Oligoamine compounds and derivatives thereof for cancer therapy

Abstract

Oligoamine compounds with anti-cancer and anti-proliferative activity are provided, as well as methods for making and using the compounds. The compounds are shown to be active against prostate cancer cell lines and against prostate cancer tumors in mice. The compounds are also useful in treatment of breast cancer and other cancers.

What is claimed is:  
     
         1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       where 
 R 10 , R 20 , R 60 , and R 70  are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl;  
 each R 80  and R 90  are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl;  
 R 30 , each R 40,  and R 50  are independently selected from:  
 —CH 2 CH 2 CH 2 CH 2 ——CHOHCH 2 CH 2 CH 2 ——CH 2 CHOHCH 2 CH 2 ——CH 2 CH 2 CHOHCH 2 ——CH 2 CH 2 CH 2 CHOH——CH 2 CH 2 CH 2 ——CHOHCH 2 CH 2 ——CH 2 CHOHCH 2 — and —CH 2 CH 2 CHOH—;  
 and where y is an integer selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13;  
 and all salts thereof.  
 
     
     
         2 . A compound according to  claim 1 , where each R 40  is independently selected from the group consisting of —CH 2 CH 2 CH 2 — and —CH 2 CH 2 CH 2 CH 2 —.  
     
     
         3 . A compound according to  claim 2 , where each R 40  is —CH 2 CH 2 CH 2 CH 2 —.  
     
     
         4 . A compound according to  claim 3 , where R 30  and R 50  are —CH 2 CH 2 CH 2 CH 2 —.  
     
     
         5 . A compound according to  claim 4 , where R 90  and each R 80  are H.  
     
     
         6 . A compound according to  claim 5 , where R 10  is H, R 20  is ethyl, R60 is H, and R 70  is ethyl.  
     
     
         7 . A compound according to  claim 6 , where y is an integer selected from 5, 7, 9, 11, and 13.  
     
     
         8 . A compound according to  claim 7 , where y is an integer selected from 5, 9, and 11.  
     
     
         9 . A compound according to  claim 1  of the formula  
       
         
           
           
               
               
           
         
       
       and all salts thereof.  
     
     
         10 . A compound according to  claim 1  of the formula  
       
         
           
           
               
               
           
         
       
       and all salts thereof.  
     
     
         11 . A compound according to  claim 1  of the formula  
       
         
           
           
               
               
           
         
       
       and all salts thereof.  
     
     
         12 . A compound according to  claim 1  of the formula  
       
         
           
           
               
               
           
         
       
       and all salts thereof.  
     
     
         13 . A compound according to  claim 1 , where R 90  and each R 80  are independently selected from the group consisting of H, methyl, and ethyl.  
     
     
         14 . A compound according to  claim 1 , where R 90  and each R 80  are H.  
     
     
         15 . A compound according to  claim 1 , where R 30 , each R 40,  and R 50  are independently selected from:  
       —CH 2 CH 2 CH 2 CH 2 ——CHOHCH 2 CH 2 CH 2 ——CH 2 CHOHCH 2 CH 2 ——CH 2 CH 2 CHOHCH 2 —, and —CH 2 CH 2 CH 2 CHOH—.  
     
     
         16 . A compound according to  claim 11 , where each R 40  is —CH 2 CH 2 CH 2 CH 2 — and R 30  and R 50  are independently selected from:  
       —CH 2 CH 2 CH 2 CH 2 — 
       —CHOHCH 2 CH 2 CH 2 ——CH 2 CHOHCH 2 CH 2 ——CH 2 CH 2 CHOHCH 2 —, and —CH 2 CH 2 CH 2 CHOH—.  
     
     
         17 . A compound according to  claim 16 , where R 30  and R 50  are independently selected from:  
       —CHOHCH 2 CH 2 CH 2 ——CH 2 CHOHCH 2 CH 2 ——CH 2 CH 2 CHOHCH 2 —, and —CH 2 CH 2 CH 2 CHOH—.  
     
     
         18 . A compound according to  claim 1 , where R 10 , R 20 , R 60 , and R 70  are independently selected from H, methyl, or ethyl.  
     
     
         19 . A compound according to  claim 18 , where R 10  is H and R 60  is H.  
     
     
         20 . A compound according to  claim 19 , where R 20  and R 70  are ethyl.  
     
     
         21 . A compound according to  claim 1 , with the proviso that at least one R 30 , R 40,  or R 50  is independently selected from:  
       —CHOHCH 2 CH 2 CH 2 ——CH 2 CHOHCH 2 CH 2 ——CH 2 CH 2 CHOHCH 2 ——CH 2 CH 2 CH 2 CHOH——CHOHCH 2 CH 2 ——CH 2 CHOHCH 2 — and  
       —CH 2 CH 2 CHOH—.  
     
     
         22 . A compound according to  claim 21 , with the proviso that at least one R 30 , R 40,  or R 50  is independently selected from:  
       —CHOHCH 2 CH 2 CH 2 ——CH 2 CHOHCH 2 CH 2 ——CH 2 CH 2 CHOHCH 2 —; and —CH 2 CH 2 CH 2 CHOH—.  
     
     
         23 . A compound according to  claim 22 , with the proviso that at least one of R 30  and R 50  is independently selected from:  
       —CHOHCH 2 CH 2 CH 2 ——CH 2 CHOHCH 2 CH 2 ——CH 2 CH 2 CHOHCH 2 —; and —CH 2 CH 2 CH 2 CHOH—.  
     
     
         24 . A method of treating cancer in an individual, comprising the step of administering a therapeutic amount of a compound according to  claim 1 .  
     
     
         25 . A method of treating cancer in an individual, comprising the step of administering a therapeutic amount of a compound according to  claim 7 .  
     
     
         26 . A method of making a compound according to  claim 1 , comprising the steps of: 
 a) providing a first compound of the form    H—N(R 90 )—R 51 —CON(R 60 )(R 70 )    where R 90  is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl;    R 60  and R 70  are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl;    R 51  is selected from the group consisting of    —CH 2 CH 2 CH 2 ——CHO(PG Hy )CH 2 CH 2 ——CH 2 CHO(PG Hy )CH 2 ——CH 2 CH 2 CHO(PG Hy )——CH 2 CH 2 ——CHO(PG Hy )CH 2 — and —C H 2 CHO(PG Hy )—   where PG Hy  is a hydroxy protecting group;    b) providing a second compound of the form    BG N N(R 80 )—R 41 —COOH    where blocking group BG N  is selected from the group consisting of an amino protecting group and methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl;    R 4  is selected from the group consisting of    —CH 2 CH 2 CH 2 ——CHO(PG Hy )CH 2 CH 2 ——CH 2 CHO(PG Hy )CH 2 ——CH 2 CH 2 CHO(PG Hy )——CH 2 CH 2 ——CHO(PG Hy )CH 2 — and —CH 2 CHO(PG Hy )—;    c) activating the carboxyl group of the second compound;    d) coupling the second compound to the first compound to form a compound of the formula    BG N [N(R 80 )—R 41 —CO] g —N(R 90 )—R 51 —CON(R 60 )(R 70 )    where g is 1;    e) repeating step c) and repeating the coupling step of step d) for (g-1) additional cycles to form a compound of the formula    BG N [N(R 80 )—R 41 —CO] g —N(R 90 )—R 51 —CON(R 60 )(R 70 )    where g is an integer from 7 to 15;    f) reducing the amide groups to amine groups; and    g) removing any protecting groups BG N  and PG Hy  that may be present in the compound.