18-substituted-19-nor-vitamin D compounds

Details 18-substituted-19-nor-vitamin D compounds 18-substituted-19-nor-vitamin D compounds

1999-07-15

2001-08-28

Qazi, Sabiha (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ketone doai

C514S675000, C568S309000

Reexamination Certificate

active

06281249

ABSTRACT:

BACKGROUND OF THE INVENTION
This patent invention relates to vitamin D compounds, and more particularly to vitamin D derivatives substituted at the carbon 18 position.
Vitamin D is essential for life in higher animals. It is one of the important regulators of calcium and phosphorus and is required for proper development and maintenance of bone. However, during the past decade, the spectrum of activities promoted by 1,25-(OH)
2
D
3
has been found to extend far beyond a role in calcium homeostasis. In addition to its action on the intestine, bone, kidney, and parathyroid glands to control serum calcium, this hormone has been shown to have important cell differentiating activity. Ostrem et al, Proc. Natl. Acad. Sci. USA, 84, 2610 (1987). Receptors for this hormone have been identified in several different target cells that respond to 1,25-(OH)
2
D
3
with a diverse range of biological action. These newly discovered activities have suggested other therapeutic applications of 1,25-(OH)
2
D
3
including hyperparathyroidism, psoriasis, cancer, and immune regulation.
Secondary hyperparathyroidism is a universal complication in patients with chronic renal failure. Because of its ability to suppress parathyroid hormone (PTH), 1,25-(OH)
2
D
3
has been used with success in the treatment of secondary hyperparathyroidism, Slatopolsky, et al, “Marked Suppression of Secondary Hyperparathroidism by Intravenous Administration of 1,25-dihydroxycholecalciferol in Uremic Patients”, J. Clin. Invest. 74:2136-2143, 1984. Its use is often precluded, however, by the development of hypercalcemia resulting from its potent action on intestinal absorption and bone mineral mobilization.
From the clinical point of view, one of the most difficult biochemical alterations to correct in hemodialysis patients is hyperphosphatemia. Patients on dialysis usually ingest approximately 1.0 to 1.4 grams of phosphorus per day. Since the maximum amount of phosphorus that is removed during each dialysis approximates 800 to 1,000 mg, Hou et al, “Calcium and Phosphorus Fluxes During Hemodialysis with Low Calcium Dialysate”, Am. J. Kidney Dis. 18:217-224, 1991, the remaining 2.5 to 3.5 grams of phosphorus ingested per week must be removed by other means. Thus, the use of phosphate binders such as calcium carbonate and calcium acetate are usually utilized to correct the hyperphosphatemia, Emmett et al, “Calcium Acetate Control of Serum Phosphorus in Hemodialysis Patients”, Am. J. Kidney Dis. 24:544-550, 1991; Schaefer et al, “The Treatment of Uraemic Hyperphosphataemia with Calcium Acetate and Calcium Carbonate: A Comparative Study”, Nephrol Dial Transplant 6:170-175, 1991; Delmez et al, “Calcium Acetate as a Phosphorus Binder in Hemodialysis Patients”, J. Am. Soc. Nephrol 3:96-102, 1992. Unfortunately, 1,25-(OH)
2
D
3
not only increases the absorption of calcium but also of phosphorus, making hyperphosphatemia more difficult to be treated. Thus, the hyperphosphatemia induced in part by the action of 1,25-(OH)
2
D
3
requires a further addition of calcium carbonate or calcium acetate, which can greatly increase the levels of serum ionized calcium. The high calcium-phosphate product that the patient may develop imposes a tremendous risk for the development of hypercalcemia and metastatic calcifications, Arora et al, “Calcific Cardiomyopathy in Advanced Renal Failure”, Arch. Inter. Med. 1335:603-605 1975; Rostand et al, “Myocardial Calcification and Cardiac Dysfunction in Chronic Renal Failure”, Am. J. ed. 85:651-657, 1988; Gipstein et al, “Calcification and Cardiac Dysfunction in Chronic Renal Failure”, Am. J. Med. 85:651-657, 1988: Gipstein et al, “Calciphylaxis in Man A Syndrome of Tissue Necrosis and Vascular Calcifications in 11 Patients with Chronic Renal Failure”, Arch. Intern. Med. 136:1273-1280, 176; Milliner et al, “Soft Tissue Calcification in Pediatric Patients with End-stage Renal Disease”, Kidney Int. 38:931-936, 1990. Therefore, the treatment demands a decrease in the amount of 1,25-(OH)
