Heterocyclic aromatic oxazole compounds and use thereof

Abstract

A heterocyclic aromatic oxazole compound of the formula (I) wherein Z is an oxygen atom; one of R and R 1 is a group of the formula wherein R 3 is lower alkyl, amino or lower alkylamino, and R 4 , R 5 , R 6 and R 7 are the same or different and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or amino, provided that at least one of R 4 , R 5 , R 6 and R 7 is not hydrogen atom, and the other is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group or an optionally substituted aryl; and R 2 is a lower alkyl or a halogenated lower alkyl, and a pharmaceutically acceptable salt thereof. The heterocyclic aromatic oxazole compound and pharmaceutically acceptable salts thereof have antipyretic action, analgesic action, anti-inflammatory action, and particularly, selective inhibitory action on cyclooxygenase-2 (COX-2), and are expected to be useful as anti-inflammatory agents with less side-effects such as digestive tract disorders.

What is claimed is  
     
         1 . A heterocyclic aromatic oxazole compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 Z is an oxygen atom;  
 one of R and R 1  is a group of the formula  
                     wherein R 3  is lower alkyl, amino or lower alkylamino, and R 4 , R 5 , R 6  and R 7  are the same or different and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or amino, provided that at least one of R 4 , R 5 , R 6  and R 7  is not hydrogen atom, and the other is optionally substituted cycloalkyl, optionally substituted heterocyclic group or optionally substituted aryl; and    
 R 2  is a lower alkyl or a halogenated lower alkyl, or a pharmaceutically acceptable salt thereof:  
 
     
     
         2 . The heterocyclic aromatic oxazole compound of  claim 1 , wherein R 1  is a group of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 3 ′ is lower alkyl or amino, at least one of R 4 ′, R 5 ′, R 6 ′ and R 7 ′ is halogen atom or lower alkyl and the rest is hydrogen atom or halogen atom, or a pharmaceutically acceptable salt thereof.  
     
     
         3 . The heterocyclic aromatic oxazole compound of  claim 1 , wherein R 1  is a group of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 3 ″ is methyl or amino, R 5 ″ is fluorine atom and R 6 ″ is hydrogen atom or fluorine atom, and R 2  is methyl, or a pharmaceutically acceptable salt thereof.  
     
     
         4 . The heterocyclic aromatic oxazole compound of  claim 1 , wherein R 1  is a group of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 3 ″, R 5 ″ and R 6 ″ are as defined in claim  3 ; R is optionally substituted cycloalkyl having 5 to 7 carbon atoms, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyrrolyl, optionally substituted morpholino, optionally substituted piperazinyl, optionally substituted piperidyl, optionally substituted phenyl, optionally substituted naphthyl or optionally substituted biphenyl, and R 2  is methyl, or a pharmaceutically acceptable salt thereof.  
     
     
         5 . The heterocyclic aromatic oxazole compound of  claim 4 , wherein R 3 ″ is amino, or a pharmaceutically acceptable salt thereof.  
     
     
         6 . The heterocyclic aromatic oxazole compound of  claim 4 , wherein R is optionally substituted cycloalkyl having 5 to 7 carbon atoms, optionally substituted phenyl or optionally substituted thienyl, or a pharmaceutically acceptable salt thereof.  
     
     
         7 . The heterocyclic aromatic oxazole compound of  claim 4 , wherein R is cyclohexyl or 4-fluorophenyl, and R 1  is 4-aminosulfonyl-3-fluorophenyl, 4-aminosulfonyl-3,5-difluorophenyl, 3-fluoro-4-methylsulfonylphenyl or 3,5-difluoro-4-methylsulfonylphenyl, or a pharmaceutically acceptable salt thereof.  
     
     
         8 . The heterocyclic aromatic oxazole compound of  claim 1 , which is selected from the group consisting of: 
 4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole,    5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole,    5-(4-aminosulfonyl-3,5-difluorophenyl)-4-cyclohexyl-2-methyloxazole,    4-cyclohexyl-5-(3,5-difluoro-4-methylsulfonylphenyl)-2-methyloxazole, and    5-(4-aminosulfonyl-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyloxazole,    or a pharmaceutically acceptable salt thereof.    
     
     
         9 . An oxime compound of the following formula (XI′)  
       
         
           
           
               
               
           
         
       
       wherein R 4 , R 5 , R 6  and R 7  are as defined in  claim 1 , and R″ is optionally substituted cycloalkyl or optionally substituted aryl.  
     
     
         10 . The oxime compound of  claim 9  wherein R 1 ″ is 3-fluorophenyl or 3,5-difluorophenyl, and R″ is cyclohexyl or 4-fluorophenyl.  
     
     
         11 . A ketone compound of the following formula (IV″)  
       
         
           
           
               
               
           
         
       
       wherein R 1 ″ and R″ are respectively as defined in  claim 9 .  
     
     
         12 . The ketone compound of  claim 11 , wherein R 1 ″ is 3-fluorophenyl or 3,5-difluorophenyl, and R″ is cyclohexyl or 4-fluorophenyl.  
     
     
         13 . A ketomethylene compound of the following formula (IV′″)  
       
         
           
           
               
               
           
         
       
       wherein R′″ is an optionally substituted cycloalkyl having 5 to 7 carbon atoms, an optionally substituted phenyl or an optionally substituted thienyl, and R 1 ′″ is a group of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 3 ′, R 4 ′, R 5 ′, R 6 ′ and R 7 ′ are as defined in  claim 2 .  
     
     
         14 . The ketomethylene compound of  claim 13 , wherein R′″ is cyclo-hexyl, and R 1 ′″ is 4-aminosulfonyl-3-fluorophenyl, 4-aminosulfonyl-3,5-difluorophenyl, 3-fluoro-4-methylsulfonylphenyl or 3,5-difluoro-4-methylsulfonylphenyl.  
     
     
         15 . An ester compound of the following formula (V)  
       
         
           
           
               
               
           
         
       
       wherein R, R 1 , R 2  and Z are as defined in  claim 1 .  
     
     
         16 . The ester compound of  claim 15 , wherein R is cycloalkyl and R 2  is lower alkyl.  
     
     
         17 . An amide compound of the following formula (XVIII′)  
       
         
           
           
               
               
           
         
       
       wherein R 1 ″ and R″ are respectively as defined in  claim 9 , and Z and R 2  are as defined in  claim 1 .  
     
     
         18 . The amide compound of  claim 17 , wherein R 1 ″ is 3-fluorophenyl or 3,5-difluorophenyl, R″ is cyclohexyl or 4-fluorophenyl, and R 2  is lower alkyl.  
     
     
         19 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         20 . A cyclooxygenase-2 inhibitor comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of  claim 1  or a pharmaceutically acceptable salt thereof as an active ingredient.  
     
     
         21 . An anti-inflammatory agent comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of  claim 1  or a pharmaceutically acceptable salt thereof as an active ingredient.