NL9900020A - NMR, X=ray and ultrasonic diagnostic compsns. - Google Patents

Abstract

Diagnostic compsns. contg. one or more complex salts (I) dissolved or suspended in an H2O-contg. medium are new, where (I) are salts of the anion of a complex-forming acid and one or more central ions of elements with atomic nos. of 21-29, 42, 44 or 57-83 and opt. one or more cations of inorganic and/or organic bases or amino acids. Complex salts of formula (Ia) are new (where X is COOY, PO3HY or CONHOY; A is CHR2CHR3, CH2CH2(ZCH2CH2)m, CH2CH(N(CH2X)2)CH2 or CH2CH2N(CH2CH2N(CH2X)2)CH2CH2; R1 is H or Me; R2 and R3 are H, lower alkyl, phenyl or benzyl, or R2+R3 is (CH2)3 or (CH2)4, or R2 is H and R3 is (CH2)p-C6H4-W-protein; p= 0 or 1; W is NH, NHCOCH2 or NHCS; m= 1-3; Z is O, S, NCH2X or NCH2CH2OR4; R4 is lower alkyl; V is as defined for X or is CH2OH, CONH(CH2)nX or COB, or V+V is (CH2)wN(CH2X)CH2CH2N(CH2X)(CH2)w when R1= R2= R3= H; B is a protein or lipid residue; n= 1-12; w= 1-3; with the proviso that there are 3-12 Y substituents, at least 2 being an equiv. of an ion of a metal with an atomic no. of 21-29, 32, 3 44 or 57-83 and at least one being a cation of an organic base or amino acid, any others being H or cations of an inorganic base). The compsns. may be used as NMR contrast agents for nuclear spin tomography, as X-ray contrast agents for radiography or as ultrasonic diagnostic agents.

Description

Title: Diagnostic

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

Complexes or their salts have been used in medicine for a long time, for example as an aid for the administration of sparingly soluble ions (for example iron) and as antidotes (calcium or zinc complexes are preferred here) to detoxify by mistake. incorporation of heavy metals or their radioactive isotopes. It has now been found that physiologically tolerable complex salts, from the anion of a complexing acid and one or more central ions of an element with the atomic numbers 21 to 29, 42, 44 or 57 to 83 and optionally of one or more cations of an inorganic and / or organic base or amino acid, against which there are no physiological objections, are surprisingly excellent for the preparation of diagnostic agents suitable for use in NMR or X-ray diagnostics or ultrasonic diagnostics.

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

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

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

Both the agents according to the invention intended for use in NMR diagnostics and those intended for use in X-ray diagnostics are suitable for use in ultrasonic diagnostics.

Suitable complexing acids are those representatives which are usually used for complexing the aforementioned central ions. Suitable complexing acids are, for example, those which contain 3 to 12, preferably 3 to 8 methylene phosphonic acid groups, methylene carbohydroxamic acid groups, carboxyethylidene groups, or in particular carbomethylene groups, one, two or three of which are each attached to a nitrogen atom supporting the complex formation. If three of the azidic groups are bonded to a nitrogen atom, then the complexing acids underlying the complex salts of the general formula 2 according to claim 2 are present. If in each case only one or two of the azidic groups are bonded to a nitrogen atom, then the nitrogen via an optionally substituted ethylene or via at most four ethylene units separated by a nitrogen or oxygen or sulfur atom supporting the complex formation is attached to a nitrogen atom. another nitrogen atom.

Preferred complexing acids of this type are those of the general formula 1 according to claim 2.

The complexing acids can be crosslinked as conjugates with biomolecules, which are known to greatly increase their concentration in the organ or organ portion to be examined. Such biomolecules are, for example, hormones such as insulin, prostaglandin, steroid hormones, amino sugars, peptides, proteins or lipids. Particular emphasis should be placed on conjugates with albumin such as human serum albumin, antibodies such as, for example, monoclonal, tumor-specific antigen or antimyosine. The diagnostic agents formed therefrom are suitable, for example, for use in tumor and infarct diagnostics. For liver research, suitable conjugates or cage compounds with liposomes are used, for example, which are used as unilamellar or multilamellar phosphatidylcholine cholesterol vesicles. The conjugate formation takes place either via a carboxyl group of the complexing acid, or in the case of the proteins or peptides also via a group:

as defined in claim 2. In the conjugate formation of the complexing acids with proteins, peptides or lipids, various acid residues can be partially bound to the macromolecular biomolecule. In this case, any complexing acid residue can carry a central ion. If the complexing acids are not bound to biomolecules, they optionally carry two central ions, in particular a central ion.

Suitable complex salts of the general formula 1 according to claim 2 are, for example, those representatives of the general formula la, wherein X, V, R 1, R 2 and R 3 have the meaning mentioned in claim 2.

For the preparation of the complex salts of the general formula la, the following complexing acids are suitable, inter alia: ethylenediamine-tetraacetic acid, ethylenediamine-tetra-acetamic acid, trans-1,2-cyclohexylenediamine-tetraacetic acid, DL-2,3 -butylenediamine-tetra-acetic acid, DL-1,2-butylenediamine-tetra-acetic acid, DL-1,2,2-propylene-diamine-tetra-acetic acid, 1,2-diphenylethylene-diamine-tetra-acetic acid, ethylenedinitrilotetrakis (methane phosphonic acid) ) and N- (2-hydroxyethyl) -ethylenediamine-tri-acetic acid.

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

The following complexing acids are suitable for the preparation of the complex salts of the general formula Ib: diethylenetriamine-penta-acetic acid, triethylene-tetramine-hexa-acetic acid, tetraethylene-pentamine-hepta-acetic acid, 13.23-dixo -15,18,21-tris (carboxymethyl) -12,15,18,21,24-penta-aza-penta-triacontanedioic acid, 3,9-bis (1-carboxyethyl) -3,6,9-tri-aza -undanedioic acid, diethylenetriamine-pentakis- (methylene phosphonic acid), 1,10-diaza-4, 7-dioxadecane-1,1,1,10,10-tetraacetic acid and 1,110-diaza-4,7-dithiadecane-1,1 , 10,10-tetraacetic acid.

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

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

If not all azidic hydrogen atoms of the complexing acid are substituted by the central ion or ions, it is expedient to increase the solubility of the complex salt the remaining hydrogen atoms by cations of inorganic and / or organic bases or amino acids against which cations no physiological objection. 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, for example, ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethyl glucamine or in particular N-methyl glucamine. Suitable cations of amino acids are, for example, those of the lysine, arginine or ornithine.

