Inhibitors of the plasmodial surface anion channel as antimalarials

Abstract

Disclosed are inhibitors of the plasmodial surface anion channel (PSAC) inhibitors and the use thereof in treating or preventing malaria in an animal such as a human, comprising administering an effective amount of an inhibitor or a combination of inhibitors. An example of such an inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 to R 7 are as described herein.

1 .- 49 . (canceled) 
     
     
         50 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and
 (i) a compound of formula IV:   
       
         
           
           
               
               
           
         
         wherein 
         Z is a group having one or more 4-7 membered rings, wherein at least one of the rings has at least one heteroatom selected from the group consisting of O, S, and N; and when two or more 4-7 membered rings are present, the rings may be fused or unfused; wherein the rings are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; 
         R a  is hydrogen, alkyl, or alkoxy; 
         P is a bond, alkyl, alkoxy, (CH 2 ) r , or (CH 2 O) s , wherein r and s are independently 1 to 6; 
         Q is a heterocyclic group, an aryl group, or an heterocyclyl aryl group, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; and 
         when P is alkyl or alkoxy, Q is absent; 
         or a pharmaceutically acceptable salt thereof; 
         (ii) a compound of formula V: 
       
       
         
           
           
               
               
           
         
         wherein R 11  and R 12  are independently hydrogen, alkyl, cycloalkyl, or aryl which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halo, hydroxy, nitro, cyano, amino, alkylamino, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; 
         R 13 -R 15  are independently selected from the group consisting of alkyl, halo, alkoxy, hydroxy, nitro, cyano, amino, alkylamino, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; 
         or a pharmaceutically acceptable salt thereof; or 
         (iii) any combination of the compounds of formulas IV and V, or pharmaceutically acceptable salts thereof. 
       
     
     
         51 .- 99 . (canceled) 
     
     
         100 . The pharmaceutical composition of  claim 50 , wherein, in the compound of formula IV, P is a bond or (CH 2 O) s , and Q is a heterocyclic group, an aryl group, or an heterocyclyl aryl group, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl, and
 wherein Z is a group having one or two 4-7 membered rings, wherein at least one of the rings has at least one heteroatom selected from the group consisting of O, S, and N; and when two 4-7 membered rings are present, they may be fused or unfused; wherein the rings are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.   
     
     
         101 . The pharmaceutical composition of  claim 100 , wherein the compound of formula IV is: 
       
         
           
           
               
               
           
         
       
     
     
         102 . The pharmaceutical composition of  claim 100 , wherein the compound of formula IV is: 
       
         
           
           
               
               
           
         
       
     
     
         103 . The pharmaceutical composition of  claim 100 , wherein the compound of formula IV is: 
       
         
           
           
               
               
           
         
       
     
     
         104 . The pharmaceutical composition of  claim 50 , wherein, in the compound of formula V, R — is alkyl or alkoxy and R 14  and R 15  are hydrogen, wherein R 11  is H or alkyl and R 12  is alkyl, cycloalkyl, or aryl, wherein said aryl is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halo, hydroxy, nitro, cyano, amino, alkylamino, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl. 
     
     
         105 . The pharmaceutical composition of  claim 104 , wherein the compound of formula V is: 
       
         
           
           
               
               
           
         
       
     
     
         106 . The pharmaceutical composition of  claim 104 , wherein the compound of formula V is: 
       
         
           
           
               
               
           
         
       
     
     
         107 . The pharmaceutical composition of  claim 50 , wherein the pharmaceutical composition is a formulation suitable for oral administration selected from capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the compound as solid or as granules.