IE53639B1 - Paramagnetic complex salts, their preparation, and their use in nmr-diagnostics - Google Patents

Paramagnetic complex salts, their preparation, and their use in nmr-diagnostics

Info

Publication number
IE53639B1
IE53639B1 IE1766/82A IE176682A IE53639B1 IE 53639 B1 IE53639 B1 IE 53639B1 IE 1766/82 A IE1766/82 A IE 1766/82A IE 176682 A IE176682 A IE 176682A IE 53639 B1 IE53639 B1 IE 53639B1
Authority
IE
Ireland
Prior art keywords
complex
preparation
salt
acid
acetic acid
Prior art date
Application number
IE1766/82A
Other versions
IE821766L (en
Original Assignee
Schering Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=6137999&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=IE53639(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Schering Ag filed Critical Schering Ag
Publication of IE821766L publication Critical patent/IE821766L/en
Publication of IE53639B1 publication Critical patent/IE53639B1/en

Links

Classifications

    • 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

Landscapes

  • 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)
  • Optics & Photonics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Signal Processing (AREA)
  • High Energy & Nuclear Physics (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

The present invention provides a preparation for influencing the relaxation times in NMR-diagnostics, which comprises a paramagnetic physiologically tolerable complex salt containing (a) an organic component com5 prising one or more elements selected from nitrogen, phosphorus, oxygen and sulphur, and (b) a paramagnetic element selected from lanthanide elements having the atomic numbers of from 57 to 70 and transition metals having the atomic numbers of from 21 to 29, 42 and 44, and a physiologically tolerable carrier and, if desired, (c) an inorganic or organic base or acid.
As the organic component (a) there may be used, for example, aminopolycarboxylic acids. Suitable aminopolycarboxylic acids are those compounds of this class of substances which can form chelate complexes, for example: formula Nitrilo-triacetic acid (NTA) (I) N, N, N1, N'-ethylenediamine-tetra-acetic 20 acid (EDTA) (II) N-hydroxyethyl-N, N', N1 -ethylenediaminetriacetic acid (HEDTA) (III) Ν,Ν,Ν* ,N,N-diethylenetriamine-penta-acetic acid (DTPA), and (IV) N-hydroxyethylimino-diacetic acid. (V) EDTA (II) and DTPA (IV) are preferred.
Also suitable for complex formation and as the organic component (a) are the aminopolycarboxylic acids 5363d - 3 of the general formula CH, N-iCH^-CC^-N-C^Jn-CCH^-N HOOCCH, .CHjCOOH CHjCOOH (ix) wherein m represents the integers 1 to 4, n represents the integers 0 to 2, and 5 R represents a saturated or unsaturated hydrocarbon radical having from 4 to 12 carbon atoms or the group -CHj-COOH.
As the organic component (a) there may also be mentioned amines capable of complex formation corresponding to the general formula N - H2C -H2C - N - CH2 - CH2 - N (VI) in which R^ and RJ are the same or different and represent hydrogen or an alkyl radical having 1 to 4 carbon atoms, and represents the integers 0 to 4. - 4 Such amines are, for example, ethylenediaraine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine and pentaethylenehexamine.
There may also be used as the organic component 5 the macroeyclic compounds of the general formula (VII) wherein in each case represents a hydrogen atom, a hydrocarbon radical or an alkoxycar10 bonyl radical, or both radicals R2 together form a group of the general formula (VII a) in which A in each case represents a hydrocarbon radical, X in each case represents a nitrogen or phosphurus atom, and - 5 D in each case represents an oxygen or sulphur atom, a group of the formula J^N-R (in which R represents a hydrogen atom or a hydrocarbon radical) or a hydrocarbon radical, with the proviso that at least two of the groups or atoms which D represents are oxygen or sulphur atoms or a group of the formula N-R, ahd that when each R2 is a hydrogen atom, a hydrocarbon radical or an alkoxycarbonyl radical and X is a nitrogen atom, one of the two radicals or atoms which D represents is an oxygen or sulphur atom and the other radical is an oxygen atom or a group of the formula ^7N-R, and m, n and p are integers from 0 to 5.
When A -and D in formula (VII) represent hydrocarbon radicals, these are preferably straight-chain or branchedchain alkylene or alkenylene radicals having from 2 to 8 carbon atoms, for example ethylene, propylene, butylene 20 and hexylene and their unsaturated analogues, also cycloalkylene and cycloalkenylene radicals, for example cyclopropylene cyclobutylene, cyclohexylene and cycloheptylene and their unsaturated analogues, as well as aromatic radicals, for example phenylene. The hydrocarbon radicals designated by R2 are preferably straightchain or branched-chain alkyl or alkenyl radicals having I - 6 from 1 to 8 carbon atoms, also cycloalkyl, aralkyl and aryl radicals having from 3 to 12 carbon atoms. Of the alkoxycarbonyl radicals designated by Rj, those having up to 10 carbon atoms are preferred. Especially preferred are macrocyclic complex components •which contain nitrogen and oxygen, for example 5,6-benzo-4,7,l3,16,21,24-hexaoxa1.10- diazabicyclo[8.8.8]hexacosane, 1,7,10,16-tetraoxa4,13-diazacyclo-oetadecane and 4,7,73,16,21,24-hexaoxa1.10- diazabicyclo[8.8.8]hexacosane.
In preparations comprising a complex salt containing an organic component (a) of the formulae (VI) or (VII) the optional component (c) is preferably an inorganic or organic acid.
There are also suitable as the organic component (a) diphosphonic acids of the general formula PO3H2 (VIII) PO3H2 wherein Rj and R^ are the same or different and represent a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms, a halogen atom, or an hydroxy, amino or -CHg-COOH-group. - 7 There may be mentioned, more especially, ethane-1hydroxy-1,1-diphosphonic acid, methane-diphosphonic acid and ethane-1-amino-1,1-diphosphonic acid. In preparations comprising a complex salt containing an organic component of the formula (VIII) the optional component (c) is preferably an inorganic or organic base.
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 complex salt to be conveyed to a particular area of the living body.
Bio-molecules which may be used are, for exanple, immunoglobulins, hormones such, for example, as insulin, glucagon, prostaglandins, steroidal hormones, proteins, 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 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 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 derivative of the complex compound.
Inorganic acids may be used as the acids for salt formation, for example hydrochloric acid and sulphuric acid, and also organic acids, for example acetic acid, citric acid, aspartic acid, glutamic acid, etc..
As inorganic bases for salt formation there may be used, for example, sodium hydroxide, and as organic bases, there may be used, for example, primary, secondary or tertiary amines, especially glucamine, N-methylglucamine, Ν,Ν-dimethylglucamine, ethanolamine, diethanolamine, morpholine, etc., N-methylglucamine being preferred. Basic amino-acids are also suitable for salt formation, for example lysine, ornithine, arginine, etc..
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 compatible buffer solutions (for example sodium dihydrogen phosphate solution), and sterilising the solution. The aqueous solutions can be administered orally, neurally and especially intravasally. If suspensions of the paramagnetic complex salts in water or physiological salt solution are desired, especially for oral administration, the - 9 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 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 carboxyroethyleellulose are used.
For NMR-diagnosis in humans, the preparations 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.
Solutions of the complex salts appear to be particularly suitable for greater definition or local25 isation 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 - 10 solution of the paramagnetic complex salt which is isotonic with blood is, for example, administered intravenously at a dosage of from 1 to 100 (imols/kg.
With a concentration of the complex salt of from 50 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.
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 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, 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 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 i - 11 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 resonance is shown by atomic nuclei which, like hydrogen - mainly present in biological tissues as water - have a magnetic moment and therefrom 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.
The image which is obtained by measuring the 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, 53G39 - 12 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 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 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 that the required detoxication of the otherwise toxic metal salts can he 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 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 με with exposure times of 2 minutes in each case made 10 minutes after intravenous injection of 20 pmols/kg of manganese edetate as an aqueous methylglucamine salt solution having a concentration of 6 mmols/litre, a noticeably - 13 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 LD5Q of only 0.5 mmol/kg when used on rats under identical conditions.
