Diagnostic agent, manufacture and complex salt

Patent and Patent Specification of SCHERING AKTIENGESELLSCHAFT, German, Industrial and Commercial, headquartered in Berlin and Bergkatnen (postal address: 170-178.Mullerstrasse, Berlin 65), Federal Republic of Germany, for the preparation of auxiliary agents. DIAGNOSIS.

DESCRIPTIVE MEMORY

description

The present invention relates to the object of the patent claims.

Complexes and their salts have long been used in medicine, for example as auxiliary means for the delivery of poorly soluble ions (eg iron) and as antidotes (in this case, calcium complexes or zinc) for development when heavy metals or their radioactive isotopes have been mistakenly incorporated. The Applicant has just discovered that physiologically acceptable complex salts derived from the anion of an acid forming complexes and one or central elements of an element with the atomic number from 21, 29, 42, 44 or 57. ^The Eventually one or more physiologically acceptable cations of an inorganic and / or organic base or an amino acid are surprisingly well suited for the preparation of diagnostic aids which are usable for

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diagnosis by nuclear magnetic resonance, X-ray or ultrasound.

The above-mentioned atomic number element forming the central ion or the central ions of the physiologically acceptable complex salt must of course be unreactive in order to be employed in the diagnostic auxiliary agent of the present invention.

If the diagnostic auxiliary agent according to the present invention is to be used for nuclear magnetic resonance diagnosis (see European Patent Application No.^s 71 564), then the central ion of the complex salt must be paramagnetic. This is especially one of the bivalent or trivalent ions of elements with the atomic number 21-29> 42, 44 and 58 to 7θ. Suitable ions are for example chromium- (iii), ferro- (III) ions. ), ferre- (11), cochalto- (11), nickel- (11), copper- (11), praseodymium- (iii), neodymium- (iii), samarium (iii) and ytterbium- (III). Because of their very intense magnetic moment, gadolinium- (iii), terbium- (iii), dysprosium- (iii), holmium- (III) and erbium- (III) ions are especially preferred.

If the diagnostic auxiliary agent of the present invention is to be used for x-ray diagnosis, then the center ion must be derived from a higher atomic number element to achieve sufficient x-ray absorption. The Applicant has found that diagnostic auxiliaries for this purpose must contain a physiologically acceptable complex salt with central ions of atomic number elements ranging from 57 to 83; these are, for example, lanthanium- (lll) ions, the aforementioned lanthanide ions, the oiro- (lll) ion, the chunybo- (ll) ion or especially the bismuth- ( iii).

Both diagnostic aids for use in nuclear magnetic resonance diagnostics and those for use in X-ray diagnostics in accordance with the present invention are suitable for use in ultrasound diagnostics.

Suitable complex-forming acids are those used for complex formation of the above mentioned central ions. Suitable acids for complex formation are for example those containing methylenephosphonic acid groups, methylene carbohydramic acid groups, carboxyethylidene groups or especially carboxymethylene groups, one, two or three of which they are attached to the nitrogen atom that serves as the basis for complex formation. If three azide groups are attached to a nitrogen atom, then the complex salts present are derived primarily from the complex forming acids of general formula II according to claim 2 of the patent. If, respectively, only one or two azide groups are attached to one nitrogen atom, then the nitrogen is attached to another nitrogen atom via an optionally substituted ethylene group or up to four ethylene units respectively separated by one. a nitrogen atom that supports the formation of the complex or an oxygen or sulfur atom. Preferred complex forming salts of this type are those of the general formula I according to claim 2 of the patent.

Acids that form complexes may be coupled with biomolecules as conjugates, in which it is known that the organ or part of the organ to be examined is particularly enriched. Such biomolecules are, for example, hormones such as insulin, prostaglandins, steroid hormones, amino sugars, peptides, proteins or lipids. Of particular note are albumin conjugates such as human serum albumin, antibodies such as, for example, tumor-specific antigen-associated monoclonal antibodies or antimiosin. Diagnostic aids thus formed are especially suitable for example for use in the diagnosis of tumors and infarction. For liver assays, for example, conjugates or liposome inclusion compounds which are, for example, used as unilamellar or multilamellar phosphatidylcholine / cholesterol vesicles are suitable. Formation of the conjugate is carried out either by a carboxyl group of the acid forming the complex or, in the case of proteins or peptides, also by a group of the formula as defined in claim 2 of the patent. In the formation of the conjugate of acid forming complexes with proteins, peptides or lipids, various acid radicals may be paroyably linked to macromolecular biomolecules. In this case, each complexing acid radical may have a central ion. If the acids that form the complexes are not bound to the biomolecule, they eventually have two central ions, in particular a central ion.

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

X-CH,

N-CHR₂-CHR -Ν ' _χ0Κ₂-L (la), v-chr:

in which

X, V, R4, R₂ and R 4 have the meanings mentioned in claim 2.

For the preparation of complex salts of the general formula Ia, the following complex forming acids are suitable, among others: ethylene diamine tetraacetic acid, ethylenediamine tetracetohydroxamic acid, trans-1,2-cyclohexylene diamine tetraacetic acid, D, L-butylene diamine tetraacetic acid, D, L- 1,2-butylene diamino tetracetic acid, D, L 1, 2-propylene diamino tetracetic acid, 1,2-diphenyl ethylenediamine tetracotic acid, ethylenedinitrile tetrakis (methanophosphonic acid) and N- (2-hydroxyethyl) -ethenediamino-triacetic.

Other suitable complex salts of formula I according to claim 2 are, for example, salts of formula Ib

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X-CH CIÇ-X n-oh₂-oh₂- (z-oh₂-oh₂)_B^

V-CHR₁ CHR.JV (lb), in which

X, V, Z, R 3 and m have the meanings mentioned in claim 2. If Z means an oxygen atom or a sulfur atom, complex salts wherein m is 1 or 2 are preferred.

For the preparation of the complex salts of general formula Ib, the following complex forming acids are suitable among others; diethylene triamine pentacetic acid, triethylene tetraminohexacetic acid, tetraethylene pentaminoheptacetic acid, 13,23-dioxo-15 ·, 18,21-tris- (carboxymethyl) -12,15,18 , 21,24-penta-aza-pentatriacontane-dioic acid, 3,9-bis- (1-carboxyethyl) -3, 6,9-triaza-undecanedioic acid, diethylene triamino-pentachis (phenylphenophonic) acid, 1,10-diaza-4,7-dioxadecane-1,1,10,10-tetracetic acid and 1,10-diaza-4,7-dithia-1,1,1,10-tetracetic acid.

Further complex salts of the general formula I according to claim 2, the complex salts of the general formula Ic.

X-CH „^ CH_-X ²\ X ²

N-CH.-CEL-N I 2 2, θ^Η2 ?^H2 (oh₂)„ ^(l°> 'n them₂-oh₂-H_x

X-CH₂^CH2“^X in which

X and w have the meanings referred to in claim 2,

For the preparation of the complex salts of the general formula Ic, the following complex forming acids are suitable, among others; 1,4,8,11-tetrazaoolotetradecane tetracetic acid and especially 1,4,7,10-tetraza-cyclododeoano tetracetic acid.

,_Λκϊΐ «

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Other complex forming 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 acid and nitrile tris acid - (ethylenenitrile) -hexacetic. As an example of an acid forming complexes for the preparation of complex salts of the general formula II, nitrilotriacetic acid may be mentioned.

If not all hydrogen azide atoms of the acid forming complexes are substituted by the central ion or the central ions, to increase the solubility of the complex salt it is convenient to replace the hydrogen atoms which are maintained by physiologically acceptable cations. inorganic and / or organic bases or amino acids. Suitable inorganic cations are for example lithium ion, potassium ion or, in particular, sodium ion. Suitable organic base cations are, among others, primary, secondary or tertiary amine cations such as ethanolamine, diethanolamine. morpholine, glucamine, N, N-dimethyl glucamine or in particular N-methyl glucamine. Suitable amino acid cations are for example lysine, arginine or ornithine cations.

The complex-forming acids necessary for the compositions according to the present invention are known or may be prepared in a known manner.

Thus, for example, the preparation of 13,23-dioxo-15,18,21-tris- (carboxymethyl) -12,15,18,21,24-penta-aza-triacontane dioic acid is carried out by the improved process. described by R. A. Bulman et al. in Katurwissenschaften 68, (1981) 483:

17.85 grams (= 5θ millimoles) of 1,5-bis- (2,6-dioxo-morpholino) -3-aza-pentane-3-acetic acid are suspended in 400 milliliters of water-free dimethylformamide and then When 20.13 grams (= 100 millimoles) of 11-amino-undecanoic acid is added, it is heated at -0 ° C for 6 hours. The clear solution is concentrated to dryness in vacuo. Stir the yellow oily residue with 5θθ milliliters of water at room temperature.

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ambient temperature. Under these conditions, an off-white bulk precipitate forms which is filtered off under suction and washed with water several times. For further purification, the product thus obtained is introduced into 200 milliliters of acetone and stirred at room temperature for 30 minutes. After separation by suction filtration and vacuum drying at 50 ° C, 36.9 grams (= 97% of theory) of a white powder with a melting point of 134 - 138 ° C are obtained. .

Conjugation of the complex forming acids with biomolecules is also carried out according to methods known per se, for example by reacting nucleophilic groups of the molecule - such as amino, hydroxy, thio or imidazole groups - as an activated derivative. of the acid that forms complexes.

As activated derivatives of acids which are complexes are of interest, for example, acid chlorides, acid anhydrides, activated esters, nitrenes or isothiocyanates. On the other hand, it is also possible to react an activated biomolecule with the acid forming complexes.

For protein conjugation substituents may also be used with the formulas of the structure -CgH4 N * or CgH4 NHCOCHgHalogen.

The preparation of the complex salts is also in part known or may be carried out in a known manner by dissolving or suspending the metal oxide or a metal salt (e.g. nitrate, chloride or sulfate) of the atomic number element. 21 to 29, 42, 44 or 57 θ- 83 in water and / or a lower alcohol (such as methanol, ethanol or isopropanol) and reacting with the solution or suspending the equivalent amount of the acid forming complexes in water and / or a lower alcohol and stirring, if necessary, by moderate heating or boiling to reaction is over. If the complex salt formed is insoluble in the solvent employed, it is isolated by filtration. If it is soluble then it can be isolated by evaporating the solution to dryness, for example by drying it.

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spray drying.

If in the complex salt thus obtained there are still aza groups, then it is often convenient to transform the acid complex salt into neutral complex salt by reaction with inorganic and / or organic bases or with physiologically acceptable cation-producing amino acids and to isolate the neutral salt. In many cases the neutral salt itself is not processable because the dissociation of the complex salt is impaired by shifting the value of pl-Ι to the neutral value in such a way that only homogeneous or at least isolated isolation is possible. its purification.

Conveniently, the preparation is carried out with the aid of organic bases or basic amino acids. But it may also be advantageous to carry out the neutralization by sodium, potassium or lithium inorganic bases (hydroxides, carbonates or bicarbonates) mentioned above.

For the preparation of neutral salts, such an amount of the desired base which reaches the neutral point may be added to the acid complex salts in aqueous solution or in suspension. The solution thus obtained can then be concentrated to dryness under vacuum. It is often advantageous to precipitate neutral salts formed by the addition of water-miscible solvents such as lower alcohols (methanol, ethanol, isopropanol, etc.), lower ketones (acetone, etc.), polar ethers (tetrahydrofuran, dioxane , 1,2-dimethoxyethane, etc.) and thus easily isolate them and obtain a suitable crystallized product for purification. It has been found to be especially advantageous to add the desired base already during the formation of the complex to the reaction mixture and thereby to save a process step.

If the acid complex salts contain several free azide groups, then it is often convenient to prepare neutral mixed salts which contain not only physiologically acceptable inorganic but also organic cations as counterions. This can for example be accomplished by reacting the acid forming complexes in aqueous suspension.

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6OS0Ò ·

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or in solution with the oxide or salt of the element that gives rise to the central ion and with half of an organic base, isolating the complex salt, purifying it if desired, and then adding the required amount of inorganic base for complete neutralization. The sequence order of the base addition may also change.

The preparation of the diagnostic auxiliaries according to the present invention is also carried out in a manner known per se by suspending or dissolving in complex aqueous salts optionally with the addition of pharmacologically usual additives and then sterilizing the solution with the suspension. Suitable additives are for example physiologically acceptable buffers (such as Tromethamine hydrochloride), minor additions of complexing agents (such as diethylene tri amino pentacetic acid) or, if necessary, electrolytes (such as e.g. sodium chloride).

In principle, it is also possible to prepare diagnostic aids according to the present invention without isolating the complex salts. In each case, care should be taken when using the formation of chelates such that the salts and salt solutions of the present invention are practically free of toxically uncomplexed acting ions. This can for example be ensured with the aid of colored indicators such as xylenol orange by controlled titration during the preparation process. Accordingly, the invention also relates to processes for the preparation of the complex compound and its salts. For better safety, purification of the isolated complex salt is performed.

If suspensions of the complex salts in water or saline solution for oral administration or other purposes are desired, a poorly soluble complex salt is mixed with one or more pharmacological adjuvants and / or surfactants. -active and / or aromatic substances for taste correction.

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Diagnostic aids according to the present invention preferably contain 1 µmole to 1 mole of the complex salt per liter and are generally dosed in the range from 0.001 to 5 millimoles / kg. They are intended for administration by orally and especially parenterally.

Diagnostic aids according to the present invention - corresponding to claim 4 - satisfy the multiple requirements for contrast agents appropriate for nuclear spin tomography. Thus, they are extraordinarily appropriate after oral or parenteral administration to improve the intensity of the image obtained with the aid of spin tomography.¹¹ nuclear power by increasing the signal strength. They also possess the high activity that is indispensable for carrying organisms in as small quantities as possible and the good compatibility that is indispensable for maintaining the non-invasive character of the assay (the compounds given in J, Comput. Tomography jq, 6: 54- 3,546 (1998), Radiology 1444, 343 (1982) and Brevet Special of Medicament.^s 484 Μ (ΐ9όθ) are for example too toxic). The good water solubility of the agents according to the present invention makes it possible to prepare very concentrated solutions in order to keep the volumetric load of the circulatory apparatus within the allowable limits and to compensate for dilution by body fluid, i.e. diagnostic aids for Nuclear magnetic resonance should be 100 to 1000 times more water soluble than those for nuclear magnetic resonance spectroscopy. Moreover, the agents according to the present invention have not only high in vitro stability but also surprisingly high in vivo stability so that only an unusually slow restitution or exchange of the non-covalently bound poisonous ions themselves is carried out. in complexes for 24 hours, where - as found in pharmacological trials - the new contrast agents are completely separated again. Protein and antibody conjugates, for example used for the diagnosis of tumors, already produce at a very small dosage a surprisingly high signal strength such that^:6O $ 0a / |

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solutions with a correspondingly low concentration may be employed.

Diagnostic aids according to the present invention are - corresponding to claim 5 - excellently suitable as x-ray contrast agents, and it is especially emphasized that in the case of their use there are no signs of Known anaphylaxis-type reactions of iodine-containing contrast agents in biochemical and pharmacological assays. They are especially valuable because, because of their good favorable absorption properties, they can be used in regions with the highest blood stresses for digital substrate techniques.

The diagnostic auxiliary agents of the present invention are - corresponding to claim 3 - also suitable as diagnostic auxiliary agents for ultrasound testing because of their ability to favorably influence the ultrasound velocity.

Unlike X-ray contrast agents for conventional shadow-based X-ray diagnostics, in nu clear magnetic resonance diagnosis with paramagnetic contrast agents there is no linear relationship between signal strength and the concentration employed. As the control assays show, increasing the applied dose does not necessarily give rise to signal strength and, with a high dose of paramagnetic contrast agent, signal attenuation may actually occur. It is therefore surprising that some processes are only visible after application of higher doses than those given in European Patent 71564 (which may range from 0.001 millimole / kg to 5 millimoles / kg) of a strongly paramagnetic contrast agent. according to the present invention. Thus, for example, the presence of a defective blood / brain barrier in the domain of a cranial abscess can only be demonstrated after administration of 0.05 -2.5 millimoles / kg, preferably 0.1 - 0.5. millimoles / kg of paramagnetic complex salts such as diethylene-

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gadolinium triamino pentacetate or manganese 1,2-cyclohexylene diamino tetracetate as its very water-soluble salts. For a dose greater than 0.1 millimole / kg, solutions of higher concentrations of up to 1 mole / liter are required, preferably 0.25 to 0.75 mole / liter as this reduces the volume load and ensures handling the injection solution.

For organ-specific diagnosis by nuclear magnetic resonance, for example for the identification of tumors and heart infarction, especially small dosages (less than 1 mg / kg) and, as a consequence, less concentrated solutions (1 yimole / liter up to 5 millimoles / liter) as indicated in European Patent 71564,

The following embodiments serve for further clarification of the present invention.

