Compositions and methods using same for treating amyloid-associated diseases

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.

What is claimed is: 
     
         1 . 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: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Z is sulfur, and R 5  and R 6  are each oxo; 
         Y is oxygen, and R 7  and R 8  are each absent; 
         X is carbon; and 
         R 1 -R 4 , R 9  and R 10  are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, phenyl, alkoxyphenyl, thioalkoxyphenyl, aryloxyphenyl, thioaryloxyphenyl, carboxyphenyl, thiocarboxyphenyl, phenol, hydroxyphenol, dihydroxyphenol, aryl, alkenyl, alkynyl, heteroaryl, heteroalicyclic, halo, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, C-carboxy, O-carboxy, thiocarboxy, carbonyl, oxo, thiocarbonyl, sulfinyl, and sulfonyl, 
         wherein at least one of R 9  and R 10  is selected from the group consisting of phenol, hydroxyphenol, dihydroxyphenol, alkoxyphenyl, thioalkoxyphenyl, aryloxyphenyl, thioaryloxyphenyl, carboxyphenyl and thiocarboxyphenyl, 
         and a pharmaceutically acceptable carrier. 
       
     
     
         2 . The article-of-manufacture 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, tocopherol, and bromophenol red. 
     
     
         3 . The article-of-manufacture of  claim 1 , wherein said compound is selected from the group consisting of phenol red and diacetoxy phenol red. 
     
     
         4 . The article-of-manufacture of  claim 3 , wherein said pharmaceutical acceptable carrier comprises a mixture of polyethylene glycol, saturated sodium chloride and N,N-Dimethylacetamide. 
     
     
         5 . The article-of-manufacture of  claim 4 , wherein said pharmaceutical composition is formulated for oral administration of said compound. 
     
     
         6 . The pharmaceutical composition of  claim 4 , wherein said pharmaceutical composition is formulated for intravenous administration of said compound. 
     
     
         7 . 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: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Z is sulfur, and R 5  and R 6  are each oxo; 
         Y is oxygen, and R 7  and R 8  are each absent; 
         X is carbon; and 
         R 1 -R 4 , R 9  and R 10  are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, phenyl, alkoxyphenyl, thioalkoxyphenyl, aryloxyphenyl, thioaryloxyphenyl, carboxyphenyl, thiocarboxyphenyl, phenol, hydroxyphenol, dihydroxyphenol, aryl, alkenyl, alkynyl, heteroaryl, heteroalicyclic, halo, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, C-carboxy, O-carboxy, thiocarboxy, carbonyl, oxo, thiocarbonyl, sulfinyl, and sulfonyl, 
         wherein at least one of R 9  and R 10  is selected from the group consisting of phenol, hydroxyphenol, dihydroxyphenol, alkoxyphenyl, thioalkoxyphenyl, aryloxyphenyl, thioaryloxyphenyl, carboxyphenyl and thiocarboxyphenyl. 
       
     
     
         8 . The method of  claim 7 , wherein said administering is effected orally. 
     
     
         9 . The method of  claim 7 , 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 method of  claim 7 , wherein said compound is selected from the group consisting of phenol red and diacetoxy phenol red. 
     
     
         11 . The method of  claim 10 , wherein said administering is effected orally. 
     
     
         12 . 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: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Z is sulfur, and R 5  and R 6  are each oxo; 
         Y is oxygen, and R 7  and R 8  are each absent; 
         X is carbon; and 
         R 1 -R 4 , R 9  and R 10  are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, phenyl, alkoxyphenyl, thioalkoxyphenyl, aryloxyphenyl, thioaryloxyphenyl, carboxyphenyl, thiocarboxyphenyl, phenol, hydroxyphenol, dihydroxyphenol, aryl, alkenyl, alkynyl, heteroaryl, heteroalicyclic, halo, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, C-carboxy, O-carboxy, thiocarboxy, carbonyl, oxo, thiocarbonyl, sulfinyl, and sulfonyl, 
         wherein at least one of R 9  and R 10  is selected from the group consisting of phenol, hydroxyphenol, dihydroxyphenol, alkoxyphenyl, thioalkoxyphenyl, aryloxyphenyl, thioaryloxyphenyl, carboxyphenyl and thiocarboxyphenyl. 
       
     
     
         13 . The pharmaceutical composition of  claim 12 , 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. 
     
     
         14 . The pharmaceutical composition of  claim 12 , wherein said compound is selected from the group consisting of phenol red and diacetoxy phenol red. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein said pharmaceutical acceptable carrier comprises a mixture of polyethylene glycol, saturated sodium chloride and N,N-Dimethylacetamide. 
     
     
         16 . The pharmaceutical composition of  claim 15 , being formulated for oral administration of said compound. 
     
     
         17 . The pharmaceutical composition of  claim 15 , being formulated for intravenous administration of said compound. 
     
     
         18 . The pharmaceutical composition of  claim 12 , further comprising an anti-amyloid drug. 
     
     
         19 . The pharmaceutical composition of  claim 18 , 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. 
     
     
         20 . A compound having the general formula II: 
       
         
           
           
               
               
           
         
         a pharmaceutically acceptable salt thereof or a prodrug thereof, 
         wherein: 
         Q 1  and Q 2  are each independently selected from the group consisting of oxygen and sulfur; and 
         A 1  and A 2  are each independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl and carbonyl, 
         whereas when Q 1  and Q 2  are each oxygen, one of A 1  and A 2  is hydrogen and the other is selected from the group consisting of alkyl, cycloalkyl, aryl and carbonyl. 
       
     
     
         21 . The compound of  claim 20 , wherein Q 1  and Q 2  are each oxygen, one of A 1  and A 2  is hydrogen and the other is methyl. 
     
     
         22 . The compound of  claim 20 , wherein Q 1  and Q 2  are each oxygen, one of A 1  and A 2  is hydrogen and the other is acetyl.