2-Amino-2-alkyl-4 hexenoic and hexynoic acid derivatives useful as nitric oxide synthase inhibitors

Abstract

The present invention relates to 2-amino-2-alkyl-4 hexenoic and hexynoic acid derivatives and their use in therapy, in particular their use as nitric oxide synthase inhibitors.

1 . A method of treating a condition mediated by excessive nitric oxide production by the inducible isoform of nitric oxide synthase in a subject in need of such treatment, the method comprising administering to said subject an effective amount of a compound of Formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
 R 1  is selected from the group consisting of hydrogen, halo, C 1 -C 5 alkyl and C 1 -C 5  alkyl substituted by alkoxy or one or more halo;  
 R 2  is selected from the group consisting of hydrogen, halo, C 1 -C 5  alkyl and C 1 -C 5  alkyl substituted by alkoxy or one or more halo;  
 R 3  is C 1 -C 5  alkyl or C 1 -C 5  alkyl be substituted by alkoxy or one or more halo.  
 
   
   
       2 . The method of  claim 1  wherein said compound is selected from the group consisting of: (E)-2-amino-2-methyl-6-[(1-iminoethyl)amino]-4-hexenoic acid; 
 (S,E)-2-amino-2-methyl-5-fluoro-6-[(1-iminoethyl)amino]-4-hexenoic acid;    (S,E)-2-amino-2-methyl-4-fluoro-6-[(1-iminoethyl)amino]-4-hexenoic acid;    (S,E)-2-amino-2-methyl-4,5-difluoro-6-[(1-iminoethyl)amino]4-hexenoic acid;    (R,E)-2-amino-2-methyl-6-[(1-iminoethyl)amino]4-hexenoic acid;    (S,E)-2-amino-2-methyl-6-[(1-iminoethyl)amino]-4-hexenoic acid;    2-amino-2-methyl-6-[(1-iminoethyl)amino]4-hexynoic acid;    (Z)-2-amino-2-methyl-6-[(1-iminoethyl)amino]-4-hexenoic acid;    (S,E)-2-amino-2-methyl-6-[(1-iminoethyl)amino]-4-hexenoic acid;    (2S,4E)-2-amino-2-methyl-6-(3-methyl-5-oxo-1,2,4-oxadiazol-4 (5H)-yl) hex-4-enoic acid;    (2S,4E)-2-amnio-6 {[(1 Z-N-hydroxyl)ethanimidoyl]amino}-2-methyl hex-4-enoic acid;    (E)-2-amino-2-methyl-6-[(1-iminoethyl)amino]-4-hexenoic acid, dihydrochloride;    (S,E)-2-amino-2-methyl-5-fluoro-6-[(1-iminoethyl)amino]-4-hexenoic acid, dihydrochloride;    (S,E)-2-amino-2-methyl-4-fluoro-6-[(1-iminoethyl)amino]-4-hexenoic acid, dihydrochloride;    (S,E)-2-amino-2-methyl-4,5-difluoro-6-[(1-iminoethyl)amino]-4-hexenoic acid, dihydrochloride;    (R,E)-2-amino-2-methyl-6-[(1-iminoethyl)amino]-4-hexenoic acid, dihydrochloride; and    (S,E)-2-amino-2-methyl-6-[(1-iminoethyl)amino]-4-hexenoic acid, dihydrochloride, or a pharmaceutically acceptable salt thereof.    
   
   
       3 . The method of  claim 1  wherein said compound is (S,E)-2-amino-2-methyl-6-[(1-iminoethyl)amino]-4-hexenoic acid, or a pharmaceutically acceptable salt thereof.  
   
   
       4 . The method of  claim 1  wherein said condition mediated by excessive nitric oxide production by the inducible isoform of nitric oxide synthase is an arthritis.  
   
   
       5 . The method of  claim 4  wherein said arthritis is osteoarthritis.  
   
   
       6 . The method of  claim 1  wherein said condition mediated by excessive nitric oxide production by the inducible isoform of nitric oxide synthase is pain.  
   
   
       7 . The method of  claim 6  wherein said pain is neuropathic pain.  
   
   
       8 . The method of  claim 1  wherein said condition mediated by excessive nitric oxide production by the inducible isoform of nitric oxide synthase is asthma.  
   
   
       9 . The method of  claim 3  wherein said condition mediated by excessive nitric oxide production by the inducible isoform of nitric oxide synthase is an arthritis.  
   
   
       10 . The method of  claim 9  wherein said arthritis is osteoarthritis.  
   
   
       11 . The method of  claim 3  wherein said condition mediated by excessive nitric oxide production by the inducible isoform of nitric oxide synthase is pain.  
   
   
       12 . The method of  claim 11  wherein said pain is neuropathic pain.  
   
   
       13 . The method of  claim 3  wherein said condition mediated by excessive nitric oxide production by the inducible isoform of nitric oxide synthase is asthma.