DESFERRITHIOCIN POLYETHER ANALOGUES

• US 20160022645A1
• Filed: 10/05/2015
• Published: 01/28/2016
• Est. Priority Date: 03/15/2007
• Status: Active Grant

• Current Assignee: University of Florida Research Foundation, Incorporated (State University System of Florida)
• Original Assignee: University of Florida Research Foundation, Incorporated (State University System of Florida)
• Inventors: Bergeron, Raymond J. Jr.
• Granted Patent: US 9,730,917 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• 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 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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

A relatively non-toxic desazadesferrithiocin analog having the formula:

• • wherein: R₁, R₂, R₄ and R₅ may be the same or different and may be H, straight or branched chain alkyl having up to 14 carbon atoms, e.g., methyl, ethyl, propyl and butyl, or arylalkyl wherein the aryl portion is hydrocarbyl and the alkyl portion is straight or branched chain, the arylalkyl group having up to 14 carbon atoms, R₂ optionally being alkoxy having up to 14 carbon atoms;
    • R₃ is [(CH₂)_n—O]_x—[(CH₂)_n—O]_y-alkyl;
    • n is, independently, an integer from 1 to 8;
    • x is an integer from 1 to 8;
    • y is an integer from 0 to 8, and
    • R₃O may occupy any position on the phenyl ring except the 4-position, or
  • a salt, hydrate or solvate thereof; and methods and compositions for treating the effects of trivalent metal, i.e., iron, overload.

Claims

1. A method of treating a pathological condition in a subject comprising administering to the subject a therapeutically effective amount of a desazadesferrithiocin analog of formula:

2. The method of claim 1, wherein R₁ is H or —

CH₃.

3. The method of claim 1 wherein R₂ is H or —

OCH₃.

4. The method of claim 1, wherein —

OR₃ is —

O—

[(CH₂)₂—

O]₃—

CH₃.

5. The method of claim 1, wherein R₄ and R₅ are each H.

6. The method of claim 1, wherein R₁ is —

CH₃.

7. The method of claim 1, wherein R₂ is H.

8. The method of claim 1, wherein each instance of n is 2.

9. The method of claim 1, wherein the salt is an alkali or alkaline earth metal salt.

10. The method of claim 1, wherein the salt is a sodium salt, potassium salt, magnesium salt, or calcium salt.

11. The method of claim 1, wherein the metal is trivalent.

12. The method of claim 1, wherein the pathological condition is metal overload.

13. The method of claim 12, wherein the metal overload is iron overload.

14. The method of claim 13, wherein the iron overload is primary hemochromatosis.

15. The method of claim 13, wherein the iron overload is secondary hemochromatosis.

16. The method of claim 13, wherein the iron overload is focal iron overload.

17. The method of claim 13, wherein the iron overload is thalassemia.

18. The method of claim 1, wherein the pathological condition is diabetes.

19. The method of claim 1, wherein the pathological condition is liver disease.

20. The method of claim 1, wherein the pathological condition is Friedreich ataxia (FRDA).

21. The method of claim 1, wherein the pathological condition is heart disease.

22. The method of claim 1, wherein the pathological condition is radiation injury.

23. A method of treating iron overload due to blood transfusions in a subject suffering therefrom comprising administering to the subject a therapeutically effective amount of a desazadesferrithiocin analog of formula:

24. The method of claim 23, wherein the analog is of the formula:

25. The method of reducing oxidative stress in a subject comprising administering to the subject a therapeutically effective amount of a desazadesferrithiocin analog of formula: