Hsiang-ssu-tzu (Abrus precatorius L.), a medical plant of leguminosae, was described for the first time in the ancient Chinese medicine book, "Pen-Tsao-Kan-Mu" (Shin-Chen, Li; 1518-1593), by its therapeutical use in folk medicine:
Cardiovascular diseases, especially the various forms of thrombosis, such as coronary, embolic, venous, and traumatic thrombosis, account for a large number of deaths per year. In fact, it is estimated by the American Heart Association that 54% of all deaths in the United States are attributed to cardiovascular disease. It is therefore important for us to be familiar with the physical, chemical, and clinical aspects of drugs used to treat these forms of thrombosis. Since it is believed that initiation of thrombus formation is dependent of platelet aggregation, inhibitors of platelet aggregation may be prototypes of drugs that can effectively combat thrombosis, which leads to heart attacks and stokes. It has prompted us to search for novel compounds possessing more potent inhibitive activity on platelet aggregation.
On the other hand, rheumatic diseases are classified as chronic connective tissue diseases and belong to the complex group of active immunity inflammatory conditions. They may disable single or multiple organ systems of the body and affect approximately 20 million Americans. Therapy is not directed primarily to the inflammatory processes. The development of antiinflammatory drugs started with the use of salicylates at the end of the nineteenth century. Interest in the pyrazolones resulted in the discovery of phenylbutazone. The 1950's was the decade of the corticosteroids; this was followed by an effort to find potent non-steroidal substances that do not have the side effects of corticosteroids, which were culminated in the 1960's with indomethacin. More recently, many laboratories are engaged in the synthesis and evaluation of compounds belonging to different chemical classes. However, few attention is paid to plant constituents which may possess immunosuppressive nature. The present invention discloses the potent antiinflammatory property of the novel abruquinone derivatives determined by measuring the inhibitory activity on the release of B-glucuronidase, glucuronidase, lysozyme, and superoxide from neutrophils induced by FMLP.
Similar evaluation, which was carried out by measuring the inhibitory activity of the novel abruquinone derivatives on the release of B-glucuronidase and histamine from mast cells using compound 48/80 as an inducer, also revealed their antiallergic property. Hypersensitivity or allergic reactions cause many chronic and acute illnesses, including hay fever, pruritus, contact dermatitis, drug rashes, urticaria, atopic dermatitis, and analphylactic shock. In fact, about 1 in 10 Americans have allergy. Desensitization is the most common treatment for allergy. The procedure is undertaken to prevent antigen-antibody reactions and thus stop the release of chemical mediators. This led the allergists to attempt to build up the patient's immunity to the antigen. Thus, many natural products and synthetic compounds were investigated. The isolation of khellin (VI) led to the finding of cromolyn sodium (VII). However, cromolyn sodium is poorly absorbed orally and thus is administered in the form of a powder aerosol. This drug is prophylactic and does not inhibit the action of histamine, SRS-A, or any other phylactic chemical mediators. So far, the experimental results show that the potency of compounds disclosed in this invention are superior than indomethacin (Compound VI) and cromolyn sodium (Compound VII) in antiinflammatory and antiallergic evaluations. Compounds VI and VII are shown below:
The investigation of the contents of Hsiang-ssu-tzu (Abrus precatorius L.) was performed in some laboratories (Khaleque, A. et al., Sci. Res. 3, 203, 1996; Ghosal, S. et al., Phytochemistry, 10, 159, 1971.; Chiang, T. C. et al., J. Chem. Soc. Chem. Comm., 20, 1197, 1982; Planta medica 49, 165, 1983). Abruquinone A, B, C were isolated for the first time from the roots of this plant by Lupi, A. et al., (Gazz. Chim. Ital., 109, 9, 1979). These authors have tried to synthesize Abruquinones A and B (Lupi, A. et al., Gazz. Chim. Ital., 110, 625, 1980). As to their biological activity, only one paper has described the inhibitory activity of Abruquinone A on the growth of Trypanosoma cruz and Crithidia fasciculata (Goijman, S. G. et al., Experientia, 41, 646, 1985).
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USPTO Backgrounds