Fc RECEPTOR MODULATING COMPOUNDS AND COMPOSITIONS

Abstract

The present invention provides compounds capable of binding to an Fc receptor and modulating Fc receptor activity comprising a core lipophilic group in the form of an Aryl zing substituted with a group rich in p-electrons. The invention further provides for a method of treating an autoimmune disease involving Fc receptor activity using such compounds. A method for obtaining a compound which modulates Fc receptor activity is also provided, the method comprising: (a) providing or designing compounds having structural characteristics to fit in the groove of the FcγRIIa structure; and (b) screening the compounds for modulating activity on the Fc receptor.

1 . A compound having the general formula I: 
       
         
           
           
               
               
           
         
         wherein 
         R1, R2, R3, R4, R5, are each independently selected from H, halogen, NO 2 , CN, C 1-6  alkyl, CF 3 , aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, OCF 3 , OR18, SR18, OC 1-6  alkyl, OC 2-6 alkylNR18R19, Oaryl, Oheteroaryl, Ocycloalkyl, Ocycloheteroalkyl, OC 1-6 alkylaryl, OC 1-6 alkylheteroaryl, OC 1-6 alkylcycloalkyl, OC 1-6  cycloheteroalkyl, CO 2 R18, C 1-6  alkylCO 2 R18, CONR18R19, C 1-6  alkylCONR18R19, NR18R19, C 1-6  alkylNR18R19, NR20C 1-6  alkylNR18R19, C 1-6  alkylNR20C 1-6 alkylNR18R19, NR18COR19, C 1-6  alkylNR18COR19, C 1-6  alkylNR20CONR18R19, NR20CONR18R19, C 1-6  alkylNR18SO 2 R19, NR18SO 2 R19;
 R18 and R19 are each independently selected from H, C 1-4  alkyl, C 1-4  alkyl cycloheteroalkyl, aryl, heteroaryl, C 1-4  alkyl aryl, C 1-4  alkyl heteroaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
 R20, R21 are each independently selected from H, C 1-4  alkyl; 
 
 
         R6 is selected from H, C 1-4  alkyl, 
         R7 is selected from H, C 1-4  alkyl, SH, CN; 
         R8 is selected from OR9, NR9R10; 
         R9, R10 are each independently selected from H, C 1-4  alkyl, C 1-4  alkylCO 2 H, C 1-4  alkyl cycloheteroalkyl, aryl, heteroaryl, C 1-4  alkyl aryl, C 1-4  alkyl heteroaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR11;
 R11 is selected from H, C 1-4  alkyl. 
 
       
     
     
         2 . A compound according to  claim 1  wherein
 R1, R2, R3, R4 and R5, are each independently selected from H, OH, OC 1-4 alkyl, OC 1-4  alkylaryl, C 1-4 alkyl, halogen; 
 R6 is selected from H, 
 R7 is selected from H, SH, CN; 
 R8 is selected from OH, NR9R10;
 R9, R10 are each independently selected from H, C 1-4  alkyl, C 1-4 alkylCO 2 H. 
 
 
     
     
         3 . A compound having the general formula II: 
       
         
           
           
               
               
           
         
         wherein 
         R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are each independently selected from H, halogen, NO 2 , CN, C 1-6  alkyl, CF 3 , aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, OCF 3 , OR18, SR18, OC 1-6  alkyl, OC 2-6  alkylNR18R19, Oaryl, Oheteroaryl, Ocycloalkyl, Ocycloheteroalkyl, OC — 6 alkylaryl, OC 1-6  alkylheteroaryl, OC 1-6 alkylcycloalkyl, OC 1-6  cycloheteroalkyl, CO 2 R18, C 1-6  alkylCO 2 R18, CONR18R19, C 1-6  alkylCONR18R19, NR18R19, C 1-6  alkylNR18R19, NR20C 1-6 alkylNR18R19, C 1-6  alkylNR20C 1-6  alkylNR18R19, NR18COR19, C 1-6  alkylNR18COR19, C 1-6  alkylNR20CONR18R19, NR20CONR18R19, C 1-6  alkylNR18SO 2 R19, NR18SO 2 R19;
 R18, R19 are each independently selected from H, C 1-4  alkyl, C 1-4  alkyl cycloheteroalkyl, aryl, heteroaryl, C 1-4  alkyl aryl, C 1-4  alkyl heteroaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
 R20, R21 are each independently selected from H, C 1-4  alkyl; 
 
 
         R11R, R12 are each independently selected from H, C 1-4  alkyl, halogen, OC 1-4  alkyl. 
       
     
     
         4 . A compound according to  claim 3  wherein
 R1, R2, R3, R4, R5, R6, R7, R8, R10 are each independently selected from H, C 1-4  alkyl, OC 1-4  alkyl, CO 2 H, CN; 
 R11 and R12 are each independently selected H, C 1-4  alkyl. 
 
