Desleucyl glycopeptide antibiotics and methods of making same

Abstract

Compounds that are analogs of glycopeptide antibiotics are disclosed. The compounds have the formula A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 wherein each of the groups A 2 to A 7 is a modified or unmodified α-amino acid residue, A 1 is optional and, when present, is an organic group other than N-substituted leucine, and at least one of the groups A 1 to A 7 is linked via a glycosidic bond to one or more glycosidic groups each having one or more sugar residues, wherein at least one of said sugar residues is modified to bear at least one hydrophobic substituent. Methods of making these compounds, compositions including these compounds, and methods of using the compounds to treat infections in a host are also disclosed.

What is claimed is:  
     
         1 . A compound having the formula A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7  wherein each of the groups A 2  to A 7  comprises a modified or unmodified α-amino acid residue, A 1  is optional and, when present, comprises an organic group other than N-substituted leucine, and at least one of the groups A 1  to A 7  is linked via a glycosidic bond to one or more glycosidic groups each having one or more sugar residues, wherein at least one of said sugar residues is modified to bear at least one hydrophobic substituent.  
     
     
         2 . The compound of  claim 1  wherein said glycosidic group is a disaccharide modified to bear said at least one hydrophobic substituent.  
     
     
         3 . The compound of  claim 1  wherein each of the groups A 2 , A 4 , A 5 , A 6  and A 7  bears an aromatic side chain and the aromatic side chains of groups A 2  and A 6  are linked to the aromatic side chain of group A 4  via ether linkages and the aromatic side chains of groups A 5  and A 7  are linked to each other via a carbon-carbon bond.  
     
     
         4 . The compound of  claim 3  wherein the group A 4  is linked to a glycosidic group modified to bear said at least one hydrophobic substituent.  
     
     
         5 . The compound of  claim 4  wherein said glycosidic group is a disaccharide comprising a glucose residue directly bonded to group A 4  and a vancosamine residue bonded to said glucose residue.  
     
     
         6 . The compound of  claim 5  wherein A 2 -A 3 -A 4 -A 5 -A 6 -A 7  is as found in a compound selected from the group consisting of vancomycin, eremomycin, chloroeremomycin, and β-avoparcin.  
     
     
         7 . The compound of  claim 6  wherein A 2 -A 3 -A 4 -A 5 -A 6 -A 7  is as found in vancomycin.  
     
     
         8 . The compound of  claim 7  wherein the C 6  position of said glucose residue is modified to bear at least one substituent other than hydroxyl.  
     
     
         9 . The compound of  claim 8  wherein said at least one substituent other than hydroxyl is a polar substituent.  
     
     
         10 . The compound of  claim 8  wherein said at least substituent other than hydroxyl is a hydrophobic substituent.  
     
     
         11 . The compound of  claim 7  wherein the vancosamine residue in vancomycin is N-substituted with said at least one hydrophobic substituent.  
     
     
         12 . The compound of  claim 7  wherein said glucose residue is modified to bear at least one substituent other than hydroxyl and said vancosamine residue is N-substituted with said at least one hydrophobic substituent.  
     
     
         13 . The compound of  claim 12  wherein said at least one substituent other than hydroxyl is a polar substituent.  
     
     
         14 . The compound of  claim 1  wherein said at least one hydrophobic substituent is R, OR, NR 1 R, SR, SO 2 R, C(O)OR, C(O)SR, C(S)OR, C(S)SR, NR 1 C(O)R, C(O)NR 1 R, or halo and R is alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl or arylsulfonyl; R 1  is hydrogen, alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl or arylsulfonyl; and any pharmaceutically acceptable salts thereof; and if two or more of said substituents are present, they can be the same or different.  
     
     
         15 . The compound of  claim 1  wherein said organic group is selected from the group consisting of a modified or unmodified alpha amino acid residue, alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl, arylsulfonyl, guanidinyl, carbamoyl, or xanthyl.  
     
     
         16 . The compound of  claim 1  wherein the group A 7  bears a terminal carboxyl, ester, thioester, amide, N-substituted amide, or other carboxylic acid derivative.  
     
