Novel azole compound

Abstract

Azole compounds represented by formula I: wherein ring A is isoxazole and the like, R1 is a substituted or unsubstituted aryl group and the like, R2 is a hydrogen atom and the like, and R3 is a substituted or unsubstituted alkyl group and the like, and pharmaceutically acceptable salts thereof inhibit the physiological activity of lysophosphatidic acid (LPA), and are useful as for the prophylaxis or treatment of diseases in which inhibition of the physiological activity of LPA is useful for the prophylaxis or treatment thereof, such as diseases involving the LPA receptor.

1 - 25 . (canceled) 
     
     
         26 . An azole compound represented by formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 ring A is 
 
       
         
           
           
               
               
           
         
         R1 is a substituted or unsubstituted aryl group; 
         R2 is a hydrogen atom, and 
         R3 is any of a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, and a group represented by formula II: 
       
       
         
           
           
               
               
           
         
       
       wherein
 R4 is any of a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a halogen atom, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaryloxy group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted arylthio group, a substituted or unsubstituted heteroarylthio group, a substituted or unsubstituted alkylamino group, a substituted or unsubstituted dialkylamino group, a substituted or unsubstituted cycloalkylamino group, a substituted or unsubstituted dicycloalkylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted heteroarylamino group, and an amino group optionally substituted by amino-protecting group(s); and 
 R5 and R6 may be the same or different and each is any of a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, and a substituted or unsubstituted aralkyl group, or R5 and R6 optionally form, together with the carbon atom bonded thereto, a 3- to 8-membered ring, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         27 . The azole compound of  claim 26 , wherein
 R4 is any of a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a halogen atom, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaryloxy group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted arylthio group, a substituted or unsubstituted heteroarylthio group, a substituted or unsubstituted alkylamino group, a substituted or unsubstituted dialkylamino group, a substituted or unsubstituted cycloalkylamino group, a substituted or unsubstituted dicycloalkylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted heteroarylamino group, and an amino group optionally substituted by amino-protecting group(s),   or a pharmaceutically acceptable salt thereof.   
     
     
         28 . The azole compound of  claim 26 , wherein
 R3 is a group represented by formula II:   
       
         
           
           
               
               
           
         
       
       wherein
 R4 is any of a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a halogen atom, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaryloxy group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted arylthio group, a substituted or unsubstituted heteroarylthio group, a substituted or unsubstituted alkylamino group, a substituted or unsubstituted dialkylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted heteroarylamino group, and an amino group optionally substituted by amino-protecting group(s); and 
 R5 and R6 may be the same or different and each is any of a hydrogen atom and a substituted or unsubstituted lower alkyl group, or R5 and R6 optionally form, together with the carbon atom bonded thereto, a 3- to 8-membered ring, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         29 . The azole compound of  claim 28 , wherein
 R4 is any of a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a halogen atom, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaryloxy group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted arylthio group, a substituted or unsubstituted heteroarylthio group, a substituted or unsubstituted alkylamino group, a substituted or unsubstituted dialkylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted heteroarylamino group, and an amino group optionally substituted by amino-protecting group(s),   or a pharmaceutically acceptable salt thereof.   
     
     
         30 . The azole compound of  claim 28 , wherein
 the substituent of the group for R1 is any of a cyano group and a group represented by formula III:
   Z-Y-X-  formula III
 
   
       wherein
 X and Y may be the same or different and each is any of a substituted or unsubstituted lower alkylene group, a substituted or unsubstituted lower alkenylene group, a substituted or unsubstituted lower alkynylene group, a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted arylene group, a substituted or unsubstituted heteroarylene group, a substituted or unsubstituted heterocyclylene group, a carbonyl group, an oxygen atom, an sulfur atom, a sulfinyl group, a sulfonyl group, a substituted or unsubstituted amino group, and a bond, and 
 Z is any of a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted lower alkynyl group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaryloxy group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted arylthio group, a substituted or unsubstituted heteroarylthio group, a substituted or unsubstituted alkylamino group, a substituted or unsubstituted dialkylamino group, a substituted or unsubstituted cycloalkylamino group, a substituted or unsubstituted dicycloalkylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted heteroarylamino group, and a substituted or unsubstituted carbamoyl group, 
 wherein the substituent of the group for Z is any of a carboxyl group, a carboxylic acid ester group, a substituted or unsubstituted carbamoyl group, a cyano group, a hydroxyl group, a sulfonic acid group, a sulfonamido group, a phosphoric acid group, phosphoric acid monoester group, phosphoric acid diester group, an amino group optionally substituted by amino-protecting group(s), a thiol group, a halogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted arylcarbonyl group, and a substituted or unsubstituted heteroarylcarbonyl group, and the group for Z optionally has multiple substituents described above that may be the same or different; 
 R4 is any of a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, and a halogen atom; and 
 R5 and R6 may be the same or different and each is any of a hydrogen atom and a substituted or unsubstituted lower alkyl group, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         31 . The azole compound of  claim 28 , wherein the substituent of the group for R1 is any of a hydroxyl group and a group represented by formula III:
   Z-Y-X-  formula III
   
       wherein
 X is any of an oxygen atom, a substituted or unsubstituted amino group, a sulfur atom, and a bond, 
 Y is any of a carbonyl group, a sulfonyl group, and a bond, and 
 Z is any of a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaryloxy group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted arylthio group, a substituted or unsubstituted heteroarylthio group, a substituted or unsubstituted alkylamino group, a substituted or unsubstituted dialkylamino group, a substituted or unsubstituted cycloalkylamino group, a substituted or unsubstituted dicycloalkylamino group, a substituted or unsubstituted arylamino group, and a substituted or unsubstituted heteroarylamino group, 
 wherein the substituent of the group for Z is any of a lower alkyl group, a carboxyl group, a carboxylic acid ester group, a substituted or unsubstituted alkanoyloxy group, a substituted or unsubstituted carbamoyl group, a cyano group, a hydroxyl group, a sulfonic acid group, a sulfonamido group, a phosphoric acid group, a phosphoric acid monoester group, a phosphoric acid diester group, an amino group optionally substituted by amino-protecting group(s), a thiol group, a halogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted arylcarbonyl group, and a substituted or unsubstituted heteroarylcarbonyl group, and the group for Z optionally has multiple substituents described above that may be the same or different; 
 R4 is any of a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, and a halogen atom; and 
 R5 and R6 may be the same or different and each is any of a hydrogen atom and a substituted or unsubstituted lower alkyl group, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         32 . The azole compound of  claim 30 , wherein
 R4 is any of a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, and a halogen atom,   or a pharmaceutically acceptable salt thereof.   
     
     
         33 . The azole compound of  claim 27 , wherein
 R1 is a substituted phenyl group,   wherein the substituent of the group for R1 is any of a cyano group and a group represented by formula III:
   Z-Y-X-  formula III
 
   
       wherein
 X is any of a methylene group and a ethylene group, 
 Y is any of a sulfur atom, a sulfinyl group, a sulfonyl group, an oxygen atom, a substituted or unsubstituted amino group, and a methylene group, and 
 Z is any of a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted triazole group, and a substituted or unsubstituted tetrazole group, 
 wherein the substituent of the group for Z is any of a carboxyl group, an alkoxycarbonyl group, a furyl group, a phenyl group, a hydroxyl group, a carbamoyl group, a carbamoyl group substituted by lower alkyl group(s), a carbamoyl group substituted by carboxy lower alkyl group(s), a carbamoyl group substituted by lower alkyl group(s) substituted by a furyl group, an amino group optionally substituted by amino-protecting group(s), a sulfonic acid group, a pyrrolylcarbonyl group, a pyridyl group, and a halogen atom, and the group for Z optionally has multiple substituents described above that may be the same or different; 
 R3 is a group represented by formula II: 
 
       
         
           
           
               
               
           
         
       
       wherein
 R4 is a substituted or unsubstituted phenyl group wherein the substituent of the group for R4 is a halogen atom, 
 R5 is any of a hydrogen atom, a lower alkyl group, and a lower alkyl group substituted by 1 to 3 halogen atoms, and 
 R6 is a hydrogen atom, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         34 . The azole compound of  claim 31 , wherein
 R1 is a substituted or unsubstituted phenyl group wherein the substituent of the group for R1 is any of a hydroxyl group and a group represented by formula III:
   Z-Y-X-  formula III
 
   
       wherein
 X is any of an oxygen atom, a substituted or unsubstituted amino group, a sulfur atom, and a bond, 
 Y is any of a carbonyl group, a sulfonyl group, and a bond, and 
 Z is a substituted or unsubstituted alkyl group, 
 wherein the substituent of the group for Z is any of a lower alkyl group, a carboxyl group, a carboxylic acid ester group, a substituted or unsubstituted alkanoyloxy group, a substituted or unsubstituted carbamoyl group, a cyano group, a hydroxyl group, a sulfonic acid group, a sulfonamido group, a phosphoric acid group, a phosphoric acid monoester group, a phosphoric acid diester group, an amino group optionally substituted by amino-protecting group(s), a thiol group, a halogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted arylcarbonyl group, and a substituted or unsubstituted heteroarylcarbonyl group, and the group for Z optionally has multiple substituents described above that may be the same or different, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         35 . The azole compound of  claim 30 , wherein
 the substituent of the group for R1 is a group represented by formula III:
   Z-Y-X-  formula III
 
   wherein X, Y and Z are as defined in  claim 30 ;   R4 is any of a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted cycloalkyl group, and a substituted or unsubstituted cycloalkenyl group;   R5 is a substituted or unsubstituted lower alkyl group; and   R6 is a hydrogen atom,   or a pharmaceutically acceptable salt thereof.   
     
     
         36 . The azole compound of  claim 35 , wherein
 R4 is a substituted or unsubstituted cycloalkenyl group,   or a pharmaceutically acceptable salt thereof.   
     
     
         37 . The azole compound of  claim 34 , wherein
 R1 is a substituted phenyl group,   wherein the substituent of the group for R1 is any of a hydroxyl group and a group represented by formula III:
   Z-Y-X-  formula III
 
   
       wherein
 X is any of an oxygen atom and a substituted or unsubstituted amino group, 
 Y is any of a carbonyl group and a bond, and 
 Z is a substituted or unsubstituted alkyl group 
 wherein the substituent of the group for Z is any of a lower alkyl group, a carboxyl group, a carboxylic acid ester group, a substituted or unsubstituted alkanoyloxy group, a substituted or unsubstituted carbamoyl group, a cyano group, a hydroxyl group, a sulfonic acid group, a sulfonamido group, a phosphoric acid group, a phosphoric acid monoester group, a phosphoric acid diester group, an amino group optionally substituted by amino-protecting group(s), a thiol group, a halogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted arylcarbonyl group, and a substituted or unsubstituted heteroarylcarbonyl group, and the group for Z optionally has multiple substituents described above that may be the same or different, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         38 . The azole compound of  claim 35 , wherein
 R1 is a substituted phenyl group;   X is any of a substituted or unsubstituted methylene group, a substituted or unsubstituted ethylene group, and a substituted or unsubstituted vinylene group;   Y is any of a sulfur atom, a sulfonyl group, a substituted or unsubstituted methylene group, and an oxygen atom;   Z is any of a substituted methyl group, a substituted ethyl group, a substituted propyl group, and a substituted carbamoyl group,   wherein the substituent of the group for Z is any of a carboxyl group, a carboxylic acid ester group, an acetylamino group, a sulfonic acid group, and a hydroxyl group, and the group for Z optionally has multiple substituents described above that may be the same or different;   R4 is any of a substituted phenyl group, a substituted cyclopentenyl group, a substituted cyclohexenyl group, and a substituted thienyl group,   wherein the substituent of the group for R4 is any of a chlorine atom, a bromine atom, and a substituted or unsubstituted lower alkyl group; and   R5 is a methyl group,   or a pharmaceutically acceptable salt thereof.   
     
     
         39 . The azole compound of  claim 37 , wherein
 the substituent of the group for R1 is any of a hydroxyl group and a group represented by formula III:
   Z-Y-X-  formula III
 
   
       wherein
 X is any of an oxygen atom and a substituted or unsubstituted amino group, 
 Y is any of a carbonyl group and a bond, and 
 Z is a substituted or unsubstituted alkyl group, 
 wherein the substituent of the group for Z is any of a lower alkyl group, a carboxyl group, a carboxylic acid ester group, an alkanoyloxy group, a hydroxyl group, a sulfonic acid group, and an amino group optionally substituted by amino-protecting group(s), and the group for Z optionally has multiple substituents described above that may be the same or different, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         40 . The azole compound of  claim 38 , wherein
 X is any of a methylene group, a ethylene group, and a vinylene group;   Y is any of a sulfur atom, a sulfonyl group, a methylene group, and an oxygen atom;   Z is any of a substituted methyl group, a substituted ethyl group, a substituted propyl group, and a substituted carbamoyl group,   wherein the substituent of the group for Z is any of a carboxyl group, a carboxylic acid ester group, an acetylamino group, and a sulfonic acid group, and the group for Z optionally has multiple substituents described above that may be the same or different; and   R4 is any of a substituted phenyl group, a substituted cyclopentenyl group, and a substituted cyclohexenyl group,   wherein the substituent of the group for R4 is any of a chlorine atom and a bromine atom,   or a pharmaceutically acceptable salt thereof.   
     
     
         41 . A pharmaceutical composition, comprising a compound according to  claim 26  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         42 . A method of inhibiting the physiological activity of LPA, which comprises administering an effective amount of a compound according to  claim 26  or a pharmaceutically acceptable salt thereof to a mammal in need thereof. 
     
     
         43 . A method for the prophylaxis or treatment of hepatic disease, which comprises administering an effective amount of a compound according to  claim 26  or a pharmaceutically acceptable salt thereof to a mammal in need thereof. 
     
     
         44 . A method for the prophylaxis or treatment of organ fibrosis, which comprises administering an effective amount of a compound according to  claim 26  or a pharmaceutically acceptable salt thereof to a mammal in need thereof. 
     
     
         45 . A method of improving liver function, which comprises administering an effective amount of a compound according to  claim 26  or a pharmaceutically acceptable salt thereof to a mammal in need thereof. 
     
     
         46 . A package, comprising a pharmaceutical composition according to  claim 41  and written matter, wherein said written matter states that said pharmaceutical composition can or should be used for inhibiting the physiological activity of LPA.