Combination therapy comprising sglt inhibitors and dpp4 inhibitors

Abstract

The present invention relates to combination therapy comprising a DPP4 inhibitor and an SGLT inhibitor. The combination of the present invention leads to increase plasma GLP-1 level and the combination is useful for prevention or treatment of conditions such as diabetes and diseases related to diabetes.

1 . A method for treating or preventing diabetes or a condition related to diabetes comprising administering to a patient in need thereof a therapeutically effective amount of an SGLT inhibitor and a DPP4 inhibitor. 
     
     
         2 . A method according to  claim 1 , wherein the SGLT inhibitor and the DPP4 inhibitor are administered in amounts sufficient to lower a blood glucose level in the patient. 
     
     
         3 . A method for preventing or treating a disease which is associated with plasma active GLP-1 level comprising administering to a patient in need thereof a therapeutically effective amount of an SGLT inhibitor and a DPP4 inhibitor. 
     
     
         4 . A method according to  claim 3 , wherein the SGLT inhibitor and the DPP4 inhibitor are administered in amounts sufficient to increase plasma active GLP-1 level in the patient. 
     
     
         5 . A method for increasing plasma active GLP-1 level comprising administering to a patient a therapeutically effective amount of an SGLT inhibitor and a DPP4 inhibitor. 
     
     
         6 . A method according to  claim 1 , wherein diabetes is Type 2 diabetes. 
     
     
         7 . A method according to  claim 3 , wherein the disease which is associated with plasma active GLP-1 level is selected from diabetes, a condition related to diabetes, myocardial infarction, learning impairment, memory impairment, stroke and a neurodegenerative disorder. 
     
     
         8 . A method according to  claim 1  or  7 , wherein the condition related to diabetes is selected from hyperglycemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, metabolic syndrome, hyperlipidemia, atherosclerosis, hypertension, and obesity. 
     
     
         9 . A method according to  claim 7 , wherein the neurodegenerative disorder is selected from excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion-associated disease, motor-neuron disease, traumatic brain injury, spinal cord injury, and peripheral neuropathy. 
     
     
         10 . A pharmaceutical composition comprising an SGLT inhibitor, a DPP4 inhibitor and a pharmaceutically acceptable carrier or diluent, wherein the SGLT inhibitor and the DPP4 inhibitor are in amounts sufficient to increase plasma active GLP-1 level in a patient. 
     
     
         11 . A method of preventing or treating diabetes or a condition related thereto comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition as set forth in  claim 10 . 
     
     
         12 . A method of preventing or treating a disease which is associated with plasma active GLP-1 level comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition as set forth in  claim 10 . 
     
     
         13 . A method of increasing plasma active GLP-1 level comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition as set forth in  claim 10 . 
     
     
         14 . The method according to  claim 1 , wherein the SGLT inhibitor is a compound of Formula (23): 
       
         
           
           
               
               
           
         
         wherein Ring A and Ring B are one of the followings: (1) Ring A is optionally substituted unsaturated heteromonocyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene, (2) Ring A is optionally substituted benzene, and Ring B is optionally substituted unsaturated heteromonocyclic, or optionally substituted unsaturated fused heterobicyclic wherein Y is linked to the heterocyclic ring of said fused heterobicyclic, or (3) Ring A is optionally substituted unsaturated fused heterobicyclic, wherein the sugar moiety X-(sugar) and the moiety —Y-(Ring B) are both on the same heterocyclic ring of said fused heterobicyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene;
 X is carbon or nitrogen; and 
 Y is —(CH 2 ) n — (wherein n is 1 or 2); or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         15 . The method according to  claim 1 , wherein the SGLT inhibitor is a compound of Formula (24): 
       
         
           
           
               
               
           
         
         wherein R A  is a halogen atom, or a lower alkyl group; 
         Ring C is a phenyl group substituted by 1-3 substituents 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 methylenedioxy group, an ethyleneoxy group, a mono- or di-lower alkylamino group, a carbamoyl group, and a mono- or di-lower alkylcarbamoyl group; or a heterocyclyl group substituted by 1-3 substituents 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 pharmaceutically acceptable salt thereof. 
       
     
     
         16 . The method according to  claim 1 , wherein the SGLT inhibitor is a compound of Formula (25): 
       
         
           
           
               
               
           
         
         wherein R 1  is halogen, or alkyl, 
         R 2  is hydrogen, or halogen, and 
         Ar is one of the following groups: 
       
       
         
           
           
               
               
           
         
         in which R 3  and R 4  are independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, hydroxy, phenyl, halophenyl, cyanophenyl, pyridyl, halopyridyl, thienyl, or halothienyl, or R 3  and R 4  together with carbon atoms to which they are attached form a fused benzene, furan or dihydrofuran ring; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . The method according to  claim 1 , wherein the SGLT inhibitor is a compound of Formula (26): 
       
         
           
           
               
               
           
         
         wherein R 1  is fluorine, or chlorine, and R 2  is hydrogen, or fluorine, or a pharmaceutically acceptable salt thereof. 
       
