Antimicrobial sulfonamide derivatives of lipopeptide...

Details Antimicrobial sulfonamide derivatives of lipopeptide... Antimicrobial sulfonamide derivatives of lipopeptide...

2001-07-13

2004-06-15

Russel, Jeffrey Edwin (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S317000

Reexamination Certificate

active

06750199

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel antibiotics and antimicrobial agents. More particularly, the present invention relates to antimicrobial sulfonamide derivatives of lipopeptide antibiotics.
BACKGROUND OF THE INVENTION
An important class of antibiotics that inhibit Gram-positive bacteria are the acidic lipopeptide antibiotics. Generally, acidic lipopeptide antibiotics consist of either a cyclic peptide core or a cyclic depsipeptide core acylated with a lipophilic fragment. The lipophilic fragment, typically an unsaturated fatty acid, may be of varying length. Frequently, the antibiotic activity of lipopeptide antibiotics is related to the length of the lipophilic fragment.
Examples of acidic lipopeptide antibiotics include, but are not limited to, 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), zaomycin (Kuroya, 1960,
Antibiotics Ann.,
194; Kuroya, Japanese Patent No. 8150), crystallomycin (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), brevistin (Shoji et al., 1976,
J. Antibiotics,
29, 380), cerexin A (Shoji et al., 1976,
J. Antibiotics,
29, 1268), cerexin B (Shoji et al., 1976,
J. Antibiotics,
29, 1275), Antibiotic A-30912 (Hoehn et al., U.S. Pat. No. 5,039,789), Antibiotic A-1437 (Hammann et al., EP 0 629 636 B1; Lattrell et al., U.S. Pat. No. 5,629,288), Antibiotic A-54145 (Fukada et al., U.S. Pat. No. 5,039,789; Boeck et al., 1990,
J. Antibiotics,
43, 587), Antibiotic A-21978C (Debono et al., 1988,
J. Antibiotics,
41, 1093) and tsushimycin (Shoji et. al., 1968,
J. Antibiot.,
21, 439). See also Berdy, “CRC Handbook of Antibiotic Compounds,” Volume IV, Part 1, pages 313-327, CRC Press, Boca Raton, Fla., (1980); Korzybinski et al., “Antibiotics-Origin Nature and Properties,” Vol. 1, Pergamon Press, pp. 397-401 and 404-408, New York, N.Y. (1967).
Despite the efficacy of lipopeptide antibiotics against Gram-positive bacteria, the medicinal chemistry of these antibiotics 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). Methicillin resistant bacteria are a particular problem, since they are also frequently resistant to a wide variety of other antibiotics (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, vancomycin-resistant strains of
Enterococcus faecium
have been 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 need to explore the medicinal chemistry of lipopeptide antibiotics to develop novel antimicrobial agents. The discovery of new lipopeptide antibiotics will increase the repertoire of antibiotics available to combat pathogens resistant to currently available antibiotics.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides antimicrobial sulfonamide derivatives of lipopeptide antibiotics. The sulfonamide derivatives generally comprise the peptidic portion of a lipopeptide antibiotic (“core antibiotic” or “core cyclic peptide”) and a lipophilic moiety. The lipophilic moiety is linked to the amino core antibiotic or amino core cyclic peptide, either directly or by way of an optional intervening linker. The lipophilic moiety and core antibiotic or core cyclic peptide are connected by a linkage containing at least one sulfonamide group. When an optional linker is used, the sulfonamide linkage may be between (i) the linker and the core antibiotic or core cyclic peptide; (ii) the lipophilic moiety and the linker; or both (i) and (ii) above.
The core antibiotic is the molecule obtained by enzymatic removal of the lipophilic moiety of a lipopeptide antibiotic, typically with a deacylase such as that produced by
Actinoplanes utahensis
(NRRL 12052). Lipopeptide antibiotics which may be used to provide a core antibiotic, include by way of example and not limitation, laspartomycin, zaomycin, crystallomycin, aspartocin, amphomycin, glumamycin, brevistin, cerexin A, cerexin B, Antibiotic A-30912, Antibiotic A-1437, Antibiotic A-54145, Antibiotic A-21978C and tsushimycin. Those of skill in the art will recognize that for some of these lipopeptide antibiotics, removal of the lipophilic portion via enzymatic deacylation yields a cyclic peptide or depsipeptide having one or more additional amino acids attached thereto. In some instances these additional exocyclic amino acids may be necessary for activity and should not be removed by further enzymatic degradation. When enzymatic deacylation yields a cyclic peptide or depsipeptide having additional exocyclic amino acids attached thereto, the “core antibiotic” includes the exocyclic amino acids. The core cyclic peptide is a cyclic peptide or depsipeptide with no exocyclic amino acids. In some situations the core cyclic peptide and the core antibiotic may refer to the same molecule (e.g., Antibiotic A-30912).
The lipophilic moiety may be a saturated or unsaturated fatty acid. The fatty acid may be branched or a straight-chain. Unsaturated fatty acids may be mono, di, tri, or polyunsaturated. The lipophilic moiety may also be substituted with heteroatoms, aryl groups, heteroaryl groups and the like and may also be mono, di, tri, or polyunsaturated. In some situations the lipophilic moiety may consist of a aryl group, arylaryl group, biaryl group, heteroaryl group and the like.
The optional linker may comprise virtually any molecule capable of linking the lipophilic moiety to the core antibiotic. Linkers suitable for use are typically at least bi-functional, having one functional group capable of forming a covalent linkage with an exocyclic amine of the core antibiotic and another functional group capable of forming a covalent linkage with a complementary functional group on a precursor of the lipophilic moiety. At least one of the linkages formed and optionally both of the linkages formed are a sulfonamide linkage.
A wide variety of linkers suitable for spacing the lipophilic group from the core antibiotic or core cyclic peptide of a lipopeptide antibiotic are known in the art and include by way of example and not limitation, linkers that contain alkyl, heteroalkyl, acyclic heteroatomic bridges, aryl, arylaryl, arylalkyl, heteroaryl, heteroaryl-heteroaryl, substituted heteroaryl-heteroaryl, heteroarylalkyl, heteroaryl-heteroalkyl and the like. Linkers may include single, double, triple or aromatic carbon-carbon bonds, nitrogen-nitrogen bonds, carbon-nitrogen, carbon-oxygen bonds and/or carbon-sulfur bonds and include functionalities such as carbonyls, ethers, thioethers, carboxamides, sulfonamides, ureas, urethanes, hydrazines, etc.
The linker may be flexible or rigid. Rigid linkers include, for example, polyunsaturated alkyl, aryl, biaryl, heteroaryl, etc. Flexible linkers include, for example, a flexible peptide such as Gly-Gly-Gly or a flexible saturated alkanyl or heteroalkanyl. The linker may be hydrophilic or hydrophobic. Hydrophilic linkers include, for example, polyalcohols or polyethers such as polyalkyleneglycols. Hydrophobic linkers may be, for example, alkyls or aryls.
In another aspect, the present invention provides methods for making antimicrobial sulfonamide derivatives. Generally the methods involve assembling three fragments of the sulfonamide derivatives: the amino core a

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