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 compound represented by formula (I) or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein (A) Ar represents a group represented by the following formula: 
       
       
         
           
           
               
               
           
         
         wherein R 1  represents a methyl group, R 2  represents an ethyl group or a C 4 -C 6  alkyl group, n represents 1 or 2, X each independently represents 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 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;
 (B) 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 X each 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; or (C) Ar represents a group represented by the following formula: 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are the same or different and represent a C 1 -C 6  alkyl group or a C 3 -C 6  cycloalkyl group, R 5  represents a hydrogen atom, and R 6  represents a halogen atom. 
       
     
     
         2 . The compound according to  claim 1  represented by formula (I-1) or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  represents a methyl group, R 2  represents an ethyl group or a C 4 -C 6  alkyl group, n represents 1 or 2, and X each independently represents 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 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. 
       
     
     
         3 . The compound according to  claim 2  represented by formula (I-2) or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  represents a methyl group, R 2  represents an ethyl group or a C 4 -C 6  alkyl group, R 3  represents a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano group, and R 4  represents 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 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. 
       
     
     
         4 . The compound according to  claim 2 , or a pharmacologically acceptable salt thereof, wherein R 2  represents an ethyl group. 
     
     
         5 . The compound according to  claim 3 , or a pharmacologically acceptable salt thereof, wherein R 3  represents a hydrogen atom, a fluorine atom or a cyano group. 
     
     
         6 . The compound according to  claim 3 , or a pharmacologically acceptable salt thereof, wherein R 4  represents a fluorine atom, a chlorine atom, a 2,2,2-trifluoroethyl group, a difluoromethoxy group or a trifluoromethoxy group. 
     
     
         7 . The compound according to  claim 1  represented by formula (I-5), 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, n represents 1 or 2, and X each 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. 
       
     
     
         8 . The compound according to  claim 7  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 hydrogen atom, a fluorine atom, a chlorine atom, or a cyano group, and R 4  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 R 4  does not represent a fluorine atom, a chlorine atom, or a cyano group when R 3  represents a hydrogen atom. 
       
     
     
         9 . The compound according to  claim 7 , 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. 
     
     
         10 . The compound according to  claim 7 , 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. 
     
     
         11 . The compound according to  claim 7 , or a pharmacologically acceptable salt thereof, wherein R 1  and R 2  both represent an ethyl group. 
     
     
         12 . The compound according to  claim 8 , or a pharmacologically acceptable salt thereof, wherein R 3  represents a hydrogen atom. 
     
     
         13 . The compound according to  claim 8 , 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. 
     
     
         14 . The compound according to  claim 1  represented by formula (I-7), or a pharmacologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are the same or different and represent a C 1 -C 6  alkyl group or a C 3 -C 6  cycloalkyl group, R 5  represents a hydrogen atom, and R 6  represents a halogen atom. 
       
     
     
         15 . The compound according to  claim 14 , or a pharmacologically acceptable salt thereof, wherein R 1  and R 2  both represent an ethyl group. 
     
     
         16 . The compound according to  claim 14 , or a pharmacologically acceptable salt thereof, wherein R 6  represents a chlorine atom. 
     
     
         17 . The compound according to  claim 1 , or a pharmacologically acceptable salt thereof, selected from the group consisting of: N-{[4-(difluoromethoxy)phenyl]carbamoyl}-D-isovaline, N-{[4-(2,2,2-trifluoroethyl)phenyl]carbamoyl}-D-isovaline, N-{[4-(difluoromethoxy)-3-fluorophenyl]carbamoyl}-D-isovaline, N-[(4-chlorophenyl)carbamoyl]-D-isovaline, 2-{[(5-chlorothiophen-3-yl)carbamoyl]amino}-2-ethylbutanoic acid, N-[(4-bromophenyl)carbamoyl]-D-isovaline, and N-[(4-iodophenyl)carbamoyl]-D-isovaline. 
     