The performance of an NMR-diagnostic investiga15 tion 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 diethylenetriamine-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 536 39 - 14 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 106 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 53638 - 15 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 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 this purpose, 5 ml of the N-methylglucamine solution of the gadolinium complex of diethylenetriaminepenta-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 of the contrast agent (Figures 5, 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 that the N-methylglucamine of the gadolinium complex 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 eliminated with the faeces is less than 5 % of the dose administered. - 16 53639 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 12O°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: - 17 Preparation Of the manganese(II) complex of ethylenediaminetetraacetic 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 11O°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(IIl) complex of diethylenetriaminepentaacetic 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 1OO°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 g; (molecular weight 547.58) M.p.: melts from 235° and remains undecomposed up to 320°C. - 18 If there is/are still one or more acidic or basic group(s) in the resulting paramagnetic complex compound, the resulting complex compound can then, if desired, be dissolved or suspended in water and the desired inorganic or organic base or acid can be added thereto until the neutral point is reached. After filtering off the undissolved constituents, the solution is concentrated by evaporation and the desired complex salt is obtained as the residue.
These compounds are new.
The invention also provides, as new compounds, physiologically tolerable complex salts containing (a) an organic component comprising one or more elements selected from nitrogen, phosphorus, oxygen and sulphur, (b) a paramagnetic element selected from lanthanide elements having the atomic numbers of from 57 to 70 and transition metals having the atomic numbers of from to 29, 42 and 44, and (c) an organic base.
The organic component (a) is preferably an aminopolycarboxylic acid of the general formulae (I) to (V) or a disulphonic acid of the general formula {VIII) above.
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 of ethylenediamine-tetra-acetic acid. - 19 The di-ethanolamine salt of the cobalt(II)-complex of ethylenediamine-tetra-acetic acid.
The di-morpholine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic acid.
F 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)10 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)20 complex of diethylenetriamine-penta-acetic acid.
The di-lysine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid. - 20 The following Examples illustrate the invention:Example 1 Preparation of the di-N-methylglucamine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic acid. gMn 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-methylglucamine 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 (titration 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: - 21 The di-N-methylglucamine salt of the nickel(II)-complex of ethylenediamine-tetra-acetic acid, ^Ni, as a blue powder.
The di-ethanolamine salt of the cobalt(II)-complex of 5 ethylenediamine-tetra-acetic acid, C^H^gN^O^gCo, as a pink-coloured powder.
The di-morpholine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic acid, Ο,,θΗ^Ν^Ο,,θΜη, as a white powder.
The di-diethanolamine salt of the copper(II)-complex of ethylenediamine-tetra-acetic acid, c-jgH36N4°-|2Cu' as a blue powder.
The tri-diethanolamine salt of the manganese(II)complex of diethylenetriamine-penta-acetic acid, C26H54N6°1 δ11"' as a yellow powder.
The tri-N-methylglucamine salt of the manganese(II)complex of diethylenetriamine-penta-acetic acid, C35H72NgO25Mn, as a white powder.
Example 2 Preparation of the N-methylglucamine salt of the gadolinium(III)-complex of ethylenediamine-tetra-acetic acid The substarice starts to sinter at 90°C, and foam begins 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 with tetramethylammonium 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^Hg^gO^Dy.
The di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriamine-penta-acetic acid, C28H54N5020Iio‘ The di-lysine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid, C2gH^gN^Oi^Gd.
The N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid, C28H54N5 °20Gd. - 23 Example 3 Preparation of a solution of the di-N-methylglucamine salt of the manganese(II)-complex of ethylenediaminetetra-acetic acid 3.68 g (= 5 mmols) of the substance described in Example 1 are dissolved in 70 ml of water pro injectione (p.j.) 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 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 ethylenediamine15 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. 2θ Example 5 Preparation of a solution of the di-N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid - 24 5.35 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 (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 heatsterilised. The concentration of the solution is made isotonic with blood (approximately 280 mOsm.).
Example 6 Preparation of a solution of the di-N-methylglucamine salt of the dysprosium{III)-complex of diethylenetriaminepenta-acetic acid 8.00 g (= 15 mmols) of the dysprosium(III)15 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. - 25 Example 7 Preparation of a solution of the di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriaminepenta-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 of the manganese(II)-complex of ethylenediamine-tetra-acetic acid .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.
Example 9 Preparation of a solution of the N-methylglucamine salt of the iron(II)-complex of ethane-1-hydroxy-1,1diphosphonic 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 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 mmols) of N-methylglucamine. The solution is then made up to 100 ml with water p.i. and introduced into ampoules after sterile filtration.
Example 10 Preparation of a solution of the complex [Ni2(CgH^gN4)3] Cl4 . 2 H20 3.58 g (= 5 mmols) of the nickel(II) chloridetriethylenetetra-amine-complex are dissolved in 80 ml of water p.i. at a pH of 7.6 with the addition of dilute hydrochloric acid p.a., and the solution is then made up to 100 ml with water p.i.. After filtration through a sterile filter the solution is introduced into - 27 ampoules.
Example 11 Preparation of a solution of the copper(XX) chloride complex of 4,7,13,16,21,24-hexaoxa-1,10-diaza5 bicyclo[8.8.8.]-hexacosane 2.55 g (= 5 mmols) of the complex obtained from copper(IX) chloride and 4,7,13,16,21,24-hexaoxa-1,10diaza-bicyclo[8.8.8.]-hexacosane are dissolved in 80 ml of water p.i. at a pH of 7.3 with the addition of dilute hydrochloric acid p.a.. and the solution is then mace up to 100 ml with water p.i.. After sterile filtration, the solution is introduced into ampoules.
Example 12 Preparation of the manganese complex salt with diethylene15 triamine [MnCC^H^N^^fc^j To the solution of 3.94 g of manganese(II) chloride in 200 ml of ethanol (95%) there is added dropwise, while stirring,a solution of 41.2 g of diethylenetriamine in 100 ml of 50% ethyl alcohol. The temperature increases to 42°C. The precipitate produced initially dissolves after a time. After being stirred for 15 hours at room temperature, the solution is concentrated by evaporation and 70 g of crude product are obtained. This is heated - 28 to boiling for 30 minutes with 350 ml of ethanol, filtered with suction while hot, washed with ethanol and dried. 57 g of crude product are obtained, which is recrystallised from 400 ml of methanol over carbon.
Yield: 40 g (60% of theoretical yield).
Analysis: Calculated: C 28.92 H 7.89 N 25.30 Cl 21.35 Mn 16.54 Found: C 29.16 H 7.86 N 25.09 Cl 21.39 Mn 16.73 Example 13 Preparation of a solution of the N-methylglucamine salt of the manganese(II)-complex of Ν,Ν,Ν1-tris-carboxymethylN1-benzyl-ethylenediamine In analogy with Example 6, 5.65 g (15 mmols) of the manganese(II)-complex of Ν,Ν,Ν*-tris-carboxymethyl15 N'-benzyl-ethylenediamine are dissolved in 80 ml of water (pro injectione) at a pH of 7.5 with the addition of approximately 2.93 g (~20 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 sterilised.
I - 29 Example 14 Preparation of a solution of the N-methylglucamine salt of the gadolinium(III)-complex of bis-[2-(biscarboxy-methyl-amino)-ethyl]-methylamine According to the method described in Example 6 a solution which is ready for use is prepared from 7.55 g (~15 mmols) of the gadolinium(III)-complex of bis-[2-(bis-carboxy-methyl-amino)-ethyl]-methylamine and 2.93 g (~15 mmols) of N-methylglucamine.
Example 15 Preparation of a solution of the di-N-methylglucamine salt of the manganese(II)-complex of hexanediyliminotetra-acetic acid In analogy with the method described in Example 6, a solution which is ready for use is prepared from 6.02 g (-^15 mmols) of the manganese(II)-complex of hexanediyl-diamine-tetra-acetic acid and 5.86 g (^30 mmols) of N-methylglucamine. - 30 Example 16 (Composition of a powder for the preparation of a suspension] 4.000 g 5 gadolinium(III) complex of diethylenetriamine-

Claims (55)

1. What we claim is:
1. A preparation for influencing the relaxation times in NMR-diagnostics, which comprises a physiologically tolerable complex salt containing 5 (a) an organic component comprising one or more elements selected from nitrogen, phosphorus, oxygen and sulphur, and (b) a paramagnetic element selected from lanthanide elements having the atomic numbers of from 57 to 70 and transition metals having the atomic 10 numbers of from 21 to 29, 42 and 44, and a physiologically tolerable carrier, and if desired (c) an inorganic or organic base or acid.
2. A preparation as claimed in claim 1, wherein the carrier is an aqueous carrier. 15 -
3. A preparation as claimed in claim 2, wherein the carrier is water or physiological salt solution, and the complex salt is dissolved or suspended in it.
4. A preparation as claimed in claim 2 or claim 3, wherein the complex salt is present in a concentration 20 of from 5 to 250 mmol per litre.
5. A preparation as claimed in any one of claims 1 to 4, wherein the organic component (a) is an aminopolycarboxylic acid selected from nitrilo-triacetic - 32 acid, Ν,Ν,Ν',N*-ethylenediamine-tetra-acetic acid, Nhydroxyethyl-N,N’ ,Ν'-ethylenediamine-triacetic acid, Ν,Ν,Ν' ,N M ,N-diethylenetriamine-penta-acetic acid or N-hydroxyethylimino-diacetic acid, and optional component (c) is an inorganic or organic base.
6. A preparation as claimed in any one of claims 1 to 4, wherein the organic component is an amine of the general formula N - H 2 C H 2 C - N - CH 2 - CH 2 - N *1 R i (VI) in which 10 and are the same or different and represent hydrogen or an alkyl radical having 1 to 4 carbon atoms, and n represents the integers 0 to 4, and optional component (c) is an inorganic or 15 organic acid.
7. A preparation as claimed in any one of claims 1 to 4, wherein the organic component (a) is a macrocyclic compound of the general formula - 33 53039 (VII) wherein Rg in each case represents a hydrogen atom, a hydrocarbon radical or an alkoxycarbonyl 5 radical, or both radicals Rg together form a group of the formula in which A in each case represents a hydrocarbon 10 radical, X in each case represents a nitrogen or phosphorus atom, and D in each case represents an oxygen or sulphur atom, a group of the formula^N-R 15 (in which R represents a hydrogen atom or a hydrocarbon radical) or a hydrocarbon radical. - 34 with the proviso that at least two of the groups or atoms which D represents are oxygen or sulphur atoms or a group of the formula ^N-R, and that when each R 2 is a hydrogen atom, a hydrocarbon radical or an alkoxycarbonyl radical and X is a nitrogen atom, one of the two radicals or atoms which D represents is an oxygen or sulphur atom and the other radical is an oxygen atom or a group of the formula^N-R, and m, n and p are integers from 0 to 5, and optional component (c) is an inorganic or organic acid.
8. A preparation as claimed in any one of claims 1 to 4, wherein the organic component (a) is a diphosphonic acid of the general formula po 3 h 2 (VIII) p° 3 h 2 wherein R 3 and R^ are the same or different and represent a hydrogen atom, an alkyl radical having from S3C39 - 35 1 to 4 carbon atoms, a halogen atom, or an hydroxy, amino or -CH^-COOH-group, and optional component (c) is an inorganic or organic base. 5
9. A preparation as claimed in any one of claims 1 to 4, wherein the organic component (a) is as specified in claim 5, the paramagnetic element (b) is a lanthanide element having an atomic number of from 57 to 70, and optional component (c) is an inorganic 1O or organic base.
10. A preparation as claimed in any one of claims 1 to 4, wherein the organic component (a) is as specified in claim 5, the paramagnetic element (b) is a transition metal having an atomic number of from 15 21 to 29, or of 42 or 44, and the optional component (c) is an inorganic or organic base.
11. A preparation as claimed in any one of claims 1 to 4, wherein the organic component (a) is an amine as specified in claim 6, the paramagnetic 20 element is a lanthanide element having an atomic number of from 57 to 70, and the optional component (c) is an inorganic or organic acid. - 36
12. A preparation as claimed in any one of claims 1 to 4, wherein the organic component (a) is an amine as specified in claim 6, the paramagnetic element is a transition metal having an atomic number of from 21 to 29, or 42 or 44, and the optional component (c) is an inorganic or organic acid.
13. A preparation as claimed in any one of claims 1 to 4, wherein the organic component (a) is a macrocyclic compound as specified in claim 7, the paramagnetic element (b) is a lanthanide element having an atomic number of from 57 to 70, and the optional component (c) is an inorganic or organic acid.
14. A preparation as claimed in any one of claims 1 to 4, wherein the organic component (a) is a . macrocyclic compound as specified in claim 7, the paramagnetic element (b) is a transition metal having an atomic number of from 21 to 29, or 42 or 44, and the optional component (c) is an inorganic or organic acid.
15. A preparation as claimed in any one of claims 1 to 4, wherein the organic component (a) is a diphosphonic acid as specified in claim 8, the paramagnetic element (b) is a lanthanide element having an atomic number of from 57 to 70, and the optional eoWP°hent (c) is an inorganic or organic base. - 37
16. A preparation as claimed in any one of claims 1 to 4, wherein the organic component (a) is a diphosphonic acid as specified in claim 8, the paramagnetic element is a transition metal having an 5 atomic number of from 21 to 29, or 42 or 44, and the optional component (c) is an inorganic or organic base.
17. A preparation as claimed in any one of claims 1 to 4, wherein the complex salt is the di-N10 methylglucamine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic acid.
18. A preparation as claimed in any one of claims 1 to 4, wherein the complex salt is the N-methylglucamine salt of the gadolinium(III)-complex of ethyl15 enediamine-tetra-acetic acid.
19. A preparation as claimed in any one of claims 1 to 4, wherein the complex salt is the di-Nmethylglucamine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetio acid.
20. 20. A preparation as claimed in any one of claims 1 to 4, wherein the complex salt is the di-Nmethylglucamine salt of the dysprosiumtIII)-complex of diethylenetriamine-penta-acetic acid. - 38
21. A preparation as claimed in any one of claims 1 to 4, wherein the complex salt is the di-N-methylglucamine salt of the holmium{III)-complex of diethylenetriamine-penta-acetic acid. 5
22. A preparation as claimed in any one of claims 1 to 4, wherein the complex salt is the di-sodium salt of the manganese(II)-complex of ethylenediamine-tetraacetic acid.
23. A preparation as claimed in any one of claims 10 1 to 4, wherein the complex salt is the complex cl 4 · 2 h 2°
24. A preparation as claimed in any one of claims 1 to 4, wherein the complex salt is the copper(II). chloride-complex of 4,7,13,16,21,24-hexaoxa-1, ΙΟΙ 5 diaza-bicyclo[8.8.8]hexacosane.
25. A preparation as claimed in any one of claims 1 to 4, wherein the complex salt is the N-methyl glucamine salt of the iron(II)-complex of ethane-1hydroxy-1,1-diphosphonic acid. 20
26. A preparation as claimed in any one of claims 1 to 4, wherein the complex salt is the Nmethylglucamine salt of the gadoliniuin{IIl)-complex of diethylenetriamine-penta-acetic acid. - 39
27. A preparation as claimed in any one of claims 1 to 4, wherein the organic component (a) is an aminopolycarboxylic acid of the general formula R 5 CH 3 CHgCOOH HOOCCHg CHgCOOH (IX) 5 in which m represents the integers 1 to 4, n represents the integers 0 to 2, and R represents a saturated or unsaturated hydrocarbon radical having from 4 to 12 10 carbon atoms, or the group -CHg-COOH.
28. A preparation as claimed in claim 1, substantially as described in any one of Examples 3 to 11 and 13 to 15 herein.
29. A preparation as claimed in any one of claims 15 2 to 28, which is in a dosage form suitable for administration orally, neurally or intravasally. - 40
30. to ampoule containing a preparation as claimed in claim 29, in an injection suitable form.
31. A physiologically tolerable complex salt containing (a) an organic component comprising one 5 or more elements selected from nitrogen, phosphorus, oxygen and sulphur, (b) a paramagnetic element selected from lanthanide elements having the atomic numbers of from 57 to 70 and transition metals having the atomic numbers of from 21 to 29, 42 and 44, and (c) an 10 organic base.
32. A physiologically tolerable complex salt as claimed in claim 31, in which the organic component (a) is an aminopolycarboxylic acid as specified in claim 5 or a diphosphonic acid as specified in claim 8. 15
33. The di-N-methylglucamine salt of the manganese(Xl)-complex of ethylenediamine-tetra-acetic acid.
34. The di-N-methylglucamine salt of the nickel(XI) complex of ethylenediamine-tetra-acetic acid.
35. The di-ethanolamine salt of the cobalt(XX)20 complex of ethylenediamine-tetra-acetic acid. - 41
36. The di-morpholine salt of the manganese(II)complex of ethylenediamine-tetra-acetic acid.
37. The di-diethanolamine salt of the copper(Il)complex of ethylenediamine-tetra-acetic acid. 5
38. The tri-diethanolamine salt of the manganese(II)complex of diethylenetriamine-penta-acetic acid.
39. The tri-N-methylglucamine salt of the manganese(II)-complex of diethylenetriamine-penta-acetic acid. 10
40. The N-methylglucamine salt of the gadolinium(III)-complex of ethylenediamine-tetra-acetie acid. .
41. The’N-methylglucamine salt of the dysprosium(III)-complex of ethylenediamine-tetra-acetic acid.
42. The di-N-methylglucamine salt of the holmium15 (III)-complex of diethylenetriamine-penta-acetic acid.
43. The N-methylglucamine salt of the iron(II)complex of ethane-1-hydroxy-1,1-diphosphonic acid.
44. The N-methylglucamine salt of the gadolinium(III) complex of diethylenetriaminepentaacetic acid. - 42
45. The di-lysine salt of the gadolinium(IIX)complex of diethylenetriamine-penta-acetic acid.
46. A preparation as claimed in claim 1, substantially as described in Example 16 herein. 5
47. A process for the manufacture of a preparation as claimed in any one of claims 1 to 29 and claim 46, substantially as described herein.
48. A process for the manufacture of a physiologic ally tolerable complex salt as claimed in any one of 1O claims 31 to 45, substantially as described herein.
49. A method of diagnosis using NMR, wherein . a preparation as claimed in any one of claims 1 to 29 and 46 is administered to a human or animal body.
50. A method as claimed in claim 49, wherein the 15 preparation is administered intravasally.
51. A method as claimed in claim 49 or claim 50, substantially as described herein with reference to and as illustrated in Figures 1 to 7 of the accompanying drawings.
52. A preparation substantially as hereinbefore described with reference to the examples.
53. A physiologically tolerable complex salt substantially as hereinbefore described with reference to the examples.
54. A process substantially as hereinbefore described with reference to the examples.
55. A method of diagnosis substantially as hereinbefore described with reference to the drawings.
IE1766/82A 1981-07-24 1982-07-23 Paramagnetic complex salts, their preparation, and their use in nmr-diagnostics IE53639B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE3129906A DE3129906C3 (en) 1981-07-24 1981-07-24 Paramagnetic complex salts, their preparation and agents for use in NMR diagnostics

