Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

• the present invention relates to novel depsipeptides compounds.
• the invention also relates to pharmaceutical compositions of these compounds and methods of using these compounds as antibacterial agents.
• R 2 is an amino acid side chain
• R 9 is C0 * H , or an amino acid side chain substituted with at least one carboxylic acid; j) R 11 is an amino acid side chain, methyl,
• each of R 1 and R 6* is independently amino, monosubstituted amino, disubstituted amino, NH-amino protecting group, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino;
• the present invention provides, in another aspect, compounds of Formula F2:
• R 6 is methyl
• the alkanoylamino group is a "C 10 -C 13 - alkanoylamino" group which is defined as an alkanoylamino group containing a total of 1 to 13 carbon atoms, including the carbonyl carbon.
• the carbon atoms can be arranged in a straight chain or branched chain.
• the alkanoylamino group is
• 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 enyl.
• a subset of term alkenyl is "unsubstituted alkenyl" which is defined as an alkenyl group that bears no substituent groups.
• the alkyl group is a "C 1 -C 13 - alkyl” group which is defined as an alkyl group containing a total of 1 to 13 carbon atoms.
• the carbon atoms can be arranged in a straight chain or branched chain.
• the alkyl group is a "C 5 -C 20 -alkanoyl” group which is defined as a alkyl group containing a total of 5 to 20 carbon atoms.
• the carbon atoms can be arranged in a straight chain or branched chain.
• ⁇ -carboxy amino acid side chain is defined as a carbon radical of the formula
• the invention also embraces isolated compounds, preferably compounds of Formula I or compounds of any of Formulas F1-F22.
• An isolated compound refers to a compound, preferably a compound of Formula I or a compound of any of Formulas F1-F22, which represents at least about 1%, preferably at least aboutlO%, more preferably at least about 20%, even more preferably at least about 50%, yet more preferably at least about 80%, yet even more preferably at least about 90% and most preferably at least about 99% of the compound present in the mixture.
• the compound, preferably a compound of Formula I or a compound of any of Formulas F1-F22 is present in at least about 80% to about 90% of the composition.
• Substituent R 11 of Formula I is an amino acid side chain, methyl
• R 8 is hydroge
• the invention provides a compound of the Formula F6:
• R 11 is, methyl
• R 9 i . c) R 12 is H or CH 3 ; and d) each of R 1 and R 8** is independently amino, monosubstituted amino, disubstituted amino, NH-amino protecting group, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino.
• a compound of Formula F7 is selected from
• the invention provides a compound of the Formula F19:
• NRPSs non-ribosomal peptide synthetases
• PKSs polyketide synthetases
• the acyl adenylate intermediate is next transferred to the T (thiolation) domain (also referred to as a peptidyl carrier protein or PCP domain) of the module where it is converted to a thioester intermediate and tethered via a transthiolation reaction to a covalently bound enzyme cofactor (4'- phosphopantetheinyl (4'-PP) intermediate).
• T (thiolation) domain also referred to as a peptidyl carrier protein or PCP domain
• PCP domain covalently bound enzyme cofactor
• Modules responsible for incorporating D-configured or N-methylated amino acids may have extra modifying domains which, in several NRPSs studied, are located between the A and T domains.
• Reaction 5 Preparation of Resin-Glv-Thr-AspfOtBuVDAsnfNHTrtVNHFmoc (6)
