Triazole antifungal agent

Abstract

A compound having the formula: [wherein Ar 1 represents a phenyl which may be substituted, Ar 2 represents a phenyl which may be substituted or a heterocyclic group which may be substituted, R 0 represents a hydrogen atom or a lower alkyl; R 1 represents a lower alkyl; R 2 to R 5 represent a hydrogen atom or an alkyl which may be substituted with halogen, n represents 0 to 2; p represents 0 or 1; q, r and s represent 0 to 2; A represents a 4- to 7-membered carbon ring or a 4- to 7-membered heterocyclic group]. The compound of the present invention exhibits excellent antifungal activities.

1 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein Ar 1  represents a phenyl group or a phenyl group having 1 to 3 substituent(s) (said substituent(s) represent(s) a halogen atom or a trifluoromethyl group); 
 Ar 2  represents phenyl, a 5- or 6-membered aromatic heterocyclic group (said aromatic heterocyclic group has at least one nitrogen, oxygen or sulfur atom) or a phenyl group or a 5- to 6-membered aromatic heterocyclic group having 1 to 3 substituent(s) (said substituent(s) represent(s) a lower alkyl group, a lower alkoxy group, a halogen atom, a lower alkyl group substituted with a halogen atom or halogen atoms, a lower alkoxy group substituted with a halogen atom or halogen atoms, a nitro group, a cyano group, a —S(O) m R 6  group (R 6  represents a lower alkyl group which may be substituted with a halogen atom or halogen atoms and m represents 0, 1 or 2) or a —NHCOR 7  group (R 7  represents a lower alkyl group) and said aromatic heterocyclic group has at least one nitrogen, oxygen or sulfur atom);  
 R O  represents a hydrogen atom or a lower alkyl group;  
 R 1  represents a lower alkyl group;  
 R 2 , R 3 , R 4  and R 5  may be the same or different and represent a hydrogen atom, a lower alkyl group or a lower alkyl group substituted with a halogen atom or halogen atoms and, where q and/or s represent 2, each of R 2 , R 3 , R 4  and R 5  represents independently a group which is the same or different from the other R 2 , R 3 , R 4  and R 5  respectively;  
 n represents 0, 1 or 2;  
 p represents 0 or 1;  
 q, r and s represent 0, 1 or 2; and  
 A represents a 4- to 7-membered aliphatic carbocyclic group comprising 4 to 7 carbon atoms or a 4- to 7-membered aliphatic heterocyclic group having at least one nitrogen, oxygen or sulfur atom,  
 or a pharmacologically acceptable salt thereof.  
 
     
     
         2 . A triazole compound or a pharmacologically acceptable salt thereof according to    claim 1   , wherein Ar 1  is a phenyl group having 1 to 3 substituent(s) (said substituent(s) represent(s) a halogen atom or a trifluoromethyl group).  
     
     
         3 . A triazole compound or a pharmacologically acceptable salt thereof according to    claim 1   , wherein Ar 1  is a phenyl group having 1 or 2 substituent(s) (said substituent(s) represent(s) a fluorine atom, a chlorine atom or a trifluoromethyl group).  
     
     
         4 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    3   , wherein Ar 2  represents a phenyl group, a 5- or 6-membered aromatic heterocyclic group (said aromatic heterocyclic group has at least one nitrogen, oxygen or sulfur atom) or a phenyl group or a 5- or 6-membered aromatic heterocyclic group having 1 to 3 substituent(s) (said substituent(s) represent(s) a lower alkyl group, a halogen atom, a lower alkyl group substituted with a halogen atom or halogen atoms, a lower alkoxy group substituted with a halogen atom or halogen atoms, a nitro group, a cyano group or a —S(O) m R 6  group (R 6  represents a lower alkyl group which may be substituted with a halogen atom or halogen atoms and m represents 0, 1 or 2) and said aromatic heterocyclic group has at least one nitrogen, oxygen or sulfur atom).  
     
     
         5 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    3   , wherein Ar 2  represents a phenyl group, a 5- or 6-membered aromatic heterocyclic group (said aromatic heterocycdic group has one nitrogen, oxygen or sulfur atom) or a phenyl group or a 5- to 6-membered aromatic heterocyclic group having 1 to 3 substituent(s) (said substituent(s) represents() a lower alkyl group, a halogen atom, a lower alkyl group substituted with a halogen atom or halogen atoms, a lower alkoxy group substituted with a halogen atom or halogen atoms, a nitro group, a cyano group or a —S(O) m R 6  group (R 6  represents a lower alkyl group which may be substituted with a halogen atom or halogen atoms and m represents 0, 1 or 2) and said aromatic heterocyclic group has one nitrogen, oxygen or sulfur atom).  
     
     
         6 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    3   , wherein Ar 2  represents a phenyl group, a 5- or 6-membered aromatic heterocyclic group (said aromatic heterocyclic group has one nitrogen or sulfur atom) or a phenyl group or a 5- or 6-membered aromatic heterocyclic group having 1 or 2 substituent(s) (said substituent(s) represent(s) a lower alkyl group, a halogen atom, a lower alkyl group substituted with a halogen atom or halogen atoms, a lower alkoxy group substituted with a halogen atom or halogen atoms, a nitro group, a cyano group or a —S(O) m R 6  group (R 6  represents a lower alkyl group which may be substituted with a halogen atom or halogen atoms and m represents 0, 1 or 2) and said aromatic heterocyclic group has one nitrogen or sulfur atom).  
     
     
         7 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    3   , wherein Ar 2  represents a phenyl group or a pyridyl group or a phenyl group, a pyridyl group or a thienyl group having 1 or 2 substituent(s) (said substituent(s) represent(s) a lower alkyl group, a halogen atom, a lower alkyl group substituted with a halogen atom or halogen atoms, a lower alkoxy group substituted with a halogen atom or halogen atoms, a nitro group, a cyano group or a —S(O) m R 6  group (R 6  represents a lower alkyl group which may be substituted with a halogen atom or halogen atoms and m represents 0, 1 or 2).  
     
     
         8 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    7   , wherein R 0  is a hydrogen atom, a methyl group, an ethyl group or a propyl group.  
     
     
         9 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    7   , wherein R 0  is a hydrogen atom, a methyl group or an ethyl group.  
     
     
         10 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    7   , wherein R 0  is a hydrgen atom or a methyl group.  
     
     
         11 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    10   , wherein R 1  is a methyl group, an ethyl group or a propyl group.  
     
     
         12 . A triazole compund or a pharmacologically acceptable salt thereof according to    claims 1    to    10   , wherein R 1  is a methyl group or an ethyl group.  
     
     
         13 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    10   , wherein R 1  is a methyl group.  
     
     
         14 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    13   , wherein R 2 , R 3 , R 4  and R 5  may be the same or different and are a hydrogen atom, a lower alkyl group or a lower alkyl group substituted with a fluorine or chlorine atom or atoms.  
     
     
         15 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    13   , wherein R 2 , R 3 , R 4  and R 5  may be the same or different and are a hydrogen atom, a methyl group, an ethyl group or a propyl group or a methyl group, an ethyl group or a propyl group substituted with a fluorine or chlorine atom or atoms.  
     
     
         16 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    13   , wherein R 2 , R 3 , R 4  and R 5  may be the same or different and are a hydrogen atom, a methyl group or an ethyl group or a methyl group or an ethyl group substituted with a fluorine or chlorine atom or atoms.  
     
     
         17 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    13   , wherein R 2 , R 3 , R 4  and R 5  may be the same or different and are a hydrogen atom or a methyl group or a methyl group substituted with a fluorine or chlorine atom or atoms.  
     
     
         18 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 2    to    17   , wherein n is 0, 1 or 2.  
     
     
         19 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    17   , wherein n is 0.  
     
     
         20 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 2    to    19   , wherein p is 0 or 1.  
     
     
         21 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 2    to    20   , wherein q, r and s are 0, 1 or 2.  
     
     
         22 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    21   , wherein A is a 5- or 6-membered aliphatic carbocyclic group comprising 5 or 6 carbon atoms or a 4- to 6-membered aliphatic heterocyclic group having at least one nitrogen, oxygen or sulfur atom.  
     
     
         23 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    21   , wherein A is a 5- or 6-membered aliphatic carbocyclic group comprising 5 or 6 carbon atoms or a 4- to 6-membered aliphatic heterocyclic group having 1 or 2 nitrogen, oxygen or sulfur atom(s).  
     
     
         24 . A triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    21   , wherein A is cyclohexane, piperidine, 1,3-dioxane or 1,3-dithiane ring.  
     
     
         25 . 2-(2,4-Difluorophenyl)-3-[[2-[2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-1-(1 H-1,2,4-triazol-1-yl)-2-butanol,  
       2-(2, 4-difluorophenyl)-1-(1 H-1,2,4-triazol-1-yl)-3-[[2-[2-[4-(trifluoromethoxy)phenyl]vinyl]-1,3-dioxan-5-yl]thio]-2-butanol, 2-(2,4-difluorophenyl)-1-(1 H-1,2,4-triazol-1-yl)-3-[[2-[4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol,  
       2-(2,4-difluorophenyl)-1-(1 H-1,2,4-triazol-1-yl)-3-[[2-[4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol,  
       2-(2,4-difluorophenyl)-3-([[2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(1 H-1,2,4-triazol-1-yl)-2-butanol,  
       2-(2,4-difluorophenyl)-3-[[2-[4-[4-(chlorophenyl)-4,4,4-trifluoro-1,3-pentadien-1-yl]-1,3-dioxan-1-yl]thio]-1-(1 H-1,2,4-triazol-1-yl)-2-butanol,  
       2-(2,4-difluorophenyl)-3-[[1-[4-(trifluoromethoxy)cinnamoyl]piperidin-4-yl]thio]-1-(1 H-1,2,4-triazol-1-yl)-2-butanol,  
       2-(2,4-difluorophenyl)-3- [[1-[4-nitrocinnamoyl]piperidin-4-yl]thio]-1-(1 H-1,2,4-triazol-1-yl)-2-butanol,  
       2-(2,4-difluorophenyl)-1-(1 H-1,2,4-triazol-1-yl)-3-[[1-[5-[4-(trifluoromethoxy)phenyl]-2,4-pentadienoyl]piperidin-4-yl]thio]-2-butanol,  
       3-methyl-1-(1 H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-3-[[2-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol,  
       2-(2,4-difluorophenyl)-1-(1 H-1,2,4-triazol-1-yl)-3-[[2-[4-(trifluoromethylthio)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol,  
       3-[[2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(1 H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-2-butanol,  
       1-(1 H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-3-[[2-[4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol,  
       2-(2,4-difluorophenyl)-1-(1 H-1,2,4-triazol-1-yl)-3-[[2-[4-[4-(trifluoromethylsulfinyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol,  
       2-(2,4-difluorophenyl)-1-(1 H-1,2,4-triazol-1-yl)-3-[[4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-cyclohexyl]thio]-2-butanol,  
       2-(2,4-difluorophenyl)-1-(1 H-1,2,4-triazol-1-yl)-3-[[2-[6-[4-(trifluoromethyl)phenyl]-1,3,5-hexatrien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol,  
       2-(2,4-difluorophenyl)-3-methyl-1-(1 H-1,2,4-triazol-1-yl)-3-[[2-[4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol or  
       2-(2,4-difluorophenyl)-1-(1 H-1,2,4-triazol-1-yl)-3-[[2-[4-[4-(trifluoromethyl)phenyl]-1-buten-3-yn-1-yl]-1,3-dioxan-5-yl]thio]-2-butanol,  
       or a pharmacologically acceptable salt thereof.  
     
     
         26 . An antifungal agent containing the triazole compound or a pharmacologically acceptable salt thereof according to    claims 1    to    25    as an active ingredient.