3-,8-substituted deuteroporphyrin derivatives, pharmaceutical ag

Details 3-,8-substituted deuteroporphyrin derivatives, pharmaceutical ag 3-,8-substituted deuteroporphyrin derivatives, pharmaceutical ag

1995-05-24

1998-12-15

Kight, John

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

424 111, 424 91, 424 93, 424 94, 424 9362, A61K 5100, A61M 3614

Patent

active

058492593

DESCRIPTION:

BRIEF SUMMARY
The invention relates to porphyrin complex compounds with various substituents in positions 3, 8, 13 and 17 of the porphyrin skeleton, pharmaceutical agents containing these compounds, their use in diagnosis as well as process for the production of these compounds and agents.
The use of complexing agents or complexes or their salts in medicine has long been known. As examples can be mentioned: complexing agents as stabilizers of pharmaceutical preparations, complexes and their salts as auxiliary agents for administration of poorly soluble ions (e.g., iron), complexing agents and complexes (preferably calcium or zinc), optionally as salts with inorganic and/or organic bases, as antidotes for detoxification in accidental incorporation of heavy metals or their radioactive isotopes and complexing agents as auxiliary agents in nuclear medicine by using radioactive isotopes such as .sup.99m Tc for scintigraphy.
Complexes and complex salts have been presented as diagnostic agents, mainly as NMR diagnostic agents, in patents EP 0 071 564, EP 0 139 934 and DE 34 01 052. However, they do not yet optimally meet all requirements which determine the relative effectiveness of an NMR contrast medium, of which the following are to be mentioned as examples: possible concentrations reduces in vivo the relaxation times of the protons in tissue fluids and other nuclei relevant for the NMR (such as phosphorus, fluorine, sodium) and makes possible, for example, the localization of tumors by increasing the signal intensity of the image obtained with the help of the nuclear spin tomograph; a concentration and/or retention of the contrast medium in the target organ as selective as possible; sufficient water solubility; high effectiveness; good compatibility; good chemical and biochemical stability.
Thus above all the two first mentioned points are relevant for imaging. Since the relaxation times between the tissues differ mostly only by the factor of 2-3 (T. E. Budinger and P. C. Lauterbur, Science 226, pp. 288-298, 1984; J. M. S. Hutchinson and F. W. Smith in Nuclear Magnetic Resonance Imaging Edit. C. L. Partain et al., pp. 231-249, Saunders, N.Y. 1983) and the complexes and complex salts of the mentioned patents generally have the drawback that they only spread relatively nonspecifically in the extracellular space and therefore a detection of pathologically changed tissues is not always possible, above all there is a need for selectively binding, tumor-specific compounds that can be used in diagnosis and radiation therapy.
It has been known for some years that porphyrin derivatives selectively accumulate in human and animal tumors (D. Kessel and T.-H. Chou, Cancer Res. 43, pp. 1994-1999, 1983, P. Hambright, Bioinorg. Chem. 5, pp. 87-92, 1975; R. Lipson et al., Cancer 20, pp. 2250-2257, 1967; D. Sanderson et al., Cancer 30, pp. 1368-1372, 1972). First attempts to use this class of compound as diagnostic agents were also described (J. Winkelmann et al., Cancer Research 27, pp. 2060-2064, 1967; N. J. Patronas et al., Cancer Treatment Reports 70, pp. 391-395, 1986).
However, the compounds so far described are far from being able to meet satisfactorily the above-mentioned criteria; their deficient concentration in the target organs still requires special attention. An improvement of this property should at the same time help reduce the existing problems with toxicity and compatibility of the previously known compounds.
Substituted hematoporphyrin complex compounds used in diagnosis and treatment are described in patent application EP 0 355 041.
While these compounds show a good concentration behavior in various target organs, the described compounds used as NMR diagnostic agents have a not yet completely satisfactory ratio between the dose necessary for optimal imaging and the lethal dose. Hematoporphyrin derivatives also have the drawback that they can eliminate both pseudobenzylic OH groups in the hydroxyethyl side chains.
In patent EP 0 071 569 NMR diagnostic agents are described based on DTPA complexes which, while having a favo

REFERENCES:
patent: 4485086 (1984-11-01), Wong
patent: 4935498 (1990-06-01), Sessler et al.
patent: 5275801 (1994-01-01), Niedballa et al.
patent: 5283255 (1994-02-01), Levy et al.
patent: 5371199 (1994-12-01), Theiren et al.

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