| 摘要 |
PCT No. PCT/EP97/00440 Sec. 371 Date Jul. 30, 1998 Sec. 102(e) Date Jul. 30, 1998 PCT Filed Jan. 31, 1997 PCT Pub. No. WO97/28156 PCT Pub. Date Aug. 7, 1997The 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-tumor 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 characteristics of neoplastic cells, mitosis toxins have a certain selectivity for tumor 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 broneols 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 By synthesising the taxol derivatives described herein, in which the isoserine chain of the taxol has been replaced by Sk, the intention was to study whether it is also possible in that class of substances to achieve an improved stabilisation of microtubules, compared with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. |
