Spiro compounds and pharmaceutical use thereof

Abstract

The spiro compound represented by the following general formula [Ia], its pharmaceutically acceptable salt or a solvate thereof

1 . A spiro compound of the following general formula [Ia]: 
       
         
           
           
               
               
           
         
         (wherein R 1  is 
         (1) a hydrogen atom, 
         (2) a C 1 -C 6  alkyl group, 
         (3) a C 2 -C 6  alkenyl group, 
         (4) a C 2 -C 6  alkynyl group, 
         (5) a C 1 -C 6  alkoxy group, 
         (6) a hydroxy C 1 -C 6  alkyl group, 
         (7) a C 1 -C 6  alkoxy(C 1 -C 6 )alkyl group, 
         (8) —CONR 11 R 12  in which R 11  and R 12  are the same or different and each represents a hydrogen atom or a C 1 -C 6  alkyl group, 
         (9) a phenyl group or 
         (10) a five-membered heteroaryl group which has at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and which may be substituted by a C 1 -C 6  alkyl group; 
         R 2  is 
         (1) a halogen atom, 
         (2) a C 1 -C 6  alkyl group, 
         (3) a hydroxy group or 
         (4) a C 1 -C 6  alkoxy group; 
         p is 0, 1, 2 or 3; 
         X is a carbon atom or a nitrogen atom; 
         m1 is 0, 1 or 2; 
         m2 is 0 or 1; 
         a spiro-ring AB may be substituted by 1 to 5 same or different substituent(s) selected from the group consisting of 
         (1) a hydroxy group, 
         (2) a C 1 -C 6  alkyl group, 
         (3) a C 1 -C 6  alkoxy group and 
         (4) an oxo group; 
         n1 is 0, 1, 2, 3 or 4; 
         n2 is 1, 2, 3 or 4; 
         n3 is 0, 1 or 2 with the proviso that n2+n3 is 2, 3 or 4; and 
         a bond represented by the symbol: 
         
           
         
         means a single bond or a double bond with proviso that three contiguous carbon atoms do not constitute an allene bond represented by the formula:
   C═C═C
 
 
         ), 
         a pharmaceutically acceptable salt thereof or a solvate thereof. 
       
     
     
         2 . The spiro compound, the pharmaceutically acceptable salt thereof or the solvate thereof as claimed in  claim 1 , wherein the spiro-ring AB is represented by the formula: 
       
         
           
           
               
               
           
         
         (wherein each symbol is as defined above). 
       
     
     
         3 . The spiro compound, the pharmaceutically acceptable salt thereof or the solvate thereof as claimed in  claim 1 , wherein the number of the double bond in ring A of the spiro-ring AB is 0 or 1. 
     
     
         4 . The spiro compound, the pharmaceutically acceptable salt thereof or the solvate thereof as claimed in  claim 1 , wherein the number of the double bond in ring B of the spiro-ring AB is 0 or 1. 
     
     
         5 . The spiro compound, the pharmaceutically acceptable salt thereof or the solvate thereof as claimed in  claim 1 , wherein n3 is 1 or 2. 
     
     
         6 . The spiro compound, the pharmaceutically acceptable salt thereof or the solvate thereof as claimed  claim 1 , wherein the spiro-ring AB may be substituted by 1 to 3 same or different substituent(s). 
     
     
         7 . The spiro compound, the pharmaceutically acceptable salt thereof or the solvate thereof as claimed in  claim 1 ,
 wherein R 1  is   (1) a hydrogen atom,   (2) a C 1 -C 6  alkyl group,   (3) a C 2 -C 6  alkenyl group,   (4) a C 2 -C 6  alkynyl group,   (5) a C 1 -C 6  alkoxy group,   (6) a C 1 -C 6  alkoxy(C 1 -C 6 )alkyl group,   (7) —CONR 11 R 12  in which R 11  and R 12  are the same or different and each represents a hydrogen atom or a C 1 -C 6  alkyl group, or   (8) a five-membered heteroaryl group which has at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and which may be substituted by a C 1 -C 6  alkyl group.   
     
     
         8 . The spiro compound, the pharmaceutically acceptable salt thereof or the solvate thereof as claimed in  claim 1 ,
 wherein R 1  is   (1) a hydrogen atom,   (2) a C 2 -C 6  alkenyl group,   (3) a C 2 -C 6  alkynyl group,   (4) a C 1 -C 6  alkoxy group or   (5) a five-membered heteroaryl group which has at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and which may be substituted by a C 1 -C 6  alkyl group.   
     
     
         9 . The spiro compound, the pharmaceutically acceptable salt thereof or the solvate thereof as claimed in  claim 1 , wherein p is 0 or 1. 
     
     
         10 . The spiro compound, the pharmaceutically acceptable salt thereof or the solvate thereof as claimed in  claim 1 ,
 wherein R 2  is   (1) a C 1 -C 6  alkyl group,   (2) a hydroxy group or   (3) a C 1 -C 6  alkoxy group.   
     
     
         11 . The spiro compound, the pharmaceutically acceptable salt thereof or the solvate thereof as claimed in  claim 1 , wherein m1 is 0 or 1. 
     
     
         12 . A pharmaceutical composition, which comprises the spiro compound, the pharmaceutically acceptable salt thereof or the solvate thereof as claimed in  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         13 .- 18 . (canceled) 
     
     
         19 . A method for activating GPR40, which comprises administration of the spiro compound, the pharmaceutically acceptable salt thereof or the solvate thereof as claimed in  claim 1  to a mammal in a pharmaceutically effective amount. 
     
     
         20 . A method for promoting insulin secretion or lowering blood glucose level, which comprises administration of the spiro compound, the pharmaceutically acceptable salt thereof or the solvate thereof as claimed in  claim 1  to a mammal in a pharmaceutically effective amount. 
     
     
         21 . A method for treating or preventing a disease selected from the group consisting of diabetes mellitus, hyperglycemia, impaired glucose tolerance and impaired fasting glucose, which comprises administration of the spiro compound, the pharmaceutically acceptable salt thereof or the solvate thereof as claimed in  claim 1  to a mammal in a pharmaceutically effective amount.