Stabilized thyroxine compounds

• US 20040116391A1
• Filed: 07/31/2003
• Published: 06/17/2004
• Est. Priority Date: 11/16/1999
• Status: Abandoned Application

• Current Assignee: New River Pharmaceuticals Inc. (Shire plc)
• Original Assignee: New River Pharmaceuticals Inc. (Shire plc)
• Inventors: Le Clercq, Anne-Frederique, Piccariello, Thomas
• Application Number:
  US10/630,650
• Publication Number:
  US 20040116391A1
• Time in Patent Office: Days
• US Class Current: 514/114
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4

Abstract

Throxinyldimethylphosphinate was invented as a prodrug to stabilize thyroxine, a drug widely used to treat hypothyroidism and depression. The presence of the dimethylphosphinate group at the phenolic hydroxyl of thyroxine is key to preventing thyroxine from decomposing through the proposed pathway. The prodrug will be hydrolyzed in the stomach or the gut into thyroxine and the biologically inert dimethylphosphinic acid. Related products may be stabilized with the same or similar protecting groups.

Claims

1. A composition comprising a triiodothyronine protected at a phenolic hydroxyl with a protecting group said protecting group selected from the group consisting of dialkylphosphinate, diarylphosphinate, alkylarylphosphinate, dialkylphosphate, diarylphosphate, aklylarylphosphate, acetyl, trialkylsilyl, and benzyloxy carbonyl.

2. The composition claim 1, wherein the dialkylphosphinate is selected from a C₁ to C₁₈ substituted alkyl.

3. The composition claim 1, wherein the dialkylphosphinate is selected from a C₁ to C₁₈ unsubstituted alkyl.

4. The composition of claim 1, wherein the dialkylphosphinate is dimethylphosphinate

5. The composition of claim 1, wherein the dialkylphosphinate is diethylphosphinate.

6. The composition of claim 1, wherein the diarylphosphinate is a substituted phenyl.

7. The composition of claim 1, wherein the diarylphosphinate is an unsubstituted phenyl.

8. The composition claim 1, wherein the dialkylphosphate is selected from a C₁ to C₁₈ substituted or unsubstituted alkyl.

9. The composition of claim 1, wherein the dialkylphosphate is dimethylphosphate

10. The composition of claim 1, wherein the dialkylphosphate is diethylphosphate.

11. The composition of claim 1, wherein the diarylphosphate is a substituted phenyl.

12. The composition of claim 1, wherein the diarylphosphate is an unsubstituted phenyl.

13. The composition of claim 1, further comprising a pharmaceutically acceptable excipient.

14. A method of treating a thyroid related condition comprising treating a patient in need thereof with the composition of claim 13.

15. The method of claim 14 wherein said condition is hypothyroidism or depression.

16. A method of stabilizing and increasing the shelf life of a thyroid hormone comprising the composition of claim 1.

38. The pharmaceutical composition of claim 13, 18, 24, 29, or 34 wherein said composition is in the form of an ingestible tablet.

39. The pharmaceutical composition of claim 13, 18, 24, 29, or 34 wherein said composition is in the form of an intravenous preparation.

40. The pharmaceutical composition of claim 13, 18, 24, 29, or 34 wherein said composition is in the form of an oral dosage.

17. A composition comprising a reverse triiodothyronine protected at a phenolic hydroxyl with a protecting group, said protecting group selected from the group consisting of dialkylphosphinate, diarylphosphinate, alkylarylphosphinate, dialkylphosphate, diarylphosphate, acetyl, and benzyloxy carbonyl.

18. The composition of claim 17, further comprising a pharmaceutically acceptable excipient.

19. A method of treating a thyroid related condition comprising treating a patient in need thereof with the composition of claim 18.

20. The method of claim 19 wherein said condition is hypothyroidism or depression.

21. A method of stabilizing and increasing the shelf life of a thyroid hormone comprising the composition of claim 17.

22. A composition comprising a 3,5 diiodothyronine protected at a phenolic hydroxyl with a protecting group, said protecting group selected from dialkylphosphinate, diarylphosphinate, alkylarylphosphinate, dialkylphosphate, diarylphosphate, acetyl, and benzyloxy carbonyl

23. The composition of claim 22 wherein the 3,5 diiodothyronine is selected from 3,5 diiodothyronine, 3′

,5′

diiodothyronine, and 3,3′

diiodothyronine.

24. The composition of claim 23, further comprising a pharmaceutically acceptable excipient.

25. A method of treating a thyroid related condition comprising treating a patient in need thereof with the composition of claim 24.

26. The method of claim 25 wherein said condition is hypothyroidism or depression.

27. A method of stabilizing and increasing the shelf life of a thyroid hormone comprising the composition of claim 22.

28. A composition comprising a 3-monoiodothyronine protected at a phenolic hydroxyl with a protecting group selected dialkylphosphinate, diarylphosphinate, alkylarylphosphinate, dialkylphosphate, diarylphosphate, acetyl, and benzyloxy carbonyl.

29. The composition of claim 28, further comprising a pharmaceutically acceptable excipient.

30. A method of treating a thyroid related condition comprising treating a patient in need thereof with the composition of claim 29.

31. The method of claim 30 wherein said condition is hypothyroidism or depression.

32. A method of stabilizing and increasing the shelf life of a thyroid hormone comprising the composition of claim 28.

33. A composition comprising a thyroxine protected at the phenolic hydroxyl with a protecting group selected from diarylphosphinate, alkylarylphosphinate, diarylphosphate, acetyl, and benzyloxy carbonyl.

34. The composition of claim 33, further comprising a pharmaceutically acceptable excipient.

35. A method of treating a thyroid related condition comprising treating a patient in need thereof with the composition of claim 34.

36. The method of claim 35 wherein said condition is hypothyroidism or depression.

37. A method of stabilizing and increasing the shelf life of a thyroid hormone comprising the composition of claim 33.