Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-11-27
1998-10-27
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540545, A61K 3155
Patent
active
058278460
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP 95/01909, filed May 19, 1995.
The invention relates to the use of known or novel staurosporin derivatives (indolocarbazole derivatives) for avoiding or removing multi-drug resistance to anti-tumour agents, to the novel derivatives as products, to a process for the preparation of the novel staurosporin derivatives and to pharmaceutical compositions comprising the novel derivatives.
Staurosporin, which forms the basis of the derivatives according to the invention, was isolated as early as 1977 from cultures of Streptomyces staurosporeus AWAYA, TAKAHASHI and OMURA, sp. nov. AM 2282, see S. Omura et al., J. Antibiot. 30, 275-281 (1977). Hitherto, only the relative, but not the absolute, configuration of staurosporin was known. The absolute configuration has been published only recently by N. Funato et al., Tetrahedron Letters 35:8, 1251-1254 (1994) and corresponds to the mirror image of the structure previously used in the literature to indicate the relative configuration of staurosporin. Accordingly, the Tetrahedron Letters publication recommends verbatim "that the stereochemical notation for staurosporine which has been in common use hitherto should be revised". Although the absolute configuration was not known hitherto, it was clearly established by the term "staurosporin derivative". In this text, the new formulae are used.
Staurosporin and most of the staurosporin derivatives known hitherto show a strong inhibitory action on protein kinase C. Protein kinase C, which is dependent upon phospholipids and calcium, occurs within the cell in several forms and participates in various fundamental processes, such as signal transmission, proliferation and differentiation and also secretion of hormones and neurotransmitters. Activation of that enzyme is brought about either by receptor-mediated hydrolysis of phospholipids of the cell membrane or by direct interaction with certain tumour-promoting active agents. The sensitivity of the cell towards receptor-mediated signal transmission can be significantly influenced by modifying the activity of protein kinase C (as the signal transmitter). Compounds that are capable of influencing the activity of protein kinase C may be used as tumour-inhibiting, anti-inflammatory, immuno-modulating and antibacterial active ingredients and may even be of interest as agents against atherosclerosis and disorders of the cardiovascular system and the central nervous system.
The inhibitory action on protein kinase C is weakened by a factor of from approximately 20 to over 1000 if the lactam nitrogen of staurosporin carries instead of hydrogen another substituent, that is to say, if the substituent R.sub.1 in formula I shown hereinafter is other than hydrogen. Especially when in formula I below the radical R.sub.2 is, at the same time, also other than hydrogen, the inhibitory action on protein kinase C is to all practical purposes lost. When the substituent R.sub.1 in formula I shown below is other than hydrogen, the anti-tumour activity also decreases markedly. It is presumably for that reason that only few staurosporin derivatives wherein R.sub.1 is other than hydrogen are described in the literature, although much work has been undertaken in the field in recent years and very many derivatives wherein R.sub.1 is hydrogen have been prepared. Thus, the compound corresponding to formula I below wherein R.sub.1 is benzyl, R.sub.2 is benzoyl and R.sub.3 is hydrogen, has mostly been mentioned only as a negative control.
The appearance of resistance to classical cytostatic agents is a great problem in cancer chemotherapy. The resistance is in many cases accompanied by a reduction in the intracellular concentration of active ingredient. That reduction is often associated with the appearance of a membrane-bound 170 kilodalton glycoprotein (Pgp). That protein acts as a pump having a broad specificity and is capable of transporting frequently used anti-tumour agents, such as the Vinca alkaloids, anthracyclins, podophyllotoxins and actinomycin D, out of the cell.
Caravatti Giorgio
Regenass Urs
Wacker Oskar
Borovian Joseph J.
Novartis Corp.
Richter Johann
Stockton Laura L.
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