2
D
3
administered to the patient thus decreasing the effectiveness of 1,25-(OH)
2
D
3
therapy for controlling PTH secretion. Thus, an analog of 1,25-(OH)
2
D
3
that can suppress PTH with minor effects on calcium and phosphate metabolism would be an ideal tool for the control of secondary hyperparathyroidism, and the treatment of renal osteodystrophy.
Many structural analogs of 1,25-(OH)
2
D
3
have been prepared and tested, including 1&agr;-hydroxyvitamin D
3
, 1&agr;-hydroxyvitamin D
2
, various side chain homologated D
3
and D
2
vitamins and fluorinated D
3
and D
2
analogs. Some of these compounds exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity may be useful in the treatment of a variety of diseases as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
Several analogs of 1,25-(OH)
2
D
3
modified at the carbon 18 position are described in Nilsson et al, “Synthesis and Biological Evaluation of 18-Substituted Analogs of 1&agr;,25-Dihydroxyvitamin D
3
”, Bioorganic and Medicinal Chemistry Letters, Vol. 3, No. 9, pp. 1855-1858, 1993, and their in vitro biological behavior reported. 18-hydroxylated analogs are disclosed in Valles et al, “Functionalization of Vitamin D Metabolites at C-18 and Application to the Synthesis of 1&agr;,18,25-Trihydroxyvitamin D
3
and 18,25-Dihydroxyvitamin D
3
”, Tetrahedron Letters, Vol. 33, No. 1, pp. 1503-1506, 1992. 18-acetoxy analogs are described in Maynard et al, “18-Substituted Derivatives of Vitamin D: 18-Acetoxy-1&agr;,25-Dihydroxyvitamin D
3
and Related Analogues,” J. Org. Chem., Vol. 57, No. 11, pp. 3214-3217, 1992, and are reported to be nearly devoid of in vivo biological activity.
Another class of vitamin D analogs, i.e. the so called 19-nor-vitamin D compounds, are characterized by the replacement of the A-ring exocyclic methylene group (carbon 19), typical of the vitamin D system, by two hydrogen atoms. Biological testing of such 19-nor-analogs (e.g., 1&agr;,25-dihydroxy-19-nor-vitamin D
3
) revealed a selective activity profile with high potency in inducing cellular differentiation, and very low intestinal calcemic transport activity as well as very low bone calcium mobilizing activity. Thus, these 19-nor compounds are potentially useful as therapeutic agents for the treatment of malignancies, (see U.S. Pat. No. 5,587,497) or the treatment of various skin disorders (see U.S. Pat. No. 5,578,587) as well as for the treatment of hyperphosphatemia (see U.S. Pat. No. 5,597,815), and hyperparathyroidism (see U.S. Pat. No. 5,246,925). Two different methods of synthesis of such 19-nor-vitamin D analogs have been described (Perlman et al., Tetrahedron Lett. 31, 1823 (1990); Perlman et al., Tetrahedron Lett. 32, 7663 (1991), and DeLuca et al., U.S. Pat. No. 5,086,191).
Recently, 2-substituted analogs of 1&agr;,25-dihydroxy-19-norvitamin D
3
have also been synthesized, i.e. compounds substituted at 2-position with hydroxy or alkoxy groups (DeLuca et al, U.S. Pat. No. 5,536,713). These compounds exhibit interesting and selective activity profiles making them useful for the treatment of osteoporosis.
SUMMARY OF THE INVENTION
A series of 1&agr;-hydroxylated vitamin D compounds not known heretofore are the 19-nor-vitamin D analogs having a methyl or methylene group at the 18-position, i.e. 13-ethyl-18,19-dinor-vitamin D compounds and 13-vinyl-18,19-dinor-vitamin D compounds, particularly 13-ethyl-18,19-dinor-1&agr;,25-dihydroxyvitamin D
3
and 13-vinyl-18,19-dinor-1&agr;,25-dihydroxyvitamin D
3
.
Structurally these novel analogs are characterized by the general formula I shown below:
where Y
1
and Y
2
, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R
6
is selected from the group consisting of an ethyl or vinyl radical, and where the group R represents any of the typical side chains known for vitamin D type compounds.
The above novel compounds exhibit a desired, and highly advantageous

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