4-aryl quinols and analogs thereof as therapeutic agents

Abstract

The present invention pertains to compounds of the following formula, which are, inter alia, antiproliferative agents, anticancer agents, antimycobacterial agents, antituberculosis agents, and/or thioredoxin/thioredoxin reductase inhibitors: wherein: Q is ═O or ═N—S(═O) 2 —R Q ; R Q is —H or optionally substituted C 1-7 alkyl, C 3-20 heterocyclyl, or C 5-20 aryl; Ar is optionally substituted C 5-20 aryl; R O is an oxy substituent; the bond marked α is a single bond or a double bond; the bond marked β is a single bond or a double bond; R 3 and R 5 are each independently ring substituents; R 2 and R 6 are each independently ring substituents; and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, for example, in the treatment of proliferative conditions, (e.g., cancer), mycobacterial infections (e.g., tuberculosis), and/or conditions mediated by thioredoxin/thioredoxin reductase.

1 . A method for the treatment of colon cancer comprising administering to a subject suffering from said cancer a therapeutically-effective amount of a compound selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
       wherein: 
 Q is ═O or ═N—S(═O) 2 —R Q ;  
 R Q  is —H or optionally substituted C 1-7 alkyl, C 3-20 heterocyclyl, or C 5-20 aryl;  
 Ar is optionally substituted C 5-20 aryl;  
 R O  is an oxy substituent;  
 the bond marked α is a single bond or a double bond;  
 the bond marked β is a single bond or a double bond;  
 R 3  and R 5  are each independently ring substituents;  
 R 2  and R 6  are each independently ring substituents; and,  
 and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof;  
 
       and wherein: 
 R O  is —H or optionally substituted C 1-7 alkyl, C 3-20 heterocyclyl, C 5-20 aryl, C 1-7 alkyl-acyl, C 3-20 heterocyclyl-acyl, or C 5-20 aryl-acy;  
 
       and wherein: 
 each of the ring substituents, R 3 , R 4 , R 5 , and R 6 , is:  
 (a) H; or:  
 (b) a ring substituent which, together with an adjacent ring substituent, and together with the ring atoms to which these ring substituents are attached, form a fused ring; or:  
 (c) a divalent monodentate substituent selected from optionally substituted C 1-7 alkylidene and C 5-20 aryl-C 1-7 alkylidene;  
 and if one or both of R 2  and R 3  is a divalent monodentate group, then α is a single bond;  
 and if one or both of R 5  and R 5  is a divalent monodentate group, then β is a single bond. or:  
 (d) a monovalent monodentate substituent;  
 
       wherein said monovalent monodentate group is selected from: 
 halo; hydroxy; ether; formyl; acyl; carboxy; ester; acyloxy; amido; acylamido; thioamido; tetrazolyl; amino; nitro; azido; cyano; cyanato; thiocyano; isothiocyano; sulfhydryl; thioether; sulfonic acid; sulfonate; sulfone; sulfonyloxy; sulfinyloxy; sulfamino; sulfonamino; sulfinamino; sulfamyl; sulfonamido; C 1-7 alkyl, and C 5-20 aryl;  
 with the proviso that, if Q is ═O, α is a double bond, β is a double bond, each of R 2 , R 3 , R 5 , and R 6  is —H; and Ar is benzothiazol-2-yl, then R O  is other than: -Me, -Et, -Pr, —CH 2 —C≡CH, and —C(═O)CH 3 ; and, with the proviso that, if Q is ═O, α is a double bond, β is a double bond, then Ar is other than: phenyl, substituted phenyl, thiophenyl, chromone, or substituted chromone.  
 
     
   
   
       2 . A method according to  claim 1 , wherein each of the ring substituents, R 3 , R 4 , R 5 , and R 6 , is: 
 (a) H; or:    (b) a monovalent monodentate substituent.    
   
   
       3 . A method according to  claim 2 , wherein R O  is —H.  
   
   
       4 . A method according to  claim 2 , wherein R O  is C 1-7 alkyl; C 3-20 heterocyclyl; C 5-20 aryl; C 1-7 alkyl-acyl; C 3-20 heterocyclyl-acyl; or C 5-20 aryl-acyl; and is optionally substituted.  
   
   
       5 . A method according to  claim 2 , wherein Q is ═O.  
   
   
       6 . A method according to  claim 2 , wherein Q is ═N—S(═O) 2 —R Q , wherein R O  is —H or optionally substituted C 1-7 alkyl, C 3-20 heterocyclyl, or C 5-20 aryl.  
   
   
       7 . A method according to  claim 4 , wherein R Q  is selected from methyl, ethyl, phenyl, tolyl, and halo-substituted analogs thereof.  
   
   
       8 . A method according to  claim 3 , wherein Q is ═O.  
   
   
       9 . A method according to  claim 3 , wherein Q is ═N—S(═O) 2 —R Q , wherein R Q  is —H or optionally substituted C 1-7 alkyl, C 3-20 heterocyclyl, or C 5-20 aryl.  
   
   
       10 . A method according to  claim 9 , wherein R Q  is selected from methyl, ethyl, phenyl, tolyl, and halo-substituted analogs thereof.  
   
   
       11 . A method according to  claim 2 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       12 . A method according to  claim 2 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       13 . A method according to  claim 2 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       14 . A method according to  claim 2 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       15 . A method according to  claim 2 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       16 . A method according to  claim 2 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       17 . A method according to  claim 2 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       18 . A method according to  claim 2 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       19 . A method according to  claim 2 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       20 . A method according to any  claim 1 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       21 . A method according to  claim 1 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       22 . A method according to  claim 1 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       23 . A method according to  claim 2 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       24 . A method according to  claim 2 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       25 . A method according to  claim 2 , wherein the compound is selected from compounds of the following formula and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       26 . A method according to  claim 2 , wherein said monovalent monodentate group is selected from: 
 halo; C 1-7 alkyl; acyl; and, thioether.    
   
   
       27 . A method according to  claim 2 , wherein said monovalent monodentate group is selected from: 
 —F, —Cl, —Br, —I;    -Me, -Et, -nPr, -iPr, —CH 2 C≡CH;    —C(═O)Me, —C(═O)Et, —C(═O) n Pr, —C(═O)iPr, —C(═O)tBu;    —C(═O)Ph; and,    —SR S , wherein R S  is optionally substituted C 1-7 alkyl, C 3-20 heterocyclyl, C 5-20 aryl, or C 5-20 aryl-C 1-7 alkyl.    
   
   
       28 . A method according to  claim 2 , wherein each of the ring substituents, R 3  and R 5 , is a thioether group, —SR S ; and the ring substituents, R 2  and R 6 , are —H.  
   
   
       29 . A method according to  claim 8 , wherein said monovalent monodentate group is selected from: 
 halo; C 1-7 alkyl; acyl; and, thioether.    
   
   
       30 . A method according to  claim 8 , wherein said monovalent monodentate group is selected from: 
 —F, —Cl, —Br, —I;    -Me, -Et, -nPr, -iPr, —CH 2 C≡CH;    —C(═O)Me, —C(═O)Et, —C(═O) n Pr, —C(═O)iPr, —C(═O)tBu;    —C(═O)Ph; and,    —SR S , wherein R S  is optionally substituted C 1-7 alkyl, C 3-20 heterocyclyl, C 5-20 aryl, or C 5-20 aryl-C 1-7 alkyl.    
   
   
       31 . A method according to  claim 8 , wherein each of the ring substituents, R 3  and R 5 , is a thioether group, —SR S ; and the ring substituents, R 2  and R 6 , are —H.  
   
   
       32 . A method according to  claim 2 , wherein Ar is one of the following groups, and is optionally substituted:  
     
       
         
         
             
             
         
       
       wherein: 
 X 1  is ═CH— or ═N—;  
 Y 1  is —NR N —, O—, or —S—;  
 X 2  is ═CH— or ═N—;  
 Y 2  is —NR N —, —O—, or —S—;  
 X 3  is ═CH— or ═N—;  
 Y 3  is —CH═ or —N═;  
 Z 3  is ═CH— or ═N—;  
 X 4  is ═CH— or ═N—;  
 Y 4  is —CH═ or —N═;  
 Z 4  is ═CH— or ═N—;  
 X 5  is ═CH— or ═N—;  
 Y 5  is —CH═ or —N═; and,  
 Z 5  is ═CH— or ═N—;  
 
       wherein RN is —H, C 1-7 alkyl, C 3-20 heterocyclyl, or C 5-20 aryl.  
     
   
   
       33 . A method according to  claim 2 , wherein Ar is one of the following groups, and is optionally substituted, wherein R N  is —H, C 1-7 alkyl, C 3-20 heterocyclyl, or C 5-20 aryl:  
     
       
         
         
             
             
         
       
     
   
   
       34 . A method according to  claim 2 , wherein Ar is the following group, and is optionally substituted:  
     
       
         
         
             
             
         
       
     
   
   
       35 . A method according to  claim 8 , wherein Ar is the following group, and is optionally substituted:  
     
       
         
         
             
             
         
       
     
   
   
       36 . A method according to  claim 12 , wherein Ar is the following group, and is optionally substituted:  
     
       
         
         
             
             
         
       
     
   
   
       37 . A method according to  claim 13 , wherein Ar is the following group, and is optionally substituted:  
     
       
         
         
             
             
         
       
     
   
   
       38 . A method according to  claim 15 , wherein Ar is the following group, and is optionally substituted:  
     
       
         
         
             
             
         
       
     
   
   
       39 . A method according to  claim 16 , wherein Ar is the following group, and is optionally substituted:  
     
       
         
         
             
             
         
       
     
   
   
       40 . A method according to  claim 18 , wherein Ar is the following group, and is optionally substituted:  
     
       
         
         
             
             
         
       
     
   
   
       41 . A method according to  claim 19 , wherein Ar is the following group, and is optionally substituted:  
     
       
         
         
             
             
         
       
     
   
   
       42 . A method according to  claim 21 , wherein Ar is the following group, and is optionally substituted:  
     
       
         
         
             
             
         
       
     
   
   
       43 . A method according to  claim 22 , wherein Ar is the following group, and is optionally substituted:  
     
       
         
         
             
             
         
       
     
   
   
       44 . A method according to  claim 24 , wherein Ar is the following group, and is optionally substituted:  
     
       
         
         
             
             
         
       
     
   
   
       45 . A method according to  claim 25 , wherein Ar is the following group, and is optionally substituted:  
     
       
         
         
             
             
         
       
     
   
   
       46 . A method according to  claim 27 , wherein Ar is unsubstituted or substituted with one or more of: 
 halo; hydroxy; ether; formyl; acyl; carboxy; ester; acyloxy; amido; acylamido; thioamido; tetrazolyl; amino; nitro; azido; cyano; cyanato; thiocyano; isothiocyano; sulfhydryl; thioether; sulfonic acid; sulfonate; sulfonyl; sulfonyloxy; sulfinyloxy; sulfamino; sulfonamino; sulfinamino; sulfamyl; sulfonamido; C 1-7 alkyl; C 3-20 heterocyclyl; and C 5-20 aryl.    
   
   
       47 . A method according to  claim 27 , wherein Ar is unsubstituted or substituted with one or more of: 
 halo; hydroxy; ether; formyl; acyl; carboxy; ester; acyloxy; amido; acylamido; amino; sulfonyl; sulfonamido; C 1-7 alkyl; C 3-20 heterocyclyl; and C 5-20 aryl.    
   
   
       48 . A method according to  claim 27 , wherein Ar is unsubstituted or substituted with one or more of: 
 halo; C 1-7 alkyl; C 1-7 haloalkyl; C 1-7 alkoxy; C 1-7 haloalkoxy; and sulfonyl.    
   
   
       49 . A method according to  claim 27 , wherein Ar is unsubstituted or substituted with one or more of: 
 —F, —Cl, —Br, —I, -Me, -Et, —CF 3 , —CCl 3 , —OMe, —OEt, —SO 2 Me, and —SO 2 Et.    
   