Example 1

Preparation of the gadolinium-XII complex of nitrile acid-N, N,

N-triacetic, CgHgGdNOg

Under stirring, the suspension of 33.2 grams (= 100 millimoles) of gadolinium oxide (Gd ^O ^) and 33.2 grams (= 200 millimoles) of nitrile acid is heated at 90 ° C to 100 ° C. -triacetic acid in 1.2 liters of water and stir at this temperature for 48 hours. Then, filter through active charcoal by separating the insoluble products and evaporate the filtrate to dryness. The amorphous residue is sprayed.

Yields 60 grams (879θ of theory).

Melting point: 300 ° C.

Gadolinium: calculated 45.5%, determined 44.9%.

The nitrile-N, N, N-triacetic acid iron-III complex is obtained with the aid of iron-III chloride, FeCl3.

Example 2

Preparation of the gadolinium-III complex disodium salt of

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13123-dioxo-151.18T21-tr1- (carboxymethyl) -12,15,18,21,24-penta-aza-pentatriaoontane dicarboxylic acid, C ???_OGdN4 .O · 2Na.

15.2 grams (= 20 millimoles) of 13,23-dioxo-15,18,21-tris- (carboxymethyl) -12,15,18,21,24penta-aza-pentatriphenecarboxylic acid in 400 milliliters of water and heat to 95 ° C. 7.43 grams (= 20 millimoles) of gadolinium chloride III hexahydrate dissolved in 60 milliliters of water are slowly added dropwise. Store at this temperature for 2 hours and then treat. with 60 milliliters of normal sodium hydroxide 1 to neutralize the released hydrochloric acid.

After completion of the reaction (xylene orange assay), the precipitate obtained is filtered off and washed with water until free of chlorides. 17.60 grams of theory (96 ° C) is obtained from a white, water-insoluble powder with a melting point equal to 290-292 °.

13,23-dioxo-15,18,21-tris- (carboxymethyl) -12,15,18,21,24-penta-aza-pentatriacontane-dicarboxylic acid gadolinium-III complex:

Analyze ;

(calculated); C 47.30; H 6.84; W 7.66; Gd 17.20 (found) tC 47.13; H 6.83} N 7.60; had 17.06

14.6 grams (= 16 millimoles) of the gadolinium-III complex thus obtained are suspended in 200 milliliters of water and 31.4 milliliters of normal sodium hydroxide 1 bleach are added dropwise. After 1 hour, a clear solution is obtained, which is filtered and then concentrated to dryness in vacuo. After vacuum drying at 80 ° C, 13.2 grams (87% of theory) of a very water-soluble white powder with a melting point of 279-285 ° C are obtained,

Analyze;

(calculated); C 45.13} H 6.31} N 7.31} Gd 16.4l} Na4 O (determined): C 45.20; H 6.12} N 7.28} Gd 16.26} Na 4.75

Proceeding the same way but employing

N-methyl glucamine instead of sodium hydroxide bleach,

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the di-N-methyl-glucarnamine salt of the gadolinium-III complex of 13,23-dioxo-15,18,21-tris- (carboxymethyl) -12,15) 18,21, 24-penta-aza-pentatriacontane-dicarboxylic, ^Ç5th^d93rd^GdN7^O22·

Example 3

Preparation of the 3,9-bis- (1-carboxy-ethoxy) -6-carboxymethyl-3,6,7-triaza-undecane-dicarboxylic acid gadolinium-rll complex disodium salt, ^Çlot^H22^GdN3 -102 Na

In 250 milliliters of water 36.2 grams (= 0.1 mole) of gadolinium-III oxide and 84.2 grams (= 0.2 mole) of 3.9-bis- (1-carboxy) acid are suspended. ethyl) -6-carboxymethyl-3, 6,9-triaza-undecane-dicarboxylic acid and reflux for 1 hour. A small amount of insoluble products are filtered off and the solution is concentrated to dryness under vacuum. The residue is checked and dried under vacuum at 60 ° C. 112.8 grams (= 9θ / 'ο of theory) of chelate as a white powder are obtained. Elemental Analysis for Ο ^ Η ^ ΰόΝ ^ Ο ^ θ

Calculated values: C 33.39! H 4.20; Gd 27.32; N 7.30 Determined values ​​C 33.25ί H 4.49; Gd 27.42; N 7.21

57.6 grams (= 0.1 mole) of chelate are introduced into a solution of 0.1 mole of caustic soda in 100 milli liters of water. By adding another 0.1 mole of pulverized caustic soda, the solution is adjusted to pH 7.5, the solution is boiled and ethanol is added to a permanent turbidity. After stirring for several hours in an ice bath, the crystals are filtered off under suction, washed with ethanol and dried in vacuo. The disodium salt is obtained as a white powder in quantitative yield.

Analyze:

(calculated): C 31.02; H 3.59! Gd 25.38; N 6.78 (found) C 31.10; H 3.7U Od 25.5 °! N 6.61

Example 4

Preparation of gadolinium complex dlmorpholine salt · !!!

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3.9-bjs- (1-carboxy-ethyl) -6-carboxymethyl-3,6,9-traza acid

-undecano-dioic, 'C_O,₁II |_{1 no}GdNj, —12

17.4 grams (= 0.2 mole) of morpholine is dissolved in 50 milliliters of water. Add 42.1 grams (= 0.1 mole) of 3,9-bis- (1-carboxyethyl) -6-carboxymethyl • 3,6,6-triaza-undecane dioic acid and then 18, 2 grams (= 0.05 mol) of gadolinium oxide-III and the mixture is heated at reflux for as long as necessary until a clear solution is obtained. Then acetone is added dropwise until permanent turbidity is obtained. After stirring on an ice bath for several hours, the crystalline product is filtered off under suction, washed with acetone and dried in vacuo. The white dimorpholine salt is obtained as a white powder. quantitative.

Elemental analysis!

(Calculated)! C 38.44 H 5.66 Gd 20.97 N 9.34 (Determined) t O 38.41 H 5.72 Gd 20.76 N 9.32

Example 5

Preparation of the di-N-methylgluamine salt of the gadolinium-III complex of djetylene triamino acid-N, N, N^t , N^ll-p6ntacetic, C₂₈H_gZjGdN₅ °20

39.3 grams (= 100 millimoles) of thiethylene triamino-Ν, Ν, Ν¹, N, N-pentacetic in 200 milliliters of water and mix with 19.5 grams (= 100 mils) of N-methyl glucamine. Thereafter, 18.12 grams (= 50 millimoles) of gadolinium-III oxide (Gd ^O ^) are added in several portions and the suspension thus obtained is heated to 95 ° C. After about 1 hour, an additional 19.5 grams (= 100 millimoles) of N-methyl glucamine is added and after a further 2 hours of heating, a clear solution is obtained. After completion of the reaction (xylenol orange control), insoluble material is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is redissolved in 100 milliliters of water and stirred in 250 milliliters of ethanol. After cooling for several hours, the crystals are filtered off under suction, washed with ethanol.

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cold and dried under vacuum at 60 ° C. 92.7 grams (99% of theory) of a white powder with uncharacteristic melting point is obtained.

Elemental Analysis:

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

For purification of the complex salt, instead of ethanol, acetone, propanol or isopropanol may also be used.

