Chemistry of carbon compounds – Miscellaneous organic carbon compounds – C-metal
Patent
1987-07-08
1989-05-23
Robinson, Douglas W.
Chemistry of carbon compounds
Miscellaneous organic carbon compounds
C-metal
C07J 900
Patent
active
048328758
DESCRIPTION:
BRIEF SUMMARY
TECHNOLOGICAL FIELD
This invention relates to a novel vitamin D.sub.3 derivative, and more specifically, to 1.alpha.,25-dihydroxy-24a,24a-difluoro-24-homovitamin D.sub.3 (1.alpha.,25-dihydroxy-24a,24a-difluoro-24-homocholecalciferol) and a process for its production.
Active-form vitamins D are drugs useful for preventing and improving bone symptoms in renal failure, reduced function of the parathyroid gland and osteoporosis. Furthermore, the activities of vitamin D homologs as an anticancer agent or a cancer eliminating agent have recently attracted attention. Much research has therefore been undertaken on their synthesis.
The vitamin D derivatives proposed heretofore, however, have not proved to be entirely satisfactory in regard to efficacy and toxicity, and it has been desired to develop vitamin D derivatives having higher pharmacological efficacy and lower toxicity.
Physiological functions well known as the mechanism of calcium metabolizing action of vitamin D include (1) absorption of calcium in the small intestines, (2) dissolution of calcium and inorganic phosphorus from bones, and (3) deposition of calcium on bones. When vitamin D is considered from the viewpoint of a therapeutic agent for diseases induced by bone calcium disorders such as osteoporosis and rachitis, the greatest problem is a side-effect such as calcification of tissues other than bones owing to a rise in blood calcium level.
Accordingly, an ideal vitamin D derivative would be one which has a weak action of dissolving calcium and inorganic phosphorus from the bones as compared with its action of absorbing calcium from the small intestines, or inhibits such dissolving action, and has a strong action of depositing calcium on the bones.
In spite of the recent research and development of many vitamin D derivatives, an ideal vitamin D derivative has not yet been developed. This means that in drug design, it is very difficult to separate the action of absorbing calcium from the small intestines, the action of dissolving calcium and inorganic phosphorus from bones and the action of depositing calcium on bones.
It has been made clear that many vitamin D derivatives so far synthesized all show actions of dissolving calcium from the bones, and these actions are stronger as the action of absorbing calcium from the small intestines is stronger. See, for example, Tateo Suda, Eiji Ozawa, and Eimei Takahashi: "Science of Bones" pages 176-177 (1985), Ishiyaku Shuppan, Tokyo; Raisz, L. G., Trummel, C. L., Holick, M. F. and DeLuca, H. F.: Science, 175, 768 (1972); C. Kaneko, S. Yamada, A. Sugimoto, T. Suda, M. Suzuki, C. Kakuta and S. Sasaki; Steroids, 23, 75 (1974); M. F. Holick, M. Garakedian, H. F. DeLuca: Science, 176, 1146 (1972); and N. Ikegawa, Biochemistry, 55, 1297 (1983).
The present inventor has conducted extensive work in search of a very ideal vitamin D derivative which has strong vitamin D activity and inhibits dissolution of calcium from bones. Unexpectedly, the inventor has found that by introducing fluorine atoms into the carbon skeleton at the 24a-positions of 24-homovitamin D.sub.3, a vitamin D homolog can be obtained which in spite of having strong vitamin D activity, shows an action of inhibiting dissolution of calcium from bones and has low toxicity. This discovery has led to the accomplishment of the present invention.
DISCLOSURE OF THE INVENTION
According to this invention, 24a,24a-difluoro-1.alpha.,25-dihydroxy-24-homovitamin D.sub.3 represented by the following formula ##STR1## is provided as a novel compound.
According to this invention, the compound of formula (I) can be produced by the route shown by the following reaction scheme. In the following scheme, Ac represents an acyl group such as acetyl, and R represents a lower alkyl group such as methyl. ##STR2##
First, 1.alpha.,38-diacetoxychol-5-en-24-ol represented by formula (1) is oxidized by the method of Swern et al. [J. Org. Chem., vol. 43, p. 2480 (1975)] to form the corresponding 24-aldehyde represented by formula (2). It is then treated with an anion prepared f
REFERENCES:
patent: 4226788 (1980-10-01), DeLuca et al.
patent: 4552698 (1985-11-01), DeLuca et al.
Lipovsky Joseph A.
Robinson Douglas W.
Taisho Pharmaceutical Co. Ltd.
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