AU601916B2 - Paramagnetic complex salts, their preparation and their use in nmr-diagnostics - Google Patents

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

Info

Publication number
AU601916B2
AU601916B2 AU10186/88A AU1018688A AU601916B2 AU 601916 B2 AU601916 B2 AU 601916B2 AU 10186/88 A AU10186/88 A AU 10186/88A AU 1018688 A AU1018688 A AU 1018688A AU 601916 B2 AU601916 B2 AU 601916B2
Authority
AU
Australia
Prior art keywords
complex
salt
acetic acid
ethylenediamine
methylglucamine
Prior art date
Legal status (The legal status 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 status listed.)
Expired, expires
Application number
AU10186/88A
Other versions
AU1018688A (en
Inventor
Heinz Dr. Gries
Douwe Dr. Rosenberg
Hanns-Joachim Dr. Weinmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
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=AU601916(B2) "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 AU1018688A publication Critical patent/AU1018688A/en
Application granted granted Critical
Publication of AU601916B2 publication Critical patent/AU601916B2/en
Adjusted expiration legal-status Critical
Expired legal-status Critical Current

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)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Physics & Mathematics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • Radiology & Medical Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Optics & Photonics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Signal Processing (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (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

8-,1317/,D:n/0105.4 601916
AUSTRALIA
PATENTS ACT 1952 COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art: This do'urnent contains the amendments made under Sectibn 49 and is correct for printing.
Cf c f r c TO BE COMPLETED BY APPLICANT Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: SCHERING AKTIENGESELLSCHAFT HA Gewerblicher Rechtsschutz Postfach 65 03 11 D-1000 Berlin
GERMANY
Dr Heinz Gries Dr Douwe Rosenberg Dr Hans-Joachim Weinmann ARTHUR S. CAVE CO.
Patent Trade Mark Attorneys Level Barrack Street SYDNEY N.S.W. 2000
AUSTRALIA
Complete Specification for the invention entitled PARAMAGNETIC COMPLEX SALTS, THEIR PREPARATION, AND THEIR USE IN
NMR-DIAGNOSTICS.
The following statement is a full description of this invention including the best method of performing it known to me:- 1 ASC 49 The present invention relates to new paramagnetic compounds which are useful for affecting the relaxation times of atoms in body tissues undergoing NMR diagnosis.
The present invention thus provides physiologically compatible paramagnetic complex salts containing: an organic component selected from the aminopolycarboxylic acids; N-Hydroxyethyl-N,N',N'-ethylenediaminetriacetic acid (HEDTA), N,N,N',N"N"-Diethylenetriaminepentaacetic acid (DPTA), N-Hydroxyethyliminodiacetic acid, and R1 CH CH COOH R3 2
N-(CH
2 )m4(H 2
-NCH
2 H 2 )mN 2 2CH
HOOCCH,
wherein a, a a a, a. i at t r m represents the integers 1 to 4 n represents the integers 0 to 2 1 R represents a saturated or unsaturated hydrocarbon group with 4 to 12 carbon atoms or the group -CH 2
-COOH,
or diphosphonic acids of the general formula VIII oucs ma a oeat a a 4 a a .aaa a c ii 1
PO
3H 2 R3 C R 4 P3 H 0 3H2
(VIII)
AMD/0277g 2 i a; ii F:r s v iwherein
R
3 represents hydrogen, alkyl of 1 to 4 carbon atoms, halogen, the hydroxy-, amino- or CH 2 -COOH groups, and
R
4 represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -CH -COOH group; ions of the lanthanide elements of numbers 57 to 70 or ions of the transition metals of numbers 21 to 29, 42 and ~44; and an organic base selected from glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, diethanolamine, morpholine, lysine, ornithine and arginine.
New preparations containing the novel compounds and a method of diagnosis using NMR are also provided.
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.
3- 0905E ~Th The di-ethanolamine salt of the cobalt(II)-complex of ethylenediarnine-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-dietanolanine salt of~the zanganese(II)complex of diethylenetri amine-penta--acetic acid.
