Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Peptides containing saccharide radicals – e.g. – bleomycins – etc.
Reexamination Certificate
1997-09-25
2001-08-07
Low, Christopher S. F. (Department: 1654)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Peptides containing saccharide radicals, e.g., bleomycins, etc.
C514S025000, C514S034000, C514S312000, C514S019300
Reexamination Certificate
active
06271342
ABSTRACT:
BACKGROUND OF THE INVENTION
This application is a 371 of PCT/EP96/01279, which was filed on Mar. 11, 1996.
1. Field of the Invention
The invention relates to cytostatics which, due to modification with carbohydrates, are tumour-specific. Suitable spacers ensure serum stability and at the same time an intracellular action.
2. Description of Related Art
Chemotherapy of tumour diseases is accompanied by usually serious side effects caused by the toxicity of chemotherapeutics on proliferating cells of other tissue. For many years, scientists have been addressing the problem of improving the selectivity of the active compounds used. One approach which is often followed is the synthesis of prodrugs, which are liberated more or less selectively in the target tissue, for example by a change in the pH (Tietze et al., for example DE-4 229 903), by enzymes (for example glucuronidases; Jacquesy et al., EP-511 917; Bosslet et al., EP-595 133) or by antibody-enzyme conjugates (Bagshawe et al. WO 88/07378; Senter et al., U.S. Pat. No. 4,975,278; Bosslet et al., EP-595 133). Problems of these approaches are, inter alia, the lack of stability of the conjugates in other tissues and organs and, in particular, the ubiquitous distribution of the active compound, which follows extracellular liberation of the active compound in the tumour tissue.
The pronounced lectin pattern on the surfaces of tumour cells (Gabius; Onkologie 12, (1989), 175) opens up the chief possibility of addressing these specifically on tumour cells by linking the corresponding carbohydrate units to cytostatics. These perspectives are limited by the fact that lectins with similar carbohydrate specificities (galactose, lactose, mannose, N-acetyl-glucosamine, fucose and the like) also occur in other tissues, in particular in the liver (Ashwell et al., Annu. Rev. Biochem. 46 (1982), 531; Stahl et al. Proc. Natl. Acad. Sci. U.S.A. 74 (1977), 1521; Hill et al., J. Biol. Chem. 262 (1986), 7433; Jansen et al., J. Biol. Chem. 266 (1991), 3343). A significant concentration of glycoconjugates containing the active compound in the liver and other lectin-rich organs must consequently be expected if such non-modified sugars are used.
The heterocyclic amine batracyline (1) shows a good antitumoural action in various intestinal cancer models (U.S. Pat. No. 4,757,072).
Peptide conjugates of (1) with a good in vitro action and more favourable solubility properties (U.S. Pat. No. 4,180,343) are tolerated more poorly than batracyline in animal studies. The fucose conjugates described in EP-501 250 become very highly concentrated in the liver.
Quinolone-a (2), 7-[(3aRS,4RS,7aSR)-4-amino-1,3,3a,4,7,7a-hexahydro-isoindol-2-yl]-8-chloro1-cyclopropyl-6-fluoro-1,4-dihydro4-oxo-3-quinolinecarboxylic acid also shows, in addition to its outstanding antibacterial activity, a very good activity against various tumour cell lines (EP-520 240, JP-4 253 973). However, this is faced with considerable toxicological problems (for example genotoxicity, bone marrow toxicity, high acute toxicity in vivo and the like).
BRIEF SUMMARY OF THE INVENTION
By a novel modification of cytostatics, we have found, surprisingly, a new class of conjugates which are distinguished by the following properties: A novel linkage of carbohydrates with cytostatics (for example batracyline, quinolone-a) leads to glycoconjungates which are serum-stable. The action does not depend on extracellular liberation of the active compound. The in vitro activities against various tumour cell lines are comparable to that of the cytostatic on which they are based. The cell-specific absorption depends on the carbohydrate.
The cell and tissue selectivity (in particular tumour to liver) is significantly improved by the regioselective modifications in the carbohydrate part of the conjugates described.
In vivo, the conjugates according to the invention are distinguished by a significantly improved tolerance compared to the active compound and the corresponding peptide conjugates.
Furthermore, in comparison with the cytostatics on which they are based, the conjugates according to the invention show considerably improved solubility properties.
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Antonicek Horst-Peter
Baumgarten Jorg
Bremm Klaus Dieter
Lerchen Hans-Georg
Petersen Uwe
Bayer Aktiengesellschaft
Low Christopher S. F.
Lukton David
Norris & McLaughlin & Marcus
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