Glycopeptide derivatives and pharmaceutical compositions...

Details Glycopeptide derivatives and pharmaceutical compositions... Glycopeptide derivatives and pharmaceutical compositions...

2000-11-01

2002-09-24

Low, Christopher S. F. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Cyclic peptides

C530S322000, C514S008100, C514S011400

Reexamination Certificate

active

06455669

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel derivatives of glycopeptide antibiotics. This invention also relates to pharmaceutical compositions containing such glycopeptide derivatives, to methods of using such glycopeptide derivatives as antibacterial agents, and to processes for preparing such glycopeptide derivatives.
2. Background
Glycopeptides are a well-known class of antibiotics produced by various microorganisms. These complex multi-ring peptide compounds are effective antibacterial agents against a majority of Gram-positive bacteria. The use of glycopeptides as antibiotics, however, has been overshadowed by the semi-synthetic penicillins, cephalosporins and lincomycin due to the higher levels of mammalian toxicity observed with the glycopeptides. In recent years, however, bacteria resistant to the penicillins, cephalosporins and the like have emerged resulting in, for example, multiple-resistant and methicillin-resistant staphylococcal (MRS) infections. Glycopeptides, such as vancomycin, are typically effective against such microorganisms and vancomycin has become the drug of last resort for MRS and other infections. The glycopeptides are believed to be effective against such resistant microorganism because they have a different mode of action than other antibiotics. In this regard, the glycopeptides are believed to selectively inhibit a different step in bacterial cell wall synthesis than the penicillin-type antibiotics.
More specifically, the cell wall of bacteria consists of linear polysaccharide chains cross-linked by short peptides. This arrangement of cross-linked polysaccharides confers mechanical support to the cell wall, thus preventing the bacteria from bursting due to its high internal osmotic pressure. During the synthesis of the bacterial cell wall, cross-linking of the polysaccharides takes place after lipid-linked disaccharide-pentapeptide constructs are incorporated into linear polysaccharide chains by a transglycolase enzyme. The subsequent cross-linking reaction is the last step in the synthesis of the cell wall and is catalyzed by an enzyme known as peptidoglycan transpeptidase.
One method by which antibacterial agents exert their antibacterial activity is by inhibiting the transglycosylase enzyme, thus interfering with the penultimate step in the synthesis of the bacterial cell wall. Although not wishing to be bound by theory, it is believed that glycopeptide antibiotics, such as vancomycin, bind with high affinity and specificity to N-terminal sequences (i.e., L-lysyl-D-alanyl-D-alanine in vancomycin-sensitive organisms) of the peptidoglycan precursors (known as lipid intermediate II). By binding to and sequestering these precursors, vancomycin prevents their utilization in cell wall biosynthesis. Thus, vancomycin inhibits the bacterial transglycosylase that is responsible for adding lipid intermediate II subunits to growing peptidoglycan chains. This step of bacterial cell wall synthesis preceeds the cross-linking transpeptidation step which is known to be inhibited by beta-lactams antibiotics. It is also believed that vancomycin inhibits transpeptidation which involves the D-alanyl-D-alanine termini. However, since this step occurs subsequent to transglycosylation, inhibition of transpeptidation is not directly observed.
A number of derivatives of vancomycin and other glycopeptides are known in the art. For example, see U.S. Pat. Nos. 4,639,433; 4,643,987; 4,497,802; 4,698,327; 5,591,714; 5,840,684; and 5,843,889. Other derivatives are disclosed in EP 0 802 199; EP 0 801 075; EP 0 667 353; WO 97/28812; WO 97/38702; WO 98/52589; WO 98/52592; and in
J. Amer. Chem. Soc
., 1996, 118, 13107-13108
; J. Amer. Chem. Soc
., 1997, 119, 12041-12047; and
J. Amer. Chem. Soc
., 1994, 116, 45734590. The disclosures of these and other documents referred to throughout this application are incorporated herein by reference in their entirety.
A need exists, however, for glycopeptide derivatives having improved activity, selectivity and reduced mammalian toxicity. Moreover, certain microorganisms are beginning to develop resistance to vancomycin, such as vancomycin-resistant enterococci (VRE). Accordingly, it would be highly desirable to provide novel glycopeptide derivatives which are effective against a broad spectrum of bacteria, including resistant strains such as VRE. Moreover, it would be highly advantageous to provide glycopeptide derivatives having improved antibacterial activity and selectivity, and low mammalian toxicity.
SUMMARY OF THE INVENTION
The present invention provides novel derivatives of glycopeptide antibiotics having improved properties compared to the unsubstituted glycopeptide, including enhanced activity, selectivity and reduced mammalian toxicity. For example, certain vancomycin derivatives of this invention demonstrate greatly enhanced antibacterial activity compared to vancomycin itself. Such vancomycin derivatives are also highly effective against vancomycin-resistant enterococci strains while exhibiting reduced mammalian toxicity.
Accordingly, in one of its composition aspects, this invention provides a glycopeptide compound having at least one substituent of the formula:
—R
a
—Y—R
b
—(Z)
x
wherein
each R
a
is independently selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene;
each R
b
is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene, provided R
b
is not a covalent bond when Z is hydrogen;
each Y is independently selected from the group consisting of oxygen, sulfur, —S—S—, —NR
c
—, —S(O)—, —SO
2
—, —NR
c
C(O)—, —OC(O)—, —NR
c
SO
2
—, —OSO
2
—, —C(O)NR
c
—, —C(O)O—, —SO
2
NR
c
—, —SO
2
O—, —P(O)(OR
c
)O—, —P(O)(OR
c
)NR
c
—, —OP(O)(OR
c
)O—, —OP(O)(OR
c
)NR
c
—, —OC(O)O—, —NR
c
C(O)O—, —NR
c
C(O)NR
c
—, —OC(O)NR
c
— and —NR
c
SO
2
NR
c
—;
each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
each R
c
is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and —C(O)R
d
;
each R
d
is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
x is 1 or 2;
and pharmaceutically acceptable salts thereof;
provided that:
(i) when Y is —NR
c
—, R
c
is alkyl of 1 to 4 carbon atoms, Z is hydrogen and R
b
is alkylene, then R
b
contains at least 5 carbon atoms;
(ii) when Y is —C(O)NR
c
—, Z is hydrogen and R
b
is alkylene, then R
b
contains at least 5 carbon atoms;
(iii) when Y is sulfur, Z is hydrogen and R
b
is alkylene, then R
b
contains at least 7 carbon atoms; and
(iv) when Y is oxygen, Z is hydrogen and R
b
is alkylene, then R
b
contains at least 11 carbon atoms.
Preferably, the glycopeptide compound is substituted with from 1 to 3 substituents of the formula —R
a
—Y—R
b
—(Z)
x
.
Each R
a
is preferably independently selected from alkylene having from 1 to 10 carbon atoms, more preferably, from 1 to 6 carbon atoms. In a preferred embodiment, R
a
is ethylene (—CH
2
CH
2
—), propylene (—CH
2
CH
2
CH
2
—) or butylene (—CH
2
CH
2
CH
2
CH
2
—). Still more preferably, R
a
is ethylene or propylene.
When Z is hydrogen, R
b
is preferably alkylene of from 8 to 12 carbon atoms. Accordingly, in this embodiment, R
b
and Z preferably form an n-octyl, n-nonyl, n-decyl, n-undecyl or n-dodecyl group. When Z is other than hydrogen, R
b
is preferably a covalent bond or alkylene of from 1 to 10 carbon atoms. In this embodiment, R
b
is preferably, a covalent bond, methylene, —(CH
2
)
6
—, —(CH
2
)
7
—, —(CH
2
)
8
—, —(CH
2
)
9
— or —(CH
2
)
10
—.

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