US20030083240A1 - Novel depsipeptides and process for preparing same - Google Patents

Novel depsipeptides and process for preparing same Download PDF

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Publication number
US20030083240A1
US20030083240A1 US10/213,389 US21338902A US2003083240A1 US 20030083240 A1 US20030083240 A1 US 20030083240A1 US 21338902 A US21338902 A US 21338902A US 2003083240 A1 US2003083240 A1 US 2003083240A1
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Prior art keywords
compound
amino
methyl
formula
hydrido
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John Finn
Michael Morytko
Ian Parr
Michael Jung
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Cubist Pharmaceuticals LLC
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Cubist Pharmaceuticals LLC
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Priority to US10/213,389 priority Critical patent/US20030083240A1/en
Publication of US20030083240A1 publication Critical patent/US20030083240A1/en
Assigned to CUBIST PHARMACEUTICALS, INC. reassignment CUBIST PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: JUNG, MICHAEL, FINN, JOHN, MORYTKO, MICHAEL, PARR, BARRIE IAN
Priority to US11/414,762 priority patent/US20060194714A1/en
Priority to US12/022,470 priority patent/US20080119395A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/15—Depsipeptides; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel depsipeptides compounds.
  • the invention also relates to pharmaceutical compositions of these compounds and methods of using these compounds as antibacterial agents.
  • the invention also relates to methods of producing these novel depsipeptide compounds and intermediates used in producing these compounds.
  • a class of compounds that have shown potential as useful antibiotic agents is the cyclic depsipeptides.
  • a notable member of the cyclic depsipeptides is the A-21978C lipopeptides described in, for example, U.S. Pat. Nos. RE 32,333; RE 32,455; RE 32,311; RE 32,310; 4,482,487; 4,537,717; and 5,912,226 and International Patent Applications WO01/44272; WO01/44274; and WO01/44271.
  • the A54145 class of compounds described in U.S. Pat. Nos. 4,994,270; 5,039,789; and 5,028,590 have also been shown to possess antibiotic activity.
  • Daptomycin also known as LY 146032, is comprised of an n-decanoyl side chain linked to the N-terminal tryptophan of a three-amino acid chain linked to a cyclic 10-amino acid peptide. Daptomycin has potent bactericidal activity in vitro and in vivo against clinically relevant gram-positive bacteria that cause serious and life-threatening diseases.
  • VRE vancomycin-resistant enterococci
  • MRSA methicillin-resistant Staphylococcus aureus
  • GISA glycopeptide intermediate susceptible Staphylococcus aureus
  • VRSA vancomycin-resistant Staphylococcus aureus
  • CNS coagulase-negative staphylococci
  • PRSP penicillin-resistant Streptococcus pneumoniae
  • novel antibacterial agents would be expected to be useful to treat not only “natural” pathogens, but also intermediate drug resistant and drug resistant pathogens because the pathogen has never been exposed to the novel antibacterial agent.
  • New antibacterial agents may exhibit differential effectiveness against different types of pathogens.
  • the present invention provides novel compounds that have antibacterial activity against a broad spectrum of bacteria, including drug-resistant bacteria, and processes for making these compounds.
  • R is 2-butyl, isopropyl or 2-(2′-aminophenacyl);
  • each R 1 and R 6 is independently hydrido or methyl
  • R 2 is methyl or —CH 2 CH 2 CH 2 R 8 ;
  • R 3 is methyl or —CH 2 CH 2 CH 2 CH 2 R 9 ;
  • R 4 is hydrido or methoxy
  • R 5 is hydroxy or carboxyamino
  • each of R 7 , R 8 and R 9 is independently amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino;
  • R 10 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, iminoamino, or phosphonamino;
  • each of R 11 and R 12 is hydrido, C 6 -C 18 unsubstituted alkanoyl, C 8 -C 18 unsubstituted alkenoyl, C 8 -C 18 unsubstituted alkyl, or C 8 -C 18 select substituted alkyl; or alternatively, R 11 and R 12 together are C 8 -C 18 alkylidenyl.
  • the present invention also provides pharmaceutical compositions including compounds of Formula I and methods of use thereof.
  • the present invention provides a process for preparing the compounds of Formula I.
  • the invention provides compounds useful as intermediates for the preparation of the compounds of Formula I.
  • activating group denotes a group that when adjacent to a carbonyl group activates the carbonyl group to attack by a nucleophilic amine, resulting in the loss of the activating group and the formation of an amide bond.
  • activating groups are aryloxy, acyloxy, imidazolyl
  • Preferred activating groups are aryloxy groups.
  • the most preferred activating group is pentafluorophenoxy.
  • acyl denotes a carbonyl radical attached to an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycyl, aryl or heteroaryl group, examples including, without limitation, such radicals as acetyl and benzoyl.
  • Subsets of the term acyl are (1) “unsubstituted alkanoyl” which is defined as carbonyl radical attached to an unsubstituted alkyl group and (2) “unsubstituted alkenoyl” which is defined as carbonyl radical attached to an unsubsituted alkenyl group.
  • acylamino is defined as a nitrogen radical adjacent to an acyl group.
  • acyloxy denotes an oxygen radical adjacent to an acyl group.
  • alkenyl is defined as linear or branched radicals having two to about twenty carbon atoms, preferably three to about ten carbon atoms, and containing at least one carbon-carbon double bond.
  • One or more hydrogen atoms can also be replaced by a substituent group selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryloxy, carbamoyl, carboalkoxy, carboxy, carboxyamido, carboxyamino, cyano, disubstituted amino, formyl, guanidino, halo, heteroaryl, heterocyclyl, hydroxy, iminoamino, monosubstituted amino, nitro, oxo, phosphonamino, sulfinyl, sulfonamino, sulfonyl, thio, thioacylamino, thioure
  • the double bond portion(s) of the unsaturated hydrocarbon chain may be either in the cis or trans configuration.
  • alkenyl groups include, without limitation, ethylenyl or phenyl ethylenyl.
  • a subset of term alkenyl is “unsubstituted alkenyl” which is defined as an alkenyl group that bears no substituent groups.
  • alkoxy denotes oxygen radical substituted with an alkyl, cycloalkyl or heterocyclyl group. Examples include, without limitation, methoxy, tert-butoxy, benzyloxy and cyclohexyloxy.
  • alkyl is defined as a linear or branched, saturated radical having one to about twenty carbon atoms unless otherwise specified.
  • lower alkyl is defined as an alkyl group containing 1-4 carbon atoms.
  • One or more hydrogen atoms can also be replaced by a substitutent group selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryloxy, carbamoyl, carboalkoxy, carboxy, carboxyamido, carboxyamino, cyano, disubstituted amino, formyl, guanidino, halo, heteroaryl, heterocyclyl, hydroxy, iminoamino, monosubstituted amino, nitro, oxo, phosphonamino, sulfinyl, sulfonamino, sulfonyl, thio, thioacylamino, thioureido, or ureido.
  • a substitutent group selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl
  • alkyl groups include, without limitation, methyl, butyl, tert-butyl, isopropyl, trifluoromethyl, nonyl, undecyl, octyl, dodecyl, methoxymethyl, 2-(2′-aminophenacyl), 3-indolylmethyl, benzyl, and carboxymethyl.
  • alkyl is defined as an alkyl group that bears no substituent groups
  • substituted alkyl which denotes an alkyl radical in which one or more hydrogen atoms is replaced by a substitutent group selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryloxy, carbamoyl, carboalkoxy, carboxy, carboxyamido, carboxyamino, cyano, disubstituted amino, formyl, guanidino, halo, heteroaryl, heterocyclyl, hydroxy, iminoamino, monosubstituted amino, nitro, oxo, phosphonamino, sulfinyl, sulfonamino, sulfonyl, thio, thioacylamino,
  • alkylidenyl is defined as a carbon radical of the formula
  • R x and R x1 are independently selected from hydrido or C 7 -C 17 unsubstituted alkyl, wherein the total number of carbons from R x and R x1 does not exceed 17.
  • alkynyl denotes linear or branched radicals having from two to about ten carbon atoms, and containing at least one carbon-carbon triple bond.
  • One or more hydrogen atoms can also be replaced by a substituent group selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryloxy, carbamoyl, carboalkoxy, carboxy, carboxyamido, carboxyamino, cyano, disubstituted amino, formyl, guanidino, halo, heteroaryl, heterocyclyl, hydroxy, iminoamino, monosubstituted amino, nitro, oxo, phosphonamino, sulfinyl, sulfonamino, sulfonyl, thio, thioacylamino, thioureido, or ureid
  • amino is defined as an NH 2 radical.