Publications (2)

Publication Number Publication Date
IE821766L IE821766L (en) 1983-01-24
IE53639B1 true IE53639B1 (en) 1989-01-04

Family

ID=6137999

Family Applications (1)

Application Number Title Priority Date Filing Date
IE1766/82A IE53639B1 (en) 1981-07-24 1982-07-23 Paramagnetic complex salts, their preparation, and their use in nmr-diagnostics

Country Status (12)

Country Link
EP (2) EP0169299B1 (en)
JP (3) JPS5829718A (en)
AT (2) ATE18719T1 (en)
AU (2) AU566007B2 (en)
CA (2) CA1218597A (en)
DE (3) DE3129906C3 (en)
IE (1) IE53639B1 (en)
LU (1) LU88291I2 (en)
NL (1) NL930072I2 (en)
NO (2) NO164458C (en)
NZ (1) NZ201372A (en)
ZA (1) ZA825313B (en)

Families Citing this family (136)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3129906C3 (en) * 1981-07-24 1996-12-19 Schering Ag Paramagnetic complex salts, their preparation and agents for use in NMR diagnostics
US4957939A (en) * 1981-07-24 1990-09-18 Schering Aktiengesellschaft Sterile pharmaceutical compositions of gadolinium chelates useful enhancing NMR imaging
NL194579C (en) * 1983-01-21 2002-08-05 Schering Ag Diagnostic.
DE3448606C2 (en) * 1983-01-21 2001-12-13 Schering Ag Diagnostic agents, processes for their production and their use
EP0330801A1 (en) * 1983-02-08 1989-09-06 Schering Aktiengesellschaft Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease
US4735796A (en) * 1983-12-08 1988-04-05 Gordon Robert T Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease
SE8301395L (en) * 1983-03-15 1984-09-16 Wallac Oy KELATIZING COMPOUNDS WITH FUNCTIONAL GROUPS WHICH ALLOW COVALENT COUPLING TO BIO-ORGANIC MOLECULES
US4972837A (en) * 1983-04-26 1990-11-27 Regents Of The University Of California Contrast agents for nuclear magnetic resonance imaging
DE3316703A1 (en) * 1983-05-04 1984-11-08 Schering AG, 1000 Berlin und 4709 Bergkamen ORAL CONTRAST AGENT FOR MRI MRI AND THE PRODUCTION THEREOF
DE3324235A1 (en) * 1983-07-01 1985-01-10 Schering AG, 1000 Berlin und 4709 Bergkamen NEW COMPLEX ILLUMINATORS, COMPLEX AND COMPLEX SALTS
DE3328365A1 (en) * 1983-08-03 1985-02-21 Schering AG, 1000 Berlin und 4709 Bergkamen NEW DIAGNOSTIC AGENTS
FR2550449B1 (en) * 1983-08-12 1986-01-31 Commissariat Energie Atomique SPECIFIC ORGAN OR PATHOLOGY RELAXATION AGENTS FOR USE IN MODIFYING CONTRASTS IN MEDICAL IMAGING BY NUCLEAR MAGNETIC RESONANCE
CA1242643A (en) * 1983-08-12 1988-10-04 Eric T. Fossel Nmr imaging utilizing chemical shift reagents
CA1243602A (en) * 1983-08-25 1988-10-25 Hong-Ning Yeung Methods for enhancing the contrast in nmr imaging
US4615879A (en) * 1983-11-14 1986-10-07 Vanderbilt University Particulate NMR contrast agents for gastrointestinal application
US5618514A (en) 1983-12-21 1997-04-08 Nycomed Imaging As Diagnostic and contrast agent
US5720939A (en) * 1985-08-15 1998-02-24 Nycomed Imaging As Method of contrast enhanced magnetic resonance imaging using magnetically responsive-particles
GB8408127D0 (en) * 1984-03-29 1984-05-10 Nyegaard & Co As Contrast agents
US4728575A (en) * 1984-04-27 1988-03-01 Vestar, Inc. Contrast agents for NMR imaging
GB8413772D0 (en) * 1984-05-30 1984-07-04 Nyegaard & Co As Chemical compounds
GB8413849D0 (en) * 1984-05-31 1984-07-04 Amersham Int Plc Nmr contrast agents
CA1268208A (en) * 1984-08-10 1990-04-24 Truman Brown Magnetic micro-particles as contrast agents in nuclear magnetic resonance imaging
US4859450A (en) * 1984-08-13 1989-08-22 The General Hospital Corporation Method of NMR imaging using antibody to cardiac myosin
US4749560A (en) * 1984-08-13 1988-06-07 Research Corporation Metal organo phosphorous compounds for NMR analysis
US4687658A (en) * 1984-10-04 1987-08-18 Salutar, Inc. Metal chelates of diethylenetriaminepentaacetic acid partial esters for NMR imaging
US4687659A (en) * 1984-11-13 1987-08-18 Salutar, Inc. Diamide-DTPA-paramagnetic contrast agents for MR imaging
US4859451A (en) * 1984-10-04 1989-08-22 Salutar, Inc. Paramagnetic contrast agents for MR imaging
US4639365A (en) * 1984-10-18 1987-01-27 The Board Of Regents, The University Of Texas System Gadolinium chelates as NMR contrast agents
US5362476A (en) * 1984-10-18 1994-11-08 Board Of Regents, The University Of Texas System Alkyl phosphonate polyazamacrocyclic cheates for MRI
US5342606A (en) * 1984-10-18 1994-08-30 Board Of Regents, The University Of Texas System Polyazamacrocyclic compounds for complexation of metal ions
US5316757A (en) * 1984-10-18 1994-05-31 Board Of Regents, The University Of Texas System Synthesis of polyazamacrocycles with more than one type of side-chain chelating groups
SE465907B (en) * 1984-11-01 1991-11-18 Nyegaard & Co As DIAGNOSTIC AGENT CONTENT AND PARAMAGNETIC METAL
EP0184899B1 (en) * 1984-11-01 1990-04-18 Nycomed As Paramagnetic contrast agents for use in "in vivo" diagnostic methods using nmr, and their preparation
DE3443252A1 (en) * 1984-11-23 1986-05-28 Schering AG, 1000 Berlin und 4709 Bergkamen Dextran-magnetite complexes for NMR diagnosis
DE3508000A1 (en) * 1985-03-04 1986-09-04 Schering AG, Berlin und Bergkamen, 1000 Berlin Ferromagnetic particles for NMR diagnosis
DE3443251C2 (en) * 1984-11-23 1998-03-12 Schering Ag Iron oxide complexes for NMR diagnosis, diagnostic compounds containing these compounds, their use and process for their preparation
PT81498B (en) * 1984-11-23 1987-12-30 Schering Ag METHOD FOR PREPARING COMPOSITIONS FOR DIAGNOSTICS CONTAINING MAGNETIC PARTICLES
US4637929A (en) * 1985-01-04 1987-01-20 Salutar, Inc. Ferrioxamine-paramagnetic contrast agents for MR imaging, composition, apparatus and use
US5089644A (en) * 1985-01-04 1992-02-18 Salutar Inc. Preparation of oxamine complexes
US4758422A (en) * 1985-01-04 1988-07-19 Salutar Inc. Ferrioxamine paramagnetic contrast agents for MR imaging
US4986256A (en) * 1985-02-28 1991-01-22 The United States Of America As Represented By The Department Of Health And Human Services Use of paramagnetic metalloporphyrins as contrast agents for tumors in MRI imaging
US4746507A (en) * 1985-04-02 1988-05-24 Salutar, Inc. EDHPA based contrast agents for MR imaging, apparatus and methods
US5422096A (en) * 1985-05-08 1995-06-06 The General Hospital Corporation Hydroxy-aryl metal chelates for diagnostic NMR imaging
US4899755A (en) * 1985-05-08 1990-02-13 The General Hospital Corporation Hepatobiliary NMR contrast agents
US4880008A (en) * 1985-05-08 1989-11-14 The General Hospital Corporation Vivo enhancement of NMR relaxivity
US4830847A (en) * 1985-06-28 1989-05-16 The Procter & Gamble Company Diphosphonate-derivatized macromolecules
US4735210A (en) * 1985-07-05 1988-04-05 Immunomedics, Inc. Lymphographic and organ imaging method and kit
US5776093A (en) 1985-07-05 1998-07-07 Immunomedics, Inc. Method for imaging and treating organs and tissues
GB8518300D0 (en) * 1985-07-19 1985-08-29 Amersham Int Plc Contrast agent
