Thiophosphonate inhibitors of phosphatase enzymes and metallophosphatases

Abstract

Compounds of the general formula wherein R is selected from the group consisting essentially of hydrogen, methyl, ethyl, phenyl, a carboxyl, or naphthyl substituted or a carbonyl substituted, alkyl of from 3 to 20 carbon atoms, a mono, bi or tri cyclic aryl or substituted aryl for the inhibition of phosphatase enzymes, including metallophosphatases; and, novel methods for synthesizing such compounds. The methods of use include the administration of an effective amount of the compound to provide effective phosphatase inhibition and therapeutic use to treat or prevent certain diseases, which utilize specific phosphatase enzymes.

1 . (Canceled)  
     
     
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         9 . (Canceled)  
     
     
         10 . A method for inhibiting phosphatases comprising: 
 contacting said phosphatase with an effective amount of a compound having the formula                          wherein R is selected from the group consisting essentially of hydrogen, methyl, ethyl, phenyl, a carboxyl, or naphthyl substituted or a carboxylic acid substituted, naphthyl; alkyl of from 3 to 20 carbon atoms, a mono cyclic, bicyclic or polycyclic aryl or substituted aryl.    
     
     
         11 . The method of  claim 10  wherein said R is selected from the group consisting of imidazole, indole, pyrrole, morpholine, isoxazole, pyrazole, amino acid or a polypeptide.  
     
     
         12 . The method of  claim 11  wherein said wherein R is selected from the group consisting of propyl, benzyl, 6-hexanyl-carboxylic acid, 7-1 methanylnaphthalene-carboxylic acid, 6-hexanyl carboxylic acid methyl ester.  
     
     
         13 . The method of  claim 10  wherein said wherein said compound is selected from a group consisting essentially of: trimethylammonium salt of propylphosphonothioic acid, the trimethylammonium salt of benzylphosphonothioic acid, the anilinium salt of 6-thiophosphonohexanoic acid methyl ester, the p-methylanilinium salt of 6-thiophosphonohexanoid acid; and, p-methylanilinium salt of 7-thiophosphonomethylnaphthalene-1-carboxylic acid.  
     
     
         14 . The method of  claim 10 , wherein said phosphatase enzymes are selected from the group consisting of metallophosphatase enzymes.  
     
     
         15 . The method of  claim 14 , wherein said metallophosphatase enzymes are selected from the group consisting of human alkaline phosphatases,  E. coli  alkaline phosphatases, human serine-threonine phosphatases and bacterial serine-threonine phosphatases.  
     
     
         16 . The method of  claim 15 , wherein said serine-threonine phosphatase is from the PPM family.  
     
     
         17 . The method of  claim 16 , wherein said PPM family member is serine-threonine protein phosphatase 2C.  
     
     
         18 . A composition of matter comprising a thiophosphonate of the general formula:  
       
         
           
           
               
               
           
         
       
       wherein R is selected from the group consisting essentially of hydrogen, methyl, ethyl, phenyl, a carboxyl, or naphthyl substituted or a carbonyl substituted, alkyl of from 3 to 20 carbon atoms, a mono, di, or tricyclic carbonyl substituted aryl.  
     
     
         19 . A composition of matter according to  claim 17  wherein R is selected from the group consisting essentially of imidazole, indole, pyrrole, morpholine, isoxazole, pyrazole, amino acid or a polypeptide.  
     
     
         20 . A composition of matter according to  claim 17  selected from the group comprising: trimethylammonium salt of propylphosphonothioic acid, the trimethylammonium salt of benzylphosphonothioic acid, the anilinium salt of 6-thiophosphonohexanoic acid methyl ester, the p-methylanilinium salt of 6-thiophosphonohexanoid acid; and, p-methylanilinium salt of 7-thiophosphonomethylnaphthalene-1-carboxylic acid.