2-halogenated derivatives of 5-0-desosaminyl-erythronolide A, their preparation process and their antibiotic use

Abstract

Novel compounds of the formula wherein the substituents are defined as in the application having antibiotic properties.

What we claim is:  
     
         1 . A compound selected from the group consisting of a compound of the formula  
       
         
           
           
               
               
           
         
         wherein A is nitrogen or N—>O, R 1  and R 2  are individually selected from the group consisting of hydrogen and alkyl of 1 to 18 carbon atoms, R is selected from the group consisting of hydrogen and —(CH 2 ) m OB, Hal is halogen, m and n are individually an integer from 1 to 8, B is hydrogen or  
         
           
             
             
                 
                 
             
           
         
         Ar is a mono- or polycyclic aryl or heteroaryl, Z is hydrogen or acyl of an organic carboxylic acid of up to 18 carbon atoms and its non-toxic, pharmaceutically acceptable acid addition salts.  
       
     
     
         2 . A compound of  claim 1  wherein R 1  and R 2  are hydrogen.  
     
     
         3 . A compound of  claim 1  wherein A is nitrogen.  
     
     
         4 . A compound of  claim 1  wherein Hal is fluorine.  
     
     
         5 . A compound of  claim 1  wherein R is hydrogen.  
     
     
         6 . A compound of  claim 1  wherein R is —CH 2 OH.  
     
     
         7 . A compound of  claim 1  selected from the group consisting of [3aS-(3aR*,4S*,7R*,9S*,10S*,11S*,13S*,15S*,15aS*)]-4-ethyl-7-fluoro-3a,4,10,11,12,13,15,15a-octahydro-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-[[3,4,6-trideoxy-3-(dimethyl-amino)-.beta.-D-xylo-hexopyranosyl]oxy]-14,1-(nitriloethano)-2H-oxacyclotetradecino[4,3-d]oxazole-2,6,8(9H)-trione and 
 [3aS-(3aR*,4S*,7R*,9S*,10S*,11S*,13S*,15S*,15aS*,17R*)]-4-ethyl-7-fluoro-3a,4,10,11,12,13,15,15a-octahydro-17-hydroxymethyl)-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-[[3-4,6-trideoxy-3-(dimethylamino)-.beta.-D-xylohexopyranosyl]oxy]-14,1-nitriloethano)-2H-oxacyclotetradecino[4,3-d]oxazole-2,6,8(9H)-trione.  
 
     
     
         8 . An antibiotic composition comprising an antibiotically effective amount of a compound of  claim 1  and an inert pharmaceutical carrier.  
     
     
         9 . An antibiotic composition comprising an antibiotically effective amount of a compound of  claim 7  and an inert pharmaceutical carrier.  
     
     
         10 . A method of treating bacterial infections in warm-blooded animals comprising administering to warm-blooded animals an antibiotically effective amount of a compound of  claim 1 .  
     
     
         11 . A method of treating bacterial infections in warm-blooded animals comprising administering to warm-blooded animals an antibiotically effective amount of a compound of  claim 7 .  
     
     
         12 . A process for the preparation of a compound of  claim 1  comprising reacting a compound of the formula  
       
         
           
           
               
               
           
         
         wherein Hal is halogen and OM is a protected hydroxyl with a compound of the formula  
         
           
             
             
                 
                 
             
           
         
         wherein m is an integer from 1 to 8 to obtain a compound of the formula  
         
           
             
             
                 
                 
             
           
         
         deprotecting the 2′-hydroxyl to obtain a compound of the formula  
         
           
             
             
                 
                 
             
           
         
         reacting the latter with a debenzylating agent to obtain a compound of the formula  
         
           
             
             
                 
                 
             
           
         
         reacting the latter with a cyclization agent to form a compound of the formulae  
         
           
             
             
                 
                 
             
           
         
         wherein R is —(CH 2 ) m —OH and optionally subjecting the latter to an aralkylating or acylating agent to obtain a compound of  claim 1  wherein B is —(CH 2 ) n —Ar or  
         
           
             
             
                 
                 
             
           
         
       
     
     
         13 . A compound selected from the group consisting of  
       
         
           
           
               
               
           
         
         where the substituents are defined as in claim  12 .