Hydrophobic polyamine analogs and methods for their use

Abstract

The disclosed invention provides new polyamine analogs and derivatives containing a hydrophobic region and a polyamine region as well as methods and compositions for their use.

1. A polyamine analog or derivative represented by formula II: 
       
         
           
           
               
               
           
         
         wherein a, b, and c independently range from 1 to 10; d and e independently range from 0 to 30; each X is independently either a carbon (C) or sulfur (S) atom, and R 1  and R 2  are independently selected from H or from the group of a straight or branched C1-50 saturated or unsaturated aliphatic, carboxyalkyl, carbalkoxyalkyl, or alkoxy; a C1-8 alicyclic; a single or multiring aryl substituted or unsubstituted aliphatic; an aliphatic-substituted or unsubstituted single or multiring aromatic; a single or multiring heterocyclic; a single or multiring heterocyclic aliphatic; a C1-10 alkyl; an aryl sulfonyl; or cyano; or 
         each of R 1 X{O} n — and R 2 X{O} n — are independently is replaced by H; 
         wherein * denotes a chiral carbon position; and 
         wherein if X is C, then n is 1; if X is S, then n is 2; and if X is C, then the XO group may be CH 2  such that n is 0. 
       
     
     
       2. A polyamine analog or derivative represented by formula III: 
       
         
           
           
               
               
           
         
         wherein a, b, and c independently range from 1 to 10 and d and e independently range from 0 to 30; and R 1  , R 2 , and R 3  , and R 4  may be the same or different and are independently selected from H or from the group of a straight or branched C1-50 saturated or unsaturated aliphatic, carboxyalkyl, carbalkoxyalkyl, or alkoxy; a C1-8 alicyclic; a single or multiring aryl substituted or unsubstituted aliphatic; an aliphatic-substituted or unsubstituted single or multiring aromatic; a single or multiring heterocyclic; a single or multiring heterocyclic aliphatic; a C1-10 alkyl; an aryl sulfonyl; or cyano; and R 2  and R 4  may be the same or different and are independently selected from the group of a straight or branched C1-50 saturated or unsaturated aliphatic, carboxyalkyl, carbalkoxyalkyl, or alkoxy; a C1-8 alicyclic; a single or multiring aryl substituted or unsubstituted aliphatic; an aliphatic-substituted or unsubstituted single or multiring aromatic; a single or multiring heterocyclic; a single or multiring heterocyclic aliphatic; a C1-10 alkyl; an aryl sulfonyl; or cyano. 
       
     
     
       3. A polyamine analog or derivative represented by formula IV: 
       
         
           
           
               
               
           
         
         wherein a, b, and c independently range from 1 to 10 and d and e independently range from 0 to 30; and R 1  , R 2 , and R 3  , and R 4  may be the same or different and are independently selected from H or from the group of a straight or branched C1-50 saturated or unsaturated aliphatic, carboxyalkyl, carbalkoxyalkyl, or alkoxy; a C1-8 alicyclic; a single or multiring aryl substituted or unsubstituted aliphatic; an aliphatic-substituted or unsubstituted single or multiring aromatic; a single or multiring heterocyclic; a single or multiring heterocyclic aliphatic; a C1-10 alkyl; an aryl sulfonyl; or cyano; and R 2  and R 4  may be the same or different and are independently selected from the group of a straight or branched C1-50 saturated or unsaturated aliphatic, carboxyalkyl, carbalkoxyalkyl, or alkoxy; a C1-8 alicyclic; a single or multiring aryl substituted or unsubstituted aliphatic; an aliphatic-substituted or unsubstituted single or multiring aromatic; a single or multiring heterocyclic; a single or multiring heterocyclic aliphatic; a C1-10 alkyl; an aryl sulfonyl; or cyano. 
       
