Substituted phenoxyacetic acids

Abstract

Disclosed are substituted phenoxyacetic acids useful in the treatment of chronic complications arising from diabetes mellitus. Also disclosed are pharmaceutical compositions containing the compounds, alone or in combination with other therapeutic agents, and methods of treatment employing the compounds and pharmaceutical compositions, as well as methods for their synthesis.

We claim:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof wherein 
 A is a covalent bond, C 1 -C 4  alkylene group optionally substituted with C 1 -C 2  alkyl or mono- or disubstituted with halogen, preferably fluoro or chloro;  
 X is oxygen, sulfur or NR 6 , wherein each R 6  is hydrogen, cyano or an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens);  
 R 1 , R 2 , R 3  and R 4  are each independently 
 hydrogen, halogen, or nitro, or an alkyl group of 1-6 carbon atoms optionally substituted with one or more halogens;  
 OR 7 , SR 7 , S(O)R 7 , S(O) 2 R 7 , C(O)N(R 7 ) 2 , or N(R 7 ) 2 , wherein each R 7  is independently hydrogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens) or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino;  
 phenyl or heteroaryl each of which phenyl or heteroaryl is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino;  
 phenoxy where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino; or  
 a group of the formula  
                     
  where  
 J is a bond, CH 2 , oxygen, or nitrogen; and  
 each r is independently 2 or 3;  
 
 R 5  is hydroxy or a prodrug group; and  
 Ar represents aryl or heteroaryl, each of which is optionally substituted with up to five groups.  
 
     
     
         2 . A compound according to  claim 1 , wherein 
 Ar is optionally substituted benzothiazolyl, benzoxazolyl, isoquinolyl, benzothiophen-yl, benzofuran-yl or benzimidazolyl, or substituted oxadiazolyl or indolyl.    
     
     
         3 . A compound according to  claim 1 , wherein A is a covalent bond or CH 2 ; R 5  is hydroxy; and each of R 1 -R 4  are independently hydrogen, halogen, more preferably bromo, chloro or fluoro, C 1 -C 2  alkyl, phenoxy, benzyloxy, or C 1 -C 2  alkoxy.  
     
     
         4 . A compound accoriding to  claim 2 , wherein A is a covalent bond or CH 2 ; R 5  is hydroxy; and each of R 1 -R 4  are independently hydrogen, halogen, C 1 -C 2  alkyl, phenoxy, benzyloxy, or C 1 -C 2  alkoxy.  
     
     
         5 . A compound according to  claim 2 , wherein R 1  and R 4  are hydrogen, methyl or ethyl; and R 2  and R 3  are independently hydrogen, bromo, chloro, fluoro, C 1 -C 2  alkyl, phenoxy, benzyloxy, C 1 -C 2  alkoxy, amino, mono or di(C 1 -C 3  alkyl)amino, morpholinyl, piperidin-1-yl, or piperazin-1-yl.  
     
     
         6 . A compound according to  claim 5 , wherein at least one of R 2  and R 3  is hydrogen, and both R 1  and R 4  are hydrogen.  
     
     
         7 . A compound according to  claim 1 , wherein 
 A is methylene;    R 5  is hydroxy;    Ar is optionally substituted benzothiazol-2-yl, benzothiazol-5-yl, benzoisothiazol-3-yl, benzoxazol-2-yl, 2-quinolyl, 2-quinoxalyl, oxazolo[4,5-b]pyridine-2-yl, benzothiophen-2-yl, benzofuran-2-yl, or thazolo[4,5-pyridine-2-y, thieno[2,3-b]pyridine2-yl, imidazo[1,5-a]pyridine-2-yl, or indol-2-yl, or substituted 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, isothiazol-5-yl, isothiazol-4-yl, 1,3,4-oxadiazol-5-yl, 1,2,5-thiadiazol-3-yl, oxazol-2-yl, thiazol-2-yl, or thiazol-4-yl; and    R 1 -R 4  are independently hydrogen, halogen, more preferably bromo, chloro or fluoro, C 1 -C 2  alkyl, phenoxy, benzyloxy or phenyl where each phenyl portion is optionally substituted with C 1 -C 6  alkyl, halogen, C 1 -C 6  alkoxy, hydroxy, amino or mono- or di(C 1 -C 6 )alkylamino.    
     
