Dehydroleucodine derivatives and uses thereof

Abstract

The present invention provides dehydroleucodine derivatives. In particular, the present invention provides amine derivatives of dehydroleucodine and methods of using dehydroleucodine and the amine derivatives of dehydroleucodine to inhibit the growth of cancer cells.

1 . A compound comprising Formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, or R 1  and R 2  together form an optionally substituted, saturated or unsaturated, carbocyclic or heterocyclic ring or ring system; 
 R 3  is hydrogen, hydroxy, amine, cyano, halo, nitro, phospho, sulfo, thiol, hydrocarbyl, or substituted hydrocarbyl; 
 R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are independently hydrogen, hydroxy, amine, cyano, halo, nitro, phospho, sulfo, thiol, hydrocarbyl, or substituted hydrocarbyl; or any pair of R 4  and R 5 , R 6  and R 7 , or R 8  and R 9  together form ═O, ═S, ═CH 2 , or ═NR a , wherein R a  is hydrogen, hydrocarbyl, or substituted hydrocarbyl; 
 Z 1  and Z 2  are independently oxygen, sulfur, nitrogen, or CH 2 ; and 
    is a single or double bond. 
 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  and R 2  are independently hydrogen, alkyl, substituted alkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R 1  and R 2  together form a heterocylic, substituted heterocyclic, heteroaryl, or substituted heteroaryl ring or ring system. 
     
     
         3 . The compound of  claim 1 , wherein the compound comprising Formula (I) comprises Formula (Ia): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, haloalkyl, alkoxy, hydroxyalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, heteroaryl, substituted heteroaryl, carbonylalkyl, carbonyl substituted alkyl, carbonylalkoxy, carbonylaminoalkyl, carbonylaryl, carbonyl substituted aryl, carbonylaryloxy, or carbonylaminoaryl, or R 1  and R 2  together form a heterocylic, substituted heterocyclic, heteroaryl, or substituted heteroaryl ring or ring system; 
 R 3 , R 6 , and R 8  are independently hydrogen, hydroxy, amine, cyano, halo, nitro, phospho, sulfo, thiol, hydrocarbyl, or substituted hydrocarbyl; and 
 R 4  and R 5  are independently hydrogen, hydroxy, amine, cyano, halo, nitro, phospho, sulfo, thiol, hydrocarbyl, or substituted hydrocarbyl, or R 4  and R 5  together form ═O, ═S, ═CH 2 , or ═NR a , wherein R a  is hydrogen, hydrocarbyl, or substituted hydrocarbyl. 
 
       
     
     
         4 . The compound of  claim 3 , wherein R 3  is C 1 -C 6  alkyl, R 5  and R 6  are hydrogen, and R 8  is C 1 -C 6  alkyl. 
     
     
         5 . The compound of  claim 4 , wherein R 4  is —XR b , wherein X is —O—, —NH—, —S—, —SO—, —SO 2 —, —CO—, —CO 2 — and R b  is hydrogen, alkyl, substituted alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, heteroaryl, substituted heteroaryl, carbonylaminoalkyl, carbonylamino substituted alkyl, carbonylaminoaryl, or carbonylamino substituted aryl. 
     
     
         6 . The compound of  claim 4 , wherein R 1  and R 2  together form an optionally substituted ring chosen from aziridinyl, azetidinyl, pyrrolidinyl, piperidynyl, or heptamethyleneiminyl. 
     
     
         7 . The compound of  claim 1 , wherein the compound comprising Formula (I) comprises Formula (Ib): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, haloalkyl, alkoxy, hydroxyalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, heteroaryl, substituted heteroaryl, carbonylalkyl, carbonyl substituted alkyl, carbonylalkoxy, carbonylaminoalkyl, carbonylaryl, carbonyl substituted aryl, carbonylaryloxy, or carbonylaminoaryl, or R 1  and R 2  together form a heterocylic, substituted heterocyclic, heteroaryl, or substituted heteroaryl ring or ring system; 
 R 3 , R 4 , and R 6  are independently hydrogen, hydroxy, amine, cyano, halo, nitro, phospho, sulfo, thiol, hydrocarbyl, or substituted hydrocarbyl; and 
 R 8  and R 9  are independently are independently hydrogen, hydroxy, amine, cyano, halo, nitro, phospho, sulfo, thiol, hydrocarbyl, or substituted hydrocarbyl, or R 8  and R 9  together form ═O, ═S, ═CH 2 , or ═NR a , wherein R a  is hydrogen, hydrocarbyl, or substituted hydrocarbyl. 
 
       
     
     
         8 . The compound of  claim 7 , wherein R 3  is C 1 -C 6  alkyl, R 4  and R 6  are hydrogen, and R 6  is C 1 -C 6  alkyl. 
     
     
         9 . The compound of  claim 8 , wherein R 9  is —XR c , wherein X is —O—, —NH—, —S—, —SO—, —SO 2 —, —CO—, —CO 2 — and R c  is hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl. 
     
