Aromatic dicarboxylic acid derivatives

Abstract

Compounds of formula I wherein A, R 1 and R 2 are defined in the specification. These compounds are useful as HDAC inhibitors. Also disclosed are methods of making and using said compounds.

1 . A compound of formula I  
       
         
           
           
               
               
           
         
         is a phenyl ring that may be unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, C 1-4 -alkyl-, trifluoromethyl-, hydroxy-, C 1-4 -alkoxy-, nitro-, amino-, C 1-4 -alkylamino-, di[C 1-4 -alkyl]-amino-, C 1-4 -alkanoylamino, C 1-3 -alkylenedioxy or an acyl group;  
          and  
         R1 and R2 are each independently selected from  
         hydrogen,  
         a branched or unbranched C 1-14 -alkyl group that 
 may be unsubstituted or substituted with 1 or more substituents independently selected from halogen, hydroxy-, nitro-, an amino group, a carbocyclic group or a heterocyclic group,  
 and wherein at a chain length of longer than 2 carbon atoms, one or more non adjacent atoms may be replaced by oxygen, nitrogen or sulfur atoms,  
 and wherein 2 atoms may be bound together by a double or triple bond,  
 
         a carbocyclic group, and  
         a heterocyclic group,  
         or alternatively, the group —NR 1 R 2  forms a 3-6 membered ring that may contain additional heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring optionally being annulated to a carbocyclic ring or a heterocyclic ring, and said —NR 1 R 2  ring being unsubstituted or optionally substituted by 1, 2, or 3 substituents independently selected from a halogen atom, an C 1-4 -alkyl-, trifluoromethyl-, hydroxy-, C 1-4 -alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, C 1-3 -alkylenedioxy-, nitro-, amino-, C 1-4 -alkylamino-, di[C 1-4 -alkyl]amino-, C 1-4 -alkanoylamino- or an acyl-group; or  
         the enantiomers, diastereoisomers, racemates and physiologically acceptable salts thereof.  
       
     
     
         2 . The compound of  claim 1  wherein R 2  is benzyl or substituted benzyl.  
     
     
         3 . The compound of  claim 1  wherein R 2  is benzyl or substituted benzyl.  
     
     
         4 . A compound selected from the group consisting of 
 N-hydroxy-N′-naphthalen-1-ylmethyl-terephthalamide;    4-(4-benzhydryl-piperazine-1-carbonyl)-N-hydroxy-benzamide;    N-hydroxy-N′-pyridin-3-ylmethyl-terephthalamide;    N-benzyl-N′-hydroxy-terephthalamide;    N-cyclohexyl-N′-hydroxy-terephthalamide;    N-cyclopropyl-N′-hydroxy-terephthalamide;    N-hexyl-N′-hydroxy-terephthalamide;    N-hydroxy-N′-(3-methyl-butyl)-terephthalamide;    N-hydroxy-N′-phenethyl-terephthalamide; and    N-hydroxy-N′-[2-(4-methoxy-phenyl)-ethyl]-terephthalamide.    
     
     
         5 . A compound selected from the group consisting of 
 N-(3-chloro-benzyl)-N′-hydroxy-terephthalamide;    N-hydroxy-N′-(2-methoxy-benzyl)-terephthalamide;    N-(4-fluoro-benzyl)-N′-hydroxy-terephthalamide;    N-hydroxy-N′-(1,2,3,4-tetrahydro-naphthalen-1-yl)-terephthalamide;    N-hydroxy-N′-(4-trifluoromethyl-benzyl)-terephthalamide;    N-(2,4-difluoro-benzyl)-N′-hydroxy-terephthalamide;    N-hydroxy-N′-indan-1-yl-terephthalamide;    N-benzo [1,3]dioxol-5-ylmethyl-N′-hydroxy-terephthalamide;    N-hydroxy-4-(4-phenyl-piperazine-1-carbonyl)-benzamide; and    N-(3,5-dimethyl-benzyl)-N′-hydroxy-terephthalamide.    
     
