Urea derivative

Abstract

An object of the present invention is to find a novel pharmaceutical that has an excellent tryptophanase inhibitory effect and suppresses worsening of renal function to preserve the kidney by reducing production of indoxyl sulfate in the blood. The present invention provides a pharmaceutical composition containing, as an active ingredient, a compound represented by the following formula, or a pharmacologically acceptable salt thereof:wherein R1 and R2 are the same or different, and represent a C1-C6 alkyl group or the like, and Ar represents an optionally substituted phenyl group or an optionally substituted thienyl group.

1 . A pharmaceutical composition comprising, as an active ingredient, a compound represented by formula (I) or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are the same or different, and represent a C 2 -C 6  alkyl group; and Ar represents an optionally substituted phenyl group, the substituent being the same or different one to two substituents selected from a fluorine atom, a chlorine atom, a cyano group, a C 1 -C 6  alkyl group, a halogeno C 1 -C 6  alkyl group, a cyano C 1 -C 6  alkyl group, a C 3 -C 6  cycloalkyl group, a cyano C 3 -C 6  cycloalkyl group, a C 1 -C 6  alkoxy group, a halogeno C 1 -C 6  alkoxy group, a C 1 -C 6  alkylthio group, a halogeno C 1 -C 6  alkylthio group, a di(C 1 -C 3  alkyl)amino group, a saturated cyclic amino group, a halogeno saturated cyclic amino group, a phenyl group and a halogeno phenyl group. 
       
     
     
         2 . The pharmaceutical composition according to  claim 1 , comprising, as an active ingredient, a compound represented by formula (I) or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are the same or different, and represent a C2-C 6  alkyl group; and Ar represents an optionally substituted phenyl group, the substituent being the same or different one to two substituents selected from a fluorine atom, a chlorine atom, a cyano group, a halogeno C 1 -C 6  alkyl group, a cyano C 1 -C 6  alkyl group, a cyano C3-C 6  cycloalkyl group, a halogeno C 1 -C 6  alkoxy group, a halogeno C 1 -C 6  alkylthio group, a saturated cyclic amino group, a halogeno saturated cyclic amino group, a phenyl group and a halogeno phenyl group. 
       
     
     
         3 . A compound represented by formula (I) or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         Ar represents a group represented by the following formula: 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are the same or different and represent a C 2 -C 6  alkyl group, n represents 1 or 2, and each X independently represents a fluorine atom, a chlorine atom, a cyano group, a halogeno C 1 -C 6  alkyl group, a cyano C 2 -C 6  alkyl group, a cyano C 3 -C 6  cycloalkyl group, a halogeno C 1 -C 6  alkoxy group, a halogeno C 1 -C 6  alkylthio group, a saturated cyclic amino group, a halogeno saturated cyclic amino group, a phenyl group or a halogeno phenyl group, provided that X does not represent a halogen atom or a cyano group when n represents 1. 
       
     
     
         4 . The compound according to  claim 3  represented by formula (I-6), or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are the same or different and represent a C 2 -C 6  alkyl group, R 3  represents a fluorine atom, a chlorine atom, a halogen atom or a cyano group, and R 4  represents a halogen atom, a cyano group, a halogeno C 1 -C 6  alkyl group, a cyano C 2 -C 6  alkyl group, a cyano C 3 -C 6  cycloalkyl group, a halogeno C 1 -C 6  alkoxy group, a halogeno C 1 -C 6  alkylthio group, a saturated cyclic amino group, a halogeno saturated cyclic amino group, a phenyl group or a halogeno phenyl group, provided that R 4  does not represent a halogen atom or a cyano group when R 3  represents a hydrogen atom. 
       
     
     
         5 . The compound according to  claim 3 , or a pharmacologically acceptable salt thereof, wherein R 1  and R 2  are the same or different and represent an ethyl group, a propyl group or an isopropyl group. 
     
     
         6 . The compound according to  claim 3 , or a pharmacologically acceptable salt thereof, wherein R 1  and R 2  represent a combination of an ethyl group and an ethyl group, or an ethyl group and a propyl group. 
     
     
         7 . The compound according to  claim 3 , or a pharmacologically acceptable salt thereof, wherein R 1  and R 2  both represent an ethyl group. 
     
     
         8 . The compound according to  claim 4 , or a pharmacologically acceptable salt thereof, wherein R 3  represents a hydrogen atom. 
     
     
         9 . The compound according to  claim 4 , or a pharmacologically acceptable salt thereof, wherein R 4  represents a trifluoromethyl group, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a trifluoromethylthio group, a phenyl group or a 2-fluorophenyl group. 
     
     
         10 . A pharmaceutical composition comprising, as an active ingredient, the compound according to  claim 3 , or a pharmacologically acceptable salt thereof. 
     
     
         11 . The pharmaceutical composition according to  claim 1 , comprising, as an active ingredient, a compound selected from the group consisting of:
 2-ethyl-2-[(phenylcarbamoyl)amino]butanoic acid,   2-{[3-(chlorophenyl)carbamoyl]amino}-2-ethylbutanoic acid,   2-{[4-(chlorophenyl)carbamoyl]amino}-2-ethylbutanoic acid,   2-ethyl-2-{[(4-fluorophenyl)carbamoyl]amino}butanoic acid,   2-ethyl-2-{[(3-fluorophenyl)carbamoyl]amino}butanoic acid,   2-{[(3-cyanophenyl)carbamoyl]amino}-2-ethylbutanoic acid,   2-({[4-(cyanomethyl)phenyl]carbamoyl}amino)-2-ethylbutanoic acid, and   2-ethyl-2-[(thiophen-3-ylcarbamoyl)amino]butanoic acid,   or a pharmacologically acceptable salt thereof.   
     
     
         12 . A method for reducing indoxyl sulfate in the blood, comprising administering to a mammal, an effective dose of the compound according to  claim 3  or a pharmacologically acceptable salt thereof. 
     
     
         13 . The method according to  claim 12 , wherein the mammal is a human. 
     
     
         14 . A method for preventing or treating a disease, comprising administering to a mammal, an effective dose of the compound according to  claim 3  or a pharmacologically acceptable salt thereof. 
     
     
         15 . The method according to  claim 14 , wherein the mammal is a human. 
     
     
         16 . The method according to  claim 14 , wherein the disease is a disease caused by an increase in indoxyl sulfate in the blood. 
     
     
         17 . A method for delaying transition to renal replacement therapy in a patient in a period of conservative treatment of chronic kidney disease, comprising administering to a patient, an effective dose of the compound according to  claim 3  or a pharmacologically acceptable salt thereof. 
     
     
         18 . The method according to  claim 17 , wherein the patient is a human. 
     
     
         19 . A method for suppressing worsening of remaining renal function in a patient after transition to renal replacement therapy, comprising administering to a patient, an effective dose of the compound according to  claim 3  or a pharmacologically acceptable salt thereof. 
     
     
         20 . The method according to  claim 19 , wherein the patient is a human. 
     
     
         21 . A method for inhibiting tryptophanase in a patient, comprising administering to a patient, an effective dose of the compound according to  claim 3  or a pharmacologically acceptable salt thereof. 
     
     
         22 . The method according to  claim 21 , wherein the patient is a human.