Vitamin D3 derivative and production process thereof

Details Vitamin D3 derivative and production process thereof Vitamin D3 derivative and production process thereof

1999-06-08

2001-01-23

Trinh, Ba K. (Department: 1612)

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

Organic compounds

Silicon containing

C560S119000, C560S256000, C562S501000, C568S374000, C568S819000

Reexamination Certificate

active

06177586

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a vitamin D
3
derivative useful as a pharmaceutical. More specifically, it relates to a 1&agr;-hydroxy vitamin D
3
derivative useful as a pharmaceutical such as an agent for promoting bone formation, an agent for suppressing proliferation of tumor cells, an agent for high calcium blood diseases, and an immunosuppression agent, a production process thereof, and a production intermediate.
BACKGROUND ART
It is fully recognized through disclosures in patent publications and a large number of general references that vitamin D
3
metabolites play an extremely important role as substances controlling the metabolism of calcium and phosphates in the body. Recently, further, an increase has been seen in clinical application as drugs for the treatment of various diseases such as with the numerous vitamin D
3
metabolites found to have the function of inducing differentiation of tumorous bone marrow cells. On the other hand, recently, a novel vitamin D
3
active metabolite having an &agr;-hydroxylactone ring at the steroid side chain has been found. [Arch. Bio-chem. Biophys., 204, 339-391 (1980); FEBS LETTERS, 134, 207-211 (1981)]. This compound is 1&agr;,25-dihydroxy-vitamin D
3
-26,23-lactone and is represented by the following structural formula:
This compound has been reported to have an action for reducing the concentration of calcium in blood serum (Japanese Unexamined Patent Publication (Kokai) No. 58-118516), an action for suppressing the proliferation of tumor cells (Japanese Unexamined Patent Publication (Kokai) No. 58-210011), an action for promoting bone formation (Japanese Unexamined Patent Publication (Kokai) No. 60-185715), etc.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide a novel vitamin D
3
derivative having activity to promote bone formation, a production process therefor, and production intermediates.
In accordance with the present invention, there is provided a vitamin D
3
derivative having the following formula (I):
wherein, R is, independently, a hydrogen atom, tri(C
1
to C
7
hydrocarbon)silyl group, C
2
to C
8
acyl group, or a group forming an acetal bond together with an oxygen atom of a hydroxyl group, A is
where, R
1
is a methyl group or methylene group, and when R
1
is a methylene group, the bond between R
1
and the 3-position of the lactone ring is a double bond, R
2
is a hydrogen atom or C
1
to C
3
alkyl group, R
3
is a hydrogen atom, or R
2
and R
3
together are a substitutable single methylene group.


REFERENCES:
patent: 0619305 (1994-10-01), None
patent: 712843A1 (1996-05-01), None
patent: 58-118516 (1983-07-01), None
patent: 58-210011 (1983-12-01), None
patent: 60-185715 (1985-09-01), None
Journal of Organic Chemistry,48(23):4433-4436, Easton US (1983).
Journal of the American Chemical Society,114(5):1924-1925, DC US (1992).
Horst et al,Proc. Workshop Vitam. D, 6th(Vitam. D):807-816 (1985).
Ishizuka et al,Proc. Workshop Vitam. D, 6th(Vitam. D):402-403 (1985).
Archives of Biochemistry and Biophysics,204:387-391 (1980).
Febs Letter,134:207-211 (1981).
Shiina et al,Arch. Biochem. Biophys.,220(1):90-94 (1983), Chemical Abstract No. 106082, vol. No. 098, No. 13 (Mar. 1983).
Biological Activity and Characteristics of 1 Alpha, 25-(OH)2D-26,23.Lactone, Vitamin D Chemical Biochemical and Clinical Update. Proceedings of the Workshop on Vitamin D, Jan. 1985, pp. 402-403.
Chemical Abstracts, vol. 98, No. 13, Mar. 28, 1983, abstract No. 106082, “Biological activity of 24,24-difluoro-1.alpha., 25-dihydroxyvitamin D3 and 1.alpha., 25-dihydroxyvitamin D3-26 . . . ”.
Chemcial Abstract, vol. 100, No. 14, Apr. 2, 1984, abstract No. 109113, Antitumor capsules containing 1.alpha., 25-dihydroxyvitamin D3-26, 23-lactone.
Total Synthesis of 1.alpha., 25(R)-Dihydroxy Vitamin D3 26,23(S)-Lactone (Calcitriol Lactone) a Natural Metabolite of Vitamin D3., Journal of Organic Chemistry, vol. 48, No. 23, 1983, pp. 4433-4436.
New Strategy for the Total Synthesis of 1.alpha-hydroxyvitamin D Derivatives, Journal of the American Chemical Society, Feb. 26, 1992, vol. 114, pp. 1924-1925.

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