Borneol derivatives, methods of manufacturing them, and their ph

Details Borneol derivatives, methods of manufacturing them, and their ph Borneol derivatives, methods of manufacturing them, and their ph

1998-08-28

2000-02-15

Trinh, Ba K.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

560 23, 560 29, 514475, 514507, C07D30316, C07C27122, A61K 31325, A61K 31335

Patent

active

060255072

DESCRIPTION:

BRIEF SUMMARY
The invention relates to new pharmacologically active compounds, which have the power to influence tubulin polymerization or tubulin depolymerization.
A number of natural mitotic poisons are used as anti-tumor agents or are undergoing clinical trials. Various classes of these mitotic poisons exist that exert their cytotoxic action either by inhibiting the polymerization of microtubuli in a spindle device (e.g., vinca alkaloids, colchicine) or accomplish this by a GTP-independent increase of the polymerization of the tubulin and prevention of the depolymerization of microtubuli (e.g., taxol, taxotere). Owing to previously little-understood physicochemical properties and the characteristics of neoplastic cells, mitotic poisons have a certain selectivity for tumor cells, but there is also significant cytotoxicity with regard to nontransformed cells.
Up until now, vinca alkaloids have had great importance in the combined chemotherapy of myeloid tumors. Taxanes have very recently opened up important applications that were not accessible by previously available cytostatic agents, e.g., ovarian cancers, malignant melanomas. The side effects of taxanes are comparable to those of other cytostatic agents, however (e.g., loss of hair, sensory neuropathy). Multi-drug-resistant tumor cells, which over-express the P-glycoprotein, are resistant to taxanes. The limited availability of the natural substance taxol also inhibits broader clinical trials.
Natural substances and synthetic pharmaceutical agents that have a spectrum of action unlike that of the previous mitotic poisons were therefore tested. An in vitro experimental arrangement makes it possible to search for substances that do not influence the GTP-dependent polymerization of tubulin, but influence the depolymerization of the microtubuli formed. Substances with such a profile of action should influence the versatile functions of microtubuli in extranuclear cell compartments less strongly than the dynamic of the spindle device during mitosis (metaphase/anaphase). Logically, such compounds should have fewer side effects in vivo than taxanes or vinca alkaloids.
Tubulin is an essential component of the mitotic spindle. It is used, i.a., to preserve the cell shape, to transport organelles inside the cell, and to influence cell mobility.
Up until now, taxanes have represented the only known structural class that is able to accelerate the polymerization of tubulin (mainly in the G2 phase), as well as to stabilize the microtubuli polymers formed. This mechanism is clearly distinguishable from those that have other structural classes which also influence the phase-specific cell division. Thus, for example, substances from the group of vinca alkaloids (e.g., vincristines and vinblastines) but also colchicine inhibit the polymerization of the tubulin dimers in the M phase.
It has now been found that compounds of formula I that are comparatively simple to produce are able to inhibit the depolymerization of microtubuli without increasing the formation of microtubuli in a GTP-independent manner. Moreover, compounds with a completely new profile of action that are able to accelerate the depolymerization of microtubuli were identified. On the basis of these properties, the compounds of formula I represent valuable pharmaceutical agents that are basically able to supplement or replace taxanes, which are difficult to synthesize and which are still not available in sufficient quantities, such as, e.g., taxol and Taxotere.sup.(R), in the treatment of malignant tumors (EP-A 253739).
The new borneol derivatives are characterized by general formula I ##STR2## in which R.sup.1 means C(O)--CH(OR.sup.6)--CH(NHR.sup.7a R.sup.7b)--R.sup.8, C(O)--CH(OR.sup.6a)--CH[NH(C(O)--CH(OR.sup.6b)--CH(NR.sup.7a R.sup.7b)--R.sup.8)]--R.sup.8, alkoxy, --OC(O)R.sup.9a, --OSO.sub.2 R.sup.9a, --OP(O)(OH).sub.2, NHR.sup.9a, NR.sup.9a R.sup.9b, --OSO.sub.2 R.sup.9b, --OP(O)(OH).sub.2, or --OR.sup.11a, --OR.sup.11b, or --C(O)SR.sup.12, --C(O)NHR.sup.9d, --C(O)NR.sup.9d R.sup.9e, C.sub.1 -C.sub.10 alkyl, ##STR

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