• a solution of commercially available N ⁇ -(9-Fluorenylmethoxycarbonyl)-D- asparagine ⁇ -N-trityl (2 mL of a 0.5 molar solution in N-methylpyrolidine), 1,3- diisopropylcarbodiimide (2 mL of a 0.5 molar solution in N-methylpyrolidine), and 1-hydroxy- benzotriazole (2 mL of a 0.5 molar solution in N-methylpyrolidine) was added to resin 5.
• the dried resin 27 was placed under an argon atmosphere, and treated with a solution of tetrakis-(triphenylphosphine)palladium(0) (19 mg) in dichloromethane(1.47 mL), acetic acid (74 ⁇ L), and N-methylmorpholine (37 ⁇ L). The mixture was shaken for 4 hours at ambient temperature, filtered through a glass sinter funnel, and the solid was washed with two times with N-methylmorpholine, two times with methanol, and again two times with N-methylmorpholine .
• reaction mixture was filtered through a glass sinter funnel then the solid was washed with N-methylpyrolidine (3 x 30 mL), methanol (3 x 30 mL), and again with N-methylpyrolidine (3 x 30 mL) to give compound 44.
• Example 1-12 Synthesis of Peptide Resin Compound 56 Resin-Glu( ⁇ OAUyl)-DAsn(NHTrt)-Gly-Asp(OtBu)-DLys(NHBoc)-Asp(OtBu)-NH 2 (56)
• Reaction 8 Preparation of Resin-Ala-Glv-Thr-Aspf OtBu)-D AsnWHTrt)-NH? (97) [0501]
• Compound 96 was agitated in 20% piperidine in N-methylpyrolidine (20 mL) for 2 hours. The reaction mixture was filtered through a glass sinter funnel then the solid washed with N-methylpyrolidine (3 x 15 mL), methanol (3 x 15 mL), and again with N-methylpyrolidine (3 x 15 mL) to give compound 97.
• reaction mixture was filtered through a glass sinter funnel, re-suspended in 20% piperidine in N-methylpyrolidine (100 mL) and agitated for 30 minutes.
• the reaction mixture was filtered through a glass sinter funnel then the solid was washed with N-methylpyrolidine (3 x 130 mL), methanol (3 x 130 mL), and again with N-methylpyrolidine (3 x 130 mL) to give compound 110.
• reaction mixture was filtered through a glass sinter funnel, re-suspended in 20% piperidine in N-methylpyrolidine (110 mL) and agitated for 30 minutes.
• the reaction mixture was filtered through a glass sinter funnel then the solid was washed with N-methylpyrolidine (3 x 110 mL), methanol (3 x 110 mL), and again with N-methylpyrolidine (3 x 110 mL) to give compound 112.
• N ⁇ -(9-Fluorenylmethoxycarbonyl)-D-asparagine 5.0 g
• 2- (lH-Benzotriazol-yl)-l,l,3,3-tetramethyluronium tetrafluroborate TBTU, 2.7 g
• HOBt 1.13 g
• DIPEA diisopropylethylamine
• Reaction 12 Preparation of Resin-Om(NHBoc)-Sar-TruvAsp(OtBu)-DAsn(NHTrt)-

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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• Molecular Biology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Peptides Or Proteins (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)
• Micro-Organisms Or Cultivation Processes Thereof (AREA)

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• 2005
  • 2005-11-11 WO PCT/US2005/040919 patent/WO2006110185A2/en active Application Filing
  • 2005-11-11 KR KR1020077013150A patent/KR20070086038A/ko not_active Application Discontinuation
  • 2005-11-11 AU AU2005330517A patent/AU2005330517A1/en not_active Abandoned
  • 2005-11-11 BR BRPI0517830-4A patent/BRPI0517830A/pt not_active IP Right Cessation
  • 2005-11-11 CA CA002587848A patent/CA2587848A1/en not_active Abandoned
  • 2005-11-11 RU RU2007121705/04A patent/RU2007121705A/ru not_active Application Discontinuation
  • 2005-11-11 JP JP2007541346A patent/JP2008519848A/ja not_active Withdrawn
  • 2005-11-11 EP EP05857738A patent/EP1814588A2/en not_active Withdrawn
• 2007
  • 2007-05-10 IL IL183109A patent/IL183109A0/en unknown
  • 2007-05-24 NO NO20072634A patent/NO20072634L/no not_active Application Discontinuation

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