Oxazolidinone derivative having inhibitory activity on 11beta-hydroxysteroid dehydrogenase type 1

Abstract

Disclosed is a compound which is useful as an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. A compound represented by the formula: its pharmaceutically acceptable salt, or a solvate thereof, wherein R 1 is optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl, X is —O—, —NR 3 —, —NR 3 C(═O)— or —NR 3 S(═O) 2 —, R 2 is optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, R 3 is hydrogen or optionally substituted alkyl.

1 . A pharmaceutical composition having inhibitory activity on 11β-hydroxysteroid dehydrogenase type 1 comprising a compound represented by the Formula (I): 
       
         
           
           
               
               
           
         
       
       its pharmaceutically acceptable salt, or a solvate thereof,
 wherein R 1  is optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl, 
 X is —O—, —NR 3 —, —NR 3 C(═O)— or —NR 3 S(═O) 2 —, 
 R 2  is optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl, 
 R 3  is hydrogen or optionally substituted alkyl, 
 Y is —(CR 4 R 5 ) n —, 
 R 4  and R 5  are each independently hydrogen, optionally substituted alkyl, halogen or hydroxy, and 
 n is an integer of 1 to 6, 
 provided that, when R 1  is optionally substituted arylalkyl and X is —O—, R 2  is not optionally substituted pyrano[2,3-d]pyrimidinyl or aryl substituted with thiazolidinedione-5-yl methyl. 
 
     
     
         2 . The pharmaceutical composition having inhibitory activity on 11β-hydroxysteroid dehydrogenase type 1 comprising the compound according to  claim 1 , its pharmaceutically acceptable salt, or a solvate thereof, wherein n is 1, and R 4  and R 5  are hydrogen. 
     
     
         3 . The pharmaceutical composition having inhibitory activity on 11β-hydroxysteroid dehydrogenase type 1 comprising the compound according to  claim 2 , its pharmaceutically acceptable salt, or a solvate thereof, wherein R 1  is optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl. 
     
     
         4 . A compound represented by the Formula (I): 
       
         
           
           
               
               
           
         
       
       its pharmaceutically acceptable salt, or a solvate thereof,
 wherein R 1  is optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl, 
 X is —O—, —NR 3 —, —NR 3 C(═O)— or —NR 3 S(═O) 2 —, 
 R 2  is optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl, 
 R 3  is hydrogen or optionally substituted alkyl, 
 Y is —(CR 4 R 5 )n-, 
 R 4  and R 5  are each independently hydrogen, optionally substituted alkyl, halogen or hydroxy, and 
 n is an integer of 1 to 6, 
 provided that, when R 1  is optionally substituted arylalkyl, R 2  is pyridyl substituted with trifluoromethyl group, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl, while when R 1  is unsubstituted cyclohexyl and X is —O—, R 2  is not optionally substituted phenyl or unsubstituted benzyl. 
 
     
     
         5 . The compound according to  claim 4 , its pharmaceutically acceptable salt, or a solvate thereof, wherein n is 1, and R 4  and R 5  are hydrogen. 
     
     
         6 . The compound according to  claim 5 , its pharmaceutically acceptable salt, or a solvate thereof, wherein R 1  is optionally substituted cycloalkyl having 7 or more carbon atoms, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl, and R 2  is optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl. 
     
     
         7 . The compound according to  claim 5 , its pharmaceutically acceptable salt, or a solvate thereof, wherein R 1  is optionally substituted arylalkyl or optionally substituted cycloalkyl, and R 2  is optionally substituted aryl, optionally substituted arylalkyl or optionally substituted heteroaryl. 
     
     
         8 . The compound according to any one of  claims 5  to  7 , its pharmaceutically acceptable salt, or a solvate thereof, wherein R 1  is optionally substituted cycloalkyl. 
     
     
         9 . The compound according to  claim 8 , its pharmaceutically acceptable salt, or a solvate thereof, wherein R 1  is optionally substituted cyclooctyl. 
     
     
         10 . The compound according to any one of  claims 5  to  9 , its pharmaceutically acceptable salt, or a solvate thereof, wherein R 2  is optionally substituted aryl, optionally substituted arylalkyl or optionally substituted heteroaryl. 
     
     
         11 . The compound according to any one of  claims 5  to  10 , its pharmaceutically acceptable salt, or a solvate thereof, wherein R 3  is optionally substituted alkyl. 
     
     
         12 . A pharmaceutical composition comprising the compound according to any one of  claims 4  to  11 , its pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         13 . The pharmaceutical composition according to  claim 12 , which is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. 
     
     
         14 . The pharmaceutical composition according to any one of  claims 1  to  3 ,  12  or  13 , for treatment and/or prevention of diabetes. 
     
     
         15 . A method for preventing or treating diabetes, comprising administering the compound according to any one of  claims 1  to  11 , its pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         16 . A use of the compound according to any one of  claims 1  to  11 , its pharmaceutically acceptable salt, or a solvate thereof for manufacturing a medicament of treatment and/or prevention of diabetes. 
     
     
         17 . The compound according to any one of  claims 1  to  11 , its pharmaceutically acceptable salt, or a solvate thereof for treatment and/or prevention of diabetes.