NL195071C - Diagnostic. - Google Patents

Description

1 195071

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) for detoxing in the event of a 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 a 10 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 20 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. Because of their very strong magnetic moment, gadolinium (III), terbium (III), dysprosium (III), holmlum (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 (III) ion, the aforementioned ions of the lanthanide series, the gold (III) ion, the lead (III) ion or in particular the bismuth (III) ion.

Both the means 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 above-mentioned central ions. Suitable complexing acids are, for example, those which contain 3-12, preferably 3-8 methylene phosphonic acid groups, methylene carbohydroxamic acid groups, carboxyethylidene groups, or in particular carbomethylene groups, one, two or three of which to a nitrogen atom supporting the complex formation are bound. 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 that are known to increase their concentration in the organ or organ section 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 195071 2, also via a group: (CH2) P-Ce4-W- as defined in claim 2. During the conjugate formation of the complexing acids with proteins, peptides or lipids, various acid residues can be partially bound to the macromolecular biomolecule. In this case, any complexing acid residue can carry a central ion. If the complexing acids are not bound to biomolecules, they optionally carry two central ions, in particular a central ion.

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

For the preparation of the complex salts of the general formula 1a, the following complexing acids are suitable, inter alia, ethylenediamine tetraacetic acid, ethylenediamine tetraacetahydroxamic acid, trans 1,2-cyclohexylenediamine tetraacetic acid, DL-2,3-butylenediamine- tetra-acetic acid, DL-1,2-butylenediamine-tetra-acetic acid, DL-1,2-15 propylene-diamine-tetra-acetic acid, 1,2-diphenylethylenediamine-tetra-acetic acid, ethylenedinitrilotetrakis (methane phosphonic acid) and N- (2-hydroxyethyl) ethylenediamine triacetic acid.

Other suitable complex salts of the general formula 1 according to claim 2 are, for example, those of the general formula 1b, wherein X, V, Z, R 1 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.

For the preparation of the complex salts of the general formula 1b, the following complexing acids are suitable, inter alia, diethylenetriamine-pentaacetic acid, triethylene-tetramine-hexa-acetic acid, tetraethylene-pentamine-hepta-acetic acid, 13.23-dixo 15.18.21-tris (carboxymethyl) -1.15.18.21.24-penta-aza-penta-triacontanedioic acid, 3.9 bis (1-carboxyethyl) -3.6.9-tri-aza- undecanedioic acid, diethylene triamine pentakis- (methylene phosphonic acid), 1,10-diaza-4,7-dioxadecane-1,1,10,10-tetraacetic acid and 1,10-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. For the preparation of complex salts of the general formula 1c, the following complexing acids are suitable, inter alia: 1,4,8,11-tetra-aza-cyclotetradecane-tetra-acetic acid and in particular 1,4,7,10- tetra-aza-cyclododecane-tetra-acetic acid.

Other complexing acids which are 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) hexaacetic acid. Nitrilotriacetic acid is mentioned as an example of a complexing acid for the preparation of complex salts of the general formula II.

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, Ν, Ν-dimethylglucamine or in particular N-methylglucamine. 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-a-za-penta-triacontanedioic acid takes place according to the method described by R.A. Bulman et al. In Naturwissenschaften 68, (1981) 483 proposed improved form: 50 In 400 ml of dry dimethylformamide 17.85 g (= 50 mmol) of 1.5 bis ((2,6-dioxomorpholino) -3-azapentane-3-acetic acid) is added. suspended and the suspension after addition of 20.13 g (= 100 mmol) of 11-amino-undecanoic acid heated to 70 ° C for 6 hours. The clear solution is concentrated 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.

3 195071

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.

Substituents with the structure -CeH4N2 + or CeH4NHCOCH2-halogen are also available for conjugation with proteins.

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 up to and including 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 to add and stir, 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, then 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, so much of the desired base can be added to the acid complex salts dissolved or suspended in water 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 easy to isolate and properly purify 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 in 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. isolate the complex salt formed, purify it if desired and then, to completely neutralize it, add the required amount of inorganic base. The order of addition of the bases can also be reversed.

