Cationic substituted benzofurans as antimicrobial agents

Abstract

A method of treating a Mycobacterium tuberculosis infection in a subject in need thereof by administering to the subject an effective amount of a cationic substituted benzofuran compound. Methods of treating microbial infections, including infections from protozoan pathogens, such as Leishmania donovani, Trypanosoma brucei rhodesiense , a Trypanosoma cruzi , and Plasmodium falciparum , and fungal pathogens, such as Candida albicans, Aspergillus fumigatus , and Cryptococcus neoformans , in a subject in need thereof by administering to the subject an effective amount of a cationic substituted benzofuran compound. Methods of synthesizing novel cationic substituted benzofuran compounds and the novel compounds themselves.

1 - 22 . (canceled)  
     
     
         23 . A method of treating a microbial infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (III):  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is an integer from 1 to 8;  
 p and q are integers from 0 to 3;  
 R 1  and R 2  are each independently selected from the group consisting of alkyl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl; and  
 R 3  and R 4  are each independently selected from the group consisting of:  
                     
 wherein: 
 R 6 , R 7 , R 8 , and R 9  are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; or 
 R 6  and R 7  together represent a C 2  to C 10  alkyl, C 2  to C 10  hydroxyalkyl, or C 2  to C 10  alkylene.  
 
 
 
     
     
         24 . The method of  claim 23 , wherein the microbial infection is selected from the group consisting of a  Mycobacterium tuberculosis  infection, a  Leishmania donovani  infection, a  Trypanosoma brucei rhodesiense  infection, a  Trypanosoma cruzi  infection, a  Plasmodium falciparum  infection, a  Candida albicans  infection, an  Aspergillus fumigatus  infection, and a  Cryptococcus neoformans  infection.  
     
     
         25 . The method of  claim 23 , wherein: 
 n is an integer from 1 to 5;    R 3  and R 4  are each                          R 3  is at one of the 4-position, 5-position, and 6-position of ring C; and    R 4  is at one of the 4′-position, 5′-position, and 6′-position of ring C′.    
     
     
         26 . The method of  claim 23 , wherein: 
 n is an integer from 1 to 5;    R 3  and R 4  are each                          R 3  is at one of the 4-position, 5-position, and 6-position of ring C; and    R 4  is at one of the 4′-position, 5′-position, and 6′-position of ring C′.    
     
     
         27 . The method of  claim 23 , wherein: 
 n is an integer from 1 to 5;    R 3  and R 4  are each                          R 3  is at one of the 4-position, 5-position, and 6-position of ring C; and    R 4  is at one of the 4′-position, 5′-position, and 6′-position of ring C′.    
     
     
         28 . The method of  claim 23 , wherein: 
 n is an integer from 1 to 5;    R 3  and R 4  are each                          R 3  is at one of the 4-position, 5-position, and 6-position of ring C; and    R 4  is at one of the 4′-position, 5′-position, and 6′-position of ring C′.    
     
     
         29 . The method of  claim 23 , wherein: 
 n is an integer from 1 to 5;    R 3  and R 4  are each                          R 3  is at one of the 4-position, 5-position, and 6-position of ring C; and    R 4  is at one of the 4′-position, 5′-position, and 6′-position of ring C.    
     
     
         30 . The method of  claim 23 , wherein the compound is selected from the group consisting of: 
 2-((4-Amidinobenzofuran-2-yl)methyl)benzofuran-4-carboxamidine;    2-((4-Amidinobenzofuran-2-yl)methyl)-N-isopropylbenzofuran-4-carboxamidine;    Bis(4-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)methane;    2-((5-Amidinobenzofuran-2-yl)methyl)benzofuran-5-carboxamidine;    2-((5-Amidinobenzofuran-2-yl)methyl)-N-isopropylbenzofuran-5-carboxamidine;    Bis(5-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)methane;    Bis(6-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)methane;    2-(2-(5-Amidinobenzofuran-2-yl)ethyl)benzofuran-5-carboxamidine;    2-(2-(5-Amidinobenzofuran-2-yl)ethyl)-N-isopropylbenzofuran-5-carboxamidine;    4,5-Dihydro-2-(2-(2-(5-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)ethyl)benzofuran-5-yl)-1H-imidazole;    2-(2-(6-Amidinobenzofuran-2-yl)ethyl)benzofuran-6-carboxamidine;    2-(2-(6-Amidinobenzofuran-2-yl)ethyl)-N-isopropylbenzofuran-6-carboxamidine;    4,5-dihydro-2-(2-(2-(6-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)ethyl)benzofuran-6-yl)-1H-imidazole;    2-(3-(5-Amidinobenzofuran-2-yl)propyl)benzofuran-5-carboxamidine;    2-(3-(5-Amidinobenzofuran-2-yl)propyl)-N-isopropylbenzofuran-5-carboxamidine;    4,5-Dihydro-2-(2-(3-(5-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)propyl)benzofuran-5-yl)-1H-imidazole;    2-(3-(6-Amidinobenzofuran-2-yl)propyl)benzofuran-6-carboxamidine;    2-(3-(6-Amidinobenzofuran-2-yl)propyl)-N-isopropylbenzofuran-6-carboxamidine;    4,5-Dihydro-2-(2-(3-(6-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)propyl)benzofuran-6-yl)-1H-imidazole;    2-(4-(5-Amidinobenzofuran-2-yl)butyl)benzofuran-5-carboxamidine;    2-(4-(5-Amidinobenzofuran-2-yl)butyl)-N-isopropylbenzofuran-5-carboxamidine;    4,5-Dihydro-2-(2-(4-(5-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)butyl)benzofuran-5-yl)-1H-imidazole;    2-(4-(6-Amidinobenzofuran-2-yl)butyl)benzofuran-6-carboxamidine;    2-(4-(6-Amidinobenzofuran-2-yl)butyl)-N-isopropylbenzofuran-6-carboxamidine;    4,5-Dihydro-2-(2-(4-(6-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)butyl)benzofuran-6-yl)-1H-imidazole;    2-(5-(5-Amidinobenzofuran-2-yl)pentyl)benzofuran-5-carboxamidine;    2-(5-(5-Amidinobenzofuran-2-yl)pentyl)-N-isopropylbenzofuran-5-carboxamidine;    4,5-Dihydro-2-(2-(5-(5-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)pentyl)benzofuran-5-yl)-1H-imidazole;    2-(5-(6-Amidinobenzofuran-2-yl)pentyl)benzofuran-6-carboxamidine;    2-(5-(6-Amidinobenzofuran-2-yl)pentyl)-N-isopropylbenzofuran-6-carboxamidine;    4,5-Dihydro-2-(2-(5-(6-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)pentyl)benzofuran-6-yl)-1H-imidazole;    2-(5-(6-(N-hydroxycarbamimidoyl)benzofuran-2-yl)pentyl)-N-hydroxybenzofuran-6-carboxamidine;    2-(3-(5-(N-hydroxycarbamimidoyl)benzofuran-2-yl)propyl)-N-hydroxybenzofuran-5-carboxamidine;    2-(4-(5-(N-hydroxycarbamimidoyl)benzofuran-2-yl)butyl)-N-hydroxybenzofuran-5-carboxamidine;    2-(5-(6-(N-methoxycarbamimidoyl)benzofuran-2-yl)pentyl)-N-methoxybenzofuran-6-carboxamidine;    2-(3-(5-(N-methoxycarbamimidoyl)benzofuran-2-yl)propyl)-N-methoxybenzofuran-5-carboxamidine;    2-(4-(5-(N-methoxycarbamimidoyl)benzofuran-2-yl)butyl)-N-methoxybenzofuran-5-carboxamidine;    2-(2-(5-(N-hydroxycarbamimidoyl)benzofuran-2-yl)ethyl)-N-hydroxybenzofuran-5-carboxamidine;    2-(2-(5-(N-methoxycarbamimidoyl)benzofuran-2-yl)ethyl)-N-methoxybenzofuran-5-carboxamidine;    2-(5-(5-(N-hydroxycarbamimidoyl)benzofuran-2-yl)pentyl)-N-hydroxybenzofuran-5-carboxamidine; and    2-(5-(5-(N-methoxycarbamimidoyl)benzofuran-2-yl)pentyl)-N-methoxybenzofuran-5-carboxamidine.    
     
     
         31 . The method of  claim 23 , wherein the compound of Formula III is administered in the form of a pharmaceutically acceptable salt.  
     
     
         32 . The method of  claim 31- , wherein the pharmaceutically acceptable salt is a hydrochloride salt.  
     
     
         33 - 51 . (canceled)  
     
     
         52 . A compound of Formula (III):  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is an integer from 1 to 8;  
 p and q are integers from 0 to 3;  
 R 1  and R 2  are each independently selected from the group consisting of alkyl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl; and  
 R 3  and R 4  are each independently selected from the group consisting of:  
                     
 wherein: 
 R 6 , R 7 , R 8 , and R 9  are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; or 
 R 6  and R 7  together represent a C 2  to C 10  alkyl, C 2  to C 10  hydroxyalkyl, or C 2  to C 10  alkylene.  
 
 
 
     
     
         53 . The compound of  claim 52 , wherein: 
 n is an integer from 1 to 5;    R 3  and R 4  are each                          R 3  is at one of the 4-position, 5-position, and 6-position of ring C; and    R 4  is at one of the 4′-position, 5′-position, and 6′-position of ring C′.    
     
     
         54 . The compound of  claim 52 , wherein: 
 n is an integer from 1 to 5;    R 3  and R 4  are each                          R 3  is at one of the 4-position, 5-position, and 6-position of ring C; and    R 4  is at one of the 4′-position, 5′-position, and 6′-position of ring C′.    
     
     
         55 . The compound of  claim 52 , wherein: 
 n is an integer from 1 to 5;    R 3  and R 4  are each                          R 3  is at one of the 4-position, 5-position, and 6-position of ring C; and    R 4  is at one of the 4′-position, 5′-position, and 6′-position of ring C′.    
     
     
         56 . The compound of  claim 52;  wherein: 
 n is an integer from 1 to 5;    R 3  and R 4  are each                          R 3  is at one of the 4-position, 5-position, and 6-position of ring C; and    R 4  is at one of the 4′-position, 5′-position, and 6′-position of ring C′.    
     
     
         57 . The compound of  claim 52 , wherein: 
 n is an integer from 1 to 5;    R 3  and R 4  are each                          R 3  is at one of the 4-position, 5-position, and 6-position of ring C; and    R 4  is at one of the 4′-position, 5′-position, and 6′-position of ring C′.    
     
     
         58 . The compound of  claim 52 , wherein the compound is selected from the group consisting of: 
 2-((4-Amidinobenzofuran-2-yl)methyl)benzofuran-4-carboxamidine;    2-((4-Amidinobenzofuran-2-yl)methyl)-N-isopropylbenzofuran-4-carboxamidine;    Bis(4-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)methane;    2-((5-Amidinobenzofuran-2-yl)methyl)benzofuran-5-carboxamidine;    2-((5-Amidinobenzofuran-2-yl)methyl)-N-isopropylbenzofuran-5-carboxamidine;    Bis(5-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)methane;    Bis(6-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)methane;    2-(2-(5-Amidinobenzofuran-2-yl)ethyl)benzofuran-5-carboxamidine;    2-(2-(5-Amidinobenzofuran-2-yl)ethyl)-N-isopropylbenzofuran-5-carboxamidine;    4,5-Dihydro-2-(2-(2-(5-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)ethyl)benzofuran-5-yl)-1H-imidazole;    2-(2-(6-Amidinobenzofuran-2-yl)ethyl)benzofuran-6-carboxamidine;    2-(2-(6-Amidinobenzofuran-2-yl)ethyl)-N-isopropylbenzofuran-6-carboxamidine;    4,5-dihydro-2-(2-(2-(6-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)ethyl)benzofuran-6-yl)-1H-imidazole;    2-(3-(5-Amidinobenzofuran-2-yl)propyl)benzofuran-5-carboxamidine;    2-(3-(5-Amidinobenzofuran-2-yl)propyl)-N-isopropylbenzofuran-5-carboxamidine;    4,5-Dihydro-2-(2-(3-(5-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)propyl)benzofuran-5-yl)-1H-imidazole;    2-(3-(6-Amidinobenzofuran-2-yl)propyl)benzofuran-6-carboxamidine;    2-(3-(6-Amidinobenzofuran-2-yl)propyl)-N-isopropylbenzofuran-6-carboxamidine;    4,5-Dihydro-2-(2-(3-(6-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)propyl)benzofuran-6-yl)-1H-imidazole;    2-(4-(5-Amidinobenzofuran-2-yl)butyl)benzofuran-5-carboxamidine;    2-(4-(5-Amidinobenzofuran-2-yl)butyl)-N-isopropylbenzofuran-5-carboxamidine;    4,5-Dihydro-2-(2-(4-(5-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)butyl)benzofuran-5-yl)-1H-imidazole;    2-(4-(6-Amidinobenzofuran-2-yl)butyl)benzofuran-6-carboxamidine;    2-(4-(6-Amidinobenzofuran-2-yl)butyl)-N-isopropylbenzofuran-6-carboxamidine;    4,5-Dihydro-2-(2-(4-(6-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)butyl)benzofuran-6-yl)-1H-imidazole;    2-(5-(5-Amidinobenzofuran-2-yl)pentyl)benzofuran-5-carboxamidine;    2-(5-(5-Amidinobenzofuran-2-yl)pentyl)-N-isopropylbenzofuran-5-carboxamidine;    4,5-Dihydro-2-(2-(5-(5-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)pentyl)benzofuran-5-yl)-1H-imidazole;    2-(5-(6-Amidinobenzofuran-2-yl)pentyl)benzofuran-6-carboxamidine;    2-(5-(6-Amidinobenzofuran-2-yl)pentyl)-N-isopropylbenzofuran-6-carboxamidine;    4,5-Dihydro-2-(2-(5-(6-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)pentyl)benzofuran-6-yl)-1H-imidazole;    2-(5-(6-(N-hydroxycarbamimidoyl)benzofuran-2-yl)pentyl)-N-hydroxybenzofuran-6-carboxamidine;    2-(3-(5-(N-hydroxycarbamimidoyl)benzofuran-2-yl)propyl)-N-hydroxybenzofuran-5-carboxamidine;    2-(4-(5-(N-hydroxycarbamimidoyl)benzofuran-2-yl)butyl)-N-hydroxybenzofuran-5-carboxamidine; and    2-(5-(6-(N-methoxycarbamimidoyl)benzofuran-2-yl)pentyl)-N-methoxybenzofuran-6-carboxamidine.    
     
     
         59 . A pharmaceutically acceptable salt of a compound of  claim 52 .  
     
     
         60 . The pharmaceutically acceptable salt of  claim 59 , wherein the salt is a hydrochloride salt.  
     
     
         61 - 62 . (canceled)  
     
     
         63 . A pharmaceutical formulation comprising: 
 (a) a compound of Formula (III); and    (b) a pharmaceutically acceptable carrier.    
     
     
         64 - 70 . (canceled)  
     
     
         71 . A method of preparing compound of Formula (III):  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is an integer from 1 to 8;  
 p and q are integers from 0 to 3;  
 R 1  and R 2  are each independently selected from the group consisting of alkyl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl;  
 R 3  and R 4  are each independently selected from the group consisting of:  
                     
 wherein: 
 R 6 , R 7 , R 8 , and R 9  are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; or 
 R 6  and R 7  together represent a C 2  to C 10  alkyl, C 2  to C 10  hydroxyalkyl, or C 2  to C 10  alkylene;  
 
 
 the method comprising: 
 (a) mixing anhydrous 1,4-dioxane and an anhydrous alkyl alcohol to form a first reaction mixture;  
 (b) saturating the first reaction mixture with an anhydrous gaseous acid to form a second reaction mixture;  
 (c) adding a bis-benzofuran carbodinitrile to the second reaction mixture to form a diimidate;  
 (d) suspending the diimidate in an anhydrous protic solvent to form a third reaction mixture; and  
 (e) saturating the third reaction mixture with an amine to form a compound of Formula (III).  
 