By proceeding accordingly, you get!

with dysprosium-III oxide, Dy ^ Oçj, the di-N-methyl-glucamine salt of the diethylene triamino-Ν, Ν, Ν *, N, NTpentacetic acid dysprosium-III complex, ^Ç28^H54^DyN5 ° 2O⁵ with lanthanum-III oxide, La2 O4, the di-N-methyl-glucamine salt of the diethylene triamino-Ν, Ν, Ν ', N, N-pentacetic acid lanthanum-III complex, ^Ç28^II54^LaN5 ° 2Oⁱ with ytterbium-III oxide, Yb2 O4, the di-N-methyl-glucamine salt of the diethylene triamino-γ, Ν, Ν ', N, N-pentacotic acid ytterbium complex, c₂₈^H54YbN5^O2_O;

with samarium-III oxide, Sm2 O4, the di-N-methyl-glucamine salt of the diethylene triamino-β, Ν, Ν ', N, N-pentacotic acid samarium-III complex, ^G28^H54^SlIlN5^O2O⁵ with holmium oxide-III, Ho_no0 ', the di-N-methyl-glucamine salt of the diethylene triamino-β, Ν, Ν', N, N-pentacotic acid holmium-III complex, ° 28^¡54^ΗοΝ5^θ20^! with bismuth-III oxide, Di3 O4, the di-N-methyl glucamine salt of the bismuth-III complex of

ItWwWjl hCTiHIftWi

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diethylene triamino-Ν, Ν, Ν ', N, N-pentacetic acid, 0₂₈H_5UBiN₅⁰20i with gadolinium-III oxide, GddO ^, the tri-N-methylethyl glucamine salt of the triethylene-tetramino-gadolinium-III complex of β, Ν, Ν¹, Ν, Ν^¡, Ν ', N'-hexa acetic, CopH ^ gGdN ^ O ^ j

Holmium-III oxide HogQ4 and with ethanolamine instead of N-methylglucamine are also obtained, the diethanolamine salt of diethylene triamino-β, Ν, Ν¹, N, N-pentacetic, ^Ç18^H18^HoN5°12⁵ with gadolinium-III oxide, Gd ^ O ^, and lysine instead of N-methyl-glucamine, the lysine salt of the diethylene-trlamino-β, Ν, Ν ', N, N-, gadolinium-III complex. pentacetic, ^Ç26^H48^GdN7 ° M using diethanolamine, the di-diethanolamine salt of the diethylene triamino-pentacetic acid holmium-III complex, ^Ç22^H42^HoN5^H1^

The salts are obtained as white feet with uncharacteristic melting points. · They are very soluble in water.

Example 6

Preparation of the gadolinium-III complex disodium salt of diethylene triamino-N, N, N^>, N-pentacetic, ^Çl4^Hl8^GdN3°10 -²^

18.2 grams (= 0.05 mole) of gadolinium-III oxide and 39.3 grams (= 0.1 mole) of diethylene pentacetic acid are suspended in 110 milliliters of water and refluxed for 1 hour. The clear solution is cooled and, with the addition of about 80 milliliters of normal sodium hydroxide bleach, adjusted to pH 7.5. Warmed again to boiling and added dropwise. 250 milliliters of

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ethanol. After stirring for several hours in an ice bath, it is filtered off under suction, washed with ice cold ethanol and dried at 60 ° C under vacuum. A white powder in quantitative yield that does not melt to 300 ° C is obtained.

Elemental Analysis (Calculated): C 28.4 H 3 3.07 N 7.10 Gd 26.58 (Found) 1 C 28.35 H 2.95 N 7.05 Gd 23, 37

Proceeding accordingly, you get

up:

with dysprosium-III oxide, DygO ^, the disodium salt of the diethylene triamino-Ν, Ν, Ν ', N, N-pentacotic acid dysprosium-III complex, Ο- ^ Η- ^ ΏγΝ ^ Ο ^ θ 2_At.

with lanthanum oxide-III, La₂0 ^, the disodium salt of the diethylene triamino-N, Ν, Ν ', N, N-pentacetic acid, lanthanum-III complex^ba^ 3 ^ 10 *² ^^The'with holmium oxide-III, Ho₀0„,

THE.

the disodium salt of the diethyl-triamino-N, Ν, Ν ', N, N-pentacetic acid holmium-III complex. C - ^H H gHHN ^O O ^. 2 Na;

with Ytterbium-III oxide, Yb „0_O, -) the disodium salt of diethylene-triamino-γ, Ν, Ν ', N, N-pentacetic acid, ytterbium-III complex, ^Çthere^Hl8^YbN3°10 ·^{2 Nai} with samarium-III oxide, SnigO4, the disodium salt of the samarium-III complex of diethylene triamino-Ν, Ν, Ν¹, N, N-pentacetic, Na2 with erbium III oxide, Eb2_O,

J is the disodium salt of diethylene acid triamino-β, β, Ν orbium-III complex¹, N, N-pentacetic. 2 Na; with gadolinium-III oxide, Gd ^O ^, the sodium salt of the tetraethylene-pentamino-N, Ν, Ν ', N, N', N, N-heptacetic acid digadolinium-III complex,^Ç22^H30^Gd2^N5 ° 14

At.

<img file="PT77983B_D0017.tif" />

<img file="PT77983B_D0018.tif" />

These parents precipitate as non-characteristic melting point and are very soluble in water.

Example 7

Preparation of the N-Methyl-glucamine salt of the djetylene triamino-pentacetic acid iron-III complex, Cθ ^ FeN ^ O ^

35.40 grams (= 90 millimoles) of diethylene triamino-pentacotic acid is suspended in 100 milliliters of water and mixed with 24.3 grams (= 9 millimoles) of iron-III chloride hexahydrate (FeCl (6 H 2 O) dissolved in 100 milliliters of water. The first obtained dark brown suspension is heated to 95 ° C. After about 1 hour, the color turns light yellow. 270 milliliters of sodium hydroxide bleach 3 is added. normal to neutralize the hydrochloric acid thus obtained and heat at 95 ° C for a further 3 hours. The light yellow precipitate thus obtained is suction filtered off under suction, washed with water until free of chlorides and dried at 60 ° C under vacuum. Get

17.85 grams (45 of theory) of a light yellow powder whose melting point is greater than 300 ° C.

They are suspended in 200 milliliters of water.

17.85 grams (= 80 millimoles) of the iron-III complex thus obtained and 7.8 grams (= 40 millimoles) of solid N-methylglucamine are added in several portions. Heat at 50 ° C for about 3 hours and give an almost clear reddish-brown solution which is filtered and then concentrated to dryness in vacuo. The residue is dried at 5 ° C under vacuum. 24.3 grams (95% of theory) of red-brown dunate with a melting point of 131-133 ° C are obtained.

Elemental Analysis:

(Calculated) C 39.82 H 5.89 N 8.85 Fe 8.81 (Determined) C 39.7 ° H 6.00 N 8.65 Fe 9.01

Using sodium hydroxide bleach instead of the organic base yields:

<img file="PT77983B_D0019.tif" />

the sodium salt of the iron-III complex of ethylene diaminetetraacetic acid;^H12^Faith^2°8 * ^^The>

the sodium salt of the trans-1,2-cyclohexylene diamino tetraacetic acid iron-III complex, C C-H ^ gFFNgOg, Na;

the disodium salt of the diethylene trinitrile-penta- (methane-phosphonic acid) iron-III complex, 2 Ns;

the sodium salt of the 1,110-diaza-4,7-dioxadecane-1,1,10,10-tetracetic acid iron-III complex, Ο- ^ Η ^ θΕο ^ Ο ^ θ. At;

the sodium salt of the iron-III complex of ethylene diamine tetraacethydroxameter acid, G g gH ^EENgOO. At.

Proceeding accordingly with N-methylglucamine yields the di-N-methylglucamine salt of the diethylene triamino-β, Ν, Ν ', N, N-pentacetic acid iron-III complex, Ο ^ θΗ ^^ ΡβΝ ^ Ο ^ θ the N-methyl glucamine salt of the iron-III complex of trans-1,2-cyclohexylene diamino-N, N, N ', N'-tetraoetic acid ^Ç2l^H36^FON3°13^! the N-methyl glucamine salt of the ethylene diamino-Ν, Ν, Ν ', Ν'-tetraoetic acid iron-I ± I complex

Ci₇^H30 ^ N3 °₁₃the tri-N-methyl glucamine salt of the iron-III triethylene tetramino acid complex-Ν, Ν, Ν ', N, N¹N'-hexacetic

Ç₃₉H_7gPeN₇O₂₇.

Example 8

Preparation of the trans-1,2-Î ± -cyclohexylene diamino-N-N-N-tetraoetic acid gadolinium-ITI complex N-methylgluamine salt of N-N-tetraoetic acid CL „

- &lt;di — Joj — 1J

20.78 grams (= 60 millimoles) of trans-1,2-cyclohexylene diamino-N, N,, ', Ν'-tetracetic acid is suspended in 150 milliliters of water. After adding 11.7 grams (= 60 millimoles) of N-methyl glucamine, a_Uase 10.88 grams (= 30 millimoles) of gadolinium oxide (Gd ^O ^) is added. The suspension obtained at 95 ° C is heated for 6 hours. The small amount of insoluble matter is filtered off. and concen

II

<img file="PT77983B_D0020.tif" />

The filtrate is evaporated to dryness. The residue is dried under vacuum at 60 ° C and sprayed. 38.6 grams (92% of theory) of a white powder with a melting point of 258-261 ° C is obtained.

