Combination therapy comprising glucose reabsorption inhibitors and PPAR modulators

Abstract

Combination therapy comprising PPAR modulators and glucose reabsorption inhibitors useful for the treatment of diabetes and Syndrome X are disclosed.

What is claimed is:  
     
         1 . A method for treating diabetes, Syndrome X, or associated symptoms or complications in a subject, said method comprising 
 (a) administering to said subject a jointly effective amount of a glucose reabsorption inhibitor; and    (b) administering to said subject a jointly effective amount of a PPAR modulator, 
 said co-administration being in any order and the combined jointly effective amounts providing the desired therapeutic effect.  
   
     
     
         2 . The method of  claim 1 , wherein the PPAR modulator is a PPARγ agonist.  
     
     
         3 . The method of  claim 1 , wherein the PPAR modulator is a thiazolidinedione or a non-thiazolidinedione insulin sensitizer.  
     
     
         4 . The method of  claim 1 , wherein the PPAR modulator is selected from 
 (a) rosiglitazone;    (b) pioglitazone;    (c) troglitazone;    (d) isaglitazone;    (e) 5-BTZD;    (f) JT-501;    (g) KRP-297;    (h) Farglitazar;    (i) Risarestat;    (j) YM 440;    (k) NN 2344;    (l) NN 622;    (m) AR-H039242;    (n) Fenofibrate; and    (o) bexarotene.    
     
     
         5 . The method of  claim 1 , wherein the diabetes or Syndrome X, or associated symptoms or complications thereof is selected from IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy, retinopathy, atherosclerosis, polycystic ovary syndrome, hypertension, ischemia, stroke, heart disease, irritable bowel disorder, inflammation, and cataracts.  
     
     
         6 . The method of  claim 1  or  2 , wherein the diabetes or Syndrome X, or associated symptoms or complication thereof is IDDM.  
     
     
         7 . The method of  claim 1  or  2 , wherein the diabetes or Syndrome X, or associated symptoms or complications thereof is NIDDM.  
     
     
         8 . The method of  claim 1  or  2 , wherein the diabetes or Syndrome X, or associated symptoms or complications thereof is IGT or IFG.  
     
     
         9 . The method of  claim 1  or  2 , further comprising administering to said subject a jointly effective amount of a third antidiabetic agent.  
     
     
         10 . The method of  claim 9 , wherein the third antidiabetic agent is selected from 
 (aa) insulins,    (bb) insulin analogues;    (cc) insulin secretion modulators, and    (dd) insulin secretagogues.    
     
     
         11 . The method of  claim 10 , wherein the diabetes or Syndrome X, or associated symptoms or complications thereof is IDDM.  
     
     
         12 . The method of  claim 1  or  2 , wherein the glucose reabsorption inhibitor is an SGLT inhibitor.  
     
     
         13 . The method of  claim 12 , wherein the glucose reabsorption inhibitor is an SGLT1 inhibitor.  
     
     
         14 . The method of  claim 12 , wherein the glucose reabsorption inhibitor is an SGLT2 inhibitor.  
     
     
         15 . The method of  claim 12 , wherein the glucose reabsorption inhibitor is selected from a dihydrochalcone, a propiophenone and a derivative thereof.  
     
     
         16 . The method of  claim 15 , wherein the glucose reabsorption inhibitor is a compound of Formula (V)  
       
         
           
           
               
               
           
         
       
       or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug form, or a pharmaceutically acceptable salt thereof, wherein 
 Ar is aryl or heteroaryl;  
 OX is an optionally protected hydroxy group;  
 Y is hydrogen or alkyl; and  
 Z is glucopyranosyl wherein one or more hydroxy groups thereof may optionally be substituted with one or more groups selected from α-D-glucopyranosyl, alkanoyl, alkoxycarbonyl, and substituted alkyl.  
 
     
     
         17 . The method of  claim 16 , wherein the glucose reabsorption inhibitor is a compound of Formula (IV)  
       
         
           
           
               
               
           
         
       
       wherein Ar is an aryl group, R 1  is hydrogen atom or an acyl group, R 2  is hydrogen atom, an acyl group or α-D-glucopyranosyl group, or R′ and R2 may combine together to form a substituted methylene group, R 3  and R 4  are each hydrogen atom or an acyl group, and OR 5  is a protected or unprotected hydroxy group or a lower alkoxy group.  
     
