Biologically active 1-thio derivatives of vitamin D

United States Patent [19]

Holick et al.

[ii] Patent Number: 4,661,294 [45] Date of Patent: Apr. 28, 1987

[54] BIOLOGICALLY ACTIVE 1-THIO DERIVATIVES OF VITAMIN D

[75] Inventors: Michael F. Holick, Sudbury; Brian de Costa, Cambridge, both of Mass.

[73] Assignee: The General Hospital Corporation, Boston, Mass.

[21] Appl. No.: 712,712

[22] Filed: Mar. 18,1985

[51] Int. CI.4 C07J 9/00; A61K 31/59

[52] U.S. CI 260/397.2

[58] Field of Search 514/167; 260/397.2

[56] References Cited

U.S. PATENT DOCUMENTS

3,158,626 11/1964 Stuckwisch et al 260/397.2

3,627,757 12/1971 Komeno 260/397.2

3,715,350 2/1973 Hamashima 260/397.2

4,188,345 2/1980 De Luca et al 568/665

4,225,596 9/1980 De Luca et al 514/167

4,234,493 11/1980 De Luca et al 549/396

4,269,777 5/1981 De Luca et al 260/397.1

4,367,177 1/1983 De Luca et al 260/397.2

4,410,515 10/1983 Holick et al 423/648 R

4,448,726 5/1984 De Luca et al 260/397.2

4,521,410 6/1985 Holick et al 260/397.2

4,560,557 12/1985 Wilson et al 260/397.2

OTHER PUBLICATIONS

Holick et al., Biochemistry, vol. 10, No. 14, pp. 2799-2804 (1971).

Sheves et al., J. Am. Chem. Soc, vol. 97, pp. 6249-6250 (1975).

Haussler et al., Life Sci., vol. 18, pp. 1049-1056 (1976). Paaren et al., Arch. Biochem. Biophys., vol. 209, No. 2, pp. 579-583 (1981).

Sheves et al., Tetrahedron Letters, No. 34, pp. 2987-2990 (1976).

Paaren et al., Proc. Nat'l. Acad. Sci. USA, vol. 75, No. 5, pp. 2080-2081 (1978).

Esvelt et al., J. Org. Chem., vol. 46, pp. 556-558 (1981). Paaren et al., Proc. Nat'l. Acad. Sci. USA, vol. 78, No. 10, pp. 6173-6175 (1981).

Morrison and Boyd, Organic Chemistry, 3d ed., Allyn &
Bacon, Boston 1973, p. 458.

Primary Examiner—Leonard Schenkman
Assistant Examiner—Joseph A. Lipovsky
Attorney, Agent, or Firm—Saidman, Sterne, Kessler &
Goldstein

[57] ABSTRACT

Novel synthetic derivatives of vitamin D compounds are disclosed as well as processes for their synthesis. The novel compounds are 1-alpha-thio and acylated, 1-beta-thio derivatives of vitamin D compounds and the glycosylated, hydroxylated, fluorinated, and glycosylated orthoester analogues thereof.

17 Claims, 4 Drawing Figures