The tri-N-methylglucanine salt of the manganese(II)complex of diethylenetriamnine-penta-acetic acid.
The N-methylglucamine salt of the gadolinium(III)complex of ethylenedi arine-tetra-acetic acid.
The N-methylglucanine salt of the dysprosiunC III)complex of ethylenediamine-tetra-acetic acid.
The di-N-methylglucamine salt of the holrniuin(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 gadoliniuxn(III)complex of diethylenetriamine-penta-acetic acid.
The di-lysine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid.
-4-
C.
C
N
0 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 example, 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 i 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.
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 0905E S. 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 befbre 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, Shighly disperse silica, polyoxyethylenepolyoxypropylene polymers, starch, magnesium stearate, sodium lauryl sulphate, talcum, lactose, sodium carboxymethylcellulose 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 mnmols/litre, preferably 50 to 200 mmols/litre, of the paramagnetic complex salt. The pH of the aqueous S. 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 Sreadily soluble therein in the physiological pH range.
Solutions of the' complex salts appear to be 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 6 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 to 200 mmols/litre, approximately I 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 iinutes 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 dis- Sadvantages, 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 -7-
V
Kr.
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 10 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. Ganssen and others, Computertomographie 1, [1981'] pp. 2-10; Georg Thieme Verlag, Stuttgart, New York).
;It has now been found that paramagnetic ionsF' -8f. 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 T1 is greatly reduced in a manner which is as organ-specific as possible, whilst at the same time the spin-spin-relaxation time T 2 is kept constant to a great extent. We have now found 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 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 180°-pulse of 720 ps with exposure times of 2 minutes in each case made 10 minutes after intravenous injection of 20 pmols/kg of manganese t> Ae t ce c Ao'c edetate as an aqueous methylglucamine salt solution having a concentration of 6 mmols/litre, a noticeably CO 9- 4 0^
~E~
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 Ssalts is achieved by the complex.formation. Thus in rats, after intravenous injection of an aqueous solution of 10 the N-methylglucamine salt of manganese edetate an
LD
50 of 4 mmols/kg was found. In contrast, manganese chloride showed an LD 50 of only 0.5 mmol/kg when used on rats under identical conditions.
i The performance of an NMR-diagnostic investigarr 15 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 25 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 :ize 10 i I i 1 i i.
t i: r- 6 ii; i: i i: e i.
:I
jto 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 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 r |3 and 4, which were taken between 22 and 25 minutes after administration, a marked increase in brightness Sin 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 1 ),-which 11 /2 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 plp~ aMdifferences increase in the intensity relaxaof the signal. Only The definition of structures was also improved after oral administration of the contrast agent was the this purpose, 5 m. of the N-methylglucamine solution of the gadolinium complex of diethylenetriaminepentumorous fuid acid hcumulation and improved definition ofol/litre was administered by means of a probe to an anaesthetised mathe rat (body weight: 250 Only after administration of the contrast agent, struct(Figures in the abdomen 7) was could hardly be recognised, since the organs show only small S, differences in proton density and relaxation times.
