Thiosemicarbazones as anti-virals and immunopotentiators

Abstract

Novel immune potentiators, novel vaccine adjuvants, novel compounds and pharmaceutical compositions, as well as novel methods for treating viral infections, including HCV, by administering the compounds and compositions, and novel methods for modulating the immune response by administering the compounds and/or compositions.

1 - 74 . (canceled) 
     
     
         75 . A compound of formula IX: 
       
         
           
           
               
               
           
         
       
       wherein:
 R′ is H or lower alkyl; 
 Y is an aryl or heteroaryl group having one ring or two fused rings; 
 Y′ is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino; and 
 Y″ is absent or is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino; 
 or a pharmaceutically acceptable salt or tautomer thereof. 
 
     
     
         76 . The compound of  claim 75  wherein Y is selected from the group consisting of phenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, and imidazolyl. 
     
     
         77 . A pharmaceutical composition comprising a compound of  claim 75 , and a pharmaceutically acceptable carrier. 
     
     
         78 . The pharmaceutical composition of  claim 77 , further comprising an antigen. 
     
     
         79 . The pharmaceutical composition of  claim 78 , wherein the antigen is conjugated to a carrier protein. 
     
     
         80 . The pharmaceutical composition of  claim 79 , wherein the carrier protein is CRM197 diphtheria toxoid. 
     
     
         81 . A method to induce an immunostimulatory effect in a patient, comprising administering to the patient the pharmaceutical composition of  claim 78 . 
     
     
         82 . A composition comprising:
 a vaccine in an amount effective to stimulate a cell-mediated immune response; and   a vaccine adjuvant comprising a thiosemicarbazone in an amount effective to potentiate the cell-mediated immune response to the vaccine,   
       wherein the thiosemicarbazone is a compound of  claim 75 . 
     
     
         83 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and the pharmaceutically acceptable salts or tautomers thereof. 
       
     
     
         84 . A pharmaceutical composition comprising a compound of  claim 75 , and a pharmaceutically acceptable carrier. 
     
     
         85 . The pharmaceutical composition of  claim 84 , further comprising an antigen. 
     
     
         86 . A method to induce an immunostimulatory effect in a patient, comprising administering to the patient the pharmaceutical composition of  claim 84 . 
     
     
         87 . A method to treat a viral infection, comprising administering to a subject in need thereof a compound of formula II: 
       
         
           
           
               
               
           
         
       
       wherein:
 W is selected from aryl, substituted aryl, and a substituted or unsubstituted heteroaryl group having one ring or two fused rings; 
 X is absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, and carbocyclyl, wherein if X is absent, Y and W together form an optionally substituted aryl or heteroaryl group having at least two fused rings; 
 Y is selected from aryl, substituted aryl, and a substituted or unsubstituted heteroaryl group having one ring or two fused rings; 
 Y′ is absent or is selected from the group consisting of F, Cl, Br, I, nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino; 
 Y″ is absent or is selected from the group consisting of F, Cl, Br, I, nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino; 
 R′ is H or CH 3 ; 
 Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, and optionally substituted heterocyclylalkyl; 
 
       substituted;
 or a tautomer or a pharmaceutically acceptable salt thereof. 
 
     
     
         88 . The method of  claim 87 , wherein the compound is a compound of formula III, 
       
         
           
           
               
               
           
         
       
       wherein:
 W is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl groups; 
 X and L are each independently absent or independently selected from the group consisting of lower alkyl and carbonyl; 
 R is absent or selected from the group consisting of carbonyl, amino, alkyl, substituted alkyl, alkylamino, and dialkylamino; 
 Y is an aryl or heteroaryl group; 
 Y′ is absent or selected from the group consisting of F, Cl, Br, I, alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro; 
 Y″ is absent or selected from the group consisting of F, Cl, Br, I, alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro; 
 Z is hydrogen, or if Y is furanyl, then Z may be selected from the group consisting of alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro;
 or a pharmaceutically acceptable salt or a tautomer thereof. 
 
 
     
     
         89 . The composition of  claim 88  wherein Y is selected from the group consisting of phenyl, furanyl, pyridinyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, imidazolyl and pyrimidinyl. 
     
