Bicyclic Pyrrole Derivatives

Abstract

Compounds represented by the general formula (I), prodrugs thereof, or pharmaceutically acceptable salts of both are provided as compounds which have high DPP-IV inhibiting activity and are improved in safety, toxicity and so on: (I) wherein the solid line and dotted line between A 1 and A 2 represents a double bond (A 1 =A 2 ) or the like; A 1 is C(R 4 ) or the like; A 2 is nitrogen atom or the like; R 1 is hydrogen atom, optionally substituted alkyl group, or the like; R 2 is hydrogen atom, optionally substituted alkyl group, or the like; R 3 is hydrogen atom, halogen atom, or the like; R 4 is hydrogen atom, hydroxyl, halogen atom, or the like; and Y is a group represented by the general formula (A) or the like; (A) [wherein m1 is 0, 1, 2 or 3; and the group (A) may be freed from R 6 or substituted with one or two R 6 's which are each independently halogen atom or the like.]

1 . A compound represented by the formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R 1  is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;
 the solid line and dotted line between A 1  and A 2  indicate a double bond (A 1 =A 2 ) or a single bond (A 1 -A 2 ); 
 A 1  is a group represented by the formula C(R 4 ) and A 2  is a nitrogen atom, in the case of the solid line and dotted line between A 1  and A 2  being a double bond (A 1 =A 2 ); 
 Λ 1  is a group represented by the formula C═O and A 2  is a group represented by the formula N(R 5 ), in the case of the solid line and dotted line between A 1  and A 2  being a single bond (A 1 -A 2 ); 
 R 2  is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group; 
 R 3  is a hydrogen atom, a halogen atom, a cyano group, a formyl group, a carboxyl group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted alkylcarbonyl group, an optionally substituted cycloalkylcarbonyl group, an optionally substituted aroyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted carbamoyl group, a hydroxyl group, an optionally substituted alkoxy group, or the formula: -Rd-C(O)O—Re wherein Rd is a single bond, an alkylene group or an alkenylene group and Re is tetrahydrofuranyl, cinnamyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, 5-(tert-butyl)-2-oxo-1,3-dioxolen-4-ylmethyl or the formula: —CH(R 4a )OC(O)R 4b  wherein R 4a  is a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group or an alkoxy group and R 4b  is an optionally substituted alkyl group, an optionally substituted alkenyl group, a cycloalkyl group, a cycloalkyloxy group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, a 2-indanyloxy group, a 5-indanyloxy group or an optionally substituted aryloxy group; 
 R 4  is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a formyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, a carboxyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted aralkyl group, an optionally substituted aralkyloxy group, an optionally substituted aroyl group, an optionally substituted arylthio group, an optionally substituted arylsulfinyl group, an optionally substituted arylsulfonyl group, an optionally substituted alkylthio group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted heteroaryloxy group, an optionally substituted alkylcarbonyl group, an optionally substituted nitrogen-containing saturated heterocyclic group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, an optionally substituted cycloalkyloxycarbonyl group, or the formula: -Rd-C(O)O—Re wherein Rd and Re are as defined above; 
 R 5  is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted vinyl group, an optionally substituted nitrogen-containing saturated heterocyclic group, or an optionally substituted heteroaryl group; 
 —Y is a group represented by any of the formula (A), formula (B), formula (C) and formula (D) shown below: 
 
     
       
         
         
             
             
         
       
     
     wherein m1 is 0, 1, 2 or 3, and R 6  is absent or one or two R 6 s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R 6 s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring; 
     
       
         
         
             
             
         
       
     
     wherein m2 is 0, 1, 2 or 3, and R 7  is absent or one or two R 7 s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R 7 s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring; 
     
       
         
         
             
             
         
       
     
     wherein m3 and m4 are independently 0 or 1, and R 8  is absent or one or two R 8 s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R 8 s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring; and 
     
       
         
         
             
             
         
       
     
     wherein m5 is 1, 2 or 3, R 9  is absent or one or two R 9 s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R 9 s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring, and R 10  and R 11  are independently a hydrogen atom, methyl, ethyl, propyl or isopropyl, or R 10  and R 11 , when taken together, represent cyclopropyl, cyclobutyl or cyclopentyl, 
     a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug. 
   
   
       2 . A compound according to  claim 1 , which is represented by the formula (II): 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3  and Y are as defined in  claim 1  and R 12  is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug. 
   
   
       3 . A compound according to  claim 1 , which is represented by the formula (III): 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3  and Y are as defined in  claim 1  and R 13  is a hydrogen atom, a hydroxyl group, a cyano group, a carboxyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted aralkyl group, an optionally substituted aralkyloxy group, an optionally substituted aroyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted heteroaryloxy group, an optionally substituted alkylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, an optionally substituted cycloalkyloxycarbonyl group, an optionally substituted alkylsulfonyl group, or the formula: -Rd-C(O)O—Re wherein Rd and Re are as defined in  claim 1 , a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug. 
   
