CA1240679A - Paramagnetic complex salts, their preparation, and their use in nmr-diagnostics - Google Patents
Paramagnetic complex salts, their preparation, and their use in nmr-diagnosticsInfo
- Publication number
- CA1240679A CA1240679A CA000487858A CA487858A CA1240679A CA 1240679 A CA1240679 A CA 1240679A CA 000487858 A CA000487858 A CA 000487858A CA 487858 A CA487858 A CA 487858A CA 1240679 A CA1240679 A CA 1240679A
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- CA
- Canada
- Prior art keywords
- complex
- acid
- ethylene
- iii
- salt
- 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
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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 System
- 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, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, 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
Abstract
ABSTRACT OF THE DISCLOSURE
Paramagnetic, physiologically compatible paramag-netic complex salts from aminopolycarboxylic acids having the formulae I to IV
(I) N-hydroxy-ethyl-N,N',N'-ethylene-diamine triacetic (HEDTA), (II) N,N,N',N",N"-diethylene-tirami.ne pentaace-tic (DTPA), HOH2C-CH2N(CH2COOH)Z (III) N-hydroxy-ethyl-imino diacetic acid, (IV) wherein m represents the numbers 1 to 4, n repesents the numbers 0 to 2, R' represents a saturated or unsaturated hydrocarbon radical containing 4 to 12 hydrocarbon atoms or the group -CH2-COOH, or diphosphonic acids having the general formula V
Paramagnetic, physiologically compatible paramag-netic complex salts from aminopolycarboxylic acids having the formulae I to IV
(I) N-hydroxy-ethyl-N,N',N'-ethylene-diamine triacetic (HEDTA), (II) N,N,N',N",N"-diethylene-tirami.ne pentaace-tic (DTPA), HOH2C-CH2N(CH2COOH)Z (III) N-hydroxy-ethyl-imino diacetic acid, (IV) wherein m represents the numbers 1 to 4, n repesents the numbers 0 to 2, R' represents a saturated or unsaturated hydrocarbon radical containing 4 to 12 hydrocarbon atoms or the group -CH2-COOH, or diphosphonic acids having the general formula V
Description
- lZ4~67Cl The present invention provides a paramagnetic com-plex salts for influenclng the relaxation times in NMR-dlagnostics.
According to the present invention there is pro-vided physiologically compatible paramagnetic complex salts from aminopolycarboxylic acids having the formulae I to IV
HOOCC~
According to the present invention there is pro-vided physiologically compatible paramagnetic complex salts from aminopolycarboxylic acids having the formulae I to IV
HOOCC~
2~ CR CoO~
~ N- ( C ~ 2 ) 2 - ,~ ~ 2 ~ I ) N-hydroxy-ethyl-N,N',N'-ethylene-diamine triacetic acid (HEDTA), HC~oCH2C CH2cooH ~ CH2C~H
U~ ; C~ (Cr~ 2)2 ~ (CH2) 2 ~\C- C;!O~
N,N,N'N",N"-diethylene-triamine pentaacetic acid (DTPA), HOH2C-CH2N(CH COOH) (III) 25 N-hydroxy-ethyl-imino diacetic acid, H~G ~ / N-(C~2)--(CHz-.N-CH ) -(CH ) ~ 2 ( IV ), 30 wherein m represents the numbers l -to 4, n represents the numbers 0 to 2, Rl represents a saturated or unsaturated hydrocarbon radical containing 4 to 12 hydrocarbon atoms or the group ~-CH2-COOH, or diphosphonic acids having the general formu]a V
R~ C- -R3 (V) wherein R2 represents hydrogen, alkyl containing 1 to 4 car-bon atoms, halogen, the hydroxy, amino or CH2~COOH group and R3 represents hydrogen, alkyl containing l to 4 carbon atoms, the -CH2-COOII group or also halogen when R2 represents halo-gen, and from the ions of the lanthamide elements having the atomic numbers 57 to 70 or from the ions of the transi-tion metals having the atomis numbers 21 -to 29, 42 and 44 and from an organic base, glucamine, N-me-thyl glucamine, N,N-dimethyl glucamine, ethanol amine, diethanol amine, morpho-line, lysine, ornnithine and arginine being suitable as the organic base.
The aminopolycarboxylic acids are those compounds of this class of substances which can form chelate complexes, for example:
formula N-hydroxyethyl-N,N',N'-ethylenediamine-triacetic acid (HEDTA) (I) N,N,N',N",N"-deithylemetriamine-penta-acetic acid (DTPA), and (II) N-hydroxye-thylimino-diacetic acid (III) DPTA is preferred.
Also suitable for complex formation are the amino-polycarboxylic acids of the general formula ~45~i79 N-(CH2)m-(CH2-N-cH2)n (CH2)m (IV) HOOCCH2 \ CH2COOH
wherein m represents the integers 1 to 4, n represents the integers O to 2, and R5 represents a saturated or unsaturated hydrocarbon radical having from 4 to 12 carbon atoms or the group -CH2-COOH. Preferred is N,N,N',N'-ethylenediamine-tetra-acetic acid (EDTA).
There are also suitable phosphonic acids of the general formula R2 C R3 (V) wherein R2 represents hydrogen, alkyl containing 1 to 4 car-bon atoms, halogen, the hydroxy, amino or CH2-COOH group and R3 represents hydrogen, alkyl containing 1 to 4 carbon atoms, the -CH2-COOH group or also halogen when R2 represents halogen. There may be mentioned, more especially, ethane-l-hydroxy-l,l-diphosphonic acid, methane-diphosphonic acid and ethane-l-amino~ diposphonic acid.
If desired, it is also possible to bind the physiologically tolerable complex salts of the invention to -~24~679 bio-molecules in order in this way ~o ena~le ~lle co~ lex salts to be conveyèd 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, pep-tides, amino-sugars and lipids.
The coupling of the paramagnetic complex salts to the desired bio-molecules may be effected by means of me-thods which are known per se, for example by reac-ting the nucleo-philic group of a bio-molecule such as the amino, phenol, mercapto or imidazole group with an activated derivative of the complex comound.
