CN109476704B - Antibacterial cyclic lipopeptides - Google Patents

Abstract

Cyclic lipopeptides having one or more modifications relative to daptomycin are provided, as well as methods for making the same. Cyclic lipopeptides are useful as antibacterial agents. Daptomycin analogs are prepared by chemical synthesis, which makes possible the introduction of unnatural amino acids and any modifications to daptomycin. Pharmaceutical compositions of the disclosed daptomycin analogs and methods of use thereof are also provided.

Description

Antibacterial cyclic lipopeptides

Cross Reference to Related Applications

This application claims the benefit and priority of the following applications: united states utility application 15/093950 filed on 8/4/2016, united states provisional application 62/438138 filed on 22/12/2016, and each is permitted to be specifically incorporated by reference herein in its entirety.

Technical Field

The present invention is in the field of antibacterial agents, particularly antibacterial cyclic lipopeptides.

Background

Despite the wide variety of antibacterial agents currently available, there is a need for improved antibiotics. One reason is the varying efficacy of antibiotics against different pathogenic organisms. In addition, pathogenic organisms are known to develop resistance to antibiotics that were once effective against the organism. This situation is exacerbated by hypersensitivity and/or toxic effects, which often exacerbate the individual patient's severe response to specific antibiotics. Thus, there is a continuing need for new and improved antibiotics.

Many cyclic peptides have potent antibacterial activity. For example,daptomycin is a cyclic lipopeptide consisting of 13 amino acids, 10 of which form a 31-membered ring and 3 of which are anchored as exocyclic tails, the N-terminus containing N-decanoyl lipids. Within this structure are two unnatural amino acids (kynurenine (Kyn) and 3-methyl-glutamic acid (3-mGlu)), and three D amino acids (i.e., D-Asn, D-Ala, and D-Ser). Functionally, the compound shows a unique mode of action that is significantly different from other currently used antibiotics: it is first reacted with Ca ²⁺ Ion binding undergoes a conformational change, allowing the entire structure to be inserted into the bacterial membrane through the lipid tail, and then inducing membrane leakage and cell death.

Various research groups have previously attempted to establish the structure-activity relationship (SAR) of daptomycin and to prepare analogs thereof. However, since daptomycin can only be produced by fermentation, only a limited number of daptomycin analogs with few structural changes can be produced by genetic engineering of non-ribosomal peptide synthetases in the daptomycin biosynthetic pathway, as well as by chemoenzymatic and semi-synthetic methods. These analogs are limited to the exchange of natural amino acids. None of these daptomycin analogs exhibit greater antibacterial activity than the parent daptomycin. Indeed, these methods described above do not allow the production of analogs containing modifications at the Trp1, Thr4, Gly5, Orn6, and Kyn13 positions of daptomycin, and do not allow the substitution of non-natural amino acids for daptomycin residues.

Accordingly, it is an object of the present invention to provide analogues of daptomycin.

It is a further object of the present invention to provide analogues of daptomycin that include modifications at Trp1, Thr4, Gly5, Orn6, Kyn13, and combinations thereof.

It is a further object of the present invention to provide daptomycin analogs that contain unnatural amino acids.

It is another object of the present invention to provide a method of making an analog of daptomycin that includes modifications on Trp1, Thr4, Gly5, Orn6, Kyn13, and combinations thereof.

It is a further object of the present invention to provide a method of using the disclosed compounds, particularly as antimicrobial agents.

Summary of The Invention

Described herein are a group of daptomycin-based modified cyclic lipopeptides, methods of making and using the same. The cyclic lipopeptides are useful as antibacterial agents.

The cyclic lipopeptides have the general formula:

preferably, when present, R is a substituted aryl or substituted alkenyl; r ₅ Is- (CH) ₂ ) _x -NR* ₂ X is 3, and each R is independently an unsubstituted alkyl, substituted aryl or unsubstituted aryl, preferably both unsubstituted alkyl (e.g. methyl); r is ₁ Is a substituted polyheteroaralkyl group (e.g., N-alkylated indol-3-ylalkyl such as N-methylindol-3-ylmethyl), an unsubstituted polyheteroaralkyl group (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; and R is ₁₂ Is a substituted alkyl group containing a substituted aniline; and X is O or NH.

The cyclic lipopeptides are preferably produced by chemical synthesis, which facilitates the introduction of unnatural amino acids or modifications to daptomycin. Chemical synthesis was used to generate analogs with more extensive modifications and to introduce modifications at Trp1, Thr4, Gly5, and Kyn 13. In some forms, these resulting cyclic lipopeptides have an N-alkylated or N-acylated kynurenine in place of kynurenine (Kyn 13); n-alkylindol-3-ylalkyl (N-methylindol-3-ylmethyl, i.e., merrp), 1-naphthylmethyl, or 2-naphthylmethyl to replace Trp 1; sarcosine in place of Gly 5; alkylated Orn to replace Orn 6; and/or 2, 3-diaminobutyric acid or 2, 3-diaminopropionic acid to replace Thr 4.

Also provided are pharmaceutical compositions comprising the disclosed compounds and methods of using the same to treat a subject in need thereof.

Brief Description of Drawings

FIG. 1 shows the chemical structure of daptomycin with amino acid numbering.

FIG. 2 shows the chemical structure of methylation at Gly5 in daptomycin.

FIG. 3 shows the chemical structure of methylation at Kyn13 within daptomycin.

FIG. 4 shows the chemical structure of methylation at Trp1 in daptomycin.

FIG. 5 shows the chemical structure of methylation at Orn5 within daptomycin.

FIG. 6 shows the chemical structure of acylation at a lipid within daptomycin, as well as alternative structures for the acylation group.

FIG. 7 shows two chemical structures for replacement of Trp1 with either a 1-naphthylmethyl or a 2-naphthylmethyl group in daptomycin.

Detailed Description

I. Definition of

To facilitate an understanding of the subject matter disclosed herein, a number of terms, abbreviations, or other shorthand definitions used herein follow. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The practice of the present invention employs, unless otherwise indicated, conventional techniques of chemistry, biochemistry and microbiology and the basic terminology used therein.

It is to be understood that unless otherwise specified, the disclosed compounds, compositions, and methods are not limited to specific synthetic methods, specific analytical techniques, or specific reagents, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular forms and embodiments only, and is not intended to be limiting.

The term "amino acid" as used herein refers to a molecule containing both amino and carboxyl groups. Amino acids include alpha-amino acids and beta-amino acids. In some forms, the amino acid is an alpha-amino acid. The amino acids may be natural or synthetic. Amino acids include, but are not limited to, 20 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). Common non-standard or non-canonical amino acids include, but are not limited to, selenocysteine, pyrrolysine, and N-formylmethionine.

The term "natural amino acid" as used herein 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 (known by single letter abbreviations)).

The terms "synthetic amino acid", "non-natural amino acid" and "unnatural amino acid" are used interchangeably and refer to organic compounds having an amino group and a carboxyl group, and are not one of the D-and L-isomers of the 20 common naturally occurring amino acids found in peptides. In general, it mimics the reactivity of natural amino acids due to the presence of amino and carboxyl groups. "synthetic amino acid", "unnatural amino acid" or "unnatural amino acid" also refers to amino acids that are not genetically engineered, not produced by an organism. Synthetic amino acids, as defined herein, generally increase or enhance various properties (e.g., selectivity, stability) of a peptide when substituted for natural amino acids or incorporated into a peptide. Non-limiting examples include N-methyl kynurenine, N-dimethyl kynurenine, N-methyl ornithine, N-dimethyl ornithine, N-methyl glycine (sarcosine), 2, 3-diaminobutyric acid, 2, 3-diaminopropionic acid, and alpha-amino acids having the following side chains: 1-naphthylmethyl, 1-naphthylmethyl and N-methylindol-3-ylmethyl.

The term "isolated" refers to a compound or product that means that a compound represents at least 10% by weight, at least 20% by weight, at least 30% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, or at least 95% by weight of the compounds present in a mixture.

The term "lipopeptide" refers to molecules comprising a lipid-like moiety covalently linked to a peptide moiety, and salts, esters, amides, and ethers thereof. The term "lipopeptide" also includes protected forms of lipopeptides in which one or more amino, carboxylate, or hydroxyl groups are protected.

As used herein, "amino" and "amine" are well known in the art and refer to primary, secondary or tertiary amines, which may be optionally substituted, such as moieties that may be represented by the general formula:

wherein R, R 'and R' each independently represent 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' together with the N atom to which they are attached complete a heterocyclic ring having from 3 to 14 atoms in the ring structure; r' "represents hydroxy, substituted or unsubstituted carbonyl, aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and m is zero or an integer from 1 to 8. In a preferred embodiment, only one of R and R 'may be a carbonyl group, e.g., R and R' together with the nitrogen do not form an imide. In a preferred embodiment, R and R' (and optionally R ") each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or- (CH) ₂ ) _m -R' ". Thus, the term "alkylamine" as used herein refers to an amine group, as defined above, having a substituted alkyl group or an unsubstituted alkyl group attached thereto (i.e., at least one of R, R' or R "is an alkyl group). The term "dialkylamine" refers to an amine group as defined above having two substituted alkyl groups or unsubstituted alkyl groups attached thereto. Specifically included are secondary or tertiary amine nitrogen atoms which are members of the heterocyclic ring. Also specifically included are those substituted with acyl moietiesSecondary or tertiary amino groups. Some non-limiting examples of amino groups include-NR 'R ", where each R' and R" is independently H, alkyl, aryl, aralkyl, alkaryl, cycloalkyl, acyl, heteroalkyl, heteroaryl, or heterocyclyl.

As used herein, "alkyl" refers to the radical of a saturated aliphatic group, including straight-chain alkyl, branched-chain alkyl, cycloalkyl (alicyclic), alkyl-substituted cycloalkyl, and cycloalkyl-substituted alkyl. In a preferred form, the linear or branched alkyl group has 30 or fewer in its backbone (e.g., C for linear ₁ -C ₃₀ For the side chain is C ₃ -C ₃₀ ) Preferably 20 or less, more preferably 15 or less, and most preferably 10 or less carbon atoms. Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.

Likewise, preferred cycloalkyl groups have 3 to 10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbon atoms in the ring structure. The term "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. Such substituents include, but are not limited to, halogen, hydroxy, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphatidic acid, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, mercapto, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

As used herein, unless the number of carbons is otherwise specified, "lower alkyl" refers to an alkyl group as defined above, but having from one to ten carbon atoms, more preferably from one to six carbon atoms, in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyl groups. In a preferred form, the substituents labeled herein as alkyl are lower alkyl.

"alkyl" and heteroalkyl include one or more substituents at one or more carbon atoms of a hydrocarbon group. Suitable substituents include, but are not limited to, halogen, such as fluorine, chlorine, bromine, or iodine; a hydroxyl group; -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 (ii) a -COOH; a carboxylic acid ester; -COR, -COOR or-CON (R) ₂ Wherein R is hydrogen, alkyl or aryl; azides, aralkyls, alkoxys, iminos, phosphonates, phosphinates, silyls, ethers, sulfonyls, sulfonamido, heterocyclyls, aromatic or heteroaromatic moieties, haloalkyl (e.g., -CF) ₃ 、-CH ₂ -CF ₃ 、-CCl ₃ )；-CN；-NCOCOCH ₂ CH ₂ (ii) a -NCOCOCHCH; -NCS; and combinations thereof.