US5010191A (en) * 1985-08-19 1991-04-23 The Regents Of The University Of California Imaging agents for in vivo magnetic resonance and scintigraphic imaging
GB8522535D0 (en) * 1985-09-11 1985-10-16 Amersham Int Plc Contrast agent
US5336762A (en) * 1985-11-18 1994-08-09 Access Pharmaceuticals, Inc. Polychelating agents for image and spectral enhancement (and spectral shift)
AU6621586A (en) * 1985-11-18 1987-06-02 University Of Texas System, The Polychelating agents for image and spectral enhancement (and spectral shift)
DE3772785D1 (en) * 1986-01-23 1991-10-17 Squibb & Sons Inc 1-SUBSTITUTED-4,7,10-TRISCARBOXYMETHYL-1,4,7,10-TETRAAZACYCLODODECAN AND ANALOG.
US4885363A (en) * 1987-04-24 1989-12-05 E. R. Squibb & Sons, Inc. 1-substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs
MX174467B (en) * 1986-01-23 1994-05-17 Squibb & Sons Inc 1,4,7-TRISCARBOXIMETHYL-1,4,7,10-TETRAAZACICLODO DECAN SUBSTITUTE IN 1 AND ANALOG COMPOUNDS
IT1213029B (en) * 1986-01-30 1989-12-07 Bracco Ind Chimica Spa PARAMAGNETIC METAL ION CHELATES.
JPS62231168A (en) * 1986-03-21 1987-10-09 ハイブリテツク・インコ−ポレイテツド Improvement method for forming internal standard for analyzing analite-receptor
WO1987006139A1 (en) * 1986-04-07 1987-10-22 Dietlin Francois New compositions usable in tomo-densitometry
US5679323A (en) * 1986-07-03 1997-10-21 Advanced Magnetics, Inc. Hepatocyte-specific receptor-mediated endocytosis-type compositions
US5342607A (en) * 1986-07-03 1994-08-30 Advanced Magnetics, Inc. Receptor mediated endocytosis type magnetic resonance imaging contrast agents
US5352432A (en) * 1986-07-03 1994-10-04 Advanced Magnetics, Inc. Hepatocyte specific composition and their use as diagnostic imaging agents
AU608759B2 (en) * 1986-08-04 1991-04-18 Amersham Health Salutar Inc NMR imaging with paramagnetic polyvalents metal salts of poly-(acid-alkylene-amido)-alkanes
IL83966A (en) * 1986-09-26 1992-03-29 Schering Ag Amides of aminopolycarboxylic acids and pharmaceutical compositions containing them
US5672334A (en) * 1991-01-16 1997-09-30 Access Pharmaceuticals, Inc. Invivo agents comprising cationic metal chelators with acidic saccharides and glycosaminoglycans
US5707604A (en) * 1986-11-18 1998-01-13 Access Pharmaceuticals, Inc. Vivo agents comprising metal-ion chelates with acidic saccharides and glycosaminoglycans, giving improved site-selective localization, uptake mechanism, sensitivity and kinetic-spatial profiles
DE3640708C2 (en) * 1986-11-28 1995-05-18 Schering Ag Improved pharmaceuticals containing metals
GB8700431D0 (en) * 1987-01-09 1987-02-11 Amersham Int Plc Contrast agents
DE3709851A1 (en) * 1987-03-24 1988-10-06 Silica Gel Gmbh Adsorptions Te NMR DIAGNOSTIC LIQUID COMPOSITIONS
DE3710730A1 (en) * 1987-03-31 1988-10-20 Schering Ag SUBSTITUTED COMPLEX ILLUMINATORS, COMPLEX AND COMPLEX SALTS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM
WO1988010419A1 (en) * 1987-06-23 1988-12-29 Cockbain, Julian, Roderick, Michaelson Improvements in and relating to magnetic resonance imaging
US5531978A (en) * 1987-07-16 1996-07-02 Nycomed Imaging As Aminopolycarboxylic acids and derivatives thereof
DE3855239T2 (en) * 1987-07-16 1996-10-31 Nycomed Imaging As Aminocarboxylic acid and derivatives
DE3724188C2 (en) * 1987-07-17 1995-05-18 Heinz Dr Gries Metal-containing oligosaccharide polysulfates, process for their preparation and pharmaceutical compositions containing them
DE3927444A1 (en) * 1989-08-16 1991-02-28 Schering Ag USE OF AMID COMPLEX COMPOUNDS
GB8801646D0 (en) * 1988-01-26 1988-02-24 Nycomed As Chemical compounds
DE3806795A1 (en) * 1988-02-29 1989-09-07 Schering Ag POLYMER-TIED COMPLEX IMAGERS, THEIR COMPLEXES AND CONJUGATES, METHOD FOR THEIR PRODUCTION AND PHARMACEUTICAL AGENTS CONTAINING THEM
DE3809671A1 (en) * 1988-03-18 1989-09-28 Schering Ag PORPHYRINE COMPLEX COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM
ATE145337T1 (en) * 1988-05-02 1996-12-15 Phanos Tech Inc COMPOUNDS, COMPOSITIONS AND METHODS FOR BONDING BIO-AFFECTION SUBSTANCES TO SURFACE MEMBRANES OF BIO-PARTICLES
GB8813144D0 (en) * 1988-06-03 1988-07-06 Nycomed As Compositions
GB8817137D0 (en) * 1988-07-19 1988-08-24 Nycomed As Compositions
US5137711A (en) † 1988-07-19 1992-08-11 Mallickrodt Medical, Inc. Paramagnetic dtpa and edta alkoxyalkylamide complexes as mri agents
DE3825040A1 (en) * 1988-07-20 1990-01-25 Schering Ag 5- OR 6-RING MACROCYCLIC POLYAZA COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM
DE4001655A1 (en) * 1990-01-18 1991-07-25 Schering Ag 6-RING MACROCYCLIC TETRAAZA COMPOUNDS, METHOD FOR PRODUCING THE SAME AND PHARMACEUTICAL PRODUCTS CONTAINING THEM
DE68926708T2 (en) * 1988-08-04 1996-10-31 Advanced Magnetics Inc CONTRAST AGENT FOR ENDOCYTOSE TYPE MRI INDUCED BY A RECEPTOR
GB8819753D0 (en) * 1988-08-19 1988-09-21 Nycomed As Apparatus
US5314681A (en) * 1988-12-23 1994-05-24 Nycomed Innovation Ab Composition of positive and negative contrast agents for electron spin resonance enhanced magnetic resonance imaging
GB8900719D0 (en) * 1989-01-13 1989-03-08 Nycomed As Compounds
US5516503A (en) * 1989-11-16 1996-05-14 Guerbet S.A. Diagnostic composition comprising a binuclear complex, its method of preparation and its use in magnetic resonance imaging
FR2654344B1 (en) * 1989-11-16 1994-09-23 Cis Bio Int GADOLINIUM PARAMAGNETIC COMPLEX, ITS PREPARATION METHOD AND ITS USE FOR MRI DIAGNOSIS.
DE3938992A1 (en) 1989-11-21 1991-05-23 Schering Ag Cascade polymer-bound complex formers, their complexes and conjugates, process for their preparation and pharmaceutical compositions containing them
DK0513000T3 (en) * 1989-11-27 1996-12-30 Concat Ltd Quality improvement of IMR images of bones and similar tissues using paramagnetic cation complexes and polyphosphonate ligands
CH679742A5 (en) * 1990-01-09 1992-04-15 Byk Gulden Lomberg Chem Fab
CA2072080A1 (en) * 1990-01-19 1991-07-20 Jo Klaveness Chelating compounds
FR2667506B1 (en) * 1990-10-05 1993-08-20 Medgenix Group Sa CONTRAST AGENT COMPRISING A PARAMAGNETIC CATION ASSOCIATED WITH A SCHIFF BASE.
FR2670113A1 (en) * 1990-12-06 1992-06-12 Medgenix Group Sa CONTRAST AGENT CONSTITUTED BY A NEUTRAL COMPLEX OF A PARAMAGNETIC CATION AND LIGAND TO FORM A COMPLEX.
US5885549A (en) * 1991-02-01 1999-03-23 Imarx Pharmaceutical Corp. Phosphorylated materials as contrast agents for use in magnetic resonance imaging of the gastrointestinal region
US5143716A (en) * 1991-02-01 1992-09-01 Unger Evan C Phosphorylated sugar alcohols, Mono- and Di-Saccharides as contrast agents for use in magnetic resonance imaging of the gastrointestinal region
US5360459A (en) 1991-05-13 1994-11-01 The Lubrizol Corporation Copper-containing organometallic complexes and concentrates and diesel fuels containing same
GB9208908D0 (en) * 1992-04-24 1992-06-10 Nycomed As Contrast agents
DE4302287A1 (en) * 1993-01-25 1994-07-28 Schering Ag Derivatized DTPA complexes, pharmaceutical compositions containing these compounds, their use and processes for their preparation
DE4340809C2 (en) * 1993-11-24 2000-08-03 Schering Ag 1.4,7,10-tetraazacyclododecane derivatives, pharmaceutical compositions containing them and process for their preparation
US5582814A (en) * 1994-04-15 1996-12-10 Metasyn, Inc. 1-(p-n-butylbenzyl) DTPA for magnetic resonance imaging
US6693190B1 (en) 1994-05-11 2004-02-17 Bracco International B.V. Enhanced relaxivity monomeric and multimeric compounds
US5672335A (en) * 1994-11-30 1997-09-30 Schering Aktiengesellschaft Use of metal complexes as liver and gallbladder X-ray diagnostic agents
TW319763B (en) 1995-02-01 1997-11-11 Epix Medical Inc
DE19508058A1 (en) * 1995-02-21 1996-08-22 Schering Ag Process for the preparation of DTPA tetraesters of the terminal carboxylic acids and their use for the production of pharmaceutical agents
DE19507822B4 (en) * 1995-02-21 2006-07-20 Schering Ag Substituted DTPA monoamides of the central carboxylic acid and its metal complexes, pharmaceutical compositions containing these complexes, their use in diagnostics and therapy, and methods for the preparation of the complexes and agents
DE19507819A1 (en) * 1995-02-21 1996-08-22 Schering Ag New di:ethylene-tri:amine penta:acetic acid amide complexes
DE19507820A1 (en) * 1995-02-21 1996-08-22 Schering Ag Novel substituted DTPA derivatives, their metal complexes, pharmaceutical compositions containing these complexes, their use in diagnostics, and methods for producing the complexes and compositions
US6106866A (en) * 1995-07-31 2000-08-22 Access Pharmaceuticals, Inc. In vivo agents comprising cationic drugs, peptides and metal chelators with acidic saccharides and glycosaminoglycans, giving improved site-selective localization, uptake mechanism, sensitivity and kinetic-spatial profiles, including tumor sites
US5804164A (en) * 1996-03-13 1998-09-08 Research Corporation Technologies, Inc. Water-soluble lipophilic contrast agents
DE19646762B4 (en) * 1996-11-04 2004-05-13 Schering Ag Use of metal compounds for the production of agents for radiotherapy of tumors
DE19719033C1 (en) * 1997-04-29 1999-01-28 Schering Ag Ion pairs, processes for their preparation and their use as contrast agents
EP1060174B1 (en) * 1997-12-23 2004-09-22 Amersham Health AS Nitric oxide releasing chelating agents and their therapeutic use
IT1297035B1 (en) 1997-12-30 1999-08-03 Bracco Spa 1,4,7,10-TETRAAZACICLODODECAN-1,4-DIACETIC ACID DERIVATIVES
US7169410B1 (en) 1998-05-19 2007-01-30 Sdg, Inc. Targeted liposomal drug delivery system
DE59900055D1 (en) * 1999-09-09 2001-04-12 Schering Ag Calcium complex of (4R) -4-bis (carboxy-kappa.O) methyl amino-.kappa.N-6,9-bis (carboxy-.kappa.O) methyl-1- (4,4-diphenylcyclohexyl) oxy-1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecan-11-yl-acid-.kappa.N6, .kappa.N9, .kappa.O11 1-oxidato (6 -) -, hexahydrogen , its salts, pharmaceutical compositions containing these complexes, their use in therapy and as an additive in diagnostics, and methods for producing the complexes and compositions
DE19964224B4 (en) * 1999-09-09 2005-09-01 Schering Ag Pharmaceutical compositions containing calcium complex of [[(4R) -4- [bis [(carboxy-.kappa.O) methyl] amino-.kappa.N] -6,9-bis [(carboxy-.kappa.O) methyl] -1 - [(4,4-diphenylcyclohexyl) oxy] -1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecan-11-yl-acid-.kappa.N6, .kappa.N9, .kappa.011] 1-oxidato (6 -)], tetrahydrogen (MS-325) and its salts, and process for their preparation
DE19944893C2 (en) * 1999-09-09 2001-09-20 Schering Ag Calcium complex of [[(4R) -4- [bis [(carboxy-.kappa.O) methyl] amino-. kappa.N] -6,9-bis [(carboxy-.kappa.O) methyl] -1 - [(4,4-diphenylcyclohexyl) oxy] -1-hydroxy-2-oxa-6,9-diaza-1 -phosphaundecan-11-yl-acid-.kappa.N6, .kappa.N9, .kappa.O11] 1-oxidato (6 -)] -, hexahydrogen, its salts and pharmaceutical compositions containing these complexes
US6559330B1 (en) 1999-09-09 2003-05-06 Schering Aktiengesellschaft Calcium complex of [[(4r)-4-[bis{carboxy-.kappa.o)methyl]amino-.kappa.n]-6,9-bis[(carboxy.kappa.o)methyl]-1-[(4,4-diphenylcyclohexyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecan-11-ylic-acid-.kappa.n6,.kappa.n9,.kappa.011]1-oxidato(6-)]-, hexahydrogen, its salts, pharmaceutical agents that contain these complexes, their use in treatment and as additives in diagnosis, as well as processes for the production of the complexes and agents
CA2471363C (en) 2001-12-21 2014-02-11 Human Genome Sciences, Inc. Albumin fusion proteins
DE10305462A1 (en) * 2003-02-04 2004-08-12 Schering Ag Conjugates of enantiomerically pure (4S, 8S) - and (4R, 8R) -4-p-benzyl-8-methyl-3,6,9-triaza-3N, 6N, 9N-tricarboxymethyl-1,11-undecanedioic acid with biomolecules, method for their manufacture and use for manufacture
FR2867473B1 (en) 2004-03-12 2006-06-23 Guerbet Sa PORPHYRINE COMPOUND AND HIGH FIELD USE IN MRI
JP4956426B2 (en) 2004-07-02 2012-06-20 ブラッコ・イメージング・ソシエタ・ペル・アチオニ High relaxivity contrast agent
US8669236B2 (en) 2005-05-12 2014-03-11 The General Hospital Corporation Biotinylated compositions
DOP2007000020A (en) 2006-01-31 2007-09-15 Bayer Schering Pharma Ag MODULATION OF THE ACTIVITY OF MDL-1 FOR THE TREATMENT OF INFLAMMATORY DISEASES
DE102007058220A1 (en) 2007-12-03 2009-06-04 Bayer Schering Pharma Aktiengesellschaft New metal complexes useful e.g. for manufacturing agent for X-ray diagnostics and magnetic resonance tomography-diagnostics of brain infarcts and liver tumor, and/or space-process in liver and abdomen tumors and musculoskeletal tumors
EP2237792B1 (en) 2007-12-26 2017-05-24 Vaccinex, Inc. Anti-c35 antibody combination therapies and methods
US8722020B2 (en) * 2010-03-31 2014-05-13 General Electric Company Hydroxylated contrast enhancement agents
WO2014036427A1 (en) 2012-08-31 2014-03-06 The General Hospital Corporation Biotin complexes for treatment and diagnosis of alzheimer's disease
CN103664672B (en) * 2013-10-21 2016-01-13 河北一品制药有限公司 A kind of preparation method of suitability for industrialized production Gadopentetate Meglumine
WO2018125916A1 (en) 2016-12-29 2018-07-05 Inventure, LLC Solvent-free gadolinium contrast agents
CN106928078A (en) * 2017-02-27 2017-07-07 南昌大学 A kind of threonine chelated iron and its application
CN107632037A (en) * 2017-08-24 2018-01-26 北京中科乾和环保科技服务有限公司 Based on liquid phase31The analysis method of organophosphor in the deposit of P NMR technologies
CN112525943B (en) * 2020-11-19 2024-04-19 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) Q is adopted1Method for quantitatively analyzing ethanol and acetic acid in fermented fruit and vegetable juice by H-NMR technology

