Combbretastatin a-4 as an anti-angiogenic agent

Abstract

The application discloses methods of treating mammalian diseases characterized by abnormal cell mitosis by administering estradiol derivatives including those comprising colchicine or combretastatin A-4 structural motifs of the general formulae found below in a dosage sufficient to inhibit cell mitosis. The application discloses novel compounds used in the methods.

1 . A method for treating a mammalian disease characterized by abnormal cell mitosis, said method comprising administering to a mammal a cell-mitosis-inhibiting compound of the formula below, said compound being administered in an amount sufficient to inhibit cell mitosis:  
       
         
           
           
               
               
           
         
       
       wherein: 
 I. R a —R o  are defined as follows: 
 A) each R a , R b , R c , R d , R e , R f , R i , R j , R k , R L , R m , R o , independently is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, or —I; and R g  is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, —I, or —C≡CH; or  
 B) each R a , R b , R c , R f , R k , R L , R o , independently is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, or —I; and each R d , R e , R i , R j , R m , independently is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br or —I; and R g  is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, —I, or —C≡CH and  
 
 II. Z′ is defined as follows:  
                     
  and X′ is X, as defined above; or X′ is >C═O; and  
 III. Z″ is defined as follows:  
                     
 and  
 IV. provided that when each R b , R c , R d , R e , R i , R j , R k , R L , R m  and R o  is H; 
 R f  is —CH 3 ;  
 Rg is —OH;  
 Z′ is >COH; and  
 Z″ is >CH 2 ; 
 then R a  is not —H;  
 where, in each formula set forth above, each R 1  and R 2  independently is —H, or a substituted or unsubstituted alkyl, alkenyl or alkenyl group of up to 6 carbons.  
 
 
 
     
     
         2 . A method for treating a mammalian disease characterized by undesirable cell mitosis, said method comprising administering to a mammal a cell-mitosis-inhibiting compound of the formula below, said compound being administered in an amount sufficient to inhibit cell mitosis:  
       
         
           
           
               
               
           
         
         I. R a —R k  are defined as follows: 
 A) each R a , R b , R c , R d , R g , R h , R i , R k  independently is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NH 2 , —Br, or —I; and R e  is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NH 2 , —Br, —I or —C≡CH; or  
 B) each R a , R b , R c , R d , R k , independently is —R 1 , —OR 1 , OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, or —I; and each Re g , R h , R i , independently is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —Br, or —I; and R e  is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —Br, —I or —C≡CH; and  
 
         II. Z′ is defined as follows:  
         
           
             
             
                 
                 
             
           
         
          where, in each formula set forth above, each R 1  and R 2  independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkenyl group of 1-6 carbons.  
       
     
     
         3 . A method for treating a mammalian disease characterized by abnormal cell mitosis, said method comprising administering to a mammal a cell-mitosis-inhibiting compound of the formula below, said compound being administered in an amount sufficient to inhibit cell mitosis:  
       
         
           
           
               
               
           
         
       
       wherein: 
 I. R a —R o  are defined as follows: 
 A) each R a , R b , R c , R d , R e , R f , R i , R j , R k , R L , R m , R o , independently is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, or —I; and R g  is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, —I, or —C≡CH; or  
 B) each R a , R b , R c , R f , R k , R L , independently is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, or —I; and each R d , R e , R i , R j , R m , R o  independently is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, NHR 2 , —Br or —I; and R g  is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, —I, or —C═CH  
 
 II. Z is defined as follows:  
                     
  is —R 1 , OR 1 , —SR 1 , —F, —NHR 2 , —Br or —I; 
 where, in each formula set forth above, each R 1  and R 2  independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkenyl group of 1-6 carbons.  
 
 
     
     
         4 . A method for treating a mammalian disease characterized by abnormal cell mitosis, said method comprising administering to a mammal a cell-mitosis-inhibiting compound of the formula below, said compound being administered in an amount sufficient to inhibit cell mitosis:  
       
         
           
           
               
               
           
         
       
       wherein: 
 I. R a —R k  are defined as follows: 
 A) each R a , R b , R c , R d , R g , R h , R i , R k  independently is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 1 , —Br, or —I; and R e  is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 1 , —Br, —I or —C≡CH; or  
 B) each R a , R b , R c , R d , independently is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 1 , —Br, or —I; and each R g , R h , R i , R k  independently is ═O, —R 1 , OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 1 , —Br or —I; and R e  is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 1 , —Br, —I or —C≡CH;  
 
 II. Z is defined as follows:  
                     
  where, in each formula set forth above, each R 1  and R 2  independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkenyl group of 1-6 carbons.  
 
     
     
         5 . A method for treating a mammalian disease characterized by abnormal cell mitosis, said method comprising administering to a mammal a cell-mitosis-inhibiting compound of the formula below, said compound being administered in an amount sufficient to inhibit cell mitosis:  
       
         
           
           
               
               
           
         
       
       wherein: 
 I. R a —R o  are defined as follows: 
 A) each R a , R b , R c , R d , R e , R f , R g , R h , R j , R k , R L , R m , R n , R o  independently is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, or —I; and R i  is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, —I or —C≡CH; or  
 B) each R a , R d , R f , R j , R m , R n , R o  independently is —R 1 , —OR 1 , —OCR 1 , —SR 1 , —F, —NHR 2 , —Br, or —I; and each R b , R c , R e , R g , R h , R k , R L  independently is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 1 , —Br or —I; and R i  is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —Br, —I or —C≡CH;  
 C) each R a , R b , R c , R d , R f , R j , R m , R n , R o  independently is —R 1 , —OR 1 , —OCR 1 , —SR 1 , —F, —NHR 2 , —Br, —I; and each R e , R g , R h , R k , R L , R k , independently is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 1 , —Br or —I; and R i  is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —Br, —I or —C≡CH;  
 
 II. Z is defined as follows:  
                     
  is —R 1 , —OR 1 , —SR 1 , —F, —NHR 2 , —Br or —I; and X′ is X, as defined above; or X′ is >C═O; 
 where, in each formula set forth above, each R 1  and R 2  independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkenyl group of 1-6 carbons; and the bond indicated by CC is absent or, in combination with the C—C bond, is the unit HC═CH.  
 
 
     
     
         6 . A method for treating a mammalian disease characterized by abnormal cell mitosis, said method comprising administering to a mammal a cell-mitosis-inhibiting compound of the formula below, said compound being administered in an amount sufficient to inhibit cell mitosis:  
       
         
           
           
               
               
           
         
       
       wherein: 
 I. R a —R o  are defined as follows: 
 A) each R a , R b , R c , R e , R g , R h , R k , R L , R m , R n , R o  independently is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, or —I; and R i  is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, —I or —C≡CH; or  
 B) each R a , R e , R L , R m , R n , R o  independently is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, —I; and each R b , R c , R g , R h  is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 1 , —Br or —I; and R i  is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 1 , —Br, —I or —C≡CH; or  
 C) each R a , R b , R c , R e , R k , R m , R n , R o  independently is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, —I, and each R h , R i  independently is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 1 , —Br or —I; and R i  is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 1 , —Br, —I or —C≡CH; and  
 
 II. Z is defined as follows:  
                     
  is —R 1 , —OR 1 , —SR 1 , —F, —NHR 2 , —Br or —I, and X′ is X, as defined above; or X′ is ═O; 
 where, in each formula set forth above, each R 1  and R 2  independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkenyl group of 1-6 carbons; and the bond indicated by CC is absent or, in combination with the C—C bond is the unit HC═CH.  
 
 
     
     
         7 . A compound of the general formula below, said compound being a cell-mitosis-inhibiting compound:  
       
         
           
           
               
               
           
         
       
       wherein: 
 I. R a —R o  are defined as follows: 
 A) each R a , R b , R c , R d , R e , R f , R i , R j , R k , R L , R m , R o , independently is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, or —I; and R g  is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, —I, or —C≡CH; or  
 B) each R a , R b , R c , R f , R k , R L , R o , independently is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, or —I; and each R d , R e , R i , R j , R m , independently is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, NHR 2 , —Br or —I; and R g  is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, —I, or —C≡CH and  
 
 II. Z′ is defined as follows:  
                     
  where R n  is —R 1 , —OR 1 , —SR 1 , —F, —NHR 2 , —Br or —I; or X′ is X, as defined above; or X′ is >C═O;  
 III. Z″ is defined as follows:  
                     
  when: 
 3) each R b , R c , R d , R e , R j , R k , R L , R m  is —H; 
 R f  is —CH 3 ;  
 R g  is —OH;  
                     
 R i  is —H, —OH, or ═O;  
 R o  is —H or —Br;  
 Z′ is >COH; and  
 Z″ is >CH 2  or —OH; then  
 then R a  is not —F, —Br, —OH or —H; and  
 
 4) each R b , R c , R d , R e , R i , R j , R k , R L , R m  is —H; 
 R f  is —CH 3 ;  
 R g  is —OH; and  
 Z″ is >CH 2 ; then  
 Z′ is not >COCH 3  or  
                     
  and each R a , R o  independently or together are not —OCH 3  or —H; and  
 
 5) each R c , R e , R j , R k , R L , R m , R o  is —H; 
 R a  is —H or —OCH 3    
 R b  is —H or —CH 3 ;  
 R d  is —OH  
 R f  is —CH 3    
 R g  is ═O;  
 R i  is —OH, ═O or —C≡CH; and  
 Z″ is >CH 2 ; then  
 Z′ is not >COH;  
                     
  or —H; 
 where, in each formula set forth above, each R 1  and R 2  independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkenyl group of 1-6 carbons.  
 
 
 
 
     
     
         8 . A compound of the general formula below, said compound being a cell-mitosis-inhibiting compound:  
       
         
           
           
               
               
           
         
       
       wherein: 
 I. R a —R k  are defined as follows: 
 A) each R a , R b , R c , R d , R g , R h , R i , R k  independently is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, or —I; and R e  is —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, —I or —C≡CH; or  
 B) each R a , R b , R c , R d , R k , is —R 1 , —OR 1 , OCOR 1 , —SR 1 , —F, —NHR 2 , —Br, or —I; and each R g , R h , R i , independently is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —Br, or —I; and R e  is ═O, —R 1 , —OR 1 , —OCOR 1 , —SR 1 , —F, —Br, —I or —C≡CH; and  
 
 I. Z′ is defined as follows:  
                     
  is —R 1 , —OR 1 , —SR 1 , —F, —NHR 2 , —Br, or —I, and X′ is X, as defined above; 
 or X′ is also >C═O; and  
 
 II. Z″ is defined as follows: