Methods and compositions for modulating sphingosine -1- phosphate (S1P) receptor activity

Abstract

The present invention relates to compounds which modulate the activity of the S1P1 receptor, the use of these compounds for treating conditions associated with signaling through the S1P1 receptor, and pharmaceutical compositions comprising these compounds.

1 . A compound of Formula IV:  
       
         
           
           
               
               
           
         
       
       wherein: 
 L is alkoxy, a covalent bond, substituted or unsubstituted alkyl, alkylcarbonyl, thioether, alkylsulfonyl, alkylcarbonylamino, alkylaminocarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, or substituted or unsubstituted heteroaryl;  
 Z and A are each independently substituted or unsubstituted aryl, wherein Z and A may be linked by a covalent bond, substituted or unsubstituted alkyl, NH, alkyloxy, O, thioether, S, aminocarbonyl, carbonylamino, carbonyloxy, or oxycarbonyl;  
 R 1 , R 2 , R 5  and R 12  are each independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted aryl, straight chain or branched C 1 -C 6 -alkyl, straight chain or branched C 1 -C 6 -alkoxy, straight chain or branched halo-C 1 -C 6 -alkyl, straight chain or branched halo-C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxyl-C 1 -C 6 -alkyl, carboxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-SO 2  or N(R)R′, wherein R and R′ are each independently hydrogen, straight chain or branched C 1 -C 6 -alkyl, straight chain or branched C 1 -C 6 -alkoxy, straight chain or branched halo-C 1 -C 6 -alkyl, straight chain or branched halo-C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxyl-C 1 -C 6 -alkyl, carboxy-C 1 -C 6 -alkyl or C 1 -C 6 -alkyl-SO 2 ;  
 Q is —CH 2 NR—, —CH 2 NR(CO)—, —NH(CO)—, —(CO)NH—, —(CO)—, —O—, —S—, —SO—, —SO 2 —, —NRSO 2 —, —SO 2 —NR— or heteroaryl, where R is hydrogen or straight chain or branched C 1 -C 6 -alkyl;  
 R 6  is —OH, —CO 2 R 9 , —CH 2 ═CH(CO)OR 9 , —OPO 2 R 10 R 11 , —OPO 3 R 10 R 11 , —CH 2 PO 3 R 10 R 11 , —OPO 2 (S)R 10 R 11  or —C(Y)(X)PO 3 R 10 R 11 , where X is hydroxyl or halide and Y is H or halide; or analogues of other carboxylate, phosphate or phosphonate isosteres not limited to those shown below; R 9  is H, straight chain or branched C 1 -C 6 -alkyl, or a substituted or unsubstituted aryl group; R10 and R11 are each independently H, straight chain or branched C 1 -C 6 -alkyl, a substituted or unsubstituted aryl group or selected from, but not limited to, the prodrugs listed below:  
                     
 R 7 is H, C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, aryl, or together with R8 form a C 2 -C 5 -alkylene or a C 2 -C 5 -alkenylene group;  
 R 8  is H or C 1 -C 6 -alkyl; and  
 m and n are each, independently, an integer from 0 to 3; and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is hydrogen.  
     
     
         3 . The compound of  claim 1 , wherein R 2  is hydrogen.  
     
     
         4 . The compound of  claim 1 , wherein R 2  is alkyl.  
     
     
         5 . The compound of  claim 1 , wherein R 2  is a halogen.  
     
     
         6 . The compound of  claim 1 , wherein R 5  is hydrogen.  
     
     
         7 . The compound of  claim 1 , wherein R 5  is a substituted or unsubstituted alkyl group or a halogen.  
     
     
         8 . The compound of  claim 1 , wherein Q is selected from the group consisting of —NH—CO—, —CO—NH—, a substituted or unsubstituted aryl group, and a carbonyl group.  
     
     
         9 . The compound of  claim 1 , wherein R 6  is selected from the group consisting of hydrogen, an alkoxy group, an alkyl ether group, a hydroxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryloxy group, a carboxylic acid, a phosphate, an alkyl phosphate, a cycloalkyl phosphate, a phosphonate, a thiophosphate, an alkythiophosphate, a cycloalkylthiophosphate, a thiophosphonate and a substituted or unsubstituted alkyl or aryl ester.  
     
     
         10 . The compound of  claim 9 , wherein substituted or unsubstituted R 6  aryloxy group is a substituted or unsubstituted phenoxy group.  
     
     
         11 . The compound of  claim 10 , wherein said R 6  substituted phenoxy group is substituted with one or more substituted or unsubstituted alkyl groups.  
     
     
         12 . The compound of  claim 1 , wherein R 7  is hydrogen, or a substituted or unsubstituted alkyl group.  
     
     
         13 . The compound of  claim 1 , wherein R 8  is selected from the group consisting of hydrogen, a hydroxy group and a substituted or unsubstituted alkyl.  
     
     
         14 . The compound of  claim 1 , wherein R 12  is meta to Q.  
     
     
         15 . The compound of  claim 14 , wherein R 12  is cyano, hydrogen, trifluoroalkyl, or halogen.  
     
     
         16 . The compound of  claim 1 , wherein R 12  is para to Q.  
     
     
         17 . The compound of  claim 16 , wherein R 12  is hydrogen.  
     
     
         18 . The compound of  claim 1 , wherein L is C 1 -C 5  alkoxy.  
     
     
         19 . The compound of  claim 1 , wherein Z is substituted or unsubstituted phenyl.  
     
     
         20 . The compound of  claim 1 , wherein A is selected from the group consisting of substituted or unsubstituted phenyl and a substituted or unsubstituted heteroaryl.  
     
     
         21 . The compound of  claim 1 , wherein A is linked to Z through a single covalent bond.  
     
     
         22 . The compound of  claim 1 , wherein A is linked to Z through a covalent bond and NH to form a fused ring structure.  
     
     
         23 . The compound of  claim 1 , wherein said compound is an agonist of a sphingosine 1-phosphate 1 receptor.  
     
     
         24 . The compound of  claim 1 , wherein said compound has an IC 50  in the S1P-1 assay of about 100 nM or less.  
     
     
         25 . A compound selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         26 . A method for treating a sphingosine 1-phosphate associated disorder in a subject, comprising administering to said subject an effective amount of a compound of formula (IV), such that said subject is treated for said sphingosine 1-phosphate associated disorder, wherein said compound of formula (IV) is:  
       
         
           
           
               
               
           
         
       
       wherein: 
 L is alkoxy, a covalent bond, substituted or unsubstituted alkyl, alkylcarbonyl, thioether, alkylsulfonyl, alkylcarbonylamino, alkylaminocarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, or substituted or unsubstituted heteroaryl;  
 Z and A are each independently substituted or unsubstituted aryl, wherein Z and A may be linked by a covalent bond, substituted or unsubstituted alkyl, NH, alkyloxy, O, thioether, S, aminocarbonyl, carbonylamino, carbonyloxy, or oxycarbonyl;  
 R 1 , R 2 , R 5  and R 12  are each independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted aryl, straight chain or branched C 1 -C 6 -alkyl, straight chain or branched C 1 -C 6 -alkoxy, straight chain or branched halo-C 1 -C 6 -alkyl, straight chain or branched halo-C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxyl-C 1 -C 6 -alkyl, carboxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-SO 2  or N(R)R′, wherein R and R′ are each independently hydrogen, straight chain or branched C 1 -C 6 -alkyl, straight chain or branched C 1 -C 6 -alkoxy, straight chain or branched halo-C 1 -C 6 -alkyl, straight chain or branched halo-C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxyl-C 1 -C 6 -alkyl, carboxy-C 1 -C 6 -alkyl or C 1 -C 6 -alkyl-SO 2 ;  
 Q is —CH 2 NR—, —CH 2 NR(CO)—, —NH(CO)—, —(CO)NH—, —(CO)—, —O—, —S—, —SO—, —SO 2 —, —NRSO 2 —, —SO 2 —NR— or heteroaryl, where R is hydrogen or straight chain or branched C 1 -C 6 -alkyl;  
 R 6  is —OH, —CO 2 R 9 , —CH 2 ═CH(CO)OR 9 , —OPO 2 R 10 R 11 , —OPO 3 R 10 R 11 , —CH 2 PO 3 R 10 R 11 , —OPO 2 (S)R 10 R 11  or —C(Y)(X)PO 3 R 10 R 11 , where X is hydroxyl or halide and Y is H or halide; or analogues of other carboxylate, phosphate or phosphonate isosteres not limited to those shown below; R 9  is H, straight chain or branched C 1 -C 6 -alkyl, or a substituted or unsubstituted aryl group; R10 and R11 are each independently H, straight chain or branched C 1 -C 6 -alkyl, a substituted or unsubstituted aryl group or selected from, but not limited to, the prodrugs listed below:  
                     
 R 7  is H, C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, aryl, or together with R8 form a C 2 -C 5 -alkylene or a C 2 -C 5 -alkenylene group;  
 R 8  is H or C 1 -C 6 -alkyl; and  
 m and n are each, independently, an integer from 0 to 3; and pharmaceutically acceptable salts thereof.  
 
     
     
         27 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.