   
       50 . A method according to  claim 28 , wherein Ar is unsubstituted or substituted with one or more of: 
 halo; hydroxy; ether; formyl; acyl; carboxy; ester; acyloxy; amido; acylamido; thioamido; tetrazolyl; amino; nitro; azido; cyano; cyanato; thiocyano; isothiocyano; sulfhydryl; thioether; sulfonic acid; sulfonate; sulfonyl; sulfonyloxy; sulfinyloxy; sulfamino; sulfonamino; sulfinamino; sulfamyl; sulfonamido; C 1-7 alkyl; C 3-20 heterocyclyl; and C 5-20 aryl.    
   
   
       51 . A method according to  claim 28 , wherein Ar is unsubstituted or substituted with one or more of: 
 halo; hydroxy; ether; formyl; acyl; carboxy; ester; acyloxy; amido; acylamido; amino; sulfonyl; sulfonamido; C 1-7 alkyl; C 3-20 heterocyclyl; and C 5-20 aryl.    
   
   
       52 . A method according to  claim 28 , wherein Ar is unsubstituted or substituted with one or more of: 
 halo; C 1-7 alkyl; C 1-7 haloalkyl; C 1-7 alkoxy; C 1-7 haloalkoxy; and sulfonyl.    
   
   
       53 . A method according to  claim 28 , wherein Ar is unsubstituted or substituted with one or more of: 
 —F, —Cl, —Br, —I, -Me, -Et, —CF 3 , —CCl 3 , —OMe, —OEt, —SO 2 Me, and —SO 2 Et.    
   
   
       54 . A method according to  claim 37 , wherein Ar is unsubstituted or substituted with one or more of: 
 halo; hydroxy; ether; formyl; acyl; carboxy; ester; acyloxy; amido; acylamido; thioamido; tetrazolyl; amino; nitro; azido; cyano; cyanato; thiocyano; isothiocyano; sulfhydryl; thioether; sulfonic acid; sulfonate; sulfonyl; sulfonyloxy; sulfinyloxy; sulfamino; sulfonamino; sulfinamino; sulfamyl; sulfonamido; C 1-7 alkyl; C 3-20 heterocyclyl; and C 5-20 aryl.    
   
   
       55 . A method according to  claim 37 , wherein Ar is unsubstituted or substituted with one or more of: 
 halo; hydroxy; ether; formyl; acyl; carboxy; ester; acyloxy; amido; acylamido; amino; sulfonyl; sulfonamido; C 1-7 alkyl; C 3-20 heterocyclyl; and C 5-20 aryl.    
   
   
       56 . A method according to  claim 37 , wherein Ar is unsubstituted or substituted with one or more of: 
 halo; C 1-7 alkyl; C 1-7 haloalkyl; C 1-7 alkoxy; C 1-7 haloalkoxy; and sulfonyl.    
   
   
       57 . A method according to  claim 37 , wherein Ar is unsubstituted or substituted with one or more of: 
 —F, —Cl, —Br, —I, -Me, -Et, —CF 3 , —CCl 3 , —OMe, —OEt, —SO 2 Me, and —SO 2 Et.    
   
   
       58 . A method according to  claim 1 , wherein the compound is selected from the following compounds and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       59 . A method according to  claim 1 , wherein the compound is selected from the following compounds and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof:  
     
       
         
         
             
             
         
       
     
   
   
       60 . A method for the treatment of breast cancer comprising administering to a subject suffering from said cancer a therapeutically-effective amount of a compound as defined in  claim 1 .  
   
   
       61 . A method for the treatment of lung cancer comprising administering to a subject suffering from said cancer a therapeutically-effective amount of a compound as defined in  claim 1 .  
   
   
       62 . A method for the treatment of a mycobacterial condition comprising administering to a subject suffering from said condition a therapeutically-effective amount of a compound as defined in  claim 1 .  
   
   
       63 . A method for the treatment of tuberculosis comprising administering to a subject suffering from said tuberculosis a therapeutically-effective amount of a compound as defined in  claim 1.