Elemental Analysis:

(Calculated) C 36.25 H 5.22 N 6.04 Gd 22.60 (Determined): C 36.4θ H 5.50 N 5.98 Gd 22.52

Proceeding in the same manner but using sodium hydroxide bleach instead of N-methyl glucamine yields the sodium salt of the trans-1,2-cyclohexylene diamine-N, N gadolinium-III complex of the gadolinium-III complex. , N *, Ν'-tetracetic, ^Çl4^H18^GdN2°8 * ^Na>

With freshly precipitated chromium-III hydroxide, Cr (OH) 4, the sodium salt of ethylenediamine TN, N, N ', t'-tetraacetic acid, C ^ QÍ ^ gGrGrGrGrGrGrGrGrgg. At.

Example 9

Preparation of the trans-1,2-oleylhexylene diamylno-N, N, N trans manganese-II complex disodium salt^l, N'-tetracetic, ^Çl4^Hl8^MnN2°8 * ^{2 At}

Under nitrogen atmosphere, 34.6 grams (= 100 millimoles) of trans -1,2-cyclohexylene diamine-Ν, Ν, Ν ', N * -tetraacetic acid are suspended in 100 milliliters of water and treated. with 11.5 grams (= 100 millimoles) of manganese-II carbonate, KnCO3. It is heated to 95 ° C and 200 milliliters of normal sodium hydroxide 1 is added dropwise. The clear solution is concentrated in vacuo and the residue is dried at 60 ° C under vacuum. 40.8 grams (92% of theory) of a pink powder is obtained.

Elemental Analysis:

(Calculated) C 39.94 II 4.09 N 6.32 Mn 12.40 (Determined): C 37.78 H 4.12 N 6.20 Mn 12.31

Proceeding accordingly gets

up:

from copper-II carbonate, the disodium salt of copper 21 -

<img file="PT77983B_D0021.tif" />

trans-1,2-cyclohexylene diaminotetraacetic acid copper-II plexus, Ο ^ Η ^ θΟυ, Ν ^ Οθ. 2 Na;

from cobalt-II carbonate, the trans-1,2-cyclohexylene-diamino-tetraacetic acid cobalt-II complex disodium salt, ^Ç]_4^Hq8^GoN2°8 * ^{2 Na5} from nickel-II carbonate, the trans-1,2-cyclohexylene diamino tetracetic acid disodium salt,

Ç_{12 +}H₁₈NiN₂0g 2 Na.

N-methyl glucamine instead of sodium hydroxide bleach gives:

the di-N-methyl glucamine salt of the trans-1,2-cyclohexylene diamino tetracotic acid manganese-II complex, ^Ç28^K54^MnNU18¹ the di-N-methyl glucamine salt of the DL-2,3-butylene diamino tetracetic acid manganese-II complex, ;ΟΟΗΜΜΜΜΝΟ ^ ^;

the di-N-methyl glucamine salt of the manganese-II complex of ethylene diamino acid-Ν, Ν, Ν¹, N *-tetraacetic, C DL ^H H gMMNN ^ ^ii o The di-N-methyl-glucamine salt of DL-1,2-butylene diamino-N, N, N manganese-II complex¹, N'-tetracetioo, ^G23rd^H52^Mn° A ° 18 'is the di-N-methyl glucamine salt of DL-1,2-propylene diaraino-β, Δ, Δ', N'-tetraacetic acid, diethylene triamine-pentaeetic acid manganese-II complex II-N-methyl glucamine, nickel-II carbonate, NiCOy the di-N-methyl glucamine salt of the nickel Ethylene diamidetetraacetic acid II, C ^ I ^ ^NNN ^ O ^ ^ *, with cobalt-II carbonate, CoCO ^ and ethanolamine, the diethanolamine salt of the cobalt-II complex of ethylene diamino acid-Ν, Ν, Ν¹ , N'-tetraacetic, ° qi [.^H28^Co^4^G10^! with copper-II carbonate, GuCO4 and ethanolamine, the diethanolamine salt of the ethylene diamino-β, Ν, Ν copper-II complex¹ Manganese carbonate, MnCO, and diethanolamine, the tri-diethanolamine salt of the acid manganese-II complex.

<img file="PT77983B_D0022.tif" />

of diethylene triamino-Ν, Ν, Ν, Ν *, N, N-pentacetic, ^Ç26^H58^KnN6^Ol6^{5th and} with manganese-II carbonate, MnCO ^ β morpholine, the; di-morpholine salt of the manganese-II complex of ethylene-diamino-N, N, N, N-tetraacetic acid, Ο ^ βΗ ^ ΜηΝ ^ Ο ^ θ;

Example 10

N-Methyl-glucamine salt of ethylene-dlamino acid gadolinium-III complex-Ν, Ν, Ν¹, Ν¹-tetracetic, 0_QGdN ^ O

29.2 grams (= 100 millimoles) of ethylene diamino-N, N,, ', Ν'-tetracetic acid are suspended in 100 milliliters of water and heated to 95 ° C with 18.1 grams (= 50 milli les) of gadolinium-III oxide, Gd OO,. During heating, 19.5 grams (= 100 millimoles) of N-methyl glucamine are added in portions. After about 3 hours, a clear solution is obtained which is filtered and concentrated to dryness in vacuo. The residue is dried under vacuum at 60 ° C. This yields 61.3 grams (95% of theory) of a white shovel with an uncertained melting point.

Elemental Analysis:

(Calculated): C 31.82 H 4.71 N 6.55 Gd 24.51 (Determined): 0 31.65 H 4.59 N 6.52 Cd 24.56

Proceeding analogously, we obtain: with dysprosium-III oxide, Dy₂0 ^, the N-methyl-glucamine salt of the ethylene diamino-N-N, N, Ν ', N * -tetraacetic acid dysprosium-III complex, Ο ^ ρ, Η ^ θΏγΝ ^ Ο ^^ Ι salt 1,10-Diaza-4,7-dioxa-decane-1,1,1,10-tetracetic acid N-methyl-glucamine, C_O-H_whatGdN_ON-methylglucamine salt of 1,2-diphenylethylene diamino tetraacetic acid gadolinium-III complex.

with lead oxide II, PbO, and sodium chloride, the disodium salt of the ethylene diamine tetraacetic acid lead II complex, C * ² ^ a;

<img file="PT77983B_D0023.tif" />

with freshly precipitated chromium-III hydroxide, Cr (OH), the sodium salt of chromium-III complex of ethylene diamino tetracetic acid, ^Çwhat^Hq2^CrN2 ° 8. At; and proceeding analogously, the sodium salt of the gadolinium-III complex of ethylene acid

diamino tetracotic hydroxamic, Câmico gH ^ gGGGNGOg. At;

the gadolinium-III complex sodium salt of ethylene acid

-diamino-N, N, N ¹ , N'-tetraacetic, C ^ QHH gGG OgN Og Ogg. At.

Example 11

Preparation of the sodium salt of the gadolinium-III acid complex 1,4,7,10-1 et raza-cyclo decane-N, 14¹, Ν, N¹-t et ethical rac, ^Çlot^K24^GdN4°8 ’ ^At

4 grams (= 10 railimoles) of 1,4,7,10-tetraza-cyclododecane-N, N¹, Ν, N¹tetraacetic acid in 20 milliliters of water and 10 milliliters of normal sodium hydroxide lye is added. 1.8 grams (= 5 millimoles) of gadolinium-III oxide, Gd ^O ^, is added and the suspension is heated at 50 ° C for 2 hours. The clear solution is filtered off and concentrated to dryness in vacuo. Get

5.5 grams (95 of theory) of a white powder.

Elemental Analysis:

(Calculated): C 33.10 H 4.17 N 9.65 Gd 27.08 (Determined): C 33.01 H 4.20 N 9.57 Gd 27.16

Proceeding in the same manner gives: the N-methyl-glucamine salt of the 1,4,7,10-tetraza-cyclododecane-N, N *, N, 14 gadolinium-III complex ¹_Tt et rac ethic, ^G23^H42^GdN5 ° 13 'the sodium salt of 11-tetraza-cyclotetradecane-N, N gadolinium-III complex¹, Ν, N'-tetracetic, ^Çl8^H28^GdN4°8 * ^Wa*

1,4,8,

Example 12

Preparation of the ethylene-dinitrile-tetrakis (methanesphonic) gadolinium-III complex of tetra-N-methyl-gluoamine salt;₂P ^

<img file="PT77983B_D0024.tif" />

9.11 grams (= 20 millimoles) of ethylene dinitrile tetrakis (methane phosphonic acid) is suspended and adjusted to a pH of 5 with the corresponding amount of N-methyl glucamine. 3.6 grams (= 10 millimoles) of gadolinium-III oxide (Gd ^Oj) is added and heated to 70 ° C. After about 1 hour, a clear solution is obtained which is mixed with the remaining part of N-methyl glucamine. In all, 15.6 grams (> 80 millimoles) of N-methyl glucamine is consumed. The solution is concentrated in vacuo to dryness and the gelatinous residue obtained in 20 milliliters of acetonitrile is introduced. Stir at 30 ° C for about 20 hours and separate the fine precipitate thus obtained by suction filtration. After drying under vacuum at 4 ° C, 23.4 grams (857 ° of theory) are obtained. ) of a white powder with a melting point of 115-118 ° C.