     
         10 . The compound of  claim 1 , wherein the compound comprising Formula (I) comprises Formula (Ic): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, haloalkyl, alkoxy, hydroxyalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, heteroaryl, substituted heteroaryl, carbonylalkyl, carbonyl substituted alkyl, carbonylalkoxy, carbonylaminoalkyl, carbonylaryl, carbonyl substituted aryl, carbonylaryloxy, or carbonylaminoaryl, or R 1  and R 2  together form a heterocylic, substituted heterocyclic, heteroaryl, or substituted heteroaryl ring or ring system; 
 R 3  and R 6  are independently hydrogen, hydroxy, amine, cyano, halo, nitro, phospho, sulfo, thiol, hydrocarbyl, or substituted hydrocarbyl; and 
 R 8  and R 9  are independently are independently hydrogen, hydroxy, amine, cyano, halo, nitro, phospho, sulfo, thiol, hydrocarbyl, or substituted hydrocarbyl, or R 8  and R 9  together form ═O, ═S, ═CH 2 , or ═NR a , wherein R a  is hydrogen, hydrocarbyl, or substituted hydrocarbyl. 
 
       
     
     
         11 . The compound of  claim 10 , wherein R 3  and R 8  are C 1 -C 6  alkyl. 
     
     
         12 . The compound of  claim 11 , wherein R 6  is hydrogen or hydroxy. 
     
     
         13 . The compound of  claim 12 , wherein R 9  is hydrogen, alkyl, substituted alkyl, cycloalkyl, haloalkyl, alkoxy, aminoalkyl, hydroxyalkyl, sulfoxyalkyl, sulfonylalkyl, thioalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, aryloxy, aminoaryl, thioaryl, sulfoxyaryl, sulfonylaryl, heteroaryl, substituted heteroaryl, cyano, carboxy, alkylcarboxylate, aryl carboxylate, carboxamide, N-alkyl carboxamide, N-aryl carboxamide, N,N-dialkyl carboxamide, N,N-diaryl carboxamide, N-alky N-aryl carboxamide, carbonyl aminoalkyl, carbonylamino substituted alkyl, carbonylaminoaryl, carbonylamino substituted aryl, carbonylalkoxy, or carbonylaryloxy. 
     
     
         14 . The compound of  claim 1 , wherein the compound comprising Formula (I) comprises Formula (Id): 
       
         
           
           
               
               
           
         
         wherein:
 R is N-hydrocarbyl or N-substituted hydrocarbyl; and 
 R 3 , R 6 , and R 8  are independently hydrogen, hydroxy, amine, cyano, halo, nitro, phospho, sulfo, thiol, hydrocarbyl, or substituted hydrocarbyl. 
 
       
     
     
         15 . The compound of  claim 14 , wherein R is N-alkyl, N-cycloalkyl, N-alkenyl, N-alkynyl, N-aryl, N-substituted alkyl, N-substituted cycloalkyl, N-substituted alkenyl, N-substituted alkynyl, or N-substituted aryl. 
     
     
         16 . The compound of  claim 15 , wherein R 6  is hydrogen, and R 3  and R 8  are C 1 -C 6  alkyl. 
     
     
         17 . (canceled) 
     
     
         18 . A method for inhibiting growth of a cancer cell, the method comprising contacting the cancer cell with an amount of a compound comprising Formula (I), or a pharmaceutically acceptable salt thereof, effective to inhibit growth of the cancer cell, the compound comprising Formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, or R 1  and R 2  together form an optionally substituted, saturated or unsaturated, carbocyclic or heterocyclic ring or ring system; 
 R 3  is hydrogen, hydroxy, amine, cyano, halo, nitro, phospho, sulfo, thiol, hydrocarbyl, or substituted hydrocarbyl; 
 R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are independently hydrogen, hydroxy, amine, cyano, halo, nitro, phospho, sulfo, thiol, hydrocarbyl, or substituted hydrocarbyl; or any pair of R 4  and R 5 , R 6  and R 7 , or R 8  and R 9  together form ═O, ═S, ═CH 2 , or ═NR a , wherein R a  is hydrogen, hydrocarbyl, or substituted hydrocarbyl; 
 Z 1  and Z 2  are independently oxygen, sulfur, nitrogen, or CH 2 ; and 
    is a single or double bond. 
 
       
     
     
         19 .- 31 . (canceled) 
     
     
         32 . The method of  claim 18 , wherein the cancer cell is a leukemic cell. 
     
     
         33 .- 36 . (canceled) 
     
     
         37 . The method of  claim 18 , wherein the cancer cell is a solid tumor cell. 
     
     
         38 . The method of  claim 37 , wherein the solid tumor cell is selected from the group consisting of a colon cancer cell, a prostate cancer cell and a central nervous system cancer cell. 
     
     
         39 .- 48 . (canceled)