Vancomycin analogs

Details Vancomycin analogs Vancomycin analogs

2001-03-28

2004-03-02

Tate, Christopher R. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S001000, C514S008100, C514S023000, C530S322000, C536S016800

Reexamination Certificate

active

06699836

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to vancomycin analogs having antibacterial activity; methods of making vancomycin analogs having antibacterial activity; and, methods of treating a bacterial infection in a host with a vancomycin analog having antibacterial activity.
BACKGROUND OF THE INVENTION
Vancomycin is a very important drug for the treatment of gram positive infections. It has been proposed that vancomycin works by binding to the D-ala-D-ala termini of Lipid II molecules and/or to nascent peptidoglycan, preventing maturation of the cell wall. Vancomycin is used to treat infections that are resistant to antibiotics. Hence, vancomycin has been called the “drug of last resort” because it is often the last remaining option for the treatment of gram positive infections caused by strains that have become resistant to all other antibiotics.
Resistance to vancomycin first appeared about fifteen years ago and the frequency of resistance is increasing. There have been numerous efforts to develop vancomycin analogs that overcome this resistance. For example, it has been reported that certain derivatives of vancomycin containing hydrophobic substituents at the vancosamine nitrogen are active against vancomycin resistant enterococcal strains. The inventors of the present application have also reported activity against resistant and sensitive strains of vancomycin analogs in which the C6 position of the glucose residue directly attached to amino acid four of the heptapeptide chain of vancomycin is modified to bear a substituent other than a naturally occuring hydroxyl and the vancosamine nitrogen is optionally modified. In some cases, compounds in which both the C6 position of the glucose residue and the vancosamine nitrogen are modified are more active than the singly substituted parent compounds, and even have good activity against staphylococcal strains.
Attempts have been made to modify the terminal carboxyl group of the peptide chain in certain glycopeptide antibiotics. For example, terminal carboxyl group modifications to vancomycin, chloroeremomycin and teicoplanin derivatives have been reported. U.S. Pat. No. 5,919,756, incorporated herein in its entirety, discloses amide modifications of the terminal carboxyl group in chloroeremomycin in combination with modifications to the vancosamine nitrogen. U.S. Pat. No. 5,194,424, incorporated herein in its entirety, discloses amide modifications of the terminal carboxyl group in certain teicoplanin derivatives. The present inventors are unaware of any reported vancomycin analogs in which both the terminal carboxyl group of the heptapeptide chain and the vancosamine nitrogen of vancomycin are modified, and in which the C6 position of the glucose residue directly attached to amino acid four of the heptapeptide chain is optionally modified to bear a substituent other than a naturally occurring hydroxyl group.
It is believed that substitution of the vancosamine nitrogen, especially with a hydrophobic substituent, generally reduces solubility of the compound relative to the unsubstituted vancomycin parent compound. Delivery of these vancosamino-substituted compounds is complicated by the decreased solubility of these compounds, particularly through intravenous delivery routes. While not wishing to be bound by theory, the present inventors believe that this decreased solubility may be mitigated by modification of the terminal carboxyl group in vancomycin also bearing a vancosamine nitrogen substituent. Additional modifications may also be made, particularly to the C6 position of the glucose residue directly attached to amino acid four in the heptapeptide chain of vancomycin. These additional modifications may also improve the physical properties (i.e. solubility) and or activity of the compounds of the present invention relative to known vancomycin analogs.
DEFINITIONS
A “glycoconjugate” comprises any molecule linked to at least one carbohydrate of any size. The molecule can be a peptide or protein, a nucleic acid, a small molecule, a lipid, or another carbohydrate; it may be of natural or non-natural origin.
A “glycopeptide” is a glycoconjugate comprising a peptide linked to at least one carbohydrate.
A “glycopeptide antibiotic” is a glycopeptide having antibacterial activity, including, e.g., vancomycin, eremomycin, chloroeremomycin and &bgr;-avoparcin as well as any synthetic and semi-synthetic derivatives thereof. The term “glycopeptide antibiotic” is meant to encompass any naturally occurring antibiotic as well semi-synthetic derivatives thereof.
An “aglycone” is the result of removing the carbohydrate residues from a glycopeptide, leaving only a peptide core.
A “pseudoaglycone” is the result of removing only one of two sugar residues from a disaccharide residue linked to amino acid residue four of the peptide chain of glycopeptide. Thus, a pseudoaglycone comprises an aglycone in which amino acid four of the peptide chain is linked to a monosaccharide residue.
A “dalbaheptide” is a glycopeptide containing a heptapeptide moiety which is held in a rigid conformation by cross-links between the aromatic substituent groups of at least five of the seven &agr;-amino acid residues, including a cross-link comprising a direct carbon—carbon bond between the aryl substituents of amino acid residues 5 and 7, and aryl ether cross-links between the substituents of amino acid residues 2 and 4, and 4 and 6. Amino acid residues 2 and 4-7 in different dalbaheptides are those found in the naturally occurring glycopeptide antibiotics. These amino acid residues differ only in that residues 2 and 6 do not always have a chlorine substituent on their aromatic rings, and in that substitution on free hydroxyl or amino groups may be present. Amino acids residues 1 and 3 may differ substantially in different dalbaheptides; if both bear aryl substituents, these may be cross-linked. Molecules having a dalbaheptide structure include, e.g., the glycopeptide antibiotics mentioned above.
The term “alkyl” refers to a linear or branched acyclic or non-aromatic cyclic group having from one to twenty carbon atoms connected by single or multiple bonds. Thus, the term “alkyl” is meant to encompass linear or branched acyclic or non-aromatic groups having one or more carbon—carbon double or triple bonds, i.e., alkenyl and alkynyl groups. An alkyl group may be substituted by one or more of halo, hydroxyl, protected hydroxyl, amino, protected amino, nitro, cyano, alkoxy, aryloxy, aralkyloxy, COOH, aroyloxy, alkylamino, dialkylamino, trialkylammonium, alkylthio, arylthio, alkanoyl, alkanoyloxy, alkanoylamido, alkylsulfonyl, arylsulfonyl, aroyl, aralkanoyl, heterocyclic, CONH
2
, CONH-alkyl, CON(alkyl)
2
, COO-aralkyl, COO-aryl or COO-alkyl.
The term “cycloalkyl” embraces substituents having from four to ten carbon atoms, such as cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl which may be unsubstituted or substituted with any of the groups with which alkyl may be substituted. This term also embraces C
5
to C
10
cycloalkenyl groups such as cyclopentenyl and cyclohexenyl. The term “cycloalkyl” also embraces bicyclic and tricyclic cycloalkyls such as bicyclopentyl, bicylohexyl, bicycloheptyl, and adamantyl.
The term “aryl” refers to a group derived from a non-heterocyclic aromatic compound having from six to twenty carbon atoms and from one to four rings which may be fused or connected by single bonds. An aryl group may be substituted by one or more of alkyl, aralkyl, heterocyclic, heterocyclic-alkyl, heterocyclic-carbonyl, halo, hydroxyl, protected hydroxyl, amino, protected amino, hydrazino, alkylhydrazino, nitro, cyano, alkoxy, aryloxy, aralkyloxy, aroyloxy, alkylamino, dialkylamino, trialkylammonium, alkylthio, arylthio, alkanoyl, alkanoyloxy, alkanoylamido, alkylsulfonyl, arylsulfonyl, aroyl, aralkanoyl, COO-alkyl, COO-aralkyl, COO-aryl, CONH
2
, CONH-alkyl or CON(alkyl)
2
. Examples of fused aryl groups include, e.g., fluorenyl, naphthyl, anthranyl, phenanthranyl, biphenylene and pyrenyl.
The term “aralkyl” refers to an alkyl group substituted by an a

Affiliated with

Also associated with

Rating

Vancomycin analogs does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Vancomycin analogs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Vancomycin analogs will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3251039