Pharmaceutical compositions comprising antibacterial agents

Abstract

A pharmaceutical compositions comprising: (a) a carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or a pharmaceutically acceptable derivative thereof, and (b) a compound of Formula (I), or a stereoisomer or a pharmaceutical acceptable derivative thereof, are disclosed. wherein, R is heterocycloalkyl

1 . A pharmaceutical composition comprising: (a) a carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or a pharmaceutically acceptable salt thereof, and (b) a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R is heterocycloalkyl. 
       
     
     
         2 . A pharmaceutical composition comprising active ingredients, said active ingredients consisting of: (a) a carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or a pharmaceutically acceptable salt thereof, and (b) a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R is heterocycloalkyl. 
       
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof is present in the composition in an amount from about 0.25 gram to about 4 grams per gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof is present in the composition in an amount from about 0.01 gram to about 10 grams. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof is present in the composition in an amount from about 0.01 gram to about 10 grams. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , comprising: (a) the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof, and (b) the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, in any one of following amounts:
 (i) about 0.25 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 0.5 gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (ii) about 0.5 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 0.5 gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (iii) about 1 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 0.5 gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (iv) about 0.25 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 1 gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (v) about 0.5 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 1 gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (vi) about 1 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 1 gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (vii) about 2 grams of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 1 gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (viii) about 0.25 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 2 grams of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (ix) about 0.5 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 2 grams of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (x) about 1 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 2 grams of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof; or   (xi) about 2 grams of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 2 grams of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof.   
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein R is piperidine. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , wherein R is pyrrolidine. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein the composition is formulated into a dosage form such that the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof, are present in the composition as admixture or as separate components. 
     
     
         10 . The pharmaceutical composition according to  claim 9 , wherein the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof, are present in the composition as separate components. 
     
     
         11 . The pharmaceutical composition according to  claim 1 , wherein the composition is in form of a powder or a solution. 
     
     
         12 . The pharmaceutical composition according to  claim 11 , wherein the powder or solution can be reconstituted by addition of a compatible reconstitution diluent for use in parenteral or oral administration. 
     
     
         13 . A pharmaceutical composition according to any one of  claims 1 - 12  for use in treatment or prevention of a bacterial infection. 
     
     
         14 . A method for preventing or treating a bacterial infection comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition according to any one of  claims 1 - 12 . 
     
     
         15 . The method according to  claim 14 , wherein a compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, is administered before, after, or simultaneously with the administration of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof. 
     
     
         16 . A method for treating or preventing a bacterial infection comprising administering to a subject in need thereof an effective amount of: (a) carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or a pharmaceutically acceptable salt thereof, and (b) a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R is heterocycloalkyl. 
       
     
     
         17 . The method according to  claim 16 , wherein the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, is administered in an amount from about 0.25 gram to about 4 grams per gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof. 
     
     
         18 . The method according to  claim 16 , wherein the compound of Formula (I) or stereoisomer or pharmaceutically acceptable salt thereof, is administered in an amount from about 0.01 gram to about 10 grams. 
     
     
         19 . The method according to  claim 16 , wherein the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof, is administered in an amount from about 0.01 gram to about 10 grams. 
     
     
         20 . The method according to  claim 16 , wherein the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof, and the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, is administered in any of the following amounts:
 (i) about 0.25 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 0.5 gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (ii) about 0.5 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 0.5 gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (iii) about 1 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 0.5 gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (iv) about 0.25 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 1 gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (v) about 0.5 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 1 gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (vi) about 1 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 1 gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (vii) about 2 grams of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 1 gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (viii) about 0.25 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 2 grams of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (ix) about 0.5 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 2 grams of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof;   (x) about 1 gram of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 2 grams of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof; or (xi) about 2 grams of the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, and about 2 grams of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof.   
     
     
         21 . The method according to  claim 16 , wherein the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, is administered before administration of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof. 
     
     
         22 . The method according to any one of  claims 16 - 21 , wherein R is piperidine. 
     
     
         23 . A method according to any of  claims 16 - 21 , wherein R is pyrrolidine. 
     
     
         24 . A method for increasing antibacterial effectiveness of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or a pharmaceutically acceptable salt thereof comprising co-administering to a subject in need thereof said carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof, with a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R is heterocycloalkyl. 
       
     
     
         25 . The method according to  claim 24 , wherein the compound of Formula (I), or stereoisomer or pharmaceutically acceptable salt thereof, is administered in an amount from about 0.25 gram to about 4 grams per gram of the carbapenem antibacterial agent selected from imipenem, meropenem, ertapenem, doripenem or pharmaceutically acceptable salt thereof.