Use of a polyene macrolide antifungal agent in combination with a glycopeptide antibacterial agent

Abstract

This invention is directed to methods of administering a polyene macrolide antifungal agent in combination with a glycopeptide antibacterial agent having a substituent comprising at least about 8 carbon atoms. The invention is also directed to methods of using a polyene macrolide antifungal agent in combination with a specified glycopeptide antibacterial agent to treat fungal infections; and to compositions, kits and systems comprising a polyene macrolide antifungal agent and a specified glycopeptide antibacterial agent.

1 - 26 . (canceled) 
   
   
       27 . A pharmaceutical composition comprising:
 (a) a polyene macrolide antifungal agent;   (b) a glycopeptide antibacterial agent having a substituent comprising at least about 8 carbon atoms; and   (c) a pharmaceutically acceptable carrier.   
   
   
       28 . The pharmaceutical composition according to  claim 27 , wherein the polyene macrolide antifungal agent is amphotericin B, candidin, candidoin, candidinin, mycoheptin, nystatin, polyfungin, aureofacin, vacidin, trichomycin, candicidin or pimaricin; or a pharmaceutically acceptable salt thereof. 
   
   
       29 . The pharmaceutical composition according to  claim 27 , wherein the glycopeptide antibacterial agent is selected from telavancin, oritavancin, dalbavancin and teicoplanin; or a pharmaceutically acceptable salt thereof. 
   
   
       30 . The pharmaceutical composition according to  claim 27 , wherein the glycopeptide antibacterial agent is a compound of formula I: 
     
       
         
         
             
             
         
       
     
     wherein 
     X 1  and X 2  are independently hydrogen or chloro; 
     R 1  is selected from the group consisting of:
 (a) —R a ; 
 (b) —C(O)—R b ; 
 (c) —R c —W 1 ; 
 (d) —C(O)—R d —W 2 ; and 
 (e) —R e —Y—R f ; 
 
     where
 R a  and R b  are independently C 8-14  alkyl, C 8-14  alkenyl or C 8-14  alkynyl; 
 R c  and R d  are independently C 1-8  alkylene; 
 R e  is C 2-8  alkylene; 
 R f  is C 1-12  alkyl, C 2-12  alkenyl or C 2-12  alkynyl; 
 W 1  and W 2  are independently phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6  alkyl, C 1-6  alkoxy, halo, -(phenyl), —CH 2 — (phenyl), —O-(phenyl), and 
 —O—CH 2 — (phenyl); wherein each -(phenyl) group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1-6  alkyl, C 1-6  alkoxy and halo; 
 Y is O, S or NH; 
 and provided that R 1  comprises at least 8 carbon atoms; 
 
     one of R 2  and R 3  is hydroxy and the other is hydrogen; 
     R 4  and R 5  are independently hydrogen or methyl; 
     R 6  is hydrogen or a group of formula (f): 
     
       
         
         
             
             
         
       
     
     R 7  is hydrogen or a group of formula (g): 
     
       
         
         
             
             
         
       
     
     n is an integer from 1 to 6; 
     or a pharmaceutically-acceptable salt thereof or stereoisomer thereof. 
   
   
       31 . The pharmaceutical composition according to  claim 30 , wherein:
 X 1  and X 2  are both chloro;   R 1  is —CH 2 CH 2 —NH—(CH 2 ) 9 CH 3 ;   R 2  is hydroxy;   R 3  is hydrogen;   R 4  is methyl;   R 5  is hydrogen;   R 6  is hydrogen; and   R 7  is —CH 2 —NH—CH 2 —P(O)(OH) 2 .   
   
   
       32 . The pharmaceutical composition according to any one of  claims 29 ,  30  and  31 , wherein the polyene macrolide antifungal agent is amphotericin B. 
   
   
       33 . A kit comprising:
 (a) a polyene macrolide antifungal agent; and   (b) a glycopeptide antibacterial agent having a substituent comprising at least about 8 carbon atoms.   
   
   
       34 . The kit according to  claim 33 , wherein the kit further comprises instructions for administering the polyene macrolide antifungal agent and the glycopeptide antibacterial agent to a subject. 
   
   
       35 . The kit according to  claim 33 , wherein the polyene macrolide antifungal agent and the glycopeptide antibacterial agent are present as separate pharmaceutical compositions. 
   
   
       36 . The kit according to  claim 33 , wherein the polyene macrolide antifungal agent and the glycopeptide antibacterial agent are present in a single pharmaceutical composition. 
   
   
       37 . The kit according to  claim 33 , wherein the polyene macrolide antifungal agent is amphotericin B, candidin, candidoin, candidinin, mycoheptin, nystatin, polyfungin, aureofacin, vacidin, trichomycin, candicidin or pimaricin; or a pharmaceutically acceptable salt thereof. 
   
   
       38 . The kit according to  claim 33 , wherein the glycopeptide antibacterial agent is selected from telavancin, oritavancin, dalbavancin and teicoplanin; or a pharmaceutically acceptable salt thereof. 
   