     
     
         18 . The method according to  claim 1 , wherein the DPP4 inhibitor is a compound of Formula (29): 
       
         
           
           
               
               
           
         
         wherein A represents —CH 2 — or —S—, R 1  represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R 2  represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or a pharmaceutically acceptable salt thereof. 
       
     
     
         19 . The method according to  claim 1 , wherein the DPP4 inhibitor is a compound of Formula (30): 
       
         
           
           
               
               
           
         
         wherein A is —CH 2 —, R 1  is H, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R 2  is a piperazinyl group which may be substituted, or a pharmaceutically acceptable salt thereof. 
       
     
     
         20 . The method according to  claim 1 , wherein the SGLT inhibitor is Sergliflozin, Remogliflozin or Dapagliflozin, and the DPP4 inhibitor is Sitagliptin, Vildagliptin, Saxagliptin or Alogliptin. 
     
     
         21 . The method according to  claim 1 , wherein the SGLT inhibitor is a compound of Formula (23): 
       
         
           
           
               
               
           
         
         wherein Ring A and Ring B are one of the followings: (1) Ring A is optionally substituted unsaturated heteromonocyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene, (2) Ring A is optionally substituted benzene, and Ring B is optionally substituted unsaturated heteromonocyclic, or optionally substituted unsaturated fused heterobicyclic wherein Y is linked to the heterocyclic ring of said fused heterobicyclic, or (3) Ring A is optionally substituted unsaturated fused heterobicyclic, wherein the sugar moiety X-(sugar) and the moiety —Y-(Ring B) are both on the same heterocyclic ring of said fused heterobicyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene; 
         X is carbon or nitrogen; and 
         Y is —(CH 2 ) n — (wherein n is 1 or 2); or a pharmaceutically acceptable salt thereof; and the DPP4 inhibitor is a compound of formula (28): 
       
       
         
           
           
               
               
           
         
         wherein A represents —CH 2 — or —S—, R 1  represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R 2  represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or pharmaceutically acceptable salt thereof; or 
         a compound of Formula (31): 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is —NR 1 R 2  wherein R 1  and R 2  may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring, 
         —NR 3 COR 4  wherein R 3  and R 4  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl, 
         —NR 5 CONR 6 R 7  or —NR 5 CH 2 CH 2 NR 6 R 7  wherein R 5 , R 6  and R 7  are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R 6  and R 7  may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, 
         —NR 8 SO 2 R 9  wherein R 8  and R 9  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or 
         —OR 10  or —OCOR 11  wherein R 10  and R 11  are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, 
         Y is CH 2 , CH—OH, S, S═O or SO 2 , 
         Z is a hydrogen atom or cyano, and 
         of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, or a pharmaceutically acceptable salt thereof; or 
         Sitagliptin or a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . The method according to  claim 1 , wherein the SGLT inhibitor is a compound of Formula (24): 
       
         
           
           
               
               
           
         
         wherein R A  is a halogen atom, or a lower alkyl group; 
         Ring C is a phenyl group substituted by 1-3 substituents 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 methylenedioxy group, an ethyleneoxy group, a mono- or di-lower alkylamino group, a carbamoyl group, and a mono- or di-lower alkylcarbamoyl group; or a heterocyclyl group substituted by 1-3 substituents 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 pharmaceutically acceptable salt thereof, or a prodrug thereof; and 
         the DPP4 inhibitor is a compound of formula (29): 
       
       
         
           
           
               
               
           
         
         wherein A represents —CH 2 — or —S—, R 1  represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R 2  represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or pharmaceutically acceptable salt thereof; or 
         a compound of Formula (31): 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is —NR 1 R 2  wherein R 1  and R 2  may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring, 
         —NR 3 COR 4  wherein R 3  and R 4  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl, 
         —NR 5 CONR 6 R 7  or —NR 5 CH 2 CH 2 NR 6 R 7  wherein R 5 , R 6  and R 7  are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R 6  and R 7  may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, 
         —NR 8 SO 2 R 9  wherein R 8  and R 9  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or 
         —OR 10  or —OCOR 11  wherein R 10  and R 11  are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, 
         Y is CH 2 , CH—OH, S, S═O or SO 2 , 
         Z is a hydrogen atom or cyano, and 
         of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, 
         or a pharmaceutically acceptable salt thereof; or 
         Sitagliptin or a pharmaceutically acceptable salt thereof. 
       
