Compositions and methods using same for treating amyloid-associated diseases

• US 20060194777A1
• Filed: 03/23/2006
• Published: 08/31/2006
• Est. Priority Date: 09/25/2003
• Status: Active Grant

• Current Assignee: Tel Aviv University Future Technology Development L.P. (Tel Aviv University)
• Original Assignee: Tel Aviv University Future Technology Development L.P. (Tel Aviv University)
• Inventors: Porat, Yair, Gazit, Ehud
• Granted Patent: US 8,372,880 B2
• Time in Patent Office: Days
• US Class Current: 514/183
• CPC Class Codes: A61K 31/33 Heterocyclic compounds
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/39 having oxygen in the same ring
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 327/04 Five-membered rings

Abstract

Compounds having one or more phenol moieties, derivatives thereof, compositions containing same and uses thereof for the treatment of amyloid-associated diseases are provided.

Claims

1. Use of a compound having the general Formula I:

2. The use of claim 1, wherein:

X is carbon;

Y is oxygen;

Z is carbon or sulfur; and

at least one of R₅ and R₆ is oxo.

3. The use of claim 2, wherein at least one of R₉ and R₁₀ is selected from the group consisting of alkoxyphenyl, thioalkoxyphenyl, aryloxyphenyl, thioaryloxyphenyl, carboxyphenyl, thiocarboxyphenyl, phenol, hydroxyphenol and dihydroxyphenol.

4. The use of claim 1, wherein said compound is selected from the group consisting of phenol red, dimethoxy phenol red, methoxy phenol red, diacetoxy phenol red, acetoxy phenol red, pyrocatechol violet, phenolphthalein, hydroxyphenyl, and bromophenol red.

5. The use of claim 1, wherein said compound is diacetoxy phenol red.

13. The pharmaceutical composition of claim 11, wherein said pharmaceutical composition is formulated for intravenous administration of said compound.

6. An article-of-manufacture comprising a packaging material and a pharmaceutical composition identified for treating amyloid-associated diseases being contained within said packaging material, said pharmaceutical composition including, as an active ingredient, a compound having the general Formula I:

7. The article-of-manufacture of claim 6, wherein:

X is carbon;

Y is oxygen;

Z is carbon or sulfur; and

at least one of R₅ and R₆ is oxo.

8. The article-of-manufacture of claim 7, wherein at least one of R₉ and R₁₀ is selected from the group consisting of alkoxyphenyl, thioalkoxyphenyl, aryloxyphenyl, thioaryloxyphenyl, carboxyphenyl, thiocarboxyphenyl, phenol, hydroxyphenol and dihydroxyphenol.

9. The article-of-manufacture of claim 6, wherein said compound is selected from the group consisting of phenol red, dimethoxy phenol red, methoxy phenol red, diacetoxy phenol red, acetoxy phenol red, pyrocatechol violet, phenolphthalein, hydroxyphenyl, tocopherol, and bromophenol red.

10. The article-of-manufacture of claim 6, wherein said compound is diacetoxy phenol red.

11. The article-of-manufacture of claim 10, wherein said pharmaceutical acceptable carrier comprises a mixture of polyethylene glycol, saturated sodium chloride and N,N-Dimethylacetamide.

12. The article-of-manufacture of claim 11, wherein said pharmaceutical composition is formulated for oral administration of said compound.

14. A method of treating an amyloid-associated disease in a subject, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a compound having the general Formula I:

15. The method of claim 14, wherein said administering is effected at a concentration of said compound not exceeding 4 mg/Kg body weight/hour.

16. The method of claim 14, wherein said administering is effected orally.

17. The method of claim 14, wherein:

X is carbon;

Y is oxygen;

Z is carbon or sulfur; and

at least one of R₅ and R₆ is oxo.

18. The method of claim 17, wherein at least one of R₉ and R₁₀ is selected from the group consisting of alkoxyphenyl, thioalkoxyphenyl, aryloxyphenyl, thioaryloxyphenyl, carboxyphenyl, thiocarboxyphenyl, phenol, hydroxyphenol and dihydroxyphenol.

19. The method of claim 14, wherein said compound is selected from the group consisting of phenol red, dimethoxy phenol red, methoxy phenol red, diacetoxy phenol red, acetoxy phenol red, pyrocatechol violet, phenolphthalein, hydroxyphenyl, tocopherol, and bromophenol red.

20. The method of claim 14, wherein said compound is diacetoxy phenol red.

21. The method of claim 20, wherein said administering is effected orally.

22. A pharmaceutical composition, for use in the treatment of amyloid-associated diseases, comprising a therapeutically effective amount of a compound having the general Formula I:

23. The pharmaceutical composition of claim 22, wherein:

X is carbon;

Y is oxygen;

Z is carbon or sulfur; and

at least one of R₅ and R₆ is oxo.

24. The pharmaceutical composition of claim 23, wherein at least one of R₉ and R₁₀ is selected from the group consisting of alkoxyphenyl, thioalkoxyphenyl, aryloxyphenyl, thioaryloxyphenyl, carboxyphenyl, thiocarboxyphenyl, phenol, hydroxyphenol and dihydroxyphenol.

25. The pharmaceutical composition of claim 22, wherein said compound is selected from the group consisting of phenol red, dimethoxy phenol red, methoxy phenol red, diacetoxy phenol red, acetoxy phenol red, pyrocatechol violet, phenolphthalein, hydroxyphenyl, tocopherol, and bromophenol red.

26. The pharmaceutical composition of claim 22, wherein said compound is diacetoxy phenol red.

27. The pharmaceutical composition of claim 26, wherein said pharmaceutical acceptable carrier comprises a mixture of polyethylene glycol, saturated sodium chloride and N,N-Dimethylacetamide.

28. The pharmaceutical composition of claim 27, being formulated for oral administration of said compound.

29. The pharmaceutical composition of claim 27, being formulated for intravenous administration of said compound.

30. The pharmaceutical composition of claim 22, further comprising an anti-amyloid drug.

31. The pharmaceutical composition of claim 30, wherein said anti-amyloid drug is selected from the group consisting of an amyloid-destabilizing antibody, an amyloid-destabilizing peptide and an anti-amyloid small molecule.

32. A compound having the general formula II:

33. The compound of claim 32, wherein Q₁ and Q₂ are each oxygen, one of A₁ and A₂ is hydrogen and the other is methyl.

34. The compound of claim 32, wherein Q₁ and Q₂ are each oxygen, one of A₁ and A₂ is hydrogen and the other is acetyl.