Combination therapy for the treatment of diabetes

Abstract

The present invention is directed to co-therapy and methods for the treatment and prevention of glucose-related disorders such as Type 2 diabetes mellitus and Syndrome X. The present invention is further directed to pharmaceutical compositions for the co-therapy and methods described herein.

1 . A method for treating a glucose related disorder selected from the group consisting of diabetes mellitus, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, elevated blood levels of glucose, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis and hypertension comprising administering to a subject in need thereof a pharmaceutical composition comprising
 (a) metformin or a pharmaceutically acceptable salt thereof in an amount in the range of from about 500 mg to about 2000 mg; and   (b) a compound of formula (I)   
       
         
           
           
               
               
           
         
         wherein 
         Ring A is 
       
       
         
           
           
               
               
           
         
         wherein R 1a  is a halogen atom, a lower alkyl group, or a lower alkoxy group, and R 2a  and R 3a  are hydrogen atoms; 
         and Ring B is 
       
       
         
           
           
               
               
           
         
         wherein R 4a  is a phenyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a mono- or di-lower alkylamino group, a carbamoyl group, and a mono- or di-lower alkylcarbamoyl group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a carbamoyl group, or a mono- or di-lower alkylcarbamoyl group, and R 5a  is a hydrogen atom; and 
         Y is —CH 2 —; 
         or a pharmaceutically acceptable salt thereof; in an amount of from about 10 mg to about 300 mg; and 
         between about 5% and about 50% by weight of diluent comprising microcrystalline cellulose; 
         between about 1% and about 10% by weight of binder; and 
         between about 1% and about 10% by weight of disintegrant comprising croscarmellose sodium. 
       
     
     
         2 . (canceled) 
     
     
         3 . A method as in  claim 1 , wherein the glucose related disorder is type 2 diabetes mellitus. 
     
     
         4 . A method as in  claim 1 , wherein the compound of formula (I) is a compound of formula (I-X) 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof. 
       
     
     
         5 . A method as in  claim 4 , wherein the compound of formula (I-X) is a crystalline hemihydrate. 
     
     
         6 . A method as in  claim 1 , wherein the metformin or pharmaceutically acceptable salt thereof is metformin hydrochloride. 
     
     
         7 - 12 . (canceled) 
     
     
         13 . A pharmaceutical composition comprising
 (a) metformin hydrochloride in an amount in the range of from about 100 mg to about 2000 mg;   (b) a compound of formula (I-X)   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof in an amount in the range of from about 50 mg to about 500 mg; and 
         (c) between about 5% and about 50% by weight of diluent comprising microcrystalline cellulose; 
         (d) between about 1% and about 10% by weight of binder; and 
         (e) between about 1% and about 10% by weight of disintegrant comprising croscarmellose sodium. 
       
     
     
         14 . (canceled) 
     
     
         15 . A pharmaceutical composition as in  claim 13 , wherein the metformin hydrochloride is present in an amount of about 250 mg, about 500 mg, about 750 mg, about 850 mg, or about 1000 mg; and wherein the compound of formula (I-X) or pharmaceutically acceptable salt thereof is present in an amount of about 100 mg, about 150 mg or about 300 mg. 
     
     
         16 - 19 . (canceled) 
     
     
         20 . A pharmaceutical composition as in  claim 13 , wherein the compound of formula (I-X) is a crystalline hemihydrate.