CA1218597A - Paramagnetic complex salts, their preparation, and their use in nmr-diagnostics - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Preparations for influencing the relaxation times in NMR-diagnostics, comprising at least one physiologically compatible paramagnetic complex salt from aminopolycarboxy-lic acids having the formulae I to IV

(I) N-hydroxy-ethyl-N,N',N'-ethylene-diamine triacetic acid, (II) N,N,N',N",N"-diethylene-triamine pentaacetic acid, 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 radical containing 1 to 4 hydrocarbon atoms or the group -CH2-COOH, or disphosphonic acids having the general formula V

Description

The present invention provides a preparation for influencing the relaxation times in NMR-diagnostics.

According to the present invention there is pro-vided a pharmaceutical preparation for use in influencing the relation ti.mes in NMR diagnostics which comprises a physiologically acceptable carrier and at least one phy-siologically compatible paramagnetic complex salt from ani.mopolycarboxyl.ic acids having the formulae I to IV
],0 ooCC~i z Cii C~Or.
N- ( C ~ ~ Z
~ 0~ CCil/ CH2COO~ (I) N-hydroxy-ethyl-N,N',N'-ethylene-diamine -tri.acetic acid, ~50~:. C C~2C0~-; /c~ZC^

2 ~_(rH~ -(C~
u_r'~zC~ ~ 2 2 2 ~ C~i2c~c~(1~) N,N,N',N",N"-diethylene-triamine pentaacetic acid, HOH2C-CH2N(cH2cOoH)2 (III) N-hydroxy-ethyl-imino diacetic acid, nl C~
0 ~ N-(C'~ ) -(C~ ) -(CH ) -~\ l H3GrCH2/ ~ 2 2 n .z m 2 H(IV), wherein m represents the numbers 1 to 4, n represents tlle numbers 0 to 2, Rl represents a saturated or unsaturated hydrocarbon radical containing 1 to 4 hydrocarbon atoms or the group -CH2-COOH, or disphosphonic acids having the general .~ 2 formula V

. ' '.
R - C R
~ 1 3 (V), where.i.n R2 represents hydrogen, alkyl containing 1 to 4 carbon atoms, halogen, the hydroxy, amino or-CH2-COOH group and R3 represents hydrogen, alkyl containing 1 to 4 carbon atoms, the -Cl-12-COOH group or also halogen when R2 represents halogen, and from the ions of the lanthanide elements having the atomic numbers 57 to 7 or from the ions of the transi-tion metals having the atomic numbers 21 to 29, 42 and 44, and, if desired, an inorganic base.

Suitable aminopolycarboxylic acids are those com-pounds of this class of substances which can form chelate complexes, for example:

1~185~7 formula N-hydroxyethyl-N,N',N'-ethylenediamine-triacetic acid (HEDTA) s N~N~Nl~Nll~N~-diethylenetriamine-penta-acetic acid (DTPA), and II

N-hydroxyethylimino-diacetic acid III
DTPA is preferred.
Also suitable are the aminopolycarboxylic acids of the ~eneral formula CH3 / CHzCOOH
N-(CH2)m~(CH2_N_CH2)n (CH2)m (IV) HOOCCH

., ~

~21~5~

wherein m represents the integers 1 to 4, n represents the integers 0 to 2, and R5 represents a saturated or unsatura-ted 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) ~ ;

~21~9'~

There are also suitable phosphoric acids of the general f ormula 1, R2~ R3 (V) wherein R2 represents hydrogen, alkyl containing 1 to 4 carbon 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 lS halogen. There may be mentioned, more especially, ethane-l-hydroxy-l,l-diphosphonic acid, methane-diphosphonic acid and ethane-l-amino-l,l-diphosphonic acid.

If desired, it is also possible to bind the phy-siologically tolerable complex salts of the invention tobio-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 paramagentic 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 deri-vative of the complex compound.
The activated derivatives which may be considered ~, "; l;~l~S~

are for example, acid chlorides, mixed anhydrides (whieh ean be prepared from the carboxyl derivative of the eomplex compound with chlorocarbonic acid ester), activated esters, nitrenes or isothiocyanates.

It is also possible to reaet an aetivated deriva-tive of the biomolecule with a nucleophilie derivative of the eomplex compound. As organic bases for salt formation there may be used, for example, sodium hydroxide.

~ - 7 -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 compa-tible buffer solutions (for example sodium dihydrogen phos-phate solution), and sterilising the solution. The aqueous solutions can be administered orally, neurally and especially intervascularly. If suspensions of the paramagnetic complex salts in water or physiological salt solution are desired, especi.ally for oral administration, the 5~

paramagnetic complex salt is mixed with one or more auxiliaries usual in galenics and/or surfactants and/or aromatic substances for taste correction and suspended in water or physiological salt solution before oral administration. In this case, preferably from 3 to 10 g of paramagnetic complex salt and from 2 to 8 g of one or more auxiliaries, such as, for example, saccharose, highly disperse silica, polyoxyethylenepolyoxypropylene polymers, starch, magnesium stearate, sodium lauryl sulphate, talcum, lactose, sodium carboxymethylcellulose are used.
For ~MR-diagnosis in humans, the preparations of the invention are suitable in the form of aqueous solutions os suspensions which contain from 5 to 250 mmols/litre, preferably 50 to 200 mmols/litre, of the paramagnetic complex salt. The p~ of the aqueous . solutions may range between 6.5 and 8.0, preferably between 6.5 and 7.5. As a result of the formation of the complex salt according to the present invention the paramagnetic salt is detoxicated, and the effect also achieved is that the salts are stable in water and readily soluble therein in the physiological pH range.
Solutions of the complex salts appear to be particularly suitable for greater definition or local-isation of lesions of the pancreas and liver, and alsoof tumours and haemorrhages in the cranial area. For diagnosis of the area under examination an aqueous ' ;