     
         8 . A compound according to  claim 2 , wherein R 1  and R 4  are hydrogen, methyl or ethyl; and R 2  and R 3  are independently hydrogen, bromo, chloro, fluoro, C 1 -C 2  alkyl, phenoxy, benzyloxy, C 1 -C 2  alkoxy, amino, mono or di(C 1 -C 3  alkyl)amino, morpholinyl, piperidin-1-yl, or piperazin-1-yl.  
     
     
         9 . A compound according to  claim 1 , wherein 
 A is methylene;    R 5  is hydroxy;    Ar is an optionally 4,5,6 or 7-substituted benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, or indolyl, or    Ar is 2-benzothiazolyl substituted on benzo by one trifluoroacetyl or trifluoromethylthio, or one or two of fluoro chloro, bromo, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, or one or, preferably, two fluoro and one trifluoromethyl, or two fluoro or two trifluoromethyl with one methoxy, or three fluoro, or by 6,7-benzo.    
     
     
         10 . A compound according to  claim 7 , wherein both R 1  and R 4  are hydrogen or C 1 -C 3  alkyl.  
     
     
         11 . A compound according to  claim 10 , wherein at least one of R 2  and R 3  is hydrogen, and both R 1  and R 4  are hydrogen.  
     
     
         12 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein 
 A is a C 1 -C 4  alkylene group optionally substituted with C 1 -C 2  alkyl;  
 X is oxygen, sulfur or NR 6 , wherein each R 6  is hydrogen, cyano or an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens);  
 R 1 , R 2 , R 3  and R 4  are each independently 
 hydrogen, halogen, an alkyl group of 1-6 carbon atoms optionally substituted with one or more halogens, nitro, OR 7 , SR 7 , S(O)R 7 , S(O) 2 NR 7 , C(O)N(R 7 ) 2 , or N(R 7 ) 2 , wherein each R 7  is independently hydrogen, an alkyl group of 1-6 carbon atoms optionally substituted with one or more halogens or benzyl where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino;  
 phenyl or heteroaryl such as 2-, 3- or 4-imidazolyl or 2-, 3-, or 4-pyridyl, each of which phenyl or heteroaryl is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino;  
 phenoxy where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino; or  
 a group of the formula  
                     
  where  
 J is a bond, CH 2 , oxygen, or nitrogen; and  
 each r is independently 2, or 3;  
 
 R 5  is hydroxy, an alkoxy group of 1-6 carbon atoms, or —O-M+ where M+ is a cation forming a pharmaceutically acceptable salt; and  
 R 8 , R 9 , R 10 , R 11  and R 12  in combination, represent hydrogen, or 1-3 groups selected from fluorine, chlorine, bromine, trifluoromethyl or nitro.  
 
     
     
         13 . A compound according to  claim 12 , wherein R 1  and R 4  are hydrogen, methyl or ethyl; and R 2  and R 3  are independently hydrogen, bromo, chloro, fluoro, C 1 -C 2  alkyl, phenoxy, benzyloxy, C 1 -C 2  alkoxy, amino, mono or di(C 1 -C 3  alkyl)amino, morpholinyl, piperidin-1-yl, or piperazin-1-yl.  
     
     
         14 . A compound according to  claim 13 , wherein R 8 -R 12  represent one trifluoroacetyl or trifluoromethylthio, or one or two of fluoro chloro, bromo, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, or one or, preferably, two fluoro and one trifluoromethyl, or two fluoro or two trifluoromethyl with one methoxy, or three fluoro.  
     
     
         15 . A compound according to  claim 12 , wherein R 1  and R 4  are hydrogen, methyl or ethyl; and R 2  and R 3  are independently hydrogen, bromo, chloro, fluoro, C 1 -C 2  alkyl, phenoxy, benzyloxy, C 1 -C 2  alkoxy, amino, mono or di(C 1 -C 3  alkyl)amino, morpholinyl, piperidin-1-yl, or piperazin-1-yl.  
     
     
         16 . A compound according to  claim 15 , wherein both R 1  and R 4  are hydrogen or C 1 -C 3  alkyl.  
     
     
         17 . A compound according to  claim 16 , wherein at least one of R 2  and R 3  is hydrogen, and both R 1  and R 4  are hydrogen.  
     
