NL194579C - Diagnostic. - Google Patents

Description

1 194579> Diagnostic agent

The present invention relates to a diagnostic agent for use in in vivo NMR diagnostics, which agent comprises at least one physiologically acceptable complex salt of the formula XCH 2 CH 2 X

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N-A-N

VCHRt chf ^ v 10, with additives customary in galenic pharmacy, dissolved or suspended in an aqueous medium, in which formula X is-COOY, POgHY or CONHOY; YH, a metal ion equivalent of an element with the atomic numbers 21 to 29, 42, 44 or 58 15 to 70 or a cation of an inorganic or organic base, against which there is no physiological objection, represents which organic base chosen is from the group consisting of ethanolamine diethanolamine, morpholine, glucamine, Ν, Ν-dimethylglucamine, N-methylglucamine, lysine, arginine and ornithine; R., is H.

European application 0.071.564 describes such a means for influencing relaxation times in NMR diagnostics. The agents described contain a paramagnetic, organic, nitrogen, phosphorus, oxygen and / or sulfur-containing complex with said lanthanides or transition metal ions and an organic or inorganic base.

Complexes or salts of the above-mentioned types of compounds have, incidentally, been used in medicine for a long time, for example as an aid for the administration of sparingly soluble ions (for example iron) and as anti-drugs (calcium or zinc complexes are preferred) for detoxification at a accidental uptake of heavy metals or radioactive isotopes thereof.

When using paramagnetic compounds for in-vivo NMR, a large number of parameters play an important role, such as, for example, a high signal intensity and strong performance; good solubility in water and good stability in vitro and in vivo.

It is an object of the present invention to provide alternative diagnostic agents with suitable properties for use in in vivo NMR.

It has been found that this object can be achieved with certain new agents containing at least one physiologically acceptable complex salt of the above formula, characterized in that further in this formula at least two of the groups Y represent metal ion equivalents, and wherein A is CHR 2 -CH 3, wherein R 2 and R 3 are H and both groups V together (CH 2) w N-CH 2 -CH 2 -N- (CH 2) w II

ch2x represents ch2x 40, wherein w is 1, 2 or 3.

Such an agent has been found to be excellent for use in in vivo NMR diagnostics.

An agent according to the invention, for example, satisfies the multiple requirements for use as a contrast agent for the nuclear spinomography and is excellent for, after oral or parenteral administration, increasing the signal intensity obtained with the aid of the nuclear spinintograph by increasing the signal intensity, , to improve.

Furthermore, an agent according to the invention exhibits the strong effect which is necessary to burden the body with the smallest possible quantities of foreign substances and the good tolerance which is necessary to maintain the non-invasive character of the test (the method described in J. For example, Comput Tomography, 5, 6, 543-546 (1981), in Radiology, 144, 343 (1982) and in Brevet Special de Medicament No. 484 M 50 (1960) are too toxic).

The good solubility in water of an agent according to the invention makes it possible to prepare highly concentrated solutions, so that the volume load of the cycle can be kept within defensible limits and the dilution by the body fluid can be equalized; that is, NMR diagnostics should generally be 100-1000 times more water-soluble than the 55 compounds for NMR spectroscopy.

Furthermore, an agent according to the invention shows not only a great stability in vitro but also in vivo, so that a dissociation or exchange of the ions that are not covalently bonded in the complexes and that are toxic in themselves within the 24 hours in which the new contrast agents are fully restored excreted (as pharmacological testing has shown), takes place extremely slowly.

The element with the above-mentioned atomic number, which forms the central ion or ions of the physiologically tolerated complex salt, may of course not be radioactive for the intended purpose of the diagnostic agent according to the invention.

The central ion of the complex salt must be paramagnetic. These are in particular the 2 and 3-valued ions of the elements with the atomic numbers 21 to 29, 42, 44 and 58 to 70. Suitable ions are, for example, the chromium (III), manganese (III). -, iron (ll) -, iron (ll) -, cobalt (ll) -, nickel (ll) -, copper (ll) -, praseodymium (lll) -, neodymium (lll) -, samarium (lll) - and ytterbium (III) ion. Because of their very strong magnetic moment, the gadolinium (III) terbium (III), dysprosium (III), holmium (III) and arbium (III) ion are particularly preferred.

Suitable complexing acids are those representatives which are usually used for complexing the above-mentioned central ions. Suitable complexing acids are, for example, those which contain 3-12, preferably 3-8 methylene phosphonic acid groups, methylene carbohydroxamic acid groups, carboxyethylidene groups, or in particular carboxymethylene groups, one, two or three of which are in each case bonded to a nitrogen atom supporting the complex formation . If three of the azidic groups are attached to a nitrogen atom, then the complexing acids underlying the complex salts of the general Formula 2 are present. If in each case only one or two of the azidic groups are bonded to a nitrogen atom, then the nitrogen is connected via an optionally substituted ethylene or via at most four ethylene units separated by a nitrogen or oxygen or sulfur atom supporting the complex formation. another nitrogen atom. Preferred complexing acids of this type are those of the general formula 1.

For the preparation of the complex salts of the general formula 1a, the following complexing acids are suitable, inter alia: ethylenediamine tetraacetic acid, ethylenediamine tetraacetahydroxamic acid, trans 1,2-cyclohexylenediamine tetraacetic acid, DL-2, 3-butylenediamine-tetra-acetic acid, DL-1,2-butylenediamine-tetra-acetic acid, DL-1,2-propylene-diamine-tetra-acetic acid, 1,2-diphenylethylene-dlamine-tetra-acetic acid, ethylenedinitrile-tetrakis ( methane phosphonic acid) and N- (2-hydroxyethyl) -ethylene diamine triacetic acid.

Suitable complex salts of the general formula 1 according to claim 1 are furthermore those of the general formula 1c, wherein X and w have the meaning mentioned in claim 1. For the preparation of complex salts of the general formula 1c, the following complexing acids are suitable, inter alia: 1,4,8,11-tetra-aza-cyclotetradecane-tetra-acetic acid, and in particular 1,4,7,10-tetra -aza-cyclododecane-tetra-acetic acid.

Other complexing acids which are suitable for the preparation of the complex salts of the general formula I are, for example: 1,2,3-tris [bis (carboxymethyl) amino] propane and nitrilotris (ethylene nitrile) hexaacetic acid. Nitrilotriacetic acid is mentioned as an example of a complexing acid for the preparation of complex salts of the general formula.

If not all azidic hydrogen atoms of the complexing acid are substituted by the central ion or the 40 central ions, it is expedient to increase the solubility of the complex salt the remaining hydrogen atoms by cations of inorganic and / or organic bases or amino acids against which substituting physiological cations. Suitable inorganic cations are, for example, the lithium ion, the potassium ion or in particular the natrimion.

The complexing acids required for the agents according to the invention are known or can be prepared in a manner known per se.

For example, the preparation of 13,23-dioxo-15,18-21-tris (carboxymethyl) -12,15,18,21,24-penta-aza-penta-triacontane diacid (formula 1d) takes place according to the RA Bulman et al. In Naturwissenschaften 68, (1981) 483 proposed improved form:

17.85 g (= 50 mmol) of 1,5-bis- (2,6-dioxomorpholino) -3-50 azapentane-3-acetic acid are suspended in 400 ml of dry dimethylformamide and the suspension after addition of 20.13 g (= 100 mmol) 11-amino-undecanoic acid heated at 70 ° C for 6 hours. The clear solution is concentrated under reduced pressure. The yellow oily residue is stirred together with 500 ml of water at ambient temperature. An almost white, voluminous solid precipitates out, which is suctioned off and washed several times with water. The resulting product is charged to 200 ml of acetone for further purification and stirred at ambient temperature for 30 minutes. After suctioning and drying under reduced pressure at 50 ° C, 36.9 g (= 97% of theory) of a white powder with a melting point of 134-138 ° C are obtained.

The preparation of the complex salts is also partly known or can take place in a manner known per se by the metal oxide or a metal salt (for example the nitrate, chloride or sulphate) of the element with the atomic numbers 21 to 29, 42 , 44 or 57 to 83 in water and / or a low alcohol (such as methanol, ethanol or isopropyl alcohol) to dissolve or suspend and to the solution or suspension the equivalent amount of the complexing acid in water and / or a add low alcohol and stir, if necessary with heating or heating to the boiling point, until the conversion is complete. When the complex salt formed is insoluble in the solvent used, it is isolated by filtration. If it is soluble, it can be isolated by evaporating the solution to dryness, for example by spray drying.

If azide groups are still present in the complex salt obtained, then it is often expedient to convert the acid complex salt into neutral complex salts by means of inorganic and / or organic bases or amino acids, which form cations, against which physiologically no objection exists. and isolate it. In many cases, this is even unavoidable, since the dissociation of the complex salt is reduced to neutral by shifting the pH value, so that it is only in this way that the isolation of uniform products or at least the purification thereof is made possible.

