Pyridine derivative

Abstract

Provided is a pyridine derivative represented by formula (I), a prodrug thereof, a pharmaceutically acceptable salt of the pyridine derivative or the prodrug, or a solvate of the pyridine derivative, the prodrug or the pharmaceutically acceptable salt, which is useful for treatment or prophylaxis of diseases associated with URAT1 such as gout, hyperuricemia, hypertension, kidney diseases such as interstitial nephritis, diabetes, arteriosclerosis and Lesch-Nyhan syndrome.

1 - 23 . (canceled) 
     
     
         24 . A method for inhibiting URAT1, comprising administering to a subject an effective amount of a pyridine derivative represented by the following formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         A represents a single bond, an oxygen atom, a sulfur atom, NH, or CH 2 ; 
         R 1  represents a nitrogen atom or CH; one of X 1  to X 5  represents a nitrogen atom and the remaining four represent CR 2 ; 
         R 2  each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, a halogen atom, a trifluoromethyl group, a difluoromethyl group, a cyano group, an alkylcarbonyl group having 2 to 7 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, a nitro group, an amino group, a dialkylamino group having 1 to 6 carbon atoms which may optionally form a ring, a formyl group, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (which may optionally be substituted with one or more of a hydroxyl group, a phenyl group, a cyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6 carbon atoms, a phenyl group (which may optionally be substituted with one or more of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom), or a phenoxy group (which may optionally be substituted with one or more of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom), with the proviso that when two CR 2 's are adjacent, the two R 2 's may optionally be joined together to form a ring; 
         R 3  represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (which may optionally be substituted with one or more of a hydroxyl group, an amino group, a dialkylamino group having 1 to 6 carbon atoms which may optionally form a ring, an imidazole ring, a pyrazole ring, a pyrrolidine ring, a piperidine ring, a morpholine ring, and a piperazine ring (which may optionally be substituted with one or more of an alkyl group having 1 to 6 carbon atoms and an alkylsulfonyl group having 1 to 6 carbon atoms)), an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms (which may optionally be substituted with one or more of a hydroxyl group and a halogen atom), an alkylcarbonyl group having 2 to 7 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an alkylsulfinyl group having 1 to 6 carbon atoms, a halogen atom, a trifluoromethyl group, a difluoromethyl group, a cyano group, a phenyl group (which may optionally be substituted with one or more of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom), a pyridyl group (which may optionally be substituted with one or more of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom), a phenoxy group (which may optionally be substituted with one or more of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom), a carboxyl group, or —CO 2 R 5 ; 
         R 4  represents a carboxyl group, a tetrazolyl group, —CONHSO 2 R 5 , —CO 2 R 5 , or any of the following substituents: 
       
       
         
           
           
               
               
           
         
         with the proviso that when R 3  is an alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group and when R 4  is a carboxyl group, then R 3  and R 4  may optionally be fused to form a lactone ring; 
         R 5  in R 3  and R 4  each independently represents an alkyl group having 1 to 6 carbon atoms; 
         Z represents any of the following substituents designated Z1 to Z7: 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 6  and R 7  each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group, or a cyano group, with the proviso that the case where R 6  and R 7  are simultaneously hydrogen atoms is excluded; 
         R 8  represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 9  represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 10  represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 11  and R 12  each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 13  and R 14  each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 15  represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         Y represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and 
         W represents a sulfur atom, an oxygen atom, or NR 16  (where R 16  represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group) 
         or the pharmaceutically acceptable salt thereof. 
       
     
     
         25 . A method for treatment or prevention of one or more diseases selected from the group consisting of gout, hyperuricemia, hypertension, renal diseases such as interstitial nephritis and the like, diabetes, arteriosclerosis, and Lesch-Nyhan syndrome, comprising administering to a subject an effective amount of a pyridine derivative represented by the following formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         A represents a single bond, an oxygen atom, a sulfur atom, NH, or CH 2 ; 
         R 1  represents a nitrogen atom or CH; one of X 1  to X 5  represents a nitrogen atom and the remaining four represent CR 2 ; 
         R 2  each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, a halogen atom, a trifluoromethyl group, a difluoromethyl group, a cyano group, an alkylcarbonyl group having 2 to 7 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, a nitro group, an amino group, a dialkylamino group having 1 to 6 carbon atoms which may optionally form a ring, a formyl group, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms (which may optionally be substituted with one or more of a hydroxyl group, a phenyl group, a cyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6 carbon atoms, a phenyl group (which may optionally be substituted with one or more of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom), or a phenoxy group (which may optionally be substituted with one or more of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom), with the proviso that when two CR 2 's are adjacent, the two R 2 's may optionally be joined together to form a ring; 
         R 3  represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (which may optionally be substituted with one or more of a hydroxyl group, an amino group, a dialkylamino group having 1 to 6 carbon atoms which may optionally form a ring, an imidazole ring, a pyrazole ring, a pyrrolidine ring, a piperidine ring, a morpholine ring, and a piperazine ring (which may optionally be substituted with one or more of an alkyl group having 1 to 6 carbon atoms and an alkylsulfonyl group having 1 to 6 carbon atoms)), an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms (which may optionally be substituted with one or more of a hydroxyl group and a halogen atom), an alkylcarbonyl group having 2 to 7 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an alkylsulfinyl group having 1 to 6 carbon atoms, a halogen atom, a trifluoromethyl group, a difluoromethyl group, a cyano group, a phenyl group (which may optionally be substituted with one or more of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom), a pyridyl group (which may optionally be substituted with one or more of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom), a phenoxy group (which may optionally be substituted with one or more of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom), a carboxyl group, or —CO 2 R 5 ; 
         R 4  represents a carboxyl group, a tetrazolyl group, —CONHSO 2 R 5 , —CO 2 R 5 , or any of the following substituents: 
       
       
         
           
           
               
               
           
         
         with the proviso that when R 3  is an alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group and when R 4  is a carboxyl group, then R 3  and R 4  may optionally be fused to form a lactone ring; 
         R 5  in R 3  and R 4  each independently represents an alkyl group having 1 to 6 carbon atoms; 
         Z represents any of the following substituents designated Z1 to Z7: 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 6  and R 7  each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group, or a cyano group, with the proviso that the case where R 6  and R 7  are simultaneously hydrogen atoms is excluded; 
         R 8  represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 9  represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 10  represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 11  and R 12  each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 13  and R 14  each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 15  represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         Y represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and 
         W represents a sulfur atom, an oxygen atom, or NR 16  (where R 16  represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group) 
         or the pharmaceutically acceptable salt thereof. 
       
     
     
         26 . A compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof, or a solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents a nitrogen atom; 
         R 3  represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; 
         R 17  represents a chlorine atom, a bromine atom, or an iodine atom; 
         R 18  represents a formyl group or —CO 2 R 5 ; 
         R 5  represents an alkyl group having 1 to 6 carbon atoms; and 
         Z represents any of the following substituents designated Z1 to Z7: 
       
       
         
           
           
               
               
           
         
         wherein 
         R 6  and R 7  each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group, or a cyano group, with the proviso that the case where R 6  and R 7  are simultaneously hydrogen atoms is excluded; 
         R 8  represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 9  represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 10  represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 11  and R 12  each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 13  and R 14  each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         R 15  represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; 
         Y represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and 
         W represents a sulfur atom, an oxygen atom, or NR 16  (where R 16  represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group). 
       
     
     
         27 . A compound represented by the following formula (III) or a pharmaceutically acceptable salt thereof, or a solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 3  represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; 
         R 19  represents —CO 2 R 5 ; 
         R 5  represents an alkyl group having 1 to 6 carbon atoms; and 
         Za represents a 2,5-dichlorobenzyl group, a 3,5-dichlorobenzyl group, a 2,5-dimethylbenzyl group, a 2,5-bis(trifluoromethyl)benzyl group, a 2-chloro-5-methylbenzyl group, a naphthalen-1-ylmethyl group, a (2-methylnaphthalen-1-yl)methyl group, a (4-methylnaphthalen-1-yl)methyl group, a (8-methylnaphthalen-1-yl)methyl group, a (8-bromonaphthalen-1-yl)methyl group, a benzo[b]thiophen-3-ylmethyl group, a (4-methylbenzo[b]thiophen-3-yl)methyl group, a (4-chlorobenzo[b]thiophen-3-yl)methyl group, a (4-bromobenzo[b]thiophen-3-yl)methyl group, a (4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, a (5-methylbenzo[b]thiophen-3-yl)methyl group, a (5-chlorobenzo[b]thiophen-3-yl)methyl group, a (5-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, a benzo[b]thiophen-7-ylmethyl group, a (5-fluorobenzo[b]thiophen-7-yl)methyl group, a (2,5-dichlorothiophen-3-yl)methyl group, a (2,4-dichlorothiophen-5-yl)methyl group, or a quinolin-8-ylmethyl group.