Antimicrobial quinolones, their compositions and uses

Abstract

Compounds of the following formula: are effective antimicrobial agents.

What is claimed is:  
     
         1 . A compound having a structure according to Formula (I)  
       
         
           
           
               
               
           
         
       
       wherein: 
 (A) 
 (1) A 1  is selected from —N— and —C(R 8 )—, where 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, C 1  to about C 6  alkene and alkyne;  
 (2) 
 (a) X is selected from —C— and —N—, where (i) if X is —C—, a is a double bond and b is a single bond, and (ii) if X is —N—, a is a single bond and b is a double bond; and  
 (b) Y is selected from —N(R 1 )— and —C(R 1 )—;  
 (c) provided that Y is N(R 1 ) only if X is —C— and Y is —C(R 1 )— only if X is —N—;  
 
 (3) 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 1  to about C 6  alkene, a 6-membered aryl and a 6-membered heteroaryl;  
 (4) R 2 is hydrogen;  
 (5) R 3  is selected from hydrogen and hydroxy;  
 (6) R 5  is selected from hydrogen, hydroxy, amino, halo, C 1  to about C 6  alkyl, C 1  to about C 6  alkene-and C 1  to about C 6  alkoxy;  
 (7) R 6  is selected from fluoro and chloro;  
 (8) R 7  is -Q-C(R 11 )(R 11′ )(R 11″ ), where Q is selected from —S—, —O— and —C(R 12 )(R 12′ )—, where R 12  and R 12′  are each independently selected from hydrogen and fluoro; where R 11 , R 11′  and R 11″  are each independently selected from hydrogen, hydroxy and halo; and where R 11  and R 12  may also both be nil, such that a double bond is formed between the respective carbon atoms;  
 (9) R 9  and R 9′  are each independently selected from hydrogen and C 1  to about C 15  alkyl, or R 9  and R 9′  join to form a heterocyclic ring containing the nitrogen atom to which they are bonded; and  
 (10) R 10  represents the moieties on the piperidine ring other than R 7  and —NR 9 R 9′ , where each R 10  is independently selected from hydrogen, C 1  to about C 6  alkyl and fluoro; or  
 
 (B) if A 1  is —C(R 8 )—, X is —C— and Y is —N(R 1 )—, then R 8  and R 1  can join to form a 6-membered heterocyclic ring, where R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 9′  and R 10  are as described in (A); or  
 (C) if A 1  is —C(R 8 )—, X is —C— and Y is —N(R 1 )—, then R 1  and R 2  can join to form a monocyclic or bicyclic heterocyclic ring, where R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 9′  and R 10  are as described in (A); or  
 (D) if A 1 is —C(R 8 )—, X is —C— and Y is —N(R 1 )—, then R 2  and R 3  can join to form a 5-membered heterocycloalkyl that is substituted with a carbonyl moiety, where R 1 , R 5 , R 6 , R 7 , R 8 , R 9 , R 9′  and R 10  are as described in (A);  
 or an optical isomer, diastereomer or enantiomer thereof; 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, C 3  to about C 6  heterocycloalkyl, C 1  to about C 4  alkyl and C 2  to about C 4  alkene.  
     
     
         3 . A compound of  claim 2  wherein R 1  is selected from cyclopropyl, methyl, ethyl, t-butyl, 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 each of R 11 , R 11′  and R 11″  is hydrogen.  
     
     
         7 . A compound of  claim 1  wherein R 7  is selected from methoxy, thiomethoxy and ethyl.  
     
     
         8 . A compound of  claim 7  wherein R 7  is ethyl.  
     
     
         9 . A compound of  claim 1  wherein R 9  and R 9′  are each independently selected from hydrogen and methyl.  
     
     
         10 . A compound of  claim 9  wherein R 9  and R 9′  are both hydrogen and each R 10  is hydrogen.  
     
     
         11 . A compound having a structure according to Formula (II)  
       
         
           
           
               
               
           
         
       
       wherein: 
 (A) 
 (1) A 1 is selected from —N— and —C(R 8 )— where 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, C 1  to about C 6  alkene and C 1  to about C 6  alkyne;  
 (2) R 1  is selected from C 3  to about C 6  cycloalkyl, C 4  to about C 6  heterocycloalkyl, C 1  to about C6 alkyl, C 1  to about C 6  alkene, a 6-membered aryl and a 6-membered heteroaryl;  
 (5) R 5  is selected from hydrogen, hydroxy, amino, halo, C 1  to about C 6  alkyl, C 1  to about C 6  alkene-and C 1  to about C 6  alkoxy;  
 (6) R 6  is selected from fluoro and chloro; and  
 (7) R 7 is -Q-C(R 11 )(R 11′ )(R 11″ ), where Q is selected from —S—, —O— and —C(R 12 )(R 12′ )—, where R 12  and R 12′  are each independently selected from hydrogen and fluoro; where R 11 , R 11′ and R   11″  are each independently selected from hydrogen, hydroxy and halo; and where R 11  and R 12  may also both be nil, such that a double bond is formed between the respective carbon atoms; or  
 
 (B) R 8  and R 1  join to form a 6-membered heterocyclic ring, where R 5 , R 6  and R 7  are as described in part (A);  
 or an optical isomer, diastereomer or enantiomer thereof, or a pharmaceutically-acceptable salt, hydrate, or biohydrolyzable ester, amide or imide thereof.  
 
     
     
         12 . A compound of  claim 11  wherein A 1  is —C(R 8 )—.  
     
     
         13 . A compound of  claim 12  wherein R 6  is fluoro.  
     
     
         14 . A compound of  claim 12  wherein R 8  and R 1  do not join to form a 6-membered heterocyclic ring.  
     
     
         15 . A compound of  claim 14  wherein R 1  is selected from cyclopropyl, methyl, ethyl, t-butyl, 4-hydroxyphenyl and 2,4-difluorophenyl.  
     
     
         16 . A compound of  claim 13  wherein R 5  is selected from hydrogen, hydroxy, chloro, bromo, amino, methyl, monofluoromethyl, difluoromethyl and trifluoromethyl.  
     
     
         17 . A compound of  claim 13  wherein R 7  is selected from methoxy, thiomethoxy and ethyl.  
     
     
         18 . A compound of  claim 17  wherein R 7  is ethyl.  
     
     
         19 . A compound having a structure according to Formula (III)  
       
         
           
           
               
               
           
         
       
       wherein: 
 (A) 
 (1) 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, C 1  to about C 6  alkene and C 1  to about C 6  alkyne;  
 (2) 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 1  to about C 6  alkene, a 6-membered aryl and a 6-membered heteroaryl;  
 (5) R 5  is selected from hydrogen, hydroxy, amino, halo, C 1  to about C 6  alkyl, C 1  to about C 6  alkene-and C 1  to about C 6  alkoxy;  
 (6) R 6  is selected from fluoro and chloro;  
 (7) R 7  is -Q-C(R 11 )(R 1′1 )(R 11″ ), where Q is selected from —S—, —O— and —C(R 12 )(R 12′ )—, where R 12  and R 12′  are each independently selected from hydrogen and fluoro; where R 11 , R 11′  and R 11″  are each independently selected from hydrogen, hydroxy and halo; and where R 11  and R 12  may also both be nil, such that a double bond is formed the respective carbon atoms;  
 or an optical isomer, diastereomer or enantiomer thereof, or a pharmaceutically-acceptable salt, hydrate, or biohydrolyzable ester, amide or imide thereof.  
 
 
     
     
         20 . A compound of  claim 19  wherein R 6  is fluoro.  
     
     
         21 . A compound of  claim 20  wherein R 1  is selected from cyclopropyl, methyl, ethyl, t-butyl, 4-hydroxyphenyl and 2,4-difluorophenyl.  
     
     
         22 . A compound of  claim 20  wherein R 5  is selected from hydrogen, hydroxy, chloro, bromo, amino, methyl, monofluoromethyl, difluoromethyl and trifluoromethyl.  
     