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

For example, the preparation of 13,23-dioxo-15,18,21-tris (carboxymethyl) -12,15,18,21,24-penta-aza-penta-triacontane diacid takes place according to the method described by R.A. Bulman et al. In Naturwissenschaften 68, (1981) 483 proposed improved form:

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

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

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 reactivate an activated biomolecule with the complexing acid.

For conjugation with proteins, substituents with the structure -C 8 H 4 N 2+ or CeHoNHCOC 4 -halogen are also available.

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

If azide groups are still present in the complex salt obtained, it is often expedient to convert the acid complex salt into neutral complex salts by means of inorganic and / or organic bases or amino acids, which form cations, against which physiologically no objection exists. and isolate it. In many cases this is even unavoidable, since the dissociation of the complex salt is reduced to neutral by shifting the pH value, so that it is only in this way that the isolation of uniform products or at least the purification thereof is made possible.

It is expedient for the preparation to take place with the aid of organic bases or basic amino acids. However, it can also be advantageous to carry out the neutralization by means of inorganic bases (hydroxides, carbonates or hydrogen carbonates) of sodium, potassium or lithium.

To prepare the neutral salts, for example, to the acid complex salts, dissolved or suspended in water, so much of the desired base can be added that the neutral point is reached. The resulting solution can then be evaporated to dryness under reduced pressure. It is often advantageous for the neutral salts formed by adding water-miscible solvents, such as, for example, low alcohols (methanol, ethanol, isopropanol, etc.), low ketones (acetone, etc.), polar ethers (tetrahydrofuran, dioxane, 1, etc.). 2-dimethoxyethane, etc.) and thus obtain easily crystallizable and easily purified crystallization products. It has been found that it is particularly advantageous to add the desired base to the reaction mixture already during complex formation and thereby to save a process step.

When the acid complex salts contain several free azide groups, it is often expedient to prepare neutral mixed salts which contain both inorganic and organic cations, which are physiologically safe, as counter ions. This can be done, for example, by converting the complexing acid into an aqueous suspension or solution, with the oxide or salt of the element providing the central ion, and with half the amount of an organic base required for neutralization isolating the complex salt formed, purifying it if desired and then adding the required amount of inorganic base to it to completely neutralize it. The order of addition of the bases can also be reversed.

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

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 in order to carry out chelating in such a way that the salts and salt solutions according to the invention are practically free from non-complexed, toxic-acting metal ions. This can be guaranteed, for example, by means of color indicators, such as xylenol orange, by control titrations during the preparation process. The invention therefore also relates to processes for the preparation of the complex compound and its salts. The final safety remains a purification of the isolated complex salt.

When suspensions of the complex salts in water or in a physiological saline solution are desired for oral administration or other purposes, a slightly soluble complex salt with one or more excipients and / or surfactants and / or flavoring agents customary in galenic pharmacy becomes of the taste.

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

The agents according to the invention meet - according to claim 4 - the multiple conditions for being suitable as a contrast agent for nuclear spinography. Thus, after oral or parenteral administration, they are excellently suited to improve the image intensity obtained with the aid of the nuclear spinograph by increasing the signal intensity. Furthermore, they show the strong effect that is necessary to burden the bodies with the smallest possible quantities of foreign substances and the good tolerance that is necessary to maintain the non-invasive character of the study (the J. Comput. Tomography For example, 5.6: 543-46 (1981), in Radiology, 144 343 (1982) and in Brevet Special, the medications No. 484 M (1960) indicated are too toxic). The good solubility in water of the agents according to the invention makes it possible to prepare highly concentrated solutions, thereby keeping the volume load of the cycle within defensible limits and to compensate for the dilution by the body fluid, i.e. NMR diagnostics must be 100 - 1000 times more soluble in water than the compounds for NMR spectroscopy. Furthermore, the agents according to the invention exhibit not only a high stability in vitro, but also a surprisingly high stability in vivo, so that an ions that are not covalently bound in the complexes in themselves or released within themselves are toxic within 24 hours. in which - as pharmacological research has shown - the new contrast agents are completely excreted again, only takes place extremely slowly. The conjugates with proteins and antibodies used for tumor diagnosis, for example, effect a surprisingly large signal amplification at such a low dosage that solutions with correspondingly lower concentrations can be used here.

The agents according to the invention are - in accordance with claim 5 - extremely suitable as X-ray contrast agents, in which particular emphasis must be placed on the fact that no indications can thereby be given for the anaphylaxis-like reactions in biochemical-pharmacological known to the iodine-containing contrast agents. investigation. They are particularly valuable because of the favorable absorption properties in areas of higher tube voltages for digital subtraction techniques.

The means according to the invention are - according to claim 3 - also suitable as ultrasonic diagnostics because of their property to influence the ultrasonic speed favorably.

In contrast to conventional X-ray diagnostics with shading contrast agents, there is no linear dependence on signal amplification due to the applied concentration in NMR diagnostics with paramagnetic contrast agents. As control research shows, an increase in the dose administered does not unconditionally lead to signal enhancement, and with a large dose of paramagnetic contrast agent, it may even lead to a quenching of the signal. It was surprising on this basis that some pathological processes only after the administration of larger doses than the doses indicated in British Patent Specification 71 564 (which can be 0.001 mmol / kg to 5 mmol / kg) of a strong paramagnetic contrast agent according to the invention become visible. For example, evidence of a defective blood-brain barrier in the area of cranial abscess can only be applied after administration of 0.05 - 2.5 mmol / kg, preferably 0.1 - 0.5 mmol / kg, of paramagnetic complex salts such as, for example, gadolinium-diethylene-triamine-pentaacetic acid or manganese-1,2-cyclohexylenediamino-tetraacetic acid are supplied in the form of their water-soluble salts. For a dose of more than 0.1 mmol / kg, solutions of higher concentrations up to 1 mol / liter, preferably 0.25 - 0.75 mol / liter, are required, since only in this way the volume load is reduced and the handling of the injection solution is guaranteed.

Particularly low doses (less than 1 mg / kg) and thus lower concentrated solutions (1 pmol / liter to 5 mmol / liter) than indicated in British Patent Specification 71,564 are for organ-specific NMR diagnostics, for example, for detecting tumors and from heart attacks.

The following exemplary embodiments serve to further illustrate the invention.

EXAMPLE 1

Preparation of the gadolinium III complex of nitrilo-N.N.N-tri-acetic acid. C «HfiGdNOfi

A suspension of 36.2 g (= 100 mmol) of gadolinium oxide (Gd2C> 3) and 38.2 g (= 200 mmol) of nitrilotriacetic acid in 1.2 liters of water was stirred at 90 ° C to 100 ° C heated and stirred at this temperature for 48 hours. The undissolved substance was then filtered off over activated carbon and the filtrate was evaporated. The amorphous residue was powdered.

Yield: 60 g (87% of theory);

Melting point: 300 ° C;

Gadolinium: calculated 45.5%, found 44.9%

The iron-II complex of the nitrilo-N, N, N-triacetic acid was obtained with the aid of iron-III chloride, FeCE.

EXAMPLE II

Preparation of the disodium sodium of the gadolinium III complex of 13.23-dioxo-15.18.21-tris (carboxymethyl) -12.15.18.21.24-penta-aza-nenta-triacontane diacid. CMHfioGdNsOi? .. 2Na

In 400 ml of water, 15.2 g (+ 20 mmol) of 13.23-dioxo-15.18.21-tris (carboxymethyl) -12.15.18.21.24-penta-aza-penta-triacontanedioic acid was added suspended and heated to 95 ° C. 7.43 g (= 20 mmol) of gadolinium III chloride hexahydrate, dissolved in 60 ml of water, were then slowly added dropwise. The mixture was kept at this temperature for 2 hours, after which 60 ml of 1 n-sodium hydroxide solution was added to neutralize the hydrochloric acid formed.

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

Gadolmium III complex of 13.23-dioxo-15.18.21-tris (carboxymethyl) -12.15.18.21.24-penta-aza-pentatriacontane diacid.

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

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

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

Similarly, with N-methylglucamine instead of caustic soda, the di-N-methylglucamine salt of the gadolinium-III complex of 13.23-dioxo-15.18.21-tris (carboxymethyl) -12.15.18.21 , 24-penta-aza-penta-triacontanedioic acid, C 50 H 20 O 4.

EXAMPLE III

Preparation of the di-sodium salt of the gadolinium III complex of 3,9-bis (1-carboxymethyl-6-carboxymethyl-3,6,9-triaza-undecanedioic acid. Cir, H22GdN5O2.2Na

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

Analysis: C 18 H 24 GdN 3 O (Calculated) C 33.39, H 4.20, Gd 27.32, N 7.30 (Found) C 33.25, H 4.49, Gd 27.42, N 7.21

57.6 g (= 0.1 mole) of the chelate was introduced into a solution of 0.1 mole of sodium hydroxide in 100 ml of water. By adding a further 0.1 mol of sodium hydroxide powder, the pH of the solution was adjusted to a pH of 7.5, after which the solution was boiled and ethanol was added until lasting turbidity. After stirring for several hours in an ice bath, the crystallization product was filtered off with suction, washed with ethanol and dried under reduced pressure. The di-sodium salt was obtained in quantitative yield as a white powder.

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

EXAMPLE IV

Preparation of the di-morpholine salt of the gadolinium III complex of 3,9-bis (1-carboxymethyl) -6-carboxymethyl-3,6,9-triaza-undecanic diacid. C ^ iH49.GdNsOig

17.4 g (= 0.2 mol) of morpholine were dissolved in 50 ml of water. Then 42.1 g (= 0.1 mole) of 3,9-bis (1-carboxyethyl) -6-carboxymethyl-3,6,9-triaza-undecanedioic acid and then 18.2 g (= 0.05 mole) gadolinium III oxide and was refluxed until a clear solution was formed. Acetone was then added dropwise to persistent turbidity. After stirring for several hours in an ice bath, the crystallization product was filtered off with suction, washed with acetone and dried under reduced pressure. The dimorpholine salt was obtained in quantitative yield as a white powder.

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

Example V

Preparation of the di-N-methylglucamine salt of the gadolinium III complex of diethylenetriamine-N.N., N1 -N ".N" -pentaacetic acid. C28H54GdNsOao

39.3 g (= 100 mmol) of diethyl triamine, N, N, N ', N ", N" pentaacetic acid were suspended in 200 ml of water, and 19.5 g (= 100 mmol) of N-methylglucamine was added. Then 18.12 g (= 50 mmol) of gadolinium III oxide, Gd 2 O 3, were added portionwise and the resulting suspension was heated to 95 ° C. After about 1 hour, another 19.5 g (= 100 mmol) of N-methylglucamine was added and a clear solution was obtained after heating for 2 hours. After complete conversion (control with xylenol orange), the small amount of undissolved substance was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was redissolved in 100 ml of water and introduced into 250 ml of ethanol with stirring. After cooling for several hours, the crystallization product was filtered off with suction, washed with cold ethanol and dried under reduced pressure at 60 ° C. 92.7 g (99% of theory) of a white powder with a non-characteristic melting point were obtained.

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

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

Similarly were obtained with dysprosium III oxide, Dy 2 O 3: the di-N-methylglucamine salt of the dysprosium III complex of diethylenetriamine N, N, N ', N ", N" -pentaacetic acid, C28Hr> 4DyN502O ; with lanthanum III oxide, La 2 O 3: the di-N-methylglucamine salt of the lanthanum III complex of diethylene triamine N, N, N ', N ", N" -pentaacetic acid, C 28 H 54 LaN 50 O; with ytterbium III oxide, Yn 2 O 3 '.

the di-N-methylglucamine salt of the ytterbium III complex of diethylene triamine-N, N, N ', N ", N" -pentaacetic acid, C 28 Hr> 4 YbNr 3 O 30; with samarium III oxide, Sm 2 O 3: the di-N-methylglucamine salt of the samarium III complex of diethylene triamine N, N, N ', N ", N" -pentaacetic acid, C 25 H 54 SmN 5 O 20; with holmium III oxide, H02O3: the di-N-methylglucamine salt of the holmium II1 complex of diethylene triamine-N, N, N ', N ", N" -pentaacetic acid, C28H54H0N5O20; with bismuth III-oxide, B12O3: the di-N-methylglucamine salt of the bismuth III complex of diethylene triamine-N, N, N ', N ", N" -pentaacetic acid, C28H54B1N5O20; with gadolinium * III oxide, Gd2O3.

the tri-N-methylglucamine salt of the galodinium III complex of triethylene-tetramine-N, N, N "N", N '", N'" - hexa-acetic acid, C39 H78 GdN7027;

Furthermore, with holmium III oxide, H02O3 and ethanolamine instead of N-methylglucamine, the diethanolamine salt of the holmium III complex of diethylenetetramine-N, N, N ', N', N ', N', N '- N' - penta- acetic acid, C 18 H 34 HoN 8 O 12; with gadolinium III oxide, Gd2 O5, and lysine instead of n-methyl glucamine: the didysin salt of the gadolinium III complex of diethylenetriamine N, N, N ', N ", N" -pentaacetic acid, C26H4sGdN70i4.

Using diethanolamine was obtained the diethanolamine salt of the holmium III complex of diethylenetriamine-pentaacetic acid, C 22 H 42 HNO 5 O 4.

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

Example VI

Preparation of the disodium salt of the gadolinium III complex of disethylene triamine N, N, N ", N". N "-penta-acetic acid, CnHiaGdNsOm. 2Na

18.2 g (= 0.05 mole) of gadolinium III oxide and 39.3 g (= 0.1 mole) of diethylenetriamine-pentaacetic acid were suspended in 110 ml of water, followed by refluxing for 1 hour. The clear solution was cooled and brought to a pH of 7.5 by adding about 80 ml of 5 n sodium hydroxide solution. The mixture was then boiled again and 250 ml of ethanol were added dropwise. After stirring for several hours in an ice bath, the crystallization product was filtered off with suction, washed with ice-cold ethanol and dried under reduced pressure at 60 ° C. In quantitative yield, a white powder was obtained, which did not melt to 300 ° C.

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

Similarly obtained with dysprosium III oxide, Dy 2 O 3: the di-sodium salt of the dysprosium III complex of diethylenetriamine N, N, N ', N ", N" -pentaacetic acid

Ci / iHieDyNeO10. 2Na: with lanthanum III oxide, La 2 O 3: the di-sodium salt of the lanthanum III complex of diethylenetriamine N, N, N ', N ", N" -pentaacetic acid

CnHisLaNsO 10. 2Na; with holmium III oxide, H02O3: the di-sodium salt of the holmium III complex of diethylenetriamine N, N, N ', N ", N" -pentaacetic acid C14H18H0N3O10. 2Na; with ytterbium III oxide, Yb2O3: the di-sodium salt of the ytterbium III complex of diethylenetriamine N, N, N ', N ", N" -pentaacetic acid

CuHieYbNsO 10. 2Na; with samarium III oxide, Sm 2 O 3: the di-sodium salt of the samarium III complex of diethylenetriamine N, N, N ', N ", N" -pentaacetic acid CHHisSmNsO 10. 2Na; with erbium III oxide, Eb2O3: the di-sodium salt of the erbium III complex of diethylenetriamine N, N, N ', N ", N" -pentaacetic acid

CuHisEbNaOio. 2Na; with gadolinium III oxide, Gd 2 O 3: the sodium salt of the di-gadolinium IIB complex of tetraethylene pentamine N, N, N "> N", N, ", NiV) Level heptaacetic acid C 22 H 30 Gd 2 N 5 O 4. After.

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

EXAMPLE VII

Preparation of the N-methylglucamine salt of the iizer-III complex of diethylene triamine-pentaacetic acid, C 21 H 17 FeN 4 O 5

35.40 g (= 90 mmol) of diethylenetriamine-pentaacetic acid were suspended in 100 ml of water, after which 24.3 g (= 90 mmol) of iron III chloride hexahydrate (FeCl3.6 H2 O) dissolved in 100 ml of water, was added. The initially dark brown suspension was heated to 95 ° C. After about 1 hour the color changed to light yellow. To neutralize the hydrochloric acid formed, 270 ml of 1 n sodium hydroxide solution was added and subsequently heated at 95 ° C for a further 3 hours. The resulting light yellow precipitate was filtered off with suction, washed with water, chloride-free and dried under reduced pressure at 60 ° C. 17.85 g (45% of theory) of a pale yellow powder, the melting point of which was above 300 ° C, was obtained.

Of the iron-II1 complex obtained, 17.85 g (= 40 mmol) was suspended in 200 ml of water, after which 7.8 g (= 40 mmol) of N-methylglucamine in the solid state were added portionwise. The mixture was then heated to 50 ° C for about 3 hours, after which an almost clear, red-brown solution was obtained, which was filtered and then evaporated to dryness under reduced pressure. The residue was dried at 50 ° C under reduced pressure. 24.3 g (95% of theory) of a red-brown powder with a melting point of 131-133 ° C were 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.

Using sodium hydroxide instead of the organic base, the following were obtained: the sodium salt of the iron-II complex of ethylenediamine-tetraacetic acid, C10 H12 FeN2 O5. After; the sodium salt of the iron-II complex of trans-1,2-cyclohexylene-diamine-tetra-acetic acid, C11 H15 Fe2 Os. After; the di-sodium salt of the iron-II1 complex of diethylenetrin trinoprenta (methane phosphonic acid), CfdFeNsOisPs · 2Na; the sodium salt of the iron-II complex of 1,1-diaza-4,7-dioxadecane-1,1,10,10-tetraacetic acid, C14 H20 FeN2 O10. After; the sodium salt of the iron-II1 complex of ethylenediamine-tetraacetate hydroxamic acid, C 10 H 18 FeNeO 3. After.

Similarly obtained with N-methylglucamine: the di-N-methylglucamine salt of the iron-II1 complex of diethylenetriamine-N, N, N ', N ", N" -pentaacetic acid, C2aH.v1FeN5O20; the N-methylglucamine salt of the iron-II1 complex of trans-1,2-cyclohexylenediamine-N, N, N ', N'-tetraacetic acid, C2] HseFeNsOie; the N-methylglucamine salt of the iron-II complex of ethylenediamine-Ν, Ν, Ν ', Ν'-tetraacetic acid, CnHaoFeNsOie; the tri-N-methylglucamine salt of the iron III complex of triethylenetetramine-N, N, N ', N ", N'", N "" - hexa-acetic acid, C: wH7aFeN7027.

Using diethanolamine instead of N-methylglucamine, the diethanolamine salt of the iron-II complex of diethylenetriamine N, N, N ", N", N ", penta-acetic acid, C 22 H 42 FeN 5 O 14 was obtained.

EXAMPLE VIII

Preparation of the N-methylglucamine salt of the gadolinium III complex of trans-1-β-cyclohexfleendiamine-N.N.N'.N'-tetra-acetic acid. CaiHafiGdNaOn

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

Analysis: (Calculated) C 36.25, H 5.22, N 6.04, Gd 22.60 (Found) C 36.40, H 5.50 N 5.98, Gd 22.52

Similarly, with sodium hydroxide solution instead of N-methylglucamine, the sodium salt of the gadolinium III complex of trans-1,2-cyclohexylenediamine-N, N, N ', N'-tetraacetic acid, C1.1H8GdN2O8.Na, obtained.

With freshly precipitated chromium III hydroxide, Cr (OH) 3, the sodium salt of the chromium III complex of ethylenediamine Ν, Ν, Ν ', Ν'-tetraacetic acid, C10 H12 CrN2 O8 Na was obtained.

