Antimicrobial quinolones, their compositions and uses

Abstract

Compounds having the general structure: which are effective antimicrobial agents.

What is claimed is:  
     
         1 . A compound having the following formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 (a) X is selected from the group consisting of  
                     
 (b) R1 is selected from the group consisting of C 3  to about C 5  cycloalkyl, C 1  to about C 2  alkanyl, C 2  to about C 3  linear alkenyl, C 3  to about C 4  branched alkanyl or alkenyl, all such alkyl or cycloalkyl moieties being unsubstituted or substituted with from 1 to about 3 fluoro; and phenyl, unsubstituted or substituted with from 1 to about 3 fluoro, or with one hydroxy in the 4-position;  
 (c) R3 is hydrogen or hydroxy;  
 (d) R5 is selected from the group consisting of hydrogen, hydroxy, amino, halo, C 1  to about C 2  alkanyl, C 2  alkenyl, and methoxy, all such alkyl and methoxy moieties being unsubstituted or substituted with from 1 to about 3 fluoro;  
 (e) R8 is selected from the group consisting of fluoro, chloro and bromo;  
 (f) R7 is amino which is attached to a ring carbon of X which is not adjacent to the ring nitrogen, the amino being unsubstituted or substituted with one or two C 1  to about C 3  alkanyl; or aminoalkanyl which is attached to any ring carbon of X and is C 1  to about C 3  alkanyl substituted with one amino, the amino being unsubstituted or substituted with one or two C 1  to about C 3  alkanyl;  
 (g) each R9 is independently selected from the group consisting of hydrogen, C 1  to about C 4  alkanyl, C 2  to about C 6  alkenyl or alkynyl, and a C 3  to about C 6  fused or spirocycle alkyl ring; or one R9 may optionally be selected from the group consisting of hydroxy, C 1  to about C 4  alkoxy, aryl and heteroaryl, all other R9 being hydrogen; all alkyl and aryl portions of R9 moieties being unsubstituted or substituted with one hydroxy or with from 1 to about 3 fluoro; and  
 (h) a R7 moiety described in (f) and a R9 moiety described in (g) may optionally be connected thus forming a fused or spirocycle ring with the N-containing ring shown in (a), the fused or spirocycle ring comprising from 2 to about 5 ring carbons and 0 or 1 ring nitrogen;  
 or an optical isomer, diastereomer or enantiomer thereof; a pharmaceutically-acceptable salt, hydrate, or biohydrolyzable ester, amide or imide thereof.  
 
     
     
         2 . The compound of  claim 1  wherein R3 is hydroxy, and X is  
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2  wherein each R9 is independently selected from the group consisting of hydrogen, C 1  to about C 4  alkanyl, C 2  to about C 6  alkenyl or alkynyl, and a C 3  to about C 6  fused or spirocycle alkyl ring; all such alkyl moieties being unsubstituted or substituted with from 1 to about 3 fluoro.  
     
     
         4 . The compound of  claim 3  wherein: 
 (a) R1 is selected from the group consisting of C 3  to C 5  cycloalkanyl, methyl, ethyl, ethenyl, isopropyl, isopropenyl, isobutyl, isobutenyl, t-butyl, all such alkyl or cycloalkanyl moieties being unsubstituted or substituted with from 1 to 3 fluoro; and phenyl, unsubstituted or substituted with from 1 to 3 fluoro, or with one hydroxy in the 4-position;  
 (b) R5 is selected from the group consisting of hydrogen, hydroxy, amino, fluoro, chloro, bromo, and methyl, the methyl being unsubstituted or substituted with from 1 to 3 fluoro;  
 (c) R7 is attached to a ring carbon of X which is not adjacent to the ring nitrogen; and  
 (d) no more than two ring carbons of X have non-hydrogen R9's attached thereto.  
 
     
     
         5 . The compound of  claim 4  wherein: 
 (a) R7 is amino which is attached to a ring carbon of X which is not adjacent to the ring N, the amino being unsubstituted or substituted with one or two C 1  to about C 3  alkanyl; or is C 1  to about C 3  alkanyl substituted with one amino;  
 (b) R9 is selected from the group consisting of hydrogen, C 1  to about C 4  alkanyl, C 2  to about C 6  alkenyl or alkynyl, and a C 3  to about C 6  spirocycle alkyl ring; all such alkyl moieties being unsubstituted or substituted with from 1 to about 3 fluoro.  
 
     
     
         6 . The compound of  claim 5  wherein R8 is chloro.  
     
     
         7 . The compound of  claim 4  wherein; 
 (a) R1 is selected from the group consisting of cyclopropyl, ethyl, phenyl substituted with 1 to 3 fluoro, and 4-hydroxyphenyl;  
 (b) R5 is selected from the group consisting of hydrogen, hydroxy, amino, and methyl;  
 (c) X comprises the piperidinyl ring;  
 (d) R7 is amino in the 3-position of the piperidinyl ring; and  
 (e) all R9 are hydrogen, or one non-hydrogen R9 is in the 4-position or 5-position of the piperidinyl ring.  
 
     
     
         8 . The compound of  claim 7  wherein: 
 (a) R1 is cyclopropyl;  
 (b) R5 is hydrogen, and  
 (c) all R9 are hydrogen, or one non-hydrogen R9 is selected from the group consisting of methyl, ethyl, dimethyl, spirocyclopropyl, methoxy, 2-thienyl and 2-furyl.  
 
     
     
         9 . The compound of  claim 8  wherein R8 is chloro.  
     
     
         10 . The compound of  claim 4  wherein: 
 (a) R1 is selected from the group consisting of cyclopropyl, ethyl, phenyl substituted with 1 to 3 fluoro, and 4-hydroxyphenyl;  
 (b) R5 is selected from the group consisting of hydrogen, hydroxy, chloro, bromo, amino, and methyl, the methyl being unsubstituted or substituted with from 1 to 3 fluoro;  
 (c) when X comprises the piperidinyl ring, R7 is amino unsubstituted or substituted with one C 1  to C 3  alkanyl or two methyl; when X comprises the pyrrolidinyl ring, R7 is aminoalkanyl which is methyl or ethyl or isopropyl substituted with one amino unsubstituted or substituted with one methyl or ethyl or dimethyl.  
 
     
     
         11 . The compound of  claim 10  wherein: 
 (a) R1 is cyclopropyl or ethyl, unsubstituted or substituted with from 1 to about 3 fluoro;  
 (b) R5 is selected from the group consisting of hydrogen, hydroxy, amino, and methyl;  
 (c) when X comprises the piperidinyl ring, R7 is amino or methylamino in the 3-position or 4-position of the ring; when X comprises the pyrrolidinyl ring, R7 is selected from the group consisting of aminomethyl, methylaminomethyl, 1-aminoethyl, 1-methylaminoethyl, 1-amino-1-methylethyl and 1-methylamino-1-methylethyl in the 3-position of the ring.  
 (d) all R9 are hydrogen or only one ring carbon of X has a non-hydrogen R9 attached thereto, such non-hydrogen R9 being selected from the group consisting of methyl, ethyl, dimethyl and spirocyclopropyl.  
 
     
     
         12 . The compound of  claim 11  wherein X comprises the pyrrolidinyl ring.  
     
     
         13 . The compound of  claim 12  wherein R1 is cyclopropyl, R5 is hydrogen, and all R9 are hydrogen.  
     
     
         14 . The compound of  claim 13  wherein R8 is chloro.  
     
     
         15 . A compound selected from the group consisting of: 
 7-[3R-(1S-aminoethylpyrrolidinyl)]-1-ethyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1S-aminoethylpyrrolidinyl)-1-(2-fluoroethyl)]-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1S-aminoethylpyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1S-methylaminoethylpyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1-amino-methylethylpyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1-methylamino-methylethylpyrrolidinyl)]1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1S-aminoethyl-5-methyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1S-aminoethyl-5,5-dimethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1-aminomethylethyl-5,5-dimethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1S-methylaminoethyl-5,5-dimethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1-methylaminomethylethyl-5,5-dimethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1S-aminoethyl-5-ethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1-aminomethylethyl-5-ethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1S-methylaminoethyl-5-ethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1-methylaminomethylethyl-5-ethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3R-(1-amino-1-cyclopropyl-methylpyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[6R-(1S-aminoethyl)-4-azaspiro[2.4]heptanyl]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[6R-(1S-methylaminoethyl)-4-azaspiro[2.4]heptanyl]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[6R-(1S-amino-methylethyl)-4-azaspiro[2.4]heptanyl]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[6R-(1S-methylamino-methylethyl)-4-azaspiro[2.4]heptanyl]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    or a pharmaceutically-acceptable salt thereof.    
     
     
         16 . A compound selected from the group consisting of: 
 7-[3S-aminopiperidinyl]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3S-methylaminopiperidinyl]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3S-amino-4R-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3S-amino-5S-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3S-amino-5R-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3S-amino-4R-ethyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3S-amino-6,6-dimethyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[3S-amino-6-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[7-amino-5-azaspiro [2.5]-octanyl]1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    7-[4-amino-6-azaspiro[2.5]-octanyl]-1-cyclopropyl-1,4-dihydro-8-chloro-6-hydroxy-4-oxo-3-quinolinecarboxylic acid;    or a pharmaceutically-acceptable salt thereof.    
     
     
         17 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of  claim 1  or  14 ; and    (b) a pharmaceutically-acceptable excipient.    
     
     
         18 . A method for preventing or 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  or  14 .