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NZ201372A - Paramagnetic complex salts,and use in nmr-diagnostics - Google Patents

Paramagnetic complex salts,and use in nmr-diagnostics

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Publication number
NZ201372A
NZ201372A NZ201372A NZ20137282A NZ201372A NZ 201372 A NZ201372 A NZ 201372A NZ 201372 A NZ201372 A NZ 201372A NZ 20137282 A NZ20137282 A NZ 20137282A NZ 201372 A NZ201372 A NZ 201372A
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New Zealand
Prior art keywords
acid
complex
salt
ch2cooh
methylglucamine
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NZ201372A
Inventor
H Gries
D Rosenberg
H-J Weinmann
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Schering Ag
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Publication of NZ201372A publication Critical patent/NZ201372A/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/28—Details of apparatus provided for in groups G01R33/44 - G01R33/64
    • G01R33/281—Means for the use of in vitro contrast agents

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  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • Signal Processing (AREA)
  • Engineering & Computer Science (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Optics & Photonics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

1. The use of at least one physiologically tolerable paramagnetic complex salt made from aminopolycarboxylic acids having the formulae I to IV see diagramm : EP0169299,P6,F1 N-hydroxyethyl-N,N',N'-ethylenediaminetriacetic acid (HEDTA), see diagramm : EP0169299,P6,F2 N,N,N',N",N"-diethylenetriaminepenta-acetic acid (DTPA), HOH2 C-CH2 N(CH2 COOH)2 N-hydroxyethylimino-diacetic acid, see diagramm : EP0169299,P6,F3 wherein m represents the numbers 1 to 4, n the numbers 0 to 2, R**1 a saturated or unsaturated hydrocarbon radical having from 4 to 12 hydrocarbon atoms or the group -CH2 -COOH, and from the ions of the lanthanide elements having the atomic numbers 57 to 70 or from the ions of the transition metals having the atomic numbers 21 to 29, 42 and 44 and, optionally from an inorganic base for the preparation of agents for NMR diagnostics.

Description

80137a Priority Date(s)c .. P.fi'.
Complete Specification Filed: \ Class: f.°. IF. 3$....
C°l. &9J. fotff.WJflf.1* q.ot. ma/PX . ML« U/A ?, */£. *9, J* COTCto.fop. AI0(KJt*[°° I- g y\ug iqoc Publication Date: P.O. Journal, No: .. J.
NEW ZEALAND Patents Act. 1953 COMPLETE SPECIFICATION "PARAMAGNETIC COMPLEX SALTS, THEIR PREPARATION, AND THEIR USE IN NMR-DIAGNOSTICS." We, SCHERING AKTIENGESELLSCHAFT, a body corporate organized according to the laws of Germany, of 170-178 Mullerstrasse, D-1000 Berlin 65, Germany and Waldstrasse 14, 4619 Bergkamen, Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method t by which it is to be performed to be particularly described in and by the following statement ; 201372 The present invention relates to new paramagnetic complex salts, to pharmaceutical preparations comprising them, a process for the preparation thereof and to their use as NMR-diagnostics and a preparation for use in NMR-diagnostics. According to one aspect of the present invention there is provided a physiologically compatible paramagnetic complex salt of (a) an aminopolycarboxylic acid of anyone of the formulae I to IV hoocch- ch cooh \ / n-(ch_)_-n (i) 2 2 X hoh2cch2 ^ ch2cooh N-Hydroxyethyl-N.N',N'-ethylenediaminetriacetic acid (hedta) ch—cooh pu paatj hooch.c r 2 ch cooh 2 \ i / 2 ^n-(ch2)2-n-(ch2)2-n (ii) hooch2c ^ ch2cooh n.n.n',n",N"-Diethylenetriaminepentaacetic acid (dtpa) hoh2c-ch2n(ch2cooh)2 (iii) N-Hydroxyethyliminodiacetic acid ! ch- ch cooh 8 \ I / n n-(ch2)i!1-(ch2-n-ch2)n-(ch2)m -n^civ) hoocch2 ^ ch2cooh , v. V/ oir wherein m represents an integer from 1 to 4, 7 / n represents an integer from 0 to 2, and represents a saturated or unsaturated hydrocarbon group with 4 to 12 — j - <• carbon atoms or the group -ch2-cooh, or a. diphosphonic acid of the general formula V 201372 P°3H2 r2-c-r3 P°3H2 (v) wherein 2 R represents hydrogen, alkyl of 1 to 4 carbon atoms, halogen, or a hydroxy, . amino or -CH2COOH group, and represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -CH2-COOH group. (b) an ion of any one of the lanthanide elements of numbers 57 to 70 or an ion of any one of the transition metals of numbers 21 to 29. 42 and 44 and (c) a baoo which ic oithor an inorganio baooj—for eutamplc oodium hydroaiidoi er an organic base, for example, primary, secondary or tertiary amines, especially glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, diethanolamine or morpholine, or a basic amino acid, for example lysine, o^^iithine or arginine.
According to another aspect of the present invention there is provided a pharmaceutical preparation for use in NMR diagnosis which comprises a physiologically acceptable carrier and at least one physiologically compatible paramagnetic complex salt of (a) an aminopolycarboxylic acid of any one of the formulae I to IV 201372 ~ 4 - HOOCCH- CH-COOH \ / N-(CH2)j-N (i) hoh2cch2 ^ CH2COOH N-Kydroxyethyl-N.N",N'-ethylenediaminetriacetic acid (HEDTA)^ HOOCH C CH2COOB CH-COOH \ i / 2 N-(CH2)2-N-(CH2)2-N^ (I1, HOOCH2C CH2COOH N.N.N',N",N"-Diethylenetriaminepentaacetic acid (DTPA) HOH2C-CH2N(CH2COOH)2 (in) N-Hydroxyethyliminodiacetic acid, pi CH- CH-COOH \ I / .N-(CH2)B-(CH2-N-CH2>n-«CB2)« "N s HOOCCH2 CH-COOH wherein in represents an integer from 1 to 4, n represents an integer from 0 to 2, and R1 represents a saturated or unsaturated hydrocarbon group with 4 to 12 carbon atoms or the group -CH2-COOHj 201372 or a diphosphonicacid of the general formula V f°3H2 R2-C-R3 (V) I P°3H2 wherein 2 R represents hydrogen, alkyl of 1 to 4 carbon atoms, halogen, or a hydroxy, amino or -CH2COOH group, and 3 R represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -CH2-COOH group, and • — (b) an ion of any one of the lanthanide elements of numbers 57 to 70 or an ion of any one of the transition metals of numbers 21 ai\ orcein 1 c or- to 29. 42 and 44,^ and if desired,l-eni inorganic base.
Preferred complexing agents are N,N,N', N'-ethylene-diamine-tetra-acetic acid (EDTA), N,N,N', N", N"-diethyl- enetriamine-penta-acetic acid (DPTA), ethane-1-hydroxy-l, .< 1-diphosphonic acid, metharie-diphosphonic acid and ethane-1- amino-l, 1-diphosphonic acid. - v 201372 - 6 ~ i15 JAN1986 If desired, it is also possible to bind the physiologically tolerable complex salts of the invention to bio-molecules in order in this way to enable the 10 complex salt to be conveyed to a particular area of the living body.
Bio-molecules which may be used are, for example, immunoglobulins, hormones such, for example, as insulin, glucagon, prostaglandins, steroidal hormones, proteins, 15 peptides, amino-sugars and lipids.
The coupling of the paramagnetic complex salts to the desired bio-molecules may be effected by means of methods which are known per se. for example by reacting the nucleophilic group of a bio-molecule such as the 20 amino, phenol, mercapto or imidazole group with an activated derivative of the complex compound.
The activated derivatives which may be considered are for example acid chlorides, mixed anhydrides (which can be prepared from the carboxyl derivative of 25 the complex compound with chlorocarbonic acid ester), activated esters, nitrenes or isothiocyanates.
It is also possible to react an activated derivative of the biomolecule with a nucleophilic t 301372 derivative of the complex compound.
As inorganic bases for salt formation there may be used, for-example, sodium iiy^-rwi, an The new preparations of the invention may be made up in a manner known per se by dissolving the paramagnetic complex salt in water or physiological salt solution, if desired with the addition of one or more additives usual in galenics, such as, for example, physiologically conpatible buffer solutions (for example sodium dihydrogen phosphate solution), and sterilising the solution. The aqueous solutions can be administered orally, neurally and especially intra-vascularly. if suspensions of the paramagnetic complex salts in water or physiological salt solution are desired, especially for oral administration, the 8 JAN 1986 llECBVED 201372 paramagnetic complex salt is mixed with one or more auxiliaries usual in galenics and/or surfactants and/or aromatic substances for taste correction and suspended in water or physiological salt solution before oral administration. In this case, preferably from 3 to 10 g of paramagnetic complex salt and from 2 to 8 g of one or more auxiliaries, such as, for example, saccharose, highly disperse silica, polyoxyethylenepolyoxypropylene polymers, starch, magnesium stearate, sodium lauryl sulphate, talcum, lactose, sodium carboxyroethylcellulose are used. of the invention are suitable in the form of aqueous solutions or suspensions which contain from 5 to 250 mmols/litre, preferably 50 to 200 mmols/litre, of the paramagnetic complex salt. The pH of the aqueous solutions may range between 6.5 and 8.0, preferably between 6.5 and 7.5. As a result of the formation of the complex salt according to the present invention the paramagnetic salt is detoxicated, and the effect also achieved is that the salts are stable in water and readily soluble therein in the physiological pH range. particularly suitable for greater definition or localisation of lesions of the pancreas and liver, and also of tumours and haemorrhages in the cranial area. For diagnosis of the area under examination an aqueous For NMR-diagnosis in humans, the preparations Solutions of the complex salts appear to be 201372 solution of the paramagnetic complex salt which is isotonic with blood is, for example, administered intravenously at a dosage of from 1 to 100 pmols/kg.
With a concentration of the complex salt of from 50 5 to 200 mmols/litre, approximately 1 to 50 ml of solution is required for examination of human patients. The exposure of the layer in question is taken approximately 15 to 60 minutes after intravenous administration of the aqueous solution of the paramagnetic complex salt. 10 The physical methods of diagnosis usual in the practice of medicine which can be carried out with little or no operative intervention are, for example, the irradiation of the body with X-rays, scintiscanning and sonography. All these methods either involve risks 15 to health or have a limited range of application. In the case of X-ray procedures and scintiscanning the patient is exposed to the ionising radiation, so that these methods cannot be used as often as might be required or cannot be used at all for groups at risk, 20 for instance for babies or pregnant women.
Sonography does not in fact have these disadvantages , but instead has a very limited range of application, especially in the cranial area.
Since in spite of a great deal of research it 25 has not yet been possible to eliminate completely the above-mentioned disadvantages, attempts have been made to discover image-producing processes which do not have these disadvantages but which provide comparable o>- 201372 information for diagnostic purposes.
One of these image-producing processes is spin-imaging, which is based on the physical effect of nuclear magnetic resonance (NMR). This method of diagnosis makes it possible to obtain sectional images of the living body and an insight into metabolic processes without the use of ionising rays. The effect of nuclear J resonance is shown by atomic nuclei which, like hydrogen - mainly present in biological tissues as water - have a magnetic moment and therefore align themselves in a strong external magnetic field. By means of a high-frequency impulse (resonant frequency) they are brought out of their position of equilibrium, to which they return at a characteristic speed. The duration of the return to the state of equilibrium, the so-called relaxation time, provides information on the classification of the atoms and on their interaction with their surroundings. proton density or the relaxation times is of great diagnostic value and provides information concerning the water content and the state of the tissues being examined. For example, tumour tissue displays longer relaxation times than healthy tissue. (A. Ganssen and others, Computertomographie 1, [1981] pp. 2-10: Georg Thieme Verlag, Stuttgart, New York).
It has now been found that paramagnetic ions, magnetic The image which is obtained by measuring the r 15 JAN 1986 - H - 2-Lr" 201372 for example Mn (manganese) or Cu (copper) influence the relaxation times and thus increase the information content.
