Conformationally restricted polyamine analogs as disease therapies

Abstract

Novel conformationally restricted polyamine analogs are provided, as well as compositions comprising these novel polyamine analogs. Methods of using the novel polyamine analogs in treatment of diseases such as cancer are also provided. Also provided is a method of delivering these analogs specifically to tumor cells by covalently attaching polyamine analogs to porphyrin compounds, along with novel polyamine-porphyrin covalent conjugates.

1 . A conformationally restricted polyamine analog of the formula:  
       E-NH—B-A-B—NH—B-A-B—NH—B-A-B—NH—B-A-B—NH-E  
     wherein each A is independently selected from the group consisting of: a single bond, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl; 
 each B is independently selected from the group consisting of: a single bond, C 1 -C 6  alkyl, and C 2 -C 6  alkenyl;  
 and each E is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl;  
 with the proviso that either at least one A moiety is selected from the group consisting of C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl, or at least one B moiety is selected from the group consisting of C 2 -C 6  alkenyl;  
 and any salt or stereoisomer thereof.  
 
   
   
       2 . A conformationally restricted polyamine analog according to  claim 1 , selected from the group consisting of  
     
       
         
         
             
             
         
       
     
     and any salt or stereoisomer thereof.  
   
   
       3 . A conformationally restricted polyamine analog of the formula:  
       E-NH—B-A-B—NH—B-A-B—NH—B-A-B—NH(—B-A-B—NH) x -E  
     wherein each A is independently selected from the group consisting of: a single bond, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl; 
 each B is independently selected from the group consisting of: a single bond, C 1 -C 6  alkyl, and C 2 -C 6  alkenyl;  
 each E is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl; and x is an integer from 2 to 16;  
 with the proviso that either at least one A moiety is selected from the group consisting of C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl, or at least one B moiety is selected from the group consisting of C 2 -C 6  alkenyl;  
 and any salt or stereoisomer thereof.  
 
   
   
       4 . A conformationally restricted polyamine analog according to  claim 3 , selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     and any salt or stereoisomer thereof.  
   
   
       5 . A polyamine analog of the formula:  
       E-NH—B-A-B—NH—B-A-B—NH—B-A-B—NH(—B-A-B—NH) x -E  
     wherein each A is independently selected from the group consisting of: a single bond, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl; 
 each B is independently selected from the group consisting of: a single bond, C 1 -C 6  alkyl, and C 2 -C 6  alkenyl;  
 each E is independently selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkanol, C 3 -C 6  cycloalkanol, and C 3 -C 6  hydroxyaryl,  
 with the proviso that at least one E moiety be selected from the group consisting of C 1 -C 6  alkanol, C 3 -C 6  cycloalkanol, and C 3 -C 6  hydroxyaryl;  
 and x is an integer from 0 to 16;  
 and any salt or stereoisomer thereof.  
 
   
   
       6 . A polyamine analog according to  claim 5 , selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     and all salts and stereoisomers thereof.  
   
   
       7 . A conformationally restricted polyamine analog of the formula:  
       E-N H-D-NH—B-A-B—NH-D-NH-E  
     wherein each A is selected from the group consisting of C 2 -C 6  alkynyl; 
 each B is independently selected from the group consisting of: a single bond, C 1 -C 6  alkyl, and C 2 -C 6  alkenyl;  
 each D is independently selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkenyl, and C 3 -C 6  cycloaryl; and  
 each E is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl;  
 and any salt or stereoisomer thereof.  
 
   
   
       8 . A conformationally restricted polyamine analog according to  claim 7 , selected from the group consisting of  
     
       
         
         
             
             
         
       
     
     and any salt or stereoisomer thereof.  
   
   
       9 . A conformationally restricted polyamine analog of the formula:  
       E-NH—B-A-B—NH—F—NH—B-A-B—N H-E  
     wherein F is selected from the group consisting of C 1 -C 6  alkyl; 
 each A is independently selected from the group consisting of: a single bond, C 1 -C 6  alkyl; C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl;  
 each B is independently selected from the group consisting of: a single bond, C 1 -C 6  alkyl, and C 2 -C 6  alkenyl; and  
 each E is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl;  
 with the proviso that either at least one A moiety is selected from the group consisting of C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl, or at least one B moiety is selected from the group consisting of C 2 -C 6  alkenyl;  
 and any salt or stereoisomer thereof.  
 
   
   
       10 . A conformationally restricted polyamine analog according to  claim 9 , selected from the group consisting of  
     
       
         
         
             
             
         
       
     
     and any salt or stereoisomer thereof.  
   
   
       11 . A conformationally restricted polyamine analog of the formula:  
     
       
         
         
             
             
         
       
     
     wherein A is independently selected from the group consisting of: a single bond, C 1 -C 6  alkyl; C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl; 
 each B is independently selected from the group consisting of: a single bond, C 1 -C 6  alkyl, and C 2 -C 6  alkenyl;  
 with the proviso that A and both B moieties are not all a single bond;  
 and any salt or stereoisomer thereof.  
 
   
   
       12 . A conformationally restricted polyamine analog according to  claim 11 , selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     and any salt or stereoisomer thereof.  
   
   
       13 . A conformationally restricted polyamine analog of the formula:  
       E-NH-D-NH—B-A-B—NH-D-NH-E  
     wherein A is selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkenyl, and C 3 -C 6  cycloaryl; 
 each B is independently selected from the group consisting of: a single bond, C 1 -C 6  alkyl, and C 2 -C 6  alkenyl;  
 each D is independently selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkenyl, and C 3 -C 6  cycloaryl; and  
 each E is independently selected from the group consisting of H and C 1 -C 6  alkyl;  
 with the proviso that either at least one A moiety is selected from the group consisting of C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl, or at least one B moiety is selected from the group consisting of C 2 -C 6  alkenyl;  
 and the proviso that at least one E is selected from the group consisting of H or methyl;  
 and any salt or stereoisomer thereof.  
 
   
   
       14 . A conformationally restricted polyamine analog according to  claim 13  of the formula  
     
       
         
         
             
             
         
       
     
     and any salt or stereoisomer thereof.  
   
   
       15 . A conformationally restricted polyamine analog of the formula:  
     
       
         
         
             
             
         
       
     
     wherein A is trans-ethene 
 each B is independently selected from the group consisting of: a single bond, C 1 -C 6  alkyl, and C 2 -C 6  alkenyl;  
 each D is independently selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl, with the proviso that D is not C 3  alkyl; and  
 each E is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloaryl, and C 3 -C 6  cycloalkenyl;  
 and any salt thereof.  
 
   
   
       16 . The polyamine analog of  claim 1 , further comprising a pharmaceutically acceptable excipient.  
   
   
       17 . A method of treating an indication in an individual comprising the step of administering to the individual a therapeutic amount of a polyamine analog of  claim 1 .  
   
   
       18 . The method of  claim 17 , wherein the individual is a human.  
   
   
       19 . The method of  claim 17 , wherein the indication is a cancer.  
   
   
       20 . The method of  claim 19 , wherein the cancer affects cells of the bladder, blood, brain, breast, colon, digestive tract, lung, ovaries, pancreas, prostate gland, or skin.  
   
   
       21 . The method of  claim 17 , wherein the indication is Alzheimer's disease, epilepsy, multiple sclerosis, problems associated with tissue grafts and organ transplants, psoriasis, restenosis, stomach ulcers, or tissue overgrowth after surgery, or an infection or infestation of parasites, bacteria, fungi or insects.  
   
   
       22 . A method of suppressing cell growth in an individual comprising the step of administering to the individual a therapeutic amount of a polyamine analog of  claim 1 .  
   
   
       23 . The method of  claim 22 , wherein the individual is a human.  
   
   
       24 - 31 . (canceled)