Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
1999-12-21
2002-12-03
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C534S010000, C534S014000, C424S001110, C424S001650, C424S001690
Reexamination Certificate
active
06488909
ABSTRACT:
The invention relates to the field of radiopharmaceuticals and describes new chelating agents as well as their tricarbonyl complexes with technetium and rhenium.
Complexes with radioactive metals have already been used for a very long time in radiodiagnosis and radiotherapy. The radionuclide technetium-99m is used most frequently, since it is especially well suited for in-vivo use because of its advantageous physical properties (no corpuscular radiation, short half-life of 6.02 h, good detectability by its 140 KeV &ggr;-radiation), its short biological half-life and its broad availability. For synthesis of technetium-99m-complexes, pertechnetate is first obtained from a nuclide generator and converted by using suitable reducing agents (e.g., SnCl
2
) into a lower oxidation stage, which then is stabilized by a suitable chelating agent. Since technetium can be present in a number of oxidation stages (+7 to −1), which can greatly alter the pharmacological properties by altering the charge of a complex, it is necessary to provide chelating agents or complex ligands for technetium-99m, which can bind technetium in a more secure, tight and stable manner in a defined oxidation stage. The chelating agents inhibit redox processes or technetium-release reactions that occur in vivo. Such undesirable reactions make a reliable diagnosis of diseases more difficult, since the build-up of the radiopharmaceutical agent is determined in lesions, while the pharmacokinetics of the radiopharmaceutical agent and its excretion are determined by its metabolites.
For example, cyclic amines are regarded as suitable complexing agents for technetium and rhenium isotopes [Troutner, D. E. et al., J. Nucl. Med. 21, 443 (1980)], but said amines have the drawback that they are able to bind technetium-99m in good yields only starting from a pH>9. N
2
O
2
systems [Pillai, M. R. A., Troutner, D. E. et al., Inorg. Chem. 29, 1850 (1990)] are undergoing clinical use. Non-cyclic N
4
-systems, such as, e.g., the HMPAO, have only a low complex stability. Tc-99m-HMPAO, because of its instability [Ballinger, J. R. et al., Appl. Radiat. Isot. 42, 315 (1991); Billinghurst, M. W. et al., Appl. Radiat. Isot. 42, 607 (1991)], must be administered immediately after its labeling, so that the proportion of decomposition products that have a pharmacokinetics and excretion other than the diagnostic agent can be kept small. The radiochemical contaminants impede the detection of the diseases that are to be diagnosed. N
2
S
2
chelating agents [Bormans, G. et al., Nucl. Med. Biol. 17, 499 (1990)], such as, e.g., ethylene dicysteine [Verbruggen, A. M. et al., J. Nucl. Med. 33, 551 (1992)] comply, with the requirement for adequate stability of the corresponding technetium-99m complex, but radiodiagnostic agents with a purity above 69% form only starting from a pH>9. N
3
S systems (Fritzberg, A., EPA 0 173 424 and EPA 0 250 013) form stable technetium-99m complexes, but must be heated to temperatures of about 100° C. to incorporate the radioisotope. Another drawback of the N
2
S
2
and N
3
S systems consists in that the latter are partially excreted quickly and without specific build-up of the organism, so that the latter are used clinically only as renal functional diagnostic agents. They therefore have only a limited suitability. The coupling of such chelates or chelating agents to substances that accumulate selectively in foci of disease cannot be triggered with simple agents, so that the latter are generally distributed non-specifically in the organism.
In recent years, the demand for radiodiagnostic agents and radiotherapeutic agents that accumulate specifically in diseased tissues has increased. This can be achieved if complexing agents can be coupled easily to substances that accumulate selectively in lesions and in this process do not lose their advantageous complexing properties. Since a weakening of the complex stability is observed frequently after a complexing agent is coupled to such a molecule, the previous attempts to couple chelating agents to selectively accumulating substances do not appear to be very satisfactory. The reason lies in the fact that a diagnostically intolerable proportion of the isotope is released from the conjugate in vivo [Brechbiel, M. W. et al., Inorg. Chem. 25, 2772 (1986)]. It is therefore necessary to provide bifunctional complexing agents that carry both functional groups for stable binding of the desired metal ion and one or more other functional groups for binding the selectively accumulating molecule. Such bifunctional ligands make possible a specific, chemically defined binding of technetium or rhenium isotopes to the most varied biological materials even if a so-called prelabeling is performed. Some chelating agents were described that were coupled to, e.g., monoclonal antibodies (e.g., EP 247 866 and EP 188 256) or fatty acids (EP 200 492). As chelating agents, however, the already mentioned N
2
S
2
systems were used, which were not very suitable because of their poor stability. Since both the properties of the selectively accumulating substances and the mechanisms according to which they are concentrated in lesions are very different, it is also necessary to vary the chelating agents that can be coupled and to be able to adapt the physiological requirements of the coupling partner with respect to its lipophilia and hydrophilia, membrane permeability or impermeability.
To deal with the above-mentioned drawbacks and limitations of the established chelating groups as well as their conjugates with biomolecules, which accumulate selectively in diseased tissues, it has been attempted in recent years to use tricarbonyl-technetium-I compounds and tricarbonyl-rhenium-I compounds for labeling such biomolecules (Lit. R. Alberto et al., Achievements and Prospects of New Radiotracers, 1997, C3, p. 57 (Abstracts)). Since, however, tricarbonyl-technetium-I-triaqua ions and tricarbonyl-rhenium-I-triaqua ions with high stability are bonded non-specifically and quickly by serum proteins, however, it has not yet been possible to synthesize adequately stable conjugates between substances that accumulate selectively in diseased tissues with tricarbonyl-technetium-I complexes and tricarbonyl-rhenium-I complexes.
International Patent Application WO 98/48848 describes a general method for the production of tricarbonyl-technetium-I complexes and tricarbonyl-rhenium-I complexes. Special chelating agents, which can be coupled to biomolecules and with whose aid especially stable complexes are obtained, are not mentioned in this application.
The object of this invention was therefore to develop stable tricarbonyl-technetium-I complexes and tricarbonyl-rhenium-I complexes that can be coupled to various compounds that selectively accumulate in diseased tissues. Another object of the invention was to provide such chelating agents or complexes that can be coupled and that have a large chemical range of variation of the substituents so as to be able to adapt the latter to the above-referenced requirements. Another aspect of the invention relates to processes for the production of the compounds as well as the pharmaceutical agents that contain the compounds.
This object is achieved by the compounds of general formula (I)
Y—CR
1
R
2
—(CR
3
R
4
)
n
—N (CR
5
R
6
—COOR
7
)—CR
8
R
9
—CO—X (I)
in which
n stands for numbers 0, 1 or 2;
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
8
and R
9
are the same or different and in each case represent a hydrogen atom or an unbranched, branched, cyclic or polycyclic C
1
-C
60
alkyl, C
1
-C
60
alkenyl, C
5
-C
60
polyalkenyl, C
1
-C
60
alkinyl; C
5
-C
60
polyalkinyl, C
5
-C
60
aryl, C
5
-C
60
alkylaryl or C
5
-C
60
arylalkyl radical, which optionally is substituted with hydroxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As, Se;
R
7
Berndorff Dietmar
Blume Friedhelm
Dinkelborg Ludger
Heldmann Dieter
Hilger Stephan
Jones Dameron L.
Millen White Zelano & Branigan P.C.
Schering Aktiengesellschaft
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