definition of the stomach or of the intestine improved relation to the remation of the contrast agent. For 0 this pur own pharmaco-kin-methylglucmiic tests on rats have shown that the N-methylglucamine of the gadolinium complex of diethyenetriamineof diethylenetriine-penta-acetic acid after intravmol/litrenous and subcutaneous administered by means of a probe to an anaesthetisminated male rat (body weight: 250 Only after The gadolminium cstrationmplex is5 of the contrast agent (Figures 5 6 rulary filtration withs clear a haldefinition of apprthe stomatelych or of the intestine proportion relation to the remaining organs to be seen.
Our own pharmaco-kinetic tests on rats have shown 25 eliminated with the N-methylglufaeces is less than 5 of the gadolinium complex V 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 eliminated with the faeces is less than 5 of the dose administered.
12 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 0 C to 120 0 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 t 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 |i way of example, with the aid of the following instructions for procedure: 13 r 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 110 0
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°/258-2590C Preparation of the gadolinium(III) complex of diethylenetriaminepentaacetic acid: 0 A suspension of 435 g of gadolinium oxide (Gd 2 0 3 and 944 g of diethylenetriaminepentaacetic acid in 12 litres of water is heated while stirring to from 90 C to 100 0 C and stirred at this temperature for 48 S.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) melts from 235° and remains undecomposed up to-320 0
C.
14 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, C24H 4 8
N
4 0 1 8 Mn p t r i g 10
C
e
SCC
C V C 7.4 20 mmols) of the'manganese(II)-complex of ethylenediamine-tetra-acetic acid (water content 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 0 °C and becoming viscous at 170 0
C.
Analysis: calculated C 39.19% H 6.58% N 7.61% Mn 7.47% Found in the dry r C <s c l i t substance C 39.23% E 7.10% N 7.26% Mn 7.S3%
H
2 0 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 -L analogous manner: ,kr The di-N-rnethylglucarnine salt of the nickel(II)-complex of ethylenediaxine-tetra--acetic acid, C 24
H
48
N
4 0 1 8 8 Ni, as a blue powder.
The di-ethanolamine salt of the cobalt(II)-complex of ethylenediamine-tetra-acetic acid, C 14 28
N
4 0OCo, as a pink-coloured powder.
The di-morpholine salt of the rnanganese(II)-complex of ethylenediamine-tetra-acetic acid, C 18
H
3 N 0 Mn, as a white powder.
The di-diethanolamine salt of the copper(II)-complex of ethylenediamine-tetra-acetic acid, C 1 8 8
H
36 N 4 0 1 2 Cu, as a blue powder.
The tri-diethanolamine salt of the mariqaneseC II)complex of diethylenetriamine-penta-acetic acid, C26 H 54
N
6
O
16 Mi, as a yellow powder.
The tri-N-methylglucamine salt of the rnanganese(II)complex of diethylenetriaxnine-penta-acetic acid, C H N 0 Mn, as a white powder.
72 6 Example 2 Preparation of the N-niethylglucamine salt of the gadolinium( 111)-complex of ethylenediLamine-tetra-acetic acid P~LI~ 17
H
30
N
3 0 13
G)
4.58 g 10 mmols) of the gadolinium(III)complex of ethylenediamine-tetra-acetic acid (water content: are suspended in 15 ml of water and by the addition of 1.95 g 10 mmols) of N-methylglucamine 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%0, is practically quantitative.
The substance~starts to sinter ato90 0 C, and foam begins 10 to develop at 140 0
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 17
H
30 N30 13 Dy.
The di-N-methylglucamine salt of the holmium(III)-complex Sof diethylenetriamine-penta-acetic acid, C 28
H
54
N
5 2 0 Ho.
The di-lysine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid, C 26
H
48
N
7
O
14 Gd.
The N-methylglucamine salt of the gadolinium(III)-complex Sof diethylenetriamine-penta-acetic acid, C 28
H
54 N 02 Gd i 17 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 I are dissolved in 70 ml of water pro injectione 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 ethylenediaminetetra-acetic acid 9.63 g 15 mmols) of the substance described in Example 2 are dissolved in 100 ml of water 'The solution, which is approximately isotonic with blood, is introduced into ampoules through a sterile filter.