  • amino acid resisue denotes a compound of the formula
  • R aa is an amino acid side chain.
  • amino acid side chain denotes any side chain (R group) from a naturally-occurring or synthetic amino acid.
  • R group side chain from a naturally-occurring or synthetic amino acid.
  • 3-indolylmethyl could also be called a tryptophan side chain.
  • amino protecting group refers to any chemical compound that may be used to prevent an amino group on a molecule from undergoing a chemical reaction while chemical change occurs elsewhere in the molecule. Numerous amino protecting groups are known to those skilled in the art and examples can be found in “Protective Groups in Organic Synthesis” by Theodora W. Greene, John Wiley and Sons, New York, 1981.
  • amino protecting groups examples include phthalimido, trichloroacetyl, STA-base, benzyloxycarbonyl, t-butoxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl, adamantyloxycarbonyl, chlorobenzyloxycarbonyl, nitrobenzyloxycarbonyl or the like.
  • Preferred amino protecting groups are “carbamate amino protecting groups” which are defined as an amino protecting group that when bound to an amino group forms a carbamate.
  • Preferred amino carbamate protecting groups are allyloxycarbonyl (alloc), carbobenzyloxy (CBZ), and tert-butoxycarbonyl protecting groups.
  • aryl or “aryl ring” is defined as an aromatic radical in a single or fused carbocyclic ring system, having from five to fourteen ring members.
  • the ring system has from six to ten ring members.
  • One or more hydrogen atoms may also be replaced by a substituent group selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryloxy, azido, carbamoyl, carboalkoxy, carboxy, carboxyamido, carboxyamino, cyano, disubstituted amino, formyl, guanidino, halo, heteroaryl, heterocyclyl, hydroxy, iminoamino, monosubstituted amino, nitro, oxo, phosphonamino, sulfinyl, sulfonamino, sulfonyl, thio, thioacylamino, thioureido, or ureido.
  • aryl groups include, without limitation, phenyl, napheptyl, phen
  • aryloxy denotes oxy-containing radicals substituted with an aryl or heteroaryl group. Examples include, without limitation, phenoxy.
  • R x2 is selected from hydrido, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl and R x3 is selected from alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl
  • carboalkoxy is defined as a carbonyl radical adjacent to an alkoxy or aryloxy group.
  • carboxyamido is defined as a carbonyl radical adjacent to a monosubstituted amino or disubstituted amino group.
  • ⁇ -carboxy amino acid side chain is defined as a carbon radical of the formula
  • R x4 is defined as an amino acid side chain.
  • cycloalkyl or “cycloalkyl ring” denotes a saturated or partially unsaturated carbocyclic ring in a single or fused carbocyclic ring system having from three to twelve ring members.
  • a cycloalkyl is a ring system having three to seven ring members.
  • One or more hydrogen atoms may also be replaced by a substituent group selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryloxy, carbamoyl, carboalkoxy, carboxy, carboxyamido, carboxyamino, cyano, disubstituted amino, formyl, guanidino, halo, heteroaryl, heterocyclyl, hydroxy, iminoamino, monosubstituted amino, nitro, oxo, phosphonamino, sulfinyl, sulfonamino, sulfonyl, thio, thioacylamino, thioureido, or ureido.
  • a cycloalkyl group include, without limitation, cyclopropyl, cyclobutyl, cyclohexyl, and cyclohept
  • disubstituted amino is defined as a nitrogen radical containing two substituent groups independently selected from, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • Preferred disubstituted amino radicals are “lower disubstituted amino” radicals, whereby the substituent groups are lower alkyl.
  • Also preferred disubstituted amino radicals are amino radicals wherein one substituent is a lower alkyl group and the other substituent is an ⁇ -carboxy amino acid side chain.
  • the group “Fmoc” is a 9-fluorenylmethoxycarbonyl group.
  • each of R x5 , R x7 and R x8 is independently selected from hydrido, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group; and R x6 is selected from alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group.
  • halo denotes a bromo, chloro, fluoro or iodo radical.
  • Heteroaryl or “heteroaryl ring” is defined as an aromatic radical which contain one to four hetero atoms or hetero groups selected from O, N, S, or SO in a single or fused heterocyclic ring system, having from five to fifteen ring members.
  • the heteroaryl ring system has from six to ten ring members.
  • One or more hydrogen atoms may also be replaced by a substituent group selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryloxy, carbamoyl, carboalkoxy, carboxy, carboxyamido, carboxyamino, cyano, disubstituted amino, formyl, guanidino, halo, heteroaryl, heterocyclyl, hydroxy, iminoamino, monosubstituted amino, nitro, oxo, phosphonamino, sulfinyl, sulfonamino, sulfonyl, thio, thioacylamino, thioureido, or ureido.
  • a substituent group selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, amino
  • heteroaryl groups include, without limitation, pyridinyl, thiazolyl, thiadiazoyl, isoquinolinyl, pyrazolyl, oxazolyl, oxadiazoyl, triazolyl, and pyrrolyl groups.
  • heterocyclyl denotes a saturated or partially unsaturated ring containing one to four hetero atoms or hetero groups selected from O, N, NE, N(lower alkyl), S, SO or SO 2 , in a single or fused heterocyclic ring system having from three to twelve ring members.
  • a heterocyclyl is a ring system having three to seven ring members.
  • One or more hydrogen atoms may also be replaced by a substituent group selected from acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryloxy, carbamoyl, carboalkoxy, carboxy, carboxyamido, carboxyamino, cyano, disubstituted amino, formyl, guanidino, halo, heteroaryl, heterocyclyl, hydroxy, iminoamino, monosubstituted amino, nitro, oxo, phosphonamino, sulfinyl, sulfonamino, sulfonyl, thio, thioacylamino, thioureido, or ureido.
  • a heterocyclyl group include, without limitation, morpholinyl, piperidinyl, and pyrrolidinyl.
  • hydro is defined as a single hydrogen atom (H).
  • aminoamino denotes a nitrogen radical of the formula:
  • each of R x9 and R x11 is independently selected from a hydrido, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group; and R x10 is selected from an alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group.
  • modifying agent is defined as (a) a nucleophilic acceptor or (b) an aldehyde or ketone that reacts with an amine under reductive conditions to form an alkylated amine.
  • monosubstituted amino denotes a nitrogen radical containing a hydrido group and a substituent group selected from alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • Preferred monosubstituted amino radicals are “lower monosubstituted amino” radicals, whereby the substituent group is a lower alkyl group. More preferred monosubstituted amino radicals are amino radicals containing an ⁇ -carboxy amino acid side chain.
  • nucleophilic acceptor is defined as a compound that is susceptible to nucleophilic attack by a primary or secondary amine.
  • nucleophilic acceptors include, without limitation, isocyanates, isothiocyanates, activated esters, acid chlorides, sulfonyl chlorides, activated sulfonamides, activated heterocycles, activated heteroaryls, chloroformates, cyanoformates, thioesters, phosphoryl chlorides, phosphoramidates, imidates, and lactones.
  • R x12 is selected from hydrido, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl; wherein each of R x13 and R x14 is independently selected from alkyl, alkoxy, aryl, aryloxy, cycloalkyl, heteroaryl and heterocyclyl.
  • sulfinyl denotes a tetravalent sulfur radical substituted with an oxo substituent and a second substituent selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group.
  • sulfonamino is defined as an amino radical of the formula:
  • R x15 is selected from a hydrido, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group; and R x16 is selected from alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group.
  • sulfonyl denotes a hexavalent sulfur radical substituted with two oxo substituents and a third substituent selected from alkyl, cycloalkyl, heterocyclyl aryl, or heteroaryl.
  • thio is defined as a radical containing a substituent group independently selected from hydrido, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, attached to a divalent sulfur atom, such as, methylthio and phenylthio.
  • thioacylamino denotes an amino radical of the formula
  • R x17 is selected from a hydrido, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group; and wherein R x18 is selected from an alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group.
  • thioureido is defined as a sulfur radical of the formula
  • each of R x19 and R x20 is independently selected from hydrido, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group; and R x21 is selected from an alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group.
  • the group trityl is a triphenylmethyl group.
  • ureido is defined as a nitrogen radical of the formula
  • each of R x21 and R x22 is independently selected from hydrido, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group; and R x23 is selected from an alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl group.
  • the salts of the compounds of the invention include acid addition salts and base addition salts.
  • the salt is a pharmaceutically acceptable salt of the compound of Formula I.
  • pharmaceutically acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention may be prepared from an inorganic acid or an organic acid. Examples of such inorganic acids include, without limitation, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include, without limitation, formic, acetic, propionic, succinic, glycolic, gluconic, maleic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, ⁇ -hydroxybutyric, malonic, galactic, and galacturonic acid.
  • Suitable pharmaceutically-acceptable base addition salts of compounds of the invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, lysine and procaine. All of these salts may be prepared by conventional means from the corresponding compound of the invention by treating, for example, the compound of the invention with the appropriate acid or base.
  • the compounds of the invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof.
  • the compounds of the invention can be utilized in the present invention as a single isomer or as a mixture of stereochemical isomeric forms.
  • Diastereoisomers, i.e., nonsuperimposable stereochemical isomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base.
  • Examples of appropriate acids include, without limitation, tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • the mixture of diastereomers can be separated by crystallization followed by liberation of the optically active bases from the optically active salts.
  • An alternative process for separation of optical isomers includes the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
  • Still another method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain the enantiomerically pure compound.
  • the optically active compounds of the invention can likewise be obtained by utilizing optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
  • the invention also embraces isolated compounds.
  • An isolated compound refers to a compound which represents at least 10%, preferably at least 20%, more preferably at least 50% and most preferably at least 80% of the compound present in the mixture.
  • the compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound exhibits a detectable (i.e. statistically significant) antimicrobial activity when tested in conventional biological assays such as those described herein.
  • the invention provides compounds of Formula I
  • R is 2-butyl, isopropyl or 2-(2′-aminophenacyl);
  • each R 1 and R 6 is independently hydrido or methyl
  • R 2 is methyl or —CH 2 CH 2 CH 2 R 8 ;
  • R 3 is methyl or —CH 2 CH 2 CH 2 CH 2 R 9 ;
  • R 4 is hydrido or methoxy
  • R 5 is hydroxy or carboxyamino
  • each of R 7 , R 8 and R 9 is independently amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino;
  • R 10 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, and phosphonamino;
  • each of R 11 and R 12 is hydrido, C 6 -C 18 unsubstituted alkanoyl, C 8 -C 18 unsubstituted alkenoyl, C 8 -C 18 unsubstituted alkyl, or C 8 -C 18 select substituted alkyl; or alternatively, R 11 and R 12 together are C 8 -C 18 alkylidenyl.
  • R 7 is
  • each of R aa , R aa2 and R aa3 is independently an amino acid side chain and wherein R 13 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino.
  • R is 2-(2′-aminophenacyl); each of R 1 and R 4 is hydrido; R 2 is —CH 2 CH 2 CH 2 R 8 ; each of R 3 and R 6 is methyl; and R 5 is hydroxyl.
  • This embodiment provides a compound of Formula II.
  • R is isopropyl or 2-butyl; each of R 1 and R 2 is methyl; R 3 is —CH 2 CH 2 CH 2 CH 2 R 9 ; R 4 is methoxy, and R 5 is carboxyamino.
  • R is isopropyl or 2-butyl; each of R 1 and R 2 is methyl; R 3 is —CH 2 CH 2 CH 2 CH 2 R 9 ; R 4 is methoxy, and R 5 is carboxyamino.
  • R 14 is hydrido or methyl.
  • Table I provides exemplary compounds of Formula II. TABLE I Compounds of Formula II R 7 R 8 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2
  • R 7** is an amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino and each of R aa4 , R aa5 , and R aa6 is independently an amino acid side chain.
  • Table II provides exemplary compounds of Formula III. TABLE II Compounds of Formula III R 7 R 9 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2 NH 2
  • R 7** is an amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino and each of R aa4 , R aa5 , and R aa6 is independently an amino acid side chain.
  • the present invention also provides compounds of the Formula IV that are particularly useful as intermediates for the preparation of the compounds of Formula I.
  • R is 2-butyl, isopropyl or 2-(2′-aminophenacyl);
  • each R 1 and R 6 is independently hydrido or methyl
  • R 4 is hydrido or methoxy
  • R 5 is hydroxy or carboxyamino
  • R 18 is amino or hydroxy
  • R 19 is hydrido or hydroxy
  • R 20 is carboxyamino or carboxymethyl
  • R 16 is methyl or —CH 2 CH 2 CH 2 R 21 ;
  • R 17 is methyl or —CH 2 CH 2 CH 2 CH 2 R 22 ;
  • each of R 21 and R 22 is independently amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino.
  • each of R 21 and R 22 is —NHR 23 , wherein R 23 is an amino protecting group.
  • R 23 is a carbamate amino protecting group selected from allyloxycarbonyl, carbobenzyloxycarbonyl and tert-butoxycarbonyl. In the most preferred embodiment R 23 is allyloxycarbonyl.
  • the present invention provides intermediates of the Formulas V, VI, VII, VIII, IX and X that are particularly useful as intermediates for the preparation of the compounds of Formula I.
  • the instant invention provides pharmaceutical compositions or formulations comprising compounds of Formula I, or salts thereof.
  • Compounds of the present invention can be formulated for oral, intravenous, intramuscular, subcutaneous or parenteral administration for the therapeutic or prophylactic treatment of diseases, particularly bacterial infections.
  • compounds of the present invention can be mixed with conventional pharmaceutical carriers and excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers and the like.
  • the compositions comprising a compound of this invention will contain from about 0.1 to about 99% by weight of the active compound, and more generally from about 10 to about 30%.
  • compositions of the present invention preferably compounds of Formula I, can be delivered using controlled (e.g., capsules) or sustained release delivery systems (e.g., bioerodable matrices).
  • compositions of the present invention comprise one or more compounds of the invention, preferably compounds of Formula I, in association with one or more nontoxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants and/or excipients, collectively referred to herein as “carrier” materials, and if desired other active ingredients.
  • carrier materials
  • the compositions may contain common carriers and excipients, such as corn starch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid.
  • the compositions may contain croscarmellose sodium, microcrystalline cellulose, corn starch, sodium starch glycolate and alginic acid.
  • Tablet binders that can be included are acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.
  • Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.
  • Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring or the like can also be used. It may also be desirable to add a coloring agent to make the dosage form more aesthetic in appearance or to help identify the product.
  • the pharmaceutical compositions are in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a therapeutically-effective amount of the active ingredient. Examples of such dosage units are tablets and capsules.
  • the tablets and capsules which can contain, in addition to the active ingredient, conventional carriers such as binding agents, for example, acacia gum, gelatin, polyvinylpyrrolidone, sorbitol, or tragacanth; fillers, for example, calcium phosphate, glycine, lactose, maize-starch, sorbitol, or sucrose; lubricants, for example, magnesium stearate, polyethylene glycol, silica, or talc; disintegrants, for example, potato starch, flavoring or coloring agents, or acceptable wetting agents.
  • binding agents for example, acacia gum, gelatin, polyvinylpyrrolidone, sorbitol, or tragacanth
  • fillers for example, calcium phosphate, glycine, lactose, maize-starch, sorbitol, or sucrose
  • lubricants for example, magnesium stearate, polyethylene glycol, silica, or talc
  • disintegrants
  • Oral liquid preparations generally are in the form of aqueous or oily solutions, suspensions, emulsions, syrups or elixirs may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous agents, preservatives, coloring agents and flavoring agents.
  • additives for liquid preparations include acacia, almond oil, ethyl alcohol, fractionated coconut oil, gelatin, glucose syrup, glycerin, hydrogenated edible fats, lecithin, methyl cellulose, methyl or propyl para-hydroxybenzoate, propylene glycol, sorbitol, or sorbic acid.
  • IV intravenous
  • a compound of the present invention can be dissolved or suspended in any of the commonly used intravenous fluids and administered by infusion.
  • Intravenous fluids include, without limitation, physiological saline or Ringer's solution.
  • Intravenous administration may be accomplished by using, without limitation, syringe, minipump or intravenous line.
  • Formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions or suspensions can be prepared from sterile powders or granules having one or more of the carriers mentioned for use in the formulations for oral administration.
  • the compounds can be dissolved in polyethylene glycol, propylene glycol, ethanol, corn oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • a sterile formulation of a compound of the present invention, or a suitable soluble salt form of the compound, for example the hydrochloride salt can be dissolved and administered in a pharmaceutical diluent such as Water-for-Injection (WFI), physiological saline or 5% glucose.
  • WFI Water-for-Injection
  • a suitable insoluble form of the compound may be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, e.g., an ester of a long chain fatty acid such as ethyl oleate.
  • a dose of an intravenous, intramuscular or parental formulation of a compound of the present invention may be adminstered as a bolus or by slow infusion.
  • a bolus is a dose that is administered in less than 30 minutes. In a preferred embodiment, a bolus is administered in less than 15 or less than 10 minutes. In a more preferred embodiment, a bolus is administered in less than 5 minutes. In an even more preferred embodiment, a bolus is administered in one minute or less.
  • An infusion is a dose that is administered at a rate of 30 minutes or greater. In a preferred embodiment, the infusion is one hour or greater. In another embodiment, the infusion is substantially constant.
  • the compounds of the present invention preferably compounds of Formula I, can also be prepared in suitable forms to be applied to the skin, or mucus membranes of the nose and throat, and can take the form of creams, ointments, liquid sprays or inhalants, lozenges, or throat paints.
  • suitable forms can take the form of creams, ointments, liquid sprays or inhalants, lozenges, or throat paints.
  • Such topical formulations further can include chemical compounds such as dimethylsulfoxide (DMSO) to facilitate surface penetration of the active ingredient.
  • DMSO dimethylsulfoxide
  • the compounds of the present invention preferably compounds of Formula I, can be presented in liquid or semi-liquid form formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints or powders.
  • the compounds of the present invention preferably compounds of Formula I, can be administered in the form of suppositories admixed with conventional carriers such as cocoa butter, wax or other glyceride.
  • the compounds of the present invention can be in powder form for reconstitution in the appropriate pharmaceutically acceptable carrier at the time of delivery.
  • the unit dosage form of the compound can be a solution of the compound or preferably a salt thereof in a suitable diluent in sterile, hermetically sealed ampoules or sterile syringes.
  • the concentration of the compound in the unit dosage may vary, e.g. from about 1 percent to about 50 percent, depending on the compound used and its solubility and the dose desired by the physician.
  • each dosage unit preferably contains from 1-500 mg of the active material.
  • the dosage employed preferably ranges from 5 mg to 10 g, per day, depending on the route and frequency of administration.
  • the invention provides a method for inhibiting the growth of microorganisms, preferably bacteria, comprising contacting said organisms with a compound of the present invention under conditions which permit contact of the compound with said organism and with said microorganism.
  • a compound of the present invention under conditions which permit contact of the compound with said organism and with said microorganism.
  • This method involves contacting a microbial cell with a therapeutically-effective amount of compound(s) of the invention, preferably compound(s) of Formula I, in vivo or in vitro.
  • the novel compositions disclosed herein are placed in a pharmaceutically acceptable carrier and are delivered to a recipient subject (preferably a human) in accordance with known methods of drug delivery.
  • a recipient subject preferably a human
  • the methods of the invention for delivering the compositions of the invention in vivo utilize art-recognized protocols for delivering the agent with the only substantial procedural modification being the substitution of the compounds of the present invention, preferably compounds of Formula I, for the drugs in the art-recognized protocols.
  • the methods for using the claimed composition for treating cells in culture utilize art-recognized protocols for treating cell cultures with antibacterial agent(s) with the only substantial procedural modification being the substitution of the compounds of the invention, preferably compounds of Formula I, for the agents used in the art-recognized protocols.
  • the invention provides a method for treating an infection, especially those caused by gram-positive bacteria, in a subject with a therapeutically-effective amount of a compound of the invention.
  • a therapeutically-effective amount means an amount of a compound of the present invention that prevents the onset, alleviates the symptoms, or stops the progression of a bacterial infection.
  • treating is defined as administering, to a subject, a therapeutically-effective amount of a compound of the invention both to prevent the occurrence of an infection and to control or eliminate an infection.
  • subject as described herein, is defined as a mammal, a plant or a cell culture. In a preferred embodiment, a subject is a human or other animal patient in need of antibacterial treatment.
  • the method comprises administering to the subject an effective dose of a compound of the present invention.
  • An effective dose is generally between about 0.1 and about 100 mg/kg of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • a preferred dose is from about 0.1 to about 50 mg/kg of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • a more preferred dose is from about 1 to 25 mg/kg of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • An effective dose for cell culture is usually between 0.1 and 1000 ⁇ g/mL, more preferably between 0.1 and 200 ⁇ g/mL.
  • compositions containing the compounds of the invention can be administered as a single daily dose or in multiple doses per day.
  • the treatment regime may require administration over extended periods of time, e.g., for several days or for from two to four weeks.
  • the amount per administered dose or the total amount administered will depend on such factors as the nature and severity of the infection, the age and general health of the patient, the tolerance of the patient to the compound and the microorganism or microorganisms involved in the infection.
  • a method of administration to a patient of daptomycin, another member of the depsipeptide compound class is disclosed in U.S. Ser. No. 09/406,568, filed Sep. 24, 1999, which claims the benefit of U.S. Provisional Application Nos. 60/101,828, filed Sep. 25, 1998, and 60/125,750, filed Mar. 24, 1999, the contents of which are herein incorporated by reference.
  • a compound of the present invention may also be administered in the diet or feed of a patient or animal. If administered as part of a total dietary intake, the amount of compound employed can be less than 1% by weight of the diet and preferably no more than 0.5% by weight.
  • the diet for animals can be normal foodstuffs to which the compound can be added or it can be added to a premix.
  • the present invention also provides methods of administering a compound of Formula I or a pharmaceutical composition thereof to a subject in need thereof in an amount that is efficacious in reducing or eliminating the bacterial infection.
  • the compound may be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, vaginally, or by an implanted reservoir, external pump or catheter.
  • the compound may be prepared for opthalmic or aerosolized uses.
  • the compounds of the present invention can be administered as an aerosol for the treatment of pneumonia or other lung-based infections.
  • a preferred aerosol delivery vehicle is an anhydrous or dry powder inhaler.
  • Compounds of Formula I or a pharmaceutical composition thereof may also be directly injected or administered into an abscess, ventricle or joint.
  • Parenteral administration includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, cistermal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion.
  • the compounds of the present invention are administered intravenously, subcutaneously or orally.
  • the compound may be administered in a nutrient medium.
  • the method of the instant invention may be used to treat a subject having a bacterial infection in which the infection is caused or exacerbated by any type of bacteria, particularly gram-positive bacteria.
  • a compound of the present invention or a pharmaceutical composition thereof is administered to a patient according to the methods of this invention.
  • the bacterial infection may be caused or exacerbated by gram-positive bacteria.
  • gram-positive bacteria include, but are not limited to, methicillin-susceptible and methicillin-resistant staphylococci (including Staphylococcus aureus, S. epidermidis, S. haemolyticus, S. hominis, S.
  • GISA glycopeptide intermediary-susceptible S. aureus
  • VRSA vancomycin-resistant Staphylococcus aureus
  • penicillin-susceptible and penicillin-resistant streptococci including Streptococcus pneumoniae, S. pyogenes, S. agalactiae, S. avium, S. bovis, S. lactis, S. sangius and Streptococci Group C, Streptococci Group G and viridans streptococci
  • enterococci including vancomycin-susceptible and vancomycin-resistant strains such as Enterococcus faecalis and E.
  • Clostridium difficile Clostridium difficile, C. clostridiiforme, C. innocuum, C. perfringens, C. ramosum, Haemophilus influenzae, Listeria monocytogenes, Corynebacterium jeikeium, Bifidobacterium spp., Eubacteriurn aerofaciens, E. lentum, Lactobacillus acidophilus, L. casei, L. plantarum, Lactococcus spp., Leuconostoc spp., Pediococcus, Peptostreptococcus anaerobius, P. asaccarolyticus, P. magnus, P. micros, P.
  • the antibacterial activity of compounds of Formula I against classically “resistant” strains is comparable to that against classically “susceptible” strains in in vitro experiments.
  • the minimum inhibitory concentration (MIC) value for compounds according to this invention against susceptible strains is typically the same or lower than that of vancomycin.
  • a compound of this invention or a pharmaceutical composition thereof is administered according to the methods of this invention to a patient who exhibits a bacterial infection that is resistant to other compounds, including vancomycin or daptomycin.
  • depsipeptide compounds such as those disclosed in the present invention, exhibit rapid, concentration-dependent bactericidal activity against gram-positive organisms.
  • a compound according to this invention or a pharmaceutical composition thereof is administered according to the methods of this invention to a patient in need of rapidly acting antibiotic therapy.
  • the method of the instant invention may be used for any bacterial infection of any organ or tissue in the body.
  • the bacterial infection is caused by gram-positive bacteria.
  • organs or tissue include, without limitation, skeletal muscle, skin, bloodstream, kidneys, heart, lung and bone.
  • the method of the invention may be used to treat, without limitation, skin and soft tissue infections, bacteremia and urinary tract infections.
  • the method of the invention may be used to treat community acquired respiratory infections, including, without limitation, otitis media, sinusitis, chronic bronchitis and pneumonia, including pneumonia caused by drug-resistant S. pneumoniae or H. influenzae.
  • the method of the invention also may be used to treat mixed infections that comprise different types of gram-positive bacteria, or which comprise both gram-positive and gram-negative bacteria. These types of infections include intra-abdominal infections and obstetrical/gynecological infections.
  • the method of the invention also may be used to treat an infection including, without limitation, endocarditis, nephritis, septic arthritis, intra-abdominal sepsis, bone and joint infections. and osteomyelitis.
  • any of the above-described diseases may be treated using compounds according to this invention or pharmaceutical compositions thereof.
  • the method of the present invention may also be practiced while concurrently administering one or more other antimicrobial agents, such as antibacterial agents (antibiotics) or antifungal agents.
  • the method may be practiced by administering more than one compound according to this invention.
  • the method may be practiced by administering a compound according to this invention with a lipopeptide compound, such as daptomycin or the lipopeptide compounds described, for example in International Patent Applications WO01/44272; WO01/44274; and WO01/44271.
  • Antibacterial agents and classes thereof that may be co-administered with a compound according to the invention include, without limitation, penicillins and related drugs, carbapenems, cephalosporins and related drugs, aminoglycosides, bacitracin, gramicidin, mupirocin, chloramphenicol, thiamphenicol, fusidate sodium, lincomycin, clindamycin, macrolides, novobiocin, polymyxins, rifamycins, spectinomycin, tetracyclines, vancomycin, teicoplanin, streptogramins, anti-folate agents including sulfonamides, trimethoprim and its combinations and pyrimethamine, synthetic antibacterials including nitrofurans, methenamine mandelate and methenamine hippurate, nitroimidazoles, quinolones, fluoroquinolones, isoniazid, ethambutol, pyr
  • Antifungal agents that may be co-administered with a compound according to the invention include, without limitation, Caspofonne, Voriconazole, Sertaconazole, IB-367, FK-463, LY-303366, Sch-56592, Sitafloxacin, DB-289 polyenes, such as Amphotericin, Nystatin, Primaricin; azoles, such as Fluconazole, Itraconazole, and Ketoconazole; allylamines, such as Naftifine and Terbinafine; and anti-metabolites such as Flucytosine.
  • Fostel et al. discloses antifungal compounds including Corynecandin, Mer-WF3010, Fusacandins, Artrichitin/LL 15G256, Sordarins, Cispentacin, Azoxybacillin, Aureobasidin and Khafrefungin.
  • a compound according to this invention may be administered according to this method until the bacterial infection is eradicated or reduced.
  • a compound of Formula I is administered for a period of time from 2 days to 6 months.
  • a compound of Formula I is administered for 7 to 56 days.
  • a compound of Formula I is administered for 7 to 28 days.
  • a compound of Formula I is administered for 7 to 14 days.
  • a compound of Formula I may be administered for a longer or shorter time period if it is so desired.
  • R, R 1 , R 4 , R 5 , R 6 , R 18 , R 19 , and R 20 are as previously described;
  • R 25 is an alkyl group;
  • R 26 is methyl or —CH 2 CH 2 CH 2 NH 2 ;
  • R 27 is methyl or —CH 2 CH 2 CH 2 CH 2 NH 2 ; or a salt thereof
  • the semisynthetic process comprises providing a compound of the Formula XI (step(a)).
  • Compounds of Formula XI can be obtained by methods disclosed in U.S. Pat. Nos. RE 32 , 333 ; RE 32,455; RE 32,311; 4,482,487; 4,537,717; 4,800,157, 4,874,843; 4,885,243; 5,912,226; 4,994,270; 5,039,789; and 5,028,590; International Patent Application Serial Numbers WO01/44272, WO01/44274, WO01/44271, WO01/53330, and WO02/059,322 each of which is incorporated herein by reference.
  • the compound of Formula XI is one in which, each of R 1 and R 4 is hydrido; each of R 3 and R 6 is methyl; R 5 is hydroxyl; R 25 is 7-methylnonyl, 9-methyldecyl, 9-methylundecyl, nonyl, decyl or mixtures thereof and R 26 is —CH 2 CH 2 CH 2 NH 2 .
  • the compound of Formula XI is one in which R is isopropyl or 2-butyl; each of R 1 and R 2 is methyl; R 4 is methoxy, R 5 is carboxyamino; R 25 is 8-methylnonanoyl, n-decanoyl, or 8-methyldecanoyl; and R 27 is —CH 2 CH 2 CH 2 CH 2 NH 2 ;
  • R, R 1 , R 4 , R 5 , R 6 , R 18 , R 19 , R 20 , and R 25 are as described previously;
  • R 28 is methyl or —CH 2 CH 2 CH 2 NHP;
  • R 29 is methyl or —CH 2 CH 2 CH 2 CH 2 NHP; wherein P is an amino protecting group or a salt thereof.
  • amino protecting groups and methods for protecting amines with said groups can be found in Protective Groups in Organic Synthesis by Theodora W. Greene, (New York: John Wiley and Sons, Inc.), 1981, hereafter “Greene”, incorporated herein by reference.
  • Preferred amino protecting groups are carbamate amino protecting groups. More preferred amino groups are allyloxycarbonyl (alloc), carbobenzyloxy (CBZ), and tert-butoxycarbonyl protecting groups. The most preferred carbamate amino protecting group is allylyoxycarbonyl.
  • the protected depsipeptide compound is then treated with a deacylating agent to form the terminal amino compound of Formula XIII (step(c)).
  • Deacylating agents suitable for the invention are enzymatic deacylating agents.
  • An enzyme which is useful for deacylation of a compound of Formula XII is produced by certain microorganism of the family Actinoplanaceae.
  • Actinoplanes philippinensis Actinoplanes armeniacus, Actinoplanes utahensis, Actinoplanes missouriensis, Spirillospora albida, Streptosporiangium roseum, Streptosporangium vulgare, Streptosporangium roseum var hollandernsi, Streptosporangium album, Streptosporangium viridialbum, Amorphosporangium auranticolor, Ampullariella regularis, Ampullariella canipanulata, Ampullariella lobata, Ampullariella digitata, Pilimelia terevasa, Pimelia anulata, Planomonospora parontospora, Planomonospora venezuelensis, Planobispora longispora, Planobispora rosea, Dactylosporangium aurantiacum , and Dactyl
  • Preferred sources of the deacylation enzyme are Actinoplanes utahensi: NRRL 12052; Actinoplanes missouriensis NRRL 12053; Actinoplanes sp.: NRRL8122, Actinoplanes sp.: NRRL 12065, Streptosporsngium roseum var hollandernsis: NRRL 12064 , Actinoplanes utahenis ATCC 14539 and Actinoplanes missouriensis ATCC 14538.
  • the more preferred source of deacylation enzyme is the species Actinoplanes utahensi.
  • deacylation enzyme is one produced from recombinant Streptomyces lividans, which expresses the Actinoplanes utahensis deacylation enzyme as described in J. Ind. Microbiol. Biotechnol. 2000, 24(3) 173-180. This enzyme is also known as echinocandin B deacylase or ECB deacylase.
  • Suitable methods for enzymatic deacylation of compounds of Formula XII can be found in U.S. Pat. Nos. 4,524,135; 4,537,717; 4,482,487; RE 32,310, RE 32,311 5,039,789 and 5,028590; International Patent Application Serial Numbers WO01/44272, WO01/44274, and WO01/44271; each herein incorporated by reference.
  • R 30 , R 31 , and R 32 are each an amino acid side chain; and R 33 is an aryl or alkyl group.
  • the Edman degradation can be carried out under a variety of conditions.
  • the isothiocyanate reacts with the amine under neutral to mildly basic (pH ⁇ 9.5) conditions in solvents such as tetrahydrofuran, N,N′-dimethylformamide, dichloromethane, dioxane or ethanol.
  • solvents such as tetrahydrofuran, N,N′-dimethylformamide, dichloromethane, dioxane or ethanol.
  • isothiocyanates can be used (see K. K. Han et al. Biochemie 1977, 59: 557-576.
  • the thiourea peptide (the compound of Formula XVIII) formed upon reaction of the thioisocyanate with a compound of Formula XIII is treated under acidic conditions to provide a compound of Formula XIV.
  • a compound of Formula XVIII is treated with trifluoroacetic acid to give the compound of Formula XIV (Scheme III).
  • R 33 is phenyl, n-decyl, nonyl or octyl. In a more preferred embodiment, R 33 is n-decyl.
  • the thiourea peptide (the compound of Formula XIX) formed upon reaction of the thioisocyanate with a compound of Formula XIV, is treated under acidic conditions to provide desdipeptide compound of Formula XV.
  • a compound of Formula XIX is treated with trifluoroacetic acid to give the compound of Formula XV (Scheme IV).
  • R 34 is alkyl or aryl.
  • the thiourea peptide (the compound of Formula XX) formed upon reaction of the thioisocyanate with a compound of Formula XV, is treated under acidic conditions to provide the depsipeptide core compound of Formula XVI.
  • a compound of Formula XX is treated with trifluoroacetic acid to give the compound of Formula XVI (Scheme IV A).
  • R 35 is alkyl or aryl.
  • Treatment of the depsipeptide core compound of Formula XVI with a modifying agent results in the formation of protected Formula I compound (the compound of Formula XVII, step(f)).
  • the reaction of an amine with modifying agents, as defined herein, is well known to those skilled in the art.
  • treatment of a compound of Formula XVI with an isocyanate gives compounds of Formula XVII in which R 7 is ureido.
  • treatment of a compound of Formula XVI with an activated ester, lactone or acid chloride yields compounds of Formula XVII in which R 7 is acylamino.
  • Treatment of a compound of Formula XVI with a sulfonyl chloride or activated sulfonamide results in Formula XVII in which R 7 is a sulfonamino.
  • Treatment of a compound of the Formula XVI with an activated heterocycle results in a compound of Formula XVII in which R 7 is a heterocyclic amino.
  • Treatment of a compound of the Formula XVI with an activated heteroaryl results in a compound of Formula XVII in which R 7 is a heteroaryl amino.
  • Treatment of a compound of Formula XVI with a carbonate, chloroformate, or cyanoformate gives compounds of Formula XVII in which R 7 is a carbamate.
  • Treatment of a compound of Formula XVI with a thioester gives compounds of Formula XVII in which R 7 is thioacylamino.
  • Treatment of a compound of Formula XVI with a phosphoryl chloride or phosphoramidate gives compounds of Formula XVII in which R 7 is phosphonamino.
  • Treatment of a compound of Formula XVI with an imidate gives compounds of Formula XVII in which R 7 is iminoamino.
  • Treatment of a compound of Formula XVI with a thioisocyanate gives compounds of Formula XVII in which R 7 is thioureido.
  • the modifying agent is an activated ester. In a more preferred embodiment of the reaction the modifying agent
  • each of R aa1 , R aa2 , and R aa3 is an amino acid side chain or a protected form of an amino acid side chain;
  • R 36 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino;
  • X is an activating group.
  • X is an aryloxy group.
  • X is pentafluorophenoxy.
  • Compounds of Formulas XXI, XXII and XXIII can be prepared from the corresponding peptide or amino acid upon treatment with an activating agent such as anhydrides, chloroformates, pentafluorophenol/dicyclohexylcarbodiimide, N′,N′-carbonyldiimidazole, hydroxybenzotriazole or N-hydroxysuccinimide.
  • the peptides can be prepared by any standard peptide procedure. For an overview of some standard peptide formation procedures see Vogel's Textbook of Practical Organic Chemistry, 5 th Ed., eds. B. S. Furniss, A. J. Hannaford; P. W. G. Smith; A. R.
  • Tatchell New York: John Wiley and Sons, Inc.
  • 1989 pp750-763 and Introduction to Organic Chemistry, 2 nd Ed. by A. Streitwieser, Jr. and C. H. Heathcock (New York: MacMillan Publishing Co., Inc.), pp 954-962.
  • Other methods that are useful for the preparation of peptides of the present invention involve synthesis on a solid support. Specific examples of such procedures are detailed in the examples (vide infra).
  • the modifying agent contains one or more protecting group(s)
  • said protecting group(s) must also be removed.
  • the choice of the protecting group(s) utilized on the modifying agent substituent(s) will dictate the reagents and procedures used in removing said protecting group(s).
  • the protecting groups may be removed in a single step. However, when the protecting group(s) are incompatable multiple steps may be required to remove all of the protecting groups.
  • R 7 or the modifying agent of step (i) contain substituents that are incompatible with the reaction conditions under which the compound of Formula I is formed, said substituents will have to be protected prior to step (i). Suitable protecting groups and methods of making them can be found in Greene (vide supra).
  • R 7 , and the modifying agent of step(i) contain protecting group(s), said protecting group(s) may be removed.
  • the choice of the protecting group(s) utilized on R 7 and the modifying agent substituent(s) will dictate the reagents and procedures used in removing said protecting group(s).
  • the protecting groups may be removed in a single step. However, when the protecting group(s) are incompatable multiple steps may be required to remove all of the protecting groups.
  • An alternate procedure for preparing compounds of Formula I wherein at least one of R 2 and R 3 is other than methyl and each of R 8 and R 9 is other than NH 2 comprises the steps of:
  • R, R 1 , R 4 , R 5 , R 6 , R 18 , R 19 , R 20 , R 25 , R 26 , and R 27 are as previously described;
  • step (b) treating the free amino group(s) of the compound of Formula XI with a modifying agent to obtain a blocked depsipeptide compound wherein said modifying agent is selected such that the blocked depsipeptide compound formed is stable to step (c), (d), (e) (f) and (g);
  • protecting groups may be removed.
  • the protecting groups may be removed in a single step.
  • multiple steps may be required to remove all of the protecting groups.
  • each of R 18 , R 19 , and R 20 is as previously described and R 39 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino; can be prepared from compound XIII, as described in Scheme VI, or by compound XXV as described in Scheme VII.
  • each of R 18 , R 19 , and R 20 is as previously described and R 39 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, tbioureido, iminoamino, or phosphonamino; can be prepared from compound XIV, as described Scheme VIII, or by compound XXVI as described in Scheme IX.
  • each of R 18 and R 19 is as previously described and R 39 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino; can be prepared from compound XV, as described Scheme X, or by compound XXVII as described in Scheme XI.
  • the depsipeptide compounds of Formula I may be synthesized on a solid support (Scheme XII, Scheme XIII and Scheme XV).
  • step 1 an N-protected- ⁇ -methyl glutamic acid-O-allyl ester or a protected glutamic acid-O-allyl ester is coupled to a resin to give Compound 101, wherein R 6 is as described previously.
  • a resin or solid support such as, but not limited to, Wang, HMPA, Safety Catch, Rink Acid, 2-chlorotrityl-chloride resin, trityl-chloride resin, 4-methyltrityl-chloride resin, 4-methoxytrityl-chloride resin or PAM resin may be used in this reaction.
  • R 44 is methyl or —CH 2 CH 2 CH 2 CH 2 NP 5 , wherein P 5 is an amino protecting group;
  • a 6 is
  • R 45 is methyl or —CH 2 CH 2 CH 2 NP 7 , wherein P 7 is an amino protecting group.
  • a second peptide is coupled to a resin in a similar fashion, as outlined in Scheme XIII.
  • step 1 a N-protected-glycine or a sarcosine is coupled to a resin to give Compound 104 wherein R 1 is as described previously and P 8 is an amino protecting group.
  • R 1 is as described previously and P 8 is an amino protecting group.
  • the choice of resin used in step 1 is dependent upon the nature of the amino acid that is coupled in steps 2-6. If the amino acid side chains contain protecting groups, a resin must be chosen such that the protecting groups remain intact when the resin is removed from the peptide in step 7.
  • Resins that can be cleaved while preserving the protecting groups of peptides include, but are not limited to, Safety Catch, Rink Acid, 2-chlorotrityl-chloride resin, trityl-chloride resin, 4-methyltrityl-chloride resin, 4-methoxytrityl-chloride resin or PAM resin.
  • R 41 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino.
