Desleucyl glycopeptide antibiotics and methods of making same

• US 6,518,243 B1
• Filed: 03/31/2000
• Issued: 02/11/2003
• Est. Priority Date: 04/02/1999
• Status: Expired due to Fees

• Current Assignee: The Trustees of Princeton University (Princeton University)
• Original Assignee: The Trustees of Princeton University (Princeton University)
• Inventors: Kahne, Daniel, Walker, Suzanne
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US09/540,761
• Time in Patent Office: 1,047 Days
• Field of Search: 436/89, 436/90, 514/7, 514/8, 514/9, 514/11, 514/16, 514/17, 530/322, 530/343, 530/345
• US Class Current: 514/2.4
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 9/008 directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin

Abstract

Compounds that are analogs of glycopeptide antibiotics are disclosed. The compounds have the formula A₁-A₂-A₃-A₄-A₅-A₆-A₇ wherein each of the groups A₂ to A₇ is a modified or unmodified α-amino acid residue, A₁ is optional and, when present, is an organic group other than N-substituted leucine, and at least one of the groups A₁ to A₇ 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.

Claims

1. A compound having the formula A₁-A₂-A₃-A₄-A₅-A₆-A₇ wherein each of the groups A₂ to A₇ comprises a modified or unmodified α

-amino acid residue, A₁ is optional and, when present, comprises an organic group-other than N-substituted leucine, and at least one of the groups A₁ to A₇ 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 one or more glycosidic groups comprises a glucose residue with the C₆ position of said glucose residue modified to bear at least one substituent other than hydroxyl, and wherein at least one of said sugar residues is modified to bear at least one hydrophobic substituent.

2. The compound of claim 1 wherein at least one of said one or more glycosidic groups is a disaccharide modified to bear said at least one hydrophobic substituent.

3. The compound of claim 1 wherein each of the groups A₂, A₄, A₅, A₆ and A₇ bears an aromatic side chain and the aromatic side chains of groups A₂ and A₆ are linked to the aromatic side chain of group A₄ via ether linkages and the aromatic side chains of groups A₅ and A₇ are linked to each other via a carbon-carbon bond.

4. The compound of claim 3 wherein the group A₄ is linked to a glycosidic group modified to bear said at least one hydrophobic substituent.

5. The compound of claim 4 wherein at least one of said one or more glycosidic groups is a disaccharide comprising a glucose residue directly bonded to group A₄ and a vancosamine residue bonded to said glucose residue.

6. The compound of claim 5 wherein A₂-A₃-A₄-A₅-A₆-A₇ 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 A₂-A₃-A₄-A₅-A₆-A₇ is as found in vancomycin.

8. The compound of claim 1 wherein said at least one substituent other than hydroxyl is a polar substituent.

9. The compound of claim 1 wherein said at least one substituent other than hydroxyl is a hydrophobic substituent.

10. The compound of claim 7 wherein the vancosamine residue in vancomycin is N-substituted with said at least one hydrophobic substituent.

11. The compound of claim 7 wherein said glucose residue directly bonded to group A₄ 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.

12. The compound of claim 11 wherein said at least one substituent other than hydroxyl is a polar substituent.

13. The compound of claim 1 wherein said at least one hydrophobic substituent is R, OR, NR₁R, SR, SO₂R, C(O)OR, C(O)SR, C(S)OR, C(S)SR, NR₁C(O)R, C(O)NR₁R, or their halogen substituted derivatives and R is alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl or arylsulfonyl;

R₁ 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

when two or more of said substituents are present, they are the same or different.

14. 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, and xanthyl.

15. The compound of claim 1 wherein the group A₇ bears a terminal carboxyl, ester, thioester, amide, N-substituted amide, or other carboxylic acid derivative.

35. A method of treating a gram-positive bacterial infection 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.

36. The method of claim 35 wherein the host is a mammal.

37. The method of claim 36 where the mammal is a human.

38. The method of claim 35 further comprising administering to said host one or more additional drugs or therapeutic agents in combination with a compound of claim 1 or a pharmaceutically acceptable salt or ester thereof.

39. A composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier or excipient.

40. The composition of claim 39 further comprising one or more additional drugs or therapeutic agents.

16. A method for making a compound of the formula A₁-A₂-A₃-A₄-A₅-A₆-A₇ wherein each of the groups A₂ to A₇ comprises a modified or unmodified α

-amino acid residue, A₁ comprises an organic group other than N-substituted leucine, and at least one of the groups A₁ to A₇ 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 one or more glycosidic groups comprises a glucose residue with the C₆ position of said glucose residue modified to bear at least one substituent other than hydroxyl, and 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-A₂-A₃-A₄-A₅-A₆-A₇ thereby forming a compound having a free amino group at A₂; and

attaching an organic group A₁ to the free amino group at A₂.

17. The method of claim 16 wherein the N-substituted leucine residue is N-methyl leucine.

18. The method of claim 16 wherein at least one of said one or more glycosidic groups is a disaccharide modified to bear said at least one hydrophobic substituent.

19. The method of claim 16 wherein each of the groups A₂, A₄, A₅, A₆ and A₇ bears an aromatic side chain and the aromatic side chains of groups A₂ and A₆ are linked to the aromatic side chain of group A₄ via ether linkages and the aromatic side chains of groups A₅ and A₇ are linked to each other via a carbon-carbon bond.

20. The method of claim 19 wherein the group A₄ is linked to a glycosidic group having one or more sugar residues modified to bear said at least one hydrophobic substituent.

21. The method of claim 20 wherein said glycosidic group is a disaccharide comprising a glucose residue directly bonded to group A₄ and a vancosamine residue bonded to said glucose residue.

22. The method of claim 21 wherein A₂-A₃-A₄-A₅-A₆-A₇ is as found in a compound selected from the group consisting of vancomycin, eremomycin, chloroeremomycin, and β

-avoparcin.

23. The method of claim 22 wherein A₂-A₃-A₄-A₅-A₆-A₇ is as found in vancomycin.

24. The method of claim 16 wherein said at least one substituent other than hydroxyl is a polar substituent.

25. The compound of claim 16 wherein said at least one substituent other than hydroxyl is a hydrophobic substitutent.

26. The method of claim 23 wherein the vancosamine residue in vancomycin is N-substituted with said least one hydrophobic substituent.

27. The method of claim 23 wherein said glucose residue directly bonded to group A₄ is modified to bear at least one substituent other than hydroxyl and said vancosamine residue is N-substituted with said least one hydrophobic substituent.

28. The method of claim 27 wherein said substituent other than hydroxyl is a polar substituent.

29. The method of claim 16 wherein said at least one hydrophobic substituent is R, OR, NR₁R, SR, SO₂R, C(O)OR, C(O)SR, C(S)OR, C(S,)SR, NR₁C(O)R, C(O)NR₁R, or their halogen substituted derivatives and R is alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl or arylsulfonyl;

R₁ 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

when two or more of said substituents are present, they are the same or different.

30. The method of claim 16 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, and xanthyl.

31. The method of claim 16 wherein the group A₇ bears a terminal carboxyl, ester, thioester, amide, N-substituted amide, or other carboxylic acid derivative.

32. A method for making a glycopeptide antibiotic having the formula A₁-A₂-A₃-A₄-A₅-A₆-A₇ wherein A₂-A₃-A₄-A₅-A₆-A₇ is as found in vancomycin and A₁ 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 C₆ position of the glucose attached to A₄ 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 A₂; and

,

attaching an organic group A₁ to the amino group at A₂.

33. The method of claim 32 wherein said substituent other than hydroxyl is a polar substituent.

34. The method of claim 32 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, and xanthyl.