Drug efflux pump inhibitor

Abstract

A medicament for preventive and/or therapeutic treatment of a microbial infection which comprises as an active ingredient a compound represented by the following general formula (I): wherein, R 1 and R 2 represent hydrogen atom, a halogen atom, hydroxyl group or the like, W 1 represents —CH═CH—, —CH 2 O—, —CH 2 CH 2 — or the like; R 3 represents hydrogen atom, a halogen atom, hydroxyl group or an amino group; R 4 represents hydrogen atom, a group of —OZ 0-4 R 5 (Z 0-4 represents an alkylene group, a fluorine-substituted alkylene group or a single bond, and R 5 represents a cyclic alkyl group, an aryl group or the like); W 2 represents a single bond or —C(R 8 )═C(R 9 )−(R 8 and R 9 represent hydrogen atom, a halogen atom, a lower alkyl group or the like, Q represents an acidic group, but W 2 and Q may together form vinylidenethiazolidinedione or an equivalent heterocyclic ring; m and n represent an integer of 0 to 2, and q represents an integer of 0 to 3.

1 . A method for therapeutic treatment of microbial infection comprising administering to a mammal in need thereof a therapeutically effective amount of a compound represented by the following formula (I) or a physiologically acceptable salt, or a hydrate thereof:  
     
       
         
         
             
             
         
       
     
     wherein, R 1  and R 2  each independently represent hydrogen atom, a halogen atom, hydroxyl group, a group of OZ 1-6  (the group of OZ 1-6  represents an alkyl group having 1-6 carbon atoms or a fluoroalkyl group having 1-6 carbon atoms, which bonds via the oxygen atom), a group of S(O) n Z 1-4  (Z 1-4  represents an alkyl group having 1-4 carbon atoms or a fluoroalkyl group having 1-4 carbon atoms or an alkylene group derived therefrom), a group of N(R 12 )(R 13 ) (R 12  and R 13  each independently represent hydrogen atom, an alkyl group having 1-4 carbon atoms or a fluoroalkyl group having 1-4 carbon atoms), a group of Z 1-8  which may be substituted (Z 1-8  represents an alkyl group having 1-8 carbon atoms or a fluoroalkyl group having 1-8 carbon atoms), a 5- to 7-membered cyclic alkyl group, an aryl group, a heteroaryl group, or a 4- to 7-membered saturated or partially saturated heterocyclic group (the cyclic alkyl group, aryl group, heteroaryl group and heterocyclic group may have one to three substituents selected from the group consisting of a halogen atom, hydroxyl group, a group of OZ 1-4 , a group of S(O) n Z 1-4 , a group of N(R 12 )(R 13 ), a group of Z 1-4 , carboxyl group, a group of CO 2 Z 1-4 , group of CONH 2 , a group of CONH(Z 1-4 ) and a group of CON(Z 1-4 )(Z 1-4 )); 
 W 1  represents a group selected from the group consisting of —CH═CH—, —N(R 12 )CO—, —CON(R 12 )—, —CH 2 O— and —CH 2 CH 2 — (each of the aforementioned groups binds to the thiazole ring at the left end);  
 R 3  represents hydrogen atom, a halogen atom, hydroxyl group or an amino group;  
 R 4  represents a group selected from the group consisting of hydrogen atom, a group of —OZ 0-4 R 5  (Z 0-4  represents an alkylene group having 1-4 carbon atoms, a fluorine-substituted alkylene group having 1-4 carbon atoms or a single bond, and R 5  represents a 5- to 7-membered cyclic alkyl group, an aryl group, a heteroaryl group or a 4- to 7-membered saturated or partially saturated heterocyclic group (the cyclic alkyl group, aryl group, heteroaryl group and heterocyclic group may have one to three substituents selected from the group consisting of a halogen atom, hydroxyl group, a group of OZ 1-4 , a group of S(O) n Z 1-4 , a group of N(R 12 )(R 13 ), a group of Z 1-4 , carboxyl group, a group of CO 2 Z 1-4 , group of CONH 2 , a group of CONH(Z 1-4 ) and a group of CON(Z 1-4 )(Z 1-4 )), a group of —S(O) n Z 0-4 R 5 , a group of —N(R 6 )(R 7 ) {R 6  and R 7  each independently represent hydrogen atom or Z 1-4 , or they may bind to each other to form a saturated or unsaturated 5- to 7-membered ring (the ring may contain one or two hetero atoms as ring constituting atoms), and R 6  and R 7  may have one to three substituents selected from the group consisting of a halogen atom, hydroxyl group, a group of OCON(R 12 )(R 13 ), a group of CON(R 12 )(R 13 ), a group of N(R 12 )CON(R 12 )(R 13 ), a group of Z 1-4 , a group of OZ 1-4 , a group S(O) n Z 1-4 , group of CH 2 OH, a group of (CH 2 ) m N(R 12 )(R 13 ), carboxyl group, cyano group, a group of CO-Z 1-4 (R 10 )—N(R 12 )(R 13 ) (R 10  is a substituent corresponding to a side chain on an amino acid carbon or a group of -Z 1-4 -R 11  (R 11  represents a substituent which forms a quaternary salt) and a group of  
                     
 a 5- or 6-membered aryl group which may be substituted and a 5- or 6-membered unsaturated heterocyclic group which may be substituted;  
 W 2  represents a single bond or —C(R 8 )═C(R 9 )— (R 8  and R 9  each independently represent hydrogen atom, a halogen atom, a lower alkyl group, an alkoxy group, cyano group, carboxyl group, hydroxymethyl group, cyanomethyl group, vinyl group or a group of N(R 12 )(R 13 )), Q represents an acidic group, and W 2  and Q may bind together to form vinylidenethiazolidinedione in E- or Z-configuration or an equivalent heterocyclic ring; m and n each independently represent an integer of 0 to 2, and q represents an integer of 0 to 3.  
 
   
   
       2 . The method according to  claim 1 , further comprising administering at least one antimicrobial agent.  
   
   
       3 . The method according to  claim 2 , wherein the compound is an active ingredient in a composition.  
   
   
       4 . The method according to  claim 3 , wherein the at least one antimicrobial agent is simultaneously administered with the composition.  
   
   
       5 . The method according to  claim 3 , wherein the at least one antimicrobial agent is separately administered from the composition.  
   
   
       6 . The method according to  claim 3 , wherein the at least one antimicrobial agent is successively administered with the composition.  
   
   
       7 . The method according to  claim 1  wherein the mammal is a human.  
   
   
       8 . The method according to  claim 1  wherein the microbial infection comprises an infection by bacteria having a genetically homologous drug efflux pump to  Pseudomonas aeruginosa    
   
   
       9 . A method for preventive treatment of a microbial infection comprising administering to a mammal a preventively effective amount of a compound represented by the following formula (I) or a physiologically acceptable salt, or a hydrate thereof:  
     
       
         
         
             
             
         
       
     
     wherein, R 1  and R 2  each independently represent hydrogen atom, a halogen atom, hydroxyl group, a group of OZ 1-6  (the group of OZ 1-6  represents an alkyl group having 1-6 carbon atoms or a fluoroalkyl group having 1-6 carbon atoms, which bonds via the oxygen atom), a group of S(O) n Z 1-4  (Z 1-4  represents an alkyl group having 1-4 carbon atoms or a fluoroalkyl group having 1-4 carbon atoms or an alkylene group derived therefrom), a group of N(R 12 )(R 13 ) (R 12  and R 13  each independently represent hydrogen atom, an alkyl group having 1-4 carbon atoms or a fluoroalkyl group having 1-4 carbon atoms), a group of Z 1-8  which may be substituted (Z 1-8  represents an alkyl group having 1-8 carbon atoms or a fluoroalkyl group having 1-8 carbon atoms), a 5- to 7-membered cyclic alkyl group, an aryl group, a heteroaryl group, or a 4- to 7-membered saturated or partially saturated heterocyclic group (the cyclic alkyl group, aryl group, heteroaryl group and heterocyclic group may have one to three substituents selected from the group consisting of a halogen atom, hydroxyl group, a group of OZ 1-4 , a group of S(O) n Z 1-4 , a group of N(R 12 )(R 13 ), a group of Z 1-4 , carboxyl group, a group of CO 2 Z 1-4 , group of CONH 2 , a group of CONH(Z 1-4 ) and a group of CON(Z 1-4 )(Z 1-4 )); 
 W 1  represents a group selected from the group consisting of —CH═CH—, —N(R 12 )CO—, —CON(R 12 )—, —CH 2 O— and —CH 2 CH 2 — (each of the aforementioned groups binds to the thiazole ring at the left end);  
 R 3  represents hydrogen atom, a halogen atom, hydroxyl group or an amino group;  
 R 4  represents a group selected from the group consisting of hydrogen atom, a group of —OZ 0-4 R 5  (Z 0-4  represents an alkylene group having 1-4 carbon atoms, a fluorine-substituted alkylene group having 1-4 carbon atoms or a single bond, and R 5  represents a 5- to 7-membered cyclic alkyl group, an aryl group, a heteroaryl group or a 4- to 7-membered saturated or partially saturated heterocyclic group (the cyclic alkyl group, aryl group, heteroaryl group and heterocyclic group may have one to three substituents selected from the group consisting of a halogen atom, hydroxyl group, a group of OZ 1-4 , a group of S(O) n Z 1-4 , a group of N(R 12 )(R 13 ), a group of Z 1-4 , carboxyl group, a group of CO 2 Z 1-4 , group of CONH 2 , a group of CONH(Z 1-4 ) and a group of CON(Z 1-4 )(Z 1-4 )), a group of —S(O) n Z 0-4 R 5 , a group of —N(R 6 )(R 7 ) {R 6  and R 7  each independently represent hydrogen atom or Z 1-4 , or they may bind to each other to form a saturated or unsaturated 5- to 7-membered ring (the ring may contain one or two hetero atoms as ring constituting atoms), and R 6  and R 7  may have one to three substituents selected from the group consisting of a halogen atom, hydroxyl group, a group of OCON(R 12 )(R 13 ), a group of CON(R 12 )(R 13 ), a group of N(R 12 )CON(R 12 )(R 13 ), a group of Z 1-4 , a group of OZ 1-4 , a group S(O) n Z 1-4 , group of CH 2 OH, a group of (CH 2 ) m N(R 12 )(R 13 ), carboxyl group, cyano group, a group of CO-Z 1-4 (R 10 )—N(R 12 )(R 13 ) (R 10  is a substituent corresponding to a side chain on an amino acid carbon or a group of -Z 1-4 -R 11  (R 11  represents a substituent which forms a quaternary salt) and a group of  
                     
 a 5- or 6-membered aryl group which may be substituted and a 5- or 6-membered unsaturated heterocyclic group which may be substituted;  
 W 2  represents a single bond or —C(R 8 )═C(R 9 )— (R 8  and R 9  each independently represent hydrogen atom, a halogen atom, a lower alkyl group, an alkoxy group, cyano group, carboxyl group, hydroxymethyl group, cyanomethyl group, vinyl group or a group of N(R 12 )(R 13 )), Q represents an acidic group, and W 2  and Q may bind together to form vinylidenethiazolidinedione in E- or Z-configuration or an equivalent heterocyclic ring; m and n each independently represent an integer of 0 to 2, and q represents an integer of 0 to 3.  
 
   
   
       10 . The method according to  claim 9 , further comprising administering at least one antimicrobial agent.  
   
   
       11 . The method according to  claim 10 , wherein the compound is an active ingredient in a composition.  
   
