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 the formula  
         R—X-L-polyamine  wherein R is a straight or branched C10-50 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; an aryl sulfonyl;    X is —CO—, —SO 2 —, or —CH 2 —; and    L is a covalent bond or a naturally occurring amino acid, ornithine, 2,4-diaminobutyric acid, or derivatives thereof.    
     
     
         2 . 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, carboxylalkyl, 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 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  and such that n is 0.  
       
     
     
         3 . 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 , 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.  
       
     
     
         4 . 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 , 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, carboxylalkyl, 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 multiming heterocyclic aliphatic; a C1-10 alkyl; an aryl sulfonyl; or cyano.  
       
     
     
         5 . A polyamine analog or derivative represented by formula V:  
       
         
           
           
               
               
           
         
         wherein a, b, and c independently range from 1 to 10 and d and 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 —R 1 R 2 R 3  or Z 2  is NR 2 R 4  and Z 1  is selected from —R 1 , —CHR 1 R 2  or —CR 1 R 2 R 3    
         wherein R 1 , 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, caraboxyalkyl, 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.  
       
     
     
         6 . The analog or derivative of  claim 1  wherein said a, b, and c are such that the analog or derivative is putrescine, spermine or spermidine based.  
     
     
         7 . The analog or derivative of  claim 1  wherein each 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.  
     
     
         8 . The analog or derivative of  claim 1  wherein L is an amino acid selected from lysine, aspartic acid, glutamic acid, ornithine, or 2,4-diaminobutyric acid.  
     
     
         9 . A polyamine analog or derivative selected from spermine based compounds IA4, IB4, IA7, IVB22 or IVA22 as illustrated in  FIG. 2 .  
     
     
         10 . A polyamine analog or derivative selected from the compounds depicted in  FIG. 12 .  
     
     
         11 . The analog or derivative of  claim 1  wherein d is 4 and e is 0.  
     
     
         12 . The analog or derivative of  claim 1  wherein each 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”.  
       
     
     
         13 . A composition comprising a polyamine analog or derivative according to  claim 1  and an excipient, diluent or vehicle.  
     
     
         14 . The composition of  claim 13  wherein said excipient, diluent or vehicle is pharmaceutically or cosmetically acceptable.  
     
     
         15 . The composition of  claim 13  wherein said excipient, diluent or vehicle is for topical or intra-aural administration.  
     
     
         16 . The composition of  claim 13  further comprising a polyamine biosynthesis inhibitor.  
     
     
         17 . The composition of  claim 16  wherein said inhibitor is DFMO.  
     
     
         18 . The composition of  claim 13  formulated for intravenous, subcutaneous, intramuscular, intracranial, intraperitoneal, topical, transdermal, intravaginal, intranasal, intrabronchial, intracranial, intraocular, intraaural, rectal, or parenteral administration.  
     
     
         19 . A method of treating one or more conditions selected from cancer, osteoporosis, asthma, autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus, Type I insulin dependent diabetes, psoriasis, restenosis, inhibition of unwanted proliferation of hair on skin, tissue transplantation, African sleeping sickness, inflammation, hyperparathyroidism, treatment of peptic ulcer, glaucoma, Alzheimer's disease, suppression of atrial tachycardias, stimulation or inhibition of intestinal motility, Crohn's disease and other inflammatory bowel diseases, high blood pressure (vasodilation), stroke, epilepsy, anxiety, neurodegenerative diseases, hyperalgesic states, the protection of hair cells from chemotherapeutic-induced loss of hearing, and pharmacological manipulation of cocaine reinforcement and craving in treating cocaine addiction and overdose comprising administration of an analog or derivative of  claim 1  or a composition of  claim 13  to a subject afflicted with said one or more conditions.  
     
     
         20 . The method of  claim 19  wherein said administration is systemic.  
     
     
         21 . The method of  claim 19  or wherein said administration is oral.  
     
     
         22 . The method of  claim 19  wherein said administration is via a time release vehicle.  
     
     
         23 . A method of treating fungal, bacterial, viral, or parasitic diseases comprising administration of an analog or derivative of  claim 1   claim 1  or a composition of  claim 13  to subject afflicted with said disease.  
     
     
         24 . A method of enhancing cellular uptake of nucleic acids comprising contacting a cell with an analog or derivative of  claim 1 .  
     
     
         25 . A method of inhibiting hair growth comprising topical administration of an analog or derivative of  claim 1  or a composition of  claim 13  to a subject in need of hair growth inhibition.  
     
     
         26 . The method of  claim 25  wherein said analog or derivative is formulated as a cosmetic.  
     
     
         27 . A method of inhibiting hearing loss comprising administration of an analog or derivative of  claim 1  to a subject in need of said inhibition.  
     
     
         28 . The method of  claim 27  wherein said subject is susceptible to hearing loss due to cancer chemotherapy.