The solutions of heavy metal salts hitherto used 5 on experimental animals are not, however, suitable for intravenous administration to humans because of their high level of toxicity. Paramagnetic substances which are well tolerated and have a favourable influence on the imaging process are therefore being sought. The 10 latter effect may be produced for example, in that the spin-lattice-relaxation time is greatly reduced in a manner which is as organ-specific as possible, whilst at the same time the spin-spin-relaxation time T2 is kept constant to a great extent. We have now found 15 that the required detoxication of the otherwise toxic metal salts can be effected by complexing, without the . paramagnetic properties being adversely affected. This is surprising, since it is known that the distribution of the d- and f-electrons over the d- and f- orbitals 20 is altered thereby.
Thus in tests on rats in the scanner, with a magnetic field of 0.15 Tesla, an input energy of 300 watt/pulse and a l80°-pulse of 720 |is with exposure times of 2 minutes in each case made 10 minutes after 25 intravenous injection of 20 pmols/kg of manganese edetate as an aqueous methylglucamine salt solution having a concentration of 6 mmols/litre, a noticeably Hxew&tfomct 201372 i ,15 jan 1986 greater alteration in the signal in the region of the liver parenchyma was observed than for an exposure without the substance, whilst with an aqueous manganese(II) chloride solution of the same molarity under the same test conditions only a comparatively limited contrast was obtained. On the other hand, the desired detoxication of the otherwise toxic paramagnetic salts is achieved by the complex formation. Thus in rats, after intravenous injection of an aqueous solution of the N-methylglucamine salt of manganese edetate an LD^q of 4 mmols/kg was found. In contrast, manganese chloride showed an of only 0.5 mmol/kg when used on rats under identical conditions.
The performance of an NMR-diagnostic investigation using a preparation of the invention is explained in greater detail by means of the following example: A sterile aqueous solution of the N-methylglucamine salt of the gadolinium-III-complex of diethylene-triamine-penta-acetic acid having a concentration of 0.1 mol/litre was prepared. The pH value of the clear solution is 7.2.
The whole body scanner (Siemens AG/Erlangen) used for the NMR-tomography operated with a magnetic field of 0.1 T, corresponding to a Larmor proton frequency of 4.99 MHz. The apparatus was equipped with a high frequency transmitting and receiving coil of reduced size in order to allow objects of small size : 15 JAN 1986 2013*' to be imaged with sufficient resolution. The investigations were carried out according to a spin-echo method. The time taken for an exposure was between 1 and 3 minutes.
The tests were carried out on male rats of the Wistar-Han-Schering strain (SPF) having a body weight of 250 g. Eight days before the investigation, a Novikoff hepatoma tumour cell suspension is administered to the animals intraperitoneally (0.5 ml with 1 x 10^ cells).
The animals were anaesthetised by means of an intraperitoneal injection of pentobarbital sodium (60 mg/kg of body weight). The animals then have a vaned cannula inserted into one of the tail veins.
The accompanying Figures 1 to 7 show the results of exposures made on the test animals. Figures 1 and 2 show exposures made, before the administration of the contrast agent, in the sagittal and horizontal planes of the body respectively.
The contrast agent is administered intravenously within one minute at a dosage of 1 mmol/kg. In Figures 3 and 4, which were taken between 22 and 25 minutes after administration, a marked increase in brightness in the abdomen was to be observed. After intravenous administration the contrast agent reaches the pathological fluid accumulations and there produced a marked reduction of the spin-lattice-relaxation time (T^), which :N2.PA>'i^r ■ - jan 1986 2013^^ led to an increase in the intensity of the signal. Only after administration of the contrast agent was the tumorous fluid accumulation and improved definition of the organs to be observed. Without the administration 5 of a contrast agent, structures in the abdomen could hardly be recognised, since the organs show only small differences in proton density and relaxation times.
The definition of structures was also improved after oral administration of the contrast agent.. For ~ salt this purpose, 5 ml of the N-methylglucamine I solution of the gadolinium complex of diethylenetriamine-penta-acetic acid having a concentration of 1 mmol/litre was administered by means of a probe to an anaesthetised male rat (body weight: 250 g). Only after administration 15 of the contrast agent (Figures 6 and 7) was clear definition of the stomach or of the intestine in relation to the remaining organs to be seen.
Our own pharmaco-kinetic tests on rats have shown r salt that the N-methylglucamine [of the gadolinium complex 20 of diethylenetriamine-penta-acetic acid after intravenous and subcutaneous administration is completely eliminated, mostly renally, within 24 hours. The gadolinium complex is eliminated from rats by glomerulary filtration with a half life of approximately 20 minutes. The proportion 25 eliminated with the faeces is less than 5 % of the dose administered. 201372 - 15 jan 1986 i^jwobv® After oral administration no reabsorption of the substance is observed. The pharmaco-kinetic behaviour is similar to that of the classic X-ray contrast agents for uro-angiography.
The paramagnetic complex salts may be prepared according to processes known per se to the man skilled in the art or described in the literature, by dissolving the paramagnetic metal salt of a lanthanide element having an atomic number of from 57 to 70 or of a transition metal having an atomic number of from 21 to 29, or 42 or 44, in water and/or alcohol and adding a solution of the equivalent quantity of the organic component capable of forming a complex in water and/or alcohol and stirring, if necessary while heating at from 50°C to 120°C until the reaction is complete. If alcohol is employed as the solvent, methanol or ethanol is used. If the complex salt formed is insoluble in the solvent used, it crystallises and can be filtered off. If it is soluble in the solvent used, it can be isolated by evaporating the solution to dryness.
