Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-07-30
2000-12-19
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
5462817, 536107, 536109, 424450, A61K 3144, C07D40504
Patent
active
061629200
DESCRIPTION:
BRIEF SUMMARY
The invention relates to pharmacologically active compounds that have the ability to influence the polymerisation and depolymerisation of tubulin.
A range of natural mitosis toxins are used as anti-tumour agents or are in the process of being clinically tested. There are various classes of such mitosis toxins that either demonstrate their cytotoxic action by inhibiting the polymerisation of microtubules in the spindle system (for example, Vinca alkaloids, colchicine) or achieve their cytotoxic action by a GTP-independent increase in the polymerisation of the tubulin and by preventing the depolymerisation of microtubules (for example, taxol, taxoters).
Owing to their physico-chemical properties, hitherto not understood, and as a result of the characterstics of neoplastic cells, mitosis toxins have a certain selectivity for tumour cells, but there still remains a not inconsiderable cytotoxicity towards non-transformed cells. The search for more selective compounds that are easier to manufacture and--like the taxane class of substances--are able to inhibit the depolymerisation of microtubules, had, surprisingly, led to the discovery of borneol esters, as described in P 4416374.6 and 19513040.5. Structural modifications in that class of compounds have revealed a considerable potential for optimisation in respect of the action on microtubules. Outstanding results have been obtained, inter alia, by formal esterification of those borneols with an acid of the Sk-H type. By synthesising the taxol derivatives described herein, in which the isoserine chain of the taxol has been replaced by Sk, the intention was to study whether it is also possible in that class of substances to achieve an improved stabilisation of microtubules, compared with taxol.
Further, the following documents disclose compounds showing pharmacological activity:
However, compounds disclosed in WO-A-94 21 252 form the closest state of the art.
Surprisingly, it has now been found that the compounds of formula I according to the invention, compared with taxol and state of the art compounds, have an advantageously altered activity profile. In addition to a clearly improved stabilisation of microtubules, the compounds of formula I demonstrate an additional influence on the polymerisation of tubulin.
The taxanes according to the invention are characterised by the general formula I ##STR1## wherein Sk may be ##STR2## R.sup.1 may be hydrogen or C.sub.1 -C.sub.10 acyl, R.sup.2 may be .alpha.-OH or .beta.-OH, -C.sub.10 alkoxy, etherification or esterification, and also compounds of the general formula I encapsulated with liposomes.
There come into consideration as alkyl group R.sup.3 straight-chained or branched alkyl groups having from 1 to 10 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl and decyl. Alkyl groups having from 1 to 4 carbon atoms are preferred. The acyl and alkoxy groups contained in R.sup.1 and R.sup.3, respectively, of general formula I contain from 1 to 10 carbon atoms, with formyl, acetyl, propionyl and isopropionyl groups, and methoxy, ethoxy, propoxy, isopropoxy and t-butoxy groups, respectively, being preferred.
Halogen in the definition of X is fluorine, chlorine, bromine or iodine.
Preferred compounds of the general formula I are: and l-taxol.
The invention relates also to a process for the preparation of borneol derivatives of formula I, which process is characterised in that an alcohol of the general formula II ##STR3## wherein R.sup.1 and R.sup.2 are as defined hereinabove and hydroxy groups contained in II are optionally protected, is reacted with a compound of the general formula IIIa, IIIb or IIIc, ##STR4## wherein R.sup.3 is as defined hereinabove and X' may be hydroxy, O-alkyl or halogen, and wherein free hydroxy groups are protected by etherification or esterification, to form compounds of the general formula I in which free hydroxy groups may be functionally modified further by etherification or esterification.
For the esterifi
REFERENCES:
patent: 5489601 (1996-02-01), Holton et al.
patent: 5760219 (1998-06-01), Holton et al.
Sharma et al., "Pharmaceutical and Physical Properties of Paclitaxel (Taxol.uparw.) Complexes with Cyclodextrin," Journal of Pharmaceutical Sciences, vol. 84, pp. 1223-1230 (1995).
Nicolaou et al., "Chemistry and Biology of Taxol," Angew. Chem. Int. Ed. Engl., vol. 33, pp. 15-44 (1994).
Georg et al., "Heteroaromatic Taxol Analogues: The Chemistry and Biological Activities of 3'-Furyl and 3'-Pyridyl Substituted Taxanes," Bioorganic & Medicinal Chemistry Letters, vol. 4, No. 11, pp. 1381-1384 (1994).
Graf Hermann
Klar Ulrich
Neef Gunter
Rotman Alan L.
Schering Aktiensgesellschaft
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