Novel aromatic compounds

Abstract

Disclosed are compounds of formula I wherein A, R1, R2, R3, R4 and R5 are described in the specification, pharmaceutical formulations comprising these compounds, the use of these compounds as medicaments, the use of these medicaments in the treatment of and/or prevention of diabetes, especially non-insulin dependent diabetes (NIDDM or Type 2 diabetes), as well as methods for treating diabetes comprising administration of these compounds.

What is claimed is:  
     
         1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       as well as any optical or geometric isomer or tautomeric form thereof and mixtures of these or a pharmaceutically acceptable basic organic or inorganic addition salt or hydrate or prodrug thereof, wherein 
 A is —O—, —S—, >SO, >SO 2 , >CO, >CR9R10, or >NR11;  
 R1 and R2 independently are one of the following groups: hydrogen, CN, —C(O)NR6R7, —COOH, —PO(OH) 2 , —SO 2 OH, tetrazole, 1-hydroxy-1,2-diazole, 1-hydroxytriazole, 1-hydroxyimidazole, 2-hydroxytriazole, or 1-hydroxytetrazole; when R1 or R2 is hydrogen, the other of R1 and R2 is —PO(OH) 2  or —SO 2 OH; R1 and R2 together may form an anhydride or an imide;  
 R3 and R4 independently are C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, or C 3-8 -cycloalkyl, each optionally substituted with halogen, hydroxy, —SH, —SOR6, —SO 2 R6, —NR6R7, —NHCOR7, C 1-8 -alkoxy, NO 2 , trifluoromethoxy, carbamoyl, or —CONR6R7; or R3 and R4 independently are hydrogen, halogen, perhalomethyl, C 1-8 -alkoxy, C 1-8 -alkylthio, —SH, —SOR6, —SO 2 R6, trifluoromethoxy, —SO 2 OH, —PO(OH) 2 , —COOR6, —CN, hydroxy, —OCOR6, —NR6R7, —NHCOR7, —COC 1-8 -alkyl, —CONR6R7, —CONHSO 2 R7, —SO 2 NHR7, NO 2 , C 1-8 alkoxycarbonyl, aryl, heteroaryl, C 1-8 alkylphenyl, or tetrazole;  
 R5 is —CO—R8, —CH 2 —R8, or —CS—R8; wherein R8 is aryl, C 1-8 -alkyl, C 2-8 -alkene, phenyl-C 1-8 -alkyl, hetereoaryl, or C 3-8 -cycloalkyl, each optionally substituted with one or more substituents selected from halogen, hydroxy, —SH, —SOR6, —SO 2 R6, NO 2 , —NR6R7, —NHCOR7, C 1-8 alkyl, C 1-8 -alkoxy, perhalomethoxy, carbamoyl, —CONR6R7, perhalomethyl, —OCOR6, —CO—R6, —OR6, C 1-8 -alkylthio, —COOR6, —SO 2 OH, —SO 2 CH 3 , —PO(OH) 2 , —CN, —NHCOR7, —CONHSO 2 R7, —SO 2 NHR7, C 1-8 -alkoxycarbonyl, and tetrazole; wherein 
 R6 and R7 independently are hydrogen, C 1-8 -alkyl, aryl, phenyl-C 1-8 alkyl, or heteroaryl, each optionally substituted with one or more substituents selected from halogen, OH, NH 2 , NO 2 , —NH(C 1-8 -alkyl), —N(C 1-8 -alkyl) 2 , —NHCO(C 1-8 alkyl), C 1-8 -alkoxy, and trifluoromethoxy;  
 R9 and R10 independently are hydrogen, hydroxy, —SH, halogen, or C 1-8 -alkyl; and  
 R11 is hydrogen, C 1-8 -alkyl, -carbonyl-C 1-8 -alkyl, or phenyl-C 1-8 -alkyl.  
 
 
     
     
         2 . A compound according to  claim 1 , wherein A is —O— or —S—.  
     
     
         3 . A compound according to  claim 2 , wherein A is —O—.  
     