     
         18 . The compound according to  claim 1 , or a pharmacologically acceptable salt thereof, selected from the group consisting of: N-{[4-(difluoromethoxy)phenyl]carbamoyl}-D-isovaline, N-{[4-(difluoromethoxy)-3-fluorophenyl]carbamoyl}-D-isovaline, N-[(4-chlorophenyl)carbamoyl]-D-isovaline, N-[(4-bromophenyl)carbamoyl]-D-isovaline, N-[(4-iodophenyl)carbamoyl]-D-isovaline, and 2-{[(5-chlorothiophen-3-yl)carbamoyl]amino}-2-ethylbutanoic acid. 
     
     
         19 . A pharmaceutical composition comprising, as an active ingredient, the compound according to  claim 1 , or a pharmacologically acceptable salt thereof. 
     
     
         20 . A crystal of the compound according to  claim 1 , selected from the group consisting of:
 a crystal of N-{[4-(difluoromethoxy)phenyl]carbamoyl}-D-isovaline having characteristic peaks at interplanar spacings d of 7.51, 7.33, 6.67, 6.15, 5.32, 5.24, 4.98, 4.79, 3.96 and 3.59 angstroms;   a crystal of N-{[4-(difluoromethoxy)-3-fluorophenyl]carbamoyl}-D-isovaline having characteristic peaks at interplanar spacings of 9.52, 6.10, 5.45, 5.29, 4.94, 4.89, 4.75, 3.80, 3.48 and 3.44 angstroms;   a crystal of N-[(4-chlorophenyl)carbamoyl]-D-isovaline having characteristic peaks at interplanar spacings of 15.60, 6.23, 5.68, 5.34, 5.20, 4.59, 4.53, 3.83, 3.37 and 3.15 angstroms;   a crystal of N-[(4-bromophenyl)carbamoyl]-D-isovaline having characteristic peaks at interplanar spacings of 15.82, 6.50, 6.25, 5.39, 4.67, 3.92, 3.86, 3.59, 3.39 and 3.16 angstroms;   a crystal of N-[(4-iodophenyl)carbamoyl]-D-isovaline having characteristic peaks at interplanar spacings of 16.92, 6.62, 4.99, 4.44, 4.30, 4.18, 3.30, 3.21, 3.07 and 3.02 angstroms; and   a crystal of 2-{[(5-chlorothiophen-3-yl)carbamoyl]amino}-2-ethylbutanoic acid having characteristic peaks at interplanar spacings of 15.82, 9.42, 6.53, 5.85, 5.48, 5.24, 4.69, 4.46, 3.58 and 3.12 angstroms, all in powder X-ray diffraction obtained through irradiation with copper KU line (wavelength λ=1.54 angstroms).   
     
     
         21 . A pharmaceutical composition comprising, as an active ingredient, any one of the crystals of the compound according to  claim 20 . 
     
     
         22 . A method for inhibiting tryptophanase in a mammal, comprising administering to a mammal an effective amount of a compound according to  claim 1 . 
     
     
         23 . The method of  claim 22 , wherein the compound, or a pharmacologically acceptable salt thereof, is selected from the group consisting of:
 N-{[4-(difluoromethoxy)phenyl]carbamoyl}-D-isovaline,   N-{[4-(2,2,2-trifluoroethyl)phenyl]carbamoyl}-D-isovaline,   N-{[4-(difluoromethoxy)-3-fluorophenyl]carbamoyl}-D-isovaline,   N-[(4-chlorophenyl)carbamoyl]-D-isovaline,   2-{[(5-chlorothiophen-3-yl)carbamoyl]amino}-2-ethylbutanoic acid,   N-[(4-bromophenyl)carbamoyl]-D-isovaline,   N-[(4-iodophenyl)carbamoyl]-D-isovaline,   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.   
     
     
         24 . The method of  claim 22 , wherein the mammal is a human. 
     
     
         25 . A method for reducing indoxyl sulfate in the blood of a mammal, comprising administering to a mammal an effective amount of a compound according to  claim 1 . 
     
