Substituted aryl 1 ,2,4-oxadiazoles derivatives as sphingosine-1 phosphate receptors modulators

Abstract

The present invention relates to substituted aryl 1,2,4-oxadiazoles 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 modulation, wherein the immunosuppressant disorder is selected from: rheumatoid arthritis, psoriasis, atherosclerosis, autoimmune uveitis, dry eye, inflammatory bowel diseases, atopic allergy, atopic dermatitis, contact dermatitis, multiple sclerosis, Sjogren's syndrome and organ transplant rejection, 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: 
         R 1  is substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 5-8  cycloalkyl, substituted or unsubstituted C 5-8  cycloalkenyl; 
         R 2  is hydrogen, —OC 1-3  alkyl or substituted or unsubstituted C 1-3  alkyl; 
         R 3  is hydrogen, halogen, substituted or unsubstituted C 1-3  alkyl, C(O)R 10  or hydroxyl; 
         R 4  is hydrogen, halogen, substituted or unsubstituted C 1-3  alkyl, C(O)R 10  or hydroxyl; 
         R 5  is hydrogen, halogen, substituted or unsubstituted C 1-3  alkyl, C(O)R 10  or hydroxyl or substituted or unsubstituted heterocycle; 
         R 6  is hydrogen, halogen, substituted or unsubstituted C 1-3  alkyl, C(O)R 10  or hydroxyl or substituted or unsubstituted heterocycle; 
         R 7  is hydrogen, —OC 1-3  alkyl or substituted or unsubstituted C 1-3  alkyl; 
         R 8  is H or C 1-3  alkyl; 
         R 9  is PO 3 H 2 , —P(O)MeOH, or —P(O)(H)OH; 
         R 10  is H or C 1-3  alkyl; 
         a is 2 or 3; 
         b is 1, 2 or 3; 
         c is 1, 2, 3, 4, 5 or 6; 
         with the proviso that the compound of Formula I is not of structure 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The method according to  claim 1 , wherein said compound is represented by Formula I wherein:
 [3-({3-(Furan-2-yl)-4-[5-(4-phenylbutyl)-1,2,4-oxadiazol-3-yl]benzyl}amino) propyl]phosphonic acid;   [3-({3-Bromo-4-[5-(4-phenylbutyl)-1,2,4-oxadiazol-3-yl]benzyl}amino) propyl]phosphonic acid;   [3-({3-Fluoro-4-[5-(4-phenylbutyl)-1,2,4-oxadiazol-3-yl]benzyl}amino)propyl]phosphonic acid;   [3-({4-[5-(5-Phenylpentyl)-1,2,4-oxadiazol-3-yl]benzyl}amino)propyl]phosphonic acid;   [3-({4-[5-(3-Phenylpropyl)-1,2,4-oxadiazol-3-yl]benzyl}amino)propyl]phosphonic acid;   3-({4-[5-(4-Phenylbutyl)-1,2,4-oxadiazol-3-yl]benzyl}amino)propanoic acid;   [3-({4-[5-(4-Phenylbutyl)-1,2,4-oxadiazol-3-yl]benzyl}amino)propyl]phosphonic acid; and   [3-({2-Ethyl-4-[5-(4-phenylbutyl)-1,2,4-oxadiazol-3-yl]benzyl}amino)propyl]phosphonic acid.   
     
     
         3 . The method of  claim 1  wherein the mammal is a human.