Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity

Abstract

The following compound is provided as an agent for treating a disease induced by production, secretion and/or deposition of amyloid β protein, for example, a compound represented by the formula (I): wherein ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, R 1 is optionally substituted lower alkyl or the like, R 2a and R 2b are each independently hydrogen, optionally substituted lower alkyl or the like, R 3a and R 3c are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl or the like, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

1 . A compound represented by the formula (I): 
       
         
           
           
               
               
           
         
         wherein ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; 
         R 1  is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, cyano, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; 
         R 2a  and R 2b  are each independently hydrogen, optionally substituted lower alkyl or optionally substituted acyl; 
         R 3a  and R 3c  are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted lower alkoxy, optionally substituted aryl lower alkyl, optionally substituted heteroaryl lower alkyl, optionally substituted aryl lower alkoxy, optionally substituted heteroaryl lower alkoxy, optionally substituted lower alkylthio, carboxy, cyano, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, or R 3a  and R 3c  may be taken together to form a ring, 
         or its pharmaceutically acceptable salt, or a solvate thereof. 
       
     
     
         2 . A compound represented by the formula (II): 
       
         
           
           
               
               
           
         
         wherein R x  is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; 
         R 3a  and R 3b  are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted lower alkoxy, optionally substituted aryl lower alkyl, optionally substituted heteroaryl lower alkyl, optionally substituted aryl lower alkoxy, optionally substituted heteroaryl lower alkoxy, optionally substituted lower alkylthio, carboxy, cyano, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; and 
         ring A, R 2a  and R 2b  are as defined in  claim 1 , 
         or its pharmaceutically acceptable salt or a solvate thereof. 
       
     
     
         3 . A compound represented by the following formula (III): 
       
         
           
           
               
               
           
         
         wherein R y  is halogeno lower alkyl; 
         R 3a , R 3b , R 3c  and R 3d  are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted lower alkoxy, optionally substituted aryl lower alkyl, optionally substituted heteroaryl lower alkyl, optionally substituted aryl lower alkoxy, optionally substituted heteroaryl lower alkoxy, optionally substituted lower alkylthio, carboxy, cyano, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; and 
         ring A, R 2a , and R 2b  are as defined in  claim 1 , 
         or its pharmaceutically acceptable salt or a solvate thereof. 
       
     
     
         4 . A compound represented by the formula (IV): 
       
         
           
           
               
               
           
         
         wherein R Za  and R Zb  are each independently hydrogen, halogen, optionally substituted lower alkyl, or are taken together with a carbon atom to which they bind to form a carbocycle; and 
         ring A, R 1 , R 2a , and R 2b  are as defined in  claim 1 , and R 3c  and R 3d  are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted lower alkoxy, optionally substituted aryl lower alkyl, optionally substituted heteroaryl lower alkyl, optionally substituted aryl lower alkoxy, optionally substituted heteroaryl lower alkoxy, optionally substituted lower alkylthio, carboxy, cyano, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, 
         or its pharmaceutically acceptable salt or a solvate thereof. 
       
     
     
         5 . The compound according to  claim 1 , wherein R 3a  and R 3c  are both hydrogen, or its pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         6 . The compound according to  claim 1 , wherein R 1  is alkyl of a carbon number of 1 to 3, or its pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         7 . The compound according to  claim 2 , wherein R X  is optionally substituted cycloalkyl, optionally substituted phenyl, or an optionally substituted nitrogen-containing aromatic heterocyclic group, or its pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         8 . The compound according to  claim 2 , wherein R 3a  and R 3b  are both hydrogen, or its pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         9 . The compound according to  claim 3 , wherein R 3a , R 3b , R 3c  and R 3d  are all hydrogen, or its pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         10 . The compound according to  claim 1 , wherein R 2a  and R 2b  are both hydrogen, or its pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         11 . The compound according to  claim 1 , wherein ring A is 
       
         
           
           
               
               
           
         
         wherein ring A′ is a carbocyclic group or a heterocyclic group; 
         G is 
       
       
         
           
           
               
               
           
         
         wherein R 5  is hydrogen, lower alkyl or acyl; 
         R 6  is optionally substituted lower alkyl, optionally substituted lower alkenyl, or optionally substituted lower alkynyl; 
         W 1  is O or S; 
         W 2  is O, S or NR 5 ; 
         Ak is optionally substituted lower alkylene, optionally substituted lower alkenylene, or optionally substituted lower alkynylene; 
         ring B is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; 
         R 4  is each independently halogen, hydroxy, mercapto, halogeno lower alkyl, lower alkyl, lower alkoxy, optionally substituted amino, or lower alkylthio, and n is an integer of 0 to 2; 
         or its pharmaceutically acceptable salt, or a solvate thereof. 
       
     
     
         12 . The compound according to  claim 11 , wherein ring A′ is phenyl or a nitrogen-containing aromatic heterocyclic group, or its pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         13 . The compound according to  claim 11 , wherein ring A′ is a nitrogen-containing aromatic heteromonocyclic group, or its pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         14 . The compound according to  claim 11 , wherein ring B is a nitrogen-containing aromatic heteromonocyclic group, or its pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         15 . A pharmaceutical composition comprising, as an active ingredient, the compound according to  claim 1 , or its pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         16 . A pharmaceutical composition having β secretase inhibitory activity, comprising, as an active ingredient, the compound according to  claim 1 , or its pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         17 . A method for inhibiting β secretase activity, comprising administering the compound according to  claim 1 , or its pharmaceutically acceptable salt, or a solvate thereof. 
     
     
         18 . Use of the compound according to  claim 1 , or its pharmaceutically acceptable salt, or a solvate thereof in the manufacture of a medicament for inhibiting β secretase activity. 
     
     
         19 . The compound according to  claim 1 , or its pharmaceutically acceptable salt, or a solvate thereof for use in a method for inhibiting β secretase activity.