Bicyclic sphingosine 1-phosphate analogs

Abstract

Compounds that have agonist activity at one or more of the S1P receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at S1P receptors.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 X 1 , Y 1  and Z 1  are independently O, CR a , CR a R b , N, NR c , or S; 
 R 1  is hydrogen, halo (C 1 -C 10 )alkyl, (C 1 -C 10 )haloalkyl, or (C 1 -C 10 )alkoxy; 
 R 2  is hydrogen, halo, (C 1 -C 20 )alkyl, (C 1 -C 20 )alkoxy; (C 2 -C 26 )alkoxyalkyl; 
 (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 3 -C 12 )cycloalkyl, (C 6 -C 10 )aryl, (C 7 -C 30 )arylalkyl, (C 2 -C 10 )heterocyclic, and (C 5 -C 10 )heteroaryl; or R 2  can be a group having formula II, III, IV, V, or VI; 
 
       
         
           
           
               
               
           
         
         where R 7 , R 8 , R 9 , R 10 , R 11 , R 12 R 13 , and R 14  are independently O, S, C, CR 15 CR 16 R 17 ,C═O, N or NR 18    
         R 15 , R 16  and R 17  are independently hydrogen, halo, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkyl substituted with halo, hydroxy, (C 1 -C 10 )alkoxy, or cyano; and where R 18  can be hydrogen or (C 1 -C 10 )alkyl; 
         where at least one of R 10 , R 11 R 12 , R 13 , or R 14  is a heteroatom; 
         where Z 2  is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, substituted alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, alkyl substituted aryl, arylalkyl, or aryl substituted arylalkyl; wherein the alkyl groups of Z 2  are optionally substituted with 1, 2, 3, or 4 substituent groups where the substituent groups independently are halo, (C 1 -C 10 )alkoxy or cyano; 
       
       
         
           
           
               
               
           
         
         indicates one or more optional double bonds; 
         wherein Y 2  is O, C═O, or CH 2 ; W 1  is a bond or —CH 2 —CH 2 —CH 2 —; W 2  is a bond or —CH 2 — and m is 1, 2, or 3, or (C═O)(CH 2 ) 1-5  and m is 1; and n is 0, 1, 2, or 3; 
         each   represents an optional double bond; R 3  is hydrogen, (C 1 -C 10 )alkyl, or (C 1 -C 10 )alkoxy; 
         R 4  is hydroxyl (—OH), phosphate (—OPO 3 H 2 ), phosphonate (—CH 2 PO 3 H 2 ), or alpha-substituted phosphonate; 
         R a , R b , and R c  are independently hydrogen, or (C 1 -C 10 )alkyl; 
         wherein the alkyl groups of R 1  are optionally substituted with 1, 2, 3, or 4 substituent groups where the substituent groups independently are halo, (C 1 -C 10 )alkoxy or cyano; 
         wherein any of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, or heteroaryl groups of R 2  are optionally substituted with 1, 2, 3, or 4 substituent groups where the substituent groups independently are oxo (═O), imino (═NR d ), (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, or C 6 -aryl; or wherein one or more of the carbon atoms in the R 2  alkyl groups can be independently replaced with non-peroxide oxygen, sulfur or NR c ; the alkyl groups of R 3  are optionally substituted with 1, or 2 hydroxy groups; and R d  is hydrogen, or (C 1 -C 10 )alkyl; or 
         a pharmaceutically acceptable salt or ester thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl substituted with, alkoxy or cyano, alkyl-substituted aryl, aryl-substituted alkyl, or aryl-substituted arylalkyl. 
     
     
         3 . The compound of  claim 2 , wherein R 1  is hydrogen, trifluoromethyl, or —CH 2 CF 3 . 
     
     
         4 . The compound of  claim 2 , wherein R 1  is benzyl, phenylethyl, or methyl benzyl. 
     
     
         5 . The compound of  claim 1 , wherein R 2  comprises —CH 2 —CH 2 —O—CH 2 —CH 2 —O—. 
     
     
         6 . The compound of  claim 1 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 6 , wherein R 2  is: 
       
         
           
           
               
               
           
         
       
       where Y 3  is (CH 3 ) 3 C—, CH 3 CH 2 (CH 3 ) 2 C—, CH 3 CH 2 CH 2 —, CH 3 (CH 2 ) 2 CH 2 —, CH 3 (CH 2 ) 4 —CH 2 —, (CH 3 ) 2 CHCH 2 —, (CH 3 ) 3 CCH 2 —, CH 3 CH 2 O—, (CH 3 ) 2 CHO—, or CF 3 CH 2 CH 2 — or a group having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 7 , wherein R 2  is: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 8 , wherein R 2  is: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 6 , wherein R 2  is: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 10 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1 , wherein R 2  has formula IV 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 12 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , wherein R 2  is (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl and (C 2 -C 14 )alkynyl, (C 1 -C 10 )alkoxy or (C 2 -C 16 )alkoxyalkyl. 
     
     
         15 . The compound of  claim 14 , wherein R 2  is (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy or (C 2 -C 12 )alkoxyalkyl. 
     
     
         16 . The compound of  claim 15 , wherein R 2  is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, heptoxy, or octoxy. 
     
     
         17 . The compound of  claim 1 , wherein each of X 1 , Y 1  and Z 1  is CH 2 . 
     
     
         18 . The compound of  claim 1 , wherein R 3  is hydrogen, methyl, hydroxymethyl, ethyl, hydroxyethyl, propyl, or isopropyl. 
     
     
         19 . The compound of  claim 18 , wherein R 3  is hydrogen, methyl, hydroxymethyl, ethyl, or hydroxyethyl. 
     
     
         20 . The compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 20 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         22 . A method for prevention or treatment of a pathological condition or symptom in a mammal, wherein the activity of sphingosine 1-phosphate receptors is implicated and agonism of such activity is desired, comprising administering to said mammal an effective amount of a compound of  claim 1 . 
     
     
         23 . The method of  claim 21 , wherein the pathological condition is an autoimmune disease. 
     
     
         24 . The method of  claim 22 , wherein the autoimmune disease is uveitis, type I diabetes, rheumatoid arthritis, inflammatory bowel diseases, or multiple sclerosis. 
     
     
         25 . The method of  claim 24 , wherein the autoimmune disease is multiple sclerosis. 
     
     
         26 . The method of  claim 22 , wherein the prevention or treatment of a pathological condition is altering lymphocyte trafficking. 
     
     
         27 . The method of  claim 26 , wherein altering lymphocyte trafficking provides prolonged allograft survival. 
     
     
         28 . The method of  claim 27 , wherein the allograft is for transplantation. 
     
     
         29 . A method for prevention or treatment of a pathological condition or symptom in a mammal, wherein the activity S1P lyase implicated and inhibition of the S1P lyase is desired, comprising administering to said mammal an effective amount of a compound of  claim 1 .