N¹- modified glycopeptides

Abstract

Described herein are N′-acylated derivatives of desleucylA82846B. The compounds are useful as antibacterial agents.

1 . A compound of the formula  
     
       
         
         
             
             
         
       
     
     wherein R 1  represents 
 alkanoyl of C 2 -C 10  which is unsubstituted, or which is substituted by a phenyl, or which is substituted on other than the α-carbon atom by an amino or protected amino group;  
 benzoyl or substituted benzoyl bearing one or two substituents each of which is independently halo, loweralkyl of C 1 -C 4 , loweralkoxy of C 1 -C 4  or phenyl;  
 an acyl derived from an α-amino acid or an acyl derived from a protected α-amino acid, said α-amino acid being selected from the group consisting of: 
 alanine,  
 arginine,  
 asparagine,  
 aspartic acid,  
 cysteine,  
 glutamic acid,  
 glutamine,  
 glycine,  
 histidine,  
 isoleucine,  
 leucine,  
 lysine,  
 methionine,  
 3-phenylalanine,  
 3-(p-chlorophenyl)alanine,  
 proline,  
 serine,  
 threonine,  
 tryptophan and  
 valine,  
 in either D- or L-form; or  
 an acyl derived from an a-amino acid as defined above which bears on the amine a substituent which is alkyl of C 1 -C 10 , benzyl, phenylbenzyl, or p-chlorobenzyl, with the proviso that the acyl derived from N-methyl-D-leucine is excluded;  
 R 2  represents hydrogen or an epivancosaminyl of the formula  
                     
 wherein R 2a  represents hydrogen or —CH 2 —R 3 ; and R 3  represents  
 
 hydrogen,  
 alkyl of C 1 -C 11 ,  
 alkyl of C 1 -C 11 —R 4 , or  
 R 4 -(linker 0 or 1) -R 4 ) 0 or 1 ;  
 wherein each R 4  is independently phenyl or phenyl substituted by one or two substituents, each of which is independently halo, loweralkyl of C 1 -C 8 , loweralkoxy of C 1 -C 8 , loweralkylthio of C 1 -C 4 , or trifluoromethyl, and “linker” is —O—, —CH 2 —, or —O—(CH 2 ) n — wherein n is 1-3;  
 
   
   
       2 . A compound of  claim 1  in which R 2  is an epivancosaminyl radical wherein R 2a  represents hydrogen,  
   
   
       3 . A compound of  claim 2  in which R 2  is an epivancosaminyl radical wherein R 2a  represents —CH 2 —R 3 .  
   
   
       4 . A compound of  claim 3  in which R 3  is p-biphenylyl.  
   
   
       5 . A compound of  claim 3  in which R 3  is p-(p-chlorophenyl)phenyl.  
   
   
       6 . A pharmaceutical formulation comprising a compound of any of claims  1 - 5  in combination with a pharmaceutically-acceptable diluent or carrier.  
   
   
       7 . A method of treating a bacterial infection in a host comprising the step of administering to the host an effective amount of a formulation of  claim 6 .  
   
   
       8 . A method of  claim 7  wherein the bacterial infection is attributable to a vancomycin-resistant- enterococcus.    
   
   
       9 . A compound of any of claims  1 - 5  for use in antibacterial therapy.  
   
   
       10 . A compound of any of claims  1 - 5  for use in antibacterial therapy against vancomycin-resistant- enterococcus.    
   
   
       11 . A process for the preparation of a compound as claimed in any one of claims  1 - 5  which comprises reacting a parent glycopeptide of the formula  
     
       
         
         
             
             
         
       
     
     wherein R 2  is as defined in  claim 1 , with an activated ester of an alkanoic acid of the desired R 1  as defined in  claim 1 , and if desired, thereafter reductively alkylating the N DISACC  amine and/or forming a pharmaceutically acceptable salt.