  • R 46 is hydrido, an amino acid side chain or a protected amino acid side chain;
  • a 9 is
  • R 47 is hydrido, an amino acid side chain or a protected amino acid side chain;
  • a 10 is
  • R 48 is hydrido, an amino acid side chain or a protected amino acid side chain and R 49 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino.
  • Compound 108 is coupled with
  • R 43 is a group capable of being converted to an amino group.
  • R 43 may be azido, a protected amino phthalimido or nitro.
  • the peptide fragments 103 and 112 are coupled to yield the resin bound peptide 113.
  • Deprotection of the P 9 protecting group and O-allyl ester, followed by cyclization affords a resin-bound depsipeptide 114.
  • Cleavage of the depsipeptide from the resin followed by deprotection of any remaining protecting groups yields compounds of Formula I (Scheme XVI).
  • compound 105 can be used in place of compound 108 (Scheme XV).
  • Compound 105 is coupled with Compound 110 to give Compound 115; removed from the resin to give Compound 116; coupled with Compound 103 to give Compound 117; then deprotected and cyclized to yield a resin bound depsipeptide (118) and cleaved from the resin as described previously in Schemes XIII and XIV (vide supra).
  • compound 106 can be used in place of compound 108 (Scheme XVII).
  • Compound 106 is coupled with Compound 110 to give Compound 119; removed from the resin to give Compound 120; coupled with Compound 103 to give Compound 121; then deprotected and cyclized to yield a resin bound depsipeptide (122) and cleaved from the resin as described previously in Schemes XIII and XIV (vide supra).
  • compound 107 can be used in place of compound 108 (Scheme XVIII).
  • Compound 106 is coupled with Compound 110 to give Compound 123; removed from the resin to give Compound 124; coupled with Compound 103 to give Compound 125; then deprotected and cyclized to yield a resin bound depsipeptide (126) and cleaved from the resin as described previously in Schemes XIII and XIV (vide supra).
  • Suitable protecting groups can be any amino protecting group useful in peptide synthesis. Such pairings of protecting groups are well known. See, e.g., “Synthesis Notes” in the Novabiochem Catalog and Peptide Synthesis Handbook (1999), pages S1-S93 and references cited therein.
  • the compounds of the present invention can also be prepared by recombinant methods.
  • a modified non-ribosomal peptide synthetase of daptomycin is introduced into a cell capable of producing a compound of Formula I and the cell is cultured to form a compound of Formula I.
  • the non-ribosomal peptide synthetases of daptomycin as well as modifications of these synthetases have been reported (see International Patent Application Serial Number 02/059,322).
  • N ⁇ -(9-Fluorenylmethoxycarbonyl)-L-serine-tert-butyl ether (2 mL of a 0.5 molar solution in N-methylpyrolidine), 1,3-diisopropylcarbodiimide (2 mL of a 0.5 molar solution in N-methylpyrolidine), and 1-hydroxy-benzotriazole (2 mL of a 0.5 molar solution in N-methylpyrolidine) were added to resin 11.
  • the reaction mixture was shaken for one hour, then filtered and the coupling was repeated.
  • the reaction mixture was filtered then the solid was washed with N-methylpyrolidine (3 ⁇ 6 mL), methanol (3 ⁇ 6 mL ), and again with N-methylpyrolidine (3 ⁇ 6 mL) to give compound 12.
  • N ⁇ -(9-Fluorenylmethoxycarbonyl)-L-glycine ((2 mL of a 0.5 molar solution in N-methylpyrolidine), 1,3-diisopropylcarbodiimide (2 mL of a 0.5 molar solution in N-methylpyrolidine), and 1-hydroxy-benzotriazole (2 mL of a 0.5 molar solution in N-methylpyrolidine) were added to resin 13.
  • the reaction mixture was shaken for one hour, then filtered and the coupling was repeated.
  • the reaction mixture was filtered then the solid was washed with N-methylpyrolidine (3 ⁇ 6 mL), methanol (3 ⁇ 6 mL), and again with N-methylpyrolidine (3 ⁇ 6 mL) to give compound 14.
  • N ⁇ -(9-Fluorenylmethoxycarbonyl)-L-aspartic acid ⁇ -tert-butyl ester ((2 mL of a 0.5 molar solution in N-methylpyrolidine), 1,3-diisopropylcarbodiimide (2 mL of a 0.5 molar solution in N-methylpyrolidine), and 1-hydroxy-benzotriazole (2 mL of a 0.5 molar solution in N-methylpyrolidine) were added to resin 15.
  • the reaction mixture was shaken for one hour, filtered and the coupling was repeated.
  • the reaction mixture was filtered then the solid was washed with N-methylpyrolidine (3 ⁇ 6 mL), methanol (3 ⁇ 6 mL), and again with N-methylpyrolidine (3 ⁇ 6 mL) to give compound 16.
  • N ⁇ -(9-Fluorenylmethoxycarbonyl)-L-alanine ((2 mL of a 0.5 molar solution in N-methylpyrolidine), 1,3-diisopropylcarbodiimide (2 mL of a 0.5 molar solution in N-methylpyrolidine), and 1-hydroxy-benzotriazole (2 mL of a 0.5 molar solution in N-methylpyrolidine) was added to resin 17.
  • the reaction mixture was shaken for one hour, filtered and the coupling was repeated.
  • the reaction mixture was filtered then the solid was washed with N-methylpyrolidine (3 ⁇ 6 mL), methanol (3 ⁇ 6 mL ), and again with N-methylpyrolidine (3 ⁇ 6 mL) to give compound 18.
  • N ⁇ -(9-Fluorenylmethoxycarbonyl)-L-aspartic acid ⁇ -tertbutyl ester ((2 mL of a 0.5 molar solution in N-methylpyrolidine), 1,3-diisopropylcarbodiimide (2 mL of a 0.5 molar solution in N-methylpyrolidine), and 1-hydroxy-benzotriazole (2 mL of a 0.5 molar solution in N-methylpyrolidine) was added to resin 19. The reaction mixture was shaken for one hour, filtered and the coupling was repeated. The reaction mixture was filtered then the solid was washed with N-methylpyrolidine (3 ⁇ 6 mL), methanol (3 ⁇ 6 mL), and again with N-methylpyrolidine (3 ⁇ 6 mL) to give compound 20.
  • N ⁇ -(9-Fluorenylmethoxycarbonyl)-N ⁇ -(tertbutoxycarbonyl)-L-ornithine (2 mL of a 0.5 molar solution in N-methylpyrolidine), 1,3-diisopropylcarbodiimide (2 mL of a 0.5 molar solution in N-methylpyrolidine), and 1-hydroxy-benzotriazole (2 mL of a 0.5 molar solution in N-methylpyrolidine) was added to resin 21.
  • the reaction mixture was shaken for one hour, then filtered and the coupling was repeated.
  • the reaction mixture was filtered then the solid was washed with N-methylpyrolidine (3 ⁇ 6 mL), methanol (3 ⁇ 6 mL), and again with N-methylpyrolidine (3 ⁇ 6 mL) to give compound 22.
  • Resin peptide 1 (2 g) was added to a solution of the pentafluorophenyl ester of decanoic acid 24 (440 mg, for the preparation of compound 24 see Example 6, Reaction 1) in dichloromethane. The mixture was shaken for 17 hours, filtered, and the reaction was judged to be incomplete using the Kaiser Test (vide supra). Decanoic acid (517 mg), 1-hydroxy-benzotriazole (446 mg), and 1,3-diisopropylcarbodiimide (438 ⁇ L) were dissolved in N-methylpyrolidine (8 mL) and stirred for one hour.
  • the dried resin 27 was placed under an argon atmosphere, and treated with a solution of tetrakis-(triphenylphosphine)palladium(0) (19 mg) in dichloromethane (1.47 mL), acetic acid (74 ⁇ L), and N-methylmorpholine (37 ⁇ L). The mixture was shaken for 4. hours at ambient temperature, filtered, and the solid was washed with two times with N-methylmorpholine, two times with methanol, and again two times with N-methylmorpholine.
  • the dried resin 28 was suspended in dichloromethane, (4 mL) trifluoroacetic acid, (6 mL) ethanedithiol (250 ⁇ l), and triisopropylsilane(250 ⁇ l), and the reaction mixture was stirred for 3 hours at ambient temperature. The resin was filtered and the combined filtrates were evaporated under reduced pressure. Crude product was then partitioned between diethyl ether (6 mL), and water (3 mL). The aqueous layer was freeze-dried to give crude product.