It will be appreciated by those skilled in the art that the moiety substituted on the hydrocarbon chain may itself be substituted, if appropriate. For example, substituents of substituted alkyl groups may include halogen, hydroxy, nitro, thiol, amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate) and silyl groups, as well as ether, alkylthio, carbonyl (including ketones, aldehydes, carboxylates and esters), haloalkyl, -CN, and the like. Cycloalkyl groups may be substituted in the same manner.

As used herein, "heteroalkyl" refers to a straight-chain or branched-chain or cyclic carbon-containing group containing at least one heteroatom, or combinations thereof. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, wherein the nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized.

The term "hydroxyalkyl" refers to an alkyl group as defined herein substituted with one or more, preferably one, two or three, hydroxy groups. Representative examples of hydroxyalkyl groups 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-hydroxypropyl, preferably 2-hydroxyethyl, 2, 3-dihydroxypropyl and 1- (hydroxymethyl) 2-hydroxyethyl.

The term "alkoxy" OR "alkoxy", "aryloxy" OR "aryloxy" is generally described by the formula-OR ^v A compound represented by the formula (I) wherein R ^v Including but not limited to substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, heteroalkyl, alkylaryl, alkylheteroaryl.

The term "alkoxy" or "alkoxy" as used herein refers to an alkyl group as defined above having an oxy group attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, t-butoxy, and the like. An "ether" is two hydrocarbons covalently linked by oxygen. Thus, the substituent of an alkyl group that renders the alkyl group an ether is or resembles an alkoxy group, as may be represented by one of-O-alkyl, -O-alkenyl, and O-alkynyl. The term alkoxy also includes cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkenyl, and aralkyl groups having an oxy group attached to at least one carbon atom, as valence permits. "lower alkoxy" is an alkoxy group containing 1 to 6 carbon atoms.

The term "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. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate, or thiocarbamate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

The term "alkenyl" as used herein refers to a hydrocarbon group of the formula having from 2 to 24 carbon atoms and containing at least one carbon-carbon double bond. Asymmetric structures such As (AB) C ═ C (cd) are intended to include the E and Z isomers. This is presumed to be the case in the structural formulae herein, in which an asymmetric olefin is present, or may be explicitly represented by the bond symbol C.

The term "alkynyl" as used herein refers to a hydrocarbon group of the formula having from 2 to 24 carbon atoms and containing at least one carbon-carbon triple bond.

The term "aryl" as used herein is any C ₅ -C ₂₆ A carbon-based aromatic group, a fused aromatic, a fused heterocyclic ring, or a biaromatic (bi-aromatic) ring system. As broadly defined, "aryl" as used herein includes 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered monocyclic aromatic groups, including, but not limited to, benzene, naphthalene, anthracene, phenanthrene, naphthalene, and naphthalene,

Pyrene, caryophyllene (corannulene), coronene (coronene), and the like. "aryl" also includes 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 and the other ring or rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and/or heterocyclic. The aryl group may be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxyl, carboxylic acid, or alkoxy.

The term "substituted aryl" refers to an aryl group in which 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, hydroxy, alkoxy, carbonyl (such as ketone, aldehyde, carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate, or thiocarbamate), alkaneOxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, mercapto, imino, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (e.g., CF) ₃ 、-CH ₂ -CF ₃ ，-CCl ₃ ) CN, -aryl, heteroaryl, and combinations thereof.

"heterocycle", "heterocyclic" and "heterocyclyl" are used interchangeably and refer to a cyclic group attached via a monocyclic or bicyclic ring carbon or nitrogen atom containing 3 to 10 ring atoms, preferably 5 to 6 ring atoms, consisting of carbon and 1 to 4 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 contains 1-3 double bonds and is optionally substituted with one or more substituents. Heterocyclic and heteroaryl groups are distinguished by definition. Examples of heterocycles include, but are not limited to, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, dihydrofuro [2,3-b ]]Tetrahydrofuran, morpholinyl, piperazinyl, piperidinyl, piperidyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl, 2H-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuryl, 6H-1,2, 5-thiadiazinyl. The heterocyclic group may be optionally substituted with one or more substituents as defined above for alkyl and aryl.

The term "heteroaryl" refers to C ₅ -C ₂₆ -a membered aromatic, fused aromatic, biaromatic (bi-aromatic) ring system or combinations thereof wherein one or more carbon atoms in one or more aromatic ring structures are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen. As broadly defined, "heteroaryl" as used herein includes 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered monocyclic aromatic groups, which may include one to four heteroatoms, such as 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 an "aryl heterocycle" or a "heteroaromatic group". "heteroaryl" is alsoIncluded are 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 a heteroaromatic ring and the other ring or rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic, or combinations thereof.

Examples of heteroaryl rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5, 2-dithiazacyclohexane (dithiazinyl), furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolylenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindolyl, isoindolinyl, isoquinolinyl, isothiazolyl, and the like, Isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl (phenoxathinyl), phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl (pyridinyl), pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl (thienyl), thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl (thiophenyl) and xanthenyl. One or more rings may be replaced as defined below for "substituted heteroaryl".

The term "substituted heteroaryl" refers to heteroaryl groups in which one or more hydrogen atoms in one or more of the heteroaryl rings are substituted with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, carbonyl (such as ketone, aldehyde, carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, mercapto, imino, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (such as CF) ₃ 、-CH ₂ -CF ₃ 、-CCl ₃ ) CN, -aryl, heteroaryl, and combinations thereof.

The term "substituted alkenyl" refers to an alkenyl moiety having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate, or thiocarbamate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

The term "substituted alkynyl" refers to an alkynyl moiety having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate, or thiocarbamate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

The term "cycloalkyl" as used herein is a non-aromatic carbon-based ring consisting of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term "heterocycloalkyl" is a cycloalkyl group as defined above in which at least one of the carbon atoms of the ring is replaced by a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur or phosphorus.

"aralkyl" refers to an alkyl group substituted with an aryl group. Some non-limiting examples of aralkyl groups include benzyl and phenethyl.

"acyl" refers to a monovalent group of the formula-C (═ O) H, -C (═ O) -alkyl, -C (═ O) -aryl, -C (═ O) -aralkyl, or-C (═ O) -alkaryl.

"halogen" refers to fluorine, chlorine, bromine and iodine.

"styryl" refers to a monovalent C derived from styrene ₆ H ₅ -CH ═ CH-group.

"substituted" as used herein refers to all permissible substituents of compounds or functional groups described herein. In the broadest sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Exemplary substituents include, but are not limited to, halogen, hydroxyl, or any other organic group containing any number of carbon atoms, preferably 1-14 carbon atoms, and optionally including one or more heteroatoms (such as oxygen, sulfur, or nitrogen), in the form of linear, branched, or cyclic structures. Representative substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, alkoxy, substituted alkoxyPhenoxy, substituted phenoxy, aryloxy, substituted aryloxy, 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, substituted polyaryl, C ₃ -C ₂₀ Cyclic group, substituted C ₃ -C ₂₀ Cyclic groups, heterocyclic groups, substituted heterocyclic groups, amino acids, poly (lactic-co-glycolic acid), peptides, and polypeptide groups. Such alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halogen, hydroxy, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aryloxy, substituted aryloxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxy, substituted carboxy, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C ₃ -C ₂₀ Cyclic group, substituted C ₃ -C ₂₀ Cyclic groups, heterocyclic groups, substituted heterocyclic groups, amino acids, poly (lactic-co-glycolic acid), peptide and polypeptide groups may be further substituted.

A heteroatom such as nitrogen may have a hydrogen substituent and/or any permissible substituents of organic compounds described herein that satisfy the valencies of the heteroatoms. It is understood that "substitution" or "substituted" includes the implicit proviso that such substitution is made according to the valency allowed by the atom and substituent being substituted, and that the substitution results in a stable compound, i.e., the compound does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, and the like.

The term "alkoxyalkyl" is defined as an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, haloalkyl, or heterocycloalkyl group described above having at least one hydrogen atom substituted with an alkoxy group described above.

"carbonyl" as used herein is well known in the art and includes moieties that can be represented by the general formula:

wherein X is a bond, or represents oxygen or sulfur, and R represents hydrogen, 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 pharmaceutically acceptable salt, R' represents hydrogen, 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, or- (CH) ₂ ) _m -R "; r' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, an aryl group, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle or a polycycle; m is zero or an integer from 1 to 8. When X is oxygen and R is as defined above, the moiety is also referred to as a carboxyl group. When X is oxygen and R is hydrogen, the formula represents "carboxylic acid". When X is oxygen and R' is hydrogen, the formula represents a "formate". When X is oxygen and R or R' is not hydrogen, the formula represents an "ester". In general, when the oxygen atom of the above formula is replaced by a sulfur atom, the formula represents a "thiocarbonyl" group. When X is sulfur and R or R' is not hydrogen, the formula represents a "thioester". When X is sulfur and R is hydrogen, the formula represents a "thiocarboxylic acid". When X is sulfur and R' is hydrogen, the formula represents a "thioformate". When X is a bond and R is not hydrogen, the above formula represents a "ketone". When X is a bond and R is hydrogenThe formula represents an "aldehyde".

The term "substituted carbonyl" refers to a carbonyl as defined above in which R, R' or one or more hydrogen atoms in the group to which the following moiety is attached is independently substituted:

such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate, or thiocarbamate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

The term "carboxy" is as defined above for the formula:

and more specifically of the formula-R ^iv COOH in which R ^iv Is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylaryl, arylalkyl, aryl or heteroaryl. In preferred forms, the linear or branched alkyl, alkenyl and alkynyl groups have 30 or fewer groups in their backbone (e.g., C for linear alkyl groups) ₁ -C ₃₀ For branched alkyl is C ₃ -C ₃₀ For linear alkenyl and alkynyl is C ₂ -C ₃₀ For branched alkenyl and alkynyl is C ₃ -C ₃₀ ) Preferably 20 or less, more preferably 15 or less, and most preferably 10 or less carbon atoms. Also, preferred cycloalkyl, heterocyclyl, aryl and heteroaryl groups have 3 to 10 carbon atoms in their ring structure, and more preferredHaving 5, 6 or 7 carbon atoms in the ring structure.

The term "substituted carboxy" refers to wherein R ^iv A carboxyl group as defined above in which one or more hydrogen atoms are replaced. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate, or thiocarbamate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

The term "phenoxy" is well known in the art and refers to the group wherein R is ^v Is of the formula-OR ^v Compound of (i.e., -O-C) ₆ H ₅ ). Phenoxy groups are considered by those skilled in the art to be of the aryloxy type.

The term "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. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate, or thiocarbamate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

The terms "aryloxy" and "aryloxy" are used interchangeably herein and are represented by-O-aryl or-O-heteroaryl, wherein aryl and heteroaryl are as defined herein.

The terms "substituted aryloxy" and "substituted aryloxy" are used interchangeably herein to mean an-O-aryl or-O-heteroaryl group having one or more substituents replacing one or more hydrogen atoms on one or more ring atoms of the aryl and heteroaryl groups as defined herein. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate, or thiocarbamate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

The term "alkylthio" refers to an alkyl group as defined above having a thio group attached thereto. The "alkylthio" moiety is represented by-S-alkyl. Representative alkylthio groups include methylthio, ethylthio, and the like. The term "alkylthio" also includes cycloalkyl groups having a thio group attached thereto.

The term "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 backbone of the alkylthio group. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate, or thiocarbamate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

The term "thiophenyl" is well known in the art and refers to-S-C ₆ H ₅ I.e. a phenyl group attached to a sulphur atom.

The term "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. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate, or thiocarbamate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

"arylthio" means-S-aryl or-S-heteroaryl, wherein aryl and heteroaryl are as defined herein.

The term "substituted arylthio" denotes an-S-aryl or-S-heteroaryl group having one or more substituents replacing a hydrogen atom on one or more ring atoms in the aryl and heteroaryl rings as defined herein. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate, or thiocarbamate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

The terms "amide" or "amido" are used interchangeably to refer to both "unsubstituted amido" and "substituted amido" and are represented by the general formula:

wherein 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 E, R and R' each independently represent 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, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, - (CH) ₂ ) _m -R '", or R and R', together with the N atom to which they are attached, complete a heterocyclic ring having 3 to 14 atoms in the ring structure; r' "represents hydroxyl, substituted or unsubstituted carbonyl, aryl, cycloalkyl, cycloalkenyl, heterocyclic, or polycyclic; and m is zero or an integer from 1 to 8. In preferred forms only one of R and R 'may be a carbonyl group, e.g. R and R' together with the nitrogen do not form an imide. In a preferred form, R and R' each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group or- (CH) ₂ ) _m -R' ". When E is oxygen, a carbamate is formed. The carbamate may not be linked to another chemical species, such as to form an oxygen-oxygen bond, or other labile bond, as would be understood by one of ordinary skill in the art.

The term "sulfonyl" is represented by the formula:

wherein E is absent, or E is alkyl, alkenyl, alkynyl, aralkyl, alkylaryl, cycloalkyl, aryl, heteroaryl, heterocyclyl, wherein E, R independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyneA substituted or unsubstituted amine, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, - (CH) ₂ ) _m -R' ", or E and R together with the S atom to which they are attached complete a heterocyclic ring having 3 to 14 atoms in the ring structure; r' "represents hydroxyl, substituted or unsubstituted carbonyl, aryl, cycloalkyl, cycloalkenyl, heterocyclic, or polycyclic; and m is zero or an integer from 1 to 8. In preferred forms, only one of E and R may be a substituted or unsubstituted amine to form a "sulfonamide" or "sulfonamido". The substituted or unsubstituted amines are as defined above.

The term "substituted sulfonyl" denotes a sulfonyl group, wherein E, R or both are independently substituted. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate, or thiocarbamate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

The term "sulfonic acid" refers to a sulfonyl group as defined above, wherein R is hydroxyl and E is absent, or E is a 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.

The term "sulfate" refers to a sulfonyl group as defined above, wherein E is absent, oxygen, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy (as defined above), and R is independently hydroxy, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy (as defined above). When E is oxygen, the sulfate may not be attached to another chemical species, such as to form an oxygen-oxygen bond, or other labile bond, as will be appreciated by those of ordinary skill in the art.

The term "sulfonate" refers to a sulfonyl group as defined above, wherein E is oxygen, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy (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'" representing a hydroxyl group, a substituted or unsubstituted carbonyl group, an aryl group, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle or a polycycle; and m is zero or an integer from 1 to 8. When E is oxygen, the sulfonate ester may not be attached to another chemical species, such as to form an oxygen-oxygen bond, or other labile bond, as would be understood by one of ordinary skill in the art.

The term "sulfamoyl" refers to a sulfonamide or a sulfonamide represented by the formula

Wherein 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 E, R and R' each independently represent 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, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, - (CH) ₂ ) _m -R '", or R and R' together with the N atom to which they are attached complete a heterocyclic ring having 3 to 14 atoms in the ring structure; r' "represents hydroxyl, substituted or unsubstituted carbonyl, aryl, cycloalkyl, cycloalkenyl, heterocyclic, or polycyclic; and m is zero or an integer from 1 to 8. In preferred forms only one of R and R 'may be a carbonyl group, e.g. R and R' together with the nitrogen do not form an imide.

The term "phosphono" is represented by the formula:

wherein 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, E, R ^vi And R ^vii 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, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, - (CH) ₂ ) _m -R '", or R and R', together with the P atom to which they are attached, complete a heterocyclic ring having 3 to 14 atoms in the ring structure; r' "represents hydroxyl, substituted or unsubstituted carbonyl, aryl, cycloalkyl, cycloalkenyl, heterocyclic, or polycyclic; and m is zero or an integer from 1 to 8.

The term "substituted phosphono" denotes a radical wherein E, R ^vi And R ^vii Independently substituted phosphono groups. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester)Thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidino, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

The term "phosphoryl" defines a phosphoryl group wherein E is absent, oxo, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy (as defined above), and is independently E, R ^vi And R ^vii Independently a hydroxyl group, an alkoxy group, an aryloxy group, a substituted alkoxy group, or a substituted aryloxy group (as defined above). When E is oxygen, the phosphoryl group may not be attached to another chemical species, such as to form an oxygen-oxygen bond, or other labile bond, as will be appreciated by those of ordinary skill in the art. When E, R ^vi And R ^vii When substituted, the substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, thiol, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

The term "polyaryl" refers to a chemical moiety that includes two or more aryl groups, heteroaryl groups, and combinations thereof. The aryl, heteroaryl, and combinations thereof are fused or linked by single bonds, ethers, esters, carbonyls, amides, sulfonyls, sulfonamides, alkyls, azos, and combinations thereof. When two or more heteroaryl groups are involved, the chemical moiety may be referred to as a "polyhaloaryl".

The term "substituted polyaryl" refers to a polyaryl in which one or more of the aryl, heteroaryl groups are substituted with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quaternized amino), amido, amidino, imine, cyano, nitro, azido, mercapto, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof. When two or more heteroaryl groups are involved, the chemical moiety may be referred to as a "substituted polyheteroaryl".

The term "polyaryl" refers to a polyaryl group attached to an alkyl group. The polyaryl can be substituted or unsubstituted.

The term "polyheteroaralkyl" refers to a polyheteroaryl group attached to an alkyl group. The polyheteroaralkyl may be substituted or unsubstituted.

The term "C ₃ -C ₂₀ By "cyclic ring" is meant a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl group, if geometry permits, having from 3 to 20 carbon atoms. The cyclic structure is formed of a single ring or a fused ring system. Substituted cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl are substituted as defined above for alkyl, alkenyl, alkynyl, and heterocyclyl, respectively.

The term "ether" as used herein is defined by the formula AOA ¹ Is represented by the formula, wherein A and A ¹ May independently be an alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group (as described above) as described above.

The term "carbamate" as used herein is represented by the formula-oc (o) NRR ', wherein R and R' may be independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, haloalkyl, or heterocycloalkyl (as described above).

The term "silyl" as used herein is represented by the formula-SiRR 'R ", where R, R' and R" can be independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, haloalkyl, alkoxy, or heterocycloalkyl (as described above).

The terms "hydroxyl" and "hydroxy" are used interchangeably and are represented by-OH.

The terms "thiol" and "mercapto" are used interchangeably and are represented by-SH.

The term "oxo" refers to ═ O bonded to a carbon atom.

The terms "cyano" and "nitrile" are used interchangeably to refer to — CN.

The term "nitro" means-NO ₂ 。

The term "phosphate ester" means-O-PO ₃ 。

The terms "azide" or "azido" are used interchangeably to refer to-N ₃ 。

The disclosed compounds and substituents may independently have two or more of the groups listed above. For example, if the compound or substituent is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group may be substituted with a hydroxyl group, an alkoxy group, or the like. Depending on the group selected, the first group may be incorporated within the second group, or the first group may be pendant (i.e., attached) to the second group. For example, for the phrase "alkyl group comprising an ester group," the ester group may be incorporated into the backbone of the alkyl group. Alternatively, the ester may be attached to the backbone of the alkyl group. The nature of the group selected will determine whether the first group is intercalated or attached to the second group.

The compounds and substituents may be independently substituted with the substituents described above in the definition of "substituted".

The terms "effective amount" and "therapeutically effective amount" when used in the context of the compounds, antibiotics, and pharmaceutical compositions described herein are used interchangeably to refer to the amount necessary to confer the desired therapeutic result. For example, an effective amount is an amount that administers the composition and/or the anti-tumor agent or pharmaceutical composition to effectively treat, cure, or alleviate the symptoms of the disease. The effective amount sought for a particular therapeutic goal depends on a number of factors, including the disease to be treated, its severity and/or the stage of development/progression; bioavailability and activity of the particular compound and/or antineoplastic agent or pharmaceutical composition used; a route or method of administration and a site of introduction on a subject; clearance and other pharmacokinetic properties of a particular composition; the duration of treatment; an inoculation scheme; drugs used in combination or concomitantly with the specified compositions; the age, weight, sex, diet, physiology, and general health of the subject to be treated; similar factors well known to those skilled in the relevant scientific arts. Some variation in dosage will necessarily be made depending on the condition of the subject to be treated, and in any event, the treatment administered by the surgeon or other individual will determine the appropriate dosage for the individual patient.

The term "inhibition" refers to a reduction or decrease in activity or expression. This may be a complete or partial inhibition of activity or expression. Inhibition is comparable to control or standard levels. 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, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%.

By "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject with a selected compound without producing any undesirable biological effect or interacting in a deleterious manner with any of the other ingredients of the pharmaceutical composition in which it is contained.

As used herein, "treatment" or "treating" refers to preventing or inhibiting, or attempting to prevent or inhibit the development or progression of a disease, and/or causing or attempting to cause a reduction, inhibition, regression, or remission of a disease and/or its symptoms. As will be appreciated by those skilled in the art, various clinical scientific methods and assays can be used to assess the development or progression of an infection, and similarly, various clinical scientific methods and assays can be used to assess the reduction, decline or remission of an infection or symptoms thereof. "treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already infected, as well as those susceptible to or to be prevented from disease.

Composition II

A. Compound (I)

Daptomycin, approved by the FDA in 2003, represents a good example of an antibacterial cyclic lipopeptide. Daptomycin is a cyclic lipopeptide containing 13 amino acids, 10 of which form a 31-membered ring and 3 of which are anchored as exocyclic tails, with the N-terminus containing N-decanoyl lipids. 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 analogs. The cyclic lipopeptides may have antibacterial properties. The cyclic lipopeptides include kynurenines with alkylation or acylation to replace Kyn 13; n-methylindol-3-ylmethyl (i.e., merrp), 1-naphthylmethyl, or 2-naphthylmethyl to replace Trp 1; sarcosine in place of Gly 5; dialkylated Orn to replace Orn 6; and/or 2, 3-diaminobutyric acid or 2, 3-diaminopropionic acid to replace Thr 4. That is, at least one of the five general modifications described in the preceding sentence was performed to provide the cyclic lipopeptide. In particular embodiments, the modification comprises methylation at one or more of Gly (e.g., Gly between Thr and Orn), Orn, Kyn, and/or Trp (or dimethylation for Orn).

The cyclic lipopeptides have the general formula:

wherein the content of the first and second substances,

R ₁ -R ₁₂ independently is a substituted polyheteroaralkyl radicalA group, unsubstituted polyheteroaralkyl, substituted polyarylalkyl, unsubstituted polyarylalkyl, 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 radical, unsubstituted C ₃ -C ₂₀ Cycloalkenyl, substituted C ₃ -C ₂₀ Cycloalkynyl, unsubstituted C ₃ -C ₂₀ Cycloalkynyl, hydrogen, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, or the side chain of any natural or unnatural amino acid. Preferably, R ₁ Is a substituted polyheteroaralkyl, unsubstituted polyheteroaralkyl, substituted polyarralkyl, unsubstituted polyarralkyl, 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 R ₁ Is the side chain of Trp (indol-3-ylmethyl), MeTrp (i.e. the nitrogen atom of the indole ring is methylated, N-methylindol-3-ylmethyl), unsubstituted 1-naphthylmethyl, unsubstituted 2-naphthylmethyl, substituted 1-naphthylmethyl or substituted 2-naphthylmethyl. Preferably R ₂ -R ₁₂ Independently, a side chain of any natural or unnatural amino acid;

r 'and R' are independently hydrogen, unsubstituted 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, unsubstitutedC of (A) ₃ -C ₂₀ Cycloalkyl, substituted C ₃ -C ₂₀ Heterocyclyl, unsubstituted C ₃ -C ₂₀ Heterocyclyl, substituted C ₃ -C ₂₀ Cycloalkenyl radical, unsubstituted C ₃ -C ₂₀ Cycloalkenyl, substituted C ₃ -C ₂₀ Cycloalkynyl or unsubstituted C ₃ -C ₂₀ Cycloalkynyl. Preferably, 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 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 radical, unsubstituted C ₃ -C ₂₀ Cycloalkenyl, substituted C ₃ -C ₂₀ Cycloalkynyl or unsubstituted C ₃ -C ₂₀ Cycloalkynyl. Preferably, Ra is hydrogen;

r is substituted aryl, unsubstituted aryl, substituted alkenyl, unsubstituted 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 radical, unsubstituted C ₃ -C ₂₀ Cycloalkenyl, substituted C ₃ -C ₂₀ CycloalkynesOr unsubstituted C ₃ -C ₂₀ Cycloalkynyl. Preferably, R is a substituted aryl or substituted alkenyl.

In some forms of formula I, R, R ₁ -R ₁₂ At least one of R ', R' is substituted aryl, unsubstituted aryl, substituted alkenyl, unsubstituted alkenyl, - (CH) ₂ ) _x -NR* ₂ Substituted polyheteroaralkyl, substituted polyarylalkyl, unsubstituted polyarylalkyl, substituted aralkyl, unsubstituted aralkyl, or substituted alkyl containing substituted aniline, wherein x is an integer from 1 to 10, inclusive (e.g., 1,2,3, 4, 5, 6, 7, 8, 9, and 10), and each R is independently unsubstituted alkyl, substituted aryl, or unsubstituted aryl. Preferably, when present, R is a substituted aryl or substituted alkenyl; x is 3; each R is independently an unsubstituted alkyl, substituted aryl or unsubstituted aryl, preferably all unsubstituted alkyl (e.g. methyl); r ₁ Is a substituted polyheteroaralkyl group (e.g., N-alkylated indol-3-ylalkyl such as N-alkylated indol-3-ylmethyl), an unsubstituted polyaryl group (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; and R is ₁₂ Is a substituted alkyl group containing a substituted aniline.

In some forms, R' is unsubstituted alkyl, substituted alkyl, unsubstituted aryl, or substituted aryl; r ₁ Is a substituted polyheteroaralkyl or unsubstituted polyarylalkyl group; r ₂ -R ₁₂ Independently, a side chain of any natural or unnatural amino acid; and R is a substituted alkenyl or substituted aryl.

In some forms, the cyclic lipopeptide has the formula:

wherein the content of the first and second substances,

R ₁ -R ₁₁ independently is unsubstituted polyheteroaralkyl, substituted polyheteroaralkyl, unsubstituted polyararalkyl, polyararalkyl or the side chain of any natural or unnatural amino acid; and

r' "and R" "are independently hydrogen, 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, 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 radical, unsubstituted C ₃ -C ₂₀ Cycloalkenyl, substituted C ₃ -C ₂₀ Cycloalkynyl or unsubstituted C ₃ -C ₂₀ Cycloalkynyl, substituted alkoxy, unsubstituted alkoxy, substituted aryloxy, unsubstituted aryloxy, substituted alkylthio, unsubstituted alkylthio, substituted arylthio, unsubstituted arylthio, substituted carbonyl, unsubstituted carbonyl, substituted carboxyl, unsubstituted carboxyl, substituted amino, unsubstituted amino, substituted amido, unsubstituted amido, substituted sulfonyl, unsubstituted sulfonyl, substituted sulfonic acid, unsubstituted sulfonic acid, substituted phosphoryl, unsubstituted phosphoryl, substituted phosphonyl, or unsubstituted phosphonyl. In some forms, at least one of R' "and R" "is not hydrogen. Preferably, R '"is hydrogen and R" "is unsubstituted alkyl (e.g., methyl, such that R'" is hydrogen and R "" is unsubstituted alkyl ₁₂ Is N-methyl kynurenine) or a substituted carbonyl group (e.g., acyl).

Preferably, R ', R "and R'" are independently H, unsubstituted alkyl (e.g., methyl, ethyl) or substituted alkyl, R "" is a substituted carbonyl (e.g., acyl) or unsubstitutedAlkyl (e.g., methyl) or substituted alkyl, X is O or NH; and R is unsubstituted C ₅ -C ₁₄ Alkyl, substituted C ₅ -C ₁₄ Alkyl, unsubstituted C ₅ -C ₁₄ Alkenyl, substituted C ₅ -C ₁₄ Alkenyl, unsubstituted C ₅ -C ₁₄ Alkynyl, substituted C ₅ -C ₁₄ Alkynyl, unsubstituted C ₅ -C ₁₄ Aryl, substituted C ₅ -C ₁₄ Aryl, unsubstituted C ₅ -C ₁₄ Polyaryl, substituted C ₅ -C ₁₄ Polyaryl, unsubstituted C ₅ -C ₁₄ Polyheteroaryl or substituted C ₅ -C ₁₄ A polyhalogen group. Substituted C ₅ -C ₁₄ Examples of alkenyl groups may be (E) -2- (4-pentylphenyl) propenyl, and substituted C ₅ -C ₁₄ An example of aryl may be 4- (phenylethynyl) phenyl.

In some forms of formula IV, R' "is hydrogen, unsubstituted alkyl, or substituted alkyl, and R" "is unsubstituted alkyl, substituted alkyl, unsubstituted aryl, or substituted aryl.

In some forms, the cyclic lipopeptide is as described above for formula IV, wherein R is 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-methylindol-3-ylmethyl), unsubstituted polyaryl (e.g. 1-naphthylmethyl or 2-naphthylmethyl) or substituted polyaryl; and R is ₂ -R ₁₁ Each independently the side chain of any natural or unnatural amino acid.

In some forms, the cyclic lipopeptide has the formula:

wherein the content of the first and second substances,

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 capped with a methyl group)Alkylated, i.e. N-methylindol-3-yl), unsubstituted polyaryl (e.g. 1-naphthylmethyl or 2-naphthylmethyl) or substituted polyaryl, and

R ₅ is the side chain of a natural or unnatural amino acid. Preferably, 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 a substituted carbonyl (e.g., acyl) or unsubstituted alkyl (e.g., methyl); x is O or NH; and R is unsubstituted C ₅ -C ₁₄ Alkyl, substituted C ₅ -C ₁₄ Alkyl, unsubstituted C ₅ -C ₁₄ Alkenyl, substituted C ₅ -C ₁₄ Alkenyl, unsubstituted C ₅ -C ₁₄ Alkynyl, substituted C ₅ -C ₁₄ Alkynyl, unsubstituted C ₅ -C ₁₄ Aryl, substituted C ₅ -C ₁₄ Aryl, unsubstituted C ₅ -C ₁₄ Polyaryl, substituted C ₅ -C ₁₄ Polyaryl, unsubstituted C ₅ -C ₁₄ Polyheteroaryl or substituted C ₅ -C ₁₄ A polyhalogen group. Substituted C ₅ -C ₁₄ Examples of alkenyl groups may be (E) -2- (4-pentylphenyl) propenyl, and substituted C ₅ -C ₁₄ An example of aryl may be 4- (phenylethynyl) phenyl.

In some forms of formula I, R has the formula:

wherein R is ₁₃ 、R ₁₄ 、R ₁₅ 、R ₁₆ And R ₁₇ Independently hydrogen, unsubstituted 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 radical, unsubstituted C ₃ -C ₂₀ Cycloalkenyl, substituted C ₃ -C ₂₀ Cycloalkynyl or unsubstituted C ₃ -C ₂₀ Cycloalkynyl, substituted alkoxy, unsubstituted alkoxy, substituted aryloxy, unsubstituted aryloxy, substituted alkylthio, unsubstituted alkylthio, substituted arylthio, unsubstituted arylthio, substituted carbonyl, unsubstituted carbonyl, substituted carboxyl, unsubstituted carboxyl, substituted amino, unsubstituted amino, substituted acylamino, unsubstituted acylamino, substituted sulphonyl, unsubstituted sulphonyl, substituted sulphonic acid, unsubstituted sulphonic acid, substituted phosphoryl, unsubstituted phosphoryl, substituted phosphonyl, unsubstituted phosphonyl, hydroxy, halogen, cyano or nitro. Preferably, R ₁₃ -R ₁₇ Is not hydrogen.

In some forms of formula IX, R ₁₃ -R ₁₇ At least one of which is a substituted alkynyl group.

In some forms of the cyclic lipopeptide, R has the formula:

wherein R is ₁₃ 、R ₁₄ 、R ₁₆ And R ₁₇ As described above with respect to formula IX,

wherein 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 Heterocyclic ringsAlkyl, unsubstituted C ₃ -C ₂₀ Heterocyclic radical, 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, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, or unsubstituted alkynyl.

In some forms, R is a substituted aryl group having the formula:

wherein R is ₁₃ 、R ₁₄ 、R ₁₆ And R ₁₇ As described above for formula IX, and

wherein R is ₁₈ 、R ₁₉ 、R ₂₀ 、R ₂₁ And R ₂₂ Independently hydrogen, unsubstituted 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 Heterocyclic radical, substituted C ₃ -C ₂₀ Cycloalkenyl radical, unsubstituted C ₃ -C ₂₀ Cycloalkenyl, substituted C ₃ -C ₂₀ Cycloalkynyl or unsubstituted C ₃ -C ₂₀ Cycloalkynyl, substituted alkoxy, unsubstituted alkoxy, substituted aryloxy, unsubstituted aryloxy, substituted alkylthio, unsubstituted alkylthio, substituted arylthio, unsubstituted arylthio, substituted carbonyl, unsubstituted carbonyl, substituted carboxyl, unsubstituted carboxyl, substituted amino, unsubstituted amino, substituted acylamino, unsubstituted acylamino, substituted sulphonyl, unsubstituted sulphonyl, substituted sulphonic acid, sulphonyl, and sulphonyl, and sulphonyl, and sulphonyl,Unsubstituted sulfonic acid, substituted phosphoryl, unsubstituted phosphoryl, substituted phosphonyl, unsubstituted phosphonyl, hydroxyl, halogen, cyano, or nitro.

In some forms of formula XI, R ₁₃ 、R ₁₄ 、R ₁₆ And R ₁₇ Is hydrogen, R ₁₈ 、R ₁₉ 、R ₂₀ 、R ₂₁ And R ₂₂ Four of (a) are hydrogen and one is unsubstituted 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 radical, unsubstituted C ₃ -C ₂₀ Cycloalkenyl, substituted C ₃ -C ₂₀ Cycloalkynyl or unsubstituted C ₃ -C ₂₀ Cycloalkynyl, substituted alkoxy, unsubstituted alkoxy, substituted aryloxy, unsubstituted aryloxy, substituted alkylthio, unsubstituted alkylthio, substituted arylthio, unsubstituted arylthio, substituted carbonyl, unsubstituted carbonyl, substituted carboxyl, unsubstituted carboxyl, substituted amino, unsubstituted amino, substituted amido, unsubstituted amido, substituted sulfonyl, unsubstituted sulfonyl, substituted sulfonic acid, unsubstituted sulfonic acid, substituted phosphoryl, unsubstituted phosphoryl, substituted phosphonyl, unsubstituted phosphonyl, hydroxyl, halogen, cyano, or nitro.

In some forms of formula XI, R ₁₃ 、R ₁₄ 、R ₁₆ And R ₁₇ Is hydrogen, R ₁₈ 、R ₁₉ 、R ₂₀ 、R ₂₁ And R ₂₂ Four of (a) are hydrogen and one is unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted heteroaryl, unsubstituted C ₃ -C ₂₀ Heterocyclyl, hydroxyl or nitro.

In some forms of formula XI, R ₁₃ 、R ₁₄ 、R ₁₆ 、R ₁₇ And R ₁₈ -R ₂₂ Is hydrogen, i.e. R ₁ Is 4- (phenylethynyl) phenyl

In some forms, R is a substituted alkenyl having the formula:

wherein R is ₂₃ And R ₂₄ Independently hydrogen, unsubstituted 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 radical, unsubstituted C ₃ -C ₂₀ Cycloalkenyl, substituted C ₃ -C ₂₀ Cycloalkynyl or unsubstituted C ₃ -C ₂₀ Cycloalkynyl, substituted alkoxy, unsubstituted alkoxy, substituted aryloxy, unsubstituted aryloxy, substituted alkylthio, unsubstituted alkylthio, substituted arylthio, unsubstituted arylthio, substituted carbonyl, unsubstituted carbonyl, substituted carboxyl, unsubstituted carboxyl, substituted amino, unsubstituted amino, substituted acylamino, unsubstituted acylamino, substituted sulphonyl, unsubstituted sulphonyl, substituted sulphonic acid, unsubstituted sulphonic acid, substituted phosphoryl, unsubstituted phosphoryl, substituted phosphonyl, unsubstituted phosphonyl, hydroxy, halogen, cyanoOr a nitro group. Preferably, R ₂₃ And R ₂₄ Is not hydrogen.

In some forms of formula XII, R ₂₃ And R ₂₄ Independently is unsubstituted 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 radical, unsubstituted C ₃ -C ₂₀ Cycloalkenyl, substituted C ₃ -C ₂₀ Cycloalkynyl or unsubstituted C ₃ -C ₂₀ Cycloalkynyl.

In some forms of formula XII, R ₂₃ Is an unsubstituted alkyl group.

In some forms of formula XII, R ₂₄ Is a substituted aryl group or an unsubstituted aryl group.

In some forms of formula XII, R ₂₃ Is unsubstituted alkyl, and R ₂₄ Is a substituted aryl or unsubstituted aryl having the formula:

wherein R is ₂₅ 、R ₂₆ 、R ₂₇ 、R ₂₈ And R ₂₉ Independently hydrogen, unsubstituted 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 radical, unsubstituted C ₃ -C ₂₀ Cycloalkenyl, substituted C ₃ -C ₂₀ Cycloalkynyl or unsubstituted C ₃ -C ₂₀ Cycloalkynyl, substituted alkoxy, unsubstituted alkoxy, substituted aryloxy, unsubstituted aryloxy, substituted alkylthio, unsubstituted alkylthio, substituted arylthio, unsubstituted arylthio, substituted carbonyl, unsubstituted carbonyl, substituted carboxyl, unsubstituted carboxyl, substituted amino, unsubstituted amino, substituted acylamino, unsubstituted acylamino, substituted sulphonyl, unsubstituted sulphonyl, substituted sulphonic acid, unsubstituted sulphonic acid, substituted phosphoryl, unsubstituted phosphoryl, substituted phosphonyl, unsubstituted phosphonyl, hydroxy, halogen, cyano or nitro.

In some forms of formula XIII, R ₂₇ Is a substituted alkyl group or an unsubstituted alkyl group.

In some forms of formula XIII, R ₂₇ Is unsubstituted alkyl, and R ₂₅ 、R ₂₆ 、R ₂₈ 、R ₂₉ Each is hydrogen.

In some forms of formula XIII, R ₂₃ And R ₂₇ Is unsubstituted alkyl, and R ₂₅ 、R ₂₆ 、R ₂₈ And R ₂₉ Each is hydrogen.

In some forms of formula XIII, R ₂₃ And R ₂₇ Independently is unsubstituted C ₁ -C ₁₀ Alkyl, and R ₂₅ 、R ₂₆ 、R ₂₈ And R ₂₉ Each is hydrogen.

In some forms of formula XIII, R ₂₃ Is unsubstituted C ₁ Alkyl radical, R ₂₇ Is unsubstituted C ₅ Alkyl, and R ₂₅ 、R ₂₆ 、R ₂₈ And R ₂₉ Each is hydrogen, i.e. R is

Specific examples include:when R is ₅ Is- (CH) ₂ ) ₃ -NR* ₂ Each R is an alkyl group; each R is methyl; r is ₁ Is MeTrp; r' is methyl; r ₁₂ Is MeKyn; r ₁ Is 1-naphthylalanine (naphtylalanine); r ₁ Is 2-naphthylalanine; and R is

In some forms, the cyclic lipopeptide comprises a methylated Kyn having the formula

Wherein, the first and the second end of the pipe are connected with each other,

R ₁ -R ₁₁ independently an unsubstituted polyheteroaralkyl, substituted polyheteroaralkyl, unsubstituted polyarralkyl, or the side chain of any natural or unnatural amino acid.

Preferably, R' is H or unsubstituted alkyl (e.g., methyl); r "is H, unsubstituted alkyl (e.g., methyl or ethyl); and R is unsubstituted C ₅ -C ₁₄ Alkyl, substituted C ₅ -C ₁₄ Alkyl, unsubstituted C ₅ -C ₁₄ Alkenyl, substituted C ₅ -C ₁₄ Alkenyl, unsubstituted C ₅ -C ₁₄ Alkynyl, substituted C ₅ -C ₁₄ Alkynyl, unsubstituted C ₅ -C ₁₄ Aryl, substituted C ₅ -C ₁₄ Aryl, unsubstituted C ₅ -C ₁₄ Polyaryl, substituted C ₅ -C ₁₄ Polyaryl, unsubstituted C ₅ -C ₁₄ Polyheteroaryl or substituted C ₅ -C ₁₄ A polyhalogen group. Substituted C ₅ -C ₁₄ Examples of alkenyl groups may be (E) -2- (4-pentylphenyl) propenyl, and substituted C ₅ -C ₁₄ An example of aryl may be 4- (phenylethynyl) phenyl.

In some forms, the cyclic lipopeptide has the formula:

wherein the content of the first and second substances,

r', Rb, Rc, and Rd are independently hydrogen, unsubstituted 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 Heterocyclic radical, substituted C ₃ -C ₂₀ Cycloalkenyl radical, unsubstituted C ₃ -C ₂₀ Cycloalkenyl, substituted C ₃ -C ₂₀ Cycloalkynyl or unsubstituted C ₃ -C ₂₀ Cycloalkynyl.

In some forms of formula VII, R', Rb, Rc, and Rd are independently hydrogen, substituted alkyl, or unsubstituted alkyl (e.g., methyl, ethyl, etc.).

In some forms of formula VII, Rb is H or methyl; r' is H or methyl or ethyl; rc and Rd are independently H or methyl; x is O or NH; and R is unsubstituted C ₅ -C ₁₄ Alkyl, substituted C ₅ -C ₁₄ Alkyl, unsubstituted C ₅ -C ₁₄ Alkenyl, substituted C ₅ -C ₁₄ Alkenyl, unsubstituted C ₅ -C ₁₄ Alkynyl, substituted C ₅ -C ₁₄ Alkynyl, unsubstituted C ₅ -C ₁₄ Aryl, substituted C ₅ -C ₁₄ Aryl, unsubstituted C ₅ -C ₁₄ Polyaryl, substituted C ₅ -C ₁₄ Polyaryl, unsubstituted C ₅ -C ₁₄ Polyheteroaryl or substituted C ₅ -C ₁₄ A polyhalogen group.

In some forms, the cyclic lipopeptide has the formula:

in some forms of formula VIII, R is (R is) unsubstituted C ₅ -C ₁₄ Alkyl, substituted C ₅ -C ₁₄ Alkyl, unsubstituted C ₅ -C ₁₄ Alkenyl, substituted C ₅ -C ₁₄ Alkenyl, unsubstituted C ₅ -C ₁₄ Alkynyl, substituted C ₅ -C ₁₄ Alkynyl, unsubstituted C ₅ -C ₁₄ Aryl, substituted C ₅ -C ₁₄ Aryl, unsubstituted C ₅ -C ₁₄ Polyaryl, substituted C ₅ -C ₁₄ Polyaryl, unsubstituted C ₅ -C ₁₄ Polyheteroaryl or substituted C ₅ -C ₁₄ Polyheteroaryl, preferably R is C ₉ H ₁₉ Or (E) -2- (4-pentylphenyl) propenyl.

Each compound within the above definitions is intended and should be considered as specifically disclosed herein. Further, it can be determined that subsets within the above definitions are intended and should be considered as specifically disclosed herein. Thus, it is specifically contemplated that any compound or subset of compounds may be specifically included or excluded from the application, or any compound or subset of compounds may be included or excluded from the list of compounds. For example, any one or more compounds described herein or mentioned in tables or examples having a structure depicted herein may be specifically included in, excluded from, or combined in any combination with such a group or subset of compounds. Such specific groups, subsets, inclusions, and exclusions apply to any aspect of the compositions and methods described herein. For example, a group of compounds specifically excluding one or more specific compounds can be used or applied in the context of the compounds themselves (e.g., a list or set of compounds), compositions including the compounds (including, e.g., pharmaceutical compositions), any one or more of the disclosed methods, or combinations thereof. Different groups and subsets of compounds having such specific inclusions and exclusions may be used or applied in the context of the compounds themselves, compositions comprising one or more of the compounds, or any of the disclosed methods. All such different groups and subsets of compounds-as well as different groups of compounds, compositions, and methods of using or applying the compounds-are specifically and individually contemplated and should be considered as specifically and individually described. For example, any natural or unnatural amino acid as defined above can be specifically included as a collection or individually in any position of the compounds themselves (e.g., a list or set of compounds), in a composition (including, e.g., a pharmaceutical composition), or in or excluded from any one or more of the disclosed methods or combinations of these. In addition, specific cyclic compounds may be excluded from the list of compounds. For example, daptomycin may be excluded.

B. Pharmaceutical compositions and routes of administration

Pharmaceutical compositions comprising one or more of the disclosed compounds are also provided. The composition may be formulated into a dosage form suitable for each route of administration. Daptomycin is most commonly administered by infusion (e.g., 30 minutes) or injection (e.g., 2 minutes). Studies have also shown efficacy of local delivery, which can be enhanced when the formulation includes a delivery vehicle such as a liposome (see, e.g., mengelglu et al, jocul pharmacol ther.2013 for 12 months; 29 (10): 893-9. doi: 10.1089/jop.2013.0120.epub 2013Sep 26; and Li et al, IntJ nanomedicine.2013; 8:1285-92. doi: 10.2147/ijn.s 41695.Epub 2013Mar 24).

Thus, preferred routes of administration for the disclosed lipopeptides include parenteral, particularly intravenous injection or infusion, as well as topical administration, although variations in the composition of the disclosed compounds may also improve their delivery relative to daptomycin by other routes (e.g., oral). Thus, in some embodiments, a cyclic lipopeptide or pharmaceutical composition comprising one or more lipopeptides described herein is administered orally, parenterally, by inhalation, topically, transdermally (passively or using iontophoresis or electroporation) or transmucosally (nasal, vaginal, rectal, buccal, or sublingual), or by implanted reservoir, external pump, or catheter. The cyclic lipopeptides described herein may be injected or administered directly into the abscess, ventricle or joint. Parenteral administration includes intraperitoneal, subcutaneous, Intravenous (IV), intramuscular, intraarticular, intrasynovial, cerebral cistern, intrathecal, intrahepatic, intralesional and intracranial injection or infusion. The compositions may also be administered using bioerodible inserts and may be delivered directly to the appropriate target tissue or organ.

Pharmaceutical compositions generally comprise an effective amount of the disclosed compounds. The precise dosage will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), the disease, and the treatment to be administered. The dosage will be discussed in more detail below.

1. Parenteral formulations

In a preferred embodiment, the disclosed compounds are administered in the form of an aqueous solution by parenteral injection or infusion. The formulations may also be in the form of suspensions or emulsions. Generally, pharmaceutical compositions are provided that include an effective amount of a peptide or polypeptide, and optionally include pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers. Such compositions include sterile water, buffered saline (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; and optionally additives such as detergents and solubilizers (e.g.

20. TWEEN 80, Polysorbate 80), antioxidants (e.g. ascorbic acid, sodium metabisulfite) and preservatives (e.g. thimerosal, benzyl alcohol) and bulking substances (e.g. lactose, mannitol). Examples of nonaqueous solvents or carriers are propylene glycol, polyethylene glycol, vegetable oils (such as olive oil and corn oil), gelatin, and injectable organic esters (such as ethyl oleate). The formulation may be lyophilized and re-dissolved/re-suspended just prior to use. The formulation may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the composition, by irradiating the composition, or by heating the composition.

2. Controlled release polymer matrix

Compositions containing one or more of the disclosed compounds may be administered in a controlled release formulation. The controlled release polymer device can be made to release systemically for long periods of time after implantation of the polymer device (rod, cylinder, membrane, disc) or injection (microparticles). The matrix may be in the form of microparticles, such as microspheres, in which the peptide is dispersed within a solid polymeric matrix or microcapsules, in which the core is a different material from the polymeric shell, and the peptide is dispersed or suspended in the core, which may be liquid or solid in nature. Unless specifically defined herein, microparticles, microspheres, and microcapsules may be used interchangeably. Alternatively, the polymer may be cast as a sheet or film (ranging from nanometers to 4 centimeters), a powder produced by grinding or other standard techniques, or even a gel (e.g., a hydrogel). The matrix may also be incorporated into or onto a medical device, for example to prevent infection or to aid healing. In some embodiments, the matrix is used to promote healing of pressure sores, decubitus ulcers, and the like.

Non-biodegradable or biodegradable matrices can be used to deliver the compounds, although biodegradable matrices are preferred. For example, liposome or polymer encapsulation may be used to formulate the composition. The polymers may be natural or synthetic, although synthetic polymers are preferred due to better degradation and release profile characteristics. The polymer is selected based on the period of desired release. In some cases, a linear release may be most useful, although in other cases, a pulsed release or "bulk release" may provide more effective results. The polymer may be in the form of a hydrogel (typically absorbing up to about 90% by weight water), and may optionally be crosslinked with a multivalent ion or polymer.

The matrix may 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 method developed for preparing microspheres for drug delivery, for example, as described in Mathiowitz and Langer, j.controlledrelease, 5: 13-22 (1987); mathiowitz et al, reactive polymers, 6: 275-283 (1987); and Mathiowitz et al, j.appl.polymersci, 35: 755, 774 (1988).

The devices can be formulated for local release to treat the area of implantation or injection, and typically deliver much smaller doses than those used to treat the whole body. The device may also be formulated for systemic delivery. These may be implanted subcutaneously or injected.

3. Local part

These are typically ointments, creams, gels, oils, foams, lotions, sprays or patches, all of which can be prepared using standard techniques. Such formulations may be used for local delivery, e.g. on/to the skin, as well as regional and even systemic delivery. Buffering agents may be used to control the pH of the composition. Preferably, the buffering agent buffers the pH of the composition from 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. In a preferred embodiment, 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, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, and thimerosal.

Other agents that may be added to the formulation include penetration enhancers. In some embodiments, the penetration enhancer increases the solubility of the drug, improves transdermal delivery of the drug through the skin, particularly through the stratum corneum, or a combination thereof, preferably without decreasing the activity of the lipopeptide. Methods of chemical permeation and enhancing transdermal drug delivery are known in the art, see, e.g., Inayat et al, tropical journal of pharmaceutical research, 8 (2): 173-179(2009) and Fox et al, Molecules, 16: 10507-10540(2011).

Method of use

The method of administration can be in clinical use for human patients and in veterinary use. The methods generally comprise administering to a subject in need thereof an effective amount of one or more of the disclosed peptides or pharmaceutical compositions thereof. Exemplary subjects in need thereof are infected or at risk of infection, particularly bacterial infection. In a most preferred embodiment, the subject has or is at risk of having a gram-positive bacterial infection.

A. Exemplary dosages and treatment regimens

The dosages and dosing intervals for the methods of the invention are those that are safe and effective in clinical or veterinary use. In some embodiments, the method of administration involves a longer dosing interval (e.g., once daily or longer), a higher dose (e.g., 15mg/kg or more) of a cyclic lipopeptide described herein. In other embodiments, the method of administration involves a relatively short dosing interval (e.g., twice daily or less), a low dose (e.g., 15mg/kg or less) of a cyclic lipopeptide as described herein.

The cyclic lipopeptides described herein may be administered once daily, twice daily, or three times daily. Daptomycin is known to have skeletal muscle toxicity, particularly when the time between administrations is relatively short. The cyclic lipopeptides described herein are administered once daily to provide a longer period of time between administrations than is provided by multiple daily doses. In some cases, once daily administration of a cyclic lipopeptide described herein allows for repair of subclinical muscle damage that may be associated with use of a cyclic lipopeptide described herein, thereby avoiding long-term and/or permanent physical damage. In other words, in some embodiments, once daily administration of a cyclic lipopeptide as described herein results in lower toxicity.

For example, the dose may be 1 to 100mg/kg of the cyclic lipopeptide described herein. In another embodiment, the dose is 5 to 50mg/kg of a cyclic lipopeptide as described herein. In another embodiment, the dose for the human patient is from 2 to 15 mg/kg. In yet another embodiment, the dose of the human patient is 3 to 12mg/kg of the cyclic lipopeptide described herein. Examples of specific doses that may be used include 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22 or 25mg/kg of the cyclic lipopeptide described herein. In some embodiments for veterinary use, the dose is 2 to 40mg/kg of the cyclic lipopeptide described herein.

In some embodiments, the cyclic lipopeptides described herein can be administered in smaller doses as compared to the administration of daptomycin. In one embodiment, the cyclic lipopeptides described herein can be administered at a dose that is 10% less than the dose used to administer daptomycin to the same patient for the same disease. In another embodiment, the cyclic lipopeptides described herein can be administered at a dosage that is 25% less than the dosage for daptomycin administered to the same patient for the same disease. In another embodiment, a cyclic lipopeptide as described herein can be administered at a dose that is 40% less than the dose at which daptomycin is administered to the same patient for the same disease.

In some embodiments, the cyclic lipopeptide described herein is administered at an interval of 6 hours to weekly. In specific embodiments, the cyclic lipopeptides described herein are administered at dosing intervals of once every 12 hours, once every 24 hours, once every 48 hours, once every 72 hours, once every 96 hours, or once a week. For patients with impaired renal function or requiring hemodialysis, it may be desirable to administer the drug at less frequent dosing intervals, such as once every 96 hours or once a week. The dosing interval for veterinary use may be slightly shorter or longer than that of a human patient, depending on whether the cyclic lipopeptides described herein have a shorter or longer half-life in a particular animal species than humans, respectively. The skilled artisan can determine the specific dosing intervals for clinical and veterinary use according to the methods described herein.

In some embodiments, the method of administration comprises administering a dose of 1 to 100mg/kg of a cyclic lipopeptide described herein once every 6 hours to once a week. In some embodiments, a cyclic lipopeptide described herein is administered at a dose of 5-50mg/kg once every 24, 48, 72, or 96 hours.

The cyclic lipopeptides described herein may 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 ranging from 3 days to 6 months. In another embodiment, a cyclic lipopeptide described herein is administered for 7 to 50 days. In another embodiment, a cyclic lipopeptide described herein is administered for 10 to 20 days.

Methods of using the cyclic lipopeptides described herein include administering the cyclic lipopeptides to a patient in need thereof in an amount effective to reduce or eliminate gram-positive bacterial infection. The methods further comprise administering a cyclic lipopeptide to a patient in need thereof in an amount effective to reduce or eliminate gram-positive bacterial infection and result in reduced skeletal muscle toxicity compared to other methods (e.g., those methods comprising administration of daptomycin, other lipopeptide antibiotics, or quinupristin/dalfopristin).