     
     
         23 . The method according to  claim 1 , wherein the SGLT inhibitor is a compound of Formula (26): 
       
         
           
           
               
               
           
         
         wherein R 1  is fluorine, or chlorine, and R 2  is hydrogen, or fluorine, or a pharmaceutically acceptable salt thereof; and 
         the DPP4 inhibitor is a compound of formula (29): 
       
       
         
           
           
               
               
           
         
         wherein A represents —CH 2 — or —S—, R 1  represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R 2  represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or pharmaceutically acceptable salt thereof; or 
         a compound of Formula (31): 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is —NR 1 R 2  wherein R 1  and R 2  may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring, 
         —NR 3 COR 4  wherein R 3  and R 4  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl, 
         —NR 5 CONR 6 R 7  or —NR 5 CH 2 CH 2 NR 6 R 7  wherein R 5 , R 6  and R 7  are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R 6  and R 7  may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, 
         —NR 8 SO 2 R 9  wherein R 8  and R 9  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or 
         —OR 10  or —OCOR 11  wherein R 10  and R 11  are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, 
         Y is CH 2 , CH—OH, S, S═O or SO 2 , 
         Z is a hydrogen atom or cyano, and 
         of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, or a pharmaceutically acceptable salt thereof; or 
         Sitagliptin or a pharmaceutically acceptable salt thereof. 
       
     
     
         24 . The method according to  claim 1 , wherein the SGLT inhibitor is selected from:
 1-(β-D-Glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene or a pharmaceutically acceptable salt thereof;   3-(5-(4-Fluorophenyl)-2-thienylmethyl)-1-(β-D-glucopyranosyl)-4-methylbenzene or a pharmaceutically acceptable salt thereof;   1-(β-D-Glucopyranosyl)-4-chloro-3-[5-(6-fluoro-3-pyridyl)-2-thienylmethyl]benzene or a pharmaceutically acceptable salt thereof;   3-(4-Cyclopropylphenylmethyl)-4-fluoro-1-(β-D-glucopyranosyl)indole or a pharmaceutically acceptable salt thereof; and   3-(4-Cyclopropylphenylmethyl)-4,6-difluoro-1-(β-D-glucopyranosyl)indole or a pharmaceutically acceptable salt thereof; and   the DPP4 inhibitor is selected from:   3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine or a pharmaceutically acceptable salt thereof;   Sitagliptin or a pharmaceutically acceptable salt thereof; and   (2S)-2-cyano-1-[trans-4-(dimethylaminocarbonyl)cyclohexylamino]acetylpyrrolidine or a pharmaceutically acceptable salt thereof.   
     
     
         25 . The pharmaceutical composition according to  claim 10 , wherein the SGLT inhibitor is a compound of Formula (23): 
       
         
           
           
               
               
           
         
         wherein Ring A and Ring B are one of the followings: (1) Ring A is optionally substituted unsaturated heteromonocyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene, (2) Ring A is optionally substituted benzene, and Ring B is optionally substituted unsaturated heteromonocyclic, or optionally substituted unsaturated fused heterobicyclic wherein Y is linked to the heterocyclic ring of said fused heterobicyclic, or (3) Ring A is optionally substituted unsaturated fused heterobicyclic, wherein the sugar moiety X-(sugar) and the moiety —Y-(Ring B) are both on the same heterocyclic ring of said fused heterobicyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene; 
         X is carbon or nitrogen; and 
         Y is —(CH 2 ) n — (wherein n is 1 or 2); or a pharmaceutically acceptable salt thereof; and 
         the DPP4 inhibitor is a compound of formula (29): 
       
       
         
           
           
               
               
           
         
         wherein A represents —CH 2 — or —S—, R 1  represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R 2  represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or pharmaceutically acceptable salt thereof; or 
         the DPP4 inhibitor is a compound of Formula (31): 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is —NR 1 R 2  wherein R 1  and R 2  may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring, 
         —NR 3 COR 4  wherein R 3  and R 4  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl, 
         —NR 5 CONR 6 R 7  or —NR 5 CH 2 CH 2 NR 6 R 7  wherein R 5 , R 6  and R 7  are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R 6  and R 7  may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, 
         —NR 8 SO 2 R 9  wherein R 8  and R 9  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or 
         —OR 10  or —OCOR 11  wherein R 10  and R 11  are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, 
         Y is CH 2 , CH—OH, S, S═O or SO 2 , 
         Z is a hydrogen atom or cyano, and 
         of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, 
         or a pharmaceutically acceptable salt thereof; or 
         the DPP4 inhibitor is Sitagliptin or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 . The pharmaceutical composition according to  claim 10 , wherein the SGLT inhibitor is a compound of Formula (24): 
       
         
           
           
               
               
           
         
         wherein R A  is a halogen atom, or a lower alkyl group; 
         Ring C is a phenyl group substituted by 1-3 substituents 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 methylenedioxy group, an ethyleneoxy group, a mono- or di-lower alkylamino group, a carbamoyl group, and a mono- or di-lower alkylcarbamoyl group; or a heterocyclyl group substituted by 1-3 substituents 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 pharmaceutically acceptable salt thereof, or a prodrug thereof, and 
         the DPP4 inhibitor is a compound of formula (29): 
       
       
         
           
           
               
               
           
         
         wherein A represents —CH 2 — or —S—, R 1  represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R 2  represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or pharmaceutically acceptable salt thereof; or 
         the DPP4 inhibitor is a compound of Formula (31): 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is —NR 1 R 2  wherein R 1  and R 2  may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring, 
         —NR 3 COR 4  wherein R 3  and R 4  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl, 
         —NR 5 CONR 6 R 7  or —NR 5 CH 2 CH 2 NR 6 R 7  wherein R 5 , R 6  and R 7  are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R 6  and R 7  may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, 
         —NR 8 SO 2 R 9  wherein R 8  and R 9  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or 
         —OR 10  or —OCOR 11  wherein R 10  and R 11  are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, 
         Y is CH 2 , CH—OH, S, S═O or SO 2 , 
         Z is a hydrogen atom or cyano, and 
         of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, 
         or a pharmaceutically acceptable salt thereof; or 
         the DPP4 inhibitor is Sitagliptin or a pharmaceutically acceptable salt thereof. 
       
     
     
         27 . The pharmaceutical composition according to  claim 10 , wherein the SGLT inhibitor is a compound of Formula (26): 
       
         
           
           
               
               
           
         
         wherein R 1  is fluorine, or chlorine, and R 2  is hydrogen, or fluorine, or a pharmaceutically acceptable salt thereof; and 
         the DPP4 inhibitor is a compound of formula (29): 
       
       
         
           
           
               
               
           
         
         wherein A represents —CH 2 — or —S—, R 1  represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R 2  represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or a pharmaceutically acceptable salt thereof; or 
         the DPP4 inhibitor is a compound of Formula (31): 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is —NR 1 R 2  wherein R 1  and R 2  may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring, 
         —NR 3 COR 4  wherein R 3  and R 4  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl, 
         —NR 5 CONR 6 R 7  or —NR 5 CH 2 CH 2 NR 6 R 7  wherein R 5 , R 6  and R 7  are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R 6  and R 7  may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, 
         —NR 8 SO 2 R 9  wherein R 8  and R 9  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or 
         —OR 10  or —OCOR 11  wherein R 10  and R 11  are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, 
         Y is CH 2 , CH—OH, S, S═O or SO 2 , 
         Z is a hydrogen atom or cyano, and 
         of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, 
         or a pharmaceutically acceptable salt thereof; or 
         the DPP4 inhibitor is Sitagliptin or a pharmaceutically acceptable salt thereof. 
       
     
     
         28 . The pharmaceutical composition according to  claim 10 , wherein the SGLT inhibitor is selected from:
 1-(β-D-Glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene or a pharmaceutically acceptable salt thereof;   3-(5-(4-Fluorophenyl)-2-thienylmethyl)-1-(β-D-glucopyranosyl)-4-methylbenzene or a pharmaceutically acceptable salt thereof;   1-(β-D-Glucopyranosyl)-4-chloro-3-[5-(6-fluoro-3-pyridyl)-2-thienylmethyl]benzene or a pharmaceutically acceptable salt thereof;   3-(4-Cyclopropylphenylmethyl)-4-fluoro-1-(β-D-glucopyranosyl)indole or a pharmaceutically acceptable salt thereof; and   3-(4-Cyclopropylphenylmethyl)-4,6-difluoro-1-(β-D-glucopyranosyl)indole or a pharmaceutically acceptable salt thereof; and   the DPP4 inhibitor is selected from:   3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine or a pharmaceutically acceptable salt thereof;   Sitagliptin or a pharmaceutically acceptable salt thereof; and   (2S)-2-cyano-1-[trans-4-(dimethylaminocarbonyl)cyclohexylamino]acetylpyrrolidine or a pharmaceutically acceptable salt thereof.   
     
     
         29 . Use of an SGLT inhibitor in combination with a DPP4 inhibitor as active ingredients for manufacture of a pharmaceutical preparation for treating or preventing a disease associated with plasma active GLP-1 level. 
     
     
         30 . A product containing an SGLT inhibitor and a DPP4 inhibitor as a combined preparation for simultaneous, separate or sequential administration for preventing or treating a disease associated with plasma active GLP-1 level.