     
         18 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein 
 A is a covalent bond, C 1 -C 4  alkylene group optionally substituted with C 1 -C 2  alkyl;  
 X is oxygen, sulfur or NR 6 , wherein each R 6  is hydrogen, cyano or an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens);  
 R 1 , R 2 , R 3  and R 4  are each independently hydrogen, halogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens), nitro, OR 7 , SR 7 , S(O)R 7 , S(O) 2 NR 7  C(O)N(R 7 ) 2  or N(R 7 ) 2 , wherein each R 7  is independently hydrogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens) or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino; 
 phenyl or heteroaryl such as 2-, 3- or 4-imidazolyl or 2-, 3-, or 4-pyridyl, each of which phenyl or heteroaryl is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino;  
 phenoxy where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino; or  
 a group of the formula  
                     
  where  
 J is a bond, CH 2 , oxygen, or nitrogen; and  
 each r is independently 2 or 3;  
 
 R 5  is hydroxy, C 1 -C 6  alkoxy, or —O − M +  where M +  is a cation forming a pharmaceutically acceptable salt; and  
 R 13 , R 14 , R 15  and R 16  are independently hydrogen, halogen, nitro, hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, trifluoromethyl, trifluoromethoxy, C 1 -C 6  alkylsulfinyl, or C 1 -C 6  alkylsulfonyl.  
 
     
     
         19 . A compound according to  claim 18 , wherein R 13 , R 14 , R 15  and R 16 , in combination, represent one of bromo, cyano or nitro, one or two of fluoro, chloro, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or trifluoromethyl, or two fluoro or two methyl with one hydroxy or one (C 1 -C 6 )alkoxy, or two fluoro and one methyl, or three fluoro groups.  
     
     
         20 . A compound according to  claim 18 , wherein R 13 , R 14 , R 15  and R 16  independently represent fluorine, chlorine, nitro, and trifluoromethyl.  
     
     
         21 . A compound according to  claim 19 , wherein A is methylene, methylene substituted with a methyl group, or ethylene.  
     
     
         22 . A compound according to  claim 21 , wherein R 13 , R 14 , R 15  and R 16  independently represent nitro, one, two, or three of fluoro, one or two of chloro, or one trifluoromethyl group.  
     
     
         23 . A compound according to  claim 22 , wherein A is methylene, and R 5  is hydroxy or C 1 -C 6  alkoxy.  
     
     
         24 . A compound according to  claim 23 , wherein R 2  and R 3  are independently hydrogen, halogen, C 1 -C 6  alkyl, alkoxy, amino, mono or di(C 1 -C 3  alkyl)amino, morpholinyl, piperidin-1-yl, or piperazin-1-yl.  
     
     
         25 . A compound according to  claim 24 , wherein R 13 , R 14  and R 16  are fluorines and R 15  is hydrogen.  
     
     
         26 . A compound according to  claim 18 , wherein R 1  and R 4  are hydrogen, methyl or ethyl; and R 2  and R 3  are independently hydrogen, bromo, chloro, fluoro, C 1 -C 2  alkyl, phenoxy, benzyloxy, C 1 -C 2  alkoxy, amino, mono or di(C 1 -C 3  alkyl)amino, morpholinyl, piperidin-1-yl, or piperazin-1-yl.  
     
     
         27 . A compound according to  claim 26 , wherein R 8 -R 12  represent one trifluoroacetyl or trifluoromethylthio, or one or two of fluoro chloro, bromo, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, or one or, preferably, two fluoro and one trifluoromethyl, or two fluoro or two trifluoromethyl with one methoxy, or three fluoro.  
     
     
         28 . A compound according to  claim 27 , wherein R 1  and R 4  are hydrogen, methyl or ethyl; and R 2  and R 3  are independently hydrogen, bromo, chloro, fluoro, C 1 -C 2  alkyl, phenoxy, benzyloxy, C 1 -C 2  alkoxy, amino, mono or di(C 1 -C 3  alkyl)amino, morpholinyl, piperidin-1-yl, or piperazin-1-yl.  
     
     
         29 . A compound according to  claim 28 , wherein both R 1  and R 4  are hydrogen or C 1 -C 3  alkyl.  
     
     
         30 . A compound according to  claim 29 , wherein at least one of R 2  and R 3  is hydrogen, and both R 1  and R 4  are hydrogen. which is selected from:  
     
     
         31 . A compound according to  claim 1 , which is 
 [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid.    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid ethyl ester;    (2-Benzylcarbamoyl-5-chloro-phenoxy)-acetic acid;    [5-Chloro-2-(3-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid;    [5-Chloro-2-(3-trifluoromethyl-benzylcarbamoyl)-phenoxy]-acetic acid;    [2-(3-Nitro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid;    [5-Chloro-2-(4-chloro-benzylcarbamoyl)-phenoxy]-acetic acid;    [2-(4-Bromo-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid;    [5-Chloro-2-(4-methoxy-benzylcarbamoyl)-phenoxy]-acetic acid; or    [5-Chloro-2-(4-trifluoromethoxy-benzylcarbamoyl)-phenoxy]-acetic acid.    
     
