Phorboxazole Compounds and Methods of Their Preparation

Abstract

Novel macrolactone compounds, their methods of preparation, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the macrolactone compounds may be useful, inter alia, for treating various cancers, inducing apoptosis in malignant cells, or inhibiting cancer cell division.

1 - 5 . (canceled) 
   
   
       6 . A process for preparing a compound of formula XX: 
     
       
         
         
             
             
         
       
       wherein:
 each R 2  is independently H, alkyl, aralkyl, aryl, or an hydroxyl protecting group; and 
 each Z is H or taken together form an exocyclic methylene moiety, 
 
       comprising the steps of: 
       contacting a compound of formula: 
     
     
       
         
         
             
             
         
       
       with a compound of formula: 
     
     
       
         
         
             
             
         
       
        a lactonization agent, and a base 
       for a time and under conditions effective to provide a compound of formula XX. 
     
   
   
       7 - 8 . (canceled) 
   
   
       9 . A method of inducing apoptosis in malignant cells, comprising the step of:
 contacting said cells with an effective amount of a compound of formula XIX:   
     
       
         
         
             
             
         
       
       wherein:
 R 1  is alkyl, alkenyl, haloalkenyl, or alkynyl; 
 each R 2  is independently H, alkyl, aralkyl, aryl, or an hydroxyl protecting group; 
 each dotted line indicates independently the presence of a single or double bond; and 
 each Z is H or taken together form an exocyclic methylene moiety 
 
       provided that when the compound of formula XIX has the structure: 
     
     
       
         
         
             
             
         
       
        and 
       R 2  is H or methyl: 
       then R 1  is other than: 
     
     
       
         
         
             
             
         
       
     
   
   
       10 . A method according to  claim 9 , wherein said apoptosis occurs in vitro. 
   
   
       11 . A method according to  claim 9 , wherein said apoptosis occurs in vivo. 
   
   
       12 . A method for inhibiting cancer cell division, comprising the step of:
 contacting said cells with an effective amount of a compound of formula XIX:   
     
       
         
         
             
             
         
       
       wherein:
 R 1  is alkyl, alkenyl, haloalkenyl, or alkynyl; 
 each R 2  is independently H, alkyl, aralkyl, aryl, or an hydroxyl protecting group; 
 each dotted line indicates independently the presence of a single or double bond; and 
 each Z is H or taken together form an exocyclic methylene moiety; 
 
       provided that when the compound of formula XIX has the structure: 
     
     
       
         
         
             
             
         
       
        and
 R 2  is H or methyl; 
 then R 1  is other than: 
 
     
     
       
         
         
             
             
         
       
     
   
   
       13 . (canceled) 
   
   
       14 . A method for treating cancer in a patient in need thereof, comprising the step of:
 administering to said patient an effective amount of a compound of formula XIX:   
     
       
         
         
             
             
         
       
       wherein:
 R 1  is alkyl alkenyl haloalkenyl or alkynyl: 
 each R 2  is independently H, alkyl, aralkyl, aryl, or an hydroxyl protecting group; 
 each dotted line indicates independently the presence of a single or double bond; and 
 each Z is H or taken together form an exocyclic methylene moiety; 
 
       provided that when the compound of formula XIX has the structure: 
     
     
       
         
         
             
             
         
       
        and 
       R 2  is H or methyl: 
       then R 1  is other than: 
     
     
       
         
         
             
             
         
       
        wherein the cancer treated is selected from the group consisting of pancreatic, breast, central nervous system, non-small lung, colon, and prostate cancers. 
     
   
   
       15 - 23 . (canceled) 
   
   
       24 . A process for preparing a compound of formula XXIII: 
     
       
         
         
             
             
         
       
       wherein: 
       each R 2  is independently H, alkyl, aralkyl, aryl, or an hydroxyl protecting group; and 
       each Z is H or taken together form an exocyclic methylene moiety, 
       comprising the steps of: 
       contacting a compound of formula: 
     
     
       
         
         
             
             
         
       
       with a compound of formula: 
     
     
       
         
         
             
             
         
       
        a lactonization agent, and a base 
       for a time and under conditions effective to provide a compound of formula XXIII. 
     