lZ1~35~7 solution of the paramagnetic complex salt which is isotonic with blood is, for example, administered intravenously at a dosage of from 1 to ~00 ~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 ap~lication, 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 S~
- 11 _ information for diagnostic purposes.
One of these image-producing processes is spin-imaging, which is based on the physical effect of nuclear magnetic resonance tNMR). 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 ~iological tissues as water - have a magnetic moment and therefrom align themselves in a strong external magnetic field. By means of a high-frequency impulse (resonant frequency) they are brought out of their position of equilibrium, to which they return at a characteristic speed. The duration of the return to the state of equilibrium, the so-called relaxation time, provides information on the classification of the atoms and on their interaction with their surroundings.
The image which is obtained by measuring the proton density or the relaxation times is of great diagnostic value and provides information concerning the water content and the state of the tissues being examined~ For example, tumour tissue displays longer relaxation times than healthy tissue. (A. Ganssen and others, Computertomographie 1, ~1981] pp. 2-10, Georg Thieme Verlag, Stuttgart, New York).
It has now been found that paramagnetic ions, 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 Tl is greatly reduced in a man-ner 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 otherwlse toxic metal salts can be effected by complexing, with-out the paramagnetic properties being adversely affected. Thisis surprising, since it is known that the distribution of the d-and f-electrons over the d- and f- orbitals is altered thereby.

~.

The paramagnetic complex salts may be prepared accord-ing 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 elemen~ 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 neces-sary while heating at from 50C to 120C until the reaction is complete. If alcohol is employed as the solvent, methanol or ethanol is used. If the complex salt formed is insoluble in the solvent used, it crystallises and can be filtered off. If it is soluble in the solvent used, it can be isolated by evaporating the solution to dryness.

The process is to be explained in detail, by way of example, with the aid of the following instructions for procedure:

. ~.

121~5~

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 of diethylenetriaminepentaacetic acid in 12 litres of water is heated while stirring to from 90C to 100C and stirred at this temperature for 48 hours. The undissolved portion is filtered off and the filtrate is evaporated to dryness. The amorphous residue is pulverised.
Yield 144 g, (molecular weight 547.58) ~p.: melts from 235 and remains undecomposed up to 320C.

35~

If there is/are still one or more acidic group(s) in the resulting paramagnetic complex compound, the result-ing complex compound can then, if desired, be dissolved or suspended in water and the desired inorganic base can be added thereto until the neutral point is reached. After filtering off the undissolved constituents, the solution is concentrated by evaporation and the desired complex salt is obtained as the residue.

The following Example illustrates the invention:-Example 1 Preparation of a solution of the di-sodium sal-t of the manganese(II)-complex of ethylenediamine-tetra-acetic acid 5.55 g (15 mmoles) of the manganese(II)-complex of ethylenediamine-tetra-acetic acid (water content: 6.9%) are dissolved in 80 ml of water p.i. at a pH of 7.5 wi-th the addition of dilute sodium hydroxide solution. The solu-tion is then made up to 170 ml with water p , filtered into ampoules and heat-sterilised.

1~
-- ~} --1~8597 1~ .

.~`.,.
Example ~

(Composition of a powder for the preparation of a suspension) 4.000 g gadolinium(III) complex of diethylenetriamine-pentaacetic acid (water content 8%)

3.895 g saccharose 0,100 g polyoxyethylenepolyoxypropylene polymer 0.005 g aromatic substances 8.000 g

Claims (8)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical preparation for use in influen-cing the relation times in NMR diagnostics which comprises a physiologically acceptable carrier and at least one phy-siologically compatible paramagnetic complex salt from animopolycarboxylic acids having the formulae I to IV

(I) n-hydroxy-ethyl-N,N',N'-ethylene-diamine triacetic acid, (II) N,N,N',N",N"-diethylene-triamine pentaacetic acid, 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 radical containing 1 to 4 hydrocarbon atoms or the group -CH2-COOH, or disphosphonic 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 represents 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 numbers 57 to 70 or from the ions of the transi-tion metals having the atomic numbers 21 to 29, 42 and 44.

2. A preparation according to claim 1, in which the complex salt includes an inorganic base.

3. A preparation according to claim 2, in which the inorganic base is sodium hydroxide.

4. A preparation according to claim 1 or 2, in which the aminopolycarboxylic acid is N,N,N',N'-ethylene-diamine tetraacetic acid.

5. A preparation according to claim 1 or 2, in which the aminopolycarboxylic acid is N,N,N',N",N"-diethylene-triamine pentaacetic acid.

6. A preparation according to claim 1 or 2 in which the diphosphonic acid is ethane-1-hydroxy-1,1-diphos-phonic acid, methane diphosponic acid or ethane-1-amino-1,1-diphosphonic acid.

7. A preparation according to claim 2, in which the complex salt is the disodium salt of the gadolinium(III) complex of diethylene-triamine pentaacetic acid.

8. A preparation according to claim 1 or 2, in which the ion is gadolinium.