  • the crude product was purified by reverse phase HPLC (C18 10 uM Jupiter column 250 ⁇ 21.2 mm) eluting with a gradient from 20% acetonitrile 0.5% formic acid: 80% water 0.5% formic acid to 80% acetonitrile 0.5% formic acid: 20% water 0.5% formic acid over 25 minutes.
  • the product bearing fractions were combined and freeze-dried to give the pure product 29 (1.0 mg).
  • the dried resin 31 was placed under an argon atmosphere, and treated with a solution of tetrakis-(triphenylphosphine)palladium(0) (48 mg in dichloromethane (7.63 mL)), acetic acid (0.38 mL), and N-methylmorpholine (0.19 mL). The mixture was shaken for 4 hours at ambient temperature, filtered, and the solid was washed two times with N-methylmorpholine, two times with methanol, and again two times with N-methylmorpholine. The solid resin was suspended in 20% piperidine in N-methylmorpholine (7 mL) for 105 minutes, filtered and the solid was washed well with N-methylmorpholine.
  • the dried resin 32 was suspended in dichloromethane (4 mL), trifluoroacetic acid (6 mL), ethanedithiol (250 ⁇ l), and triisopropylsilane (250 ⁇ l), and stirred for 3 hours at ambient temperature.
  • the reaction mixture was filtered an washed with dichloromethane (2 ⁇ 2 mL) and the combined filtrates were evaporated under reduced pressure.
  • Crude product was then partitioned between diethyl ether (6 mL) and water (3 mL). The aqueous layer was separated and freeze dried to give the crude product 33 (21.5 mgs).
  • the crude product was then purified by reverse phase HPLC (C18 10 uM Jupiter column 250 ⁇ 21.2 mm) eluting with a gradient from 20% acetonitrile 0.5% formic acid: 80% water 0.5% formic acid to 80% acetonitrile 0.5% formic acid : 20% water 0.5% formic acid over 25 minutes.
  • the product bearing fractions were combined and freeze-dried to give the pure product 33 (1.8 mg).
  • 1,3-Diisopropylcarbodiimide (121 mg) was added to a solution of the compound 38 (200 mg), and pentafluorophenol (108 mg) in tetrahydrofuran (5 mL) and the reaction mixture was stirred for one hour. The resulting mixture was filtered, the solvent was evaporated and the residue was purified on silica gel. Using 9:1 hexane: ethyl acetate as an eluent gave the faster running impurity and 4:1 hexane : ethyl acetate as an eluent gave the product 34 (80 mg).
  • Compound 39 was prepared from commercially available 40 via the conditions described above as follows: Compound 39 was converted to the corresponding methyl ester under the conditions described in Example 6, Reaction 2. The methyl ester was acylated under the conditions described in Example 6, Reaction 3. The acylated compound was then saponified under the reaction conditions described in Example 6, Reaction 4. The saponified material was then converted to compound 39 via the conditions described in Example 6, Reaction 5.
  • Compound 44 was converted to compound 41 via the conditions described in the as follows. Compound 44 was saponified under the reaction conditions described in Example 6, Reaction 4. The saponified material was then converted to compound 41 via the conditions described in Example 6, Reaction 5.
  • Compound 45 was prepared from commercially available 46 via the conditions described above as follows: Compound 46 was converted to the corresponding methyl ester under the conditions described in Example 6, Reaction 2. The methyl ester was acylated under the conditions described in Example 8, Reaction 2. The acylated compound was then saponified under the reaction conditions described in Example 6, Reaction 4. The saponified material was then converted to compound 45 via the conditions described in Example 6, Reaction 5.
  • 1,3-Diisopropylcarbodiimide (206 mg) was added to a solution of the compound 56 (340 mg), and pentafluorophenol (227 mg) in dichloromethane (5 mL) and the reaction mixture was stirred for 15 hours. The mixture was quenched with hexane, filtered, and the solvent was evaporated. Purification of the residue on silica gel with 20:1 hexane: ethyl acetate gave the product 53 (490 mg).
  • Compound 63 is then converted to Compound 64 utilizing the conditions described in Example 12, Reaction 1 using methyl iodide in place of iododecane.
  • a preparation of deacylase enzyme was produced from recombinant Streptomyces lividans , which expresses the Actinoplanes utahensis deacylase enzyme.
  • the enzyme in aqueous ethylene glycol (10 mL) was added to a solution of compound 67 (15 g in water; 1.9 L) at pH 8.
  • the reaction mixture was stirred at room temperature for 18 hours and the pH was adjusted to 8 using 1 M sodium hydroxide.
  • the reaction mixture was poured on to Bondesil 40 ⁇ M C8 resin (400 g) that had been prewashed 10 with methanol (1 L) and water (1 L).
  • the product was eluted with 20% acetonitrile in water (1 L) and freeze-dried to give compound 68 as a yellow solid (9.1 g).
  • Phenylisothiocyanate (1 mmol) is added to a suspension of compound 72 (1.0 mmol) in dry N,N′-dimethylformamide (5 mL). The reaction is stirred at ambient temperature for 18 hours, then evaporated to dryness. The residue is titurated with diethyl ether (5 mL) to give the product 73.
  • Tetrakis-(triphenylphosphine)paladium(0) (631 mg) was added to a solution of Compound 75 (631 mg), N-methyl morpholine (631 ⁇ l) in dioxane (10 mL) and 1 N hydrochloric acid (6.31 mL). After stirring for 16 hours the reaction was filtered, and purified by reverse phase HPLC using C18 10 uM Jupiter column 250 ⁇ 21.2 mm, eluting with a gradient from acetonitrile:water:formic acid 30:70:0.1 to acetonitrie:water:forrnic acid 90:10:0.1 over 25 minutes. Evaporation of the product bearing fractions gave the product 76 (44 mg).
  • MIC minimum inhibitory concentration
  • SA42 is Wild Type Staphylococcus aureus.
  • EF14 is Wild Type Enterococcus faecium.
  • EF201 is Wild Type Enterococcus faecalis.
  • “++” indicates that the compound has an MIC ( ⁇ g/ml) or ED 50 of greater than 1 ⁇ g/ml or 1 mg/kg, respectively but less than or equal to 10 ⁇ g/ml or ED 50 of 10 mg/kg, respectively;
  • the mouse protection test is an industry standard for measuring the efficacy of a test compound in vivo [for examples of this model see J. J. Clement, et al., Antimicrobial Agents and Chemotherapy, 38 (5), 1071-1078, (1994)]. As exemplified below, this test is used to demonstrate the in vivo efficacy of the compounds of the present invention against bacteria.
  • the in vivo antibacterial activity is established by infecting female CD-1 mice (Charles River Lab, MA) weighing 19-23 g intraperitoneally with Methicillin Resistant S. aureus (MRSA) inoculum.
  • MRSA Methicillin Resistant S. aureus
  • the inoculum is prepared from Methicillin Resistant S. aureus (ATCC 43300).
  • the MRSA inoculum is cultured in Mueller-Hinton (MH) broth at 37° C. for 18 hours.
  • MH Mueller-Hinton
  • the optical density at 600 nm (OD 600 ) is determined for a 1:10 dilution of the overnight culture.
  • Bacteria (8 ⁇ 10 8 cfu) is added to 20 ml of phosphate buffered saline (Sigma P-0261) containing 5% hog gastric mucin (Sigma M-2378). All animals are injected with 0.5 ml of the inoculum, equivalent to 2 ⁇ 10 7 cfu/mouse, which is the dose causing ⁇ 100% death of the animals without treatment.
  • Group 6 animals receive test compound sc at 10 mg/kg (or the highest therapeutic dose of a given compound) only for monitoring acute toxicity. These injections are repeated once at 4 hours after the inoculation for the respective groups. The injection volume at each time is 10 ml per kilogram of body weight. The 50% protective dose (PD 50 ) is calculated on the basis of the number of mice surviving 7 days after inoculation.

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EP1423414A1 (de) 2004-06-02
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RU2348647C2 (ru) 2009-03-10
DE60232158D1 (de) 2009-06-10
KR20040022233A (ko) 2004-03-11
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US20060223983A1 (en) 2006-10-05
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EP1423414A4 (de) 2005-11-30
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CN1551887A (zh) 2004-12-01
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CA2456761A1 (en) 2003-02-20
IL160171A0 (en) 2004-07-25
EP1423137A4 (de) 2005-11-30
ATE430160T1 (de) 2009-05-15
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