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 deriva-tive of the bio-molecule with a nucleophilic derivative of the complex compound.
As organic bases, there may be used, for example, primary, secondary or tertiary amines, especially glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, diethanol-amine, morpholine, etc., N-methylglucamine being preferred.
Basic amino-acids are also suitable for salt formation, for example lysine, ornithine, arginine.
A
1;~4~679 Preparations of the complex salts of the invention may be made up in a manner known ~ se by dissolving the paramag-netic complex salt in water or physiological salt solution, if desired with the addition of one or more additives usual in -galencies, such as, for example, physiolgically compatible buffersolutions (for example sodium dihydrogen phosphate solution), and sterilizing the solution. The aqueous solutions can be adminis-tered orally, neurally and especially intravascularly. If sus-pensions of the paramagnetic complex salts in water or physiolo-gical salt solution .
. ~ 4a -~s lZ4U679 are desired, especially for oral aclministration, the para-megnetic complex salt is mixed with one or more auxiliaries usual in galenics and/or surfactants and/or aromatic sub-stances for taste correction and suspended in water or phy-sio]ogical salt solution before oral administration. Inth1s case, preferably from 3 -to 10 g of paramagnetic complex salt and from 2 to 8 g of one or more auxiliaries, such as, for example, saccharose, highly disperse silica, polyoxy-ethylenepolyoxypropylene polymers, starch, magnesium stear-ate, sodium lauryl sulphate, talcum, lactose, sodium carboxy-methylcellu]ose are ~sed.
~ -or NMR-diagnosis in humans, the preparations are ~ itable in tile fo~m of aqueous solutions or suspensions which contain 5 to 250 mmols/litre, preferably 50 to 200 mmols/litre, of the paramagnetic compLex salt. The pllof the aqueous solutions may range between 6.5 ar~ .0, preferably between 6.5 and 7.5. As a resu]t of the fo~ma-tion of the complex salt according to the present invention the pararragnetic 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 parti-cularly suitable for greater definition or localisation of leslons of the pancreas and liver, and also of tumours and haemorrhages in the cranial area. For diagnosis of the area under examination an aqueous 1 ~41~679 solution of the paramagnetic complex salt which is isotonic with blood is, for example, administered intravenously at a dosage of from 1 to 100 ~mols/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 approxi-mately 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 dis-advantages, 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 haue these disadvantages but which provide comparable 129~6'~9 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. ~or example, tumour tissue displays longer relaxation times than healthy tissue. (A. Ganssen and others, Computertomographie 1, [19~1] pp 2-10, Georg Thieme Verlag, Stuttgart, New York).
It has now been found that paramagnetic ions, ;/79 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 ~hich 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 T2 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 o,15 Tesla, an input energy of 300 watt/pulse and a 180-pulse of 720 ~s with exposure times of 2 minutes in each case made 10 minutes after intravenous injection of 20 ~mols/kg of manganese edetate as an aqueous methylglucamine salt solution having a concentration of 6 mmols/litre, a noticeably lZgL~67~
g 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 LD50 of 4 mmols/kg was found. In contrast, manganese chloride showed an LD50 of only 0.5 mmol/kg when used on rats under identical conditions.
The performance of an NMR-diagnostic investiga-tion using a preparation of th~ invention is explained in greater detail by means of the following example:
A sterile aqueous solution of the N-methylgluc-amine salt of the gadolinium-III-complex of diethylene-triamine-penta-acetic acid having a concentration of o,1 mol/litr5e 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 o.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 lZ44~79 to be imaged with sufficient resolution. The investi-gations 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 ~ithin one minute at a dosage of 1 mmol/kg. In Figures
~ N- ( C ~ 2 ) 2 - ,~ ~ 2 ~ I ) N-hydroxy-ethyl-N,N',N'-ethylene-diamine triacetic acid (HEDTA), HC~oCH2C CH2cooH ~ CH2C~H
U~ ; C~ (Cr~ 2)2 ~ (CH2) 2 ~\C- C;!O~
N,N,N'N",N"-diethylene-triamine pentaacetic acid (DTPA), HOH2C-CH2N(CH COOH) (III) 25 N-hydroxy-ethyl-imino diacetic acid, H~G ~ / N-(C~2)--(CHz-.N-CH ) -(CH ) ~ 2 ( IV ), 30 wherein m represents the numbers l -to 4, n represents the numbers 0 to 2, Rl represents a saturated or unsaturated hydrocarbon radical containing 4 to 12 hydrocarbon atoms or the group ~-CH2-COOH, or diphosphonic acids having the general formu]a V
R~ C- -R3 (V) wherein R2 represents hydrogen, alkyl containing 1 to 4 car-bon atoms, halogen, the hydroxy, amino or CH2~COOH group and R3 represents hydrogen, alkyl containing l to 4 carbon atoms, the -CH2-COOII group or also halogen when R2 represents halo-gen, and from the ions of the lanthamide elements having the atomic numbers 57 to 70 or from the ions of the transi-tion metals having the atomis numbers 21 -to 29, 42 and 44 and from an organic base, glucamine, N-me-thyl glucamine, N,N-dimethyl glucamine, ethanol amine, diethanol amine, morpho-line, lysine, ornnithine and arginine being suitable as the organic base.
The aminopolycarboxylic acids are those compounds of this class of substances which can form chelate complexes, for example:
formula N-hydroxyethyl-N,N',N'-ethylenediamine-triacetic acid (HEDTA) (I) N,N,N',N",N"-deithylemetriamine-penta-acetic acid (DTPA), and (II) N-hydroxye-thylimino-diacetic acid (III) DPTA is preferred.
Also suitable for complex formation are the amino-polycarboxylic acids of the general formula ~45~i79 N-(CH2)m-(CH2-N-cH2)n (CH2)m (IV) HOOCCH2 \ CH2COOH
wherein m represents the integers 1 to 4, n represents the integers O to 2, and R5 represents a saturated or unsaturated hydrocarbon radical having from 4 to 12 carbon atoms or the group -CH2-COOH. Preferred is N,N,N',N'-ethylenediamine-tetra-acetic acid (EDTA).
There are also suitable phosphonic acids of the general formula R2 C R3 (V) wherein R2 represents hydrogen, alkyl containing 1 to 4 car-bon atoms, halogen, the hydroxy, amino or CH2-COOH group and R3 represents hydrogen, alkyl containing 1 to 4 carbon atoms, the -CH2-COOH group or also halogen when R2 represents halogen. There may be mentioned, more especially, ethane-l-hydroxy-l,l-diphosphonic acid, methane-diphosphonic acid and ethane-l-amino~ diposphonic acid.
If desired, it is also possible to bind the physiologically tolerable complex salts of the invention to -~24~679 bio-molecules in order in this way ~o ena~le ~lle co~ lex salts to be conveyèd 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, pep-tides, amino-sugars and lipids.
The coupling of the paramagnetic complex salts to the desired bio-molecules may be effected by means of me-thods which are known per se, for example by reac-ting the nucleo-philic group of a bio-molecule such as the amino, phenol, mercapto or imidazole group with an activated derivative of the complex comound.
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 deriva-tive of the bio-molecule with a nucleophilic derivative of the complex compound.
As organic bases, there may be used, for example, primary, secondary or tertiary amines, especially glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, diethanol-amine, morpholine, etc., N-methylglucamine being preferred.
Basic amino-acids are also suitable for salt formation, for example lysine, ornithine, arginine.
A
1;~4~679 Preparations of the complex salts of the invention may be made up in a manner known ~ se by dissolving the paramag-netic complex salt in water or physiological salt solution, if desired with the addition of one or more additives usual in -galencies, such as, for example, physiolgically compatible buffersolutions (for example sodium dihydrogen phosphate solution), and sterilizing the solution. The aqueous solutions can be adminis-tered orally, neurally and especially intravascularly. If sus-pensions of the paramagnetic complex salts in water or physiolo-gical salt solution .
. ~ 4a -~s lZ4U679 are desired, especially for oral aclministration, the para-megnetic complex salt is mixed with one or more auxiliaries usual in galenics and/or surfactants and/or aromatic sub-stances for taste correction and suspended in water or phy-sio]ogical salt solution before oral administration. Inth1s case, preferably from 3 -to 10 g of paramagnetic complex salt and from 2 to 8 g of one or more auxiliaries, such as, for example, saccharose, highly disperse silica, polyoxy-ethylenepolyoxypropylene polymers, starch, magnesium stear-ate, sodium lauryl sulphate, talcum, lactose, sodium carboxy-methylcellu]ose are ~sed.
~ -or NMR-diagnosis in humans, the preparations are ~ itable in tile fo~m of aqueous solutions or suspensions which contain 5 to 250 mmols/litre, preferably 50 to 200 mmols/litre, of the paramagnetic compLex salt. The pllof the aqueous solutions may range between 6.5 ar~ .0, preferably between 6.5 and 7.5. As a resu]t of the fo~ma-tion of the complex salt according to the present invention the pararragnetic 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 parti-cularly suitable for greater definition or localisation of leslons of the pancreas and liver, and also of tumours and haemorrhages in the cranial area. For diagnosis of the area under examination an aqueous 1 ~41~679 solution of the paramagnetic complex salt which is isotonic with blood is, for example, administered intravenously at a dosage of from 1 to 100 ~mols/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 approxi-mately 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 dis-advantages, 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 haue these disadvantages but which provide comparable 129~6'~9 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. ~or example, tumour tissue displays longer relaxation times than healthy tissue. (A. Ganssen and others, Computertomographie 1, [19~1] pp 2-10, Georg Thieme Verlag, Stuttgart, New York).
It has now been found that paramagnetic ions, ;/79 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 ~hich 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 T2 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 o,15 Tesla, an input energy of 300 watt/pulse and a 180-pulse of 720 ~s with exposure times of 2 minutes in each case made 10 minutes after intravenous injection of 20 ~mols/kg of manganese edetate as an aqueous methylglucamine salt solution having a concentration of 6 mmols/litre, a noticeably lZgL~67~
g 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 LD50 of 4 mmols/kg was found. In contrast, manganese chloride showed an LD50 of only 0.5 mmol/kg when used on rats under identical conditions.
The performance of an NMR-diagnostic investiga-tion using a preparation of th~ invention is explained in greater detail by means of the following example:
A sterile aqueous solution of the N-methylgluc-amine salt of the gadolinium-III-complex of diethylene-triamine-penta-acetic acid having a concentration of o,1 mol/litr5e 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 o.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 lZ44~79 to be imaged with sufficient resolution. The investi-gations 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 ~ithin 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 patholog-ical fluid accumulations and there produced a marXed reduction of the spin-lattice-relaxation time (T1), which 6~9 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 diethylenetriamine-penta-acetic acid having a concentration of 1 mmol/litre was administered by means of a probe to an anaesthetised male rat (body weight: 250 g). Only after administration 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.
~2~679 After oral administration no reabsorption of the substance is observed. The pharmaco-kinetic behavoiur is similar to that of the classic X-ray contrast agents for uro-angiography.
s The paramagnetic complex salts may be prepared according to processes known per se to the man skilled in the art or described in the li-terature, 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 amino polycarboxylic acid capable of forming a complex in wa-ter and/or alcohol and stirring, if necessary while heating at from 50C to 120C until the reaction is complete. If alcohol is employed as the solvent, me-thanol or ethanol is used. If the complex salt formed is insoluble in the solvent used, it craystallises and can be filtered off. It if is soluble in the solvent used, it can be iso-lated 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:
~ ~'U67~
Preparation of the manganese(II) complex of ethylene-diaminetetraacetic acid:
14.6 g of ethylenediaminetetraacetic acid are added to a suspension of 6.17 g of manganese(II) carbonate in 500 ml of water and the whole is heated on a vapour bath while stirring, gas being evolved. The initially pink colour disappears after approximately 20 minutes and the whole mixture goes into solution except for a small residue. After stirring for one hour at 110C
the undissolved portion is filtered off and the filtrate is cooled. After standing for 15 hours the crystallisate is filtered off with suction and dried:
Yield = 14.1 g (molecular weight 345~17) M.p. : 256 /258 259 C
Preparation of the gadolinium(III~ complex of diethylene-triaminepentaacetic acid:
A suspension of 435 g of gadolinium oxide (Gd203) and 944 g of5 diethylenetriaminepentaacetic acid in 12 litres of water is heated while stirring to from 90C to 100C and stirred at this temperature for 4 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 320C.
~Z4~679 With an excess of one or more acidic group(s) in the resulting paramagnetic complex compound, the resuiting complex compound is then dissolved or suspended in water tnd the desired organic baseis added thereto until the neutral point is reached. After filtering off the undissolved con-stituents, the solution is concentrated by evaporation and the desired complex salt is obtained as -the residue.
The following complex salts may be mentioned more especially The di-N-methylglucarnine 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.
3n 1~4~
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.
The di-diethanolamine salt of the copper(II)-complex of ethylenediamine-tetra-acetic acid.
The tri-diethanolamine salt of the manganese(II)-complex of diethylenetriamine-penta-acetic acid.
The tri-N-methylglucamine salt of the manganese(II)-complex of diethylenetriamine-penta-acetic acid.
The N-methylglucamine salt of the gadolinium(III)-complex of ethylenediamine-tetra-acetic acid.
The N-methylglucamine salt of the dysprosium(III)-complex of ethylenediamine-tetra-acetic acid.
The di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriamine-penta-acetic acid.
The N-methylglucamine salt of the iron(II)-complex of ethane-1-hydroxy-1,1,-diphosphonic acid.
The N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid.
The di-lysine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid.
lZ4~7~
- ~6 -The followin~ Examples illustrate the invention:-Example 1 Preparation of the di-N-methylglucamine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic acid, C24H48N418 _ 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 y ( = approx. 40 mmols~ of N-methyl-glucamine are dissolved at a pH of 7.5. After filteringoff 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 95C and becoming viscous at 170oc.
Analysiso calculated C 39,19% ~ 6.58% N 7.61% Mn 7.47% -Found in the dry substance C 39.23% H 7~1~/o N 7.26% Mn 7.~3%
H20 3.26%
Equivalent weight: calculated 367.8, found 369 (titra-tion with tetramethylammonium hydroxide in aqueous acetone).
By dissolving in hot ethanol and evaporating to dryness under vacuum the substance is obtained as a white, hydroscopic powder.
The following compounds are obtained in an analogous manner:
- 17 _ ~2~67,~
The di-N-methylglucamine salt of the nickel(II)-complex of ethylenediamine-tetra-acetic acid, C24H48N4018Ni, as a blue powder.
The di-ethanolamine salt of the cobalt(II)-complex of ethylenediamine-tetra-acetic acid, C14H28N4O10Co, as a pink-coloured powder.
The di-morpholine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic acid, C1~H32N4O1OMn, as a white powder.
The di-diethanolamine salt of the copper(II)-complex of ethylenediamine-tetra-acetic acid, C18H36N4O12Cu, as a blue powder.
The tri-diethanolamine salt of the manganese(II)-complex of diethylenetriamine-penta-acetic acid, C26H54N6O16Mn, as a yellow powder.
The tri-N-methylglucamine salt of the manganese(II)-complex of diethylenetriamine-penta-acetic acid, C35H72N6o25Mn~ as a white powder, Example 2 Preparation of the N-methylglucamine salt of the gadolin-ium(III)-complex of ethylenediamine-tetra-acetic acid (C17H30N3o13Gd)~
- 18 ~ 79
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 diethylenetriamine-penta-acetic acid having a concentration of 1 mmol/litre was administered by means of a probe to an anaesthetised male rat (body weight: 250 g). Only after administration 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.
~2~679 After oral administration no reabsorption of the substance is observed. The pharmaco-kinetic behavoiur is similar to that of the classic X-ray contrast agents for uro-angiography.
s The paramagnetic complex salts may be prepared according to processes known per se to the man skilled in the art or described in the li-terature, 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 amino polycarboxylic acid capable of forming a complex in wa-ter and/or alcohol and stirring, if necessary while heating at from 50C to 120C until the reaction is complete. If alcohol is employed as the solvent, me-thanol or ethanol is used. If the complex salt formed is insoluble in the solvent used, it craystallises and can be filtered off. It if is soluble in the solvent used, it can be iso-lated 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:
~ ~'U67~
Preparation of the manganese(II) complex of ethylene-diaminetetraacetic acid:
14.6 g of ethylenediaminetetraacetic acid are added to a suspension of 6.17 g of manganese(II) carbonate in 500 ml of water and the whole is heated on a vapour bath while stirring, gas being evolved. The initially pink colour disappears after approximately 20 minutes and the whole mixture goes into solution except for a small residue. After stirring for one hour at 110C
the undissolved portion is filtered off and the filtrate is cooled. After standing for 15 hours the crystallisate is filtered off with suction and dried:
Yield = 14.1 g (molecular weight 345~17) M.p. : 256 /258 259 C
Preparation of the gadolinium(III~ complex of diethylene-triaminepentaacetic acid:
A suspension of 435 g of gadolinium oxide (Gd203) and 944 g of5 diethylenetriaminepentaacetic acid in 12 litres of water is heated while stirring to from 90C to 100C and stirred at this temperature for 4 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 320C.
~Z4~679 With an excess of one or more acidic group(s) in the resulting paramagnetic complex compound, the resuiting complex compound is then dissolved or suspended in water tnd the desired organic baseis added thereto until the neutral point is reached. After filtering off the undissolved con-stituents, the solution is concentrated by evaporation and the desired complex salt is obtained as -the residue.
The following complex salts may be mentioned more especially The di-N-methylglucarnine 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.
3n 1~4~
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.
The di-diethanolamine salt of the copper(II)-complex of ethylenediamine-tetra-acetic acid.
The tri-diethanolamine salt of the manganese(II)-complex of diethylenetriamine-penta-acetic acid.
The tri-N-methylglucamine salt of the manganese(II)-complex of diethylenetriamine-penta-acetic acid.
The N-methylglucamine salt of the gadolinium(III)-complex of ethylenediamine-tetra-acetic acid.
The N-methylglucamine salt of the dysprosium(III)-complex of ethylenediamine-tetra-acetic acid.
The di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriamine-penta-acetic acid.
The N-methylglucamine salt of the iron(II)-complex of ethane-1-hydroxy-1,1,-diphosphonic acid.
The N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid.
The di-lysine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid.
lZ4~7~
- ~6 -The followin~ Examples illustrate the invention:-Example 1 Preparation of the di-N-methylglucamine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic acid, C24H48N418 _ 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 y ( = approx. 40 mmols~ of N-methyl-glucamine are dissolved at a pH of 7.5. After filteringoff 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 95C and becoming viscous at 170oc.
Analysiso calculated C 39,19% ~ 6.58% N 7.61% Mn 7.47% -Found in the dry substance C 39.23% H 7~1~/o N 7.26% Mn 7.~3%
H20 3.26%
Equivalent weight: calculated 367.8, found 369 (titra-tion with tetramethylammonium hydroxide in aqueous acetone).
By dissolving in hot ethanol and evaporating to dryness under vacuum the substance is obtained as a white, hydroscopic powder.
The following compounds are obtained in an analogous manner:
- 17 _ ~2~67,~
The di-N-methylglucamine salt of the nickel(II)-complex of ethylenediamine-tetra-acetic acid, C24H48N4018Ni, as a blue powder.
The di-ethanolamine salt of the cobalt(II)-complex of ethylenediamine-tetra-acetic acid, C14H28N4O10Co, as a pink-coloured powder.
The di-morpholine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic acid, C1~H32N4O1OMn, as a white powder.
The di-diethanolamine salt of the copper(II)-complex of ethylenediamine-tetra-acetic acid, C18H36N4O12Cu, as a blue powder.
The tri-diethanolamine salt of the manganese(II)-complex of diethylenetriamine-penta-acetic acid, C26H54N6O16Mn, as a yellow powder.
The tri-N-methylglucamine salt of the manganese(II)-complex of diethylenetriamine-penta-acetic acid, C35H72N6o25Mn~ as a white powder, Example 2 Preparation of the N-methylglucamine salt of the gadolin-ium(III)-complex of ethylenediamine-tetra-acetic acid (C17H30N3o13Gd)~
- 18 ~ 79
4.58 g (= 10 mmols) of the gadolinium(III)-complex of ethylenediamine-tetra-acetic acid (water content: 2.7%) are suspended in 15 ml of water and by the addition of 1.95 g (= 10 mmols) of N-methylglucamine are dissolved in a pH of 7.4. The solution is filtered ' and then evaporated to dryness under vacuum, whereupon a solid foam is produced. The yield, taking into account the water content of 8.5%, is ~ractically quantitative.
The substance starts to sinter at 90C, and foam begins to develop at 140C.
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, C17H30N3013Dy.
The di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriamine-penta-acetic acid, C28H54N502oHo.
The di-ly9ine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid, C26H48N7014Gd.
T~e N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid, C28H54N5020Gd.
12~67~
Example 3 Preparation of a solution of the di-N-methylglucamine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic acid 3.68 g (= 5 mmols) of the substance described in Example 1 are dissolved in 70 ml of water pro injectione (p.i.) and 0.4 g of sodium chloride are added to the solution. The solution is then made up to 100 ml with water p.i. and the solution is introduced into ampoules through a sterile filter. The solution is isotonic with blood at 280 mOsm.
Example 4 Preparation of a solution of the N-methylglucamine salt of the gadolinium(III)-complex of ethylenediamine-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.
Example 5 Preparation of a solution of the di-N-methylglucamine salt of the gadolinium(III)-complex of diethylene-triamine-penta-acetic acid - 20 - 1~67~
The substance starts to sinter at 90C, and foam begins to develop at 140C.
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, C17H30N3013Dy.
The di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriamine-penta-acetic acid, C28H54N502oHo.
The di-ly9ine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid, C26H48N7014Gd.
T~e N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid, C28H54N5020Gd.
12~67~
Example 3 Preparation of a solution of the di-N-methylglucamine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic acid 3.68 g (= 5 mmols) of the substance described in Example 1 are dissolved in 70 ml of water pro injectione (p.i.) and 0.4 g of sodium chloride are added to the solution. The solution is then made up to 100 ml with water p.i. and the solution is introduced into ampoules through a sterile filter. The solution is isotonic with blood at 280 mOsm.
Example 4 Preparation of a solution of the N-methylglucamine salt of the gadolinium(III)-complex of ethylenediamine-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.
Example 5 Preparation of a solution of the di-N-methylglucamine salt of the gadolinium(III)-complex of diethylene-triamine-penta-acetic acid - 20 - 1~67~
5.35 g t= 9 mmols) of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid (water content 8%) are dissolved in 50 ml of water i. and neutralised to pH 7.5 by the addition of approximately 3.2 g (corresponding to approximately 18 mmols~ of N-methyl-glucamine. The solution is then made up to 100 ml with water p.i., introduced into ampoules and heat-sterilised. The concentration of the solution is made isotonic with blood (approximately 280 mOsm.).
Example 6 Preparation of a solution of the di-N-methylglucamine salt of the dysprosium(III)-complex of diethylenetriamine-penta-acetic acid -8.00 g (= 15 mmols) of the dysprosium(IIIj-complex of diethylenetriamine-penta-acetic acid are dissolved in 80 ml of water p 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 ~ ~.
The solution, which is approximately isotonic with blood, is introduced into ampoules and heat-sterilised.
12~ti7~
Example 7 Preparation of a solution of the di-N-methylglucamine salt of the holmium(III)-complex of diethylenetramine-penta-acetic acid 8.02 g (= 15 mmols) of the holmium(III)-complex of diethylenetramine-penta-acetic acid are dissolved in 80 ml of water p.i. at a pH of 7.2 with the addition of approxi-mately 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 soution, which is approximately isotonic with blood, is introduced into ampoules and heat-s-terilised.
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 N-methylglucamine salt of the iron(II)-complex of ethane-l-hydroxy-l,l-diphosphonic acid 1.27 g (=10 mmols) of iron(II) chloride are dis-solved in 8.8 ml of methanol and there are added to the solution 3.2 ml of a 60% by weight solution of ethane-l-hydroxy-l,l-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 wa-ter p.i. and dissolved at a pH of 7.5 by the addition of approximately 1.8 g (corres-ponding to approximately 10 mmols) of N-methylglucamine.
The solution is then made up to 100 ml with water p l. and introduced into ampoules after sterile fil-tration.
~4U~79 Example 9 Preparation of a solution of the N-methylglucamine salt of the gadolinium(III)-complex of bis-[2-(bis-carboxy-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 10 Preparation of a solution of the di-N-methylglucamine salt of the manganese(II)-complex of hexanediylimino-tetra-acetic acid In analogy with the method described in Example 6, a solution which is readyfor use is prepared from 6.02 g (~l5 mmols) of the manganese(II)-complex of hexanediyl-diamine-tetra-acetic acid and 5.86 g (~ 30 mmols) of N-methylglucamine.
Example 11 (Composition of a powder for the preparation of a suspension) 4.000 g gadolinium(III) complex of diethylenetriamine--pentaacetic acid (water con-tent 8%) 3.895 g saccharose 0.100 g polyoxye-thylenepolyoxypropylene polymer 0.005 g armoatic substances 8.000 g
Example 6 Preparation of a solution of the di-N-methylglucamine salt of the dysprosium(III)-complex of diethylenetriamine-penta-acetic acid -8.00 g (= 15 mmols) of the dysprosium(IIIj-complex of diethylenetriamine-penta-acetic acid are dissolved in 80 ml of water p 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 ~ ~.
The solution, which is approximately isotonic with blood, is introduced into ampoules and heat-sterilised.
12~ti7~
Example 7 Preparation of a solution of the di-N-methylglucamine salt of the holmium(III)-complex of diethylenetramine-penta-acetic acid 8.02 g (= 15 mmols) of the holmium(III)-complex of diethylenetramine-penta-acetic acid are dissolved in 80 ml of water p.i. at a pH of 7.2 with the addition of approxi-mately 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 soution, which is approximately isotonic with blood, is introduced into ampoules and heat-s-terilised.
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 N-methylglucamine salt of the iron(II)-complex of ethane-l-hydroxy-l,l-diphosphonic acid 1.27 g (=10 mmols) of iron(II) chloride are dis-solved in 8.8 ml of methanol and there are added to the solution 3.2 ml of a 60% by weight solution of ethane-l-hydroxy-l,l-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 wa-ter p.i. and dissolved at a pH of 7.5 by the addition of approximately 1.8 g (corres-ponding to approximately 10 mmols) of N-methylglucamine.
The solution is then made up to 100 ml with water p l. and introduced into ampoules after sterile fil-tration.
~4U~79 Example 9 Preparation of a solution of the N-methylglucamine salt of the gadolinium(III)-complex of bis-[2-(bis-carboxy-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 10 Preparation of a solution of the di-N-methylglucamine salt of the manganese(II)-complex of hexanediylimino-tetra-acetic acid In analogy with the method described in Example 6, a solution which is readyfor use is prepared from 6.02 g (~l5 mmols) of the manganese(II)-complex of hexanediyl-diamine-tetra-acetic acid and 5.86 g (~ 30 mmols) of N-methylglucamine.
Example 11 (Composition of a powder for the preparation of a suspension) 4.000 g gadolinium(III) complex of diethylenetriamine--pentaacetic acid (water con-tent 8%) 3.895 g saccharose 0.100 g polyoxye-thylenepolyoxypropylene polymer 0.005 g armoatic substances 8.000 g
Claims (18)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of physiologically compatible paramagnetic complex salts from aminopolycarboxylic acids having the formulae I to IV
(I) N-hydroxy-ethyl-N,N',N'-ethylene-diamine triacetic acid (HEDTA), (II) N,N,N',N",N"-diethylene-triamine pentaacetic acid (DTPA), HOH2C-CH2N(CH2COOH)2 (III) N-hydroxy-ethyl-imino diacetic acid, (IV), wherein m represents the numbers 1 to 4, n represents the numbers 0 to 2, R1 represents a saturated or unsaturated hydrocarbon rad-ical containing 4 to 12 hydrocarbon atoms or the group -CH2-COOH, or diphosphonic acids having the general formula V
(V) wherein R2 represents hydrogen, alkyl containing 1 to 4 carbon atoms, halogen, the hydroxy, amino or CH2-COOH group and R3 rep-resents hydrogen, alkyl containing 1 to 4 carbon atoms, the -CH2-COOH group or also halogen when R2 represents halogen, and from the ions of the lanthanide elements having the atomic num-bers 57 to 70 or from the ions of the transition metals having the atomic numbers 21 to 29, 42 and 44 and from an organic base, selected from glucamine, N-methyl glucamine, N,N-dimethyl glu-camine, ethanol amine, diethanol amine, morpholine, lysine, ornithine and arginine which comprises dissolving or suspending the paramagnetic complex compound in water and adding the organic base thereto until the neutral point is reached.
(I) N-hydroxy-ethyl-N,N',N'-ethylene-diamine triacetic acid (HEDTA), (II) N,N,N',N",N"-diethylene-triamine pentaacetic acid (DTPA), HOH2C-CH2N(CH2COOH)2 (III) N-hydroxy-ethyl-imino diacetic acid, (IV), wherein m represents the numbers 1 to 4, n represents the numbers 0 to 2, R1 represents a saturated or unsaturated hydrocarbon rad-ical containing 4 to 12 hydrocarbon atoms or the group -CH2-COOH, or diphosphonic acids having the general formula V
(V) wherein R2 represents hydrogen, alkyl containing 1 to 4 carbon atoms, halogen, the hydroxy, amino or CH2-COOH group and R3 rep-resents hydrogen, alkyl containing 1 to 4 carbon atoms, the -CH2-COOH group or also halogen when R2 represents halogen, and from the ions of the lanthanide elements having the atomic num-bers 57 to 70 or from the ions of the transition metals having the atomic numbers 21 to 29, 42 and 44 and from an organic base, selected from glucamine, N-methyl glucamine, N,N-dimethyl glu-camine, ethanol amine, diethanol amine, morpholine, lysine, ornithine and arginine which comprises dissolving or suspending the paramagnetic complex compound in water and adding the organic base thereto until the neutral point is reached.