   
       12 . The method according to  claim 11 , wherein the at least one antimicrobial agent is simultaneously administered with the composition.  
   
   
       13 . The method according to  claim 11 , wherein the at least one antimicrobial agent is separately administered from the composition.  
   
   
       14 . The method according to  claim 11 , wherein the at least one antimicrobial agent is successively administered with the composition.  
   
   
       15 . The method according to  claim 9  wherein the mammal is a human.  
   
   
       16 . The method according to  claim 9  wherein the microbial infection comprises an infection by microorganisms selected from  Pseudomonas aeruginosa  and bacteria having a genetically homologous drug efflux pump to  Pseudomonas aeruginosa.    
   
   
       17 . A method for therapeutic treatment of a microbial infection comprising administering to a mammal in need thereof a therapeutically effective amount of a compound represented by the following formula (I) or a physiologically acceptable salt, or a hydrate thereof:  
     
       
         
         
             
             
         
       
     
     wherein, R 1  and R 2  each independently represent hydrogen atom, a halogen atom, hydroxyl group, a group of OZ 1-6  (the group of OZ 1-6  represents an alkyl group having 1-6 carbon atoms or a fluoroalkyl group having 1-6 carbon atoms, which bonds via the oxygen atom), a group of S(O) n Z 1-4  (Z 1-4  represents an alkyl group having 1-4 carbon atoms or a fluoroalkyl group having 1-4 carbon atoms or an alkylene group derived therefrom), a group of N(R 12 )(R 13 ) (R 12  and R 13  each independently represent hydrogen atom, an alkyl group having 1-4 carbon atoms or a fluoroalkyl group having 1-4 carbon atoms), a group of Z 1-8  which may be substituted (Z 1-8  represents an alkyl group having 1-8 carbon atoms or a fluoroalkyl group having 1-8 carbon atoms), a 5- to 7-membered cyclic alkyl group, an aryl group, a heteroaryl group, or a 4- to 7-membered saturated or partially saturated heterocyclic group (the cyclic alkyl group, aryl group, heteroaryl group and heterocyclic group may have one to three substituents selected from the group consisting of a halogen atom, hydroxyl group, a group of OZ 1-4 , a group of S(O) n Z 1-4 , a group of N(R 12 )(R 13 ), a group of Z 1-4 , carboxyl group, a group of CO 2 Z 1-4 , group of CONH 2 , a group of CONH(Z 1-4 ) and a group of CON(Z 1-4 )(Z 1-4 )); 
 W 1  represents a group selected from the group consisting of —CH═CH—, —N(R 12 )CO—, —CON(R 12 )—, —CH 2 O— and —CH 2 CH 2 — (each of the aforementioned groups binds to the thiazole ring at the left end);  
 R 3  represents hydrogen atom, a halogen atom, hydroxyl group or an amino group;  
 R 4  represents a group selected from the group consisting of hydrogen atom, a group of —OZ 0-4 R 5  (Z 0-4  represents an alkylene group having 1-4 carbon atoms, a fluorine-substituted alkylene group having 1-4 carbon atoms or a single bond, and R 5  represents a 5- to 7-membered cyclic alkyl group, an aryl group, a heteroaryl group or a 4- to 7-membered saturated or partially saturated heterocyclic group (the cyclic alkyl group, aryl group, heteroaryl group and heterocyclic group may have one to three substituents selected from the group consisting of a halogen atom, hydroxyl group, a group of OZ 1-4 , a group of S(O) n Z 1-4 , a group of N(R 12 )(R 13 ), a group of Z 1-4 , carboxyl group, a group of CO 2 Z 1-4 , group of CONH 2 , a group of CONH(Z 1-4 ) and a group of CON(Z 1-4 )(Z 1-4 )), a group of —S(O) n Z 0-4 R 5 , a group of —N(R 6 )(R 7 ) {R 6  and R 7  each independently represent hydrogen atom or Z 1-4 , or they may bind to each other to form a saturated or unsaturated 5- to 7-membered ring (the ring may contain one or two hetero atoms as ring constituting atoms), and R 6  and R 7  may have one to three substituents selected from the group consisting of a halogen atom, hydroxyl group, a group of OCON(R 12 )(R 13 ), a group of CON(R 12 )(R 13 ), a group of N(R 12 )CON(R 12 )(R 13 ), a group of Z 1-4 , a group of OZ 1-4 , a group S(O) n Z 1-4 , group of CH 2 OH, a group of (CH 2 ) m N(R 12 )(R 13 ), carboxyl group, cyano group, a group of CO-Z 1-4 (R 10 )—N(R 12 )(R 13 ) (R 10  is a substituent corresponding to a side chain on an amino acid carbon or a group of -Z 1-4 -R 11  (R 11  represents a substituent which forms a quaternary salt) and a group of  
                     
 a 5- or 6-membered aryl group which may be substituted and a 5- or 6-membered unsaturated heterocyclic group which may be substituted;  
 W 2  represents a single bond or —C(R 8 )═C(R 9 )— (R 8  and R 9  each independently represent hydrogen atom, a halogen atom, a lower alkyl group, an alkoxy group, cyano group, carboxyl group, hydroxymethyl group, cyanomethyl group, vinyl group or a group of N(R 12 )(R 13 )), Q represents an acidic group, and W 2  and Q may bind together to form vinylidenethiazolidinedione in E- or Z-configuration or an equivalent heterocyclic ring; m and n each independently represent an integer of 0 to 2, and q represents an integer of 0 to 3; R 14  represents hydrogen atom, Z 1-4 , Z 1-4 R 5  or Z 1-4 OR 5 ; and X represents C—H and Y represents C—H or nitrogen atom.  
 
   
   
       18 . The method according to  claim 17 , further comprising administering at least one antimicrobial agent.  
   
   
       19 . The method according to  claim 18 , wherein the compound is an active ingredient in a composition.  
   
   
       20 . The method according to  claim 17 , wherein the microbial infection comprises an infection by bacteria having a genetically homologous drug efflux pump to  Pseudomonas aeruginosa.    
   
   
       21 . The method according to  claim 17 , wherein the at least one antimicrobial agent and the compound are present in a composition.  
   
   
       22 . A method for preventive treatment of a microbial infection comprising administering to a mammal a preventively effective amount of a compound represented by the following formula (I) or a physiologically acceptable salt, or a hydrate thereof:  
     
       
         
         
             
             
         
       
     