 
     
     
         72 . The method of  claim 71 , wherein n is an integer from 3 to 8 and the bis-benzofuran carbodinitrile is prepared from the method comprising 
 (a) contacting a halogenated alkyl-hydroxybenzoate and an alkadiyne with a metal halide and an alkylguanidine in the presence of a catalyst in an anhydrous aprotic solvent to form a first reaction mixture;    (b) stirring the first reaction mixture for a period of time to form a alkyl-((alkoxycarbonyl)benzofuran-2-yl)alkyl)benzofuran carboxylate;    (c) passing anhydrous NH 3  through an anhydrous nonpolar aprotic solvent for a period of time to form a second reaction mixture;    (d) adding a solution of a metal alkyl in a nonpolar aprotic solvent to the second reaction mixture to form a third reaction mixture;    (e) passing NH 3  through the third second reaction mixture for a period of time to form a fourth reaction mixture; and    (f) adding the alkyl-((alkoxycarbonyl)benzofuran-2-yl)alkyl)benzofuran carboxylate to the fourth reaction mixture to form a ((cyanobenzofuran-2-yl)alkyl)benzofuran carbonitrile.    
     
     
         73 . The method of  claim 71 , wherein n is an integer from 3 to 8 and the bis-benzofuran carbodinitrile is prepared from the method comprising 
 (a) contacting a halogenated alkyl-hydroxybenzoate and an alkadiyne with a metal oxide in an anhydrous aprotic solvent to form a first reaction mixture;    (b) stirring the first reaction mixture for a period of time to form a alkyl-((alkoxycarbonyl)benzofuran-2-yl)alkyl)benzofuran carboxylate;    (c) passing anhydrous NH 3  through an anhydrous nonpolar aprotic solvent for a period of time to form a second reaction mixture;    (d) adding a solution of a metal alkyl in a nonpolar aprotic solvent to the second reaction mixture to form a third reaction mixture;    (e) passing NH 3  through the third second reaction mixture for a period of time to form a fourth reaction mixture; and    (e) adding the alkyl-((alkoxycarbonyl)benzofuran-2-yl)alkyl)benzofuran carboxylate to the fourth reaction mixture to form a ((cyanobenzofuran-2-yl)alkyl)benzofuran carbonitrile.    
     
     
         74 . The method of  claim 71 , wherein n is 1 and the bis-benzofuran carbodinitrile is prepared from the method comprising: 
 (a) contacting a halogenated hydroxybenzaldehyde with a dihalogenated ketone and a carbonate salt in an aprotic solvent to from a first reaction mixture;    (b) refluxing the first reaction mixture for a period of time to form a bis-benzofuranmethanone;    (c) dissolving a metal halide in an anhydrous nonpolar aprotic solvent to form a second reaction mixture;    (d) adding the second reaction mixture under an inert gas to a suspension of a metal hydride in an anhydrous nonpolar aprotic solvent to form a third reaction mixture;    (e) adding a bis-benzofuranmethanone to the third reaction mixture to form a fourth reaction mixture;    adding an aqueous acid to the fourth reaction mixture to form a bis-benzofuranmethane;    (g) mixing the bis-benzofuranmethane and metal cyanide in anhydrous quinoline to form a sixth reaction mixture;    (h) refluxing the sixth reaction mixture for a period of time; and    (i) contacting the sixth reaction mixture with an aqueous acid solution to form a bis-benzofuranmethane carbodinitrile.    
     
     
         75 . The method of  claim 71 , wherein n is 2 and the bis-benzofuran carbodinitrile is prepared from a method comprising: 
 (a) mixing a halogenated alkyl-hydroxybenzoate mixture with an alkynyl alcohol in an anhydrous aprotic solvent to form a first reaction mixture;    (b) contacting the first reaction mixture with a metal oxide in an anhydrous aprotic solvent to form a alkyl-(hydroxypropyl)benzofuran carboxylate;    (c) adding the alkyl-(hydroxypropyl)benzofuran carboxylate to a mixture of oxalyl chloride, a polar aprotic solvent and an anhydrous halogenated aprotic solvent to form a second reaction mixture;    (d) adding an alkylamine to the second reaction mixture to form a alkyl-(formylethyl)benzofuran carboxylate;    (e) adding the alkyl-(formylethyl)benzofuran carboxylate to a mixture of a dialkyl-diazo-oxopropylphosphonate and a carbonate salt in an anhydrous protic solvent to form a alkyl-(alkynyl)benzofuran carboxylate;    (f) adding the alkyl-(alkynyl)benzofuran carboxylate to a mixture of a halogenated alkyl-hydroxybenzoate and a metal oxide in an anhydrous aprotic solvent to form a alkyl-(alkoxycarbonyl)benzofuran-2-yl)alkyl)benzofuran carboxylate;    (g) passing anhydrous NH 3  through an anhydrous nonpolar aprotic solvent for a period of time to form a third reaction mixture;    (h) adding a solution of a metal alkyl in a nonpolar aprotic solvent to the third reaction mixture to form a fourth reaction mixture;    (i) passing NH 3  through the fourth reaction mixture for a period of time to form a fifth reaction mixture; and    (j) adding the alkyl-(alkoxycarbonyl)benzofuran-2-yl)alkyl)benzofuran carboxylate to the fifth reaction mixture to form a ((cyanobenzofuran-2-yl)alkyl)benzofuran carbonitrile.    
     
     
         76 . A method of preparing a bis-amidoxime compound of Formula (III), the method comprising: 
 (a) adding an alkali metal alcoholate to a solution of NH 2 OH—HCl in an anhydrous polar aprotic solvent to form a first reaction mixture;    (b) adding a benzofuran carbonitrile to the first reaction mixture to form a second reaction mixture;    (c) stirring the second reaction mixture for a period of time;    (d) pouring the second reaction mixture into ice water to form a precipitate;    (e) filtering the precipitate;    (f) washing the precipitate with a mixture of protic solvents;    (g) drying the washed precipitate; and    (h) recrystallizing the washed precipitate to form a bis-amidoxime.    
     
     
         77 . A method for preparing a bis-alkylamidoxime of Formula (III), the method comprising: 
 (a) adding an aqueous hydroxide solution to a stirred solution of a benzofuran carboxamidine in a polar aprotic solvent to form a first reaction mixture;    (b) cooling the first reaction mixture;    (c) adding a dialkyl sulfate to the cooled first reaction mixture to form a second reaction mixture;    (d) stirring the second reaction mixture for a period of time;    (e) diluting the second reaction mixture with a protic solvent to form a residue;    (e) separating the residue;    (g) purifying the residue; and    (h) recrystallizing the residue from aqueous acid to form a bis-alkylamidoxime.    
     
     
         78 . A method for preparing a bis-amidoxime of Formula (III), the method comprising: 
 (a) mixing anhydrous 1,4-dioxane and an anhydrous alkyl alcohol to form a first reaction mixture;    (b) saturating the first reaction mixture with an anhydrous gaseous acid to form a second reaction mixture;    (c) adding a bis-benzofuran carbodinitrile to the second reaction mixture to form a diimidate; and    (d) contacting the imidate with hydroxylamine in a solution of an alkali metal alcoholate in a protic solvent to form a bis-amidoxime of Formula (III).    
     
     
         79 . A method for preparing a bis-alkylamidoxime of Formula (III), the method comprising: 
 (a) mixing anhydrous 1,4-dioxane and an anhydrous alkyl alcohol to form a first reaction mixture;    (b) saturating the first reaction mixture with an anhydrous gaseous acid to form a second reaction mixture;    (c) adding a benzofuran carbodinitrile to the second reaction mixture to form an imidate; and    (d) contacting the imidate with alkylhydroxylamine in a solution of an alkali metal alcoholate in a protic solvent to form a bis-alkylamidoxime of Formula (III).