   
   
       25 - 27 . (canceled) 
   
   
       28 . A method of inducing apoptosis in malignant cells, comprising the step of:
 contacting said cells with an effective amount of a compound of formula XXII:   
     
       
         
         
             
             
         
       
       wherein:
 G is —O— or —CH 2 —: 
 Q is H or OR 2 , provided that when G is —O— then Q is H; 
 R 1  is alkyl, alkenyl, haloalkenyl, or alkynyl; 
 each R 2  is independently H, alkyl, aralkyl, aryl, or an hydroxyl protecting group; 
 each dotted line indicates independently the presence of a single or double bond; and 
 each Z is H or taken together form an exocyclic methylene moiety; 
 
       provided that when the compound of formula XXII has the structure: 
     
     
       
         
         
             
             
         
       
        and 
       R 2  is H or methyl; 
       then R 1  is other than: 
     
     
       
         
         
             
             
         
       
     
     wherein said apoptosis occurs in vitro. 
   
   
       29 . A method of inducing apoptosis in malignant cells, comprising the step of:
 contacting said cells with an effective amount of a compound of formula XXII:   
     
       
         
         
             
             
         
       
       wherein:
 G is —O— or —CH 2 —: 
 Q is H or OR provided that when G is —O— then Q is H; 
 R 1  is alkyl alkenyl haloalkenyl or alkynyl; 
 each R 2  is independently H, alkyl aralkyl aryl or an hydroxyl protecting group; 
 each dotted line indicates independently the presence of a single or double bond; and 
 each Z is H or taken together form an exocyclic methylene moiety; 
 
       provided that when the compound of formula XXII has the structure: 
     
     
       
         
         
             
             
         
       
        and 
       R 2  is H or methyl; 
       then R 1  is other than: 
     
     
       
         
         
             
             
         
       
     
     wherein said apoptosis occurs in vivo. 
   
   
       30 . A method for inhibiting cancer cell division, comprising the step of:
 contacting said cells with an effective amount of a compound of formula XXII:   
     
       
         
         
             
             
         
       
       wherein:
 G is —O— or —CH 2 —; 
 Q is H or OR 2 , provided that when G is —O—, then Q is H; 
 R 1  is alkyl alkenyl haloalkenyl or alkynyl: 
 each R 2  is independently H, alkyl aralkyl aryl or an hydroxyl protecting group; 
 each dotted line indicates independently the presence of a single or double bond; and 
 each Z is H or taken together form an exocyclic methylene moiety: 
 
       provided that when the compound of formula XXII has the structure: 
     
     
       
         
         
             
             
         
       
        and 
       R 2  is H or methyl; 
       then R 1  is other than: 
     
     
       
         
         
             
             
         
       
     
   
   
       31 . (canceled) 
   
   
       32 . A method for treating cancer in a patient in need thereof comprising the step of:
 administering to said patient an effective amount of a compound of formula   
     
       
         
         
             
             
         
       
       wherein:
 G is —O— or —CH 2 —; 
 Q is H or OR 2 , provided that when G is —O— then Q is H; 
 R 1  is alkyl alkenyl haloalkenyl or alkynyl; 
 each R 2  is independently H, alkyl aralkyl aryl or an hydroxyl protecting group; 
 each dotted line indicates independently the presence of a single or double bond; and 
 
       each Z is H or taken together form an exocyclic methylene moiety provided that when the compound of formula XXII has the structure: 
     
     
       
         
         
             
             
         
       
        and 
       R 2  is H or methyl; 
       then R 1  is other than: 
     
     
       
         
         
             
             
         
       
        wherein the cancer treated is selected from the group consisting of pancreatic, breast, central nervous system, non-small lung, colon, and prostate cancers.