     
     
       4. A polyamine analog or derivative represented by formula V: 
       
         
           
           
               
               
           
         
         wherein a, b, and c independently range from 1 to 10 and d and C e independently range from 0 to 30; and wherein Z 1  is NR 1 R 3  and Z 2  is selected from —R 1 , —CHR 1 R 2  or —CR 1 R 2 R 3  or Z 2  is NR 2 R 4  NR 1 R 3  and Z 1  is selected from —R 1 , —CHR 1 R 2  or —CR 1 R 2 R 3 , wherein R 1 , and R 2 , and R 3  may be the same or different and are independently selected from H or from the group of a straight or branched C1-50 saturated or unsaturated aliphatic, carboxyalkyl, carbalkoxyalkyl, or alkoxy; a C1-8 alicyclic; a single or multiring aryl substituted or unsubstituted aliphatic; an aliphatic-substituted or unsubstituted single or multiring aromatic; a single or multiring heterocyclic; a single or multiring heterocyclic aliphatic; a C1-10 alkyl; an aryl sulfonyl; or cyano;  
         and wherein R 3  is selected from the group of a straight or branched C1-50 saturated or unsaturated aliphatic, carboxyalkyl, carbalkoxyalkyl, or alkoxy; a C1-8 alicyclic; a single or multiring aryl substituted or unsubstituted aliphatic; an aliphatic-substituted or unsubstituted single or multiring aromatic; a single or multiring heterocyclic; a single or multiring heterocyclic aliphatic; a C1-10 alkyl; an aryl sulfonyl; or cyano. 
       
     
     
       5. The polyamine analog or derivative of  claims 1 – 4  wherein said a, b, and c are such that the analog or derivative is putrescine, spermine or spermidine based. 
     
     
       6. The polyamine analog or derivative of  claims 1 – 4  wherein each of R 1 , R 2 , R 3 , and R 4  is independently selected from H or a straight or branched C10-50 saturated or unsaturated aliphatic, carboxyalkyl, carbalkoxyalkyl, or alkoxy. 
     
     
       7. A polyamine analog or derivative selected from spermine based compounds IA4, IB4, IA7, IVB22 or IVA22 as illustrated in  FIG. 2 . 
     
     
       8. A polyamine analog or derivative selected from the compounds depicted in  FIG. 12 . 
     
     
       9. The polyamine analog or derivative of  claims 1 – 4  wherein d is 4 and e is 0. 
     
     
       10. The polyamine analog or derivative of  claims 1 – 4  wherein each of R 1 , R 2 , R 3 , and R 4  is independently selected from H or from 
       
         
           
           
               
               
           
         
         wherein each of g, h, i, j, and k are independently selected from 0 to 15 and wherein E refers to “entgegen” and Z refers to “zusammen”. 
       
     
     
       11. A composition comprising a the polyamine analog or derivative according to  claims 1 – 4  and an excipient, diluent or vehicle. 
     
     
       12. The composition of  claim 11  wherein said excipient, diluent or vehicle is pharmaceutically or cosmetically acceptable. 
     
     
       13. The composition of  claim 11  wherein said excipient, diluent or vehicle is for topical or intra-aural administration. 
     
     
       14. The composition of  claim 11  further comprising a polyamine biosynthesis inhibitor. 
     
     
       15. The composition of  claim 14  wherein said inhibitor is DFMO difluoromethylornithine (DFMO). 
     
     
       16. The composition of  claim 11  formulated for intravenous, subcutaneous, intramuscular, intracranial, intraperitoneal, topical, transdermal, intravaginal, intranasal, intrabronchial, intracranial, intraocular, intraaural, rectal, or parenteral administration. 
     
     
       17. A polyamine analog or representative represented by formula: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       18. A polyamine analog or representative represented by formula: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       19. A polyamine analog or representative represented by formula: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       20. A polyamine analog or representative represented by formula: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       21. A composition comprising the polyamine analog or derivative according to claims 17-20 and an excipient, diluent or vehicle. 
     
     
       22. The composition of claim 21 further comprising a polyamine biosynthesis inhibitor. 
     
     
       23. The composition of claim 22 wherein said inhibitor is difluoromethylornithine (DFMO). 
     
     
       24. The composition of claim 21 formulated for intravenous, subcutaneous, intramuscular, intracranial, intraperitoneal, topical, transdermal, intravaginal, intranasal, intrabronchial, intraocular, intraaural, rectal, or parenteral administration.