Novel oxime derivatives as sphingosine 1-phosphate (s1p) receptor modulators

Abstract

The present invention relates to novel oxime derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

What is claimed is: 
     
         1 . A method of treating an immunosuppressant disorder associated with the sphingosine-1-phosphate receptor inhibition, wherein the disorder is selected from rheumatoid arthritis, psoriasis, atherosclerosis, autoimmune uveitis, dry eye and multiple sclerosis, in a mammal in need thereof, which comprises administering to a mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound represented by Formula I or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         A is C 6-10  aryl; 
         B is C 6-10  aryl; 
         R 1  is H, halogen or C 1-8  alkyl; 
         R 2  is H, halogen or C 1-8  alkyl; 
         R 3  is H, halogen or C 1-8  alkyl; 
         R 4  is H, halogen or C 1-8  alkyl; 
         R 5  is H, halogen or C 1-8  alkyl; 
         R 6  is H, halogen or C 1-8  alkyl; 
         R 7  is H, halogen or C 1-8  alkyl; 
         L 1  is O or CH 2 ; 
         R 9  is CH 2 ; 
         R 10  is H; 
         L 2  is CHR 16 ; 
         D is a group of formula 
       
       
         
           
           
               
               
           
         
       
       “*” indicating the point of attachment to the rest of the molecule;
 R 11  is carboxylic acid or PO 3 H 2 ; 
 a is 0; 
 b is 1; 
 c is 0 or 1; 
 R 13  is H, C 1-8  alkyl; 
 R 16  is H. 
 
     
     
         2 . The method according to  claim 1 , wherein: L 1  is CH 2 . 
     
     
         3 . The method according to  claim 1 , wherein: L 1  is O. 
     
     
         4 . The method according to  claim 1 , wherein D is a group of formula 
       
         
           
           
               
               
           
         
       
       “*” indicates the point of attachment to the rest of the molecule. 
     
     
         5 . The method according to  claim 1 , wherein D is a group of formula 
       
         
           
           
               
               
           
         
       
       “*” indicates the point of attachment to the rest of the molecule. 
     
     
         6 . The method according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method according to  claim 1 , wherein D is a group of formula 
       
         
           
           
               
               
           
         
       
       “*” indicates the point of attachment to the rest of the molecule; and L 1  is CH 2 . 
     
     
         8 . The method according to  claim 1 , wherein D is a group of formula 
       
         
           
           
               
               
           
         
       
       “*” indicates the point of attachment to the rest of the molecule; and L 1  is CH 2 . 
     
     
         9 . The method according to  claim 1 , wherein D is a group of formula 
       
         
           
           
               
               
           
         
       
       “*” indicates the point of attachment to the rest of the molecule; and L 1  is O. 
     
     
         10 . The method according to  claim 1 , wherein D is a group of formula 
       
         
           
           
               
               
           
         
       
       “*” indicates the point of attachment to the rest of the molecule; and L 1  is CH 2 . 
     
     
         11 . The method according to  claim 1 , wherein said compound selected from:
 3-({4-[({[(1E)-2-(3,5-difluorophenyl)-3-(3,4-dimethylphenyl)-1-methylpropylidene]amino}oxy)methyl]benzyl}amino)propanoic acid;   [3-({4-[({[(1E)-2-(3,5-difluorophenyl)-3-(3,4-dimethylphenyl)-1-methylpropylidene]amino}oxy)methyl]benzyl}amino)propyl]phosphonic acid;   [3-({4-[({[(1E)-2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)-1-methylpropylidene]amino}oxy)methyl]benzyl}amino)propyl]phosphonic acid;   3-[(4-{(1E)-N-[3-(3,4-dimethylphenyl)-2-(3-methylphenyl)propoxy]ethanimidoyl}benzyl)amino]propanoic acid;   3-[(4-{(1E)-N-[2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)propoxy]ethanimidoyl}benzyl)amino]propanoic acid;   {3-[(4-{(1E)-N-[2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)propoxy]ethanimidoyl}benzyl)amino]propyl}phosphonic acid;   {3-[(4-{(1E)-N-[3-(3,4-dimethylphenyl)-2-(3-methylphenyl)propoxy]ethanimidoyl}benzyl)amino]propyl}phosphonic acid;   [3-({4-[(1E)-N-{2-[(3,4-dimethylphenyl)sulfonyl]-2-(3-fluorophenyl)ethoxy}ethanimidoyl]benzyl}amino)propyl]phosphonic acid;   3-({4-[(1E)-N-{2-[(3,4-dimethylphenyl)thio]-2-(3-fluorophenyl)ethoxy}ethanimidoyl]benzyl}amino)propanoic acid;   {3-[(4-{[({(1E)-2-(3-chlorophenyl)-2-[(3,4-dimethylphenyl)thio]-1-methylethylidene}amino)oxy]methyl}benzyl)amino]propyl}phosphonic acid;   3-[(4-{[({(1E)-2-(3-chlorophenyl)-2-[(3,4-dimethylphenyl)thio]-1-methylethylidene}amino)oxy]methyl}benzyl)amino]propanoic acid;   3-({4-[({[(1E)-2-(3-chlorophenyl)-2-(3,4-dimethylphenoxy)-1-methylethylidene]amino}oxy)methyl]benzyl}amino)propanoic acid;   [3-({4-[({[(1E)-2-(3-chlorophenyl)-2-(3,4-dimethylphenoxy)-1-methylethylidene]amino}oxy)methyl]benzyl}amino)propyl]phosphonic acid;   3-[(4-{(1E)-N-[2-(3-chlorophenyl)-2-(3,4-dimethylphenoxy)ethoxy]ethanimidoyl}benzyl)amino]propanoic acid; and   {3-[(4-{(1E)-N-[2-(3-chlorophenyl)-2-(3,4-dimethylphenoxy)ethoxy]ethanimidoyl}benzyl)amino]propyl}phosphonic acid.   
     
     
         12 . The method according to  claim 1 , wherein the pharmaceutical composition further comprises pharmaceutically acceptable adjuvants, diluents or carriers. 
     
     
         13 . The method according to  claim 1 , wherein the mammal is a human.