US20080287347A1 - Novel Lipopeptides as Antibacterial Agents - Google Patents

Novel Lipopeptides as Antibacterial Agents Download PDF

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Publication number
US20080287347A1
US20080287347A1 US12/163,299 US16329908A US2008287347A1 US 20080287347 A1 US20080287347 A1 US 20080287347A1 US 16329908 A US16329908 A US 16329908A US 2008287347 A1 US2008287347 A1 US 2008287347A1
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nhco
alkyl
amino
heterocyclyl
heteroaryl
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US12/163,299
Inventor
Jason Hill
Ian Parr
Michael Morytko
Jim Siedlecki
Xiang Yang Yu
Jared Silverman
Dennis Keith
John Finn
Dale Christensen
Tsvetelina Lazarova
Alan D. Watson
Yan Zhang
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Cubist Pharmaceuticals LLC
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Cubist Pharmaceuticals LLC
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Priority to US12/163,299 priority Critical patent/US20080287347A1/en
Assigned to CUBIST PHARMACEUTICALS, INC. reassignment CUBIST PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LAZAROVA, TSVETELINA, WATSON, ALAN D., KEITH, DENNIS, FINN, JOHN, HILL, JASON, MORYTKO, MICHAEL, PARR, IAN, SIEDLECKI, JIM, SILVERMAN, JARED, YU, XIANG YANG, ZHANG, YAN, CHRISTENSEN, DALE
Publication of US20080287347A1 publication Critical patent/US20080287347A1/en
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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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel lipopeptide compounds.
  • the invention also relates to pharmaceutical compositions of these compounds and methods of using these compounds as antibacterial compounds.
  • the invention also relates to methods of producing these novel lipopeptide compounds and intermediates used in producing these compounds.
  • a class of compounds which have shown potential as useful antibiotics includes 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. Daptomycin, a member of this class, 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 areus
  • GISA glycopeptide intermediate susceptible Staphylococcus areus
  • CNS coagulase-negative staphylococci
  • PRSP penicillin-resistant Streptococcus pneumoniae
  • novel synthetic 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. Additionally, new antibacterial agents may exhibit differential effectiveness against different types of pathogens.
  • the present invention addresses this problem by providing novel lipopeptide compounds which have antibacterial activity against a broad spectrum of bacteria, including drug-resistant bacteria. Further, the compounds of the present invention exhibit bacteriacidal activity.
  • the present invention comprises, in one aspect, antibacterial compounds of Formula I:
  • R is:
  • X and X′′ are independently selected from C ⁇ O, C ⁇ S, C ⁇ NH, C ⁇ NR X , S ⁇ O or SO 2 ;
  • n 0 or 1
  • R X is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
  • B is X′′R Y , H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
  • R Y is selected from hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;
  • A is H, NH 2 , NHR A , NR A R B , alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl or heterocyclyl;
  • R A and R B are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
  • A is additionally selected from:
  • each of R 50 -R 53 is independently selected from C 1 -C 15 alkyl
  • R 1 is
  • X′ and X′′′ are independently selected from C ⁇ O, C ⁇ S, C ⁇ NH, C ⁇ NR X′ , S ⁇ O or SO 2 ;
  • n 0 or 1
  • R X′ is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
  • B′ is X′′′R Y′ , H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
  • R Y′ is selected from hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl.
  • A′ is H, NH 2 , NHR A′ , NR A′ R B′ , heteroaryl, cycloalkyl or heterocyclyl;
  • R A′ and R B′ are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
  • A′ is additionally selected from:
  • each of R 50 -R 53 is independently selected from C 1 -C 15 alkyl
  • A′ is aryl
  • A′ is other than a phenyl ring substituted with substitutent NHC(O)R D , wherein R D is defined as above, which may be further optionally substituted on the phenyl ring with 1-2 substituents independently selected from amino, nitro, C 1 -C 3 alkyl, hydroxyl, C 1 -C 3 alkoxy, halo, mercapto, C 1 -C 3 alkylthio, carbamyl or C 1 -C 3 alkyl carbamyl.
  • A′ is alkyl, alkenyl, alkynyl, alkoxy or aryloxy
  • R 54 is selected from C 1 -C 17 -unsubstituted alkyl or C 2 -C 17 -unsubstituted alkenyl; wherein R 55 is selected from hydroxyethyl, hydroxymethyl, mercaptomethyl, mercaptoethyl, methylthioethyl, 2-thienyl, 3-indolemethyl, phenyl optionally substituted with a group selected from halo, nitro, C 1 -C 3 -unsubstituted alkyl, hydroxy, C 1 -C 3 -unsubstituted alkoxy, C 1 -C 3 -unsubstituted alkylthio, carbamyl or C 1 -C 3 unsubstituted alkylcarbamyl; or benzyl optionally substituted with a group selected from halo, nitro, C 1 -C 3 -unsubstituted alkyl, hydroxy, C 1 -C 3 -un
  • A′ is other than C 4 -C 14 unsubstituted alkyl.
  • B′ and A′ together form a 5-7 membered heterocyclic or heteroaryl ring.
  • R 2 is
  • K and K′ together form a C 3 -C 7 cycloalkyl or heterocyclyl ring or a C 5 -C 10 aryl or heteroaryl ring;
  • J is selected from the group consisting of hydrido, amino, NHR J , NR J R K , alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylamino, hydroxyl, thio, alkylthio, alkenylthio, sulfinyl, sulfonyl, azido, cyano, halo,
  • each of R 24 , R 25 , and R 26 is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or R 24 and R 25 together form a 5-8 membered heterocyclyl ring;
  • R J and R K are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; or
  • each of R 17 and R 18 is independently selected from the group consisting of hydrido, halo, hydroxyl, alkoxy, amino, thio, sulfinyl, sulfonyl and
  • R 17 and R 18 taken together can form a group consisting of ketal, thioketal,
  • each of R 22 and R 23 is independently selected from the group consisting of hydrido and alkyl.
  • the invention also provides pharmaceutical compositions comprising compounds of Formula I and methods of use thereof.
  • the invention provides methods of making compounds of Formula I and pharmaceutical compositions thereof.
  • the invention provides compounds useful as intermediates for the preparation of compounds of Formula I.
  • the invention provides methods of use of the compounds of Formula I to treat bacterial infections in humans.
  • hydro denotes a single hydrogen atom (H).
  • acyl is defined as 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.
  • amino denotes a nitrogen radical containing two substituents independently selected from the group consisting of hydrido, alkyl, cycloalkyl, carboalkoxy, heterocyclyl, aryl, heteroaryl and sulfonyl.
  • Subsets of the term amino are (1) the term “unsubstituted amino” which denotes an NH 2 radical, (2) the term “mono substituted amino” which is defined as a nitrogen radical containing a hydrido group and a substituent group selected from alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and (3) the term “disubstituted amino” which is defined as a nitrogen radical containing two substituent groups independently selected from, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • Preferred mono substituted amino radicals are “lower mono substituted amino” radicals, whereby the substituent group is a lower alkyl group.
  • Preferred disubstituted amino radicals are “lower disubstituted amino” radicals, whereby the substituent groups are lower alkyl.
  • acyloxy denotes an oxygen radical adjacent to an acyl group.
  • acylamino denotes a nitrogen radical adjacent to an acyl group.
  • carboalkoxy is defined as a carbonyl radical adjacent to an alkoxy or aryloxy group.
  • carboxyamido denotes a carbonyl radical adjacent to an amino group.
  • halo is defined as a bromo, chloro, fluoro or iodo radical.
  • thio denotes 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.
  • alkyl is defined as a linear or branched, saturated radical having one to about twenty carbon atoms unless otherwise specified. Preferred alkyl radicals are “lower alkyl” radicals having one to about five carbon atoms.
  • One or more hydrogen atoms can also be replaced by a substitutent group selected from acyl, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, oxo, guanidino, formyl and an amino acid side chain.
  • alkyl groups include, without limitation, methyl, tert-butyl, isopropyl, and methoxymethyl.
  • Subsets of the term alkyl are (1) “unsubstituted alkyl” which is defined as an alkyl group that bears no substituent groups (2) “substituted alkyl” which denotes an alkyl radical in which (a) one or more hydrogen atoms is replaced by a substitutent group selected from acyl, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, N-sulfonylcarboxyamido, N-acylaminosulfonyl or (b) two or more hydrogen atoms are each replaced by a substitu
  • 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, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, formyl, oxo and guanidino.
  • 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 ethyl
  • 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, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, formyl, oxo and guanidino.
  • An example of alkynyl group includes, without limitation, propynyl.
  • aryl or “aryl ring” denotes aromatic radicals in a single or fused carbocyclic ring system, having from five to fourteen ring members. In a preferred embodiment, 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, amino, acylamino, acyloxy, azido, alkylthio, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl and formyl.
  • aryl groups include, without limitation, phenyl, naphthyl, biphenyl, terphenyl. Subsets of the term aryl are (1) the term “phen
  • substituted phenyl which is defined as a phenyl radical in which one or more protons are replaced by a substituent group selected from acyl, amino, acyloxy, azido, alkylthio, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, N-sulfonylcarboxyamido, and N-acylaminosulfonyl and (3) the term “acylamino phenyl” denotes a phenyl radical in which one hydrogen atom is replaced by an acylamino group.
  • One or more additional hydrogen atoms can also be replaced by a substituent group selected from acyl, amino, acylamino, acyloxy, azido, alkylthio, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, N-sulfonylcarboxyamido, and N-acylaminosulfonyl.
  • a substituent group selected from acyl, amino, acylamino, acyloxy, azido, alkylthio, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl,
  • Heteroaryl or “heteroaryl ring” denotes an aromatic radical which contain one to four hetero atoms or hetero groups selected from O, N, S.
  • 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, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, thiocarbonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, and formyl.
  • heteroaryl groups include, without limitation, pyridinyl, thiazolyl, thiadiazoyl, isoquinolinyl, pyrazolyl, oxazolyl, oxadiazoyl, triazolyl, and pyrrolyl groups.
  • heteroaryl is (1) the term “pyridinyl” which denotes compounds of the formula:
  • substituted pyridinyl which is defined as a pyridinyl radical in which one or more protons is replaced by a substituent group selected from acyl, amino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, N-sulfonylcarboxyamido, and N-acylaminosulfonyl and (3) the term “acylamino pyridinyl” which denotes a pyridinyl radical in which one hydrogen atom is replaced by an acylamino group, additionally, one or more additional hydrogen atoms can also be replaced by a substituent group selected from acyl, amino, acyla
  • cycloalkyl or “cycloalkyl ring” is defined as 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, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl and formyl.
  • a cycloalkyl group include, without limitation, cyclopropyl, cyclobutyl, cyclohexyl, and cycloheptyl.
  • heterocyclyl is defined as a saturated or partially unsaturated ring containing one to four hetero atoms or hetero groups selected from O, N, NH,
  • R Z is as defined for R X ,
  • 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, amino, acylamino, acyloxy, oxo, thiocarbonyl, imino, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl and formyl.
  • Examples of a heterocyclyl group include, without limitation, morpholinyl, piperidinyl, and pyrrolidinyl.
  • alkoxy denotes oxy-containing radicals substituted with an alkyl, cycloalkyl or heterocyclyl group. Examples include, without limitation, methoxy, tert-butoxy, benzyloxy and cyclohexyloxy.
  • aryloxy denotes oxy-containing radicals substituted with an aryl or heteroaryl group. Examples include, without limitation, phenoxy.
  • amino acid side chain denotes any side chain (R group) from a naturally-occurring or a non-naturally occurring amino acid.
  • sulfinyl is defined as 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.
  • sulfonyl is defined as a hexavalent sulfur radical substituted with two oxo substituents and a third substituent selected from alkyl, cycloalkyl, heterocyclyl aryl, or heteroaryl.
  • carbamate amino protecting group is defined as a recognized amino protecting group that when bound to an amino group forms a carbamate.
  • Examples of carbamate amino protecting groups can be found in “Protective Groups in Organic Synthesis” by Theodora W. Greene, John Wiley and Sons, New York, 1981.
  • Examples of carbamate amino protecting groups include benzyloxycarbonyl, t-butoxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl, adamantyloxycarbonyl, chlorobenzyloxycarbonyl, nitrobenzyloxycarbonyl or the like.
  • 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 (preferably a compound of Formula I) by treating, for example, the compound of the invention (preferably a compound of Formula I) 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 preferably compounds of Formula I
  • 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 these 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 available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention (preferably compounds of Formula I) 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 (preferably compounds of Formula I) 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.
  • R is:
  • X and X′′ are independently selected from C ⁇ O, C ⁇ S, C ⁇ NH, C ⁇ NR X , S ⁇ O or SO 2 ;
  • n 0 or 1
  • R X is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
  • B is X′′R Y , H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
  • R Y is selected from hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;
  • A is H, NH 2 , NHR A , NR A R B , alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl or heterocyclyl;
  • R A and R B are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
  • A is additionally selected from:
  • each of R 50 -R 53 is independently selected from C 1 -C 15 alkyl
  • R 1 is
  • X′ and X′′′ are independently selected from C ⁇ O, C ⁇ S, C ⁇ NH, C ⁇ NR X′ , S ⁇ O or SO 2 ;
  • n 0 or 1
  • Rx is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
  • B′ is X′′′R Y′ , H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
  • R Y′ is selected from hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl.
  • A′ is H, NH 2 , NHR A′ , NR A′ R B′ , heteroaryl, cycloalkyl or heterocyclyl;
  • R A′ and R B′ are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
  • A′ is additionally selected from:
  • each of R 50 -R 53 is independently selected from C 1 -C 15 alkyl
  • A′ is aryl
  • A′ is other than a phenyl ring substituted with substitutent NHC(O)R D , wherein R D is defined as above, which may be further optionally substituted on the phenyl ring with 1-2 substituents independently selected from amino, nitro, C 1 -C 3 alkyl, hydroxyl, C 1 -C 3 alkoxy, halo, mercapto, C 1 -C 3 alkylthio, carbamyl or C 1 -C 3 alkyl carbamyl.
  • A′ is alkyl, alkenyl, alkynyl, alkoxy or aryloxy
  • R 54 is selected from C 1 -C 17 -unsubstituted alkyl or C 2 -C 17 -unsubstituted alkenyl; wherein R 55 is selected from hydroxyethyl, hydroxymethyl, mercaptomethyl, mercaptoethyl, methylthioethyl, 2-thienyl, 3-indolemethyl, phenyl optionally substituted with a group selected from halo, nitro, C 1 -C 3 -unsubstituted alkyl, hydroxy, C 1 -C 3 -unsubstituted alkoxy, C 1 -C 3 -unsubstituted alkylthio, carbamyl or C 1 -C 3 unsubstituted alkylcarbamyl; or benzyl optionally substituted with a group selected from halo, nitro, C 1 -C 3 -unsubstituted alkyl, hydroxy, C 1 -C 3 -un
  • A′ is other than C 4 -C 14 unsubstituted alkyl.
  • B′ and A′ together form a 5-7 membered heterocyclic or heteroaryl ring.
  • R 2 is
  • K and K′ together form a C 3 -C 7 cycloalkyl or heterocyclyl ring or a C 5 -C 10 aryl or heteroaryl ring;
  • J is selected from the group consisting of hydrido, amino, NHR J , NR J R K , alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylamino, hydroxyl, thio, alkylthio, alkenylthio, sulfinyl, sulfonyl, azido, cyano, halo,
  • each of R 24 , R 25 , and R 26 is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or R 24 and R 25 together form a 5-8 membered heterocyclyl ring;
  • R J and R K are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; or
  • each of R 17 and R 18 is independently selected from the group consisting of hydrido, halo, hydroxyl, alkoxy, amino, thio, sulfinyl, sulfonyl and
  • R 17 and R 18 taken together can form a group consisting of ketal, thioketal,
  • each of R 22 and R 23 is independently selected from the group consisting of hydrido and alkyl.
  • R is selected from
  • each of R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of hydrido, alkyl, aryl, heterocyclyl and heteroaryl, and wherein R 44 is selected from the group consisting of alkyl, aryl, heterocyclyl and heteroaryl.
  • R 4 ′ is selected from the group consisting of alkyl, aryl-substituted alkyl, substituted phenyl, heteroaryl, heterocyclyl, optionally substituted (C 8 -C 14 )-straight chain alkyl and
  • R 7 is an alkyl group.
  • R is
  • X 3 is chloro or trifluoromethyl and wherein q is 0 or 1.
  • R 1 is selected from the group consisting of:
  • R 8 is selected from an amino acid side chain, wherein said amino acid side chain may be one that is naturally occurring or one that is not naturally occurring, wherein each of R 9 , R 10 and R 11 is selected from hydrido, alkyl, aryl, heterocyclyl and heteroaryl; wherein R 12 is selected from the group consisting of heterocyclyl, heteroaryl, aryl, and alkyl and wherein R 13 is selected from (C 1 -C 3 )-alkyl and aryl.
  • R 1 is selected from the group consisting of
  • R 8 is selected from tryptophan side chain and lysine side chain; wherein each of R 10 and R 11 is independently selected from hydrido and alkyl; wherein R 12 is selected from imidazolyl, N-methylimidazolyl, indolyl, quinolinyl, benzyloxybenzyl, and benzylpiperidenylbenzyl; and wherein X 4 is selected from fluoro and trifluoromethyl.
  • J is selected from the group consisting of hydrido, amino, azido and
  • R 17 and R 18 taken together form a group selected from the group consisting of ketal,
  • R 17 is hydroxyl when R 18 is hydrido.
  • J, together with R 17 forms a heterocyclyl ring.
  • R 2 is selected from
  • R 22 is selected from the group consisting of H and alkyl; wherein R 19 is selected from the group consisting of hydrido, amino, azido and
  • R 2 is
  • R is selected from NHCO—[(C 6 -C 14 )-alkyl]CH 3
  • R 1 and R 2 are selected from Table A below. More preferably, R is selected from NHCO—[(CH 2 ) 6-14 ]—CH 3 .
  • Preferred compounds of the present invention are compounds 45, 54, 76, 81, 85, 102, 209, 212, 253, 260, 262, 282, 285, 319, 322, 333, 334, 335, 336, 344 and 355.
  • the present invention provides one or more crystalline forms of compounds of formula (I) and salts thereof
  • the present invention also provides compounds that are particularly useful as intermediates for the preparation of the compounds of Formula I. These compounds may also have antibacterial properties, as discussed above.
  • compounds of Formula II are provided:
  • R 14 is selected from the group consisting of
  • R 56 is an optionally substituted straight-chain C 8 -C 14 alkyl group and wherein q′ is 0-3.
  • compounds of Formula III are provided as useful intermediates for the preparation of compounds of Formula I and/or as antibacterial compounds:
  • R 15 is selected from hydrido and a carbamate amino protecting group, preferably a tert-butoxycarbonyl group; wherein R 16 is selected from the group consisting of
  • R 57 is a halo or halo substituted alkyl group, preferably a fluoro or trifluoromethyl group; wherein, R 20 is an amino acid side chain, preferably a lysine or tryptophan side chain.
  • Another object of the instant invention is to provide lipopeptide compounds or salts thereof, as well as pharmaceutical compositions or formulations comprising lipopeptide compounds or its salts.
  • Lipopeptide compounds, or pharmaceutically acceptable salts thereof can be formulated for oral, intravenous, intramuscular, subcutaneous or parenteral administration for the therapeutic or prophylactic treatment of diseases, particularly bacterial infections.
  • lipopeptide compounds of this 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 invention are prepared in accordance with standard procedures and are administered at dosages that are selected to reduce, prevent or eliminate the infection (See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. and Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Pergamon Press, New York, N.Y., the contents of which are incorporated herein by reference, for a general description of the methods for administering various antimicrobial agents for human therapy).
  • the compositions of the invention (preferably of Formula I) can be delivered using controlled (e.g., capsules) or sustained release delivery systems (e.g., bioerodable matrices).
  • compositions of the invention preferably of Formula I
  • exemplary delayed release delivery systems for drug delivery that are suitable for administration of the compositions of the invention (preferably of Formula I) are described in U.S. Pat. Nos. 4,452,775 (issued to Kent), 5,239,660 (issued to Leonard), 3,854,480 (issued to Zaffaroni).
  • 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.
  • a lipopeptide compound according to the 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 lipopeptide compound or a suitable soluble salt form of the compound, for example the hydrochloride salt can be dissolved and administered in a pharmaceutical diluent
  • 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 lipopeptide compound 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 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 include chemical compounds such as dimethylsulfoxide (DMSO) to facilitate surface penetration of the active ingredient.
  • DMSO dimethylsulfoxide
  • the compounds of the present invention 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 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 invention, preferably a compound of Formula I, under conditions which permit entry of the compound into said organism and into said microorganism.
  • a compound of the invention preferably a compound of Formula I
  • 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 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 lipopeptide compound according to Formula I.
  • a lipopeptide compound according to Formula I Exemplary procedures for delivering an antibacterial agent are described in U.S. Pat. No. 5,041,567, issued to Rogers and in PCT patent application number EP94/02552 (publication no. WO 95/05384), the entire contents of which documents are incorporated in their entirety herein by reference.
  • 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 (preferably a compound of Formula I) 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 lipopeptide compound treatment.
  • the method comprises administering to the subject an effective dose of a compound of this invention.
  • An effective dose is generally between about 0.1 and about 100 mg/kg of a lipopeptide compound of Formula I or a pharmaceutically acceptable salt thereof.
  • a preferred dose is from about 0.1 to about 50 mg/kg of a lipopeptide compound of Formula I or a pharmaceutically acceptable salt thereof.
  • a more preferred dose is from about 1 to 25 mg/kg of a lipopeptide compound of Formula I 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.
  • the compound of Formula I 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 lipopeptide 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.
  • a lipopeptide compound according to this 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 methods of the present invention comprise administering a lipopeptide 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.
  • Lipopeptide compounds of Formula I or a pharmaceutical composition thereof also may be directly injected or administered into an abscess, ventricle or joint.
  • Parenteral administration includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, cisternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion.
  • lipopeptide compounds 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 lipopeptide compound 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.
  • glycopeptide intermediary-susceptible S. areus GISA
  • 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. faecium ), Clostridium difficile, C.
  • the antibacterial activity of lipopeptide 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 lipopeptide compounds according to this invention against susceptible strains is typically the same or lower than that of vancomycin.
  • a lipopeptide 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.
  • lipopeptide compounds exhibits rapid, concentration-dependent bactericidal activity against gram-positive organisms.
  • a lipopeptide 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 lipopeptide compounds according to this invention or pharmaceutical compositions thereof.
  • the method of the instant 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 lipopeptide compounds according to this invention.
  • the method may be practiced by administering a lipopeptide compound according to this invention with another lipopeptide compound, such as daptomycin.
  • Antibacterial agents and classes thereof that may be co-administered with a compound of the present 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, pyrazinamide
  • antibacterial agents that may be co-administered with a compound according to this invention include, without limitation, imipenen, amikacin, netilmicin, fosfomycin, gentamicin, ceftriaxone, teicoplanin, Ziracin, LY 333328, CL 331002, HMR 3647, Linezolid, Synercid, Aztreonam, and Metronidazole.
  • Antifungal agents that may be co-administered with a compound according to this 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. disclose antifungal compounds including Corynecandin, Mer-WF3010, Fusacandins, Artrichitin/LL 15G256, Sordarins, Cispentacin, Azoxybacillin, Aureobasidin and Khafrefungin.
  • Lipopeptide compounds may be administered according to this method until the bacterial infection is eradicated or reduced.
  • a lipopeptide compound is administered for a period of time from 3 days to 6 months.
  • a lipopeptide compound is administered for 7 to 56 days.
  • a lipopeptide compound is administered for 7 to 28 days.
  • a lipopeptide compound is administered for 7 to 14 days. Lipopeptide compounds may be administered for a longer or shorter time period if it is so desired.
  • Lipopeptide compounds of Formula I may be produced as described below.
  • the lipopeptide compounds of the instant invention may be produced semi-synthetically using daptomycin as a starting point or may be produced by a total synthesis approach.
  • daptomycin may be prepared by any method known in the art. See, e.g., U.S. Pat. Nos. 4,885,243 and 4,874,843. Daptomycin may be used in its acylated state or it may be deacylated prior to its use as described herein. Daptomycin may be deacylated using Actinoplanes utahensis as described in U.S. Pat. No. 4,482,487. Alternatively, daptomycin may be deacylated as follows:
  • Daptomycin (5.0 g) was dissolved in water (25 ml) and adjusted to pH 9 with 5M sodium hydroxide.
  • Ditert-butyldicarbonate (1.5 g) was added and the mixture was adjusted to maintain pH 9 with 5 M sodium hydroxide until the reaction was complete (4 hours).
  • the pH was adjusted to 7 and the mixture was loaded onto a Bondesil 40 ⁇ C8 resin column. The column was washed with water and the product was eluted from the column with methanol. Evaporation of the methanol gave BOC-protected daptomycin as a yellow powder.
  • a preparation of deacylase enzyme was produced from recombinant Streptomyces lividans , which expresses the Actinoplanes utahensis deacylase enzyme.
  • the enzyme in ethylene glycol (400 ⁇ l) was added to BOC-protected daptomycin (1 g) in water (100 ml) at pH 7-8. After incubation for 72 hours, the mixture was loaded on a Bondesil 40 ⁇ C8 resin column. The column was washed with water and the product was eluted from the column with 10% acetonitrile in water. The product was evaporated to give deacylated BOC-protected daptomycin as a yellow powder.
  • Daptomycin can be converted into analogs bearing modifications at the R 2 position by converting the aromatic amino group to the diazonium salt compound I with reagents such as sodium nitrite/hydrochloric acid or isoamylnitrite. Using chemistry known to those skilled in the art and following the teachings of the disclosure, the diazonium group can then be displaced by reagents such as sodium azide, potassium ethylxanthate or copper chloride to yield derivative compounds II, wherein R 19 is as previously defined.
  • reagents such as sodium azide, potassium ethylxanthate or copper chloride
  • compound I can be converted to the azide compound III by reaction with an azide source, typically sodium azide. Modifications to the ketone group can then be undertaken using chemistry known to those having ordinary skill in the art, such as reduction, oxime formation, ketalization conversion to a leaving group and displacement to give compounds of formula IV, wherein R 17 and R 18 are as previously defined.
  • an azide source typically sodium azide.
  • Compound IV may also be converted to compound V by reducing the azide group to the amine using chemistry known to those having ordinary skill in the art, and following the teachings of the disclosure, such as reaction with triphenyl phosphine and water, or reducing agents such as sodium borohydride wherein R 17 and R 18 are as previously defined.
  • compound I can be converted into compound VI by reduction with hypophosphorus acid. Modifications to the ketone group can then be undertaken using chemistry known to those having ordinary skill in the art similar to those used in scheme 2, wherein R 17 and R 18 are as previously defined.
  • Daptomycin can be converted into analogs bearing modifications at the R 1 position by treating the aromatic amino group of the ornithine with reagents such as isocyanates, isothiocyanates, activated esters, acid chlorides, sulfonylchlorides or activated sulfonamides, heterocycles bearing readily displaceable groups, imidates, lactones or reductively with aldehydes to yield compound VIII, wherein R 1 is as previously defined.
  • reagents such as isocyanates, isothiocyanates, activated esters, acid chlorides, sulfonylchlorides or activated sulfonamides, heterocycles bearing readily displaceable groups, imidates, lactones or reductively with aldehydes to yield compound VIII, wherein R 1 is as previously defined.
  • Daptomycin can be converted into compound IX by first protecting the ornithine amine with an appropriate amino protecting group (P) known to those skilled in the art and following the teachings of the disclosure.
  • P amino protecting group
  • the decyl side chain on the tryptophan is then removed using an enzyme capable of deacylating daptomycin, such as that described above.
  • Compound IX can be modified at the tryptophan amine with reagents such as isocyanates, isothiocyanates, activated esters, acid chlorides, sulfonylchlorides or activated sulfonamides, heterocycles bearing readily displaceable groups, imidates, lactones or reductively with aldehydes to yield compound X.
  • reagents such as isocyanates, isothiocyanates, activated esters, acid chlorides, sulfonylchlorides or activated sulfonamides, heterocycles bearing readily displaceable groups, imidates, lactones or reductively with aldehydes to yield compound X.
  • Compound X can be deprotected to give compound XI according to procedures known to those skilled in the art following the disclosure of this invention, wherein R is as previously defined.
  • the lipopeptide compounds of Formula I may be synthesized on a solid support as outlined below.
  • a suitably-N-protected- ⁇ MeGlu(OH)—OAllyl ester is coupled to a suitable resin to give Compound XII.
  • Deprotection of the amino group of Compound XII, followed by coupling of the amino group with a suitably protected seryl derivative (A1) gives Compound XIII, wherein P is a suitable protecting group.
  • This peptide coupling process i.e., deprotection of the alpha-amino group, followed by coupling to a suitably protected amino acid, is repeated until the desired number of amino acids have been coupled to the resin.
  • step 4 Compound XV is cyclized to give Compound XVI. Subsequently, in step 5, Compound XVI is removed from the resin to give the lipopeptide Compound XVII.
  • a 1 is a suitably protected serine derivative, wherein R 31 is a suitable, cleavable hydroxyl protecting group as outlined below.
  • a 2 and A 7 are suitably protected glycine derivatives as outlined below.
  • a 3 , A 5 and A 9 are suitably protected aspartic acid derivatives as outlined below, wherein 28 R, 29 R and 30 R are cleavable protecting groups, preferably t-butyl groups.
  • a 4 is a suitably protected alanine derivative as outlined below.
  • a 6 is a suitably protected ornithine derivative as outlined below, or derivatized ornthine wherein *R 1 is R 1 as previously described or alternatively a protected form of R 1 that would yield R 1 upon subsequent deprotection.
  • a 8 is a suitably protected depsipeptide as outlined below
  • Y is a protecting group that is cleavable under conditions that leave other protecting groups intact to the others used, i.e., Alloc; and wherein *R 2 is R 2 as previously described or alternatively a protected form of R 2 that would yield R 2 upon subsequent deprotection.
  • R 2 *R is a kynurenine, or substituted kynurenine side chain, most preferably
  • a 10 is a suitably protected asparagine derivative as outlined below.
  • a 11 is a suitably protected tryptophan derivative as outlined below, wherein R* 37 is hydrido or a suitable protecting group, preferably t-butoxy carbonyl.
  • Suitable protecting groups can be any group known in the art to be 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. Following the disclosure of the present application, the selection of protecting groups and method of use thereof will be known to one skilled in the art.
  • Step 1 Coupling Suitably-N-Protected- ⁇ MeGlu(OH)—OAllyl Ester to a Resin
  • Step 2 (A) General Coupling Cycle for Amino Acids with an N-9-Fluorenylmethoxycarbonyl (Fmoc) Protecting Group
  • the Fmoc group of the newly coupled amino acid A 1-11 is deprotected by stirring the resin product in one working volume of a solution of 20% piperidine in N-methylpyrrolidine for five minutes, filtering the resin, and stirring the resin in 20% piperidine in N-methylpyrrolidine again for 20 minutes.
  • the resin is washed twice with DMF, twice with methanol, and twice again with DMF.
  • the dried resin XV is placed under an argon atmosphere, and treated with a solution of Pd(PPh 3 ) 4 125 mgs/0.1 mmol peptide substrate, in CH 2 Cl 2 :Acetic acid:N-Methylmorpholine, 40:2:1, 1 ml/0.1 mmol peptide substrate.
  • the mixture is stirred for 3 hours at ambient temperature, filtered, and washed twice with DMF, twice with methanol, and twice again with DMF.
  • Five molar equivalents each, with respect to the resin, of DIC, and HOAt are added to the resin, along with sufficient DMF to give a working volume.
  • the reaction is shaken for 17 hours, filtered, and washed twice with DMF, twice with methanol, and twice again with DMF to give resin XVI.
  • the desired lipopeptide is cleaved from resin XVI and isolated, resulting in a compound in which R 27 is OH or NH 2 .
  • Fmoc chemistry is used, the dried resin is suspended in 1 ml/0.1 mmol peptide substrate of CH 2 Cl 2 :TFA:Ethanedithiol (EDT):Triisopropylsilane (TIS), 16:22:1:1, and stirred for 6-8 hours at ambient temperature.
  • the resin is filtered, washed with 1 equal volume of cold TFA, and the combined filtrates are evaporated under reduced pressure.
  • Crude product XVII is then precipitated by the addition of diethyl ether, and isolated by centrifugation. This product may be further purified by preparative reverse phase HPLC.
  • the dried resin is suspended in hydrogen fluoride (HF):anisole:dimethylsulfide (DMS), 10:1:1, and stirred for 2 hours at 0° C.
  • HF hydrogen fluoride
  • DMS dimethylsulfide
  • the volitiles are evaporated under a stream of nitrogen.
  • the resin is then extracted with TFA, filtered and washed twice with TFA, and the combined TFA filtrates evaporated under reduced pressure. Crude product is then precipitated by the addition of diethyl ether, and isolated by centrifugation. This product may be further purified by preparative reverse phase HPLC.
  • the resin is a Safety Catch resin, then R 27 ⁇ OR or NRH.
  • the dried resin XVI is suspended in N-methylpyrrolidine (NMP) or dimethylsulphoxide (DMSO) (8 ml/g resin), Five equivalents of DIPEA (with respect to resin substitution) and 24 equivalents of iodo or bromoacetonitrile (with respect to resin substitution) are added. The suspension is stirred for 24 hours at ambient temperature under inert atmosphere. The resin is filtered, washed with tetrahydrofuran (THF) and DMSO. For an ester, the resin is then treated with an alcohol, hydroxide or alkoxide (20 equivalents with respect to resin substitution) in THF for 20 hours.
  • NMP N-methylpyrrolidine
  • DMSO dimethylsulphoxide
  • THF tetrahydrofuran
  • DMSO tetrahydrofuran
  • the resin is filtered, washed with THF and water, and the combined filtrates are evaporated under reduced pressure. Crude product is precipitated by the addition of diethyl ether, and isolated by centrifugation. The product may be further purified by preparative reverse phase HPLC.
  • the resin is then treated with a primary or secondary amine (20 equivalents with respect to resin substitution) in THF for 12-40 hours, at a gentle reflux under inert atmosphere.
  • the resin is filtered, washed with THF and water, and the combined filtrates are evaporated under reduced pressure. Crude product is then precipitated by the addition of diethyl ether, and isolated by centrifugation. This product may be further purified by preparative reverse phase HPLC.
  • a suspension of daptomycin in dry dimethylformamide (0.6 ml) was treated with a solution of 4-Fluorobenzaldehyde (0.2 ml) and a suspension of sodium triacetoxyborohydride (0.2 ml, 1.5M in dry dimethylformamide). After 24 hours, the reaction mixture was diluted with water/acetonitrile (1:1; 0.4 ml) and purified by preparative HPLC. The reaction mixture was loaded onto an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column and eluted at 20 ml/min with 30-60% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing product were collected and freeze-dried.
  • compounds 40, 50, 52, 77-80, 82-84, 87-100, 103-169, 171-176, 183-187, 194-199, 201-204, 208, 210-211, 222-244, 252, 265-267, 271-281, 283-284, 286-291, 323-331, 358-395 and 398-410 can be prepared as detailed in the above example by appropriate substitutions of reagents obvious to those skilled in the art following the teachings of the disclosure.
  • 2-Methyl-6-nitroquinoline (0.4 ml, 0.5M solution in dioxane) was treated with selenium dioxide (0.2 ml, 0.9M solution in 9/1 dioxane/water) and heated to 90° C. overnight. The mixture was cooled to room temperature and diluted with water (1 ml). The mixture was then extracted with ethyl acetate (3 ⁇ 2 ml). The organic extract was then dried in vacuo to give 6-nitro-2-quinolinecarboxaldehyde which was carried forward without further purification.
  • Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with 6-nitro-2-quinolinecarboxaldehyde prepared above in dry dimethylformamide (0.2 ml) and sodium triacetoxyborohydride (0.4 ml, 1.5M solution in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h, the mixture was treated with water (0.2 ml) and loaded onto an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column.
  • the column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min.
  • the desired fractions were collected and the acetonitrile was removed by evaporation.
  • the residue was applied to a Bondesil 40 ⁇ C8 resin column, washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 282 as a pale yellow solid.
  • Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with 4-chloro-2-quinolinecarboxaldehyde prepared above and diluted in dry dimethylformamide (0.2 ml) and sodium triacetoxyborohydride (0.4 ml, 1.5M in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h the mixture was treated with water (0.2 ml) and loaded on an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column.
  • the column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min.
  • the desired fractions were collected and the acetonitrile was removed by evaporation.
  • the residue was applied to a Bondesil 40 ⁇ C8 resin column, washed with water and the product eluted off with methanol. Evaporation of the methanol gave compound 285 as a yellow solid.
  • Daptomycin (1 ml, 0.1M in dry dimethylformamide) was treated successively with 1-methyl-2-imidazolecarboxaldehyde (0.2 ml, 0.5M solution in dry dimethylformamide) and sodium triacetoxyborohydride (0.4 ml, 1.5M solution in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h the mixture was treated with water (0.2 ml) and loaded onto an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column. The column was eluted at 30 ml/min under the gradient conditions of 35-40% acetonitrile in 5 mM ammonium phosphate buffer over 30 min.
  • the desired fractions were collected and the acetonitrile was removed by evaporation.
  • the residue was applied to a Bondesil 40 ⁇ C8 resin column, washed with water and eluted with methanol. This mixture was then loaded on a Prodigy ODS 10 ⁇ 250 ⁇ 21.2 mm column eluted at 50 ml/min at 33% acetonitrile in 5 mM ammonium phosphate buffer adjusted to pH 3.2.
  • the desired fractions were collected and the acetonitrile was removed by evaporation.
  • the residue was applied to a Bondesil 40 ⁇ C8 resin column, washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 85 as a pale yellow solid.
  • Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with 2-imidazolecarboxaldehyde (0.2 ml, 0.5M solution in dry dimethylformamide) and sodium triacetoxyborohydride (0.4 ml, 1.5M solution in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h, the mixture was treated with water (0.2 ml) and the mixture was loaded on an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column. The column was eluted at 30 ml/min under the gradient conditions of 35-40% acetonitrile in 5 mM ammonium phosphate buffer over 30 min.
  • the desired fractions were collected and the acetonitrile was removed by evaporation.
  • the residue was applied to a Bondesil 40 ⁇ C8 resin column, washed with water and eluted with methanol. This mixture was then loaded on a Prodigy ODS 10 ⁇ 250 ⁇ 21.2 mm column and eluted at 50 ml/min at 33% acetonitrile in 5 mM ammonium phosphate buffer adjusted to pH 3.2.
  • the desired fractions were collected and the acetonitrile was removed by evaporation.
  • the residue was applied to a Bondesil 40 ⁇ C8 resin column, washed with water and the product eluted with methanol. Evaporation of the methanol gave compound 212 as a yellow solid.
  • Daptomycin (1 ml, 0.1M in dry dimethylformamide) was treated successively with 5-fluoroindole-3-carboxaldehyde (0.2 ml, 0.5M solution in dry dimethylformamide) and sodium triacetoxyborohydride (0.4 ml, 1.5M solution in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h the mixture was treated with water (0.2 ml) and loaded on an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column.
  • the column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min.
  • the desired fractions were collected, the acetonitrile was removed by evaporation and the residue applied to a Bondesil 40 ⁇ C8 resin column.
  • the column was washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 81 as a pale yellow solid.
  • p-N,N-Bis(2-chloroethyl)aminobenzaldehyde 0.3 g was dissolved in acetone (2.5 ml) and treated with sodium iodide (0.4 g). The mixture was warmed to 40° C. for 3 h then treated with benzylamine (0.2 ml) and triethylamine (0.4 ml). The mixture was diluted to 7 ml with acetonitrile and then heated to 60° C. After 24 h, the mixture was cooled to room temperature and the solvent was removed by evaporation. 4-(4-Benzylpiperazino)benzaldehyde was purified by silica gel chromatography eluting with (10% triethylamine/methanol/dichloromethane).
  • Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with the 4-(4-benzylpiperazino)benzaldehyde prepared above diluted in dry dimethylformamide (0.2 ml), and sodium triacetoxyborohydride (0.4 ml, 1.5M solution in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h the mixture was treated with water (0.2 ml) and loaded on an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column.
  • the column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min.
  • the desired fractions were collected, the acetonitrile was removed by evaporation and the residue was applied to a Bondesil 40 ⁇ C8 resin column.
  • the column was washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 253 as a pale yellow solid.
  • Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with 4-phenylbenzaldehyde (0.2 ml, 0.5M in dry dimethylformamide) and sodium triacetoxyborohydride (0.4 ml, 1.5M in dry dimethylformamide).
  • the reaction mixture was capped and shaken briefly to mix the solution. After 24 h the mixture was treated with water (0.2 ml) and loaded on an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column.
  • the column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min.
  • the desired fractions were collected, the acetonitrile was removed by evaporation and the residue was applied to a Bondesil 40 ⁇ C8 resin column.
  • the column was washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 76 as a pale yellow solid.
  • Compound 177 was obtained by deacylation of compound 76 according to Example 7.
  • Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with, 4-(4-fluorobenzyloxy)-3-nitro-benzaldehyde previously prepared above diluted in dry dimethylformamide (0.2 ml), and sodium triacetoxyborohydride (0.4 ml, 1.5M in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h the mixture was treated with water (0.2 ml) and loaded onto an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column.
  • the column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min.
  • the desired fractions were collected, the acetonitrile was removed by evaporation and the residue was applied to a Bondesil 40 ⁇ C8 resin column.
  • the column was washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 209 as a pale yellow solid.
  • Daptomycin (972 mg) was dissolved in dry dimethylformamide (20 ml), and isatoic anhydride (979 mg) was added. The mixture was stirred at ambient temperature for 10 days, then quenched by the addition of water (20 ml). The mixture was loaded onto a Bondesil 40 ⁇ C8 resin column (25 g), which had been previously washed with methanol (50 ml) and water (100 ml). The column was then eluted with water (200 ml), 15% methanol/water (1200 ml), 20% methanol/water (200 ml), 30% methanol/water (200 ml) and 40% methanol/water (200 ml). The product bearing fractions were combined and freeze dried to give compound 10 as a white solid (870 mg).
  • Daptomycin (500 mg) and Boc-tryptophan-p-nitrophenyl ester (157.5 mg) were stirred at room temperature in dry dimethylformamide (30 ml) for 3 days.
  • Daptomycin (400 mg) and N,N-bis(tert-butoxycarbonyl)-L-lysine-4-nitrophenyl ester (173 mg) were stirred in dry dimethylformamide (5 ml) at room temperature for two days.
  • the mixture was loaded onto an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column and was eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer.
  • Fractions containing the desired compound were collected and freeze-dried.
  • the freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40 ⁇ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave the Boc protected intermediate as a pale yellow solid (370 mg).
  • Boc protected intermediate (200 mg) was stirred in trifluoroacetic acid (5 ml) and anisole (0.25 ml) at room temperature for 2 hours. Removal of the solvents under reduced pressure gave a residue which was loaded on an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column and eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing the desired compound were collected and freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40 ⁇ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave compound 54 as a pale yellow solid (100 mg).
  • Daptomycin (162 mg) and 2-methylthiobenzoic acid pentafluorophenol ester (37 mg) were stirred at room temperature in dry dimethylformamide (10 ml) for 5 days.
  • the dimethylformamide was evaporated under reduced pressure and the residue was purified by preparative HPLC on an IBS-C8 5 ⁇ 250 ⁇ 20.2 mm column.
  • the column was eluted at 20 ml/min with 36% acetonitrile in 5 mM ammonium phosphate buffer. Fractions collected at 7.3 minutes were freeze-dried.
  • the freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40 ⁇ C8 resin column. The column was washed with water and eluted with methanol. Evaporation of the methanol gave compound 32 as a pale yellow solid (47 mg).
  • Daptomycin (16 mg) was dissolved in dry dimethylformamide (0.5 ml) and methyl isothiocyanate (37 mg) was added. The mixture was stirred at ambient temperature for 24 hours, then quenched by the addition of 5% ammonium phosphate buffer (1 ml).
  • the mixture was purified by preparative HPLC on an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column. The column was eluted at 20 ml/min with 36% acetonitrile in 5 mM ammonium phosphate buffer. The product bearing fractions were combined and freeze dried. The freeze-dried residue was dissolved in water (1.5 ml) and applied to a Bondesil 40 ⁇ C8 resin column. The column was washed with water and eluted with methanol. Evaporation of the methanol gave compound 5 as a pale yellow solid (5.2 mg).
  • Daptomycin (16 mg) and N-benzotriazole phenylsulfonamide (2.6 mg) were stirred at room temperature in dry pyridine for 6 days.
  • the solvent was evaporated and the residue was purified by preparative HPLC using an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column.
  • the column was eluted at 20 ml/min with 36% acetonitrile in 5 mM ammonium phosphate buffer and product containing fractions were freeze-dried.
  • the freeze dried residue was dissolved in water (5 ml) and applied to a Bondesil 40 ⁇ C8 resin column.
  • the column was washed with water and eluted with methanol. Evaporation of the methanol gave compound 3 as a pale yellow solid (4 mg).
  • Daptomycin 32 mg was dissolved in dry dimethylformamide (20 ml), and N,N′-bis-Boc-1-guanidinylpyrazole (31 mg) was added. The mixture was stirred at ambient temperature for 5 days, then quenched by the addition of water (3 ml). The resultant mixture was loaded onto a Bondesil 40 ⁇ C8 resin (900 mg) that had been previously washed with methanol and water. The column was eluted with water (30 ml) followed by methanol. The product-bearing fractions were combined and evaporated to give compound 1 as a white solid.
  • Daptomycin (10 g) was dissolved in dry dimethylformamide (100 ml). N,N′-bis-Boc-guanidinylpyrazole (2.3 g) in dry dimethylformamide (5 ml) was added. The mixture was stirred under nitrogen at room temperature overnight. The mixture was purified on a Bondesil 40 ⁇ C8 resin column. The product containing fractions were freeze-dried to give compound 1 (7.4 g) as pale yellow fluffy solid.
  • Compound 1 (2.6 g) was added to a preparation of deacylase enzyme produced from recombinant Streptomyces lividans , which expresses the Actinoplanes utahensis deacylase enzyme in ethylene glycol (1.2 ml) and water (25 ml). The pH of the solution was adjusted to 9 with 1.0M sodium hydroxide solution and stirred at room temperature. After 24 hours the mixture was purified on a Bondesil 40 ⁇ C8 resin column by eluting with 10% acetonitrile/water, then 40% acetonitrile/water. The product-containing fractions were freeze dried to give deacylated bis-Boc-guanidinylated daptomycin (0.69 g) as a pale yellow solid.
  • Undecanoyl pentafluorophenol ester (40.3 mg) was added to deacylated bis-Boc-guanidinylated daptomycin (171.5 mg) in dry dimethylformamide (2 ml). The mixture was stirred overnight at room temperature before being concentrated to give compound 255 (105 mg) as a yellow solid.
  • Tetradecanoyl pentafluorophenol ester (35.5 mg) and deacylated bis-Boc-guanidinylated daptomycin (102.5 mg) in dry dimethylformamide (2 ml). The mixture was stirred overnight at room temperature before being concentrated to give compound 258 (38.8 mg) as a yellow solid.
  • Daptomycin (162 mg) was stirred in 0.1 M hydrochloric acid (5 ml) at 0° C. for 10 minutes before sodium nitrite (8 mg) in water (0.2 ml) was added dropwise. Sulfamic acid (11 mg) was added after 15 minutes, followed by sodium azide (8 mg) 10 minutes later. The mixture was maintained at 0° C. for 4 hours and then neutralized with a saturated sodium bicarbonate solution and purified by preparative HPLC. An IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column was loaded with the mixture and eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions were collected at 6.9 minutes and freeze dried.
  • the freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40 ⁇ C8 resin column. The column was washed with water and eluted with methanol. Evaporation of the methanol gave the azido daptomycin as a pale yellow solid (60 mg).
  • the azido daptomycin (69 mg) was dissolved in dry dimethylformamide (4 ml) and iminobiotin-N-hydroxysuccinimide ester (53 mg) was added. The mixture was covered to exclude light and stirred at ambient temperature for 3 days. The mixture was quenched by the addition of water (20 ml). The resultant mixture was loaded onto a Bondesil 40 ⁇ C8 resin (25 g) column, which had been previously washed with methanol and water, and the column was eluted with water. The product-bearing fractions were combined and freeze dried to give Compound 37 as a white solid (49 mg).
  • Daptomycin (250 mg) and N-tBoc-L-tryptophan-p-nitrophenyl ester (144 mg) were stirred in dry dimethylformamide (3 ml) at room temperature for two days.
  • the mixture was loaded on an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column and was eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing the desired compound were collected and freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40 ⁇ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave N-Boc tryptophan daptomycin as a pale yellow solid (130 mg).
  • a preparation of deacylase enzyme was produced from recombinant Streptomyces lividans , which expresses the Actinoplanes utahensis deacylase enzyme.
  • the enzyme in ethylene glycol (400 ⁇ l) was added to the solution of N-Boc tryptophan daptomycin (100 mg) in HPLC grade water (20 ml). The solution was adjusted to pH 8.5 with sodium hydroxide (1 M). The mixture was stirred for 24 hours. The mixture was loaded on a C8 resin plug column, washed with water and eluted with methanol.
  • Deacylated N-Boc tryptophan daptomycin (20 mg) was stirred in dry dimethylformamide (2 ml) at room temperature. Undecyl isocyanate (2.25 mg) was added to the solution. After stirring at ambient temperature for 24 hours, the mixture was diluted with water (10 ml) and applied to a Bondesil 40 ⁇ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave the undecyl urea of N-Boc tryptophan daptomycin as a pale yellow solid (21 mg).
  • N-Boc tryptophan daptomycin undecyl urea (21 mg) was stirred in trifluoroacetic acid (2 ml) and anisole (0.1 ml) at room temperature for 2 hours. Removal of the solvents under reduced pressure gave a residue which was loaded on an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column and eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing the desired compound were collected and freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40 ⁇ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave compound 181 as a pale yellow solid (0.8 mg).
  • Nonyl amino N-Boc tryptophan daptomycin 14 mg was stirred in trifluoroacetic acid (2 ml) and anisole (0.1 ml) at room temperature for 2 hours. Removal of the solvents under reduced pressure gave a residue which was loaded on an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column and was eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing the desired compound were collected and freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40 ⁇ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave compound 7 as a pale yellow solid (5 mg).
  • Daptomycin (5.0 g) was dissolved in water (25 ml) and adjusted to pH 9 with 5M sodium hydroxide. Di-tert-butyldicarbonate (1.5 g) was added and the mixture was adjusted to maintain pH 9 with 5 M sodium hydroxide until the reaction was complete (4 hours). The pH was adjusted to 7 and the mixture was loaded onto a Bondesil 40 ⁇ C8 resin column. The column was washed with water and the product was eluted from the column with methanol. Evaporation of the methanol gave Boc-protected daptomycin (5.08 g) as a yellow powder.
  • a preparation of deacylase enzyme was produced from recombinant Streptomyces lividans , which expresses the Actinoplanes utahensis deacylase enzyme.
  • the enzyme in ethylene glycol (400 ⁇ l) was added to Boc-protected daptomycin (1 g) in water (100 ml) at pH 7-8. After incubation for 72 hours, the mixture was loaded on a Bondesil 40 ⁇ C8 resin column. The column was washed with water and the product was eluted from the column with 10% acetonitrile in water. The solvent was removed by evaporation to give deacylated Boc-protected daptomycin (440 mg) as a yellow powder.
  • Daptomycin undecyl urea synthesized from deacylated Boc protected daptomycin above using undecyl isocyanate instead of undecanoyl pentafluorophenol ester according to example 7 (100 mg) and 5-methoxyindole-3-carboxaldehyde (11 mg) in dry dimethylformamide (0.6 ml) was added sodium triacetoxyborohydride (76 mg). The mixture was stirred at room temperature for 24 hours before purification by preparative HPLC. The mixture was loaded on an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column and eluted at 25 ml/min with 30-60% acetonitrile in 5 mM ammonium phosphate gradient over 30 minutes.
  • compounds 315-322, 332-337, 345-349 and 355 can be prepared as detailed in the above example by appropriate substitutions of reagents obvious to those skilled in the art.
  • Daptomycin undecanoyl amide synthesized from deacylated Boc protected daptomycin by using undecanoyl pentafluorophenol ester according to examples 10 and 7 (60 mg) was stirred in dry dimethylformamide (2 ml) at room temperature. N-tBoc-L-tryptophan-p-nitrophenyl ester (31 mg) was added to the solution. The mixture was stirred for 24 hours. The mixture was loaded onto an IBSIL-C8 5 ⁇ 250 ⁇ 20.2 mm column and was eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing the desired compound were collected and freeze-dried.
  • compounds 295-306, 308-309, 311-312, 338-344 and 350-352 can be prepared as detailed in the above example by appropriate substitutions of reagents obvious to those skilled in the art.
  • MIC minimum inhibitory concentration
  • 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 was established by infecting female CD-1 mice (Charles River Lab, MA) weighing 19-23 g intraperitoneally with from Methicillin Resistant S. aureus (MRSA) inoculum.
  • MRSA Methicillin Resistant S. aureus
  • the inoculum was prepared from Methicillin Resistant S. areus (ATCC 43300).
  • the MRSA inoculum was cultured in Mueller-Hinton (MH) broth at 37° C. for 18 hours.
  • the optical density at 600 nm (OD 600 ) was determined for a 1:10 dilution of the overnight culture.
  • Bacteria (8 ⁇ 10 8 cfu) was added to 20 ml of phosphate buffered saline (Sigma P-0261) containing 5% hog gastric mucin (Sigma M-2378). All animals were 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 received test compound sc at 10 mg/kg (or the highest therapeutic dose of a given compound) only for monitoring acute toxicity. These injections were repeated once at 4 hours after the inoculation for the respective groups. The injection volume at each time was 10 ml per kilogram of body weight.
  • Table II The results of the in vivo efficacy test are summarized in Table II, which provides a representative example of the results obtained for Compound 70.
  • the 50% effective dose (ED 50 ) is calculated on the basis of the number of mice surviving 7 days after inoculation. The ED 50 was determined for other compounds of this invention in a similar manner. The ED 50 in mg/kg of other representative compounds of the present invention are listed in Table III.

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Abstract

The present invention relates to novel lipopeptide compounds. The invention also relates to pharmaceutical compositions of these compounds and methods of using these compounds as antibacterial compounds. The invention also relates to methods of producing these novel lipopeptide compounds and intermediates used in producing these compounds.

Description

  • This application is a divisional of U.S. patent application Ser. No. 09/737,908 filed Dec. 15, 2000, which claims priority to U.S. Provisional Application No. 60/170,946, filed Dec. 15, 1999 and U.S. Provisional Application No. 60/208,222, filed May 30, 2000.
    • FIELD OF THE INVENTION
  • The present invention relates to novel lipopeptide compounds. The invention also relates to pharmaceutical compositions of these compounds and methods of using these compounds as antibacterial compounds. The invention also relates to methods of producing these novel lipopeptide compounds and intermediates used in producing these compounds.
    • BACKGROUND OF THE INVENTION
  • The rapid increase in the incidence of gram-positive infections—including those caused by resistant bacteria—has sparked renewed interest in the development of novel classes of antibiotics. A class of compounds which have shown potential as useful antibiotics includes 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. Daptomycin, a member of this class, has potent bactericidal activity in vitro and in vivo against clinically relevant gram-positive bacteria that cause serious and life-threatening diseases. These bacteria include resistant pathogens, such as vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus areus (MRSA), glycopeptide intermediate susceptible Staphylococcus areus (GISA), coagulase-negative staphylococci (CNS), and penicillin-resistant Streptococcus pneumoniae (PRSP), for which there are few therapeutic alternatives. See, e.g. Tally et al., 1999, Exp. Opin. Invest. Drugs 8:1223-1238.
  • Despite the promise that antibacterial agents such as daptomycin offer, the need for novel antibiotics continues. Many pathogens have been repeatedly exposed to commonly-used antibiotics. This exposure has led to the selection of variant antibacterial strains resistant to a broad spectrum of antibiotics. The loss of potency and effectiveness of an antibiotic caused by resistant mechanisms renders the
  • antibiotic ineffective and consequently can lead to life-threatening infections that are virtually untreatable. As new antibiotics come to market pathogens may develop resistance or intermediate resistance to these new drugs, effectively creating a need for a stream of new antibacterial agents to combat these emerging strains. In addition compounds that exhibit bacteriacidal activity would offer advantages over present bacteriastatic compounds. Thus, novel synthetic 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. Additionally, new antibacterial agents may exhibit differential effectiveness against different types of pathogens.
    • SUMMARY OF THE INVENTION
  • The present invention addresses this problem by providing novel lipopeptide compounds which have antibacterial activity against a broad spectrum of bacteria, including drug-resistant bacteria. Further, the compounds of the present invention exhibit bacteriacidal activity.
  • The present invention comprises, in one aspect, antibacterial compounds of Formula I:
  • Figure US20080287347A1-20081120-C00001
  • and salts thereof,
  • wherein R is:
  • Figure US20080287347A1-20081120-C00002
  • wherein X and X″ are independently selected from C═O, C═S, C═NH, C═NRX, S═O or SO2;
  • wherein n is 0 or 1;
  • wherein RX is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
  • wherein B is X″RY, H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
  • wherein RY is selected from hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;
  • wherein A is H, NH2, NHRA, NRARB, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl or heterocyclyl;
  • wherein RA and RB are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
  • wherein when n is 0, then A is additionally selected from:
  • Figure US20080287347A1-20081120-C00003
  • wherein each of R50-R53 is independently selected from C1-C15 alkyl;
  • alternatively, wherein B and A together form a 5-7 membered heterocyclic or heteroaryl ring.
  • Wherein R1 is
  • Figure US20080287347A1-20081120-C00004
  • wherein X′ and X″′ are independently selected from C═O, C═S, C═NH, C═NRX′, S═O or SO2;
  • wherein m is 0 or 1;
  • wherein RX′ is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
  • wherein B′ is X″′RY′, H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and
  • wherein RY′ is selected from hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl.
  • In one aspect of the invention, A′ is H, NH2, NHRA′, NRA′RB′, heteroaryl, cycloalkyl or heterocyclyl;
  • wherein RA′ and RB′ are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
  • wherein when m is 0, then A′ is additionally selected from:
  • Figure US20080287347A1-20081120-C00005
  • wherein each of R50-R53 is independently selected from C1-C15 alkyl;
  • provided that when B′ is H and X′ is C═O, then A′ is other than
  • (a) a pyridinyl ring substituted with one substitutent NHC(O)RD or
  • (b) a C5-C6 saturated cycloalkyl ring substituted with one substitutent NHC(O)RD;
  • wherein RD is C1-C17 unsubstituted alkyl or C2-C17 unsubstituted alkenyl; and when B′ is H and m=0, then A′ is not H.
  • In another aspect of the invention, A′ is aryl;
  • provided that when B′ is H and X′ is C═O, then A′ is other than a phenyl ring substituted with substitutent NHC(O)RD, wherein RD is defined as above, which may be further optionally substituted on the phenyl ring with 1-2 substituents independently selected from amino, nitro, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, halo, mercapto, C1-C3 alkylthio, carbamyl or C1-C3 alkyl carbamyl.
  • In a third aspect of the invention, A′ is alkyl, alkenyl, alkynyl, alkoxy or aryloxy;
  • provided that when B′ is H and X′ is C═O, then A′ is other than
  • (a) —(C1-C16unsubstituted alkyl)-NH2;
  • (b) —(C1-C10 unsubstituted alkyl)-NHC(O)RD, wherein RD is defined as described above;
  • (c) —C1-C18 alkyl, optionally substituted with up to one hydroxyl, carboxyl or C1-C3 alkoxy, or one to three halo substituents;
  • (d) —C4-C18 unsubstituted alkenyl;
  • Figure US20080287347A1-20081120-C00006
  • wherein R54 is selected from C1-C17-unsubstituted alkyl or C2-C17-unsubstituted alkenyl; wherein R55 is selected from hydroxyethyl, hydroxymethyl, mercaptomethyl, mercaptoethyl, methylthioethyl, 2-thienyl, 3-indolemethyl, phenyl optionally substituted with a group selected from halo, nitro, C1-C3-unsubstituted alkyl, hydroxy, C1-C3-unsubstituted alkoxy, C1-C3-unsubstituted alkylthio, carbamyl or C1-C3 unsubstituted alkylcarbamyl; or benzyl optionally substituted with a group selected from halo, nitro, C1-C3-unsubstituted alkyl, hydroxy, C1-C3-unsubstituted alkoxy, C1-C3-unsubstituted alkylthio, carbamyl or C1-C3 unsubstituted alkylcarbamyl; wherein t is 0 or 1 and wherein u is an integer from 1-3; and
  • when B′ is H and X′ is C═O, then X′, together with A′, does not form a carbamate amino protecting group; and
  • when B′ is H and m is 0, then A′ is other than C4-C14 unsubstituted alkyl.
  • In a fourth aspect of the invention, B′ and A′ together form a 5-7 membered heterocyclic or heteroaryl ring.
  • Wherein R2 is
  • Figure US20080287347A1-20081120-C00007
  • wherein K and K′ together form a C3-C7 cycloalkyl or heterocyclyl ring or a C5-C10 aryl or heteroaryl ring;
  • wherein J is selected from the group consisting of hydrido, amino, NHRJ, NRJRK, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylamino, hydroxyl, thio, alkylthio, alkenylthio, sulfinyl, sulfonyl, azido, cyano, halo,
  • Figure US20080287347A1-20081120-C00008
  • wherein each of R24, R25, and R26 is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or R24 and R25 together form a 5-8 membered heterocyclyl ring;
  • wherein RJ and RK are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; or
  • alternatively, wherein J, together with R17, forms a 5-8 membered heterocyclyl or cycloalkyl ring; or
  • alternatively, wherein J, together with both R17 and R18, forms a 5-8 membered aryl, cycloalkyl, heterocyclyl or heteroaryl ring; and
  • wherein each of R17 and R18 is independently selected from the group consisting of hydrido, halo, hydroxyl, alkoxy, amino, thio, sulfinyl, sulfonyl and
  • Figure US20080287347A1-20081120-C00009
  • wherein R17 and R18 taken together can form a group consisting of ketal, thioketal,
  • Figure US20080287347A1-20081120-C00010
  • wherein each of R22 and R23 is independently selected from the group consisting of hydrido and alkyl.
  • In another embodiment, the invention also provides pharmaceutical compositions comprising compounds of Formula I and methods of use thereof.
  • In a further embodiment, the invention provides methods of making compounds of Formula I and pharmaceutical compositions thereof.
  • In a further embodiment, the invention provides compounds useful as intermediates for the preparation of compounds of Formula I.
  • In a still further embodiment, the invention provides methods of use of the compounds of Formula I to treat bacterial infections in humans.
    • DETAILED DESCRIPTION OF THE INVENTION Definitions
  • Molecular terms, when used in this application, have their common meaning unless otherwise specified.
  • The term “hydrido” denotes a single hydrogen atom (H).
  • The term “acyl” is defined as 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.
  • The term “amino” denotes a nitrogen radical containing two substituents independently selected from the group consisting of hydrido, alkyl, cycloalkyl, carboalkoxy, heterocyclyl, aryl, heteroaryl and sulfonyl. Subsets of the term amino are (1) the term “unsubstituted amino” which denotes an NH2 radical, (2) the term “mono substituted amino” which is defined as a nitrogen radical containing a hydrido group and a substituent group selected from alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and (3) the term “disubstituted amino” which is defined as a nitrogen radical containing two substituent groups independently selected from, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Preferred mono substituted amino radicals are “lower mono substituted amino” radicals, whereby the substituent group is a lower alkyl group. Preferred disubstituted amino radicals are “lower disubstituted amino” radicals, whereby the substituent groups are lower alkyl.
  • The term “acyloxy” denotes an oxygen radical adjacent to an acyl group.
  • The term “acylamino” denotes a nitrogen radical adjacent to an acyl group.
  • The term “carboalkoxy” is defined as a carbonyl radical adjacent to an alkoxy or aryloxy group.
  • The term “carboxyamido” denotes a carbonyl radical adjacent to an amino group.
  • The term “halo” is defined as a bromo, chloro, fluoro or iodo radical.
  • The term “thio” denotes 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.
  • The term “alkyl” is defined as a linear or branched, saturated radical having one to about twenty carbon atoms unless otherwise specified. Preferred alkyl radicals are “lower alkyl” radicals having one to about five carbon atoms. One or more hydrogen atoms can also be replaced by a substitutent group selected from acyl, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, oxo, guanidino, formyl and an amino acid side chain. Examples of alkyl groups include, without limitation, methyl, tert-butyl, isopropyl, and methoxymethyl. Subsets of the term alkyl are (1) “unsubstituted alkyl” which is defined as an alkyl group that bears no substituent groups (2) “substituted alkyl” which denotes an alkyl radical in which (a) one or more hydrogen atoms is replaced by a substitutent group selected from acyl, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, N-sulfonylcarboxyamido, N-acylaminosulfonyl or (b) two or more hydrogen atoms are each replaced by a substituent group independently selected from hydroxyl, carboxy, C1-C3 alkoxy, amino, acylamino, oxo or guanidino; and (3) the term “selected substituted alkyl” which denotes an alkyl radical in which (a) one proton is replaced by a group selected from hydroxyl, carboxy C1-C3 alkoxy, unsubstituted amino, acylamino, or acylamino phenyl or (b) one to three protons is replaced by a halo substituent.
  • The term “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, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, formyl, oxo and guanidino. The double bond portion(s) of the unsaturated hydrocarbon chain may be either in the cis or trans configuration. Examples of alkenyl groups include, without limitation, ethylenyl or phenyl ethylenyl.
  • The term “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, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, formyl, oxo and guanidino. An example of alkynyl group includes, without limitation, propynyl.
  • The term “aryl” or “aryl ring” denotes aromatic radicals in a single or fused carbocyclic ring system, having from five to fourteen ring members. In a preferred embodiment, 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, amino, acylamino, acyloxy, azido, alkylthio, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl and formyl. Examples of aryl groups include, without limitation, phenyl, naphthyl, biphenyl, terphenyl. Subsets of the term aryl are (1) the term “phenyl” which denotes a compound of the formula:
  • Figure US20080287347A1-20081120-C00011
  • (2) the term “substituted phenyl” which is defined as a phenyl radical in which one or more protons are replaced by a substituent group selected from acyl, amino, acyloxy, azido, alkylthio, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, N-sulfonylcarboxyamido, and N-acylaminosulfonyl and (3) the term “acylamino phenyl” denotes a phenyl radical in which one hydrogen atom is replaced by an acylamino group. One or more additional hydrogen atoms can also be replaced by a substituent group selected from acyl, amino, acylamino, acyloxy, azido, alkylthio, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, N-sulfonylcarboxyamido, and N-acylaminosulfonyl.
  • “Heteroaryl” or “heteroaryl ring” denotes an aromatic radical which contain one to four hetero atoms or hetero groups selected from O, N, S.
  • Figure US20080287347A1-20081120-C00012
  • in a single or fused heterocyclic ring system, having from five to fifteen ring members. In a preferred embodiment, 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, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, thiocarbonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, and formyl. Examples of heteroaryl groups include, without limitation, pyridinyl, thiazolyl, thiadiazoyl, isoquinolinyl, pyrazolyl, oxazolyl, oxadiazoyl, triazolyl, and pyrrolyl groups. Subsets of the term heteroaryl are (1) the term “pyridinyl” which denotes compounds of the formula:
  • Figure US20080287347A1-20081120-C00013
  • (2) the term “substituted pyridinyl” which is defined as a pyridinyl radical in which one or more protons is replaced by a substituent group selected from acyl, amino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, N-sulfonylcarboxyamido, and N-acylaminosulfonyl and (3) the term “acylamino pyridinyl” which denotes a pyridinyl radical in which one hydrogen atom is replaced by an acylamino group, additionally, one or more additional hydrogen atoms can also be replaced by a substituent group selected from acyl, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, thiocarbonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, N-sulfonylcarboxyamido, and N-acylaminosulfonyl.
  • The term “cycloalkyl” or “cycloalkyl ring” is defined as a saturated or partially unsaturated carbocyclic ring in a single or fused carbocyclic ring system having from three to twelve ring members. In a preferred embodiment, 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, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl and formyl. Examples of a cycloalkyl group include, without limitation, cyclopropyl, cyclobutyl, cyclohexyl, and cycloheptyl.
  • The term “heterocyclyl,” “heterocyclic” or “heterocyclyl ring” is defined as a saturated or partially unsaturated ring containing one to four hetero atoms or hetero groups selected from O, N, NH,
  • Figure US20080287347A1-20081120-C00014
  • wherein RZ is as defined for RX,
  • Figure US20080287347A1-20081120-C00015
  • in a single or fused heterocyclic ring system having from three to twelve ring members. In a preferred embodiment, 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, amino, acylamino, acyloxy, oxo, thiocarbonyl, imino, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl and formyl. Examples of a heterocyclyl group include, without limitation, morpholinyl, piperidinyl, and pyrrolidinyl.
  • The term “alkoxy” denotes oxy-containing radicals substituted with an alkyl, cycloalkyl or heterocyclyl group. Examples include, without limitation, methoxy, tert-butoxy, benzyloxy and cyclohexyloxy.
  • The term “aryloxy” denotes oxy-containing radicals substituted with an aryl or heteroaryl group. Examples include, without limitation, phenoxy.
  • The term “amino acid side chain” denotes any side chain (R group) from a naturally-occurring or a non-naturally occurring amino acid.
  • The term “sulfinyl” is defined as 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.
  • The term “sulfonyl” is defined as a hexavalent sulfur radical substituted with two oxo substituents and a third substituent selected from alkyl, cycloalkyl, heterocyclyl aryl, or heteroaryl.
  • The term “carbamate amino protecting group” is defined as a recognized amino protecting group that when bound to an amino group forms a carbamate. Examples of carbamate amino protecting groups can be found in “Protective Groups in Organic Synthesis” by Theodora W. Greene, John Wiley and Sons, New York, 1981. Examples of carbamate amino protecting groups include benzyloxycarbonyl, t-butoxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl, adamantyloxycarbonyl, chlorobenzyloxycarbonyl, nitrobenzyloxycarbonyl or the like.
  • The salts of the compounds of the invention (preferably a compound of Formula I) include acid addition salts and base addition salts. In a preferred embodiment, the salt is a pharmaceutically acceptable salt of the compound of Formula I. The term “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 (preferably a compound of Formula I) 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, β-hydroxybutyric, malonic, galactic, and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of the invention (preferably a compound of Formula I) 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 (preferably a compound of Formula I) by treating, for example, the compound of the invention (preferably a compound of Formula I) with the appropriate acid or base.
  • The compounds of the invention (preferably compounds of Formula I) 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 (preferably compounds of Formula I) 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 these 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 available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention (preferably compounds of Formula I) 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 (preferably compounds of Formula I) 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. In a preferred embodiment, 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.
    • Lipopeptide Compounds
  • A compound of the formula (I):
  • Figure US20080287347A1-20081120-C00016
  • and salts thereof,
  • wherein R is:
  • Figure US20080287347A1-20081120-C00017
  • wherein X and X″ are independently selected from C═O, C═S, C═NH, C═NRX, S═O or SO2;
  • wherein n is 0 or 1;
  • wherein RX is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
  • wherein B is X″RY, H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
  • wherein RY is selected from hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;
  • wherein A is H, NH2, NHRA, NRARB, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl or heterocyclyl;
  • wherein RA and RB are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
  • wherein when n is 0, then A is additionally selected from:
  • Figure US20080287347A1-20081120-C00018
  • wherein each of R50-R53 is independently selected from C1-C15 alkyl;
  • alternatively, wherein B and A together form a 5-7 membered heterocyclic or heteroaryl ring.
  • Wherein R1 is
  • Figure US20080287347A1-20081120-C00019
  • wherein X′ and X″′ are independently selected from C═O, C═S, C═NH, C═NRX′, S═O or SO2;
  • wherein m is 0 or 1;
  • wherein Rx is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
  • wherein B′ is X″′RY′, H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and
  • wherein RY′ is selected from hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl.
  • In one aspect of the invention, A′ is H, NH2, NHRA′, NRA′RB′, heteroaryl, cycloalkyl or heterocyclyl;
  • wherein RA′ and RB′ are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
  • wherein when m is 0, then A′ is additionally selected from:
  • Figure US20080287347A1-20081120-C00020
  • wherein each of R50-R53 is independently selected from C1-C15 alkyl;
  • provided that when B′ is H and X′ is C═O, then A′ is other than
  • (a) a pyridinyl ring substituted with one substitutent NHC(O)RD or
  • (b) a C5-C6 saturated cycloalkyl ring substituted with one substitutent NHC(O)RD;
  • wherein RD is C1-C17 unsubstituted alkyl or C2-C17 unsubstituted alkenyl; and when B′ is H and m=0, then A′ is not H.
  • In another aspect of the invention, A′ is aryl;
  • provided that when B′ is H and X′ is C═O, then A′ is other than a phenyl ring substituted with substitutent NHC(O)RD, wherein RD is defined as above, which may be further optionally substituted on the phenyl ring with 1-2 substituents independently selected from amino, nitro, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, halo, mercapto, C1-C3 alkylthio, carbamyl or C1-C3 alkyl carbamyl.
  • In a third aspect of the invention, A′ is alkyl, alkenyl, alkynyl, alkoxy or aryloxy;
  • provided that when B′ is H and X′ is C═O, then A′ is other than
  • (a) —(C1-C16 unsubstituted alkyl)-NH2;
  • (b) —(C1-C10 unsubstituted alkyl)-NHC(O)RD, wherein RD is defined as described above;
  • (c) —C1-C18 alkyl, optionally substituted with up to one hydroxyl, carboxyl or C1-C3 alkoxy, or one to three halo substituents;
  • (d) —C4-C18 unsubstituted alkenyl;
  • Figure US20080287347A1-20081120-C00021
  • wherein R54 is selected from C1-C17-unsubstituted alkyl or C2-C17-unsubstituted alkenyl; wherein R55 is selected from hydroxyethyl, hydroxymethyl, mercaptomethyl, mercaptoethyl, methylthioethyl, 2-thienyl, 3-indolemethyl, phenyl optionally substituted with a group selected from halo, nitro, C1-C3-unsubstituted alkyl, hydroxy, C1-C3-unsubstituted alkoxy, C1-C3-unsubstituted alkylthio, carbamyl or C1-C3 unsubstituted alkylcarbamyl; or benzyl optionally substituted with a group selected from halo, nitro, C1-C3-unsubstituted alkyl, hydroxy, C1-C3-unsubstituted alkoxy, C1-C3-unsubstituted alkylthio, carbamyl or C1-C3 unsubstituted alkylcarbamyl; wherein t is 0 or 1 and wherein u is an integer from 1-3; and
  • when B is H and X is C═O, then X, together with A, does not form a carbamate amino protecting group; and
  • when B′ is H and m is 0, then A′ is other than C4-C14 unsubstituted alkyl.
  • In a fourth aspect of the invention, B′ and A′ together form a 5-7 membered heterocyclic or heteroaryl ring.
  • Wherein R2 is
  • Figure US20080287347A1-20081120-C00022
  • wherein K and K′ together form a C3-C7 cycloalkyl or heterocyclyl ring or a C5-C10 aryl or heteroaryl ring;
  • wherein J is selected from the group consisting of hydrido, amino, NHRJ, NRJRK, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylamino, hydroxyl, thio, alkylthio, alkenylthio, sulfinyl, sulfonyl, azido, cyano, halo,
  • Figure US20080287347A1-20081120-C00023
  • wherein each of R24, R25, and R26 is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or R24 and R25 together form a 5-8 membered heterocyclyl ring;
  • wherein RJ and RK are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; or
  • alternatively, wherein J, together with R17, forms a 5-8 membered heterocyclyl or cycloalkyl ring; or
  • alternatively, wherein J, together with both R17 and R18, forms a 5-8 membered aryl, cycloalkyl, heterocyclyl or heteroaryl ring; and
  • wherein each of R17 and R18 is independently selected from the group consisting of hydrido, halo, hydroxyl, alkoxy, amino, thio, sulfinyl, sulfonyl and
  • Figure US20080287347A1-20081120-C00024
  • wherein R17 and R18 taken together can form a group consisting of ketal, thioketal,
  • Figure US20080287347A1-20081120-C00025
  • wherein each of R22 and R23 is independently selected from the group consisting of hydrido and alkyl.
  • In a preferred embodiment of the invention, R is selected from
  • Figure US20080287347A1-20081120-C00026
  • wherein each of R3, R4, R5, and R6 is independently selected from the group consisting of hydrido, alkyl, aryl, heterocyclyl and heteroaryl, and wherein R44 is selected from the group consisting of alkyl, aryl, heterocyclyl and heteroaryl.
  • In a more preferred embodiment of the invention R is selected from
  • Figure US20080287347A1-20081120-C00027
  • wherein R4′ is selected from the group consisting of alkyl, aryl-substituted alkyl, substituted phenyl, heteroaryl, heterocyclyl, optionally substituted (C8-C14)-straight chain alkyl and
  • Figure US20080287347A1-20081120-C00028
  • wherein R7 is an alkyl group.
  • In an even more preferred embodiment of the invention, R is
  • Figure US20080287347A1-20081120-C00029
  • wherein X3 is chloro or trifluoromethyl and wherein q is 0 or 1.
  • In a preferred embodiment of the invention, R1 is selected from the group consisting of:
  • Figure US20080287347A1-20081120-C00030
  • wherein R8 is selected from an amino acid side chain, wherein said amino acid side chain may be one that is naturally occurring or one that is not naturally occurring, wherein each of R9, R10 and R11 is selected from hydrido, alkyl, aryl, heterocyclyl and heteroaryl; wherein R12 is selected from the group consisting of heterocyclyl, heteroaryl, aryl, and alkyl and wherein R13 is selected from (C1-C3)-alkyl and aryl.
  • In a more preferred embodiment of the invention, R1 is selected from the group consisting of
  • Figure US20080287347A1-20081120-C00031
  • wherein R8 is selected from tryptophan side chain and lysine side chain; wherein each of R10 and R11 is independently selected from hydrido and alkyl; wherein R12 is selected from imidazolyl, N-methylimidazolyl, indolyl, quinolinyl, benzyloxybenzyl, and benzylpiperidenylbenzyl; and wherein X4 is selected from fluoro and trifluoromethyl.
  • In a preferred embodiment of R2, J is selected from the group consisting of hydrido, amino, azido and
  • Figure US20080287347A1-20081120-C00032
  • wherein R17 and R18 taken together form a group selected from the group consisting of ketal,
  • Figure US20080287347A1-20081120-C00033
  • alternatively, R17 is hydroxyl when R18 is hydrido. Alternatively, wherein J, together with R17, forms a heterocyclyl ring.
  • In a more preferred embodiment of the invention, R2 is selected from
  • Figure US20080287347A1-20081120-C00034
  • wherein R17 and R18 taken together form a group selected from
  • Figure US20080287347A1-20081120-C00035
  • wherein R22 is selected from the group consisting of H and alkyl; wherein R19 is selected from the group consisting of hydrido, amino, azido and
  • Figure US20080287347A1-20081120-C00036
  • In an even more preferred embodiment of the invention R2 is
  • Figure US20080287347A1-20081120-C00037
  • Another aspect of the present invention provides compounds of formula (I), wherein R is selected from NHCO—[(C6-C14)-alkyl]CH3, and R1 and R2 are selected from Table A below. More preferably, R is selected from NHCO—[(CH2)6-14]—CH3.
  • TABLE A
    R1 R2
    Figure US20080287347A1-20081120-C00038
    Figure US20080287347A1-20081120-C00039
    Figure US20080287347A1-20081120-C00040
    Figure US20080287347A1-20081120-C00041
    NHSO2Ph
    Figure US20080287347A1-20081120-C00042
    Figure US20080287347A1-20081120-C00043
    Figure US20080287347A1-20081120-C00044
    Figure US20080287347A1-20081120-C00045
    Figure US20080287347A1-20081120-C00046
    Figure US20080287347A1-20081120-C00047
    Figure US20080287347A1-20081120-C00048
    Figure US20080287347A1-20081120-C00049
    Figure US20080287347A1-20081120-C00050
    Figure US20080287347A1-20081120-C00051
    Figure US20080287347A1-20081120-C00052
    Figure US20080287347A1-20081120-C00053
    Figure US20080287347A1-20081120-C00054
    Figure US20080287347A1-20081120-C00055
    Figure US20080287347A1-20081120-C00056
    Figure US20080287347A1-20081120-C00057
    Figure US20080287347A1-20081120-C00058
    Figure US20080287347A1-20081120-C00059
    Figure US20080287347A1-20081120-C00060
    Figure US20080287347A1-20081120-C00061
    Figure US20080287347A1-20081120-C00062
    Figure US20080287347A1-20081120-C00063
    Figure US20080287347A1-20081120-C00064
    Figure US20080287347A1-20081120-C00065
    Figure US20080287347A1-20081120-C00066
    Figure US20080287347A1-20081120-C00067
    Figure US20080287347A1-20081120-C00068
    Figure US20080287347A1-20081120-C00069
    Figure US20080287347A1-20081120-C00070
    Figure US20080287347A1-20081120-C00071
    Figure US20080287347A1-20081120-C00072
    Figure US20080287347A1-20081120-C00073
    Figure US20080287347A1-20081120-C00074
    Figure US20080287347A1-20081120-C00075
    Figure US20080287347A1-20081120-C00076
    Figure US20080287347A1-20081120-C00077
    Figure US20080287347A1-20081120-C00078
    Figure US20080287347A1-20081120-C00079
    Figure US20080287347A1-20081120-C00080
    Figure US20080287347A1-20081120-C00081
    Figure US20080287347A1-20081120-C00082
    Figure US20080287347A1-20081120-C00083
    Figure US20080287347A1-20081120-C00084
    Figure US20080287347A1-20081120-C00085
    Figure US20080287347A1-20081120-C00086
    Figure US20080287347A1-20081120-C00087
    Figure US20080287347A1-20081120-C00088
    Figure US20080287347A1-20081120-C00089
    Figure US20080287347A1-20081120-C00090
    Figure US20080287347A1-20081120-C00091
    Figure US20080287347A1-20081120-C00092
    Figure US20080287347A1-20081120-C00093
    Figure US20080287347A1-20081120-C00094
    Figure US20080287347A1-20081120-C00095
    Figure US20080287347A1-20081120-C00096
    Figure US20080287347A1-20081120-C00097
    Figure US20080287347A1-20081120-C00098
    Figure US20080287347A1-20081120-C00099
    Figure US20080287347A1-20081120-C00100
    Figure US20080287347A1-20081120-C00101
    Figure US20080287347A1-20081120-C00102
    Figure US20080287347A1-20081120-C00103
    Figure US20080287347A1-20081120-C00104
    Figure US20080287347A1-20081120-C00105
    Figure US20080287347A1-20081120-C00106
    Figure US20080287347A1-20081120-C00107
    Figure US20080287347A1-20081120-C00108
    Figure US20080287347A1-20081120-C00109
    Figure US20080287347A1-20081120-C00110
    Figure US20080287347A1-20081120-C00111
    Figure US20080287347A1-20081120-C00112
    Figure US20080287347A1-20081120-C00113
    Figure US20080287347A1-20081120-C00114
    Figure US20080287347A1-20081120-C00115
    Figure US20080287347A1-20081120-C00116
    Figure US20080287347A1-20081120-C00117
    Figure US20080287347A1-20081120-C00118
    Figure US20080287347A1-20081120-C00119
    Figure US20080287347A1-20081120-C00120
    Figure US20080287347A1-20081120-C00121
    Figure US20080287347A1-20081120-C00122
    Figure US20080287347A1-20081120-C00123
    Figure US20080287347A1-20081120-C00124
    Figure US20080287347A1-20081120-C00125
    Figure US20080287347A1-20081120-C00126
    Figure US20080287347A1-20081120-C00127
    Figure US20080287347A1-20081120-C00128
    Figure US20080287347A1-20081120-C00129
    Figure US20080287347A1-20081120-C00130
    Figure US20080287347A1-20081120-C00131
    Figure US20080287347A1-20081120-C00132
    Figure US20080287347A1-20081120-C00133
    Figure US20080287347A1-20081120-C00134
    Figure US20080287347A1-20081120-C00135
    Figure US20080287347A1-20081120-C00136
    Figure US20080287347A1-20081120-C00137
    Figure US20080287347A1-20081120-C00138
    Figure US20080287347A1-20081120-C00139
    Figure US20080287347A1-20081120-C00140
    Figure US20080287347A1-20081120-C00141
    Figure US20080287347A1-20081120-C00142
    Figure US20080287347A1-20081120-C00143
    Figure US20080287347A1-20081120-C00144
    Figure US20080287347A1-20081120-C00145
    Figure US20080287347A1-20081120-C00146
    Figure US20080287347A1-20081120-C00147
    Figure US20080287347A1-20081120-C00148
    Figure US20080287347A1-20081120-C00149
    Figure US20080287347A1-20081120-C00150
    Figure US20080287347A1-20081120-C00151
    Figure US20080287347A1-20081120-C00152
    Figure US20080287347A1-20081120-C00153
    Figure US20080287347A1-20081120-C00154
    Figure US20080287347A1-20081120-C00155
    Figure US20080287347A1-20081120-C00156
    Figure US20080287347A1-20081120-C00157
    Figure US20080287347A1-20081120-C00158
    Figure US20080287347A1-20081120-C00159
    Figure US20080287347A1-20081120-C00160
    Figure US20080287347A1-20081120-C00161
    Figure US20080287347A1-20081120-C00162
    Figure US20080287347A1-20081120-C00163
    Figure US20080287347A1-20081120-C00164
    Figure US20080287347A1-20081120-C00165
    Figure US20080287347A1-20081120-C00166
    Figure US20080287347A1-20081120-C00167
    Figure US20080287347A1-20081120-C00168
    Figure US20080287347A1-20081120-C00169
    Figure US20080287347A1-20081120-C00170
    Figure US20080287347A1-20081120-C00171
    Figure US20080287347A1-20081120-C00172
    Figure US20080287347A1-20081120-C00173
    Figure US20080287347A1-20081120-C00174
    Figure US20080287347A1-20081120-C00175
    Figure US20080287347A1-20081120-C00176
    Figure US20080287347A1-20081120-C00177
    Figure US20080287347A1-20081120-C00178
    Figure US20080287347A1-20081120-C00179
    Figure US20080287347A1-20081120-C00180
    NH(CH2)2OH
    Figure US20080287347A1-20081120-C00181
    Figure US20080287347A1-20081120-C00182
    Figure US20080287347A1-20081120-C00183
    Figure US20080287347A1-20081120-C00184
    Figure US20080287347A1-20081120-C00185
    Figure US20080287347A1-20081120-C00186
    Figure US20080287347A1-20081120-C00187
    Figure US20080287347A1-20081120-C00188
    Figure US20080287347A1-20081120-C00189
    Figure US20080287347A1-20081120-C00190
    Figure US20080287347A1-20081120-C00191
    Figure US20080287347A1-20081120-C00192
    Figure US20080287347A1-20081120-C00193
    Figure US20080287347A1-20081120-C00194
    Figure US20080287347A1-20081120-C00195
    Figure US20080287347A1-20081120-C00196
    Figure US20080287347A1-20081120-C00197
    Figure US20080287347A1-20081120-C00198
    Figure US20080287347A1-20081120-C00199
    Figure US20080287347A1-20081120-C00200
    Figure US20080287347A1-20081120-C00201
    Figure US20080287347A1-20081120-C00202
    Figure US20080287347A1-20081120-C00203
    Figure US20080287347A1-20081120-C00204
    Figure US20080287347A1-20081120-C00205
    Figure US20080287347A1-20081120-C00206
    Figure US20080287347A1-20081120-C00207
    Figure US20080287347A1-20081120-C00208
    Figure US20080287347A1-20081120-C00209
    Figure US20080287347A1-20081120-C00210
    Figure US20080287347A1-20081120-C00211
    Figure US20080287347A1-20081120-C00212
    Figure US20080287347A1-20081120-C00213
    Figure US20080287347A1-20081120-C00214
    Figure US20080287347A1-20081120-C00215
    Figure US20080287347A1-20081120-C00216
    Figure US20080287347A1-20081120-C00217
    Figure US20080287347A1-20081120-C00218
    Figure US20080287347A1-20081120-C00219
    Figure US20080287347A1-20081120-C00220
    Figure US20080287347A1-20081120-C00221
    Figure US20080287347A1-20081120-C00222
    Figure US20080287347A1-20081120-C00223
    Figure US20080287347A1-20081120-C00224
    Figure US20080287347A1-20081120-C00225
    Figure US20080287347A1-20081120-C00226
    Figure US20080287347A1-20081120-C00227
    Figure US20080287347A1-20081120-C00228
    Figure US20080287347A1-20081120-C00229
    Figure US20080287347A1-20081120-C00230
    Figure US20080287347A1-20081120-C00231
    Figure US20080287347A1-20081120-C00232
    Figure US20080287347A1-20081120-C00233
    Figure US20080287347A1-20081120-C00234
    Figure US20080287347A1-20081120-C00235
    Figure US20080287347A1-20081120-C00236
    Figure US20080287347A1-20081120-C00237
    Figure US20080287347A1-20081120-C00238
    Figure US20080287347A1-20081120-C00239
    Figure US20080287347A1-20081120-C00240
    Figure US20080287347A1-20081120-C00241
    Figure US20080287347A1-20081120-C00242
    Figure US20080287347A1-20081120-C00243
    Figure US20080287347A1-20081120-C00244
    Figure US20080287347A1-20081120-C00245
    Figure US20080287347A1-20081120-C00246
    Figure US20080287347A1-20081120-C00247
    Figure US20080287347A1-20081120-C00248
    Figure US20080287347A1-20081120-C00249
    Figure US20080287347A1-20081120-C00250
    Figure US20080287347A1-20081120-C00251
    Figure US20080287347A1-20081120-C00252
    Figure US20080287347A1-20081120-C00253
    Figure US20080287347A1-20081120-C00254
    Figure US20080287347A1-20081120-C00255
    Figure US20080287347A1-20081120-C00256
    Figure US20080287347A1-20081120-C00257
    Figure US20080287347A1-20081120-C00258
    Figure US20080287347A1-20081120-C00259
    Figure US20080287347A1-20081120-C00260
    Figure US20080287347A1-20081120-C00261
    Figure US20080287347A1-20081120-C00262
    Figure US20080287347A1-20081120-C00263
    Figure US20080287347A1-20081120-C00264
    Figure US20080287347A1-20081120-C00265
    Figure US20080287347A1-20081120-C00266
    Figure US20080287347A1-20081120-C00267
    Figure US20080287347A1-20081120-C00268
    Figure US20080287347A1-20081120-C00269
    Figure US20080287347A1-20081120-C00270
    Figure US20080287347A1-20081120-C00271
    Figure US20080287347A1-20081120-C00272
    Figure US20080287347A1-20081120-C00273
    Figure US20080287347A1-20081120-C00274
    Figure US20080287347A1-20081120-C00275
    Figure US20080287347A1-20081120-C00276
    Figure US20080287347A1-20081120-C00277
    Figure US20080287347A1-20081120-C00278
    Figure US20080287347A1-20081120-C00279
    Figure US20080287347A1-20081120-C00280
    Figure US20080287347A1-20081120-C00281
    Figure US20080287347A1-20081120-C00282
    Figure US20080287347A1-20081120-C00283
    Figure US20080287347A1-20081120-C00284
    Figure US20080287347A1-20081120-C00285
    Figure US20080287347A1-20081120-C00286
    Figure US20080287347A1-20081120-C00287
    Figure US20080287347A1-20081120-C00288
    Figure US20080287347A1-20081120-C00289
    Figure US20080287347A1-20081120-C00290
    Figure US20080287347A1-20081120-C00291
    Figure US20080287347A1-20081120-C00292
    Figure US20080287347A1-20081120-C00293
    Figure US20080287347A1-20081120-C00294
    Figure US20080287347A1-20081120-C00295
    Figure US20080287347A1-20081120-C00296
    Figure US20080287347A1-20081120-C00297
    Figure US20080287347A1-20081120-C00298
    Figure US20080287347A1-20081120-C00299
    Figure US20080287347A1-20081120-C00300
    Figure US20080287347A1-20081120-C00301
    Figure US20080287347A1-20081120-C00302
    Figure US20080287347A1-20081120-C00303
    Figure US20080287347A1-20081120-C00304
    Figure US20080287347A1-20081120-C00305
    Figure US20080287347A1-20081120-C00306
    Figure US20080287347A1-20081120-C00307
    Figure US20080287347A1-20081120-C00308
    Figure US20080287347A1-20081120-C00309
    Figure US20080287347A1-20081120-C00310
    Figure US20080287347A1-20081120-C00311
    Figure US20080287347A1-20081120-C00312
    Figure US20080287347A1-20081120-C00313
    Figure US20080287347A1-20081120-C00314
    Figure US20080287347A1-20081120-C00315
    Figure US20080287347A1-20081120-C00316
    Figure US20080287347A1-20081120-C00317
    Figure US20080287347A1-20081120-C00318
    Figure US20080287347A1-20081120-C00319
    Figure US20080287347A1-20081120-C00320
    Figure US20080287347A1-20081120-C00321
    Figure US20080287347A1-20081120-C00322
    Figure US20080287347A1-20081120-C00323
    Figure US20080287347A1-20081120-C00324
    Figure US20080287347A1-20081120-C00325
    Figure US20080287347A1-20081120-C00326
    Figure US20080287347A1-20081120-C00327
    Figure US20080287347A1-20081120-C00328
    Figure US20080287347A1-20081120-C00329
    Figure US20080287347A1-20081120-C00330
    Figure US20080287347A1-20081120-C00331
    Figure US20080287347A1-20081120-C00332
    Figure US20080287347A1-20081120-C00333
    Figure US20080287347A1-20081120-C00334
    Figure US20080287347A1-20081120-C00335
    Figure US20080287347A1-20081120-C00336
    Figure US20080287347A1-20081120-C00337
    Figure US20080287347A1-20081120-C00338
    Figure US20080287347A1-20081120-C00339
    Figure US20080287347A1-20081120-C00340
    Figure US20080287347A1-20081120-C00341
    Figure US20080287347A1-20081120-C00342
    Figure US20080287347A1-20081120-C00343
    Figure US20080287347A1-20081120-C00344
    Figure US20080287347A1-20081120-C00345
    Figure US20080287347A1-20081120-C00346
    Figure US20080287347A1-20081120-C00347
    Figure US20080287347A1-20081120-C00348
    Figure US20080287347A1-20081120-C00349
    Figure US20080287347A1-20081120-C00350
    Figure US20080287347A1-20081120-C00351
    Figure US20080287347A1-20081120-C00352
    Figure US20080287347A1-20081120-C00353
    Figure US20080287347A1-20081120-C00354
    Figure US20080287347A1-20081120-C00355
    Figure US20080287347A1-20081120-C00356
    Figure US20080287347A1-20081120-C00357
    Figure US20080287347A1-20081120-C00358
    Figure US20080287347A1-20081120-C00359
    Figure US20080287347A1-20081120-C00360
    Figure US20080287347A1-20081120-C00361
    Figure US20080287347A1-20081120-C00362
    Figure US20080287347A1-20081120-C00363
    Figure US20080287347A1-20081120-C00364
    Figure US20080287347A1-20081120-C00365
    Figure US20080287347A1-20081120-C00366
    Figure US20080287347A1-20081120-C00367
    Figure US20080287347A1-20081120-C00368
    Figure US20080287347A1-20081120-C00369
    Figure US20080287347A1-20081120-C00370
    Figure US20080287347A1-20081120-C00371
    Figure US20080287347A1-20081120-C00372
    Figure US20080287347A1-20081120-C00373
    Figure US20080287347A1-20081120-C00374
    Figure US20080287347A1-20081120-C00375
    Figure US20080287347A1-20081120-C00376
    Figure US20080287347A1-20081120-C00377
    Figure US20080287347A1-20081120-C00378
    Figure US20080287347A1-20081120-C00379
    Figure US20080287347A1-20081120-C00380
    Figure US20080287347A1-20081120-C00381
    Figure US20080287347A1-20081120-C00382
    Figure US20080287347A1-20081120-C00383
    Figure US20080287347A1-20081120-C00384
    Figure US20080287347A1-20081120-C00385
    Figure US20080287347A1-20081120-C00386
    Figure US20080287347A1-20081120-C00387
    Figure US20080287347A1-20081120-C00388
    Figure US20080287347A1-20081120-C00389
    Figure US20080287347A1-20081120-C00390
    Figure US20080287347A1-20081120-C00391
    Figure US20080287347A1-20081120-C00392
    Figure US20080287347A1-20081120-C00393
    Figure US20080287347A1-20081120-C00394
    Figure US20080287347A1-20081120-C00395
    Figure US20080287347A1-20081120-C00396
    Figure US20080287347A1-20081120-C00397
    Figure US20080287347A1-20081120-C00398
    Figure US20080287347A1-20081120-C00399
    Figure US20080287347A1-20081120-C00400
    Figure US20080287347A1-20081120-C00401
    Figure US20080287347A1-20081120-C00402
    Figure US20080287347A1-20081120-C00403
    Figure US20080287347A1-20081120-C00404
    Figure US20080287347A1-20081120-C00405
    Figure US20080287347A1-20081120-C00406
    Figure US20080287347A1-20081120-C00407
    Figure US20080287347A1-20081120-C00408
    Figure US20080287347A1-20081120-C00409
    Figure US20080287347A1-20081120-C00410
    Figure US20080287347A1-20081120-C00411
    Figure US20080287347A1-20081120-C00412
    Figure US20080287347A1-20081120-C00413
    Figure US20080287347A1-20081120-C00414
    Figure US20080287347A1-20081120-C00415
    Figure US20080287347A1-20081120-C00416
    Figure US20080287347A1-20081120-C00417
    Figure US20080287347A1-20081120-C00418
    Figure US20080287347A1-20081120-C00419
    Figure US20080287347A1-20081120-C00420
    Figure US20080287347A1-20081120-C00421
    Figure US20080287347A1-20081120-C00422
    Figure US20080287347A1-20081120-C00423
    Figure US20080287347A1-20081120-C00424
    Figure US20080287347A1-20081120-C00425
    Figure US20080287347A1-20081120-C00426
    Figure US20080287347A1-20081120-C00427
    Figure US20080287347A1-20081120-C00428
    Figure US20080287347A1-20081120-C00429
    Figure US20080287347A1-20081120-C00430
    Figure US20080287347A1-20081120-C00431
    Figure US20080287347A1-20081120-C00432
    Figure US20080287347A1-20081120-C00433
    Figure US20080287347A1-20081120-C00434
    Figure US20080287347A1-20081120-C00435
    Figure US20080287347A1-20081120-C00436
    Figure US20080287347A1-20081120-C00437
    Figure US20080287347A1-20081120-C00438
    Figure US20080287347A1-20081120-C00439
    Figure US20080287347A1-20081120-C00440
    Figure US20080287347A1-20081120-C00441
    Figure US20080287347A1-20081120-C00442
    Figure US20080287347A1-20081120-C00443
    Figure US20080287347A1-20081120-C00444
    Figure US20080287347A1-20081120-C00445
    Figure US20080287347A1-20081120-C00446
    Figure US20080287347A1-20081120-C00447
    Figure US20080287347A1-20081120-C00448
    Figure US20080287347A1-20081120-C00449
    Figure US20080287347A1-20081120-C00450
    Figure US20080287347A1-20081120-C00451
    Figure US20080287347A1-20081120-C00452
    Figure US20080287347A1-20081120-C00453
    Figure US20080287347A1-20081120-C00454
    Figure US20080287347A1-20081120-C00455
    Figure US20080287347A1-20081120-C00456
    Figure US20080287347A1-20081120-C00457
    Figure US20080287347A1-20081120-C00458
    Figure US20080287347A1-20081120-C00459
    Figure US20080287347A1-20081120-C00460
    Figure US20080287347A1-20081120-C00461
    Figure US20080287347A1-20081120-C00462
    Figure US20080287347A1-20081120-C00463
    Figure US20080287347A1-20081120-C00464
    Figure US20080287347A1-20081120-C00465
    Figure US20080287347A1-20081120-C00466
    Figure US20080287347A1-20081120-C00467
    Figure US20080287347A1-20081120-C00468
    Figure US20080287347A1-20081120-C00469
    Figure US20080287347A1-20081120-C00470
    Figure US20080287347A1-20081120-C00471
    Figure US20080287347A1-20081120-C00472
    Figure US20080287347A1-20081120-C00473
    Figure US20080287347A1-20081120-C00474
    Figure US20080287347A1-20081120-C00475
    Figure US20080287347A1-20081120-C00476
    Figure US20080287347A1-20081120-C00477
    Figure US20080287347A1-20081120-C00478
    Figure US20080287347A1-20081120-C00479
    Figure US20080287347A1-20081120-C00480
    Figure US20080287347A1-20081120-C00481
    Figure US20080287347A1-20081120-C00482
    Figure US20080287347A1-20081120-C00483
    Figure US20080287347A1-20081120-C00484
    Figure US20080287347A1-20081120-C00485
    Figure US20080287347A1-20081120-C00486
    Figure US20080287347A1-20081120-C00487
    Figure US20080287347A1-20081120-C00488
    Figure US20080287347A1-20081120-C00489
    Figure US20080287347A1-20081120-C00490
    Figure US20080287347A1-20081120-C00491
    Figure US20080287347A1-20081120-C00492
    Figure US20080287347A1-20081120-C00493
    Figure US20080287347A1-20081120-C00494
    Figure US20080287347A1-20081120-C00495
    Figure US20080287347A1-20081120-C00496
    Figure US20080287347A1-20081120-C00497
    Figure US20080287347A1-20081120-C00498
    Figure US20080287347A1-20081120-C00499
    Figure US20080287347A1-20081120-C00500
    Figure US20080287347A1-20081120-C00501
    Figure US20080287347A1-20081120-C00502
    Figure US20080287347A1-20081120-C00503
    Figure US20080287347A1-20081120-C00504
    Figure US20080287347A1-20081120-C00505
    Figure US20080287347A1-20081120-C00506
    Figure US20080287347A1-20081120-C00507
    Figure US20080287347A1-20081120-C00508
    Figure US20080287347A1-20081120-C00509
    Figure US20080287347A1-20081120-C00510
    Figure US20080287347A1-20081120-C00511
    Figure US20080287347A1-20081120-C00512
    Figure US20080287347A1-20081120-C00513
    Figure US20080287347A1-20081120-C00514
    Figure US20080287347A1-20081120-C00515
    Figure US20080287347A1-20081120-C00516
    Figure US20080287347A1-20081120-C00517
    Figure US20080287347A1-20081120-C00518
    Figure US20080287347A1-20081120-C00519
    Figure US20080287347A1-20081120-C00520
    Figure US20080287347A1-20081120-C00521
    Figure US20080287347A1-20081120-C00522
    Figure US20080287347A1-20081120-C00523
    Figure US20080287347A1-20081120-C00524
    Figure US20080287347A1-20081120-C00525
    Figure US20080287347A1-20081120-C00526
    Figure US20080287347A1-20081120-C00527
    Figure US20080287347A1-20081120-C00528
    Figure US20080287347A1-20081120-C00529
    Figure US20080287347A1-20081120-C00530
    Figure US20080287347A1-20081120-C00531
    Figure US20080287347A1-20081120-C00532
    Figure US20080287347A1-20081120-C00533
    Figure US20080287347A1-20081120-C00534
    Figure US20080287347A1-20081120-C00535
    Figure US20080287347A1-20081120-C00536
    Figure US20080287347A1-20081120-C00537
    Figure US20080287347A1-20081120-C00538
    Figure US20080287347A1-20081120-C00539
    Figure US20080287347A1-20081120-C00540
    Figure US20080287347A1-20081120-C00541
    Figure US20080287347A1-20081120-C00542
    Figure US20080287347A1-20081120-C00543
    Figure US20080287347A1-20081120-C00544
    Figure US20080287347A1-20081120-C00545
    Figure US20080287347A1-20081120-C00546
    Figure US20080287347A1-20081120-C00547
    Figure US20080287347A1-20081120-C00548
    Figure US20080287347A1-20081120-C00549
    Figure US20080287347A1-20081120-C00550
    Figure US20080287347A1-20081120-C00551
    Figure US20080287347A1-20081120-C00552
    Figure US20080287347A1-20081120-C00553
    Figure US20080287347A1-20081120-C00554
    Figure US20080287347A1-20081120-C00555
    Figure US20080287347A1-20081120-C00556
    Figure US20080287347A1-20081120-C00557
    Figure US20080287347A1-20081120-C00558
    Figure US20080287347A1-20081120-C00559
    Figure US20080287347A1-20081120-C00560
    Figure US20080287347A1-20081120-C00561
    Figure US20080287347A1-20081120-C00562
    Figure US20080287347A1-20081120-C00563
    Figure US20080287347A1-20081120-C00564
    Figure US20080287347A1-20081120-C00565
    Figure US20080287347A1-20081120-C00566
    Figure US20080287347A1-20081120-C00567
    Figure US20080287347A1-20081120-C00568
    Figure US20080287347A1-20081120-C00569
    Figure US20080287347A1-20081120-C00570
    Figure US20080287347A1-20081120-C00571
    Figure US20080287347A1-20081120-C00572
    Figure US20080287347A1-20081120-C00573
    Figure US20080287347A1-20081120-C00574
    Figure US20080287347A1-20081120-C00575
    Figure US20080287347A1-20081120-C00576
    Figure US20080287347A1-20081120-C00577
    Figure US20080287347A1-20081120-C00578
    Figure US20080287347A1-20081120-C00579
    Figure US20080287347A1-20081120-C00580
    Figure US20080287347A1-20081120-C00581
    Figure US20080287347A1-20081120-C00582
    Figure US20080287347A1-20081120-C00583
    Figure US20080287347A1-20081120-C00584
    Figure US20080287347A1-20081120-C00585
    Figure US20080287347A1-20081120-C00586
    Figure US20080287347A1-20081120-C00587
    Figure US20080287347A1-20081120-C00588
    Figure US20080287347A1-20081120-C00589
    Figure US20080287347A1-20081120-C00590
    Figure US20080287347A1-20081120-C00591
    Figure US20080287347A1-20081120-C00592
    Figure US20080287347A1-20081120-C00593
    Figure US20080287347A1-20081120-C00594
    Figure US20080287347A1-20081120-C00595
    Figure US20080287347A1-20081120-C00596
    Figure US20080287347A1-20081120-C00597
    Figure US20080287347A1-20081120-C00598
    Figure US20080287347A1-20081120-C00599
    Figure US20080287347A1-20081120-C00600
    Figure US20080287347A1-20081120-C00601
    Figure US20080287347A1-20081120-C00602
    Figure US20080287347A1-20081120-C00603
    Figure US20080287347A1-20081120-C00604
    Figure US20080287347A1-20081120-C00605
    Figure US20080287347A1-20081120-C00606
    Figure US20080287347A1-20081120-C00607
    Figure US20080287347A1-20081120-C00608
    Figure US20080287347A1-20081120-C00609
    Figure US20080287347A1-20081120-C00610
    Figure US20080287347A1-20081120-C00611
    Figure US20080287347A1-20081120-C00612
    Figure US20080287347A1-20081120-C00613
    Figure US20080287347A1-20081120-C00614
    Figure US20080287347A1-20081120-C00615
    Figure US20080287347A1-20081120-C00616
    Figure US20080287347A1-20081120-C00617
    Figure US20080287347A1-20081120-C00618
    Figure US20080287347A1-20081120-C00619
    Figure US20080287347A1-20081120-C00620
    Figure US20080287347A1-20081120-C00621
    Figure US20080287347A1-20081120-C00622
    Figure US20080287347A1-20081120-C00623
    Figure US20080287347A1-20081120-C00624
    Figure US20080287347A1-20081120-C00625
    Figure US20080287347A1-20081120-C00626
    Figure US20080287347A1-20081120-C00627
    Figure US20080287347A1-20081120-C00628
    Figure US20080287347A1-20081120-C00629
    Figure US20080287347A1-20081120-C00630
    Figure US20080287347A1-20081120-C00631
    Figure US20080287347A1-20081120-C00632
    Figure US20080287347A1-20081120-C00633
    Figure US20080287347A1-20081120-C00634
    Figure US20080287347A1-20081120-C00635
    Figure US20080287347A1-20081120-C00636
    Figure US20080287347A1-20081120-C00637
    Figure US20080287347A1-20081120-C00638
    Figure US20080287347A1-20081120-C00639
    Figure US20080287347A1-20081120-C00640
    Figure US20080287347A1-20081120-C00641
    Figure US20080287347A1-20081120-C00642
    Figure US20080287347A1-20081120-C00643
    Figure US20080287347A1-20081120-C00644
    Figure US20080287347A1-20081120-C00645
    Figure US20080287347A1-20081120-C00646
    Figure US20080287347A1-20081120-C00647
    Figure US20080287347A1-20081120-C00648
    Figure US20080287347A1-20081120-C00649
    Figure US20080287347A1-20081120-C00650
    Figure US20080287347A1-20081120-C00651
    Figure US20080287347A1-20081120-C00652
    Figure US20080287347A1-20081120-C00653
    Figure US20080287347A1-20081120-C00654
    Figure US20080287347A1-20081120-C00655
    Figure US20080287347A1-20081120-C00656
    Figure US20080287347A1-20081120-C00657
    Figure US20080287347A1-20081120-C00658
    Figure US20080287347A1-20081120-C00659
    Figure US20080287347A1-20081120-C00660
    Figure US20080287347A1-20081120-C00661
    Figure US20080287347A1-20081120-C00662
    Figure US20080287347A1-20081120-C00663
    Figure US20080287347A1-20081120-C00664
    Figure US20080287347A1-20081120-C00665
    Figure US20080287347A1-20081120-C00666
    Figure US20080287347A1-20081120-C00667
  • TABLE I
    Table I provides exemplary compounds of Formula I:
    Synth
    Mass Ex
    Cpd # R R1 R2 Spec #
    1 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00668
    Figure US20080287347A1-20081120-C00669
         		1863 6
    2 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00670
    Figure US20080287347A1-20081120-C00671
         		1663 6
    3 NHCO(CH2)8CH3 NHSO2Ph
    Figure US20080287347A1-20081120-C00672
         		1762 5
    4 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00673
    Figure US20080287347A1-20081120-C00674
         		1792 4
    5 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00675
    Figure US20080287347A1-20081120-C00676
         		1694 4
    6 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00677
    Figure US20080287347A1-20081120-C00678
         		1722 4
    7 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00679
    Figure US20080287347A1-20081120-C00680
         		1764 4
    8 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00681
    Figure US20080287347A1-20081120-C00682
         		1720 4
    9 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00683
    Figure US20080287347A1-20081120-C00684
         		1775 4
    10 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00685
    Figure US20080287347A1-20081120-C00686
         		1740 2
    11 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00687
    Figure US20080287347A1-20081120-C00688
         		1775 2
    12 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00689
    Figure US20080287347A1-20081120-C00690
         		1820 2
    13 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00691
    Figure US20080287347A1-20081120-C00692
         		1755 2
    14 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00693
    Figure US20080287347A1-20081120-C00694
         		1755 2
    15 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00695
    Figure US20080287347A1-20081120-C00696
         		1771 2
    16 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00697
    Figure US20080287347A1-20081120-C00698
         		1771 2
    17 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00699
    Figure US20080287347A1-20081120-C00700
         		1775 2
    18 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00701
    Figure US20080287347A1-20081120-C00702
         		1812  3b
    19 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00703
    Figure US20080287347A1-20081120-C00704
         		1785 2
    20 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00705
    Figure US20080287347A1-20081120-C00706
         		1755 2
    21 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00707
    Figure US20080287347A1-20081120-C00708
         		1756  3b
    22 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00709
    Figure US20080287347A1-20081120-C00710
         		1757 2
    23 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00711
    Figure US20080287347A1-20081120-C00712
         		1742 2
    24 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00713
    Figure US20080287347A1-20081120-C00714
         		1790 2
    25 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00715
    Figure US20080287347A1-20081120-C00716
         		1758 2
    26 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00717
    Figure US20080287347A1-20081120-C00718
         		1758 2
    27 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00719
    Figure US20080287347A1-20081120-C00720
         		1758 2
    28 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00721
    Figure US20080287347A1-20081120-C00722
         		1726  3b
    29 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00723
    Figure US20080287347A1-20081120-C00724
         		1728  3b
    30 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00725
    Figure US20080287347A1-20081120-C00726
         		1741  3b
    31 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00727
    Figure US20080287347A1-20081120-C00728
         		1741  3b
    32 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00729
    Figure US20080287347A1-20081120-C00730
         		1771  3b
    33 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00731
    Figure US20080287347A1-20081120-C00732
         		1851  3b
    34 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00733
    Figure US20080287347A1-20081120-C00734
         		1767  3b
    35 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00735
    Figure US20080287347A1-20081120-C00736
         		1782  3b
    36 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00737
    Figure US20080287347A1-20081120-C00738
         		1780 8
    37 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00739
    Figure US20080287347A1-20081120-C00740
         		1873 8
    38 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00741
    Figure US20080287347A1-20081120-C00742
         		1729 1
    39 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00743
    Figure US20080287347A1-20081120-C00744
         		1838  3b
    40 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00745
    Figure US20080287347A1-20081120-C00746
         		1741 1
    41 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00747
    Figure US20080287347A1-20081120-C00748
         		1908 3
    42 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00749
    Figure US20080287347A1-20081120-C00750
         		1865 3
    43 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00751
    Figure US20080287347A1-20081120-C00752
         		1893 3
    44 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00753
    Figure US20080287347A1-20081120-C00754
         		1908 3
    45 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00755
    Figure US20080287347A1-20081120-C00756
         		1808 3
    46 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00757
    Figure US20080287347A1-20081120-C00758
         		1764 3
    47 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00759
    Figure US20080287347A1-20081120-C00760
         		1750 3
    48 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00761
    Figure US20080287347A1-20081120-C00762
         		1736 3
    49 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00763
    Figure US20080287347A1-20081120-C00764
         		2004  3a
    50 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00765
    Figure US20080287347A1-20081120-C00766
         		1712 1
    51 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00767
    Figure US20080287347A1-20081120-C00768
         		1904  3a
    52 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00769
    Figure US20080287347A1-20081120-C00770
         		1725 1
    54 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00771
    Figure US20080287347A1-20081120-C00772
         		1749  3a
    55 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00773
    Figure US20080287347A1-20081120-C00774
         		1884 3
    56 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00775
    Figure US20080287347A1-20081120-C00776
         		1785 3
    57 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00777
    Figure US20080287347A1-20081120-C00778
         		1853 3
    58 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00779
    Figure US20080287347A1-20081120-C00780
         		1847 3
    60 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00781
    Figure US20080287347A1-20081120-C00782
         		1778 3
    61 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00783
    Figure US20080287347A1-20081120-C00784
         		1792 3
    62 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00785
    Figure US20080287347A1-20081120-C00786
         		1826 3
    63 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00787
    Figure US20080287347A1-20081120-C00788
         		1826 3
    64 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00789
    Figure US20080287347A1-20081120-C00790
         		1838 3
    65 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00791
    Figure US20080287347A1-20081120-C00792
         		1812 3
    66 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00793
    Figure US20080287347A1-20081120-C00794
         		1808 3
    67 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00795
    Figure US20080287347A1-20081120-C00796
         		1769 3
    68 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00797
    Figure US20080287347A1-20081120-C00798
         		1824 3
    69 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00799
    Figure US20080287347A1-20081120-C00800
         		1775 3
    70 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00801
    Figure US20080287347A1-20081120-C00802
         		1820 3
    72 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00803
    Figure US20080287347A1-20081120-C00804
         		1707 3
    73 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00805
    Figure US20080287347A1-20081120-C00806
         		1758 3
    74 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00807
    Figure US20080287347A1-20081120-C00808
         		1959 3
    75 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00809
    Figure US20080287347A1-20081120-C00810
         		1810 3
    76 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00811
    Figure US20080287347A1-20081120-C00812
         		1787  1g
    77 NHCO(CH2)8CH3 NH(CH2)2OH
    Figure US20080287347A1-20081120-C00813
         		1665 1
    78 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00814
    Figure US20080287347A1-20081120-C00815
         		1820 1
    79 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00816
    Figure US20080287347A1-20081120-C00817
         		1750 1
    80 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00818
    Figure US20080287347A1-20081120-C00819
         		1779 1
    81 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00820
    Figure US20080287347A1-20081120-C00821
         		1767  1e
    82 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00822
    Figure US20080287347A1-20081120-C00823
         		1763 1
    83 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00824
    Figure US20080287347A1-20081120-C00825
         		1869 1
    84 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00826
    Figure US20080287347A1-20081120-C00827
         		1764 1
    85 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00828
    Figure US20080287347A1-20081120-C00829
         		1714  1c
    86
    Figure US20080287347A1-20081120-C00830
    Figure US20080287347A1-20081120-C00831
    Figure US20080287347A1-20081120-C00832
         		1935 9
    87 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00833
    Figure US20080287347A1-20081120-C00834
         		1863 1
    88 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00835
    Figure US20080287347A1-20081120-C00836
         		2151 1
    89 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00837
    Figure US20080287347A1-20081120-C00838
         		1887 1
    90 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00839
    Figure US20080287347A1-20081120-C00840
         		2046 1
    91 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00841
    Figure US20080287347A1-20081120-C00842
         		1996 1
    92 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00843
    Figure US20080287347A1-20081120-C00844
         		1809 1
    93 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00845
    Figure US20080287347A1-20081120-C00846
         		1783 1
    94 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00847
    Figure US20080287347A1-20081120-C00848
         		1770 1
    95 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00849
    Figure US20080287347A1-20081120-C00850
         		1836 1
    96 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00851
    Figure US20080287347A1-20081120-C00852
         		1792 1
    97 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00853
    Figure US20080287347A1-20081120-C00854
         		1847 1
    98 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00855
    Figure US20080287347A1-20081120-C00856
         		1838 1
    99 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00857
    Figure US20080287347A1-20081120-C00858
         		1837 1
    100 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00859
    Figure US20080287347A1-20081120-C00860
         		1817 1
    101
    Figure US20080287347A1-20081120-C00861
    Figure US20080287347A1-20081120-C00862
    Figure US20080287347A1-20081120-C00863
         		1867 9
    102 NHCO(CH2)11CH3
    Figure US20080287347A1-20081120-C00864
    Figure US20080287347A1-20081120-C00865
         		1849 9
    103 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00866
    Figure US20080287347A1-20081120-C00867
         		1885 1
    104 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00868
    Figure US20080287347A1-20081120-C00869
         		2150 1
    105 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00870
    Figure US20080287347A1-20081120-C00871
         		1756 1
    106 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00872
    Figure US20080287347A1-20081120-C00873
         		1833 1
    107 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00874
    Figure US20080287347A1-20081120-C00875
         		1871 1
    108 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00876
    Figure US20080287347A1-20081120-C00877
         		1873 1
    109 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00878
    Figure US20080287347A1-20081120-C00879
         		1872 1
    110 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00880
    Figure US20080287347A1-20081120-C00881
         		2014 1
    111 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00882
    Figure US20080287347A1-20081120-C00883
         		1817 1
    112 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00884
    Figure US20080287347A1-20081120-C00885
         		2121 1
    113 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00886
    Figure US20080287347A1-20081120-C00887
         		2036 1
    114 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00888
    Figure US20080287347A1-20081120-C00889
         		1826 1
    115 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00890
    Figure US20080287347A1-20081120-C00891
         		1736 1
    116 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00892
    Figure US20080287347A1-20081120-C00893
         		1797 1
    117 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00894
    Figure US20080287347A1-20081120-C00895
         		1860 1
    118 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00896
    Figure US20080287347A1-20081120-C00897
         		2055 1
    119 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00898
    Figure US20080287347A1-20081120-C00899
         		1837 1
    120 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00900
    Figure US20080287347A1-20081120-C00901
         		2104 1
    121 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00902
    Figure US20080287347A1-20081120-C00903
         		1803 1
    122 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00904
    Figure US20080287347A1-20081120-C00905
         		1755 1
    123 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00906
    Figure US20080287347A1-20081120-C00907
         		1812 1
    124 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00908
    Figure US20080287347A1-20081120-C00909
         		2002 1
    125 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00910
    Figure US20080287347A1-20081120-C00911
         		1946 1
    126 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00912
    Figure US20080287347A1-20081120-C00913
         		1918 1
    127 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00914
    Figure US20080287347A1-20081120-C00915
         		1811 1
    128 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00916
    Figure US20080287347A1-20081120-C00917
         		2050 1
    129 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00918
    Figure US20080287347A1-20081120-C00919
         		1756 1
    130 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00920
    Figure US20080287347A1-20081120-C00921
         		1762 1
    131 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00922
    Figure US20080287347A1-20081120-C00923
         		1904 1
    132 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00924
    Figure US20080287347A1-20081120-C00925
         		1962 1
    133 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00926
    Figure US20080287347A1-20081120-C00927
         		1726 1
    134 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00928
    Figure US20080287347A1-20081120-C00929
         		2074 1
    135 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00930
    Figure US20080287347A1-20081120-C00931
         		1729 1
    136 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00932
    Figure US20080287347A1-20081120-C00933
         		1729 1
    137 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00934
    Figure US20080287347A1-20081120-C00935
         		2014 1
    138 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00936
    Figure US20080287347A1-20081120-C00937
         		1762 1
    139 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00938
    Figure US20080287347A1-20081120-C00939
         		1751 1
    140 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00940
    Figure US20080287347A1-20081120-C00941
         		1881 1
    141 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00942
    Figure US20080287347A1-20081120-C00943
         		1914 1
    142 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00944
    Figure US20080287347A1-20081120-C00945
         		1753 1
    143 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00946
    Figure US20080287347A1-20081120-C00947
         		1803 1
    144 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00948
    Figure US20080287347A1-20081120-C00949
         		1813 1
    145 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00950
    Figure US20080287347A1-20081120-C00951
         		2006 1
    146 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00952
    Figure US20080287347A1-20081120-C00953
         		1701 1
    147 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00954
    Figure US20080287347A1-20081120-C00955
         		1799 1
    148 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00956
    Figure US20080287347A1-20081120-C00957
         		1978 1
    149 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00958
    Figure US20080287347A1-20081120-C00959
         		1834 1
    150 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00960
    Figure US20080287347A1-20081120-C00961
         		1777 1
    151 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00962
    Figure US20080287347A1-20081120-C00963
         		1847 1
    152 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00964
    Figure US20080287347A1-20081120-C00965
         		2074 1
    153 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00966
    Figure US20080287347A1-20081120-C00967
         		1895 1
    154 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00968
    Figure US20080287347A1-20081120-C00969
         		1867 1
    155 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00970
    Figure US20080287347A1-20081120-C00971
         		1839 1
    156 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00972
    Figure US20080287347A1-20081120-C00973
         		1781 1
    157 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00974
    Figure US20080287347A1-20081120-C00975
         		1780 1
    158 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00976
    Figure US20080287347A1-20081120-C00977
         		1781 1
    159 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00978
    Figure US20080287347A1-20081120-C00979
         		1805 1
    160 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00980
    Figure US20080287347A1-20081120-C00981
         		1990 1
    161 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00982
    Figure US20080287347A1-20081120-C00983
         		1785 1
    162 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00984
    Figure US20080287347A1-20081120-C00985
         		2092 1
    163 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00986
    Figure US20080287347A1-20081120-C00987
         		1944 1
    164 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00988
    Figure US20080287347A1-20081120-C00989
         		1817 1
    165 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00990
    Figure US20080287347A1-20081120-C00991
         		2014 1
    166 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00992
    Figure US20080287347A1-20081120-C00993
         		1747 1
    167 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00994
    Figure US20080287347A1-20081120-C00995
         		1853 1
    168 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00996
    Figure US20080287347A1-20081120-C00997
         		1762 1
    169 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C00998
    Figure US20080287347A1-20081120-C00999
         		1829 1
    171 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01000
    Figure US20080287347A1-20081120-C01001
         		1914 1
    172 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01002
    Figure US20080287347A1-20081120-C01003
         		1767 1
    173 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01004
    Figure US20080287347A1-20081120-C01005
         		1736 1
    174 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01006
    Figure US20080287347A1-20081120-C01007
         		1718 1
    175 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01008
    Figure US20080287347A1-20081120-C01009
         		1808 1
    176 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01010
    Figure US20080287347A1-20081120-C01011
         		1781 1
    177 NH2
    Figure US20080287347A1-20081120-C01012
    Figure US20080287347A1-20081120-C01013
         		1632 1
    178 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01014
    Figure US20080287347A1-20081120-C01015
         		1783 3
    179 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01016
    Figure US20080287347A1-20081120-C01017
         		1884 3
    180 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01018
    Figure US20080287347A1-20081120-C01019
         		1905 3
    181 NHCONH(CH2)10CH3
    Figure US20080287347A1-20081120-C01020
    Figure US20080287347A1-20081120-C01021
         		1851 9
    182 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01022
    Figure US20080287347A1-20081120-C01023
         		1801  3b
    183 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01024
    Figure US20080287347A1-20081120-C01025
         		1833 1
    184 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01026
    Figure US20080287347A1-20081120-C01027
         		1727 1
    185 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01028
    Figure US20080287347A1-20081120-C01029
         		1743 1
    186 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01030
    Figure US20080287347A1-20081120-C01031
         		1890 1
    187 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01032
    Figure US20080287347A1-20081120-C01033
         		1756 1
    189 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01034
    Figure US20080287347A1-20081120-C01035
         		1717  3b
    190 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01036
    Figure US20080287347A1-20081120-C01037
         		1805 2
    192 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01038
    Figure US20080287347A1-20081120-C01039
         		1811 8
    193 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01040
    Figure US20080287347A1-20081120-C01041
         		1836 3
    194 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01042
    Figure US20080287347A1-20081120-C01043
         		1795 1
    195 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01044
    Figure US20080287347A1-20081120-C01045
         		1862 1
    196 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01046
    Figure US20080287347A1-20081120-C01047
         		1780 1
    197 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01048
    Figure US20080287347A1-20081120-C01049
         		1746 1
    198 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01050
    Figure US20080287347A1-20081120-C01051
         		1754 1
    199 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01052
    Figure US20080287347A1-20081120-C01053
         		1780 1
    200 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01054
    Figure US20080287347A1-20081120-C01055
         		1792  8a
    201 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01056
    Figure US20080287347A1-20081120-C01057
         		1821 1
    202 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01058
    Figure US20080287347A1-20081120-C01059
         		1
    203 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01060
    Figure US20080287347A1-20081120-C01061
         		1793 1
    204 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01062
    Figure US20080287347A1-20081120-C01063
         		1893
    205 NH(CH2)8CH3
    Figure US20080287347A1-20081120-C01064
    Figure US20080287347A1-20081120-C01065
         		1779  9a
    206 NHCO(CH2)8CO2Me
    Figure US20080287347A1-20081120-C01066
    Figure US20080287347A1-20081120-C01067
         		1851 9
    207 NHCO(CH2)6CO2Me
    Figure US20080287347A1-20081120-C01068
    Figure US20080287347A1-20081120-C01069
         		1823 9
    208 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01070
    Figure US20080287347A1-20081120-C01071
         		1878 1
    209 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01072
    Figure US20080287347A1-20081120-C01073
         		1880  1h
    210 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01074
    Figure US20080287347A1-20081120-C01075
         		1851 1
    211 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01076
    Figure US20080287347A1-20081120-C01077
         		1924 1
    212 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01078
    Figure US20080287347A1-20081120-C01079
         		1701  1d
    213 NHCO(CH2)6NHBoc
    Figure US20080287347A1-20081120-C01080
    Figure US20080287347A1-20081120-C01081
         		1980 9
    214 NHCO(CH2)7NHBoc
    Figure US20080287347A1-20081120-C01082
    Figure US20080287347A1-20081120-C01083
         		1994 9
    215 NHCO(CH2)10NHBoc
    Figure US20080287347A1-20081120-C01084
    Figure US20080287347A1-20081120-C01085
         		2036 9
    216 NHCO(CH2)11NHBoc
    Figure US20080287347A1-20081120-C01086
    Figure US20080287347A1-20081120-C01087
         		2050 9
    217 NHCO(CH2)10NH2
    Figure US20080287347A1-20081120-C01088
    Figure US20080287347A1-20081120-C01089
         		1836 9
    218 NHCO(CH2)11NH2
    Figure US20080287347A1-20081120-C01090
    Figure US20080287347A1-20081120-C01091
         		1850 9
    219 NHCO(CH2)6CH(CH3)2
    Figure US20080287347A1-20081120-C01092
    Figure US20080287347A1-20081120-C01093
         		1807 9
    220 NHCONH(CH2)11CH3
    Figure US20080287347A1-20081120-C01094
    Figure US20080287347A1-20081120-C01095
         		1865 9
    221 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01096
    Figure US20080287347A1-20081120-C01097
         		1807 6
    222 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01098
    Figure US20080287347A1-20081120-C01099
         		1935 1
    223 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01100
    Figure US20080287347A1-20081120-C01101
         		1779 1
    224 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01102
    Figure US20080287347A1-20081120-C01103
         		1936 1
    225 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01104
    Figure US20080287347A1-20081120-C01105
         		1735 1
    226 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01106
    Figure US20080287347A1-20081120-C01107
         		1958 1
    227 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01108
    Figure US20080287347A1-20081120-C01109
         		1899 1
    228 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01110
    Figure US20080287347A1-20081120-C01111
         		1917 1
    229 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01112
    Figure US20080287347A1-20081120-C01113
         		1914 1
    230 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01114
    Figure US20080287347A1-20081120-C01115
         		1969 1
    231 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01116
    Figure US20080287347A1-20081120-C01117
         		1990 1
    232 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01118
    Figure US20080287347A1-20081120-C01119
         		1940 1
    233 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01120
    Figure US20080287347A1-20081120-C01121
         		1902 1
    234 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01122
    Figure US20080287347A1-20081120-C01123
         		1901 1
    235 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01124
    Figure US20080287347A1-20081120-C01125
         		1934 1
    236 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01126
    Figure US20080287347A1-20081120-C01127
         		1984 1
    237 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01128
    Figure US20080287347A1-20081120-C01129
         		1926 1
    238 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01130
    Figure US20080287347A1-20081120-C01131
         		1944 1
    239 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01132
    Figure US20080287347A1-20081120-C01133
         		1940 1
    240 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01134
    Figure US20080287347A1-20081120-C01135
         		1995 1
    241 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01136
    Figure US20080287347A1-20081120-C01137
         		2016 1
    242 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01138
    Figure US20080287347A1-20081120-C01139
         		1928 1
    243 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01140
    Figure US20080287347A1-20081120-C01141
         		1927 1
    244 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01142
    Figure US20080287347A1-20081120-C01143
         		1960 1
    245 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01144
    Figure US20080287347A1-20081120-C01145
         		1790 3
    246
    Figure US20080287347A1-20081120-C01146
    Figure US20080287347A1-20081120-C01147
    Figure US20080287347A1-20081120-C01148
         		1807 9
    247
    Figure US20080287347A1-20081120-C01149
    Figure US20080287347A1-20081120-C01150
    Figure US20080287347A1-20081120-C01151
         		1841 9
    248
    Figure US20080287347A1-20081120-C01152
    Figure US20080287347A1-20081120-C01153
    Figure US20080287347A1-20081120-C01154
         		1864 9
    249
    Figure US20080287347A1-20081120-C01155
    Figure US20080287347A1-20081120-C01156
    Figure US20080287347A1-20081120-C01157
         		1843 9
    250
    Figure US20080287347A1-20081120-C01158
    Figure US20080287347A1-20081120-C01159
    Figure US20080287347A1-20081120-C01160
         		1882 9
    251
    Figure US20080287347A1-20081120-C01161
    Figure US20080287347A1-20081120-C01162
    Figure US20080287347A1-20081120-C01163
         		1823 9
    252 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01164
    Figure US20080287347A1-20081120-C01165
         		1931 1
    253 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01166
    Figure US20080287347A1-20081120-C01167
         		1886  1f
    254 NHCO(CH2)7CH3
    Figure US20080287347A1-20081120-C01168
    Figure US20080287347A1-20081120-C01169
         		1650 7
    255 NHCO(CH2)9CH3
    Figure US20080287347A1-20081120-C01170
    Figure US20080287347A1-20081120-C01171
         		1678 7
    256 NHCO(CH2)10CH3
    Figure US20080287347A1-20081120-C01172
    Figure US20080287347A1-20081120-C01173
         		1692 7
    257 NHCO(CH2)11CH3
    Figure US20080287347A1-20081120-C01174
    Figure US20080287347A1-20081120-C01175
         		1706 7
    258 NHCO(CH2)12CH3
    Figure US20080287347A1-20081120-C01176
    Figure US20080287347A1-20081120-C01177
         		1720  7a
    259 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01178
    Figure US20080287347A1-20081120-C01179
         		1706 6
    260 NHCO(CH2)9CH3
    Figure US20080287347A1-20081120-C01180
    Figure US20080287347A1-20081120-C01181
         		1678 7
    261 NHCO(CH2)11CH3
    Figure US20080287347A1-20081120-C01182
    Figure US20080287347A1-20081120-C01183
         		1705 7
    262 NHCO(CH2)12CH3
    Figure US20080287347A1-20081120-C01184
    Figure US20080287347A1-20081120-C01185
         		1719  7a
    263
    Figure US20080287347A1-20081120-C01186
    Figure US20080287347A1-20081120-C01187
    Figure US20080287347A1-20081120-C01188
         		1738 7
    264
    Figure US20080287347A1-20081120-C01189
    Figure US20080287347A1-20081120-C01190
    Figure US20080287347A1-20081120-C01191
         		1862 9
    265 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01192
    Figure US20080287347A1-20081120-C01193
         		1890 1
    266 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01194
    Figure US20080287347A1-20081120-C01195
         		1841 1
    267 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01196
    Figure US20080287347A1-20081120-C01197
         		1910 1
    268 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01198
    Figure US20080287347A1-20081120-C01199
         		1940 9
    269
    Figure US20080287347A1-20081120-C01200
    Figure US20080287347A1-20081120-C01201
    Figure US20080287347A1-20081120-C01202
         		1862 6
    270 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01203
    Figure US20080287347A1-20081120-C01204
         		1706 6
    271 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01205
    Figure US20080287347A1-20081120-C01206
         		1851 1
    272 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01207
    Figure US20080287347A1-20081120-C01208
         		2081 1
    273 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01209
    Figure US20080287347A1-20081120-C01210
         		1964 1
    274 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01211
    Figure US20080287347A1-20081120-C01212
         		1793 1
    275 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01213
    Figure US20080287347A1-20081120-C01214
         		1797 1
    276 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01215
    Figure US20080287347A1-20081120-C01216
         		1973 1
    277 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01217
    Figure US20080287347A1-20081120-C01218
         		1778 1
    278 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01219
    Figure US20080287347A1-20081120-C01220
         		1780 1
    279 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01221
    Figure US20080287347A1-20081120-C01222
         		1940 1
    280 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01223
    Figure US20080287347A1-20081120-C01224
         		1797 1
    281 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01225
    Figure US20080287347A1-20081120-C01226
         		1974 1
    282 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01227
    Figure US20080287347A1-20081120-C01228
         		1807  1a
    283 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01229
    Figure US20080287347A1-20081120-C01230
         		1797 1
    284 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01231
    Figure US20080287347A1-20081120-C01232
         		1973 1
    285 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01233
    Figure US20080287347A1-20081120-C01234
         		1796  1b
    286 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01235
    Figure US20080287347A1-20081120-C01236
         		1898 1
    287 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01237
    Figure US20080287347A1-20081120-C01238
         		1806 1
    288 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01239
    Figure US20080287347A1-20081120-C01240
         		1812 1
    289 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01241
    Figure US20080287347A1-20081120-C01242
         		1806 1
    290 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01243
    Figure US20080287347A1-20081120-C01244
         		1806 1
    291 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01245
    Figure US20080287347A1-20081120-C01246
         		1848 1
    292
    Figure US20080287347A1-20081120-C01247
    Figure US20080287347A1-20081120-C01248
    Figure US20080287347A1-20081120-C01249
         		1738 7
    293 NHCO(CH2)10CH3
    Figure US20080287347A1-20081120-C01250
    Figure US20080287347A1-20081120-C01251
         		1692 7
    294 NHCO(CH2)7CH3
    Figure US20080287347A1-20081120-C01252
    Figure US20080287347A1-20081120-C01253
         		1650 7
    295 NHCO(CH2)11CH3
    Figure US20080287347A1-20081120-C01254
    Figure US20080287347A1-20081120-C01255
         		1991 10b
    296 NHCO(CH2)10CH3
    Figure US20080287347A1-20081120-C01256
    Figure US20080287347A1-20081120-C01257
         		1978 10b
    297 NHCO(CH2)9CH3
    Figure US20080287347A1-20081120-C01258
    Figure US20080287347A1-20081120-C01259
         		1964 10b
    298 NHCONH(CH2)7CH3
    Figure US20080287347A1-20081120-C01260
    Figure US20080287347A1-20081120-C01261
         		1950 10b
    299 NHCONH(CH2)10CH3
    Figure US20080287347A1-20081120-C01262
    Figure US20080287347A1-20081120-C01263
         		1992 10b
    300 NHCONH(CH2)11CH3
    Figure US20080287347A1-20081120-C01264
    Figure US20080287347A1-20081120-C01265
         		2006 10b
    301 NHCO(CH2)11CH3
    Figure US20080287347A1-20081120-C01266
    Figure US20080287347A1-20081120-C01267
         		1791 10b
    302 NHCO(CH2)10CH3
    Figure US20080287347A1-20081120-C01268
    Figure US20080287347A1-20081120-C01269
         		1778 10b
    303 NHCO(CH2)9CH3
    Figure US20080287347A1-20081120-C01270
    Figure US20080287347A1-20081120-C01271
         		1764 10b
    304 NHCONH(CH2)7CH3
    Figure US20080287347A1-20081120-C01272
    Figure US20080287347A1-20081120-C01273
         		1750 10b
    305 NHCONH(CH2)10CH3
    Figure US20080287347A1-20081120-C01274
    Figure US20080287347A1-20081120-C01275
         		1792 10b
    306 NHCONH(CH2)11CH3
    Figure US20080287347A1-20081120-C01276
    Figure US20080287347A1-20081120-C01277
         		1806 10b
    307 NHCO(CH2)9CH3
    Figure US20080287347A1-20081120-C01278
    Figure US20080287347A1-20081120-C01279
         		1922 10b
    308 NHCO(CH2)10CH3
    Figure US20080287347A1-20081120-C01280
    Figure US20080287347A1-20081120-C01281
         		1936 10b
    309 NHCO(CH2)10CH3
    Figure US20080287347A1-20081120-C01282
    Figure US20080287347A1-20081120-C01283
         		1836 10b
    310 NHCO(CH2)9CH3
    Figure US20080287347A1-20081120-C01284
    Figure US20080287347A1-20081120-C01285
         		1821 10b
    311 NHCONH(CH2)7CH3
    Figure US20080287347A1-20081120-C01286
    Figure US20080287347A1-20081120-C01287
         		1808 10b
    312 NHCONH(CH2)7CH3
    Figure US20080287347A1-20081120-C01288
    Figure US20080287347A1-20081120-C01289
         		1759 10b
    313 NHCONH(CH2)7CH3
    Figure US20080287347A1-20081120-C01290
    Figure US20080287347A1-20081120-C01291
         		1665 7
    314 NHCONH(CH2)10CH3
    Figure US20080287347A1-20081120-C01292
    Figure US20080287347A1-20081120-C01293
         		1707 7
    315 NHCONH(CH2)7CH3
    Figure US20080287347A1-20081120-C01294
    Figure US20080287347A1-20081120-C01295
         		1779 10a
    316 NHCONH(CH2)7CH3
    Figure US20080287347A1-20081120-C01296
    Figure US20080287347A1-20081120-C01297
         		1700 10a
    317 NHCONH(CH2)7CH3
    Figure US20080287347A1-20081120-C01298
    Figure US20080287347A1-20081120-C01299
         		1806 10a
    318 NHCO(CH2)9CH3
    Figure US20080287347A1-20081120-C01300
    Figure US20080287347A1-20081120-C01301
         		1793 10a
    319 NHCO(CH2)9CH3
    Figure US20080287347A1-20081120-C01302
    Figure US20080287347A1-20081120-C01303
         		1714 10a
    320 NHCO(CH2)11CH3
    Figure US20080287347A1-20081120-C01304
    Figure US20080287347A1-20081120-C01305
         		1821 10a
    321 NHCO(CH2)11CH3
    Figure US20080287347A1-20081120-C01306
    Figure US20080287347A1-20081120-C01307
         		1848 10a
    322 NHCO(CH2)11CH3
    Figure US20080287347A1-20081120-C01308
    Figure US20080287347A1-20081120-C01309
         		1742 10a
    323 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01310
    Figure US20080287347A1-20081120-C01311
         		1943 1
    324 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01312
    Figure US20080287347A1-20081120-C01313
         		2010 1
    325 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01314
    Figure US20080287347A1-20081120-C01315
         		1893 1
    326 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01316
    Figure US20080287347A1-20081120-C01317
         		 956 1
    327 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01318
    Figure US20080287347A1-20081120-C01319
         		1875 1
    328 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01320
    Figure US20080287347A1-20081120-C01321
         		1919 1
    329 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01322
    Figure US20080287347A1-20081120-C01323
         		1987 1
    330 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01324
    Figure US20080287347A1-20081120-C01325
         		1909 1
    331 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01326
    Figure US20080287347A1-20081120-C01327
         		1998 1
    332 NHCO(CH2)10CH3
    Figure US20080287347A1-20081120-C01328
    Figure US20080287347A1-20081120-C01329
         		1807 10a
    333 NHCO(CH2)10CH3
    Figure US20080287347A1-20081120-C01330
    Figure US20080287347A1-20081120-C01331
         		1834 10a
    334 NHCO(CH2)10CH3
    Figure US20080287347A1-20081120-C01332
    Figure US20080287347A1-20081120-C01333
         		1728 10a
    335 NHCONH(CH2)11CH3
    Figure US20080287347A1-20081120-C01334
    Figure US20080287347A1-20081120-C01335
         		1757 10a
    336 NHCONH(CH2)11CH3
    Figure US20080287347A1-20081120-C01336
    Figure US20080287347A1-20081120-C01337
         		1864 10a
    337 NHCONH(CH2)11CH3
    Figure US20080287347A1-20081120-C01338
    Figure US20080287347A1-20081120-C01339
         		1836 10a
    338 NHCO(CH2)12CH3
    Figure US20080287347A1-20081120-C01340
    Figure US20080287347A1-20081120-C01341
         		1963 10b
    339 NHCO(CH2)12CH3
    Figure US20080287347A1-20081120-C01342
    Figure US20080287347A1-20081120-C01343
         		1863 10b
    340 NHCO(CH2)12CH3
    Figure US20080287347A1-20081120-C01344
    Figure US20080287347A1-20081120-C01345
         		2006 10b
    341 NHCO(CH2)12CH3
    Figure US20080287347A1-20081120-C01346
    Figure US20080287347A1-20081120-C01347
         		1805 10b
    342 NHCO(CH2)9CH3
    Figure US20080287347A1-20081120-C01348
    Figure US20080287347A1-20081120-C01349
         		1773 10b
    343 NHCO(CH2)10CH3
    Figure US20080287347A1-20081120-C01350
    Figure US20080287347A1-20081120-C01351
         		1786 10b
    344 NHCO(CH2)12CH3
    Figure US20080287347A1-20081120-C01352
    Figure US20080287347A1-20081120-C01353
         		1814 10b
    345 NHCO(CH2)12CH3
    Figure US20080287347A1-20081120-C01354
    Figure US20080287347A1-20081120-C01355
         		1756 10a
    346 NHCO(CH2)12CH3
    Figure US20080287347A1-20081120-C01356
    Figure US20080287347A1-20081120-C01357
         		1836 10a
    347 NHCO(CH2)7CH3
    Figure US20080287347A1-20081120-C01358
    Figure US20080287347A1-20081120-C01359
         		1765 10a
    348 NHCO(CH2)7CH3
    Figure US20080287347A1-20081120-C01360
    Figure US20080287347A1-20081120-C01361
         		1686 10a
    349 NHCO(CH2)7CH3
    Figure US20080287347A1-20081120-C01362
    Figure US20080287347A1-20081120-C01363
         		1792 10a
    350
    Figure US20080287347A1-20081120-C01364
    Figure US20080287347A1-20081120-C01365
    Figure US20080287347A1-20081120-C01366
         		1832 10b
    351 NHCO(CH2)11CH3
    Figure US20080287347A1-20081120-C01367
    Figure US20080287347A1-20081120-C01368
         		1801 10b
    352 NHCONH(CH2)10CH3
    Figure US20080287347A1-20081120-C01369
    Figure US20080287347A1-20081120-C01370
         		1801 10b
    355 NHCONH(CH2)10CH3
    Figure US20080287347A1-20081120-C01371
    Figure US20080287347A1-20081120-C01372
         		1743 10a
    356 NHCONH(CH2)10CH3
    Figure US20080287347A1-20081120-C01373
    Figure US20080287347A1-20081120-C01374
         		1822 10a
    358 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01375
    Figure US20080287347A1-20081120-C01376
         		1893 1
    359 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01377
    Figure US20080287347A1-20081120-C01378
         		 948 1
    360 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01379
    Figure US20080287347A1-20081120-C01380
         		 938 1
    361 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01381
    Figure US20080287347A1-20081120-C01382
         		 952 1
    362 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01383
    Figure US20080287347A1-20081120-C01384
         		 969 1
    363 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01385
    Figure US20080287347A1-20081120-C01386
         		 970 1
    364 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01387
    Figure US20080287347A1-20081120-C01388
         		 976 1
    365 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01389
    Figure US20080287347A1-20081120-C01390
         		 976 1
    366 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01391
    Figure US20080287347A1-20081120-C01392
         		 984 1
    367 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01393
    Figure US20080287347A1-20081120-C01394
         		 984 1
    368 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01395
    Figure US20080287347A1-20081120-C01396
         		 986 1
    369 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01397
    Figure US20080287347A1-20081120-C01398
         		 987 1
    370 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01399
    Figure US20080287347A1-20081120-C01400
         		 978 1
    371 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01401
    Figure US20080287347A1-20081120-C01402
         		 998 1
    372 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01403
    Figure US20080287347A1-20081120-C01404
         		1003 1
    373 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01405
    Figure US20080287347A1-20081120-C01406
         		1003 1
    374 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01407
    Figure US20080287347A1-20081120-C01408
         		 970 1
    375 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01409
    Figure US20080287347A1-20081120-C01410
         		 950 1
    376 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01411
    Figure US20080287347A1-20081120-C01412
         		 950 1
    377 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01413
    Figure US20080287347A1-20081120-C01414
         		 950 1
    378 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01415
    Figure US20080287347A1-20081120-C01416
         		 955 1
    379 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01417
    Figure US20080287347A1-20081120-C01418
         		 957 1
    380 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01419
    Figure US20080287347A1-20081120-C01420
         		 958 1
    381 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01421
    Figure US20080287347A1-20081120-C01422
         		 959 1
    382 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01423
    Figure US20080287347A1-20081120-C01424
         		 959 1
    383 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01425
    Figure US20080287347A1-20081120-C01426
         		 965 1
    384 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01427
    Figure US20080287347A1-20081120-C01428
         		 965 1
    385 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01429
    Figure US20080287347A1-20081120-C01430
         		 975 1
    386 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01431
    Figure US20080287347A1-20081120-C01432
         		 975 1
    387 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01433
    Figure US20080287347A1-20081120-C01434
         		 975 1
    388 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01435
    Figure US20080287347A1-20081120-C01436
         		 957 1
    389 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01437
    Figure US20080287347A1-20081120-C01438
         		 976 1
    390 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01439
    Figure US20080287347A1-20081120-C01440
         		 976 1
    391 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01441
    Figure US20080287347A1-20081120-C01442
         		 976 1
    392 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01443
    Figure US20080287347A1-20081120-C01444
         		 983 1
    393 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01445
    Figure US20080287347A1-20081120-C01446
         		 983 1
    394 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01447
    Figure US20080287347A1-20081120-C01448
         		 948 1
    395 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01449
    Figure US20080287347A1-20081120-C01450
         		 941 1
    398 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01451
    Figure US20080287347A1-20081120-C01452
         		1
    399 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01453
    Figure US20080287347A1-20081120-C01454
         		1
    400 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01455
    Figure US20080287347A1-20081120-C01456
         		1
    401 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01457
    Figure US20080287347A1-20081120-C01458
         		1
    402 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01459
    Figure US20080287347A1-20081120-C01460
         		1
    403 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01461
    Figure US20080287347A1-20081120-C01462
         		1
    404 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01463
    Figure US20080287347A1-20081120-C01464
         		1
    405 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01465
    Figure US20080287347A1-20081120-C01466
         		1
    406 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01467
    Figure US20080287347A1-20081120-C01468
         		1
    407 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01469
    Figure US20080287347A1-20081120-C01470
         		1
    408 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01471
    Figure US20080287347A1-20081120-C01472
         		1
    409 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01473
    Figure US20080287347A1-20081120-C01474
         		1
    410 NHCO(CH2)8CH3
    Figure US20080287347A1-20081120-C01475
    Figure US20080287347A1-20081120-C01476
         		1
  • Preferred compounds of the present invention are compounds 45, 54, 76, 81, 85, 102, 209, 212, 253, 260, 262, 282, 285, 319, 322, 333, 334, 335, 336, 344 and 355.
  • According to a preferred embodiment, the present invention provides one or more crystalline forms of compounds of formula (I) and salts thereof
    • Lipopeptide Intermediates
  • The present invention also provides compounds that are particularly useful as intermediates for the preparation of the compounds of Formula I. These compounds may also have antibacterial properties, as discussed above. In one aspect of the invention, compounds of Formula II are provided:
  • Figure US20080287347A1-20081120-C01477
  • wherein R14 is selected from the group consisting of
  • Figure US20080287347A1-20081120-C01478
  • wherein R56 is an optionally substituted straight-chain C8-C14 alkyl group and wherein q′ is 0-3.
  • In another aspect of the invention, compounds of Formula III are provided as useful intermediates for the preparation of compounds of Formula I and/or as antibacterial compounds:
  • Figure US20080287347A1-20081120-C01479
  • wherein R15 is selected from hydrido and a carbamate amino protecting group, preferably a tert-butoxycarbonyl group; wherein R16 is selected from the group consisting of
  • Figure US20080287347A1-20081120-C01480
  • wherein R57 is a halo or halo substituted alkyl group, preferably a fluoro or trifluoromethyl group; wherein, R20 is an amino acid side chain, preferably a lysine or tryptophan side chain.
  • Compounds 2, 10, 25, 38, 45, 50, 54, 76, 78, 79, 80, 81, 82, 84, 85, 103, 105, 107, 111, 115, 130, 138, 139, 146, 147, 150, 158, 164, 168, 174, 210, 212, 227, 253, 274, 275, 280, 283, 285, 317, 372 and 386 are useful both as antibacterial compounds and as intermediates in the synthesis of compounds of this invention.
    • Lipopeptide Compound Pharmaceutical Compositions and Methods of Use Thereof
  • Another object of the instant invention is to provide lipopeptide compounds or salts thereof, as well as pharmaceutical compositions or formulations comprising lipopeptide compounds or its salts.
  • Lipopeptide compounds, or pharmaceutically acceptable salts thereof, can be formulated for oral, intravenous, intramuscular, subcutaneous or parenteral administration for the therapeutic or prophylactic treatment of diseases, particularly bacterial infections. For oral or parenteral administration, lipopeptide compounds of this 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%.
  • The pharmaceutical preparations disclosed herein are prepared in accordance with standard procedures and are administered at dosages that are selected to reduce, prevent or eliminate the infection (See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. and Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Pergamon Press, New York, N.Y., the contents of which are incorporated herein by reference, for a general description of the methods for administering various antimicrobial agents for human therapy). The compositions of the invention (preferably of Formula I) can be delivered using controlled (e.g., capsules) or sustained release delivery systems (e.g., bioerodable matrices). Exemplary delayed release delivery systems for drug delivery that are suitable for administration of the compositions of the invention (preferably of Formula I) are described in U.S. Pat. Nos. 4,452,775 (issued to Kent), 5,239,660 (issued to Leonard), 3,854,480 (issued to Zaffaroni).
  • The pharmaceutically-acceptable 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. 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.
  • For oral use, solid formulations such as tablets and capsules are particularly useful. Sustained release or enterically coated preparations may also be devised. For pediatric and geriatric applications, suspensions, syrups and chewable tablets are especially suitable. For oral administration, 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. For therapeutic purposes, 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. 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. Examples of 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.
  • For intravenous (IV) use, a lipopeptide compound according to the 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.
  • For intramuscular preparations, a sterile formulation of a lipopeptide compound 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. 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 lipopeptide compound 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.
  • For topical use the compounds of the present invention 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. Such topical formulations further can include chemical compounds such as dimethylsulfoxide (DMSO) to facilitate surface penetration of the active ingredient.
  • For application to the eyes or ears, the compounds of the present invention can be presented in liquid or semi-liquid form formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints or powders.
  • For rectal administration the compounds of the present invention can be administered in the form of suppositories admixed with conventional carriers such as cocoa butter, wax or other glyceride.
  • Alternatively, the compounds of the present invention can be in powder form for reconstitution in the appropriate pharmaceutically acceptable carrier at the time of delivery. In another embodiment, 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. If the compositions contain dosage units, each dosage unit preferably contains from 1-500 mg of the active material. For adult human treatment, the dosage employed preferably ranges from 5 mg to 10 g, per day, depending on the route and frequency of administration.
  • In another aspect, the invention provides a method for inhibiting the growth of microorganisms, preferably bacteria, comprising contacting said organisms with a compound of the invention, preferably a compound of Formula I, under conditions which permit entry of the compound into said organism and into said microorganism. Such conditions are known to one skilled in the art and are exemplified in the Examples. 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.
  • According to this aspect of the invention, 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. In general, 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 invention (preferably compounds of Formula I) for the drugs in the art-recognized protocols. Likewise, the methods for using the claimed composition for treating cells in culture, for example, to eliminate or reduce the level of bacterial contamination of a cell 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.
  • In one embodiment, 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 lipopeptide compound according to Formula I. Exemplary procedures for delivering an antibacterial agent are described in U.S. Pat. No. 5,041,567, issued to Rogers and in PCT patent application number EP94/02552 (publication no. WO 95/05384), the entire contents of which documents are incorporated in their entirety herein by reference. As used herein the phrase “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. The term “treating” is defined as administering, to a subject, a therapeutically-effective amount of a compound of the invention (preferably a compound of Formula I) both to prevent the occurrence of an infection and to control or eliminate an infection. The term “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 lipopeptide compound treatment.
  • The method comprises administering to the subject an effective dose of a compound of this invention. An effective dose is generally between about 0.1 and about 100 mg/kg of a lipopeptide compound of Formula I or a pharmaceutically acceptable salt thereof. A preferred dose is from about 0.1 to about 50 mg/kg of a lipopeptide compound of Formula I or a pharmaceutically acceptable salt thereof. A more preferred dose is from about 1 to 25 mg/kg of a lipopeptide compound of Formula I or a pharmaceutically acceptable salt thereof. An effective dose for cell culture is usually between 0.1 and 1000 μg/mL, more preferably between 0.1 and 200 μg/mL.
  • The compound of Formula I 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 lipopeptide 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.
  • A lipopeptide compound according to this 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 methods of the present invention comprise administering a lipopeptide 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. Lipopeptide compounds of Formula I or a pharmaceutical composition thereof also may be directly injected or administered into an abscess, ventricle or joint. Parenteral administration includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, cisternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion. In a preferred embodiment, lipopeptide compounds are administered intravenously, subcutaneously or orally. In a preferred embodiment for administering a lipopeptide compound according to Formula I to a cell culture, 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. In one embodiment, a lipopeptide compound or a pharmaceutical composition thereof is administered to a patient according to the methods of this invention. In a preferred embodiment, the bacterial infection may be caused or exacerbated by gram-positive bacteria. These 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. saprophyticus, and coagulase-negative staphylococci), glycopeptide intermediary-susceptible S. areus (GISA), 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. faecium), Clostridium difficile, C. clostridiiforme, C. innocuum, C. perfringens, C. ramosum, Haemophilus influenzae, Listeria monocytogenes, Corynebacterium jeikeium, Bifidobacterium spp., Eubacterium aerofaciens, E. lentum, Lactobacillus acidophilus, L. casei, L. plantarum, Lactococcus spp., Leuconostoc spp., Pediococcus, Peptostreptococcus anaerobius, P. asaccarolyticus, P. magnus, P. micros, P. prevotii, P. productus, Propionibacterium acnes, Actinomyces spp., Moraxella spp. (including M. catarrhalis) and Escherichia spp. (including E. coli).
  • In a preferred embodiment, the antibacterial activity of lipopeptide compounds of Formula I against classically “resistant” strains is comparable to that against classically “susceptible” strains in in vitro experiments. In another preferred embodiment, the minimum inhibitory concentration (MIC) value for lipopeptide compounds according to this invention against susceptible strains is typically the same or lower than that of vancomycin. Thus, in a preferred embodiment, a lipopeptide 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. In addition, unlike glycopeptide antibiotics, lipopeptide compounds exhibits rapid, concentration-dependent bactericidal activity against gram-positive organisms. Thus, in a preferred embodiment, a lipopeptide 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. In a preferred embodiment, the bacterial infection is caused by gram-positive bacteria. These 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. In a preferred embodiment, any of the above-described diseases may be treated using lipopeptide compounds according to this invention or pharmaceutical compositions thereof.
  • The method of the instant invention may also be practiced while concurrently administering one or more other antimicrobial agents, such as antibacterial agents (antibiotics) or antifungal agents. In one aspect, the method may be practiced by administering more than one lipopeptide compounds according to this invention. In another embodiment, the method may be practiced by administering a lipopeptide compound according to this invention with another lipopeptide compound, such as daptomycin.
  • Antibacterial agents and classes thereof that may be co-administered with a compound of the present 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, pyrazinamide, para-aminosalicylic acid (PAS), cycloserine, capreomycin, ethionamide, prothionamide, thiacetazone, viomycin, eveminomycin, glycopeptide, glycylcylcline, ketolides, oxazolidinone; imipenen, amikacin, netilmicin, fosfomycin, gentamicin, ceftriaxone, Ziracin, LY 333328, CL 331002, HMR 3647, Linezolid, Synercid, Aztreonam, and Metronidazole, Epiroprim, OCA-983, GV-143253, Sanfetrinem sodium, CS-834, Biapenem, A-99058.1, A-165600, A-179796, KA 159, Dynemicin A, DX8739, DU 6681; Cefluprenam, ER 35786, Cefoselis, Sanfetrinem celexetil, HGP-31, Cefpirome, HMR-3647, RU-59863, Mersacidin, KP 736, Rifalazil; Kosan, AM 1732, MEN 10700, Lenapenem, BO 2502A, NE-1530, PR 39, K130, OPC 20000, OPC 2045, Veneprim, PD 138312, PD 140248, CP 111905, Sulopenem, ritipenam acoxyl, RO-65-5788, Cyclothialidine, Sch-40832, SEP-132613, micacocidin A, SB-275833, SR-15402, SUN A0026, TOC 39, carumonam, Cefozopran, Cefetamet pivoxil, and T 3811.
  • In a preferred embodiment, antibacterial agents that may be co-administered with a compound according to this invention include, without limitation, imipenen, amikacin, netilmicin, fosfomycin, gentamicin, ceftriaxone, teicoplanin, Ziracin, LY 333328, CL 331002, HMR 3647, Linezolid, Synercid, Aztreonam, and Metronidazole.
  • Antifungal agents that may be co-administered with a compound according to this invention include, without limitation, Caspofungen, 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. Other antifungal agents include without limitation, those disclosed in Fostel et al., Drug Discovery Today 5:25-32 (2000), herein incorporated by reference. Fostel et al. disclose antifungal compounds including Corynecandin, Mer-WF3010, Fusacandins, Artrichitin/LL 15G256, Sordarins, Cispentacin, Azoxybacillin, Aureobasidin and Khafrefungin.
  • Lipopeptide compounds may be administered according to this method until the bacterial infection is eradicated or reduced. In one embodiment, a lipopeptide compound is administered for a period of time from 3 days to 6 months. In a preferred embodiment, a lipopeptide compound is administered for 7 to 56 days. In a more preferred embodiment, a lipopeptide compound is administered for 7 to 28 days. In an even more preferred embodiment, a lipopeptide compound is administered for 7 to 14 days. Lipopeptide compounds may be administered for a longer or shorter time period if it is so desired.
    • General Procedures for Lipopeptide Compound Synthesis
  • Lipopeptide compounds of Formula I may be produced as described below. The lipopeptide compounds of the instant invention may be produced semi-synthetically using daptomycin as a starting point or may be produced by a total synthesis approach.
  • For the semi-synthetic approach according to the present invention, daptomycin may be prepared by any method known in the art. See, e.g., U.S. Pat. Nos. 4,885,243 and 4,874,843. Daptomycin may be used in its acylated state or it may be deacylated prior to its use as described herein. Daptomycin may be deacylated using Actinoplanes utahensis as described in U.S. Pat. No. 4,482,487. Alternatively, daptomycin may be deacylated as follows:
  • Daptomycin (5.0 g) was dissolved in water (25 ml) and adjusted to pH 9 with 5M sodium hydroxide. Ditert-butyldicarbonate (1.5 g) was added and the mixture was adjusted to maintain pH 9 with 5 M sodium hydroxide until the reaction was complete (4 hours). The pH was adjusted to 7 and the mixture was loaded onto a Bondesil 40μ C8 resin column. The column was washed with water and the product was eluted from the column with methanol. Evaporation of the methanol gave BOC-protected daptomycin as a yellow powder.
  • A preparation of deacylase enzyme was produced from recombinant Streptomyces lividans, which expresses the Actinoplanes utahensis deacylase enzyme. The enzyme in ethylene glycol (400 μl) was added to BOC-protected daptomycin (1 g) in water (100 ml) at pH 7-8. After incubation for 72 hours, the mixture was loaded on a Bondesil 40μ C8 resin column. The column was washed with water and the product was eluted from the column with 10% acetonitrile in water. The product was evaporated to give deacylated BOC-protected daptomycin as a yellow powder.
    • Kynurenine Derivatives
  • Figure US20080287347A1-20081120-C01481
  • Daptomycin can be converted into analogs bearing modifications at the R2 position by converting the aromatic amino group to the diazonium salt compound I with reagents such as sodium nitrite/hydrochloric acid or isoamylnitrite. Using chemistry known to those skilled in the art and following the teachings of the disclosure, the diazonium group can then be displaced by reagents such as sodium azide, potassium ethylxanthate or copper chloride to yield derivative compounds II, wherein R19 is as previously defined.
  • Figure US20080287347A1-20081120-C01482
  • Additionally, compound I can be converted to the azide compound III by reaction with an azide source, typically sodium azide. Modifications to the ketone group can then be undertaken using chemistry known to those having ordinary skill in the art, such as reduction, oxime formation, ketalization conversion to a leaving group and displacement to give compounds of formula IV, wherein R17 and R18 are as previously defined.
  • Figure US20080287347A1-20081120-C01483
  • Compound IV may also be converted to compound V by reducing the azide group to the amine using chemistry known to those having ordinary skill in the art, and following the teachings of the disclosure, such as reaction with triphenyl phosphine and water, or reducing agents such as sodium borohydride wherein R17 and R18 are as previously defined.
  • Figure US20080287347A1-20081120-C01484
  • Additionally compound I can be converted into compound VI by reduction with hypophosphorus acid. Modifications to the ketone group can then be undertaken using chemistry known to those having ordinary skill in the art similar to those used in scheme 2, wherein R17 and R18 are as previously defined.
    • Ornithine Derivatives
  • Figure US20080287347A1-20081120-C01485
  • Daptomycin can be converted into analogs bearing modifications at the R1 position by treating the aromatic amino group of the ornithine with reagents such as isocyanates, isothiocyanates, activated esters, acid chlorides, sulfonylchlorides or activated sulfonamides, heterocycles bearing readily displaceable groups, imidates, lactones or reductively with aldehydes to yield compound VIII, wherein R1 is as previously defined.
    • Tryptophan Amine Derivatives
  • Figure US20080287347A1-20081120-C01486
  • Daptomycin can be converted into compound IX by first protecting the ornithine amine with an appropriate amino protecting group (P) known to those skilled in the art and following the teachings of the disclosure. The decyl side chain on the tryptophan is then removed using an enzyme capable of deacylating daptomycin, such as that described above.
  • Figure US20080287347A1-20081120-C01487
  • Compound IX can be modified at the tryptophan amine with reagents such as isocyanates, isothiocyanates, activated esters, acid chlorides, sulfonylchlorides or activated sulfonamides, heterocycles bearing readily displaceable groups, imidates, lactones or reductively with aldehydes to yield compound X. Compound X can be deprotected to give compound XI according to procedures known to those skilled in the art following the disclosure of this invention, wherein R is as previously defined.
  • The above modifications to the ornithine amine R1, tryptophan amine R or kynurenine side chain R2 may be independently combined to yield additional compounds that are modified at up to all three sites. In order to achieve these modifications, it may be necessary to protect certain functionalities in the molecule. Protecting these functionalities should be within the expertise of one skilled in the art following the disclosure of this invention. See, e.g., Greene, supra.
    • Solid Support Synthesis of Lipopeptide Compounds
  • In an alternative embodiment of the invention, the lipopeptide compounds of Formula I may be synthesized on a solid support as outlined below. In step 1, a suitably-N-protected-βMeGlu(OH)—OAllyl ester is coupled to a suitable resin to give Compound XII. Deprotection of the amino group of Compound XII, followed by coupling of the amino group with a suitably protected seryl derivative (A1) gives Compound XIII, wherein P is a suitable protecting group. This peptide coupling process, i.e., deprotection of the alpha-amino group, followed by coupling to a suitably protected amino acid, is repeated until the desired number of amino acids have been coupled to the resin. In the scheme shown below, eleven amino acids have been coupled to give Compound XIV. Addition of an activated R group, R*, is added to Compound XIV to give Compound XV. In step 4, Compound XV is cyclized to give Compound XVI. Subsequently, in step 5, Compound XVI is removed from the resin to give the lipopeptide Compound XVII.
  • Figure US20080287347A1-20081120-C01488
  • Figure US20080287347A1-20081120-C01489
  • wherein A1, is a suitably protected serine derivative, wherein R31 is a suitable, cleavable hydroxyl protecting group as outlined below.
  • Figure US20080287347A1-20081120-C01490
  • wherein A2 and A7, are suitably protected glycine derivatives as outlined below.
  • Figure US20080287347A1-20081120-C01491
  • wherein A3, A5 and A9 are suitably protected aspartic acid derivatives as outlined below, wherein 28R, 29R and 30R are cleavable protecting groups, preferably t-butyl groups.
  • Figure US20080287347A1-20081120-C01492
  • wherein A4 is a suitably protected alanine derivative as outlined below.
  • Figure US20080287347A1-20081120-C01493
  • wherein A6 is a suitably protected ornithine derivative as outlined below, or derivatized ornthine wherein *R1 is R1 as previously described or alternatively a protected form of R1 that would yield R1 upon subsequent deprotection.
  • Figure US20080287347A1-20081120-C01494
  • wherein A8 is a suitably protected depsipeptide as outlined below, Y is a protecting group that is cleavable under conditions that leave other protecting groups intact to the others used, i.e., Alloc; and wherein *R2 is R2 as previously described or alternatively a protected form of R2 that would yield R2 upon subsequent deprotection. Preferably 2*R is a kynurenine, or substituted kynurenine side chain, most preferably
  • Figure US20080287347A1-20081120-C01495
  • wherein A10 is a suitably protected asparagine derivative as outlined below.
  • Figure US20080287347A1-20081120-C01496
  • wherein A11 is a suitably protected tryptophan derivative as outlined below, wherein R*37 is hydrido or a suitable protecting group, preferably t-butoxy carbonyl.
  • It will be understood by those skilled in the art that both the amino and the side chain functional groups must be suitably protected prior to attaching them to the growing peptide chain. Suitable protecting groups can be any group known in the art to be 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. Following the disclosure of the present application, the selection of protecting groups and method of use thereof will be known to one skilled in the art.
  • It will also be understood by those skilled in the art that the choice of protecting group on the side chain functional groups will either result or not result in the protecting group being cleaved concomitantly with the peptide's final cleavage from the resin, which will give the natural amino acid functionality or a protected derivative thereof, respectively.
  • The following general procedures serve to exemplify the solid support synthesis of compounds of Formula I.
    • Step 1: Coupling Suitably-N-Protected-βMeGlu(OH)—OAllyl Ester to a Resin
  • Five molar equivalents each, with respect to the resin, of a suitably-N-protected-βMeGlu(OH)—OAllyl ester, 1,3-Diisopropylcarbodiimide (DIC) and 1-Hydroxy-7-azabenzotriazole (HOAt) are stirred for 30 mins in dimethylformamide (DMF; 5 ml/g resin). A suitably functionalised resin or solid support, such as, but not limited to, Wang, Safety Catch, Rink, Knorr, PAL, or PAM resin, is added and the resulting suspension is stirred for 16 hrs. The resin-N-protected-βMeGlu(OH)—OAllyl ester is then filtered, dried and the coupling is repeated. The N-protecting group is then removed using the appropriate conditions given in the coupling steps below.
    • Step 2: (A) General Coupling Cycle for Amino Acids with an N-9-Fluorenylmethoxycarbonyl (Fmoc) Protecting Group
  • Five molar equivalents each, with respect to the resin-AA (wherein resin-AA is defined as the resin attached the growing amino acid chain), of a suitably protected Fmoc amino acid, DIC, and HOAt (0.5 molar solution in DMF) are added to the resin-AA, along with sufficient DMF to give a working volume. The mixture is shaken for one hour, filtered, and the coupling is repeated. After the second coupling the resin is washed twice with DMF, twice with methanol, and twice again with DMF. The Fmoc group of the newly coupled amino acid A1-11 is deprotected by stirring the resin product in one working volume of a solution of 20% piperidine in N-methylpyrrolidine for five minutes, filtering the resin, and stirring the resin in 20% piperidine in N-methylpyrrolidine again for 20 minutes. The resin is washed twice with DMF, twice with methanol, and twice again with DMF.
    • Step 2 (B): General Coupling Cycle of Amino Acids with an N-tert-Butoxy-carbonyl (N-Boc) Protecting Group
  • Five molar equivalents each, with respect to the resin-AA, of a suitably protected N-Boc amino acid, DIC, and HOAt (0.5 molar solution in DMF) are added to the resin-AA, along with sufficient DMF to give a working volume. The mixture is shaken for one hour, filtered, and the coupling is repeated. After the repeated coupling the resin is washed twice with DMF, twice with methanol, and twice again with DMF. The Boc group of the newly coupled amino acid A1-11, is then deprotected by stirring the resin in one working volume of CH2Cl2:trifluoroacetic acid (TFA) 1:1 for 15 minutes, filtering, and stirring in one working volume of CH2Cl2:TFA 1:1 for another 15 minutes. The resin is neutralized by washing with excess diisopropylethylamine (DIPEA) in CH2Cl2 and then washed twice with DMF, twice with methanol, and twice again with DMF.
    • Step 3: Terminal Amine Capping Reaction
  • Ten molar equivalents, with respect to the resin XV, of a suitable reagent containing R* such as an activated ester, isocyanate, thioisocyanate, anhydride, acid chloride, chloroformate, or reactive salt thereof, in one working volume of DMF is added to the resin XIV and agitated for 25 hours. The resulting resin XV is washed twice with DMF, twice with methanol, and twice again with DMF.
    • Step 4: Cyclization
  • The dried resin XV is placed under an argon atmosphere, and treated with a solution of Pd(PPh3)4 125 mgs/0.1 mmol peptide substrate, in CH2Cl2:Acetic acid:N-Methylmorpholine, 40:2:1, 1 ml/0.1 mmol peptide substrate. The mixture is stirred for 3 hours at ambient temperature, filtered, and washed twice with DMF, twice with methanol, and twice again with DMF. Five molar equivalents each, with respect to the resin, of DIC, and HOAt (0.5 molar solution in DMF) are added to the resin, along with sufficient DMF to give a working volume. The reaction is shaken for 17 hours, filtered, and washed twice with DMF, twice with methanol, and twice again with DMF to give resin XVI.
    • Step 5: Cleavage and Isolation of the Lipopeptide
  • The desired lipopeptide is cleaved from resin XVI and isolated, resulting in a compound in which R27 is OH or NH2. If Fmoc chemistry is used, the dried resin is suspended in 1 ml/0.1 mmol peptide substrate of CH2Cl2:TFA:Ethanedithiol (EDT):Triisopropylsilane (TIS), 16:22:1:1, and stirred for 6-8 hours at ambient temperature. The resin is filtered, washed with 1 equal volume of cold TFA, and the combined filtrates are evaporated under reduced pressure. Crude product XVII is then precipitated by the addition of diethyl ether, and isolated by centrifugation. This product may be further purified by preparative reverse phase HPLC.
  • If N-Boc chemistry is used, the dried resin is suspended in hydrogen fluoride (HF):anisole:dimethylsulfide (DMS), 10:1:1, and stirred for 2 hours at 0° C. The volitiles are evaporated under a stream of nitrogen. The resin is then extracted with TFA, filtered and washed twice with TFA, and the combined TFA filtrates evaporated under reduced pressure. Crude product is then precipitated by the addition of diethyl ether, and isolated by centrifugation. This product may be further purified by preparative reverse phase HPLC.
  • If the resin is a Safety Catch resin, then R27═OR or NRH. The dried resin XVI is suspended in N-methylpyrrolidine (NMP) or dimethylsulphoxide (DMSO) (8 ml/g resin), Five equivalents of DIPEA (with respect to resin substitution) and 24 equivalents of iodo or bromoacetonitrile (with respect to resin substitution) are added. The suspension is stirred for 24 hours at ambient temperature under inert atmosphere. The resin is filtered, washed with tetrahydrofuran (THF) and DMSO. For an ester, the resin is then treated with an alcohol, hydroxide or alkoxide (20 equivalents with respect to resin substitution) in THF for 20 hours. The resin is filtered, washed with THF and water, and the combined filtrates are evaporated under reduced pressure. Crude product is precipitated by the addition of diethyl ether, and isolated by centrifugation. The product may be further purified by preparative reverse phase HPLC. For amides the resin is then treated with a primary or secondary amine (20 equivalents with respect to resin substitution) in THF for 12-40 hours, at a gentle reflux under inert atmosphere. The resin is filtered, washed with THF and water, and the combined filtrates are evaporated under reduced pressure. Crude product is then precipitated by the addition of diethyl ether, and isolated by centrifugation. This product may be further purified by preparative reverse phase HPLC.
  • In order that this invention may be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.
    • EXAMPLE 1 Preparation of Compounds 38, 40, 50, 52, 77-80, 82-84, 87-100, 103-169, 171-176, 183-187, 194-199, 201-204, 208, 210-211, 222-244, 252, 265-267, 271-281, 283-284, 286-291, 323-331, 358-395 and 398-410
  • A suspension of daptomycin in dry dimethylformamide (0.6 ml) was treated with a solution of 4-Fluorobenzaldehyde (0.2 ml) and a suspension of sodium triacetoxyborohydride (0.2 ml, 1.5M in dry dimethylformamide). After 24 hours, the reaction mixture was diluted with water/acetonitrile (1:1; 0.4 ml) and purified by preparative HPLC. The reaction mixture was loaded onto an IBSIL-C8 5μ 250×20.2 mm column and eluted at 20 ml/min with 30-60% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing product were collected and freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column. The column was washed with water and eluted with methanol. Evaporation of the methanol gave compound 38 as a pale yellow solid (23 mg).
  • In an analogous manner, compounds 40, 50, 52, 77-80, 82-84, 87-100, 103-169, 171-176, 183-187, 194-199, 201-204, 208, 210-211, 222-244, 252, 265-267, 271-281, 283-284, 286-291, 323-331, 358-395 and 398-410 can be prepared as detailed in the above example by appropriate substitutions of reagents obvious to those skilled in the art following the teachings of the disclosure.
    • EXAMPLE 1a Preparation of Compound 282
  • 2-Methyl-6-nitroquinoline (0.4 ml, 0.5M solution in dioxane) was treated with selenium dioxide (0.2 ml, 0.9M solution in 9/1 dioxane/water) and heated to 90° C. overnight. The mixture was cooled to room temperature and diluted with water (1 ml). The mixture was then extracted with ethyl acetate (3×2 ml). The organic extract was then dried in vacuo to give 6-nitro-2-quinolinecarboxaldehyde which was carried forward without further purification. Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with 6-nitro-2-quinolinecarboxaldehyde prepared above in dry dimethylformamide (0.2 ml) and sodium triacetoxyborohydride (0.4 ml, 1.5M solution in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h, the mixture was treated with water (0.2 ml) and loaded onto an IBSIL-C8 5μ 250×20.2 mm column. The column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min. The desired fractions were collected and the acetonitrile was removed by evaporation. The residue was applied to a Bondesil 40μ C8 resin column, washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 282 as a pale yellow solid.
    • EXAMPLE 1b Preparation of Compound 285
  • 4-Chloro-2-methylquinoline (0.4 ml, 0.5M solution in dioxane) was treated with selenium dioxide (0.2 ml, 0.9M solution in 9/1 dioxane/water) and heated to 90° C. overnight. The mixture was cooled to room temperature and diluted with water (1 ml). The mixture was then extracted with ethyl acetate (3×2 ml). The organic extract was then dried in vacuo to give 4-chloro-2-quinolinecarboxaldehyde which was carried forward without further purification. Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with 4-chloro-2-quinolinecarboxaldehyde prepared above and diluted in dry dimethylformamide (0.2 ml) and sodium triacetoxyborohydride (0.4 ml, 1.5M in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h the mixture was treated with water (0.2 ml) and loaded on an IBSIL-C8 5μ 250×20.2 mm column. The column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min. The desired fractions were collected and the acetonitrile was removed by evaporation. The residue was applied to a Bondesil 40μ C8 resin column, washed with water and the product eluted off with methanol. Evaporation of the methanol gave compound 285 as a yellow solid.
    • EXAMPLE 1c Preparation of Compound 85
  • Daptomycin (1 ml, 0.1M in dry dimethylformamide) was treated successively with 1-methyl-2-imidazolecarboxaldehyde (0.2 ml, 0.5M solution in dry dimethylformamide) and sodium triacetoxyborohydride (0.4 ml, 1.5M solution in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h the mixture was treated with water (0.2 ml) and loaded onto an IBSIL-C8 5μ 250×20.2 mm column. The column was eluted at 30 ml/min under the gradient conditions of 35-40% acetonitrile in 5 mM ammonium phosphate buffer over 30 min. The desired fractions were collected and the acetonitrile was removed by evaporation. The residue was applied to a Bondesil 40μ C8 resin column, washed with water and eluted with methanol. This mixture was then loaded on a Prodigy ODS 10μ 250×21.2 mm column eluted at 50 ml/min at 33% acetonitrile in 5 mM ammonium phosphate buffer adjusted to pH 3.2. The desired fractions were collected and the acetonitrile was removed by evaporation. The residue was applied to a Bondesil 40μ C8 resin column, washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 85 as a pale yellow solid.
    • EXAMPLE 1d Preparation of Compound 212
  • Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with 2-imidazolecarboxaldehyde (0.2 ml, 0.5M solution in dry dimethylformamide) and sodium triacetoxyborohydride (0.4 ml, 1.5M solution in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h, the mixture was treated with water (0.2 ml) and the mixture was loaded on an IBSIL-C8 5μ 250×20.2 mm column. The column was eluted at 30 ml/min under the gradient conditions of 35-40% acetonitrile in 5 mM ammonium phosphate buffer over 30 min. The desired fractions were collected and the acetonitrile was removed by evaporation. The residue was applied to a Bondesil 40μ C8 resin column, washed with water and eluted with methanol. This mixture was then loaded on a Prodigy ODS 10μ 250×21.2 mm column and eluted at 50 ml/min at 33% acetonitrile in 5 mM ammonium phosphate buffer adjusted to pH 3.2. The desired fractions were collected and the acetonitrile was removed by evaporation. The residue was applied to a Bondesil 40μ C8 resin column, washed with water and the product eluted with methanol. Evaporation of the methanol gave compound 212 as a yellow solid.
    • EXAMPLE 1e Preparation of Compound 81
  • Daptomycin (1 ml, 0.1M in dry dimethylformamide) was treated successively with 5-fluoroindole-3-carboxaldehyde (0.2 ml, 0.5M solution in dry dimethylformamide) and sodium triacetoxyborohydride (0.4 ml, 1.5M solution in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h the mixture was treated with water (0.2 ml) and loaded on an IBSIL-C8 5μ 250×20.2 mm column. The column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min. The desired fractions were collected, the acetonitrile was removed by evaporation and the residue applied to a Bondesil 40μ C8 resin column. The column was washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 81 as a pale yellow solid.
    • EXAMPLE 1f Preparation of Compound 253
  • p-N,N-Bis(2-chloroethyl)aminobenzaldehyde (0.3 g) was dissolved in acetone (2.5 ml) and treated with sodium iodide (0.4 g). The mixture was warmed to 40° C. for 3 h then treated with benzylamine (0.2 ml) and triethylamine (0.4 ml). The mixture was diluted to 7 ml with acetonitrile and then heated to 60° C. After 24 h, the mixture was cooled to room temperature and the solvent was removed by evaporation. 4-(4-Benzylpiperazino)benzaldehyde was purified by silica gel chromatography eluting with (10% triethylamine/methanol/dichloromethane).
  • Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with the 4-(4-benzylpiperazino)benzaldehyde prepared above diluted in dry dimethylformamide (0.2 ml), and sodium triacetoxyborohydride (0.4 ml, 1.5M solution in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h the mixture was treated with water (0.2 ml) and loaded on an IBSIL-C8 5μ 250×20.2 mm column. The column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min. The desired fractions were collected, the acetonitrile was removed by evaporation and the residue was applied to a Bondesil 40μ C8 resin column. The column was washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 253 as a pale yellow solid.
    • EXAMPLE 1g Preparation of Compound 76 and 177
  • Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with 4-phenylbenzaldehyde (0.2 ml, 0.5M in dry dimethylformamide) and sodium triacetoxyborohydride (0.4 ml, 1.5M in dry dimethylformamide). The reaction mixture was capped and shaken briefly to mix the solution. After 24 h the mixture was treated with water (0.2 ml) and loaded on an IBSIL-C8 5μ 250×20.2 mm column. The column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min. The desired fractions were collected, the acetonitrile was removed by evaporation and the residue was applied to a Bondesil 40μ C8 resin column. The column was washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 76 as a pale yellow solid. Compound 177 was obtained by deacylation of compound 76 according to Example 7.
    • EXAMPLE 1h Preparation of Compound 209
  • 4-Hydroxy-3-nitrobenzaldehyde (0.4 ml, 0.2M in acetone) was successively treated with potassium hydroxide (0.1 ml, 1M in water) and 4-fluorobenzylbromide (0.4 ml, 0.2M in acetone). After 24 h the mixture was dried in vacuo to give 4-(4-fluorobenzyloxy)-3-nitro-benzaldehyde which was carried forward without further purification.
  • Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with, 4-(4-fluorobenzyloxy)-3-nitro-benzaldehyde previously prepared above diluted in dry dimethylformamide (0.2 ml), and sodium triacetoxyborohydride (0.4 ml, 1.5M in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h the mixture was treated with water (0.2 ml) and loaded onto an IBSIL-C8 5μ 250×20.2 mm column. The column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min. The desired fractions were collected, the acetonitrile was removed by evaporation and the residue was applied to a Bondesil 40μ C8 resin column. The column was washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 209 as a pale yellow solid.
    • EXAMPLE 2 Preparation of Compounds 10, 11-17, 19-20, 22-27 and 190
  • Daptomycin (972 mg) was dissolved in dry dimethylformamide (20 ml), and isatoic anhydride (979 mg) was added. The mixture was stirred at ambient temperature for 10 days, then quenched by the addition of water (20 ml). The mixture was loaded onto a Bondesil 40μ C8 resin column (25 g), which had been previously washed with methanol (50 ml) and water (100 ml). The column was then eluted with water (200 ml), 15% methanol/water (1200 ml), 20% methanol/water (200 ml), 30% methanol/water (200 ml) and 40% methanol/water (200 ml). The product bearing fractions were combined and freeze dried to give compound 10 as a white solid (870 mg).
  • In an analogous manner, compounds 11-17, 19-20, 22-27 and 190 can be prepared as detailed in the above example by appropriate substitutions of reagents obvious to those skilled in the art following the teachings of the disclosure.
    • EXAMPLE 3 Preparation of Compounds 44, 45, 41-43, 46-48, 55-58, 60-75, 178-180, 193 and 245
  • Daptomycin (500 mg) and Boc-tryptophan-p-nitrophenyl ester (157.5 mg) were stirred at room temperature in dry dimethylformamide (30 ml) for 3 days. Water (30 ml) was added and the mixture was purified on a Bondesil 40μ C8 resin column (25 g). The column was eluted with 20% acetonitrile in water (200 ml), 40% acetonitrile in water (200 ml) and finally with methanol. Evaporation of the solvent from the product-containing fractions gave compound 44 as a pale yellow solid (450 mg).
  • Compound 44 (200 mg) was cooled to 0° C. and a 0° C. solution of 5% thioanisole in trifluoroacetic acid (10 ml) was added. After 3 hours at 0° C. the mixture was evaporated to dryness and the residue was purified by preparative HPLC on an IBSIL-C8 5μ 250×20.2 mm column. The column was eluted at 20 ml/min with 38% acetonitrile in 5 mM ammonium phosphate buffer. The product containing fractions were freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column. The column was washed with water and eluted with methanol. Evaporation of the methanol gave compound 45 as a pale yellow solid.
  • In an analogous manner, compounds 41-43, 46-48, 55-58, 60-75, 178-180, 193 and 245 can be prepared as detailed in the above example by appropriate substitutions of reagents obvious to those skilled in the art following the teachings of the disclosure.
    • EXAMPLE 3a Preparation of Compounds 54, 49 and 51
  • Daptomycin (400 mg) and N,N-bis(tert-butoxycarbonyl)-L-lysine-4-nitrophenyl ester (173 mg) were stirred in dry dimethylformamide (5 ml) at room temperature for two days. The mixture was loaded onto an IBSIL-C8 5μ 250×20.2 mm column and was eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing the desired compound were collected and freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave the Boc protected intermediate as a pale yellow solid (370 mg).
  • Boc protected intermediate (200 mg) was stirred in trifluoroacetic acid (5 ml) and anisole (0.25 ml) at room temperature for 2 hours. Removal of the solvents under reduced pressure gave a residue which was loaded on an IBSIL-C8 5μ 250×20.2 mm column and eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing the desired compound were collected and freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave compound 54 as a pale yellow solid (100 mg).
  • In an analogous manner, compounds 49 and 51 can be prepared as detailed in the above example by appropriate substitutions of reagents obvious to those skilled in the art following the teachings of the disclosure.
    • EXAMPLE 3 Preparation of Compounds 32, 18, 21, 28-31, 33-35, 39, 182 and 189
  • Daptomycin (162 mg) and 2-methylthiobenzoic acid pentafluorophenol ester (37 mg) were stirred at room temperature in dry dimethylformamide (10 ml) for 5 days. The dimethylformamide was evaporated under reduced pressure and the residue was purified by preparative HPLC on an IBS-C8 5μ 250×20.2 mm column. The column was eluted at 20 ml/min with 36% acetonitrile in 5 mM ammonium phosphate buffer. Fractions collected at 7.3 minutes were freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column. The column was washed with water and eluted with methanol. Evaporation of the methanol gave compound 32 as a pale yellow solid (47 mg).
  • In an analogous manner, compounds 18, 21, 28-31, 33-35, 39, 182 and 189 can be prepared as detailed in the above example by appropriate substitutions of reagents by one having ordinary skill in the art following the teachings of the disclosure.
    • EXAMPLE 4 Preparation of Compounds 5, 4, 6-8 and 9
  • Daptomycin (16 mg) was dissolved in dry dimethylformamide (0.5 ml) and methyl isothiocyanate (37 mg) was added. The mixture was stirred at ambient temperature for 24 hours, then quenched by the addition of 5% ammonium phosphate buffer (1 ml). The mixture was purified by preparative HPLC on an IBSIL-C8 5μ 250×20.2 mm column. The column was eluted at 20 ml/min with 36% acetonitrile in 5 mM ammonium phosphate buffer. The product bearing fractions were combined and freeze dried. The freeze-dried residue was dissolved in water (1.5 ml) and applied to a Bondesil 40μ C8 resin column. The column was washed with water and eluted with methanol. Evaporation of the methanol gave compound 5 as a pale yellow solid (5.2 mg).
  • In an analogous manner, compounds 4, 6-8 and 9 can be prepared as detailed in the above example by appropriate substitutions of reagents obvious to those having ordinary skill in the art.
    • EXAMPLE 5 Preparation of Compound 3
  • Daptomycin (16 mg) and N-benzotriazole phenylsulfonamide (2.6 mg) were stirred at room temperature in dry pyridine for 6 days. The solvent was evaporated and the residue was purified by preparative HPLC using an IBSIL-C8 5μ 250×20.2 mm column. The column was eluted at 20 ml/min with 36% acetonitrile in 5 mM ammonium phosphate buffer and product containing fractions were freeze-dried. The freeze dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column. The column was washed with water and eluted with methanol. Evaporation of the methanol gave compound 3 as a pale yellow solid (4 mg).
    • EXAMPLE 6 Preparation of Compounds 1, 2, 221, 259 and 270
  • Daptomycin (32 mg) was dissolved in dry dimethylformamide (20 ml), and N,N′-bis-Boc-1-guanidinylpyrazole (31 mg) was added. The mixture was stirred at ambient temperature for 5 days, then quenched by the addition of water (3 ml). The resultant mixture was loaded onto a Bondesil 40μ C8 resin (900 mg) that had been previously washed with methanol and water. The column was eluted with water (30 ml) followed by methanol. The product-bearing fractions were combined and evaporated to give compound 1 as a white solid.
  • Compound 1 (30 mg) was dissolved in trifluoroacetic acid/dichloromethane/tri-isopropylsilane/ethane dithiol (11/8/0.5/0.5, 3 ml) and stirred at ambient temperature for 90 minutes. The mixture was evaporated to dryness and the residue was precipitated by the addition of diethyl ether (10 ml). The residue was purified by preparative HPLC on an IBSIL-C8 5μ 250×20.2 mm column. The column was eluted at 20 ml/min with 38% acetonitrile in 5 mM ammonium phosphate buffer. The product-bearing fractions were combined and freeze dried. The freeze-dried residue was dissolved in water (1.5 ml) and applied to a Bondesil 40μ C8 resin column. The column was washed with water and eluted with methanol. Evaporation of the methanol gave compound 2 as a white solid (6.4 mg).
  • In an analogous manner, compounds 221, 259 and 270 can be prepared as detailed in the above example by appropriate substitutions of reagents obvious to those having ordinary skill in the art following the teachings of the disclosure.
    • EXAMPLE 7 Preparation of Compounds 255, 260, 254, 256-257, 261, 263, 292-294 and 313-314
  • Daptomycin (10 g) was dissolved in dry dimethylformamide (100 ml). N,N′-bis-Boc-guanidinylpyrazole (2.3 g) in dry dimethylformamide (5 ml) was added. The mixture was stirred under nitrogen at room temperature overnight. The mixture was purified on a Bondesil 40μ C8 resin column. The product containing fractions were freeze-dried to give compound 1 (7.4 g) as pale yellow fluffy solid.
  • Compound 1 (2.6 g) was added to a preparation of deacylase enzyme produced from recombinant Streptomyces lividans, which expresses the Actinoplanes utahensis deacylase enzyme in ethylene glycol (1.2 ml) and water (25 ml). The pH of the solution was adjusted to 9 with 1.0M sodium hydroxide solution and stirred at room temperature. After 24 hours the mixture was purified on a Bondesil 40μ C8 resin column by eluting with 10% acetonitrile/water, then 40% acetonitrile/water. The product-containing fractions were freeze dried to give deacylated bis-Boc-guanidinylated daptomycin (0.69 g) as a pale yellow solid.
  • Undecanoyl pentafluorophenol ester (40.3 mg) was added to deacylated bis-Boc-guanidinylated daptomycin (171.5 mg) in dry dimethylformamide (2 ml). The mixture was stirred overnight at room temperature before being concentrated to give compound 255 (105 mg) as a yellow solid.
  • Compound 255 was dissolved in trifluoroacetic acid (5.5 ml), dichloromethane (4 ml), ethane dithiol (0.25 ml) and triisopropylsilane (0.25 ml). The mixture was stirred for 4 hours at room temperature before being concentrated and purified by preparative HPLC on an IB-SIL 5μ 250×20.2 mm column. The column was eluted at 25 ml/min with acetonitrile and ammonium phosphate buffer 30%-60% gradient for 40 min. The desired fractions were collected at 21 minutes and freeze dried. The freeze-dried residue was dissolved in water and applied to a Bondesil C8 resin column. The column was washed with water and eluted with methanol. Evaporation of the methanol gave compound 260 (27.8 mg) as a pale yellow solid.
  • In an analogous manner, compounds 254, 256-257, 261, 263, 292-294 and 313-314 can be prepared as detailed in the above example by appropriate substitutions of reagents obvious to those having ordinary skill in the art following the disclosure of the invention.
    • EXAMPLE 7a Preparation of Compounds 258 and 262
  • Tetradecanoyl pentafluorophenol ester (35.5 mg) and deacylated bis-Boc-guanidinylated daptomycin (102.5 mg) in dry dimethylformamide (2 ml). The mixture was stirred overnight at room temperature before being concentrated to give compound 258 (38.8 mg) as a yellow solid.
  • Compound 258 (38.8 mg) was dissolved in trifluoroacetic acid (5.5 ml), dichloromethane (4 ml), ethane dithiol (0.25 ml) and triisopropylsilane (0.25 ml). The mixture was stirred for 4 hours at room temperature before being concentrated and purified by preparative HPLC on an IB-SIL 5μ 250×20.2 mm column. The column was eluted at 25 ml/min with acetonitrile and ammonium phosphate buffer 30%-60% gradient for 40 min. The desired fractions were collected at 21 minutes and freeze dried. The freeze-dried residue was dissolved in water and applied to a Bondesil C8 resin column. The column was washed with water and eluted with methanol. Evaporation of the methanol gave compound 262 (2.1 mg) as a pale yellow solid.
    • EXAMPLE 8 Preparation of Compound 37, 36 and 192
  • Daptomycin (162 mg) was stirred in 0.1 M hydrochloric acid (5 ml) at 0° C. for 10 minutes before sodium nitrite (8 mg) in water (0.2 ml) was added dropwise. Sulfamic acid (11 mg) was added after 15 minutes, followed by sodium azide (8 mg) 10 minutes later. The mixture was maintained at 0° C. for 4 hours and then neutralized with a saturated sodium bicarbonate solution and purified by preparative HPLC. An IBSIL-C8 5μ 250×20.2 mm column was loaded with the mixture and eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions were collected at 6.9 minutes and freeze dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column. The column was washed with water and eluted with methanol. Evaporation of the methanol gave the azido daptomycin as a pale yellow solid (60 mg).
  • The azido daptomycin (69 mg) was dissolved in dry dimethylformamide (4 ml) and iminobiotin-N-hydroxysuccinimide ester (53 mg) was added. The mixture was covered to exclude light and stirred at ambient temperature for 3 days. The mixture was quenched by the addition of water (20 ml). The resultant mixture was loaded onto a Bondesil 40μ C8 resin (25 g) column, which had been previously washed with methanol and water, and the column was eluted with water. The product-bearing fractions were combined and freeze dried to give Compound 37 as a white solid (49 mg).
  • In an analogous manner, compounds 36 and 192 can be prepared as detailed in the above example by appropriate substitutions of reagents obvious to those having ordinary skill in the art by following the disclosure of the invention.
    • EXAMPLE 8 Preparation of Compound 200
  • Daptomycin (1.62 g) in 50% wt aqueous solution of hypophosphorus acid (10 ml) was stirred at 0° C. for 30 minutes before adding dropwise a solution of sodium nitrite (76 mg) in water (0.5 ml). The mixture was allowed to come to room temperature and stirred for 24 hours. The mixture was purified by preparative HPLC by loading the mixture on an IBSIL-C8 5μ 250×20.2 mm column and eluting the column at 20 ml/min with 32% acetonitrile in 5 mM ammonium phosphate buffer. The desired fractions were collected at 30 minutes and freeze dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column. The column was washed with water and eluted with methanol. Evaporation of the methanol gave desamino daptomycin as a pale yellow solid (200 mg).
  • To desamino daptomycin (80 mg) in dry dimethylformamide (2 ml) was added N-t-butoxycarbonyl-L-tryptophan-p-nitrophenyl ester (32 mg). The mixture was stirred at room temperature for 24 hours before being purified by preparative HPLC. The mixture was loaded on an IBSIL-C8 5μ 250×20.2 mm column and eluted at 20 ml/min with 40% acetonitrile in 5 mM ammonium phosphate buffer. The desired fractions were collected at 19 minutes and freeze-dried. The freeze-dried residue was dissolved in water (2 ml) and applied to a plug of Bondesil 40μ C8 resin (500 mg). The Bondesil resin was washed with water (10 ml) and then the product was eluted with methanol (10 ml). Evaporation of the methanol gave Boc protected compound 200 as a pale yellow solid (20 mg).
  • To Boc protected compound 200 (20 mg) in 60% trifluoroacetic acid in dichloromethane (0.5 ml) was added anisole (10 μL). The mixture was stirred at room temperature for 6 hours before being evaporated to dryness. Preparative HPLC purification of the residue was done on an IBSIL-C8 5μ 250×20.2 mm column and eluted at 20 ml/min with 38% acetonitrile in 5 mM ammonium phosphate buffer. The desired fractions were collected at 15 minutes and freeze-dried. The freeze-dried residue was dissolved in water (2 ml) and applied to a plug of Bondesil 40μ C8 resin (500 mg). The Bondesil resin was washed with water (10 ml) and the product was eluted with methanol (10 ml). Evaporation of the methanol gave compound 200 as a pale yellow solid (4 mg).
    • EXAMPLE 9 Preparation of Compounds 181, 86, 101-102, 206-207, 213-220, 246-251, 264 and 269
  • Daptomycin (250 mg) and N-tBoc-L-tryptophan-p-nitrophenyl ester (144 mg) were stirred in dry dimethylformamide (3 ml) at room temperature for two days. The mixture was loaded on an IBSIL-C8 5μ 250×20.2 mm column and was eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing the desired compound were collected and freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave N-Boc tryptophan daptomycin as a pale yellow solid (130 mg).
  • A preparation of deacylase enzyme was produced from recombinant Streptomyces lividans, which expresses the Actinoplanes utahensis deacylase enzyme. The enzyme in ethylene glycol (400 μl) was added to the solution of N-Boc tryptophan daptomycin (100 mg) in HPLC grade water (20 ml). The solution was adjusted to pH 8.5 with sodium hydroxide (1 M). The mixture was stirred for 24 hours. The mixture was loaded on a C8 resin plug column, washed with water and eluted with methanol. Evaporation of the methanol gave a residue which was applied to an IBSIL-C8 5μ 250×20.2 mm column and was eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing the desired compound were collected and freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave deacylated N-Boc tryptophan daptomycin as a pale yellow solid (42 mg).
  • Deacylated N-Boc tryptophan daptomycin (20 mg) was stirred in dry dimethylformamide (2 ml) at room temperature. Undecyl isocyanate (2.25 mg) was added to the solution. After stirring at ambient temperature for 24 hours, the mixture was diluted with water (10 ml) and applied to a Bondesil 40μ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave the undecyl urea of N-Boc tryptophan daptomycin as a pale yellow solid (21 mg).
  • N-Boc tryptophan daptomycin undecyl urea (21 mg) was stirred in trifluoroacetic acid (2 ml) and anisole (0.1 ml) at room temperature for 2 hours. Removal of the solvents under reduced pressure gave a residue which was loaded on an IBSIL-C8 5μ 250×20.2 mm column and eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing the desired compound were collected and freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave compound 181 as a pale yellow solid (0.8 mg).
  • In an analogous manner, compounds 86, 101-102, 206-207, 213-220, 246-251, 264 and 269 can be prepared as detailed in the above example by appropriate substitutions of reagents obvious to those having ordinary skill in the art following the disclosure of the invention.
    • EXAMPLE 9 Preparation of Compound 205
  • Deacylated N-Boc tryptophan daptomycin (50 mg) and nonaldehyde (4.1 mg) were stirred in dry dimethylformamide (2 ml) at room temperature. Sodium triacetoxy borohydride (3.6 mg) was added to the solution. The mixture was stirred for 24 hours, then loaded on an IBSIL-C8 5μ 250×20.2 mm column and eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing the desired compound were collected and freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave nonyl amino N-Boc tryptophan daptomycin as a pale yellow solid (14 mg).
  • Nonyl amino N-Boc tryptophan daptomycin (14 mg) was stirred in trifluoroacetic acid (2 ml) and anisole (0.1 ml) at room temperature for 2 hours. Removal of the solvents under reduced pressure gave a residue which was loaded on an IBSIL-C8 5μ 250×20.2 mm column and was eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing the desired compound were collected and freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave compound 7 as a pale yellow solid (5 mg).
    • EXAMPLE 10 Preparation of Compounds 356, 315-322, 332-337, 345-349 and 355
  • Daptomycin (5.0 g) was dissolved in water (25 ml) and adjusted to pH 9 with 5M sodium hydroxide. Di-tert-butyldicarbonate (1.5 g) was added and the mixture was adjusted to maintain pH 9 with 5 M sodium hydroxide until the reaction was complete (4 hours). The pH was adjusted to 7 and the mixture was loaded onto a Bondesil 40μ C8 resin column. The column was washed with water and the product was eluted from the column with methanol. Evaporation of the methanol gave Boc-protected daptomycin (5.08 g) as a yellow powder.
  • A preparation of deacylase enzyme was produced from recombinant Streptomyces lividans, which expresses the Actinoplanes utahensis deacylase enzyme. The enzyme in ethylene glycol (400 μl) was added to Boc-protected daptomycin (1 g) in water (100 ml) at pH 7-8. After incubation for 72 hours, the mixture was loaded on a Bondesil 40μ C8 resin column. The column was washed with water and the product was eluted from the column with 10% acetonitrile in water. The solvent was removed by evaporation to give deacylated Boc-protected daptomycin (440 mg) as a yellow powder.
  • Daptomycin undecyl urea synthesized from deacylated Boc protected daptomycin above using undecyl isocyanate instead of undecanoyl pentafluorophenol ester according to example 7 (100 mg) and 5-methoxyindole-3-carboxaldehyde (11 mg) in dry dimethylformamide (0.6 ml) was added sodium triacetoxyborohydride (76 mg). The mixture was stirred at room temperature for 24 hours before purification by preparative HPLC. The mixture was loaded on an IBSIL-C8 5μ 250×20.2 mm column and eluted at 25 ml/min with 30-60% acetonitrile in 5 mM ammonium phosphate gradient over 30 minutes. The desired fractions were collected at 21 minutes and freeze-dried. The freeze-dried residue was dissolved in water (2 ml) and applied to a plug of Bondesil 40μ C8 resin (500 mg). The Bondesil resin was washed with water (10 ml) and then the product was eluted with methanol (10 ml). Evaporation of the methanol gave compound 114 as a pale yellow solid (10 mg).
  • In an analogous manner, compounds 315-322, 332-337, 345-349 and 355 can be prepared as detailed in the above example by appropriate substitutions of reagents obvious to those skilled in the art.
    • EXAMPLE 10a Preparation of Compounds 307, 310, 295-306, 308-309, 311-312, 338-344 and 350-352
  • Daptomycin undecanoyl amide synthesized from deacylated Boc protected daptomycin by using undecanoyl pentafluorophenol ester according to examples 10 and 7 (60 mg) was stirred in dry dimethylformamide (2 ml) at room temperature. N-tBoc-L-tryptophan-p-nitrophenyl ester (31 mg) was added to the solution. The mixture was stirred for 24 hours. The mixture was loaded onto an IBSIL-C8 5μ 250×20.2 mm column and was eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing the desired compound were collected and freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave compound 307 as a pale yellow solid (25 mg).
  • Compound 307 (20 mg) was stirred in trifluoroacetic acid (2 ml) and anisole (0.1 ml) at room temperature for 2 hours. Removal of the solvents under reduced pressure gave a residue which was loaded on an IBSIL-C8 5μ 250×20.2 mm column and was eluted at 20 ml/min with 37% acetonitrile in 5 mM ammonium phosphate buffer. Fractions containing the desired compound were collected and freeze-dried. The freeze-dried residue was dissolved in water (5 ml) and applied to a Bondesil 40μ C8 resin column, washed with water and eluted with methanol. Evaporation of the methanol gave compound 310 as a pale yellow solid (4 mg).
  • In an analogous manner, compounds 295-306, 308-309, 311-312, 338-344 and 350-352 can be prepared as detailed in the above example by appropriate substitutions of reagents obvious to those skilled in the art.
    • EXAMPLE 11
  • Compounds according to Formula I were tested for antimicrobial activity against a panel of organisms according to standard procedures described by the National Committee for Clinical Laboratory Standards (NCCLS document M7-A5, Vol. 20, No. 2, 2000) except that all testing was performed at 37° C. Compounds were dissolved in 100% dimethyl sulfoxide and were diluted to the final reaction concentration (0.1 μg/mL-100 μg/mL) in microbial growth media. In all cases the final concentration of dimethyl sulfoxide incubated with cells is less than or equal to 1%. For minimum inhibitory concentration (MIC) calculations, 2-fold dilutions of compounds were added to wells of a microtiter plate containing 5×104 bacteria cells in a final volume of 100 μL of media (Mueller-Hinton Broth supplemented with 50 mg/L Ca2+). The optical densities (OD) of the bacterial cells, which measures bacterial cell growth and proliferation, were measured using a commercial plate reader. The MIC value is defined as the lowest compound concentration inhibiting growth of the test organism. The MIC (in μg/ml) values of representative compounds of the present invention are listed in Table III.
    • EXAMPLE 12
  • 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 was established by infecting female CD-1 mice (Charles River Lab, MA) weighing 19-23 g intraperitoneally with from Methicillin Resistant S. aureus (MRSA) inoculum. The inoculum was prepared from Methicillin Resistant S. areus (ATCC 43300). The MRSA inoculum was cultured in Mueller-Hinton (MH) broth at 37° C. for 18 hours. The optical density at 600 nm (OD600) was determined for a 1:10 dilution of the overnight culture. Bacteria (8×108 cfu) was added to 20 ml of phosphate buffered saline (Sigma P-0261) containing 5% hog gastric mucin (Sigma M-2378). All animals were injected with 0.5 ml of the inoculum, equivalent to 2×107 cfu/mouse, which is the dose causing 100% death of the animals without treatment.
  • The test compound was dissolved in 10.0 ml of 50 mM phosphate buffer to give a solution of 1 mg/ml (pH=7.0). This solution was serially diluted with vehicle by 4-fold (1.5 ml to 6.0 ml) to give 0.25, 0.063 and 0.016 mg/ml solutions. All the solutions were filtered with 0.2 m Nalgene syringe filter. Immediately after the bacterial inoculation, group 1 animals were subcutaneously (sc) injected with buffer (no test compound) and groups 2 to 5 were given test compound sc at 10.0, 2.5, 0.63, and 0.16 mg/kg, respectively. Group 6 animals received test compound sc at 10 mg/kg (or the highest therapeutic dose of a given compound) only for monitoring acute toxicity. These injections were repeated once at 4 hours after the inoculation for the respective groups. The injection volume at each time was 10 ml per kilogram of body weight. The results of the in vivo efficacy test are summarized in Table II, which provides a representative example of the results obtained for Compound 70. The 50% effective dose (ED50) is calculated on the basis of the number of mice surviving 7 days after inoculation. The ED50 was determined for other compounds of this invention in a similar manner. The ED50 in mg/kg of other representative compounds of the present invention are listed in Table III.
  • TABLE II
    # of Survival (7
    Group mice Inoculated with Treatment days)
    1 5 MRSA #43300 Phosphate buffer 0/5
    2 × 107 cfu/mouse 10 ml/kg, s.c. x2
    2 5 MRSA #43300 Compound 70 5/5
    2 × 107 cfu/mouse 10 mg/kg, s.c. x2
    3 5 MRSA #43300 Compound 70 3/5
    2 × 107 cfu/mouse 2.5 mg/kg, s.c. x2
    4 5 MRSA #43300 Compound 70 1/5
    2 × 107 cfu/mouse 0.63 mg/kg, s.c. x2
    5 5 MRSA #43300 Compound 70 0/5
    2 × 107 cfu/mouse 0.16 mg/kg, s.c. x2
    6 5 No Compound 70 5/5
    10 mg/kg, s.c. x2
    The ED50 of compound 70 is calculated to be 1.51 mg/kg
  • TABLE III
    MIC MIC ED50
    (μg/ml) (μg/ml) mg/kg
    Compound # S. aureus E. faecalis S. aureus
    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 +++ +
    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 +++ ++
    100 +++ ++
    101 ++ ++
    102 +++ +++
    103 +++ +
    104 ++ ++
    105 +++ ++
    106 +++ ++
    107 ++ ++
    108 ++ ++
    109 ++ ++
    110 ++ ++
    111 +++ ++
    112 ++ +
    113 ++ ++
    114 ++ +
    115 +++ +
    116 +++ ++
    117 ++ ++
    118 ++ ++
    119 +++ ++
    120 ++ ++
    121 +++ ++
    122 +++ +
    123 ++ +
    124 ++ +
    125 ++ ++
    126 ++ ++
    127 +++ ++
    128 ++ ++
    129 +++ +
    130 +++ ++
    131 +++ +
    132 ++ ++
    133 +++ ++
    134 ++ +
    135 +++ +
    136 +++ ++
    137 ++ +
    138 +++ +
    139 +++ ++
    140 +++ ++
    141 ++ +
    142 +++ +
    143 ++ +
    144 +++ ++
    145 ++ ++
    146 +++ +
    147 +++ ++
    148 ++ ++
    149 ++ +
    150 +++ ++
    151 +++ ++
    152 ++ ++
    153 ++ +
    154 ++ ++
    155 ++ ++
    156 +++ +
    157 ++ +
    158 ++ +
    159 +++ +
    160 ++ +
    161 +++ +
    162 ++ ++
    163 +++ ++
    164 +++ ++
    165 ++ ++
    166 +++ ++
    167 +++ ++
    168 +++ ++
    169 +++ +
    170 ++ ++
    171 ++ ++
    172 +++ ++
    173 +++ ++
    174 +++ ++
    175 ++ ++
    176 +++ ++
    177 + +
    178 ++ +
    179 ++ +
    180 ++ ++
    181 +++ +++ +++
    182 ++ +
    183 +++ +
    184 +++ +
    185 ++ +
    186 ++ +
    187 +++ +
    189
    190
    192 ++ +
    193 ++ +
    194 ++ +
    195 ++ +
    196 +++ +
    197 ++ +
    198 ++ +
    199 +++ +
    200 +
    201 ++ ++
    202
    203 ++ +
    204 +++ ++
    205 ++ +
    206
    207
    208 ++ ++
    209 +++ ++
    210 +++ ++
    211 ++
    212 +++ ++ +++
    213
    214
    215
    216 ++ +
    217
    218 +
    219 +++ ++
    220 +++ +++
    221 + +
    222 ++ ++
    223 +++ ++
    224 ++ +
    225 ++ +
    226 ++ +
    227 +++ ++
    228 +++ ++
    229 +++ ++
    230 +++ +++
    231 +++ ++
    232 +++ ++
    233 ++ +
    234 ++ +
    235 +++ ++
    236 ++ +
    237 +++ ++
    238 +++ ++
    239 +++ +
    240 +++ ++
    241 ++ ++
    242 ++ +
    243 ++ +
    244 +++ ++
    245
    246 +
    247 +
    248 +
    249 +
    250 +++ +
    251 ++ +
    252 ++ ++
    253 +++ ++
    254 ++ +
    255 +++ ++
    256 +++ +++
    257 ++ +
    258 +++ ++
    259 +++ +++
    260 +++ ++
    261 ++ ++
    262 ++ ++
    263 +++ ++
    264 ++ +
    265 ++ ++
    266 +++ +
    267 ++ +
    268 ++ ++
    269 +
    270 +++ +
    271 +++ +++
    272 ++ +
    273 +++ ++
    274 +++ +++
    275 +++ ++
    276 +++ +++
    277 +++ +++
    278 +++ +++
    279 +++ ++
    280 +++ ++
    281 +++ ++
    282 +++ +++ +++
    283 +++ ++
    284 +++ +++
    285 +++ +++ +++
    286 +++ +++
    287 +++ +++
    288 +++ +++
    289 +++ ++
    290 ++ ++
    291 +++ +++
    292 +++ ++
    293 +++ ++
    294 ++ +
    295 ++
    296
    297 ++
    298
    299 ++
    300 ++
    301 +++ ++
    302 +++ ++
    303 +++ ++
    304
    305 +++ ++
    306 +++ ++
    307 +++ ++
    308 +++ ++
    309 +++ ++
    310 +++ ++
    311 +++
    312
    313 +++
    314 +++ ++
    315 ++ +
    316 +++
    317
    318 +++ +++
    319 +++ ++
    320 +++ ++
    321 +++ ++
    322 +++ ++
    323 +++ ++
    324 ++
    325 +++ ++
    326 +++ ++
    327 +++ ++
    328 ++
    329
    330 +++ ++
    331 ++
    332 +++ ++
    333 ++
    334 +++ +++
    335 +++ ++
    336 +++ ++
    337 +++ +++
    338 ++ ++
    339 +++ ++
    340 + +
    341 ++ ++
    342 +++ ++
    343 +++ ++
    344 +++ ++
    345 ++ +++
    346 +++ +++
    347 ++ +
    348 ++ +
    349 ++ +
    350 ++ +
    351 ++ ++
    352 ++ ++
    355 ++ ++
    356 +++ +++
    358 ++ ++
    359 +++
    360 +++ ++
    361 +++
    362 +++ ++
    363 +++
    364 +++ ++
    365 +++
    366 +++ ++
    367 +++ ++
    368 +++ ++
    369 +++
    370 +++ ++
    371 +++ ++
    372 +++ ++
    373 +++ ++
    374 +++ ++
    375 +++
    376 +++ ++
    377 +++ ++
    378 +++ ++
    379 +++ ++
    380 +++ ++
    381 +++ ++
    382 +++ ++
    383 +++ ++
    384 +++ ++
    385 +++ ++
    386 +++ ++
    387 +++ +++
    388 ++ ++
    389 +++ ++
    390 +++ ++
    391 +++ ++
    392 +++ ++
    393 +++ ++
    394 +++ ++
    395 +++ ++
    Wherein
    “+++” indicates that the compound has an MIC (μg/ml) of 1 μg/ml or less or an ED50 of 1 mg/kg or less;
    “++” indicates that the compound has an MIC (μg/ml) or ED50 of greater than 1 μg/ml or 1 mg/kg, respectively but less than or equal to10 μg/ml or ED50 of 10 mg/kg, respectively; and
    “+” indicates that the compound has an MIC (μg/ml) of greater than 10 μg/ml or an ED50 of greater than 10 mg/kg.
  • All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims (29)

1. A compound having the formula (I):
Figure US20080287347A1-20081120-C01497
and salts thereof,
wherein R is:
Figure US20080287347A1-20081120-C01498
wherein X and X″ are independently C═O, C═S, C═NH, C═NRX, S═O or SO2;
wherein n is 0 or 1;
wherein RX is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
wherein B is X″RY, H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
wherein RY is hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;
wherein A is H, NH2, NHRA, NRARB, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl or heterocyclyl;
wherein RA and RB are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
wherein when n is 0, then A is additionally:
Figure US20080287347A1-20081120-C01499
wherein each of R50-R53 is independently C1-C15 alkyl;
alternatively, wherein B and A together form a 5-7 membered heterocyclic or heteroaryl ring;
wherein R1 is
Figure US20080287347A1-20081120-C01500
wherein X′ and X″′ are independently C═O, C═S, C═NH, C═NRX′, S═O or SO2;
wherein m is 0 or 1;
wherein RX′ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
wherein B′ is X″′RY′, H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
wherein RY′ is hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;
wherein A′ is H, NH2, NHRA′, NRA′RB′, heteroaryl, cycloalkyl or heterocyclyl;
wherein RA′ and RB′ are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
wherein when m is 0, then A′ is additionally:
Figure US20080287347A1-20081120-C01501
wherein each of R50-R53 is independently C1-C15 alkyl;
provided that when B′ is H and X′ is C═O, then A′ is other than
(a) a pyridinyl ring substituted with one substitutent NHC(O)RD or
(b) a C5-C6 saturated cycloalkyl ring substituted with one substitutent NHC(O)RD;
wherein RD is C1-C17 unsubstituted alkyl or C2-C17 unsubstituted alkenyl; and
when B′ is H and m=0, then A′ is not H;
wherein R2 is
Figure US20080287347A1-20081120-C01502
wherein K and K′ together form a C3-C7 cycloalkyl or heterocyclyl ring or a C5-C10 aryl or heteroaryl ring;
wherein J is hydrido, amino, NHRJ, NRJRK, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylamino, hydroxyl, thio, alkylthio, alkenylthio, sulfinyl, sulfonyl, azido, cyano, halo,
Figure US20080287347A1-20081120-C01503
wherein each of R24, R25, and R26 is independently alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or R24 and R25 together form a 5-8 membered heterocyclyl ring;
wherein RJ and RK are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; or
alternatively, wherein J, together with R17, forms a 5-8 membered heterocyclyl or cycloalkyl ring; or
alternatively, wherein J, together with both R17 and R18, forms a 5-8 membered aryl, cycloalkyl, heterocyclyl or heteroaryl ring; and
wherein each of R17 and R18 is independently hydrido, halo, hydroxyl, alkoxy, amino, thio, sulfinyl, sulfonyl or
Figure US20080287347A1-20081120-C01504
or
wherein R17 and R18 taken together can form a ketal, thioketal,
Figure US20080287347A1-20081120-C01505
wherein each of R22 and R23 is independently hydrido or alkyl.
2. A compound having the formula (I):
Figure US20080287347A1-20081120-C01506
and salts thereof;
wherein R is:
Figure US20080287347A1-20081120-C01507
wherein X and X″ are independently C═O, C═S, C═NH, C═NRX, S═O or SO2;
wherein n is 0 or 1;
wherein RX is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
wherein B is X″RY, H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
wherein RY is hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;
wherein A is H, NH2, NHRA, NRARB, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl or heterocyclyl;
wherein RA and RB are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
wherein when n is 0, then A is additionally selected from:
Figure US20080287347A1-20081120-C01508
wherein each of R50-R53 is independently C1-C15 alkyl;
alternatively, wherein B and A together form a 5-7 membered heterocyclic or heteroaryl ring;
wherein R1 is
Figure US20080287347A1-20081120-C01509
wherein X′ and X″′ are independently C═O, C═S, C═NH, C═NRX′, S═O or SO2;
wherein m is 0 or 1;
wherein RX′ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
wherein B′ is X″′RY′, H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
wherein RY′ is hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;
wherein A′ is aryl;
provided that when B′ is H and X′ is C═O, then A′ is other than a phenyl ring substituted with substitutent NHC(O)RD, wherein RD is C1-C17 unsubstituted alkyl or C2-C17 unsubstituted alkenyl, wherein said phenyl ring may be further optionally substituted with 1-2 substituents independently selected from amino, nitro, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, halo, mercapto, C1-C3 alkylthio, carbamyl or C1-C3 alkyl carbamyl;
wherein R2 is
Figure US20080287347A1-20081120-C01510
wherein K and K′ together form a C3-C7 cycloalkyl or heterocyclyl ring or a C5-C10 aryl or heteroaryl ring;
wherein J is hydrido, amino, NHRJ, NRJRK, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylamino, hydroxyl, thio, alkylthio, alkenylthio, sulfinyl, sulfonyl, azido, cyano, halo,
Figure US20080287347A1-20081120-C01511
wherein each of R24, R25, and R26 is independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or R24 and R25 together form a 5-8 membered heterocyclyl ring;
wherein RJ and RK are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; or
alternatively, wherein J, together with R17, forms a 5-8 membered heterocyclyl or cycloalkyl ring; or
alternatively, wherein J, together with both R17 and R18, forms a 5-8 membered aryl, cycloalkyl, heterocyclyl or heteroaryl ring; and
wherein each of R17 and R18 is independently hydrido, halo, hydroxyl, alkoxy, amino, thio, sulfinyl, sulfonyl or
Figure US20080287347A1-20081120-C01512
or
wherein R17 and R18 taken together can form a ketal, thioketal,
Figure US20080287347A1-20081120-C01513
wherein each of R22 and R23 is independently hydrido or alkyl.
3. The compound according to either of claims 1 or 2, wherein R is
Figure US20080287347A1-20081120-C01514
wherein each of R3, R4, R5, and R6 is independently hydrido, alkyl, aryl, heterocyclyl or heteroaryl, and wherein R44 is s alkyl, aryl, heterocyclyl or heteroaryl.
4. The compound according to claim 3, wherein R is
Figure US20080287347A1-20081120-C01515
wherein R4′ is s alkyl, aryl-substituted alkyl, substituted phenyl, heteroaryl, heterocyclyl, optionally substituted (C8-C14)-straight chain alkyl or
Figure US20080287347A1-20081120-C01516
wherein R7 is an alkyl group.
5. The compound according to claim 4, wherein R is
Figure US20080287347A1-20081120-C01517
wherein X3 is chloro or trifluoromethyl and wherein q is 0 or 1.
6. The compound according to either of claims 1 or 2, wherein R1 is
Figure US20080287347A1-20081120-C01518
wherein each of R10 and R11 is independently hydrido, alkyl, aryl, heterocyclyl or heteroaryl; and
wherein R13 is aryl.
7. The compound according to claim 6, wherein R1 is
Figure US20080287347A1-20081120-C01519
wherein each of R10 and R11 is independently hydrido or alkyl; and
wherein X4 is fluoro or trifluoromethyl.
8. The compound according to either of claims 1 or 2, wherein J is hydrido, amino, azido or
Figure US20080287347A1-20081120-C01520
wherein R17 and R18 taken together form a group selected from ketal,
Figure US20080287347A1-20081120-C01521
or wherein R17 is hydroxyl when R18 is hydrido;
or wherein J, together with R17, forms a heterocyclyl ring.
9. The compound according to claim 8, wherein R2 is
Figure US20080287347A1-20081120-C01522
wherein R17 and R18 taken together form
Figure US20080287347A1-20081120-C01523
wherein R22 is H or alkyl; and wherein R19 is hydrido, amino, azido or
Figure US20080287347A1-20081120-C01524
10. The compound according to claim 9, wherein R2 is
Figure US20080287347A1-20081120-C01525
11. The compound according to either of claims 1 or 2 wherein said compound is
Cpd # R R1 R2 1 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01526
Figure US20080287347A1-20081120-C01527
 2 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01528
Figure US20080287347A1-20081120-C01529
 3 NHCO(CH2)8CH3 NHSO2Ph
Figure US20080287347A1-20081120-C01530
 4 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01531
Figure US20080287347A1-20081120-C01532
 5 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01533
Figure US20080287347A1-20081120-C01534
 6 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01535
Figure US20080287347A1-20081120-C01536
 7 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01537
Figure US20080287347A1-20081120-C01538
 8 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01539
Figure US20080287347A1-20081120-C01540
 9 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01541
Figure US20080287347A1-20081120-C01542
 10 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01543
Figure US20080287347A1-20081120-C01544
 11 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01545
Figure US20080287347A1-20081120-C01546
 12 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01547
Figure US20080287347A1-20081120-C01548
 13 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01549
Figure US20080287347A1-20081120-C01550
 14 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01551
Figure US20080287347A1-20081120-C01552
 15 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01553
Figure US20080287347A1-20081120-C01554
 16 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01555
Figure US20080287347A1-20081120-C01556
 17 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01557
Figure US20080287347A1-20081120-C01558
 18 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01559
Figure US20080287347A1-20081120-C01560
 19 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01561
Figure US20080287347A1-20081120-C01562
 20 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01563
Figure US20080287347A1-20081120-C01564
 21 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01565
Figure US20080287347A1-20081120-C01566
 22 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01567
Figure US20080287347A1-20081120-C01568
 23 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01569
Figure US20080287347A1-20081120-C01570
 24 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01571
Figure US20080287347A1-20081120-C01572
 25 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01573
Figure US20080287347A1-20081120-C01574
 26 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01575
Figure US20080287347A1-20081120-C01576
 27 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01577
Figure US20080287347A1-20081120-C01578
 28 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01579
Figure US20080287347A1-20081120-C01580
 29 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01581
Figure US20080287347A1-20081120-C01582
 30 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01583
Figure US20080287347A1-20081120-C01584
 31 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01585
Figure US20080287347A1-20081120-C01586
 32 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01587
Figure US20080287347A1-20081120-C01588
 33 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01589
Figure US20080287347A1-20081120-C01590
 34 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01591
Figure US20080287347A1-20081120-C01592
 35 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01593
Figure US20080287347A1-20081120-C01594
 36 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01595
Figure US20080287347A1-20081120-C01596
 57 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01597
Figure US20080287347A1-20081120-C01598
 70 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01599
Figure US20080287347A1-20081120-C01600
 182 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01601
Figure US20080287347A1-20081120-C01602
 190 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01603
Figure US20080287347A1-20081120-C01604
 193 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01605
Figure US20080287347A1-20081120-C01606
 221 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01607
Figure US20080287347A1-20081120-C01608
 254 NHCO(CH2)7CH3
Figure US20080287347A1-20081120-C01609
Figure US20080287347A1-20081120-C01610
 255 NHCO(CH2)9CH3
Figure US20080287347A1-20081120-C01611
Figure US20080287347A1-20081120-C01612
 256 NHCO(CH2)10CH3
Figure US20080287347A1-20081120-C01613
Figure US20080287347A1-20081120-C01614
 257 NHCO(CH2)11CH3
Figure US20080287347A1-20081120-C01615
Figure US20080287347A1-20081120-C01616
 258 NHCO(CH2)12CH3
Figure US20080287347A1-20081120-C01617
Figure US20080287347A1-20081120-C01618
 259 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01619
Figure US20080287347A1-20081120-C01620
 260 NHCO(CH2)9CH3
Figure US20080287347A1-20081120-C01621
Figure US20080287347A1-20081120-C01622
 261 NHCO(CH2)11CH3
Figure US20080287347A1-20081120-C01623
Figure US20080287347A1-20081120-C01624
 262 NHCO(CH2)12CH3
Figure US20080287347A1-20081120-C01625
Figure US20080287347A1-20081120-C01626
 263
Figure US20080287347A1-20081120-C01627
Figure US20080287347A1-20081120-C01628
Figure US20080287347A1-20081120-C01629
 270 NHCO(CH2)8CH3
Figure US20080287347A1-20081120-C01630
Figure US20080287347A1-20081120-C01631
 292
Figure US20080287347A1-20081120-C01632
Figure US20080287347A1-20081120-C01633
Figure US20080287347A1-20081120-C01634
 293 NHCO(CH2)10CH3
Figure US20080287347A1-20081120-C01635
Figure US20080287347A1-20081120-C01636
 294 NHCO(CH2)7CH3
Figure US20080287347A1-20081120-C01637
Figure US20080287347A1-20081120-C01638
 312 NHCONH(CH2)7CH3
Figure US20080287347A1-20081120-C01639
Figure US20080287347A1-20081120-C01640
 313 NHCONH(CH2)7CH3
Figure US20080287347A1-20081120-C01641
Figure US20080287347A1-20081120-C01642
 314 NHCONH(CH2)10CH3
Figure US20080287347A1-20081120-C01643
Figure US20080287347A1-20081120-C01644
 342 NHCO(CH2)9CH3
Figure US20080287347A1-20081120-C01645
Figure US20080287347A1-20081120-C01646
 343 NHCO(CH2)10CH3
Figure US20080287347A1-20081120-C01647
Figure US20080287347A1-20081120-C01648
 344 NHCO(CH2)12CH3
Figure US20080287347A1-20081120-C01649
Figure US20080287347A1-20081120-C01650
 350
Figure US20080287347A1-20081120-C01651
Figure US20080287347A1-20081120-C01652
Figure US20080287347A1-20081120-C01653
 351 NHCO(CH2)11CH3
Figure US20080287347A1-20081120-C01654
Figure US20080287347A1-20081120-C01655
 352 NHCONH(CH2)10CH3
Figure US20080287347A1-20081120-C01656
Figure US20080287347A1-20081120-C01657
12. The compound according to claim 11 wherein the compound is
Cpd # R R1 R2 260 NHCO(CH2)9CH3
Figure US20080287347A1-20081120-C01658
Figure US20080287347A1-20081120-C01659
 262 NHCO(CH2)12CH3
Figure US20080287347A1-20081120-C01660
Figure US20080287347A1-20081120-C01661
 344 NHCO(CH2)12CH3
Figure US20080287347A1-20081120-C01662
Figure US20080287347A1-20081120-C01663
13. A compound of formula (I) according to either of claim 1 or claim 2, wherein R is NHCO—[(C6-C14)-alkyl]-CH3, and R1 and R2 are selected from:
R1 R2
Figure US20080287347A1-20081120-C01664
Figure US20080287347A1-20081120-C01665
Figure US20080287347A1-20081120-C01666
Figure US20080287347A1-20081120-C01667
 NHSO2Ph
Figure US20080287347A1-20081120-C01668
Figure US20080287347A1-20081120-C01669
Figure US20080287347A1-20081120-C01670
Figure US20080287347A1-20081120-C01671
Figure US20080287347A1-20081120-C01672
Figure US20080287347A1-20081120-C01673
Figure US20080287347A1-20081120-C01674
Figure US20080287347A1-20081120-C01675
Figure US20080287347A1-20081120-C01676
Figure US20080287347A1-20081120-C01677
Figure US20080287347A1-20081120-C01678
Figure US20080287347A1-20081120-C01679
Figure US20080287347A1-20081120-C01680
Figure US20080287347A1-20081120-C01681
Figure US20080287347A1-20081120-C01682
Figure US20080287347A1-20081120-C01683
Figure US20080287347A1-20081120-C01684
Figure US20080287347A1-20081120-C01685
Figure US20080287347A1-20081120-C01686
Figure US20080287347A1-20081120-C01687
Figure US20080287347A1-20081120-C01688
Figure US20080287347A1-20081120-C01689
Figure US20080287347A1-20081120-C01690
Figure US20080287347A1-20081120-C01691
Figure US20080287347A1-20081120-C01692
Figure US20080287347A1-20081120-C01693
Figure US20080287347A1-20081120-C01694
Figure US20080287347A1-20081120-C01695
Figure US20080287347A1-20081120-C01696
Figure US20080287347A1-20081120-C01697
Figure US20080287347A1-20081120-C01698
Figure US20080287347A1-20081120-C01699
Figure US20080287347A1-20081120-C01700
Figure US20080287347A1-20081120-C01701
Figure US20080287347A1-20081120-C01702
Figure US20080287347A1-20081120-C01703
Figure US20080287347A1-20081120-C01704
Figure US20080287347A1-20081120-C01705
Figure US20080287347A1-20081120-C01706
Figure US20080287347A1-20081120-C01707
Figure US20080287347A1-20081120-C01708
Figure US20080287347A1-20081120-C01709
Figure US20080287347A1-20081120-C01710
Figure US20080287347A1-20081120-C01711
Figure US20080287347A1-20081120-C01712
Figure US20080287347A1-20081120-C01713
Figure US20080287347A1-20081120-C01714
Figure US20080287347A1-20081120-C01715
Figure US20080287347A1-20081120-C01716
Figure US20080287347A1-20081120-C01717
Figure US20080287347A1-20081120-C01718
Figure US20080287347A1-20081120-C01719
Figure US20080287347A1-20081120-C01720
Figure US20080287347A1-20081120-C01721
Figure US20080287347A1-20081120-C01722
Figure US20080287347A1-20081120-C01723
Figure US20080287347A1-20081120-C01724
Figure US20080287347A1-20081120-C01725
Figure US20080287347A1-20081120-C01726
Figure US20080287347A1-20081120-C01727
Figure US20080287347A1-20081120-C01728
Figure US20080287347A1-20081120-C01729
Figure US20080287347A1-20081120-C01730
Figure US20080287347A1-20081120-C01731
Figure US20080287347A1-20081120-C01732
Figure US20080287347A1-20081120-C01733
Figure US20080287347A1-20081120-C01734
Figure US20080287347A1-20081120-C01735
Figure US20080287347A1-20081120-C01736
Figure US20080287347A1-20081120-C01737
Figure US20080287347A1-20081120-C01738
Figure US20080287347A1-20081120-C01739
Figure US20080287347A1-20081120-C01740
Figure US20080287347A1-20081120-C01741
Figure US20080287347A1-20081120-C01742
Figure US20080287347A1-20081120-C01743
Figure US20080287347A1-20081120-C01744
Figure US20080287347A1-20081120-C01745
Figure US20080287347A1-20081120-C01746
Figure US20080287347A1-20081120-C01747
Figure US20080287347A1-20081120-C01748
Figure US20080287347A1-20081120-C01749
Figure US20080287347A1-20081120-C01750
14. The compound according to claim 13, wherein R is NHCO—[(CH2)6-14]-CH3.
15. A pharmaceutical composition comprising the compound according to either of claims 1 or 2 and a pharmaceutically acceptable carrier.
16. A method of treating a bacterial infection in a subject, comprising the step of administering the pharmaceutical composition according to claim 15 to a subject in need thereof for a time and under conditions effective to ameliorate said bacterial infection.
17. The method according to claim 16, wherein said subject is a human, an animal, a cell culture or a plant.
18. The method according to claim 16, wherein said bacterial infection is caused by a gram-positive bacteria.
19. The method according to claim 18, wherein said bacteria is an antibiotic-resistant bacteria.
20. The method according to claim 19, wherein said antibiotic-resistant bacteria are resistant to vancomycin, methicillin, glycopeptide antibiotics, penicillin or daptomycin.
21. The method according to claim 16, further comprising the step of co-administering more than one compound of Formula (I) according to either of claims 1 or 2 to a subject in need thereof.
22. The method according to claim 16, further comprising the step of co-administering a second antimicrobial agent wherein said second antimicrobial agent is not included within the scope of Formula (I).
23. The method according to claim 22, wherein said antimicrobial agent is penicillins, carbapenems, cephalosporins, aminoglycosides, bacitracin, gramicidin, mupirocin, chloramphenicol, thiamphenicol, fusidate sodium, lincomycin, clindamycin, macrolides, novobiocin, polymyxins, rifamycins, spectinomycin, tetracyclines, vancomycin, teicoplanin, streptogramins, anti-folate agents, trimethoprim, pyrimethamine, nitroimidazoles, quinolones, fluoroquinolones, isoniazid, ethambutol, pyrazinamide, para-aminosalicylic acid (PAS), cycloserine, capreomycin, ethionamide, prothionamide, thiacetazone, viomycin, everninomicin, glycopeptide, glycylcycline, ketolides, oxazolidinones, imipenen, amikacin, netilmicin, fosfomycin, gentamicin, ceftriaxone, ZIRACIN (56-deacetyl-57-demethyl-45-O-de(2-methyl-1-oxopropyl)-12-O-(2,3,6-trideoxy-3-C-methyl-4-O-methyl-3-nitro-alpha-L-arabino-hexopyranosyl)flambamycin), LY333328 (oritavancin), linezolid (N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide), SYNERCID (dalfopristin-quinupristin), aztreonam (2-[[(Z)-[1-(2-amino-4-thiazolyl)-2-[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methyl-propanoic acid), metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol), epiroprim (5-[[3,5-diethoxy-4-(1H-pyrrol-1-yl)phenyl]methyl]-2,4-pyrimidinediamine), OCA-983 (1-[[(2S)-2-amino-3-methyl-1-oxobutyl]amino]-2,5-anhydro-3-S-[(4R,5S,6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]-1,4-dideoxy-3-thio-D-threo-pentitol), GV-143253 (trinem), sanfetrinem((1S,5S,8aS,8bR)-1,2,5,6,7,8,8a,8b-octahydro-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-azeto[2,1-a]isoindole-4-carboxylic acid), CS-834 ((4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-oxo-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (2,2-dimethyl-1-oxopropoxy)methyl ester), biapenem(6-[[(4R,5S,6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium inner salt), KA 159 (stipiamide), dynemicin A ((1S,4R,4aR,14S,14aS,18Z)-1,4,7,12,13,14-hexahydro-6,8,11-trihydroxy-3-methoxy-1-methyl-7,12-dioxo-4a,14a-epoxy-4,14-[3]hexene[1,5]diynonaphtho[2,3-c]phenanthridine-2-carboxylic acid), DX8739 ((4R,5S,6S)-3-[[(3S,5S)-5-[[4-[(2S)-5-amino-2-hydroxy-1-oxopentyl]-1-piperazinyl]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), DU 6681 ((4R,5S,6S)-3-[[(6S)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), cefluprenam ((2E)-N-(2-amino-2-oxoethyl)-3-[(6R,7R)-7-[[(2Z)-(5-amino-1,2,4-thiadiazol-3-yl)[(fluoro methoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]-N-ethyl-N-methyl-2-propen-1-aminium inner salt), ER 35786 ((4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[[(3S,5S)-5-[(R)-hydroxy(3R)-3-pyrrolidinylmethyl]-3-pyrrolidinyl]thio]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrochloride), cefoselis ((6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(methoxy imino)acetyl]amino]-3-[[2,3-dihydro-2-(2-hydroxyethyl)-3-imino-1H-pyrazol-1-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid), sanfetrinem celexetil ((1S,5S,8aS,8bR)-1,2,5,6,7,8,8a,8b-octahydro-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-azeto[2,1-a]isoindole-4-carboxylic acid 1-[(cyclohexyloxy)carbonyl]oxy]ethyl ester), cefpirome (1-[[(6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-6,7-dihydro-5H-cyclopenta[b]pyridinium inner salt), HMR-3647 (3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)oxy]-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl[[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]imino]]-erythromycin), RU-59863 (C-7 catechol substituted cephalosporin), KP 736 ((6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)[[(1,4-dihydro-1,5-dihydroxy-4-oxo-2-pyridinyl)methoxy]imino]acetyl]amino]-8-oxo-3-[(1,2,3-thiadiazol-5-ylthio)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt), Rifalazil (1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-[4-(2-methylpropyl)-1-piperazinyl]-1-oxo-rifamycin VIII, MEN 10700 ((5R,6S)-3-[[(2-amino-2-oxoethyl)methylamino]methyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), lenapenem ((4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[[(3S,5S)-5-[(1R)-1-hydroxy-3-(methylamino)propyl]-3-pyrrolidinyl]thio]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), BO 2502A ((4R,5S,6S)-3-[(2S,3′S,4S)-[2,3′-bipyrrolidin]-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), NE-1530 (3′-sialyllacto-N-neotetraose), K130 (5-[[4-[3-[[4-[(4-aminophenyl)sulfonyl]phenyl]amino]propoxy]-3,5-dimethoxyphenyl]methyl]-2,4-pyrimidinediamine), PD 138312 ((R)-7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid), PD 140248 (7-[(3R)-3-[(1S)-1-aminoethyl]-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid), CP 111905 (5-deoxy-5-[[(2E)-3-[3-hydroxy-4-(2-propenyloxy)phenyl]-2-methyl-1-oxo-2-propenyl]amino]-1,2-O-methylene-D-neo-inositol), sulopenem ((5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(1R,3S)-tetrahydro-1-oxido-3-thienyl]thio]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), ritipenam acoxyl ((5R,6R)-3-[[(aminocarbonyl)oxy]methyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (acetyloxy)methyl ester), RO-65-5788 ((6R,7R)-7-[[(2Z)-(5-amino-1,2,4-thiadiazol-3-yl)(hydroxyimino)acetyl]amino]-3-[(E)-[(3′R)-1′-[[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy]carbonyl]-2-oxo[1,3′-bipyrrolidin]-3-ylidene]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt), Sch-40832 (N-[[48-[1-[[2,6-dideoxy-3-O-(2,6-dideoxy-D-arabino-hexopyranosyl)-D-arabino-hexopyranosyl]oxy]ethyl]-15-ethylidene-1,3a,4,5,10,11,12,13,14,15,19,20,21,22,28,29,41,42-octadecahydro-41-hydroxy-12,45-bis(1-hydroxyethyl)-1-(hydroxymethyl)-22-(1-hydroxy-1-methylpropyl)-36-methyl-51,54,57-tris(methylene)-3-(methylthio)-10,13,20,27,38,49,52,55,58-nonaoxo-18H,27H-5a,29-(iminoethaniminoethanimino ethaniminoethanimino[7,2]quinolinomethanoxy methano)-9,6:19,16:26,23:33,30-tetranitrilo-16H,33aH-imidazo[1′,5′:1,6]pyrido[3,2-m][1,11,17,24,4,7,20,27]tetrathiatetraazacyclotriacontin-1-yl]carbonyl]-2,3-didehydroalanyl-2,3-didehydro-alanine methyl ester stereoisomer), micacocidin A ((OC-6-26-A)-[(4S)-2-[(2S)-2-[(2R,4R)-2-[(4R)-4,5-dihydro-2-[2-(hydroxy-.kappa.O)-6-pentylphenyl]-4-thiazolyl-.kappa.N3]-3-methyl-4-thiazolidinyl-.kappa.N3]-2-(hydroxy-.kappa.O)-1,1-dimethylethyl]-4,5-dihydro-4-methyl-4-thiazolecarboxylato(2-)-.kappa.N3, .kappa.O4]-Zinc), SR-15402 ((1S,5S,8aS,8bR)-1,2,5,6,7,8,8a,8b-octahydro-1-[(1R)-1-hydroxyethyl]-2-oxo-5-[(3S)-3-pyrrolidinylthio]-azeto[2,1-a]isoindole-4-carboxylic acid), TOC 39 (1-(2-amino-2-oxoethyl)-4-[[(1E)-2-[(6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(hydroxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]ethenyl]thio]-pyridinium inner salt), carumonam ([[(Z)-[2-[[(2S,3S)-2-[[(aminocarbonyl)oxy]methyl]-4-oxo-1-sulfo-3-azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]oxy]-acetic acid), cefozopran (1-[[(6R,7R)-7-[[(2Z)-(5-amino-1,2,4-thiadiazol-3-yl)(methoxy imino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-imidazo[1,2-b]pyridazinium inner salt), cefetamet pivoxil ((6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(methoxy imino)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (2,2-dimethyl-1-oxopropoxy)methyl ester), or T 3811 (des-F(6)-quinolone).
24. The method according to claim 22, wherein said second antimicrobial agent is imipenen, amikacin, netilmicin, fosfomycin, gentamicin, ceftriaxone, teicoplanin, Ziracin, LY333328, CL331022, HMR3647, Linezolid, Synercid, Aztreonam or Metronidazole.
25. The method according to claim 17, wherein said subject is a human or an animal.
26. The method according to claim 25, wherein said subject is a human.
27. The compound of claim 1 having the formula (III):
Figure US20080287347A1-20081120-C01751
wherein R15 is hydrido or a carbamate amino protecting group; and wherein R16 is
Figure US20080287347A1-20081120-C01752
28. The compound of claim 2 having the formula (III):
Figure US20080287347A1-20081120-C01753
wherein R15 is hydrido or a carbamate amino protecting group; wherein R16 is
Figure US20080287347A1-20081120-C01754
and wherein R57 is a halo or halo substituted alkyl group.
29. The compound according to either of claim 27 or 28 wherein said compound is
Compound # R16 2
Figure US20080287347A1-20081120-C01755
 10
Figure US20080287347A1-20081120-C01756
 25
Figure US20080287347A1-20081120-C01757
US12/163,299 1999-12-15 2008-06-27 Novel Lipopeptides as Antibacterial Agents Abandoned US20080287347A1 (en)

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