The process is to be explained in detail, by way of example, with the aid of the following instructions for procedure: ' v ■ JAN 1986 - 16 - is received m iriTn ■ • II I-Tiiri Preparation of the manganese(II) complex of ethylene-diaminetetraacetic acid: 14.6 g of ethylenediaminetetraacetic acid are added to a suspension of 6.17 g of manganese(II) carbonate in 500 ml of water and the whole is heated on a vapour bath while stirring, gas being evolved. The initially pink colour disappears after approximately 20 minutes and the whole mixture goes into solution except for a small residue. After stirring for one hour at 110°C the undissolved portion is filtered off and the filtrate is cooled. After standing for 15 hours the crystallisate is filtered off with suction and dried: Yield = 14.1 g (molecular weight 345.17) M.p. : 256°/258-259°C Preparation of the gadolinium(III) complex of diethylene-triaminepentaacetic acid: A suspension of 435 g of gadolinium oxide (GdjO^) and 944 g of diethylenetriaminepentaacetic acid in 12 litres of water is heated while stirring to from 90°C to 100°C and stirred at this temperature for 48 hours. The undissolved portion is filtered off and the filtrate is evaporated to dryness. The amorphous residue is pulverised.
Yield 144 gr (molecular weight 547.58) M.p.: melts from 235° and remains undecomposed up to 320°C. 20137* / 201372 If there is/are still one or more acidic group(s) in the resulting paragmagnetic complex compound, the resulting complex compound can then, if desired, be dissolved or suspended in water and the desired inorganic or organic base can be added thereto until the neutral point is reached. After filtering off the undissolved constituents, the solution is concentrated by evaporating and the desired complex salt is obtained as the residue. Those compounds comprising an organic base component are new.
The following complex salts may be mentioned more especially.
The di-N-methylglucamine salt of the manganese (II)-complex of ethylenediamine-tetra-acetic acid.
The di-N-methylglucamine salt of the nickel (II)-complex The di-ethanolamine salt of the c< 18 115 JAN 1986 201372 Kece I)-complex of ethylenediamine-tetra-acetic acid.
The di-morpholine salt of the manganese (II)-complex of ethylenediamine-tetra-acetic acid.
The di-diethanolamine salt of the copper(II)-complex of ethylenediamine-tetra-acetic acid.
The tri-diethanolamine salt of*the manganese(II)-complex of diethylenetriamine-penta-acetic acid.
The tri-N-methylglucamine salt of the manganese (II)-complex of diethylenetriamine-penta-acetic acid.
The N-methylglucamine salt of the gadolinium(III)-complex of ethylenediamine-tetra-acetic acid.
The N-methylglucamine salt of the dysprosium(III)-complex of ethylenediamine-tetra-acetic acid.
The di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriamine-penta-acetic acid.
The N-methylglucamine salt of the iron (II)-complex of ethane-1-hydroxy-1,1,-diphosphonic acid.
The N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid.
The di-lysine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid. 201372 15JANI986 - 19 - _ IKBVEC The following Examples illustrate the invention:- Example 1 Preparation of the di-N-methylglucamine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic 5 acid, C24H48N4Ol8Mn 7.4 g (= 20 mmols) of the manganese(II)-complex of ethylenediamine-tetra-acetic acid (water content : 6.9%) are suspended in 30 ml of water and by the addition of approximately 7.8 g ( = approx. 40 mmols) of N-methyl-10 glucamine are dissolved at a pH of 7.5. After filtering off a little undissolved material the solution is evaporated to dryness under vacuum. A solid foam is produced in a quantitative yield, starting to melt at 95°C and becoming viscous at 170°C.
. Analysis: calculated C 39.19% H 6.58% N 7.61% Mn 7.47% Found in the dry substance C 39.23% H 7.10% N 7.26% Mn 7.53% H20 3.26% Equivalent weight: calculated 367.8, found 369 (titra-20 tion with tetramethylammonium hydroxide in aqueous acetone).
By dissolving in hot ethanol and evaporating to dryness under vacuum the substance is obtained as a white, hydroscopic powder.
The following compounds are obtained in an analogous manner: 201372 The di-N-methylglucamine salt of the nickel(II)-complex of ethylenediamine-tetra-acetic acid, C^H^l^O^gNi, as a blue powder.
The di-ethanolamine salt of the cobalt(II)-complex of ethylenediamine-tetra-acetic acid, 4H28N4°1qCo, as a pink-coloured powder.
The di-morpholine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic acid, C^gH^l^O^QMn, as a white powder.
The di-diethanolamine salt of the copper(II)-complex of ethylenediamine-tetra-acetic acid, Cj gH^N^^ 2Cu, as a blue powder.
The tri-diethanolamine salt of the manganese(II)-complex of diethylenetriamine-penta-acetic acid, C26H54N6°16*^' as a ye3-*ow powder.
The tri-N-methylglucamine salt of the manganese(II)-complex of diethylenetriamine-penta-acetic acid, C^H^NgO^Mn, as a white powder.
Example 2 Preparation of the N-methylglucamine salt of the gadolin-ium(III)-complex of ethylenediamine-tetra-acetic acid (a.,HonN„O^Gd) 17 30 3 13 4.58 g (= 10 mmols) of the geee*8rnnam\ x 11) - 201372 complex of ethylenediamine-tetra-acetic acid (water content: 2.7%) are suspended in 15 ml of water and by the addition of 1.95 g (= 10 mmols) of N-methylglucamine 5 are dissolved in a pH of 7.4. The solution is filtered and then evaporated to dryness under vacuum, whereupon a solid foam is produced. The yield, taking into account the water content of 8.5%, is practically quantitative. The substance starts to sinter at 90°C, and foam begins 10 to develop at 140°C.
Analysis: Calculated C 26.90% H 2.44% N 6.27% Gd 35.22% Found in the dry substance C 26.78% H 2.96% N 5.77% Gd 34.99% Equivalent weight: calculated 641.7, found 634 (titration 15 with tetramethylammoniuro hydroxide in aqueous acetone).
By dissolving in hot ethanol and evaporating to dryness under vacuum the substance is obtained as a white powder.
The following are obtained in an analogous manner: The N-methylglucamine salt of the dysprosium(III)-complex of ethylenediamine-tetra-acetic acid, C^H^QN^O^Dy- The di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriamine-penta-acetic acid, ^28H54^5°20Ho" The di-lysine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid, C26B48N7°14Gd- The N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid, C28H54N5°20Gd' / Example 3 SS, 201372 L4 5 JAN 1986 Preparation of a solution of the di-N-methylglucamine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic acid 3.68 g (= 5 mmols) of the substance described in Example 1 are dissolved in 70 ml of water pro iniectione (p.i.) and 0.4 g of sodium chloride are added to the solution. The solution is then made up to 100 ml with water p.i. and the solution is introduced into ampoules 10 through a sterile filter. The solution is isotonic with blood at 280 mOsm.
Example 4 Preparation of a solution of the N-methylglucamine salt of the gadolinium(III)-complex of ethylenediamine-15 tetra-acetic acid 9.63 g ( = 15 mmols) of the substance described in Example 2 are dissolved in 100 ml of water p.i.. The solution, which is approximately isotonic with blood, is introduced into ampoules through a sterile filter. 2q Example 5 Preparation of a solution of the di-N-methylglucamine salt of the gadolinium(III)-complex of diethylene-triamine-penta-acetic acid 201372 .35 g (= 9 mmols) of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid (water content 8%) are dissolved in 50 ml of water p.i. and neutralised to pH 7.5 by the addition of approximately 3.2 g 5 (corresponding to approximately 18 mmols) of N-methylglucamine. The solution is then made up to 100 ml with water p.i., introduced into ampoules and heat-sterilised. The concentration of the solution is made isotonic with blood (approximately 280 mOsm.). ^ o Example 6 Preparation of a solution of the di-N-methylglucamine salt of the dysprosium(III)-complex of diethylenetriamine-penta-acetic acid 8.00 g (= 15 mmols) of the dysprosium(III)- complex of diethylenetriamine-penta-acetic acid are dissolved in 80 ml of water p.i. at a pH of 7.5 with the addition of approximately 5.3 g (corresponding to approximately 30 mmols) of N-methylglucamine. The solution is then made up to 170 ml with water p.i..
The solution, which is approximately isotonic with blood, is introduced into ampoules and heat-sterilised.
PAcmx jan1986 201372 Example 7 Preparation of a solution of the di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriamine-penta-acetic acid 8.02 g (= 15 mmols) of the holmium(III)-complex of diethylenetriamine-penta-acetic acid are dissolved in 80 ml of water p.i. at a pH of 7.2 with the addition of approximately 5.3 g (corresponding to approximately 30 mmols) of N-methylglucamine. The solution is then made up to 170 ml with water p.i. The solution, which is approximately isotonic with blood, is introduced into ampoules and heat-sterilised.
The solution may also be prepared by dissolving the complex salt isolated according to Example 2 in...... water p.i..
Example 8 Preparation of a solution of the di-sodium salt manganese(II)-complex of ethylenediamine-tetra-acetic acid 5.55 g (15 mmols) of the manganese(II)-complex of ethylenediamine-tetra-acetic acid (water content: 6.9%) are dissolved in 80 ml of water p.i. at a pH of 7.5 with the addition of dilute sodium hydroxide solution. The solution is then made up to 170 ml with water p.i.. filtered into ampoules and heat-sterilised.
"A solution of the di-sodium salt of the gadolinium (III)complex of N,N,N',N",N"-diethylene-triamine pentaacetic acid can be t-* v Arv ^ z-\ t f i m n 1 2 V fa cV\ T 201372 Example 9 Preparation of a solution of the N-methylglucamine salt of the iron(II)-complex of ethane-1-hydroxy-1,1-diphosphonic acid 1.27 g (= 10 mmols) of iron(II) chloride are dissolved in 8.8 ml of methanol and there are added to the solution 3.2 ml of a 60% by weight solution of ethane-1-hydroxy-1,1-diphosphonic acid in water. The solution is evaporated to dryness under vacuum and 10 the residue is washed three times with anhydrous methanol. After drying, the residue is taken up in 50 ml of water p.i. and dissolved at a pH of 7.5 by the addition of approximately 1.8 g (corresponding to approximately 10 mmols) of N-methylglucamine. The solution is then 15 made up to 100 ml with water p.i. and introduced into ampoules after sterile filtration. - 26 - 201372 Example 10 Preparation of a solution of the di-N-methylglucamine salt of the manganese(II)-complex of hexy.lenediainine-tetra-acetic acid In analogy with the method described in Example 6f a solution which is ready for use is prepared from 6.02 g (-^15 mmols) of the manganese(II)-complex of hexylene -diamine-tetra-acetic acid and 5.86 g (^30 mmols) of N-methylglucamine Example 11 (Composition of a powder for the preparation of a suspension) 4.000 g gadolinium(III) complex of diethylenetriamine-pentaacetic acid (water content 8%) \ 3.895 g saccharose 0.100 g polyoxyethylenepolyoxypropylene polymer 0.005 g aromatic substances 8.000 g

Claims (9)

1. -27 - 201372 What we claim is: l.A physiologically compatible paramagnetic complex salt of (a) an aminopolycarboxylic acid of any one of the formulae 1 to IV HOOCCH_ CH_COOH \ / 2 N-(CH_)_-N (I) / \ HOH2CCH2 CH2COOH N-hydroxyethyl-N.N*,N'-ethylenediaminetriacetic acid (HEDTA)^ HOOCH C CH2COOH CH-COOH 2 \ ' / 2 N-(CH2)2-N-(CH2)2-N (II) HOOCH2C ^ CH2COOH N.N,N'.N".N"-diethylenetriaminepentaacetic acid (DTPA) hoh2c-ch2n(ch2cooh)2 (iii) N-hydroxyethyl iminodiacetic acid/ ri ch3 ch2cooh \ N-(CH2'ir,-(CH2-N-CH2)n- hoocch2 ch2cooh wherein m represents an integer from 1 to 4, n represents an integer from 0 to 2, and '4L 1 R represents a saturated or unsaturated hydrocarbon group with 4 to 12 _28 201372 carbon atoms" or the group -ch2-cooh, or a diphosphonic acid of the general formula V» P03H2 r2-c-r3 (v) P03H2 wherein R represents hydrogen, alkyl of 1 to 4 carbon atoms, halogen, or a hydroxy . amino or -ch-cooh group , and F? represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -ch2~cooh group, an ion of any one of the lanthanide elements of numbers 57 to 70 or an ion of any one of the transition metals of numbers 21 to 29, 42 and 44 and an organic base.