     
         90 . The method of  claim 89  wherein Y is phenyl, furanyl, or pyrimidinyl. 
     
     
         91 . The method of  claim 87  wherein the compound is a compound of formula IV, 
       
         
           
           
               
               
           
         
         wherein:
 W is an optionally substituted phenyl or pyridinyl group; 
 X is alkoxy or alkylamino; 
 Y′ is H or fluoro; 
 Y″ is dialkylamino, fluoro, or nitro; 
 
         a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         92 . The method of  claim 87  wherein the compound is of the formula 
       
         
           
           
               
               
           
         
       
       wherein:
 W is phenyl substituted with at least one member selected from the group consisting of —Cl; —F; —Br; —CF 3 ; —OCH 3 ; —NO 2 ; —CH 3 ; —N(CH 3 ) 2 ; and —OCF 3 ; 
 X is alkoxy;
 or a pharmaceutically acceptable salt or a tautomer thereof. 
 
 
     
     
         93 . The method of  claim 87  wherein the compound is 
       
         
           
           
               
               
           
         
       
       wherein:
 W is pyridinyl or is phenyl substituted with at least one member selected from the group consisting of Cl, F, and CF 3 ; 
 X is alkylamino;
 or a pharmaceutically acceptable salt or a tautomer thereof. 
 
 
     
     
         94 . The method of  claim 87  wherein the compound is a compound of Formula IVc 
       
         
           
           
               
               
           
         
       
       wherein:
 W is phenyl substituted with at least one member selected from the group consisting of —Cl; —F; —Br; —CF 3 ; —OCH 3 ; —NO 2 ; —CH 3 ; N(CH 3 ) 2 ; and —OCF 3 ; 
 X is alkoxy; and 
 n is an integer from 1 to 3;
 or a pharmaceutically acceptable salt or tautomer thereof. 
 
 
     
     
         95 . The method of  claim 87  wherein the thiosemicarbazone is a compound of Formula V 
       
         
           
           
               
               
           
         
       
       wherein:
 R is an alkyl group; 
 X is alkoxy; and
 or a pharmaceutically acceptable salt or tautomer thereof. 
 
 
     
     
         96 . The method of  claim 87  wherein the compound is a compound of Formula VI 
       
         
           
           
               
               
           
         
       
       wherein:
 X is absent or an alkylene; 
 Y′ is absent or is an alkyl group; and 
 R is a halogen;
 or a pharmaceutically acceptable salt or tautomer thereof. 
 
 
     
     
         97 . The method of  claim 87  wherein the compound is a compound of Formula VII 
       
         
           
           
               
               
           
         
       
       wherein:
 R is nitro and Z is H; or 
 R is Cl and Z is selected from the group consisting of alkyl, pyridylalkylene, piperidinylalkylene, morpholinylalkylene, and piperazinylalkylene;
 or a pharmaceutically acceptable salt or tautomer thereof. 
 
 
     
     
         98 . The method of  claim 87  wherein the compound is a compound of formula VIII or a pharmaceutically acceptable salt or tautomer thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 W is a phenyl, substituted phenyl, pyridinyl, or substituted pyridinyl group; 
 X is absent or is selected from the group consisting of oxo, amino, alkylene, and substituted alkylene; and 
 Y is an aryl or heteroaryl group. 
 
     
     
         99 . The method of  claim 98 , wherein Y is selected from the group consisting of phenyl, furanyl, pyridinyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, and imidazolyl. 
     
     
         100 . The method of  claim 87  wherein the compound is a compound of formula IX: 
       
         
           
           
               
               
           
         
       
       wherein:
 R′ is H or lower alkyl; 
 Y is an aryl or heteroaryl group having one ring or two fused rings; 
 Y′ is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino; and 
 Y″ is absent or is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino;
 or a pharmaceutically acceptable salt or tautomer thereof. 
 
 
     
     
         101 . The method of  claim 100  wherein Y is selected from the group consisting of phenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, and imidazolyl. 
     
     
         102 . A method to treat a viral infection, comprising administering to a subject a compound selected from the compounds in Tables I, II, and III, and the pharmaceutically acceptable salts of these compounds. 
     
     
         103 . The method of  claim 102  wherein the compound is selected from the group consisting of: