Anthracycline derivatives having 4-amino-2,4,6-trideoxy-2-fluoro

Details Anthracycline derivatives having 4-amino-2,4,6-trideoxy-2-fluoro Anthracycline derivatives having 4-amino-2,4,6-trideoxy-2-fluoro

1997-12-22

1999-09-28

Peselev, Elli

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

536 64, 536 185, 536 186, C07H 100, C07H 1524, A61K 3170

Patent

active

059588896

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to novel anthracycline derivatives which exhibit an excellent anticancer or antitumor activity at a low dosage thereof and which have 4-amino-2,4,6-trideoxy-2-fluoro-.alpha.-L-mannopyranosyl group as the sugar moiety. This invention also relates to processes for the preparation of said novel anthracycline derivatives and further to a pharmaceutical composition comprising the same as an active ingredient. More particularly, this invention relates to 7-O-(4-amino-2,4,6-trideoxy-2-fluoro-.alpha.-L-mannopyranosyl)daunomycinon e and 7-O-(4-amino-2,4,6-trideoxy-2-fluoro-.alpha.-L-mannopyranosyl)adriamycinon e or their acid addition salts as the novel anthracycline derivatives having an anticancer or antitumor activity and a low toxicity. This invention also relates to a pharmaceutical composition containing the novel anthyracycline derivative or an acid addition salt thereof. Further, this invention relates to processes for the preparation of these novel anthracycline derivatives. Yet further, this invention relates to a novel compound useful as an intermediate for the synthesis of these novel anthracycline derivatives.


BACKGROUND ART OF INVENTION

As antibiotics of the anthracycline type are known daunomycin which is also named daunorubicin in the specification of U.S. Pat. No. 3,616,242, as well as adriamycin which is also named doxorubicin in the specification of U.S. Pat. No. 3,590,028. These compounds have broad anticancer spectra against experimental tumors and have widely been utilized for clinical purposes as a chemotherapeutic anticancer agent.
While, daunomycin and adriamycin can exhibit a somewhat strong anticancer or antitumor activity against various kinds of cancers or tumors, but are not necessarily satisfactory as the anticancer agent or antitumor agent. That is, daunomycin and adriamycin have been utitlized widely as a chemotherapeutic anticancer agent for clinical treatment of cancer-bearing patients, but they are also known to bring about serious side-effects such as leukocytopenia, alopecia, myocardiopathy and others, in many instances.
Therefore, it has hitherto been attempted to produce newly a variety of novel daunomycin-related compounds with the intention of providing such novel daunomycin-related compounds which would have a much enhanced anticancer or antitumor activity but with exhibiting a low toxicity. As some outcome of the attempts hitherto made, there have been proposed several compounds, for example, those known as aclacinomycins A and B; 4'-O-tetrahydropyranyl-adriamycin; N-monobenzyl- or N-dibenzyl-adriamycin.
Besides, U.S. Pat. No. 4,427,664 specification discloses 7-O-(3,4-di-O-acetyl-2,6-dideoxy-2-iodo-.alpha.-L-manno-hexopyranosyl)duan omycinone and 7-O-(3,4-di-O-acetyl-2,6-dideoxy-2-iodo-.alpha.-L-talo-hexopyranosyl)dauno mycinone.
We, the present inventors, proceeded with our investigations in an attempt to provide novel derivatives of daunomycin and adriamycin which will exhibit a higher anticancer or antitumor activity than those of daunomycin or adriamycin but with a low toxicity. As a part of our investigations, we have already synthesized some derivatives of daunomycin and adriamycin in which the sugar moiety of daunomycin and adriamycin has been chemically modified. For example, the present inventors already reported 4'-O-tetrahydropyranyl-daunomycin or -adriamycin as well as 3'-deamino-3'-morpholino-daunomycin or -adriamycin.
Further, the present inventors succeeded in synthesizing such anthracycline derivatives having antitumor activities which are represented by the following general formula (A) ##STR2## wherein R.sup.a stands for a hydrogen atom or a hydroxyl group, that is, 7-O-(2,6-dideoxy-2-fluoro-.alpha.-L-talopyranosyl)-daunomycinone and 7-O-(2,6-dideoxy-2-fluoro-.alpha.-L-talopyranosyl)adriamycinone, which possess an anticancer or antitumor activity (see Japanese Patent Publication "Kokoku" Hei 6-31298 and European Patent No. 0230013).
The present inventors also succeeded in synthesizing such anthracycline derivat

REFERENCES:
patent: 4427664 (1984-01-01), Horton et al.
patent: 4987126 (1991-01-01), Bargiotti et al.
patent: 5719130 (1998-02-01), Takeuchi et al.

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