Perfluoroalkylamides, their production and their use in...

Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent

Reexamination Certificate

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C534S007000, C534S014000, C424S009100, C424S009300, C424S009320, C424S009400, C424S009420

Reexamination Certificate

active

06461587

ABSTRACT:

The invention relates to the subject that is characterized in the claims, i.e., macrocyclic perfluoroalkylamides, their production and their use in diagnosis.
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 nuclear magnetic 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
2
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:
Compounds of considerably simpler structure are also claimed for fluorine-19-imaging. Thus, U.S. Pat. No. 4,586,511 (Children's Hospital Medical Center) mentions perfluorooctyl bromide
CF
3
(CF
2
)
7
—Br
European Patent EP 307863 (Air Products) mentions perfluoro-15-crown-ether
and U.S. Pat. No. 4,588,279 (University of Cincinnati, Children's Hospital Research Foundation) mentions perfluorocarbon compounds, such as perfluorocyclononane or -octane, perfluorinated ethers such as tetrahydrofuran
or diethers such as perfluoro-propyleneglycol-diether
The compounds that are mentioned in Application WO 94/22368 (Molecular Biosystems), e.g.,
which as fluorine-containing radicals have the perfluoro-1H,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 (TERUM Kabushiki Kaisha) with e.g.:
but also for cyclic compounds, as they are mentioned in EP 628 316 (TERUMO Kabushiki Kaisha)
The fluorine atom-rare earth metal combination is also claimed for NMR-spectroscopic temperature measurements in DE 4317588 (Schering).
Ln: Rare earths: La, Pr, Dy, Eu
While no interactions between the two nuclei occur in compounds that contain the elements fluorine and iodine, intensive interaction does occur in compounds that contain fluorine and paramagnetic centers (radicals, metal ions), which 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 they 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; therefore, there is wide use as contrast media in nuclear spin tomography (Magnevist
(R)
, Prohance
(R)
, Omniscan
(R)
, 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 relaxation 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 the relaxation times. In the following table, the relaxivity of some commercial preparations is indicated:
T
1
-Relaxivity in
T
1
-Relaxivity in
Water [L/mmol · s,
Plasma [L/mmol · s,
39° C., 0.47 T]
39° C., 0.47 T]
MAGNEVIST
(R)
3.8
4.8
DOTAREM
(R)
3.5
4.3
OMNISCAN
(R)
3.8
4.4
PRO HANCE
(R)
3.7
4.9
In these compounds, only interactions between protons and the gadolinium ion occur. For these contrast media in water, a relaxivity of about 4 [L/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 the 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 increases rapidly, surprisingly enough, with compounds that were used for proton imaging. It now reaches values of 10-50 [L/mmol·s] in comparison to values between 3.5 and 3.8 [L/mmol·s] as they were already cited for some commercial products in the table above.
Perfluoroalkyl-containing metal complexes are known from DE 196 03 033.1. The compounds of this invention are distinguished, however, by better properties, such as, for example, higher lymph node accumulation in three successive lymph node stations, better elimination, greater compatibility (which is especially advantageous for i.v. lymphography) and very good local compatibility in the case of interstitial administration. This opens up the possibility of adding the compounds at higher doses.
The MRI contrast media are used mainly for the visualization of malignant tumors.
Malignant tumors metastasize in clusters in regional lymph nodes, whereby multiple lymph node stations may also be involved. Thus, lymph node metastases 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 Practice], Volume IV, Thieme Verlag Stuttgart, 7th Edition, 434-496, 1984)). The diagnosis of a metastatic attack of lymph nodes is of great importance with respect to the therapy and prognosis of malignant diseases. With modern imaging methods (CT, US and MRI), lymphogenous metastases 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; Differential Diagnostik von reaktiver Lymphknotenvergrö&bgr;erung und Lymphknotenmetastasen am Hals [Sonography and Nuclear Spin Tomography: Differential Diagnosis of Reactive Lymph Node Enlargement and Lymph Node Metastases on the Neck], Radiol. Diagn. 33: 158, 1992).
It would be desirable if lymph nodes with metastatic attack an

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