EXAMPLE IX

Preparation of the di-sodium salt of the manganese-II complex of trans-1-cyclohexylenediamine-N.N.N'.N'-tetraacetic acid, CuHisMnNaOs ^ Na

In 100 ml of water, 34.6 g (= 100 mmol) of trans-1,2-cyclohexylene diamine N, N, N ', N'-tetraacetic acid were suspended under nitrogen, after which 11.5 g (= 100 mmol) manganese II carbonate, Mn CO3, was added. The mixture was then heated to 95 ° C and 200 ml of 1 n sodium hydroxide solution was added dropwise. The clear solution was concentrated under reduced pressure and the residue dried at 60 ° C under reduced pressure. 40.8 g (92% of theory) of a pink powder were obtained. Analysis: (Calculated) C 37.94, H 4.09, N 6.32, Mn 12.40 (Found) C 37.78, H4.12, N 6.20, Mn 12.31.

Similarly obtained were: from copper II carbonate the disodium salt of the copper II complex of trans-1,2-cyclohexylenediamine-tetraacetic acid, C 14 H 18 CuN 2 O 2 · 2 Na; from cobalt II carbonate the disodium salt of the cobalt II complex of trans 1,2-cyclohexylenediamine tetraacetic acid, C 14 H 15 CoN 2 O 8.2 Na; from nickel-II carbonate, the di-sodium salt of the nickel-II complex of trans-1,2-cyclohexylenediamine-tetraacetic acid, C14 H18 NiN2 O2.2Na.

With N-methylglucamine instead of caustic soda were obtained: the di-N-methylglucamine salt of the mangaane II complex of trans-1,2-cyclohexylenediamine-tetraacetic acid,

CasH ^ Mn ^ Ois; the di-N-methylglucamine salt of the manganese U-complex of DL-2,3-butylene diamine tetraacetic acid, C 26 H 25 Mn N 4 O 18; the di-N-methylglucamine salt of the manganese-II complex of ethylenediamine-N, N, N ', N'-tetraacetic acid, C 24 H 48 Mn N 4 O; the di-N-methylglucamine salt of the manganese-II complex of DL-1,2-butylenediamine-N, N, N ', N'-tetraacetic acid, C 26 H 25 Mn N 4 O 18; the di-N-methylglucamine salt of the manganese-II complex of DL-1,2-propylenediamine-N, N, N ', N'-tetraacetic acid, C 25 H 50 Mn N 4 O 18; the tri-N-methylglucamine salt of the manganese-II complex of diethylenetriamine-pentaacetic acid, C35H72MnNe025; with nickel II carbonate, N1 CO3 the di-N-methylglucamine salt of the nickel II complex of ethylenediamine N, N, N ', N'-tetraacetic acid, C24 H48 N1 N4 O18; with cobalt II carbonate, COCO3 and ethanolamine the diethanolamine salt of the cobalt II complex of ethylenediamine Ν, Ν, Ν ', Ν'-tetraacetic acid, C14H28C0N4O10; with copper II carbonate, CuCO, 3 and ethanolamine the diethanolamine salt of the copper II complex of ethylenediamine Ν, Ν, Ν ', Ν'-tetraacetic acid, C14 H28 CUN4 O10; with manganese II carbonate, MnCO 3 and diethanolamine the tri-diethanolamine salt of the manganese II complex of diethylenetriamine N, N, N ', N ", N" -pentaacetic acid, C 26 H 54 MnNeO 16; with manganese II carbonate, MnCO, 3 and morpholine, the di-morpholine salt of the manganese II complex of ethylenediamine N, N; N ", N", tetra-acetic acid, C 18 H 32 Mn N 4 O 10.

Example X

N-Methyl glucamine salt of the gadolinium III complex of ethylene diamine N.N.N'.N'-tetraacetic acid, C 17 H 30 GdN 3 O 13.

29.2 g (= 100 mmol) of ethylenediamine Ν, Ν, Ν ', Ν'-tetraacetic acid were suspended in 100 ml of water and with 18.1 g (= 50 mmol) of gadolinmml II-oxide, Gd2C> 3 , heated to 95 ° C. During heating, 19.5 g (= 100 mmol) of N-methylglucamine were added portionwise. After about 3 hours a clear solution was obtained, which was filtered and evaporated to dryness under reduced pressure. The residue was dried under reduced pressure at 60 ° C. 61.3 g (95% of theory) of a white powder with a non-characteristic melting point were obtained.

Analysis: (Calculated) C 31.82, H 4.71, N 6.55, Gd 24.51 (Found) C 31.65, H 4.59, N 6.52, Gd 24.56

The following were obtained in an analogous manner: with dysprosium III oxide, Dy 2 O 3: the N-methylglucamine salt of the dysprosium III complex of ethylenediamine N, N, N ', N'-tetraacetic acid, C 17 H 30 D y N 3 O 13; the N-methylglucamine salt of the gadolinium III complex of 1,10-diaza-4,7-dioxadecane-1,1,1,10-tetraacetic acid, C 21 H 35 GdN 3 O 15; the N-methylglucamine salt of the gadolinium III complex of 1,2-diphenylethylenediamino-tetraacetic acid, C 29 H 38 N 3 O 13 Gd; with lead II oxide, PbO and sodium hydrochloride the di-sodium salt of the lead II complex of ethylenediamine tetraacetic acid, C10 H12 N2 O8 Pb.2 Na; with freshly precipitated chromium III hydroxide, Cr (OH) 3 the sodium salt of the chromium III complex of ethylenediamine tetraacetic acid, C 10 H 12 CrN 2 O 3 .Na; and in an analogous manner the sodium salt of the gadolinium III complex of ethylenediamine tetraacetamic acid, C 10 H 18 N 3 O 6 Na; the sodium salt of the gadolinium III complex of ethylenediamine-Ν, Ν, Ν ', Ν'-tetraacetic acid, C 10 H 12 GdN 2 O 3 .Na.

Example XI

Preparation of the sodium salt of the gadolinium-III complex of 1,4,7,10-tetra-azacyclododecane-N, N ', N ", N"' - tetra-amino acid. C1r.H24GdN4Q8.Na

4.0 g (= 10 mmol) of 1,4,7,10-tetra-azacyclododecane-N, N ', N ", N'" -tetraacetic acid were suspended in 20 ml of water, after which 10 ml of 1 n sodium hydroxide solution added. Then 1.8 g (= 5 mmol) of gadolinium III oxide, Gd 2 C> 3, was added and the suspension was heated at 50 ° C for 2 hours. The clear solution was filtered and concentrated under reduced pressure. The residue was dried and powdered. 5.5 g (95% of theory) of a white powder was obtained.

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

The following were obtained in the same way:

the N-methylglucamine salt of the gadolinium III complex of 1,4,7,10-tetraazacyclododecane-N, N ', N ", N'" - tetraacetic acid, C23 H42 GdN5 O3; the sodium salt of the gadolinium III complex of 1,4,8,11-tetraazacyclotetradecane-N, N ', N ", N" - tetraacetic acid, CistGsGdN ^ s.Na. Example XII

Preparation of the tetra-N-methylglucamine salt of the gadolinium III complex of ethylenedinitrilotetrakis (methane phosphonic acid). C. ^ HssGdNftO ^ P ,,

9.11 g (= 20 mmol) of ethylenedinintrilotetrakis (methane phosphonic acid) were suspended in 150 ml of water and the suspension was adjusted to a pH value of 5 with the appropriate amount of N-methylglucamine. Then 3.6 g (= 10 mmol) of gadolinium III oxide, Gd 2 O 3, were added and heated to 70 ° C. After about 1 hour a clear solution was obtained to which the remaining portion of N-methylglucamine was added. A total of 15.6 g (= 80 mmol) of N-methylglucamine was consumed. The solution was evaporated to dryness under reduced pressure and the remaining gel-like residue was placed in 200 ml of acetonitrile. The mixture was then stirred for about 20 hours at 30 ° C and the resulting fine precipitate was filtered off with suction. After drying under reduced pressure at 40 ° C, 23.4 g (85% of theory) of a white powder with a melting point of 115-118 ° C were obtained.

Analysis: (Calculated) C 29.78, H 6.25, N 6.13, P 9.04, Gd 11.47 (Found) C 29.85, H 6.57, N 5.98, P 8, 78, Gd 11.26

In the same way, the following were obtained: the hepta-N-methylglucamine salt of the gadolinium III complex of diethylenetriamine-N, N, N ', N ", N" -penta (methane phosphonure), CssHmGdN10O50s; and using sodium hydroxide solution in place of N-methylglucamine: the di-sodium salt of the gadolinium III complex of diethylene trinitrilopenta (methane phosphonic acid), C9 H23 GdN3 O5 P5.2 Na.

EXAMPLE XIII

Preparation of the di-sodium sun of the manganese-II complex of ethylene-dinitrile-tetra (acetanoicamic acid). CmHifiMnNfiOB.2Na

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

(found) 11.12 Example XIV

Preparation of a solution of a mixed salt ("Mischsalz") of the sodium and N-methylglucamine salt of the gadolinium-III complex of diethylenetriamine-nenta-acetic acid a.

195.2 g (1 mol) of N-methylglucamine were dissolved in 7 liters of water. Then 393.3 g (1 mole) of diethylenetriamine-pentaacetic acid and 181.3 g (0.5 mole) of gadolinium oxide, Gd 2 O 3, were added and refluxed for 2 hours. The filtered clear solution was spray-dried. A white crystalline powder with a water content of 2.6% was obtained, which sintered at 133 ° C and melted at 190 ° C with foaming.

Gd (calculated) 21.17 (Found) 21.34 bJ_Bere 1 thing of the "mixed salt" solution

In 630 ml of water p.i. (p.i. = pro injectione) 730.8 g (= 1 mole) of the salt obtained according to a) was suspended, after which 40 g (= 1 mole) of sodium hydroxide powder were added portionwise. The neutral solution was p.i. supplemented to 1000 ml, bottled through a pyrogenic filter and heat-sterilized. This 1 molar solution contained 753.8 g of the "mixed salt" per liter.

Example XV

Preparation of a solution of the di-N-methylglucamine salt of the gadolinium III complex of diethylenetriamine-nenta-amino acid

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

Example XVI

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

In 500 ml of water p.i. 485.1 g (= 820 mmol) of the di-sodium salt obtained according to Example 6 was slurried. Then p.i. to 1000 ml, put the solution in ampoules and sterilized by heat treatment.

Example XVII

Preparation of a solution of the di-sodium salt of the quinium-III complex of 13.23-dioxo-15.18.21-tris (carboxymethyl-D-12.15.18.21.24-pentaazone-sodium-sodium-diacetic acid diacid)

In 500 ml of water p.i. 392.0 g (= 400 mmol) of the salt described in Example II was slurried and supplemented with water p.i. dissolved to 1000 ml with gentle heating. The solution was bottled and heat sterilized.

Example XVIII

Preparation of a solution of the N-methyl-glucamine salt of the gadolinium II complex of 1.4.7.10-tetra-aza-cyclododecane-tetra-amino acid in 500 ml of water p.i. 370.9 g (= 500 mmol) of the salt mentioned in Example XI were slurried and supplemented with water p.i. dissolved to 1000 ml. The solution was placed in ampoules and heat sterilized.

Example XIX

Preparation of a solution of the di-N-methylglucamine salt of the manganese-II complex of trans-1,2-cyclohexfleendiamine-tetra-amino acid

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

Example XX

Preparation of a solution of the tri-N-methylglucamine salt of the manganese-II complex of diethylenetriamine-pentaacetic acid

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

Example XXI

Preparation of a solution of the di-N-methylglucamine salt of the Iizer III complex of diethylenetriamine-penta-acetic acid in 40 ml of water p.i. 44.6 g (= 0.1 mole) of the iron III complex of diethylenetriamine-pentaacetic acid obtained in Example 7 were suspended. After addition of 0.18 g of tromethamine hydrochloride and 39.1 g (= 0.2 mol) of N-methylglucamine, the solution was neutral and the solution was p.i. to 100 ml, replenished in ampoules and heat sterilized.

Example XXII

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

In 100 ml of water p.i. 1.9 g (= 10 mmol) of nitrilotriacetic acid and 1.8 g (= 5 mmol) of gadolinium III oxide were dissolved with heating. The solution was placed in ampoules and heat sterilized.

Example XXIII

Preparation of a solution of the N-methylglucamine salt of the gadolinium III complex of ethylene diamine tetra-amino acid

In 70 ml of water p.i. 38.62 g (= 60 mmol) of the substance described in Example X was dissolved. After addition of 0.12 g of tromethamine, p.i. to 100 ml, put the solution in ampoules and heat sterilized.

Example XXIV

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

In 70 ml of water p.i. 35.7 g (= 60 mmol) of the dysprosium II1 complex of diethylenetriamine-pentaacetic acid (water content 8.0%) were suspended, and by adding 21.2 g (= 120 mmol) of N-methylglucamine to a pH 7.5 in solution. Then p.i. to 100 ml, put the solution in ampoules and heat sterilized.

Example XXV

Preparation of a solution of the N-methylglucamine salt of the gadolinium III complex of trans-1,2-cyclohexlene-diamine-tetra-amino acid

Of the salt described in Example VIII, 555.8 g (= 0.8 mol) in water p.i. dissolved to 1000 ml under replenishment. After filtration through a pyrogenic filter, the solution was placed in ampoules and heat sterilized.

Example XXVI

Preparation of a solution of the N-methylglucamine salt of the ruthenium III complex of 1,10-diaza-4,7-dithiadecane-1,1,110,110-tetra-amino acid

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

Example XXVII

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

In 500 ml of water p.i. 273.8 g (= 0.5 mole) of the gadolinium III complex of diethylene triamine pentaacetic acid was suspended. Then 292.4 g (= 1 mol) of lysine was added, after which it was stirred for several hours with gentle heating and then with water p.i. to 1000 ml. The solution was bottled and heat sterilized.

Example XXVIII

Preparation of a solution of the tri-N-methylene glucamine salt of the molybdenum VI complex of diethylenetriamine-penta-acetic acid

In 50 ml of water p.i. 18.8 g (= 0.28 mol) of the Η3 [Μθ2θ2 (ΟΗ) <ι.Οΐ4Η23Ν3θιο] complex was suspended and neutralized by adding 16.4 g (= 0.84 mol) of N-methylglucamine. Then 0.15 g of tromethamine was added, p.i. made up to 100 ml, after which the solution was subjected to a sterile filtration and placed in ampoules.

Example XXIX

Preparation of a solution of the di-sodium salt of the manganese-II complex of ethylene diamine-tetra-amino acid

In 500 ml of water p.i. 343.2 g (= 1 mole) of the manganese-II complex of ethylenediamine-tetra-acetic acid were suspended and neutralized by portionwise addition of 80 g (= 2 moles) of sodium hydroxide. After adding 1.5 g of tromethamine, the solution was washed with water p.i. replenished to 1000 ml, bottled and heat sterilized.

Example XXX

Preparation of a solution of the sodium salt of the Iizer III complex of ethylene diamine tetraacetic acid in 500 ml of water p.i. 345.7 g (= 1 mole) of the iron III complex of ethylenediamine tetraacetic acid was suspended and neutral dissolved portionwise by adding 40 g (= 1 mole) of sodium hydroxide. After adding 1.5 g of tromethamine, the solution was washed with water p.i. replenished to 1000 ml, bottled and heat sterilized.

Example XXXI

Preparation of a solution of the di-sodium salt of the Iizer III complex of diethylenetriamine-penta-acetic acid

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

Example XXXII

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

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

Example XXXIII

Preparation of a solution of the N-methylglucamine salt of the gadolinium III complex of 1,2-diphenylenediamine-tetra-amino acid in 600 ml of water p.i. 396.9 g (= 500 mmol) of the salt described in Example X was slurried and dissolved by making up to 1000 ml. The solution was placed in ampoules and heat sterilized.

Example XXXIV

Preparation of a solution of the sodium salt of the iizer-IH complex of ethylene diamine: tetra-amino acid

In 500 ml of water p.i. 183.5 g (= 500 mmol) of the salt mentioned in Example VII were slurried. Then 1.0 g of tromethamine was added, p.i. to 1000 ml, and the solution was placed in ampoules and heat sterilized. Example XXXV

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

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

Example XXXVI

Preparation of a solution of the di-N-methylglucamine salt of the bismuth III complex of diethylenetriamine-penta-acetic acid

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

Example XXXVII

Preparation of a solution of the di-N-methylglucamine salt of the holmium III complex of diethylenetriamine-penta-acetic acid

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

Example XXXVIII

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

In 650 ml of water p.i. 476.9 g (= 400 mmol) of the salt mentioned in Example V was slurried and, after addition of 1.5 g of tromethamine, supplemented with water p.i. dissolved to 1000 ml. The solution was placed in ampoules and heat sterilized.

Example XXXIX

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

In 650 ml of water p.i. 573.2 g (= 1000 mmol) of the salt mentioned in Example VI were slurried and supplemented with water p.i. dissolved to 1000 ml. The solution was placed in ampoules and heat sterilized.

Example XL

Preparation of a solution of the di-sodium salt of the dvsprosium III complex of diethylenetriamine-pentaacetic acid in 600 ml of water p.i. 477.4 g (= 800 mmol) of the salt mentioned in Example VI was slurried and supplemented with water p.i. dissolved to 1000 ml. The solution was placed in ampoules and heat sterilized.

Example XLI

Preparation of a solution of the di-sodium salt of the holmium III complex of diethylenetriamine-nenta-amino acid

In 500 ml of water p.i. 299.6 g (= 500 mmol) of the salt mentioned in Example VI were slurried on and by adding water p.i. dissolved to 1000 ml. The solution was placed in ampoules and heat sterilized.

Example XLII

Preparation of a solution of the di-sodium salt of the vtterbium III complex of diethylenetriamine-penta-acetic acid

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

Example XLIII

Preparation of a solution of the tetra-N-methylglucamine salt of the gadolinium III complex of ethylenedinitrilotetrakis (methane phosphonic acid) in 500 ml of water p.i. 137.1 g (= 100 mmol) of the salt mentioned in Example XII were slurried and, after addition of 0.8 g of tromethamine, supplemented with water p.i. dissolved to 1000 ml. The solution was placed in ampoules and heat sterilized.

Example XLIV

Preparation of a solution of the diamine III complex of N '- (2-hydroxyethyl ethylene diamine-N.N.N'-tri-amino acid)

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

Example XLV

Preparation of a solution of the di-sodium salt of the manganese-II complex of trans-1,2-cyclohexfleendiamine-tetra-amino acid

With protection from nitrogen, p.i. 44.3 g (= 100 mmol) of the salt mentioned in example IX were slurried and supplemented with water p.i. to 100 ml. The solution was placed in ampoules and heat sterilized.

Example XLVI

Preparation of a solution of the sodium salt of the gadolinium III complex of 1.4.8.1 -1-tetraaza-cyclotetradecane -N.N1, N ", N", - tetraacetic acid In water p.i. 552.6 g (= 1 mol) of the salt mentioned in Example XI were dissolved with replenishment to 1000 ml. The solution was bottled and heat sterilized.

Example XLVII

Preparation of a solution of the di-sodium salt of the bismuth III complex of diethylenetriamine-penta-acetic acid

In 50 ml of water p.i. 23.4 g (= 50 mmol) of bismuth III oxide was suspended. After addition of 39.3 g (= 100 mmol) of diethylene triamine pentaacetic acid and 4.0 g (= 50 mmol) of sodium hydroxide, the mixture was refluxed until a clear solution was obtained. The solution cooled to ambient temperature was neutralized by the addition of 4.0 g of sodium hydroxide and p.i. supplemented to 100 ml. The solution was placed in ampoules and heat sterilized. Example XLVIII

Preparation of a solution of the di-sodium salt of the samarium III complex of diethylenetriamine-penta-acetic acid

In 65 ml of water p.i. 58.5 g (= 100 mmol) of the salt mentioned in Example 6 were dissolved with heating. Then p.i. to a total volume of 100 ml, after which the solution was placed in ampoules and heat sterilized.

Example XLIX

Preparation of a solution of the di-N-methylglucamine salt of the gadolinium III complex of 13.23-dioxo-15.18.21-tris (carboxymethyl-D-12,15,18,21,24-penta-aza-pentatriacontane diacid

130.4 g (= 100 mmol) of the salt mentioned in Example II were slurried in 250 ml of water and dissolved with heating. Then p.i. made up to 500 ml, after which the solution was placed in ampoules and heat sterilized.

Example L

Preparation of a solution of the di-N-methylglucamine salt of the manganese-II complex of ethylene diamine-tetra-amino acid

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

Example LI

Preparation of a solution of the di-sodium salt of the gadolinium III complex of diethyl trinitrile penta (methane phosphonic acid)

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

Example Lil

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

In 100 ml of water p.i. 39.3 g (= 100 mmol) of diethylenetriamine-pentaacetic acid was suspended, after which 11.5 g of manganese II carbonate was added. The mixture was then heated to 95 ° C and 300 ml of 1 n sodium hydroxide solution was added dropwise. The neutral solution was sterile filtered and placed in ampoules.

Example L1II

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

Example LIV

Preparation of a solution of the gadolinium III complex of the diethylenetriamine-penta-aziic acid conjugate with human serum albumin

To 20 ml of a solution of 3 mg of the protein in 0.05 molar sodium hydrogen carbonate buffer (pH 7-8) was added 10 mg of 1,5-bis (2,6-dioxomorpholino) -3-aza-pentane-3-acetic acid . Stirring was then carried out for 30 minutes at ambient temperature and then dialysed against a 0.3 molar sodium phosphate buffer. 50 mg of gadolinium III acetate was then added and purified by gel chromatography on a Sephadex G 25 column. The resulting fraction was sterile filtered and placed in multivials. A dry preparation was obtained by freeze drying, which could be stored.

An analogous solution was obtained with immunoglobulin of the corresponding complex conjugate.

Example LV

Preparation of a solution of the gadolinium III complex of the diethylenetriamine-pentaacetic acid conjugate (DTPA1 with a monoclonal antibody

To 20 μΐ of a 0.3 mg solution of a monoclonal antibody in 0.05 molar sodium hydrogen carbonate buffer (pH 7-8) was added 1 mg of a mixed DTP A anhydride (obtained for example from DTPA and isobutyl chloroformate) and Stirred at ambient temperature for 30 minutes. Dialysis was then carried out against 0.3 molar sodium phosphate buffer and 2 mg of the gadolinium III complex of the ethylenediamine tetraacetic acid (EDTA) was added to the resulting antibody fraction. After purification by gel chromatography on Sephadex G 25, the sterile filtered solution was placed in multivials and freeze-dried.

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

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

Example LVI

Preparation of a solution of the gadolinium III complex of the conjugate of 1-phenyl-ethenediamine-tetra-amino acid with immunoglobulin

According to the in J. Med. Chem. 1974, vol. 17, p. 1307, a 2% solution of the protein in a 0.12 molar sodium hydrogen carbonate solution containing 0.01 mol of ethylenediamine tetraacetic acid was cooled to + 4 ° C and thereto an equivalent to the protein. amount of a freshly prepared, ice-cold diazonium salt solution of 1- (p-aminophenyl) ethylenediamine tetraacetic acid was added dropwise. The mixture was stirred overnight at + 4 ° C (pH 8.1), followed by dialysis against a 0.1 molar sodium citrate solution. After the termination of the dialysis, an excess of gadolinium III chloride was added to the solution of the conjugate and the mixture was subjected to an ultrafiltration to remove ions. Finally, the sterile filtered solution was placed in multivials and freeze-dried.

Example LVII

Preparation of a colloidal dispersion of an Mn-CDTA-lipid coniugate In 50 ml of water, 0.1 mmol distearoyl phosphatidyl ethanolamine and 0.1 mmol bisanhydride of trans-1,2-diamino-cyclohexane-tetra-acetic acid were mixed for 24 hours at ambient temperature stirred. 0.1 mmol of manganese II carbonate was then added and stirred for an additional 6 hours at ambient temperature. After purification on a Sephadex G 50 column, the sterile filtered solution was placed in multivials and freeze-dried. A colloidal dispersion of the gadolinium-DTPA-lipid conjugate could be obtained with gadolinium III oxide. Example LVIII

Preparation of gadolinium DTPA-loaded linosomes

According to the in Proc. Natl., Acad. Sci. U.S.A. 75, 4194, a lipid mixture of 75 mol% egg phosphatidylcholine and 25 mol% cholesterol was prepared as a dry substance. 500 mg of this was dissolved in 30 ml of diethyl ether and 3 ml of a 0.1 molar solution of the di-N-methylglucamine salt of the gadolinium III complex of diethylenetriamine-pentaacetic acid in water p.i. added. After complete addition of the solution, the ultrasonic treatment is continued for another 10 minutes and is then concentrated in a Rotavapor. The gel-like residue was suspended in 0.125 molar sodium chloride solution and freed repeatedly at 0 ° C by centrifugation (20,000 g / 20 minutes) of unencapsulated contrast agents. The thus obtained liposomes were then lyophilized in multivials. The administration took place as a colloidal dispersion in a 0.9% by weight sodium chloride solution.

Claims (1)

A diagnostic agent for use in in vivo NMR diagnostics, which agent comprises at least one physiologically acceptable complex salt of the formula

contains, with additives customary in galenic pharmacy, dissolved or suspended in an aqueous medium, in which formula X has the meaning of -COOY, -PO3HY or-CONHOY; Y has the meaning of H, a metal ion equivalent of an element with the atomic numbers 21 to 29, 42, 44 or 58 to 70 or a cation of an inorganic or organic base or amino acid, against which there is no physiological objection, characterized in that further in this formula V has the meaning of X, CH 2 OH or COB, wherein B is a protein or lipid residue or NH (CH 2) n X, wherein n represents an integer from 1-12; at least two of the Y groups represent metal ion equivalents; and further that A is represented by the general formula CH 2 -CH 2 - (ZCH 2 -CH 2) m, wherein m is 1, 2 or 3, wherein Z has the meaning of NCH 2 X; provided that at least one substituent V represents the group COB.