Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
2001-06-26
2003-03-25
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
Reexamination Certificate
active
06538037
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable
This invention relates to the hormonally active, natural metabolite 1&agr;,24(S)-dihydroxyvitamin D
2
and to methods of preparing this metabolite and the nonbiological epimer 1&agr;,24(R)-dihydroxyvitamin D
2
. This invention also relates to a pharmaceutical composition which includes a pharmaceutically effective amount of 1&agr;,24(S)-dihydroxyvitamin D
2
, to a method of controlling abnormal calcium metabolism by administering a pharmaceutically effective amount of the compound, and to a method of treating hyperproliferative diseases by administering the compound.
Vitamin D and its active metabolites are known to be important in regulating calcium metabolism in animals and humans. The naturally occurring form of vitamin D in animals and humans is vitamin D
3
. It has been shown that in animals, including humans, vitamin D
3
is activated by being hydroxylated in the C
25
position in the liver, followed by 1&agr;-hydroxylation in the kidney to produce the hormone 1&agr;,25-dihydroxyvitamin D
3
[“1&agr;,25-(OH)
2
D
3
”]. See, U.S. Pat. No. 3,880,894. The major physiological pathway for catabolism of the vitamin D
3
metabolites, 25-hydroxyvitamin D
3
and 1&agr;,25-(OH)
2
D
3
, is initiated by C
24
-oxidation. Holick, M. F., Kleiner-Bossallier, A., Schnoes, H. K., Kasten, P. M., Boyle, I. T., and DeLuca, H. F.,
J. Biol. Chem
., 248, 6691-6696 (1973).
Vitamin D
2
, on the other hand, is the major, naturally occurring form of vitamin D found in plants. Vitamin D
2
differs structurally from vitamin D
3
in that vitamin D
2
has a methyl group at C
24
and has a double bond between C
22
and C
23
.
Shortly after their discovery, it seemed apparent that vitamin D
3
and vitamin D
2
had similar, if not equivalent, biological activity. It has also been commonly believed that the metabolism (i.e., the activation and catabolism) of vitamin D
2
was the same as for vitamin D
3
. See, Harrison's Principles of Internal Medicine: Part Seven, “Disorders of Bone and Mineral Metabolism: Chap. 35,” in E. Braunwald, K. J. Isselbacher, R. G. Petersdorf, J. D. Wilson, J. B. Martin and H. S. Fauci (eds.),
Calcium, Phosphorus and Bone Metabolism: Calcium Regulating Hormones
, McGraw-Hill, New York, pp. 1860-1865. In this regard, the active form of vitamin D
2
is believed to be 1&agr;,25-dihydroxyvitamin D
2
[“1&agr;,25-(OH)
2
D
2
”]. Further, 24-hydroxy derivatives of 25-hydroxyvitamin D
2
and 1&agr;,25-(OH)
2
D
2
, i.e., 24,25-dihydroxyvitamin D
2
and 1&agr;,24,25-trihydroxyvitamin D
2
, are known, suggesting that catabolism of vitamin D
2
, like vitamin D
3
, proceeds through the same C
24
oxidation step. Jones, G., Rosenthal, D., Segev, D., Mazur, Y., Frolow, F., Halfon, Y., Robinavich, D. and Shakked, Z.,
Biochemistry
, 18:1094-1101 (1979).
It has recently been found, however, that an active analogue of vitamin D
2
, 1&agr;-hydroxyvitamin D
2
[“1&agr;-(OH)D
2
”] has pharmacological properties distinctly different than those exhibited by its vitamin D
3
counterpart, 1&agr;-hydroxyvitamin D
3
[“1&agr;-(OH)D
3
”]. U.S. Pat. No. 5,104,864 discloses that 1&agr;-(OH)D
2
will reverse the loss of bone mass in human osteoporotic patients when administered at dosages of 2.0 &mgr;g/day or higher. Because of toxicity, dosage levels of 2.0 &mgr;g/day or greater are not safely obtained with 1&agr;-(OH)D
3
.
Such distinct pharmacological properties may be explained fully, or in part, by the present inventors' discovery that pharmacological dosages of 1&agr;-(OH)D
2
administered to humans are metabolized in part to biologically active 1&agr;,24(S)-dihydroxyvitamin D
2
[“1&agr;,24(S)-(OH)
2
D
2
”]. As explained in more detail below, the hydroxylation at the carbon-24 position of the 1-hydroxylated vitamin D
2
molecule, represents an activation pathway peculiar to the vitamin D
2
molecule.
While 1&agr;,24(S)-dihydroxyvitamin D
3
and 1&agr;,24(R)-dihydroxyvitamin D
3
[“1&agr;,24(R/S)-(OH)
2
D
3
”] have been chemically synthesized (U.S. Pat. No. 4,022,891) it has not been demonstrated that either is a natural compound found in biological systems. Furthermore, the present inventors have discovered that 1&agr;,24(S)-(OH)
2
D
2
has distinctly different biological activity from that exhibited by 1&agr;,24(R/S)-(OH)
2
D
3
. For example, Ishizuka et al. have found that 1&agr;,24(R)-(OH)
2
D
3
binds the 1,25-(OH)
2
D
3
receptor site more tightly than does 1,25-(OH)
2
D
3
itself. Ishizuka, S., Bannai, K., Naruchi, T. and Hashimoto, Y.,
Steroids
, 37:1,33-42 (1981); Ishizuka, S., Bannai, K., Naruchi, T. and Hashimoto, Y.,
Steroids
, 39:1,53-62 (1982). Using a similar assay, the present inventors have discovered that the 1&agr;,24(S)-(OH)
2
D
2
is two-fold less competitive in binding the 1,25-(OH)
2
D
3
receptor site than is 1,25-(OH)
2
D
3
. The present inventors have also found that 1&agr;,24(S)-(OH)
2
D
2
shows a relatively poor binding affinity for the vitamin D serum binding protein which is evidence of a rather short half life indicative of low toxicity.
The present inventors have demonstrated the presence of circulating 1&agr;,24(S)-(OH)
2
D
2
in humans administered 1&agr;-(OH)D
2
. This indicates that in animals and man, vitamin D
2
is naturally metabolized to both 1&agr;,25-(OH)
2
D
2
and 1&agr;,24(S)-(OH)
2
D
2
. The relative ratios of the two vitamin D
2
hormones appear to vary according to the precursor and the amount of precursor presented to the C
24
pathway. Thus, it appears that as dosages of 1&agr;-(OH)D
2
are increased, the ratio of 1&agr;,24(S)-(OH)
2
D
2
to 1&agr;,25-(OH)
2
D
2
increases.
These results which are presented in more detail below, indicate that 1&agr;,24(S)-(OH)
2
D
2
has the desirable characteristic of high biological activity with low toxicity. The fact that 1&agr;,24(S)-(OH)
2
D
2
is a significant metabolite when pharmacological levels of 1&agr;-(OH)D
2
are administered indicates that 1&agr;,24(S)-(OH)
2
D
2
may be mediating the desirable pharmacological effects of 1&agr;-(OH)D
2
and is a useful therapeutic drug for treating various types of disorders involving calcium metabolism.
Extensive research during the past two decades has also established important biologic roles for vitamin D apart from its classic role in bone and mineral metabolism. Specific nuclear receptors for 1&agr;,25-dihydroxyvitamin D
3
, the hormonally active form of vitamin D, are present in cells from diverse organs not involved in calcium homeostasis. For example, specific, biologically active vitamin D receptors have been demonstrated in the human prostatic carcinoma cell line, LNCaP, (Miller et al., 52
Cancer Res
. (1992) 515-520). Vitamin D receptors have also been described for many other neoplastic cells, e.g., carcinomas of the breast and of the colon.
It has been demonstrated that certain vitamin D compounds and analogues are potent antiproliferative and prodifferentiative agents. For example, U.S. Pat. No. 4,391,802 issued to Suda et al. discloses that 1&agr;-hydroxyvitamin D compounds, specifically 1&agr;,25-dihydroxyvitamin D
3
and 1&agr;-hydroxyvitamin D
3
, possess potent antileukemic activity by virtue of inducing the differentiation of malignant cells (specifically leukemia cells) to nonmalignant macrophages (monocytes), and are useful in the treatment of leukemia. Antiproliferative and differentiating actions of 1&agr;,25-dihydroxyvitamin D
3
and other vitamin D
3
analogues have also been reported with respect to prostate cancer cell lines. More recently, an association between vitamin D receptor gene polymorphism and prostate cancer risk has been reported, suggesting that vitamin D receptors may have a role in the development, and possible treatment, of prostate cancer.
These previous studies have focused exclusively on vitamin D
3
compounds. Even though these compounds may be highly effective in promoting differentiation in malignant cells in culture, their practical use in differentiation therapy as an
Bishop Charles W.
Knutson Joyce C.
Mazess Richard B.
Strugnell Stephen
Bone Care International, Inc.
Jones Dwayne C.
Michael & Best & Friedrich LLP
Peterson Jeffrey D.
Welch Teresa J.
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