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

Abstract

The present invention provides the use of (−) (3-halomethylphenoxy) (4-halophenyl) acetic acid derivatives and compositions in the treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia. It further provides (−) (3-halomethylphenoxy) (4-halophenyl) acetic acid derivatives that are useful for the treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia.

What is claimed is:  
     
         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, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, 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 1  is a halogen; and  
 X 2 , X 3  and X 4  are each independently selected from hydrogen and halogen with the proviso that no more than two of X 2 , X 3  and X 4  are hydrogen;  
 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: C 1 -C 5  alkyl, C 1 -C 8 -cyclic alkyl, C 2 -C 5  alkenyl, and C 2 -C 5  alkynyl, wherein the groups are optionally substituted with one or more halogen atoms; phenyl, naphthyl and pyridyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; —(CHR 3 )R 4 ; —R 7 OR 3 ; —R 7 O 2 CR 8 NR 3 R 4 ; —R 7 COR 6 ; —R 7 NR 3 COR 6 ; —R 7 NR 3 R 6 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q O 2 CR 9 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 COR 9 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 CONR 3 R 4 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 COOR 10 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 SO 2 R 11 ; —(CHR 3 ) p CO 2 R 12 ; —(CHR 3 ) p NR 3 R 4 ; —(CHR 3 ) s CONR 13 R 14 ;  
                     
 wherein m is 0 to 2, o and q are 0 to 5, p is 1 to 5, s is 1 to 3, t is 1 to 5, u is 0 to 1, v is 1 to 3, and w is 1 to (2v+1); and wherein R 3  and R 4  are independently H, C 1 -C 5  alkyl, phenyl or benzyl; and wherein R 5  is H, C 1 -C 5  alkyl or NR 3 R 4 ; and wherein R 6  is phenyl, naphthyl, pyridyl, imidazolyl, indoxyl, indolizinyl, oxazolyl, thiazolyl, thienyl, pyrimidyl, or 1-pyrazolyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 7  is a C 1 -C 8  saturated or unsaturated, straight-chain, branched or cyclic alkylene or alkylidene group optionally substituted with one or more groups selected from halo, hydroxyl, thiol, amino, monoalkyl amino, dialkyl amino, acylamino, carboxyl, alkylcarboxyl, acyl, aryl, aroyl, aralkyl, cyano, nitro, alkoxy, alkenyloxy, alkylcarbonyloxy and arylcarbonyloxy; and wherein R 8  is a C 1 -C 8  straight-chain or branched alkylene or alkylidene optionally substituted with one or more groups selected from amino, monoalkyl amino, dialkyl amino, acylamino, hydroxyl, thiol, methylthiol, carboxyl and phenyl; and wherein R 9  and R 10  are independently H, C 1 -C 5  alkyl, optionally substituted with one or more groups consisting of C 1 -C 5  alkoxy aryl and heteroaryl, wherein the aryl is phenyl or naphthyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w , and wherein the heteroaryl is pyridyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 11  is methyl or phenyl, wherein the phenyl is optionally substituted with methyl and/or —NO 2 ; and wherein R 12  is H, C 1 -C 5  alkyl, phenyl, benzyl, naphthyl or pyridyl, wherein the C 1 -C 5  alkyl, phenyl, naphthyl, benzyl and pyridyl are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C—C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 13  and R 14  are independently the following: alkyl, alkenyl, aryl, aralkyl or cycloalkyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4 , —CH 2 NR 3 R 4 , OOCR 18  and —C v F w ; and wherein when R 13  and R 14  are included as —(CHR 3 )CONR 13 R 14 , NR 13 R 14  is  
                     
 and wherein R 15  is C v F w , or C 1 -C 5  alkyl, wherein C 1 -C 5  alkyl is optionally substituted with the following substituents: C 1 -C 5  alkoxy; phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; benzyl, optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 16  is H, C 1 -C 5  alkyl or benzyl; and wherein R 17  is C 1 -C 5  alkyl, C 3 -C 8  cyclic alkyl, phenyl or benzyl; and wherein R 18  is H, alkyl, aryl, aralkyl or cycloalkyl, where the group is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w .  
 