     
         26 . The method of  claim 25 , wherein the compound, or a pharmacologically acceptable salt thereof, is selected from the group consisting of:
 N-{[4-(difluoromethoxy)phenyl]carbamoyl}-D-isovaline,   2-cyclopropyl-2-({[4-(difluoromethoxy)phenyl]carbamoyl}amino)butanoic acid,   N-{[4-(2,2,2-trifluoroethyl)phenyl]carbamoyl}-D-isovaline,   N-{[4-(difluoromethoxy)-3-fluorophenyl]carbamoyl}-D-isovaline,   N-[(4-chlorophenyl)carbamoyl]-D-isovaline,   2-{[(5-chlorothiophen-3-yl)carbamoyl]amino}-2-ethylbutanoic acid,   N-[(4-bromophenyl)carbamoyl]-D-isovaline,   N-[(4-iodophenyl)carbamoyl]-D-isovaline,   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.   
     
     
         27 . The method of  claim 25 , wherein the mammal is a human. 
     
     
         28 . A method for suppressing worsening of renal function in a mammal, comprising administering to a mammal an effective amount of a compound according to  claim 1 . 
     
     
         29 . The method of  claim 28 , wherein the compound, or a pharmacologically acceptable salt thereof, is selected from the group consisting of:
 N-{[4-(difluoromethoxy)phenyl]carbamoyl}-D-isovaline,   N-{[4-(2,2,2-trifluoroethyl)phenyl]carbamoyl}-D-isovaline,   N-{[4-(difluoromethoxy)-3-fluorophenyl]carbamoyl}-D-isovaline,   N-[(4-chlorophenyl)carbamoyl]-D-isovaline,   2-{[(5-chlorothiophen-3-yl)carbamoyl]amino}-2-ethylbutanoic acid,   N-[(4-bromophenyl)carbamoyl]-D-isovaline,   N-[(4-iodophenyl)carbamoyl]-D-isovaline,   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.   
     
     
         30 . The method of  claim 28 , wherein the mammal is a human. 
     
     
         31 . A method for treating a disease caused by increase of indoxyl sulfate in blood in a mammal, comprising administering to a mammal an effective amount of a compound according to  claim 1 . 
     
     
         32 . The method of  claim 31 , wherein the compound, or a pharmacologically acceptable salt thereof, is selected from the group consisting of:
 N-{[4-(difluoromethoxy)phenyl]carbamoyl}-D-isovaline,   N-{[4-(2,2,2-trifluoroethyl)phenyl]carbamoyl}-D-isovaline,   N-{[4-(difluoromethoxy)-3-fluorophenyl]carbamoyl}-D-isovaline,   N-[(4-chlorophenyl)carbamoyl]-D-isovaline,   2-{[(5-chlorothiophen-3-yl)carbamoyl]amino}-2-ethylbutanoic acid,   N-[(4-bromophenyl)carbamoyl]-D-isovaline,   N-[(4-iodophenyl)carbamoyl]-D-isovaline,   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.   
     
     
         33 . The method of  claim 31 , wherein the mammal is a human. 
     
     
         34 . A method for reducing indoxyl sulfate in blood in a mammal, comprising administering to a mammal an effective dose of a crystal according to  claim 20 . 
     
     
         35 . The method according to  claim 34 , wherein the mammal is a human. 
     
     
         36 . A method for inhibiting tryptophanase in a mammal, comprising administering to a mammal an effective amount of a crystal according to  claim 20 . 
     
     
         37 . The method according to  claim 36 , wherein the mammal is a human. 
     
     
         38 . A method for suppressing worsening of renal function in a mammal, comprising administering to a mammal an effective amount of a crystal according to  claim 20 . 
     
     
         39 . The method according to  claim 38 , wherein the mammal is a human. 
     
     
         40 . A method for treating a disease caused by increase of indoxyl sulfate in blood in a mammal, comprising administering to a mammal an effective amount of a crystal according to  claim 20 . 
     
     
         41 . The method according to  claim 40 , wherein the mammal is a human.