     wherein, R 1  and R 2  each independently represent hydrogen atom, a halogen atom, hydroxyl group, a group of OZ 1-6  (the group of OZ 1-6  represents an alkyl group having 1-6 carbon atoms or a fluoroalkyl group having 1-6 carbon atoms, which bonds via the oxygen atom), a group of S(O) n Z 1-4  (Z 0-4  represents an alkyl group having 1-4 carbon atoms or a fluoroalkyl group having 1-4 carbon atoms or an alkylene group derived therefrom), a group of N(R 12 )(R 13 ) (R 12  and R 13  each independently represent hydrogen atom, an alkyl group having 1-4 carbon atoms or a fluoroalkyl group having 1-4 carbon atoms), a group of Z 1-8  which may be substituted (Z 1-8  represents an alkyl group having 1-8 carbon atoms or a fluoroalkyl group having 1-8 carbon atoms), a 5- to 7-membered cyclic alkyl group, an aryl group, a heteroaryl group, or a 4- to 7-membered saturated or partially saturated heterocyclic group (the cyclic alkyl group, aryl group, heteroaryl group and heterocyclic group may have one to three substituents selected from the group consisting of a halogen atom, hydroxyl group, a group of OZ 1-4 , a group of S(O) n Z 1-4 , a group of N(R 12 )(R 13 ), a group of Z 1-4 , carboxyl group, a group of CO 2 Z 1-4 , group of CONH 2 , a group of CONH(Z 1-4 ) and a group of CON(Z 1-4 )(Z 1-4 )); 
 W 1  represents a group selected from the group consisting of —CH═CH—, —N(R 12 )CO—, —CON(R 12 )—, —CH 2 O— and —CH 2 CH 2 — (each of the aforementioned groups binds to the thiazole ring at the left end);  
 R 3  represents hydrogen atom, a halogen atom, hydroxyl group or an amino group;  
 R 4  represents a group selected from the group consisting of hydrogen atom, a group of —OZ 0-4 R 5  (Z 0-4  represents an alkylene group having 1-4 carbon atoms, a fluorine-substituted alkylene group having 1-4 carbon atoms or a single bond, and R 5  represents a 5- to 7-membered cyclic alkyl group, an aryl group, a heteroaryl group or a 4- to 7-membered saturated or partially saturated heterocyclic group (the cyclic alkyl group, aryl group, heteroaryl group and heterocyclic group may have one to three substituents selected from the group consisting of a halogen atom, hydroxyl group, a group of OZ 1-4 , a group of S(O) n Z 1-4 , a group of N(R 12 )(R 13 ), a group of Z 1-4 , carboxyl group, a group of CO 2 Z 1-4 , group of CONH 2 , a group of CONH(Z 1-4 ) and a group of CON(Z 1-4 )(Z 1-4 )), a group of —S(O) n Z 0-4 R 5 , a group of —N(R 6 )(R 7 ) {R 6  and R 7  each independently represent hydrogen atom or Z 1-4 , or they may bind to each other to form a saturated or unsaturated 5- to 7-membered ring (the ring may contain one or two hetero atoms as ring constituting atoms), and R 6  and R 7  may have one to three substituents selected from the group consisting of a halogen atom, hydroxyl group, a group of OCON(R 12 )(R 13 ), a group of CON(R 12 )(R 13 ), a group of N(R 12 )CON(R 12 )(R 13 ), a group of Z 1-4 , a group of OZ 1-4 , a group S(O) n Z 1-4 , group of CH 2 OH, a group of (CH 2 ) m N(R 12 )(R 13 ), carboxyl group, cyano group, a group of CO-Z 1-4 (R 10 )—N(R 12 )(R 13 ) (R 10  is a substituent corresponding to a side chain on an amino acid carbon or a group of -Z 1-4 -R 11  (R 1  represents a substituent which forms a quaternary salt) and a group of  
                     
 a 5- or 6-membered aryl group which may be substituted and a 5- or 6-membered unsaturated heterocyclic group which may be substituted;  
 W 2  represents a single bond or —C(R 8 )═C(R 9 )— (R 8  and R 9  each independently represent hydrogen atom, a halogen atom, a lower alkyl group, an alkoxy group, cyano group, carboxyl group, hydroxymethyl group, cyanomethyl group, vinyl group or a group of N(R 12 )(R 13 )), Q represents an acidic group, and W 2  and Q may bind together to form vinylidenethiazolidinedione in E- or Z-configuration or an equivalent heterocyclic ring; m and n each independently represent an integer of 0 to 2, and q represents an integer of 0 to 3; R 14  represents hydrogen atom, Z 1-4 , Z 1-4 R 5  or Z 1-4 OR 5 ; and X represents C—H and Y represents C—H or nitrogen atom.  
 
   
   
       23 . The method according to  claim 22 , wherein the compound is an active ingredient in a composition.  
   
   
       24 . The method according to  claim 22 , wherein the microbial infection comprises an infection by microorganisms selected from  Pseudomonas aeruginosa  and bacteria having a genetically homologous drug efflux pump to  Pseudomonas aeruginosa.    
   
   
       25 . The method according to  claim 22 , wherein the at least one antimicrobial agent and the compound are present in a composition.