HoN ^ O · ^ » with gadolinium (III) oxide and using lysine instead of N-methylglucamine diethylenetriamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid gadolinium (III) complex dilysine salt, C26H48GdN7 ° 14.

When diethanolamine is used, the di-diethanolamine salt of diethylenetriaminepentaacetic acid holmium (III) complex.

The salts occur as white powders which do not have a precise melting point, they are very well water soluble.

Example 6

Preparation of the disodium salt of the gadolinium (III) complex of diethylenetriamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid, C, .H.oGdNo0.n · 2 Na, 14 18 3 10 25 18.2 g (= 0.05 mol) of gadolinium (III) oxide and 39.3 g (= 0.1 mol) of diethylenetriaminepentaacetic acid are suspended in 110 ml of water and refluxed for one hour. The clear solution is cooled and its pH is adjusted to 7.5 by adding about 80 ml of 5N sodium hydroxide. Bring to the boil again and add dropwise 250 ml of ethanol. After stirring for several hours in an ice bath, the crystallized product is filtered off with suction, washed with ice-cold ethanol and dried at 60 [deg.] C. in vacuo. A white powder which does not melt by 300 ° C is obtained in quantitative yields.

18 79026

Analysis: (calculated) 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.

In a similar manner there are obtained: 5 with dysprosium (III) oxide, DY2 ° 3 ', the disodium salt of the dysprosium (III) complex of diethylenetriamine-Ν, Ν, Ν', N ", N" -pentaacetic acid, C14H18DyN3 ° 10 · 2 Na! with lanthanum (III) oxide, La 2 -, disodium salt of the lanthanum (III) complex of diethylenetriamine-,, Ν, Ν ', N ", N" -pentaacetic acid, c ^ 4HigLaN3 ° ^ 0' ^ Na? holmium (III) oxide, Ηθ2 ° 3 'with diethylenetriamine-Ν, Ν, Ν', N ", N" -pentaacetic acid holmium (III) complex disodium salt, C-j ^ H ^ qHON ^ P ^ q. 2 Na; 15 ytterbium (III) oxide, Yb2 ° 3 'with diethylenetriamine-N, N, N', N ", N" -pentaacetic acid ytterbium (III) complex disodium salt, C14H18YbN3 ° 10 '2 Na! with samarium (III) oxide, Sn ^ O ^, diethylenetriamine-Ν, Ν, Ν1, N ", N" -pentaacetic acid samarium (III) disodium salt, C14H18SmN3 ° 10 '2 Na; ! erbium (III) oxide, Eb 2 O 2, diethylenetriamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid erbium (III) complex disodium salt, C 2 H 2 EbN 2 O 2 g · 2 Na; with gadolinium (III) oxide, Gd20.j, tetraethylenepentamine-Ν, Ν, Ν ', N ", N"', NN-heptaacetic acid digadolinium (III) complex sodium salt, C22H30Gd2N5 ° 14 * Na * 30 These salts appear as white as powders which do not have a precise melting point and are very soluble in water.

19 79026

Example 7

Preparation of the N-methylglucamine salt of the iron (III) complex of diethylenetriaminepentaacetic acid, C ~, H0, FeN .0, c 21 37 4 15 5 35.40 g (= 90 mmol) of diethylenetriaminepentaacetic acid are suspended in 100 ml of water and added to the suspension. 24.3 g (= 90 mmol) of ferric chloride hexahydrate (FeCl 2 · 6 1 ^ 0) dissolved in 100 any water. Initially, the dark brown suspension is heated to 95 ° C.

10 After about an hour, the color turns light yellow.

Add 270 ml of 1 N sodium hydroxide to neutralize the hydrochloric acid formed and heat for a further 3 hours at 95 ° C. The resulting pale yellow precipitate is filtered off with suction, washed with water to remove chloride and dried in vacuo at 60 ° C. 17.85 g (45% of theory) of a pale yellow powder with a melting point of> 300 [deg.] C. are obtained.

17.85 g (= 40 mmol) of the obtained iron (III) complex are suspended in 200 ml of water and 7.8 g (= 40 mmol) of N-methylglucamine as a solid are added portionwise. Heat for about three hours at 50 ° C to give an almost clear reddish brown solution which is filtered and then evaporated to dryness in vacuo. The residue is dried in vacuo at 50 ° C. 24.3 g (95% of theory) of a red-brown powder with a melting point of 133-133 ° C are obtained.

Analysis: (calculated) C 39.82 H 5.89 N 8.85 Fe 8.81 (found) C 39.70 H 6.00 N 8.65 Fe 9.01.

30 Using sodium hydroxide instead of an organic base gives:

Sodium salt of the iron (III) complex of ethylenediaminetetraacetic acid, C10H12FeN2 ° 8 * Na

Sodium salt of the iron (III) complex of trans-1,2-cyclohexylenediaminetetraacetic acid, C 1-4 H 2 FeN 2 O 2 · Na, 20 79026

Disodium salt of diethylenetrianitrilopenta (metaphosphonic acid) iron (III) complex, C9H23FeN3 ^ 15P5 '^ Na 1,10-diaza-4,7-dioxadecane-1,1,10,10-tetraacetic acid iron (III) sodium salt, ci4H2Fe Na 5 Sodium salt of the iron (III) complex of ethylenediaminetetraacetoxydroxamic acid, C 10 H 16 FeN 6 ° 8 * Na *

In a similar manner with N-methylglucamine:

Di-N-methylglucamine salt of diethylenetriamine-Ν, Ν, Ν ', N ", N" -pentaacetic acid 10 complex of iron (III), C28H54FeN5 ° 20

N-methylglucamine salt of trans-1,2-cyclohexylenediamine-N, N, N ', N'-tetraacetic acid iron (III) complex, C21H36FeN3 ° 13 15 Ethylenediamine-N, N, N', N'-tetraacetic acid iron (III) ) complex N-methylglucamine salt, C] -7H3QFeN3 °] 3 Triethylenetetramine-N, N, N ', N ", N"', N "'- hexacetic acid iron (III) complex tri-N-methylglucamine salt, C39H78FeN7 ° 27' When diethanolamine is used instead of N-methylglucamine, the di (diethanolamine) salt of the iron (III) complex of diethylenetriamine-Ν, Ν, Ν ", N" -pentaacetic acid is obtained, C22H42FeN5 ° 14 *

Example 8 Preparation of the N-methyl-glucamine salt of the trans-1,2-cyclohexylenediamine-N, N, Ν ', N'-tetraacetic acid gadolinium (III) complex, C21H36G (^ N3O3), 20.78 g (= 60 mmol) of trans -1,2-Cyclohexylenediamine-N, N, Ν ', N'-tetraacetic acid is suspended in 150 ml of water, and 11.7 g (= 60 mmol) of N-methylglucamine are added to give an almost clear solution to which 10.88 g (= 30 mmol) of gadolinium oxide (Gd2 O) are added · The reconstituted suspension is heated for 6 hours at 95 [deg.] C. Filter off a small amount of insoluble matter 35 and evaporate the filtrate to dryness. 38.6 g (92% of theory) of a white powder with a melting point of 258-261 [deg.] C. are obtained.

Analysis: δ (calculated) C 36.25 H 5.22 N 6.04 Gd 22.60 (obtained) C 36.40 H 5.50 N 5.93 Gd 22.52.

In a similar manner, when sodium hydroxide is used instead of N-methylglucamine, the sodium salt of the gadolinium-10 complex of trans-1,2-cyclohexylenediamine-Ν, Ν, Ν ', N1-tetraacetic acid is obtained, C ^ H ^ gGd ^ Og · Na .

The freshly precipitated chromium (III) hydroxide, Cr (OH) g, gives the sodium salt of the chromium (III) complex of ethylenediamine-Ν, Ν, Ν ', N1-tetraacetic acid, C10H12CrN2 ° 8' Na * 15 Example 9

Preparation of 34.6 g (= 100 mmol) of trans-1,2-cyclohexylenediamine-N, N, N ', N'-tetraacetic acid manganese (II) complex, disodium salt, 1,2-Cyclohexylenedi-20-amine-Ν, Ν, Ν ', N'-tetraacetic acid is suspended in 100 ml of water under nitrogen and 11.5 g (= 100 mmol) of manganese (II) carbonate, MnCOg, are added. Heat at 95 ° C and add dropwise 200 ml of 1 N sodium hydroxide. The clear solution is evaporated in vacuo and the residue is dried at 60 ° C under vacuum. 40.8 g (92% of theory) of a pink powder are obtained.

Analysis: (calculated) C 37.94 H 4.09 N 6.32 Mn 12.40 (found) C 37.78 H 4.12 N 6.20 Mn 12.31.

30 In a similar way we obtain:

Disodium salt of copper (II) carbonate trans-1,2-cyclohexylenediaminetetraacetic acid copper (II) complex, c14H18CuN2 ° 8 · 2 Na; cobalt (II) carbonate trans-1,2-cyclohexylene di-22,79026 amine tetraacetic acid cobalt (II) complex disodium salt, C 1 H 2 gCo 2 O 2 · 2 Na; nickel (II) carbonate trans-1,2-cyclohexylenediaminetetraacetic acid nickel (II) complex disodium salt, ci4Hi8NiN2 ^ 8. 2 Na.

Using N-methylglucamine instead of sodium hydroxide gives:

Di-N-methylglucamine salt of the manganese (II) complex of trans-1,2-cyclohexylenediaminetetraacetic acid, 10 C28H54MnN4 ° 18 '

Di-N-methylglucamine salt of the manganese (II) complex of D1-2,3-butylenediaminetetraacetic acid,; ethylenediamine-N, N, N ', N'-tetraacetic acid manganese (II) complex di-N-methylglucamine salt, C24G48MnN4 ° 18;

Di-N-methylglucamine salt of D1-1,2-butylenediamine-N, N, N ', N1-tetraacetic acid manganese (II) complex, C26H52MnN4 ° 18; Di-N-methylglucamine salt of DL-1,2-propylenediamine-N, N, N ', N'-tetraacetic acid man-20 g complex (C25H50MnN4 ° 18; tri-N-methylglucamine salt of diethylenetriaminepentaacetic acid manganese (II) complex, C 35 H 72 MnN 6 ° 25; using nickel (II) carbonate, NiCO 2, ethylenediamine-N, N, N ', di-N-methylglucamine salt of the nickel (II) complex of N1-tetraacetic acid, C24H48N1N4 ° 18' using cobalt (II) carbonate, CoCO2, and ethanolamine and the diethanolamine salt of the cobalt-30 (II) complex of ethylenediamine-N, N, N ', N'-tetraacetic acid, ci4H28CoN4 ^ 10' using copper (II) carbonate, CuCO2, and ethanolamine ethylenediamine-N, N, N ', N diethanolamine salt of the copper (II) complex of 1'-tetraacetic acid, C 1 H 2 Cl 2 N 2 O 2; using manganese (II) carbonate, MnCO 3, and diethanol-35 amine diethylenetriamine-N, N, N ', N ", N" -pentaacetic acid

II

23,79026 Tri (diethanolamine) salt of manganese (II) complex, C26H54MnN6 ° 16; using manganese (II) carbonate, MnCO 2, and morpholine Morpholine salt of the manganese-5 (II) complex of ethylenediamine-Ν, Ν, N ", N" -tetraacetic acid, C18H32 ^ nN4 ° 10 '

Example 10

N-methylglucamine salt of ethylenediamine-), ', N', N'-tetraacetic acid gadolinium (III) complex, C17H30GdN3 ° 13 10 29.2 g (= 100 mmol) of ethylenediamine-Ν, ', N', N'-tetraacetic acid are suspended in 100 ml of water and together with 18.1 g (= 50 mmol) of gadolinium (III) oxide are heated to 95 ° C. During heating, 19.5 g (= 100 mmol) of N-methylglucamine-15 are added portionwise. After about three hours, a clear solution is obtained, which is filtered and evaporated to dryness in vacuo. The residue is dried in vacuo at 60 ° C. 61.3 g (95% of theory) of a white powder with an indefinite melting point are obtained.

Analysis: (calculated) C 31.82 H 4.71 N 6.55 Gd 24.51 (found C 31.65 H 4.59 N 6.52 Gd 24.56.

In an analogous manner, the following is obtained: using dysprosium (III) oxide, Dy 2 O 2, N-methylglucamine salt of the dysprosium (III) complex of ethylenediamine-Ν, Ν, N ', N 1 -tetraacetic acid, C 1-4 H 2 QDyN 2 O 3, 3; N-methylglucamine salt of 1,10-diaza-4,7-dioxadecane-1,1,10,10-tetraacetic acid gadolinium (III) complex, C21H38GdN3 ° 15? N-methylglucamine salt of 1,2-diphenylethylenediaminotetraacetic acid gadolinium (III) complex, C29H38N3 ° 13Gd; using lead (II) oxide, PbO, and sodium hydrochloride ethylenediaminetetraacetic acid lead (II) disodium salt of complex 35, c10H12N2 ° 8Pt) "2 Na; ___ - 24 79026 using freshly precipitated chromium (III) hydroxide, Cr III) the sodium salt of the complex, c10H12CrN2 ^ 8 * Na; - * a anal09; * - because: '- the sodium salt of the gadolinium-5-III complex of ethylenediaminetetraacetohydroxamic acid, c; loh16G <^ N6 ^ 8 · Na; ethylenediamine-Ν, Ν Sodium salt of the gadolinium (III) complex of, N ', N'-tetraacetic acid, c ^ qH12G <^ N2 ^ 8 "Na * Example 11 1,4,7,10-Tetrazazacyclododecane-N, N', N”, N ” Preparation of 1-10 tetraacetic acid gadolinium (III) complex sodium salt, c16H24G <N4 ° 8 * Na, 4.0 g (= 10 mmol) of 1,4,7,10-tetraazacyclododecane-N, N ' Suspend, "N", N "'- tetraacetic acid in 20 ml of water and add 10 ml of 1 N sodium hydroxide. 1.8 g (= 5 mmol) of gadolinium (III) oxide, Gd20 g, are added and the suspension is heated at 50 [deg.] C. for 2 hours. The clear solution is filtered and evaporated in vacuo. The residue is dried and triturated to give 5.5 g (95% of theory) of a white powder.

Analysis: (calculated) C 33.10 H 4.17 N 9.65 Gd 27.08 (found) C 33.01 H 4.20 N 9.57 Gd 27.16.

In the same way there are obtained: 1.4.7.10-tetraazacyclododecane-Ν, Ν ', N ", N"' - tetraacetic acid gadolinium (III) complex N-methylglucamine salt, C ~, H. „GdNc0.0 23 42 5 13 1.4.8.11 - Sodium salt of tetraazacyclotetradecane-N, N ', N ", N"' - tetraacetic acid gadolium (III) complex, C18H28GdN4 ° 8 * Na * 30 Example 12

Preparation of the tetra-N-methylglucamine salt of ethylenedinitrilotetrakis (metaphosphonic acid) gadolinium (III) complex, C34H85G <iN6 ^ 32P4 '9.11 g (= 20 mmol) of ethylenedinitrilotetrakis (meta-35 phosphonic acid) are suspended in 150 ml of water and adjusted to 150 ml of water. N-methylglucamine to pH 5. Add 3.6 g (= 10 mmol) of gadolinium (III) oxide,

Gd 2 O 3, and is heated to 70 ° C. After about an hour, a clear solution is obtained to which the final amount of N-methylglucamine-5n is added. A total of 15.6 g (= 80 mmol) of N-methylglucamine is used. The solution is evaporated to dryness in vacuo and the remaining gel-like residue is taken up in 200 ml of acetonitrile. Stir for about 20 hours at 30 ° C and separate the fine precipitate obtained by suction filtration. 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: (calculated) C 29.78 H 6.25 N 6.13 P 9.04 Gd 11.47 15 (found) C 29.85 H 6.57 N 5.98 P 8.78 Gd 11.26.

In a similar manner there are obtained: hepta-N-methylglucamine salt of diethylenetriamine--, Ν, Ν ', N ", Ν'-Penta (methanethosphonic acid) gadolinium (III) complex, C58H144GdN10 ° 50P5; 20 and using sodium hydroxide N-methylglucamine of the disodium salt of the gadolinium (III) complex of diethylenetrinitrilopenta (methanethosphonic acid), C9H23GdN3015P5 · 2 Na.

Example 13 Preparation of Ethylenitrinitrilotetra (acetohydroxamic acid) manganese (II) complex disodium salt, ^ 10 ^ 16 ^ ^ 6 ^ 8 * ^ Na '2.30 g of manganese (II) carbonate and 7.05 g of ethylene nitrinitrilotetra (acetohydroxamic acid) are heated in 18 ml. in water for 3 hours under reflux. The dilute sodium hydroxide solution is then adjusted to pH 7 and 40 ml of acetone are added dropwise. After stirring for several hours in an ice bath, the crushed crystalline product is separated by suction filtration, washed with acetone and dried at 50 ° C under vacuum. The dihydrate is obtained in quantitative yields as a white powder, 26,79026 with a melting point above 300 ° C.

Mn: (calculated) 11.30 (found) 11.12.

Example 14 Preparation of a mixed salt solution of the sodium and N-methylglucamine salts of the gadolinium (III) complex of diethylenetriaminepentaacetic acid a) Preparation of the mono-N-methylglucamine salt of the complex, C21H37G <N4 ° 15 '10 195.2 g (1 mol) of N- methylglucamine is dissolved in 7 liters of water. 393.3 g (1 mol) of diethylenetriaminepentaacetic acid and 181.3 g (0.5 mol) of gadolinium oxide, Gd2 O4, are then added and the mixture is refluxed for 2 hours. The filtered clear solution is spray dried.

A white crystalline powder with a moisture content of 2.6% is obtained, which sinter at 133 ° C. and melts at 190 ° C with foam.

Gd: (calculated) 21.17 (found) 21.34.

B) Preparation of neutral mixed salt solution 730.8 g (= 1 mol) of the salt obtained in a) are suspended in 630 ml of water p.i. and 40 g (= 1 mol) of sodium hydroxide powder are added portionwise. The neutral solution is made up to volume with water p.i. To 1000 ml by filling the flasks through a pyrogen filter and heat sterilizing. This 1 molar solution contains 753.8 g of mixed salt per liter.

Example 15

Preparation of a di-N-methylglucamine salt solution of diethylenetriaminepentaacetic acid gadolinium-30 (III) complex 535.0 g (= 730 mmol) of the salt described in Example 5 are slurried in 500 ml of water p.i. and adding 142.4 g (= 730 mmol) of N-methylglucamine to a solution at pH 7.2. Make up with water p.i. to a volume of 1000 ml, fill the ampoules with the solution and heat sterilize. * p.i. = for injection 27 7 9 0 2 6

Example 16

Preparation of the disodium salt solution of the gadolinium (III) complex of diethylenetriaminepentaacetic acid 485.1 g (= 820 mmol) of the disodium-5 rium salt obtained in Example 6 are slurried in 500 ml of water p.i. The volume is then made up to volume with water p.i. To 1000 ml, fill the ampoules with the solution and heat sterilize.

Example 17 Preparation of 13,23-dioxo-15,18,21-tris (carboxymethyl) -10 12,15,18,21,24-pentaazapentatriacontanoic acid gadolinium (III) complex disodium salt solution 392.0 g (= 400 mmol) in Example 2 described salt is slurried in 500 ml of water pi and dissolved in supplemental water p.i. to a volume of 1000 ml with gentle heating. The solution is filled into flasks and heat sterilized. Example 18 Preparation of 1,4,7,10-tetraazacyclododecanetraacetic acid gadolinium (III) complex N-methylglucamine-20 brine 370.9 g (= 500 mmol) of the salt of Example 11 are slurried in 500 ml of water p.i. and dissolved by adding water p.i. to a volume of 1000 ml: transfer the solution to ampoules and heat sterilize.

25 Example 19

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

Example 20 Preparation of a tri-N-methylglucamine salt solution of diethylenetriaminepentaacetic acid manganese (II) complex 514.4 g (= 500 mmol) of the salt of Example 9 28,79026 are suspended in 600 ml of water p.i. 1.3 g of ascorbic acid are added and dissolved by adding water p.i. to a volume of 1000 ml. The ampoules are filled with sterile filtered solution.

5 Example 21

Preparation of the di-N-methylglucamine salt solution of the iron (III) complex of diethylenetriaminepentaacetic acid 44.6 g (= 0.1 mol) of the iron (III) complex of diethylenetriaminepentaacetic acid obtained in Example 7 are suspended in 40 ml of water p.i. After the addition of 0.18 g of tromethamine hydrochloride and 39.1 g (= 0.2 mol) of N-methylglucamine are dissolved in neutral, make up to volume with water p.i. to a volume of 100 ml, transfer to ampoules and heat sterilize.

Example 22

Preparation of a gadolinium (III) complex solution 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 p.i. warming. The solution is transferred to ampoules and heat sterilized.

Example 23

Preparation of the N-methylglucamine salt solution of the gadolium (III) -25 complex of ethylenediaminetetraacetic acid 38.52 g (= 60 mmol) of the substance described in Example 10 are dissolved in 70 ml of water p.i. After the addition of 0.12 g of tromethamine, make up to 100 ml with water p.i., transfer the solution to ampoules and heat sterilize.

Example 24

Preparation of di-N-methylglucamine salt solution of diethylenetriaminepentaacetic acid dysprosium (III) complex 35.77 g (= 60 mmol) of diethylenetriaminepentaacetic acid dysprosium (III) complex (moisture 8.0%) are suspended in 70 ml of water p.i. and reconstituted at pH 7.5 by adding 21.2 g (= 120 mmol) of N-methylglucamine. It is then supplemented with water p.i. to a volume of 100 ml, transfer the solution to ampoules and heat sterile-5.

Example 25

Preparation of the N-methylglucamine salt solution of the gadolinium (III) complex of trans-1,2-cyclohexylenediaminetetraacetic acid 10,555.8 g (= 0.8 mol) of the salt described in Example 8 are dissolved in 1000 ml of water p.i. After the solution is filtered through a pyrogen filter, it is filled into ampoules and heat sterilized.

Example 26 Preparation of 1,10-diaza-4,7-dithiadecane-1,1,10,10-tetraacetic acid ruthenium (III) complex N-methylglucamine salt solution 15.6 g (= 0.03 mol) 1, The ruthenium (III) complex of 10-diaza-4,7-dithiadecane-1,1,10,10-tetraacetic acid is suspended in 50 ml of water. and reconstituted at pH 7.5 by adding 5.9 g (= 0.03 mol) of N-methylglucamine. Make up with water p.i. to a volume of 1000 ml, fill the ampoules with the solution and heat sterilize. Example 27 Preparation of a solution of the dililine salt of diethylenetriaminepentaacetic acid gadolinium (III) complex 273.8 g (= 0.5 mol) of the gadolinium (III) complex of diethylenetriaminepentaacetic acid are suspended in 500 ml of water p.i. 292.4 g (= 1 mol) of lysine are added, the mixture is stirred for several hours with gentle heating and then made up to volume with water p.i. To 1000 ml. The solution is filled into flasks and heat sterilized.

30 79026

Example 28

Preparation of a tri-N-methylglucamine salt solution of diethylenetriaminepentaacetic acid molybdenum (VI) complex 18.8 g (= 0.28 mol) of the complex (OH) ^ · “<314H23N3 <^ lo7 suspension are suspended in 50 ml of water p.i. and dissolved in a neutral solution by adding 16.4 g (= 0.84 mol) of N-methylglucamine. 0.15 g of tromethamine is added, made up to volume with water p.i. to a volume of 100 ml, perform sterile filtration on 10 solutions and fill the ampoules with it.

Example 29

Preparation of the disodium salt solution of the manganese (II) complex of ethylenediaminetetraacetic acid 343.2 g (= 1 mol) of the manganese (II) complex of ethylenediaminetetraacetic acid are suspended in 500 ml of water p.i. and dissolved in a neutral solution by adding portionwise 80 g (= 2 mol) of sodium hydroxide. After the addition of 1.5 g of tromethamine, the solution is made up with water p.i. to a volume of 1000 ml by filling the flasks and heat sterilizing.

Example 30

Preparation of sodium salt solution of ethylenediaminetetraacetic acid iron (III) complex 345.7 g (= 1 mol) of ethylenediaminetetraacetic acid iron (III) complex are suspended in 500 ml of water p.i.

and dissolved in a neutral solution by adding 40 g (= 1 mol) of sodium hydroxide. After the addition of 1.5 g of tromethamine, make up the volume with water p.i. To 1000 ml, transfer to flasks and heat sterilize.

30 Example 31

Preparation of the disodium salt solution of the iron (III) complex of diethylenetriaminepentaacetic acid 334.6 g (= 0.75 mol) of the iron (III) complex of diethylenetriaminepentaacetic acid are suspended in 500 ml of water p.i. and dissolved in neutral solution by adding 60 g (= 1.5 mol) of sodium hydroxide. The volume of the solution is made up to volume with water p.i. To 1000 ml, transfer to flasks and heat sterilize.

Example 32 Preparation of a sodium salt solution of the gadolinium (III) complex of trans-1,2-cyclohexylenediaminetetraacetic acid 558.6 (= 1 mol) of the salt mentioned in Example 8 are dissolved in water p.i. supplemented to 1000 ml. The solution is filled into bottles and heat sterilized.

Example 33 Preparation of N-methylglucamine salt solution of 1,2-diphenylethylenediaminetetraacetic acid gadolinium (III) complex 396.9 g (= 500 mmol) of the salt described in Example 10 are slurried in 600 any water p.i. and dissolved by making up to 1000 ml. The solution is filled into ampoules and heat sterilized.

Example 34 Preparation of a sodium salt solution of the iron (III) complex of ethylenediaminetetraacetic acid 183.5 g (= 500 mmol) of the salt mentioned in Example 7 are slurried in 500 g of water p.i. Add 1.0 g of tromethamine, make up to volume with water p.i. To 1000 ml, fill the ampoules with the solution and heat sterilize.

Example 35

Preparation of di-N-methylglucamine salt solution of diethylenetriaminepentaacetic acid lanthanum (III) complex 309.59 g (= 500 mmol) of the salt shown in Example 5 are slurried in 650 no water p.i. and reconstituted to 1000 ml with water p.i. The solution is filled into ampoules and heat sterilized.

32 7 9 0 2 6

Example 36

Preparation of di-N-methylglucamine salt solution of diethylenetriaminepentaacetic acid bismuth (III) complex 5,692.8 g (= 700 mmol) of the salt of Example 5 are slurried in 600 ml of water p.i. and after the addition of 1.8 g of tromethamine is dissolved by making up the volume with water p.i. To 1000 ml with slight heating. The solution is filled into ampoules and heat sterilized.

10 Example 37

Preparation of di-N-methylglucamine salt solution of diethylenetriaminepentaacetic acid holmium (III) complex 662.0 g (= 700 mmol) of the salt from Example 5 are slurried in 600 ml of water p.i. and after the addition of 1.8 g of tromethamine is dissolved by making up the volume to 1000 ml with water p.i. with slight heating. The solution is filled into ampoules and heat sterilized. Example 38 Preparation of a di-N-methylglucamine salt solution of diethylenetriaminepentaacetic acid complex ytterbium (III) complex 476.9 g (= 500 mmol) of the salt shown in Example 5 are slurried in 650 ml of water p.i. and upon addition of 25 g of 1.5 g of tromethamine is dissolved by making up the volume with water p.i. To 1000 ml. The solution is filled into ampoules and heat sterilized.

Example 39

Preparation of the disodium salt solution of the diethylenetriaminepentaacetic acid lanthanum (III) -30 complex 573.2 g (= 1000 mmol) of the salt described in Example 6. . The slurry is slurried in 650 mL of water and dissolved by making up to 1000 mL with water p.i. The solution is filled into ampoules and heat sterilized.

33 7 9 0 2 6

Example 40

Preparation of the disodium salt solution of diethylenetriaminepentaacetic acid dysprosium (III) complex 477.4 g (= 800 mmol) of the salt shown in Example 6 are slurried in 600 ml of water p.i. and completely dissolved in this water p.i. to a volume of 1000 ml. The solution is filled into ampoules and heat sterilized.

Example 41

Preparation of the disodium salt solution of the diethylenetriaminepentaacetic acid holmium (III) -10 complex 299.6 g (= 500 mmol) of the salt shown in Example 6 are slurried in 500 ml of water p.i. and dissolved by making up the volume with water p.i. 1000 million. The solution is filled into ampoules and heat sterilized.

15 Example 42

Preparation of the disodium salt solution of the ytterbium (III) complex of diethylenetriaminepentaacetic acid 303.5 g (= 500 mmol) of the salt shown in Example 6 are slurried in 500 ml of water p.i. and dissolved by making up the volume to 1000 ml with water p.i. The solution is filled into ampoules and heat sterilized.

Example 43

Preparation of tetra-N-methylglucamine-25 salt solution of ethylenitrinitrilotetrakis (methanethosphonic acid) gadolinium (III) complex 137.1 g (= 100 mmol) of the salt shown in Example 12 are suspended in 500 ml of water and, after adding 0.8 g of tromethamine, are dissolved by adding 1000 ml. with water pi The solution is filled into ampoules and heat-sterilized.

Example 44 Preparation of a complex solution of N '- (2-hydroxyethyl) ethylenediamine-Ν, Ν, Ν1-tri-acetic acid gadolinium (III) 35 1.9 g (= 6.7 mmol) of N' - (2-hydroxyethyl) ethylenediamine Dissolve -N, N, N'-triacetic acid and 1.2 g (= 3.35 mol) of 34 79026 gadolinium (III) oxide in 6 ml of water. warming. The solution is transferred to auxiliaries and heat sterilized.

Example 45 Preparation of a disodium salt solution of the manganese (II) complex of trans-1,2-cyclohexylenediaminetetraacetic acid 44.3 g (= 100 mmol) of the salt shown in Example g are slurried under nitrogen in 60 ml of water p.i. and reconstituted to 100 ml with water p.i.

The solution is transferred to ampoules and heat sterilized.

Example 46 Preparation of a sodium salt solution of 1,4,8,11-tetraazacyclotetradecane-Ν, Ν ', N ", N"' - tetraacetic acid gadolinium (III) complex 552.6 g (= 1 mol) of the salt mentioned in Example 11 dissolve in water, making up to 1000 ml. The solution is filled into flasks and heat sterilized.

Example 47 Preparation of a disodium salt solution of diethylenetriaminepentaacetic acid bismuth (III) complex 23.4 g (= 50 mmol) of bismuth (III) oxide are suspended in 50 ml of water p.i. After the addition of 39.3 g (= 100 mmol) of diethylenetriaminepentaacetic acid and 4.0 g (= 50 mmol) of sodium hydroxide, the mixture is heated to reflux until a clear solution is formed. The solution cooled to room temperature is neutralized by adding 4.0 g of sodium hydroxide and made up to volume with water p.i. To 100 ml. The solution is filled into ampoules and heat sterilized.

30 Example 48

Preparation of the disodium salt solution of the samarium (III) complex of diethylenetriaminepentaacetic acid 58.5 g (= 100 mmol) of the salt shown in Example 6 are dissolved in 65 ml of water p.i. warming. Fill li 35 79026 with water p.i. To a total volume of 100 ml, transfer to ampoules and heat sterilize.

Example 49 Preparation of 13,23-dioxo-15,18,21-tris (carboxymethyl) -5,12,15,18,21,24-di-N-methylglucamine salt solution of gadolinium (III) complex of pentaazapentatriacontanoic acid 130.4 g (= 100 mmol) of the salt shown in Example 2 is slurried in 250 ml of water pi and dissolved in warm-10. Make up with water p.i. To 500 ml, transfer the solution to ampoules and heat sterilize.

Example 50

Preparation of the di-N-methylglucamine salt solution 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 p.i. and 0.4 g of sodium chloride is added to the solution. Then make up to 100 ml with water and fill the ampoules with the solution through sterile filtration. The 280 mOsmrn solution is isoto-20 with blood.

Example 51

Preparation of the disodium salt solution of diethylenetrityltrilopenta (methanethosphonic acid) -gadolinium (III) complex 38.57 g (= 50 mmol) of the substance described in Example 12 are slurried in 50 ml of water p.i. The pH is adjusted to 7.2 by adding sodium hydroxide powder and made up to volume with water p.i. to a volume of 100 ml. The solution is transferred to ampoules and heat sterilized.

30 Example 52

Preparation of the trisodium salt solution of the manganese (II) complex of diethylenetriaminepentaacetic acid 39.3 g (= 100 mmol) of diethylenetriaminepentaacetic acid are suspended in 100 ml of water p.i. and 11.5 g of manganese (II) carbonate are added. Heat to 95 ° C and add dropwise 300 ml of 1N sodium hydroxide solution. The neutral solution is sterile filtered and filled into ampoules.

Example 53 Powder composition for the preparation of a suspension 4,000 g of diethylenetriaminepentaacetic acid gadolinium (III) complex (moisture 8.0%) 3.895 g of sucrose 0.100 g of polyoxyethylene polyoxypropylene polymer 10 0.005 g of flavors 8,000 g

Example 54

Preparation of a complex solution of the gadolinium (III) complex solution of diethylenetriaminepentaacetic acid and human serum conjugate To 20 ml of a solution of 3 mg of protein in 0.05 M sodium bicarbonate buffer (pH 7-8) is added 10 mg of 1,5-bis (2.6 -dioxomorpholino) -3-20 azapentane-3-acetic acid. Stir for 30 minutes at room temperature and then dialyze against 0.3 M sodium phosphate buffer. 50 mg of gadolinium (III) acetate are then added and purified by gel chromatography on a Sephadex G25 column. The resulting fraction is sterile filtered and transferred to multivials.

Freeze-drying gives a storage-resistant dry preparation.

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

30 Example 55

Preparation of a complex salt solution of diethylenetriaminepentaacetic acid (DTPA) and monoclonal antibody conjugate gadolinium (III) in 20 μl of a solution of 0.3 mg of mono-35 clonal antibody in 0.05 M sodium carbonate buffer (pH 7-8), 1 mg of DTPA is added to the

II

37,79026 anhydride (prepared e.g. from DTPA and isobutyl chloroformate) and stirred for 30 minutes at room temperature. Dialyze against 0.3 M sodium phosphate drop buffer and add 2 mg of ethylenediaminetetraacetic acid (EDTA) gadolinium (III) complex to the resulting antibody fraction. After purification by gel chromatography on Sephadex (G25), the sterile filtered solution is transferred to multivials and lyophilized.

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

When a manganese (II) complex of ethylenediaminetetraacetic acid is used, manganese (II) complexes of antibodies conjugated to DTPA or CDTA are obtained analogously.

Example 56 Preparation of a complex solution of gadolinium (III) conjugate of 1-phenylethylenediaminetetraacetic acid and immunoglobulin

In J. Med. Chem. 1974, Vol. 17, p. 1307, prepare a 2% solution of the protein in 0.12 molar sodium bicarbonate solution containing 0.01 mol of ethylenediaminetetraacetic acid, cool to + 4 ° C and add an equivalent amount of freshly prepared ice-cold to the protein. Diazonium salt solution of 1- (p-aminophenyl) ethylenediaminetetraacetic acid dropwise. Stir overnight at + 4 ° C (pH 8.1) and then dialyze against 0.1 M sodium citrate solution. At the end of the dialysis, an excess of gadolinium (III) chloride is added to the conjugate solution and filtered to remove ions. The multivials are then filled with sterile filtered solution and lyophilized.

38 79026

Example 57

Preparation of a colloidal dispersion of mn-CDTA-lipid conjugate 0.1 mmol of distearoylphosphatidylethanolamine 5 and 0.1 mmol of trans-1,2-diaminocyclohexanetraacetic acid bisanhydride are stirred in 50 ml of water for 24 hours at room temperature. Add 0.1 mmol of manganese (II) carbonate and stir again at room temperature for 6 hours. After purification on a Sephadex G50 column, the multivials are filled with sterile-filtered solution and lyophilized.

Similarly, a colloidal dispersion of gadolinium-DTPA lipid conjugate is obtained with gadolinium (III) oxide.

Example 58 Preparation of Gadolinium DTPA-Labeled Liposomes

In Proc. Natl. Acad. Sci. U.S. 75, 4194, a lipid mixture of 75 mole percent egg phosphatidylcholine and 25 mole to 20 lipol% cholesterol is prepared as a dry matter. From this, 500 mg of 30 ml of diethyl ether are dissolved and 3 ml of a 0.1 molar solution of the di-N-methylglucamine salt of the gadolinium (III) complex of diethylenetriaminepentaacetic acid in water, p.i., are added dropwise in an ultrasonic bath. After the entire addition has been made, the sonication is continued for a further 10 minutes and then evaporated on a rotary evaporator. The gel residue is suspended in 0.125 molar sodium chloride solution and re-purified at 0 ° C by centrifugation (2000 g / 20 minutes) of non-encapsulated contrast agents. The liposomes thus obtained are then freeze-dried in multivalents. Administration is as a colloidal dispersion in 0.9% w / v saline solution.

Claims (12)

