Method of modulating cellular activity and agents useful for same

Abstract

Described is a rational design of therapeutic and/or prophylactic methods of treating conditions characterized by aberrant or otherwise unwanted microglial cell functioning and rational design methods for treating a range of neurological disorders which are characterized by nitric oxide induced neuronal damage.

1 . A method of downregulating microglial cell functional activity, said method comprising contacting said cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein each of R 1  and R 2  is independently selected from a hydrogen atom or a C 1 -C 4 alkyl group, R 3  and R 4  are each hydrogen atoms of together form another chemical bond, each X is independently selected from a hydroxyl group, a halogen atom, a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group, or when two X groups are alkyl or alkoxy groups, they may be connected together to form a ring, and n is an integer from 1 to 3, for a time and under conditions sufficient to inhibit, retard or otherwise downregulate iNOS expression. 
       
     
     
         2 . The method according to  claim 1  wherein said microglial cell functional activity is nitric oxide synthesis. 
     
     
         3 . The method according to  claim 2  wherein said nitric oxide synthesis is inflammatory cytokine induced nitric oxide synthesis. 
     
     
         4 . The method according to  claim 3  wherein said cytokine is interferon-γ. 
     
     
         5 . The method according to  claim 2  wherein said nitric oxide synthesis is lipopolysaccharide-induced nitric oxide synthesis. 
     
     
         6 . A method of downregulating microglial cell functional activity in a mammal, said method comprising administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein each of R 1  and R 2  is independently selected from a hydrogen atom or a C 1 -C 4 alkyl group, R 3  and R 4  are each hydrogen atoms of together form another chemical bond, each X is independently selected from a hydroxyl group, a halogen atom, a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group, or when two X groups are alkyl or alkoxy groups, they may be connected together to form a ring, and n is an integer from 1 to 3, for a time and under conditions sufficient to inhibit, retard or otherwise downregulate iNOS expression. 
       
     
     
         7 . The method according to  claim 6  wherein said microglial cell functional activity is nitric oxide synthesis. 
     
     
         8 . The method according to  claim 7  wherein said nitric oxide synthesis is inflammatory cytokine induced nitric oxide synthesis. 
     
     
         9 . The method according to  claim 8  wherein said cytokine is interferon-γ. 
     
     
         10 . The method according to  claim 7  wherein said nitric oxide synthesis is lipopolysaccharide-induced nitric oxide synthesis. 
     
     
         11 . The method according to  claim 6  wherein the carboxyl group is in the 2-, 3- or 4-position of the aromatic ring, at least one of R 1  and R 2  is a hydrogen atom, R 3  and R 4  taken together form a chemical bond and n is 1 or 2 and each X, which may be the same or different, is selected from halogen, C 1 -C 4  alkyl or C 1 -C 4 alkoxy or a pharmaceutically acceptable salts thereof. 
     
     
         12 . The method of  claim 11  wherein the carboxyl group is in the 2-position, both of R 1  and R 2  are hydrogen atoms and X is selected from halogen and C 1 -C 4 alkoxy and n is 2 and both X are selected from C 1 -C 4 alkoxy or a pharmaceutically acceptable salts thereof. 
     
     
         13 . The method according to  claim 12  wherein said compound is of the formula or
 a pharmaceutically acceptable salt thereof:   
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 13  wherein said compound is selected from the list: 
       2-[[3-(2-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-methylphenyl)-1-oxo-2-propenyl]amino]-benzoic acid; 
       2-[[3-(2-ethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-ethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-ethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-propylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-propylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-propylphenyl)-1-oxo-2-propenyl]amino]benzoic acid, 
       2-[[3-(2-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-fluorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-fluorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-fluorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-bromophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-bromophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-bromophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dimethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dimethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dimethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-diethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-diethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-diethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dipropoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dipropoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dipropoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-diethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-diethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-diethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dipropylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dipropylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dipropylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-([3-(2-methoxy-3-methylphenyl)-1-oxo-2-propenyl]aminobenzoic acid; 
       2-[[3-(3-methoxy-4-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-4-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methoxy-4-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-4-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methoxy-4-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-4-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-trimethylenephenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-trimethylenephenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-methylenedioxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-ethylenedioxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; or
 a pharmaceutically acceptable salt thereof. 
 