   
       4 . A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 3 , wherein R 13  is a hydrogen atom, a hydroxyl group, a cyano group, a carboxyl group, a trifluoromethyl group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted aroyl group, an optionally substituted alkylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, an optionally substituted cycloalkyloxycarbonyl group, an optionally substituted alkylsulfonyl group, or the formula: -Rd-C(O)O—Re wherein Rd and Re are as defined in  claim 1 . 
   
   
       5 . A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 1 , wherein R 2  is a group represented by any of the following formula (E), formula (F), formula (G), formula (H), formula (I) and formula (J): 
     
       
         
         
             
             
         
       
     
     wherein each of Z 1  and Z 2  is an oxygen atom, the formula S(O) p  or the formula N(R 22 );
 each of R 14  and R 20  is absent or one or two R 14 s and/or one or two R 20 s are present and are independently a halogen atom, a hydroxyl group, a formyl group, a carboxyl group, a cyano group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an alkyl group, a haloalkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, an optionally substituted amino group, an optionally substituted carbamoyl group, an alkoxycarbonyl group, an optionally substituted alkylcarbonyl group, a cycloalkylcarbonyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted nitrogen-containing heteroaryl group, or two R 14 s or two R 20 s, when taken together, represent a C 1-3  alkylenedioxy group; 
 each of R 15  and R 21  is absent or one or two R 15 s and/or one or two R 21 s are present and are independently a halogen atom, a cyano group, an alkyl group, a haloalkyl group, a cycloalkyl group, an alkoxy group or a haloalkoxy group; 
 R 16  is methyl, ethyl, a chlorine atom or a bromine atom; 
 R 17  is a hydrogen atom, methyl, ethyl, a chlorine atom or a bromine atom; 
 R 18  is a hydrogen atom, methyl or ethyl; 
 R 19  is a hydrogen atom, methyl, ethyl, cyclopropyl or cyclobutyl; 
 p is 0, 1 or 2; and 
 R 22  is a hydrogen atom or an alkyl group. 
 
   
   
       6 . A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 1 , wherein —Y is a group represented by the formula (A) in which m1 is 1 or 2, or —Y is a group represented by the formula (B) in which m2 is 1 or 2, or —Y is a group represented by the formula (C) in which each of m3 and m4 is 1. 
   
   
       7 . A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 1 , wherein R 2  is a group represented by any of the formula (E), formula (H) and formula (I). 
   
   
       8 . A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 1 , wherein R 1  is a hydrogen atom, an optionally substituted C 1 -C 3  alkyl group or an optionally substituted aryl group, and the substituent(s) of the optionally substituted alkyl group is selected from fluorine atom, optionally substituted aroyl groups, carboxyl group, optionally substituted alkoxycarbonyl groups, optionally substituted aryl groups and optionally substituted aryloxy groups. 
   
   
       9 . A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 1 , wherein R 1  is a group represented by the formula: —Ra—Rb-Rc in which
 Ra is an alkylene group;   Rb is a single bond or a carbonyl group; and   Rc is an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted aryloxy group or an optionally substituted heteroarylamino group.   
   
   
       10 . A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 1 , wherein R 1  is a hydrogen atom, methyl or ethyl. 
   
   
       11 . A compound according to  claim 1 , which is represented by the formula (IV): 
     
       
         
         
             
             
         
       
     
     wherein R 1  and R 3  are as defined in  claim 1 ; R 23  is a hydrogen atom or an optionally substituted alkyl group; R 24  is a halogen atom, a cyano group, a carbamoyl group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a methoxy group, a trifluoromethoxy group, difluoromethoxy group or a monofluoromethoxy group; and R 25  is a hydrogen atom, a fluorine atom or a chlorine atom, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug. 
   
   
       12 . A compound according to  claim 1 , which is represented by the formula (V): 
     
       
         
         
             
             
         
       
     
     wherein R 26  is a hydrogen atom, a cyano group, an optionally substituted alkyl group, an optionally substituted carbamoyl group, a hydroxyl group or an optionally substituted alkoxy group; R 27  is a chlorine atom, a bromine atom, a cyano group, a carbamoyl group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a methoxy group, a trifluoromethoxy group, difluoromethoxy group or a monofluoromethoxy group; and R 28  is a hydrogen atom or a fluorine atom, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug. 
   
   
       13 . A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 12 , wherein R 27  is a chlorine atom or a cyano group. 
   
   
       14 . A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 12 , wherein R 26  is a hydrogen atom or an optionally substituted carbamoyl group. 
   
   
       15 . A compound represented by the formula (VI): 
     
       
         
         
             
             
         
       
     
     wherein R 2  and Y are as defined in  claim 1  and R 29  is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroarylalkyl group, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug. 
   
   
       16 . A pharmaceutical composition comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 1  as an active ingredient. 
   
   
       17 . A dipeptidyl peptidase IV inhibitor comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 1  as an active ingredient. 
   
   
       18 . A pharmaceutical composition for the treatment of diabetes comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 1  as an active ingredient. 
   
   
       19 . Use of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 1  in the manufacture of a dipeptidyl peptidase IV inhibitor. 
   
   
       20 . Use of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 1  in the manufacture of a pharmaceutical composition for the treatment of diabetes. 
   
   
       21 . A method for treating diabetes comprising administering an effective amount of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to  claim 1  to a patient who needs the treatment.