Quinolone compound

Abstract

wherein X is a hydrogen atom or a fluorine atom; R is a hydrogen atom or alkyl; R1 is (1) cyclopropyl optionally substituted by 1 to 3 halogen atoms or (2) phenyl optionally substituted by 1 to 3 halogen atoms; R2 is alkyl, alkoxy, haloalkoxy, a halogen atom, cyano, etc.; and R3 is 7-oxo-7,8-dihydro-1,8-naphthyridinyl, 3-pyridyl, etc., or a salt thereof. The compound of the present invention has excellent, antimicrobial activity against Clostridium difficile and is useful for the prevention or treatment of intestinal infection such as Clostridium difficile-associated diarrhea.

1 . A compound represented by the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 X is or a fluorine atom; 
 R is a hydrogen atom; 
 R 1  is (1) cyclopropyl optionally substituted by 1 to 3 halogen atoms or (2) phenyl optionally substituted by 1 to 3 halogen atoms; 
 R 2  is a hydrogen atom; alkyl optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom and hydroxyl; alkoxy; haloalkoxy; a halogen atom; cyano; cyclopropyl; nitro; amino; formyl; alkenyl or alkynyl; 
 R 3  is 
 (1) a fused heterocyclic group of the formula 
 
       
         
           
           
               
               
           
         
       
       wherein
    represents a single bond or a double bond, 
 X 1  is C (R 5 ) or N, 
 R 4  is a hydrogen atom or alkyl, and 
 R 5  is (a) a hydrogen atom,
 (b) a halogen atom, 
 (c) cyano, 
 (d) nitro, 
 (e) hydroxy, 
 (f) alkyl optionally substituted by 1 to 3 halogen atoms, 
 (g) alkenyl or alkynyl, 
 (h) aryl, or 
 (i) alkoxy optionally substituted by 1 to 3 halogen atoms, 
 
 when X 1  is C(R 5 ), R 4  and R 5  are optionally bonded to form a 5- or 6-membered ring optionally substituted by oxo, said fused heterocyclic group is optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom, cyano, nitro, hydroxy and alkyl, 
 (2) 3-pyridyl optionally substituted by 1 or 2 substituents selected from the group consisting of
 (a) a halogen atom, 
 (b) cyano, 
 (c) nitro, 
 (d) hydroxy, 
 (e) amino, 
 (f) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, alkylamino, dialkylamino and hydroxy, 
 (g) alkenyl, alkynyl 
 (h) aryl, 
 (i) cycloalkyl, 
 (j) alkoxy, 
 (k) alkylamino, 
 (l) dialkylamino, 
 (m) phenylamino optionally substituted by 1 to 3 halogen atoms, 
 (n) a cyclic amino group optionally substituted by alkoxycarbonyl, 
 (o) formyl, 
 (p) carbamoyl optionally substituted by alkyl optionally substituted by hydroxy, and 
 (q) a 5- to 10-membered aromatic heterocyclic group optionally substituted by alkyl, 
 
 (3) 4-pyridyl optionally substituted by a halogen atom, 
 (4) a group of the formula 
 
       
         
           
           
               
               
           
         
       
       wherein
 one of Y 1 , Y 2 , Y 3  and Y 4  is N or N + (—O − ), and the remaining three are each C(R 25 ), C(R 26 ) and C(R 27 ), 
 W is O, S, NH or N(R 23 ) 
 R 23  is a hydrogen atom or alkyl, and 
 R 24 , R 25 , R 26  and R 27  are each independently,
 (a) a hydrogen atom, 
 (b) cyano, or 
 (c) nitro, 
 
 (5) a group of the formula 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 28  is a hydrogen atom or hydroxy, and 
 R 29  is a hydrogen atom or alkyl, 
 (6) a group of the formula 
 
       
         
           
           
               
               
           
         
       
       wherein R 16  is
   (a) a hydrogen atom,   (b) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of cyano, alkylamino and dialkylamino,   (c) alkenyl optionally substituted by carboxy,   (d) formyl,   (e) carboxy,   (f) carbamoyl,   (g) —C(R 17 )═N—OH wherein R 17  is a hydrogen atom, cyano or hydroxy,   (h) a 5- to 10-membered aromatic heterocyclic group optionally substituted by alkyl, alkoxycarbonyl, carboxy or phenyl, or   (i) cyano, or   
 (7) a group of the formula 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 18  is a hydrogen atom or alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and phenyl, 
 n is 0 or 1, 
 R 19 , R 20  and R 33  are each independently,
 (a) a hydrogen atom, 
 (b) a halogen atom, 
 (c) cyano, 
 (d) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of 
 
 (i) a halogen atom 
 (ii) cyano, 
 (iii) hydroxy, 
 (iv) amino, 
 (v) alkylamino, 
 (vi) dialkylamino, and 
 (vii) a cyclic amino group optionally substituted by alkyl,
 (e) alkoxy, 
 (f) amino optionally substituted by 1 or 2 substituents selected from the group consisting of 
 
 (i) alkylcarbonyl optionally substituted by a cyclic amino group, 
 (ii) alkylsulfonyl, 
 (iii) carbamoyl, 
 (iv) alkyl, cycloalkyl or cycloalkylalkyl, and 
 (v) 5- to 10-membered saturated heterocyclic group,
 (g) carboxy, 
 (h) alkoxycarbonyl, 
 (i) carbamoyl optionally substituted by alkyl optionally substituted by amino, alkylamino, dialkylamino or alkoxycarbonylamino, 
 (j) formyl, 
 (k) a 5- to 10-membered aromatic heterocyclic group optionally substituted by alkyl, 
 (l) —CH═N—OR 21  wherein R 21  is a hydrogen atom or alkyl optionally substituted by alkylamino or dialkylamino, 
 (m) nitro, 
 (n) a 5- to 10-membered saturated heterocyclic group optionally substituted by amino, 
 (o) phenyl, or 
 (p) —NHC(SMe)═CHCN. 
 
 
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein R 3  is a fused heterocyclic group of the formula 
       
         
           
           
               
               
           
         
       
       wherein  , x 1  and R 4  are as defined in  claim 1 , and said fused heterocyclic group is optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom, cyano, nitro, hydroxy and alkyl, or a salt thereof. 
     
     
         4 - 6 . (canceled) 
     
     
         7 . The compound of  claim 1 , wherein R 3  is a group of the formula 
       
         
           
           
               
               
           
         
       
       wherein R 22  is
 (a) a halogen atom, 
 (b) cyano, 
 (c) nitro, 
 (d) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, alkylamino, dialkylamino and hydroxy, 
 (e) alkenyl, alkynyl, 
 (f) aryl, 
 (g) cycloalkyl, 
 (h) alkoxy, 
 (i) formyl, or 
 (j) carbamoyl optionally substituted by alkyl optionally substituted by hydroxyl, 
 
       or a salt thereof. 
     
     
         8 - 13 . (canceled) 
     
     
         14 . The compound of  claim 1 , wherein R 3  is a group of the formula 
       
         
           
           
               
               
           
         
       
       wherein
 R 18a  is alkyl, and 
 R 19a  is (a) a halogen atom,
 (b) cyano, 
 (c) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of 
 
 (i) a halogen atom, 
 (ii) cyano, 
 (iii) hydroxy, 
 (iv) amino, 
 (v) alkylamino, 
 (vi) dialkylamino, and 
 (vii) a cyclic amino group optionally substituted by alkyl,
 (d) alkoxy, 
 (e) amino optionally substituted by 1 or 2 substituents selected from the group consisting of 
 
 (i) alkylcarbonyl optionally substituted by a cyclic amino group, 
 (ii) alkylsulfonyl, 
 (iii) carbamoyl, and 
 (iv) alkyl or cycloalkyl,
 (f) carboxy, 
 (g) alkoxycarbonyl, 
 (h) carbamoyl optionally substituted by alkyl optionally substituted by amino, alkylamino, dialkylamino or alkoxycarbonylamino, 
 (i) formyl, 
 (j) a 5- to 10-membered aromatic heterocyclic group optionally substituted by alkyl, 
 (k) —CH═N—OR 21  wherein R 21  is a hydrogen atom or alkyl optionally substituted by alkylamino or dialkylamino, or 
 (l) nitro, 
 
 or a salt thereof. 
 
     
     
         15 - 18 . (canceled) 
     
     
         19 . The compound of  claim 1 , wherein R 1  is cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl, or a salt thereof. 
     
     
         20 . The compound of  claim 1 , wherein R 2  is methyl, methoxy or a chlorine atom, or a salt thereof. 
     
     
         21 . A pharmaceutical composition comprising a compound of  claim 1  or a salt thereof and a pharmaceutically acceptable carrier. 
     
     
         22 . An antimicrobial agent comprising a compound of  claim 1  or a salt thereof. 
     
     
         23 - 26 . (canceled) 
     
     
         27 . A method for preventing or treating a bacterial infection which comprises administering an effective amount of a compound of  claim 1  or a salt thereof to a human or an animal.