Anti tubercular drug: compostions and methods

Abstract

Methods and compositions for treating disease caused by infectious agents, particularly tuberculosis. In particular, methods and compositions comprising substituted ethylene diamines for the treatment of infectious diseases are provided. In one embodiment, these methods and compositions are used for the treatment of mycobacterial infections, including, but not limited to, tuberculosis.

We claim:  
     
         1 . A composition comprising a substituted ethylene diamine compound of the formula  
       
         
           
           
               
               
           
         
         wherein R 4  is selected from H, alkyl, aryl, heteroatom substituted alkyl and aryl, alkenyl, alkynyl, aralkyl, aralkynyl, cycloalkyl, cycloalkenyl;  
         and wherein R 1 , R 2  and R 3  are independently selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino; or  
         wherein R 1  is selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino, and NR 2 R 2  is derived from a cyclic secondary amine.  
       
     
     
         2 . The composition of  claim 1 , wherein NHR 1  or NR 2 R 3  of the substituted ethylene diamine has the chemical structure  
       
         
           
           
               
               
           
         
       
     
     
         3 . The composition of  claim 2 , wherein the substituted ethylene diamine compound is selected from  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . The composition of  claim 1 , wherein NHR 1  or NR 2 R 3  of the substituted ethylene diamine has the chemical structure  
       
         
           
           
               
               
           
         
       
     
     
         5 . The composition of  claim 4 , wherein the substituted ethylene diamine compound is selected from  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . The composition of  claim 1 , wherein NHR 1  or NR 2 R 3  of the substituted ethylene diamine has the chemical structure  
       
         
           
           
               
               
           
         
       
     
     
         7 . The composition of  claim 6 , wherein the substituted ethylene diamine compound is selected from  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The composition of  claim 1 , wherein NHR 1  or NR 2 R 3  of the substituted ethylene diamine has the chemical structure  
       
         
           
           
               
               
           
         
       
     
     
         9 . The composition of  claim 8 , wherein the substituted ethylene diamine compound is selected from  
       
         
           
           
               
               
           
         
       
     
     
         10 . The composition of  claim 9 , wherein the substituted ethylene diamine compound is  
       
         
           
           
               
               
           
         
       
     
     
         11 . The composition of  claim 1 , wherein the substituted ethylene diamine compound is selected from  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . A method of preparing a substituted ethylene diamine compound of the formula  
       
         
           
           
               
               
           
         
         wherein R 4  is selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkynyl, cycloalkyl, cycloalkenyl;  
         and wherein R 1 , R 2  and R 3  are independently selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino; or  
         wherein R 1  is selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino, and NR 2 R 2  is derived from a cyclic secondary amine;  
         comprising activating a solid-support resin containing hydroxyl groups with a halo-donating reagent in the presence of base to produce a solid-support resin containing halo groups;  
         displacing the halo groups with an initial primary amine to produce a solid-support resin containing amine groups;  
         acylating the amine groups with a halo-acylhalide in the presence of a basic compound, or with a halo-acylacid in the presence of base, to produce a solid-support resin containing α-haloacetyl amide groups;  
         displacing α-halo groups of the α-haloacetyl amides with a secondary or subsequent primary amine to produce a solid-support resin containing a-amine imide groups;  
         reducing the carbonyl moiety on the a-amine imide groups with a reducing agent to produce a solid-support resin containing two amine groups separated by two carbon atoms;  
         cleaving the amine groups separated by two carbon atoms from the solid support resin in the presence of acid to produce the substituted ethylene diamine compound.  
       
     
     
         13 . The method of  claim 12 , wherein the initial primary amine is R 1 NH 2 .  
     
     
         14 . The method of  claim 12 , wherein the secondary or subsequent primary amine is R 2 R 3 HN.  
     
     
         15 . A method of treating disease caused by an infectious agent comprising administering an effective amount of a substituted ethylene diamine compound of the formula:  
       
         
           
           
               
               
           
         
         wherein R 4  is selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkynyl, cycloalkyl, cycloalkenyl;  
         and wherein R 1 , R 2  and R 3  are independently selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino; or  
         wherein R 1  is selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino, and NR 2 R 2  is derived from a cyclic secondary amine.  
       
     
     
         16 . The method of  claim 15 , wherein the infectious agent comprises a bacterial, mycological, parasitic, or viral agent.  
     
     
         17 . The method of  claim 16 , wherein the bacterial agent comprises  M. tuberculosis, M. avium -intracellulare,  M. kansarii, M. fortuitum, M. chelonae, M. leprae, M. africanum, M. microti, M. avium paratuberculosis, M. intracellulare, M. scrofulaceum, M. xenopi, M. marinum,  or  M. ulcerans.    
     
     
         18 . The method  claim 15 , wherein the infectious disease comprises tuberculosis or Crohn's disease.  
     
     
         19 . The method  claim 15 , wherein the substituted ethylene diamine compound is  
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 19 , further comprising a pharmaceutical carrier.  
     
     
         21 . A composition comprising, a substituted ethylene diamine compound comprising,  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         22 . A method of preparing a substituted ethylene diamine compound of the formula  
       
         
           
           
               
               
           
         
         wherein R 4  is selected from H, alkyl, aryl, heteroatom substituted alkyl and aryl, alkenyl, alkynyl, aralkyl, aralkynyl, cycloalkyl, cycloalkenyl;  
         and wherein R 1 , R 2  and R 3  are independently selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino;  
         comprising activating a solid-support resin containing hydroxyl groups with a halo-donating reagent in the presence of base to produce a solid-support resin containing halo groups;  
         displacing the halo groups with an initial primary amine to produce a solid-support resin containing amine groups;  
         acylating the amine groups with a FMOC protected amino acid in the presence of a coupling reagent and a base, followed by removal of FMOC protecting group to produce a solid-support resin containing α-amino acetamide groups;  
         modification of α-amino groups of the α-amino acetamide groups with a carbonyl compound to produce a solid-support resin containing corresponding derivative of α-amino acetamide groups;  
         reducing the carbonyl moiety on the amide groups with a reducing agent to produce a solid-support resin containing two amine groups separated by two carbon atoms; and  
         cleaving the amine groups separated by two carbon atoms from the solid support resin in the presence of acid to produce the substituted ethylene diamine compound.  
       
     
     
         23 . A method for treating an infectious disease comprising administering a pharmaceutically effective amount of the composition in  claim 21 .  
     
     
         24 . A composition comprising a symmetrical substituted ethylene diamine compound of the formula  
       
         
           
           
               
               
           
         
         wherein R 4  is selected from H, alkyl, aryl, heteroatom substituted alkyl and aryl, alkenyl, alkynyl, aralkyl, aralkynyl, cycloalkyl, cycloalkenyl;  
         and wherein R 1 , R 2  and R 3  are independently selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino; or  
         wherein R 1  is selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino, and NR 2 R 2  is derived from a cyclic secondary amine.