39 7 9 026 A diagnostic agent comprising at least one complex salt of the general formula I or II X-CH-CH-X 2/2 NAN (I), N-CHR-CH 2 -CH 2 -V 10 or n ( ch2x) 3 (II), wherein X represents a group -COOY, -PO3HY or -CONHOY, in which Y represents a hydrogen atom, a metal ion equivalent and / or an alkali metal or alkaline earth metal cation or an organic base or amino acid cation, and A represents a group 20 -CHR.-CHR--, -CH -CH- (ZCH -CH) -2 3 2 2 2 2 mn (ch2x) 2 ch2-ch2-n (ch2x) 2 -ch2-ch-ch2- or -ch2- ch2-n-ch2-ch2-25 wherein X is as defined above, the symbols R1 denote hydrogen atoms or methyl groups, R2 and R3 together denote a trimethylene group or a tetramethylene group or they denote hydrogen atoms, lower alkyl groups, phenyl groups or benzyl groups, or R2 represents a hydrogen atom and R3 represents a group - (CH2) -CH.-W protein 2 p 6 4 wherein p is 0 or 1, W is -NN-, -NHCOCH2 ~ or -NHCS- 3a 35 40 79026 a porteine residue, and m represents a number 1, 2 or 3, Z represents an oxygen atom or a sulfur atom or a group> NCH 2 X or> NCH 2 CH 2 OR 4 in which X represents the same as defined above and represents a lower alkyl group, and in which V represents the same as X or a group -CH 2 OH, -CONH (CH) X or -COB 10 wherein X is as defined above, B is a protein or lipid residue and n is a number from 1 to 12, or if R 1, R 2 and R 2 are hydrogen atoms each V together represents a group 15 CH0X CH0X l Δ | * · - (CH-) -N-CH - CH - N- (CHO) -2 w 2 2 2 w where X is as defined above and w is 1, 2 or 3, provided that at least two of the substituents Y denote the metal ion equivalents of the element of order numbers 21 to 29, 42, 44 or 57 to 83, the general formula I not, however, denoting ethylenediaminetetramethylenephosphonic acid or diethylene pentamethylenephosphonic acid, optionally dissolved in conventional galenic additives or dissolved in aqueous suspension . A diagnostic agent according to claim 1 for use in ultrasound diagnostics. A diagnostic agent according to claim 1, comprising an element having an order number of 21 to 29, 42, 44 or 58 to 70 for use in NMR diagnostics. A diagnostic agent according to claim 1, comprising an element having an order number of 57 to 83 for use in X-ray diagnostics. 41 79026 Diagnostic agent according to Claim 1, characterized in that it contains the di-N-methylglucamine salt of the manganese (II) complex of ethylenediaminetetraacetic acid, the di-N-methylglucamine salt of diethylenetriaminepentaacetic acid ga-dolinium (III) complex, diethylenetriamine tritium III) the di-N-methylglucamine salt of the complex, the monosodium / mono-N-methylglucamine mixed salt of the diethylenetriaminepenacetic acid gadolinium (III) complex, the gadolinium (III) complex of diethylene triacetic acid diethylenetriaminepentaacetic acid iron (III) complex di-N-methylglucamine salt, diethylenetriaminepentaacetic acid iron (III) complex di-15 sodium salt, diethylenetriaminea pentaacetic acid manganese-acetyl , ethylenediaminetetraacetate the disodium salt of the manganese (II) complex of the acid, the di-N-methylglucamine salt of the diethylenetriamine pentaethic-20 bismuth bismuth (III) complex, the trans (III) complex disodium salt, 1,4,7,10-tetraazacyclododecane-25 tetraacetic acid gadolinium (III) complex N-methylglucamine salt, trans-1,2-cyclohexylenediamine tetraacetic acid manganese (II) complex disodium salt , the disodium salt of the bismuth (III) complex of di-ethylenetriaminepentaacetic acid, 13,23-dioxo-15,18,21-tris (carboxymethylmethyl) -12,15,18,21,24-pentaazazapentatriacontan diacid gadolinium ( III) the di-N-methylglucamine salt of the complex, the sodium salt of the 1,4,7,10-tetraazacyclododecanetraacetic acid gadolinium (III) complex, the gadolinium (III) complex of the conjugate of diethylenetriaminepentaacetic acid with immunoglobulin, 4279026 gadolinium (III) complex of the conjugate of k-acid with human serum albumin, gadolinium (III) complex of the conjugate of diethylenetriaminepentaacetic acid with the monoclonal antibody, ) complex, manganese (II) complex of the lipid conjugate of trans-1,2-cyclohexylenediaminetetraacetic acid, liposomes bearing the diethylenetriaminepentaacetic acid gadolinium (III) complex, diethylene tri-10-amine pentaacetic acid holiumum disodium salt, di-N-methylglucamine salt of diethylenetriaminepentaacetic acid ytterbium (III) complex, disodium salt of diethylenetriaminepentaacetic acid samarium (III) -15 complex or 13,23-dioxo-15,18,21-tris (carboxymethyl) , 21,24-Penta-azapentatria-contanedioic acid gadolinium (III) complex sin disodium salt. Diagnostic agent according to Claims 1 to 5, characterized in that it contains 1 μmol-1 mol of complex salt per liter. Process for the preparation of a diagnostic agent according to Claims 1 to 5, characterized in that the complex salt dissolved or suspended in water or physiological saline is brought into a form suitable for intravascular or oral administration together with customary galenical additives. Complex salts of the general formula I X-CH 2 CH_-X Ya- / (I) / \ V-CHR ^ CHR ^ -V wherein X, A, V and R ^ have the same meaning as in claim 1, provided that they have 3-12 a substituent Y, at least two of which are metal ion equivalents of an element of the order 21-29, 42, 44 or 57-83, and in addition at least one of the substituents Y is a cation of an organic base or an amino-5 acid, optionally the remaining Y substituents being hydrogen; or cations of an inorganic base, with the exception of the ammonium salts of the lanthanide complexes of ethylenediaminetetraacetic acid. Complex salt according to Claim 8, characterized in that it is the N-methylglucamine salt of the gadenedium (III) complex of ethylenediaminetetraacetic acid, the di-N-methylglucamine salt of the gadolinium (III) complex of diethylenetriaminepentaacetic acid, the diethylenetriamine pentaacetate of diethylenetriamine -methylglucamine salt, ethylenediaminetetraacetic acid manganese (II) complex di-N-methylglucamine salt, diethylenetriaminepentaacetic acid manganese (II) complex tri-N-methylglucamine salt, ethylenediaminetetraacetic acid (III) complex of N-methylglucamine salt, diethylenetriaminepentaacetic acid holmium (III) complex of di-N-methylglucamine salt, diethylenetriaminepentaacetic acid gadolinium-diacinyl-diacinylate (III) a complex of the di-N-methylglucamine salt of the complex, or the N-methylglucamine salt of the 1,4,7,10-tetraazacyclododecanetraacetic acid gadolinium (III) complex. Complex salt according to Claim 8, characterized in that it is a mixed N-methylglucamine sodium salt of the gadolinium (III) complex of diethylenetriaminepentaacetic acid. 44 79026 Use of a complex salt of formula I as defined in claim 1 for the preparation of an agent for use in NMR or ultrasound diagnostics. Use of a complex salt of formula 5 II as defined in claim 1 for the preparation of an agent for use in NMR or ultrasound diagnostics. 45 79026