The preparation of the diagnostic agents according to the invention is also carried out in a manner known per se by suspending or dissolving the complex salts, optionally with the addition of the additives customary in galenic pharmacy, in an aqueous medium and then the solution or suspension. to sterilize. Suitable additives are, for example, buffers, against which there are no physiological objections (such as, for example, trimethamine hydrochloride), small additions of complexing agents (such as, for example, diethylene triamine pentacetic acid) or, if necessary, electrolytes (such as, for example, 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 the chelate formation 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 195071 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 sparingly soluble complex salt with one or more adjuvants and / or surfactants and / or flavoring agents customary in galenic pharmacy becomes. taste improvement mixed.

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

The means according to the invention satisfy - 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 expression obtained with the aid of the nuclear spin tomograph by increasing the signal intensity. Furthermore, they exhibit the strong effect which is necessary to burden the bodies with the smallest possible quantities of foreign substances and the good tolerance which is necessary to maintain the non-invasive character of the test (the method described in J. Comput. For example, Tomography, 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, that is to say NMR diagnostics. 1000 times better water-soluble than the compounds for NMR spectroscopy. Furthermore, the agents according to the invention exhibit not only a high in vitro stability, but also a surprisingly high in vivo stability, so that an ions that are not covalently bonded in the complexes in a release or exchange are self-toxic ions within 24 hours, in which - as pharmacological research has shown - the new contrast agents are completely excreted again, only 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 the iodine-containing contrast agents. blochemical pharmacological research. 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 testing shows, an increase in the dose administered 40 does not unconditionally lead to signal enhancement, and with a large dose of paramagnetic contrast agent, it may even be extinguished. 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, the evidence of a defective blood-brain barrier in the area of a 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-cyclohexylenediaminotetraacetic 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 of heart attacks. The following exemplary embodiments serve to further illustrate the invention.

5, 195071

EXAMPLE 1

Preparation of the gadolinium-ill complex of nitrilo-N, N, N-triacetic acid, C6 H6 GdNO

A suspension of 36.2 g (= 100 mmol) of gadolinium oxide (GdjjOa) and 38.2 g (= 200 mmol) of nitrilotriacetic acid in 1.2 liters of water was heated to 90 ° C to 100 ° C with stirring and at this temperature stirred 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-III complex of the nitrilo-N, N, N-triacetic acid was obtained with the aid of iron-III chloride, FeCl3.

EXAMPLE II

Preparation of the disodium salt of the gadolinium III complex of 13.23-dioxo-15.18.21-tris (carboxymethyl) -12.15.18.21.24-penta-aza-pentatriacontanedioic acid, CgeH ^ GdNgO ^. 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 1N 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. Gadolinium III complex of 13.23-dioxo-15.18.21-tris (carboxymethyl) 12.15.18.21.24-penta-aza-pentatriacontanic acid.

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-II complex thus obtained, 14.6 g (= 16 mmol) were 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. g (87% of theory) was obtained from a water-soluble white powder with a melting point of 279-285 ° C.

Analysis: (Calculated) 0 45.13, H6.31, N 7.31, Gd 16.41, Na 4.80, 35 (Found) 0 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) -1.15.18, 21.24-penta-azapenta-triacontanedioic acid, C50 H8 gdrvO4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 2

EXAMPLE III

3

Preparation of the di-sodium salt of the gadolinium III complex of 3.9 bis (1-carboxyethyl) -6-4 carboxymethyl-3,6,9-triaza-undecanedioic acid, C 18 H 22 GdN 3 O 10 2 Na 5

In 250 ml of water, 36.2 g (= 0.1 mol) of gadollnium-11-oxide and 84.2 g (= 0.2 mol) of 3,9-bis 6 (1-carboxyethyl) -6-carboxymethyl-3 were added. , 6,9-triazaundanedanoic acid suspended and boiled for 1 hour under reflux. The small amount of undissolved substance was filtered off and the solution under 8

reduced pressure. The residue was powdered and under reduced pressure at 60 ° C

9 dried. 112.8 g (= 98% of theory) of the chelate were obtained as a white powder.

10

Analysis: C 16 H 24 GdN 3 O 10 11 (Calculated) C 33.39, H 4.20, Gd 27.32, N7.30 12 (Found) C 33.25, H4.49, Gd 27.42, N 7.21 13

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 14. 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 permanent haze. 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 195071 as a white powder.

Analysis: (Calculated) C31.Q2, H 3.58, Gd 25.38, N 6.78 (Found) C 31.10, H3.71, Gd 25.50, N6.61.

5

EXAMPLE IV

Preparation of the di-morpholine salt of the gadolinium III complex of 3.9 bis (1-carboxyethyl) -6-carboxymethyl-3,6,9-triaza-undecanic diacid, C24H42GdN5012

17.4 g (= 0.2 mol) of mprfoline were dissolved in 50 ml of water. Subsequently, 42.1 g (= 0.1 mole) of 3,9-bis 10 (1-carboxyethyl) -6-carboxymethyl3,6,9-triazedanedanedioic acid and then 18.2 g (= 0.05 mole) Gadolinium III oxide was added 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 crystalline 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) C38.44, H 5.65, Gd 20.97, N 9.34 (Found) 038.31, 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-Ν, Ν, Ν "· N", N "-pentaacetic acid, CaaH ^ GdNgOao

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, Gd2 O3, 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 crystalline 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, H5.80, N 7.47, Gd 16.77 (Found) C 35.50, H5.72, N7.20, Gd 16.54.

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

Similarly obtained with dysprosium III oxide, Dy2 O3: the di-N-methylglucamine salt of the dysprosium III complex of diethylenetriamine N, N, N ', N', N '-pentaacetic acid, CgeH ^ DyNsO »; 40 with lanthanum III oxide, La ^: the di-N-methylglucamine salt of the lanthanum III complex of diethylene triamine N, N, N ', N', N ', penta-acetic acid, C 2 H 54 LaN 50 O; with ytterbium III oxide, Yn2 O3: the di-N-methylglucamine salt of the ytterbium III complex of diethylene triamine N, N, N ", N", N "-penta-45 acetic acid, CaeH ^ YbNgOao; with samarium-ll-oxide, Sm ^: the di-N-methylglucamine salt of the samarium-ll complex of diethylene-triarnine-N, N, N ', N', N ,, - pentaacetic acid, Ο ^ Η ^ ιηΝ ^^; with holmium III oxide, Ho2 O3: 50 the di-N-methylglucamine salt of the holmium III complex of diethylene triamine N, N, N "N", N "-pentaacetic acid, Ο ^ Η ^ ΗοΝ, ρ * ,; with bismuth III oxide, Bi2 O3: the di-N-methylglucamine salt of the bismuth III complex of diethylenetriamine N, N, N ', N', N '-pentaacetic acid, CaeH ^ BiNgOao; 55 with gadolinium III oxide, Gd2 O3: the tri-N-methylglucamine salt of the galodinium-III complex of triethylene-tetramelin-N, N, N ', N ", N,", N ", - 7 195071 hexa acetic acid, C39 H7 E8 N7 O27;

Furthermore, the following were obtained with holmium III oxide, Ho2 O3 and ethanolamine instead of N-methyl glucamine: the diethanolamine salt of the holmium III complex of diethylenetetramine N, N, N ', N', N '-pentaacetic acid1 C 16 H 34 HoN 5 O 12; 5 with gadolinium III oxide, Gd2 O3, and lysine instead of n-methyl glucamine: the di-lysine salt of the gadolinium III complex of diethylenetriamine N, N, N ', N', N '-pentaacetic acid, ^ 26 ^ 4β ^^^ 7θΐ4 ·

Using diethanolamine, the diethanolamine salt of the holmium III complex of diethylenetriamine-pentaacetic acid, C ^ H ^ HoNgO ^, was obtained.

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

Example VI

Preparation of the di-sodium salt of the gadolinium III complex of diethylenetriamine-N, N, N ", N", N "-penta-15 acetic acid, C14H1BGdN3O10.2Na

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 lil oxide, Dy 2 O 3: the disodium salt of the dysprosium III complex of diethylenetriamine N, N, N ", N", N ", penta-acetic acid C 14 H 18 D y N 3 O 10. 2Na: with lanthanum III oxide, La ^: 30 the disodium salt of the lanthanum III complex of diethylene triamine N, N, N ", N", N ", pentaacetic acid C 14 H 18 LaN 3 O 10. 2Na; with holmium III oxide, Ho2 O3: the di-sodium salt of the holmium III complex of diethylenetriamine N, N, N ', N ", N' -pentaacetic acid C14 H18 HoN3 O10. 2 Na; 33 with ytterblum III-oxide , Yb203: the di-sodium salt of the ytterbium-III complex of diethylenetriamine-N, N, N ', N ", N" -pentaacetic acid