It is expedient for the preparation to take place with the aid of organic bases or basic amino acids. However, it can also be advantageous to carry out the neutralization by means of inorganic bases (hydroxides, carbonates or hydrogen carbonates) of sodium, potassium or lithium.

To prepare the neutral salts, for example, to the acid complex salts, dissolved or suspended in water, so much of the desired base can be added that the neutral point is reached. The resulting solution can then be evaporated to dryness under reduced pressure. It is often advantageous to precipitate the neutral salts formed by adding water-miscible solvents, such as, for example, low alcohols (methanol, ethanol, isopropyl alcohol), low ketones (acetone), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane) and thus obtain easily crystallizable products that can be easily isolated and purified. It has been found that it is particularly advantageous to add the desired base to the reaction mixture already during complex formation and thereby to save a process step.

When the acid complex salts contain several free azide groups, it is often expedient to prepare neutral mixed salts which contain both inorganic and organic cations, which are physiologically safe, as counter ions. This can be done, for example, by converting the complexing acid in an aqueous suspension or solution, with the oxide or salt of the element providing the central ion, and with half the amount of an organic base required for neutralization. isolate the complex salt formed, purify it if desired and then, to completely neutralize it, add the required amount of inorganic base. The order of addition of the bases can also be reversed.

The diagnostic agents according to the invention are also prepared in a manner known per se by suspending or dissolving the complex salts, optionally with the addition of the additives customary in galenic pharmacy, in an aqueous medium and then the solution or suspension. to sterilize. Suitable additives are, for example, buffers, against which there is no physiological objection (such as, for example, trimethamine hydrochloride), small additions of complexing agents (such as, for example, diethylene triamine-pentaacetic acid) or, if necessary, electrolytes (such as, for example, sodium chloride).

In principle, it is also possible to prepare the diagnostic agents according to the invention without isolating the complex salts. In any case, special care must be taken in order to carry out chelating in such a way that the salts and salt solutions according to the invention are practically free from non-complexed, toxic-acting metal ions. This can be guaranteed, for example, by means of color indicators, such as xylenol orange, by control titrations during the preparation process. The final safety remains a purification of the isolated complex salt.

When suspensions of the complex salts in water or in a physiological saline solution are desired for oral administration or other purposes, a sparingly soluble complex salt with one or more excipients and / or surfactants and / or flavoring agents customary in galenic pharmacy becomes. taste improvement mixed.

The diagnostic agents according to the invention preferably comprise 1 pmol to 1 mol per liter of the complex salt and are generally dosed in amounts of 0.001 to 5 mmol / kg. They are intended for oral and in particular parenteral administration.

The agents according to the invention which contain an element with an atomic number of 58 to 70 are excellent as X-ray contrast agents, with particular emphasis being placed on the fact that no evidence can be seen of the

Claims (2)

194579 4 contrast agents known anaphylaxis-like reactions in biochemical-pharmacological research. They are particularly valuable because of the favorable absorption properties in areas of higher tube voltages for digital subtraction techniques. The means according to the invention are also suitable as ultrasonic diagnostics due to their property to favorably influence the ultrasonic speed. Diagnostic agent for use in in vivo NMR diagnostics, which agent comprises at least one physiologically acceptable complex salt of the formula XCH2 ch2x / NAN 15 / VCHR1 CHR., V, with additives customary in galenic pharmacy, dissolved or suspended in an aqueous medium, in which formula 20 is X-COOY, PO3HY or CONHOY; YH, a metal ion equivalent of an element with the atomic numbers 21 to 29, 42, 44 or 58 to 70 or a cation of an inorganic or organic base, against which there is no physiological objection, represents which organic base has been chosen from the group consisting of ethanolamine diethanolamine, morpholine, glucamine, Ν, Ν-dimethylglucamine, N-methylglucamine, lysine, arginine and ornithine; R 1 is H, characterized in that further in this formula at least two of the Y groups represent metal ion equivalents, and wherein A further is CHR 2 - CHR 3, wherein R 2 and R 3 are H and both groups V together (CH 2 ) w N-CH 2 -CH 2 -N- (CH 2) w II CH 2 X ch 2 x 35, wherein w is 1, 2 or 3. Hereby 1 sheet drawing