Fused Substituted Aminopyrrolidine Derivative

Abstract

A quinolone synthetic antibacterial agent having excellent properties as a medicine is provided, which has strong antibacterial activity not only to Gram-negative bacteria but also to Gram-positive cocci that have low sensitivity to quinolone antibacterial agents, and which exhibits high safety and excellent pharmacokinetics. A compound represented by the formula (I) or a salt thereof, or a hydrate thereof. Specifically, a quinolone derivative of the formula (I) wherein substituents R6 and R7 taken together with the carbon atoms to which they are bonded form a cyclic structure which may contain an oxygen atom as a ring constituent atom, the cyclic structure forming a 5-4, 5-5, or 5-6 fused bicyclic pyrrolidinyl substituent, the substituent being bonded to a quinolone mother skeleton Q containing a pyridobenzoxazine structure.

1 - 46 . (canceled) 
     
     
         47 . A method of treating an infection caused by a microorganism, comprising: administering a compound of formula (I) 
       
         
           
           
               
               
           
         
         or a salt thereof, to a subject, wherein: 
         R 1  is a hydrogen atom; 
         R 2  is a hydrogen atom; 
         R 3  and R 4  area hydrogen atoms; 
         R 5  is a hydrogen atom or a fluorine atom; 
         R 6  and R 7  taken together with the carbon atoms to which they are bonded form a five- to six-membered cyclic structure, the cyclic structure representing a partial structure that together with the pyrrolidine ring forms a fused cyclic structure, wherein the five- to six-membered cyclic structure does not contain a double bond and optionally contains an oxygen atom as a ring constituent atom, 
         R 5  is optionally a methylene group taken together with R 6  to form a three-numbered fused cyclic structure; and 
         Q is a partial structure represented by formula (II): 
       
       
         
           
           
               
               
           
         
         wherein R 8  is a 1,2-cis-2-halogenocyclopropyl group, a cyclopropyl group, or a 6-amino-3,5-difluorophenyl group; 
         R 9  is a hydrogen atom; 
         R 10  is a hydrogen atom; 
         R 11  is a hydrogen atom or an amino group; 
         X 1  is a fluorine atom or a hydrogen atom; and 
         A 1  is a partial structure represented by formula (III): 
       
       
         
           
           
               
               
           
         
         
           wherein X 2  is a methyl group or a methoxy group, 
         
         or X 2  and R 8  taken together with the atoms of formula (II) though which they are connected form a cyclic structure such that Q represents a partial structure represented by the following formula: 
       
       
         
           
           
               
               
           
         
         
           wherein Y 0  is a methyl group or a fluoromethyl group, and X 1 , R 9 , R 10  and R 11  are defined as above. 
         
       
     
     
         48 . A method of inhibiting the growth of a microorganism, comprising:
 administering a compound of formula (I)   
       
         
           
           
               
               
           
         
         or a salt thereof, to a subject, wherein: 
         R 1  is a hydrogen atom; 
         R 2  is a hydrogen atom; 
         R 3  and R 4  area hydrogen atoms; 
         R 5  is a hydrogen atom or a fluorine atom; 
         R 6  and R 7  taken together with the carbon atoms to which they are bonded form a five- to six-membered cyclic structure, the cyclic structure representing a partial structure that together with the pyrrolidine ring forms a fused cyclic structure, wherein the five- to six-membered cyclic structure does not contain a double bond and optionally contains an oxygen atom as a ring constituent atom, 
         R 5  is optionally a methylene group taken together with R 6  to form a three-membered fused cyclic structure; and 
         Q is a partial structure represented by formula (II): 
       
       
         
           
           
               
               
           
         
         wherein R 8  is a 1,2-cis-2-halogenocyclopropyl group, a cyclopropyl group, or a 6-amino-3,5-difluorophenyl group; 
         R 9  is a hydrogen atom; 
         R 10  is a hydrogen atom; 
         R 11  is a hydrogen atom or an amino group; 
         X 1  is a fluorine atom or a hydrogen atom; and 
         A 1  is a partial structure represented by formula (III): 
       
       
         
           
           
               
               
           
         
         
           wherein X 2  is a methyl group or a methoxy group, 
         
         or X 2  and R 8  taken together with the atoms of formula (II) through which they are connected form a cyclic structure such that Q represents a partial structure represented by the following formula: 
       
       
         
           
           
               
               
           
         
         
           wherein Y 0  is a methyl group or a fluoromethyl group, and X 1 , R 9 , R 10  and R 11  are defined as above. 
         
       
     
     
         49 . The method of  claim 47  or  claim 48 , wherein the microorganism is selected from  Staphylococcus, Streptococcus pyogenes , hemolytic streptococcus, enterococcus, pneumococcus,  Peptostreptococcus , gonococcus,  Escherichia coli, Citrobacter, Shigella, Klebsiella pneumoniae, Enterobacter, Serratia, Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter, Campylobacter, Chlamydia trachomatis , mycobacteria and combinations of the foregoing. 
     
     
         50 . The method of  claim 47  or  claim 48 , wherein the compound or salt of formula (I) is 7-[(1R,5S)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octan-3-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. 
     
     
         51 . The method of  claim 47  or  claim 48 , wherein the compound or sat of formula (I) is 7-[(1R,5S)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octan-3-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid. 
     
     
         52 . The method of  claim 47  or  claim 48 , wherein the subject is a human. 
     
     
         53 . The method of  claim 52 , wherein the compound or salt of formula (I) is administered in an amount of 50 mg to 1 g per day. 
     
     
         54 . The method of  claim 53 , wherein the compound or salt of formula (I) is administered in an amount of 100 to 500 mg per day. 
     
     
         55 . The method of  claim 52 , wherein the compound is administered in an amount selected from one dose, two divided doses, three divided doses and four divided doses. 
     
     
         56 . The method of  claim 47  or  claim 48 , wherein the subject is an animal. 
     
     
         57 . The method of  claim 56 , wherein the compound or salt of formula (I) is administered in an amount of 1 mg to 200 mg per kg body weight of the animal per day. 
     
     
         58 . The method of  claim 56 , wherein the compound is administered in an amount selected from one dose, two divided doses, three divided doses and four divided doses.