     
     
         15 . The method according to  claim 14  wherein said compound is 2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salts thereof. 
     
     
         16 . A method of upregulating microglial cell inhibited functional activity in a mammal, said method comprising administering to said mammal an effective amount of an antagonist of a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein each of R 1  and R 2  is independently selected from a hydrogen atom or a C 1 -C 4 alkyl group, R 3  and R 4  are each hydrogen atoms of together form another chemical bond, each X is independently selected from a hydroxyl group, a halogen atom, a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group, or when two X groups are alkyl or alkoxy groups, they may be connected together to form a ring, and n is an integer from 1 to 3, for a time and under conditions sufficient to inhibit, retard or otherwise downregulate iNOS expression. 
       
     
     
         17 . The method according to  claim 16  wherein said microglial cell functional activity is nitric oxide synthesis. 
     
     
         18 . The method according to  claim 17  wherein said nitric oxide synthesis is inflammatory cytokine induced nitric oxide synthesis. 
     
     
         19 . The method according to  claim 18  wherein said cytokine is interferon-γ. 
     
     
         20 . The method according to  claim 17  wherein said nitric oxide synthesis is lipopolysaccharide-induced nitric oxide synthesis. 
     
     
         21 . The method according to  claim 16  wherein the carboxyl group is in the 2-, 3- or 4-position of the aromatic ring, at least one of R 1  and R 2  is a hydrogen atom, R 3  and R 4  taken together form a chemical bond and n is 1 or 2 and each X, which may be the same or different, is selected from halogen, C 1 -C 4  alkyl or C 1 -C 4 alkoxy or a pharmaceutically acceptable salts thereof. 
     
     
         22 . The method of  claim 21  wherein the carboxyl group is in the 2-position, both of R 1  and R 2  are hydrogen atoms and X is selected from halogen and C 1 -C 4 alkoxy and n is 2 and both X are selected from C 1 -C 4 alkoxy or a pharmaceutically acceptable salts thereof. 
     
     
         23 . The method according to  claim 22  wherein said compound is of the formula or
 a pharmaceutically acceptable salt thereof:   
       
         
           
           
               
               
           
         
       
     
     
         24 . The method of  claim 23  wherein said compound is selected from the list: 
       2-[[3-(2-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-ethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-ethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-ethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-propylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-propylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-propylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-fluorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-fluorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-fluorophenyl)-1-oxo-2-propenyi]amino]benzoic acid; 
       2-[[3-(2-bromophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-bromophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-bromophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dimethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dimethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dimethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-diethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-diethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-diethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dipropoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dipropoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dipropoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-diethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-diethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-diethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dipropylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dipropylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dipropylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methoxy-4-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-4-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methoxy-4-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-4-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methoxy-4-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-4-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-trimethylenephenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-trimethylenephenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-methylenedioxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; and 
       2-[[3-(3,4-ethylenedioxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; or
 a pharmaceutically acceptable salt thereof. 
 
     
     
         25 . The method according to  claim 24  wherein said compound is 2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salts thereof. 
     
     
         26 . A method for the treatment and/or prophylaxis of a condition characterized by aberrant, unwanted or otherwise inappropriate microglial cell functional activity in a mammal, said method comprising administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein each of R 1  and R 2  is independently selected from a hydrogen atom or a C 1 -C 4 alkyl group, R 3  and R 4  are each hydrogen atoms of together form another chemical bond, each X is independently selected from a hydroxyl group, a halogen atom, a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group, or when two X groups are alkyl or alkoxy groups, they may be connected together to form a ring, and n is an integer from 1 to 3, for a time and under conditions sufficient to inhibit, retard or otherwise downregulate iNOS expression. 
       
     
     
         27 . The method according to  claim 26  wherein said microglial cell functional activity is nitric oxide synthesis. 
     
     
         28 . The method according to  claim 27  wherein said aberrant nitric oxide synthesis is overproduction of nitric oxide. 
     
     
         29 . The method according to  claim 28  wherein said condition is nitric oxide induced neuronal damage. 
     
