Use of (-)(3-trihalomethylphenoxy)(4-halophenyl) acetic acid derivatives for treatment of insulin resistance, Type 2 diabetes and hyperlipidemia

Abstract

The present invention provides the use of (−) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives and compositions in the treatment of insulin resistance, Type 2 diabetes and hyperlipidemia.

1 . A method of modulating Type 2 diabetes in a mammal, comprising: administering to said mammal a therapeutically effective amount of the (−) stereoisomer of a compound of Formula I,  
       
         
           
           
               
               
           
         
       
       wherein: 
 R is a member selected from the group consisting of a hydroxy, lower aralkoxy, di-lower alkylamino-lower alkoxy, lower alkanamido lower alkoxy, benzamido-lower alkoxy, ureido-lower alkoxy, N′-lower alkyl-ureido-lower alkoxy, carbamoyl-lower alkoxy, halophenoxy substituted lower alkoxy, carbamoyl substituted phenoxy, carbonyl-lower alkylamino, N,N-di-lower alkylamino-lower alkylamino, halo substituted lower alkylamino, hydroxy substituted lower alkylamino, lower alkanolyloxy substituted lower alkylamino, ureido, and lower alkoxycarbonylamino; and  
 X is a halogen; or  
 a pharmaceutically acceptable salt thereof,  
 wherein the compound is substantially free of its (+) stereoisomer.  
 
     
     
         2 . The method of  claim 1 , wherein the compound is a compound of Formula II,  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 2  is a member selected from the group consisting of a phenyl-lower alkyl, lower alkanamido-lower alkyl, and benzamido-lower alkyl.  
 
     
     
         3 . The method of  claim 1 , wherein the compound is (−) 2-acetamindoethyl 4-chlorophenyl-(3-trifluoromethylphenoxy) acetate.  
     
     
         4 . The method of  claim 1 , wherein the compound is administered by intravenous infusion, transdermal delivery, or oral delivery.  
     
     
         5 . The method of  claim 1 , wherein the amount administered is about 100 mg to about 3000 mg per day.  
     
     
         6 . The method of  claim 1 , wherein the amount administered is about 500 mg to about 1500 mg per day.  
     
     
         7 . The method of  claim 1 , wherein the amount administered is about 5 to about 250 mg per kg per day.  
     
     
         8 . The method of  claim 1 , wherein the compound is administered together with a pharmaceutically acceptable carrier.  
     
     
         9 . The method of  claim 1 , wherein the compound modulates hyperglycemia by reducing blood glucose levels in the mammal.  
     
     
         10 . The method of  claim 1 , wherein the compound modulates hemoglobin A 1c  in the mammal.  
     
     
         11 . The method of  claim 1 , wherein the compound modulates a microvascular and macrovascular complication associated with diabetes.  
     
     
         12 . The method of  claim 11 , wherein the microvascular complication is retinopathy, neuropathy or nephropathy.  
     
     
         13 . The method of  claim 11 , wherein the macrovascular complication is cardiovascular disease or peripheral vascular disease.  
     
     
         14 . The method of  claim 1 , wherein the compound modulates atherosclerosis.  
     
     
         15 . The method of  claim 1 , wherein the compound prevents the development of diabetes in a mammal.  
     
     
         16 . The method of  claim 1 , wherein the compound is administered in combination with a compound selected from the group consisting of: a sulfonylurea or other insulin secretogogue, a thiazolidinedione, a fibrate, a HMG-CoA reductase inhibitor, a biguanide, a bile acid binding resin, nicotinic acid, a α-glucosidase inhibitor, and insulin.  
     
     
         17 . A method for modulating insulin resistance in a mammal, comprising: administering to said mammal a therapeutically effective amount of the (−) stereoisomer of a compound of Formula I,  
       
         
           
           
               
               
           
         
       
       wherein: 
 R is a member selected from the group consisting of a hydroxy, lower aralkoxy, di-lower alkylamino-lower alkoxy, lower alkanamido lower alkoxy, benzamido-lower alkoxy, ureido-lower alkoxy, N′-lower alkyl-ureido-lower alkoxy, carbamoyl-lower alkoxy, halophenoxy substituted lower alkoxy, carbamoyl substituted phenoxy, carbonyl-lower alkylamino, N,N-di-lower alkylamino-lower alkylamino, halo substituted lower alkylamino, hydroxy substituted lower alkylamino, lower alkanolyloxy substituted lower alkylamino, ureido, and lower alkoxycarbonylamino; and  
 X is a halogen; or  
 a pharmaceutically acceptable salt thereof,  
 wherein the compound is substantially free of its (+) stereoisomer.  
 
     
     
         18 . The method of  claim 17 , wherein the compound is a compound of Formula II,  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 2  is a member selected from the group consisting of a phenyl-lower alkyl, lower alkanamido-lower alkyl, and benzamido-lower alkyl.  
 
     
     
         19 . The method of  claim 17 , wherein the compound is (−) 2-acetamidoethyl 4-chlorophenyl-(3-trifluoromethylphenoxy) acetate.  
     
     
         20 . The method of  claim 17 , wherein the compound is administered by intravenous infusion, transdermal delivery, or oral delivery.  
     
     
         21 . The method of  claim 17 , wherein the amount administered is about 100 mg to about 3000 mg per day.  
     
     
         22 . The method of  claim 17 , wherein the amount administered is about 500 mg to about 1500 mg per day.  
     
     
         23 . The method of  claim 17 , wherein the amount administered is about 5 to about 250 mg per kg per day.  
     
     
         24 . The method of  claim 17 , wherein the compound is administered together with a pharmaceutically acceptable carrier.  
     
     
         25 . The method of  claim 17 , wherein the compound prevents the development of insulin resistance in a mammal.  
     
     
         26 . The method of  claim 17 , wherein the compound modulates polycystic ovarian syndrome.  
     
     
         27 . The method of  claim 17 , wherein the compound modulates Impaired Glucose Tolerance.  
     
     
         28 . The method of  claim 17 , wherein the compound modulates obesity.  
     
     
         29 . The method of  claim 17 , wherein the compound modulates gestational diabetes.  
     
     
         30 . The method of  claim 17 , wherein the compound modulates Syndrome X.  
     
     
         31 . The method of  claim 17 , wherein the compound modulates atherosclerosis.  
     
     
         32 . The method of  claim 17 , wherein the compound is administered in combination with a compound selected from the group consisting of: a sulfonylurea or other insulin secretogogue, a thiazolidinedione, a fibrate, a HMG-CoA reductase inhibitor, a biguanide, a bile acid binding resin, nicotinic acid, a α-glucosidase inhibitor, and insulin.  
     
     
         33 . A method of alleviating hyperlipidemia in a mammal, comprising administering to said mammal a therapeutically effective amount of the (−) stereoisomer of a compound of Formula I,  
       
         
           
           
               
               
           
         
       
       wherein: 
 R is a member selected from the group consisting of a hydroxy, lower aralkoxy, di-lower alkylamino-lower alkoxy, lower alkanamido lower alkoxy, benzamido-lower alkoxy, ureido-lower alkoxy, N′-lower alkyl-ureido-lower alkoxy, carbamoyl-lower alkoxy, halophenoxy substituted lower alkoxy, carbamoyl substituted phenoxy, carbonyl-lower alkylamino, N,N-di-lower alkylamino-lower alkylamino, halo substituted lower alkylamino, hydroxy substituted lower alkylamino, lower alkanolyloxy substituted lower alkylamino, ureido, and lower alkoxycarbonylamino; and  
 X is a halogen; or  
 a pharmaceutically acceptable salt thereof,  
 wherein the compound is substantially free of its (+) stereoisomer.  
 
     
     
         34 . The method of  claim 33 , wherein the compound is a compound of Formula II,  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 2  is a member selected from the group consisting of a phenyl-lower alkyl, lower alkanamido-lower alkyl, and benzamido-lower alky.  
 
     
     
         35 . The method of  claim 33 , wherein the compound is (−) 2-acetamidoethyl 4-chlorophenyl-(3-trifluoromethylphenoxy) acetate.  
     
     
         36 . The method of  claim 33 , wherein the compound is administered by intravenous infusion, transdermal delivery, or oral delivery.  
     
     
         37 . The method of  claim 33 , wherein the compound lowers cholesterol levels, triglyceride levels, or both.  
     
     
         38 . The method of  claim 33 , wherein the amount administered is about 100 mg to about 3000 mg per day.  
     
     
         39 . The method of  claim 33 , wherein the amount administered is about 500 mg to about 1500 mg per day.  
     
     
         40 . The method of  claim 33 , wherein the amount administered is about 5 to about 250 mg per kg per day.  
     
     
         41 . The method of  claim 33 , wherein the compound is administered together with a pharmaceutically acceptable carrier.  
     
     
         42 . The method of  claim 33 , wherein the compound is administered in combination with a compound selected from the group consisting of: a sulfonylurea or other insulin secretogogue, a thiazolidinedione, a fibrate, a HMG-CoA reductase inhibitor, a biguanide, a bile acid binding resin, nicotinic acid, a α-glucosidase inhibitor, and insulin.  
     
     
         43 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the (−) stereoisomer of a compound of Formula I,  
       
         
           
           
               
               
           
         
       
       wherein: 
 R is a member selected from the group consisting of a hydroxy, lower aralkoxy, di-lower alkylamino-lower alkoxy, lower alkanamido lower alkoxy, benzamido-lower alkoxy, ureido-lower alkoxy, N′-lower alkyl-ureido-lower alkoxy, carbamoyl-lower alkoxy, halophenoxy substituted lower alkoxy, carbamoyl substituted phenoxy, carbonyl-lower alkylamino, N,N-di-lower alkylamino-lower alkylamino, halo substituted lower alkylamino, hydroxy substituted lower alkylamino, lower alkanolyloxy substituted lower alkylamino, ureido, and lower alkoxycarbonylamino; and  
 X is a halogen; or  
 a pharmaceutically acceptable salt thereof,  
 wherein the compound is substantially free of its (+) stereoisomer.  
 
     
     
         44 . The pharmaceutical composition of  claim 43 , wherein the pharmaceutical composition modulates Type 2 diabetes.  
     
     
         45 . The pharmaceutical composition of  claim 43 , wherein the pharmaceutical composition modulates insulin resistance.  
     
     
         46 . The pharmaceutical composition of  claim 43 , wherein the pharmaceutical composition modulates hyperlipidemia.  
     
     
         47 . The pharmaceutical composition of  claim 43 , comprising a therapeutically effective amount of the (−) stereoisomer of a compound of Formula II,  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 2  is a member selected from the group consisting of a phenyl-lower alkyl, lower alkanamido-lower alkyl, and benzamido-lower alkyl.  
 
     
     
         48 . The pharmaceutical composition of  claim 43 , wherein the compound is (−) 2-acetamidoethyl 4-chlorophenyl-(3-trifluoromethylphenoxy) acetate.  
     
     
         49 . The pharmaceutical composition of  claim 43  in the form of a tablet or capsule.