2. A process according to claim 1, in which the aminopolycarboxylic acid of the paramagnetic complex compound is N,N,N',N'-ethylene-diamine tetraacetic acid (EDTA).
3. A process according to claim 1, in which the aminopolycarboxylic acid of the paramagnetic complex compound is N,N,N',N'',N''-diethylene-triamine pentaacetic acid (DTPA).
4. A process according to claim 1, in which the diphosphonic acid of the paramagnetic complex compound is ethane-1-hydroxy-1,1-diphosphonic acld, methane diphosphonic acid or ethane-1-amino-1,1-diphosphonic acid.
5. A process according to claim 1, in which N-methyl-glucamine is reacted in water with the manganese(II)-complex of ethylene-diamine tetraacetic acid, the nickel(II)-complex of ethylene-diamine tetraacetic acid, the manganese(II)-complex of diethylene-triamine pentaacetic acid, the gadolinium (III)-complex of ethylene-diamine tetraacetic acid, the dysprosium (III)-complex of ethylene-diamine tetraacetic acid, the hol-mium(III)-complex of diethylene-triamine pentaacetic acid or the iron(II)-complex of ethane-1-hydroxy-1,1-diphosphonic acid.
6. A process of claim 1, in which N-methyl-glucamine salt is reacted in water with the gadolinium(III)-complex of diethylene-triamine pentaacetic acid.
7. A process according to claim 1, in which diethanol-amine is reacted in water with the cobalt(II)-complex of ethy-lene-diamine tetraacetic acid, the copper(II)-complex of ethylene diamine tetraacetic acid or the manganese(II)-complex of diethyl-triamine pentaacetic acid.
8. A process according to claim 1, in which morpholine is reacted in water with the manganese(III)-complex of ethylene-diamine tetraacetic acid.
9. A process according to claim 1, in which iysine is reacted in water with the gadolinium(III)-complex of diethylene-triamine tetraacetic acid.
10. Physiologically compatible paramagnetic complex salts from aminopolycarboxylic acids having the formulae I to IV
(I) N-hydroxy-ethyl-N,N',N'-ethylene-diamine triacetic acid (HEDTA) (II) N,N,N',N",N"-diethylene-triamine pentaacetic acid (DTPA) HOH2C-CH2N(CH2COOH)2 (III) N-hydroxy-ethyl-imino-diacetic acid, (IV), wherein m represents the numbers 1 to 4, n represents the numbers 0 to 2, R1 represents a saturated or unsaturated hydrocarbon rad-ical containing 4 to 12 hydrocarbon atoms, or the group -CH2-COOH, or diphosphonic acids having the general formula V
(V) wherein R2 represents hydrogen, alkyl containing 1 to 4 carbon atoms, halogen, the hydroxy, amino or CH2-COOH group and R3 rep-resents hydrogen, alkyl containing 1 to 4 carbon atoms, the -CH2-COOH group or also halogen when R2 represents halogen, and from the ions of the lanthanide elements having the atomic num-bers 57 to 70 or from the ions of the transition metals having the atomic numbers 21 to 29, 42 and 44 and from an organic base, selected from glucamine, N-methyl glucamine, N,N-dimethyl glu-camine, ethanol amine, dlethanol amine, morpholine, iysine, ornithine and arginine.
(I) N-hydroxy-ethyl-N,N',N'-ethylene-diamine triacetic acid (HEDTA) (II) N,N,N',N",N"-diethylene-triamine pentaacetic acid (DTPA) HOH2C-CH2N(CH2COOH)2 (III) N-hydroxy-ethyl-imino-diacetic acid, (IV), wherein m represents the numbers 1 to 4, n represents the numbers 0 to 2, R1 represents a saturated or unsaturated hydrocarbon rad-ical containing 4 to 12 hydrocarbon atoms, or the group -CH2-COOH, or diphosphonic acids having the general formula V
(V) wherein R2 represents hydrogen, alkyl containing 1 to 4 carbon atoms, halogen, the hydroxy, amino or CH2-COOH group and R3 rep-resents hydrogen, alkyl containing 1 to 4 carbon atoms, the -CH2-COOH group or also halogen when R2 represents halogen, and from the ions of the lanthanide elements having the atomic num-bers 57 to 70 or from the ions of the transition metals having the atomic numbers 21 to 29, 42 and 44 and from an organic base, selected from glucamine, N-methyl glucamine, N,N-dimethyl glu-camine, ethanol amine, dlethanol amine, morpholine, iysine, ornithine and arginine.
11. Physiologically compatible paramagnetic complex salts according to claim 10, in which N,N,N',N'-ethylene-diamine tetraacetic acid (EDTA) is the aminopolycarboxylic acid.
12. Physiologically compatible paramagnetic salts ac-cording to claim 10, in which N,N,N',N",N"-diethylene-triamine pentaacetic acid (DTPA) is the aminopolycarboxylic acid.
13. Physiologically compatible paramagnetic complex salts according to claim 1, in which ethane-1-hydroxy-1,1-diphonic acid, methane diphosphonic acid or ethane-1-amino-1-diphosphonic acid is the diphosphonic acid.
14. Di-N-methyl-glucamine salt of the manganese(II)-complex of ethylene-diamine tetraacetic acid, di-N-methyl-glu-camine salt of the nickel(II)-complex of ethylene-diamine tetraacetic acid, tri-N-methyl-glutamine salt of the manganese (II)-complex of diethylene-triamine pentaacetic acid, N-methyl-glutamine salt of the gadolinium(III) -complex of ethylene-diamine tetraacetic acid, N-methyl-glucamine salt of the dysprosium(III)-complex of ethylene-diamine(III)-complex of diethylene-triamine pentaacetic acid and N-methyl-glucamine salt of the iron(II)-com-plex of ethylene-1-hydroxy-1,1-diphosphonic acid.
