Optically active pyridonecarboxylic acid derivatives

Abstract

N1-(1,2-cis-2-halogenocyclopropyl)-substituted pyridonecarboxylic acid derivatives represented by the following formula (I) the terms of which are defined in the specification and the salts thereof are disclosed: These compounds have patent antibacterial activities against a wide variety of infectious bacteria and are useful as antibacterial agents by oral or parenteral administration.

1. A stereoisomerically pure N 1 -(1,2-cis-2-halogenocyclopropyl)-substituted pyridonecarboxylic acid derivative represented by the following formula (I): 
                 
 
       wherein R 1  represents a hydrogen atom, an amino group, a hydroxyl group or a thiol group;
 R 2  represents a substituent represented by the following formula: 
                 
 
  wherein R 23  and R 24  together are (CH 2 )j; where j=2 to 5;  
 A represents C—X 3  or a nitrogen atom;  
 X 1  and X 2 , which may be the same or different, each represents a halogen atom;  
 and X 3  represents a halogen atom, an alkyl group of from 1 to 6 carbon atoms, an alkoxyl group from 1 to 6 carbon atoms, a cyano group, a trifluoromethyl group, or a hydrogen atom;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
       2. 7-[7-(S)-Amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[2-(S)-2-fluoro-1-(R)-cyclopropyl) ]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 
     
     
       3. A method for treating bacterial infections which comprises administering a therapeutically effective amount of 7-[7-(S)-Amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[2-(S)-2-fluoro-1-(R)-cyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 
     
     
       4. 7-[7-(S)-Amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-(1,2-cis-2-fluorocyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 
     
     
       5. An antibacterial composition comprising a therapeutically effective amount of, as an active ingredient, 7-[7-(S)-Amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[2-(S)-2-fluoro-1-(R)-cyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier. 
     
     
       6. The stereoisometrically  stereoisomerically pure N 1 -(1,2-cis-2-halogenocyclopropyl)-substituted pyridonecarboxylic acid derivative of  claim 1 , wherein R 2  represents a 7-amino-5-azaspiro[2,4]-heptan-5-yl group. 
     
     
       7. The stereoisomerically pure N 1 -(1,2-cis-2-halogenocyclopropyl)-substituted pyridonecarboxylic acid derivative of  claim 6 , wherein R 2  represents a 7-(S)-amino-5-azaspiro [2,4  2 . 4 ]heptan-5-yl group. 
     
     
       8. The stereoisomerically pure N 1 -(1,2-cis-2-halogenocyclopropyl)-substituted pyridonecarboxylic acid derivative or a pharmaceutically acceptable salt thereof of  claim 1 , wherein R 2  represents 8-amino-6-azaspiro[3,4  3 . 4 ]octan-6-yl group. 
     
     
       9. A method for treating bacterial infections which comprises administering a therapeutically effective amount of the stereoisomerically pure N 1 -(1,2-cis-2-halogenocyclopropyl)-substituted pyridonecarboxylic acid derivative or a pharmaceutically acceptable salt thereof of  claim 1 , wherein R 2  represents 8-amino-6-azaspiro[3,4  3 . 4 ]octan-6-yl group. 
     
     
       10. Stereoisomerically pure  7 -[(   7 S )-   7   - amino -   5   - azaspiro[ 2 . 4 ]heptan -   5   - yl] -   6   - fluoro -   1   -[(   1 R, 2 S )-   2   - fluoro -   1   - cyclopropyl] -   8   - methoxy -   1 , 4   - dihydro -   4   - oxo -   3   - quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof.   
     
     
       11. A method for treating bacterial infections which comprises administering a therapeutically effective amount of stereoisomerically pure  7 -[(   7 S )-   7   - amino -   5   - azaspiro[ 2 . 4 ]heptan -   5   - yl] -   6   - fluoro -   1   -[(   1 R, 2 S )-   2   - fluoro -   1   - cyclopropyl] -   8   - methoxy -   1 , 4   - dihydro -   4   - oxo -   3   - quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof.   
     
     
       12. An antibacterial composition comprising a therapeutically effective amount of, as an active ingredient, stereoisomerically pure  7 -[(   7 S )-   7   - amino -   5   - azaspiro[ 2 . 4 ]heptan -   5   - yl] -   6   - fluoro -   1   -[(   1 R, 2 S )-   2   - fluoro -   1   - cyclopropyl] -   8   - methoxy -   1 , 4   - dihydro -   4   - oxo -   3   - quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.