     
         23 . A compound of  claim 20  wherein R 7  is selected from methoxy, thiomethoxy and ethyl.  
     
     
         24 . A compound of  claim 23  wherein R 7  is ethyl.  
     
     
         25 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of  claim 1;  and    (b) a pharmaceutically-acceptable excipient.    
     
     
         26 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of  claim 11;  and    (b) a pharmaceutically-acceptable excipient.    
     
     
         27 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of  claim 19;  and    (b) a pharmaceutically-acceptable excipient.    
     
     
         28 . 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 .  
     
     
         29 . 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 11 .  
     
     
         30 . 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 19 .  
     
     
         31 . A compound having a structure according to Formula (IV):  
       
         
           
           
               
               
           
         
       
       wherein R 13  is selected from methyl, fluoro, and hydroxy;  
       or an optical isomer, diastereomer or enantiomer thereof, or a pharmaceutically-acceptable salt, hydrate, or biohydrolyzable ester, amide or imide thereof.  
     
     
         32 . A method of using a compound having a structure according to Formula (IV):  
       
         
           
           
               
               
           
         
       
       wherein R 13  is selected from methyl, fluoro, and hydroxy;  
       in a process of making a compound having a structure according to Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 (A) 
 (1) A 1  is selected from —N— and —C(R 8 )—, where 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, C 1  to about C 6  alkene and alkyne;  
 (2) 
 (a) X is selected from —C— and —N—, where (i) if X is —C—, a is a double bond and b is a single bond, and (ii) if X is —N—, a is a single bond and b is a double bond; and  
 (b) Y is selected from —N(R 1 )— and —C(R 1 )—;  
 (c) provided that Y is N(R 1 ) only if X is —C— and Y is —C(R 1 )— only if X is —N—;  
 
 (3) 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 1  to about C 6  alkene, a 6-membered aryl and a 6-membered heteroaryl;  
 (4) R 2  is hydrogen;  
 (5) R 3  is selected from hydrogen and hydroxy;  
 (6) R 5  is selected from hydrogen, hydroxy, amino, halo, C 1  to about C 6  alkyl, C 1  to about C 6  alkene-and C 1  to about C 6  alkoxy;  
 (7) R 6  is selected from fluoro and chloro;  
 (8) R 7  is -Q-C(R 11 )(R 11′ )(R 11″ ), where Q is selected from —S—, —O— and —C(R 12 )(R 12′ )—, where R 12  and R 12′  are each independently selected from hydrogen and fluoro; where R 11 , R 11′  and R 11″  are each independently selected from hydrogen, hydroxy and halo; and where R 11  and R 12  may also both be nil, such that a double bond is formed between the respective carbon atoms;  
 (9) R 9  and R 9′  are each independently selected from hydrogen and C  1  to about C 15  alkyl, or R 9  and R 9′  join to form a heterocyclic ring containing the nitrogen atom to which they are bonded; and  
 (10) R 10  represents the moieties on the piperidine ring other than R 7  and —NR 9 R 9′ , where each R 10  is independently selected from hydrogen, C 1  to about C 6  alkyl and fluoro;  
 
 or 
 (B) if A 1  is —C(R 8 )—, X is —C— and Y is —N(R 1 )—, then R 8  and R 1  can join to form a 6-membered heterocyclic ring, where R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 9′  and R 10  are as described in (A); or  
 (C) if A 1  is —C(R 8 )—, X is —C— and Y is —N(R 1 )—, then R 1  and R 2  can join to form a monocyclic or bicyclic heterocyclic ring, where R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 9′  and R 10  are as described in (A); or  
 (D) if A 1  is —C(R 8 )—, X is —C— and Y is —N(R 1 )—, then R 2  and R 3  can join to form a 5-membered heterocycloalkyl that is substituted with a carbonyl moiety, where R 1 , R 5 , R 6 , R 7 , R 8 , R 9 , R 9′  and R 10  are as described in (A);  
 or an optical isomer, diastereomer or enantiomer thereof; a pharmaceutically-acceptable salt, hydrate, or biohydrolyzable ester, amide or imide thereof.