     
         18 . The method of  claim 16 , wherein the glucose reabsorption inhibitor is a compound of Formula (III)  
       
         
           
           
               
               
           
         
       
       wherein R′ is a lower alkanoyl group, and R″ is a hydrogen atom, or R′ is a hydrogen atom, and R″ is a lower alkoxycarbonyl group.  
     
     
         19 . The method of  claim 16 , wherein the glucose reabsorption inhibitor is a compound of Formula (II)  
       
         
           
           
               
               
           
         
       
       wherein X is an oxygen atom, a sulfur atom or a methylene group, OY is a protected or unprotected hydroxy group, Z is a β-D-glucopyranosyl group or 4-O-(α-D-glucopyranosyl)-β-D-glucopyranosyl group wherein one or more hydroxy groups of these groups may optionally be acylated, and the dotted line means the presence or absence of a double bond.  
     
     
         20 . The method of  claim 16 , wherein the glucose reabsorption inhibitor is a compound of Formula (I)  
       
         
           
           
               
               
           
         
       
       wherein OX is a hydroxy group which may optionally be protected, Y is a lower alkyl group, and Z is a β-D-glucopyranosyl group wherein one or more hydroxy groups may optionally be protected.  
     
     
         21 . The method of  claim 20 , wherein the glucose reabsorption inhibitor is T-1095 or T-1095A  
       
         
           
           
               
               
           
         
       
       with one or more hydroxyl or diol protecting groups, or a pharmaceutically acceptable salt thereof.  
     
     
         22 . The method of  claim 20 , wherein the glucose reabsorption inhibitor is T-1095 or T-1095A,  
       
         
           
           
               
               
           
         
       
       or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug form, or a pharmaceutically acceptable salt thereof.  
     
     
         23 . The method of  claim 20  wherein the glucose reabsorption inhibitor is T-1095 or T-1095A with one or more hydroxyl or diol protecting groups, or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug form, or a pharmaceutically acceptable salt thereof.  
     
     
         24 . The method of  claim 23  wherein the glucose reabsorption inhibitor is T-1095.  
     
     
         25 . The method of  claim 23  wherein the glucose reabsorption inhibitor is T-1095A.  
     
     
         26 . The method of  claim 23 , wherein the jointly effective amount of T-1095 or T-1095A is an amount sufficient to reduce the plasma glucose excursion following a meal.  
     
     
         27 . A method for inhibiting the onset of diabetes or Syndrome X, or associated symptoms or complications thereof in a subject, said method comprising 
 (a) administering to said subject a jointly effective amount of a glucose reabsorption inhibitor; and    (b) administering to said subject a jointly effective amount of a PPAR modulator, 
 said co-administration being in any order and the combined jointly effective amounts providing the desired prophylactic effect.  
   
     
     
         28 . The method of  claim 27 , wherein said onset is from a prediabetic state to NIDDM.  
     
     
         29 . A pharmaceutical composition comprising a glucose reabsorption inhibitor, a PPAR modulator, and a pharmaceutically acceptable carrier.  
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein the PPAR modulator is a PPARγ agonist.  
     
     
         31 . The pharmaceutical composition of  claim 29 , wherein the PPAR modulator is selected from 
 (a) rosiglitazone;    (b) pioglitazone;    (c) troglitazone;    (d) isaglitazone;    (e) 5-BTZD;    (f JT-501;    (g) KRP-297;    (h) Farglitazar;    (i) Risarestat;    (j) YM 440;    (k) NN 2344;    (l) NN 622;    (m) AR-H039242;    (n) Fenofibrate; and    (o) bexarotene.    
     
     
         32 . The pharmaceutical composition of  claim 29 , wherein the glucose reabsorption inhibitor is an SGLT inhibitor.  
     
     
         33 . The pharmaceutical composition of  claim 32 , wherein the glucose reabsorption inhibitor is an SGLT1 inhibitor.  
     
     
         34 . The pharmaceutical composition of  claim 32 , wherein the glucose reabsorption inhibitor is an SGLT2 inhibitor.  
     
     
         35 . The pharmaceutical composition of  claim 32 , wherein the glucose reabsorption inhibitor is selected from a dihydrochalcone, a propiophenone and a derivative thereof.  
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein the glucose reabsorption inhibitor is a compound of Formula (V)  
       
         
           
           
               
               
           
         
       
       or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug form, or a pharmaceutically acceptable salt thereof, wherein 
 Ar is aryl or heteroaryl;  
 OX is an optionally protected hydroxy group;,  
 Y is hydrogen or alkyl; and  
 Z is glucopyranosyl wherein one or more hydroxy groups thereof may optionally be substituted with one or more groups selected from α-D-glucopyranosyl, alkanoyl, alkoxycarbonyl, and substituted alkyl.  
 
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein the glucose reabsorption inhibitor is a compound of Formula (I)  
       
         
           
           
               
               
           
         
       
       wherein OX is a hydroxy group which may optionally be protected, Y is a lower alkyl group, and Z is a β-D-glucopyranosyl group wherein one or more hydroxy groups may optionally be protected.  
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the glucose reabsorption inhibitor is T-1095 or T-1095A, optionally having one or more hydroxyl or diol protecting groups, or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug form, or a pharmaceutically acceptable salt thereof.  
     
     
         39 . A process for formulating a pharmaceutical composition, comprising formulating together a glucose reabsorption inhibitor, a PPAR modulator that increases insulin sensitivity, and a pharmaceutically acceptable carrier.  
     
     
         40 . The process of  claim 39 , wherein the PPAR modulator is a PPARγ agonist.  
     
     
         41 . The process of  claim 39 , wherein the glucose reabsorption inhibitor is an SGLT inhibitor.  
     
     
         42 . The process of  claim 41 , wherein the glucose reabsorption inhibitor is an SGLT1 inhibitor.  
     
     
         43 . The process of  claim 41 , wherein the glucose reabsorption inhibitor is an SGLT2 inhibitor.  
     
     
         44 . The process of  claim 41 , wherein the glucose reabsorption inhibitor is selected from a dihydrochalcone, a propiophenone and a derivative thereof.  
     
     
         45 . The process of  claim 44 , wherein the glucose reabsorption inhibitor is a compound of Formula (V)  
       
         
           
           
               
               
           
         
       
       or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug form, or a pharmaceutically acceptable salt thereof, wherein 
 Ar is aryl or heteroaryl;  
 OX is an optionally protected hydroxy group;  
 Y is hydrogen or alkyl; and  
 Z is glucopyranosyl wherein one or more hydroxy groups thereof may optionally be substituted with one or more groups selected from α-D-glucopyranosyl, alkanoyl, alkoxycarbonyl, and substituted alkyl.  
 
     
     
         46 . The process of  claim 45 , wherein the glucose reabsorption inhibitor is a compound of Formula (I)  
       
         
           
           
               
               
           
         
       
       wherein OX is a hydroxy group which may optionally be protected, Y is a lower alkyl group, and Z is a β-D-glucopyranosyl group wherein one or more hydroxy groups may optionally be protected.  
     
     
         47 . The process of  claim 46 , wherein the glucose reabsorption inhibitor is T-1095 or T-1095A, optionally having one or more hydroxyl or diol protecting groups, or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug form, or a pharmaceutically acceptable salt thereof.  
     
     
         48 . A process for making a pharmaceutical composition comprising mixing one or more glucose reabsorption inhibitors in combination with a PPAR modulator for the preparation of a medicament for treating a condition selected from IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy, retinopathy, atherosclerosis, polycystic ovary syndrome, hypertension, ischemia, stroke, heart disease, irritable bowel disorder, inflammation, and cataracts.  
     
     
         49 . The process of  claim 48 , wherein the PPAR modulator is a PPARγ agonist.  
     
     
         50 . The process of  claim 49 , wherein the PPAR modulator is selected from 
 (a) rosiglitazone;    (b) pioglitazone;    (c) troglitazone;    (d) isaglitazone;    (e) 5-BTZD;    (e JT-501;    (g) KRP-297;    (h) Farglitazar;    (i) Risarestat;    (j) YM 440;    (k) NN 2344;    (l) NN 622;    (m) AR-H039242;    (n) Fenofibrate; and    (o) bexarotene.    
     
     
         51 . The process of  claim 48 , wherein the glucose reabsorption inhibitor is an SGLT inhibitor.  
     
     
         52 . The process of  claim 51 , wherein the glucose reabsorption inhibitor is an SGLT1 inhibitor.  
     
     
         53 . The process of  claim 51 , wherein the glucose reabsorption inhibitor is an SGLT2 inhibitor.  
     
     
         54 . The process of  claim 51 , wherein the glucose reabsorption inhibitor is selected from a dihydrochalcone, a propiophenone, and a derivative thereof.  
     
     
         55 . The process of  claim 54 , wherein the glucose reabsorption inhibitor is a compound of Formula (V)  
       
         
           
           
               
               
           
         
       
       or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug form, or a pharmaceutically acceptable salt thereof, wherein 
 Ar is aryl or heteroaryl;  
 OX is an optionally protected hydroxy group;  
 Y is hydrogen or alkyl; and  
 Z is glucopyranosyl wherein one or more hydroxy groups thereof may optionally be substituted with one or more groups selected from α-D-glucopyranosyl, alkanoyl, alkoxycarbonyl, and substituted alkyl.  
 
     
     
         56 . The process of  claim 55 , wherein the glucose reabsorption inhibitor is a compound of Formula (I)  
       
         
           
           
               
               
           
         
       
       wherein OX is a hydroxy group which may optionally be protected, Y is a lower alkyl group, and Z is a β-D-glucopyranosyl group wherein one or more hydroxy groups may optionally be protected.  
     
     
         57 . The process of  claim 56 , wherein the glucose reabsorption inhibitor is T-1095 or T-1095A, optionally having one or more hydroxyl or diol protecting groups, or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug form, or a pharmaceutically acceptable salt thereof.  
     
     
         58 . A method for inhibiting the progression of a prediabetic state in a subject to a diabetic condition, comprising 
 (a) administering to said subject a jointly effective amount of a glucose reabsorption inhibitor; and    (b) administering to said subject a jointly effective amount of a PPAR modulator, 
 said co-administration being in any order and the combined jointly effective amounts providing the desired inhibiting effect.  
   
     
     
         59 . The method of  claim 58  wherein said state is IGT or IFG.  
     
     
         60 . The method of  claim 58  wherein said inhibiting of the progression of a prediabetic condition is prevention of the progression of a prediabetic state to a diabetic condition.  
     
     
         61 . The method of  claim 60  wherein the PPAR modulator is a PPARγ agonist.  
     
     
         62 . The method of  claim 61  wherein the PPAR modulator is selected from 
 (a) rosiglitazone;  
 (b) pioglitazone;  
 (c) troglitazone;  
 (d) isaglitazone;  
 (e) 5-BTZD;  
 (f) JT-501;  
 (g) KRP-297;  
 (h) Farglitazar;  
 (i) Risarestat;  
 (j) YM 440;  
 (k) NN 2344;  
 (1) NN 622;  
 (m) AR-H039242;  
 (n) Fenofibrate; and  
 (o) bexarotene.  
 
     
     
         63 . The method of  claim 61  wherein the glucose reabsorption inhibitor is an SGLT inhibitor.  
     
     
         64 . The method of  claim 61  wherein the glucose reabsorption inhibitor is selected from a dihydrochalcone, a propiophenone and a derivative thereof.  
     
     
         65 . The method of  claim 64 , wherein the glucose reabsorption inhibitor is a compound of Formula (V)  
       
         
           
           
               
               
           
         
       
       or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug form, or a pharmaceutically acceptable salt thereof, wherein 
 Ar is aryl or heteroaryl;  
 OX is an optionally protected hydroxy group;  
 Y is hydrogen or alkyl; and  
 Z is glucopyranosyl wherein one or more hydroxy groups thereof may optionally be substituted with one or more groups selected from α-D-glucopyranosyl, alkanoyl, alkoxycarbonyl, and substituted alkyl.  
 
     
     
         66 . The method of claim  68 , wherein the glucose reabsorption inhibitor is a compound of Formula (I)  
       
         
           
           
               
               
           
         
       
       wherein OX is a hydroxy group which may optionally be protected, Y is a lower alkyl group, and Z is a β-D-glucopyranosyl group wherein one or more hydroxy groups may optionally be protected.  
     
     
         67 . The method of  claim 66 , wherein the glucose reabsorption inhibitor is T-1095 or T-1095A, optionally having one or more hydroxyl or diol protecting groups, or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug form, or a pharmaceutically acceptable salt thereof.