Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Patent
1995-09-29
1998-03-31
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
424 9364, 424 9365, 424 942, 424 95, 514492, 514502, 514836, 436173, 534 16, A61B 5055, A61K 4904
Patent
active
057335222
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/00033 filed Jan. 8, 1994.
The invention relates to the object characterized in the claims, i.e. new complexes and complex salts, agents containing these compounds, their use in diagnosis and radiation therapy, as well as the process for the production of these compounds and agents.
At the beginning of the fifties, metal complexes were already under consideration as contrast media for radiology. However, the compounds used at that time were so toxic that using them in humans was out of the question. It was therefore really surprising that certain complex salts turned out to be sufficiently compatible so that routine use in humans for diagnostic purposes could be considered. As a first representative of this family of substances, the dimeglumine salt of GdDTPA (gadolinium(III) complex of diethylenetriaminepentaacetic acid; Magnevist.RTM. described in the European patent application with publication number 0 071 564 proved to be a very good contrast medium for nuclear spin tomography.
This contrast medium is especially well-suited for the diagnosis of pathological areas (e.g., inflammations, tumors, infarctions, etc.). After intravenous injection, the compound spreads extracellularly and is eliminated by glomerular secretion through the kidneys. Crossing of intact cell membranes and extrarenal elimination are practically not observed.
Also, the metal complexes described in patent applications EP 0 305 320 and EP 0 299 795 spread extracellularly and are eliminated almost exclusively renally. For the patients with limited renal function, the above-mentioned contrast media are therefore less suitable, since elimination in the case of the latter takes place only slowly, so that complete removal of the contrast medium from the organism is often successful only with the aid of a dialyzer.
Because of their pharmacokinetic behavior, these contrast media are also suitable as diagnostic agents for the hepatobiliary area only to a limited extent. Therefore, there is a need for contrast media that are taken up by the liver cells and thus make it possible to distinguish healthy parenchyma from tumorous tissue better.
Contrast media suitable for this application are described in EP 0 186 616. However, these agents based on dextran-coated, magnetic ferrous oxide particles suffer from the drawback that they unnecessarily stress the iron depot of the body. Furthermore, these compounds--as all compounds of high-molecular weight--can cause an undesirable, long-term hematoma formation in the patient in the case of inexpert injection (i.e., if the vein is missed). This danger does not exist, however, with the fast-spreading compounds of low molecular weight.
EP 0 405 704 describes metal complexes of DTPA derivatives substituted with lipophilic groups. These compounds basically show the desired elimination behavior, i.e., in addition to the renal elimination, a certain portion of the contrast medium is also eliminated with the feces, but improvement of the extrarenal/renal elimination ratio is especially desirable for use in tenally insufficient patients.
It is also important to further improve relaxivity, which can be used as a measure of the imaging effect, so that the dose necessary for a diagnostic statement can be further reduced.
Thus, the object of the invention is to provide compounds and agents that overcome the above-described drawbacks of the prior art, i.e. to find compounds (agents) which are mainly eliminated extrarenally or hepatobiliarly and whose diagnostic effectiveness is further improved, as well as to provide a process for their production.
It has now been found that this object is achieved, surprisingly enough, by complex compounds and agents containing the latter, consisting of at least one metal ion of an element of atomic numbers 21-29, 42, 44 or 58-83 and a complexing agent of general formula I ##STR2## in which
Z.sup.1 and Z.sup.2, independently of one another, stand for a hydrogen atom, the radical --(CH.sub.2).sub.m --(C.sub.6 H.sub.4).sub.q --(O).sub.k --(CH.sub.2
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Bauer Hans
Frenzel Thomas
Gries Heinz
Hilscher Jean-Claude
Muhler Andreas
Hollinden Gary E.
Schering Aktiengesellschaft
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