Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-05-07
1998-07-14
Fonda, Kathleen K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 172, 536 179, C07H 1500, A61K 3170
Patent
active
057804419
DESCRIPTION:
BRIEF SUMMARY
This is the U.S. national stage entry under 35 U.S.C. 371 of PCT/JP94/00625, filed Apr. 14, 1994.
FIELD OF THE INVENTION
The present invention relates to a novel sphingoglycolipid having a strong anti-tumor activity, a bone marrow cell-proliferation-promoting activity and an immunostimulatory activity and a use thereof. More particularly, the present invention relates to a novel sphingoglycolipid which can be used as an anti-tumor agent, a bone marrow cell-proliferation-promoting agent as well as an immunostimulating agent in the pharmaceutical field and has an improved solubility during its dissolution, and to a sphingoglycolipid-containing pharmaceutical composition, anti-tumor agent, bone marrow cell-proliferation-promoting agent as well as immunostimulating agent.
BACKGROUND OF THE INVENTION
Sphingoglycolipids have been described in Japanese Patent Laid-Open Publication Nos. 93562/1989, 59081/1993 and 9193/1993, and WO 93/05055, and particularly the sphingoglycolipid described in WO 93/05055 is a compound having a distinguished anti-tumor activity and immunostimulatory activity.
These compounds are however the cerebrosides having a ceramide portion to which a monosaccharide is linked and thus have an extremely poor solubility in water. For instance, the clinical application of the compounds as injection requires a pharmaceutically acceptable adjuvant such as surface active agent for suspending or dissolving them into water. And, Polysorvates (Tweens) may be used as a surface active agent. However, such a surfactant has been reported to have a vasostimulant effect on its intravascular administration and to exhibit the increased cardiac output and the decreased peripheral vascular resistance when administered to human subjects (Journal of the Amerikan College of Toxicology, Vol. 3, No. 5, 1-82 (1984)). Such symptoms are considered as the adverse effects of the Polysorbate administered in a high concentration as a dissolving aid. Moreover, while the compound of the present invention is aimed at its use as an anti-tumor agent, bone marrow cell-proliferation-promoting agent as well as immunostimulating agent, Polysorbate is described to have a primary antibody-reaction-suppressing effect on immune systems by Bryant R. L. et al., Arch. Allergy Appl. Immunol., Vol. 59, 69-74 (1979), and an effect of promoting the metastasis of cancer by Kiricuta I., et al., Rev. Roum. Embryol. Cytol. Ser. Cytol., Vol. 8, 29-32, (1971), so that it exhibit an effect quite adverse to the intended use of the compound according to the present invention.
In addition, polyethylene glycol which is known as another dissolving aid has been described to have adverse effects including lactic acidosis, lake, cardiac dysrhythmia and the like by Speth, P. A. J., et al., Therapeutic Drug Monitoring, Vol. 9, 255-258 (1987), and dimethylformamide and dimethylacetamide has also been described to cause hepatic disorders by Gerald, L., et al., Drug and Chemical Toxicology, Vol. 9, 147-170 (1988).
Adverse effects of only a few dissolving aids have been described above, and the other dissolving aids are also known to have adverse effects.
It is therefore essential to decrease as much as possible the amount a surface active agent such as Polysorbate in order to ensure the safety of patients in the clinical application of a sphingoglycolipid and to use the pharmaceuticals more effectively. It can be considered desirable from this viewpoint to enhance the solubility of a sphingoglycolipid in water for its clinical application.
Furthermore, insofar as we know, neither one of the compounds described above have been reported to be practically employed as an anti-tumor agent, a bone marrow cell-proliferation-promoting agent as well as an immunostimulating agent. In addition, the physiological activity of a chemical substance depends primarily on its chemical structure, so that it is always demanded to have a novel compound having an anti-tumor activity, a bone marrow cell-proliferation-promoting activity and an immunostimulating activity.
DISCLOSU
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Higa Tatsuo
Koezuka Yasuhiko
Motoki Kazuhiro
Natori Takenori
Fonda Kathleen K.
Kirin Beer Kabushiki Kaisha
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