Perfluoroalkyl-containing complexes with polar radicals,...

Details Perfluoroalkyl-containing complexes with polar radicals,... Perfluoroalkyl-containing complexes with polar radicals,...

2001-08-10

2004-01-13

Hartley, Michael G. (Department: 1616)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

Magnetic imaging agent

C424S001650, C424S009360, C424S009364, C424S009365, C424S009400, C424S009420, C540S465000, C540S474000

Reexamination Certificate

active

06676928

ABSTRACT:

DESCRIPTION
The invention relates to the subjects that are characterized in the claims, namely perfluoroalkyl-containing metal complexes with polar radicals of general formula I, process for their production and their use in NMR diagnosis and x-ray diagnosis, radiodiagnosis and radiotherapy, in MRT-lymphography and as blood-pool agents. The compounds according to the invention are quite especially suitable for intravenous lymphography, for tumor diagnosis and for infarction and necrosis imaging.
In nuclear magnetic resonance, the element fluorine is second in importance to the element hydrogen.
1) Fluorine has a high sensitivity of 83% of that of hydrogen.
2) Fluorine has only one NMR-active isotope.
3) Fluorine has a resonance frequency that is similar to hydrogen—fluorine and hydrogen can be measured with the same system.
4) Fluorine is biologically inert.
5) Fluorine does not occur in biological material (exception: teeth) and can therefore be used as a probe or contrast medium against a background that is free of interfering signals.
The effect of these properties is that fluorine occupies a broad space in diagnostic patent literature with magnetic nuclear resonance as a basis: fluorine-19-imaging, functional diagnosis, spectroscopy.
U.S. Pat. No. 4,639,364 (Mallinckrodt) thus proposes trifluoromethanesulfonamides as contrast media for fluorine-19-imaging:
CF
3
SO
2
NH
2
CF
3
SO
2
NH—CH
2
—(CHOH)
4
—CH
2
OH
German Patent DE 4203254 (Max-Planck-Gesellschaft), in which an aniline derivative is proposed:
also relates to fluorine-19-imaging.
Fluorine-19-imaging is the subject of Application WO 93/07907 (Mallinckrodt), in which phenyl derivatives are also claimed as contrast media:
For fluorine-19-imaging, compounds of considerably simpler structure are also claimed. Thus, U.S. Pat. No. 4,586,511 (Children's Hospital Medical Center) mentions perfluoroctylbromide
CF
3
(CF
2
)
7
—Br
European Patent EP 307863 (Air Products) mentions perfluoro-15-crown-5-ether
and U.S. Pat. No. 4,588,279 (University of Cincinnati, Children's Hospital Research Foundation) mentions perfluorocarbon compounds such as perfluorocyclonanone or -octane, perfluorinated ethers such as tetrahydrofuran
or diethers such as perfluoropropylene glycol-diether
The compounds that are mentioned in Application WO 94/22368 (Molecular Biosystems), e.g.,
fluorine-containing radicals have the perfluorine-1H group or 1H-neopentyl group, are also used for fluorine-19-imaging.
U.S. Pat. No. 5,362,478 (VIVORX) indicates another structural type with expanded diagnostic use, in which the fluorocarbon/polymer shell combination is claimed for imaging purposes. Perfluorononane and human serum albumin are mentioned. This combination proves suitable, moreover, for using the fluorine atom as a probe for local temperature measurement and for determining the partial oxygen pressure.
Perfluorocarbons are also claimed in U.S. Pat. No. 4,586,511 for oxygen determination.
In German Patent DE 4008179 (Schering), fluorine-containing benzenesulfonamides are claimed as pH probes:
For NMR diagnosis, compounds that contain iodine and fluorine atoms are also claimed as contrast-enhancing agents in WO 94/05335 and WO 94/22368 (both molecular biosystems):
The fluorine-paramagnetic metal ion combination is also claimed for fluorine-19-imaging, specifically for open-chain complexes in WO 94/22368 (Molecular Biosystems) with, e.g.:
and in EP 292 306 (TERUMO Kabushiki Kaisha) with, e.g.:
but also for cyclic compounds, as they are mentioned in EP 628 316 (TERUMO Kabushiki Kaisha)
The combination of fluorine atom and rare-earth metal is also claimed for NMR-spectroscopic temperature measurements in DE 4317588 (Schering):
Ln: Rare earths: La, Pr, Dy, Eu
