Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-02-06
1998-02-17
Owens, Amelia Averill
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
552653, C07D30726, C07C40100
Patent
active
057192979
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This application is a 371 of PCT/JP95/01145 filed Jun 7, 1995.
The present invention relates to a vitamin D.sub.3 derivative useful as a pharmaceutical. More specifically, it relates to a 1.alpha.-hydroxy vitamin D.sub.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.sub.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.sub.3 metabolites found to have the function of inducing differentiation of tumorous bone marrow cells. On the other hand, recently, a novel vitamin D.sub.3 active metabolite having an .alpha.-hydroxylactone ring at the steroid side chain LETTERS, 134, 207-211 (1981)!. This compound is 1.alpha.,25-dihydroxy-vitamin D.sub.3 -26,23-lactone and is represented by the following structural formula: ##STR3##
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.sub.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.sub.3 derivative having the following formula (I): ##STR4## wherein, R is, independently, a hydrogen atom, tri(C.sub.1 to C.sub.7 hydrocarbon)silyl group, C.sub.2 to C.sub.8 acyl group, or a group forming an acetal bond together with an oxygen atom of a hydroxyl group, A is ##STR5## where, R.sup.1 is a methyl group or methylene group, and when R.sup.1 is a methylene group, the bond between R.sup.1 and the 3-position of the lactone ring is a double bond, R.sup.2 is a hydrogen atom or C.sub.1 to C.sub.3 alkyl group, R.sup.3 is a hydrogen atom, or R.sup.2 and R.sup.3 together are a substitutable single methylene group.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will now be explained in further detail with reference to the drawings.
FIG. 1 and FIG. 2 are respectively figures showing the results of synthesis of collagen and synthesis of noncollagen protein in the following Examples .
BEST MODE FOR WORKING THE INVENTION
That is, according to the first aspect of the present invention, there is provided a vitamin D.sub.3 derivative represented by the following formula (1-1): ##STR6## In the above formula (1-1), the configurations of the asymmetric centers of the C-1 position and C-4 position of the cyclopentene ring may be either of the (R) configuration or (S) configuration, respectively. Further, the present invention includes mixtures of any proportions of these four types of stereo isomers. Among them, ones where the asymmetric center of the C-1 position is the (R) configuration, ones where the asymmetric center of the C-4 position is the (S) configuration, and ones where the asymmetric center of the C-1 position is the (S) configuration and the asymmetric center of the C-4 position is the (S) configuration are preferred.
Specific examples of the preferred vitamin D.sub.3 derivative of the first aspect of the present invention are as follows:
1) enten-4-yl!-vitamin D.sub.3
2) 2-cyclopenten-4-yl!-vitamin D.sub.3
3) 2-cyclopenten-4-yl!-vitamin D.sub.3
4) 2-cyclopenten-4-yl!-vitamin D.sub.3
5) 2-cyc
REFERENCES:
Journal of Organic Chemistry, vol. 48, No. 23, 1983. Easton US, pp. 4433-4436.
Journal of the American Chemical Society, vol. 114, No. 5, 26 Feb. 1992, DC US, pp.1924-1925.
Horst, R.L. et al., Recent Developments in Quantitation of Vitamin D.sub.2 and Vitamin D.sub.3 and Their Metabolites in Biologic Fluids., Proc. Workshop Vitam. D, 1985, 6th (Vitam. D), pp. 807-816.
Ishizuka, S. et al., Biological Activity and Characteristics of 1.alpha., 25-(OH).sub.2 D.sub.3 -26, 23-Lactone., Proc. Workshop Vitam. D, 1985, 6th (Vitam. D), pp. 402-403.
Archives of Biochemistry and Biophysics, 204, 387-391, Oct. 1, 1980.
FEBS Letters, 134, 207-211, Nov. 1981.
Chemical Abstracts, vol. 098, No. 13, Mar. 28, 1983 ;abstract No. 106082 Shiina Y et al: "Biological activity of 24,24-difluoro-1.alpha., 25-dihydroxyvitami n D3 and 1.alpha., 25-dihydroxyvitamin D3-26,23-lactone in inducing differentialtion of human myeloid leukemia cells" Xp002002153 * abstract * & Arch. Biochem. Biophys., vol. 220, No. 1, 1983, pp. 90-94.
Chemical Abstracts, vol. 100, No. 14, 2 Apr. 1984; abstract No. 109113, "Antitumor capsules containing 1.alpha., 25-dihydroxyvitamin D3-26, 23-lactone" & JP-A-58 210 011 (Kureha Chemical Co. Ltd.) 31 May 1982.
Gao Qingzhi
Hazato Atsuo
Manabe Kenji
Tabe Masayasu
Tanaka Hiroko
Owens Amelia Averill
Teijin Limited
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