Example Preparation of a solution of the di-N-methylglucamine salt of the gadolinium(III)-complex of diethylenef T 8 triamine-penta-acetic acid C, i
G
5.35 g 9 mmols) of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid (water content 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 mmnols) of N-methylglucamine. The solution is then made up to 100 ml with water 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)complex of diethylenetriamine-penta-acetic acid are :i dissolved in 80 ml of water p.i. at a pH of 7.5 with the addition of approximately 5.3 g (corresponding to S% approximately 30 mmols) of N-methylglucamine. The solution is then made up to 170 ml with water p.i..
S: 20 The solution, which is approximately isotonic with 7blood, is introduced into ampoules and heat-sterilised.
'ci I% I ,t rC,f 1: 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 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 5.55 g (15 mmols) of the manganese(II)-complex of ethylenediamine-tetra-acetic acid (water content: are dissolved in 80 ml of water P.i. at a pH of with the addition of dilute sodium hydroxide solution. The solution is then made up to 170 ml "ith water filtered into ampoules and heat-sterilised.
3- E t' C (C
F;
I:
i i r 6;
E:
FF
1:I; ii r a -j V U~ i ~i Imm-mi t f c Example 9 Preparation of a solution of the N-methylglucamine salt of the iron(II)-complex of ethane-l-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 o.i. and introduced into ampoules after sterile filtration.
Example Preparation of a solution of the complex [Ni 2
(C
6
H
18
N
4 3 C14 2 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 and the solution is then made up to 100 ml with water After filtration through a sterile filter the solution is introduced into 2-- 9.1 t r O iti i i i 1 )C C
TPCI
Cr ampoules.
Example 11 Preparation of a solution of the copper(II) chloride complex of 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8.]-hexacosane 2.55 g 5 mmols) of the complex obtained from copper(II) 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 and the solution is then made up to 100 ml with water After sterile filtration, the solution is introduced into ampoules.
Example 12 Preparation of the manganese complex salt with diethylenetriamine [Mn(C 4
H
13
N
3 2 ]Cl 2 To the solution of 3.94 g of manganese(II) chloride in 200 ml of ethanol 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 i>XX and 70 g of crude product are obtained. This is heated
C
f i: -i :Ir ii!
L-;
U- aX L_ 1 -3- <sa.
-i 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 t" 1 7 10 C r i, Example 13 Preparation of a solution of the K-methylglucamine salt of the manganese(II)-complex of N,N,N'-tris-carboxymethyl- N'-benzyl-ethylenediamine c cs
(S.
In analogy with Example 6, 5.65 g (15 mmols) of the manganese(II)-complex of N,N,N'-tris-carboxymethyl- 15 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 The solution, which is approximately isotonic with blood, is introduced into ampoules and sterilised.
i i t: i F VIq Example 14 Preparation of a solution of the N-methylglucamine salt of the gadolinium(III)-cornplex of bis-[2-(biscarboxy-methyl-anino )-ethyl ]-methylam-ine According to the method described in Example 6 a solution which is ready for use is prepared from 7.55 g (r'-15 rranols) of the gadoli-ium (III) -complex of bis-[ 2- (bis-carboxy-methyl-amino )-ethyl 1-methylatnine and 2.93 g C-15 minds) of N-methylglucamine.
Example Preparation of a solution of the di-N-methylglucanine salt of the inanganese(II)-cornplex of hexanediyliminotetra-acetic acid t In analogy with the method desc~ribed in Exiarple 6, 1.5 a solution which is ready for use is prepared from 6.02 g nuols) of the rnanganese(II)-complex of I' hexanediyl-diamine-tetra-acetic acid and 5.86 g miols) of N-methylglucainine.
<~I
U 1 i a~~.~~a4aa*lsprrs~ 2 Example 16 (Composition of a powder for the preparation of a suspension) 4.000 g gadolinium(III) complex of diethylenetriaminepentaacetic acid (water content 8%) 3.895 g saccharose 0.100 g polyoxyethylenepolyoxypropylene polymer 0.005 g aromatic substances 8.000 g

Claims (19)

1. Physiologically compatible paramagnetic complex salts containing: an organic component selected from the aminopoly carboxylic acids; N-Hydroxyethyl-N,N',N'-ethylenediamine triacetic acid (HEDTA), N,N,N',N"N"-diethylenetriamine pentaacetic acid (DPTA), N-Hydroxyethyliminodiacetic acid, and 1 R. CH ru rv "3 /"2 N-(CH) m-(CH 2 -N-CH2)n-(CH 2 N 2 CH 2 COOH ii i ti HOOCCH. wherein m represents the integers 1 to 4 n represents the integers 0 to 2 1 R represents a saturated or unsaturated hydrocarbon group with 4 to 12 carbon atoms or the group -CH 2 -COOH, or diphosphonic acids of the general formula VIII P0 3 H 2 0c C~ Crzv R3 C R PO H PO3H2 (VIII) t t r wherein R represents hydrogen, alkyl of 1 to 4 carbon atoms, halogen, the hydroxy-, amino- or CH 2 -COOH groups, and AMD/0277g 26 COALN 010 m i .E' I ;I i~I. L-LYCI.--- i-~i :i ;i b: R 4 represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -CH 2 -COOH group; ions of the lanthanide elements of atomic numbers 57 to or ions of the transition metals of atomic'numbers 21 to 29, 42 and 44; and an organic base selected from glucamine, N-methylglucamine, NN-dimethylglucamine, ethanolamine, diethanolamine, morpholine, lysine, ornithine and arginine.
2. The di-N-methylglucamine salt of the manganese (II)-complex of ethylenediamine-tetra-acetic acid.
3. The di-N-methylglucamine salt of the nickel(II)-complex of ethylenediamine-tetra-acetic acid.
4. 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.
6. The di-diethanolamine salt of the copper(IT)-complex of ethylenediamine-tetra-acetic acid.
7. The tri-diethanolamine salt of manganese(II)-complex of diethylenetriamine-penta-acetic acid.
8. The tri-N-methylglucamine salt of the manganese k 'I (11)-complex of diethylenetriamine-penta-acetic acid.
9. The N-methylglucamine salt of the gadolinium(III)-complex C of ethylenediamine-tetra-acetic acid.
The N-methylglucamine salt of the dysprosium(III)-complex of ethylenediamine-tetra-acetic acid.
11. The di-N-methylglucamine salt of the holmium(III)-complex AMD/0277g 27 p of diethylenetriamine-penta-acetic acid.
12. The N-methylglucamine salt of the iron(II)-complex of ethane-l-hydroxy-l,1-diphosphonic acid.
13. The N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid.
14. The di-lysine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid.
A process for the manufacture of a physiologically tolerable complex salt as claimed in any one of claims 1 to 14, substantially as described herein.
16. A preparation for influencing the relaxation times of atoms in body tissues undergoing NMR diagnosis, comprising a paramagnetic complex salt according to any of claims 1 to 14 and a physiological acceptable carrier.
17. A preparation according to claim 16, wherein the carrier is an aqueous carrier.
18. A preparation according to claim 17, wherein the carrier is water or physiological isotonic salt solution, and the complex salt is dissolved or suspended in it.
19. Physiologically compatible paramagnetic complex salts, substantially as herein described with reference to any one of Examples 1 to DATED this 3rd day of May, 1990. ii SCHERING AKTIENGESELLSCHAFT By Its Patent Attorneys ARTHUR S. CAVE CO. '0277g 28
AU10186/88A 1981-07-24 1988-01-08 Paramagnetic complex salts, their preparation and their use in nmr-diagnostics Expired AU601916B2 (en)

Applications Claiming Priority (2)

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
DE31299067 1981-07-24

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
AU86330/82A Division AU566007B2 (en) 1981-07-24 1982-07-22 Paramagnetic complex salts and their use in nmr- diagnostics

Publications (2)

Publication Number Publication Date
AU1018688A AU1018688A (en) 1988-04-28
AU601916B2 true AU601916B2 (en) 1990-09-20

Family

ID=6137999

Family Applications (2)

Application Number Title Priority Date Filing Date
AU86330/82A Expired AU566007B2 (en) 1981-07-24 1982-07-22 Paramagnetic complex salts and their use in nmr- diagnostics
AU10186/88A Expired AU601916B2 (en) 1981-07-24 1988-01-08 Paramagnetic complex salts, their preparation and their use in nmr-diagnostics

Family Applications Before (1)

Application Number Title Priority Date Filing Date
AU86330/82A Expired AU566007B2 (en) 1981-07-24 1982-07-22 Paramagnetic complex salts and their use in nmr- diagnostics

Country Status (12)

Country Link
EP (2) EP0169299B1 (en)
JP (3) JPS5829718A (en)
AT (2) ATE52247T1 (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)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU658566B2 (en) * 1986-03-21 1995-04-27 Hybritech Incorporated Improvements in or relating to methods for providing internal references for use in analyte-receptor assays

Families Citing this family (135)

* 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
US4735796A (en) * 1983-12-08 1988-04-05 Gordon Robert T Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease
EP0330801A1 (en) * 1983-02-08 1989-09-06 Schering Aktiengesellschaft 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
CA1242643A (en) * 1983-08-12 1988-10-04 Eric T. Fossel Nmr imaging utilizing chemical shift reagents
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
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
US5720939A (en) * 1985-08-15 1998-02-24 Nycomed Imaging As Method of contrast enhanced magnetic resonance imaging using magnetically responsive-particles
US5618514A (en) * 1983-12-21 1997-04-08 Nycomed Imaging As Diagnostic and contrast agent
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
US4859451A (en) * 1984-10-04 1989-08-22 Salutar, Inc. Paramagnetic contrast agents for MR imaging
US4687659A (en) * 1984-11-13 1987-08-18 Salutar, Inc. Diamide-DTPA-paramagnetic contrast agents for MR imaging
US4687658A (en) * 1984-10-04 1987-08-18 Salutar, Inc. Metal chelates of diethylenetriaminepentaacetic acid partial esters for NMR imaging
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
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
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
PT81498B (en) * 1984-11-23 1987-12-30 Schering Ag METHOD FOR PREPARING COMPOSITIONS FOR DIAGNOSTICS CONTAINING MAGNETIC PARTICLES
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
DE3443252A1 (en) * 1984-11-23 1986-05-28 Schering AG, 1000 Berlin und 4709 Bergkamen Dextran-magnetite complexes for NMR diagnosis
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
US4899755A (en) * 1985-05-08 1990-02-13 The General Hospital Corporation Hepatobiliary NMR contrast agents
US5422096A (en) * 1985-05-08 1995-06-06 The General Hospital Corporation Hydroxy-aryl metal chelates for diagnostic NMR imaging
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)
EP0247156B1 (en) * 1985-11-18 1993-06-23 Access Pharmaceuticals Inc. Polychelating agents for image and spectral enhancement (and spectral shift)
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
DE3772785D1 (en) * 1986-01-23 1991-10-17 Squibb & Sons Inc 1-SUBSTITUTED-4,7,10-TRISCARBOXYMETHYL-1,4,7,10-TETRAAZACYCLODODECAN AND ANALOG.
IT1213029B (en) * 1986-01-30 1989-12-07 Bracco Ind Chimica Spa PARAMAGNETIC METAL ION CHELATES.
KR880701111A (en) * 1986-04-07 1988-07-25 제뜨랭 프랑쎄 Composition for use in tomometry
US5352432A (en) * 1986-07-03 1994-10-04 Advanced Magnetics, Inc. Hepatocyte specific composition and their use as diagnostic imaging agents
US5342607A (en) * 1986-07-03 1994-08-30 Advanced Magnetics, Inc. Receptor mediated endocytosis type magnetic resonance imaging contrast agents
US5679323A (en) * 1986-07-03 1997-10-21 Advanced Magnetics, Inc. Hepatocyte-specific receptor-mediated endocytosis-type compositions
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
US4984573A (en) * 1987-06-23 1991-01-15 Hafslund Nycomed Innovation Ab Method of electron spin resonance enhanced magnetic resonance imaging
US5198208A (en) * 1987-07-16 1993-03-30 Nycomed Imaging As Aminopolycarboxylic acids and derivatives thereof
US5531978A (en) * 1987-07-16 1996-07-02 Nycomed Imaging As Aminopolycarboxylic acids and derivatives thereof
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
WO1989010758A1 (en) * 1988-05-02 1989-11-16 Zynaxis Technologies, Inc. Compounds, compositions and method for binding bio-affecting 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
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
DE3825040A1 (en) * 1988-07-20 1990-01-25 Schering Ag, 13353 Berlin 5- OR 6-RING MACROCYCLIC POLYAZA COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM
WO1990001295A1 (en) * 1988-08-04 1990-02-22 Advanced Magnetics, Incorporated Receptor mediated endocytosis type mri contrast agents
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
FR2654344B1 (en) * 1989-11-16 1994-09-23 Cis Bio Int GADOLINIUM PARAMAGNETIC COMPLEX, ITS PREPARATION METHOD AND ITS USE FOR MRI DIAGNOSIS.
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
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
ATE140869T1 (en) * 1989-11-27 1996-08-15 Concat Ltd QUALITY IMPROVEMENT OF MR IMAGES OF BONE AND SIMILAR TISSUE USING PARAMAGNETIC CATION COMPLEXES AND POLYPHOSPHONATE LIGANDS
CH679742A5 (en) * 1990-01-09 1992-04-15 Byk Gulden Lomberg Chem Fab
EP0511275A1 (en) * 1990-01-19 1992-11-04 Nycomed Imaging As 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.
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
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
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
AU1770299A (en) * 1997-12-23 1999-07-19 Nycomed Imaging 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
ATE199557T1 (en) * 1999-09-09 2001-03-15 Schering Ag CALCIUM COMPLEX OF (4R)-4-BIS(CARBOXY- KAPPA.O)METHYL AMINO-.KAPPA.N-6,9-BIS (CARBOXY-
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
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
EP2277910A1 (en) 2001-12-21 2011-01-26 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
CN101090739B (en) 2004-07-02 2012-10-10 伯拉考成像股份公司 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)amino]-6-methyl-perhydro-1,4-diazepine (aazta) derivatives as ligands in high relaxivity contrast agents for use in magnetic resonance imaging (mri)
WO2006124726A2 (en) 2005-05-12 2006-11-23 The General Hospital Corporation Novel 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
AU2008341050B2 (en) 2007-12-26 2013-10-24 Vaccinex, Inc. Anti-C35 antibody combination therapies and methods
US8722020B2 (en) * 2010-03-31 2014-05-13 General Electric Company Hydroxylated contrast enhancement agents
CA2883130A1 (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
CN110114093A (en) 2016-12-29 2019-08-09 创意有限责任公司 Solvent-free gadolinium contrast agent
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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0210043A2 (en) * 1985-07-19 1987-01-28 Guerbet S.A. Contrast agent for NMR scanning
AU6753987A (en) * 1986-01-30 1987-08-06 Bracco International B.V. Paramagnetic chelates

Family Cites Families (19)

* 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
NZ188912A (en) * 1977-12-01 1984-05-31 Ici Australia Ltd Prevention or treatment of copper deficiency by topical application of copper
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
US4647447A (en) * 1981-07-24 1987-03-03 Schering Aktiengesellschaft Diagnostic media
DE3129906C3 (en) * 1981-07-24 1996-12-19 Schering Ag Paramagnetic complex salts, their preparation and agents for use in NMR diagnostics
DE3518267A1 (en) * 1985-05-17 1986-11-20 Martin Prof. Dr. 1000 Berlin Wenzel Compositions for increasing contrast in magnetic resonance imaging

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0210043A2 (en) * 1985-07-19 1987-01-28 Guerbet S.A. Contrast agent for NMR scanning
AU6753987A (en) * 1986-01-30 1987-08-06 Bracco International B.V. Paramagnetic chelates

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU658566B2 (en) * 1986-03-21 1995-04-27 Hybritech Incorporated Improvements in or relating to methods for providing internal references for use in analyte-receptor assays

Also Published As

Publication number Publication date
JPS5829718A (en) 1983-02-22
NL930072I1 (en) 1993-09-01
EP0169299A2 (en) 1986-01-29
JPH0768193B2 (en) 1995-07-26
EP0169299B1 (en) 1990-04-25
DE3129906A1 (en) 1983-02-10
DE3129906C3 (en) 1996-12-19
JPH0339045B2 (en) 1991-06-12
ATE52247T1 (en) 1990-05-15
NO1994031I1 (en) 1994-12-30
AU8633082A (en) 1983-01-27
DE3280157D1 (en) 1990-05-31
NL930072I2 (en) 1994-01-17
EP0071564B1 (en) 1986-03-26
AU566007B2 (en) 1987-10-08
IE53639B1 (en) 1989-01-04
JPS62123159A (en) 1987-06-04
ATE18719T1 (en) 1986-04-15
EP0071564A1 (en) 1983-02-09
NO822546L (en) 1983-01-25
ZA825313B (en) 1983-05-25
AU1018688A (en) 1988-04-28
JPH03209389A (en) 1991-09-12
DE3270097D1 (en) 1986-04-30
NO164458C (en) 1992-11-23
IE821766L (en) 1983-01-24
EP0169299A3 (en) 1986-12-03
CA1218597A (en) 1987-03-03
NZ201372A (en) 1986-08-08
LU88291I2 (en) 1994-05-04
NO164458B (en) 1990-07-02
CA1240679A (en) 1988-08-16
JP2548436B2 (en) 1996-10-30
DE3129906C2 (en) 1990-05-17

Similar Documents

Publication Publication Date Title
AU601916B2 (en) Paramagnetic complex salts, their preparation and their use in nmr-diagnostics
AT397465B (en) DIAGNOSTIC MEANS
EP0436579B1 (en) Chelate compositions
NO180582B (en) Diethylenetriamine acetic acid monoamides (DTPA monoamides), complexes and complex salts thereof, and use of the compounds for the preparation of agents for NMR, X-ray or radio diagnostics
DE69314613T2 (en) NEW CHELATION AGENT, COMPLEX COMPOUNDS CONSTRUCTED FROM THIS AGENT AND METAL ATOMS, AND DIAGNOSTIC AGENTS CONTAINING THESE COMPOUNDS
JP3683584B2 (en) Dendritic polymer metal complexes, diagnostic agents containing the same, and methods for producing these complexes and diagnostic agents
DE69417754T2 (en) CHELATE AS A CONTRAST-IMPROVING AGENT
EP0594734B1 (en) Hydroxamate and hydrazide derivatives of polyamines and their medical use as chelating agents
US5811077A (en) Method of NMR imaging
JPH04225925A (en) Shaping agent for metal chelate contrast medium
IE904319A1 (en) 10-(2&#39;-Hydroxy-3&#39;POLYOXAALKYL)-1,4,7-TRISCARBOXYMETHYL-¹1,4,7,10-TETRAAZACYCLODODECANE
US5208375A (en) Compositions for magnetic resonance imaging
JPH06502858A (en) Complexes and compositions for magnetic resonance imaging and their use
US5858329A (en) MRI diagnostic procedures using tripodal pyridinyl metal complexes
JPH0692871A (en) Contrast medium for nmr image and chela- tion agent comprising peptide structure
EP0524239B1 (en) Insoluble salts of lanthanides for the visual display, using nuclear magnetic resonance, of the gastro-intestinal tract
US5824288A (en) Thio-substituted pyridines as MRI ligand precursors
US5820851A (en) Tripodal pyridine ligands as MRI contrast agents
WO2022129508A1 (en) Organometallic compounds and their use as multimodal contrast media for diagnostic imaging

Legal Events

Date Code Title Description
NDB Extension of term for standard patent granted (sect.76)