B. Subject to be treated

The present methods can be used to treat patients suffering from bacterial infections, wherein the infection is caused or exacerbated by any type of gram-positive bacteria. In one embodiment, a cyclic lipopeptide described herein is administered to a patient according to the methods described herein. In one embodiment, the bacterial infection may be caused or exacerbated by bacteria, including but not limited to one or more of the following: methicillin-sensitive or methicillin-resistant staphylococci (Staphylococcus aureus) (including Staphylococcus aureus (Staphylococcus aureus)), Staphylococcus epidermidis (Staphylococcus epidermidis), hemolytic staphylococci (Staphylococcus haemolyticus), human staphylococci (Staphylococcus hominis), saprophytic staphylococci (Staphylococcus epidermidis) and coagulase-negative staphylococci (coccus-newcastle glycopeptide)), intermediate-sensitive Staphylococcus aureus (Staphylococcus aureus) (GISA), penicillin-sensitive or penicillin-resistant Streptococci (Streptococcus mutans) (including Streptococcus pneumoniae (Streptococcus pneumoniae), Streptococcus pyogenes (Streptococcus pyogenes), Streptococcus agalactiae (Streptococcus agalactiae), Streptococcus agalactiae (Streptococcus mutans), avian Streptococcus ornyces (Streptococcus ornyces), Streptococcus pyogenes (Streptococcus pyogenes) (including Streptococcus pneumoniae (Streptococcus pyogenes), Streptococcus faecalis (Streptococcus faecalis), Streptococcus faecalis (Streptococcus faecalis), Streptococcus faecalis (Streptococcus faecalis strain (Streptococcus faecalis), or Streptococcus faecalis strain (e), or Streptococcus faecin G (Streptococcus faecium), or Streptococcus faecium C (Streptococcus faecium) including Streptococcus faecium C (Streptococcus faeci C), Streptococcus faeci (Streptococcus faeci C) and Streptococcus faeci (Streptococcus faeci C) or Streptococcus faeci (Streptococcus faeci, Streptococcus faeci (Streptococcus faeci C) or Streptococcus faeci C (Streptococcus faeci C) or Streptococcus faeci Coccus (enterococcus faecium), Clostridium difficile (Clostridium difficile), Clostridium clostridiforme (Clostridium clausii), Clostridium harmless Clostridium (Clostridium innoculum), Clostridium perfringens (Clostridium perfringens), Clostridium polybranchium (Clostridium ramosum), Haemophilus influenzae (Haemophilus influenzae), Listeria monocytogenes (Listeria monocytogenes), corynebacterium jejuni (corynebacterium glutamicum), Bifidobacterium (Bifidobacterium bifidum), Eubacterium aerogenes (Eubacterium aerofaciens), Eubacterium limosum (Eubacterium), Lactobacillus acidophilus (Lactobacillus acidophilus), Lactobacillus casei (Lactobacillus acidophilus), streptococcus lactis (streptococcus lactis), streptococcus lactis (streptococcus faecalis), streptococcus (streptococcus faecalis), streptococcus faecalis, streptococcus (streptococcus faecalis, streptococcus (streptococcus) Propionibacterium acnes (Propionibacterium acnes) and Actinomyces (Actinomyces spp.).

The antimicrobial activity of the cyclic lipopeptides described herein against classical "resistant" strains may be comparable to that against classical "susceptible" strains. In some embodiments, the cyclic lipopeptides described herein are administered to a patient infected with a bacterium that exhibits resistance to another antibiotic. Furthermore, unlike glycopeptide antibiotics, cyclic lipopeptides described herein can exhibit rapid, concentration-dependent bactericidal activity against gram-positive organisms. In another embodiment, a cyclic lipopeptide as described herein is administered to a patient in need of rapid-onset antibiotic treatment.

The cyclic lipopeptides described herein are useful for gram-positive bacterial infection of any organ or tissue in vivo. Examples of organs or tissues include, but are not limited to, one or more of skeletal muscle, skin, blood flow, kidney, heart, lung, and bone. The cyclic lipopeptides described herein may be used to treat one or more of skin and soft tissue infections, bacteremia, and urinary tract infections, but are not limited thereto. The cyclic lipopeptides described herein are useful in the treatment of community-acquired respiratory infections, including but not limited to one or more of otitis media, sinusitis, chronic bronchitis, and pneumonia, including pneumonia caused by drug-resistant streptococcus pneumoniae or haemophilus influenzae. The cyclic lipopeptides described herein are useful for treating mixed infections comprising different types of gram-positive bacteria, or mixed infections comprising gram-positive and gram-negative bacteria. Examples of such infections include intra-abdominal infections and obstetric/gynecological infections. The cyclic lipopeptides described herein may be used in step down therapy of nosocomial infections including, but not limited to, one or more of pneumonia, intraperitoneal sepsis, skin and soft tissue infections, and bone and joint infections. The cyclic lipopeptides described herein may be used to treat infections, including, but not limited to, one or more of endocarditis, septic arthritis, and osteomyelitis.

C. Combination therapy

The methods of using cyclic lipopeptides described herein may include the concurrent administration of one or more additional therapeutic, diagnostic, or prophylactic agents, such as an antibiotic other than a lipopeptide antibiotic. The lipopeptide and the additional therapeutic, diagnostic, or prophylactic agent can be in the same or different mixture or pharmaceutical composition. The cyclic lipopeptides described herein may exhibit high plasma protein binding and may not be able to cross cell membranes. In this context, the cyclic lipopeptides described herein are less likely to cause interactions with other antibiotics. Thus, in some embodiments, the cyclic lipopeptides described herein may function in a complementary manner, or may even function in an additive manner with one or more co-administered non-lipopeptide antibiotics. In addition, the cyclic lipopeptides described herein may improve the toxicity profile of one or more co-administered non-lipopeptide antibiotics.

Examples of antibiotics and the types thereof (non-lipopeptide antibiotics) that may be co-administered with the cyclic lipopeptides described herein include, but are not limited to, penicillins and related drugs, carbapenems, cephalosporins and related drugs, aminoglycosides, bacitracin, gramicidin, mupirocin, chloramphenicol, thiamphenicol, sodium fusidate, lincomycin, clindamycin, macrolides, novobiocins, polymyxins, rifamycins, spectinols, tetracyclines, vancomycin, teicoplanin, streptogramins, antifolates including sulfonamides, trimethoprim and combinations thereof, and pyrimethamine, synthetic antibacterial agents including nitrofuran, urotropin mandelate and urotropin hippurate, nitro, imidazoles, quinolones, fluoroquinolones, isoniazid, ethambutol, pyrazinamide, para-aminosalicylic acid (PAS), cycloserine, cysteine, and combinations thereof, One or more of capreomycin, ethionamide, prothiocyanamide, thiosemicarbazide, and erythromycin. In particular embodiments, non-lipopeptide antibiotics that may be co-administered with the cyclic lipopeptides described herein include, but are not limited to, one or more of imipenem, amikacin, netilmicin, fosfomycin, gentamicin, ceftriaxone, and teicoplanin.

Preparation method

The cyclic lipopeptides described herein can be synthesized using a variety of methods known to those skilled in the art, including, but not limited to, chemical synthesis, biochemical synthesis, chemoenzymatic synthesis, semisynthesis, or a combination thereof. Preferably, the cyclic lipopeptide can be prepared by chemical synthesis. The chemical synthesis method may be by solid phase synthesis, solution phase synthesis, or a combination thereof. Preferably, the cyclic lipopeptides may be synthesized using a hybrid approach involving both solid phase and solution phase synthesis methods. The synthesis can be performed on a resin, such as 2-chlorotrityl chloride resin (0.4 mmol/g resin loading), following standard Fmoc/TBU protocols for solid phase peptide synthesis. The Deblock mixture may be a mixture of 20/80(V/V) 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, Fmoc-Trp Boc) -OH, (Fmoc-Tyr (tBu) -OH, Fmoc-Val-OH, Boc-DSer (tBu) -OH, Fmoc-meTrp-OH, Fmoc-meKyn-OH, Fmoc-acKyn-OH, Fmoc-1Nal-OH and Fmoc-2 Nal-OH. Once synthesis is complete, the peptide resin may be subjected to a cleavage mixture (cleavage cocktail), the resin is subsequently filtered and the filtrate is blown off with a stream of compressed air. The crude product can be triturated with cold ether to give a white suspension which is centrifuged and the ether subsequently decanted. The remaining solid can be purified by HPLC purification.

Examples

The following are examples that illustrate embodiments for practicing the invention. These examples should not be construed as limiting. Unless otherwise indicated, all percentages are by weight and all solvent mixture proportions are by volume. Some of the embodiments described below are also described in U.S. application 15/093,950, the entire contents of which are specifically incorporated herein by reference.

The synthesis of these cyclic lipopeptides is shown using a hybrid strategy employing both solid phase and solution phase synthesis. The synthesis was performed manually on 2-chlorotrityl chloride resin (resin loading: 0.4 mmol/g). Peptides were synthesized according to the standard Fmoc/tBu protocol. The Deblock mixture was 20/80(v/v) piperidine/DMF mixture. The following Fmoc amino acids were used: 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-ThrtBu) -OH, Fmoc-trp (Boc) -OH, Fmoc-Tyr tBu) -OH, (Fmoc-Val-OH, Boc-DSer tBu-tBu) -OH, Fmoc-meTrp-OH, Fmoc-meKyn-OH, Fmoc-acKyn-OH, Fmoc-1Nal-OH and Fmoc-2 Nal-OH. All natural amino acids and coupling reagents (Aldrich and GL Biochem) were commercially available and used without further purification. Once synthesis is complete, the peptide resin may be subjected to a cleavage mixture. The resin was filtered and the combined filtrate was blown off with a stream of compressed air. The crude product can be triturated with cold ether to give a white suspension which is centrifuged and the ether subsequently decanted. The remaining solid was purified by HPLC. Preparative HPLC was performed on a Waters System using Vydac 218TP ^TM C18 column (10 μm, 10X 250mm) or Vydac 218TP ^TM C18 column (10 μm, 22X 250 mm). And (3) buffer solution A: 0.1% TFA/acetonitrile; and (3) buffer solution B: 0.1% TFA/water.