     
     
         3 . The method of  claim 1 , wherein the compound is administered by intravenous infusion, transdermal delivery, or oral delivery.  
     
     
         4 . The method of  claim 1 , wherein the amount administered is about 100 mg to about 3000 mg per day.  
     
     
         5 . The method of  claim 1 , wherein the amount administered is about 500 mg to about 1500 mg per day.  
     
     
         6 . The method of  claim 1 , wherein the amount administered is about 5 to about 250 mg per kg per day.  
     
     
         7 . The method of  claim 1 , wherein the compound is administered together with a pharmaceutically acceptable carrier.  
     
     
         8 . The method of  claim 1 , wherein the compound modulates hyperglycemia by reducing blood glucose levels in the mammal.  
     
     
         9 . The method of  claim 1 , wherein the compound modulates hemoglobin A 1c  in the mammal.  
     
     
         10 . The method of  claim 1 , wherein the compound modulates a microvascular and macrovascular complication associated with diabetes.  
     
     
         11 . The method of  claim 10 , wherein the microvascular complication is retinopathy, neuropathy or nephropathy.  
     
     
         12 . The method of  claim 10 , wherein the macrovascular complication is cardiovascular disease or peripheral vascular disease.  
     
     
         13 . The method of  claim 1 , wherein the compound modulates atherosclerosis.  
     
     
         14 . The method of  claim 1 , wherein the compound prevents the development of diabetes in a mammal.  
     
     
         15 . 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.  
     
     
         16 . 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, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, 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 1  is a halogen; and  
 X 2 , X 3  and X 4  are each independently selected from hydrogen and halogen with the proviso that no more than two of X 2 , X 3  and X 4  are hydrogen;  
 or a pharmaceutically acceptable salt thereof,  
 wherein the compound is substantially free of its (+) stereoisomer.  
 
     
     
         17 . The method of  claim 16 , wherein the compound is a compound of Formula II,  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 2  is a member selected from the group consisting of: C 1 -C 5  alkyl, C 1 -C 8 -cyclic alkyl, C 2 -C 5  alkenyl, and C 2 -C 5  alkynyl, wherein the groups are optionally substituted with one or more halogen atoms; phenyl, naphthyl and pyridyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; —(CHR 3 )R 4 ; —R 7 OR 3 ; —R 7 O 2 CR 8 NR 3 R 4 ; —R 7 COR 6 ; —R 7 NR 3 COR 6 ; —R 7 NR 3 R 6 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q O 2 CR 9 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 COR 9 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 CONR 3 R 4 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 COOR 10 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 SO 2 R 11 ; —(CHR 3 ) p CO 2 R 12 ; —(CHR 3 ) p NR 3 R 4 ; —(CHR 3 ) s CONR 13 R 14 ;  
                     
 wherein m is 0 to 2, o and q are 0 to 5, p is 1 to 5, s is 1 to 3, t is 1 to 5, u is 0 to 1, v is 1 to 3, and w is 1 to (2v+1); and wherein R 3  and R 4  are independently H, C 1 -C 5  alkyl, phenyl or benzyl; and wherein R 5  is H, C 1 -C 5  alkyl or NR 3 R 4 ; and wherein R 6  is phenyl, naphthyl, pyridyl, imidazolyl, indoxyl, indolizinyl, oxazolyl, thiazolyl, thienyl, pyrimidyl, or 1-pyrazolyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 7  is a C 1 -C 8  saturated or unsaturated, straight-chain, branched or cyclic alkylene or alkylidene group optionally substituted with one or more groups selected from halo, hydroxyl, thiol, amino, monoalkyl amino, dialkyl amino, acylamino, carboxyl, alkylcarboxyl, acyl, aryl, aroyl, aralkyl, cyano, nitro, alkoxy, alkenyloxy, alkylcarbonyloxy and arylcarbonyloxy; and wherein R 8  is a C 1 -C 8  straight-chain or branched alkylene or alkylidene optionally substituted with one or more groups selected from amino, monoalkyl amino, dialkyl amino, acylamino, hydroxyl, thiol, methylthiol, carboxyl and phenyl; and wherein R 9  and R 10  are independently H, C 1 -C 5  alkyl, optionally substituted with one or more groups consisting of C 1 -C 5  alkoxy aryl and heteroaryl, wherein the aryl is phenyl or naphthyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w , and wherein the heteroaryl is pyridyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —N 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 11  is methyl or phenyl, wherein the phenyl is optionally substituted with methyl and/or —NO 2 ; and wherein R 12  is H, C 1 -C 5  alkyl, phenyl, benzyl, naphthyl or pyridyl, wherein the C 1 -C 5  alkyl, phenyl, naphthyl, benzyl and pyridyl are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  allyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) r (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 13  and R 14  are independently the following: alkyl, alkenyl, aryl, aralkyl or cycloalkyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R, —CH 2 NR 3 R 4 , OOCR 18  and —C v F w ; and wherein when R 13  and R 14  are included as —(CHR 3 )CONR 13 R 14 , NR 13 R 14  is  
                     
 and wherein R 15  is C v F w  or C 1 -C 5  alkyl, wherein C 1 -C 5  alkyl is optionally substituted with the following substituents: C 1 -C 5  alkoxy; phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; benzyl, optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2   5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 16  is H, C 1 -C 5  alkyl or benzyl; and wherein R 17  is C 1 -C 5  alkyl, C 3 -C 8  cyclic alkyl, phenyl or benzyl; and wherein R 18  is H, alkyl, aryl, aralkyl or cycloalkyl, where the group is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w .  
 
     
     
         18 . The method of  claim 16 , wherein the compound is administered by intravenous infusion, transdermal delivery, or oral delivery.  
     
     
         19 . The method of  claim 16 , wherein the amount administered is about 100 mg to about 3000 mg per day.  
     
     
         20 . The method of  claim 16 , wherein the amount administered is about 500 mg to about 1500 mg per day.  
     
     
         21 . The method of  claim 16 , wherein the amount administered is about 5 to about 250 mg per kg per day.  
     
     
         22 . The method of  claim 16 , wherein the compound is administered together with a pharmaceutically acceptable carrier.  
     
     
         23 . The method of  claim 16 , wherein the compound prevents the development of insulin resistance in a mammal.  
     
     
         24 . The method of  claim 16 , wherein the compound modulates polycystic ovarian syndrome.  
     
     
         25 . The method of  claim 16 , wherein the compound modulates Impaired Glucose Tolerance.  
     
     
         26 . The method of  claim 16 , wherein the compound modulates obesity.  
     
     
         27 . The method of  claim 16 , wherein the compound modulates gestational diabetes.  
     
     
         28 . The method of  claim 16 , wherein the compound modulates Syndrome X.  
     
     
         29 . The method of  claim 16 , wherein the compound modulates atherosclerosis.  
     
     
         30 . The method of  claim 16 , 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 EMG-CoA reductase inhibitor, a biguanide, a bile acid binding resin, nicotinic acid, a α-glucosidase inhibitor, and insulin.  
     
     
         31 . 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, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, 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 1  is a halogen; and  
 X 2 , X 3  and X 4  are each independently selected from hydrogen and halogen with the proviso that no more than two of X 2 , X 3  and X 4  are hydrogen;  
 or a pharmaceutically acceptable salt thereof,  
 wherein the compound is substantially free of its (+) stereoisomer.  
 
     
     
         32 . The method of  claim 31 , wherein the compound is a compound of Formula II,  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 2  is a member selected from the group consisting of: C 1 -C 5  alkyl, C 1 -C 8 -cyclic alkyl, C 2 -C 5  alkenyl, and C 2 -C 5  alkynyl, wherein the groups are optionally substituted with one or more halogen atoms; phenyl, naphthyl and pyridyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; —(CHR 3 )R 4 ; —R 7 OR 3 ; —R 7 O 2 CR 8 NR 3 R 4 ; —R 7 COR 6 ; —R 7 NR 3 COR 6 ; —R 7 NR 3 R 6 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q O 2 CR 9 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 COR 9 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 CONR 3 R 4 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 COOR 10 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 SO 2 R 11 ; —(CHR 3 ) p CO 2 R 12 ; —(CHR 3 ) p NR 3 R 4 ; —(CHR 3 ) s CONR 13 R 14 ;  
                     
 wherein m is 0 to 2, o and q are 0 to 5, p is 1 to 5, s is 1 to 3, t is 1 to 5, u is 0 to 1, v is 1 to 3, and w is 1 to (2v+1); and wherein R 3  and R 4  are independently H, C 1 -C 5  alkyl, phenyl or benzyl; and wherein R 5  is H, C 1 -C 5  alkyl or NR 3 R 4 ; and wherein R 6  is phenyl, naphthyl, pyridyl, imidazolyl, indoxyl, indolizinyl, oxazolyl, thiazolyl, thienyl, pyrimidyl, or 1-pyrazolyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 7  is a C 1 -C 8  saturated or unsaturated, straight-chain, branched or cyclic alkylene or alkylidene group optionally substituted with one or more groups selected from halo, hydroxyl, thiol, amino, monoalkyl amino, dialkyl amino, acylamino, carboxyl, alkylcarboxyl, acyl, aryl, aroyl, aralkyl, cyano, nitro, alkoxy, alkenyloxy, alkylcarbonyloxy and arylcarbonyloxy; and wherein R 8  is a C 1 -C 8  straight-chain or branched alkylene or alkylidene optionally substituted with one or more groups selected from amino, monoalkyl amino, dialkyl amino, acylamino, hydroxyl, thiol, methylthiol, carboxyl and phenyl; and wherein R 9  and R 10  are independently H, C 1 -C 5  alkyl, optionally substituted with one or more groups consisting of C 1 -C 5  alkoxy aryl and heteroaryl, wherein the aryl is phenyl or naphthyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w , and wherein the heteroaryl is pyridyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 11  is methyl or phenyl, wherein the phenyl is optionally substituted with methyl and/or —NO 2 ; and wherein R 12  is H, C 1 -C 5  alkyl, phenyl, benzyl, naphthyl or pyridyl, wherein the C 1 -C 5  alkyl, phenyl, naphthyl, benzyl and pyridyl are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 13  and R 14  are independently the following: alkyl, alkenyl, aryl, aralkyl or cycloalkyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4 , CH 2 NR 3 R 4 , OOCR 18  and —C v F w ; and wherein when R 13  and R 14  are included as —(CHR 3 )CONR 13 R 14 , NR 13 R 14  is  
                     
 and wherein R 15  is C v F w  or C 1 -C 5  alkyl, wherein C 1 -C 5  alkyl is optionally substituted with the following substituents: C 1 -C 5  alkoxy; phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; benzyl, optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 16  is H, C 1 -C 5  alkyl or benzyl; and wherein R 17  is C 1 -C 5  alkyl, C 3 -C 8  cyclic alkyl, phenyl or benzyl; and wherein R 18  is H, alkyl, aryl, aralkyl or cycloalkyl, where the group is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  allyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w .  
 
     
     
         33 . The method of  claim 31 , wherein the compound is administered by intravenous infusion, transdermal delivery, or oral delivery.  
     
     
         34 . The method of  claim 31 , wherein the compound lowers cholesterol levels, triglyceride levels, or both.  
     
     
         35 . The method of  claim 31 , wherein the amount administered is about 100 mg to about 3000 mg per day.  
     
     
         36 . The method of  claim 31 , wherein the amount administered is about 500 mg to about 1500 mg per day.  
     
     
         37 . The method of  claim 31 , wherein the amount administered is about 5 to about 250 mg per kg per day.  
     
     
         38 . The method of  claim 31 , wherein the compound is administered together with a pharmaceutically acceptable carrier.  
     
     
         39 . The method of  claim 31 , 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.  
     
     
         40 . 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, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, 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 1  is a halogen; and  
 X 2 , X 3  and X 4  are each independently selected from hydrogen and halogen with the proviso that no more than two of X 2 , X 3  and X 4  are hydrogen;  
 or a pharmaceutically acceptable salt thereof,  
 wherein the compound is substantially free of its (+) stereoisomer.  
 
     
     
         41 . The pharmaceutical composition of  claim 40 , wherein the pharmaceutical composition modulates Type 2 diabetes.  
     
     
         42 . The pharmaceutical composition of  claim 40 , wherein the pharmaceutical composition modulates insulin resistance.  
     
     
         43 . The pharmaceutical composition of  claim 40 , wherein the pharmaceutical composition modulates hyperlipidemia.  
     
     
         44 . The pharmaceutical composition of  claim 40 , 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: C 1 -C 5  alkyl, C 1 -C 8 -cyclic alkyl, C 2 -C 5  alkenyl, and C 2 -C 5  alkynyl, wherein the groups are optionally substituted with one or more halogen atoms; phenyl, naphthyl and pyridyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; —(CHR 3 )R 4 ; —R 7 OR 3 ; —R 7 O 2 CR 8 NR 3 R 4 ; —R 7 COR 6 ; —R 7 NR 3 COR 6 ; —R 7 NR 3 R 6 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q O 2 CR 9 —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 COR 9 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 CONR 3 R 4 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 COOR 10 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 SO 2 R 11 ; —(CHR 3 ) p CO 2 R 12 ; —(CHR 3 ) p NR 3 R 4 ; —(CHR 3 ) s CONR 13 R 14 ;  
                     
 wherein m is 0 to 2, o and q are 0 to 5, p is 1 to 5, s is 1 to 3, t is 1 to 5, u is 0 to 1, v is 1 to 3, and w is 1 to (2v+1); and wherein R 3  and R 4  are independently H, C 1 -C 5  alkyl, phenyl or benzyl; and wherein R 5  is H, C 1 -C 5  alkyl or N 3 R 4 ; and wherein R is phenyl, naphthyl, pyridyl, imidazolyl, indoxyl, indolizinyl, oxazolyl, thiazolyl, thienyl, pyrimidyl, or 1-pyrazolyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4 -alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 7  is a C 1 -C 8  saturated or unsaturated, straight-chain, branched or cyclic alkylene or alkylidene group optionally substituted with one or more groups selected from halo, hydroxyl, thiol, amino, monoalkyl amino, dialkyl amino, acylamino, carboxyl, alkylcarboxyl, acyl, aryl, aroyl, aralkyl, cyano, nitro, alkoxy, alkenyloxy, alkylcarbonyloxy and arylcarbonyloxy; and wherein R 8  is a C 1 -C 8  straight-chain or branched alkylene or alkylidene optionally substituted with one or more groups selected from amino, monoalkyl amino, dialkyl amino, acylamino, hydroxyl, thiol, methylthiol, carboxyl and phenyl; and wherein R 9  and R 10  are independently H, C 1 -C 5  alkyl, optionally substituted with one or more groups consisting of C 1 -C 5  alkoxy aryl and heteroaryl, wherein the aryl is phenyl or naphthyloptionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w , and wherein the heteroaryl is pyridyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 11  is methyl or phenyl, wherein the phenyl is optionally substituted with methyl and/or —NO 2 ; and wherein R 12  is H, C 1 -C 5  alkyl, phenyl, benzyl, naphthyl or pyridyl, wherein the C 1 -C 5  alkyl, phenyl, naphthyl, benzyl and pyridyl are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 13  and R 14  are independently the following: alkyl, alkenyl, aryl, aralkyl or cycloalkyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —N 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4 , CH 2 NR 3 R 4 , OOCR 18  and —C v F w ; and wherein when R 13  and R 14  are included as —(CHR 3 )CONR 13 R 14 , NR 13 R 14  is  
                     
 and wherein R 15  is C v F w  or C 1 -C 5  alkyl, wherein C 1 -C 5  alkyl is optionally substituted with the following substituents: C 1 -C 5  alkoxy; phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; benzyl, optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 16  is H, C 1 -C 5  allyl or benzyl; and wherein R 17  is C 1 -C 5  alkyl, C 3 -C 8  cyclic alkyl, phenyl or benzyl; and wherein R 18  is H, alkyl, aryl, aralkyl or cycloalkyl, where the group is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 31 R and —C v F w .  
 
     
     
         45 . The pharmaceutical composition of  claim 40  in the form of a tablet or capsule.  
     
     
         46 . A method of treating hyperuricemia 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, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, 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 1  is a halogen; and  
 X 2 , X 3  and X 4  are each independently selected from hydrogen and halogen with the proviso that no more than two of X 2 , X 3  and X 4  are hydrogen;  
 or a pharmaceutically acceptable salt thereof,  
 wherein the compound is substantially free of its (+) stereoisomer.  
 
     
     
         47 . The method of  claim 46 , wherein the compound is a compound of Formula II,  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 2  is a member selected from the group consisting of: C 1 -C 5  alkyl, C 1 -C 5 -cyclic alkyl, C 2 -C 5  alkenyl, and C 2 -C 5  alkynyl, wherein the groups are optionally substituted with one or more halogen atoms; phenyl, naphthyl and pyridyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; —(CHR 3 )R 4 ; —R 7 OR 3 ; —R 7 O 2 CR 8 NR 3 R 4 ; —R 7 COR 6 ; —R 7 NR 3 COR 6 ; —R 7 NR 3 R 6 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q O 2 CR 9 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 COR 9 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 CONR 3 R 4 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 COOR 10 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 SO 2 R 11 ; —(CHR 3 ) p CO 2 R 12 ; —(CHR 3 ) p NR 3 R 4 ; —(CHR 3 ) s CONR 13 R 14 ;  
                     
 wherein m is 0 to 2, o and q are 0 to 5, p is 1 to 5, s is 1 to 3, t is 1 to 5, u is 0 to 1, v is 1 to 3, and w is 1 to (2v+1); and wherein R 3  and R 4  are independently H, C 1 -C 5  alkyl, phenyl or benzyl; and wherein R 5  is H, C 1 -C 5  alkyl or NR 3 R 4 ; and wherein R 6  is phenyl, naphthyl, pyridyl, imidazolyl, indoxyl, indolizinyl, oxazolyl, thiazolyl, thienyl, pyrimidyl, or 1-pyrazolyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 7  is a C 1 -C 8  saturated or unsaturated, straight-chain, branched or cyclic alkylene or alkylidene group optionally substituted with one or more groups selected from halo, hydroxyl, thiol, amino, monoalkyl amino, dialkyl amino, acylamino, carboxyl, alkylcarboxyl, acyl, aryl, aroyl, aralkyl, cyano, nitro, alkoxy, alkenyloxy, alkylcarbonyloxy and arylcarbonyloxy; and wherein R 8  is a C 1 -C 5  straight-chain or branched alkylene or alkylidene optionally substituted with one or more groups selected from amino, monoalkyl amino, dialkyl amino, acylamino, hydroxyl, thiol, methylthiol, carboxyl and phenyl; and wherein R 9  and R 10  are independently H, C 1 -C 5  alkyl, optionally substituted with one or more groups consisting of C 1 -C 5  alkoxy aryl and heteroaryl, wherein the aryl is phenyl or naphthyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w , and wherein the heteroaryl is pyridyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F v ; and wherein R 11  is methyl or phenyl, wherein the phenyl is optionally substituted with methyl and/or —NO 2 ; and wherein R 12  is H, C 1 -C 5  alkyl, phenyl, benzyl, naphthyl or pyridyl, wherein the C 1 -C 5  alkyl, phenyl, naphthyl, benzyl and pyridyl are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 13  and R 14  are independently the following: alkyl, alkenyl, aryl, aralkyl or cycloalkyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 CO 4 , —NR 3 CONR 3 R 4 , —CH 2 NR 3 R 4 , OOCR 18  and —C v F w ; and wherein when R 13  and R 14  are included as —(CHR 3 )CONR 13 R 14 , NR 13 R 14  is  
                     
 and wherein R 15  is C v F w  or C 1 -C 5  alkyl, wherein C 1 -C 5  alkyl is optionally substituted with the following substituents: C 1 -C 5  alkoxy; phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; benzyl, optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w ; and wherein R 16  is H, C 1 -C 5  alkyl or benzyl; and wherein R 17  is C 1 -C 5  alkyl, C 3 -C 8  cyclic alkyl, phenyl or benzyl; and wherein R 18  is H, alkyl, aryl, aralkyl or cycloalkyl, where the group is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4  and —C v F w .  
 
     
     
         48 . The method of  claim 46 , wherein the compound is administered together with a pharmaceutically acceptable carrier.