While no interactions occur between the two nuclei in compounds that contain the elements fluorine and iodine, intensive interaction does occur in compounds that contain fluorine and paramagnetic centers (radicals, metal ions) and that are expressed in a shortening of the relaxation time of the fluorine nucleus. The extent of this effect depends on the number of unpaired electrons of the metal ion (Gd
3+
>Mn
2+
>Fe
3+
>Cu
2+
) and on the removal between the paramagnetic ion and the
19
F-atom.
The more unpaired electrons of the metal ion are present and the closer the latter are brought to the fluorine, the greater the shortening of the relaxation time of the fluorine nucleus.
The shortening of the relaxation time as a function of the distance from the paramagnetic ion becomes apparent in all nuclei with an uneven spin number, thus also in the case of protons, and gadolinium compounds are therefore widely used as contrast media in nuclear spin tomography (Magnevist
(R)
, Prohance
(R)
, Omniscan
(R)
, and Dotarem
(R).
In
1
H-MR imaging (
1
H-MRI), however, relaxation time T
1
or T
2
of the protons, i.e., mainly the protons of water, and not the reaction time of the fluorine nuclei, is measured and used for imaging. The quantitative measurement for the shortening of the relaxation time is relaxivity [L/mmol·s]. Complexes of paramagnetic ions are successfully used for shortening relaxation times. In the following table, the relaxivity of several commercial preparations is indicated:
T
1
- Relaxivity in
Water
T
1
- Relaxivity in
[1/mmol s, 39° C.,
Plasma [1/mmol s,
0.47 T]
39° C., 0.47 T]
MAGNEVIST ®
3.8
4.8
DOTAREM ®
3.5
4.3
OMNISCAN ®
3.8
4.4
PRO HANCE ®
3.7
4.9
Only interactions between protons and the gadolinium ion are found in these compounds. For these contrast media in water, a relaxivity of about 4 [1/mmol·s] is thus observed.
Both fluorine compounds for fluorine-19-imaging, in which the shortened relaxation time of the fluorine nucleus is used, and non-fluorine-containing compounds, in which the relaxation time of protons of water is measured, are thus used successfully for MR imaging.
In the introduction of a perfluorocarbon-containing radical into a paramagnetic contrast medium, i.e., in the combination of properties that were previously known as suitable only for fluorine-imaging compounds, the relaxivity that relates to the protons of water also quickly increases, surprisingly enough, with compounds that were used for proton imaging. It now reaches values of 10-50 [1/mmol·s] in comparison to values of between 3.5 and 3.8 [1/mmol·s] as they were already cited for a few commercial products in the table above.
Perfluoroalkyl-containing metal complexes are already known from DE 196 034 033.1. These compounds, however, cannot be used satisfactorily for all applications. Thus, there is still a need for contrast media for the visualization of malignant tumors, lymph nodes and necrotic tissue.
Malignant tumors metastasize in clusters in regional lymph nodes, whereby multiple lymph node stations may also be involved. Lymph node metastases thus are found in about 50-69% of all patients with malignant tumors (Elke, Lymphographie (Lymphography), in: Frommhold, Stender, Thurn (eds.), Radiologische Diagnostik in Klinik und Praxis [Radiological Diagnosis in Clinical Studies and in Practice], Volume IV, Thieme Verlag Stuttgart, 7th Ed., 434-496, 1984).). The diagnosis of a metastatic attack of lymph nodes is of great importance with respect to the treatment and prognosis of malignant types of diseases. With modern imaging methods (CT, US and MRI), lymphogenous evacuations of malignant tumors are detected only inadequately, since in most cases only the size of the lymph node can be used as a diagnostic criterion. Thus, small metastases in non-enlarged lymph nodes (<2 cm) cannot be distinguished from lymph node hyperplasias without a malignant attack (Steinkamp et al., Sonographie und Kernspintomographie: Differentialdiagnostik von reaktiver Lymphknoten-vergröBerung und Lymphknoten-metastasen am Hals [Sonography and Nuclear Spin Tomography: Differential Diagnosis of Reactive Lymph Node Enlargement and Lymph Node Metastasis on the Neck], Radiol.

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