Dab9 DERIVATIVES OF LIPOPEPTIDE ANTIBIOTICS AND METHODS OF MAKING AND USING THE SAME

Abstract

The present invention provides Dab 9 derivatives of amphomycin-type lipopeptide antibiotics that display antimicrobial activity against Gram-positive bacteria, methods and intermediates for synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of infections.

1 . An antimicrobial compound according to structural formula (III): 
       
         
           
           
               
               
           
         
         including the salts thereof, wherein:
 R 1  is a linear or branched, saturated or singly or multiply unsaturated alkyl or hydroxy alkyl having a chain comprising from 6 to 22 carbon atoms; 
 R 2  is OH or NH 2 ; and 
 R 6  is a substitutent which includes a primary or secondary amine. 
 
       
     
     
         2 . The compound of  claim 1  in which R 2  is OH. 
     
     
         3 . The compound of  claim 1  in which R 2  is NH 2 . 
     
     
         4 . The compound of  claim 1  in which R 1  is a linear or branched, saturated or singly unsaturated alkyl comprising 11, 12, 13, 14 or 15 carbon atoms. 
     
     
         5 . The compound of  claim 4  in which the alkyl is in the iso or ante-iso configuration. 
     
     
         6 . The compound of  claim 1  in which R 6  is an amino acid which is linked to the β-amino group of the macrocyclic Dab 9  residue via its carboxyl group, and wherein the amino acid optionally includes a side chain moiety. 
     
     
         7 . The compound of  claim 1  in which R 6  has the —X—R 10 —NHR 7  or —X—(CR 11 R 11 ) n —NHR 7 , wherein:
 n is an integer from 1 to 6;   X is —C(O)—, —C(NH)— or —S(O) 2 —;   R 7  is hydrogen or (C 1 -C 4 ) alkyl;   R 10  is (C 1 -C 4 ) alkyldiyl, (C 1 -C 4 ) alkyleno or (C 1 -C 4 ) alkano;   each R 11  is independently selected from the group consisting of hydrogen, amino, amido, amidino, carboxy, guandino, hydroxy, sulfanyl, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkyl substituted with one or more of the same or different R 12 , (C 5 -C 10 ) aryl, (C 5 -C 10 ) aryl substituted with one or more of the same or different R 12 , (C 6 -C 13 ) arylalkyl, (C 6 -C 13 ) arylalkyl substituted with one or more of the same or different R 12 , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted with one or more of the same or different R 12 , 6-13 membered heteroarylalkyl and 6-13 membered heteroarylalkyl substituted with one or more of the same or different R 12 ; and   each R 12  is independently selected from the group consisting of amino, amido, amidino, carboxyl, guanidino, hydroxy and sulfanyl.   
     
     
         8 . The compound of  claim 7  in which n is 1 and R 11  is a side-chain moiety of a genetically encoded amino acid. 
     
     
         9 . The compound of  claim 7  in which n is 2 or 3 and only one R 11  is other than hydrogen. 
     
     
         10 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
         11 . A method of inhibiting the growth of a Gram-positive bacteria, comprising contacting the bacteria with an amount of a compound according to  claim 1  effective to inhibit its growth. 
     
     
         12 . The method of  claim 11  in which the amount of compound is effective to kill the bacteria. 
     
     
         13 . A method of treating an infection caused by or associated with a Gram-positive bacteria, comprising administering to a subject in need thereof an amount of a compound according to  claim 1  effect to treat the infection. 
     
     
         14 . The method of  claim 13  in which the compound is administered topically. 
     
     
         15 . The method of  claim 13  in which the compound is administered systemically. 
     
     
         16 . The method of  claim 13  in which the compound is applied therapeutically. 
     
     
         17 . The method of  claim 13  in which the compound is applied prophylactically.