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 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.

The invention claimed is: 
     
       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 lower alkyl groups, 
 (2-4) lower alkenyloxy groups, 
 (2-5) halogen atoms, 
 (2-6) lower alkanoyl groups other than a formyl group, 
 (2-7) lower alkylthio groups, 
 (2-8) lower alkylsulfonyl groups, 
 (2-9) oxo groups, and 
 (2-10) lower alkoxy lower alkoxy groups; and 
 the nitrogen atom-containing heterocyclic group in R 2  is selected from imidazolidinyl, hexahydropyrimidinyl, piperazinyl, octahydroisoindolyl, azocanyl, pyrrolyl, dihydropyrrolyl, imidazolyl, dihydroimidazolyl, triazolyl, dihydrotriazolyl, pyrazolyl, pyridyl and N-oxides thereof, dihydropyridyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, tetrazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, hexahydroisoindolinyl, benzoimidazolyl, quinolyl, isoquinolyl, indazolyl, quinazolinyl, dihydroquinazolinyl, benzotriazolyl, carbazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxazolidinyl, isooxazolidinyl, dihydrobenzoxazolyl, benzoxazinyl, dihydrobenzoxazinyl, benzoxazolyl, benzooxadiazolyl, thiazolyl, dihydrothiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolyzinyl, benzothiazolyl, and benzothiadiazolyl; 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 —C(═O)—, —C(═O)—N(R 3 )—, —S(O) m —NH—, or —S(O) n — 
 wherein R 3  is 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):
   —C(═O)-A 2 -N(R 5 )—  Formula (iii)
 
 
 wherein A 2  is a lower alkylene group, and R 5  is a hydrogen atom or a lower alkyl group; 
 or a pharmaceutically acceptable 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 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 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)— 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 3-8 , 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 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 a pharmaceutically acceptable salt according to any one of  claims 1  to  6  as an active ingredient and a pharmaceutically acceptable carrier. 
     
     
       8. A method for treating dermatosis, the method comprising administering the compound or a pharmaceutically acceptable salt according to any one of  claims 1  to  6  to a human or an animal in need thereof. 
     
     
       9. 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 pharmaceutically acceptable salt thereof, with a compound represented by Formula (3): 
       
       
         
           
           
               
               
           
         
         wherein R 1  is the same as defined above, or a salt thereof. 
       
     
     
       10. The compound or a pharmaceutically acceptable salt thereof according to  claim 6 , which is selected from the group consisting of the following compounds:
 N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-yl ethyl p-methylpicolinamide, 
 N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide,  
 N-[2-(3-cyclobutylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide, 
 N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, 
 N-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, 
 N-[2-(3-allyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, 
 N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]2-ethoxybenzamide, 
 N-[2-(3-cyclopropylmethoxy-4-d fluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, and 
 N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamine, 
 N-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, and  
 N-[2-(3-but-3-enyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide. 
 
     
     
       11. A compound which is N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, having the structure: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       12. A pharmaceutical composition comprising the compound according to claim 11 as an active ingredient and a pharmaceutically acceptable carrier.  
     
     
       13. A method for treating dermatosis, the method comprising administering the compound according to claim 11 to a human or an animal in need thereof.  
     
     
       14. A pharmaceutically acceptable salt of a compound, the compound being N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide and having the structure: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       15. A pharmaceutical composition comprising the pharmaceutically acceptable salt according to claim 14 as an active ingredient and a pharmaceutically acceptable carrier.  
     
     
       16. A method for treating dermatosis, the method comprising:
 administering the pharmaceutically acceptable salt according to claim 14 to a human or an animal in need thereof.