Novel phenicol antibacterials

Abstract

The present invention provides novel phenicol derivatives, their use for the treatment of infections in mammals, pharmaceutical compositions containing these novel compounds, and methods for the preparation of these compounds.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
       
       or pharmaceutical acceptable salts thereof wherein
 Aryl moiety is phenyl or naphthyl, optionally substituted with one to three R 6 ; 
 R 1  is 
 a. H, 
 b. —C 1-8 alkyl, optionally substituted with one or more OH, —SH, —CN, —NO 2 , —NHR 5 , —NC 1-4 alkylR 5 , —OC 1-4 alkyl, —SC 1-4 alkyl, —S(C═O)C 1-4 alkyl, —C(═O)NR 5 R 5 , —SO 2 NR 5 , —SO 2 R 5 , or —C 3-6 cycloalkyl, 
 c. —C 3-8 cycloalkyl, optionally substituted with one to three R 6 , 
 d. —SO 2 R 5 , 
 e. —C(═O)R 5 , or 
 f. 4 to 6 membered heterocyclic ring moiety optionally contains one, two or three atoms selected from the group consisting from N, S and O, wherein the heterocyclic ring is optionally substituted with one to three R 6 ; 
 R 2  is 
 a. —C 1-8 alkyl, optionally substituted with one or more OH, —SH, —CN, —NO 2 , —NC 1-4 alkylR 5 , —OC 1-4 alkyl, —SC 1-4 alkyl, —S(C═O)C 1-4 alkyl, —C(═O)NR 5 R 5 , —SO 2 NR 5 , —SO 2 R 5 , or —C 3-6 cycloalkyl, 
 b. —C 3-8 cycloalkyl, optionally substituted with one to three R 6 , 
 c. —S(═O 2 )R 5 , 
 d. —C(═O)R 5 , or 
 e. 4 to 6 membered heterocyclic ring moiety optionally contains one, two or three atoms selected from the group consisting from N, S and O, wherein the heterocyclic ring is optionally substituted with one to three R 6 ; 
 R 3  and R 4  are independently 
 a. —H, 
 b. —C 1-8 alkyl optionally substituted with OH, —SH, halo, —CN, —NO 2 , NH 2 , —NHR 5 , —NHR 5 —OC 1-4 alkyl, —SC 1-4 alkyl, —S(C═O)C 1-4 alkyl, —C(═O)NR 5 R 5 , —SO 2 NR 5 , or —SO 2 R 5 , 
 c. —C 3-8 cycloalkyl, optionally substituted with one to three R 6 , 
 d. —C(═O)C 1-8 alkyl wherein alkyl is optionally substituted with —S(═O 2 )R 5 , —SO 2 NR 5 , or —C(═O)R 5 , 
 e. 4 to 6 membered heterocyclic ring moiety optionally contains one, two or three atoms selected from the group consisting from N, S and O, wherein the heterocyclic ring is optionally substituted with one to three R 6 , 
 f. R 3  and R 4  taken together form a C 3-8 cycloalkyl, optionally substituted with one to three R 6 ; or 
 g. R 3  and R 4  taken together with one or two additional atoms selected from the group consisting from N, S and O form a 4 to 6 membered heterocyclic ring moiety, wherein the heterocyclic ring is optionally substituted with one to three R 6 ; or 
 R 1  and R 2 , R 1  and R 3 , or R 2  and R 3 , taken together form a 4 to 6 membered heterocyclic ring moiety optionally contains one or two additional atoms selected from the group consisting from N, S and O, wherein the heterocyclic ring is optionally substituted with one to three R 6 ; 
 at each occurrence, R 5  is hydrogen, or C 1-6 alkyl wherein said C 1-6 alkyl is optionally substituted with one, two or three R 6 ; 
 at each occurrence, R 6  is OH, halo, —CN, —NO 2 , —C 3-6 cycloalkyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —OC 1-4 alkyl, —SH, —SC 1-4 alkyl, —S(C═O)C 1-4 alkyl, —SONC 1-4 alkyl, —C(═O)C 1-4  alkyl, —C(═O)NH 2 , —C(═O)NHC 1-4 alkyl, —C(═O)N(C 1-4 alkyl) 2 , —NC(═O)NH 2 , —NC(═O)NHC 1-4 alkyl, or NC(═O)N(C 1-4 alkyl) 2 ; 
 W is —H, —PO(OH) 2 , —CH 2 PO(OH) 2 , —C(═O)C 1-4 alkyl, or —CH 2 OC(═O)C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with —OCO 2 H, —OCO 2 C 1-4 alkyl, or —OC(═O)NHC 1-4 alkyl; 
 X and Y are independently halo, C 1-4 alkyl, CF 3 , —NH 2 , —CN, or N 3 ; and with proviso that when one of R 3  and R 4  is —C 1-8 alkyl; then R 2  may be H. 
 
     
     
         2 . A compound of  claim 1  which is a compound of formula IA 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound of  claim 1  which is a compound of formula IB 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound of  claim 2  wherein W is H. 
     
     
         5 . A compound of  claim 4  wherein R 2  is C 1-8 alkyl. 
     
     
         6 . A compound of  claim 5  wherein said alkyl is substituted with —SO 2 R 5 , —C 3-6 cycloalkyl, —NHC 1-4 alkyl, or —N(C 1-4 alkyl) 2 . 
     
     
         7 . A compound of  claim 4  wherein R 2  is —SO 2 R 5 . 
     
     
         8 . A compound of  claim 4  wherein R 3  and R 4  are independently H. 
     
     
         9 . A compound of  claim 4  wherein R 3  and R 4  taken together form a C 3-9 cycloalkyl. 
     
     
         10 . A compound of  claim 4  wherein R 3  and R 4  taken together with one or two additional atoms selected from the group consisting from N, S and O form a 4 to 6 membered heterocyclic ring moiety. 
     
     
         11 . A compound of  claim 10  wherein R 3  and R 4  taken together form a 4 to 6 membered heterocyclic ring moiety which contains a group selected from group consisting of —S—, —S(═O)—, —S(═O 2 )—, —NH—, and —NR 5 —. 
     
     
         12 . A compound of  claim 4  wherein R 1  and R 2  taken together form a 4 to 6 membered heterocyclic ring moiety optionally contains one or two additional atoms selected from the group consisting from N, S and O. 
     
     
         13 . A compound of  claim 12  wherein the heterocyclic ring moiety optionally substituted with one or two R 6 . 
     
     
         14 . A compound of  claim 12  wherein R 1  and R 2  taken together with the nitrogen to which they are attached form a 4 to 6 membered heterocyclic ring moiety which further contains a sulfur atom. 
     
     
         15 . A compound of  claim 4  wherein R 2  and R 3  taken together form a 4 to 6 membered heterocyclic ring moiety optionally contains one or two additional atoms selected from the group consisting from N, S and O. 
     
     
         16 . A compound of  claim 15  wherein R 2  and R 3  taken together with the nitrogen to which they attach form a 4 to 6 membered heterocyclic ring moiety which further contains a sulfur atom. 
     
     
         17 . A compound of  claim 16  wherein said heterocyclic ring moiety is optionally substituted with R 6 . 
     
     
         18 . A compound of  claim 4  wherein X and Y are chloride. 
     
     
         19 . A compound of  claim 4  wherein R 3  and R 4  are independently H or —C 1-8 alkyl. 
     
     
         20 . (canceled)