Oxazole compound and pharmaceutical composition

Abstract

The present invention provides an 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 tower 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 . A method for obtaining cells expressing phosphodiesterase (PDE) 4, comprising:
 preparing a vector containing cDNA encoding human PDE4,   introducing the vector into mammalian cells,   cultivating the cells in a medium, and   collecting the cells.   
     
     
         2 . The method of  claim 1 , wherein the cells are COS-7 cells. 
     
     
         3 . The method of  claim 1 , wherein the vector is a plasmid vector. 
     
     
         4 . A method for treating or preventing phosphodiesterase 4-mediated and/or tumor necrosis factor-α-mediated disease, the method comprising administering to human or animal in need thereof 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. 
 
       
     
     
         5 . The method of  claim 4 , wherein the disease is at least one selected from the group consisting of bronchial asthma, chronic obstructive pulmonary disease, dermatoses, psoriasis, toxic and allergic contact eczema, atopic dermatitis, alopecia areata, learning, memory, and/or cognition disorders associated with Alzheimer's or Parkinson's diseases, manic-depressive psychosis, schizophrenia, anxiety disorder, systemic and local arthritic disorders, knee osteoarthritis, articular rheumatism, gastrointestinal diffuse inflammation, Crohn's disease and ulcerative colitis, allergic and/or chronic immune-mediated inflammatory diseases in the upper respiratory tract, allergic rhinitis/sinusitis, chronic rhinitis/sinusitis, and allergic conjunctivitis. 
     
     
         6 . The method of  claim 4 , 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)—, —C(═O)—N(R 3 )—   wherein R 3  is a hydrogen atom.   
     
     
         7 . The method of  claim 4 , 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)—, —C(═O)—N(R 3 )—   wherein R 3  is a hydrogen atom.   
     
     
         8 . The method of  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 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 lower alkylene group, and   Y 1  is —C(═O)—, —C(═O)—N(R 3 )—   wherein R 3  is a hydrogen atom.   
     
     
         9 . The method of  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)—.   
     
     
         10 . The method of  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.