Frangible compounds for pathogen inactivation

Abstract

Compounds and methods for inactivating pathogens in materials are described, including compositions and methods for inactivating pathogens in biological materials such as red blood cell preparations and plasma. The compounds and methods may be used to treat materials intended for in vitro or in vivo use, such as clinical testing or transfusion. The compounds are designed to specifically bind to and react with nucleic acid, and then to degrade to form breakdown products. The degradation reaction is preferably slower than the reaction with nucleic acid.

What is claimed is:  
     
         1 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein at least one of R 44 , R 55 , R 3 , R 4 , R 5 , and R 8  is —V—W—X—E, and the remainder of R 44 , R 55 , R 3 , R 4 , R 5 , and R 8  are independently selected from the group consisting of —H, —R 10 , —O—R 10 , —NO 2 , —NH 2 , —NH—R 10 , —N(R 10 ) 2 , —F, —Cl, —Br, —I, —C(═O)—R 10 , —C(═O)—O—R 10 , and —O—C(═O)—R 10 , 
 where —R 10  is independently H, —C 1-8  alkyl, —C 1-8  heteroalkyl, -aryl, -heteroaryl, —C 1-3 alkyl-aryl, —C 1-3 heteroalkyl-aryl, —C 1-3 alkyl-heteroaryl, —C 1-3 heteroalkyl-heteroaryl, -aryl-C 1-3 alkyl, -aryl-C 1-3 heteroalkyl, -heteroaryl-C 1-3 alkyl, -heteroaryl-C 1-3 heteroalkyl, —C 1-3 alkyl-aryl-C 1-3  alkyl, —C 1-3 heteroalkyl-aryl-C 1-3  alkyl, —C 1-3 alkyl-heteroaryl-C 1-3  alkyl, —C 1-3 alkyl-aryl-C 1-3  heteroalkyl, —C 1-3 heteroalkyl-heteroaryl-C 1-3  alkyl, —C 1-3 heteroalkyl-aryl-C 1-3  heteroalkyl, —C 1-3 alkyl-heteroaryl-C 1-3  heteroalkyl, or —C 1-3 heteroalkyl-heteroaryl-C 1-3  heteroalkyl;  
 V is independently —R 11 —, —NH—R 11 — or —N(CH 3 )—R 11 —, where —R 11 — is independently —C 1-8 alkyl-, —C 1-8 heteroalkyl-, -aryl-, -heteroaryl-, —C 1-3 alkyl-aryl-, —C 1-3 heteroalkyl-aryl-, —C 1-3 alkyl-heteroaryl-, —C 1-3 heteroalkyl-heteroaryl-, -aryl-C 1-3 alkyl-, -aryl-C 1-3  heteroalkyl-, -heteroaryl-C 1-3 alkyl-, -heteroaryl-C 1-3 heteroalkyl-, —C 1-3 alkyl-aryl-C 1-3  alkyl-, —C 1-3 heteroalkyl-aryl-C 1-3  alkyl-, —C 1-3 alkyl-heteroaryl-C 1-3  alkyl-, —C 1-3 alkyl-aryl-C 1-3  heteroalkyl-, —C 1-3 heteroalkyl-heteroaryl-C 1-3  alkyl-, —C 1-3 heteroalkyl-aryl-C 1-3  heteroalkyl-, —C 1-3 alkyl-heteroaryl-C 1-3  heteroalkyl-, or —C 1-3 heteroalkyl-heteroaryl-C 1-3  heteroalkyl-;  
 W is independently —C(═O)—O—, —O—C(═O)—, —C(═S)—O—, —O—C(═S)—, —C(═S)—S—, —S—C(═S)—, —C(═O)—, —S—C(═O)—, —O—S(═O) 2 —O, —S(═O) 2 —O—, —O—S(═O) 2 —, —C(═O)—NR 10 —, —NR 10 —C(═O)—, —O—P(═O)(—OR 10 )—O—, —P(═O)(—OR 10 )—O—, —O—P(═O)(—OR 10 )—;  
 X is independently —R 11 —; and  
 E is independently selected from the group consisting of —N(R 12 ) 2 , —N(R 12 )(R 13 ), —S—R 12 ,  
 and  
                     
 where —R 12  is —CH 2 CH 2 —G, where each G is independently —Cl, —Br, —I, —O—S(═O) 2 —CH 3 , —O—S(═O) 2 —CH 2 —C 6 H 5 , or —O—S(═O) 2 —C 6 H 4 —CH 3 ;  
 and where R 13  is independently —C 1-8  alkyl, —C 1-8  heteroalkyl, -aryl, -heteroaryl, —C 1-3 alkyl-aryl, —C 1-3 heteroalkyl-aryl, —C 1-3 alkyl-heteroaryl, —C 1-3 heteroalkyl-heteroaryl, -aryl-C 1-3 alkyl, -aryl-C 1-3 heteroalkyl, -heteroaryl-C 1-3 alkyl, -heteroaryl-C 1-3 heteroalkyl, —C 1-3 alkyl-aryl-C 1-3  alkyl, —C 1-3 heteroalkyl-aryl-C 1-3  alkyl, —C 1-3 alkyl-heteroaryl-C 1-3  alkyl, —C 1-3 alkyl-aryl-C 1-3  heteroalkyl, —C 1-3 heteroalkyl-heteroaryl-C 1-3  alkyl, —C 1-3 heteroalkyl-aryl-C 1-3  heteroalkyl, —C 1-3 alkyl-heteroaryl-C 1-3  heteroalkyl, or —C 1-3  heteroalkyl-heteroaryl-C 1-3  heteroalkyl;  
 and all salts and stereoisomers (including enantiomers and diastereomers) thereof.  
 
     
     
         2 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         3 . A method of making a compound of  claim 1 , wherein the method comprises the steps of: 
 a) transesterifying a psoralenacetate to provide an aminoalkyl psoralenacetate; and,    b) converting the aminoalkyl psoralenacetate into a (chloroalkyl)-aminoalkyl psoralenacetate.    
     
     
         4 . A method according to  claim 3 , wherein the psoralenacetate is a methyl-substituted psoralenacetate.  
     
     
         5 . A method according to  claim 3 , wherein the psoralenacetate is a 4′-psoralenacetate.  
     
     
         6 . A method according to  claim 3 , wherein the aminoalkyl psoralenacetate is an aminoethyl psoralenacetate.  
     
     
         7 . A method according to  claim 3 , wherein the conversion of the aminoalkyl psoralenacetate comprises a reaction that converts a hydroxyl group into a chloride group.