Identification and uses of novel PPAR ligands that do not cause fluid retention, edema or congestive heart failure

Abstract

Methods are provided for treating or prophylactically preventing metabolic disorders in humans without causing, promoting, or aggravating fluid retention, peripheral edema, pulmonary edema, or congestive heart failure, by administration of a therapeutically effective amount of a compound sufficient to partially or fully activate peroxisome proliferator activated receptors (PPARs) and partially or fully inhibit, antagonize or block the activity of angiotensin II type 1 receptors. Metabolic disorders that can be treated or prevented include but are not limited to type 2 diabetes, the metabolic syndrome; prediabetes, and other insulin resistance syndromes. Compounds are provided that antagonize or block the angiotensin II type 1 (AT1) receptor, function as partial or full activators of peroxisome proliferator activated receptors (PPARs), can be used to treat or prevent diseases known to be treatable or preventable by PPAR activators and were not previously recognized to be therapeutic targets for angiotensin II receptor antagonists.

1 - 23 . (canceled) 
     
     
         24 . A method for treating hypertension in an individual, the method comprising orally administering to the individual a combination therapy; wherein active ingredients or esters thereof of the combination therapy consist of (i) chlorthalidone and (ii) an amount of a compound or an ester of a compound that (a) increases an activity of peroxisome proliferator activated receptor-gamma (PPAR-γ), and (b) at least partially inhibits, antagonizes, or blocks-an activity of angiotensin II type 1 receptors, wherein the compound is administered to the individual at a total effective daily dose between 0.1 mg to 1,000 mg, and wherein the method treats hypertension in the individual. 
     
     
         25 . The method of  claim 24 , wherein the compound reduces fat mass. 
     
     
         26 . The method of  claim 24 , wherein the compound is telmisartan. 
     
     
         27 . The method of  claim 24 , wherein the compound is irbesartan. 
     
     
         28 . The method of  claim 24 , wherein the compound is candesartan cilexetil. 
     
     
         29 . The method of  claim 24 , wherein the compound has the general formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is an optionally substituted hydrocarbon residue which is optionally bonded through a hetero-atom; 
         R 2  is an optionally substituted 5-7 membered heterocyclic residue having a carbonyl group; 
         X is a direct bond; 
         W and Y are independently an aromatic-hydrocarbon residue; 
         n is an integer of 1; 
         a is a hetero atom; 
         b is an optionally substituted carbon; 
         c is an optionally substituted carbon; and 
         in the group of the formula: 
       
       
         
           
           
               
               
           
         
       
       substituents on adjacent two atoms forming the ring are optionally bonded to each other to form a 5-6 membered ring together with the two atoms forming the ring. 
     
     
         30 . The method of  claim 29 , wherein b and c are bonded to each other to form a 5-6 membered ring. 
     
     
         31 . The method of  claim 24 , wherein the compound at least partially activates PPAR-γ. 
     
     
         32 . The method of  claim 24 , wherein the compound is administered to the individual at a total effective daily dose between 20 mg to 1,000 mg. 
     
     
         33 . The method of  claim 24 , wherein the compound is administered to the individual at a total effective daily dose between 5 mg to 300 mg. 
     
     
         34 . A pharmaceutical composition for treating hypertension in an individual, wherein active ingredients or esters thereof of the pharmaceutical composition consist of (i) chlorthalidone and (ii) 0.1 mg to 1,000 mg of a compound or an ester of a compound that (a) increases an activity of peroxisome proliferator activated receptor-gamma (PPAR-γ), and (b) at least partially inhibits, antagonizes, or blocks-an activity of angiotensin II type 1 receptors. 
     
     
         35 . The pharmaceutical composition of  claim 34 , wherein the compound reduces fat mass. 
     
     
         36 . The pharmaceutical composition of  claim 34 , wherein compound is telmisartan. 
     
     
         37 . The pharmaceutical composition of  claim 34 , wherein the compound is irbesartan. 
     
     
         38 . The pharmaceutical composition of  claim 34 , wherein the compound is candesartan cilexetil. 
     
     
         39 . The pharmaceutical composition of  claim 34 , wherein the compound has the general formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is an optionally substituted hydrocarbon residue which is optionally bonded through a hetero-atom; 
         R 2  is an optionally substituted 5-7 membered heterocyclic residue having a carbonyl group; 
         X is a direct bond; 
         W and Y are independently an aromatic-hydrocarbon residue; 
         n is an integer of 1; 
         a is a hetero atom; 
         b is an optionally substituted carbon; 
         c is an optionally substituted carbon; and 
         in the group of the formula: 
       
       
         
           
           
               
               
           
         
       
       substituents on adjacent two atoms forming the ring are optionally bonded to each other to form a 5-6 membered ring together with the two atoms forming the ring. 
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein b and c are bonded to each other to form a 5-6 membered ring. 
     
     
         41 . The pharmaceutical composition of  claim 34 , wherein the compound at least partially activates PPAR-γ. 
     
     
         42 . The pharmaceutical composition of  claim 34 , wherein the amount of the compound is between 20 mg to 1,000 mg. 
     
     
         43 . The pharmaceutical composition of  claim 34 , wherein the amount of the compound is between 5 mg to 300 mg.