15. Di-N-methyl-glutamine salt of the gadolinium(III)-complex of diethylene-triamine pentaacetic acid.
16. Di-ethanol-amine salt of the cobalt(II)-complex of ethylene-diamine tetraacetic acid, di-diethanol-amine salt of the copper(II)-complex of ethylene-diamine tetraacetic acid or tri-diethanol-amine salt of the manganese(II)-complex of diethylene-triamine pentaacetic acid.
17. Di-morpholine salt of the manganese(II)-complex of ethylene diamine tetraacetic acid.
18. Di-lysine salt of the gadolinium(III)-complex of diethylene-triamine pentaacetic acid.
Priority Applications (1)
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|---|---|---|---|
| CA000487858A CA1240679A (en) | 1981-07-24 | 1985-07-31 | Paramagnetic complex salts, their preparation, and their use in nmr-diagnostics |
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| DEP3129906.7 | 1981-07-24 | ||
| DE3129906A DE3129906C3 (en) | 1981-07-24 | 1981-07-24 | Paramagnetic complex salts, their preparation and agents for use in NMR diagnostics |
| CA000407923A CA1218597A (en) | 1981-07-24 | 1982-07-23 | Paramagnetic complex salts, their preparation, and their use in nmr-diagnostics |
| CA000487858A CA1240679A (en) | 1981-07-24 | 1985-07-31 | Paramagnetic complex salts, their preparation, and their use in nmr-diagnostics |
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| CA000407923A Expired CA1218597A (en) | 1981-07-24 | 1982-07-23 | Paramagnetic complex salts, their preparation, and their use in nmr-diagnostics |
| CA000487858A Expired CA1240679A (en) | 1981-07-24 | 1985-07-31 | Paramagnetic complex salts, their preparation, and their use in nmr-diagnostics |
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|---|---|
| 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) |
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-
1981
- 1981-07-24 DE DE3129906A patent/DE3129906C3/en not_active Expired - Lifetime
-
1982
- 1982-07-19 DE DE8585102713T patent/DE3280157D1/en not_active Expired - Lifetime
- 1982-07-19 EP EP85102713A patent/EP0169299B1/en not_active Expired - Lifetime
- 1982-07-19 AT AT82730097T patent/ATE18719T1/en active
- 1982-07-19 DE DE8282730097T patent/DE3270097D1/en not_active Expired
- 1982-07-19 EP EP82730097A patent/EP0071564B1/en not_active Expired
- 1982-07-19 AT AT85102713T patent/ATE52247T1/en not_active IP Right Cessation
- 1982-07-22 AU AU86330/82A patent/AU566007B2/en not_active Expired
- 1982-07-23 ZA ZA825313A patent/ZA825313B/en unknown
- 1982-07-23 NZ NZ201372A patent/NZ201372A/en unknown
- 1982-07-23 NO NO822546A patent/NO164458C/en not_active IP Right Cessation
- 1982-07-23 JP JP57127810A patent/JPS5829718A/en active Granted
- 1982-07-23 CA CA000407923A patent/CA1218597A/en not_active Expired
- 1982-07-23 IE IE1766/82A patent/IE53639B1/en not_active IP Right Cessation
-
1985
- 1985-07-31 CA CA000487858A patent/CA1240679A/en not_active Expired
-
1986
- 1986-01-24 JP JP61012237A patent/JPH0768193B2/en not_active Expired - Lifetime
-
1988
- 1988-01-08 AU AU10186/88A patent/AU601916B2/en not_active Expired
-
1990
- 1990-08-15 JP JP2214464A patent/JP2548436B2/en not_active Expired - Lifetime
-
1993
- 1993-06-09 LU LU88291C patent/LU88291I2/en unknown
- 1993-06-14 NL NL930072C patent/NL930072I2/en unknown
-
1994
- 1994-12-30 NO NO1994031C patent/NO1994031I1/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250672A (en) * | 1985-09-11 | 1993-10-05 | Guerbet S.A. | Contrast agent for NMR imaging |
| CN106928078A (en) * | 2017-02-27 | 2017-07-07 | 南昌大学 | A kind of threonine chelated iron and its application |
Also Published As
| Publication number | Publication date |
|---|---|
| AU8633082A (en) | 1983-01-27 |
| NL930072I1 (en) | 1993-09-01 |
| IE53639B1 (en) | 1989-01-04 |
| NZ201372A (en) | 1986-08-08 |
| NO1994031I1 (en) | 1994-12-30 |
| AU1018688A (en) | 1988-04-28 |
| EP0169299A3 (en) | 1986-12-03 |
| AU601916B2 (en) | 1990-09-20 |
| DE3270097D1 (en) | 1986-04-30 |
| AU566007B2 (en) | 1987-10-08 |
| ATE18719T1 (en) | 1986-04-15 |
| ATE52247T1 (en) | 1990-05-15 |
| DE3129906C3 (en) | 1996-12-19 |
| NO164458C (en) | 1992-11-23 |
| EP0071564A1 (en) | 1983-02-09 |
| DE3129906C2 (en) | 1990-05-17 |
| NO164458B (en) | 1990-07-02 |
| NO822546L (en) | 1983-01-25 |
| JPH03209389A (en) | 1991-09-12 |
| JP2548436B2 (en) | 1996-10-30 |
| ZA825313B (en) | 1983-05-25 |
| JPH0339045B2 (en) | 1991-06-12 |
| DE3129906A1 (en) | 1983-02-10 |
| JPS5829718A (en) | 1983-02-22 |
| JPS62123159A (en) | 1987-06-04 |
| LU88291I2 (en) | 1994-05-04 |
| NL930072I2 (en) | 1994-01-17 |
| CA1218597A (en) | 1987-03-03 |
| DE3280157D1 (en) | 1990-05-31 |
| EP0071564B1 (en) | 1986-03-26 |
| EP0169299A2 (en) | 1986-01-29 |
| IE821766L (en) | 1983-01-24 |
| EP0169299B1 (en) | 1990-04-25 |
| JPH0768193B2 (en) | 1995-07-26 |
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