Elemental Analysis:

(Calculated) s C 29.78 H 6.25 N 6.13 P 9.04 Gd 11.47 (Determined): C 29.85 H 6.57 N 5.98 P 8.78 Gd 11.26

Proceeding in the same manner, the following are obtained: the hepta-N-methyl glucamine salt of the diethylene triamino-β, Ν, gad gadolinium-III complex¹, N, N-penta- (methane-phosphenic), σ₅₈Η₁^^ αάΝ_1θ0_5θΡ₅5th and using sodium hydroxide bleach instead of N-methyl glucamine, the disodium salt of the diethylene trinitrile-penta- (methane phosphonic) gadolinium-III complex,

ΟΗ „ΟΰΝ,_Ί0 . 2 Na.

23 J 15 5

Example 13

Preparation of the disodium salt of the manganese-11 complex of ethylene-dinitrile-tetra (α-hydroxamic acid), ^Ç10^Hl6^MnN6°8 ‘ ^{2 At}

2.30 grams of manganese-II carbonate and 7.05 grams of ethylene-dinitrile-tetra- (acetohydroxamium) acid are refluxed for 3 hours in 18 milliliters of water. It is then adjusted to pH 7 by the addition of dilute sodium hydroxide bleach and added dropwise.

- 25 seismic

<img file="PT77983B_D0025.tif" />

drop 40 milliliters of acetone. After stirring for several hours in an ice bath, the crystals formed are suction filtered off, washed with water and dried at 50 ° C under vacuum. A white powder with a melting point greater than 300 ° C is obtained in quantitative yield.

Kn: (calculated) 11.30 (determined) 11.12

Example l4

Preparation of a Sodium Sodium and N-Methyl Solution

diethylene triamino-pentacetic acid gadolinium-III complex

(a) preparation of the mono-N-methyl glucan salt of the complex;

Ç₂₁H_?7GdN₄O₁₅

195.2 grams (1 mole) of N-methyl glucamine are dissolved in 7 liters of water. Then, 393.3 grams (1 mole) of diethylene triamino-pentacetic acid and 181.3 grams (0.5 mole) of gadolinium oxide are added and refluxed for 2 hours. 8th_yuck__{if in} spray dryer the clear solution after filtration. A white crystalline powder of 2.6% water content is obtained which sinteres at 133 ° C and melts at 190 ° C with foam formation.

Gd: (calculated) 21.17 (determined): 21.34

(b) Preparation of neutral mixed salt solution

730.8 grams (= 1 mole) of the salt obtained in (a) and 630 milliliters of water for injection are suspended and 4θ grams (= 1 mole) of caustic soda paddle are added in several portions. The neutral solution is diluted with proinjection water to 1000 milliliters, packaged in vials through a pyrogenic filter and heat sterilized. This 1 molar solution contains 753.8 grams of mixed salt per liter.

<img file="PT77983B_D0026.tif" />

Example 15

Preparation of a solution of the diethylene-trlamino-pentacetic acid gadolinium-III complex di-N-methoxyamino salt

535.0 grams (= 73 ° millimoles) of the salt described in Example 5 is suspended and 500 milliliters of water injected and solubilized by the addition of 14-2.4 grams (= 730 millimoles) of N-methyl glucamine. at pH 7.2. Then dilute with water for injection until 1000 milliliters, pack the solution in ampoules and heat sterilize.

Example 16

Preparation of a solution of the dolphinjo-III complex djssódjo salt of dletjleno-triamino-pentacetic acid

48.4.1 grams (= 820 millimoles) of the disodium salt obtained in Example 6 is suspended in 500 milliliters of proinjection water. Then dilute with water for injection to 1000 milliliters, pack the solution in ampoules and heat sterilize.

Example 17

Preparation of a disodium salt solution of the 13.23 acid dolphinium-III complex^Mdioxo-15,18,11-trls- (carboxymethyl) -12,15,18,21,24-pentaza-pentatrlacontanedioid

392.0 grams (= 400 millimoles) of the salt described in Example 2 is suspended in 500 milliliters of proinjection water and solubilized by dilution with proinjection water to 1000 milliliters under slight heating. The solution is packaged in vials and sterilized by heat.

Example 18

Preparation of a solution of the 1,4,7,10-tetraza-chlodode acid gadolinium-III complex N-methoxyamino salt

<img file="PT77983B_D0027.tif" />

oano-tetracetjco

37θ, 9 grams (= 5θ0 millimoles) of the salt mentioned in Example 11 is suspended in 500 milliliters of proinjection water and solubilized by dilution with proinjection water to 1000 milliliters. The solution is packed in ampoules and heat sterilized.

Example 19

Preparation of a solution of the di-N-methyl-gluoamine salt of the trans-1,2-c-cyclohexylene diameno-tetraacetic acid manganese-II complex

395.9 grams (= 500 millimoles) of the salt mentioned in Example 9 is suspended in 5θθ milliliters of water. 1.3 grams of ascorbic acid is added and solubilized by dilution with proinjection water to 1000 milliliters. The sterilizing solution is filtered and packaged in ampoules.

Example 20

Preparation of a tri- Nmethyl-gluoamine salt solution of the manlet-II complex of dlethenyl triamino-pentacetic acid

514.4 grams (= 500 millimoles) of the salt mentioned in Example 9 is suspended in 600 milliliters of proinjection water. 1.3 grams of ascorbic acid is added and lubricated by dilution with water for injection to 1000 milliliters. It is packaged in ampoules after filtering to sterilize.

Example 21

Preparation of a solution of the di-N-methoxyamino-iron-plexus salt of djetylene triamino-pentacetic acid

In 4θ milliliters of water for injection, 44.6 grams (= 0.1 mole) of the farro-HI complex is suspended.

<img file="PT77983B_D0028.tif" />

of the diethylene triamino-pentacetic acid obtained in Example 7 · After adding 0.18 grams of tromethamine hydrochloride and 39.1 grams (= 0.2 mole) of N-methyl glucamine, dissolve to neutrality, The solution is diluted with water and injected to 100 milliliters, packaged in ampoules and sterilized by heating.

Example 22

Preparation of a solution of the gadolinium-IIl complex of nitrile triacotic acid

Under heating, 1.9 grams (= 10 millimoles) of nitrile triacetic acid and 1.8 grams (= 5 millimoles) of gadolinium-III oxide are dissolved in 100 milliliters of proinjection water. The solution is packaged in ampoules and sterilized by heating.

Example 23

Preparation of a solution of the N-methylglucamine salt of the gadolinium-III complex of ethenyl diameno-tetracetic acid

In 70 milliliters of proinject water dissolve 38.52 grams (= 60 millimoles) of the substance described in Example 10. After adding 0.12 grams of tromethamine add proinjection water to 100 milliliters. The solution is ampouled and heat sterilized.

Example 24

Preparation of a solution of the di-N-methyl-glucamine salt of the diethyl-triamine-pentacetic acid dislose-III complex.

35.7 grams (= 60 millimoles) of the diprenium-III complex of diethylene triamino-penichotic acid (8.0% water content) is suspended in 70 milliliters of pro-injected water and, by the addition of 21, 2 grams (= 120 millimoles) of N-methylglucamine gives a pH of 7.5.

<img file="PT77983B_D0029.tif" />

then diluted with water for injection, the solution is packaged in ampoules and sterilized by heating.

Example 25

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

555.8 grams (= 0.8 moles) of the salt described in Example 8 was dissolved in pro-injection water to 1000 milliliters. After filtering through a hydrogen filter, the solution is packaged in ampoules and sterilized by heating.

Example 26

Preparation of a solution of the N-methylglucamine salt of the ruthenium-III complex of 1,10-diaza-4,7-dltia-decane-1,1,10,10-ethoethoic acid

In 50 milliliters of pro-injected water 15.6 grams (= 0.03 moles) of the 1,10-diaza-4,7-dithia-decane-1,1, 10, 10 ruthenium-III complex are suspended. -tetra-skeptic and by adding 5.9 grams (= 0.03 moles) of N-methyl glucamine the solution is adjusted to pH 7.5. Dilute with water for injection to 1000 milliliters, pack the solution in ampoules and sterilize by heating.

