Antimicrobial 2-pyridones, their compositions and uses

Abstract

Compounds having the general structure: are effective antimicrobial agents.

What is claimed is:  
     
         1 . A compound having a structure according to Formula (I)  
       
         
           
           
               
               
           
         
       
       wherein: 
 (A) (1) R 1  is selected from C 3  to about C 6  cycloalkyl, C 4  to about C 6  heterocycloalkyl, C 1  to about C 6  alkyl, C 2  to about C 6  alkene, a 6-membered aryl, and a 6-membered heteroaryl;  
 (2) R 2  is hydrogen;  
 (3) R 3  is selected from hydrogen and hydroxy;  
 (4) R 5  is selected from hydrogen, hydroxy, amino, halo, C 1  to about C 6  alkyl, C 2  to about C 6  alkene, and C 1  to about C 6  alkoxy;  
 (5) R 6  is selected from hydrogen, hydroxy, aminocarbonyl, cyano, C 1  to about C 4  alkyl, and C 2  to about C 4  alkene; all such alkyl and alkene moieties being unsubstituted or substituted with from 1 to about 3 fluoro, or in the case of methyl or ethyl, optionally substituted with one hydroxy or one amino moiety;  
 (6) R 7  is selected from  
                     
  wherein 
 (a) R 9  is (i) amino which is attached to a ring carbon of R 7  which is not adjacent to the ring nitrogen of R 7 , the amino being unsubstituted or substituted with one or two C 1  to about C 3  alkyl; or (ii) aminoalkyl which is attached to any ring carbon of R 7  and is C 1  to about C 3  alkyl substituted with one amino, the amino being unsubstituted or substituted with one or two C 1  to about C 3  alkyl; and  
 (b) R 10  represents the moieties on R 7  other than R 9  and each R 10  is independently selected from hydrogen, C 1  to about C 4  alkyl, C 2  to about C 6  alkene, and a C 3  to about C 6  fused or spirocycle alkyl ring; all alkyl, alkene and cyclic R 10  moieties being unsubstituted or substituted with one hydroxy or with from 1 to about 3 fluoro moieties; and  
 
 (7) R 8  is selected from hydrogen, halo, C 1  to about C 6  alkoxy, C 1  to about C 6  alkylthio, C 1  to about C 6  alkyl and C 2  to about C 6  alkene; or  
 (B) R 8  and R 1  can join to form a 6-membered heterocyclic ring, where R 2 , R 3 , R 5 , R 6  and R 7  are as described in (A);  
 or an optical isomer, diastereomer or enantiomer thereof; or a pharmaceutically-acceptable salt, hydrate, or biohydrolyzable ester, amide or imide thereof.  
 
     
     
         2 . A compound of  claim 1  wherein R 1  is selected from C 3  to about C 6  cycloalkyl, a 6-membered aryl, C 1  to about C 2  alkyl, and C 2  to about C 3  alkene.  
     
     
         3 . A compound of  claim 2  wherein R 1  is selected from cyclopropyl, ethyl, 4-hydroxyphenyl, and 2,4-difluorophenyl.  
     
     
         4 . A compound of  claim 1  wherein R 3  is hydroxy.  
     
     
         5 . A compound of  claim 1  wherein R 5  is selected from hydrogen, hydroxy, chloro, bromo, amino, methyl, monofluoromethyl, difluoromethyl, and trifluoromethyl.  
     
     
         6 . A compound of  claim 1  wherein R 6  is selected from hydrogen, hydroxy, methyl, monofluoromethyl, difluoromethyl, and trifluoromethyl.  
     
     
         7 . A compound of  claim 6  wherein R 6  is hydrogen.  
     
     
         8 . A compound of  claim 1  wherein R 8  is selected from chloro, methyl, methoxy, methylthio, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy.  
     
     
         9 . A compound of  claim 1  wherein R 7  is selected from:  
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound of  claim 1  wherein R 1  and R 8  do not join together to form a heterocyclic ring.  
     