     
         4 . A compound according to any one of the  claims 1  to  3 , wherein R1 and R2 both are —COOH or CN, preferably —COOH, or R1 and R2 together form an imide.  
     
     
         5 . A compound according to any one of the  claims 1  to  4 , wherein R3 is hydrogen.  
     
     
         6 . A compound according to any one of the  claims 1  to  5 , wherein R4 is hydrogen.  
     
     
         7 . A compound according to any one of the  claims 1  to  6 , wherein R5 is —CO—R8, wherein R8 is as defined in  claim 1 .  
     
     
         8 . A compound according to  claim 7 , wherein R8 is aryl or hetereoaryl, each optionally substituted with one or more substituents selected from halogen, hydroxy, —SH, —SOR6, —SO 2 R6, NO 2 , —NR6R7, —NHCOR7, C 1-8 alkyl, C 1-8 -alkoxy, perhalomethoxy, carbamoyl, —CONR6R7, perhalomethyl, —OCOR6, —CO—R6, —OR6, C 1-8 -alkylthio, —COOR6, —SO 2 OH, —SO 2 CH 3 , —PO(OH) 2 , CN, —NHCOR7, —CONHSO 2 R7, —SO 2 NHR7, C 1-8 -alkoxycarbonyl, and tetrazole, wherein R6 and R7 are as defined in  claim 1 .  
     
     
         9 . A compound according to  claim 8 , wherein R8 is aryl optionally substituted with one or more substituents selected from halogen, hydroxy, —SH, —SOR6, —SO 2 R6, NO 2 , —NR6R7, —NHCOR7, C 1-8 alkyl, C 1-8 alkoxy, perhalomethoxy, carbamoyl, —CONR6R7, perhalomethyl, —OCOR6, —CO—R6, —OR6, C 1-8 -alkylthio, —COOR6, —SO 2 OH, —SO 2 CH 3 , —PO(OH) 2 , CN, —NHCOR7, —CONHSO 2 R7, —SO 2 NHR7, C 1-8 alkoxycarbonyl, or tetrazole, wherein R6 and R7 are as defined in  claim 1 .  
     
     
         10 . A compound according to  claim 9 , wherein R8 is aryl (preferably phenyl) optionally substituted with one or more substituents selected from halogen, COOR6, NO 2 , —SO 2 CH 3 , CN, C 1-8 alkyl (preferably methyl, tert-butyl, isopropyl pentyl, heptyl), perhalomethyl (preferably trifluoromethyl), C 1-8 -alkoxy (preferably methoxy or ethoxy), perhalomethoxy (preferably trifluoromethoxy), C 1-8 -alkylthio (preferably methylthio), —CO—R6, —NR6R7, —NH—CO—R7, and —OR6, wherein R6 and R7 are as defined in  claim 1 .  
     
     
         11 . A compound according to  claim 10 , wherein R8 is aryl (preferably phenyl) optionally substituted with one or more substituents and at least one of the substituents is COOH.  
     
     
         12 . A compound according to  claim 10 , wherein R8 is aryl (preferably phenyl) optionally substituted with one or more substituents and at least one of the substituents is NO 2 .  
     
     
         13 . A compound according to  claim 10 , wherein R8 is aryl (preferably phenyl) optionally substituted with one or more substituents and at least one of the substituents is halogen (preferably bromo or chloro).  
     
     
         14 . A compound according to  claim 10 , wherein R8 is aryl (preferably phenyl) substituted with one or more substituents and at least one of the substituent is —CO—R6, wherein R6 is C 1-8 alkyl (preferably CH 3 ) or substituted aryl (preferably phenyl) substituted with halogen or substituted with C 1-8 -alkyl (preferably CH 3 ).  
     
     
         15 . A compound according to  claim 10 , wherein R8 is aryl (preferably phenyl) substituted with one or more substituents and at least one of the substituents is —NH—CO—R7, wherein R7 is C 1-8 -alkyl (preferably CH 3 ).  
     