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US401594A (en) * 1889-04-16 Combined punch
FR1111504A (en) * 1950-03-06 1956-03-01 Cassella Farbwerke Mainkur Ag Process for the preparation of cobalt compounds
FR484M (en) * 1960-05-02 1961-05-08
FR988M (en) * 1960-12-01 1961-12-11
US3252082A (en) * 1964-01-02 1966-05-17 Chevron Res Method and composition for aiding nuclear magnetic well logging
US3818061A (en) * 1971-11-09 1974-06-18 Merck Sharp & Dohme Transparent nmr shift reagents
JPS5441575B2 (en) * 1972-07-28 1979-12-08
JPS49103693A (en) * 1973-02-02 1974-10-01
US4167564A (en) * 1974-09-23 1979-09-11 Albion Laboratories, Inc. Biological assimilation of metals
DE2527158A1 (en) * 1975-06-18 1976-12-23 Herz Eberhard MEDICINAL PRODUCTS FOR THE TREATMENT OF INFECTIOUS DISEASES AND INFLAMMATION IN HUMAN AND VETERINAL MEDICINE THAT CANNOT BE DETECTED BY MICROORGANISMS
US4066743A (en) * 1976-06-21 1978-01-03 Mallinckrodt, Inc. X-ray contrast agents
US4125599A (en) * 1976-08-19 1978-11-14 Mallinckrodt, Inc. X-ray contrast agents
US4176173A (en) * 1977-07-18 1979-11-27 Medi-Physics, Inc. Radiographic compositions
ZA786403B (en) * 1977-12-01 1979-10-31 Ici Australia Ltd Process
GB1598610A (en) * 1978-05-31 1981-09-23 Rexolin Chem Ab Aliphatic polyamino polycarboxylic acid and its salts and their use as chelating agents
JPS5759841A (en) * 1980-09-30 1982-04-10 Showa Denko Kk Treating method of waste liquor from preparation of metallic chelate of ethylenediaminetraacetic acid
DE3129906C3 (en) * 1981-07-24 1996-12-19 Schering Ag Paramagnetic complex salts, their preparation and agents for use in NMR diagnostics
US4647447A (en) * 1981-07-24 1987-03-03 Schering Aktiengesellschaft Diagnostic media
DE3518267A1 (en) * 1985-05-17 1986-11-20 Martin Prof. Dr. 1000 Berlin Wenzel Compositions for increasing contrast in magnetic resonance imaging
GB8518300D0 (en) * 1985-07-19 1985-08-29 Amersham Int Plc Contrast agent
IT1213029B (en) * 1986-01-30 1989-12-07 Bracco Ind Chimica Spa PARAMAGNETIC METAL ION CHELATES.

