Desferrithiocin polyether analogues

• US 9,174,948 B2
• Filed: 11/21/2012
• Issued: 11/03/2015
• 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.
• Primary Examiner(s): STOCKTON, LAURA LYNNE
• Application Number:
  US13/683,301
• Publication Number:
  US 20130210870A1
• Time in Patent Office: 1,077 Days
• Field of Search: 548/201
• 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 desazadesferrithiocin analog of the formula:

2. An analog of claim 1 wherein R₁ is H or —

CH₃.

3. An analog of claim 1 wherein R₂ is H or —

OCH₃.

4. An analog of claim 1 wherein —

OR₃ is —

O—

[(CH₂)₂—

O]₃—

CH₃.

5. A pharmaceutical composition comprising at least one analog of claim 1, or a salt, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier therefor.

6. A pharmaceutical composition of claim 5, wherein R₁ is H or —

CH₃.

7. A pharmaceutical composition of claim 5, wherein R₂ is H or —

OCH₃.

8. A pharmaceutical composition of claim 5, wherein —

O—

R₃ is —

O—

[(CH₂)₂—

O]₃—

CH₃.

9. The analog of claim 1, wherein R₄ and R₅ are each H.

16. An analog of claim 1, wherein R₁ is —

CH₃.

17. An analog of claim 1, wherein R₂ is H.

18. An analog of claim 1, wherein each instance of n is 2.

19. A pharmaceutical composition of claim 5, wherein R₁ is —

CH₃.

20. A pharmaceutical composition of claim 5, wherein R₂ is H.

21. A pharmaceutical composition of claim 5, wherein each of R₄ and R₅ is H.

22. A pharmaceutical composition of claim 5, wherein each instance of n is 2.

23. An analog of claim 1, wherein the salt is an alkali or alkaline earth metal salt.

24. An analog of claim 1, wherein the salt is a sodium salt, potassium salt, magnesium salt, or calcium salt.

10. (R)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxyl)phenyl]-4-methyl-4-thiazolecarboxylic acid, or a salt, hydrate, or solvate thereof.

13. A pharmaceutical composition comprising the compound of claim 10, or a salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier.

11. A mixture of (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxyl)phenyl]-4-methyl-4-thiazolecarboxylic acid, or a salt, hydrate, or solvate thereof, and (R)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxyl)phenyl]-4-methyl-4-thiazolecarboxylic acid, or a salt, hydrate, or solvate thereof.

12. The mixture of claim 11, wherein said mixture is racemic.

14. A pharmaceutical composition comprising the mixture of claim 11, and optionally a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14, wherein said mixture is racemic.