Polyacid glycopeptide derivatives

Details Polyacid glycopeptide derivatives Polyacid glycopeptide derivatives

2001-05-01

2004-08-03

Carlson, Karen Cochrane (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S011400, C530S317000, C530S322000

Reexamination Certificate

active

06770621

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is directed to novel polyacid derivatives of glycopeptide antibiotics and related compounds. This invention is also directed to pharmaceutical compositions containing such glycopeptide derivatives, methods of using such glycopeptide derivatives as antibacterial agents, and processes and intermediates useful for preparing such 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.
SUMMARY OF THE INVENTION
The present invention provides novel polyacid glycopeptide derivatives having highly effective antibacterial activity.
Accordingly, the invention provides a compound of the invention, which is a glycopeptide substituted at the C-terminus with a substituent that comprises two or more (e.g. 2, 3, 4, or 5) carboxy (CO
2
H) groups; or a pharmaceutically acceptable salt, or stereoisomer, or prodrug thereof.
Preferably, the substituent is attached to a carbonyl group of the C-terminus to form an amide bond, an ester bond, or a thioester bond. More preferably, the substituent is attached to a carbonyl group of the C-terminus to form an amide bond. More preferably, the substituent comprises two carboxy (CO
2
H) groups. Preferred substituents at the C-terminus include a nitrogen-linked aspartic acid or a nitrogen-linked glutamic acid.
Certain glycopeptide derivatives were disclosed by A. Malabarba, et al.,
J. Med. Chem.,
1989, 32, 2450-2460. Accordingly, the compounds of the invention may preferably exclude the glycopeptides 1) teicoplanin A2 substituted at the C-terminus with a nitrogen-linked glutamic acid, and 2) teicoplanin aglycon (TD) substituted at the C-terminus with a nitrogen-linked glutamic acid.
Other glycopeptide derivatives are also described in U.S. patent application Ser. No. 09/470,209, filed Dec. 22, 1999. Accordingly, the compounds of the invention may also preferably exclude glycopeptides of formula II:
a) wherein NR
17
is nitrogen-linked aspartic acid; R
18
is hydrogen; R
19
is hydrogen; R
20
is 2-(decylamino)ethyl; and R
21
is hydrogen;
b) wherein NR
17
is nitrogen-linked aspartic acid; R
18
is hydrogen; R
19
is hydrogen; R
20
is 2-(9-hydroxydecylamino)ethyl; and R
21
is hydrogen;
c) wherein R
17
is 1,4-dicarboxybutyl; R
18
is hydrogen; R
19
is hydrogen; R
20
is 2-(decylamino)ethyl; and R
21
is hydrogen; or
d) wherein NR
17
is nitrogen-linked aspartic acid; R
18
is hydrogen; R
19
is hydrogen; R
20
is 2-(decylamino)ethyl; and R
21
is —CH
2
—N-(D-glucamine).
The invention also preferably exclude glycopeptides of formula II:
e) wherein R
17
is nitrogen-linked aspartic acid; R
18
is hydrogen; R
19
is hydrogen; R
20
is 2-[4-(4-chlorobenzyloxy)benzylamino]ethyl; and R
21
is hydrogen;
f) wherein NR
17
is 5-(2-carboxypyrrolidin-1-ylcarbonyl)-5-(2-carboxy-3-phenylpropylamino)pentylamino; R
18
is hydrogen; R
19
is hydrogen; R
20
is 2-(decylamino)ethyl; and R
21
is hydrogen;
g) wherein NR
17
is nitrogen-linked aspartic acid; R
18
is hydrogen; R
19
is hydrogen; R
20
is 2-(decylamino)ethyl; and R
21
is —CH
2
—N—(N—CH
3
-D-glucamine);
h) wherein NR
17
is nitrogen-linked aspartic acid; R
18
is hydrogen; R
19
is hydrogen; R
20
is 2-(decylamino)ethyl; and R
21
is N-[2-(2-hydroxyethoxy)ethyl]-aminomethyl; or
i) wherein NR
17
is nitrogen-linked aspartic acid; R
18
is hydrogen; R
19
is hydrogen; R
20
is 2-(4-isobutylbenzyl)ethyl; and R
21
is N-[2-(2-hydroxyethoxy)ethyl]aminomethyl.
A preferred compound of the invention is a glycopeptide of formula I:
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 a nitrogen-linked, oxygen-linked, or sulfur-linked substituent comprising two or more carboxy groups;
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
)—R
x
, —CH(R
c
)—NR
c
—Ra—C(═O)—R
x
, and —CH(R
c
)—NR
c
—R
a
—Y—R
b
—(Z)
x
;
R
6
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 —NR
c
—R
a
—Y—R
b
—(Z)
x
, or R
5
and R
6
can be joined, together with the atoms to which they are attached, form a heterocyclic ring optionally substituted with —NR
c
—R
a
—Y—R
b—(Z)
x
;
R
7
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —R
a
—Y—R
b
—(Z)
x
, and —C(O)R
d
;
R
8
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 and heterocyclic;
R
9
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitut

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