Treating agent for Paget's disease of bone

• US 20030191094A1
• Filed: 02/21/2003
• Published: 10/09/2003
• Est. Priority Date: 02/22/2002
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Teijin Limited
• Inventors: Takenouchi, Kazuya, Ishizuka, Seiichi, Kurihara, Noriyoshi, Oue, Yasuhiro, Roodman, G. David, Imaizumi, Atsushi, Reddy, Sakamuri V.
• Granted Patent: US 7,163,933 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• CPC Class Codes: A61K 31/592 9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
• CPC Class Codes: A61K 31/593 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease

Abstract

To obtain a treating agent for Paget'"'"'s disease of bone, there is provided a method of inhibiting expression of general transcription factor of steroid hormone receptor.

Claims

1. A method for treating Paget'"'"'s disease of bone, comprising administering to a patient a compound which inhibits expression of general transcription factor with an interactive relation to steroid hormone receptor.

3. The method of claim 1 or 2, wherein said steroid hormone receptor is Vitamin D receptor.

4. The method of claim 3, wherein said general transcription factor is TATA box-binding protein-associated factor II-17 (TAFII-17), TATA box-binding protein-associated factor II-135 (TAFII-135) or Vitamin D receptor interacting proteins-205 (DRIP-205).

5. The method of claim 3, wherein said general transcription factor is TATA box-binding protein-associated factor II-17 (TAFII-17).

6. The method of claim 3, wherein said compound has the formula (1):

7. The method of claim 6, wherein m is 1 or 2.

8. The method of claim 6, wherein m is 1, q is 0, r is 1, and X is oxygen.

9. The method of claim 6, wherein m is 1, q is 0, r is 1, and X is carbon.

10. The method of claim 6, wherein m is 2, q is 0, r is 1, and x is oxygen.

11. The method of claim 6, wherein m is 1, q is 1, r is 0, and X is carbon.

12. The method of claim 3, wherein said compound has the formula (2):

13. The method of claim 12, wherein R⁴ is n-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl, 1-pentenylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, 2-methylpropoxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, n-heptyloxycarbonyl, n-butylaminocarbonyl, n-pentylaminocarbonyl, n-heptylaminocarbonyl, n-pentenylaminocarbonyl, 2-(5-butyl)oxazolyl, 2-(5-butyl)thiazolyl, 2-(4-methyl)thiazolyl or 2-(4-propyl)thiazolyl.

14. The method of claim 12, wherein R¹ and R² together form an exocyclic methylene;

R³ is a single bond;

R⁴ is n-butoxycarbonyl or 2-methylpropoxycarbonyl;

R⁵ is hydrogen.

15. The method of claim 12, wherein R¹ and R² together form an exocyclic methylene;

R³ is a single bond;

R⁴ is n-butylcarbonyl, n-pentylcarbonyl, n-heptylcarbonyl or 1-pentenylcarbonyl;

R⁵ is hydrogen.

16. The method of claim 12, wherein R¹ and R² together form an exocyclic methylene;

R³ is a single bond;

R⁴ is n-butylaminocarbonyl, n-pentylaminocarbonyl, n-heptylaminocarbonyl or 1-pentenylaminocarbonyl;

R⁵ is hydrogen.

17. The method of claim 12, wherein R¹ and R² together form an exocyclic methylene;

R³ is a single bond;

R⁴ is 2-(5-butyl)oxazolyl, 2-(5-butyl)thiazolyl, 2-(4-methyl)thiazolyl or 2-(4-propyl)thiazolyl;

R⁵ is hydrogen.

18. The method of claim 12, wherein R¹ and R² together form an exocyclic methylene;

R³ is vinylene;

R⁴ is ethoxycarbonyl or t-butoxycarbonyl;

R⁵ is hydrogen.

19. The method of claim 12, wherein R¹ and R² are each hydrogen;

R³ is a single bond;

R⁴ is n-butoxycarbonyl;

R⁵ is hydrogen.

20. The method of claim 12, wherein R¹ and R² are each hydrogen;

R³ is vinylene;

R⁴ is ethoxycarbonyl;

R⁵ is hydrogen.

21. The method of claim 12, wherein R¹ and R² are each hydrogen;

R³ is a single bond;

R⁴ is 2-(4-methyl)thiazolyl;

R⁵ is hydrogen.

22. The method of claim 1 or 2, wherein said steroid hormone receptor is Retinoid X receptor.

23. The method of claim 22, wherein said general transcription factor is TATA box-binding protein-associated factor II-17 (TAFII-17), TATA box-binding protein-associated factor II-135 (TAFII-135) or Vitamin D receptor interacting proteins-205 (DRIP-205).

24. The method of claim 22, wherein said general transcription factor is TATA box-binding protein-associated factor II-17 (TAFII-17).

25. The method of claim 22, wherein said compound is L-X-X-L-L, wherein L is leucine and X is any amino acid.

26. The method of claim 25, wherein -X-X- are -methionine-glycine-, -leucine-serine-, -isoleucine-serine-, -glutamic acid-serine-, -tyrosine-proline-, -tryptophane-glycine-, -tryptophane-serine-, -methionine-lysine-, -glycine-glycine-, -glutamic acid-glutamine-, -leucine-lysine- or -glutamic acid-arginine-.

2. A method for inhibiting expression of general transcription factor, comprising administering a compound which inhibits expression of general transcription factor with an interactive relation to steroid hormone receptor.

27. A method for screening a compound for treatment of Paget'"'"'s disease of bone, comprising the step of detecting expression of TAFII-17 gene, TAFII-135 gene or DRIP-205 gene.

28. The method of claim 27, wherein said detecting TAFII-17 gene expression comprising the steps of:

(a) incubating a compound to be tested with mononuclear cells prepared from bone mallow collected from patients with Paget'"'"'s disease of bone

(b) extracting RNA from the cells from step (a)

(c) converting the RNA of step (b) into cDNA and amplifying TAFII-17 gene; and

(d) fractionating and determining the TAFII-17 gene of step (c).

29. The method of claim 27, wherein said detecting TAFII-135 gene expression comprising the steps of:

(a) incubating a compound to be tested with mononuclear cells prepared from bone mallow collected from patients with Paget'"'"'s disease of bone

(b) extracting RNA from the cells from step (a)

(c) converting the RNA of step (b) into cDNA and amplifying TAFII-135 gene; and

(d) fractionating and determining the TAFII-135 gene of step (c).

30. The method of claim 27, wherein said detecting DRIP-205 gene expression comprising the steps of:

(a) incubating a compound to be tested with mononuclear cells prepared from bone mallow collected from patients with Paget'"'"'s disease of bone

(b) extracting RNA from the cells from step (a)

(c) converting the RNA of step (b) into cDNA and amplifying DRIP-205 gene; and

(d) fractionating and determining the DRIP-205 gene of step (c).