2. A physiologically compatible paramagnetic complex salt according to claim 1 wherein the organic base is N-methylglucamine, N,N-dimethylglucamine, ethanolamine, diethanolamine, morpholine, lysine, glucamine, ornithine or arginine. S ' .
3. a nhysiologically compatible paramagnetic complex salte> 1 or 2, p ^ j{J according to claim\> wherein as|aminopolycarboxylie \ 2 6 may 1986. 201372 -29 - acid N, N, N', N'-ethy1ened iaminetetraacetic acid (EDTA) is used. A physiologically compatible paramagnetic complex salt 1 or 2, .according to claim wherein as the aminopolycarboxylic acid N,N,N',N",N"-diethylenetriaminepentaacetic acid (DTPA) is used. A physiologically compatible paramagnetic complex salt 1 or 2. according to claimNy wherein as the diphosphonic acid ethane-l-hydroxy-1,1-diphosphonic acid, methane-diphosphonic acid or ethane-l-amino-1,1-diphosphonic acid is used. The di-N-methylglucamine salt of the manganese(II)-complex of ethylenediaminetetraacetic acid. the di-N-methylglucamine salt of the nickel(II)-complex of ethylenediaminetetraacetic acid, the tri-N-methylglucamine salt of the manganese(II)-complex of diethylenetriaminepentaacetic acid, the N-methylglucamine salt of the gadoliniumCIII)-complex of ethylenediaminetetraacetic acid, the N-methylglucaraine salt of the dysprosiumC111)-complex of ethylenediaminetetraacetic acid, the di-N-methylglucamine salt of the holmi.um(III)-complex of diethylenetriaminepentaacetic acid and the N-methylglucamine salt of the iron(II)-complex of ethane-l-hydroxy-1,1-diphosphonic acid. The di-N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriaminepentaacetic acid. ) -30 - 201375 8. The c|i-ethanolamine salt of the cobalt (II)-complex of the dy ethylenediaminetetraacetic acid .J di-^ethanolamine salt of the copper(II)-complex of ethylenediamine- the tetraacetic acid and^tri-diethanolamine salt of the manganese(II)-complex of diethylenetriaminepentaacetic acid. 9. The di-morpholine salt of the manganese(II)-complex of ethylenediaminetetraacetic acid. 10.- The di-lysine salt of the gadolinium(III)-complex of diethylenetriaminepentaacetic acid. .11. A physiologically compatible paramagnetic complex salt of (a) an aminopolycarboxylic acid of any one of the formulae 1 to IV hoocch- ch-cooh 2\ X 2 n-(ch_k-n (i) / \ hoh2cch2 ch2cooh N-kydroxyethyl-N.N',N'-ethylenediaminetriacetic acid (HEDTA) hooch2c ch2cooh ch2cooh n-(ch2)2-n-(ch2)2-nn^ (ii) hooch2c ch2cooh n.n.n' ,n" ,n"- cjlethylenetriaminepentaacetic acid (dtpa) hoh2c-ch2n(ch2cooh)2 (iii) N-hydroxy ethyl iminodiacetic acid^, •jv^ 201372 - 31 - R1 CH3 CH2COOH \ i / n-(ch2)m-(ch2-n-ch2)n-(ch2)in (iv) HOOCCH2 CH2COOH wherein m represents an integer from 1 to \ n represents integer from 0 tQ 2* and R1 represents a saturated or unsaturated hydrocarbon group with 4 to 12 carbon atoms or the group -CHj-COOH, or 21 diphosphonic acid of the general formula V: *°3H2 Ra-C-R3 (V) P03H2 wherein fft®* represents hydrogen, alkyl of 1 to 4 carbon atoms, halogen,or a hydroxy , amino or -CH-COOH group # and z \ IR7 represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -CH2-COOH group. v an ion of any one of the lanthanide elements of numbers 57 to 70 or an ion of any one of the transition metals of numbers 21 - 32 - 201372 to 29. 42 and 44 and an organic base, in a form suitable for use in NMR diagnosis. 12. A physiologically compatible paramagnetic complex salt according to claim 11 wherein the organic base is N-methylglucamine, N,N-dimethylglucamine, ethanolamine, diethanolamine, morpholine, lysine, glucamine, ornithine or arginine, in a form suitable for use in NMR diagnosis. 13 . A physiologically compatible paramagnetic complex salt 11 or 12, the according to claim wherein as^jaminopolycarboxylic acid N.N.N',N'-ethylenediaminetetraacetic acid (EDTA) is used, in a form suitable for use in NMR diagnosis. -1
4. A physiologically compatible paramagnetic complex salt 11 or 12/ the according to claim>^> wherein as^J aminopolycarboxylic acid N.N.N'.N",N"-diethylenetriaminepentaacetic acid (DT'PA) is used, in a form suitable for use in NMR diagnosis. 1
5. A physiologically compatible paramagnetic complex salt or 12, the according to claim > wherein as^diphosphonic acid ethane-l-hydroxy-1.1-diphosphonic acid. methane-diphosphonic acid or ethane-1- amino-1.1-diphosphonic acid is used, in a form suitable for use in NMR diagnosis. .1
6. The di-N-methylglucamine salt of the manganese(II)-complex of ethylenediaminetetraacetic acid,~tta_ di-N-methylglucamine salt of the nickel(II)-complex ot9- O the -vw ethylenediaminetetraacetic acidj tri-N- iz ""V H 26may 1986"! methylglucamine salt of the manganese(11)-complex of \ NX I _33 _ 201372 diethylenetriaminepentaacetic acid, the N-methylglucamine salt of the gadolinium(111)-complex of ethylenediaminetetraacetic acid, the N-methylglucamine salt of the .dysprosium(III)-complex of ethylenediaminetetraacetic acid, the di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriaminepentaacetic acid or the N-methylglucamine salt of the iron(II)-complex of ethane-l-hydroxy-1.1-diphosphonic acid, in a form suitable for use in NMR diagnosis. 1
7. The di-N-methylglucamine salt of the gadolinium(III)- complex of diethylenetriaminepentaacetic acid?in a form suitable for Use in NMR diagnosis. 1
8. The di-ethanolamine salt of the cobalt(II)-complex of ethylenediaminetetraacetic acid, the di-diethanolamine salt of the copper(II)-complex of ethylenediaminetetraacetic acid or the tri-diethanolamine salt of the manganese(II)-complex of diethylenetriaminepentaacetic acid, in a form suitable for use in NMR diagnosis. 1
9. The di-morpholine salt of the manganese(II)-complex of ethylenediaminetetraacetic acid, in a form suitable for use in NMR d iagnosis. 20. The di-lysine salt of the gadolinium(III)-complex of diethylenetriaminepentaacetic acid, in a form suitable for use in NMR diagnosis. 21. A material for NMR diagnosis containing at least one % * physiologically compatible paramagnetic complex sal^^f fV ^ 26WI986" 201.372 -34 - an aminopolycarboxylic acid of any one of the formulae 1 to IV HOOCCH, CH-COOH \ / N-(CH-)--N (I) 2 2 \ HOH2CCH2 CH2COOH N-Hydroxyethyl-N.N',N'-ethylenediaminetriacetic acid (HEDTA^ HOOCH C CH2COOH CHoC00H \ 1 / 2 N-(CH2)2-N-(CH2)2-N ^ (II) HOOCH2C ^ CH2COOH N.N.N',N",N"-diethylenetriaminepentaacetic acid (DTPA)^ HOH2C-CH2N(CH2COOH)2 (III) N-Wydroxyethyliminodiacetic acid^ D1 CH, CH-COOH \ i / x N-(CH2),,-(cH2-M-CH2)n-(CH2)» -H. (IV) \ HOOCCH2 CH2COOH wherein m represents an integer from 1 to ^ n represents an integer from 0 to 2, and R1 represents a saturated or unsaturated hydrocarbon group with 4 to 12 carbon atoms or the group -CH--COOH. \c -„g f/& <£ v> -35 - 201372 or a diphosphonic acid of the general formula V \ ?°3H2 R^-C-R3 (V) P°3H2 wherein o R represents hydrogen, alkyl of 1 to 4 carbon atoms, halogen, or a hydroxy . amino or v -CHjCOOH group , and R represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -CH2~COOH group ^ an ion of any one of the lanthanide elements of numbers 57 to 70 or an ion of any one of the transition metals of numbers 21 to 29. 42 and 44 and an organic base, optionally with the usual additives in the art,dissolved or suspended in water or physiological salt solution. A material according to claim 21 wherein the organic base is N-methylglucamine. N.N-dimethylglucamine. ethanolamine. diethanolamine. morpholine. lysine, glucamine, ornithine Of arginine. ~ E * A material for NMR diagnosis according to claim 21 or #4 the !r^ ^' wherein as^jaminopolycarboxylic acid C 20(372- r ~ 36 " N.N.N*,N'-ethylenediaminetetraacetic acid (EDTA) is used. 24. A material for NMR diagnosis according to claim 21 or 22, wherein as the aminopolycarboxylie acid N.N.N',N",N"-diethylenetriaminepentaacetic acid (DTPA) is used. / 25. A material for NMR diagnosis according to claim 21 or 22, containing at least one paramagnetic, physiologically compatible complex salt of an aminopolycarboxylic acid of any one of formulae I to IV, an ion of any one of the lanthanide elements of numbers 57 to 70 and an organic base. 26. A material for.NMR diagnosis according to claim 21 or 22, containing at least one paramagnetic, physiologically r complex compatible]salt of an aminopolycarboxylic acid of any one of formulae I to IV, an ion of any one of the transition metals of mumbeis 21 to 29, 42 and 44 and an organic base. 27. A material for NMR diagnosis according to claim 21 or 22, containing at least one paramagnetic, physiologically (compatible complex salt of a diphosphonic acid of the general formula V, an ion of any one of the lanthanide elements of numbers 57 to 70 and an organic base. 28. A imaterial for NMR diagnosis according to claim 21 or 22, (containing at least one paramagnetic, physiologically ccompatible complex salt of a diphosphonic acid of the •general formula V, an ion of any one of the transition metals of mumbers 21 to 29. 42 and 44 and an organic base. '•7 * 13JUNW86, -37 - 201372 29. A material for NMR diagnosis according to claim 21 or 22, containing at least one paramagnetic, physiologically compatible complex salt, wherein as the diphosphonic acid .ethane-l-hydroxy-1.1-diphosphonic acid, methane diphosphonic acid or ethane-l-amino-1.1-diphosphonic acid is used. 30A material for NMR diagnosis according to claim 21 or 22, containing the di-N-methylglucamine salt of the manganese(II)-complex of ethylenediaminetetraacetic acid, the di-methylglucamine salt of the nickel(II)-complex of ethylenediaminetetraacetic acid, the tri-N-methylglucamine salt of the manganese(II)- complex of diethylenetriaminepentaacetic acid, the N-methylglucamine salt of the gadolinium(III)-complex of ethylenediaminetetraacetic acid, the N-methylglucamine salt of the dysprosium(III)-complex of ethylenediaminetetraacetic acid, the di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriaminepentaacetic acid or the N-methylglucamine salt of the iron(II)-complex of ethane-l-hydroxy-1.1-diphosphonic acid. 31. A material for NMR diagnosis according to claim 21 or 22, containing the di-N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriaminepentaacetic acid. - 38 _ 201372 32. A material for NMR diagnosis according to claim 21 or 22, containing the di-ethanolamine salt of the cobalt(II)-complex of ethylenediaminetetraacetic acid. 4-y . thediVfethanolamine salt of the copper(11)-complex of ethylenediaminetetraacetic acid or the tri-diethanolamine salt of the manganese(II)-complex of diethylene— triaminepentaacetic acid. 33. a material for NMR diagnosis according to claim 21 or 22, containing the di-morpholine salt of the manganese(II)-complex of ethylenediaminetetraacetic acid. 34. A