     
         16 . A compound according to  claim 10 , wherein R8 is aryl (preferably phenyl) substituted with one or more substituents and at least one of the substituents is —NR6R7, wherein R6 and R7 independently are hydrogen or C 1-8 -alkyl (preferably CH 3 ).  
     
     
         17 . A compound according to  claim 10 , wherein R8 is aryl (preferably phenyl) substituted with one or more substituents and at least one of the substituents is —OCH 2 R6, wherein R6 is aryl (preferably phenyl).  
     
     
         18 . A compound according to  claim 8 , wherein R8 is benzo[1,3]dioxole, 2,3-dihydrobenzofuran, or benzofuran, each optionally substituted with one or more substituents selected from halogen, C 1-8 alkyl (preferably methyl), and C 1-8 -alkoxy (preferably methoxy).  
     
     
         19 . A compound according to  claim 1  and having formula (Ia):  
       
         
           
           
               
               
           
         
         wherein R1, R2 and R5 are as defined in  claim 1 .  
       
     
     
         20 . A compound according to  claim 19 , wherein R1 and R2 are —COOH.  
     
     
         21 . A compound according to  claim 20 , wherein R5 is —CO—R8 and wherein R8 is as defined in  claim 10 .  
     
     
         22 . A compound according to  claim 1  and having formula (Ib):  
       
         
           
           
               
               
           
         
         wherein R5 is as defined in  claim 7 .  
       
     
     
         23 . A compound according to  claim 22 , wherein R5 is —CO—R8 and wherein R8 is as defined in  claim 10 .  
     
     
         24 . A compound according to  claim 1  which is 
 4-[2-(3-dimethylaminobenzoylamino)phenoxy]phthalic acid,  
 4-[2-(3-dimethylaminobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(3-iodobenzoylamino)phenoxy]phthalic acid,  
 4-[2-(3-iodobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(2-fluoro-5-trifluoromethylbenzoylamino)phenoxy]phthalic acid,  
 4-[2-(2-fluoro-5-trifluoromethylbenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(2-fluorobenzoylamino)phenoxy]phthalic acid,  
 4-[2-(2-fluorobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(3-acetylbenzoylamino)phenoxy]phthalic acid,  
 4-[2-(3-acetylbenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(3-bromobenzoylamino)phenoxy]phthalic acid,  
 4-[2-(3-bromobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(3-chlorobenzoylamino)phenoxy]phthalic acid,  
 4-[2-(3-chlorobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(2,3-difluorobenzoylamino)phenoxy]phthalic acid,  
 4-[2-(2,3-difluorobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(2,4-difluorobenzoylamino)phenoxy]phthalic acid,  
 4-[2-(2,4-difluorobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(2,5-difluorobenzoylamino)phenoxy]phthalic acid,  
 4-[2-(2,5-difluorobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(4-fluorobenzoylamino)phenoxy]phthalic acid,  
 4-[2-(4-fluorobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-(2-benzoylaminophenoxy)phthalic acid,  
 4-(2-benzoylaminophenoxy)phthalic acid dimethyl ester,  
 4-[2-(3-methylbenzoylamino)phenoxy]phthalic acid,  
 4-[2-(3-methylbenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(3-cyanobenzoylamino)phenoxy]phthalic acid,  
 4-[2-(3-cyanobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[4-amino-2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[4-amino-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 N-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-5-yloxy)phenyl]-3-nitrobenzamide,  
 4-[2-(3-aminobenzoylamino)phenoxy]phthalic acid,  
 4-[2-(3-aminobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[4-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[4-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(3-nitrobenzoylamino)phenylsulphenyl]phthalic acid,  
 4-[2-(3-nitrobenzoylamino)phenylsulphenyl]phthalic acid dimethyl ester,  
 4-[2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[4-(4-iodobenzoylamino)-2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[4-(4-iodobenzoylamino)-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[4-methoxycarbonyl-2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[4-methoxycarbonyl-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[4-acetylamino-2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[4-acetylamino-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[5-fluoro-2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[5-fluoro-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[4-bromo-2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[4-bromo-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[4-benzoylamino-2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[4-benzoylamino-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[5-methyl-2,4-bis-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[5-methyl-2,4-bis-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[4-cyano-2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[4-cyano-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[4,5-dichloro-2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[4,5-dichloro-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[5-bromo-4-fluoro-2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[5-bromo-4-fluoro-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[4-methyl-2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[4-methyl-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[4-fluoro-2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[4-fluoro-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[5-methyl-2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[5-methyl-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(3-nitrobenzoylamino)-4-trifluoromethylphenoxy]phthalic acid,  
 4-[2-(3-nitrobenzoylamino)-4-trifluoromethylphenoxy]phthalic acid dimethyl ester,  
 4-[2,4-bis-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[2,4-bis-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(3-nitrobenzoylamino)benzyl]phthalic acid,  
 4-[2-(3-nitrobenzoylamino)benzyl]phthalic acid dimethyl ester,  
 4-[2-(3-fluorobenzoylamino)phenoxy]phthalic acid,  
 4-[2-(3-fluorobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(3-trifluoromethylbenzoylamino)phenoxy]phthalic acid,  
 4-[2-(3-trifluoromethylbenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(3-nitrobenzylamino)phenoxy]phthalic acid,  
 4-[2-(3-nitrobenzylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(3-trifluoromethoxybenzoylamino)phenoxy]phthalic acid,  
 4-[2-(3-trifluoromethoxybenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-{benzyl-[2-(3-nitrobenzoylamino)phenyl]amino}phthalic acid,  
 4-{benzyl-[2-(3-nitrobenzoylamino)phenyl]amino}phthalic acid dimethyl ester,  
 4-[2-(3-nitrobenzoylamino)phenoxy]phthalic acid,  
 4-[2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester,  
 4-[2-(3-methoxybenzoylamino)phenoxy]phthalic acid, or  
 4-[2-(3-methoxybenzoylamino)phenoxy]phthalic acid dimethyl ester.  
 
     
     
         25 . A compound according to any one of the  claims 1  to  24  for use as a medicament.  
     
     
         26 . A pharmaceutical composition comprising, as an active ingredient, a compound according to anyone of the  claims 1  to  24  together with one or more pharmaceutically acceptable carriers or diluents.  
     
     
         27 . A pharmaceutical composition according to  claim 26  in unit form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of a compound according to any one of the  claims 1  to  23 .  
     
     
         28 . Use of a compound according to any one of the  claims 1  to  24  for the manufacture of a medicament for the treatment or prevention of diabetes, preferably Type 2 diabetes.  
     
     
         29 . Use of a compound according to any one of the  claims 1  to  24  for the manufacture of a medicament for inhibiting the glucose production from the liver.  
     
     
         30 . Use of a compound according to any one of the  claims 1  to  24  for the manufacture of a medicament for inhibiting liver glycogen phosphorylase.  
     
     
         31 . Use of a compound according to any one of the  claims 1  to  24  for the manufacture of a medicament for the treatment or prophylactic of obesity or appetite regulation.  
     
     
         32 . A method for the treatment of diabetes, preferably Type 2 diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to any one of the  claims 1  to  24  or a pharmaceutical composition according to any one of the claims  26  or  27 .  
     
     
         33 . A method for the treatment of glycogen phosphorylase dependent diseases comprising administering to a subject in need thereof an effective amount of a compound according to any one of the  claims 1  to  24  or a pharmaceutical composition according to any one of the claims  26  or  27 .  
     
     
         34 . A method for inhibition of glucose production from the liver comprising administering to a subject in need thereof an effective amount of a compound according to any one of the  claims 1  to  24  or a pharmaceutical composition according to any one of the claims  26  or  27 .  
     
     
         35 . A method for the treatment or prophylaxis of obesity or appetite regulation comprising administering to a subject in need thereof an effective amount of a compound according to any one of the  claims 1  to  24  or a pharmaceutical composition according to any one of the claims  26  or  27 .  
     
     
         36 . A method according to any one of the  claims 32  to  35  wherein the effective amount of the compound according to any one of the  claims 1  to  24  is in the range of from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg per day.  
     
     
         37 . Any novel features or combination of features as described herein.