Glycopeptide carboxy-saccharide derivatives

Details Glycopeptide carboxy-saccharide derivatives Glycopeptide carboxy-saccharide derivatives

2001-05-01

2003-09-16

Russel, Jeffrey E. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S322000

Reexamination Certificate

active

06620781

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is directed to novel saccharide derivatives of glycopeptide antibiotics and related compounds. This invention is also directed to pharmaceutical compositions containing such saccharide glycopeptide derivatives, methods of using such saccharide glycopeptide derivatives as antibacterial agents, and processes and intermediates useful for preparing such saccharide glycopeptide derivatives.
2. Background
Glycopeptides (e.g. dalbaheptides) are a well-known class of antibiotics produced by various microorganisms (see
Glycopeptide Antibiotics,
edited by R. Nagarajan, Marcel Dekker, Inc. New York (1994)). These complex multi-ring peptide compounds are very effective antibacterial agents against a majority of Gram-positive bacteria. Although potent antibacterial agents, the glycopeptides antibiotics are not used in the treatment of bacterial diseases as often as other classes of antibiotics, such as the semi-synthetic penicillins, cephalosporins and lincomycins, due to concerns regarding toxicity.
In recent years, however, bacterial resistance to many of the commonly-used antibiotics has developed (see J. E. Geraci et al.,
Mayo Clin. Proc.
1983, 58, 88-91; and M. Foldes,
J. Antimicrob. Chemother.
1983, 11, 21-26). Since glycopeptide antibiotics are often effective against these resistant strains of bacteria, glycopeptides such as vancomycin have become the drugs of last resort for treating infections caused by these organisms. Recently, however, resistance to vancomycin has appeared in various microorganisms, such as vancomycin-resistant enterococci (VRE), leading to increasing concerns about the ability to effectively treat bacterial infections in the future (see Hospital Infection Control Practices Advisory Committee,
Infection Control Hospital Epidemiology,
1995, 17, 364-369; A. P. Johnson et al.,
Clinical Microbiology Rev.,
1990, 3, 280-291; G. M. Eliopoulos,
European J. Clinical Microbiol., Infection Disease,
1993, 12, 409-412; and P. Courvalin,
Antimicrob. Agents Chemother,
1990, 34, 2291-2296).
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, 4573-4590.
Despite the above referenced disclosures, a need currently exists for novel glycopeptide derivatives having effective antibacterial activity and an improved mammalian safety profile. In particular, a need exists for glycopeptide derivatives which are effective against a wide spectrum of pathogenic microorganisms, including vancomycin-resistant microorganisms, and which have reduced tissue accumulation and/or nephrotoxicity.
SUMMARY OF THE INVENTION
The present invention provides novel saccharide glycopeptide derivatives having highly effective antibacterial activity and an improved mammalian safety profile. More specifically, the saccharide glycopeptide derivatives of the invention unexpectedly exhibit reduced tissue accumulation and/or nephrotoxicity when administered to a mammal.
Accordingly, the invention provides a compound of the invention, which is a glycopeptide substituted at the C-terminus and/or the R-terminus with a substituent that comprises one or more (e.g. 1, 2, 3, 4, or 5) saccharide groups and a carboxy (COOH) group; or a pharmaceutically acceptable salt, or stereoisomer, or prodrug thereof.
One preferred group of compounds of the invention are glycopeptides substituted at either the C-terminus or the R-terminus with a substituent that comprises a saccharide and a carboxy group. Another preferred group of compounds of the invention are glycopeptides substituted at the C-terminus and the R-terminus with a substituent that comprises a saccharide and a carboxy group. Such saccharide/carboxy containing substituents can be derived from a dicarboxylic acid or a derivative thereof by coupling one of the carboxy groups with a saccharide.