EXAMPLE 1 Synthesis of Compound 1

Synthesis of Linear peptide resin-Gly-Asp (tBu) -DAla-Asp (tBu) -Orn (Boc) -Gly-Thr [ O-meKyn-mGlu (tBu) -DSer (tBu) by 9H-fluoren-9-yl-methoxycarbonyl (Fmoc) solid phase peptide Synthesis protocol]-Asp(tBu)-DAsn(Trt)-Trp(Boc)-C ₉ H ₁₉ . The peptide was cleaved from the 2-chlorotrityl resin under mild conditions (TFE/AcOH/DCM). After drying, the peptide was cyclized for an additional 4 hours using HATU/DCM. The solution was then concentrated and then treated with a mixture containing 95% TFA and 2.5% water (cocktail) for 10 minutes. The crude product was purified by preparative RP-HPLC to give methylated K-containingyn daptomycin analog compound 1. [ M + H ]] ⁺ Calculated 1635.7, [ M + H] ⁺ Found 1635.7, [ M +2H] ²⁺ 818.1。

EXAMPLE 2 Synthesis of Compound 2

Synthesis of Linear peptide resin-Gly-Asp (tBu) -DAla-Asp (tBu) -Orn (Boc) -Gly-Thr [ O-Kyn-mGlu (tBu) -DSer (tBu) according to the 9H-fluoren-9-yl-methoxycarbonyl (Fmoc) solid phase peptide Synthesis protocol]-Asp(tBu)-DAsn(Trt)-meTrp-C ₉ H ₁₉ . The peptide was cleaved from the 2-chlorotrityl resin under mild conditions (TFE/AcOH/DCM). After drying, the peptide was cyclized for an additional 4 hours using HATU/DCM. The solution was then concentrated and then treated with a mixture containing 95% TFA and 2.5% water for 10 minutes. The crude product was purified by preparative RP-HPLC to give methylated TRP-containing daptomycin analog compound 2. [ M + H ]] ⁺ Calculated 1635.7, [ M + H] ⁺ Found 1635.6, [ M +2H] ²⁺ 818.0。

EXAMPLE 3 Synthesis of Compound 3

Synthesis of 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 . The peptide was cleaved from the 2-chlorotrityl resin under mild conditions (TFE/AcOH/DCM). After drying, the peptide was cyclized for an additional 4 hours using HATU/DCM. The solution was then concentrated and then treated with a mixture containing 95% TFA and 2.5% water for 10 minutes. The crude product was purified by preparative RP-HPLC to provide daptomycin analog compound 3 containing 2-naphthyl Ala. [ M + H ]] ⁺ Calculated value 1630.8, [ M + H] ⁺ Found 1630.8, [ M +2H] ²⁺ 815.4。

EXAMPLE 4 Synthesis of Compound 4

Synthesis of Linear peptide resin-Gly-Asp (tBu) -DAla-Asp (tBu) -Orn (Boc) -Sar-Thr [ O-meKyn-mGlu (tBu) -DSer (tBu) according to the 9H-fluoren-9-yl-methoxycarbonyl (Fmoc) solid phase peptide Synthesis protocol]-Asp(tBu)-DAsn(Trt)-Trp(Boc)-C ₉ H ₁₉ . The peptide was cleaved from the 2-chlorotrityl resin under mild conditions (TFE/AcOH/DCM). After drying, the peptide was cyclized for an additional 4 hours using HATU/DCM. The solution was then concentrated and then treated with a mixture containing 95% TFA and 2.5% water for 10 minutes. The crude product was purified by preparative RP-HPLC to give Sar-containing daptomycin analog compound 4. [ M + H ]] ⁺ Calculated value 1648.7, [ M + H] ⁺ Found 1648.5, [ M +2H] ²⁺ 823.9。

EXAMPLE 5 Synthesis of Compound 5

Synthesis of Linear peptide resin-Gly-Asp (tBu) -DAla-Asp (tBu) -Orn (Boc) -Gly-Thr [ O-Kyn-mGlu (tBu) -DSer (tBu)]-asp (tbu) -dabn (trt) -trp (boc) -4-phenylethynyl-benzoyl. The peptide was cleaved from the 2-chlorotrityl resin under mild conditions (TFE/AcOH/DCM). After drying, the peptide was cyclized for an additional 4 hours using HATU/DCM. The solution was then concentrated and then treated with a mixture containing 95% TFA and 2.5% water (cocktail) for 10 minutes. The crude product was purified by preparative RP-HPLC to give 4-phenylethynyl-benzoyl daptomycin analog-containing compound 5. [ M + H ]] ⁺ Calculated value 1671.6, [ M + H] ⁺ Found 1671.9, [ M +2H] ²⁺ 836.1。

EXAMPLE 6 Synthesis of Compound 6

Synthesis of Linear peptide resin-Gly-Asp (tBu) -DAla-Asp (tBu) -Orn (Boc) -Sar-Thr [ O-Kyn-mGlu (tBu) -DSer (tBu) by 9H-fluoren-9-yl-methoxycarbonyl (Fmoc) solid phase peptide Synthesis protocol]-Asp (tBu) -DAsn (Trt) -Trp (Boc) -4-phenylethynyl-benzoyl. The peptide was cleaved from the 2-chlorotrityl resin under mild conditions (TFE/AcOH/DCM). After drying, the peptide was cyclized for an additional 4 hours using HATU/DCM. The solution was then concentrated and then treated with a mixture containing 95% TFA and 2.5% water for 10 minutes. The crude product was purified by preparative RP-HPLC to give daptomycin analog compound 6 containing Sar/4-phenylethynyl-benzoyl. [ M + H ]] ⁺ Calculated value 1685.7, [ M + H] ⁺ Found 1685.6, [ M +2H] ²⁺ 843.0。

Example 7 Synthesis of Compound 7

The 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) -3- (4-pentylphenyl) but-2-enoyl was synthesized by the 9H-fluoren-9-yl-methoxycarbonyl (Fmoc) solid phase peptide synthesis protocol. The peptide was cleaved from the 2-chlorotrityl resin under mild conditions (TFE/AcOH/DCM). After drying, the peptide was cyclized for an additional 4 hours using HATU/DCM. The solution was then concentrated and then treated with a mixture containing 95% TFA and 2.5% water for 10 minutes. The crude product was purified by preparative RP-HPLC to give methylated Kyn-containing daptomycin analog compound 7.

Example 8 Compound 1 shows better antibacterial activity than daptomycin in a neutropenic mouse model of thigh infection

Materials and methods

Biological assays were designed to compare the efficacy of compound 1 and compound 7 with daptomycin and other commonly used antibiotics.

Compound 1 was tested for resistance to mrsatcc 33591 in a neutropenic mouse thigh infection model. Female and male ICR mice were rendered neutropenic by cyclophosphamide (three consecutive doses of 150mg/kg were given prior to infection). On day 4, the bacteria were resuspended in sterile saline and 0.1ml of inoculum (MRSAATCC33591, 5.0X 10) ⁶ U/ml) was injected into the left thigh of the mouse. 2 hours after infection, mice received compound 1 treatment with a single dose of 0.63, 1.25, 2.5, 5.0mg/kg administered intravenously (five mice per group) (10 ml/kg). After 24 hours of infection, the left thigh was removed under aseptic conditions, weighed, homogenized, serially diluted, and plated on tryptic soy agar to obtain the c.f.u titer.

Results

From these in vivo studies, compound 1 showed significantly better antibacterial activity at doses of 1.25 and 2.50mg/kg in thigh staphylococcus aureus (s. aureus) mice than daptomycin. The results are shown in table 1.

TABLE 1 mouse thigh infection model (MRSA, ATCC 33591)

Control group vs. all treatment groups, P < 0.05; control group vs. all

Example 9 Compound 1 reduces infection by Staphylococcus aureus in right endocarditis rats

Materials and methods

Male Sprague-Dawley rats (280-300 g) were anesthetized intraperitoneally with a sodium pentobarbital solution (40 mg/kg). The rat mandible area was treated with 75% alcohol. The right carotid artery was exposed through a slightly right anterior incision in the middle above the clavicle. Polyethylene pipe 4-4A 5 cm lead placement through the right carotid artery into the left ventricle until resistance is encountered. The beating heart of the catheter indicates that the catheter tip is properly placed at the apex of the heart. 0.5ml of an inoculum of overnight culture (ATCC43300m 3.5.5X 10) was injected via the tail vein ⁴ c.f.u./mL). After 24 hours of infection, the surviving rats were randomized into control and treatment groups. Compound 1 and daptomycin were administered via the tail vein for 2 days (1 time/day). 24 hours after the last dose, animals were anesthetized and sacrificed. Propagules and tissue samples were excised, weighed, homogenized, serially diluted and plated on trypticase soy agar to obtain c.f.u titers.

As a result, the

Intraperitoneal injection of compound 1 significantly reduced infection with staphylococcus aureus in right endocarditis rats compared to the control group, which is also superior to daptomycin. The results are shown in table 2.

TABLE 2 Right endocarditis rat model (MRSA ATCC43300)

Control group vs. all treatment groups, P < 0.05;

control group vs. all treatment groups, P < 0.01;

compound 1vs. control p > 0.05

Example 10 Compounds 1 and 7 show better in vitro antibacterial activity than daptomycin and vancomycin

Materials and methods

Compound 1 was tested for Clostridium difficile (Clostridium difficile) activity against two strains-c.difficile BAA-1382 and ATCC3255, using Standard broth dilution methods described by the Clinical Laboratory standards Institute.

Results

Both compound 1 and compound 7 showed better activity than vancomycin and daptomycin. The results are shown in Table 3.

TABLE 3 in vitro resistance to Clostridium difficile (MICs, μ g/mL)

For any number or range of numbers for a given feature, a number or parameter from one range may be combined with another number or parameter from or from a different range of the same feature to produce a range of numbers.

Other than in the operating examples, or where otherwise indicated, all numbers, values and/or expressions referring to quantities of ingredients, reaction conditions and the like used in the specification and claims are to be understood as modified in all instances by the term "about".

While the invention has been explained in relation to certain embodiments, it is to be understood that various modifications thereof will become apparent to those skilled in the art upon reading the specification. It is, therefore, to be understood that the invention disclosed herein is intended to cover such modifications as fall within the scope of the appended claims.

Claims (7)

1. A cyclic lipopeptide of the formula:

wherein

R1 is the side chain of Trp, N-alkylated Trp or substituted 1-or 2-naphthylalanine;

r2 is H or methyl;

r3 is the side chain of Orn;

r4 is H or methyl;

r5 is H;

r6 is H, methyl or ethyl;

x is O;

r is straight chain C ₉ C ₁₉ Or 4-phenylethynyl-phenyl of the formula wherein Y is a substituent at any position of the aromatic ring:

(ii) a And

y is H, methyl or ethyl.

2. The cyclic lipopeptide of claim 1 wherein

R1 is the side chain of Trp;

r2 is H;

r3 is the side chain of Orn;

r4 is methyl;

x is O;

r is 4-phenylethynyl-phenyl of the formula wherein Y is a substituent at any position of the aromatic ring:

(ii) a And

y is H, methyl or ethyl.

3. The cyclic lipopeptide of claim 1 wherein

R1 is the side chain of Trp;

r2 is H;

r3 is the side chain of Orn;

r4 is methyl;

r5 is H;

r6 is methyl or ethyl;

x is O; and

r is straight chain C ₉ C ₁₉ 。

4. A pharmaceutical composition comprising a cyclic lipopeptide according to any one of claims 1 to 3.

5. Use of a cyclic lipopeptide according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment of a subject in need thereof, wherein the subject has an infection caused by a gram positive bacterium.

6. RightsUse according to claim 5, wherein the gram-positive bacteria are selected from the group consisting of Staphylococcus aureus (S.aureus) ((S.aureus))Staphylococcus aureus) Clostridium difficile: (C. difficile: (C. difficile))Clostridium difficile) Staphylococcus epidermidis: (Staphylococcus epidermidis) Staphylococcus saprophyticus (A. sup.: B.)Staphylococcus saprophyticus) Staphylococcus hominis (Staphylococcus hominis) Enterococcus faecalis: (A)Enterococcus faecalis) And enterococcus faecium (A), (B), (C)Enterococcus faecium)。

7. A cyclic lipopeptide having the structure of any one of compounds 1-7 below:

and

。

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