Example 27

Preparation of the gadolinium III complex diethylene salt of diethylene tretamino tetracetic acid

273.8 grams (= 0.5 mol) of the gadolinium-III complex of diethylene triamino-pentacetic acid is suspended in 500 milliliters of proinjection water. 292.4 grams (= 1 mole) of Plant are added, stirred for several hours under slight heating and then diluted to 1000 milliliters with water for injection. The solution is packaged in vials and sterilized by heating.

<img file="PT77983B_D0030.tif" />

Example 28

Preparation of a solution of the tri-N-methyl-glucamino salt of the diethylene triamino-pentacetic acid molyldene-VI complex

18.8 grams (= 0.28 mol) of the formula complex is suspended. H2 O (H2 O4 OH). In 5θ milliliters of water, inject and dissolve to neutrality by adding 16.4 grams (θ, 84 mole) of N-methyl glucamine. Add 0.15 grams of tromethamine, dilute with water for injection until 100 milliliters, sterilize the solution and pack in ampoules.

Example 29

Preparation of a disodium salt solution of the manganese-II complex of ethylene dianylno tetracetic acid

3.25 grams (= 1 mole) of the tnanganese-II complex of ethylene diamine tetraacetic acid is suspended in 500 milliliters of water for injection and solubilized to neutrality by the addition of 80 grams of sodium hydroxide. (= 2 moles) in several portions. After 1.5 grams of tromethamine is added, the solution is diluted with water for injection until 1000 milliliters, packaged in vials and sterilized by heating.

Example 30

Preparation of a sodium salt solution of the iron complex ·

-III of ethylene dlamino tetracotic acid

34-5.7 grams (= 1 mole) of the ethylene diamino-tetraacetic acid iron-III complex is suspended in 500 milliliters of water for injection and solubilized by the addition of 4-0 grams (= 1 mole). ) of sodium hydroxide to neutrality in several portions. After the addition of 1.5 grams of tromethine, the solution is diluted with water for injection to 1000 milliliters, packaged in vials and es. sterilized by heating.

- 31 ι / Λ £ ΐΟ'Λ &lt;· £ ^ - * '^{ιίί: ι}^^ϊ·’··’' ”

<img file="PT77983B_D0031.tif" />

Sxemp1ο

Preparation of a dislet salt solution of the dletllene-triamino-pentacetic acid iron-III complex

334.6 grams (= 0.75 moles) of the diethylene triamine-pentacetic acid iron-III complex is suspended in 5θθ milliliters of water for injection and solubilized by the addition of 60 grams (= 1.5 moles) of sodium hydroxide to neutrality, in several portions. The solution is diluted with water for injection until 1000 milliliters. It is packaged in vials and sterilized by heating.

Example 32

Preparation of a solution of the sodium salt of the gadolinium-III complex of trans-1,2-cyclohexylene-diamine-tetraoethoxy acid

558.6 grams (= 1 mole) of the salt mentioned in Example 8 is dissolved in water for injection to 1000 milliliters. The solution is packaged in vials and sterilized by heating.

Example 33

Preparation of a solution of the N-methyl glucamine salt of 1,2-diphenyl-ethylene-diamino-tetraoic acid gadolinium-III complex

396.9 grams (= 5θθ millimoles) of the salt described in Example 10 is suspended in 600 milliliters of pro-injected water and diluted solubilized to 1000 milliliters. The solution is packaged in ampoules and sterilized by heating.

Example 34

Preparation of a solution of the sodium salt of the ethylene-diamino tetraacetic acid iron-111 complex

183.5 grams (= 5θθ millimoles) is suspended

<img file="PT77983B_D0032.tif" />

of the salt mentioned in Example 7 in 500 milliliters of water for injection. Add 1.0 grams of troraetin, dilute with water for injection until 1000 milliliters, pack the solution in ampoules and sterilize by heating.

Example 35

Preparation of a solution of the di-N-methylgluoamine salt of the dletllene triamino tetacetic acid lanthanlo-111 complex

459.8 grams (= 500 millimoles) of the salt mentioned in Example 5 is suspended in 650 milliliters of proinjection water and solubilized by dilution with proinjection water to 1000 milliliters. The solution is packaged in ampoules and sterilized by heating.

Example 3.6

Preparation of a solution of the dl-N-methyl-glucamine balance of the dletylene triamino-pentacetic acid

692.8 grams (= 700 millimoles) of the salt mentioned in Example 5 is suspended in 600 milliliters of pro-injected water and then 1.8 grams of tromethamine is added, diluted with pro-water. injectiono to 1000 milliliters under slight cooling. The solution is packaged in ampoules and sterilized by heating.

Example 37

Preparation of a salt solution of diethylene triamino-pentacetic acid holmium-HI-complex di-N-methyl-glucamide

662.0 grams (= 700 millimoles) of the salt mentioned in Example 5 is suspended in 600 milliliters of proinjection water and, after adding 1.8 grams of tromotarain, is solubilized by dilution with proinjection water to make up. 1000 ml under slight cooling. The solution is packaged in ampoules and sterilized by heating.

- 33 Example 38

Preparation of a solution of acid Iterbium-III plexus dj-N-methylglucamine salt, diethylene triamine penbaethoid

476.9 grams (= 500 millimoles) of the salt mentioned in Example 5 is suspended in 65 milliliters of proinjection water and, after the addition of 1.5 grams of tromethamine, is solubilized by the addition of proinjection water to 1000 milliliters. It is packed in ampoules and sterilized by heating.

Example 39

Preparation of a dletllGno-triamino-pentacetic acid lannjo-111 complex disodium salt solution

573.2 grams (= 1000 millimoles) of the salt mentioned in Example 6 is suspended in 650 milliliters of proinjective water and solubilized by dilution with proinjection water to 1000 milliliters. The solution is packaged in ampoules and sterilized by heating.

Example 4

Preparation of a disodium salt solution of the disletium-III complex of dlethylene triamino-pentachlor acid

477 µg (= 800 millimoles) of the salt mentioned in Example 6 is suspended in 600 milliliters of proinjective water and solubilized by dilution with proinjection water to 1000 milliliters. The solution is packaged in ampoules and sterilized by heating.

Example 41

Preparation of a solution of the diethylene-trlamlno-tetracetium acid hol mlo-HI complex djssédjo salt

299.6 grams (= 500 millimoles) is suspended

<img file="PT77983B_D0033.tif" />

of the salt mentioned in Example 6 in 500 milliliters of water for injection and solubilize by dilution with water for injection to 1000 milliliters. The solution is packaged in ampoules and sterilized by heating.

Example 42

Preparation of a solution of the disruption salt of the iterbjo-HI complex of d-ietjlene-triamlno-pentacetic acid

3θ3.5 grams (= 500 millimoles) of salt are suspended. mentioned in Example 6 in 500 milliliters of water for injection and solubilizes by dilution with water for injection to 1000 milliliters. The solution is packaged in ampoules and sterilized by heating.

Example 43

Preparation of a solution of the tetra-N-methyl-glucamine salt of the gadolinium-111 complex of ethylene-dinitrile-tetraphalic acid (methane-phosphonic acid)

137.1 grams (= 100 millimoles) of the salt mentioned in Example 12 is suspended in 500 milliliters of proinjection water and, after adding 0.8 grams of troethin, is solubilized by dilution with proinjection water to make up. 1000 milliliters. The solution is packaged in ampoules and sterilized by heating.

Example 44

Preparation of a solution of gadolinium-III complex of acid N¹ - (2-iildroxletil) -etjene-di-amjno-Ν, Κί, Ν¹ acetic -trj

Under heating, 1.9 grams (= 6.7 millimoles) of N acid dissolve¹- (2-hydroxyethyl) -ethylene-diamjηο-Ν, Ν, N * -triacetic in 6 milliliters of pro-injection water. The solution is packaged in ampoules and sterilized by heating.

<img file="PT77983B_D0034.tif" />

Example 45

Preparation of a disodium disodium solution of the trans-1,2-cyclohexylene-dlamino-tetraacetic acid manganese-II complex suspends 44.3 grams (= 100 millimoles) of the salt mentioned in Example 9 under a protective atmosphere of nitrogen in 60 milliliters of water proinject and solubilize by dilution with water to 100 milliliters. The solution is packaged and sterilized by heating.