     
     
         5 . A compound having the general formula III: 
       
         
           
           
               
               
           
         
         wherein 
         R1, R2, R3, R4, R5 and R6 are each independently selected from H, halogen, NO 2 , CN, CF 3 , aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, OCF 3 , OR18, SR18, OC 1-6  alkyl, OC 2-6  alkylNR18R19, Oaryl, Oheteroaryl, Ocycloalkyl, Ocycloheteroalkyl, OC 1-6 alkylaryl, OC 1-6  alkylheteroaryl, OC 1-6 alkylcycloalkyl, OC 1-6  cycloheteroalkyl, CO 2 R18, C 1-6  alkylCO 2 R18, CONR18R19, C 1-6  alkylCONR18R19, NR18R19, C 1-6  alkylNR18R19, NR20C 1-6 alkylNR18R19, C 1-6  alkylNR20Cl — 6 alkylNR18R19, NR18COR19, Cl — 6 alkylNR18COR19, C 1-6  alkylNR20CONR18R19, NR20CONR18R19, C 1-6  alkylNR18SO 2 R19, NR18SO 2 R19;
 R18, R19 are each independently selected from H, C 1-4  alkyl, C 1-4  alkyl cycloheteroalkyl, aryl, heteroaryl, C 1-4  alkyl aryl, C 1-4  alkyl heteroaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
 R20, R21 are each independently selected from H, C 1-4  alkyl; 
 
 
         R7 is selected from H, CF 3 , aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, CO 2 R18, C 1-4 alkylCO 2 R18, CONR18R19, C 1-4  alkylCONR18R19, NR18R19, C 1-6 alkylNR18R19, NR20C 1-4  alkylNR18R19, C 1-6 alkylNR20C 1-4  alkylNR18R19, NR18COR19, C 1-6 alkylNR18COR19, C 1-6 alkylNR20CONR18R19, NR20CONR18R19, C 1-6 alkylNR18SO 2 R19, NR18SO 2 R19 wherein R18, R19 are as defined above. 
       
     
     
         6 . A compound according to  claim 5  wherein
 R1, R2, R3, R4, R5, and R6 are each independently selected from H, halogen, OH, OC 1-4  alkyl, C 1-4  alkyl; 
 R7 is selected from H, C 1-4  alkyl, C 1-4  alkylCO 2 H. 
 
     
     
         7 . The compound of formula V: 
       
         
           
           
               
               
           
         
       
     
     
         8 . A pharmaceutical composition comprising
 (a) one or more compounds according to  claim 1 ;   (b) a pharmaceutically acceptable diluent.   
     
     
         9 . A method for treating an autoimmune disease involving Fc receptor activity comprising administering to a subject in need of treatment with one or more compounds according to  claim 1 . 
     
     
         10 . A method according to  claim 9  wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, immune thrombocytopenia purpura, systemic lupus erythematosus and Crohn's disease. 
     
     
         11 . A method for obtaining a compound which modulates Fc receptor activity, the method comprising:
 (a) providing or designing one or more compounds having structural characteristics to fit in the groove of the FcγRIIa structure; and   (b) screening the one or more compounds for modulating activity on the Fc receptor.   
     
     
         12 . A method according to  claim 11  wherein step (a) comprises functionalising the one or more compounds with one or more substituent groups. 
     
     
         13 . A method according to  claim 11  wherein the compounds are screened by a FcγRIIa dependent platelet activation assay and/or aggregation assay where platelets are activated using heat aggregated human immunoglobulin G as an immune complex. 
     
     
         14 . A compound which modulates Fc receptor activity obtained by the method of  claim 11 . 
     
     
         15 . A method for treating an autoimmune disease involving Fc receptor activity comprising administering to a subject in need of treatment with a compound having the general formula IV: 
       
         
           
           
               
               
           
         
         wherein 
         R1, R2, R3, R4, R5 and R6 are each independently selected from H, halogen, NO 2 , CN, CF 3 , aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, OCF 3 , OR18, SR18, OC 1-6  alkyl, OC 2-6  alkylNR18R19, Oaryl, Oheteroaryl, Ocycloalkyl, Ocycloheteroalkyl, OC 1-6 alkylaryl, C 1-6 alkylheteroaryl, OC 1-6 alkylcycloalkyl, OC 1-6 cycloheteroalkyl, CO 2 R18, C 1-6  alkylCO 2 R18, CONR18R19, C 1-6  alkylCONR18R19, NR18R19, C 1-6  alkylNR18R19, NR20C 1-6 alkylNR18R19, C 1-6  alkylNR20C 1-6 alkylNR18R19, NR18COR19, C 1-6  alkylNR18COR19, C 1-6  alkylNR20CONR18R19, NR20CONR18R19, C 1-6 alkylNR18SO 2 R19, NR18SO 2 R19;
 R18, and R19 are each independently selected from H, C 1-4  alkyl, C 1-4  alkyl cycloheteroalkyl, aryl, heteroaryl, C 1-4  alkyl aryl, C 1-4  alkyl heteroaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21; 
 
         R20, R21 are each independently selected from H, C 1-4  alkyl. 
       
     
     
         16 . A method according to  claim 15  wherein
 R1, R2, R3, R4 are each independently selected from H, halogen, NO 2 , OC 1-4 alkyl, C 1-4 alkyl 
 R5 is selected from H, Cl, OC 1-4 alkyl, C 1-4 alkylaryl, OC 3-6 cycloalkyl; 
 R6 is selected from CO 2 H, CONR7R8; 
 R7, R8 are each independently selected from H, 5-tetrazole. 
 
     
     
         17 . A method for treating an autoimmune disease involving Fc receptor activity comprising administering to a subject in need of treatment a composition according to  claim 8 .