Polyhydroxy glycopeptide derivatives

Details Polyhydroxy glycopeptide derivatives Polyhydroxy glycopeptide derivatives

2001-05-01

2004-12-07

Carlson, Karen Cochrane (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S011400, C530S317000, C530S395000, C530S322000

Reexamination Certificate

active

06828299

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is directed to novel polyhydroxy derivatives of glycopeptide antibiotics and related compounds. This invention is also directed to pharmaceutical compositions containing such polyhydroxy glycopeptide derivatives, methods of using such polyhydroxy glycopeptide derivatives as antibacterial agents, and processes and intermediates useful for preparing such polyhydroxy 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 polyhydroxy glycopeptide derivatives having highly effective antibacterial activity and an improved mammalian safety profile. More specifically, the polyhydroxy 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 of formula I:
wherein:
R
1
is an amino containing saccharide group substituted on the amine with a substituent that comprises two or more (e.g. 2, 3, 4, 5, or 6) hydroxy (OH) groups;
R
2
is hydrogen or a saccharide group optionally substituted with —R
a
—Y—R
b
(Z)
x
, R
f
, —C(O)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
C
R
e
, or —O—R
e
;
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
c
, —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
;
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, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
R
10
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; or R
8
and R
10
are joined to form —Ar
1
—O—Ar
2
—, where Ar
1
and Ar
2
are independently arylene or heteroarylene;
R
11
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, or R
10
and R
11
are joined, together with the carbon and nitrogen atoms to which they are attached, to form a heterocyclic ring;
R
12
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, —C(O)R
d
, —C(NH)R
d
, —C(O)NR
c
R
c
, —C(O)OR
d
, —C(NH)NR
c
R
c
and —R
a
—Y—R
b
—(Z)
x
, or R
11
and R
12
are joined, together with the nitrogen atom to which they are attached, to form a heterocyclic ring;
R
13
is selected from the group consisting of hydrogen or —OR
14
;
R
14
is selected from hydrogen, —C(O)R
d
and a saccharide group;
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 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;
R
e
is a saccharide group;
each R
f
is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocyclic;
R
x
is a nitrogen-linked amino saccharide or a nitrogen-linked het

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