2-thio-1,3,4-oxadiazoles azetidine derivatives as sphingosine-1 phosphate receptors modulators

Abstract

The present invention relates to 2-thio-1,3,4-oxadiazoles azetidine 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: 
         X is S, SO or SO 2 ; 
         R 1  is hydrogen, halogen, substituted or unsubstituted C 1-3  alkyl, CN, NO 2 , C(O)R 12  or OR 11 ; 
         R 2  is hydrogen, halogen, substituted or unsubstituted C 1-3  alkyl, CN, NO 2 , C(O)R 12  or OR 11 ; 
         R 3  is hydrogen, halogen, substituted or unsubstituted C 1-3  alkyl, CN, NO 2 , C(O)R 12  or OR 11 ; 
         R 4  is hydrogen, halogen, substituted or unsubstituted C 1-3  alkyl, CN, NO 2 , C(O)R 12  or OR 11 ; 
         R 5  is hydrogen, halogen, substituted or unsubstituted C 1-3  alkyl, CN, NO 2 , C(O)R 12  or OR 11 ; 
         R 6  is H, halogen, —OC 1-3  alkyl, substituted or unsubstituted C 1-3  alkyl; 
         R 7  is hydrogen, halogen, substituted or unsubstituted C 1-3  alkyl, CN, NO 2 , C(O)R 12  or OR 11 ; 
         R 8  is CH, S, O, N, NH or CH 2 ; 
         R 9  is CH, N or CH 2 ; 
         R 10  is hydrogen, halogen, substituted or unsubstituted C 1-3  alkyl, CN, NO 2 , C(O)R 12  or OR 11 ; 
         a is 0 or 1; 
         b is 1, 2 or 3; 
         R 11  is H or C 1-3  alkyl; 
         R 12  is OH or C 1-3  alkyl; 
         when a is 1 then 
       
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
       
       and when a is 0 then 
       
         
           
           
               
               
           
         
       
       and R 8  is S, O, NH or CH 2 . 
     
     
         2 . The method according to  claim 1 , wherein said compound is represented by Formula I wherein:
 X is S;   R 6  is H or substituted or unsubstituted C 1-3  alkyl;   a is 1; and   
       
         
           
           
               
               
           
         
       
     
     
         3 . The method according to  claim 1 , wherein said compound is selected from:
 1-[3-methyl-4-(5-{[1-(3-nitrophenyl)propyl]thio}-1,3,4-oxadiazol-2-yl)benzyl]azetidine-3-carboxylic acid;   1-[3-methyl-4-(5{[1-(3-nitrophenyl)ethyl]thio}-1,3,4-oxadiazol-2-yl)benzyl]azetidine-3-carboxylic acid;   1-(4-{5-[(3-chloro-2-fluorobenzyl)sulfanyl]-1,3,4-oxadiazol-2-yl}benzyl)azetidine-3-carboxylic acid; and   1-(4-{5-[(1-Phenylbutyl)sulfanyl]-1,3,4-oxadiazol-2-yl}benzyl)azetidine-3-carboxylic acid.   
     
     
         4 . The method according to  claim 1 , wherein the pharmaceutical composition further comprises pharmaceutically acceptable adjuvants, diluents or carriers. 
     
     
         5 . The method of  claim 1  wherein the mammal is a human.