     
         11 . A compound of  claim 1  wherein R 9  is amino, unsubstituted or substituted with one or two alkyl moieties independently selected from methyl and ethyl.  
     
     
         12 . A compound of  claim 11  wherein R 9  is —NH 2 .  
     
     
         13 . A compound of  claim 1  wherein R 9  is aminoalkyl, wherein the alkyl is unsubstituted or substituted with one or more C 1  to about C 6  alkyl groups and the amino is unsubstituted or substituted with one or two alkyl moieties independently selected from methyl and ethyl.  
     
     
         14 . A compound of  claim 13  wherein R 9  is selected from aminomethyl, methylaminomethyl, 1-aminoethyl, 1-methylaminoethyl, 1-amino-1-methylethyl, and 1-methylamino-1-methylethyl.  
     
     
         15 . A compound of  claim 1  wherein each R 10  is independently selected from hydrogen and C 1  to about C 6  alkyl.  
     
     
         16 . A compound of  claim 15  wherein not more than one R 10  is other than hydrogen.  
     
     
         17 . A compound having a structure according to the following Formula (B):  
       
         
           
           
               
               
           
         
       
       wherein 
 (1) R 2 is hydrogen;  
 (2) R 3  is selected from hydrogen and hydroxy;  
 (3) R 5  is selected from hydrogen, hydroxy, amino, halo, C 1  to about C 6  alkyl, C 2  to about C 6  alkene, and C 1  to about C 6  alkoxy;  
 (4) R 6  is selected from hydrogen, hydroxy, aminocarbonyl, cyano, C 1  to about C 4  alkyl, and C 2  to about C 4  alkene; all such alkyl and alkene moieties being unsubstituted or substituted with from 1 to about 3 fluoro, or in the case of methyl or ethyl, optionally substituted with one hydroxy or one amino moiety;  
 (5) R 7  is selected from  
                     
  wherein 
 (a) R 9  is (i) amino which is attached to a ring carbon of R 7  which is not adjacent to the ring nitrogen of R 7 , the amino being unsubstituted or substituted with one or two C 1  to about C 3  alkyl; or (ii) aminoalkyl which is attached to any ring carbon of R 7  and is C 1  to about C 3  alkyl substituted with one amino, the amino being unsubstituted or substituted with one or two C 1  to about C 3  alkyl; and  
 (b) R 10  represents the moieties on R 7  other than R 9  and each R 10  is independently selected from hydrogen, C 1  to about C 4  alkyl, C 2  to about C 6  alkene, and a C 3  to about C 6  fused or spirocycle alkyl ring; all alkyl, alkene, and cyclic R 10  moieties being unsubstituted or substituted with one hydroxy or with from 1 to about 3 fluoro moieties;  
 
 (6) Y is selected substituted or unsubstituted —C— or —N—, or Y is —O—;  
 (7) Z is selected from —O—, —S—, substituted or unsubstituted —C—, and substituted or unsubstituted —N—; and  
 (8) R 3  and R 13′  are independently selected from hydrogen and C 1  to about C 6  alkyl; or an optical isomer, diastereomer or enantiomer thereof; a pharmaceutically-acceptable salt, hydrate, or biohydrolyzable ester, amide or imide thereof.  
 
     
     
         18 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of  claim 1;  and    (b) a pharmaceutically-acceptable excipient.    
     
     
         19 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of  claim 10;  and    (b) a pharmaceutically-acceptable excipient.    
     
     
         20 . A method for treating microbial infection comprising administering to a host in need of such a treatment a safe and antimicrobially effective amount of a compound of  claim 1 .  
     
     
         21 . A method for treating microbial infection comprising administering to a host in need of such a treatment a safe and antimicrobially effective amount of a compound of  claim 10 .  
     
     
         22 . A method of using a compound having a structure according to Formula (C)  
       
         
           
           
               
               
           
         
         wherein R 14  is selected from methoxy or methyl; R 15  is selected from ethyl or cyclopropyl;  
         in the process of making a compound according to Formula (I)