Preferably, when the glycopeptide is substituted at the C-terminus, the substituent is attached through an amide bond, an ester bond, or a thioester bond. Preferably, a nitrogen-linked substituent is attached to the carbonyl group at the C-terminus to form an amide bond. Preferably, the C-terminus substituent comprises one saccharide group and one carboxy group.
Preferably, the glycopeptide is substituted at the C-terminus with a substituent of the formula —N(R
w
)—R
y
—R
x
; wherein R
w
is hydrogen or alkyl; R
y
is substituted alkylene, which is substituted with a carboxy group; and R
x
is a saccharide.
A preferred C-terminus substituent that comprises one saccharide group and one carboxy group is a substituent of formula III:
wherein one of R
g
and R
h
is a saccharide, and the other of R
g
and R
h
is OH. Preferably, when R
g
or R
h
is a saccharide it is a N-linked or O-linked saccharide.
Preferably, when the glycopeptide is substituted at the R-terminus, the substituent is attached to the nitrogen of an aminomethyl group that is attached to the R-terminus (i.e. the resorcinol ring). Preferably, the R-terminus substituent comprises one saccharide group and one carboxy group.
Preferably, the glycopeptide is substituted at the R-terminus with a substituent of the formula —CH
2
—N(R
w
)—R
y
—R
x
; wherein R
w
is hydrogen or alkyl; R
y
is substituted alkylene, which is substituted with a carboxy group; and R
x
is a saccharide.
A preferred R-terminus substituent that comprises one saccharide group and one carboxy group is a substituent of formula IV:
wherein one of R
m
and R
n
is a saccharide, and the other is OH. Preferably, when R
m
or R
n
is a saccharide it is a N-linked or O-linked saccharide.
Another preferred R-terminus substituent is a substituent of formula V:
Certain glycopeptide derivatives are described in U.S. patent application Ser. No. 09/470,209, filed Dec.22, 1999. Accordingly, the compounds of the invention may preferably exclude glycopeptides of formula II:
Certain glycopeptide derivatives are described in U.S. patent application Ser. No. 09/470,209, filed Dec. 22, 1999 (U.S. Pat. No. 6,392,012). Accordingly, the compounds of the invention may preferably exclude glycopeptides of formula II:
wherein: R
19
is hydrogen and
a) wherein R
3
is N-(2-amino-2-deoxygluconic acid); R
5
is hydrogen; R
19
is hydrogen; and R
20
is —NH—CH
2
CH
2
—NH—(CH
2
)
9
CH
3
; or
b) wherein R
3
is OH; R
5
is —CH
2
—N—(2-amino-2-deoxycluconic acid); R
19
is hydrogen; and R
20
is —CH
2
CH
2
—NH—(CH
2
)
9
CH
3
.
wherein:
R
1
is 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 —R
a
—Y—R
b
—(Z)
x
; or R
1
is a saccharide group optionally substituted with —R
a
—Y—R
b
—(Z)
x
, R
f
, —C(O)R
f
, or —C(O)—R
a
—Y—R
b
—(Z)
x
;
R
2
is hydrogen or a saccharide group optionally substituted with —R
a
—Y—R
b
—(Z)
x
, R
f
, —C(O)R
f
, or —C(O)—R
a
—Y—R
b
—(Z)
x
;
R
3
is —OR
c
, —NR
c
R
c
, —O—R
a
—Y—R
b
—(Z)
x
, —NR
c
—R
a
—Y—R
b
—(Z)
x
, —NR
2
, or —O—R
e
; or R
3
is a substituent that comprises a saccharide group and a carboxy group;
R
4
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —R
a
—Y—R
b
—(Z)
x
, —C(O)R
d
and a saccharide group optionally substituted with —R
a
—Y—R
b
—(Z)
x
, R
f
, —C(O)R
f
, or —C(O)—R
a
—Y—R
b
—(Z)
x
;
R
5
is selected from the group consisting of hydrogen, halo, —CH(R
c
)—NR
c
R
c
, —CH(R
c
)—NR
c
R
e
, —CH(R
c
)—NR
c
—R
a
—Y—R
b
—(Z)
x
,—CH(R
c
)—R
x
, and —CH(R
c
)—NR
c
—R
a
—C(═O)—R
x
, or R
5
is substituent that comprises a saccharide group and a carboxy group;
R
6
is s

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