   
       39 . The kit according to  claim 33 , wherein the glycopeptide antibacterial agent is a compound of formula I: 
     
       
         
         
             
             
         
       
       wherein 
       X 1  and X 2  are independently hydrogen or chloro; 
       R 1  is selected from the group consisting of:
 (a) —R a ; 
 (b) —C(O)—R b ; 
 (c) —R c —W 1 ; 
 
       (d) —C(O)—R d —W 2 ; and 
       (e) —R e —Y—R f ; 
     
     where
 R a  and R b  are independently C 8-14  alkyl, C 8-14  alkenyl or C 8-14  alkynyl; 
 R c  and R d  are independently C 1-8  alkylene; 
 R e  is C 2-8  alkylene; 
 R f  is C 1-12  alkyl, C 2-12  alkenyl or C 2-12  alkynyl; 
 W 1  and W 2  are independently phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6  alkyl, C 1-6  alkoxy, halo, -(phenyl), —CH 2 — (phenyl), —O-(phenyl), and 
 —O—CH 2 — (phenyl); wherein each -(phenyl) group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1-6  alkyl, C 1-6  alkoxy and halo; 
 Y is O, S or NH; 
 and provided that R 1  comprises at least 8 carbon atoms; 
 
     one of R 2  and R 3  is hydroxy and the other is hydrogen; 
     R 4  and R 5  are independently hydrogen or methyl; 
     R 6  is hydrogen or a group of formula (f): 
     
       
         
         
             
             
         
       
     
     R 7  is hydrogen or a group of formula (g): 
     
       
         
         
             
             
         
       
     
     n is an integer from 1 to 6; 
     or a pharmaceutically-acceptable salt thereof or stereoisomer thereof. 
   
   
       40 . The kit according to  claim 39 , wherein:
 X 1  and X 2  are both chloro;   R 1  is —CH 2 CH 2 —NH—(CH 2 ) 9 CH 3 ;   R 2  is hydroxy;   R 3  is hydrogen;   R 4  is methyl;   R 5  is hydrogen;   R 6  is hydrogen; and   R 7  is —CH 2 —NH—CH 2 —P(O)(OH) 2 .   
   
   
       41 . The kit according to any one of  claims 38 ,  39  and  40 , wherein the polyene macrolide antifungal agent is amphotericin B. 
   
   
       42 . A system for treating a fungal infection in a subject, the system comprising:
 (a) a polyene macrolide antifungal agent; and   (b) a glycopeptide antibacterial agent having a substituent comprising at least about 8 carbon atoms.   
   
   
       43 . The system according to  claim 42 , wherein the polyene macrolide antifungal agent is amphotericin B, candidin, candidoin, candidinin, mycoheptin, nystatin, polyfungin, aureofacin, vacidin, trichomycin, candicidin or pimaricin; or a pharmaceutically acceptable salt thereof. 
   
   
       44 . The system according to  claim 42 , wherein the glycopeptide antibacterial agent is selected from telavancin, oritavancin, dalbavancin and teicoplanin; or a pharmaceutically acceptable salt thereof. 
   
   
       45 . The system according to  claim 42 , wherein the glycopeptide antibacterial agent is a compound of formula I: 
     
       
         
         
             
             
         
       
     
     wherein 
     X 1  and X 2  are independently hydrogen or chloro; 
     R 1  is selected from the group consisting of:
 (a) —R a ; 
 (b) —C(O)—R b ; 
 (c) —R c —W 1 ; 
 (d) —C(O)—R d —W 2 ; and 
 (e) —R e —Y—R f ; 
 
     where
 R a  and R b  are independently C 8-14  alkyl, C 8-14  alkenyl or C 8-14  alkynyl; 
 R c  and R d  are independently C 1-8  alkylene; 
 R e  is C 2-8  alkylene; 
 R f  is C 1-12  alkyl, C 2-12  alkenyl or C 2-12  alkynyl; 
 W 1  and W 2  are independently phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6  alkyl, C 1-6  alkoxy, halo, -(phenyl), —CH 2 — (phenyl), —O-(phenyl), and 
 —O—CH 2 — (phenyl); wherein each -(phenyl) group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1-6  alkyl, C 1-6  alkoxy and halo; 
 Y is O, S or NH; 
 and provided that R 1  comprises at least 8 carbon atoms; 
 
     one of R 2  and R 3  is hydroxy and the other is hydrogen; 
     R 4  and R 5  are independently hydrogen or methyl; 
     R 6  is hydrogen or a group of formula (f): 
     
       
         
         
             
             
         
       
     
     R 7  is hydrogen or a group of formula (g): 
     
       
         
         
             
             
         
       
     
     n is an integer from 1 to 6; 
     or a pharmaceutically-acceptable salt thereof or stereoisomer thereof. 
   
   
       46 . The system according to  claim 45 , wherein:
 X 1  and X 2  are both chloro;   R 1  is —CH 2 CH 2 —NH—(CH 2 ) 9 CH 3 ;   R 2  is hydroxy;   R 3  is hydrogen;   R 4  is methyl;   R 5  is hydrogen;   R 6  is hydrogen; and   R 7  is —CH 2 —NH—CH 2 —P(O)(OH) 2 .   
   
   
       47 . The system according to any one of  claims 44 ,  45  and  46 , wherein the polyene macrolide antifungal agent is amphotericin B.