     
         6 . A compound selected from the group consisting of 
 N-hydroxy-N′-(3-isopropoxy-propyl)-terephthalamide;    4-(4-acetyl-piperazine-1-carbonyl)-N-hydroxy-benzamide;    N,N-dibutyl-N′-hydroxy-terephthalamide;    4-(4-benzyl-piperidine-1-carbonyl)-N-hydroxy-benzamide;    N-hydroxy-N′-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-terephthalamide;    N-(2-ethoxy-benzyl)-N′-hydroxy-terephthalamide;    N-(2-cyclohex-1-enyl-ethyl)-N′-hydroxy-terephthalamide;    N-hydroxy-N′-(2-morpholin-4-yl-ethyl) terephthalamide;    N-hydroxy-N′-(2-methylsulfanyl-ethyl)-terephthalamide; and    N-hydroxy-N′-(tetrahydro-furan-2-ylmethyl)-terephthalamide.    
     
     
         7 . A process of manufacturing a compound of formula I comprising 
 reacting a compound of formula III                           with an amine of the formula HNR 1 R 2  in the presence of an activating agent, to give a compound of formula II                           reacting the compound of formula II with hydroxylamine in the presence of a suitable base, wherein                           is a phenyl ring that may be unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, a C 1-4 -alkyl-, trifluoromethyl-, hydroxy-, C 1-4 -alkoxy-, nitro-, amino-, C 1-4 -alkylamino-, di[C 1-4 -alkyl]-amino-, C 1-4 -alkanoylamino, a C 1-3 -alkylenedioxy-group or an acyl group;    R1 and R2 are each independently selected from    hydrogen,    a branched or unbranched C 1-14 -alkyl group that 
 may be unsubstituted or substituted with 1 or more substituents independently selected from halogen, hydroxy-, nitro-, an amino group, a carbocyclic group or a heterocyclic group,  
 and wherein at a chain length of longer than 2 carbon atoms, one or more non adjacent atoms may be replaced by oxygen, nitrogen or sulfur atoms,  
 and wherein 2 atoms may be bound together by a double or triple bond,  
   a carbocyclic group, and    a heterocyclic group,    or alternatively, the group —NR 1 R 2  forms a 3-6 membered ring that may contain additional heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring optionally being annulated to a carbocyclic ring or a heterocyclic ring, and said —NR 1 R 2  ring being unsubstituted or optionally substituted by 1, 2, or 3 substituents independently selected from a halogen atom, an C 1-4 -alkyl-, trifluoromethyl-, hydroxy-, C 1-4 -alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, C 1-3 -alkylenedioxy-, nitro-, amino-, C 1-4 -alkylamino-, di[C 1-4 -alkyl]amino-, C 1-4 -alkanoylamino- or an acyl-group; and    R3 is C 1-4 -alkyl.    
     
     
         8 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier or excipient.  
     
     
         9 . A method of treating breast, lung, colon, rectal, stomach, prostate, bladder, pancreas or ovarian cancer comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of  claim 1 .  
     
     
         10 . A compound of formula  
       
         
           
           
               
               
           
         
         is a phenyl ring that may be unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, a C 1-4 -alkyl-, trifluoromethyl-, hydroxy-, C 1-4 -alkoxy-, nitro-, amino-, C 1-4 -alkylamino-, di[C 1-4 -alkyl]-amino-, C 1-4 -alkanoylamino, a C 1-3 -alkylenedioxy-group or an acyl group;  
         R1 and R2 are each independently selected from  
         hydrogen,  
         a branched or unbranched C 1-14 -alkyl group that 
 may be unsubstituted or substituted with 1 or more substituents independently selected from halogen, hydroxy-, nitro-, an amino group, a carbocyclic group or a heterocyclic group,  
 and wherein at a chain length of longer than 2 carbon atoms, one or more non adjacent atoms may be replaced by oxygen, nitrogen or sulfur atoms,  
 and wherein 2 atoms may be bound together by a double or triple bond,  
 
         a carbocyclic group, and  
         a heterocyclic group,  
         or alternatively, the group —NR 1 R 2 , forms a 3-6 membered ring that may contain additional heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring optionally being annulated to a carbocyclic ring or a heterocyclic ring, and said —NR1R 2  ring being unsubstituted or optionally substituted by 1, 2, or 3 substituents independently selected from a halogen atom, an C 1-4 -alkyl-, trifluoromethyl-, hydroxy-, C 1-4 -alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, C 1-3 -alkylenedioxy-, nitro-, amino-, C 1-4 -alkylamino-, di[C 1-4 -alkyl]amino-, C 1-4 -alkanoylamino- or an acyl-group; and  
         Y is a protecting group.