Derivatives of laspartomycin and preparation and use thereof

Details Derivatives of laspartomycin and preparation and use thereof Derivatives of laspartomycin and preparation and use thereof

2001-01-12

2003-01-28

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C435S068100, C435S071300, C530S317000

Reexamination Certificate

active

06511962

ABSTRACT:

1. FIELD OF THE INVENTION
The present invention relates generally to antibiotics and antimicrobial derivatives. More particularly, the present invention relates to intermediates useful for synthesizing laspartomycin derivatives as well as the laspartomycin derivatives.
2. BACKGROUND OF THE INVENTION
Laspartomycin (Umezawa et al., U.S. Pat. No. 3,639,582; Naganawa et al., 1968
, J. Antibiot
., 21, 55; Naganawa et al., 1970
, J. Antibiot
., 23, 423 which are herein incorporated by reference) is closely related to antibiotics such as zaomycin (Kuroya, 1960
, Antibiotics Ann
., 194; Kuroya, JP 8150), crystalomycin (Gauze et al., 1957
, Antibiotiki
, 2, 9), aspartocin (Shay et al., 1960
, Antibiotics Annual
, 194; Hausman et al., 1964
, Antimicrob. Ag. Chemother
., 352; Hausman et al., 1969
, J. Antibiot
., 22, 207; Martin et al., 1960
, J. Am. Chem. Soc
., 2079), amphomycin (Bodanszky et. al., 1973
, J. Am. Chem. Soc
., 95, 2352), glumamycin (Fujino et al., 1965
, Bull. Chem. Soc. Jap
., 38, 515), daptomycin (Debono et. al., 1988
, J. Antibiotics
, 41, 1093), Antibiotic A-1437 (Hammann et. al., EP 0 629 636 B1; Lattrell et al., U.S. Pat. No. 5,629,288), Antibiotic A54145 (Fukada et al., U.S. Pat. No. 5,039,789; Boeck et al., 1990
, J. Antibiotics
, 43, 587), and tsushimycin (Shoji et. al., 1968
, J. Antibiot
., 21, 439). The above compounds are lipopeptide antibiotics which typically inhibit gram positive bacteria. Generally, lipopeptide antibiotics consist of either a cyclic core peptide or a cyclic core depsipeptide acylated with a lipophilic fragment such as an unsaturated fatty acid.
Laspartomycin, produced by fermenting the microorganism
Streptomyces viridochromogenes
var.
komabensis
, was first isolated while screening for compounds active against resistant staphylococci (Naganawa et al., 1968
, J. Antibiot
., 21, 55; Umezawa et al., U.S. Pat. No. 3,639,582). Laspartomycin was characterized by conventional methods and was shown to be active against a variety of gram positive bacteria, including staphylococci and some fungi (id.). Elemental analysis and amino acid analysis provided a molecular weight of about 1827 for the lipopeptide antibiotic, while amino acid analysis indicated the presence of the amino acids threonine and diaminobutryic acid in the peptide portion of laspartomycin (id.).
In other studies, the major lipophilic fragment of laspartomycin was shown to be trans-2-isopentadecanoic acid 2, illustrated below (Naganawa et al., 1970
, J. Antibiot
. 23, 423). In contrast, the lipophilic portions of antibiotics such as aspartocin (Hausmann et al., 1963
, Antimicr. Agents
&
Chemoth
., 352, 1962), glumamycin (Inoue, 1962
, Bull. Chem. Soc. Jap
., 35, 1255), tsushimycin (Shoji et al., 1968
, J. Antibiot
., 21, 439) and amphomycin (Shoji et al., 1969
, J. Antibiot
., 22, 473) are all derived from cis &bgr;-&ggr; unsaturated carboxylic acids.
The results described in the instant Application indicate that the amino acid analysis and the molecular weight disclosed in the art are incorrect (Umezawa et al., U.S. Pat. No. 3,639,582; Naganawa et al., 1968
, J. Antibiot
., 21, 55). In particular current studies disclosed in this Application show that the peptide core of laspartomycin contains novel amino acids not found in other known lipopeptide antibacterial antibiotics. For example, laspartomycin is the only member of the antibacterial lipopeptide family that contains diaminopropionic acid in the peptide core. Amphomycin, aspartocin, zaomycin, tsushimycin, and antibiotic A-1437 contain, instead, 2,3-diaminobutyric acid in the peptide portion of the molecule (Kuroya, 1960
, Antibiotics Ann
., 194; Gauze et al.,1957
, Antibiotiki
, 2, 9; Shay et al., 1960
, Antibiotics Annual
, 194-198; Hausman et al., 1964
, Antimicrob. Ag. Chemother
., 352; Hausman et al., 1969
, J. Antibiot
., 22, 207; Martin et al., 1960
, J. Am. Chem. Soc
., 2079; Bodanszky et. al., 1973
, J. Am. Chem. Soc
., 95, 2352; Fujino et al., 1965
, Bull. Chem. Soc. Jap
., 38, 515; Hammann et. al., EP 0 629 636 B1; Lattrell et al., U.S. Pat. No. 5,629,288; Shoji et al., 1968
, J. Antibiot
., 21, 439). Additionally, laspartomycin contains allothreonine, which is not found in the other known lipopeptides. Further laspartomycin is the smallest of the known lipopeptides with a molecular weight of about 1247 for the cyclic core peptide acylated with compound 2.
Despite the efficacy of laspartomycin against gram positive bacteria, the medicinal chemistry of this lipopeptide antibacterial antibiotic has remained largely unexplored. However, given the recent dramatic rise of antibiotic-resistant pathogens and infectious diseases, caused in part, by frequent over use of antibiotics, the need for new antimicrobial agents is urgent (Cohen et al., 1992
, Science
, 257, 1050-1055). Specifically, methicillin resistant bacteria are a particular problem since they are also resistant to a wide variety of antibiotics other than methicillin (Yoshida et al., U.S. Pat. No. 5,171,836). Gram positive bacteria, such as Staphylococci, which cause persistent infections, are especially dangerous when methicillin resistant. Even more alarmingly, strains of
Enterococcus faecium
that are resistant to vancomycin have been recently observed (Moellering, 1990
, Clin. Microbiol. Rev
., 3, 46). Strains resistant to vancomycin pose a serious health threat to society since vancomycin is the antibiotic of last resort for several harmful pathogens. Thus, there is a general need for antibiotic agents and a specific need for antibiotic agents that are active against microbes resistant to methicillin or vancomycin.
3. SUMMARY OF THE INVENTION
The present invention addresses this and other needs in the art by providing antimicrobial laspartomycin derivatives, pharmaceutical compositions of antimicrobial laspartomycin derivatives, methods for making antimicrobial laspartomycin derivatives, methods for inhibiting microbial growth and methods for treating or preventing microbial infections in a subject. The present invention also provides a laspartomycin core peptide, methods for making the laspartomycin core peptide and a laspartomycin core peptide derivative and methods for making the laspartomycin core peptide derivative all of which are all useful in synthesizing antimicrobial laspartomycin derivatives.
In one aspect, the present invention provides a laspartomycin core peptide derivative that may be used as a key intermediate in the synthesis of antimicrobial laspartomycin derivatives. An essential part of the laspartomycin core peptide derivative is a core cyclic peptide attached to a nitrogen atom which may be part of a variety of functional groups such as, for example, a carbamate, amide or sulfonamide.
In one embodiment, the laspartomycin core peptide derivative includes a linker which is typically attached to the nitrogen of the core cyclic peptide. The linker may be derived from compounds such as amino acids, polyamides, polyamines, polyethers, polysulfonamides or other linkers known to those of skill in the art. The linker typically includes a linking group which may be any chemical functionality that can participate in covalent bond formation. The linking group provides a site for further modification of the laspartomycin core peptide derivative. For example, the linking group may be modified with a lipophilic moiety to provide a laspartomycin derivative of the invention.
Thus, in one illustrative embodiment, the present invention provides a laspartomycin core peptide derivative according to structural formula (I):
Y
1
—L—X
1
—N(R
1
)—R  (I)
or a salt or hydrate thereof, wherein either:
(i) Y
1
—L—X
1
taken together is hydrogen; or
(ii) Y
1
is a linking group;
L is a linker;
X
1
is selected from the group consisting of —CO—, —SO
2
—, —CS—, —PO—, —OPO—, —OC(O)—, —NHCO— and —NR
1
CO—;
N is nitrogen;
R
1
is selected from the group consisting of hydrogen, (C
1
-C
10
) alkyl optionally substituted with one or more of the same or different R
2
groups, (C
1
-C
10
) heteroalkyl optionally substituted with one or more of the same or

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