C14 H18 Yb N3 O10.2 Na; with samarium III oxide, Sm2 O3: the di-sodium salt of the samarium III complex of diethylenetriamine N, N, N ", N", N "-pentaacetic acid C 40 14H18SmN3O10. 2Na; with erbium III oxide, Eb2 O3: the di-sodium salt of the erbium III complex of diethylenetriamine N, N, N "N", N "penta-acetic acid C14 H18 EbN3 O10.2 Na; with gadolinium III oxide, GdgOg! 45 the sodium salt of the di-gadolinium III complex of tetraethylene pentamine-N, N, N "N", N ", Nlv, Nlv-hepta-acetic acid C ^ H ^ GdzNgoO ^ Na.

These salts were obtained as white powders with a non-characteristic melting point and were very soluble in water. 1 2 3 4 5 6 2

EXAMPLE VII

3

Preparation of the N-methylglucamine salt of the iron III complex of diethylenetriamine-pentaacetic acid, 4 C2 H37 FeN4 O15 5

35.40 g (= 90 mmol) of diethylenetriamine-pentaacetic acid were suspended in 100 ml of water, after which 6 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 195071 was subsequently heated for an additional 3 hours at 95 ° C. 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 resulting iron III complex, 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.

10

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

Using sodium hydroxide instead of the organic base, the following were obtained: the sodium salt of the iron-III complex of ethylenediamine-tetraacetic acid, C10 H12 FeN2 O8. After; the sodium salt of the iron-II complex of trans-1,2-cyclohexylenediamine-tetraacetic acid, C14 H18 FeN2 Oe. After; the di-sodium salt of the iron-III complex of diethylenetrin trinoprenta (methane phosphonic acid), C 9 H 23 FeN 30.5 P5. 2Na; The sodium salt of the iron-11 complex of 1,10-diaza-4,7-dioxadecane-1,1,10,10-tetraacetic acid, C 10 H 10 FeN-A 0. After; the sodium salt of the iron-III complex of ethylenediamine-tetraacetate hydroxamic acid, C10HieFeNeOe. After.

Similarly, with N-methylglucamine, the di-N-methylglucamine salt of the iron-II complex of diethylenetriamine-N, N, N ', N', N ', penta-acetic acid, C28 H54 FeN6 O2 O; the N-methylglucamine salt of the iron-II complex of trans-1,2-cyclohexylenediamine-N, N, N ', N'-tetraacetic acid, C ^ HgeFeNgO ^; the N-methylglucamine salt of the iron-II complex of ethylenediamine Ν, Ν, Ν ', Ν'-tetraacetic acid, ^ C17H30FeN3O13; the tri-N-methylglucamine salt of the iron-III complex of triethylenetetramine-N, N, N ", N", N ", N", - "N-hexa-acetic acid,.

Using diethanolamine instead of N-methylglucamine, the diethanolamine salt of the iron-II complex of diethylenetriamine-N, N, N ", N", N "-pentaacetic acid, C 22 H 42 FeN 10 O 14 was obtained.

35

EXAMPLE VIII

Preparation of the N-methylglucamine salt of the gadolinium III compound of trans-1,2-cyclohexylenediamine-NNN'.N'-tetraacetic acid, C21H38GdNg013 40 20.78 g (= 60 mmol) of trans -1,2cyclohexylenediamine-N, N, N ', N'-tetraacetic acid suspended. 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., 03) 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. 45 gene was obtained 38.6 g (92% of theory) of a white powder with a melting point of 258 - 261 ° C.

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

In the same way, sodium hydroxide instead of N-methylglucamine was used to obtain the sodium salt of the gadolinium-III complex of trans-1,2-cyclohexylenediamine-N, N, N ', N'-tetraacetic acid, C14 H18 GdN2 O8 .Na .

With freshly precipitated chromium III hydroxide, Cr (OH) 3, the sodium salt of the chromium III complex of ethylenediamine-N.N.N'.N'-tetraacetic acid, C10H12CrN2O8.Na was obtained.

