Desferrithiocin polyether analogues

• US 9,994,535 B2
• Filed: 02/09/2017
• Issued: 06/12/2018
• Est. Priority Date: 04/04/2005
• Status: Active Grant

• Current Assignee: University of Florida Research Foundation, Incorporated (State University System of Florida)
• Original Assignee: University Of Florida Foundation, Inc. (State University System of Florida)
• Inventors: Bergeron, Jr., Raymond J.
• Primary Examiner(s): Stockton, Laura L.
• Application Number:
  US15/428,232
• Publication Number:
  US 20170217912A1
• Time in Patent Office: 488 Days
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 39/04 Chelating agents
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07D 277/10 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/12 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Abstract

Compounds represented by structural formulas described herein, such as Structural Formula (I):

or a pharmaceutically acceptable salt thereof are useful in treating conditions such as metal overload, oxidative stress, and neoplastic and preneoplastic conditions.

Claims

1. A compound represented by Structural Formula (I):

2. The compound of claim 1, or an alkali metal salt or alkaline earth metal salt thereof, wherein the compound is represented by any one of Structural Formulas (IV) to (IX):

3. A pharmaceutical composition comprising:

a pharmaceutically acceptable carrier or diluent; and

a compound of claim 1, or a pharmaceutically acceptable salt thereof.

4. A method of treating a pathological condition in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the pathological condition is trivalent metal overload, radiation injury, thalassemia, or sickle cell anemia, and wherein the pathological condition is responsive to chelation or sequestration of a trivalent metal.

5. The method of claim 4, wherein R₈ is —

H or —

CH₃.

6. The method of claim 5, wherein R₂ is —

[(CH₂)_n—

O]_x—

R′

;

n is an integer from 1 to 4; and

x is an integer from 1 to 4.

7. The method of claim 4 comprising administering to the subject a therapeutically effective amount of a compound represented by any one of Structural Formulas (IV) to (IX):

8. The compound of claim 1, or an alkali metal salt or alkaline earth metal salt thereof.

9. The compound of claim 1, or a sodium salt, potassium salt, magnesium salt, or calcium salt thereof.

10. The compound of claim 1, or a sodium salt thereof.

11. The compound of claim 1, wherein the compound is represented by Structural Formula (V):

12. The salt of claim 1, wherein the salt is an alkali metal salt or alkaline earth metal salt of a compound represented by Structural Formula (V):

13. The salt of claim 1, wherein the salt is a sodium salt, potassium salt, magnesium salt, or calcium salt of a compound represented by Structural Formula (V):

14. The salt of claim 1, wherein the salt is a sodium salt of a compound represented by Structural Formula (V):

15. The method of claim 4, wherein the pathological condition is iron overload.

16. The method of claim 4, wherein the pathological condition is focal iron overload.

17. The method of claim 4, wherein R₁₂ is —

H.

18. The method of claim 4, wherein R₁₂ is an alkyl group.

19. The method of claim 4, wherein R₁₂ is C_1-4 alkyl.

20. The method of claim 4, comprising administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (V):

21. The method of claim 4, wherein the pathological condition is global iron overload.

22. The method of claim 4, wherein the pathological condition is dietary iron overload or Bantu siderosis.

23. The method of claim 4, wherein the pathological condition is primary hemochromatosis.

24. The method of claim 4, wherein the pathological condition is secondary hemochromatosis.

25. The method of claim 4, wherein the pathological condition is radiation injury.

26. The method of claim 4, wherein the pathological condition is thalassemia.

27. The method of claim 4, wherein the pathological condition is sickle cell anemia.

28. The method of claim 4, wherein the pathological condition is aluminum overload.

29. The method of claim 4, wherein the pathological condition is chromium overload.

30. The salt of claim 1, wherein the salt is a salt of a compound represented by Structural Formula (V):

31. The salt of claim 1, wherein the salt is a pharmaceutically acceptable salt of a compound represented by Structural Formula (V):