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.

1. A compound selected from the group consisting 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 —(CH 2 ) m OB, Hal is halogen, m and n are individually an integer from 1 to 8, B is hydrogen or 
                 
 
       or —(CH 2 ) n —Ar, Ar is 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 —CH 2 OH. 
     
     
       6. A compound of  claim 1  which is (3aS, 4R*, 7S*, 9R*, 10R*, 11R*, 13R*, 15R*, 15aR*, 18S*)-4-ethyl-7-fluoro-3a,4,10,11,12,13,15,15a-octahydro-18-(hydroxymethyl)-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-[[3,4,6-trideoxy-3-(dimethylamino)-.beta.-D-xylo-hexopyranosyl]oxy]-14,1-(nitriloethano)-2H-oxacyclotetradecino[4,3-d]oxazole-2,6,8(7H,9H)-trione. 
     
     
       7. An antibiotic composition comprising an antibiotically effective amount of a compound of  claim 1  and an inert pharmaceutical carrier. 
     
     
       8. An antibiotic composition comprising an antibiotically effective amount of a compound of  claim 6  and an inert pharmaceutical carrier. 
     
     
       9. A method of treating bacterial infections in warm-blooded animals comprising administering to warm-blooded animals in need thereof an antibiotically effective amount of a compound of  claim 1 . 
     
     
       10. A method of treating bacterial infections in warm-blooded animals comprising administering to warm-blooded animals in need thereof an antibiotically effective amount of a compound of  claim 6 . 
     
     
       11. 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 formula 
                 
 
       corresponding to a compound of Formula I of  claim 1  wherein R is —(CH 2 ) m —OH and optionally subjecting the latter to an aralkylating or acylating agent to obtain a compound of formula I of  claim 1  wherein B is —(CH 2 ) n —Ar or 
                 
 
     
     
       12. A compound selected from the group consisting of 
                 
 
       where the substituents are defined as in  claim 11 wherein m, R 1   , R   2   , and Hal are as defined in    claim 1   ; and OM is a protected hydroxyl.