Biologically active spermidine analogues, pharmaceutical compositions and methods of treatment

Abstract

Polyamines having the formula: or a salt thereof with a pharmaceutically acceptable acid wherein: R 1 -R 5 may be the same or different and are alkyl, aryl, aryl alkyl, cycloalkyl or hydrogen; at least one of R 1 and R 2 and at least one of R 4 and R 5 are not hydrogen, and any of the alkyl chains may optionally be interrupted by at least one etheric oxygen atom, excluding N 1 ,N 3 -diethylspermidine and N 1 ,N 3 -dipropylspermidine; and A and B are bridging groups which effectively maintain the distance between the nitrogen atoms such that the polyamine: (i) is capable of uptake by a target cell upon administration of the polyamine to a human or non-human animal; and (ii) upon uptake by the target cell, competitively binds 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.

I claim:  
     
         1 . A polyamine which does not occur in nature having the formula:  
       
         
           
           
               
               
           
         
       
       or a salt thereof with a pharmaceutically acceptable acid wherein: 
 R 1 -R 5  may be the same or different and are alkyl, aryl, aryl alkyl, cycloalkyl or hydrogen; at least one of said R 1  and R 2  and at least one of said R 4  and R 5  are not hydrogen, and any of said alkyl chains may optionally be interrupted by at least one etheric oxygen atom, excluding N 1 ,N 3 -diethylspermidine and N 1 ,N 3 -dipropylspermidine; and  
 A and B may be the same or different and are bridging groups including unsubstituted heterocyclic bridging groups which effectively maintain the distance between the nitrogen atoms such that the polyamine: 
 (i) is capable of uptake by a target cell upon administration of the 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 intracellular natural polyamines in the target cell, provided that where A or B is a heterocyclic bridging group, the bridging group is an unsubstituted heterocyclic group incorporating said N 1 , N 2  or N 3  atoms in the heterocyclic ring as an unsubstituted N atom;  
 said polyamine, upon binding to the biological counter-anion in the cell, functions in a manner biologically different than said intracellular polyamines.  
 
 
     
     
         2 . A polyamine according to  claim 1 , upon binding to said biological counter-anion in said cell, exerting an anti-neoplastic function.  
     
     
         3 . A polyamine according to  claim 1 , wherein said bridging groups A and B may be the same or different and are alkylene, branched alkylene, cycloalkylene or arylalkylene.  
     
     
         4 . The polyamine according to  claim 1  having the formula:  
       R 1 —N 1 H—(CH 2 ) 3 —N 2 H—(CH 2 ) 3 —N 3 H—R 2    
       wherein: 
 R 1  and R 2  may be the same or different and are alkyl having, at most, 10 carbon atoms.  
 
     
     
         5 . The polyamine of  claim 4  wherein R 1 =R 2 =methyl.  
     
     
         6 . The polyamine of  claim 4  wherein R 1 =R 2 =ethyl.  
     
     
         7 . The polyamine of  claim 4  wherein R 1 =R 2 =n-propyl.  
     
     
         8 . The polyamine of  claim 4  wherein R 1 =H and R 2 =ethyl.  
     
     
         9 . The polyamine of  claim 4  wherein R 1 =H and R 2 =n-propyl.  
     
     
         10 . The polyamine according to  claim 1  having the formula:  
       R 1 —N 1 H—(CH 2 ) 3 —N 2 H—(CH 2 ) 4 —N 3 H—R 2    
       wherein: 
 R 1  and R 2  may be the same or different and are alkyl having, at most, 10 carbon atoms.  
 
     
     
         11 . The polyamine of  claim 10  wherein R 1 =R 2 =methyl.  
     
     
         12 . The polyamine of  claim 10  wherein R 1 =R 2 =ethyl.  
     
     
         13 . The polyamine of  claim 10  wherein R 1 =R 2 =n-propyl.  
     
     
         14 . The polyamine of  claim 10  wherein R 1 =ethyl and R 2 =H.  
     
     
         15 . The polyamine of  claim 10  wherein R 1 =H and R 2 =ethyl.  
     
     
         16 . The polyamine of  claim 10  wherein R 1 =n-propyl and R 2 =H.  
     
     
         17 . The polyamine of  claim 10  wherein R 1 =H and R 2 =n-propyl.  
     
     
         18 . The polyamine according to  claim 1  having the formula:  
       R 1 —N 1 H—(CH 2 ) 4 —N 2 H—(CH  2 ) 4 —N 3 H—R 2    
       wherein: 
 R 1  and R 2 may be the same or different and are alkyl having, at most, 10 carbon atoms.  
 
     
     
         19 . The polyamine of  claim 18  wherein R 1 =R 2 =methyl.  
     
     
         20 . The polyamine of  claim 18  wherein R 1 =R2=ethyl.  
     
     
         21 . The polyamine of  claim 18  wherein R 1 =R 2 =n-propyl.  
     
     
         22 . The polyamine of  claim 18  wherein R 1 =H and R 2 =ethyl.  
     
     
         23 . The polyamine of  claim 18  wherein R 1 =H and R 2 =n-propyl.  
     
     
         24 . The polyamine according to  claim 1  having the formula:  
       R 1 —N 1 H—(CH 2 ) 4 —N 2 H—(CH 2 ) 5 —N 3 H—R 2    
       wherein: 
 R 1  and R 2  may be the same or different and are alkyl having, at most, 10 carbon atoms.  
 
     
     
         25 . The polyamine of  claim 24  wherein R 1 =R 2 =methyl.  
     
     
         26 . The polyamine of  claim 24  wherein R 1 =R 2 =ethyl.  
     
     
         27 . The polyamine of  claim 24  wherein R 1 =R 2 =n-propyl.  
     
     
         28 . The polyamine according to  claim 1  having the formula:  
       R 1 —N 1 H—(CH 2 ) 5 —N 2 H—(CH 2 ) 5 —N 3 H—R 2    
       wherein: 
 R 1  and R 2  may be the same or different and are alkyl having at most, 10 carbon atoms.  
 
     
     
         29 . The polyamine of  claim 28  wherein R 1 =R 2 =methyl.  
     
     
         30 . The polyamine of  claim 28  wherein R 1 =R 2 =ethyl.  
     
     
         31 . The polyamine of  claim 28  wherein R 1 =R 2 =n-propyl.  
     
     
         32 . A pharmaceutical composition in unit dosage form comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a polyamine of  claim 1  or a salt thereof with a pharmaceutically acceptable acid.  
     
     
         33 . The pharmaceutical composition of  claim 32  comprising an amount of said polyamine or salt pharmaceutically effective to treat a human or non-human patient afflicted with tumor cells sensitive to said polyamine or salt thereof.  
     
     
         34 . A method of treating a human or non-human patient in need thereof comprising administering thereto a pharmaceutically effective amount of a polyamine of  claim 1  or a salt thereof with a pharmaceutically acceptable acid.  
     
     
         35 . The method according to  claim 34  comprising administering to said patient afflicted with tumor cells sensitive to said polyamine or salt thereof an amount of said polyamine or salt thereof pharmaceutically effective to inhibit the growth of said tumor cells.