9, 195071

EXAMPLE IX

Preparation of the di-sodium salt of the manganese-II complex of trans 1,2-cyclohexylenediamine-N, N, N ', N'-tetraacetic acid, C 14 H 18 MnN 2 O 8.2 Na

In 100 ml of water, 34.6 g (= 100 mmol) of trans-1'-cyclohexylenediamine-NNN'.N'-tetraacetic acid was suspended under nitrogen, after which 11.5 g (= 100 mmol) of manganese-11- carbonate, Mn CO 3, 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: 10 (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, the following were obtained from copper-11-carbonate: the di-sodium salt of the copper-11 complex of trans-1,2-cyclohexylenediamine-tetraacetic acid, C14 H18 ClN2 O8.2 Na; from cobalt-11-carbonate, the di-sodium salt of the cobalt-11-complex of trans-1,2-cyclohexylenediamine-tetraacetic acid, C 14 H 18 CoN 2 O 2. from nickel-11-carbonate, the di-sodium salt of the nickel-11 complex of trans-1,2-cyclohexylenediamine-tetra-acetic acid, C 14 H 18 NiN 2 O 8.

With N-methylglucamine instead of sodium hydroxide the following were obtained: the di-N-methylglucamine salt of the manganese-II complex of trans-1,2-cyclohexylenediamine-tetraacetic acid, C28 H54 MnN4 O18; the di-N-methylglucamine salt of the manganese-11 complex of DL-2,3-butylenediamine-tetra-acetic acid, 25 ,μΗκοΜπ methylιΟ, η, the di-N-methylglucamine salt of the manganese-11 complex of ethylene diamine-NNN'.N tetra tetraacetic acid, di-N-methylglucamine salt of the manganese-11 complex of DL-1,2-butylenediamine-N, N, N ', N'-tetraacetic acid, Ο ^ Η ^ Μη ^ Ο ^; The di-N-methylglucamine salt of the manganese-II complex of DL-1,2-propylenediamine-N, N, N ', N'-tetraacetic acid, ^ Η ^ ΜηΝ ,, Ο ^; the tri-N-methylglucamine salt of the manganese-II complex of diethylenetriamine-pentaacetic acid, nickel-11-carbonate, NiCO 3 the di-N-methylglucamine salt of the nickel-11-complex of ethylenediamine- 35 Ν, Ν, Ν ', Ν'-tetraacetic acid, Ο ^ Η ^ Νΐ ^ Ο, β; with cobalt-11 carbonate, CoCO 3 and ethanolamine, the diethanolamine salt of the cobalt-11 complex of ethylenediamine-N, N, N ', N'-tetraacetic acid, C 14 H 28 CoN 4 O 10; with copper-11-carbonate, CuCO 3 and ethanolamine the diethanolamine salt of the copper-11-complex of ethylenediamine-NNN'.N'-tetraacetic acid, C 14 H 28 CuN 4 O 10 · 40 with manganese-11-carbonate, MnCO 3 and diethanolamine tri-diethanolamine salt of the manganese-II complex of diethylenetriamine-N, N, N ', N ", N" -pentaacetic acid, C ^ H ^ MnNaO ^; with manganese-11 carbonate, MnCO 3 and morpholine, the di-morpholine salt of the manganese-11 complex of ethylenediamine-N, N 11, N "-tetra-acetic acid C 18 H 32 Mn N 4 O 10.

Example X

N-Methylglucamine salt of the gadolinium-III complex of ethylenediamine-N.N.N’.N'-tetra-acetic acid,

29.2 g (= 100 mmol) of ethylenediamine-NNN'.N'-tetraacetic acid were suspended in 100 ml of water and with 18.1 g (= 50 mmol) of gadolinium-11-oxide, Gd 2 O 3, at 95 ° C heated. During heating, 50 portions of 19.5 g (s 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: 55 (Calculated) C31.82, H4.71, N 6.55, Gd 24.51 (Found) C31 .65, H 4.59, N 6.52, Gd 24.56 195071 10

The following were obtained in an analogous manner: with dysprosium III oxide, Dy2 O3: the N-methylglucamine salt of the dysprosium III complex of ethylenediamine-N, N, N ', N'-tetraacetic acid,

Cl 7 ^ 30 ^ y ^ 30l 3! The N-methylglucamine salt of the gadolinium III complex of 1,10-diaza4,7-dioxadecane-1,1,10,10-tetraacetic acid, C21 H38 GdN3 O1s; 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-11-oxide, PbO and sodium hydrochloride, the di-sodium salt of the lead-11 complex of ethylenediamine-tetraacetic acid, C 10 H 12 N 2 O 8 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 8. Na; and in an analogous manner the sodium salt of the gadolinium III complex of ethylenediamine tetraacetatexamic acid, C10H16GdN608.Na; the sodium salt of the gadolinium-III complex of ethylenediamine-N.N.N'.N'-tetraacetic acid, C10H12GdN2Oe.Na.

Example XI

Preparation of the sodium salt of the gadolinium-III complex of 1,4,7,10-tetra-azacyciododecane-Ν, Ν ', Ν' ', Ν' '' - tetra-acetic acid, C 18 H 24 GdN 4 O 4 Na 20 In 20 ml of water 4.0 g (= 10 mmol) of 1.4.7 I10-tetraazacyclododecane-NfN-1 N ", N" -tetraacetic acid was suspended and 10 ml of 1 n sodium hydroxide solution was added. = 5 mmol) gadolinium-11-oxide, Gd 2 O 3, added and the suspension heated to 50 ° C. The clear solution was filtered and concentrated under reduced pressure, the residue was dried and powdered, 5.5 g (95 g) were obtained % of theory) of a white powder.

Analysis: (Calculated) 0 33.10, H 4.17, N 9.65, Gd 27.08 (Found) 0 33.01, H4.20, N 9.57, Gd 27.16

In the same way, the N-methylglucamine salt of the gadolinium-II complex of 1,4,7,10-tetra-azacydododecane-N, N ", N", Nm-30-tetraacetic acid, C23H42GdN6013: the sodium salt of the gadolinium were obtained -111 complex of 1,4,8,11-tetra-azacyclotetradecane-Ν, Ν ', Ν', ^ '- tetra-acetic acid, C 18 H 28 GdN 4 Oe.Na.

Example XH

Preparation of the tetra-N-methylglucamine salt of the gadolinium III complex of ethylenedinitrilotetrakis (methane phosphonic acid), C34H85GdNe032P4

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 of 5 with the appropriate amount of N-methylglucamine.

Next, 3.6 g (= 10 mmol) of gadolinium III oxide, Gd2 Oa, was 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 introduced into 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, H6.25, N6.13, P 9.04, Gd 11.47 (Found) C 29.85, H6.57, N5.98, P 8.78, Gd 11 , 26 50

The following were obtained in the same way: the hepta-N-methylglucamine salt of the gadolinium III complex of diethylenetriamine-N, N, N ", N", N "-penta (methane phosphonure), CseH ^ GdN ^ OgoPg! 55 and using sodium hydroxide solution instead of N-methylglucamine: the di-sodium salt of the gadolinium III complex of diethylenetrin trinitrile penta (methane phosphonic acid), C8H23GdN3015P5.2Na.

11 195071

EXAMPLE XIII

Preparation of the di-sodium salt of the manganese-11 complex of ethylene-dinitrile-tetra (acetylamino-acid), C 10 H 16 N 6 O 8.2 Na

In 18 ml of water, 2.30 g of manganese-11-carbonate and 7.05 g of ethylenedinitrile-tetra (acetydroxamic 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 10 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-pentaacetic acid a). Preparation of the mono-N-methylglucamine salt of the complex, C21 H37 Gd-N-401s

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 having a water content of 2.6% was sintered and melted at 133 ° C and melted at 190 ° C Gd (Calculated) 21.17 (Found) 21.34 b) Preparation of the neutral solution of the "mixed salt" 25 in 630 ml of water pl (p.l. = 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 "mixing salt" per liter.

30

Example XV

Preparation of a solution of the di-N-methylglucamine salt of the gadolinium III complex of diethylenetriamine-pentaacetic 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 the addition of 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

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

45

Example XVII

Preparation of a solution of the di-sodium salt of the gadolinium III complex of 13.23-dioxo-15.18.21-tris (carboxymethyl) -12.15.18.21.24penta-aza-pentatriacontanedioic acid

In 500 ml of water p.i. 392.0 g (= 400 mmol) of the salt described in Example II was slurried and 50 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-11 complex of 1,4,7,10-55 tetra-aza-cyclododecane-tetra-acetic acid

In 500 ml of water p.i. 370.9 g (= 500 mmol) of the salt mentioned in Example XI were slurried and 195071 was added by 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-cyclohexylenediamine-tetraacetic 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 10

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 iron-II complex of diethylenetriamine-pentaacetic acid

In 40 ml of water p.i. 44.6 g (= 0.1 mol) of the iron-III complex of diethylenetriamine-pentaacetic acid obtained in accordance with 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.

25

Example XXII

Preparation of a solution of the gadolinium III complex of nitrilotriacetic acid

In 100 ml of water p.i. 1.9 g (= 10 mmol) of nitrilotriacetic acid and 1.8 g (- 5 mmol) of gadolinium 1H oxide were dissolved with heating. The solution was placed in ampoules and heat sterilized.

30

Example XXIII

Preparation of a solution of the N-methylglucamine salt of the gadolinium III complex of ethylenedlamine tetra-acetic 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 40 diethylenetriamine-pentaacetic acid

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

45

Example XXV

Preparation of a solution of the N-methylglucamine salt of the gadolinium III complex of trans-1,2-cyclohexylene-diamine-tetraacetic acid

Of the salt described in Example VIII, 555.8 g (= 0.8 mol) in water p.i. dissolved to 1000 ml with 50 ml. 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-JII complex of 1,10-diaza-55 4,7-dithiadecane-1,1,10,10-tetraacetic acid

In 50 ml of water p.i. 15.6 g (= 0.03 mol) of the ruthenium-II complex of 1,10-diaza-4,7-dithiadecane-1,1,10,10-tetra-acetic acid was suspended and by adding 5 9 g (= 0.03 mol) of <135> 195071 N-methylglucamine were brought into solution at pH 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-lysine salt of the gadolinium III complex of diethylenetriamine-pentaacetic 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 under 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 tr1 N-methylene glucamine salt of the molybdenum VI complex of diethylene triamine-pentaacetic acid

In 50 ml of water p.i. 18.8 g (= 0.28 mol) of the H3 complex [Mo2 O2 (OH) 4.C14 H23 N3 O10] was suspended and neutralized by adding 16.4 g (= 0.84 mol) of N-methylglucamine. 0.15 g of tromethamine was then added, pj was added with water. made up to 100 ml, after which the solution was subjected to a sterile filtration and placed in ampoules 20

Example XXIX

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

In 500 ml of water p.i. 343.2 g (= 1 mole) of the manganese-ll complex of ethylenediamine-tetra-acetic acid was suspended and neutral dissolved portionwise by adding 80 g (= 2 mole) of sodium hydroxide. After addition of 1.5 g of tromethamine, the solution was made up with water, ptotinO00 ml, bottled and heat sterilized.

Example XXX

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

In 500 ml of water p.i. 345.7 g (= 1 mole) of the iron-II complex of ethylenediamine-tetraacetic acid were suspended and neutralized by portionwise addition of 40 g (= 1 mole) of sodium hydroxide. After adding 1.5 g of tromethamine, the solution was with water pi supplemented to 1000 ml, placed in bottles 35 and heat sterilized.

Example XXXI

Preparation of a solution of the di-sodium salt of the iron-III complex of diethylenetriamine-pentaacetic acid 40 In 500 ml of water p.i. 334.6 g (= 0.75 mole) of the iron-III complex of diethylenetriamine-pentaacetic acid were suspended and neutralized by portionwise addition of 60 g (= 1.5 mole) of sodium hydroxide. The solution was dissolved with water p.i. replenished to 1000 ml, bottled and heat sterilized. 1 2 3 4 5 6 7 8 9 10 11

Example XXXII

2

Preparation of a solution of the sodium salt of the gadolinium-III-compiex of trans-1,2-3-cyclohexylenediamine-tetra-acetic acid 4

In water p.i. 558.6 g (= 1 mole) of the salt mentioned in Example 8 was supplemented to 1000

ml dissolved. The solution was bottled and heat sterilized. Example XXXIII

6 7

Example XXXIII

8

Preparation of a solution of the N-methylglucamine salt of the gadolinium III complex of 1,2-9 diphenylethylenediamine-tetraacetic acid

In 600 ml of water p.i. 396.9 g (= 500 mmol) of the salt described in Example X was slurried and dissolved to 1000 ml by adding 11. The solution was placed in ampoules and heat sterilized.

195071 14

Example XXXIV

Preparation of a solution of the sodium salt of the iron-III complex of ethylenedlamine-tetraacetic acid

In 500 ml of water p.i. 183.5 g (= 500 mmol) of the salt mentioned in Example VII were slurried.