Example 46

Preparation of a solution of the sodium salt of the 1,4,8,11-tetraza-clotetradecane-N, H gadolinium-111 complex¹ , N,

N ¹ - tetracetic

552.6 grams (= 1 mol) of the salt mentioned in Example 11 is dissolved in distilled water to inject to 1000 milliliters. The solution is packaged in vials and sterilized by heating.

Example 47

Preparation of a disodium salt solution of the dichloro-trlamino-tetracetic acid blmuto-lll complex

23.4 grams (= 5θ millimoles) of bismuth-III oxide is suspended in 50 milliliters of water for injection. After adding 39.3 grams (= 100 millimoles) of diethylene triamino-pentacetic acid and 4.0 grams (= 5θ)^msodium hydroxide), heat to reflux until a clear solution is obtained. The cooled solution is neutralized to room temperature by the addition of 4.0 grams of sodium hydroxide and diluted with pro-injection water to 100 milliliters. The solution is packaged in ampoules and sterilized by heating.

Example 48

Preparation of a disodium salt solution of the sa complex

<img file="PT77983B_D0035.tif" />

> i6SÍ.Xt--

<img file="PT77983B_D0036.tif" />

mario-ΙΙΙ of diethylene triamthno-pentaethioic acid

58.5 grams (= 100 millimoles) of the salt mentioned in Example 6 is dissolved in 65 milliliters of water for injection under heating. Dilute with water for injection to a total volume of 100 milliliters, pack into ampoules and heat sterilize.

Example 49

Preparation of a solution of the 13,1-dioxo-15,18,21-trlsoarboxylmethyl) -12,15,18,21-pentaza-pentatriaconane dl-N-methyl-glucamino salt of the gadolinium-III plexus oom -djcar boxilico

130.4 grams (= 100 millimoles) of the salt mentioned in Example 2 is suspended in 250 milliliters of water for injection and solubilized by heating. Dilute with water for injection to 5θθ milliliters, pack the solution in ampoules and sterilize by heating.

Example 50

Preparation of a solution of the manganese-II plexus di-N-methyl-glucammonium salt of ethylene-diamine-tetraoethoic acid

3.68 grams (= 5 millimoles) of the substance dissolved in Example 9 is dissolved in 70 milliliters of proinjection water and 0.4 grams of sodium chloride added to the solution. Then dilute with water for injection to 100 milliliters and pack the solution into ampoules after passing through a sterilization filter. The solution is isotenic with blood with 2S0 mOsm,

Example 51

Preparation of a solution of the disodium salt of the gaolinium-HI complex of dletllene-trimethyl-penta- (methane-phosphonic acid)

3θ, 57 grams (= 50 millimoles) of the substance described in Example 12 was suspended in 5θ milliliters of water.

<img file="PT77983B_D0037.tif" />

”Pro injectione · Adjust to pH 7.2 with the addition of powdered sodium hydroxide and dilute with pro injection injection to 100 milliliters. The solution is packaged in ampoules and sterilized by heating.

Example 52

Preparation of a diethylene-trlamino-pentacetic acid trans manganese-II complex salt solution

Under a nitrogen atmosphere, 39.3 grams (= 100 millimoles) of diethylene triamine-pentacetic acid are suspended in 100 milliliters of proinjection water and 11.5 grams of manganese-II carbonate are added. Heat to 90 ° C and 300 milliliters of normal sodium hydroxide lye are added dropwise. The neutral solution is filtered through a sterilization filter and packaged in ampoules.

Example 53

Composition of a powder for the preparation of a suspension

4,000 grams of gadolinium-III complex of diethylene triamino-pentacotic acid (water content 8.0%)

3,895 grams of sucrose

0.100 grams of polox-jet polymer-polyoxypropylene polymer 0.005 grams of flavoring agent 8.000 grams

Example 54

Preparation of a solution of the gadolinium-III complex of the acid conjugate diethylene triamino-pentacetic with human serum albumin

To 20 milliliters of a solution of 3 milligrams of protein in 0.05 molar sodium bicarbonate buffer (pli 7 - 8) is added 10 milligrams of 1,5-bis- (2,0-djoxo-morpholino) -3 -Aza-pentane-3-acetic, Stir at room temperature for 30 minutes, then dialyse backcurrent with 0.3 molar phosphate buffer.

<img file="PT77983B_D0038.tif" />

50 milligrams of gadolinium acetate is added and purified by gel chromatography on a Sephadex G25 column. The fraction obtained is filtered through a sterilization filter and packaged in multiple vials. By lyophilization, a storable dry pharmaceutical composition is obtained.

Proceeding analogously with immunoglobulin, the solution of the corresponding conjugate complex is obtained.

Example 55

Preparation of a solution of the diethylene triamino-pentaoetic acid (dtpà) -carbonyl-111 complex with monoolonal antibodies

At 20 microliters of a solution of 0.3 milligrams of monoclonal antibodies in 0.05 molar sodium bicarbonate buffer (pH 7-®) is added 1 milligram of a mixed DTPÀ anhydride (obtained for example from ΏΓΡΑ and isobutylchloroformate) and stir at room temperature for 3θ minutes. Countercurrent dialyze with 0.3 molar sodium phosphate buffer and mix the antibody fraction thus obtained with 2 milligrams of the gadolinium-III-ethylene diamine tetracetic acid (EDTA) complex. After purification by gel chromatography through Sephadex G25, the filtered solution is packed through a multi-vial sterilization filter and lyophilized.

By employing the trans-1,2-diamino-cyclohexane-tetraacetic acid (CDTA) mixed anhydride, a solution of the corresponding gadolinium-III complex of the CDTA-antibody is similarly obtained.

Using the ethylene diamino tetracetic acid manganese-II complex, the manganese-II complexes of the IQ? PA or CDTA coupled anticoagulants are analogously obtained.

Example 56

Preparation of an oon39 Gadolinium-Ill complex solution ISOWtl

<img file="PT77983B_D0039.tif" />

1-Phenyl-ethylenediamine-tetraacetic acid conjugate with immunoglobulin

According to the procedure described in J. Med. Chem., 197, Volume 17, page 130, a 2 percent solution of protein in a 0.12 solution is cooled to + 4 ° C. molar of sodium bicarbonate containing 0.01 mole of ethylene-dlamino-tetraacetic acid and mixing dropwise with the protein equivalent ratio of a 1- (p-aminophenyl) -ethylene-diamino-tetraacetic acid solution of freshly prepared ice-cold diazene salt. Stir overnight at + 4 ° C (pH 8.1) and then dialysed backcurrent with a 0.1 molar solution of sodium citrate. After completion of dialysis, the conjugate solution is mixed with excess gadolinium-III chloride and filtered to remove the ions. The filtered solution is then packaged for sterilization in multiple vials and lyophilized.

Example 57

Preparation of a colodal dispersion of an Mn-CDTA / lipid conjugate

In 5θ milliliters of water, stir at room temperature for 24 hours 0,1 millimole dithearoyl phosphatidyl ethanolamine and 0,1 millimole of # rans-1,2-diamino-cycloic acid bis-anhydride hexane tetracetic. 0.1 millimole of manganese-II carbonate is added and stirred again for 6 hours at room temperature. After purification on a Sephadex G50 column, the filtered solution is packaged for sterilization in multiple vials and lyophilized.

Proceeding analogously, the gadolinium / DTPA-lipid conjugate with gadolinium oxide-III is obtained.

Example 58

Preparation of gadolinium-loaded liposomes / ΏΓΡΑ

According to the way of proceeding I described

<img file="PT77983B_D0040.tif" />

it's in Proc. Natl. Acad. Know. USA, 75, 4194, a lipid mixture containing 75 mole% El-phosphatidyl choline and 25% by weight is prepared.ⁱⁿ moles of cholesterol as a dry substance. From this 500 milligrams are dissolved in 30 milliliters of diethyl ether and mixed dropwise in an ultrasonic bath with 3 milliliters of a 0.1 molar solution of the salt. de.di-N-methyl-glucamine of the gadolinium-ΙΙΣ complex of diethylene triamino-pentacetic acid in water pro injectione. After the addition is completely completed, the ultrasound treatment is continued for a further 10 minutes and concentrated on a rotary evaporator. The gel-like residue is suspended in 0.125 molar sodium chloride solution and by repeated centrifugation (at 20,000 g / 20 minutes), separated from unencapsulated contrast agent moieties. Thereafter, the liposomes thus obtained are lyophilized in multiple vials. The application is in the form of a color dispersion in 0.9 weight percent sodium chloride solution.

CLAIMS