Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-10-02
1999-10-26
Mach, D. Margaret M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142358, 5142362, 5142365, 5142372, 514252, 514255, 514256, 514332, 514352, 544120, 544122, 544124, 544238, 544295, 544357, 546264, 546255, 546304, 546329, 546338, C07D41300, C07D24102, C07D21336, C07D21172
Patent
active
059729767
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP95/00,658, filed Apr. 5, 1995.
TECHNICAL FIELD
The present invention relates to a medicinally useful, novel aminostilbazole derivative or its hydrate and a pharmaceutically acceptable salt thereof.
BACKGROUND TECHNOLOGY
In cancer chemotherapy today, a variety of anticancer drugs such as alkylating agents, topoisomerase inhibitors, antimetabolites, cytoskeletal system inhibitors, enzymes, hormones, antihormones, antibiotics, and plant products are being employed.
Referring to anticancer hormones, particularly stilbenes having a nuclear skeletal structure resembling that of the compound of the present invention, stilbestrol phosphate and tamoxifen and so on have been used in the treatment of cancer of the prostate, breast and other tissues but they are not fully satisfactory from the standpoint of efficacy and in view of the adverse effects associated with their hormonal activity.
Antimicrotubule agents or tubulin agonists have potent anticancer activity with a broad anticancer spectrum and constitute a clinically important class of drugs.
The inhibition of tubulin polymerization is attracting attention of late as a mechanism of action of anticancer agents. The microtubule is an ubiquitous intracellular structure and, as a major component of the mitotic spindle, plays an important role in cell division. An antimicrotubule agent binds to the tublin protein of the microtubule and disrupts the dynamics of the microtubule by orienting it either in the direction of assembly or in that of disassembly, thus manifesting its anticancer activity. Vinca alkaloids, which are of plant origin, are known as representative tubulin polymerization-inhibitory anticancer agents and recently taxols are gathering attention because of their potent anticancer efficacy associated with promotion of tubulin polymerization. Being derived from plants, these compounds have availability problems. Such anticancer drugs acting on microtubules are available as injections which cannot be conveniently used and, because of their side effects, are not being used in multiple-dose regimens. Quite recently, the low molecular weight substance E7010 (Cancer and Chemotherapy, 1993 20: 34-41, JP Kokai H5-39256) has been discovered and clinical trials with the compound are now being watched by many with much interest.
It is reported that stilbene derivatives represented by (Z)-3,4,5-trimethoxy-4'-methoxystilbene as well as dihydrostilbene derivatives, which have a stilbene nucleus similar to that of the compound of the present invention, have tubulin polymerization-inhibitory activity (J. Med. Chem. 1991, 34, 2579).
Meanwhile, it is reported that hydroxamic acid derivatives substituted by a phenylethenyl-heterocyclic group show antiallergic activity (Eur. J. Med. Chem. 1985, 20, 487-491). There also is a report on the interaction between tetrahydrostilbazole and monoamine oxidase (J. Med. Chem. 1994, 37, 151-157).
DISCLOSURE OF INVENTION
The present invention has for its object to provide a novel compound which shows an excellent anticancer action without eliciting those adverse reactions which are experienced with the anticancer hormones available today and can be administered by the oral route.
To accomplish the above object, the inventors of the present invention have synthesized a variety of compounds and evaluated them. In the course of the research endeavor, they have found that the compound of the following general formula [I] has very potent anticancer activity with low toxicity and has perfected the present invention.
The present invention relates to a compound of the following general formula [I], its salt, and an anticancer composition comprising said compound or salt as an active ingredient. ##STR2## wherein R.sup.1 and R.sup.2 are the same or different and each represents hydrogen, alkyl of 1-6 carbon atoms, acyl of 1-6 carbon atoms, cyano, or --COOR (R represents hydrogen or C.sub.1-6 alkyl).
R.sup.3, R.sup.4, R.sup.13, and R.sup.14 are the same or different and each represents hydrogen, alkyl of
REFERENCES:
patent: 5534654 (1996-07-01), Ohtani et al.
Chemical Abstracts 106:6405, abstract of EP 176473, 1986.
Chemical Abstracts 106:6404, abstract of EP 176474, 1986.
J. Med. Chem. 1991, 34, 2579-2588.
J. Med. Chem. 1994, 37, 151-157.
Eur. J. Med. Chem. 1985, 20, 487-491.
Hidaka Hiroyoshi
Matsuda Masato
Matsuura Akira
M. Mach D. Margaret
Nippon Shinyaku Company Limited
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