     
         30 . The method according to  claim 29  wherein said neuronal damage is brain ischaemia, Parkinson's disease, AIDS dementia, Alzheimer's disease, oligodendrocyte cytotoxicity, demyelination in multiple sclerosis or amyototrophic lateral sclerosis. 
     
     
         31 . The method according to  claim 26  wherein the carboxyl group is in the 2-, 3- or 4-position of the aromatic ring, at least one of R 1  and R 2  is a hydrogen atom, R 3  and R 4  taken together form a chemical bond and n is 1 or 2 and each X, which may be the same or different, is selected from halogen, C 1 -C 4  alkyl or C 1 -C 4 alkoxy or a pharmaceutically acceptable salts thereof. 
     
     
         32 . The method of  claim 31  wherein the carboxyl group is in the 2-position, both or R 1  and R 2  are hydrogen atoms and X is selected from halogen and C 1 -C 4 alkoxy and n is 2 and both X are selected from C 1 -C 4 alkoxy or a pharmaceutically acceptable salts thereof. 
     
     
         33 . The method according to  claim 32  wherein said compound is of the formula or
 a pharmaceutically acceptable salt thereof:   
       
         
           
           
               
               
           
         
       
     
     
         34 . The method of  claim 33  wherein said compound is selected from the list: 
       2-[[3-(2-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-ethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-ethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-ethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-propylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-propylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-propylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-fluorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-fluorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-fluorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-bromophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-bromophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-bromophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dimethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dimethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dimethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-diethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-diethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-diethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dipropoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dipropoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dipropoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-diethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-diethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-diethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dipropylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dipropylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dipropylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methoxy-4-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-4-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methoxy-4-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-4-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methoxy-4-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-4-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-trimethylenephenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-trimethylenephenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-methylenedioxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-ethylenedioxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; or
 a pharmaceutically acceptable salt thereof. 
 
     
     
         35 . The method according to  claim 34  wherein said compound is 2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salts thereof. 
     
     
         36 . A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salts thereof or antagonist thereof and one or more pharmaceutically acceptable carriers and/or diluents. 
     
     
         37 . The composition according to  claim 36  wherein the carboxyl group is in the 2-, 3- or 4-position of the aromatic ring, at least one of R 1  and R 2  is a hydrogen atom, R 3  and R 4  taken together form a chemical bond and n is 1 or 2 and each X, which may be the same or different, is selected from halogen, C 1 -C 4  alkyl or C 1 -C 4 alkoxy or a pharmaceutically acceptable salts thereof. 
     
     
         38 . The composition according to  claim 37  wherein the carboxyl group is in the 2-position, both of R 1  and R 2  are hydrogen atoms and X is selected from halogen and C 1 -C 4 alkoxy and n is 2 and both X are selected from C 1 -C 4 alkoxy or a pharmaceutically acceptable salts thereof. 
     
     
         39 . The composition according to  claim 38  wherein said compound is of the formula or
 a pharmaceutically acceptable salt thereof:   
       
         
           
           
               
               
           
         
       
     
     
         40 . The composition according to  claim 39  wherein said compound is selected from the list: 
       2-[[3-(2-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-ethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-ethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-ethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-propylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-propylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-propylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-fluorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-fluorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-fluorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-bromophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-bromophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(4-bromophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dimethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dimethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dimethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-diethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-diethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-diethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dipropoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dipropoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dipropoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-diethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-diethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-diethylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-dipropylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-dipropylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,4-dipropylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methoxy-4-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-4-methylphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methoxy-4-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-4-chlorophenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3-methoxy-4-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-3-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2-methoxy-4-hydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-trimethylenephenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(2,3-trimethylenephenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-methylenedioxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; 
       2-[[3-(3,4-ethylenedioxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid; or
 a pharmaceutically acceptable salt thereof. 
 
     
     
         41 . The composition according to  claim 40  wherein said compound is 2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salts thereof. 
     
     
         42 . (canceled) 
     
     
         43 . The method according to  claim 1  wherein said compound is 2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid and pharmaceutically acceptable salts thereof.