material for NMR diagnosis according to claim 21 or 22, containing the di-lysine salt of the gadolinium(III)-complex of diethylenetriaminepentaacetic acid. 35 . a process for the preparation of the material according to any one of claims 21 to 34, characterised in that the paramagnetic complex saltCs)^ dissolved or suspended in water or a is/are, physiological salt solution, brought into a form suitable for oral or intravascular application, optionally with the usual additives in the art. 36. The use of at least one physiologically compatible paranja) magnetic complex salt of an aminopolycarboxylic - ,39 - 201372 acid of any one of the formulae I to IV: hoocch- ch-cooh 2\ / 2 n-(CH2)2-n (i) N-hydroxyethyl-n.n',n'-ethylenediaminetriacetic acid (HEDTA); hoh2cch2 ch2cooh hooch c ch2cooh ch-cooh 2 \ I X n-(ch2)2-n-(ch2)2-n ^ (ii) hooch2c ^ ch2cooh N.N.N'.N".N"-diethylenetriaminepentaacetic acid (DTPA), hoh2c-ch2n(ch2cooh)2 (iii) N-hydroxyethyliminodiacetic acid, _1 ch, ch cooh \ l / /N-wherein as the aminopolycarboxylic acid N,N ,N1,N",N"- diethylenetriaminepent- ris usedf aacetic acid (DTPA) Jin the preparation of a material for NMR diagnosis. 40. The use of at least one physiologically compatible paramagnetic or 37,, complex salt according to claim 36 ^wherein as the diphosphonic acid ethane-l-hydroxy-1,1-di phosphonic acid, methane-di - .is used, phosphonic acid or ethane-l-amino-1,1-diphosphonic acidj in the preparation of a material for NMR diagnosis. 41. The use of the di-N-methylglucamine salt of the manganese(II) -complex of ethylenediaminetetraacetic acid, the di-N-methyl-glucamine salt of the nickel(II)-complex of ethylenediaminetetra acetic acid, the tri-N-methylglucamine salt of the manganese (II) (M 2 6 MAY 1985 -■\ nil *>)} // JlV - 42 - 201372 complex of diethylenetriaminepentaacetic acid, the N-methylglucamine salt of the gadolinium (III)-complex of ethylene-diaminetetraacetic acid, the N-methylglucamine salt of the dysprosium(III)-complex of ethylenediaminetetraacetic acid, the di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriaminepentaacetic acid or the N-methylglucamine salt of the iron(II)-complex of ethane-l-hydroxy-1,1-diphosphonic acid in the preparation of a material for NMR diagnosis. 42. The use of the di-N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriaminepentaacetic acid in the preparation of a material for NMR diagnosis. 43. The use of the di-ethanolamine salt of the cobalt(II)-complex of ethylenediaminetetraacetic acid, the di-diethanolamine salt of the copper(II)-complex of ethylenediaminetetraacetic acid or the tri-diethanolamine salt of the manganese(II)-complex of diethylenetriaminepentaacetic acid in the preparation of a material for NMR diagnosis. 44. The use of the di-morpholine salt of the manganese(II)-complex of ethylenediaminetetraacetic acid in the preparation of a material for NMF diagnosis. 45. The use of the di-lysine salt of the gadolinium(III)-complex of diethylenetriaminepentaacetic acid in the preparation of a material for NMR diagnosis. c 201372 46;. A pharmaceutical preparation in a form suitable for use in NMR diagnosidwhich comprises a physiologically acceptable carrier and at least one physiologically compatible paramagnetic complex salt of (a) an aminopolycarboxylic acid of any one of the formulae 1 to IV HOOCCH- CH-COOH \ / N-CCH ) -N (I) / \ H0H2CCH2 CH2COOH N-bydroxyethyl-N.N',N'-ethylenediaminetriacetic acid (HEDTA) HOOCH C CH2COOH CH COOH \ i / N-(CH2)2-N-(CH2)2-N ^ (II) HOOCH2C ^ CH2COOH N.N.N',N",N"-diethylenetriaminepentaacetic acid (DTPA) HOH2C-CH2N(CH2COOH)2 (III) N-hydroxyethyliminodiacetic aci< D1 CH_ CH-COOH \ i / HOOCCH2 ' CH2COOH wherein m represents an integer from 1 to ^ n represents an integer from 0 to 2, and R1 represents a saturated or unsaturated hydrocarbon group with 4 to 12 carbon atoms or the group -ch2-coo*u " "o §* ^ 1 >- % £ \\ _ 44 _ / 201372 or a diphosphonic acid of the general formula V; *°3H2 Ra-C-Rs (V) P°3H2 vherein R2 represents hydrogen, alkyl of 1 to 4 carbon atoms,-halogen, or a hydroxy , amino or -CI^COOH group . and I? represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -CH2-COOH group, an ion of any one of the lanthanide elements of numbers 57 to 70 or an ion of any one of the transition metals of numbers 21 to 29. 42 and 44 and optionally an organic or inorganic base. 47 . A preparation according to claim 46 in which the complex salt includes an inorganic base. 48. A preparation according to claim 47 in which the inorganic base is sodium hydroxide. 49 . A preparation according to claim -46or 47 in which the aminopolycarboxylic acid is N,N,NN1-ethylene-diamine tetraacetic acid iZDrA). "4 ). ' 50 . A preparation according to claim 46 or 47 in which the aminopolycarboxylic acid is N,N,N',N",N"-diethylene-C^triamine pentaacetic ac id CDTPA) • _ 45 - 201372 51 A preparation according to claim 4 6 or 4 7 in which the diphosphonic acid is ethane-1-hydroxy-1,1-diphosphonic acid, methane diphosphonic acid or ethane-1 - ami no-1,1-diphosphonic acid. 52. A preparation according to claim 47 in which the complex salt is the disodium salt of the gadolinium (il^-complex of N,N,N',N",N"-diethyl-ene-triamine pen tabetic acid. A SCHERING AKTIENGESELLSCHAFT By their attorneys HENRY HUGHES LIMITED By:
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