Process for preparing 5,8-dihydroxynaphthoquinone derivatives, n

Details Process for preparing 5,8-dihydroxynaphthoquinone derivatives, n Process for preparing 5,8-dihydroxynaphthoquinone derivatives, n

1995-03-14

1997-12-09

Ivy, C. Warren

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

Organic compounds

Cyclohexadiene having atoms double bonded directly at the 1-...

C07C 5032

Patent

active

056962762

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a process for preparing 5,8-dihydroxynaphthoquinone derivatives represented by the following general formula (I) which has an excellent anticancer activity: ##STR2## in which R.sup.1 represents alkyl or alkenyl, alkyl, alkenyl, aryl, aralkyl or aralkenyl, which can be substituted or unsubstituted with one or more halogen(s), and
The present invention also relates to a 5,8-dihydroxynaphthoquinone derivative represented by the following general formula (IA), which is considered as the novel compound among the compounds of formula (I) above: ##STR3## in which R.sup.1 represents alkyl or alkenyl, alkyl, alkenyl, aryl, aralkyl or aralkenyl, which can be substituted or unsubstituted with one or more halogen(s), and hydrogen or a group --C(O)R and R.sup.3 is hydrogen, R.sup.1 is other than 3-methyl-2-butenyl; and when R.sup.2a and R.sup.3 independently of one another represent hydrogen or methyl, R.sup.1 is other than 3-methylbutyl.
In addition, the present invention relates to use of the novel 5,8-dihydroxynaphthoquinone derivative of formula (IA) as an anticancer agent.


BACKGROUND ART

Study of the method for treatment of cancer as one of incurable diseases of today has been actively conducted by means of chemotherapy, physical therapy and genetic engineering technique, together with study of the mechanism of attack and progress of cancer. As one of various therapeutic methods for treating cancer as mentioned above, chemotherapy attempts to treat cancer using anticancer agent. However, none of currently used anticancer agents has a satisfactory potent anticancer activity. Accordingly, attempts have been continuously made to develope an anticancer agent having a new mechanism of action and a potent anticancer activity. Such attempt to develope an anticancer agent has extended to search for substances having anticancer activity in the field of organic chemical synthesis and natural substances and further to synthesize a pharmacologically active substance from derivatives produced by transforming the component isolated from the natural product with organic chemical techniques.
As one of the progress of a series of such study, shikonin having the following formula (A) and its derivatives were proposed: ##STR4##
Shikonin was first isolated from Alkana tinctoria by H. Brockmann in 1936 Borraginaceae, and has been known as a compound having anticancer activity. However, since shikonin itself has a week anticancer activity and is difficult to absorb in the body, some derivatives wherein various substituents are introduced into a secondary alcoholic hydroxy group on 1'-position have been isolated from plants and then clinically used. Among them, typical known compounds are 1'-O-acetylshikonin 1'-O-isobutanoylshikonin ! and 1'-O-(3,3-dimethyl)acrylshikonin oquinone!.
Thereafter, extensive study to develope shikonin derivatives has been continuously made. As a result, numerous compounds having various acyl groups introduced into the alcoholic hydroxy group of shikonin have been developed. However, for preparation of such acyl derivatives of shikonin, a method for selectively acylating only the secondary alcoholic hydroxy group among three hydroxy groups, i.e. two phenolic hydroxy groups and one alcoholic hydroxy group, present in shikonin (A) is required. Conventional methods which have been generally used for this purpose include, for example, a method for protecting the phe-nolic hydroxy group with a specific method, reacting the alcoholic hydroxy group of shikonin with Patent Publication No. 2831786!; a method for reacting shikonin (A) with Publication No. (sho) 61-151151!; and the like. However, such known methods have disadvantages in that they consist of multi-step procedures and therefore are complicated, and they are lacking in selectivity to produce a lot of by-product, and therefore the yield of the desired acylshikonin derivatives is considerably low.
Thus, the present inventors have extensively studied to find the method which can prepare acylshikonin derivat

REFERENCES:
Chemical Abstracts vol. 107, No. 154,149, Terada, 1987, "Synthesis of napthoquinone derivatives".
Chemical Abstract, vol. 109, No. 230484, Tanoue et al, 1988, "Synthesis of naphthoquinone derivatives".
Chemical Abstract, vol. 115, No. 145001, Torii et al, 1991, "Manf. of 5,8-dimethoxy-1,4-naphthoquinone by electrochemical oxidation".

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