     
         32 . A compound according to  claim 1 , which is 
 [5-Chloro-2-(2,6-difluoro-benzylcarbamoyl)-phenoxy]-acetic acid;    [5-Chloro-2-(3-fluoro-5-trifluoromethyl-benzylcarbamoyl)-phenoxy]-acetic acid;    [2-(3,5-Bistrifluoromethyl-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid;    [5-Chloro-2-(3,5-dimethoxy-benzylcarbamoyl)-phenoxy]-acetic acid;    [5-Chloro-2-(3,4-dichloro-benzylcarbamoyl)-phenoxy]-acetic acid;    {2-[(Benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-5-chloro-phenoxy}-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-methoxy-phenoxy]-acetic acid; or    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-methoxy-phenoxy-acetic acid ethyl ester.    
     
     
         33 . A compound according to  claim 1 , which is 
 [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-chloro-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-fluoro-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-fluoro-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-methyl-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-nitro-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-nitro-phenoxy]-acetic acid tert-butyl ester;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-nitro-phenoxy]-acetic acid; or    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-methyl-phenoxy]-acetic acid.    
     
     
         34 . A compound according to  claim 1 , which is 
 [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-methylsulfanyl-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-methylsulfanyl-phenoxy]-acetic acid ethyl ester;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-methylsylfanyl-phenoxy]-acetic acid;    [2-(3-Nitro-benzylcarbamoyl)-4-methyl-phenoxy]-acetic acid;    [2-(3-nitro-benzylcarbamoyl)-4-trifluoromethoxy-phenoxy]-acetic acid;    [5-Fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid; or    [5-Fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester.    
     
     
         35 . A compound according to  claim 1 , which is 
 [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-phenoxy]-acetic acid;    [5-Fluoro-2-(4-methyl-3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4,5-difluoro-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-3,5-difluoro-phenoxy]-acetic acid;    [5-Fluoro-2-(3-nitro-benzylthiocarbamoyl)-phenoxy]-acetic acid;    [5-Fluoro-2-(3-nitro-benzylthiocarbamoyl)-phenoxy]-acetic acid ethyl ester;    [2-(4-Bromo-2-fluoro-benzylthiocarbamoyl)-5-fluoro-phenoxy]-acetic acid; or    [4-Bromo-2-(4-bromo-2-fluoro-benzylthiocarbamoyl)-phenoxy]-acetic acid.    
     
     
         36 . A compound according to  claim 1 , which is 
 [2-(3-Nitro-benzylthiocarbamoyl)-4-trifluoromethoxy-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylthiocarbamoyl)-4,5-difluoro-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-methanesulfonyl-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-methanesulfonyl-phenoxy]-acetic acid ethyl ester;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-methanesulfonyl-phenoxy]-acetic acid;    [4-Amino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-methoxy-phenoxy]-acetic acid; or    [4-Amino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid allyl ester.    
     
     
         37 . A compound according to  claim 1 , which is 
 [4-Acetylamino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid allyl ester;    [4-Acetylamino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-trifluoromethyl-phenoxy]-acetic acid;    (4-Allyloxy-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid;    [4-Allyloxy-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-hydroxy-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-propoxy-phenoxy]-acetic acid; or    [2-(2-Fluoro-benzylcarbamoyl)-4-propoxy-phenoxy]-acetic acid.    
     
     
         38 . A compound according to  claim 1 , which is 
 [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester;    [2-(4-Bromo-2-fluoro-benzylthiocarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylthiocarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester;    [2-(4-Bromo-2-fluoro-benzylthiocarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid;    [2-(3-Nitro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid;    [2-(3-Nitro-benzylthiocarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid; or    [4-Bromo-5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid.    
     
     
         39 . A compound according to  claim 1 , which is 
 [4-Bromo-5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid;    [5-(3-Nitro-benzylcarbamoyl)-2-fluoro-biphenyl-4-yloxy]-acetic acid;    [5-(3-Nitro-benzylthiocarbamoyl)-2-fluoro-biphenyl-4-yloxy]-acetic acid;    [2-(3-Nitro-benzylcarbamoyl)-4-cyano-5-fluoro-phenoxy]-acetic acid;    [2-(3-Nitro-benzylcarbamoyl)-5-fluoro-4-morpholin-4-yl-phenoxy]-acetic acid;    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-morpholin-4-yl-phenoxy]-acetic acid ethyl ester;    {5-Fluoro-2[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)carbamoyl]-phenoxy}-acetic acid; or    {5-Fluoro-2[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)carbamoyl]-phenoxy}-acetic acid ethyl ester.    
     
     
         40 . A compound according to  claim 1 , which is 
 {5-Fluoro-2-[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiocarbamoyl]-phenoxy}-acetic acid;    {5-Fluoro-2-[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiocarbamoyl]-phenoxy}-acetic acid ethyl ester;    {5-Fluoro-2-[(5-trifluoromethyl-benzothiazol-2-ylmethyl)-carbamoyl]-phenoxy}-acetic acid;    (5-Chloro-2-[(5-trifluoromethyl-benzothiazol-2-ylmethyl)-carbamoyl]-phenoxy}-acetic acid;    [5-Fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid benzyl ester;    [5-Fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid 3-methyl-butyl ester;    [5-Fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid octyl ester; or    [5-Fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid butyl ester.    
     
     
         41 . A compound according to  claim 1 , which is 
 [5-Fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid cyclohexyl ester;    [5-Fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid 2-ethyl-hexyl ester;    [5-Fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid 2-methoxy-ethyl ester;    [5-Fluoro-2-(3-nitro-benzylthiocarbamoyl)-phenoxy]-acetic acid octyl ester;    [5-Fluoro-2-(3-nitro-benzylthiocarbamoyl)-phenoxy]-acetic acid 3-methyl-butyl ester;    [5-Fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid 2-diethylammonium-ethyl ester hydrochloride;    [5-Fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid 2-trimethylammonium chloride-ethyl ester; or    [2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-methoxy-phenoxy]-acetic.    
     
     
         42 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an predetermined amount of a compound according to  claim 1 .  
     
     
         43 . A pharmaceutical composition according to  claim 42 , further comprising an Angotensin Converting Enzyme inhibitor.  
     
     
         44 . A pharmaceutical composition as claimed  43  wherein the angiotensin converting enzyme inhibitor is selected from benazepril, benazeprilar, captopril, delapril, fentiapril, fosinopril, libenzapril, moexipril, pentopril, petindopril, pivopril, quinapril, quinaprilat, ramipril, spirapril, spiraprilat, zofenopril, ceronapril, enalapril, indolapril, omaprilat, lisinopril, alacepril, cilazapril, and the pharmaceutically acceptable salts thereof.  
     
     
         45 . A pharmaceutical composition according to  claim 43 , wherein the angiotensin converting enzyme inhibitor is selected from the group consisting of selected from benazepril, benazeprilar, captopril, delapril, fentiapril, fosinopril, libenzapril, moexipril, pentopril, petindopril, pivopril, quinapril, quinaprilat, ramipril, spirapril, spiraprilat, zofenopril, ceronapril, enalapril, indolapril, omaprilat, lisinopril, alacepril, cilazapril, and the pharmaceutically acceptable salts thereof.  
     
     
         46 . A method for treating diabetic complications comprising administering to a patient suffering from such complications an effective amount of a compound of according to  claim 1 .  
     
     
         47 . A method according to  claim 46 , where the compound is administered to the patient as a pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         48 . A method according to  claim 47 , where the pharmaceutical composition further comprises an angiotensin converting enzyme inhibitor.  
     
     
         49 . A method for the treatment or prevention of the development of disease conditions associated with impaired neuronal conduction velocity comprising administering to a patient suffering from or prone to develop such complications an effective amount of a compound of according to  claim 1 .  
     
     
         50 . A method for the treatment or prevention of diabetic neuropathy comprising administering to a patient suffering from or prone to develop such complications an effective amount of a compound of according to  claim 1 .  
     
     
         51 . A method according to  claim 50 , where the compound is administered to the patient as a pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         52 . A method according to  claim 51 , where the pharmaceutical composition further comprises an angiotensin converting enzyme inhibitor.  
     
     
         53 . A method according to  claim 52 , wherein the angiotensin converting enzyme inhibitor is selected from the group consisting of selected from benazepril, benazeprilar, captopril, delapril, fentiapril, fosinopril, libenzapril, moexipril, pentopril, petindopril, pivopril, quinapril, quinaprilat, ramipril, spirapril, spiraprilat, zofenopril, ceronapril, enalapril, indolapril, omaprilat, lisinopril, alacepril, cilazapril, and the pharmaceutically acceptable salts thereof.