WO2002005837A1 - Derives sulfonamide antimicrobiens d'antibiotiques lipopeptidiques - Google Patents

Derives sulfonamide antimicrobiens d'antibiotiques lipopeptidiques Download PDF

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Publication number
WO2002005837A1
WO2002005837A1 PCT/US2001/022352 US0122352W WO0205837A1 WO 2002005837 A1 WO2002005837 A1 WO 2002005837A1 US 0122352 W US0122352 W US 0122352W WO 0205837 A1 WO0205837 A1 WO 0205837A1
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Prior art keywords
antibiotic
core
antimicrobial sulfonamide
antimicrobial
sulfonamide derivative
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PCT/US2001/022352
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English (en)
Inventor
William V. Curran
Richard A. Leese
Howard Jarolmen
Donald B. Borders
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Intrabiotics Pharmaceuticals, Inc.
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Priority to JP2002511769A priority Critical patent/JP2004529065A/ja
Priority to AU2001278933A priority patent/AU2001278933B2/en
Priority to DE60131085T priority patent/DE60131085T2/de
Priority to AU7893301A priority patent/AU7893301A/xx
Priority to CA002450372A priority patent/CA2450372A1/fr
Priority to EP01957162A priority patent/EP1311281B1/fr
Publication of WO2002005837A1 publication Critical patent/WO2002005837A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel antibiotics and antimicrobial agents. More particularly, the present invention relates to antimicrobial sulfonamide derivatives of lipopeptide antibiotics.
  • 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.
  • the antibiotic activity of lipopeptide antibiotics is related to the length of the lipophilic fragment.
  • acidic lipopeptide antibiotics include, but are not limited to, laspartomycin (Umezawa et al, United States Patent 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.
  • Antibiotics 29, 1275
  • Antibiotic A-30912 Hoehn et al, United States Patent No. 5,039,789
  • Antibiotic A-1437 Haehn et al, EP 0 629 636 Bl; Lattrell et al, United States Patent No. 5,629,288)
  • Antibiotic A-54145 Fukada et al, United States Patent No. 5,039,789; Boeck et al, 1990, J. Antibiotics, 43, 587
  • Antibiotic A- 21978C Debono et al, 1988, J. Antibiotics, 41, 1093
  • tsushimycin Shoji et. al, 1968, J. Antibiot, 21, 439).
  • 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.
  • 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.
  • 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.
  • the lipophilic portion via enzymatic deacylation yields a cyclic peptide or depsipeptide having one or more additional amino acids attached thereto.
  • these additional exocyclic amino acids may be necessary for activity and should not be removed by further enzymatic degradation.
  • the "core antibiotic” includes the exocyclic amino acids.
  • the core cyclic peptide is a cyclic peptide or depsipeptide with no exocyclic amino acids.
  • 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.
  • linkers suitable for spacing the lipophilic group from the core antibiotic or core cyclic peptide of a lipopeptide antibiotic 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.
  • the present invention provides methods for making antimicrobial sulfonamide derivatives.
  • the methods involve assembling three fragments of the sulfonamide derivatives: the amino core antibiotic or amino core cyclic peptide, the optional linker and the lipophilic moiety in any convenient order.
  • the precursor of the lipophilic moiety and/or linker bear appropriate functional groups such that the assembly of the fragments result in the formation of at least one sulfonamide linkage.
  • a lipophilic sulfonyl derivative may be covalently attached to a amino core antibiotic or amino core cyclic peptide.
  • a linker may be first covalently attached to an amino core antibiotic or amino core cyclic peptide and then a lipophilic sulfonyl attached therefore.
  • a lipophilic sulfonyl derivative may be covalently attached to a linker and the resultant lipophilic linker covalently attached to a amino core antibiotic or amino core cyclic peptide.
  • the present invention provides pharmaceutical compositions comprising antimicrobial sulfonamide derivatives of the invention.
  • the pharmaceutical compositions generally comprise one or more antimicrobial sulfonamide derivatives of the invention, (or salts thereof) and an adjuvant, carrier, excipient or diluent.
  • the pharmaceutical composition may be formulated for environmental use, such as for application on plants, for vetinary use or for pharmaceutical use. The choice of adjuvant, carrier, excipient or diluents will depend on the particular application.
  • the present invention provides methods of inhibiting the growth of microbes such as Gram-positive bacteria.
  • the method generally involves contacting a microbe with one or more antimicrobial sulfonamide derivatives of the invention or a salt thereof or a pharmaceutical composition thereof in an amount effective to inhibit the growth of the microbe.
  • the method maybe practical to achieve a bacteriostatic effect, where the growth of the microbe is inhibited, or to achieve a bactericidal effect, where the microbe is killed.
  • the present invention provides methods for treating and/or preventing microbial infections in a subject such as a human, a plant or an animal.
  • the methods generally involve administering to a subject one or more of the antimicrobial sulfonamide derivatives, salts or compositions of the invention in an amount effective to treat or prevent a microbial infection in the human, animal or plant.
  • the antimicrobial sulfonamide derivatives, salts or compositions may be administered systemically or applied topically, depending on the nature of the microbial infection.
  • Core cyclic peptide refers to the desamino portion cyclic peptide or cyclic depsipeptide portion of a lipopeptide antibiotic that remains after the lipophilic portion of a lipopeptide antibiotic, including any exocyclic amino acids, has been removed.
  • the core cyclic peptides derived from the lipopeptide antibiotics laspartomycin (2), aspartocin (4), antibiotic A-21978C (6), antibiotic A-54145 (8), antibiotic A-30912A (10), antibiotic A-30912B (12), antibiotic A-30912D (14) and antibiotic A-30912H (16) are depicted below:
  • R 7 is isopropyl or isobutyl
  • R6 is hydrogen or methyl
  • core cyclic peptide includes both conventional cyclic peptides, such as the cyclic peptides derived from aspartocin (4) as well as cyclic depsipeptides such as the cyclic depsipeptide derived from Antibiotic A-21978C (6) and Antibiotic A-54145 (8).
  • the dashed lines in structures 2, 4, 6, 8, 10, 12, 14 and 16 indicate points of attachment of the amido lipophilic portion of the parent lipopeptide antibiotic or, for those lipopeptide antibiotics in which the amino lipophilic portion is linked to the core peptide via intervening exocyclic amino acid residues, the dashed lines indicate the point of attachment of the amino group of exocyclic amino acid residues.
  • amino core cyclic peptide refers to a core cyclic peptide as defined above where a primary amino group is attached to the dashed lines in structures 2, 4, 6, 8, 10, 12, 14 and 16.
  • Core antibiotic refers to the des-amino peptide portion of the lipopeptide antibiotic that remains after cleavage of the lipophilic fragment.
  • core antibiotics derived from the lipopeptide antibiotics laspartomycin 18, aspartocin 20, antibiotic A-21978C 22, antibiotic A-54145 24 and Antibiotic A-30912A 26 are depicted below:
  • R is isopropyl or isobutyl R is hydrogen or methyl
  • the dashed lines indicate the point of attachment of the amine group that joins the lipophilic moiety and the core antibiotic in the naturally occurring antibiotic.
  • the structures of core antibiotics derived from Antibiotic A-30912B, Antibiotic A-30912D and Antibiotic A-30912H will be apparent to those of skill in the art.
  • Amino core antibiotic refers to a core antibiotic as defined above where a primary amino group is attached to the dashed lines in structures 18, 20, 22, 24 and 26.
  • FMOC derivative of the core antibiotic of aspartocin refers to the following compound:
  • t-butyl derivative of the core antibiotic of laspartomycin refers to the following compound:
  • the core antibiotic and core cyclic peptide of a lipopeptide antibiotic may be the same (see, e.g., the core cyclic peptide 10 and core antibiotic 26 derived from antibiotic A-30912A). Also, the core antibiotic and the core cyclic peptide may be different (see, e.g., the core cyclic peptide 2 and core antibiotic 18 derived from laspartomycin). Also, in some instances, the amino core antibiotic, which may include an exocyclic amino acid or peptide, may be further deacylated further to yield the corresponding amino core cyclic peptide.
  • deacylation of laspartomycin with a deacylase produced by fermentation of Actinop lanes utahensis yields both the amino core cyclic peptide of laspartomycin and the amino core antibiotic of laspartomycin.
  • A-30912 refers to all naturally occurring A-30912 compounds. When reference to a specific A-30912 compound or nucleus is intended, then a specific designation such as A- 30912 A, A-30912 B, A-30912 C, etc. is used.
  • A-21978C refers to all naturally occurring A-21978C compounds and is intended to include anhydro and isomeric forms (Baker et al, United States Patent No. 5,912,225). When reference to a specific A-21978C compound or nucleus is intended, then a specific designation such as anhydro- and isomer, etc. is used.
  • A-54145 refers to all naturally occurring A-54145 compounds. When reference to a specific A-54145 compound or nucleus is intended, then a specific designation is used.
  • Alkyl refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne.
  • Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), cycloprop-1-en-l-yl; cycloprop-2-en-l-yl, prop-1-yn-l-yl , prop-2-yn-l-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-l-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-yl, but-2-en-yl-yl
  • alkyl is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” are used. “Alkanyi” refers to a saturated branched, straight-chain or cyclic alkyl group.
  • Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclo ⁇ ropan-1-yl, etc.; butyanyls such as butan-1-yl, butan-2-yI (sec-butyl), 2-methyl-propan-l-yl (isobutyl), 2-methyl-pro ⁇ an-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.
  • Alkenyl refers to an unsaturated branched, straight-chain or cyclic alkyl group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • the group may be in either the cis or trans conformation about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-l-yl , prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-l-yl; cycloprop-2-en-l-yl ; butenyls such as but-1-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl , but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl, cyclobut-1-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl, etc.; and the like.
  • Alkvnyl refers to an unsaturated branched, straight-chain or cyclic alkyl group having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-l-yl, prop-2-yn-l-yl, etc.; butynyls such as but-1-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl , etc.; and the like.
  • Aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, ⁇ s-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiaden
  • Arylaryl refers to a monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a ring system in which two or more identical or non-identical parent aromatic ring systems are joined directly together by a single bond, where the number of such direct ring junctions is one less than the number of parent aromatic ring systems involved.
  • Typical arylaryl groups include, but are not limited to, biphenyl, triphenyl, phenyl-naphthyl, binaphthyl, biphenyl-naphthyl, and the like. Where the number of carbon atoms in an arylaryl group are specified, the numbers refer to the carbon atoms comprising each parent aromatic ring.
  • arylaryl is an arylaryl group in which each aromatic ring comprises from 5 to 14 carbons, e.g., biphenyl, triphenyl, binaphthyl, phenylnaphthyl, etc.
  • each parent aromatic ring system of an arylaryl group is independently a (C 5 -C 14 ) aromatic, more preferably a (C 5 -C 10 ) aromatic.
  • arylaryl groups in which all of the parent aromatic ring systems are identical, e.g., biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.
  • Biaryl refers to an arylaryl group having two identical parent aromatic systems joined directly together by a single bond.
  • Typical biaryl groups include, but are not limited to, biphenyl, binaphthyl, bianthracyl, and the like.
  • the aromatic ring systems are (C S -C I4 ) aromatic rings, more preferably (C 5 -C, 0 ) aromatic rings.
  • a particularly preferred biaryl group is biphenyl.
  • Arylalkyl refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl group.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2-naphthylethen-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like.
  • arylalkyl group is (C 6 -C 20 ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C,-C 6 ) and the aryl moiety is (C 5 -C )4 ).
  • the arylalkyl group is (C 6 -C 13 ), e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C r C 3 ) and the aryl moiety is (C 5 -C 10 ).
  • “Heteroaryl” refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
  • Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, te
  • Heteroarylalkyl refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 2 carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylakenyl and/or heterorylalkynyl is used.
  • Parent aromatic ring system refers to an unsaturated cyclic or polycyclic ring system having a conjugated ⁇ electron system.
  • parent aromatic ring system fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, indane, indene, phenalene, etc.
  • Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, ⁇ s-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.
  • Parent Heteroaromatic Ring System refers to a parent aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom. Typical heteratoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si, etc. (Including and associated hydrogen or other atoms). Specifically included within the definition of "parent heteroaromatic ring systems” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, arsindole, chromane, chromene, indole, indoline, xanthene, etc.
  • Typical parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thi
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benz
  • the present invention provides antimicrobial sulfonamide derivatives, pharmaceutical compositions comprising antimicrobial sulfonamide derivatives, methods for making antimicrobial sulfonamide derivatives, methods for inhibiting microbial growth with antimicrobial sulfonamide derivatives and methods for treating or preventing microbial infections in a subject with antimicrobial sulfonamide derivatives.
  • acidic lipopeptide antibiotics that may be converted to antimicrobial sulfonamide derivatives include, but are not limited to, laspartomycin (Umezawa et al, United States Patent 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, 19 A; Hausman et al, 1964, Antimicrob.
  • laspartomycin Umezawa et al, United States Patent No. 3,639,582; Naganawa et al, 1968, J. Antibiot., 21, 55; Naganawa et al, 1970, J. Antibiot,
  • Antibiotics 29, 1275
  • daptomycin (Debono et. al, 1988, J. Antibiotics, 41, 1093 ), Antibiotic A-30912 (Hoehn et al, United States Patent No. 5,039,789), Antibiotic A-1437 (Hammann et al, EP 0 629 636 Bl; Lattrell et al, United States Patent No. 5,629,288), Antibiotic A-54145 (Fukada et al, United States Patent 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).
  • Antimicrobial sulfonamide derivatives of the present invention offer some significant advantages over traditional antibiotics. Antimicrobial sulfonamide derivatives are generally active against many gram positive bacteria. More importantly, antimicrobial sulfonamide derivatives of the present invention may be effective against methicillin resistant bacteria and/or strains resistant to vancomycin. Thus, antimicrobial sulfonamide derivatives may inhibit or prevent growth of a number of microbes generally resistant to known antibiotics. Further, antimicrobial sulfonamide derivatives may offer greater resistance to microbial proteases than the corresponding antimicrobial amide derivatives. Accordingly, use of antimicrobial sulfonamide derivatives may be less likely to lead to the formation of antibiotic-resistant pathogens than conventional antimicrobial agents.
  • the present invention provides antimicrobial sulfonamide derivatives according to structural formula (I):
  • Y is a lipophilic moiety; each X is independently selected from the group consisting of — CO — — SO 2 — , — CS— , — PO— , — OP(O — — OC(O — , — NHCO— and — N(R 1) CO— with the proviso that at least one X is — SO 2 — ; m is 0 or 1 ;
  • L is a linker
  • N is nitrogen
  • R 1 and R 4 are each independently selected from the group consisting of hydrogen, (C,-C 25 ) alkyl optionally substituted with one or more of the same or different R 2 groups, (C,-C 25 ) heteroalkyl optionally substituted with one or more of the same or different R 2 groups, (C 5 -C 30 ) aryl optionally substituted with one or more of the same or different R 2 groups, (C 5 -C 30 ) arylaryl optionally substituted with one or more of the same or different R 2 groups, (C 5 -C 30 ) biaryl optionally substituted with one or more of the same or different R 2 groups, five to thirty membered heteroaryl optionally substituted with one or more of the same or different R 2 groups, (C 6 -C 30 ) arylalkyl optionally substituted with one or more of the same or different R 2 groups and six to thirty membered heteroarylalkyl optionally substituted with one or more of the same or different R 2 groups; each R 2 is independently
  • R is a core cyclic peptide or a core antibiotic of a lipopeptide antibiotic.
  • the nitrogen atom covalently bonded to R 1 is directly attached to the core cyclic peptide or core antibiotic of a lipopeptide antibiotic (see section 4.1).
  • the nitrogen atom covalently bonded to R 4 is covalently bonded to both the sulfonyl group and the linker L.
  • R 1 and R 4 are independently selected from the group consisting of hydrogen, (C Cjo) alkyl optionally substituted with one or more of the same or different R 2 groups, (C,-C I0 ) heteroalkyl optionally substituted with one or more of the same or different R 2 groups, (C 5 -C ]5 ) aryl optionally substituted with one or more of the same or different R 2 groups, (C 5 -C 15 ) biaryl optionally substituted with one or more of the same or different R 2 groups, five to sixteen membered heteroaryl optionally substituted with one or more of the same or different R 2 groups, (C 6 -C I6 ) arylalkyl optionally substituted with one or more of the same or different R 2 groups and six to sixteen membered heteroarylalkyl optionally substituted with one or more of the same or different R 2 groups where R 2 is a substituent as defined above in Formula (I).
  • R 1 and R 4 are independently selected from the group consisting of hydrogen, (C r C 6 ) alkanyl optionally substituted with one or more of the same or different R 2 groups, (C 3 -C 7 ) alkenyl optionally substituted with one or more of the same or different R 2 groups, C 6 aryl optionally substituted with one or more of the same or different R 2 groups, C 12 biaryl optionally substituted with one or more of the same or different R 2 groups, five to sixteen membered heteroaryl optionally substituted with one or more of the same or different R 2 groups, (C 6 -C 10 ) arylalkyl optionally substituted with one or more of the same or different R 2 groups and (C 6 -C 10 ) heteroarylalkyl optionally substituted with one or more of the same or different R 2 groups, where R 2 is a substituent as defined above in Formula (I).
  • R 1 and R 4 are independently selected from the group consisting of hydrogen, methyl, allyl, homoallyl, phenyl optionally substituted with one or more of the same or different R 2 groups and benzyl optionally substituted with one or more of the same or different R 2 groups, where R 2 is a substituent as defined above in Formula (I). Most preferably, R 1 and R 4 are hydrogen.
  • the antimicrobial sulfonamide derivative is described by structural formula (II) (i.e., Y— X— N(R 4 >— L— X— N(R')— R), the moiety X maybe any kind of chemical functionality that can form a covalent bond with nitrogen with the proviso that at least one X is — SO 2 — .
  • X is —CO—, — SO 2 — , — CS— , — PO— , — OPO— , — OC(O)— , — NHCO — or — R 5 CO — where R 7 is selected from the group consisting of hydrogen, (C r C 6 ) alkyl, (C 5 -C, 0 ) aryl, five to sixteen membered heteroaryl, (C 6 -C, 6 ) arylalkyl and six to sixteen membered heteroarylalkyl. More preferably, X is — CO — or — SO 2 — .
  • linker L Connected to X — N(R ! ) in the antimicrobial sulfonamide derivative described by Formula (II) (i.e., Y— XN(R 4 )— L— X— N(R')— R) is a linker L and a nitrogen group (i.e., N(R 4 )).
  • the nature of linker L may vary extensively. Thus, for example, L may be hydrophilic or hydrophobic, long or short, rigid, semirigid or flexible etc.
  • linkers L comprised of stable bonds suitable for spacing the lipophilic group Y from the core cyclic peptide or core antibiotic of a lipopeptide antibiotic are known in the art, and include by way of example and not limitation, linkers such as alkyl, heteroalkyl, acyclic heteroatomic bridges, aryl, arylaryl, arylalkyl, heteroaryl, heteroaryl-heteroaryl, substituted heteroaryl-heteroaryl, heteroarylalkyl, heteroaryl-heteroalkyl and the like.
  • linker L may include single, double, triple or aromatic carbon-carbon bonds, nitrogen-nitrogen bonds, carbon-nitrogen, carbon-oxygen bonds and or carbon-sulfur bonds, and may therefore include functionalities such as carbonyls, ethers, thioethers, carboxamides, sulfonamides, ureas, urethanes, hydrazines, etc.
  • L may be a rigid polyunsaturated alkyl or an aryl, biaryl, heteroaryl, etc.
  • L may be a flexible peptide such as Gly-Gly-Gly or a flexible saturated alkanyl or heteroalkanyl.
  • Hydrophilic linkers may be, for example, polyalcohols or polyethers such as polyalkyleneglycols.
  • Hydrophobic linkers may be, for example, alkyls or aryls.
  • N(R 4 ) — L include, for example, compounds where L is — (CH 2 ) — , k is an integer between 1 and 8 and the corresponding analogues where any suitable hydrogen is independently substituted with one or more of the same or different R 2 groups, where R 2 is defined as above in Formula (I).
  • Other embodiments of N(R 4 ) — L include any amino acid or peptide, which may be for example, a D or L ⁇ -amino acid, a ⁇ - amino acid, a ⁇ -amino acid, a dipeptide, a tripeptide or a tetrapeptide comprised of any combination of amino acids (preferably, ⁇ -amino acids).
  • the polarity of the peptide bond in these peptides may be either C-N or N-C.
  • L is selected from the group consisting of:
  • n is O, 1, 2 or 3; each S 1 is independently selected from the group consisting of hydrogen, ( - C 10 ) alkyl optionally substituted with one or more of the same or different R 5 groups, (C r C 10 ) heteroalkyl optionally substituted with one or more of the same or different R 5 groups, (C 5 - C 10 ) aryl optionally substituted with one or more of the same or different R 5 groups, (C 5 -C 15 ) arylaryl optionally substituted with one or more of the same or different R 5 groups,(C 5 -C 15 ) biaryl optionally substituted with one or more of the same or different R 5 groups, five to ten membered heteroaryl optionally substituted with one or more of the same or different R 5 groups, (C 6 -C 16 ) arylalkyl optionally substituted with one or more of the same or different R 5 groups and six to sixteen membered heteroarylalkyl optional
  • each S 1 is independently a side chain of a genetically encoded ⁇ amino acid.
  • K oxygen or nitrogen and S 1 is hydrogen, include the following compounds where R, R 1 , R 4 and Y are as previously defined:
  • L is:
  • each S 1 is independently the side chain of a genetically encoded ⁇ amino acid.
  • n is 0 and S 1 is -CH 2 -CO 2 H, -CH 2 -CH 2 -CO 2 H, -C(OH)H-CONH 2 , -CH 2 -CONH 2 or -CH 2 -CH 2 -CONH 2 .
  • n is 0 and S 1 is -CH 2 -indol-2-yl or -CH 2 -phenyl.
  • R 4 is hydrogen and R is the core antibiotic of aspartocin or the FMOC derivative of the core antibiotic of aspartocin.
  • S 1 is H and Y 2 is decan-yl.
  • S 1 is -CH 2 -phenyl and Y 2 is hexadecan-yl.
  • n 0, R 4 is hydrogen and R is the core antibiotic of laspartomycin.
  • S 1 is -CH 2 -indol-2-yl and Y 2 is hexadecan-yl.
  • S 1 is -CH 2 -phenyl and Y 2 is hexadecan-yl.
  • S 1 is -CH 2 -phenyl and Y 2 is decan-yl.
  • n is 0, R 4 is hydrogen and R is the core cyclic peptide of laspartomycin.
  • S 1 is -CH 2 -indol-2-yl and Y 2 is hexadecan-yl.
  • L is:
  • S 2 and S 2 are the side chain of a genetically encoded ⁇ amino acid.
  • n is 1, S 2 is hydrogen, -CH 2 -indol-2-yl, -CH 2 -CONH 2 or -CH 2 -CH 2 -CONH 2 and S 3 is -CH 2 -CO 2 H or -CH 2 -CH 2 -CO 2 H.
  • n is 1, S 2 is -CH 2 -CO 2 H or-CH 2 -CH 2 -CO 2 H and S 3 is -C(OH)H-CONH 2 .
  • L is:
  • S 2 , S 3 and S 4 are the side chain of a genetically encoded ⁇ amino acid.
  • n is 2
  • S 2 is -CH 2 -indol-2-yl
  • S 3 is -CH 2 -CONH 2 or -CH 2 -CH 2 -CONH 2
  • S 4 is -CH 2 -CO 2 H or -CH 2 -CH 2 -CO 2 H.
  • n 2
  • S 2 is -CH 2 -indol-2-yl
  • S 3 is -CH 2 -CO 2 H or CH 2 -CH 2 -CO 2 H-
  • S 4 is -CH 2 -CONH 2 , -CH 2 -CH 2 -CONH 2 or -C(OH)H-CONH 2
  • R is the core cyclic peptide or core antibiotic of laspartomycin, zaomycin, crystallomycin, aspartocin, amphomycin, glumamycin, brevistin, cerexin A, cerexin B, Antibiotic A-30912, Antibiotic A-1437, Antibiotic A-54145, Antibiotic A-21978C or tsushimycin.
  • R is the core antibiotic or core cyclic peptide of laspartomycin, aspartocin, Antibiotic A-30912, Antibiotic A-1437, Antibiotic A-54145 or Antibiotic A-21978C. Most preferably, R is the core antibiotic or core cyclic peptide of laspartomycin or aspartocin.
  • m is 0.
  • the antimicrobial sulfonamide derivative of the invention is represented by structural formula (DI):
  • R 4 is directly attached to the core cyclic peptide or core antibiotic of a lipopeptide antibiotic (see section 4.1).
  • Preferred embodiments of R and R 4 include those defined above. Particularly preferred embodiments include those where R 4 is hydrogen and/or R is the core antibiotic or core cyclic peptide of laspartomycin or aspartocin.
  • Y is hexadec-yl
  • R 4 is H
  • R is the core antibiotic of laspartomycin or the t-butyl ester of the core antibiotic of laspartomycin.
  • the lipophilic group Y will be hydrophobic and when substituted will be substituted with hydrophobic substituents.
  • the size and/or length of the lipophilic group will depend, in part, on the nature of fragments such as L, X, R', R 4 and R that comprise the antimicrobial sulfonamide derivative.
  • the lipophilic group Y is selected from the group consisting of (C 2 -C 30 ) alkyl optionally substituted with one or more of the same or different R 7 groups, (C 2 -C 30 ) heteroalkyl optionally substituted with one or more of the same or different R 7 groups, (C 5 - C 30 ) aryl optionally substituted with one or more of the same or different R 7 groups, (C 5 -C 30 ) arylaryl optionally substituted with one or more of the same or different R 7 groups, (C 5 -C 30 ) biaryl optionally substituted with one or more of the same or different R 7 groups, five to thirty membered heteroaryl optionally substituted with one or more of the same or different R 7 groups, (C 6 -C 30 ) arylalkyl optionally substituted with one or more of the same or different R 7 groups and six to thirty membered heteroarylalkyl optionally substituted with one or more of the same or different R 7 groups; each R
  • fragments such as L, X, R 1 , R 4 and R that comprise the antimicrobial sulfonamide derivative are particularly important in defining preferred embodiments of the lipophilic fragment Y.
  • preferred embodiments of Y will particularly depend on the core cyclic peptide or core antibiotic and/or the linker L. Accordingly, antimicrobial sulfonamide derivatives with different core cyclic peptides or core antibiotics and/or linkers L will have different preferred embodiments of the lipophilic fragment Y.
  • Y when m is 0, X is — SO 2 — , R 4 is previously defined, and R is the core antibiotic of anhydro-Antibiotic-21987C or isomer-Antibiotic-21987 (or amino protected versions, thereof) preferred embodiments of Y include those described in Baker et al, United States Patent No. 5,912,226. Preferred embodiments of Y described in Baker et al, United States Patent No. 5,912,226 are preferred embodiments in the current invention, when the lipophilic group Y is connected by a sulfonamide linkage to the core antibiotic of anhydro- Antibiotic-21987C or isomer-Antibiotic-21987.
  • X is — SO 2 —
  • R 4 is as previously defined and R is the core antibiotic of Antibiotic-21987C (or an amino protected version thereof)
  • preferred embodiments of the lipophilic fragment Y include those described by the Lilly group (Debono, United States Patent No. RE32,333; Debono, United States Patent No. RE32,311; Abbott et al, United States Patent No. 4,537,717; Abbott et al, United States Patent No. 4,524,135; Abbott et al, United States Patent No. 4,482,487; Debono United States Patent No. 4,399,067; Debono United States Patent No. 4,396,543).
  • X is — SO 2 —
  • R 4 is as previously defined and R is the core antibiotic of laspartomycin
  • preferred embodiments of Y include those described in Borders et al, United States Patent Application Serial No. 09/760328.
  • X is — SO 2 —
  • R 4 is as previously defined and R is the core antibiotic of Antibiotic A-1437 preferred embodiments of Y include those described in Lattrell et al, United States Patent No. 5,629,288.
  • X is — SO 2 — and —CO—
  • R 1 and R 4 is as previously defined
  • L is the des-amino derivative of asparagine
  • R is the core antibiotic of Antibiotic A-1437
  • preferred embodiments of Y may be found in Lattrell et al, United States Patent No. 5,629,288.
  • X is — SO 2 —
  • R 4 is as previously defined and R is the core antibiotic of Antibiotic A54145
  • preferred embodiments of Y include those described in Fukada et al, United States Patent No. 5,028,590 and Fukada et al, United States Patent No. 5,039 ⁇ 789.
  • Y is intimately related to the structure of the core antibiotic or core cyclic peptide and linker. Given the structure of the core antibiotic or core cyclic peptide and linker, selection of preferred embodiments of Y is well within the purview of those of ordinary skill in the art given the examples provided above.
  • Particularly preferred antimicrobial sulfonamides include the following compounds.
  • R is the core antibiotic of laspartomycin
  • R is the core cyclic peptide of laspartomycin
  • R is the core antibiotic of aspartocin
  • R is the FMOC derivative of the core antibiotic of aspartocin
  • R is the core antibiotic of aspartocin
  • Antimicrobial sulfonamide derivatives are preferably synthesized from amino core antibiotics or core cyclic peptides, which may be made by the approaches described in Section 4.5 of this Application. Those of skill in the art will appreciate antimicrobial sulfonamide derivatives maybe synthesized from a vast number of other different starting materials.
  • Starting materials useful for preparing antimicrobial sulfonamide derivatives from core antibiotics or core cyclic peptides are either commercially available or may be prepared by conventional synthetic methods.
  • a number of general synthetic approaches may be envisioned for converting core antibiotics or core cyclic peptides to antimicrobial sulfonamide derivatives. These include, but are not limited to, the approaches outlined in Schemes I-IV.
  • an activated lipophilic sulfonyl derivative (Y — SO 2 X) is reacted with a free amino group (HNCR 1 )) attached to a core cyclic peptide or to a core antibiotic to form the sulfonamide linkage.
  • activated lipophilic sulfonyl derivative Y — SO 2 X takes the same form.
  • X may be an activated derivative, such as, for example, halogen (e.g., fluoride, bromide, chloride or iodide) or active ester (e.g., pentaflourophenyl ester, N- hydroxy succinimide ester, -nitrophenylester, etc.).
  • X is a hydroxybenzotriazole ester or a sulfonyl chloride.
  • X may be OH, which is activated in situ by well known methods (aminium salts, uronium salts, carbodiimides, etc.) Methods for constructing the sulfonamide linkage are well-known to the skilled artisan and may be found in compendiums of synthetic methods (Beilstein Handbook of Organic Chemistry, Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser, L.; Feiser, M., Reagents for Organic Synthesis, Volumes 1-17, Wiley friterscience; Trost, B.; Fleming, I, Comprehensive Organic Synthesis, Pergamon Press, 1991; T eilheimer's Synthetic Methods of Organic Chemistry, Volumes 1-45, Karger, 1991; Compendium of Organic Synthetic Methods, Wiley Interscience, Volumes 1-7; March, J., Advanced Organic Chemistry, Wiley Interscience, 1991; Larock, R.; Comprehensive Organic Transformations, VCH Publishers, 1989; Paquette, L. (ed.), Encyclopedia of Reagents for Organic
  • lipophilic fragment Y and linker L attached via a sulfonamide bond, are covalently linked to, for example, a sulfonic or carboxylic acid or an activated derivative thereof (i.e., X 1' ) such as an active ester or a halogen.
  • Sulfonic acids and carboxylic acids may be activated in situ by methods known to the skilled artisan (e.g., uronium salts, phosphonium salts, carbodiimides, etc.). Methods for making activated derivatives of carboxylic acids and sulfonic acids and reacting these derivatives with amines to form amides or sulfonamides are known to those of skill in the art.
  • X 1' is a hydroxybenzotriazole ester or a chloro derivative of a sulfonic or carboxylic acid.
  • Linkages other than sulfonamides or carboxamides may be formed by methods known to those of skill in the art.
  • Scheme IV Y— SO 2 N(R 4 )— L 1 + L 2 — — N(R'>— R ⁇ Y— SO 2 N(R 4 )— L— X— N(R')— R
  • Scheme IV describes a convergent approach where Y — SO 2 N(R 4 ) — L — X — N(R ! ) — R is synthesized by combining two fragments (Y— SO 2 N(R 4 )— L 1 and L 2 — X— N(R')— R) to form the antimicrobial sulfonamide derivative.
  • L 1 and L 2 combine to form the linker L upon covalent bond formation.
  • L is an oligomer such as a polyamide or polyethers.
  • Methods for combining oligomeric subunits such as ether or amide monomers, dimers, etc. are known to those of skill in the art (Bodanzsky, M., Principles of Peptide Synthesis; Springer Verlag, 1984; Bodanzsky, M., Practice of Peptide Synthesis; Springer Verlag, 1984).
  • Fragment Y — SO 2 N(R 4 ) — L 1 may be made by forming a sulfonamide bond between Y — SO 2 X and HN(R 4 ) — L 1 using methods described above.
  • Fragment L 2 — X — N(R') — R may be made, as described above, by forming either a sulfonamide bond or an amide between L 2 — X 1' and HN(R ! ) — R, where X 1' is either a carboxylic acid or a sulfonic acid or activated derivatives thereof.
  • Culturing microorganisms that yield acidic lipopeptide antibiotics may be used to provide amino core antibiotics or amino core cyclic peptides that can be converted to antimicrobial sulfonamide derivatives.
  • Microorganisms that synthesize acidic lipopeptide antibiotics are well known in the art (see e.g., Umezawa et al, United States Patent No. 3,639,582; Debono et. al, 1988, J Antibiotics, 41, 1093; Shay et al, I960, Antibiotics Annual, 194; Hamill et al., United States Patent No. 4,331,594; Hamill et al, United States Patent No.
  • acidic lipopeptide antibiotics produced by culturing microorganisms are purified from fermentation broth or culture medium using extractive methods (Borders et al, United States Patent Application Serial No. _____).
  • the acidic lipopeptide antibiotic may be isolated as either the free acid or the salt.
  • lipopeptide antibiotics may be purified and isolated from fermentation broth or culture medium by any aft-known technique such as high performance liquid chromatography, counter current extraction, centrifugation, filtration, precipitation, ion exchange chromatography, gel electrophoresis, affinity chromatography and the like, either before or after extractive purification using the methods of the current invention.
  • the actual conditions used to purify a lipopeptide antibiotics will depend, in part, on factors such as net charge, hydrophobicity, hydrophilicity, etc., and will be apparent to those having skill in the art.
  • the lipophilic fragment of the acidic lipopeptide antibiotic is enzymatically cleaved to provide the core antibiotic or core cyclic peptide.
  • Addition of an appropriate enzyme to the culture medium may provide the core antibiotic or core cyclic peptide directly, thus obviating the need to isolate the lipopeptide antibiotic (Kreuzman et al, United States Patent No. 5,573,936).
  • the lipopeptide antibiotic may be chemically deacylated to provide the core antibiotic or core cyclic peptide, although this method frequently leads to complex mixtures (see e.g., Shoji et al, J. Antibiotics 28, 764, 1975; Shoji et al, J. Antibiotics 29, 380, 1976; Shoji et al, J. Antibiotics 29, 1268, 1976; Shoji et al, J. Antibiotics 29, 1275, 1976).
  • isolated lipopeptide antibiotics are treated with an enzyme that removes at least the lipophilic fragment of the lipopeptide antibiotic.
  • the enzyme may be, for example, a degradative enzyme such as a peptidase, esterase or thiolase, of which numerous examples exist in the art (Chihahra et al, Agr. Biol. Chem. 38, 1767, 1974; Suzuki et al, J. Biochem., 56, 335, 1964; Konishi et al, United States Patent No. 5,079,148).
  • the enzyme is a deacylase ( Abbot et al, United States Patent No. 4,299,763; Abbot et al, United States Patent No.
  • the cleavage of lipopeptide antibiotics to core antibiotics or core cyclic peptides commences by culturing a microorganism that produces a deacylase. The lipopeptide antibiotic is then contacted with the culture medium containing the deacylase.
  • Microorganisms such as those of the Actinoplanacae genera that produce deacylases are well known to those of skill in the art.
  • the microorganism Actinoplanes utahensis provides a deacylase that deacylates many lipopeptide antibiotics to yield core antibiotics or core cyclic peptides (see e.g., Lattrell et al, United States Patent No.
  • Any culturing medium which supports Actinoplanes utahensis (NRRL 12052) growth maybe used and selection of such medium is within the capability of those of skill in the art.
  • Representative examples of culturing medium which supports Actinoplanes utahensis (NRRL 12052) growth maybe found in the art (see e.g., Boeck et al, 1988, J. Antibiot, 41, 1085; Debono et. al, 1988, J. Antibiotics, 41, 1093; Lattrell et al, United States Patent No. 5,039,789; Fukada et al, United States Patent No. 5,039,789; Abbott et al, United States Patent No.
  • lipopeptide antibiotics such as aspartocin, A-30912, A- 21978C and laspartomycin with Actinoplanes utahensis (NRRL 12052)
  • NRRL 12052 lipopeptide antibiotics
  • Enzymes possess a high degree of specificity and slight differences in the peptide moiety or the lipophilic fragment may have a profound effect on the rate of deacylation.
  • the lipophilic fragment may be selectively removed to provide the core antibiotic.
  • lipophilic fragment is accompanied by hydrolysis of exocyclic peptide bonds to provide the core cyclic peptide.
  • deacylation of lipopeptide antibiotics with a deacylase may provide a number of different peptide products.
  • core antibiotics or core cyclic peptides may be produced by methods known in the art for synthesizing peptides.
  • linear peptides may be prepared using conventional solution phase or solid.phase peptide synthesis and then cyclized.
  • Core antibiotics or core cyclic peptides may be purified and isolated from either fermentation broth or synthetic reaction mixtures by any art-known technique such as high performance liquid chromatography, counter current extraction, centrifugation, filtration, precipitation, ion exchange chromatography, gel electrophoresis, affinity chromatography and the like.
  • the actual conditions used to purify a particular core antibiotic or core cyclic peptide will depend, in part, on factors such as net charge, hydrophobicity, hydrophilicity, etc. and will be apparent to those having skill in the art.
  • active antimicrobial sulfonamide derivatives of the invention are identified using in vitro screening assay. Indeed, in many instances the antimicrobial sulfonamide derivatives of the invention will be used in vitro as preservatives, topical antimicrobial treatments, etc. Additionally, despite certain apparent limitations of in vitro susceptibility tests, clinical data indicate that a good correlation exists between minimal inhibitory concentration (MIC) test results and in vivo efficacy of antibiotic compounds (Murray, 1994, Antimicrobial Susceptibility Testing, Poupard et al, eds., Plenum Press, NY; Knudsen et al, 1995, Antimicrob. Agents Chemother. 39(6):1253-1258). Thus, isolated antimicrobial sulfonamide derivatives useful for treating infections and diseases related thereto are also conveniently identified by demonstrated in vitro antimicrobial activity against specified microbial targets.
  • MIC minimal inhibitory concentration
  • the in vitro antimicrobial activity of antimicrobial agents is tested using standard NCCLS bacterial inhibition assays, or MIC tests (see, National Committee on Clinical Laboratory Standards "Perfoimance Standards for Antimicrobial Susceptibility Testing," NCCLS Document M100-S5 Vol. 14, No. 16, December 1994; “Methods for dilution antimicrobial susceptibility test for bacteria that grow aerobically- Third Edition,” Approved Standard M7-A3, National Committee for Clinical Standards, Villanova, PA).
  • the antimicrobial sulfonamide derivatives of the invention maybe assessed for antimicrobial activity using in vivo models. Again, such models are well-known in the art.
  • antimicrobial sulfonamide derivatives of the invention will exhibit MICs of less than about 64 ⁇ g/mL, usually less than about 32 ⁇ g/mL, preferably less than about 16 ⁇ g/mL and most preferably less than about 4 ⁇ g/mL.
  • the antimicrobial sulfonamide derivatives of the invention may also exhibit antifungal activity, having MICs of about 50 ⁇ g/mL or less against a variety of fungi in standard in vitro assays.
  • antimicrobial sulfonamide derivatives that exhibit significant antimicrobial activity (i.e., less than 4 ⁇ g/mL), good water-solubility (at approx. neutral pH) and low toxicity. Toxicity is less of a concern for topical administration, as is water solubility.
  • the antimicrobial sulfonamide derivatives of the invention can be used in a wide variety of applications to inhibit the growth or kill microorganisms.
  • the antimicrobial sulfonamide derivatives may be used as disinfectants or as preservatives for materials such as foodstuffs, cosmetics, medicaments and other nutrient containing materials.
  • the antimicrobial sulfonamide derivatives can also be used to treat or prevent diseases related to microbial infection in subjects such as plants and animals.
  • the antimicrobial sulfonamide derivatives can be added to the desired material singly, as mixtures of antimicrobial sulfonamide derivatives or in combination with other antifungal and/or antimicrobial agents.
  • the antimicrobial sulfonamide derivatives may be supplied as the compound per se or may be in admixture with a variety of adjuvants, carriers, diluents or excipients, which are well known in the art.
  • the antimicrobial sulfonamide derivatives of the invention can be administered or applied singly, as mixtures of two or more antimicrobial sulfonamide derivatives, in combination with other antifungal, antibiotic or antimicrobial agents or in combination with other pharmaceutically active agents.
  • the antimicrobial sulfonamide derivatives can be administered or applied per se or as pharmaceutical compositions.
  • the specific pharmaceutical formulation will depend upon the desired mode of administration, and will be apparent to those having skill in the art. Numerous compositions for the topical or systemic administration of antibiotics are described in the literature. Any of these compositions may be formulated with the antimicrobial sulfonamide derivatives of the invention.
  • compositions comprising the antimicrobial sulfonamide derivatives of the invention may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable adjuvants, carriers, diluents, excipients or auxiliaries which facilitate processing of the active antimicrobial sulfonamide derivatives into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the antimicrobial sulfonamide derivatives of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
  • Systemic formulations include those designed for administration by injection, e.g. subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.
  • the antimicrobial sulfonamide derivatives of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • the solution may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the antimicrobial sulfonamide derivatives may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art.
  • the antimicrobial sulfonamide derivatives can be readily formulated by combining them with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents; and binding agents.
  • disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • solid dosage forms may be sugar-coated or enteric-coated using standard techniques.
  • suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. Additionally, flavoring agents, preservatives, coloring agents and the like may be added.
  • compositions may take the form of tablets, lozenges, etc. formulated in conventional manner.
  • the compounds of the present invention are conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the antimicrobial sulfonamide derivatives may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the antimicrobial sulfonamide derivatives may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • Liposomes and emulsions are well known examples of delivery vehicles that may be used to deliver the antimicrobial sulfonamide derivatives of the invention.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the antimicrobial sulfonamide derivatives may be delivered using a sustained- release system, such as semipermeable matrices of solid polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • the antimicrobial sulfonamide derivatives of the invention are acidic, or the lipophilic group or linker may include acidic or basic substituents
  • the antimicrobial sulfonamide derivatives may be included in any of the above-described formulations as the free acids, the free bases or as pharmaceutically acceptable salts.
  • antimicrobial sulfonamide derivatives of the invention will generally be used in an amount effective to achieve the intended purpose.
  • amount used will depend on the particular application.
  • an antimicrobially effective amount of a antimicrobial sulfonamide derivative, or composition thereof is applied or added to the material to be disinfected or preserved.
  • antimicrobially effective amount is meant an amount of antimicrobial sulfonamide derivative or composition that inhibits the growth of, or is lethal to, a target microbe. While the actual amount will depend on a particular target microbe and application, for use as a disinfectant or preservative the antimicrobial sulfonamide derivatives, or compositions thereof, are usually added or applied to the material to be disinfected or preserved in relatively low amounts.
  • the antimicrobial sulfonamide derivatives comprises less than about 5% by weight of the disinfectant solution or material to be preserved, preferably less than about 1% by weight and more preferably less than about 0.1% by weight.
  • An ordinarily skilled artisan will be able to determine antimicrobially effective amounts of particular antimicrobial sulfonamide derivatives for particular applications without undue experimentation using, for example, the in vitro assays provided in the examples.
  • the antimicrobial sulfonamide derivatives of the invention, or compositions thereof are administered or applied in a therapeutically effective amount.
  • therapeutically effective amount is meant an amount effective to ameliorate the symptoms of, or ameliorate, treat or prevent microbial infections. Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • a therapeutically effective amount is between about 20 mg/kg and about 0.5 mg/kg, more preferably between about 10 mg/kg and about 1 mg/kg, most preferably between about 5 mg/kg and about 2 mg/kg.
  • a therapeutically effective dose for topical administration to treat or prevent microbial, yeast, fungal or other infection, can be determined using conventional methods by the skilled artisan.
  • the treatment may be applied while the infection is visible, or even when it is not visible.
  • An ordinarily skilled artisan will be able to determine therapeutically effective amounts to treat topical infections without undue experimentation.
  • a therapeutically effective dose can be estimated initially from in vitro assays.
  • a dose can be formulated in animal models to achieve a circulating antimicrobial sulfonamide derivative concentration range that includes the IC 50 as determined in cell culture (i.e., the concentration of test compound that is lethal to 50% of a cell culture), the MIC as determined in cell culture (i.e., the minimal inhibitory concentration for growth) or the IC 100 as determined in cell culture (i.e., the concentration of antimicrobial sulfonamide derivative that is lethal to 100% of a cell culture).
  • IC 50 as determined in cell culture
  • the MIC i.e., the minimal inhibitory concentration for growth
  • the IC 100 as determined in cell culture
  • Initial dosages can also be estimated from in vivo data (e.g., animal models) using techniques that are well known in the art.
  • in vivo data e.g., animal models
  • One of ordinary skill in the art can readily optimize administration to humans based on animal data.
  • initial dosages can be determined from the dosages administered of known antimicrobial agents (e.g., aspartocin, laspartomycin etc.) by comparing the IC 50 , MIC and or I 100 of the specific antimicrobial sulfonamide derivatives with that of a known antimicrobial agent, and adjusting the initial dosages accordingly.
  • the optimal dosage may be obtained from these initial values by routine optimization.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active antimicrobial sulfonamide derivatives which are sufficient to maintain therapeutic effect.
  • Usual patient dosages for administration by injection range from about 0.1 to 5 mg/kg/day, preferably from about 0.5 to 1 mg/kg/day.
  • Therapeutically effective serum levels may be achieved by administering a single daily dose or multiple doses each day.
  • the effective local concentration of antimicrobial sulfonamide derivative may not be related to plasma concentration.
  • One having skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.
  • the amount of antimicrobial sulfonamide derivative administered will, of course, be dependent on, among other factors, the subject being treated, the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • the antimicrobial therapy may be repeated intermittently while infections are detectable, or even when they are not detectable.
  • the therapy may be provided alone or in combination with other drugs, such as for example other antibiotics or antimicrobials, or other antimicrobial sulfonamide derivatives of the invention.
  • a therapeutically effective dose of the antimicrobial sulfonamide derivatives described herein will provide therapeutic benefit without causing substantial toxicity.
  • Toxicity of the antimicrobial sulfonamide derivatives can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD 50 (the dose lethal to 50% of the population) or the LD 100 (the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index.
  • Antimicrobial sulfonamide derivatives which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in subjects.
  • the dosage of the antimicrobial sulfonamide derivatives described herein lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (See, e.g., Fingl et al, 1975, In: The Pharmacological Basis of Therapeutics, Ch.l, p.l). 5.
  • the deacylase is produced by culturing Actinoplanes utahensis NRRL 12052 under submerged aerobic fermentation conditions. Because single-colony isolates from a lyophile of the culture were heterogeneous for both morphology and enzyme production capability, selections were made to recover a stable, high-producing variant. Initially, multiple fermentations were carried out using inocula prepared from strain 12052. Vegetative growth from the flask yielding high deacylating activity was plated on a differential agar (CM). Colonies were then selected for further evaluation. Generally, small colony types were better enzyme producers than large colony types. Isolate No.
  • CM agar contained corn steep liquor 0.5%, Bacto peptone 0.5%, soluble starch 1.0%. NaCl 0.05%, CaCl 2 .2H 2 O 0.05% and Bacto agar 2.0%.
  • the high-producing, natural variant was used in the known fermentation protocol employed (Boeck et al, 1988. J. Antibiot, 41, 1085).
  • the resulting mycelial suspension was transferred into 50 mL of PM3 medium in a 250 mL Erlenmeyer flask.
  • the PM3 medium contained 2.0% sucrose, 1.0% peanut meal, 0.12% K 2 HPO 4 , 0.05% KH 2 PO 4 and 0.025% MgSO 4 -7H 2 O, in tap water.
  • the flask was incubated at a temperature of 30 °C for a period of between 60 to 90 hrs.
  • the whole broth from this fermentation contained the deacylase enzyme.
  • the combined butanol extracts were mixed with an equal amount of water, the mixture adjusted to about pH 2.0 and the butanol phase washed with about 160 mL of water adjusted to approximately pH 2.0. Aspartocin, was then extracted into water at about pH 7.0 and then back into butanol at a pH of between about pH 2.0 to about pH 3.0. The butanol phase was washed with about 100 mL of water at approximately pH. 2.0, then combined with an equal volume of water and adjusted to about pH 7.0. The pH adjustments were made with 1 N HCl and 1 N NaOH. The aqueous phase is evaporated under vacuum to remove residual butanol.
  • Aspartocin (0.54g, 0.41 mmol) preferably purified as described in Section 5.2.1, and 0.30 mL (1.73 mmol) of diisopropylethylamine were dissolved in 5 mL of H 2 O, cooled in an ice bath.
  • 9-fluorenylmethyloxycarbonyl (“FMOC”) chloride 0.26 g (1.0 mmol) was dissolved in 2.0 mL of dioxane and 1.0 mL of this solution added to the cooled aspartocin solution.
  • the aqueous phase was filtered through Celite, evaporated to remove residual EtOAc, and freeze-dried to obtain 0.56 g of product.
  • the salt was then dissolved in 15 mL of H 2 O, centrifuged to remove a small amount of insoluble material, acidified to pH 1.88 with IN HCl, separated from the acidified solution by ce ⁇ trifugation, washed with H 2 O, and dried in vacuo over P 2 O 5 to yield 0.31 g of the free acid.
  • FAB-MS of the major component had m/z 1542 (M+H) + .
  • FMOC-aspartocin (476 mg of about 65% purity) prepared as described in Section 5.2.2 was dissolved in 30 mL of 0.5 M potassium phosphate buffer, pH 7.1, to which 300 mL of deacylase fermentation broth was added. The reaction mixture was incubated for about 18 hours at about 29 °C. Conversion of FMOC-Aspartocin to the deacylated product was estimated to be about 72% complete by HPLC analysis. Acetonitrile (150 mL) was added to the fermentation broth, the mixture sonicated for about 1 minute, centrifuged at 3000 rpm for 5 minutes and decanted.
  • the decanted supernatant was diluted with an equal volume of distilled water (total volume about 900 mL), split into three equal portions, and applied to three styrene-divinylbenzene resin cartridges (ENVI-Chrom P resin, 3.1g per cartridge, 25 x 30 mm).
  • the cartridges were eluted by gravity flow using a stepwise gradient in acetonitrile buffered with 0.025 M potassium phosphate at pH 7.1.
  • the deacylated product was eluted with a 23-27% acetonitrile gradient. Appropriate fractions were pooled and acetonitrile removed under vacuum at room temperature.
  • deacylated FMOC-aspartocin prepared as described in Section 5.2.3; approximately 65% pure as the major component
  • the hydroxybenzotriazole activated ester of decanesulfonylglycine was added incrementally to the above solution at room temperature and the reaction monitored by HPLC. After about 2.5 hours the conversion to product was estimated to be about 71% with the total amount of presumed product about 6 mg.
  • the reaction mixture was poured over 4.0 g ice and the pH adjusted to about 6.7 by addition of 2 drops of H 3 PO 4 , 2 mL of 0.5M ammonium phosphate buffer pH 7.2 and 2 mL of acetonitrile. After storage in the freezer for about 3 days the thawed reaction mixture was diluted with 2 mL of 0.5 M acetate buffer (pH 4.6) and 4 mL of distilled water; the pH was adjusted to about pH 4.9 by addition of acetic acid to provide a slightly turbid solution. The solution was applied to a divinylbenzene-styrene resin cartridge (Supelco ENVI-Chrom P, 5.0 g, 25 x 40 mm) with gravity flow.
  • a divinylbenzene-styrene resin cartridge Supelco ENVI-Chrom P, 5.0 g, 25 x 40 mm
  • deacylated FMOC-aspartocin prepared as described in Section 5.2.3; approximately 65% pure as the major component
  • the HOBT activated ester of decanesulfonylglycine was added incrementally to the peptide solution and the reaction was monitored by HPLC until the conversion to product was about 95%.
  • the total amount of presumed product was estimated to be about 32.0 mg.
  • the reaction mixture was diluted with about 5 mL of methanol, the apparent pH adjusted to between about 6-7 using 1.5M NH 4 OH and then filtered through a 0.45 ⁇ m membrane.
  • the filtrate was chromatographed on a Sephadex LH-20 size exclusion column, which was eluted with methanol. Fractions containing product were pooled and methanol was evaporated under vacuum to provide about 64 mg of solid residue, which contained about 29 mg of product.
  • the partially purified product was deblocked by dissolving in about 2 mL of dimethylsulfoxide/ methanol (2/1), adding 2 drops of piperdine and stirring at about 25 °C for 75 minutes. The reaction mixture was then diluted with about 20 mL of 10% acetonitrile buffered ammonium phosphate (apparent pH of about 7.8), and then filtered through a 0.45 ⁇ m membrane.
  • Laspartomycin 257 mg in about 12 mL of 0.5M phosphate buffer of about pH 7.2 was added to about 120 mL of deacylase fermentation broth prepared as in Section 5.1 and incubated for about 16 hours at about 29°C at about 180 rpm. The broth was centrifuged, the centrifugate decanted and solids were extracted with about 40 mL of distilled water. The pooled centrifugates were then applied to a 2.5 x 5.0 cm styrene-divinylbenzene resin column (ENVITM-Chrom P) and the product was eluted with a 10% and 11% acetonitrile-pH 7.2 phosphate mixture.
  • ENVITM-Chrom P 2.5 x 5.0 cm styrene-divinylbenzene resin column
  • FAB-MS m/z 910 (HR-FAB-MS of the amino core cyclic peptide of laspartomycin: found 910.4251(M+H) + , calc. 910.4270 for C 38 H 59 N n O ]5 + H). Also obtained was about 14 mg of an isomer of the amino core cyclic peptide of laspartomycin as an off white solid. FAB-MS: m/z 910(M+H) + .
  • laspartomycin was treated with the deacylase broth under conditions similar to those described in Example 5.3.1 except where explicitly noted.
  • About 1.0 g of laspartomycin was treated with deacylase fermentation broth at about 2.0 mg/mL for about 3.7 hrs to produce a sample enriched in the amino core antibiotic of laspartomycin.
  • About 1.5 g of laspartomycin was treated with deacylase fermentation broth at about 5.0 mg/mL for about 20 hours.
  • the fermentation broths were pooled and then processed as described in 5.3.1 to provide about 100 mg of the amino core antibiotic of laspartomycin and about 600 mg of the amino core cyclic peptide of laspartomycin, and an estimated 150 mg of an isomer of the amino core cyclic peptide of laspartomycin.
  • FAB-MS of the amino core antibiotic of laspartomycin m/z 1026(M+H) + , 1048(M+Na) + .
  • Hexadecylsulfonyl-L-Tryptophan (90 mg, 0183 mmol), hydroxybenzotriazole (28 mg, 0.183 mmol), and dicyclohexylcarbodiimide (38 mg, 0.183 mmol) was stirred for 40 minutes in 1.0 mL of dimethylformamide. A 0.30 mL aliquot of this solution was added to a solution of the amino core antibiotic of laspartomycin (94.5 mg, 0.0439 mmol) in 0.20 mL of dimethylformamide. The progress of the reaction was monitored by HPLC. At the completion of the reaction, the reaction mixture was diluted with 5mL of methanol and 1.5M NH 4 OH was added to an apparent pH of about 7.
  • the filtered sample solution was applied to a 2.5 x 44 cm size exclusion column (Sephadex LH-20 fine, swelled in methanol) which was eluted with methanol at about 0.8 mL/min.
  • the product eluted in about 25 L of eluate starting at about 105 mL.
  • the methanol was removed from the product pool by evaporation under vacuum at or below 30°C.
  • the solid residue was dissolved in about 12 mL of 10% acetonitrile buffered with 0.08M ammonium phosphate (aqueous pH 7.2).
  • Hexadecylsulfonyl-L-phenylalanine 60 mg, 0.132 mmol
  • hydroxybenzotriazole (19 mg, 0.132 mmol)
  • dicyclohexylcarbodiimide 32 mg, 0.151 mmol
  • a 0.30 mL aliquot of this solution was added to a solution of the amino core antibiotic of laspartomycin (50 mg., 0.0488 mmol) in 0.40 mL of dimethylformamide.
  • the progress of the reaction was monitored by HPLC and the product was isolated by chromatography in a similar fashion to that described in 5.4.3.
  • N-hexadecylsulfonyl-(O-t-butyl)-L-aspartic acid (189 mg, 0.395 mmol, 1- hydroxybenzotriazole (55 mg, 0.395 mmol) and dicyclohexylcarbodiimide (83 mg, 0.395 mmol) in 0.50 mL of dimethylformamide was stirred at room temperature for forty five minutes. A 0.050 mL aliquot of this solution was added to the tetrabutylammonium salt of the amino core cyclic peptide of laspartomycin in 0.2 mL of dimethylformamide and stirred at room temperature for sixty minutes.
  • the reaction mixture was quenched by dilution with 8 mL of 25% acetonitrile, 0.12 M in ammonium phosphate (pH 7.2), aged at room temperature, then membrane filtered (Whatman GD/X).
  • the product was isolated from the filtrate by low resolution reverse phase chromatography on a 5 g styrene-divinylbenzene resin cartridge (25 x 45 mm, Supelco EnviChrom-P).
  • the sample-loaded cartridge was eluted with stepwise increasing concentrations of acetonitrile in sodium phosphate (aqueous pH 6.9); the product was eluted with 57% acetonitrile, 0.010 M in pH 6.9 buffer.
  • the material was then desalted as described in Section 5.4.3. Yield: 4.7 mg of white solid, 69% by HPLC (215 nm area %); C 62 H ⁇ o N 12 O 20 S.
  • the product was further purified by preparative HPLC (Waters Delta-Pak C18 column, 25 x 110 mm) using 53% isopropanol and 0.03 M in ammonium acetate (aqueous pH 5.4) at a flow rate of 10 mL/min at room temperature. Isopropanol was removed under vacuum and the pH of the turbid aqueous solution was adjusted to pH 6 with dilute ammonium hydroxide. The product was desalted and freeze dried as previously described above. Yield: 16 mg of a white solid, 66% by HPLC (215 nm area %); C 85 H 120 N 14 O 24 S; FABMS m/z 1776 (M+Na) + , 1791(M+K) + . Calculated for C 85 H 120 N 14 O 24 S + Na, 1776).
  • MIC values were determined by microliter serial dilution using Staphlococcus aureus strain Smith as the assay organism, which was grown in Mueller-Hinton broth with and without CaCl 2 ..

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Abstract

L'invention concerne des dérivés sulfonamide antimicrobiens d'antibiotiques lipopeptidiques, des compositions pharmaceutiques de dérivés sulfonamide antimicrobiens, des procédés de production de dérivés sulfonamide antimicrobiens, des procédés d'inhibition de croissance microbienne au moyen de dérivés sulfonamide antimicrobiens, et des méthodes de traitement et de prévention d'infections microbiennes chez un sujet au moyen des dérivés sulfonamide antimicrobiens. Les dérivés sulfonamide antimicrobiens sont généralement un antibiotique noyau aminé ayant subi une modification supplémentaire au moyen d'un groupe sulfonyle lipophilique.
PCT/US2001/022352 2000-07-17 2001-07-17 Derives sulfonamide antimicrobiens d'antibiotiques lipopeptidiques WO2002005837A1 (fr)

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JP2002511769A JP2004529065A (ja) 2000-07-17 2001-07-17 リポペプチド抗生物質の抗菌スルホンアミド誘導体
AU2001278933A AU2001278933B2 (en) 2000-07-17 2001-07-17 Antimicrobial sulfonamide derivatives of lipopeptide antibiotics
DE60131085T DE60131085T2 (de) 2000-07-17 2001-07-17 Antimikrobielle sulfonamide-derivate von lipopeptidantibiotika
AU7893301A AU7893301A (en) 2000-07-17 2001-07-17 Antimicrobial sulfonamide derivatives of lipopeptide antibiotics
CA002450372A CA2450372A1 (fr) 2000-07-17 2001-07-17 Derives sulfonamide antimicrobiens d'antibiotiques lipopeptidiques
EP01957162A EP1311281B1 (fr) 2000-07-17 2001-07-17 Derives sulfonamide antimicrobiens d'antibiotiques lipopeptidiques

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WO2003057724A1 (fr) 2002-01-03 2003-07-17 Micrologix Biotech Inc. Derives dab9 d'antibiotiques lipopeptidiques et techniques de fabrication et d'utilisation de ceux-ci
EP1355920A1 (fr) * 2001-01-12 2003-10-29 Micrologix Biotech, Inc. Purification extractive d'antibiotiques lipopeptidiques
WO2005000878A2 (fr) * 2003-06-26 2005-01-06 Migenix Inc. Compositions a base de derives antibiotiques de la classe des lipopeptides et leurs methodes d'utilisation
WO2006083317A2 (fr) * 2004-07-01 2006-08-10 Biosource Pharm, Inc. Antibiotiques peptidiques et leurs methodes de fabrication
US8343912B2 (en) 2008-12-23 2013-01-01 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
US8415307B1 (en) 2010-06-23 2013-04-09 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
WO2017173932A1 (fr) * 2016-04-08 2017-10-12 Versitech Limited Lipopeptides cycliques antibactériens
US10647746B2 (en) 2016-04-08 2020-05-12 Versitech Limited Antibacterial cyclic lipopeptides
US10947271B2 (en) 2014-02-10 2021-03-16 The University Of Queensland Antibacterial agents
US11667674B2 (en) 2016-04-08 2023-06-06 Versitech Limited Antibacterial cyclic lipopeptides

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US4495348A (en) * 1980-12-04 1985-01-22 Nippon Kayaku Kabushiki Kaisha Derivative of cephamycin C
US5629288A (en) * 1994-03-30 1997-05-13 Hoechst Aktiengesellschaft Lipopeptide derivatives, a process for their preparation and their use
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US7138487B2 (en) 2000-07-17 2006-11-21 Migenix Inc. Extractive purification of lipopeptide antibiotics
EP1355920A1 (fr) * 2001-01-12 2003-10-29 Micrologix Biotech, Inc. Purification extractive d'antibiotiques lipopeptidiques
EP1355920A4 (fr) * 2001-01-12 2005-04-20 Micrologix Biotech Inc Purification extractive d'antibiotiques lipopeptidiques
WO2003057724A1 (fr) 2002-01-03 2003-07-17 Micrologix Biotech Inc. Derives dab9 d'antibiotiques lipopeptidiques et techniques de fabrication et d'utilisation de ceux-ci
US7655623B2 (en) 2002-01-03 2010-02-02 Migenix Inc. Dab9 derivatives of lipopeptide antibiotics and methods of making and using the same
US7125844B2 (en) 2002-01-03 2006-10-24 Migenix Inc. Dab9 derivatives of lipopeptide antibiotics and methods of making and using the same
WO2005000878A2 (fr) * 2003-06-26 2005-01-06 Migenix Inc. Compositions a base de derives antibiotiques de la classe des lipopeptides et leurs methodes d'utilisation
US7868135B2 (en) 2003-06-26 2011-01-11 Biowest Therapeutics Inc. Compositions of lipopeptide antibiotic derivatives and methods of use thereof
EP2147925A1 (fr) * 2003-07-17 2010-01-27 Migenix Inc. Compositions de dérivés d'antibiotiques lipopeptides et leurs méthodes d'utilisation
EA010294B1 (ru) * 2003-07-17 2008-08-29 Майджиникс, Инк. Композиции на основе производных липопептидных антибиотиков и способы их применения
WO2005000878A3 (fr) * 2003-07-17 2005-06-16 Migenix Inc Compositions a base de derives antibiotiques de la classe des lipopeptides et leurs methodes d'utilisation
JP2007536200A (ja) * 2003-07-17 2007-12-13 ミジェニックス インコーポレイテッド リポペプチド抗生物質誘導体の組成物およびその使用方法
US8889826B2 (en) 2004-07-01 2014-11-18 Biosource Pharm, Inc. Peptide antibiotics and methods for making same
JP2008505858A (ja) * 2004-07-01 2008-02-28 バイオソース・ファーム・インコーポレイテッド ペプチド抗生物質およびその製造方法
WO2006083317A3 (fr) * 2004-07-01 2007-01-18 Biosource Pharm Inc Antibiotiques peptidiques et leurs methodes de fabrication
WO2006083317A2 (fr) * 2004-07-01 2006-08-10 Biosource Pharm, Inc. Antibiotiques peptidiques et leurs methodes de fabrication
EP2332965A1 (fr) * 2004-07-01 2011-06-15 BioSource Pharm, Inc. Antibiotiques peptidiques et leurs methodes de fabrication
JP2011256189A (ja) * 2004-07-01 2011-12-22 Biosource Pharm Inc ペプチド抗生物質およびその製造方法
US8343912B2 (en) 2008-12-23 2013-01-01 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
US8937040B2 (en) 2008-12-23 2015-01-20 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
US8415307B1 (en) 2010-06-23 2013-04-09 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
US8906866B2 (en) 2010-06-23 2014-12-09 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
US10947271B2 (en) 2014-02-10 2021-03-16 The University Of Queensland Antibacterial agents
WO2017173932A1 (fr) * 2016-04-08 2017-10-12 Versitech Limited Lipopeptides cycliques antibactériens
US10647746B2 (en) 2016-04-08 2020-05-12 Versitech Limited Antibacterial cyclic lipopeptides
US11667674B2 (en) 2016-04-08 2023-06-06 Versitech Limited Antibacterial cyclic lipopeptides

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