Also Published As

Publication number Publication date
LU88291I2 (en) 1994-05-04
JPH0768193B2 (en) 1995-07-26
DE3280157D1 (en) 1990-05-31
AU601916B2 (en) 1990-09-20
JPS62123159A (en) 1987-06-04
EP0169299A3 (en) 1986-12-03
ATE18719T1 (en) 1986-04-15
AU1018688A (en) 1988-04-28
IE821766L (en) 1983-01-24
EP0071564B1 (en) 1986-03-26
NZ201372A (en) 1986-08-08
NO164458B (en) 1990-07-02
CA1240679A (en) 1988-08-16
EP0169299B1 (en) 1990-04-25
NL930072I1 (en) 1993-09-01
EP0071564A1 (en) 1983-02-09
NO164458C (en) 1992-11-23
DE3270097D1 (en) 1986-04-30
NO822546L (en) 1983-01-25
NO1994031I1 (en) 1994-12-30
JPH0339045B2 (en) 1991-06-12
AU8633082A (en) 1983-01-27
ATE52247T1 (en) 1990-05-15
ZA825313B (en) 1983-05-25
AU566007B2 (en) 1987-10-08
NL930072I2 (en) 1994-01-17
JP2548436B2 (en) 1996-10-30
DE3129906C3 (en) 1996-12-19
CA1218597A (en) 1987-03-03
DE3129906A1 (en) 1983-02-10
EP0169299A2 (en) 1986-01-29
JPH03209389A (en) 1991-09-12
DE3129906C2 (en) 1990-05-17
JPS5829718A (en) 1983-02-22

Similar Documents

Publication Publication Date Title
IE53639B1 (en) Paramagnetic complex salts, their preparation, and their use in nmr-diagnostics
TW319763B (en)
AT397465B (en) DIAGNOSTIC MEANS
KR100189388B1 (en) Chelating compounds and their use
EP0436579B1 (en) Chelate compositions
JPS60100526A (en) Specific alliviating agent for organ or pathology
JPH04507084A (en) Novel magnetic resonance contrast agent
JP3683584B2 (en) Dendritic polymer metal complexes, diagnostic agents containing the same, and methods for producing these complexes and diagnostic agents
US5575986A (en) Chelating agent, complex compound of said chelating agent and metallic atom, and diagnostic agent comprising same
IE67551B1 (en) Macrocyclic chelating agents and chelates thereof
CA2092596A1 (en) Tetraazacyclododecane derivative and its use
CA2053478C (en) Magnetic resonance imaging agent
EP0948361B1 (en) Magnetic resonance blood pool agents
US5274082A (en) Paramagnetic complexes of chelating compounds
JPH06502858A (en) Complexes and compositions for magnetic resonance imaging and their use
US5824288A (en) Thio-substituted pyridines as MRI ligand precursors
US5820851A (en) Tripodal pyridine ligands as MRI contrast agents
RU2059642C1 (en) Gadolinium chelates and a method of their synthesis

Legal Events

Date Code Title Description
SPCF Request for grant of supplementary protection certificate

Free format text: SPC 74/93:19930701

SPCG Supplementary protection certificate granted

Free format text: SPC 74/93 EXPIRES:20030203

MK9A Patent expired