Anthracycline compound derivative and pharmaceutical preparation

Details Anthracycline compound derivative and pharmaceutical preparation Anthracycline compound derivative and pharmaceutical preparation

1997-08-18

2000-06-27

Peselev, Elli

Drug, bio-affecting and body treating compositions

Solid synthetic organic polymer as designated organic active...

424 7817, 424450, 424451, 424489, 424501, 514 34, 536 64, A61K 9127, A61K 3170, C07M 1708

Patent

active

060803967

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to a novel anthracycline compound derivative and a high molecular block copolymer-drug complex pharmaceutical preparation which contains the derivative.


BACKGROUND ART

Daunomycin (British Patent 1003383, U.S. Pat. No. 3,616,242), adriamycin (U.S. Pat. No. 3,590,028, U.S. Pat. No. 3,803,124) and the like obtained from culture liquids of actinomycetes are known as anthracycline anticancer agents. They have broad anticancer spectrums against experimental tumors and also are clinically used widely as cancer chemotherapeutics. On the contrary, however, it is known that they frequently cause serious side effects, such as leukopenia, alopecia, myocardial disorder and the like.
In order to resolve this problem, various derivatives have been proposed. For example, pirarubicin (common name) aims at reducing its toxicity by introducing a tetrahydropyranyl group into the 4' position of the sugar moiety of adriamycin.
Also, epirubicin (common name) is a compound in which a hydroxyl group on the 4' position of the sugar moiety of adriamycin is bound to the a position, thereby attempting to reduce its toxicity.
However, though these drugs have lower toxicities in comparison with adriamycin, their problems such as limited total doses and the like are not completely settled yet.
On the other hand, it is a well known technique to make use of a high molecular micelle formed from a block copolymer to improve solubility of drugs which are slightly soluble in water. And it has been confirmed that high molecular block copolymer-drug complex pharmaceutical preparations obtained in Japanese Patent Application (Kokai) No. 2-300133, Japanese Patent Application (Kokai) No. 6-107565, Japanese Patent Application (Kokai) No. 5-955, Japanese Patent Application (Kokai) No. 5-124969, Japanese Patent Application (Kokai) No. 5-117385, Japanese Patent Application (Kokai) No. 6-206830, Japanese Patent Application (Kokai) No. 7-69900 and Japanese Patent Application (Kokai) No. 6-206815 are possessed of anticancer effects which are superior to those of adriamycin.


DISCLOSURE OF THE INVENTION

The inventors of the present invention have conducted intensive studies on a high molecular block copolymer-drug complex pharmaceutical preparation which is possessed of both higher effect and lower toxicity in comparison with the prior art high molecular block copolymer-drug complex pharmaceutical preparations, and have accomplished the present invention as a result of the efforts.
Accordingly, the present invention relates to: obtained by directly, chemically bonding anthracycline compound or compounds having anticancer activities to each other by an alkali treatment; the aforementioned item (1) wherein the anthracycline compound or compounds comprise at least one kind of compound selected from adriamycin, daunomycin, pirarubicin, epirubicin and acid salts thereof; chemically bonding adriamycin molecules or acid salts thereof to each other, or by directly, chemically bonding adriamycin or an acid salt thereof to daunomycin or an acid salt thereof, by an alkali treatment; the aforementioned item (1), (2) or (3) wherein the mutual binding mode of anthracycline compounds is Schiff base bonding; (AA): ##STR1## (6) a trimer of adriamycin which can be obtained by directly, chemically bonding adriamycin molecules or acid salts thereof to each other by an alkali treatment and has the mass spectrum shown in FIG. 7; preparation in which the high molecular block copolymer having a hydrophilic polymer segment and a hydrophobic polymer segment forms a micelle having the hydrophilic segment as its outer shell and contains in its hydrophobic inner core a dimer, trimer or tetramer of anthracycline compound, if necessary together with other drugs; preparation according to the aforementioned item (7) wherein the dimer, trimer or tetramer of anthracycline compound is the dimer, trimer or tetramer of anthracycline compound of the aforementioned item (1), (2), (3), (4), (5) or (6); preparation according to the aforementioned item (

REFERENCES:
patent: 4263428 (1981-04-01), Apple et al.
patent: 4625019 (1986-11-01), Relyveld
patent: 5412072 (1995-05-01), Sakurai et al.
patent: 5449513 (1995-09-01), Yokoyama et al.
patent: 5510103 (1996-04-01), Yokoyama et al.

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