Novel methylenedioxy phenolic compounds and their use to treat disease

Abstract

Pharmaceutical compounds and compositions are provided which are methylenedioxy phenolic compounds and their derivatives, along with methods of making them and methods of using them for therapeutic purposes. The compounds and compositions are advantageous in that they can be used to treat or prevent cardiovascular disease, vascular disease and/or inflammatory disease, as well as Type I and Type II Diabetes and Dyslipidemia patients at risk for hypertension, stroke, cardiovascular and renal disease.

What is claimed is: 
     
         1 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is acetyl, ethyl ester, propyl ester, butyl ester, hydrogen, lipoyl, dihydrolipoyl, ferulyl, or isomeric-ferulyl; 
 R 2  is absent or is O 2 N, hydroxyl, methoxy, ethoxy, branched alkyl of 1 to 8 carbons, acetyl, lipoyl, dihydrolipoyl, ferulyl, a heterocycle selected from the group consisting of imidazole, quinaline, isoquinaline, thiazolidinedione, pyrrolidone and piperidine, carboxyl, methyl ester, ethyl ester, an aliphatic amide of 1 to 3 carbons, an alicyclic amide selected from the group consisting of pyrrolidone and piperidine, an aromatic amide selected from the group consisting of aniline and substituted aniline, amine, an alkylated amine of 1 to 3 carbons, an amide functional group via lipoic acid or dihydrolipoic acid, an aromatic acid selected from the group consisting of ferulic acid and cinnamic acid, a heterocyclic amide derived from proline, substituted proline, or pipecolinic acid, or a halogen; and 
 R 3  is absent or is a linear alkyl group of 1 to 3 carbons, a branched chain alkyl group of 3 to 5 carbons, an alkyl group having a functional group of a free carboxylic acid, ester or amide, free hydroxyl derivatives or alkylated ether derivatives, an alkyl group of 1 to 3 carbons having a functional group selected from amine and alkylated amine, an aliphatic amide, an aromatic amide or a heterocyclic amide selected from the group consisting of imidazole, quinoline, isoquinoline, thiozoline, and piperazine, or a halogenated group; 
 except wherein the compound is not 3,4-methylenedioxy phenyl acetate (INV-73); 3,4-methylenedioxy-6-nitrophenol (INV-74), or 3,4-methylenedioxy-6-nitrophenyl acetate (INV-75). 
 
     
     
         2 . The compound of  claim 1 , wherein the compound is: 3,4-methylenedioxyphenyl lipoate (INV-7065): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein the compound is 3,4-methylenedioxy 6-nitrophenyl lipoate (INV-7465): 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         7 . A composition comprising a compound of  claim 1 , further including one or more therapeutic compounds selected from the group consisting of a lipoic acid, an HMG-CoA reductase inhibitor, an angiotensin converting enzyme inhibitor, a fat uptake inhibitor, an angiotensin receptor blocker, a PPARα agonist, a PPARγ agonists, acetylsalicylic acid, an inhibitor of platelet aggregation, a cholesteryl ester transfer protein inhibitor, a thiazolidinedione, niacin, a fibrate, an inhibitor of clot formation or a beta-blocker, and combinations thereof. 
     
     
         8 . A method of treating or preventing cardiovascular disease, vascular disease, inflammatory disease, and Type I and Type II diabetes and dyslipidemia patients at risk for hypertension, stroke, cardiovascular and renal disease in a patient comprising administering to the patient an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is acetyl, ethyl ester, propyl ester, butyl ester, hydrogen, lipoyl, dihydrolipoyl, ferulyl, or isomeric-ferulyl; 
 R 2  is absent or is O 2 N, hydroxyl, methoxy, ethoxy, branched alkyl of 1 to 8 carbons, acetyl, lipoyl, dihydrolipoyl, ferulyl, a heterocycle selected from the group consisting of imidazole, quinaline, isoquinaline, thiazolidinedione, pyrrolidone and piperidine, carboxyl, methyl ester, ethyl ester, an aliphatic amide of 1 to 3 carbons, an alicyclic amide selected from the group consisting of pyrrolidone and piperidine, an aromatic amide selected from the group consisting of aniline and substituted aniline, amine, an alkylated amine of 1 to 3 carbons, an amide functional group via lipoic acid or dihydrolipoic acid, an aromatic acid selected from the group consisting of ferulic acid and cinnamic acid, a heterocyclic amide derived from proline, substituted proline, or pipecolinic acid, or a halogen; and 
 R 3  is absent or is a linear alkyl group of 1 to 3 carbons, a branched chain alkyl group of 3 to 5 carbons, an alkyl group having a functional group of a free carboxylic acid, ester or amide, free hydroxyl derivatives or alkylated ether derivatives, an alkyl group of 1 to 3 carbons having a functional group selected from amine and alkylated amine, an aliphatic amide, an aromatic amide or a heterocyclic amide selected from the group consisting of imidazole, quinoline, isoquinoline, thiozoline, and piperazine, or a halogenated group. 
 
     
     
         9 . The method of  claim 8  wherein said compound is administered along with a pharmaceutically acceptable carrier. 
     
     
         10 . The method of  claim 8 , wherein R 1  is hydrogen and R 2  is O 2 N or is absent. 
     
     
         11 . The method of  claim 8 , wherein R 1  is acetyl and R 2  is O 2 N or is absent. 
     
     
         12 . The method of  claim 8 , wherein R 1  is lipoyl and R 2  is O 2 N or is absent. 
     
     
         13 . The method of  claim 8 , wherein the compound is selected from the group consisting of:
 3,4-methylenedioxyphenyl acetate (INV-73),   3,4-methylenedioxy-6-nitrophenol (INV-74),   3,4-methylenedioxy-6-nitrophenyl acetate (INV-75),   3,4-methylenedioxyphenyl lipoate (INV-7065), and   3,4-methylenedioxy 6-nitrophenyl lipoate (INV-7465).   
     
     
         14 . The method of  claim 8 , further comprising administering a lipoic acid, an HMG-CoA reductase inhibitor, an angiotensin converting enzyme inhibitor, a fat uptake inhibitor, an angiotensin receptor blocker, a PPAR-alpha agonist, a PPAR-gamma agonists, acetylsalicylic acid, an inhibitor of platelet aggregation, a cholesteryl ester transfer protein inhibitor, a thiazolidinedione, niacin, a fibrate, an inhibitor of clot formation or a beta-blocker, or a combination thereof. 
     
     
         15 . A method for treating cardiovascular disease in a subject in need thereof, comprising administering to the subject in need of such treatment an agent that modulates expression of a p65 subunit of NF-κB, in an amount effective to treat the cardiovascular disease, wherein the agent comprises a compound of  claim 1 . 
     
     
         16 . A method for reducing plaque formation in a subject in need thereof, comprising administering an effective amount of at least one compound of  claim 1  to a patient in need thereof. 
     
     
         17 . The method of  claim 16  wherein said compound is administered along with a pharmaceutically acceptable carrier. 
     
     
         18 . The method of  claim 16 , wherein R 1  is hydrogen and R 2  is O 2 N or is absent. 
     
     
         19 . The method of  claim 16 , wherein R 1  is acetyl and R 2  is O 2 N or is absent. 
     
     
         20 . The method of  claim 16 , wherein R 1  is lipoyl and R 2  is O 2 N or is absent.