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WO2017173932A1 - Lipopeptides cycliques antibactériens - Google Patents

Lipopeptides cycliques antibactériens Download PDF

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WO2017173932A1
WO2017173932A1 PCT/CN2017/078056 CN2017078056W WO2017173932A1 WO 2017173932 A1 WO2017173932 A1 WO 2017173932A1 CN 2017078056 W CN2017078056 W CN 2017078056W WO 2017173932 A1 WO2017173932 A1 WO 2017173932A1
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substituted
unsubstituted
alkyl
aryl
alkenyl
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Xuechen Li
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Versitech Ltd
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Versitech Ltd
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Priority claimed from US15/093,950 external-priority patent/US10647746B2/en
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Priority to US16/310,364 priority Critical patent/US11667674B2/en
Priority to CN201780035657.3A priority patent/CN109476704B/zh
Publication of WO2017173932A1 publication Critical patent/WO2017173932A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6018—Lipids, e.g. in lipopeptides
    • 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 invention is in the field of antibacterial agents, particularly antibacterial cyclic lipopeptides.
  • antibiotics differ in their effectiveness against different pathogenic organisms. Further, pathogenic organisms are known to develop resistance to antibiotics that were once effective against the organisms. Exacerbating this situation is that individual patients frequently suffer serious reactions to specific antibiotics, due to hypersensitivity and/or to toxic effects. Consequently, there is a continuing need for new and improved antibiotics.
  • daptomycin is a cyclic lipodepsipeptide consisting of 13 amino acids, 10 of which make up a 31-membered ring and three are anchored as an exocyclic tail with the N-terminal containing n-decanoyl lipid.
  • kynurenine Kyn
  • 3-methyl-glutamic acid 3-mGlu
  • D amino acids i.e., D-Asn, D-Ala and D-Ser
  • this compound exhibits a unique mode of action which is significantly different from that of other currently used antibiotics: it first undergoes a conformational change upon binding to Ca 2+ ions, so that the entire structure can be inserted into bacterial membranes via the lipid tail, which then induces membrane leakage and cell death.
  • Described herein are a set of cyclic lipopeptides based on modifications of daptomycin, their methods of making and using.
  • the cyclic lipopeptides can be used as antibacterial agents.
  • cyclic lipopeptides have the general formula:
  • R is substituted aryl or substituted alkenyl
  • R5 is- (CH 2 ) x -NR* 2
  • x is three and each R*is independently unsubstituted alkyl, substituted alkyl, substituted aryl, or unsubstituted aryl, preferably are both unsubstituted alkyl (e.g. methyl)
  • R1 is substituted polyheteroaralkyl (e.g. N-alkylated indol-3-ylalkyl such as N-methyl indol-3-ylmethyl) , unsubstituted polyaralkyl (e.g.
  • R’ is hydrogen, unsubstituted alkyl (e.g. methyl) , substituted alkyl, unsubstituted aryl, or unsubstituted aryl;
  • R” is hydrogen, unsubstituted alkyl (e.g. methyl and ethyl) , substituted alkyl, unsubstituted aryl, or unsubstituted aryl;
  • R12 is a substituted alkyl containing a substituted aniline; and X is O or NH.
  • the cyclic lipopeptides are generated, preferably, by chemical synthesis, which facilitates the introduction of an unnatural amino acid or modification into daptomycin. Chemical synthesis was used to generate analogues with wider modifications and to introduce modifications at Trp1, Thr4, Gly5, and Kyn13.
  • these generated cyclic lipopeptides have N-alkylated or N-acylated kynurenine to replace kynurenine (Kyn13) ; N-alkyl indol-3-ylalkyl (N-methyl indol-3-ylmethyl, i.e., MeTrp) , 1-naphthylmethyl, or 2-naphthylmethyl to replace Trp1; sarcosine to replace Gly5, an alkylated Orn to replace Orn6; and/or 2, 3-diaminobutyric acid or 2, 3-diaminopropionic acid to replace Thr4.
  • compositions including the disclosed compounds and methods of use thereof for treating subject in need thereof are also provided.
  • Fig. 1 illustrates the chemical structure of daptomycin with amino acid numbering.
  • Fig. 2 illustrates the chemical structure of methylation at Gly5 within daptomycin.
  • Fig. 3 illustrates the chemical structure of methylation at Kyn13 within daptomycin.
  • Fig. 4 illustrates the chemical structure of methylation at Trp1 within daptomycin.
  • Fig. 5 illustrates the chemical structure of methylation at Orn5 within daptomycin.
  • Fig. 6 illustrates the chemical structure of acylation at the lipid within daptomycin, and an alternative structure for the acylating group.
  • Fig. 7 illustrates two chemical structures of replacing Trp1 with 1-naphthylmethyl or 2-naphthylmethyl within daptomycin.
  • amino acid refers to a molecule containing both an amino group and a carboxyl group.
  • Amino acids include alpha- amino acids and beta-amino acids. In certain forms, an amino acid is an alpha amino acid. Amino acids can be natural or synthetic.
  • Amino acids include, but are not limited to, the twenty standard or canonical amino acids: Alanine (Ala, A) , Arginine (Arg, R) , Asparagine (Asn, N) , Aspartic Acid (Asp, D) , Cysteine (Cys, C) , Glutamine (Gln, Q) , Glutamic Acid (Glu, E) , Glycine (Gly, G) , Histidine (His, H) , Isoleucine (Ile, I) , Leucine (Leu, L) , Lysine (Lys, K) , Methionine (Met, M) , Phenylalanine (Phe, F) , Proline (Pro, P) , Serine (Ser, S) , Threonine (Thr, T) , Tryptophan (Trp, W) , Tyrosine (Tyr, Y) , and Valine (Val, V) .
  • natural amino acid refers to both the D-and L-isomers of the 20 common naturally occurring amino acids found in peptides (e.g., A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V (as known by the one letter abbreviations)) .
  • synthetic amino acid “non-natural amino acid, ” and “unnatural amino acid, ” are used interchangeably, and refer to an organic compound that has an amino group and a carboxyl group, and is not one of the D-and L-isomers of the 20 common naturally occurring amino acids found in peptides. Generally, it mimics the reactivity of a natural amino acid due to the presence of the amino and carboxyl groups. “Synthetic amino acid, ” “non-natural amino acid, ” or “unnatural amino acid” also refers to an amino acid that is not produced by an organism without genetic engineering.
  • the synthetic amino acid as defined herein generally increases or enhances the properties of a peptide (e.g., selectivity, stability) when the synthetic amino acid is either substituted for a natural amino acid or incorporated into a peptide.
  • Non-limiting examples include N-methyl kynurenine, N, N-dimethyl kynurenine, N-methyl ornithine, N, N-dimethyl ornithine, N-methyl glycine (sarcosine) , 2, 3-diaminobutyric acid, 2, 3-diamino propionic acid, and alpha-amino acids with the following side chains: 1-naphthylmethyl, 1-naphthylmethyl, and N-methyl indol-3-ylmethyl.
  • isolated refers to a compound or product that is refers to a compound which represents at least 10%by wt, at least 20%by wt, at least 30%, at least 50%by wt, at least 60%by wt, at least 70%by wt, at least 80%by wt, at least 90%by wt, or at least 95%by wt of the compound present in the mixture.
  • lipopeptide refers to a molecule that comprises a lipid-like moiety covalently linked to a peptide moiety, as well as salts, esters, amides and ethers thereof.
  • lipopeptide also encompasses protected forms of lipopeptides in which one or more amino, carboxylate or hydroxyl groups are protected.
  • Amino and “Amine, ” as used herein, are art-recognized and refer to a primary, secondary, or tertiary amine which may be optionally substituted, e.g. a moiety that can be represented by the general formula:
  • R, R’, and R each independently represent a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, - (CH 2 ) m -R”’, or R and R’taken together with the N atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure;
  • R”’ represents a hydroxy group, substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, or a polycycle; and m is zero or an integer ranging from 1 to 8.
  • R and R’ can be a carbonyl, e.g., R and R’together with the nitrogen do not form an imide.
  • R and R’ (and optionally R”) each independently represent a hydrogen atom, substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or- (CH 2 ) m -R”’.
  • alkylamine refers to an amine group, as defined above, having a substituted alkyl or unsubstituted alkyl attached thereto (i.e. at least one of R, R’, or R”is an alkyl group) .
  • dialkylamine refers to an amine group, as defined above, having two substituted alkyl or unsubstituted alkyl attached thereto. Specifically included are secondary or tertiary amine nitrogen atoms which are members of a heterocyclic ring. Also specifically included, are secondary or tertiary amino groups substituted by an acyl moiety. Some non-limiting examples of an amino group include–NR’R”wherein each of R’and R”is independently H, alkyl, aryl, aralkyl, alkaryl, cycloalkyl, acyl, heteroalkyl, heteroaryl or heterocycyl.
  • Alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl, cycloalkyl (alicyclic) , alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 30 for straight chains, C 3 -C 30 for branched chains) , preferably 20 or fewer, more preferably 15 or fewer, most preferably 10 or fewer.
  • Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • alkyl (or “lower alkyl” ) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls, ” the latter of which refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents include, but are not limited to, halogen, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, a phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In preferred forms, a substituent designated herein as alkyl is a lower alkyl.
  • Alkyl includes one or more substitutions at one or more carbon atoms of the hydrocarbon radical as well as heteroalkyls. Suitable substituents include, but are not limited to, halogens, such as fluorine, chlorine, bromine, or iodine; hydroxyl; -NRR’, wherein R and R’are independently hydrogen, alkyl, or aryl, and wherein the nitrogen atom is optionally quaternized; -SR, wherein R is hydrogen, alkyl, or aryl; -CN; -NO 2 ; -COOH; carboxylate; -COR, -COOR, or-CON (R) 2, wherein R is hydrogen, alkyl, or aryl; azide, aralkyl, alkoxyl, imino, phosphonate, phosphinate, silyl, ether, sulfonyl, sulfonamido, heterocyclyl, aromatic or heteroaromatic moieties, halo
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include halogen, hydroxy, nitro, thiols, amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate) , sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate) , and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters) , haloalkyls, -CN and the like. Cycloalkyls can be substituted in the same manner.
  • Heteroalkyl refers to straight or branched chain, or cyclic carbon-containing radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized.
  • hydroxyalkyl means an alkyl radical as defined herein, substituted with one or more, preferably one, two or three hydroxy groups.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4- hydroxybutyl, 2, 3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxy-propyl, preferably 2-hydroxyethyl, 2, 3-dihydroxypropyl, and 1- (hydroxymethyl) 2-hydroxyethyl.
  • alkoxyl or “alkoxy, ” “aroxy” or “aryloxy, ” generally describe compounds represented by the formula-OR v , wherein R v includes, but is not limited to, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, heteroalkyls, alkylaryl, alkylheteroaryl.
  • alkoxyl or "alkoxy” as used herein refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of-O-alkyl, -O-alkenyl, and-O-alkynyl.
  • alkoxy also includes cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkenyl, and arylalkyl having an oxygen radical attached to at least one of the carbon atoms, as valency permits.
  • a “lower alkoxy” group is an alkoxy group containing from one to six carbon atoms.
  • substituted alkoxy refers to an alkoxy group having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the alkoxy backbone.
  • substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulf
  • alkenyl as used herein is a hydrocarbon group of from 2 to 24 carbon atoms and structural formula containing at least one carbon-carbon double bond.
  • alkynyl group as used herein is a hydrocarbon group of 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon triple bond.
  • aryl as used herein is any C 5 -C 26 carbon-based aromatic group, fused aromatic, fused heterocyclic, or biaromatic ring systems.
  • aryl, includes 5-, 6-, 7-, 8-, 9-, 10-, 14-,18-, and 24-membered single-ring aromatic groups, including, but not limited to, benzene, naphthalene, anthracene, phenanthrene, chrysene, pyrene, corannulene, coronene, etc.
  • Aryl further encompasses polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (i.e., “fused rings” ) wherein at least one of the rings is aromatic, e.g., the other cyclic ring or rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy.
  • substituted aryl refers to an aryl group, wherein one or more hydrogen atoms on one or more aromatic rings are substituted with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, carbonyl (such as a ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio,
  • Heterocycle, ” “heterocyclic” and “heterocyclyl” are used interchangeably, and refer to a cyclic radical attached via a ring carbon or nitrogen atom of a monocyclic or bicyclic ring containing 3-10 ring atoms, and preferably from 5-6 ring atoms, consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N (Y) wherein Y is absent or is H, O, C 1 -C 10 alkyl, phenyl or benzyl, and optionally containing 1-3 double bonds and optionally substituted with one or more substituents. Heterocyclyl are distinguished from heteroaryl by definition.
  • heterocycles include, but are not limited to piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, dihydrofuro [2, 3-b] tetrahydrofuran, morpholinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl, 2H-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl, 6H-1, 2, 5-thiadiazinyl.
  • Heterocyclic groups can optionally be substituted with one or more substituents as defined above for alkyl and aryl.
  • heteroaryl refers to C 5 -C 26 -membered aromatic, fused aromatic, biaromatic ring systems, or combinations thereof, in which one or more carbon atoms on one or more aromatic ring structures have been substituted with a heteroatom.
  • Suitable heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen.
  • heteroaryl includes 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered single-ring aromatic groups that may include from one to four heteroatoms, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • the heteroaryl group may also be referred to as “aryl heterocycles” or “heteroaromatics” .
  • Heteroaryl further encompasses polycyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings (i.e., “fused rings” ) wherein at least one of the rings is heteroaromatic, e.g., the other cyclic ring or rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heterocycles, or combinations thereof.
  • heteroaryl rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1, 5, 2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, is
  • substituted heteroaryl refers to a heteroaryl group in which one or more hydrogen atoms on one or more heteroaromatic rings are substituted with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, carbonyl (such as a ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, athioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthi
  • substituted alkenyl refers to alkenyl moieties having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone.
  • substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, s
  • substituted alkynyl refers to alkynyl moieties having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone.
  • substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate,
  • cycloalkyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • heterocycloalkyl group is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulphur, or phosphorus.
  • Alkyl refers to an alkyl group which is substituted with an aryl group. Some non-limiting examples of aralkyl include benzyl and phenethyl.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic groupings containing any number of carbon atoms, preferably 1-14 carbon atoms, and optionally include one or more heteroatoms such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats.
  • substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl
  • Heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. It is understood that “substitution” or “substituted” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e. a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • alkoxyalkyl group is defined as an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above that has at least one hydrogen atom substituted with an alkoxy group described above.
  • Carbonyl, ” as used herein, is art-recognized and includes such moieties as can be represented by the general formula:
  • R represents a hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, - (CH 2 ) m -R” , or a pharmaceutical acceptable salt
  • R’ represents a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycly
  • X is oxygen and R is defines as above, the moiety is also referred to as a carboxyl group.
  • the formula represents a ‘carboxylic acid’ .
  • the formula represents a ‘formate’ .
  • the formula represents an "ester” .
  • the oxygen atom of the above formula is replaced by a sulfur atom, the formula represents a ‘thiocarbonyl’ group.
  • the formula represents a ‘thioester. ’
  • X is sulfur and R is hydrogen, the formula represents a ‘thiocarboxylic acid.
  • substituted carbonyl refers to a carbonyl, as defined above, wherein one or more hydrogen atoms in R, R’ or a group to which the moiety
  • substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, halogen, azide, alkyl
  • R iv is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylaryl, arylalkyl, aryl, or heteroaryl.
  • a straight chain or branched chain alkyl, alkenyl, and alkynyl have 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 30 for straight chain alkyl, C 3 -C 30 for branched chain alkyl, C 2 -C 30 for straight chain alkenyl and alkynyl, C 3 -C 30 for branched chain alkenyl and alkynyl) , preferably 20 or fewer, more preferably 15 or fewer, most preferably 10 or fewer.
  • preferred cycloalkyls, heterocyclyls, aryls and heteroaryls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • substituted carboxyl refers to a carboxyl, as defined above, wherein one or more hydrogen atoms in R iv are substituted.
  • substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sul
  • phenoxy is art recognized, and refers to a compound of the formula-OR v wherein R v is (i.e., -O-C 6 H 5 ) .
  • R v is (i.e., -O-C 6 H 5 ) .
  • a phenoxy is a species of the aroxy genus.
  • substituted phenoxy refers to a phenoxy group, as defined above, having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the phenyl ring.
  • substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sul
  • aromatic radicals and “aryloxy, ” as used interchangeably herein, are represented by-O-aryl or-O-heteroaryl, wherein aryl and heteroaryl are as defined herein.
  • substituted aroxy and “substituted aryloxy, ” as used interchangeably herein, represent-O-aryl or-O-heteroaryl, having one or more substituents replacing one or more hydrogen atoms on one or more ring atoms of the aryl and heteroaryl, as defined herein.
  • substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by-S-alkyl.
  • Representative alkylthio groups include methylthio, ethylthio, and the like.
  • alkylthio also encompasses cycloalkyl groups having a sulfur radical attached thereto.
  • substituted alkylthio refers to an alkylthio group having one or more substituents replacing one or more hydrogen atoms on one or more carbon atoms of the alkylthio backbone.
  • substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, s
  • phenylthio is art recognized, and refers to-S-C 6 H 5 , i.e., a phenyl group attached to a sulfur atom.
  • substituted phenylthio refers to a phenylthio group, as defined above, having one or more substituents replacing a hydrogen on one or more carbons of the phenyl ring.
  • substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,
  • Arylthio refers to -S-aryl or -S-heteroaryl groups, wherein aryl and heteroaryl as defined herein.
  • substituted arylthio represents -S-aryl or -S-heteroaryl, having one or more substituents replacing a hydrogen atom on one or more ring atoms of the aryl and heteroaryl rings as defined herein.
  • substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN
  • amide or “amido” are used interchangeably, refer to both “unsubstituted amido” and “substituted amido” and are represented by the general formula:
  • E is absent, or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, wherein independently of E, R and R’each independently represent a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl
  • R and R’ can be a carbonyl, e.g., R and R’together with the nitrogen do not form an imide.
  • E oxygen
  • a carbamate is formed. The carbamate cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art.
  • E is absent, or E is alkyl, alkenyl, alkynyl, aralkyl, alkylaryl, cycloalkyl, aryl, heteroaryl, heterocyclyl, wherein independently of E, R represents a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amine, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, - (CH 2 ) m -R”’, or E and R taken together with the S atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the atom
  • E and R can be substituted or unsubstituted amine, to form a “sulfonamide” or “sulfonamido. ”
  • the substituted or unsubstituted amine is as defined above.
  • substituted sulfonyl represents a sulfonyl in which E, R, or both, are independently substituted.
  • substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamo
  • sulfonic acid refers to a sulfonyl, as defined above, wherein R is hydroxyl, and E is absent, or E is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • sulfate refers to a sulfonyl, as defined above, wherein E is absent, oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above, and R is independently hydroxyl, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above.
  • E oxygen
  • the sulfate cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art.
  • sulfonate refers to a sulfonyl, as defined above, wherein E is oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above, and R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amine, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, - (CH 2 ) m -R”’, R”’represents a hydroxy group, substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl, R
  • sulfamoyl refers to a sulfonamide or sulfonamide represented by the formula
  • E is absent, or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, wherein independently of E, R and R’each independently represent a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted
  • E is absent, or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, , wherein, independently of E, R vi and R vii are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substitute
  • substituted phosphonyl represents a phosphonyl in which E, R vi and R vii are independently substituted.
  • substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl,
  • phosphoryl defines a phosphonyl in which E is absent, oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above, and independently of E, R vi and R vii are independently hydroxyl, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above.
  • E oxygen
  • the phosphoryl cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art.
  • the substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkyl, halogen, azide, alkyl
  • polyaryl refers to a chemical moiety that includes two or more aryls, heteroaryls, and combinations thereof.
  • the aryls, heteroaryls, and combinations thereof, are fused, or linked via a single bond, ether, ester, carbonyl, amide, sulfonyl, sulfonamide, alkyl, azo, and combinations thereof.
  • the chemical moiety can be referred to as a “polyheteroaryl. ”
  • substituted polyaryl refers to a polyaryl in which one or more of the aryls, heteroaryls are substituted, with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl) , silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino) , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulf
  • polyaralkyl refers to polyaryl that is attached to an alkyl group.
  • the polyaralkyl can be substituted or unsubstituted.
  • polyheteroaralkyl refers to a polyheteroaryl that is attached to an alkyl group.
  • the polyheteroaralkyl can be substituted or unsubstituted.
  • C 3 -C 20 cyclic refers to a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl that have from three to 20 carbon atoms, as geometric constraints permit.
  • the cyclic structures are formed from single or fused ring systems.
  • the substituted cycloalkyls, cycloalkenyls, cycloalkynyls and heterocyclyls are substituted as defined above for the alkyls, alkenyls, alkynyls and heterocyclyls, respectively.
  • ether as used herein is represented by the formula AOA 1 , where A and A 1 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • urethane as used herein is represented by the formula-OC (O) NRR’, where R and R’can be, independently, hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.
  • silica group as usedherein is represented by the formula-SiRR’R”, where R, R’, and R”can be, independently, hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, alkoxy, or heterocycloalkyl group described above.
  • hydroxyl and “hydroxy” are used interchangeably and are represented by-OH.
  • nitro refers to-NO 2 .
  • phosphate refers to-O-PO 3 .
  • azide or “azido” are used interchangeably to refer to-N 3 .
  • the disclosed compounds and substituent groups can, independently, possess two or more of the groups listed above.
  • the compound or substituent group is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can be substituted with a hydroxyl group, an alkoxy group, etc.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group.
  • the ester group can be incorporated within the backbone of the alkyl group.
  • the ester can be attached to the backbone of the alkyl group.
  • the nature of the group (s) that is (are) selected will determine if the first group is embedded or attached to the second group.
  • an effective amount and “therapeutically effective amount, ” used interchangeably, as applied to the compounds, antibiotics, and pharmaceutical compositions described herein, mean the quantity necessary to render the desired therapeutic result.
  • an effective amount is a level effective to treat, cure, or alleviate the symptoms of a disease for which the composition and/or antineoplastic, or pharmaceutical composition, is/are being administered.
  • Amounts effective for the particular therapeutic goal sought will depend upon a variety of factors including the disease being treated and its severity and/or stage of development/progression; the bioavailability and activity of the specific compound and/or antineoplastic, or pharmaceutical composition, used; the route or method of administration and introduction site on the subject; the rate of clearance of the specific composition and other pharmacokinetic properties; the duration of treatment; inoculation regimen; drugs used in combination or coincident with the specific composition; the age, body weight, sex, diet, physiology and general health of the subject being treated; and like factors well known to one of skill in the relevant scientific art. Some variation in dosage will necessarily occur depending upon the condition of the subject being treated, and the physician or other individual administering treatment will, in any event, determine the appropriate dosage for an individual patient.
  • inhibitor means to reduce or decrease in activity or expression. This can be a complete inhibition or activity or expression, or a partial inhibition. Inhibition can be compared to a control or to a standard level. Inhibition can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 15 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to a subject along with the selected compound without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • treatment refers to arresting or inhibiting, or attempting to arrest or inhibit, the development or progression of a disease and/or causing, or attempting to cause, the reduction, suppression, regression, or remission of a disease and/or a symptom thereof.
  • various clinical and scientific methodologies and assays may be used to assess the development or progression of an infection, and similarly, various clinical and scientific methodologies and assays may be used to assess the reduction, regression, or remission of an infection or its symptoms.
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the infection as well as those prone to have the disease or those in whom the disease is to be prevented.
  • Daptomycin approved by the FDA in 2003, stands as a good example of antibacterial cyclic lipopeptides.
  • Daptomycin is a cyclic lipodepsipeptide containing 13 amino acids, 10 of which make up a 31-membered ring and three are anchored as an exocyclic tail with the N-terminal containing an n-decanoyl lipid.
  • Within this structure are two unnatural amino acids, L-kynurenine (Kyn) and L-3-methyl-glutamic acid (3-mGlu) .
  • Cyclic lipopeptides having one or more modifications relative to daptomycin are provided.
  • the disclosed cyclic lipopeptides are also referred to as daptomycin analogues.
  • the cyclic lipopeptides can possess antibiotic properties.
  • the cyclic lipopeptides include those having alkylated or acylated kynurenine to replace Kyn13, N-methyl indol-3-ylmethyl, i.e., MeTrp, 1-naphthylmethyl, or 2-naphthylmethyl to replace Trp1, sarcosine to replace Gly5, dialkylated Orn to replace Orn6, and/or using 2, 3-diaminobutyric acid or 2, 3-diaminopropionic acid to replace Thr4.
  • the modification involves methylation (or dimethylation with regard to Orn) at one or more of Gly (e.g., the Gly that is between Thr and Orn) , Orn, Kyn, and/or Trp.
  • cyclic lipopeptides have the general formula:
  • R 1 -R 12 are independently substituted polyheteroaralkyl, unsubstituted polyheteroaralkyl, substituted polyaralkyl, unsubstituted polyaralkyl, substituted aralkyl, unsubstituted aralkyl, substituted alkyl, unsubstituted alkyl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyaryl, unsubstituted polyaryl, substituted C 3 -C 20 cycloalkyl, unsubstituted C 3 -C 20 cycloalkyl, substituted C 3 -C 20 heterocyclyl, unsubstituted C 3 -C 20 heterocyclyl, substituted C 3 -C 20 cycloalkenyl, unsubstituted C 3 -C 20 cycloal
  • R1 is substituted polyheteroaralkyl, unsubstituted polyheteroaralkyl, substituted polyaralkyl, unsubstituted polyaralkyl, substituted aralkyl, unsubstituted aralkyl, substituted alkyl, unsubstituted alkyl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyaryl, unsubstituted polyaryl, most preferably, R1 is the side chain of Trp (indol-3-ylmethyl) , MeTrp (i.e.
  • R 2 -R 12 are independently the side chain of any natural or unnatural amino acid;
  • R’a nd R” are independently hydrogen, unsubstituted alkyl, substituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyaryl, unsubstituted polyaryl, unsubstituted polyaryl, substituted C 3 -C 20 cycloalkyl, unsubstituted C 3 -C 20 cycloalkyl, substituted C 3 -C 20 heterocyclyl, unsubstituted C 3 -C 20 heterocyclyl, substituted C 3 -C 20 cycloalkenyl, unsubstituted C 3 -C 20 cycloalkenyl, substituted C 3 -C 20
  • R’ is hydrogen or unsubstituted alkyl, most preferably, R’is H or methyl; preferably, R”is hydrogen, unsubstituted alkyl, or substituted alkyl. Most preferably, R”is H, methyl or ethyl;
  • X is O or NRa, wherein Ra is hydrogen, unsubstituted alkyl, substituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyaryl, unsubstituted polyaryl, unsubstituted polyaryl, substituted C 3 -C 20 cycloalkyl, unsubstituted C 3 -C 20 cycloalkyl, substituted C 3 -C 20 heterocyclyl, unsubstituted C 3 -C 20 heterocyclyl, substituted C 3 -C 20 cycloalkenyl, unsubstituted C 3 -C 20 cycloalkenyl, substituted C 3
  • R is substituted aryl, unsubstituted aryl, substituted alkenyl, unsubstituted alkenyl, unsubstituted alkyl, substituted alkyl, substituted alkynyl, unsubstituted alkynyl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyaryl, unsubstituted polyaryl, substituted C 3 -C 20 cycloalkyl, unsubstituted C 3 -C 20 cycloalkyl, substituted C 3 -C 20 heterocyclyl, unsubstituted C 3 -C 20 heterocyclyl, substituted C 3 -C 20 cycloalkenyl, unsubstituted C 3 -C 20 cycloalkenyl, substituted C 3 -C 20 cycloal
  • At least one of R, R 1 -R 12 , R’ , and R” is substituted aryl, unsubstituted aryl, substituted alkenyl, unsubstituted alkenyl, - (CH 2 ) x -NR* 2 , substituted polyheteroaralkyl, substituted polyaralkyl, unsubstituted polyaralkyl, substituted aralkyl, unsubstituted aralkyl, or substituted alkyl containing a substituted aniline, wherein x is an integer between one and ten, inclusive (e.g.
  • each R* is independently unsubstituted alkyl, substituted alkyl, substituted aryl, or unsubstituted aryl.
  • R is substituted aryl or substituted alkenyl; x is three; each R* is independently unsubstituted alkyl, substituted alkyl, substituted aryl, or unsubstituted aryl, preferably are both unsubstituted alkyl (e.g. methyl) ;
  • R 1 is substituted polyheteroaralkyl (e.g.
  • N-alkylated indol-3-ylalkyl such as N-alkylated indol-3-ylmethyl
  • unsubstituted polyaralkyl e.g. 1-naphthylalkyl and 2-naphthylalkyl such as 1-naphthylmethyl and 2-naphthylmethyl, respectively
  • R’ is hydrogen, unsubstituted alkyl (e.g. methyl) , substituted alkyl, unsubstituted aryl, or unsubstituted aryl
  • R” is hydrogen, unsubstituted alkyl (e.g. methyl and ethyl) , substituted alkyl, unsubstituted aryl, or unsubstituted aryl
  • R12 is a substituted alkyl containing a substituted aniline.
  • R’ is unsubstituted alkyl, substituted alkyl, unsubstituted aryl, or substituted aryl;
  • R 1 is substituted polyheteroaralkyl or unsubstituted polyaralkyl;
  • R 2 -R 12 are independently the side chain of any natural or unnatural amino acid; and
  • R is a substituted alkenyl or a substituted aryl.
  • the cyclic lipopeptide has the formula:
  • R 1 -R 11 are independently unsubstituted polyheteroaralkyl, substituted polyheteroaralkyl, unsubstituted polyaralkyl, polyaralkyl, or the side chain of any natural or unnatural amino acid;
  • R”’ a nd R” are independently hydrogen, unsubstituted alkyl, unsubstituted alkyl, unsubstituted alkyl, unsubstituted aryl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyaryl, unsubstituted polyaryl, unsubstituted polyaryl, substituted C 3 -C 20 cycloalkyl, unsubstituted C 3 -C 20 cycloalkyl, substituted C 3 -C 20 heterocyclyl, unsubstituted C 3 -C 20 heterocyclyl, substituted C 3 -C 20 cycloalkenyl, unsubsti
  • At least one of R”’ a nd R”” is not hydrogen.
  • R”’ is hydrogen
  • R”” is unsubstituted alkyl (e.g. methyl, such that R 12 is N-methylkynurenine)
  • R 12 is N-methylkynurenine
  • substituted carbonyl e.g. acyl
  • R’ , R” , and R”’ a re independently H, unsubstituted alkyl (e.g. methyl, ethyl) or substituted alkyl, R”” is substituted carbonyl (e.g. acyl) or unsubstituted alkyl (e.g.
  • R is unsubstituted C 5 -C 14 alkyl, substituted C5-C14 alkyl, unsubstituted C5-C14 alkenyl, substituted C5-C14 alkenyl, unsubstituted C5-C14 alkynyl, substituted C5-C14 alkynyl, unsubstituted C5-C14 aryl, substituted C5-C14 aryl, unsubstituted C5-C14 polyaryl, substituted C5-C14 polyaryl, unsubstituted C5-C14 polyheteroaryl, or substituted C5-C14 polyheteroaryl.
  • An example of a substituted C5-C14 alkenyl can be (E) -2- (4-pentylphenyl) propenyl, while an example of a substituted C5-C14 aryl can be 4- (phenylethynyl) phenyl.
  • R”’ is hydrogen, unsubstituted alkyl, or substituted alkyl, and R”” is unsubstituted alkyl, substituted alkyl, unsubstituted aryl, or substituted aryl.
  • the cyclic lipopeptide is as described above for Formula IV, wherein, R 1 is unsubstituted polyheteroaralkyl (e.g. the side chain of Trp, i.e., indol-3-ylmethyl) , substituted polyheteroaralkyl (e.g. MeTrp, i.e., the nitrogen atom of the indole ring is methylated, such as N-methyl indol-3-ylmethyl) , unsubstituted polyaralkyl (e.g. 1-naphthylmethy or 2-naphthylmethyl) , or substituted polyaralkyl; and R2-R11 are independently the side chain of any natural or unnatural amino acid.
  • R 1 is unsubstituted polyheteroaralkyl (e.g. the side chain of Trp, i.e., indol-3-ylmethyl)
  • substituted polyheteroaralkyl e.g.
  • the cyclic lipopeptide has the formula:
  • R 1 is unsubstituted polyheteroaralkyl (e.g. the side chain of Trp, i.e., indol-3-ylmethyl) , substituted polyheteroaralkyl (e.g. MeTrp, i.e., the nitrogen atom of the indole ring is methylated, i.e., N-methyl indol-3-yl) , unsubstituted polyaralkyl (e.g. 1-naphthylmethyl or 2-naphthylmethyl) , or substituted polyaralkyl, and
  • R 5 is the side chain of amino acid, natural or unnatural.
  • R’ is H or unsubstituted alkyl (e.g. methyl) ;
  • R” is H, unsubstituted alkyl (e.g. methyl or ethyl) ,
  • R”’ is H or unsubstituted alkyl (e.g. methyl) ;
  • R”” is substituted carbonyl (e.g. acyl) or unsubstituted alkyl (e.g.
  • An example of a substituted C5-C14 alkenyl can be (E) -2- (4-pentylphenyl) propenyl, while an example of a substituted C5-C14 aryl can be 4- (phenylethynyl) phenyl.
  • R has the formula:
  • R 13 , R 14 , R 15 , R 16 , and R 17 are independently hydrogen, unsubstituted alkyl, substituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyaryl, unsubstituted polyaryl, substituted C 3 -C 20 cycloalkyl, unsubstituted C 3 -C 20 cycloalkyl, substituted C 3 -C 20 heterocyclyl, unsubstituted C 3 -C 20 heterocyclyl, substituted C 3 -C 20 cycloalkenyl, unsubstituted C 3 -C 20 cycloalkenyl, substituted C 3 -C
  • At least one of R 13 -R 17 is a substituted alkynyl.
  • R has the formula:
  • R 13 , R 14 , R 16 , and R 17 are as described above for Formula IX,
  • W is substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted polyaryl, unsubstituted polyaryl, substituted C 3 -C 20 cycloalkyl, unsubstituted C 3 -C 20 cycloalkyl, substituted C 3 -C 20 heterocyclyl, unsubstituted C 3 -C 20 heterocyclyl, substituted C 3 -C 20 cycloalkenyl, unsubstituted C 3 -C 20 cycloalkenyl, substituted C 3 -C 20 cycloalkynyl, unsubstituted C 3 -C 20 cycloalkynyl, hydrogen, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl,
  • R is a substituted aryl, having the formula:
  • R13, R14, R16, and R17 are as described above for Formula IX, and
  • R18, R19, R20, R21, and R22 are independently hydrogen, unsubstituted alkyl, substituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyaryl, unsubstituted polyaryl, substituted C 3 -C 20 cycloalkyl, unsubstituted C 3 -C 20 cycloalkyl, substituted C 3 -C 20 heterocyclyl, unsubstituted C 3 -C 20 heterocyclyl, substituted C 3 -C 20 cycloalkenyl, unsubstituted C 3 -C 20 cycloalkenyl, substituted C 3 -C 20 cyclo
  • R13, R14, R16, and R17 are hydrogen, four of R18, R19, R20, R21, and R22 are hydrogen, and one is unsubstituted alkyl, substituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyaryl, unsubstituted polyaryl, unsubstituted polyaryl, substituted C 3 -C 20 cycloalkyl, unsubstituted C 3 -C 20 cycloalkyl, substituted C 3 -C 20 heterocyclyl, unsubstituted C 3 -C 20 heterocyclyl, substituted C 3 -C 20 cycloalkenyl, unsub
  • R13, R14, R16, and R17 are hydrogen, four of R18, R19, R20, R21, and R22 are hydrogen, and one is unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted heteroaryl, unsubstituted C 3 -C 20 heterocyclyl, hydroxyl, or nitro.
  • R13, R14, R16, R17, and R18-R22 are hydrogen, i.e., R1 is 4- (phenylethynyl) phenyl,
  • R is a substituted alkenyl having the formula:
  • R23 and R24 are independently hydrogen, unsubstituted alkyl, substituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyaryl, unsubstituted polyaryl, unsubstituted polyaryl, substituted C 3 -C 20 cycloalkyl, unsubstituted C 3 -C 20 cycloalkyl, substituted C 3 -C 20 heterocyclyl, unsubstituted C 3 -C 20 heterocyclyl, substituted C 3 -C 20 cycloalkenyl, unsubstituted C 3 -C 20 cycloalkenyl, substituted C 3 -C 20 cyclo
  • R23 and R24 are independently unsubstituted alkyl, substituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyaryl, unsubstituted polyaryl, unsubstituted polyaryl, substituted C 3 -C 20 cycloalkyl, unsubstituted C 3 -C 20 cycloalkyl, substituted C 3 -C 20 heterocyclyl, unsubstituted C 3 -C 20 heterocyclyl, substituted C 3 -C 20 cycloalkenyl, unsubstituted C 3 -C 20 cycloalkenyl, substituted C 3 -C 20 cycloalky
  • R23 is an unsubstituted alkyl.
  • R24 is a substituted aryl or unsubstituted aryl.
  • R23 is an unsubstituted alkyl
  • R24 is a substituted aryl or unsubstituted aryl having the formula:
  • R25, R26, R27, R28, and R29 are independently hydrogen, unsubstituted alkyl, substituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyaryl, unsubstituted polyaryl, substituted C 3 -C 20 cycloalkyl, unsubstituted C 3 -C 20 cycloalkyl, substituted C 3 -C 20 heterocyclyl, unsubstituted C 3 -C 20 heterocyclyl, substituted C 3 -C 20 cycloalkenyl, unsubstituted C 3 -C 20 cycloalkenyl, substituted C 3 -C 20 cyclo
  • R27 is a substituted alkyl or unsubstituted alkyl group.
  • R27 is an unsubstituted alkyl group
  • R25, R26, R28, R29 are each hydrogen.
  • R23 and R27 are unsubstituted alkyl groups, and R25, R26, R28, and R29 are each hydrogen.
  • R23 and R27 are independently unsubstituted C1-C10 alkyl groups, and R25, R26, R28, and R29 are each hydrogen.
  • R23 is an unsubstituted C1 alkyl group
  • R27 is an unsubstituted C5 alkyl group
  • R25, R26, R28, and R29 are each hydrogen, i.e., R is
  • R5 is- (CH 2 ) 3 -NR* 2 , each R*is an alkyl group; each R*is methyl; R1 is MeTrp; R’ is methyl; R12 is MeKyn; R1 is 1-naphtylalanine; R1 is 2-naphtylalanine; and R is
  • the cyclic lipopeptide contains a methylated Kyn having the formula:
  • R1-R11 are independently unsubstituted polyheteroaralkyl, substituted polyheteroaralkyl, unsubstituted polyaralkyl, polyaralkyl, or the side chain of any natural or unnatural amino acid.
  • R’ is H or unsubstituted alkyl (e.g. methyl) ;
  • R” is H, unsubstituted alkyl (e.g. methyl or ethyl) ;
  • R is a unsubstituted C5-C14 alkyl, substituted C5-C14 alkyl, unsubstituted C5-C14 alkenyl, substituted C5-C14 alkenyl, unsubstituted C5-C14 alkynyl, substituted C5-C14 alkynyl, unsubstituted C5-C14 aryl, substituted C5-C14 aryl, unsubstituted C5-C14 polyaryl, substituted C5-C14 polyaryl, unsubstituted C5-C14 polyheteroaryl, or substituted C5-C14 polyheteroaryl.
  • An example of a substituted C5-C14 alkenyl can be (E) -2- (4-pentylphenyl) propenyl, while an example of a substituted C5-C14 aryl can be 4- (phenylethynyl) phenyl.
  • the cyclic lipopeptide has the formula:
  • R’, Rb, Rc, and Rd are independently hydrogen, unsubstituted alkyl, substituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted polyheteroaryl, unsubstituted polyheteroaryl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted polyaryl, unsubstituted polyaryl, unsubstituted polyaryl, substituted C 3 -C 20 cycloalkyl, unsubstituted C 3 -C 20 cycloalkyl, substituted C 3 -C 20 heterocyclyl, unsubstituted C 3 -C 20 heterocyclyl, substituted C 3 -C 20 cycloalkenyl, unsubstituted C 3 -C 20 cycloalkenyl, substituted C 3
  • R’, Rb, Rc, and Rd are independently hydrogen, substituted alkyl, or unsubstituted alkyl (such as methyl, ethyl, etc. ) .
  • the cyclic lipopeptide has the formula:
  • R is R is unsubstituted C5-C14 alkyl, substituted C5-C14 alkyl, unsubstituted C5-C14 alkenyl, substituted C5-C14 alkenyl, unsubstituted C5-C14 alkynyl, substituted C5-C14 alkynyl, unsubstituted C5-C14 aryl, substituted C5-C14 aryl, unsubstituted C5-C14 polyaryl, substituted C5-C14 polyaryl, unsubstituted C5-C14 polyheteroaryl, or substituted C5-C14 polyheteroaryl, preferably R is C9H19 or (E) -2- (4-pentylphenyl) propenyl.
  • any compound or subgroup of compounds can be either specifically included for or excluded from use or included in or excluded from a list of compounds.
  • any one or more of the compounds described herein, with a structure depicted herein, or referred to in the Tables or the Examples herein can be specifically included, excluded, or combined in any combination, in a set or subgroup of such compounds.
  • Such specific sets, subgroups, inclusions, and exclusions can be applied to any aspect of the compositions and methods described here.
  • a set of compounds that specifically excludes one or more particular compounds can be used or applied in the context of compounds per se (for example, a list or set of compounds) , compositions including the compound (including, for example, pharmaceutical compositions) , any one or more of the disclosed methods, or combinations of these.
  • compositions including the compound including, for example, pharmaceutical compositions
  • any one or more of the disclosed methods or combinations of these.
  • Different sets and subgroups of compounds with such specific inclusions and exclusions can be used or applied in the context of compounds per se, compositions including one or more of the compounds, or any of the disclosed methods. All of these different sets and subgroups of compounds—and the different sets of compounds, compositions, and methods using or applying the compounds—are specifically and individual contemplated and shouldbe considered as specifically and individually described.
  • any of the natural amino acids or unnatural amino acids, as defined above, can be specifically included or excluded, as a group or individually, from any position in the compounds per se (for example, a list or set of compounds) , from compounds in compositions (including, for example, pharmaceutical compositions) , or any one or more of the disclosed methods, or combinations of these.
  • specific cyclic compounds can excluded from the list of compounds.
  • daptomycin can be excluded.
  • compositions including one or more of the disclosed compounds are also provided.
  • the compositions can be formulated in dosage forms appropriate for each route of administration.
  • Daptomycin is most typically administered by infusion (e.g., 30 min) or injection (e.g., 2 min) .
  • Studies also show efficacy with topical delivery, which can be enhanced when the formulation includes a delivery vehicle such liposomes (see, e.g., Mengeloglu, et al., J Ocul Pharmacol Ther. 2013 Dec; 29 (10) : 893-9. doi: 10.1089/jop. 2013.0120. Epub 2013 Sep 26, and Li, et al., Int J Nanomedicine. 2013; 8: 1285-92. doi: 10.2147/IJN. S41695. Epub 2013 Mar 24) .
  • Preferred routes of administration for the disclosed lipopeptides therefore include parenteral, particularly intravenous injection or infusion, and topical, though alternations in the composition of the disclosed compounds may improve its delivery by other routes, for example oral, relative to daptomycin.
  • a cyclic lipopeptide described herein or pharmaceutical compositions including one or more lipopetides is administered orally, parenterally, by inhalation, topically, transdermal (either passively or using iontophoresis or electroporation) , or transmucosal (nasal, vaginal, rectal, buccally, or sublingual) , or by an implanted reservoir, external pump, or catheter.
  • the cyclic lipopeptides described herein can be directly injected or administered into an abscess, ventricle, or joint.
  • Parenteral administration includes intraperitoneal, subcutaneous, intravenous (IV) , intramuscular, intra-articular, intra-synovial, cisternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion.
  • IV intravenous
  • the compositions may also be administered using bioerodible inserts and may be delivered directly to an appropriate target tissue or organ.
  • compositions typically include an effective amount of a disclosed compound.
  • the precise dosage will vary according to a variety of factors such as subject-dependent variables (e.g., age, immune system health, etc. ) , the disease, and the treatment being effected. Dosages are discussed in more detail below.
  • the disclosed compounds are administered in an aqueous solution, by parenteral injection or infusion.
  • the formulation may also be in the form of a suspension or emulsion.
  • pharmaceutical compositions are provided including effective amounts of a peptide or polypeptide, and optionally include pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers.
  • compositions include sterile water, buffered saline (e.g., Tris-HCl, acetate, phosphate) , pH and ionic strength; and optionally, additives such as detergents and solubilizing agents (e.g., 20, TWEEN 80, Polysorbate 80) , anti-oxidants (e.g., ascorbic acid, sodium metabisulfite) , and preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol) .
  • buffered saline e.g., Tris-HCl, acetate, phosphate
  • solubilizing agents e.g. 20, TWEEN 80, Polysorbate 80
  • anti-oxidants e.g., ascorbic acid, sodium metabisulfite
  • preservatives e.g., Thimersol, benzyl alcohol
  • bulking substances e.g., lacto
  • non-aqueous solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • the formulations may be lyophilized and redissolved/resuspended immediately before use.
  • the formulation may be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions.
  • compositions containing one or more of the disclosed compounds can be administered in controlled release formulations.
  • Controlled release polymeric devices can be made for long term release systemically following implantation of a polymeric device (rod, cylinder, film, disk) or injection (microparticles) .
  • the matrix can be in the form of microparticles such as microspheres, where peptides are dispersed within a solid polymeric matrix or microcapsules, where the core is of a different material than the polymeric shell, and the peptide is dispersed or suspended in the core, which may be liquid or solid in nature.
  • microparticles, microspheres, and microcapsules are used interchangeably.
  • the polymer may be cast as a thin slab or film, ranging from nanometers to four centimeters, a powder produced by grinding or other standard techniques, or even a gel such as a hydrogel.
  • the matrix can also be incorporated into or onto a medical device to, for example, prevent infection or to aid in healing.
  • a matrix is used to facilitate healing of pressure sores, decubitis ulcers, etc.
  • Either non-biodegradable or biodegradable matrices can be used for delivery of compounds, although biodegradable matrices are preferred.
  • liposomal or polymeric encapsulation may be used to formulate the compositions.
  • the polymers can be natural or synthetic, although synthetic polymers are preferred due to the better characterization of degradation and release profiles.
  • the polymer is selected based on the period over which release is desired. In some cases linear release may be most useful, although in others a pulse release or “bulk release” may provide more effective results.
  • the polymer may be in the form of a hydrogel (typically in absorbing up to about 90%by weight of water) , and can optionally be crosslinked with multivalent ions or polymers.
  • the matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.
  • Bioerodible microspheres can be prepared using any of the methods developed for making microspheres for drug delivery, for example, as described by Mathiowitz and Langer, J. ControlledRelease, 5: 13-22 (1987) ; Mathiowitz, et al., Reactive Polymers, 6: 275-283 (1987) ; and Mathiowitz, et al., J. Appl. Polymer Sci., 35: 755-774 (1988) .
  • the devices can be formulated for local release to treat the area of implantation or injection and typically deliver a dosage that is much less than the dosage for treatment of an entire body.
  • the devices can also be formulated for systemic delivery. These can be implanted or injected subcutaneously.
  • Buffers can be used to control pH of a composition.
  • the buffers buffer the composition from a pH of about 4 to a pH of about 7.5, more preferably from a pH of about 4 to a pH of about 7, and most preferably from a pH of about 5 to a pH of about 7.
  • the buffer is triethanolamine.
  • Preservatives can be used to prevent the growth of fungi and microorganisms.
  • Suitable antifungal and antimicrobial agents include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, and thimerosal.
  • penetration enhancers Additional agents that can be added to the formulation include penetration enhancers.
  • the penetration enhancer increases the solubility of the drug, improves transdermal delivery of the drug across the skin, in particular across the stratum corneum, or a combination thereof, preferably without reducing the active of the lipopeptide.
  • Chemical penetrations and methods of increasing transdermal drug delivery are known in the art, see, for example, Inayat, et al., Tropical Journal of Pharmaceutical Research, 8 (2) : 173-179 (2009) and Fox, et al., Molecules, 16: 10507-10540 (2011) .
  • the administration methods can be used for human patients in clinical applications and in veterinary applications.
  • the methods typically include administering a subject in need thereof an effective amount of one or more the disclosed peptides, or a pharmaceutical composition thereof.
  • Exemplary subjects in need thereof have an infection or in danger of contracting an infection, particularly a bacterial infection.
  • the subject has or is at risk of having a gram-positive bacterial infection.
  • the dose and dosage interval for the methods are those that are safe and efficacious in clinical or veterinary applications.
  • the administration methods involve longer dosing intervals (such as once-daily or longer) with higher doses (such as 15 mg/kg or more) of the cyclic lipopeptides described herein.
  • the administration methods involve relatively shorter dosing intervals (such as twice-daily or shorter) with lower doses (such as 15 mg/kg or less) of the cyclic lipopeptides described herein.
  • the cyclic lipopeptides described herein can be administered once-daily, twice-daily, or thrice-daily. Daptomycin is known to have skeletal muscle toxicity, especially when the time between doses is relatively short. Once-daily administration of the cyclic lipopeptides described herein can provide greater time between doses compared to multiple daily doses. In some instances, once-daily administration of the cyclic lipopeptides described herein permits repair of subclinical muscle damage that may be associated with using the cyclic lipopeptides described herein and thereby avoid long term and/or permanent physical damage. In other words, in some embodiments, once-daily dosing of the cyclic lipopeptides described herein results in less toxicity.
  • the dose can be 1 to 100 mg/kg of the cyclic lipopeptides described herein. In another embodiment, the dose is 5 to 50 mg/kg of the cyclic lipopeptides described herein. In yet another embodiment, the dose for humans patients is 2 to 15 mg/kg. In still yet another embodiment, the dose for humans patients is 3 to 12 mg/kg of the cyclic lipopeptides described herein. Examples of specific doses that may be used include 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22 or 25 mg/kg of the cyclic lipopeptides described herein. In some embodiments for veterinary applications, the dose is 2 to 40 mg/kg of the cyclic lipopeptides described herein.
  • the cyclic lipopeptides described herein can be administered in a smaller dose compared to the administration of daptomycin. In one embodiment, the cyclic lipopeptides described herein can be administered in a 10%smaller dose compared to the administration of daptomycin to the same patient for the same ailment. In another embodiment, the cyclic lipopeptides described herein can be administered in a 25%smaller dose compared to the administration of daptomycin to the same patient for the same ailment. In yet another embodiment, the cyclic lipopeptides described herein can be administered in a 40%smaller dose compared to the administration of daptomycin to the same patient for the same ailment.
  • the dosage interval of the cyclic lipopeptides described herein is from 6 hours to weekly.
  • the cyclic lipopeptides described herein is administered at a dosage interval of once every 12 hours, once every 24 hours, once every 48 hours, once every 72 hours, once every 96 hours, or once weekly. Administration at less frequent dosage intervals, such as once every 96 hours or once weekly, may be desirable for patients who have impaired renal function or who require hemodialysis.
  • the dosage interval for veterinary applications may be somewhat shorter or longer than the dosage intervals for human patients, depending upon whether the cyclic lipopeptides described herein has a shorter or longer half-life, respectively, in a particular animal species compared to in humans. Specific dosage intervals for both clinical and veterinary applications can be determinedby one skilled in the art following the methods described herein.
  • the administration method includes administering a dose of 1 to 100 mg/kg of a cyclic lipopeptide described herein once every 6 hours to once weekly. In some embodiments, a cyclic lipopeptide described herein is administered in a dose of 5 to 50 mg/kg once every 24, 48, 72, or 96 hours.
  • the cyclic lipopeptides described herein can be administered until the bacterial infection is eradicated or reduced. In one embodiment, the cyclic lipopeptides described herein are administered for a period of time from 3 days to 6 months. In another embodiment, the cyclic lipopeptides described herein are administered for 7 to 50 days. In yet another embodiment, the cyclic lipopeptides described herein are administered for 10 to 20 days.
  • the methods of using the cyclic lipopeptides described herein include administering the cyclic lipopeptide to a patient in need thereof in an amount that is efficacious in reducing or eliminating a gram-positive bacterial infection.
  • the methods also include administering the cyclic lipopeptide to a patient in need thereof in an amount that is efficacious in reducing or eliminating a gram-positive bacterial infection and that results in reduced skeletal muscle toxicity compared to other methods, for example those that include administering daptomycin, other lipopeptide antibiotics, or quinupristin/dalfopristin.
  • the methods can be used to treat a patient having a bacterial infection in which the infection is caused or exacerbated by any type of gram-positive bacteria.
  • the cyclic lipopeptides described herein is administered to a patient according to the methods described herein.
  • the bacterial infection can be caused or exacerbated by bacteria including one or more of, but not limited to, methicillin-susceptible and methicillin-resistant staphylococci (including Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, and coagulase-negative staphylococci) , glycopeptide intermediary-susceptible Staphylococcus aureus (GISA) , penicillin-susceptible and penicillin-resistant streptococci (including Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus avium, Streptococcus bovis, Streptococcus lactis, Streptococcus sangius and Streptococci Group C, Streptococci Group G and
  • the antibacterial activity of the cyclic lipopeptides described herein against classically “resistant” strains can be comparable to that against classically “susceptible” strains.
  • the cyclic lipopeptide described herein is administered according to a patient who exhibits a bacterial infection that is resistant to other antibiotics.
  • the cyclic lipopeptides described herein can exhibit rapid, concentration-dependent bactericidal activity against gram- positive organisms.
  • the cyclic lipopeptide described herein is administered to a patient in need of rapidly acting antibiotic therapy.
  • the cyclic lipopeptides described herein can be used for a gram-positive bacterial infection of any organ or tissue in the body.
  • organs or tissue include one or more of, without limitation, skeletal muscle, skin, bloodstream, kidneys, heart, lung, and bone.
  • the cyclic lipopeptides described herein can be used to treat one or more of, without limitation, skin and soft tissue infections, bacteremia, and urinary tract infections.
  • the cyclic lipopeptides described herein can be used to treat community acquired respiratory infections, including one or more of, without limitation, otitis media, sinusitis, chronic bronchitis and pneumonia, including pneumonia caused by drug-resistant Streptococcus pneumoniae or Haemophilus influenzae.
  • the cyclic lipopeptides described herein can be used to treat mixed infections that comprise different types of gram-positive bacteria, or which comprise both gram-positive and gram-negative bacteria. Examples of such infections include intra-abdominal infections and obstetrical/gynecological infections.
  • the cyclic lipopeptides described herein can be used in step down therapy for hospital infections, including one or more of, without limitation, pneumonia, intra-abdominal sepsis, skin and soft tissue infections, and bone and joint infections.
  • the cyclic lipopeptides described herein can be used to treat an infection including one or more of, without limitation, endocarditis, septic arthritis, and osteomyelitis.
  • the methods of using the cyclic lipopeptide described herein can include concurrently administering with one or more additional therapeutic, diagnostic, or prophylactic agents, for example an antibiotic other than a lipopeptide antibiotic.
  • the lipopeptide and the additional therapeutic, diagnostic, or prophylactic agent can be in the same or different admixtures or pharmaceutical compositions.
  • the cyclic lipopeptide described herein can exhibit high plasma protein binding and may be unable to cross cell membranes. In this context, the cyclic lipopeptide described herein is unlikely to cause interactions with other antibiotics. Consequently, the cyclic lipopeptides described herein can in some embodiments work in a complimentary fashion or even more than additively with one or more co-administered non-lipopeptide antibiotic. Moreover, the cyclic lipopeptides described herein can improve the toxicity profile of one or more co-administered non-lipopeptide antibiotics.
  • non-lipopeptide antibiotics examples include one or more of, without limitation, penicillins and related drugs, carbapenems, cephalosporins and related drugs, aminoglycosides, bacitracin, gramicidin, mupirocin, chloramphenicol, thiamphenicol, fusidate sodium, lincomycin, clindamycin, macrolides, novobiocin, polymyxins, rifamycins, spectinomycin, tetracyclines, vancomycin, teicoplanin, streptogramins, anti-folate agents including sulfonamides, trimethoprim and its combinations and pyrimethamine, synthetic antibacterials including nitrofurans, methenamine mandelate and methenamine hippurate, nitroimidazoles, quinolones, fluoroquinolone
  • non-lipopeptide antibiotics that can be co-administered with the cyclic lipopeptides described herein include one or more of, without limitation, imipenen, amikacin, netilmicin, fosfomycin, gentamicin, ceftriaxone, and teicoplanin.
  • the cyclic lipopeptides described herein can be synthesized using a variety of methods known to those of skill art including, but not limited to, chemical synthesis, biochemical synthesis, chemoenzymatic synthesis, semisynthesis, or a combination thereof.
  • the cyclic lipopeptides can be produced via chemical synthesis.
  • the chemical synthetic approaches can be via solid phase synthesis, solution phase synthesis, or a combination thereof.
  • the cyclic lipopeptides can be synthesized using a hybrid approach that involves both solid phase and solution phase synthetic approaches.
  • the synthesis can be performed on a resin, such as 2-chlorotrityl chloride resin (with a resin loading of 0.4 mmol/g) , under standard Fmoc/tBu protocols of solid phase peptide synthesis.
  • the deblock mixture can be a mixture of 20/80 (v/v) of piperidine/DMF.
  • Fmoc protected amino acids that can be used include, but are not limited to, Fmoc-Ala-OH, Fmoc-DAla-OH, Fmoc-Arg (Pbf) -OH, Fmoc-Asn (Trt) -OH, Fmoc-DAsn (Trt) -OH Fmoc-Asp (tBu) -OH, Fmoc-Glu (tBu) -OH, Fmoc-Gln (Trt) -OH, Fmoc-Gly-OH, Fmoc-His (Trt) -OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys (Boc) -OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser (tBu) -OH, Fmoc-Thr (tBu) -OH,
  • the peptide resin Upon completion of the synthesis, the peptide resin can be subjected to a cleavage cocktail, followed by filtering of the resin, and the filtrates are blown off under a stream of condensed air.
  • the crude product can be triturated with cold diethyl ether to give a white suspension, which is centrifuged and the ether subsequently decanted.
  • the remaining solid can be purified via HPLC purification.
  • Fmoc amino acids were employed: Fmoc-Ala-OH, Fmoc-DAla-OH, Fmoc-Arg (Pbf) -OH, Fmoc-Asn (Trt) -OH, Fmoc- DAsn (Trt) -OH Fmoc-Asp (tBu) -OH, Fmoc-Glu (tBu) -OH, Fmoc-Gln (Trt) -OH, Fmoc-Gly-OH, Fmoc-His (Trt) -OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys (Boc) -OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser (tBu) -OH, Fmoc-Thr (tBu) -OH, Fmoc-Trp
  • Preparative HPLC was performed on a Waters system, using a Vydac 218TP TM C18 column (10 ⁇ m, 10 ⁇ 250 mm) or a Vydac 218TP TM C18 column (10 ⁇ m, 22 ⁇ 250 mm) .
  • Buffer A 0.1%TFA in acetonitrile
  • buffer B 0.1%TFA in H 2 O.
  • Linear peptide resin-Gly-Asp (tBu) -DAla-Asp (tBu) -Orn (Boc) -Gly-Thr [O-meKyn-mGlu (tBu) -DSer (tBu) ] -Asp (tBu) -DAsn (Trt) -Trp (Boc) -C 9 H 19 was synthesized by 9H-fluoren-9-yl-methoxycarbonyl (Fmoc) solid phase peptide synthesis protocol. The peptide was cleaved from the 2-chlorotrityl resin under the mild condition (TFE/AcOH/DCM) .
  • the peptide was cyclized using HATU in DCM for 4 hours. Then, the solution was concentrated, and then treated with a cocktail containing 95%TFA and 2.5%water for 10 min. The crude product was purified by preparative RP-HPLC to give the methylated Kyn-containing daptomycin analogues
  • Linear peptide resin-Gly-Asp (tBu) -DAla-Asp (tBu) -Orn (Boc) -Gly-Thr [O-Kyn-mGlu (tBu) -DSer (tBu) ] -Asp (tBu) -DAsn (Trt) -meTrp-C 9 H 19 was synthesized by 9H-fluoren-9-yl-methoxycarbonyl (Fmoc) solid phase peptide synthesis protocol. The peptide was cleaved from the 2-chlorotrityl resin under the mild condition (TFE/AcOH/DCM) .
  • Linear peptide resin-Gly-Asp (tBu) -DAla-Asp (tBu) -Orn (Boc) -Gly-Thr [O-Kyn-mGlu (tBu) -DSer (tBu) ] -Asp (tBu) -DAsn (Trt) -2Nal-C 9 H 19 was synthesized by 9H-fluoren-9-yl-methoxycarbonyl (Fmoc) solid phase peptide synthesis protocol. The peptide was cleaved from the 2-chlorotrityl resin under the mild condition (TFE/AcOH/DCM) .
  • Linear peptide resin-Gly-Asp (tBu) -DAla-Asp (tBu) -Orn (Boc) -Sar-Thr [O-meKyn-mGlu (tBu) -DSer (tBu) ] -Asp (tBu) -DAsn (Trt) -Trp (Boc) -C 9 H 19 was synthesized by 9H-fluoren-9-yl-methoxycarbonyl (Fmoc) solid phase peptide synthesis protocol. The peptide was cleaved from the 2-chlorotrityl resin under the mild condition (TFE/AcOH/DCM) .
  • Linear peptide resin-Gly-Asp (tBu) -DAla-Asp (tBu) -Orn (Boc) -Gly-Thr [O-Kyn-mGlu (tBu) -DSer (tBu) ] -Asp (tBu) -DAsn (Trt) -Trp (Boc) -4-phenylethynyl-benzoyl was synthesized by 9H-fluoren-9-yl-methoxycarbonyl (Fmoc) solid phase peptide synthesis protocol. The peptide was cleaved from the 2-chlorotrityl resin under the mild condition (TFE/AcOH/DCM) .
  • Linear peptide resin-Gly-Asp (tBu) -DAla-Asp (tBu) -Orn (Boc) -Sar-Thr [O-Kyn-mGlu (tBu) -DSer (tBu) ] -Asp (tBu) -DAsn (Trt) -Trp (Boc) -4-phenylethynyl-benzoyl was synthesized by 9H-fluoren-9-yl-methoxycarbonyl (Fmoc) solid phase peptide synthesis protocol. The peptide was cleaved from the 2-chlorotrityl resin under the mild condition (TFE/AcOH/DCM) .
  • the peptide was cleaved from the 2-chlorotrityl resin under the mild condition (TFE/AcOH/DCM) . After dryness, the peptide was cyclized using HATU in DCM for 4 hours. Then, the solution was concentrated, and then treated with a cocktail containing 95%TFA and 2.5%water for 10 min. The crude product was purified by preparative RP-HPLC to give the methylated Kyn-containing daptomycin analogues Compound 7.
  • Example 8 Compound 1 shows better antibacterial activity than daptomycin in a neutropenic mouse thigh infection model
  • Biological assays were designed to compare the efficacies of compound 1 and compound 7 to daptomycin and other common antibiotics.
  • Example 9 Compound 1 decreases infection of S. aureus in right-sided endocarditis rats
  • Example 10 Compounds 1 and 7 shows better in vitro antibacterial activity than daptomycin and vancomycin
  • Anti-Clostridium difficile activity of compound 1 was tested on two strains, C. difficile BAA-1382 and ATCC3255, using the standard broth dilution method as described by the Clinical Laboratory Standard Institute.
  • a figure or a parameter from one range may be combined with another figure or a parameter from a different range for the same characteristic to generate a numerical range.

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Abstract

L'invention concerne des lipopeptides cycliques comportant une ou plusieurs modifications par rapport à la daptomycine, et leurs procédés de fabrication. Les lipopeptides cycliques peuvent être utilisés en tant qu'agents antibactériens. Les analogues de la daptomycine sont générés par synthèse chimique, ce qui rend possible l'introduction d'un acide aminé non naturel et toute modification de la daptomycine. L'invention concerne également des compositions pharmaceutiques et un procédé d'utilisation de celles-ci pour les analogues de la daptomycine.
PCT/CN2017/078056 2016-04-08 2017-03-24 Lipopeptides cycliques antibactériens Ceased WO2017173932A1 (fr)

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US16/310,364 US11667674B2 (en) 2016-04-08 2017-03-24 Antibacterial cyclic lipopeptides
CN201780035657.3A CN109476704B (zh) 2016-04-08 2017-03-24 抗菌环脂肽

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US15/093,950 2016-04-08
US15/093,950 US10647746B2 (en) 2016-04-08 2016-04-08 Antibacterial cyclic lipopeptides
US201662438138P 2016-12-22 2016-12-22
US62/438,138 2016-12-22

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4537717A (en) * 1982-05-21 1985-08-27 Eli Lilly And Company Derivatives of A-21978C cyclic peptides
WO1999043700A1 (fr) * 1998-02-25 1999-09-02 Aventis Pharma Deutschland Gmbh Sels de calcium d'antibiotiques a base de lipopeptides, leur procede de production et leur utilisation
WO2002005837A1 (fr) * 2000-07-17 2002-01-24 Intrabiotics Pharmaceuticals, Inc. Derives sulfonamide antimicrobiens d'antibiotiques lipopeptidiques
WO2002056829A2 (fr) * 2000-12-18 2002-07-25 Cubist Pharmaceuticals, Inc. Procedes de preparations de daptomycine purifiee
WO2007072082A1 (fr) * 2005-12-21 2007-06-28 Recombinogen Ltd Lipopeptides cycliques
WO2012162567A1 (fr) * 2011-05-26 2012-11-29 Cubist Pharmaceuticals, Inc. Compositions de cb-183,315 et procédés associés

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103848894A (zh) * 2012-11-30 2014-06-11 杨子剑 含有达托霉素结构的新化合物以及制备方法和用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4537717A (en) * 1982-05-21 1985-08-27 Eli Lilly And Company Derivatives of A-21978C cyclic peptides
WO1999043700A1 (fr) * 1998-02-25 1999-09-02 Aventis Pharma Deutschland Gmbh Sels de calcium d'antibiotiques a base de lipopeptides, leur procede de production et leur utilisation
WO2002005837A1 (fr) * 2000-07-17 2002-01-24 Intrabiotics Pharmaceuticals, Inc. Derives sulfonamide antimicrobiens d'antibiotiques lipopeptidiques
WO2002056829A2 (fr) * 2000-12-18 2002-07-25 Cubist Pharmaceuticals, Inc. Procedes de preparations de daptomycine purifiee
WO2007072082A1 (fr) * 2005-12-21 2007-06-28 Recombinogen Ltd Lipopeptides cycliques
WO2012162567A1 (fr) * 2011-05-26 2012-11-29 Cubist Pharmaceuticals, Inc. Compositions de cb-183,315 et procédés associés

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