Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1998-05-29
2001-06-05
Criares, Theodore J. (Department: 3116)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06242434
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates generally to 24-hydroxyvitamin D compounds and their use in the treatment and prophylaxis of hyperparathyroidism and hyperproliferative diseases, and in the modulation of the immune response as well as the treatment of bone depletive disorders.
Vitamin D has long been established as having an important biological role in bone and mineral metabolism. For example, vitamin D plays a critical role in stimulating calcium absorption and regulating calcium metabolism. The discovery of active forms of vitamin D, (M. F. Holick et al., 68
Proc. Natl. Acad. Sci. USA,
803-804 (1971); G. Jones et al., 14
Biochemistry,
1250-1256 (1975)), and active vitamin D analogs (M. F. Holick et al., 180
Science
190-191 (1973); H. Y. Lam et al., 186
Science
1038-1040 (1974)) caused much excitement and speculation about the usefulness of these vitamin D compounds in the treatment of bone depletive disorders.
Animal studies examining the effects of these active vitamin D compounds suggested that such agents would be useful in restoring calcium balance. An early clinical study indicated that administration of 0.5 &mgr;g/day of 1&agr;,25-dihydroxyvitamin D
3
, the hormonally active form of vitamin D
3
, to a group of postmenopausal women improved intestinal calcium absorption as well as calcium balance in the women. On this basis, U.S. Pat. No. 4,225,596 (“'596 Patent”) described and claimed the use of 1&agr;,25-dihydroxyvitamin D
3
and analogs thereof for increasing calcium absorption and retention.
The best indicator of the efficacy of vitamin D compounds in the prevention or treatment of depletive bone disorders, however, is bone itself rather than calcium absorption or calcium balance. More recent clinical data indicate that, at the dosage ranges taught in the '596 Patent, 1&agr;,25-dihydroxyvitamin D
3
has, at best, modest efficacy in preventing or restoring loss of bone mass or bone mineral content (S. M. Ott and C. H. Chesnut, 110
Ann. Int. Med.
267-274 (1989); J. C. Gallagher et al., 113
Ann. Int. Med.
649-655 (1990); J. Aloia et al., 84
Amer. J. Med.
401-408 (1988)).
These clinical studies with 1&agr;,25-dihydroxyvitamin D
3
, and another conducted with 1&agr;-hydroxyvitamin D
3
(M. Shiraki et al., 32
Endocrinol. Japan
305-315 (1985)), indicate that the capacity of these two vitamin D compounds to restore lost bone mass or bone mineral content is dose-related. The studies also indicate, however, that, at the dosage ranges required for either compound to be truly effective, toxicity in the form of hypercalcemia and hypercalciuria becomes a major problem. Specifically, attempts to increase the amount of 1&agr;,25-dihydroxyvitamin D
3
above 0.5 &mgr;g/day have frequently resulted in toxicity. At dosage levels below 0.5 &mgr;g/day, no effects are observed on bone mass or mineral content. (See, G. F. Jensen et al., 16
Clin. Endocrinol.
515-524 (1982); C. Christiansen et al., 11
Eur. J. Clin. Invest.
305-309 (1981)).
Data from clinical studies in Japan, a population that has low calcium intake, indicate that efficacy is found with 1&agr;-hydroxyvitamin D
3
when administered at 1 &mgr;g/day (M. Shiraki et al., 32
EndocrinoL Japan.
305-315 (1985); H. Orimo et al., 3
Bone and Mineral
47-52 (1987)). Two &mgr;g/day of 1&agr;-hydroxyvitamin D
3
was found to have efficacy in increasing bone mass in patients exhibiting senile osteoporosis (O. H. Sorensen et al., 7
Clin. Endocrinol.
169S-175S (1977)). At 2 &mgr;g/day, however, toxicity with 1&agr;-hydroxyvitamin D
3
occurs in approximately 67 percent of the patients, and at 1 &mgr;g/day, this percentage is approximately 20 percent. Thus, these 1&agr;-hydroxylated vitamin D
3
compounds can produce dangerously elevated blood calcium levels due to their inherent calcemic activity.
Because of this toxicity, 1-hydroxylated vitamin D
3
compounds can only be administered at dosages that are, at best, modestly beneficial in preventing or treating loss of bone or bone mineral content. Indeed, Aloia recommends that alternative routes of administration be sought which might avoid the toxicity problems and allow higher dosage levels to be achieved. (J. Aloia et al., 84
Amer. J. Med.
401-408 (1988).) Yet, despite reported toxicities of 1&agr;-hydroxyvitamin D
3
and 1&agr;,25-dihydroxyvitamin D
3
, these two compounds remain the drugs of choice for many bone depletive disease treatments.
These two drugs also remain the only approved forms of 1&agr;-hydroxylated vitamin D for treating or preventing hyperparathyroidism which occurs secondary to end stage renal disease, although both drugs are not currently approved in all major pharmaceutical markets. Hyperparathyroidism is a generalized disorder resulting from excessive secretion of parathyroid hormone (PTH) by one or more parathyroid glands. It is thus characterized by elevated blood levels of parathyroid hormone. Typically, one or more parathyroid glands reveal a marked enlargement. In the case of primary hyperparathyroidism, the glandular enlargement is usually due to a neoplasm or tumor. In the case of secondary hyperparathyroidism, the parathyroid gland hyperplasia typically occurs because of resistance to the metabolic actions of the hormone. Secondary hyperparathyroidism occurs in patients with, e.g., renal failure, osteomalacia, and intestinal malabsorption syndrome. In both primary and secondary hyperparathyroidism, bone abnormalities, e.g., the loss of bone mass or decreased mineral content, are common and renal damage is possible. Hyperparathyroidism is thus also characterized by abnormal calcium, phosphorus and bone metabolism.
More recently, other roles for vitamin D have come to light. Specific nuclear receptors for 1&agr;,25-dihydroxyvitamin D
3
have been found in cells from diverse organs not involved in calcium homeostasis. For example, Miller et al., 52
Cancer Res.
(1992) 515-520, have demonstrated biologically active, specific receptors for 1&agr;,25-dihydroxyvitamin D
3
in the human prostatic carcinoma cell line, LNCaP.
It has been reported that certain vitamin D compounds and analogs are potent inhibitors of malignant cell proliferation and inducers/stimulators of cell differentiation. 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. In another example, Skowronski et al., 136
Endocrinology
20-26 (1995), have reported antiproliferative and differentiating actions of 1&agr;,25-dihydroxyvitamin D
3
and other vitamin D
3
analogs on prostate cancer cell lines.
Previous proliferation studies, such as those cited above, focused exclusively on vitamin D
3
compounds. Even though such compounds may, indeed, be highly effective in differentiating malignant cells in culture, their practical use in differentiation therapy as anticancer agents is severely limited because of their equally high potency as agents affecting calcium metabolism. At the levels required in vivo for effective use as antileukemic agents, these same compounds can induce markedly elevated and potentially dangerous blood calcium levels by virtue of their inherent calcemic activity. In other words, the clinical use of 1&agr;,25-dihydroxyvitamin D
3
and other vitamin D
3
analogs as anticancer agents is precluded, or severely limited, by the risk of hypercalcemia.
Still other metabolic conditions in which it has been suggested that vitamin D plays a role are immune response (see, e.g., U.S. Pat. No. 4,749,710 issued to Truitt et al.; U.S. Pat. No. 5,559,107 issued to Gates et al.; U.S. Pat. Nos. 5,540,919, 5,518,725 and 5,562,910 issued to Daynes et al.) and inflammatory response (e.g., U.S. Pat. No. 5,589,471 issued to Hansen et al.).
Considering the diverse biological actions of vitamin D and its
Bishop Charles W.
Knutson Joyce C.
Strugnell Stephen
Bone Care International, Inc.
Criares Theodore J.
Michael & Best & Friedrich LLP
Welch Teresa J.
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