Polyene polyketides and methods of treating bacterial infections

Abstract

This invention related to methods of inhibiting the growth of bacterial cells and methods of treating bacterial infections in mammals using a novel polyene polyketide.

1 . A method of inhibiting the growth of a bacterial infection, the method comprising contacting a bacterial cell with a therapeutically effective amount of a compound of Formula l:  
       
         
           
           
               
               
           
         
       
       such that growth of the bacterial infection is inhibited;  
       wherein, 
 A is selected from —C(NH)NHR 1 , CH 3 , H or  
                     
 R 1  is selected from H, C 1-6 alkyl, C 6-10 aryl, C(O)C 1-6 alkyl and C(O)C 6-10 aryl;  
 R 2  and R 3  are each independently selected from H, C 1-6  alkyl, C 2-7  alkene and C 6-10  aryl;  
 R 4  is selected from H or CH 3 ;  
 Z is OH or O when taken with adjacent carbon atom to form a carbonyl; or  
 Z may be a tetrahydropyranoxy of formula:  
                     
 R 5  is selected from H, COOH, C 1-6  alkyl or C(O)OC 1-6  alkyl;  
 R 6 , R 7  and R 8  are each independently selected from H, C 1-6  alkyl and C(O)C 1-6  alkyl; or  
 R 6 , R 7  and R 8  may each independently be absent when the adjacent oxygen and carbon atoms are taken together to form a carbonyl; or  
 R 6 , R 7  and R 6  may each independently be a bond when any of two neighboring R 6 , R 7  and R 8  are taken together with attached oxygen and carbon atoms to form a 1,3-dioxolane ring of formula:  
                     
 R 9  and R 10  are each independently selected from H, C 1-6  alkyl, C 2-7  alkene and C 6-10  aryl; or  
 R 9  and R 10  are taken together with adjacent carbon atom to form a ring having from 5 to 7 carbons;  
 D is selected from OH, NH 2 , NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , OC 1-3 alkyl or  
                     
 R 11  is selected from H or C 13  alkyl;  
 or a pharmaceutically acceptable salt or prodrug thereof.  
 
     
     
         2 . The method of  claim 1 , wherein said compound is selected from Compounds 1, 2, 3, 4, 5, 6, 7 and pharmaceutically acceptable salts or prodrugs thereof:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein A of said compound is selected from —C(NH)NH 2,  —C(NH)NHC(O)CH 3 , and  
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein R 4  of said compound is CH 3  or H.  
     
     
         5 . The method of  claim 1 , wherein Z of said compound is selected from —OH,  
       
         
           
           
               
               
           
         
       
       wherein R 6 , R 7  and R 8  are H;  
       and R 5  is selected from COOH or CO 2 CH 3 .  
     
     
         6 . The method of  claim 1 , wherein D of said compound is selected from the group consisting of —OH,  
       
         
           
           
               
               
           
         
       
       wherein R 11  is H or CH 3 .  
     
     
         7 . A method of inhibiting the growth of a bacterial infection, the method comprising contacting a bacterial cell with a pharmaceutical composition comprising of a therapeutically effective amount of a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein, 
 A is selected from —C(NH)NHR 1 , CH 3 , H or  
                     
 R 1  is selected from H, C 1-6 alkyl, C 6-10 aryl, C(O)C 1-6 alkyl and C(O)C 6-10 aryl;  
 R 2  and R 3  are each independently selected from H, C 1-6  alkyl, C 2-7  alkene and C 6-10  aryl;  
 R 4 is selected from H or CH 3 ;  
 Z is OH or O when taken with adjacent carbon atom to form a carbonyl; or  
 Z may be a tetrahydropyranoxy of formula:  
                     
 R 5 is selected from H, COOH, C 1-6  alkyl or C(O)OC 1-6  alkyl;  
 R 6 , R 7  and R 8  are each independently selected from H, C 1-6  alkyl and C(O)C 1-6  alkyl; or  
 R 6 , R 7  and R 8  may each independently be absent when the adjacent oxygen and carbon atoms are taken together to form a carbonyl; or  
 R 6 , R 7  and R 8  may each independently be a bond when any of two neighboring R 6 , R 7  and R 8  are taken together with attached oxygen and carbon atoms to form a 1,3-dioxolane ring of formula:  
                     
 R 9  and R 10  are each independently selected from H, C 1-6  alkyl, C 2-7  alkene and C 6-10  aryl; or  
 R 9  and R 10  are taken together with adjacent carbon atom to form a ring having from 5 to 7 carbons;  
 D is selected from OH, NH 2 , NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , OC 1-3 alkyl or  
                     
 R 11  is selected from H or C 1-3  alkyl;  
 or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier, such that growth of the bacterial infection is inhibited.  
 
     
     
         8 . The method of  claim 7 , wherein said pharmaceutical composition comprises a therapeutically effective amount of a compound selected from Compounds 1-7  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier, such that growth of the bacterial infection is inhibited.  
     
     
         9 . A method of treating a bacterial infection in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt or prodrug thereof.  
     
     
         10 . The method of  claim 9 , wherein said compound is selected from the group of Compounds 1, 2, 3, 4, 5, 6, 7 and pharmaceutically acceptable salts or prodrugs thereof.  
     
     
         11 . A method of treating a bacterial infection in a mammal, comprising the step of administering to the mammal with a pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  such that growth of the bacterial infection is inhibited;  
     
     
         12 . The method of  claim 11 , wherein said bacterial infection is from a bacteria selected from the group consisting of  Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter  spp.,  Proteus  spp.,  Pseudomonas aeruginosa, E. coli, Serratia marcesens, Staphylococcus aureus,  Coagulase negative  Staphylococcus, Haemophilus infuenzae, Bacillus anthracis, Mycoplasma pneumoniae,  and  Staphylococcus epidermidis.    
     
     
         13 . The method of  claim 11 , wherein said the bacterial infection is caused by Gram-positive bacteria.  
     
     
         14 . The method of  claim 11 , wherein said Gram-positive bacteria is selected from  Staphylococci  and  Enterococci  species.  
     
     
         15 . The method of  claim 11 , wherein said bacterial infection is from a bacteria selected from the group consisting of  Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter  spp.,  Proteus  spp.,  Pseudomonas aeruginosa, E. coli, Serratia marcesens, Staphylococcus aureus,  Coagulase negative  Staphylococcus, Haemophilus infuenzae, Bacillus anthracis, Mycoplasma pneumoniae,  and  Staphylococcus epidermidis.    
     
     
         16 . The method of  claim 11 , wherein said compound is administered orally.  
     
     
         17 . The method of  claim 11 , wherein said compound is administered intravenously.  
     
     
         18 . The method of  claim 11 , wherein said compound is administered intraperitoneally.