Analogs of biologically active, naturally occurring polyamines, pharmaceutical compositions and methods of treatment

Abstract

Polyamines having the formula: or a salt thereof with a pharmaceutically acceptable acid wherein: R 1 -R 6 may be the same or different and are alkyl, aryl, aryl alkyl, cycloalkyl, optionally having an alkyl chain interrupted by at least one etheric oxygen atom, or hydrogen; N 1 , N 2 , N 3 and N 4 are nitrogen atoms capable of protonation at physiological pH's; a and b may be the same or different and are integers from 1 to 4; A, B and C may be the same or different and are bridging groups which effectively maintain the distance between the nitrogen atoms such that the polyamines: (i) are capable of uptake by a target cell upon administration thereof to a human or non-human animal; and (ii) upon uptake by the target cell, competitively bind via an electrostatic interaction between the positively charged nitrogen atoms to substantially the same biological counter-anions as the intracellular natural polyamines in the target cell; the polyamines, upon binding to the biological counter-anion in the cell, function in a manner biologically different than the intracellular polyamines, the polyamines not occurring in nature; as well as pharmaceutical compositions embodying the polyamines and methods of treating patients requiring anti-neoplastic therapy.

I claim:  
     
         1 . A polyamine having the formula:  
       
         
           
           
               
               
           
         
       
       or a salt thereof with a pharmaceutically acceptable acid wherein: 
 R 1 -R 6  may be the same or different and are alkyl, aryl, aryl alkyl, cycloalkyl, optionally having an alkyl chains interrupted by at least one etheric oxygen atom, or hydrogen  
 N 1 , N 2 , N 3  and N 4  are nitrogen atoms capable of protonation at physiological pH's ;  
 a and b may be the same or different and are integers from 1 to 4;  
 A, B and C may be the same or different and are bridging groups which effectively maintain the distance between said nitrogen atoms such that said polyamine: 
 (i) is capable of uptake by a target cell upon administration of said polyamine to a human or non-human animal; and  
 (ii) upon uptake by said target cell, competitively binds via an electrostatic interaction between the positively charged nitrogen atoms to substantially the same biological counter-anions as the intra-cellular natural polyamines in the target cell;  
 said polyamine, upon binding to said biological counter-anion in the cell, functions in a manner biologically different than said intracellular polyamines, said polyamine not occurring in nature.  
 
 
     
     
         2 . A polyamine of  claim 1 , upon binding to said biological counter-anion in said cell, exerting an anti-neoplastic function.  
     
     
         3 . A polyamine of  claim 1  wherein said bridging groups A, B and C may be the same or different and are alkylene, branched alkylene, cycloalkylene, arylalkylene or a heterocyclic bridging group wherein one of said N 1 , N 2 , N 3  or N 4  atoms is incorporated in the ring as the hetero atom.  
     
     
         4 . A pharmaceutical composition comprising an anti-neoplastic effective amount of a polyamine of  claim 1  or a salt thereof with a pharmaceutically acceptable acid and a pharmaceutically acceptable carrier therefor.  
     
     
         5 . A method of treating a human or non-human animal in need thereof comprising administering thereto an anti-neoplastic effective amount of a polyamine of  claim 1  or a salt thereof with a pharmaceutically acceptable acid.  
     
     
         6 . A polyamine of  claim 1  having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         7 . A polyamine of  claim 1  having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         8 . A polyamine of  claim 1  having the formula: