Dolastatin 15 derivatives

Abstract

Compounds of the present invention include cell growth inhibitors which are peptides of Formula I, A-B-D-E-F-(G) r -(K) s -L  (I), and acid salts thereof, wherein A, B, D, E, F, G and K are α-amino acid residues, and s and r are each, independently, 0 or 1 . L is a monovalent radical, such as, for example, an amino group, an N-substituted amino group, a β-hydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, or an oximato group. The present invention also includes a method for treating cancer in a mammal, such as a human, comprising administering to the mammal an effective amount of a compound of Formula I in a pharmaceutically acceptable composition.

1 - 39 . (canceled) 
     
     
         40 . A compound of the formula
   A-B-D-E-F-(G) r -(K) s -L   wherein   r and s are 0;   A is   a proline derivative of Formula II a ,   
       
         
           
           
               
               
           
         
         wherein n a  is 0 to 2; R a  is hydrogen or unsubstituted normal or branched C 1 -C 3 -alkyl; R 1   a  is hydrogen; or R a  and R 1   a  together form a propylene bridge; and R 2   a , R 3   a , R 4   a , and R 5   a  are each hydrogen; 
         B is valyl, isoleucyl, or 2-tert-butylglycyl; 
         D is N-methylvalyl or N-methylisoleucyl; 
         E is prolyl, thiazolidinyl-4-carbonyl or 3,4-didehydroprolyl; 
         F is prolyl; and 
         L is N-benzylamide, N-methoxy-N-benzylamide, tert-butylamide, tert-butyl ester, N-methoxy-N-methylamide, isopropylamide, 5-phenyl isoxasolidinyl, isoxazolidinyl, pentylamide, (R) or (S) phenethylamide, —O-tert-butyl, isoxazolidinyl, 5-phenyl isoxazolidinyl, 
       
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         41 . A compound of  claim 40  selected from the group consisting of:
 Xad Ile Xaa Pro Xbx 
 Xad Ile Xaa Pro Xch 
 Xad Val Xaa Pro Xap 
 Xad Val Xaa Pro Xbr 
 Xad Val Xaa Pro Xbx 
 Xad Val Xaa Pro Xch 
 Xad Val Xaa Pro Xci 
 Xad Val Xaa Pro Xck 
 Xad Val Xaa Pro Xcl 
 Xad Val Xaa Pro Xcm 
 Xad Val Xaa Pro Xcn 
 Xad Val Xaa Pro Xco 
 Xad Val Xaa Pro Xcp 
 Xad Val Xaa Pro Xcq 
 Xad Val Xaa Pro Xcr 
 Xad Val Xaa Xal Xbx 
 Xad Val Xaa Xal Xch 
 Xad Val Xaa Xal Xcr 
 Xad Val Xaa Xan Xbx 
 Xad Val Xaa Xan Xch 
 Xad Val Xaa Xan Xcr 
 Xad Val Xct Pro Xbx 
 Xad Val Xct Pro Xch 
 Xad Xcs Xaa Pro Xbx 
 Xad Xcs Xaa Pro Xch 
 Xae Val Xaa Pro Xab 
 Xah Val Xaa Pro Xab 
 Xai Val Xaa Pro Xab 
 Xam Val Xaa Pro Xab 
 Xao Val Xaa Pro Xab 
 Xaq Val Xaa Pro Xab 
 Xas Val Xaa Pro Xab 
 Xav Val Xaa Pro Xab 
 Xaw Ile Xaa Pro Xbx 
 Xaw Ile Xaa Pro Xch 
 Xaw Val Xaa Pro Xbn 
 Xaw Val Xaa Pro Xbp 
 Xaw Val Xaa Pro Xbq 
 Xaw Val Xaa Pro Xbr 
 Xaw Val Xaa Pro Xbx 
 Xaw Val Xaa Pro Xch 
 Xaw Val Xaa Pro Xci 
 Xaw Val Xaa Pro Xck 
 Xaw Val Xaa Pro Xcl 
 Xaw Val Xaa Pro Xcm 
 Xaw Val Xaa Pro Xcn 
 Xaw Val Xaa Pro Xco 
 Xaw Val Xaa Pro Xcp 
 Xaw Val Xaa Pro Xcq 
 Xaw Val Xaa Pro Xcr 
 Xaw Val Xaa Xal Xbx 
 Xaw Val Xaa Xal Xch 
 Xaw Val Xaa Xal Xcr 
 Xaw Val Xaa Xan Xbx 
 Xaw Val Xaa Xan Xch 
 Xaw Val Xaa Xan Xcr 
 Xaw Val Xct Pro Xbx 
 Xaw Val Xct Pro Xch 
 Xaw Xcs Xaa Pro Xbx 
 Xaw Xcs Xaa Pro Xch 
 Xbo Val Xaa Pro Xbn isomer 1 
 Xbo Val Xaa Pro Xbn isomer 2 
 Xbo Val Xaa Pro Xbp isomer 1 
 Xbo Val Xaa Pro Xbp isomer 1 
 Xbo Val Xaa Pro Xbp isomer 2 
 Xbo Val Xaa Pro Xbp isomer 2 
 Xbo Val Xaa Pro Xbq isomer 1 
 Xbo Val Xaa Pro Xbq isomer 2 
 Xbo Val Xaa Pro Xbr isomer 1 
 Xbo Val Xaa Pro Xbr isomer 2 
 Xbo Val Xaa Pro Xbx isomer 1 
 Xbo Val Xaa Pro Xbx isomer 2 
 Xbs Val Xaa Pro Xbt isomer 1 and 
 Xbs Val Xaa Pro Xbt isomer 2 
 or a pharmaceutically acceptable salt thereof, 
 wherein: 
 Xaa is N-methyl-valine, Xab is Prolyl N-benzylamide, Xad is D-N-methyl-piperidine-2-carboxylic acid, Xae is N-methyl-L-proline, Xah is L-proline, Xai is L-piperidine-2-carboxylic acid, Xak is 2-[N,N-dimethylamino]-isobutyric acid, Xal is L-thiazolidine-4-carboxylic acid, Xam is N-propyl-D-piperidine-2-carboxylic acid, Xan is L-3,4-didehydroproline, Xao is D-piperidine-2-carboxylic acid, Xap is proline tertbutylester, Xaq is N-ethyl-D-piperidine-2-carboxylic acid, Xar is N-methyl-[2,2,5,5-tetramethyl]-L-thiazolidine-2-carboxylic acid, Xas is N-isopropyl-D-piperidine-2-carboxylic acid, Xav is D-proline, Xaw is N-methyl-D-proline, Xax is N,N-dimethyl-2-[2-fluoro]phenyl-glycine, Xbn is proline-N-methoxy-N-methyl-amide, Xbo is N-methyl-piperidine-2-carboxylic acid, Xbp is proline-isopropylamide, Xbq is proline-isoxazolidinyl, Xbr is proline-N-methoxy-N-benzylamide, Xbs is N-methyl-D,L-proline, Xbt is proline-[5-phenyl]isoxazolidinyl, Xbx is proline-tert-butylamide, 
 Xch is 
 
       
         
           
           
               
               
           
         
         Xci is 
       
       
         
           
           
               
               
           
         
         Xck is 
       
       
         
           
           
               
               
           
         
         Xcl is 
       
       
         
           
           
               
               
           
         
         Xcm is 
       
       
         
           
           
               
               
           
         
         Xcn is 
       
       
         
           
           
               
               
           
         
         Xco is 
       
       
         
           
           
               
               
           
         
         Xcp is 
       
       
         
           
           
               
               
           
         
         Xcq is 
       
       
         
           
           
               
               
           
         
         Xcr 
       
       
         
           
           
               
               
           
         
         Xcs is L-2-tert-butyl-glycine, and 
         Xct is N-methyl-L-isoleucine.