Combination therapy for the treatment of diabetes and related conditions

Abstract

Combinations of DPP-4 inhibitors with GPR119 agonists, as well as to the use of these combinations for treating and/or preventing metabolic diseases, particularly diabetes (especially type 2 diabetes mellitus) and conditions related thereto.

1 . A pharmaceutical composition comprising:
 (a) a GPR119 agonist selected from the group consisting of: 4-[6-(6-methanesulfonyl-2-methylpyridin-3-ylamino)-5-methylpyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester, 4-[5-methoxy-6-(2-methyl-6-[1,2,4]triazol-1-ylpyridin-3-ylamino)pyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester, 4-[5-methyl-6-(2-methylpyridin-3-yloxy)pyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester, {6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yloxy]-5-methoxypyrimidin-4-yl}-(6-methanesulfonyl-2-methylpyridin-3-yl)amine, 4-[6-(6-methanesulfonyl-2-methylpyridin-3-ylamino)-5-methylpyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester, 4-[6-(6-methanesulfonyl-4-methylpyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester, 4-[6-(6-methanesulfonyl-2-methylpyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester, (2-fluoro-4-methanesulfonylphenyl)-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yloxy]-5-methylpyrimidin-4-yl}amine, and 4-[1-(2-fluoro-4-methanesulfonylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester, or a pharmaceutically acceptable salt thereof; and   (b) a DPP-4 inhibitor of formula (I)   
       
         
           
           
               
               
           
         
       
       formula (II) 
       
         
           
           
               
               
           
         
       
       formula (III) 
       
         
           
           
               
               
           
         
       
       or formula (IV) 
       
         
           
           
               
               
           
         
       
       wherein:
 R1 is ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methylquinazolin-2-yl)methyl, 2-cyanobenzyl, (3-cyanoquinolin-2-yl)methyl, (3-cyanopyridin-2-yl)methyl, (4-methylpyrimidin-2-yl)methyl, or (4,6-dimethylpyrimidin-2-yl)methyl; and 
 R2 is 3-(R)-aminopiperidin-1-yl, (2-amino-2-methylpropyl)methylamino, or (2-(S)-aminopropyl)methylamino, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the DPP-4 inhibitor is selected from the group consisting of
 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine,   1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine,   1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine,   2-((R)-3-aminopiperidin-1-yl)-3-(but-2-ynyl)-5-(4-methylquinazolin-2-ylmethyl)-3,5-dihydroimidazo[4,5-d]pyridazin-4-one,   1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(2-amino-2-methylpropyl)methylamino]xanthine,   1-[(3-cyanoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine,   1-(2-cyanobenzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine,   1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-aminopropyl)methylamino]xanthine,   1-[(3-cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine,   1-[(4-methylpyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine,   1-[(4,6-dimethylpyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine; and   1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine,   
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein the DPP-4 inhibitor is 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the GPR119 agonist is
 4-[6-(6-methanesulfonyl-2-methylpyridin-3-ylamino)-5-methylpyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester or a pharmaceutically acceptable salt thereof.   
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the GPR119 agonist is 4-[5-methoxy-6-(2-methyl-6-[1,2,4]triazol-1-ylpyridin-3-ylamino)pyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the GPR119 agonist is 4-[5-methyl-6-(2-methylpyridin-3-yloxy)pyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein the GPR119 agonist is {6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yloxy]-5-methoxypyrimidin-4-yl}-(6-methanesulfonyl-2-methylpyridin-3-yl)amine or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , wherein the GPR119 agonist is 4-[6-(6-methanesulfonyl-2-methylpyridin-3-ylamino)-5-methylpyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein the GPR119 agonist is 4-[6-(6-methanesulfonyl-4-methylpyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein the GPR119 agonist is (2-fluoro-4-methanesulfonylphenyl)-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yloxy]-5-methylpyrimidin-4-yl}amine or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The pharmaceutical composition according to  claim 1 , wherein the GPR119 agonist is 4-[1-(2-fluoro-4-methanesulfonylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A method of preventing, slowing progression, delaying, or treating a metabolic disorder; improving glycemic control and/or for reducing fasting plasma glucose, postprandial plasma glucose, and/or glycosylated hemoglobin HbA1c; preventing, slowing, delaying, or reversing progression from impaired glucose tolerance, insulin resistance, and/or metabolic syndrome to type 2 diabetes mellitus; preventing, slowing progression, delaying, or treating complications of diabetes mellitus; reducing, preventing an increase, of the weight or facilitating a reduction of weight; preventing or treating the degeneration of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion; or for maintaining and/or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or insulin resistance, the method comprising administering to a patient in need thereof the pharmaceutical composition of  claim 1 . 
     
     
         13 . A method of lowering blood glucose level in a diabetic patients comprising administering to the patient a pharmaceutical composition of  claim 1 . 
     
     
         14 . A method of improving glycemic control in a diabetic patients comprising administering to the patient a pharmaceutical composition of  claim 1 . 
     
     
         15 . A method of improving glycemic control in the fasting and/or postprandial states in a diabetic patients comprising administering to the patient a pharmaceutical composition of  claim 1 . 
     
     
         16 . A method of increasing plasma GLP-1 level in a diabetic patient comprising administering to the patient a pharmaceutical composition of  claim 1 . 
     
     
         17 . A method of treating and/or preventing a disease, disorder, or condition responsive to the increase of plasma GLP-1 level in a patient comprising administering to the patient a pharmaceutical composition of  claim 1 . 
     
     
         18 . A method of improving glycemic control in highly insulin-resistant diabetic in a diabetic patient comprising administering to the patient a pharmaceutical composition of  claim 1 . 
     
     
         19 . A method of treating and/or preventing Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, syndrome X, metabolic syndrome, obesity, hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction, and/or osteoporosis in a patient in need thereof comprising administering to the patient a pharmaceutical composition of  claim 1 . 
     
     
         20 . A method of reducing body weight or treating obesity in a patient in need thereof comprising administering to the patient a pharmaceutical composition of  claim 1 . 
     
     
         21 . A method of treating dyslipidemia, hyperlipidemia, or hypercholesterolemia in a patient in need thereof comprising administering to the patient a pharmaceutical composition of  claim 1 . 
     
     
         22 . A method of treating metabolic syndrome (syndrome X) in a patient in need thereof comprising administering to the patient a pharmaceutical composition of  claim 1 . 
     
     
         23 . A kit comprising:
 (a) a first pharmaceutical composition comprising a GPR119 agonist of formula a GPR119 agonist selected from the group consisting of: 4-[6-(6-methanesulfonyl-2-methylpyridin-3-ylamino)-5-methylpyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester, 4-[5-methoxy-6-(2-methyl-6-[1,2,4]triazol-1-ylpyridin-3-ylamino)pyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester, 4-[5-methyl-6-(2-methylpyridin-3-yloxy)pyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester, {6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yloxy]-5-methoxypyrimidin-4-yl}-(6-methanesulfonyl-2-methylpyridin-3-yl)amine, 4-[6-(6-methanesulfonyl-2-methylpyridin-3-ylamino)-5-methylpyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester, 4-[6-(6-methanesulfonyl-4-methylpyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester, 4-[6-(6-methanesulfonyl-2-methylpyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester, (2-fluoro-4-methanesulfonylphenyl)-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)piperidin-4-yloxy]-5-methylpyrimidin-4-yl}amine, and 4-[1-(2-fluoro-4-methanesulfonylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester, or a pharmaceutically acceptable salt thereof; and   (b) a second pharmaceutical composition comprising a DPP-4 inhibitor of formula (I)   
       
         
           
           
               
               
           
         
       
       formula (II) 
       
         
           
           
               
               
           
         
       
       formula (III) 
       
         
           
           
               
               
           
         
       
       or formula (IV) 
       
         
           
           
               
               
           
         
       
       wherein:
 R1 is ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methylquinazolin-2-yl)methyl, 2-cyanobenzyl, (3-cyanoquinolin-2-yl)methyl, (3-cyanopyridin-2-yl)methyl, (4-methylpyrimidin-2-yl)methyl, or (4,6-dimethylpyrimidin-2-yl)methyl; and 
 R2 is 3-(R)-aminopiperidin-1-yl, (2-amino-2-methylpropyl)methylamino, or (2-(S)-aminopropyl)methylamino, 
 
       or a pharmaceutically acceptable salt thereof.