Metal complexes that contain perfluoroalkly, process for...

Details Metal complexes that contain perfluoroalkly, process for... Metal complexes that contain perfluoroalkly, process for...

1999-11-08

2002-10-22

Hartley, Michael G. (Department: 1619)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S009360, C424S009363, C424S009364, C424S009365, C424S009400, C424S009420, C534S010000, C534S015000, C534S016000, C540S465000, C540S474000

Reexamination Certificate

active

06468502

ABSTRACT:

The invention relates to the objects characterized in the claims, i.e., new, monomeric, perfluoroalkyl-substituted, paramagnetic metal complexes and complex salts, pharmaceutical agents containing these metal complexes, processes for their production, and their use as contrast media in
1
H-NMR diagnosis and
1
H-NMR spectroscopy, diagnostic radiology, and radiodiagnosis and as radiotherapeutic agents.
Nuclear magnetic resonance (NMR) is now a very extensively used method of medical diagnosis, used for in vivo imaging, with which vessels of the body and body tissue (including tumors) can be visualized by measuring the magnetic properties of the protons in the body water. To this end, e.g., contrast media are used that produce contrast enhancement in the resulting images or make these images readable by influencing specific NMR parameters of the body protons (e.g., relaxation times T
1
and T
2
). Mainly complexes of paramagnetic ions, such as, e.g., gadolinium-containing complexes (e.g., Magnevist
(R)
) are used owing to the effect of the paramagnetic ions on the shortening of the relaxation times. A measure of the shortening of the relaxation time is relaxivity, which is indicated in m
−1
·sec
−1
.
Paramagnetic ions, such as, e.g. , Gd
3+
, Mn
2+
, Cr
3+
, Fe
3+
and Cu
2+
cannot be administered in free form as solutions since they are too toxic. To make these ions suitable for in vivo use, they are generally complexed, which is described for the first time in EP 0 071 564 A1 (complexing with aminopolycarboxylic acids, e.g., with diethylenetriamine-pentaacetic acid [DTPA]). The di-N-methylglucamine salt of the Gd-DTPA complex is known under the name Magnevist
(R)
and is used, i.a., to diagnose tumors in the human brain and in the kidney.
The meglumine salt of Gd-DOTA (gadolinium(III) complex of 1,4,7,10-tetracarboxymethyl-1,4,7,10-tetraazacyclododecane) that is described in French Patent 25 39 996 is another contrast medium that has demonstrated its value in nuclear spin tomography and was registered under the name Dotarem
(R)
.
These contrast media cannot be used, however, in a satisfactory manner for all applications. Thus, the contrast media used clinically at present for the modern imaging processes of nuclear spin tomography (MRI) and computer tomography (CT), such as, e.g., Magnevist
(R)
, Pro Hance
(R)
, Ultravist
(R)
and Omniscan
(R)
, are dispersed into the entire extracellular space of the body (in the intravascular space and in the interstice).
Contrast media that also are dispersed exclusively in the latter when administered in the vascular space and thus label it (so-called blood-pool agents) are especially desirable, however, to visualize vessels.
An attempt was made to solve these problems by using complexing agents, which are bound to macromolecules or biomolecules. Up until now, this has had very limited success.
Thus, for example, the number of paramagnetic centers in the complexes that are described in EP 0 088 695 A1 and EP 0 150 844 A1 is inadequate for satisfactory imaging.
If the number of required metal ions is increased by repeatedly introducing complexing units into a macromolecular biomolecule, this is associated with an intolerable impairment of the affinity and/or specificity of this biomolecule [J. Nucl. Med. 24, 1158 (1983)].
Macromolecular contrast media for angiography, such as albumin-Gd-DTPA, are described in Radiology 1987; 162: 205. Twenty-four hours after intravenous injection in rats, however, albumin-Gd-DTPA shows a concentration in the liver tissue that amounts to almost 30% of the dose. In addition, only 20% of the dose is eliminated within 24 hours.
The macromolecule polylysine-Gd-DTPA (EP 0 233 619 A1) can also be used as a blood-pool agent. For production reasons, however, this compound consists of a mixture of molecules of various sizes. In excretion tests in rats, it was shown that this macromolecule is excreted unaltered by glomerular filtration via the kidney. For synthesis reasons, it contains polylysine-Gd-DTPA but also macromolecules that are so large that they cannot pass through the capillaries of the kidney in the case of glomerular filtration and thus remain in the body.
Macromolecular contrast media based on carbohydrates, e.g., dextran, have also been described (EP 0 326 226 A1). The drawback of these compounds lies in the fact that the latter generally have only about 5% of the signal-enhancing paramagnetic cation.
The object of the invention was therefore to make available new
1
H-NMR contrast media that do not exhibit the above-mentioned drawbacks and especially show a higher proton relaxivity and thus allow a reduction of the dose with increased signal intensity. The contrast media are also to be stable, well compatible and mainly exhibit organ-specific properties, whereby, on the one hand, their retention in the organs to be studied is to be sufficient to obtain the number of images that is necessary for an unambiguous diagnosis at low dosage, but, on the other hand, an excretion of metals from the body that is as fast as possible and very largely complete is then to be ensured.
The object of the invention is achieved with the monomeric, perfluoroalkyl-containing compounds of general formula I according to claim
1
, which show a surprisingly high proton relaxivity of 20-50 [mM
−1
·sec
−1
, 39° C., 0.47 T]. In comparison with this, proton relaxivity for commercially available
1
H-NMR contrast media Magnevist
(R)
, Dotarem
(R)
, Omniscan
(R)
and Pro Hance
(R)
is between 3.5-4.9 [mM
−1
·sec
−1
, 39° C., 0.47 T].
In addition, the compounds according to the invention are extremely well suited for detecting and locating vascular diseases, since they are also exclusively dispersed in the latter when administered in the intravascular space. The compounds according to the invention make it possible to distinguish tissue that is well-supplied with blood from tissue that is poorly supplied with blood with the aid of nuclear spin tomography and thus to diagnose an ischemia. Infarcted tissue can also be delimited from surrounding healthy or ischemic tissue due to its anemia, if the contrast media according to the invention are used. This is of special importance if the point is, e.g., to distinguish a myocardial infarction from an ischemia.
Compared to the macromolecular compounds that were previously used as blood-pool agents, such as, for example, Gd-DTPA polylysine, the compounds according to the invention also show a higher T
1
relaxivity (see Tab. 3) and are thus distinguished by a large increase in signal intensity in the case of NMR imaging. Since, in addition, they have an extended retention in the blood space, they can also be administered in relatively small dosages (of, e.g., ≦50 &mgr;mol of Gd/kg of body weight). Mainly, however, the compounds according to the invention, none of which are polymeric compounds, are eliminated quickly and almost completely from the body.
It was also shown that the compounds of this invention are suitable not only as blood-pool agents, but are also excellent lymph-specific MRT contrast media (lymphographic agents).
The visualization of the lymph nodes is of vital importance for early detection of metastatic invasions in cancer patients. The contrast media according to the invention allow small metastases in non-enlarged lymph nodes (<2 cm) to be distinguished from lymph node hyperplasias without malignant invasions. In this case, the contrast media can be administered intravascularly or interstitially/intracutaneously. Interstitial/intracutaneous administration has the advantage that the substance is transported directly from the scattering concentrate table (e.g., primary tumor) via the corresponding lymph tracts into the potentially affected regional lymph node stations. Likewise, a high concentration of contrast medium in the lymph nodes can be achieved with a small dose.
The compounds according to the invention meet all requirements that are called for by contrast me

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