     
         17 . A method for making a compound of the formula A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7  wherein each of the groups A 2  to A 7  comprises a modified or unmodified a-amino acid residue, A 1  comprises an organic group other than N-substituted leucine, and at least one of the groups A 1  to A 7  is linked via a glycosidic bond to one or more glycosidic groups each having one or more sugar residues, wherein at least one of said sugar residues is modified to bear at least one hydrophobic substituent, said method comprising 
 removing the N-substituted leucine residue from the compound N-substituted-leucyl-A 2 -A 3 -A 4 -A 5 -A 6 -A 7  thereby forming a compound having a free amino group at A 2 ; and    attaching an organic group A 1  to the free amino group at A 2 .    
     
     
         18 . The method of  claim 17  wherein the N-substituted leucine residue is N-methyl leucine.  
     
     
         19 . The method of  claim 17  wherein said glycosidic group is a disaccharide modified to bear said at least one hydrophobic substituent.  
     
     
         20 . The method of  claim 17  wherein each of the groups A 2 , A 4 , A 5 , A 6  and A 7  bears an aromatic side chain and the aromatic side chains of groups A 2  and A 6  are linked to the aromatic side chain of group A 4  via ether linkages and the aromatic side chains of groups A 5  and A 7  are linked to each other via a carbon-carbon bond.  
     
     
         21 . The method of  claim 20  wherein the group A 4  is linked to a glycosidic group modified to bear said at least one hydrophobic substituent.  
     
     
         22 . The method of  claim 21  wherein said glycosidic group is a disaccharide comprising a glucose residue directly bonded to group A 4  and a vancosamine residue bonded to said glucose residue.  
     
     
         23 . The method of  claim 22  wherein A 2 -A 3 -A 4 -A 5 -A 6 -A 7  is as found in a compound selected from the group consisting of vancomycin, eremomycin, chloroeremomycin, and β-avoparcin.  
     
     
         24 . The method of  claim 23  wherein A 2 -A 3 -A 4 -A 5 -A 6 -A 7  is as found in vancomycin.  
     
     
         25 . The method of  claim 24  wherein the C 6  position of said glucose residue is modified to bear at least one substituent other than hydroxyl.  
     
     
         26 . The method of  claim 25  wherein said at least one substituent other than hydroxyl is a polar substituent.  
     
     
         27 . The method of  claim 25  wherein said at least substituent other than hydroxyl is a hydrophobic substituent.  
     
     
         28 . The method of  claim 24  wherein the vancosamine residue in vancomycin is N-substituted with said least one hydrophobic substituent.  
     
     
         29 . The method of  claim 24  wherein said glucose residue is modified to bear at least one substituent other than hydroxyl and said vancosamine residue is N-substituted with said least one hydrophobic substituent.  
     
     
         30 . The method of  claim 29  wherein said substituent other than hydroxyl is a polar substituent.  
     
     
         31 . The method of  claim 17  wherein said at least one hydrophobic substituent is R, OR, NR 1 R, SR, SO 2 R, C(O)OR, C(O)SR, C(S)OR, C(S)SR, NR 1 C(O)R, C(O)NR 1 R, or halo and R is alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl or arylsulfonyl; R 1  is hydrogen, alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl or arylsulfonyl; and any pharmaceutically acceptable salts thereof; and if two or more of said substituents are present, they can be the same or different.  
     
     
         32 . The method of  claim 17  wherein said organic group is selected from the group consisting of a modified or unmodified alpha amino acid residue, alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl, arylsulfonyl, guanidinyl, carbamoyl, or xanthyl.  
     
     
         33 . The method of  claim 17  wherein the group A 7  bears a terminal carboxyl, ester, thioester, amide, N-substituted amide, or other carboxylic acid derivative.  
     
     
         34 . A method for making a glycopeptide antibiotic having the formula A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7  wherein A 2 -A 3 -A 4 -A 5 -A 6 -A 7  is as found in vancomycin and AI comprises an organic group other than N-substituted leucine, said method comprising 
 modifying vancomycin to form a modified vancomycin bearing a hydrophobic substituent at the vancosamine nitrogen;    removing the N-methyl leucine residue from the modified vancomycin to form a des-N-methyl leucyl modified vancomycin bearing a free amino group at A 2 ; and    attaching an organic group A 1  to the amino group at A 2 .    
     
