Oxazole compound and pharmaceutical composition

Abstract

The present invention provides a oxazole compound represented by Formula (1), or a salt thereof: wherein R 1 is an aryl group which may have one or more substituents; R 2 is an aryl group or a nitrogen atom-containing heterocyclic group each of which may have one or more substituents; and W is a divalent group represented by —Y 1 -A 1 - or —Y 2 —C(═O)— wherein Y 1 is a group such as —C(═O)—, A 1 is a group such as a lower alkylene group, and Y 2 is a group such as a piperazinediyl group. The oxazole compound has a specific inhibitory action against phosphodiesterase 4.

1 . An oxazole compound represented by Formula (1) 
       
         
           
           
               
               
           
         
         wherein R 1  is an aryl group which may have one or more substituents selected from the following (1-1) to (1-11): 
         (1-1) hydroxy groups, 
         (1-2) unsubstituted or halogen-substituted lower alkoxy groups, 
         (1-3) lower alkenyloxy groups, 
         (1-4) lower alkynyloxy groups, 
         (1-5) cyclo C 3-8  alkyl lower alkoxy groups, 
         (1-6) cyclo C 3-8  alkyloxy groups, 
         (1-7) cyclo C 3-8  alkenyloxy groups, 
         (1-8) dihydroindenyloxy groups, 
         (1-9) hydroxy lower alkoxy groups, 
         (1-10) oxiranyl lower alkoxy groups, and 
         (1-11) protected hydroxy groups; 
         R 2  is an aryl group or a nitrogen atom-containing heterocyclic group each of which may have one or more substituents selected from the following (2-1) to (2-10): 
         (2-1) hydroxy groups, 
         (2-2) unsubstituted or halogen-substituted lower alkoxy groups, 
         (2-3) unsubstituted or halogen-substituted lower alkyl groups, 
         (2-4) lower alkenyloxy groups, 
         (2-5) halogen atoms, 
         (2-6) lower alkanoyl groups, 
         (2-7) lower alkylthio groups, 
         (2-8) lower alkylsulfonyl groups, 
         (2-9) oxo groups, and 
         (2-10) lower alkoxy lower alkoxy groups; and 
         W is a divalent group represented by Formula (i) or (ii):
   —Y 1 -A 1 -  Formula (i)
 
   —Y 2 —C(O)—  Formula (ii)
 
 
         wherein A 1  is a lower alkenylene group, or a lower alkylene group which may have one or more substituents selected from the group consisting of hydroxy groups and lower alkoxycarbonyl groups, Y 1  is a direct bond, —C(═O)—, —C(═O)—N(R 3 )—, —N(R 4 )—C(═O)—, —S(O) m —NH—, or —S(O) n — 
         wherein R 3  and R 4  are each independently a hydrogen atom or a lower alkyl group, and m and n are each independently an integer from 0 to 2, and 
         Y 2  is a piperazinediyl group, or a divalent group represented by Formula (iii) or (iv):
   —C(═O)-A 2 -N(R 5 )—  Formula (iii)
 
   -A 3 -N(R 6 )—  Formula (iv)
 
 
         wherein A 2  and A 3  are each independently a lower alkylene group, and R 5  and R 6  are each independently a hydrogen atom or a lower alkyl group; 
         or a salt thereof. 
       
     
     
         2 . The compound according to  claim 1 ,
 wherein R 1  is a phenyl group which has 1 to 3 substituents selected from the following (1-2), (1-3), (1-4) and (1-5):   (1-2) unsubstituted or halogen-substituted lower alkoxy groups,   (1-3) lower alkenyloxy groups,   (1-4) lower alkynyloxy groups, and   (1-5) cyclo C 3-8  alkyl lower alkoxy groups;   R 2  is a phenyl group or a pyridyl group each of which may have 1 to 3 substituents selected from the group consisting of the following (2-2), (2-3), (2-4) and (2-5):   (2-2) unsubstituted or halogen-substituted lower alkoxy groups,   (2-3) unsubstituted or halogen-substituted lower alkyl groups,   (2-4) lower alkenyloxy groups, and   (2-5) halogen atoms;   W is a divalent group represented by Formula (i)
   —Y 1 -A 1 -  Formula (i)
 
   wherein A 1  is a lower alkylene group, and   Y 1  is —C(═O)— or —C(═O)—N(R 3 )—   wherein R 3  is a hydrogen atom.   
     
     
         3 . The compound according to  claim 2 ,
 wherein R 1  is a phenyl group having two substituents selected from the following   (1-2), (1-3), (1-4) and (1-5):   (1-2) unsubstituted or halogen-substituted lower alkoxy groups,   (1-3) lower alkenyloxy groups,   (1-4) lower alkynyloxy groups, and   (1-5) cyclo C 3-8  alkyl lower alkoxy groups;   R 2  is a phenyl group or a pyridyl group each of which may have 1 to 2 substituents selected from the following (2-2), (2-3), (2-4) and (2-5):   (2-2) unsubstituted or halogen-substituted lower alkoxy groups,   (2-3) unsubstituted or halogen-substituted lower alkyl groups,   (2-4) lower alkenyloxy groups, and   (2-5) halogen atoms; and   W is a divalent group represented by Formula (i);
   —Y 1 -A 1 -  Formula (i)
 
   wherein A 1  is a lower alkylene group, and   Y 1  is —C(═O)— or —C(═O)—N(R 3 )—   wherein R 3  is a hydrogen atom.   
     
     
         4 . The compound according to  claim 3 ,
 wherein R 1  is a phenyl group substituted on the phenyl ring with two lower alkoxy groups, a phenyl group substituted on the phenyl ring with one lower alkoxy group and one cyclo C m  alkyl lower alkoxy group, a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen-substituted lower alkoxy group, a phenyl group substituted on the phenyl group with one lower alkoxy group and one lower alkenyloxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one cyclo C 3-6  alkyl lower alkoxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one lower alkenyloxy group, or a phenyl group substituted on the phenyl ring with two halogen-substituted lower alkoxy groups;   R 2  is a lower alkoxyphenyl group, a lower alkenyloxyphenyl group, a halogen-substituted lower alkoxyphenyl group, a lower alkylpyridyl group, or a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen atom; and   W is a divalent group represented by Formula (i):
   —Y 1 -A 1 -  Formula (i)
 
   wherein A 1  is a C 1-4  alkylene group, and   Y 1  is —C(═O)— or —C(═O)—N(R 3 )—   wherein R 3  is a hydrogen atom.   
     
     
         5 . The compound according to  claim 4 ,
 wherein R 1  is a phenyl group substituted on the phenyl ring with two lower alkoxy groups, a phenyl group substituted on the phenyl ring with one lower alkoxy group and one cyclo C 3-8  alkyl lower alkoxy group, a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen-substituted lower alkoxy group, a phenyl group substituted on the phenyl group with one lower alkoxy group and one lower alkenyloxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one cyclo C 3-8  alkyl lower alkoxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one lower alkenyloxy group, or a phenyl group substituted on the phenyl ring with two halogen-substituted lower alkoxy groups;   R 2  is a lower alkoxyphenyl group, a lower alkenyloxy phenyl group, a halogen-substituted lower alkoxyphenyl group, a lower alkylpyridyl group, or a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen atom; and   W is a divalent group represented by Formula (i):
   —Y 1 -A 1 -  Formula (i)
 
   wherein A 1  is a C 1-4  alkylene group, and   Y 1  is —C(═O)—.   
     
     
         6 . The compound according to  claim 4 ,
 wherein R 1  is a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen-substituted lower alkoxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one cyclo C 3-8  alkyl lower alkoxy group, or a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one lower alkenyloxy group:   R 2  is a lower alkoxyphenyl group or a lower alkylpyridyl group; and   W is a divalent group represented by Formula (i):
   —Y 1 -A 1 -  Formula (i)
 
   wherein A 1  is a C 1-4  alkylene group, and   Y 1  is —C(═O)—N(R 3 )—   wherein R 3  is a hydrogen atom.   
     
     
         7 . A pharmaceutical composition comprising the compound or salt according to  claim 1  as an active ingredient and a pharmaceutically acceptable carrier. 
     
     
         8 . A pharmaceutical composition for treating or preventing phosphodiesterase 4-mediated and/or tumor necrosis factor-α-mediated diseases, the composition comprising the compound or salt according to  claim 1 . 
     
     
         9 . A pharmaceutical composition for treating or preventing atopic dermatitis, the composition comprising the compound or salt according to  claim 1 . 
     
     
         10 . A process for producing a pharmaceutical composition, the process comprising mixing the compound or salt according to  claim 1  with a pharmaceutically acceptable carrier. 
     
     
         11 . Use of the compound or salt according to  claim 1  as a drug. 
     
     
         12 . Use of the compound or salt according to  claim 1  as a phosphodiesterase 4 inhibitor and/or tumor necrosis factor-α-production inhibitor. 
     
     
         13 . A method for treatment or preventing phosphodiesterase 4-mediated and/or tumor necrosis factor-α-mediated diseases, the method comprising administering the compound or salt according to  claim 1  to human or animal. 
     
     
         14 . A process for producing an oxazole compound represented by Formula (1): 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and W are the same as defined in  claim 1 , or a salt thereof, the process comprising a reaction of a compound represented by Formula (2): 
       
       
         
           
           
               
               
           
         
         wherein R 2  and W are the same as defined above, and X is a halogen atom, or a salt thereof, with a compound represented by Formula (3): 
       
       
         
           
           
               
               
           
         
         wherein R 1  is the same as defined above, or a salt thereof.