Next, 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-pentaacetic 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-pentaacetic 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-pentaacetic 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 ytterbium-II 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.

35

Example XXXIX

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

In 650 ml of water p.i. 573.2 g (= 1000 mmol) of the salt mentioned in Example VI were slurried and 40 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 dysprosium III complex of diethylenetriamine-45 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. 1 2 3 4 5 6

Example XU

2

Preparation of a solution of the di-sodium salt of the holmium III complex of diethylenetriamine-3-pentaacetic acid 4

In 500 ml of water p.i. 299.6 g (= 500 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.

15 195071

Example XUI

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

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

Example XUU

Preparation of a solution of the tetra-N-methylglucamine salt of the gadollnium-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. ampoules and heat sterilized.

Example XLIV

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

In 6 ml of water p.i. 1.9 g (= 6.7 mmol) of N, - (2-hydroxyethyl) ethylenediamine-N, N, N'-triacetic acid and 1.2 g (= 3.35 mol) of gadolinium III oxide were added heating solved. 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-cyclohexylenediamine-tetra-acetic acid With protection from nitrogen, p.i. 44.3 g (= 100 mmol) of the salt mentioned in example IX are slurried and supplemented with water p.i. brought to 100 ml in solution. 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 1,4,8,11-tetra-aza-cyclotetradecane-N, N ", N", N ", - tetra-acetic 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-pentaacetic acid

In 50 ml of water p.i. 23.4 g (= 50 mmol) of blsmuth 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-pentaacetic acid

In 65 ml of water p.i. 58.5 g (= 100 mmol) of the salt mentioned in Example 6 were dissolved with heating. Subsequently, p.i. supplemented to a total volume of 100 ml, after which the solution was placed in ampoules of 50 and heat sterilized.

Example XUX

Preparation of a solution of 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-pentatriacontane diacid 55 130.4 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.

195071 16

Example L

Preparation of a solution of the di-N-methylglucamine salt of the manganese-II complex of ethylenediamine-tetraacetic 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 U

Preparation of a solution of the di-sodium salt of the gadolinium III complex of diethylenetrin trinitrile-10 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, followed by p.i. was made up to 100 ml. The solution was placed in ampoules and heat sterilized.

Example UI

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

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

Example Owl

Composition of a powder for the preparation of a suspension 4,000 g of gadolinium III compound of 25 diethylenetriamine-pentaacetic acid (water content 8.0%) 3,895 g of sucrose _____ _____________ 0,100 g of polyoxyethylene polyoxypropylene polymer 0.005 g of flavoring substances 8,000 g of 30

Example LIV

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

To 20 ml of a solution of 3 mg of the protein in 0.05 molar sodium hydrogen carbonate buffer (pH 35 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.

40 A solution of the corresponding complex conjugate was obtained in an analogous manner with immunoglobulin.

Example LV

Preparation of a solution of the gadolinium III complex of the conjugate of diethylenetriamine-penta-45 acetic acid (DTPA) with a monoclonate antibody

To 20 µl 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 DTPA anhydride (obtained for example from DTPA and isobutyl chloroformate) and 30 stirred at ambient temperature for 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 50 antibody fraction obtained. 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-55 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.

Claims (3)

1950-171 Example LVI • Preparation of a solution of the gadolinium III complex of the conjugate of 1-phenyl-ethylenediamine-tetraacetic acid with immunoglobulin According to the method described 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 added to the protein. equivalent 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 conjugate 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 added for 24 hours at stirred at ambient temperature. Then 0.1 mmol of manganese-l-carbonate was added and stirred for a further 6 hours at ambient temperature. After purification on a Sephadex G 50 column, the sterile filtered solution was placed in multivials and freeze-dried. Similarly, with gadolinium III oxide, a colloidal dispersion of the gadolinium DTPA-lipid conjugate could be obtained. Example LVIII Preparation of gadolinium DTPA-laden Hposomes According to the procedure described in Proc. Nat!, 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 30 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. 35. Diagnostic agent for use in in vivo NMR diagnostics, which agent comprises at least one physiologically acceptable complex salt of the formula XCH 2 CH 2 X / N-A-N / 45 contains VCHR1 CHR4, 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, 50 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; that 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 -C 1 ym, wherein m is 1, 2 or 3, 55 wherein Z has the meaning of NCH 2 X, provided that at least one substituent V is the group COB proposes