     
         35 . The method of  claim 34  wherein said organic group is selected from the group consisting of a modified or unmodified alpha amino acid residue, alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl, arylsulfonyl, guanidinyl, carbamoyl, or xanthyl.  
     
     
         36 . A method for making a glycopeptide antibiotic having the formula A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7  wherein A 2 -A 3 -A 4 -A 5 -A 6 -A 7  is as found in vancomycin and AI comprises an organic group other than N-substituted leucine, said method comprising 
 modifying vancomycin to form a first modified vancomycin bearing a substituent other than hydroxyl at the C 6  position of the glucose attached to A 4  of vancomycin;    modifying said first modified vancomycin to form a second modified vancomycin bearing a hydrophobic substituent at the vancosamine nitrogen;    removing the N-methyl leucine residue from said second modified vancomycin to form a des-N-methyl leucyl second modified vancomycin bearing a free amino group at A 2 ; and, attaching an organic group A 1  to the amino group at A 2 .    
     
     
         37 . The method of  claim 36  wherein said substituent other than hydroxyl is a polar substituent.  
     
     
         38 . The method of  claim 36  wherein said organic group is selected from the group consisting of a modified or unmodified alpha amino acid residue, alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl, arylsulfonyl, guanidinyl, carbamoyl, or xanthyl.  
     
     
         39 . A method for removing an N-terminal amino acid residue from an oligopeptide or polypeptide comprising reacting an oligopeptide or a polypeptide with phenylisothiocyanate in a pyridine-water-triethylamine solvent medium.  
     
     
         40 . The method of  claim 39  wherein the reaction is carried out in a 10:10:1 pyridine-water-triethylamine solvent medium.  
     
     
         41 . The method of  claim 39  wherein the reaction is carried out at a temperature in the range of from 40-70 C.  
     
     
         42 . The method of  claim 39  wherein the reaction is carried out for period of time in the range of from 20-60 minutes.  
     
     
         43 . The method of  claim 39  wherein the N-terminal amino acid residue is N-methyl leucine.  
     
     
         44 . The method of  claim 43  wherein the oligopeptide is selected from the group consisting of a glycopeptide antibiotic, a pseudoaglycone and an aglycone.  
     
     
         45 . The method of  claim 43  wherein the oligopeptide is a glycopeptide antibiotic or pseudoaglycone in which at least one glycosidic groups therein is modified to bear at least one hydrophobic substituent.  
     
     
         46 . The method of  claim 45  wherein the glycopeptide antibiotic is vancomycin.  
     
     
         47 . The method of  claim 46  wherein the disaccharide at A 4  of vancomycin is modified to bear at least one hydrophobic group.  
     
     
         48 . The method of  claim 47  wherein the vancosamine nitrogen at A 4  of vancomycin is modified to bear at least one hydrophobic group.  
     
     
         49 . The method of  claim 47  wherein the glucose residue attached directly to A 4  of vancomycin is modified to bear at least one substituent other than hydroxyl.  
     
     
         50 . The method of  claim 49  wherein said at least one hydrophobic substituent other than hydroxyl is a polar substituent or a hydrophobic substituent.  
     
     
         51 . The method of  claim 50  wherein the C 6  position of said glucose residue attached directly to A 4  of vancomycin is modified to bear a polar or a hydrophobic substituent.  
     
     
         52 . A method of treating an infectious disease in a host comprising administering to said host an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt or ester thereof.  
     
     
         53 . The method of  claim 52  wherein the host is a mammal.  
     
     
         54 . The method of  claim 53  where the mammal is a human.  
     
     
         55 . The method of  claim 52  wherein the infectious disease is a bacterial infection.  
     
     
         56 . The method of  claim 52  further comprising administering to said host an additional drug or therapeutic agent in combination with a compound of  claim 1  or a pharmaceutically acceptable salt or ester thereof.  
     
     
         57 . A composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier or excipient.  
     
     
         58 . The composition of  claim 57  further comprising an additional drug or therapeutic agent.