Hemiasterlin analogs

Abstract

This invention provides analogs of hemiasterlin, methods of synthesis of the analogs and use of the analogs as a cytotoxic anti-mitotic agents.

1 . A compound or pharmaceutically acceptable salt thereof, having the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 2  are independently selected from the group consisting of: H, R, and ArR—, and where at least one of R 1  and R 2  is R the other is not ArR—; R 1  and R 2  together may optionally be a three to seven member non-aromatic ring; 
       R 3  and R 4  are independently selected from the group consisting of: H, R, and ArR—, and where at least one of R 3  and R 4  is R the other is not ArR, R 3  and R 4  together may optionally be a three to seven member non-aromatic ring; 
       R 5  is selected from the group consisting of: H, R, ArR—, and Ar; 
       R 6  is selected from the group consisting of: H, R, and ArR—; 
       R 7  and R 8  are independently selected from the group consisting of: H, R, and ArR—; and 
       R 9  is: 
     
     
       
         
         
             
             
         
       
       and wherein, 
       R is defined as a saturated or unsaturated moiety having a linear, branched, or non-aromatic cyclic skeleton containing one to ten carbon atoms, zero to four nitrogen atoms, zero to four oxygen atoms, and zero to four sulfur atoms, and the carbon atoms are optionally substituted with: ═O, ═S, —OH, —OR 10 , —O 2 CR 10 , —SH, —SR 10 , —SOCR 10 , —NH 2 , —NHR 10 , —N(R 10 ) 2 , —NHCOR 10 , —NR 10 COR 10 , —I, —Br, —Cl, —F, —CN, —CO 2 H, —CO 2 R 10 , —CHO, —COR 10 , —CONH 2 , —CONHR 10 , —CON(R 10 ) 2 , —COSH, —COSR 10 , —NO 2 , —SO 3 H, —SOR 10 , —SO 2 R 10 , wherein R 10  is a linear, branched or cyclic, one to ten carbon saturated or unsaturated alkyl group, 
       X is defined as a moiety selected from the group consisting of: —OH, —OR, ═O, ═S, —O 2 CR, —SH, —SR, —SOCR, —NH 2 , —NHR, —N(R) 2 , —NHCOR, —NRCOR, —I, —Br, —Cl, —F, —CN, —CO 2 H, —CO 2 R, —CHO, —COR, —CONH 2 , —CONHR, —CON(R) 2 , —COSH, —COSR, —NO 2 , —SO 3 H, —SOR, and —SO 2 R; 
       Ar is an aromatic ring selected from the group consisting of: phenyl, naphthyl, anthracyl, phenanthryl, furyl, pyrrolyl, thiophenyl, benzofuryl, benzothiophenyl, quinolinyl, isoquinolyl, imidazolyl, thiazolyl, oxazolyl, and pyridinyl, optionally substituted with R or X; 
       Y is a linear, unsaturated, one to six carbon alkyl group, optionally substituted with R, ArR—, or X; and 
       Z is defined as a moiety selected from the group consisting of: —NHR; and —N(R) 2 . 
     
   
   
       2 . The compound of  claim 1  wherein Ar is phenyl, naphthyl, anthracyl, or pyrrolyl. 
   
   
       3 . The compound of  claim 2  wherein R 5  is phenyl, naphthyl, anthracyl, or pyrrolyl. 
   
   
       4 . The compound of  claim 1  wherein R 3  and R 4  are independently selected from the group consisting of: methyl, ethyl, n-propyl, and n-butyl; or R 3  and R 4  together are joined to form a moiety selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 
   
   
       5 . The compound of  claim 1  wherein R 1  and R 2  are independently selected from the group consisting of: H, methyl, ethyl, propyl, n-butyl and acetyl; or R 1  and R 2  together are joined to form a moiety selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 
   
   
       6 . The compound of  claim 1  wherein R 1  and R 2  are independently: H, methyl, or acetyl. 
   
   
       7 . The compound of  claim 1  wherein R 1  is H and R 2  is methyl. 
   
   
       8 . The compound of  claim 1  wherein R 7  is a three to six carbon alkyl group. 
   
   
       9 . The compound of  claim 1  wherein R 6  and R 8  are independently: H or methyl. 
   
   
       10 . The compound of  claim 1  wherein R 6  is H, R 7  is —C(CH) 3 ) 3  and R 8  methyl. 
   
   
       11 . The compound of  claim 1  wherein R 3  and R 4  are each R. 
   
   
       12 . The compound of  claim 1  wherein R 3  and R 4  are each methyl. 
   
   
       13 . The compound of  claim 1  wherein R 5  is phenyl. 
   
   
       14 . A method of inhibiting mitosis of a tumor cell comprising contacting the tumor cell with an effective amount of a compound according to  claim 1 . 
   
   
       15 . A method of treating colon cancer comprising administering to a patient in need thereof an anti-mitotic effective amount of a compound according to  claim 1 . 
   
   
       16 . A method of treating breast cancer comprising administering to a patient in need thereof an anti-mitotic effective amount of a compound according to  claim 1 . 
   
   
       17 . A method of treating lung cancer comprising administering to a patient in need thereof an anti-mitotic effective amount of a compound according to  claim 1 .