US20200368312A1 - Glycopeptide derivative compounds and uses thereof - Google Patents

Glycopeptide derivative compounds and uses thereof Download PDF

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US20200368312A1
US20200368312A1 US16/615,232 US201816615232A US2020368312A1 US 20200368312 A1 US20200368312 A1 US 20200368312A1 US 201816615232 A US201816615232 A US 201816615232A US 2020368312 A1 US2020368312 A1 US 2020368312A1
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substituted
alkyl
formula
infection
aureus
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Ryan HECKLER
Donna Konicek
Adam Plaunt
Vladimir Malinin
Walter Perkins
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Insmed Inc
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Insmed Inc
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Assigned to INSMED INCORPORATED reassignment INSMED INCORPORATED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KONICEK, DONNA M., HECKLER, Ryan, MALININ, VLADIMIR, PERKINS, WALTER R., PLAUNT, Adam
Publication of US20200368312A1 publication Critical patent/US20200368312A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • a method for treating a bacterial infection in a patient in need thereof comprises administrating to the patient a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
  • R 1 is C 1 -C 18 linear alkyl, C 1 -C 18 branched alkyl, R 5 —Y—R 6 —(Z) n , or
  • R 2 is —OH or —NH—(CH 2 ) q —R 7 ;
  • R 3 is H or
  • R 4 is H or CH 2 —NH—CH 2 —PO 3 H 2 ;
  • n 1 or 2;
  • each q is independently 1, 2, 3, 4, or 5;
  • X is O, S, NH or H 2 ;
  • each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
  • R 5 and R 6 are independently selected from the group consisting of alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene groups are optionally substituted with from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxya
  • R 7 is —N(CH 2 ) 2 ; —N + (CH 2 ) 3 ; or
  • Y is independently selected from the group consisting of oxygen, sulfur, —S—S—, —NR 8 —, —S(O)—, —SO 2 —, —NR 8 C(O)—, —OSO 2 —, —OC(O)—, —NR 8 SO 2 —, —C(O)NR 8 —, —C(O)O—, —SO 2 NR 8 —, —SO 2 O—, —P(O)(OR 8 )O—, —P(O)(OR 8 )NR 8 —, —OP(O)(OR 8 )O—, —OP(O)(OR 8 )NR 8 —, —OC(O)O—, —NR 8 C(O)O—, —NR 8 C(O)NR 8 —, —OC(O)NR 8 — and —NR 8 SO 2 NR 8 —; and
  • each R 8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic.
  • a method of the invention comprises administrating to the patient a composition comprising an effective amount of a compound of Formula (II), a prodrug thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 is C 1 -C 18 linear alkyl, C 1 -C 18 branched alkyl, R 5 —Y—R 6 —(Z) n , or
  • R 2 is —OH or —NH—(CH 2 ) q —R 7 ;
  • R 3 is H or
  • R 4 is H or CH 2 —NH—CH 2 —PO 3 H 2 ;
  • n 1 or 2;
  • each q is independently 1, 2, 3, 4, or 5;
  • X is O, S, NH or H 2 ;
  • each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
  • R 5 and R 6 are independently selected from the group consisting of alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene groups are optionally substituted with from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxya
  • R 7 is —N(CH 2 ) 2 ; —N + (CH 2 ) 3 ; or
  • Y is independently selected from the group consisting of oxygen, sulfur, —S—S—, —NR 8 —, —S(O)—, —SO 2 —, —OSO 2 —, —NR 8 SO 2 —, —SO 2 NR 8 —, —SO 2 O—, —P(O)(OR 8 )O—, —P(O)(OR 8 )NR 8 —, —OP(O)(OR 8 )O—, —OP(O)(OR 8 )NR 8 —, —NR 8 C(O)NR 8 —, and —NR 8 SO 2 NR 8 —; and
  • each R 8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic.
  • the composition comprises an effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), wherein R 1 is C 6 to C 16 linear alkyl. In a further embodiment, R 1 is C 6 , C 10 or C 16 alkyl. In even a further embodiment, R is C 10 alkyl. In a further embodiment, the bacterial infection is a pulmonary bacterial infection. In even a further embodiment, the administering comprises administering via inhalation.
  • the method for treating a bacterial infection comprises administering to the patient in need thereof, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), where R 1 is R 5 —Y—R 6 —(Z) n .
  • R 5 is —(CH 2 ) 2 —
  • R 6 is —(CH 2 ) 10 —
  • X is O
  • Y is NR 8
  • Z is hydrogen
  • n is 1.
  • R 8 is hydrogen.
  • one embodiment of the invention includes a compound of Formula (I), Formula (II) or a pharmaceutically acceptable salt thereof, where R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 .
  • the bacterial infection is a pulmonary bacterial infection.
  • the administering comprises administering via inhalation.
  • the method for treating a bacterial infection comprises administering to the patient in need thereof, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), where R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 and R 3 and R 4 are H.
  • R 2 is OH.
  • the administering comprises administering via the intravenous route.
  • X is O.
  • the method for treating a bacterial infection comprises administering to the patient in need thereof, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II) where R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 , R 2 is —NH—(CH 2 ) q —R 7 , and R 3 and R 4 are H.
  • the administering comprises administering via the intravenous or pulmonary route.
  • q is 2 or 3 and R 7 is —N(CH 2 ) 2 .
  • X is O.
  • composition administered to the patient comprises an effective amount of a compound of Formula (I) or Formula (II), where R 1 is
  • R 2 is OH and R 3 and R 4 are H.
  • the halogen is Cl and q is 1 or 2.
  • the administering comprises administering via the pulmonary or intravenous route.
  • X is O and R 1 is
  • R 2 is OH and R 3 is
  • R 4 is H.
  • the halogen is Cl and q is 1 or 2.
  • the administering comprises administering via the intravenous route.
  • X is O and R 1 is
  • the bacterial infection is a Gram-positive cocci infection and the composition administered to the patient in need thereof comprises an effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), wherein R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 .
  • the infection is a Gram-positive infection is a cocci infection
  • VRE vancomycin-resistant enterococci
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant St
  • the bacterial infection is a Gram-positive cocci infection and the composition administered to the patient in need thereof comprises an effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), wherein R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 .
  • the infection is erythromycin-resistant (erm R ), vancomycin-intermediate S. aureus (VISA) heterogenous vancomycin-intermediate S. aureus (hVISA), S. epidermidis coagulase-negative staphylococci (CoNS), penicillin-intermediate S. pneumoniae (PISP), or penicillin-resistant S. pneumoniae (PRSP).
  • R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 and the bacterial infection is Propionibacterium acnes (skin acne), Eggerthella lenta (bacteremia) or Peptostreptococcus anaerobius (gynecological infection).
  • R 2 is OH and R 3 and R 4 are H.
  • the bacterial infection is a methicillin-resistant Staphylococcus aureus (MRSA) infection and the composition administered to the patient in need thereof comprises an effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), wherein R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 .
  • the administration is conducted via a nebulizer or a dry powder inhaler and the bacterial infection is a pulmonary infection.
  • administration is intravenous, R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 ; R 2 is OH and R 3 and R 4 are H.
  • X is O.
  • FIG. 1 top shows the reductive amination of vancomycin to arrive at a glycopeptide derivative. The reaction occurs at the primary amine of vancomycin.
  • FIG. 1 bottom, shows a synthesis scheme for a chloroeremomycin derivative.
  • FIG. 2 shows synthesis schemes for making the glycopeptide derivative RV40.
  • FIG. 3 shows a synthesis scheme for making the glycopeptide derivative RV79.
  • FIG. 4 is a synthesis scheme for making alkyl vancomycin derivatives.
  • FIG. 5 shows one synthesis scheme for making decyl-vancomycin (Compound #5).
  • FIG. 6 is a bar graph showing the minimum inhibitory concentration (MIC) ( ⁇ g antibiotic/mL) for various antibiotics against 23 different S. aureus strains.
  • FIG. 7 is a scatter plot showing the minimum inhibitory concentration (MIC) ( ⁇ g antibiotic/mL) for various antibiotics against 23 different S. aureus strains. Data is plotted as geometric mean with a 95% confidence interval.
  • MIC minimum inhibitory concentration
  • FIG. 8 is a bar graph showing the minimum inhibitory concentration (MIC) ( ⁇ g antibiotic/mL) for various antibiotics against 12 different MRSA strains.
  • FIG. 9 is a scatter plot showing the minimum inhibitory concentration (MIC) ( ⁇ g antibiotic/mL) for various antibiotics against 12 different MRSA strains. Data is plotted as geometric mean with a 95% confidence interval.
  • MIC minimum inhibitory concentration
  • FIG. 10 is a graph showing the log reduction of in CFU/mL biofilm as a function of antibiotic concentration ( ⁇ g/mL).
  • FIG. 11 is a graph showing the log reduction of in CFU/mL biofilm as a function of antibiotic concentration ( ⁇ g/mL).
  • FIG. 14 is a graph showing reduction in lung CFU for inhaled RV40 targeted delivered dosed at 10, 5, 2, and 1 mg/kg vs control.
  • Drugs were administered via inhalation at 12 and 24 h after intranasal bacterial challenge with MRSA (USA300, ATCC BAA-1556) in neutropenic rats and CFUs were counted 36 h after challenge.
  • FIG. 15 is a graph showing the difference in log reduction in CFU/g lung versus control treatment (nebulized inhaled saline) for prophylactic dosing of RV40.
  • Prophylactic dosing of inhaled RV40 reduces lung bacterial burden vs. control (inhaled saline) up to 5 days before infection.
  • Single doses of RV40 (10 mg/kg delivered target) were administered by inhalation.
  • Neutropenic rats were infected with MRSA (USA300, ATCC BAA-1556) on Day 0 and CFUs were counted 36 h after challenge. Data plotted as geometric mean of CFU/g. Error bars are 95% confidence interval (CI).
  • the present invention addresses the need for new bacterial infection treatment methods, and in particular, bacterial infection treatment methods by delivering compounds of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II) to patients in need thereof, for example via the pulmonary or intravenous route.
  • the present invention relates to methods for treating bacterial infections, for example, Gram-positive bacterial infections and in some embodiments, Gram-positive bacterial pulmonary infections.
  • the method comprises administering to a patient in need thereof, a composition comprising an effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II).
  • the composition can be administered by any route.
  • the composition is administered via a nebulizer, dry powder inhaler or metered dose inhaler.
  • the composition is administered intravenously.
  • an “effective amount” of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), is an amount that can provide the desired therapeutic response.
  • the effective amount can refer to a single dose as part of multiple doses during an administration period, or as the total dosage of glycopeptide given during an administration period.
  • a treatment regimen can include substantially the same dose for each glycopeptide administration, or can comprise at least one, at least two or at least three different dosages.
  • substituted alkyl refers to an alkyl group as defined above, having from 1 to 8 substituents, e.g., from 1 to 5 substituents or from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
  • alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, for example, having from 1 to 40 carbon atoms, e.g., from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (CH 2 —), ethylene (—CH 2 CH 2 —), the propylene isomers (e.g., —CH 2 CH 2 CH 2 — and —CH(CH 3 )CCH 2 —) and the like.
  • substituted alkylene refers to an alkylene group, as defined above, having from 1 to 5 substituents, for example, from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO
  • substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group.
  • fused groups can contain from 1 to 3 fused ring structures.
  • substituted alkylene includes alkylene groups in which from 1 to 5 of the alkylene carbon atoms are replaced with oxygen, sulfur or NR— where R is hydrogen or alkyl.
  • alkaryl refers to the groups -alkylene-aryl and substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
  • alkoxy refers to the groups alkyl-O—, alkenyl-O—, cycloalkyl-O-cycloalkenyl-O—, and alkynyl-O—, where alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.
  • Alkyl-O— alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
  • substituted alkoxy refers to the groups substituted alkyl-O—, substituted alkenyl-O—, substituted cycloalkyl-O—, substituted cycloalkenyl-O—, and substituted alkynyl-O— where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.
  • alkylalkoxy refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
  • Alkylalkoxy groups are also expressed as alkylene-O-alkyl and include, by way of example, methylenemethoxy (—CH 2 OCH 3 ), ethylenemethoxy (—CH 2 CH 2 OCH 3 ), n-propylene-iso-propoxy (—CH 2 CH 2 CH 2 OCH(CH 3 ) 2 ), methylene-t-butoxy (—CH 2 —O—C(CH 3 ) 3 ) and the like.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 40 carbon atoms, e.g., 2 to 10 carbon atoms or 2 to 6 carbon atoms, and having at least 1 and in some embodiments, from 1-6 sites of vinyl unsaturation.
  • Alkenyl groups include ethenyl (—CH ⁇ CH 2 ), n-propenyl (—CH 2 CH ⁇ CH 2 ), iso-propenyl (—C(CH 3 ) ⁇ CH 2 ), and the like.
  • substituted alkenyl refers to an alkenyl group as defined above having from 1 to 5 substituents, and e.g., from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, al
  • alkenylene refers to a diradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 40 carbon atoms, for example from 2 to 10 carbon atoms or from 2 to 6 carbon atoms and having at least 1 and for example, from 1-6 sites of vinyl unsaturation.
  • This term is exemplified by groups such as ethenylene (—CH ⁇ CH—), the propenylene isomers (e.g., —CH 2 CH ⁇ CH— and —C(CH 3 ) ⁇ CH—) and the like.
  • substituted alkenylene refers to an alkenylene group as defined above having from 1 to 5 substituents, and for example, from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —
  • substituted alkenylene groups include those where 2 substituents on the alkenylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkenylene group.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon having from 2 to 40 carbon atoms, for example, from 2 to 20 carbon atoms, or from 2 to 6 carbon atoms and having at least 1 and in some embodiments from 1 to 6 sites of acetylene (triple bond) unsaturation.
  • Representative alkynyl groups include ethynyl (—C ⁇ CH), propargyl (—CH 2 C ⁇ CH) and the like.
  • substituted alkynyl refers to an alkynyl group as defined above having from 1 to 5 substituents, for example, from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,
  • alkynylene refers to a diradical of an unsaturated hydrocarbon having from 2 to 40 carbon atoms, for example from 2 to 10 carbon atoms or 2 to 6 carbon atoms and having at least 1 and in some embodiment, from 1-6 sites of acetylene (triple bond) unsaturation.
  • Representative alkynylene groups include ethynylene (—C ⁇ C—), propargylene (—CH 2 C ⁇ C—).
  • substituted alkynylene refers to an alkynylene group as defined above having from 1 to 5 substituents, for example, from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxy
  • acyl refers to the groups HC(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, aryl-C(O)—, heteroaryl-C(O)— and heterocyclic-C(O)— where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • acylamino or “aminocarbonyl” refers to the group —C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or where both R groups are joined to form a heterocyclic group (e.g., morpholino) wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • aminoacyl refers to the group —NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • aminoacyloxy or “alkoxycarbonylamino” refers to the group —NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl aryl, heteroaryl, or heterocyclic.
  • acyloxy refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—, aryl-C(O)O—, heteroaryl-C(O)O—, and heterocyclic-C(O)O— wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl).
  • Representative aryls include phenyl, naphthyl and the like.
  • such aryl groups can optionally be substituted with from 1 to 5 substituents, e.g., from 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, sulfonamide, thioalkoxy, substituted
  • aryloxy refers to the group aryl-O— wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
  • arylene refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like.
  • amino refers to the group —NH 2 .
  • substituted amino refers to the group —NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic provided that both R groups are not H.
  • amino acid refers to any of the naturally occurring amino acids, synthetic amino acids, and derivatives thereof ⁇ -Amino acids comprise a carbon atom to which is bonded an amino group, a carboxy group, a hydrogen atom, and a distinctive group referred to as a “side chain”.
  • side chains of naturally occurring amino acids include, for example, hydrogen (e.g., glycine), alkyl (e.g., alanine, valine, leucine, isoleucine, proline), substituted alkyl (e.g., as in threonine, serine, methionine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, and lysine), alkaryl (e.g., phenylalanine and tryptophan), substituted arylalkyl (e.g., tyrosine), and heteroarylalkyl (e.g., histidine).
  • hydrogen e.g., glycine
  • alkyl e.g., alanine, valine, leucine, isoleucine, proline
  • substituted alkyl e.g., as in threonine, serine, methionine, cysteine, aspartic acid,
  • carboxyalkyl or “alkoxycarbonyl” refers to the groups “—C(O)O-alkyl”, “—C(O)O-substituted alkyl”, “—C(O)O-cycloalkyl”, “—C(O)O-substituted cycloalkyl”, “—C(O)O— alkenyl”, “—C(O)O-substituted alkenyl”, “—C(O)O-alkynyl” and “—C(O)O-substituted alkynyl” where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl are as defined herein
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • substituted cycloalkyl refers to cycloalkyl groups having from 1 to 5 substituents, and for example, from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxya
  • cycloalkenyl refers to cyclic alkenyl groups of from 4 to 20 carbon atoms having a single cyclic ring and at least one point of internal unsaturation.
  • suitable cycloalkenyl groups include, e.g., cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl.
  • substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substituents, and for example, from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alk
  • halo or “halogen” refers to fluoro, chloro, bromo and/or iodo.
  • Haloalkyl refers to alkyl as defined herein substituted by 1-4 halo groups as defined herein, which may be the same or different.
  • Representative haloalkyl groups include, by way of example, trifluoromethyl, 3-fluorododecyl, 12,12,12-trifluorododecyl, 2-bromooctyl, 3-bromo-6-chloroheptyl, and the like.
  • heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring moiety.
  • heteroaryl groups can be optionally substituted with 1 to 5 substituents, for example from 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryl
  • aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
  • the heteroaryl is pyridyl, pyrrolyl or furyl.
  • “Heteroarylalkyl” refers to (heteroaryl)alkyl- where heteroaryl and alkyl are as defined herein. Representative examples include 2-pyridylmethyl and the like.
  • heteroaryloxy refers to the group heteroaryl-O—.
  • heteroarylene refers to the diradical group derived from heteroaryl (including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6-pyridylene, 2,4-pyridiylene, 1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene, 2,5-pyridnylene, 2,5-indolenyl and the like.
  • heterocycle or “heterocyclic” refers to a monoradical saturated unsaturated group having a single ring or multiple condensed rings, from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, for example from 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
  • heterocyclic groups can be optionally substituted with 1 to 5, and for example, from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,
  • nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing
  • crown compounds refers to a specific class of heterocyclic compounds having one or more repeating units of the formula [(CH 2 —) a A-] where a is equal to or greater than 2, and A at each separate occurrence can be 0, N, S or P.
  • Examples of crown compounds include, by way of example only, [—(CH 2 ) 3 —NH-]3, [—((CH 2 ) 2 —O) 4 —((CH 2 ) 2 —NH) 2 ] and the like.
  • the crown compound has from 4 to 10 heteroatoms and 8 to 40 carbon atoms.
  • heterocyclooxy refers to the group heterocyclic-O—.
  • heterocyclene refers to the diradical group formed from a heterocycle, as defined herein, and is exemplified by the groups 2,6-morpholino, 2,5-morpholino and the like.
  • oxyacylamino or “aminocarbonyloxy” refers to the group —OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • spiro-attached cycloalkyl group refers to a cycloalkyl group attached to another ring via one carbon atom common to both rings.
  • sulfonamide refers to a group of the formula —SO 2 NRR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • thiol refers to the group —SH.
  • heteroaryloxy refers to the group heteroaryl-S— wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
  • any of the above groups which contain one or more substituents it is understood that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds.
  • glycopeptide refers to heptapeptide antibiotics, characterized by a multi-ring peptide core optionally substituted with saccharide groups. Examples of glycopeptides included in this definition may be found in “Glycopeptides Classification, Occurrence, and Discovery”, by Raymond C. Rao and Louise W. Crandall, (“Drugs and the Pharmaceutical Sciences” Volume 63, edited by Ramakrishnan Nagarajan, published by Marcal Dekker, Inc.), which is hereby incorporated by reference in its entirety.
  • glycopeptides include those identified as A477, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850, A84575, AB-65, Actaplanin, Actinoidin, Ardacin, Avoparcin, Azureomycin, Balhimycin, Chloroorientiein, Chloropolysporin, Decaplanin, N-demethylvancomycin, Eremomycin, Galacardin, Helvecardin, Izupeptin, Kibdelin, LL-AM374, Mannopeptin, MM45289, MM47756, MM47761, MM49721, MM47766, MM55260, MM55266, MM55270, MM56597, MM56598, OA-7653, Orenticin, Parvodicin, Ristocetin, Ristomycin, Synmonicin, Teicoplanin, Telavancin, UK-68597, UK-695
  • glycopeptide as used herein is also intended to include the general class of peptides disclosed above on which the sugar moiety is absent, i.e., the aglycone series of glycopeptides. For example, removal of the disaccharide moiety appended to the phenol on vancomycin by mild hydrolysis gives vancomycin aglycone. Also within the scope of the invention are glycopeptides that have been further appended with additional saccharide residues, especially aminoglycosides, in a manner similar to vancosamine. In embodiments described herein, one or more of the aforementioned glycopeoptides can be used in combination with a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or (II).
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable addition salt refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid (HCl), hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,
  • a pharmaceutically acceptable base addition salt retains the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable.
  • These salts are prepared from addition of an inorganic base or an organic base to the free acid.
  • Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Inorganic salts include the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • a method for treating a bacterial infection in a patient in need thereof.
  • the method comprises administrating to the patient a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • R 1 is C 1 -C 18 linear alkyl, C 1 -C 18 branched alkyl, R 5 —Y—R 6 —(Z) n , or
  • R 2 is —OH or —NH—(CH 2 ) q —R 7 ;
  • R 3 is H or
  • R 4 is H or CH 2 —NH—CH 2 —PO 3 H 2 ;
  • n 1 or 2;
  • each q is independently 1, 2, 3, 4, or 5;
  • X is O, S, NH or H 2 ;
  • each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
  • R 5 and R 6 are independently selected from the group consisting of alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene groups are optionally substituted with from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxya
  • R 7 is —N(CH 2 ) 2 ; —N + (CH 2 ) 3 ; or
  • Y is independently selected from the group consisting of oxygen, sulfur, —S—S—, —NR 8 —, —S(O)—, —SO 2 —, —NR 8 C(O)—, —OSO 2 —, —OC(O)—, —NR 8 SO 2 —, —C(O)NR 8 —, —C(O)O—, —SO 2 NR 8 —, —SO 2 O—, —P(O)(OR 8 )O—, —P(O)(OR 8 )NR 8 —, —OP(O)(OR 8 )O—, —OP(O)(OR 8 )NR 8 —, —OC(O)O—, —NR 8 C(O)O—, —NR 8 C(O)NR 8 —, —OC(O)NR 8 — and —NR 8 SO 2 NR 8 —; and
  • each R 8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic
  • Another aspect of the invention relates to a method of treating a patient for a bacterial infection.
  • the method comprises administering a composition comprising an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, to the patient in need of treatment.
  • Formula (II) is defined as follows:
  • R 1 is C 1 -C 18 linear alkyl, C 1 -C 18 branched alkyl, R 5 —Y—R 6 —(Z) n , or
  • R 2 is —OH or —NH—(CH 2 ) q —R 7 ;
  • R 3 is H or
  • R 4 is H or CH 2 —NH—CH 2 —PO 3 H 2 ;
  • n 1 or 2;
  • each q is independently 1, 2, 3, 4, or 5;
  • X is O, S, NH or H 2 ;
  • each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
  • R 5 and R 6 are independently selected from the group consisting of alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene groups are optionally substituted with from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxy aminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino
  • R 7 is —N(CH 2 ) 2 ; —N + (CH 2 ) 3 ; or
  • Y is independently selected from the group consisting of oxygen, sulfur, —S—S—, —NR 8 —, —S(O)—, —SO 2 —, —OSO 2 —, —NR 8 SO 2 —, —SO 2 NR 8 —, —SO 2 O—, —P(O)(OR 8 )O—, —P(O)(OR 8 )NR 8 —, —OP(O)(OR 8 )O—, —OP(O)(OR 8 )NR 8 —, NR 8 C(O)NR 1 —, and —NR 8 SO 2 NR 8 —; and
  • each R 8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic.
  • the amide coupling can be carried out as described in Yarlagadda et al. (2014). J. Med. Chem. 57, pp. 4558-4568, the disclosure of which is incorporated by reference herein in its entirety for all purposes.
  • a solution of vancomycin or other glycopeptide derivative e.g., a compound of Formula (I) or Formula (II), where R 1 is
  • —NH—(CH 2 ) q —R 7 e.g., a solution of —NH—(CH 2 ) 3 —N(CH 2 ) 2 , —NH—(CH 2 ) 3 —N + (CH 2 ) 3 , or
  • N-methylmorpholine and HBTU at 25° C.
  • the reaction mixture can be stirred at 25° C. for 5 min and quenched with the addition of 50% MeOH in H 2 O at 25° C.
  • the mixture can be purified by semi-preparative reverse-phase HPLC to afford the compound as a white film.
  • the method for treating a bacterial infection comprises administering to the patient in need thereof, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), where R 1 does not include a physiologically cleavable functional group.
  • R 1 group in one embodiment, is not subject to hydrolysis or enzymatic cleavage in vivo.
  • the method for treating a bacterial infection comprises administering to the patient in need thereof, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), where R 1 does not include an amide or ester moiety.
  • the method for treating a bacterial infection comprises administering to the patient in need thereof, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), where R 1 is R 5 —Y—R 6 —(Z) n .
  • R 5 is —(CH 2 ) 2 —
  • R 6 is —(CH 2 ) 10 —
  • X is O
  • Y is NR
  • Z is hydrogen
  • n is 1.
  • R 8 is hydrogen.
  • one embodiment of the method provided herein includes delivering to a patient a composition comprising an effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), where R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 .
  • X is O
  • R 2 is OH
  • R 3 and R 4 are H.
  • administration is via the intravenous or pulmonary route.
  • a patient is administered a composition comprising an effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), where R 1 is —CH 2 —NH—(CH 2 ) 10 —CH 3 .
  • R 1 is —CH 2 —NH—(CH 2 ) 10 —CH 3 .
  • X is O
  • R 2 is OH
  • R 3 and R 4 are H.
  • administration is via the intravenous or pulmonary route.
  • a patient is administered a composition comprising an effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, where R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 10 —CH 3 .
  • R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 10 —CH 3 .
  • X is O
  • R 2 is OH and R 3 and R 4 are H.
  • administration is via the intravenous or pulmonary route.
  • a patient is administered a composition comprising an effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), where R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 11 —CH 3 .
  • R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 11 —CH 3 .
  • X is O
  • R 2 is OH
  • R 3 and R 4 are H.
  • administration is via the intravenous or pulmonary route.
  • a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), is administered to the patient in need thereof, where R 1 is
  • X is O or H 2 ; and R 2 is —NH—(CH 2 ) q —R 7 . In a further embodiment, R 2 is —NH—(CH 2 ) 3 —R 7 . In a further embodiment, R 1 is
  • R 7 is —N + (CH 2 ) 3 or —N(CH 2 ) 2 .
  • R is C 10 -C 16 alkyl. In even a further embodiment, R 1 is C 10 alkyl.
  • composition comprising an effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), is delivered to the patient, where R 2 is OH, R 3 and R 4 are H and X is O.
  • R 1 is
  • R 1 is R 5 —Y—R 6 —(Z) 1
  • R 5 is methylene, ethylene or propylene
  • R 6 is —(CH 2 ) 9 —, —(CH 2 ) 10 —, —(CH 2 ) 11 —, or —(CH 2 ) 12 —
  • Z is H and n is 1.
  • an effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II) is provided, wherein one or more hydrogen atoms is replaced with a deuterium atom.
  • the method for treating the bacterial infection comprises administering to the patient in need thereof, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), where R 1 is R 5 —Y—R 6 —(Z) n .
  • R 5 is —(CH 2 ) 2 —
  • R 6 is —(CH 2 ) 10 —
  • Y is NR 8
  • Z is hydrogen
  • n is 1.
  • R 8 is hydrogen.
  • R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 .
  • Exemplary embodiments of the compound of Formula (I) or Formula (II), for use in methods of treating bacterial infections are provided in Table 1, below. It should be noted that the compound can also be provided as a pharmaceutically acceptable salt.
  • the compounds in Table 1 are identified by their respective R 1 , R 2 and X groups. Compounds of Table 1, in one embodiment, are defined as having R 3 and R 4 as both H. In another embodiment, a compound of Table 1 is administered, where R 3 is
  • R 4 is H.
  • a compound of Table 1 is administered, where R 3 is H and R 4 is CH 2 —NH—CH 2 —PO 3 H 2 .
  • a compound of Table 1 is administered, where R 3 is
  • R 4 is CH 2 —NH—CH 2 —PO 3 H 2 .
  • OH O —(CH 2 ) 2 NH—(CH 2 ) 8 —CH ⁇ CH 2 188.
  • OH O —(CH 2 ) 2 NH—(CH 2 ) 8 —CH(OH)—CH 3 189.
  • OH O —(CH 2 ) 2 NH—(CH 2 ) 3 CH ⁇ CH(CH 2 ) 4 CH 3 (trans) 190.
  • OH O —(CH 2 ) 2 NH—CH 2 CH ⁇ C(CH 3 )(CH 2 ) 2 — CH ⁇ C(CH 3 ) 2 (trans, trans) 191.
  • OH O —(CH 2 ) 2 NHC(O)—(CH 2 ) 6 —CH(CH 3 )CH 3 192.
  • OH O —(CH 2 ) 2 NH—CH 2 —5-(PhC ⁇ C)- thiophen-2-yl 208.
  • OH O —(CH 2 ) 2 NH—CH 2 —4-(PhCH ⁇ CH—)Ph (trans) 210.
  • OH O —(CH 2 ) 2 NH—CH 2 —(CH ⁇ CH) 4 —CH 3 (trans, trans, trans, trans) 212.
  • the compound is a prodrug of Formula (I) or Formula (II), for example an alkyl ester prodrug.
  • the alkyl group in one embodiment is a straight chain C 1 -C 20 alkyl or a branched C 1 -C 20 alkyl.
  • the alkyl ester attachment can be at any oxygen in the molecule, determined by the user of the method.
  • a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), is delivered to a patient in need thereof, wherein, X is O, R 1 is a C 1 -C 18 linear alkyl, R 2 is OH, and R 3 and R 4 are H.
  • R 1 in a further embodiment is a C 7 -C 17 linear alkyl; C 7 -C 10 or C 6 -C 10 linear alkyl.
  • a compound of Formula (I), Formula (II) a prodrug thereof, or a pharmaceutically acceptable salt thereof is delivered to a patient in need thereof, wherein, X is O, R 1 is R 5 —Y—R 6 —(Z) n , R 2 is OH, and R 3 and R 4 are H.
  • R 5 is —(CH 2 ) 2 —
  • R 6 is —(CH 2 ) 10 —
  • Y is NR
  • Z is hydrogen and n is 1.
  • R 8 is hydrogen and X is O.
  • the administering is intravenous or via the pulmonary route.
  • a compound of Formula (I), Formula (II) or a pharmaceutically acceptable salt thereof is delivered to a patient in need of bacterial infection treatment, where R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 , X is O, R 2 is —NH—(CH 2 ) q —R 7 , and R 3 and R 4 are H.
  • q is 2 or 3 and R 1 is —N(CH 2 ) 2 .
  • a compound of Formula (I), Formula (II) or a pharmaceutically acceptable salt thereof is delivered to a patient in need of bacterial infection treatment, where R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 , X is O, R 2 is OH, R 3 is
  • R 4 is H.
  • a compound of Formula (I), Formula (II) or a pharmaceutically acceptable salt thereof is delivered to a patient in need of bacterial infection treatment, where R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 , X is O, R 2 is OH, and R 3 is H and R 4 is CH 2 —NH—CH 2 —PO 3 H 2 .
  • a compound of Formula (I) or Formula (II) is provided, wherein one or more hydrogen atoms is replaced with a deuterium atom.
  • R 2 —Y—R 3 —(Z) is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 .
  • the compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II) is defined as follows: R 1 is (CH 2 ) n1 —Y—(CH 2 ) n2 —CH 3 , R 2 is OH, R 3 and R 4 are H, n2 is an integer selected from 1 to 6 and n3 is an integer from 1 to 15. In a further embodiment, X is O. In even a further embodiment, the administering is intravenous or via the pulmonary route.
  • a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), is delivered to a patient in need of bacterial infection treatment, where R 1 is (CH 2 )—Y—(CH 2 ) n2 —CH 3 , R 2 is OH, R 3 and R 4 are H and X is O.
  • R 1 is (CH 2 )—Y—(CH 2 ) n2 —CH 3
  • R 2 is OH
  • R 3 and R 4 are H and X is O.
  • Y is oxygen, sulfur, —S—S—, —NH—, —S(O)— or —SO 2 —.
  • Y is —NH—.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof is delivered to a patient in need of bacterial infection treatment, where R 1 is (CH 2 ) 2 —Y—(CH 2 ) n2 —CH 3 , R 2 is OH, R 3 and R 4 are H and X is O.
  • Y is oxygen, sulfur, —S—S—, —NH—, —S(O)— or —SO 2 —.
  • Y is —NH—.
  • a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), is delivered to a patient in need of bacterial infection treatment, where R 1 is (CH 2 ) 3 —Y—(CH 2 ) 2 —CH 3 , R 2 is OH, R 3 and R 4 are H and X is O.
  • R 1 is (CH 2 ) 3 —Y—(CH 2 ) 2 —CH 3
  • R 2 is OH
  • R 3 and R 4 are H and X is O.
  • Y is oxygen, sulfur, —S—S—, —NH—, —S(O)— or —SO 2 —.
  • Y is —NH—.
  • a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), is delivered to a patient in need of bacterial infection treatment, where R 1 is (CH 2 ) 1-3 —Y—(CH 2 ) 8 —CH 3 , R 2 is OH, R 3 and R 4 are H and X is O.
  • Y is oxygen, sulfur, —S—S—, —NH—, —S(O)— or —SO 2 —.
  • Y is —NH—.
  • a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), is delivered to a patient in need of bacterial infection treatment, where R 1 is (CH 2 ) 1-3 —Y—(CH 2 ) 9 —CH 3 , R 2 is OH, R 3 and R 4 are H and X is O.
  • Y is oxygen, sulfur, —S—S—, —NH—, —S(O)— or —SO 2 —.
  • Y is —NH—.
  • a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), is delivered to a patient in need of bacterial infection treatment, where R 1 is (CH 2 ) 2 —Y—(CH 2 ) 1 —CH 3 , R 2 is OH, R 3 and R 4 are H and X is O.
  • R 1 is (CH 2 ) 2 —Y—(CH 2 ) 1 —CH 3
  • R 2 is OH
  • R 3 and R 4 are H and X is O.
  • Y is oxygen, sulfur, —S—S—, —NH—, —S(O)— or —SO 2 —.
  • Y is —NH—.
  • compositions provided herein can be in the form of a solution, suspension or dry powder.
  • Compositions can be administered by techniques known in the art, including, but not limited to intramuscular, intravenous, intratracheal, intranasal, intraocular, intraperitoneal, subcutaneous, and transdermal routes.
  • the compositions can also be administered via the pulmonary route, e.g., via inhalation with a nebulizer or a dry powder inhaler.
  • the composition provided herein comprises a plurality of nanoparticles of the antibiotic of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II) in association with a polymer.
  • the mean diameter of the plurality of nanoparticles in one embodiment, is from about 50 nm to about 900 nm, for example from about 10 nm to about 800 nm, from about 100 nm to about 700 nm, from about 100 nm to about 600 nm or from about 100 nm to about 500 nm.
  • the plurality of nanoparticles comprise a biodegradable polymer and the antibiotic of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II).
  • the biodegradable polymer is poly(D,L-lactide), poly(lactic acid) (PLA), poly(D,L-glycolide) (PLG), poly(lactide-co-glycolide) (PLGA), poly-(cyanoacrylate) (PCA), or a combination thereof.
  • the biodegradable polymer is poly(lactic-co-glycolitic acid) (PLGA).
  • Nanoparticle compositions can be prepared according to methods known to those of ordinary skill in the art. For example, coacervation, solvent evaporation, emulsification, in situ polymerization, or a combination thereof can be employed (see, e.g., Soppimath et al. (2001). Journal of Controlled Release 70, pp. 1-20, incorporated by reference herein in its entirety for all purposes).
  • the amount of polymer in the composition can be adjusted, for example, to adjust the release profile of the compound of Formula from the composition.
  • a dry powder composition disclosed in one of U.S. Pat. Nos. 5,874,064, 5,855,913 and/or U.S. Patent Application Publication No. 2008/0160092 is used to formulate one of the glycopeptides of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II).
  • the disclosures of U.S. Pat. Nos. 5,874,064, 5,855,913 and U.S. Patent Application Publication No. 2008/0160092 are each incorporated by reference herein in their entireties for all purposes.
  • the composition delivered via the methods provided herein are spray dried, hollow and porous particulate compositions.
  • the hollow and porous particulate compositions as disclosed in WO 1999/16419, hereby incorporated in its entirety by reference for all purposes, can be employed.
  • Such particulate compositions comprise particles having a relatively thin porous wall defining a large internal void, although, other void containing or perforated structures are contemplated as well.
  • compositions delivered via the methods provided herein yield powders with bulk densities less than 0.5 g/cm 3 or 0.3 g/cm 3 , for example, less 0.1 g/cm3, or less than 0.05 g/cm 3 .
  • the minimum powder mass that can be filled into a unit dose container is reduced, which eliminates the need for carrier particles.
  • the elimination of carrier particles can minimize throat deposition and any “gag” effect, since the large lactose particles can impact the throat and upper airways due to their size.
  • the particulate compositions delivered via the methods provided herein comprise a structural matrix that exhibits, defines or comprises voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations or holes.
  • the particulate compositions in one embodiment are provided in a “dry” state. That is, the particulate composition possesses a moisture content that allows the powder to remain chemically and physically stable during storage at ambient temperature and easily dispersible.
  • the moisture content of the microparticles is typically less than 6% by weight, and for example, less 3% by weight.
  • the moisture content is as low as 1% by weight.
  • the moisture content is, at least in part, dictated by the formulation and is controlled by the process conditions employed, e.g., inlet temperature, feed concentration, pump rate, and blowing agent type, concentration and post drying.
  • Reduction in bound water can lead to improvements in the dispersibility and flowability of phospholipid based powders, leading to the potential for highly efficient delivery of powdered lung surfactants or particulate composition comprising active agent dispersed in the phospholipid.
  • composition administered via the methods provided herein is a particulate composition comprising a compound of Formula (I) or Formula (II), a phospholipid and a polyvalent cation.
  • the compositions of the present invention can employ polyvalent cations in phospholipid-containing, dispersible particulate compositions for pulmonary administration to the respiratory tract for local or systemic therapy via aerosolization.
  • the polyvalent cation for use in the present invention in one embodiment, is a divalent cation.
  • the divalent cation is calcium, magnesium, zinc or iron.
  • the polyvalent cation is present in one embodiment, to increase the Tm of the phospholipid such that the particulate composition exhibits a Tm which is greater than its storage temperature Ts by at least 20° C.
  • the molar ratio of polyvalent cation to phospholipid in one embodiment, is 0.05, e.g., from about 0.05 to about 2.0, or from about 0.25 to about 1.0. In one embodiment, the molar ratio of polyvalent cation to phospholipid is about 0.50.
  • the polyvalent cation is calcium and is provided as calcium chloride.
  • the phospholipid is a saturated phospholipid.
  • the saturated phospholipid is a saturated phosphatidylcholine.
  • Acyl chain lengths that can be employed range from about C 16 to C 22 .
  • an acyl chain length of 16:0 or 18:0 i.e., palmitoyl and stearoyl
  • a natural or synthetic lung surfactant is provided as the phospholipid component.
  • the phospholipid can make up to 90 to 99.9% w/w of the lung surfactant.
  • Suitable phospholipids according to this aspect of the invention include natural or synthetic lung surfactants such as those commercially available under the trademarks ExoSurf, InfaSurf® (Ony, Inc.), Survanta, CuroSurf, and ALEC.
  • the Tm of the phospholipid-glycopeptide particles in one embodiment, is manipulated by varying the amount of polyvalent cations in the composition.
  • Phospholipids from both natural and synthetic sources are compatible with the compositions administered by the methods provided herein, and may be used in varying concentrations to form the structural matrix.
  • Generally compatible phospholipids comprise those that have a gel to liquid crystal phase transition greater than about 40° C.
  • the incorporated phospholipids in one embodiment, are relatively long chain (i.e., C 16 -C 22 ) saturated lipids and in a further embodiment, comprise saturated phospholipids.
  • the saturated phospholipid is a saturated phosphatidylcholine.
  • the saturated phosphatidylcholine has an acyl chain lengths of 16:0 or 18:0 (palmitoyl or stearoyl).
  • Exemplary phospholipids useful in the disclosed stabilized preparations comprise, phosphoglycerides such as dipalmitoylphosphatidylcholine (DPPC), disteroylphosphatidylcholine (DSPC), diarachidoylphosphatidylcholine dibehenoylphosphatidylcholine, diphosphatidyl glycerol, short-chain phosphatidylcholines, long-chain saturated phosphatidylethanolamines, long-chain saturated phosphatidylserines, long-chain saturated phosphatidylglycerols, long-chain saturated phosphatidylinositols.
  • DPPC dipalmitoylphosphatidylcholine
  • DSPC disteroylphosphatidylcholine
  • diarachidoylphosphatidylcholine dibehenoylphosphatidylcholine diphosphatidyl glycerol
  • a co-surfactant or combinations of surfactants can be used in the compositions delivered via the methods provided herein.
  • association with or comprise it is meant that the particulate compositions may incorporate, adsorb, absorb, be coated with or be formed by the surfactant.
  • surfactants include fluorinated and nonfluorinated compounds and can include saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants and combinations thereof. In one embodiment comprising stabilized dispersions, nonfluorinated surfactants are relatively insoluble in the suspension medium.
  • sorbitan esters including sorbitan trioleate (SpanTM 85), sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) (Brij® S20), sorbitan monolaurate, and polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, glycerol esters, and sucrose esters.
  • sorbitan esters including sorbitan trioleate (SpanTM 85), sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) (Brij® S20), sorbitan monolaurate, and polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, glycerol est
  • Block copolymers include diblock and triblock copolymers of polyoxyethylene and polyoxypropylene, including poloxamer 188 (Pluronic® F-68), poloxamer 407 (Pluronic® F-127), and poloxamer 338.
  • Ionic surfactants such as sodium sulfosuccinate, and fatty acid soaps may also be utilized.
  • the phospholipid-glycopeptide particulate compositions can include additional lipids such as a glycolipid, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; a lipid bearing a polymer chain such as polyethylene glycol, chitin, hyaluronic acid, or polyvinylpyrrolidone; a lipid bearing sulfonated mono-, di-, and polysaccharides; a fatty acid such as palmitic acid, stearic acid, and/or oleic acid; cholesterol, cholesterol esters, and cholesterol hemisuccinate.
  • additional lipids such as a glycolipid, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin
  • a lipid bearing a polymer chain such as polyethylene glycol, chitin, hyaluronic acid, or polyvinylpyrrolidone
  • the particulate composition delivered via the methods provided herein can also include a biocompatible, and in some embodiments, biodegradable polymer, copolymer, or blend or other combination thereof.
  • the polymer in one embodiment is a polylactide, polylactide-glycolide, cyclodextrin, polyacrylate, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydride, polylactam, polyvinyl pyrrolidone, polysaccharide (e.g., dextran, starch, chitin, chitosan), hyaluronic acid, protein (e.g., albumin, collagen, gelatin, etc.).
  • excipients can be added to a particulate composition, for example, to improve particle rigidity, production yield, emitted dose and deposition, shelf-life and/or patient acceptance.
  • excipients include, but are not limited to: coloring agents, taste masking agents, buffers, hygroscopic agents, antioxidants, and chemical stabilizers.
  • excipients may include, but are not limited to, carbohydrates including monosaccharides, disaccharides and polysaccharides.
  • monosaccharides such as dextrose (anhydrous and monohydrate), galactose, mannitol, D-mannose, sorbitol, sorbose and the like; disaccharides such as lactose, maltose, sucrose, trehalose, and the like; trisaccharides such as raffinose and the like; and other carbohydrates such as starches (hydroxyethylstarch), cyclodextrins and maltodextrins. Mixtures of carbohydrates and amino acids are further held to be within the scope of the present invention.
  • inorganic e.g., sodium chloride
  • organic acids and their salts e.g., carboxylic acids and their salts such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, etc.
  • buffers can also be undertaken.
  • Salts and/or organic solids such as ammonium carbonate, ammonium acetate, ammonium chloride or camphor can also be employed.
  • the particulate compositions may be used in the form of dry powders or in the form of stabilized dispersions comprising a non-aqueous phase.
  • the dispersions or powders of the present invention may be used in conjunction with metered dose inhalers (MDIs), dry powder inhalers (DPIs), atomizers, or nebulizers to provide for pulmonary delivery.
  • MDIs metered dose inhalers
  • DPIs dry powder inhalers
  • atomizers atomizers
  • nebulizers nebulizers
  • spray drying is a particularly useful method.
  • spray drying is a one-step process that converts a liquid feed to a dried particulate form.
  • spray drying has been used to provide powdered material for various administrative routes including inhalation. See, for example, M. Sacchetti and M. M. Van Oort in: Inhalation Aerosols: Physical and Biological Basis for Therapy, A. J. Hickey, ed. Marcel Dekkar, New York, 1996, which is incorporated herein by reference in its entirety for all purposes.
  • spray drying consists of bringing together a highly dispersed liquid, and a sufficient volume of hot air to produce evaporation and drying of the liquid droplets.
  • the preparation to be spray dried or feed (or feed stock) can be any solution, suspension, slurry, colloidal dispersion, or paste that may be atomized using the selected spray drying apparatus.
  • the feed stock comprises a colloidal system such as an emulsion, reverse emulsion, microemulsion, multiple emulsion, particulate dispersion, or slurry.
  • the feed is sprayed into a current of warm filtered air that evaporates the solvent and conveys the dried product to a collector. The spent air is then exhausted with the solvent.
  • spray dryers and specifically their atomizers, may be modified or customized for specialized applications, e.g., the simultaneous spraying of two solutions using a double nozzle technique. More specifically, a water-in-oil emulsion can be atomized from one nozzle and a solution containing an anti-adherent such as mannitol can be co-atomized from a second nozzle. In one embodiment, it may be desirable to push the feed solution though a custom designed nozzle using a high pressure liquid chromatography (HPLC) pump.
  • HPLC high pressure liquid chromatography
  • an inflating agent or blowing agent
  • an emulsion can be included with the inflating agent as the disperse or continuous phase.
  • the inflating agent can be dispersed with a surfactant solution, using, for instance, a commercially available microfluidizer at a pressure of about 5000 to 15,000 PSI.
  • a surfactant solution using, for instance, a commercially available microfluidizer at a pressure of about 5000 to 15,000 PSI.
  • This process forms an emulsion, and in some embodiments, an emulsion stabilized by an incorporated surfactant, and can comprise submicron droplets of water immiscible blowing agent dispersed in an aqueous continuous phase.
  • the blowing agent in one embodiment is a fluorinated compound (e.g., perfluorohexane, perfluorooctyl bromide, perfluorooctyl ethane, perfluorodecalin, perfluorobutyl ethane) which vaporizes during the spray-drying process, leaving behind generally hollow, porous aerodynamically light microspheres.
  • fluorinated compound e.g., perfluorohexane, perfluorooctyl bromide, perfluorooctyl ethane, perfluorodecalin, perfluorobutyl ethane
  • suitable liquid blowing agents include nonfluorinated oils, chloroform, Freons, ethyl acetate, alcohols and hydrocarbons. Nitrogen and carbon dioxide gases are also contemplated as a suitable blowing agent.
  • Perfluorooctyl ethane is the blowing agent, in one
  • the first step in particulate production in one embodiment, comprises feed stock preparation.
  • the selected glycopeptide is dissolved in a solvent, for example water, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, ethanol, methanol, or combinations thereof, to produce a concentrated solution.
  • a solvent for example water, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, ethanol, methanol, or combinations thereof.
  • the polyvalent cation may be added to the glycopeptide solution or may be added to the phospholipid emulsion as discussed below.
  • the glycopeptide may also be dispersed directly in the emulsion, particularly in the case of water insoluble agents. Alternatively, the glycopeptide is incorporated in the form of a solid particulate dispersion.
  • the concentration of the glycopeptide used is dependent on the amount of glycopeptide required in the final powder and the performance of the delivery device employed (e.g., the fine particle dose for a MDI or DPI).
  • cosurfactants such as poloxamer 188 or span 80 may be dispersed into this annex solution. Additionally, excipients such as sugars and starches can also be added.
  • a polyvalent cation-containing oil-in-water emulsion is then formed in a separate vessel.
  • the oil employed in one embodiment is a fluorocarbon (e.g., perfluorooctyl bromide, perfluorooctyl ethane, perfluorodecalin) which is emulsified with a phospholipid.
  • fluorocarbon e.g., perfluorooctyl bromide, perfluorooctyl ethane, perfluorodecalin
  • polyvalent cation and phospholipid may be homogenized in hot distilled water (e.g., 60° C.) using a suitable high shear mechanical mixer (e.g., Ultra-Turrax model T-25 mixer) at 8000 rpm for 2 to 5 minutes.
  • the emulsion is processed at 12,000 to 18,000 PSI, 5 discrete passes and kept at 50 to 80° C.
  • glycopeptide solution or suspension
  • perfluorocarbon emulsion are then combined and fed into the spray dryer.
  • the two preparations are miscible. While the glycopeptide is solubilized separately for the purposes of the instant discussion it will be appreciated that, in other embodiments, the glycopeptide may be solubilized (or dispersed) directly in the emulsion. In such cases, the glycopeptide emulsion is simply spray dried without combining a separate glycopeptide preparation.
  • the particulate composition comprises hollow, porous spray dried micro- or nano-particles.
  • particulate compositions useful in the present invention may be formed by lyophilization.
  • lyophilization is a freeze-drying process in which water is sublimed from the composition after it is frozen.
  • Methods for providing lyophilized particulates are known to those of skill in the art.
  • the lyophilized cake containing a fine foam-like structure can be micronized using techniques known in the art.
  • glycopeptide particulate compositions or glycopeptide particles provided herein may be formed using a method where a feed solution (either emulsion or aqueous) containing wall forming agents is rapidly added to a reservoir of heated oil (e.g., perflubron or other high boiling FCs) under reduced pressure.
  • heated oil e.g., perflubron or other high boiling FCs
  • the wall forming agents are insoluble in the heated oil.
  • the resulting particles can then separated from the heated oil using a filtering technique and then dried under vacuum.
  • the particulate compositions of the present invention may also be formed using a double emulsion method.
  • the double emulsion method the medicament is first dispersed in a polymer dissolved in an organic solvent (e.g., methylene chloride, ethyl acetate) by sonication or homogenization.
  • This primary emulsion is then stabilized by forming a multiple emulsion in a continuous aqueous phase containing an emulsifier such as polyvinylalcohol. Evaporation or extraction using conventional techniques and apparatus then removes the organic solvent.
  • the resulting particles are washed, filtered and dried prior to combining them with an appropriate suspension medium.
  • the mean geometric particle size of the particulate compositions in one embodiment, is from about 0.5-50 ⁇ m, for example from about 0.5 ⁇ m to about 10 ⁇ m or from about 0.5 to about 5 ⁇ m. In one embodiment, the mean geometric particle size (or diameter) of the particulate compositions is less than 20 ⁇ m or less than 10 ⁇ m. In a further embodiment, the mean geometric diameter is ⁇ about 7 ⁇ m or ⁇ 5 ⁇ m. In even a further embodiment, the mass geometric diameter is ⁇ about 2.5 ⁇ m.
  • the particulate composition comprises a powder of dry, hollow, porous spherical shells of from about 0.1 to about 10 ⁇ m, e.g., from about 0.5 to about 5 ⁇ m in diameter, with shell thicknesses of approximately 0.1 ⁇ m to about 0.5 ⁇ m.
  • one or more additional antiinfectives can be included in the composition administered to the patient in need thereof, either in the same composition, or a different composition.
  • Additional antiinfectives include an additional glycopeptide, for example, one of the glycopeptides described herein.
  • additional antiinfectives include but are not limited to aminoglycosides (e.g., dibekacin, K-4619, sisomicin, amikacin, dactimicin, isepamicin, rhodestreptomycin, apramycin, etimicin, KA-5685, sorbistin, arbekacin, framycetin, kanamycin, spectinomycin, astromicin, gentamicin, neomycin, sporaricin, bekanamycin, H107, netilmicin, streptomycin, boholmycin, hygromycin, paromomycin, tobramycin, brulamycin, hygromycin B, plazomicin, verdamicin, capreomycin, inosamycin, ribostamycin, vertilmicin), tetracyclines (e.g., chlortetracycline, oxytetracycline, methacycline, d
  • the compound of Formula (I) or (II), or pharmaceutically acceptable salt of Formula (I) or (II), is administered in combination with an aminoglycoside.
  • the compound is a compound of Formula (I) or Formula (I) wherein R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 .
  • the aminoglycoside in a further embodiment, is dibekacin, K-4619, sisomicin, amikacin, dactimicin, isepamicin, rhodestreptomycin, apramycin, etimicin, KA-5685, sorbistin, arbekacin, framycetin, kanamycin, spectinomycin, astromicin, gentamicin, neomycin, sporaricin, bekanamycin, H107, netilmicin, streptomycin, boholmycin, hygromycin, paromomycin, tobramycin, brulamycin, hygromycin B, plazomicin, verdamicin, capreomycin, inosamycin, ribostamycin or vertilmicin.
  • the aminoglycoside is amikacin or gentamicin.
  • the aminoglycoside is gentamicin.
  • the infection is a Gram-positive cocci infection, for example, a Staphylococcus, Enterococcus or Streptococcus infection.
  • Streptococcus pneumoniae is treated, in one embodiment, in a patient that has been diagnosed with community-acquired pneumonia or purulent meningitis.
  • An Enterococcus infection is treated, in one embodiment, in a patient that has been diagnosed with a urinary-catheter related infection.
  • a Staphylococcus infection e.g., S. aureus is treated in one embodiment, in a patient that has been diagnosed with mechanical ventilation-associated pneumonia.
  • the present invention addresses this need by providing a composition comprising an effective amount of a compound of Formula (I), Formula (II) or a pharmaceutically acceptable salt thereof, in a method for treating a patient in need thereof for a Gram-positive cocci infection that is resistant to a different antibacterial.
  • the Gram-positive cocci infection is a penicillin resistant or a vancomycin resistant bacterial infection.
  • the resistant bacterial infection is a methicillin-resistant Staphylococcus infection, e.g., methicillin-resistant S. aureus or a methicillin-resistant Staphylococcus epidermidis infection.
  • the resistant bacterial infection is an oxacillin-resistant Staphylococcus (e.g., S. aureus ) infection, a vancomycin-resistant Enterococcus infection or a penicillin-resistant Streptococcus (e.g., S. pneumoniae ) infection.
  • the Gram-positive cocci infection is a vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), vancomycin resistant Enterococcus faecium also resistant to teicoplanin (VRE Fm Van A), vancomycin resistant Enterococcus faecium sensitive to teicoplanin (VRE Fm Van B), vancomycin resistant Enterococcus faecalis also resistant to teicoplanin (VRE Fs Van A), vancomycin resistant Enterococcus faecalis sensitive to teicoplanin (VRE Fs Van B), or penicillin-resistant Streptococcus pneumoniae (PSRP).
  • VRE vancomycin-resistant enterococci
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant Staphylococcus epidermidis
  • a method is provided to treat an infection due to a Gram-positive bacterium, including, but not limited to, genera Staphylococcus, Streptococcus, Enlerococcus, Bacillus, Corynebaclerium, Nocardia, Clostridium , and Listeria .
  • the infection is due to a Gram-positive Cocci bacterium.
  • the infection is a pulmonary infection.
  • the infection is a Clostridium difficile infection.
  • the bacterial infection is Propionibacterium acnes (skin acne), Eggerthella lenta (bacteremia) or Peptostreptococcus anaerobius (gynecological infection).
  • the composition administered to the patient in need thereof comprises a compound of Formula (I) or Formula (II) wherein R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 and X is O.
  • Staphylococcus is Gram positive non-motile bacteria that colonizes skin and mucus membranes. Staphylococci are spherical and occur in microscopic clusters resembling grapes. The natural habitat of Staphylococcus is nose; it can be isolated in 50% of normal individuals. 20% of people are skin carriers and 10% of people harbor Staphylococcus in their intestines. Examples of Staphylococci infections treatable with the methods and compositions provided herein, include S. aureus, S. epidermidis, S. auricularis, S. carnosus, S. haemolyticus, S. hyicus, S. intermedius, S. lugdunensis, S. saprophytics , S. sciuri, S. simulans , and S. warneri.
  • Staphylococcus aureus and Staphylococcus epidermis are known to be significant in their interactions with humans.
  • the Staphylococcus species is resistant to a penicillin such as methicillin.
  • the Staphylococcus species is methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE).
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant Staphylococcus epidermidis
  • the Staphylococcus infection in another embodiment, is a methicillin-sensitive S. aureus (MSSA) infection, a vancomycin-intermediate S. aureus (VISA) infection, or a vancomycin-resistant S. aureus (VRSA) infection.
  • MSSA methicillin-sensitive S. aureus
  • VISA vancomycin-intermediate S. aureus
  • VRSA vancomycin-resistant S. aureus
  • S. aureus colonizes mainly the nasal passages, but it may be found regularly in most anatomical locales, including skin oral cavity, and gastrointestinal tract.
  • a S. aureus infection is treated with one of the methods and/or compositions provided herein.
  • the S. aureus infection is a methicillin-resistant Staphylococcus aureus (MRSA) infection.
  • MRSA methicillin-resistant Staphylococcus aureus
  • the S. aureus infection is a S. aureus (VISA) infection, or a vancomycin-resistant S. aureus (VRSA) infection.
  • the S. aureus infection can be a healthcare associated, i.e., acquired in a hospital or other healthcare setting, or community-acquired.
  • the Staphylococcal infection treated with one of the methods and/or compositions provided herein causes endocarditis or septicemia (sepsis).
  • the patient in need of treatment with one of the methods and/or compositions provided herein in one embodiment, is an endocarditis patient.
  • the patient is a septicemia (sepsis) patient.
  • the bacterial infection is erythromycin-resistant (erm R ), vancomycin-intermediate S. aureus (VISA) heterogenous vancomycin-intermediate S. aureus (hVISA), S. epidermidis coagulase-negative staphylococci (CoNS), penicillin-intermediate S. pneumoniae (PISP), or penicillin-resistant S. pneumoniae (PRSP).
  • the administering comprises administering via inhalation.
  • the compound of Formula (I) or Formula (II) is a compound wherein R 1 is —(CH 2 ) 2 —NH—(CH 2 ) 9 —CH 3 or
  • Streptococci are Gram-positive, non-motile cocci that divide in one plane, producing chains of cells.
  • the primary pathogens include S. pyrogenes and S. pneumoniae but other species can be opportunistic.
  • S. pyrogenes is the leading cause of bacterial pharyngitis and tonsillitis. It can also produce sinusitis, otitis, arthritis, and bone infections. Some strains prefer skin, producing either superficial (impetigo) or deep (cellulitis) infections.
  • S. pneumoniae is the major cause of bacterial pneumonia in adults, and in one embodiment, an infection due to S. pneumoniae is treated via one of the methods and/or compositions provided herein. Its virulence is dictated by its capsule.
  • Toxins produced by streptococci include: streptolysins (S & O), NADase, hyaluronidase, streptokinase, DNAses, erythrogenic toxin (which causes scarlet fever rash by producing damage to blood vessels; requires that bacterial cells are lysogenized by phage that encodes toxin).
  • Streptococcus infections treatable with the compositions and methods provided herein include, S. agalactiae, S.
  • the genus Enterococci consists of Gram-positive, facultatively anaerobic organisms that are ovoid in shape and appear on smear in short chains, in pairs, or as single cells. Enterococci are human pathogens that are increasingly resistant to antimicrobial agents. Examples of Enterococci treatable with the methods and compositions provided herein are E. avium, E. durans, E. faecalis, E. faecium, E. gallinarum , and E. solitarius.
  • a patient in need thereof is treated for an Enterococcus faecalis ( E. faecalis ) infection.
  • the infection is a pulmonary infection.
  • a patient in need thereof is treated for an Enterococcus faecium ( E. faecium ) infection.
  • the infection is a pulmonary infection.
  • a patient in need thereof is treated for an Enterococcus infection that is resistant or sensitive to vancomycin or resistant or sensitive to penicillin.
  • the infection is a E. faecalis or E. faecium infection.
  • Bacteria of the genus Bacillus are aerobic, endospore-forming, Gram-positive rods, and infections due to such bacteria are treatable via the methods and compositions provided herein. Bacillus species can be found in soil, air, and water where they are involved in a range of chemical transformations.
  • a method is provided herein to treat a Bacillus anthracis ( B. anthracis ) infection with a glycopeptide composition. Bacillus anthracis , the infection that causes Anthrax, is acquired via direct contact with infected herbivores or indirectly via their products.
  • the clinical forms include cutaneous anthrax, from handling infected material, intestinal anthrax, from eating infected meat, and pulmonary anthrax from inhaling spore-laden dust.
  • the route of administration of the glycopeptide will vary depending on how the patient acquires the B. anthracis infection.
  • the patient in one embodiment, is treated via a dry powder inhaler (DPI), nebulizer or metered dose inhaler (MDI).
  • DPI dry powder inhaler
  • MDI metered dose inhaler
  • Bacillus species in particular, B. cereus, B. subtilis and B. licheniformis , are associated periodically with bacteremia/septicemia, endocarditis, meningitis, and infections of wounds, the ears, eyes, respiratory tract, urinary tract, and gastrointestinal tract, and are therefore treatable with the methods and compositions provided herein.
  • pathogenic Bacillus species include, but are not limited to, B. anthracis, B. cereus and B. coagulans.
  • Corynebacteria are small, generally non-motile, Gram-positive, non sporalating, pleomorphic bacilli and infections due to these bacteria are treatable via the methods provided herein.
  • Corynebacterium diphtheria is the etiological agent of diphtheria, an upper respiratory disease mainly affecting children, and is treatable via the methods provided herein.
  • Examples of other Corynebacteria species treatable with the methods and compositions provided herein include Corynebacterium diphtheria, Corynebacterium pseudotuberculosis, Corynebacterium tenuis, Corynebacterium striatum , and Corynebacterium minutissimum.
  • Nocardia The bacteria of the genus Nocardia are Gram-positive, partially acid-fast rods, which grow slowly in branching chains resembling fungal hyphae.
  • Other Nocardial species treatable with the methods provided herein include N. aerocolonigenes, N. africana, N. argentinensis, N. asteroides, N. blackwellu, N. brasiliensis, N. brevicalena, N. cornea, N.
  • Clostridia are spore-forming, Gram-positive anaerobes, and infections due to such bacteria are treatable via the methods and compositions provided herein.
  • one of the methods provided herein are used to treat a Clostridium tetani ( C. tetani ) infection, the etiological agent of tetanus.
  • one of the methods provided herein is used to treat a Clostridium botidinum ( C. botidinum ) infection, the etiological agent of botulism.
  • one of the methods provided herein is used to treat a C. perfringens infection, one of the etiological agents of gas gangrene.
  • Other Clostridium species treatable with the methods of the present invention include, C. difficile, C. perfringens , and/or C. sordelii .
  • the infection to be treated is a C. difficile infection.
  • Listeria are non spore-forming, nonbranching Gram-positive rods that occur individually or form short chains.
  • Listeria monocytogenes L. monocytogenes
  • L. monocytogenes is the causative agent of listeriosis, and in one embodiment, a patient infected with L. monocytogenes is treated with one of the methods and compositions provided herein.
  • Examples of Listeria species treatable with the methods and compositions provided herein, include L. grayi, L. innocua, L. ivanovii, L. monocytogenes, L. seeligeri, L. murrayi , and L. welshimeri.
  • the bacterial infection in one embodiment is a respiratory tract infection.
  • the infection is a resistant bacterial infection, for example, one of the infections provided above.
  • the patient treatable by the methods provided herein in one embodiment, has been diagnosed with a community-acquired respiratory tract infection, e.g., pneumonia.
  • the bacterial infection treated in the pneumonia patient is a S. pneumoniae infection.
  • the bacterial infection treated in the pneumonia patient is Mycoplasma pneumonia or a Legionella species.
  • the bacterial infection in the pneumonia patient is penicillin resistant, e.g., penicillin-resistant S. pneumoniae.
  • the bacterial infection in one embodiment, is a hospital acquired infection (HAI), or acquired in another health care facility, e.g., a nursing home, rehabilitation facility, outpatient clinic, etc. Such infections are also referred to as nosocomial infections.
  • the infection is a respiratory tract infection or a skin infection.
  • the HAI is pneumonia.
  • the pneumonia is due to S. aureus , e.g., MRSA.
  • the inhalation delivery device employed in embodiments of the methods provided herein can be a nebulizer, dry powder inhaler (DPI), or a metered dose inhaler (MDI), or any other suitable inhalation delivery device known to one of ordinary skill in the art.
  • the device can contain and be used to deliver a single dose of the composition or the device can contain and be used to deliver multi-doses of the composition of the present invention.
  • a dry powder particulate composition is delivered to a patient in need thereof via a metered dose inhaler (MDI), dry powder inhaler (DPI), atomizer, nebulizer or liquid dose instillation (LDI) technique to provide for glycopeptide delivery.
  • MDI metered dose inhaler
  • DPI dry powder inhaler
  • atomizer atomizer
  • nebulizer nebulizer
  • LLI liquid dose instillation
  • the medicament is formulated in a way such that it readily disperses into discrete particles with an MMD between 0.5 to 20 ⁇ m, for example from 0.5-5 ⁇ m, and are further characterized by an aerosol particle size distribution less than about 10 ⁇ m mass median aerodynamic diameter (MMAD), and in some embodiments, less than 5.0 ⁇ m.
  • MMAD mass median aerodynamic diameter
  • the MMAD of the powders will characteristically range from about 0.5-10 ⁇ m, from about 0.5-5.0 ⁇ m, or from about 0.5-4.0 ⁇ m.
  • the powder is actuated either by inspiration or by some external delivery force, such as pressurized air.
  • DPIs suitable for administration of the particulate compositions of the present invention are disclosed in U.S. Pat. Nos. 5,740,794, 5,785,049, 5,673,686, and 4,995,385 and PCT application Nos. 00/72904, 00/21594, and 01/00263, the disclosure of each of which is incorporated by reference in their entireties for all purposes.
  • DPI formulations are typically packaged in single dose units such as those disclosed in the aforementioned patents or they employ reservoir systems capable of metering multiple doses with manual transfer of the dose to the device.
  • compositions disclosed herein may also be administered to the nasal or pulmonary air passages of a patient via aerosolization, such as with a metered dose inhaler (MDI).
  • MDI metered dose inhaler
  • Breath activated MDIs are also compatible with the methods provided herein.
  • compositions disclosed herein may be delivered to a patient in need thereof via a nebulizer, e.g., a nebulizer disclosed in PCT WO 99/16420, the disclosure of which is hereby incorporated in its entirety by reference, in order to provide an aerosolized medicament that may be administered to the pulmonary air passages of the patient.
  • a nebulizer type inhalation delivery device can contain the compositions of the present invention as a solution, usually aqueous, or a suspension.
  • the prostacyclin compound or composition can be suspended in saline and loaded into the inhalation delivery device.
  • the nebulizer delivery device may be driven ultrasonically, by compressed air, by other gases, electronically or mechanically (e.g., vibrating mesh or aperture plate). Vibrating mesh nebulizers generate fine particle, low velocity aerosol, and nebulize therapeutic solutions and suspensions at a faster rate than conventional jet or ultrasonic nebulizers. Accordingly, the duration of treatment can be shortened with a vibrating mesh nebulizer, as compared to a jet or ultrasonic nebulizer. Vibrating mesh nebulizers amenable for use with the methods described herein include the Philips Respironics I-Neb®, the Omron MicroAir, the Nektar Aeroneb®, and the Pari eFlow®.
  • the nebulizer may be portable and hand held in design, and may be equipped with a self contained electrical unit.
  • the nebulizer device may comprise a nozzle that has two coincident outlet channels of defined aperture size through which the liquid formulation can be accelerated. This results in impaction of the two streams and atomization of the formulation.
  • the nebulizer may use a mechanical actuator to force the liquid formulation through a multiorifice nozzle of defined aperture size(s) to produce an aerosol of the formulation for inhalation.
  • blister packs containing single doses of the formulation may be employed.
  • the nebulizer may be employed to ensure the sizing of particles is optimal for positioning of the particle within, for example, the pulmonary membrane.
  • the nebulized composition (also referred to as “aerosolized composition”) is in the form of aerosolized particles.
  • the aerosolized composition can be characterized by the particle size of the aerosol, for example, by measuring the “mass median aerodynamic diameter” or “fine particle fraction” associated with the aerosolized composition.
  • Mass median aerodynamic diameter” or “MMAD” is normalized regarding the aerodynamic separation of aqua aerosol droplets and is determined by impactor measurements, e.g., the Andersen Cascade Impactor (ACI) or the Next Generation Impactor (NGI).
  • the gas flow rate in one embodiment, is 8 Liter per minute for the ACI and 15 liters per minute for the NGI.
  • GSD Global Standard deviation
  • Low GSDs characterize a narrow droplet size distribution (homogeneously sized droplets), which is advantageous for targeting aerosol to the respiratory system.
  • the average droplet size of the nebulized composition provided herein in one embodiment is less than 5 ⁇ m or about 1 ⁇ m to about 5 ⁇ m, and has a GSD in a range of 1.0 to 2.2, or about 1.0 to about 2.2, or 1.5 to 2.2, or about 1.5 to about 2.2.
  • FPF Protein particle fraction
  • the mass median aerodynamic diameter (MMAD) of the nebulized composition is about 1 ⁇ m to about 5 ⁇ m, or about 1 ⁇ m to about 4 ⁇ m, or about 1 ⁇ m to about 3 ⁇ m or about 1 ⁇ m to about 2 ⁇ m, as measured by the Anderson Cascade Impactor (ACI) or Next Generation Impactor (NGI).
  • the MMAD of the nebulized composition is about 5 ⁇ m or less, about 4 ⁇ m or less, about 3 ⁇ m or less, about 2 ⁇ m or less, or about 1 ⁇ m or less, as measured by cascade impaction, for example, by the ACI or NGI.
  • the MMAD of the aerosol of the pharmaceutical composition is less than about 4.9 ⁇ m, less than about 4.5 ⁇ m, less than about 4.3 ⁇ m, less than about 4.2 ⁇ m, less than about 4.1 ⁇ m, less than about 4.0 ⁇ m or less than about 3.5 ⁇ m, as measured by cascade impaction.
  • the MMAD of the aerosol of the pharmaceutical composition is about 1.0 ⁇ m to about 5.0 ⁇ m, about 2.0 ⁇ m to about 4.5 ⁇ m, about 2.5 ⁇ m to about 4.0 ⁇ m, about 3.0 ⁇ m to about 4.0 ⁇ m or about 3.5 ⁇ m to about 4.5 ⁇ m, as measured by cascade impaction (e.g., by the ACI or NGI).
  • the FPF of the aerosolized composition is greater than or equal to about 50%, as measured by the ACI or NGI, greater than or equal to about 60%, as measured by the ACI or NGI or greater than or equal to about 70%, as measured by the ACI or NGI. In another embodiment, the FPF of the aerosolized composition is about 50% to about 80%, or about 50% to about 70% or about 50% to about 60%, as measured by the NGI or ACI.
  • a metered dose inhalator is employed as the inhalation delivery device for the compositions of the present invention.
  • the prostacyclin compound is suspended in a propellant (e.g., hydrofluorocarbon) prior to loading into the MDI.
  • a propellant e.g., hydrofluorocarbon
  • the basic structure of the MDI comprises a metering valve, an actuator and a container.
  • a propellant is used to discharge the formulation from the device.
  • the composition may consist of particles of a defined size suspended in the pressurized propellant(s) liquid, or the composition can be in a solution or suspension of pressurized liquid propellant(s).
  • the propellants used are primarily atmospheric friendly hydroflourocarbons (HFCs) such as 134a and 227.
  • the device of the inhalation system may deliver a single dose via, e.g., a blister pack, or it may be multi dose in design.
  • the pressurized metered dose inhalator of the inhalation system can be breath actuated to deliver an accurate dose of the lipid-containing formulation.
  • the delivery of the formulation may be programmed via a microprocessor to occur at a certain point in the inhalation cycle.
  • the MDI may be portable and hand held.
  • a dry powder inhaler (DPI) is employed as the inhalation delivery device for the compositions of the present invention.
  • the DPI generates particles having an MMAD of from about 1 ⁇ m to about 10 ⁇ m, or about 1 ⁇ m to about 9 ⁇ m, or about 1 ⁇ m to about 8 ⁇ m, or about 1 ⁇ m to about 7 ⁇ m, or about 1 ⁇ m to about 6 ⁇ m, or about 1 ⁇ m to about 5 ⁇ m, or about 1 ⁇ m to about 4 ⁇ m, or about 1 ⁇ m to about 3 ⁇ m, or about 1 ⁇ m to about 2 ⁇ m in diameter, as measured by the NGI or AC.
  • the DPI generates particles having an MMAD of from about 1 ⁇ m to about 10 ⁇ m, or about 2 ⁇ m to about 10 ⁇ m, or about 3 ⁇ m to about 10 ⁇ m, or about 4 ⁇ m to about 10 ⁇ m, or about 5 ⁇ m to about 10 ⁇ m, or about 6 ⁇ m to about 10 ⁇ m, or about 7 ⁇ m to about 10 ⁇ m, or about 8 ⁇ m to about 10 ⁇ m, or about 9 ⁇ m to about 10 ⁇ m, as measured by the NGI or ACI.
  • the MMAD of the particles generated by the DPI is about 1 ⁇ m or less, about 9 ⁇ m or less, about 8 ⁇ m or less, about 7 ⁇ m or less, 6 ⁇ m or less, 5 ⁇ m or less, about 4 ⁇ m or less, about 3 ⁇ m or less, about 2 ⁇ m or less, or about 1 ⁇ m or less, as measured by the NGI or ACI.
  • each administration comprises 1 to 5 doses (puffs) from a DPI, for example 1 dose (1 puff), 2 dose (2 puffs), 3 doses (3 puffs), 4 doses (4 puffs) or 5 doses (5 puffs).
  • the DPI in one embodiment, is small and transportable by the patient.
  • the MMAD of the particles generated by the DPI is less than about 9.9 ⁇ m, less than about 9.5 ⁇ m, less than about 9.3 ⁇ m, less than about 9.2 ⁇ m, less than about 9.1 ⁇ m, less than about 9.0 ⁇ m, less than about 8.5 ⁇ m, less than about 8.3 ⁇ m, less than about 8.2 ⁇ m, less than about 8.1 ⁇ m, less than about 8.0 ⁇ m, less than about 7.5 ⁇ m, less than about 7.3 ⁇ m, less than about 7.2 ⁇ m, less than about 7.1 ⁇ m, less than about 7.0 ⁇ m, less than about 6.5 ⁇ m, less than about 6.3 ⁇ m, less than about 6.2 ⁇ m, less than about 6.1 ⁇ m, less than about 6.0 ⁇ m, less than about 5.5 ⁇ m, less than about 5.3 ⁇ m, less than about 5.2 ⁇ m, less than about 5.1 ⁇ m, less than about 5.0 ⁇ m, less than about
  • the MMAD of the particles generated by the DPI is about 1.0 ⁇ m to about 10.0 ⁇ m, about 2.0 ⁇ m to about 9.5 ⁇ m, about 2.5 ⁇ m to about 9.0 ⁇ m, about 3.0 ⁇ m to about 9.0 ⁇ m, about 3.5 ⁇ m to about 8.5 ⁇ m or about 4.0 ⁇ m to about 8.0 ⁇ m.
  • the FPF of the prostacyclin particulate composition generated by the DPI is greater than or equal to about 40%, as measured by the ACI or NGI, greater than or equal to about 50%, as measured by the ACI or NGI, greater than or equal to about 60%, as measured by the ACI or NGI, or greater than or equal to about 70%, as measured by the ACI or NGI.
  • the FPF of the aerosolized composition is about 40% to about 70%, or about 50% to about 70% or about 40% to about 60%, as measured by the NGI or ACI.
  • Glycopeptide derivatives were prepared as follows. The synthesis scheme is also provided at FIG. 1 .
  • the beige colored solution was allowed to cool after which a solution of the desired aldehyde dissolved in DMF was added over 5-10 min. The resulting solution was allowed to stir overnight, typically producing a clear red-yellow solution. MeOH and TFA were introduced and stirring was further continued for at least 2 h. At the end of the stirring period, the imine forming reaction mixture was analyzed by HPLC which was characteristically typical. Borane tert-butylamine complex was added in portions and the reaction mixture was stirred at ambient temperature for an additional 2 h after which an in-process HPLC analysis of the reaction mixture indicated a near quantitative reduction of the intermediate imine group.
  • reaction mixture was purified using reverse phase C18 column chromatography (Phenomenex Luna 10 uM PREP C18(2) 250 ⁇ 21.2 mm column) using gradients of water and acetonitrile, each containing 0.1% (v/v) of TFA. Fractions were evaluated using HPLC and then pertinent fractions containing the target product were pooled together for the isolation of the product via lyophilization. Typical products were isolated as fluffy white solids. The procedure is shown below in Scheme 1 with vancomycin HCl as a representative starting compound.
  • reaction solvent DMF or DMA
  • organic base typically DIPEA
  • the temperature was increased to approximately 60° C. and vancomycin HCl was added.
  • the warm reaction mixture was agitated at elevated temperature for approximately 20 minutes at which point all vancomycin HCl had dissolved and the reaction mixture was returned to room temperature.
  • To the reaction mixture was then added 9H-fluoren-9-ylmethyl N-decyl-N-(2-oxoethyl)carbamate (N-Fmoc-N-decylaminoacetaldehyde) dissolved in a suitable reaction solvent (DMF or DMA).
  • reaction mixture was agitated with an overhead stirrer overnight at which point a suitable reducing agent, acid catalyst (e.g., TFA), and a protic solvent (e.g., MeOH) were added.
  • a suitable reducing agent e.g., TFA
  • a protic solvent e.g., MeOH
  • the reaction mixture was agitated by an overhead stirrer at room temperature for approximately two hours at which point solvent volume was reduced by half via rotary evaporation.
  • To the concentrated reaction mixture was then added an organic base to remove the FMOC protecting group and yield crude product (Compound 40, also referred to as “RV40”, see also Table 1).
  • Solvent was then evaporated by rotary evaporation and the crude material was dry-packed using C18 silica and purified via reverse phase C18 flash chromatography to isolate product with >97% purity.
  • Solvent was removed from the purified material using a combination of techniques including rotary evaporation, lyophilization, and spray drying to yield product (Compound 40 or RV40) as a white powder, typically in 40-75% overall yield.
  • Suitable solvents include N,N-Dimethylacetamide, N,N-Dimethylformamide, N,N-Dimethylacetamide or a combination thereof.
  • Suitable organic bases include N,N-diisopropylethylamine or trimethylamine.
  • Suitable reducing agents include NaBH 4 , NaBH 3 CN, Borane-pyridine complex, or Borane- tert butylamine complex.
  • Suitable organic bases for FMOC deprotection include piperidine, methylamine, and tert butylamine.
  • Control over the salt form and associated counter-ions for alkyl-vancomycin derivatives was managed by altering the acid species used during flash chromatography. Lactate, Acetate, HCl, and TFA salts have been prepared. To isolate free base derivatives of alkyl vancomycin derivatives the pH of purified material was adjusted between 7-8 to induce precipitation; purified free base material was then collected by filtration, rotary evaporation, lyophilization, or spray drying.
  • FIG. 2 One synthetic scheme for arriving at compound 40 (RV40) is provided at FIG. 2 (top).
  • a jacketed 1 L reactor vessel was equipped with an overhead stirrer and connected to a recirculating water bath calibrated to 65° C.
  • N,N-Dimethylformamide 75 mL
  • DIPEA 640 ⁇ L, 3.7 mmol, 2.0 equivalents.
  • Solvent was allowed to stir for 20 minutes and warmed to 65° C., at which point vancomycin HCl (2.70 g, 1.8 mmol, 1.00 equivalents) was added to the reaction mixture. Once all vancomycin HCl had dissolved the temperature was reduced to 25° C.
  • reaction solvent DMF or DMA
  • organic base typically DIPEA
  • the temperature was increased to approximately 60° C. and vancomycin HCl was added.
  • the warm reaction mixture was agitated at elevated temperature for approximately 20 minutes at which point all vancomycin HCl had dissolved and the reaction mixture was returned to room temperature.
  • To the reaction mixture was then added 9H-fluoren-9-ylmethyl N-decyl-N-(2-oxoethyl)carbamate (N-Fmoc-N-decylaminoacetaldehyde) dissolved in a suitable reaction solvent (DMF or DMA).
  • DMF or DMA 9H-fluoren-9-ylmethyl N-decyl-N-(2-oxoethyl)carbamate
  • the reaction mixture was agitated with an overhead stirrer overnight.
  • a protic solvent e.g., MeOH
  • an acid catalyst e.g., TFA
  • a suitable reducing agent e.g., borane tertbutylamine complex
  • reaction mixture was agitated by an overhead stirrer at room temperature for approximately two hours at which point an organic base (e.g., tertbutylamine) was added to remove the FMOC protecting group.
  • organic base e.g., tertbutylamine
  • the temperature was increased to 55° C. and the mixture was allowed to stir for 2 h.
  • Solvent was then evaporated by rotary evaporation and the crude material was dry-packed using C18 silica and purified via reverse phase C18 flash chromatography to isolate product with >97% purity.
  • Solvent was removed from the purified material using a combination of techniques including rotary evaporation, lyophilization, and spray drying to yield product (RV40) as a white powder, typically in 75% overall yield.
  • Suitable solvents include N,N-Dimethylacetamide, N,N-Dimethylformamide, N,N-Dimethylacetamide or a combination thereof.
  • Suitable organic bases include N,N-diisopropylethylamine or trimethylamine.
  • Suitable reducing agents include NaBH 4 , NaBH 3 CN, Borane-pyridine complex, or Borane- tert butylamine complex.
  • Suitable organic bases for FMOC deprotection include piperidine, methylamine, and tert butylamine.
  • Control over the salt form and associated counter-ions for alkyl-vancomycin derivatives was managed by altering the acid species used during flash chromatography. Lactate, Acetate, HCl, and TFA salts have been prepared. To isolate free base derivatives of the vancomycin derivative, the pH of purified material was adjusted between 7-8 to induce precipitation; purified free base material was then collected by filtration, rotary evaporation, lyophilization, or spray drying.
  • FIG. 2 One synthetic scheme for arriving at compound 40 (RV40) is provided at FIG. 2 , bottom, and is described in further detail below.
  • DMF 50 mL
  • DIPEA 1.17 mL, 6.73 mmol, 2.00 equivalents
  • the reaction mixture was heated to 55° C. at which point vancomycin HCl (5.0 g, 3.37 mmol, 1.0 equivalents) were added.
  • the mixture was stirred at 55° C. for about 15 min., or until all of the vancomycin dissolved, at which point the temperature was reduced to 25° C.
  • a 3 L three-necked flask was equipped with a mechanical stirrer, a nitrogen inlet, a condenser and an addition funnel.
  • Anhydrous DMF (900 mL) and DIPEA (21.06 mL, 0.12 mol) were charged.
  • the resulting solution was heated to 55-60° C. and vancomycin HCl (90.0 g, 0.06 mol) was added in portions. Heating was continued until all of vancomycin HCl had dissolved (15-30 min).
  • the beige colored solution was allowed to cool to ambient temperature after which a solution of N—FMOC—N-decylaminoacetaldehyde (29.34 g, 0.069 mol) and DMF (293.4 mL) was added via the addition funnel over 5-10 min. The resulting solution was allowed to stir overnight to give a clear red-yellow solution.
  • An in-process HPLC analysis of the reaction mixture at the end of the stirring period was typical. MeOH (252 mL) and TFA (18.54 mL, 0.24 mol) were introduced and stirring was further continued for at least 2 h. At the end of the stirring period, the imine forming reaction mixture was analyzed by HPLC which was characteristically typical.
  • the C-18 silica adsorbed crude RV40 (compound 40) was divided into three equal parts and each part-lot was purified by means of Biotage chromatography on a Biotage SNAP ULTRA C18 1850 g Cartridge (Biotage HP-Sphere C18 25 ⁇ m) using gradients of water and acetonitrile, each containing 0.1% (v/v) of an 85% L-(+)-Lactic acid solution in water, and collecting 240 mL fractions. Each part lot required 50 liters of eluents. After each Biotage run, the C-18 column was conditioned for the next run by running through 60 liters of methanol. Fractions were evaluated using HPLC and then pertinent fractions containing RV40 were pooled together for the isolation of the product via lyophilization.
  • Lyophilization provided RV40 lactate salt as a white solid.
  • the lyophilized RV40 lactate at this point typically contained excess lactic acid and also contained lactic acid related impurities arising from its self-condensation reactions.
  • the isolated RV40 lactate from this run was combined with two other batches of similarly isolated lyophilized RV40 lactate to form a composite batch of RV40 lactate totaling 105 g (lot 637-140A).
  • the excess lactic acid and its related impurities present in the above composite batch of RV40 lactate were removed via trituration with THF and then the final triturated material (RV40 mono lactate salts) was subjected to re-lyophilization to remove the trapped residual THF; both steps are described below.
  • THF-triturated material was first dissolved in aqueous acetonitrile (3:1 water:acetonitrile) at a concentration of 8.1 mL per gram and then lyophilized in batches using multiple flasks. Typically, about 10-12 grams (maximum) of the material was charged into each 2 L flask followed by aqueous acetonitrile (125 mL) to prepare a solution which was lyophilized. At the end of the lyophilization and drying, product was analyzed by NMR for THF levels to determine whether lyophilization was needed to be repeated.
  • each flask contents of each flask were lyophilized once more (after re-dissolving in 125 mL of aqueous acetonitrile) when no remaining THF could be detected by NMR.
  • the final lyophilized product at this point contained an average of 0.8 wt. % acetonitrile as estimated by NMR.
  • the contents of each flask were pulverized into smaller particles using spatula and then placed on high vacuum pumps to remove acetonitrile. No further reduction in acetonitrile levels was observed after 56-60 h on the vacuum pumps.
  • Alkyl vancomycin derivatives were prepared according to the procedure disclosed in Nagarajan et al., with slight modifications (Nagarajan et al. (1989). The Journal of Antibiotics 42(1), pp. 63-72, incorporated by reference herein in its entirety for all purposes).
  • Suitable solvents include either N,N-Dimethylformamide or N,N-Dimethylacetamide.
  • Suitable organic bases include N,N-diisopropylethylamine or trimethylamine.
  • Suitable reducing agents include NaBH 4 , NaBH 3 CN, Borane-pyridine complex, or Borane- tert butylamine complex.
  • FIG. 5 The synthetic route to Compound 5, decyl vancomycin, is provided at FIG. 5 .
  • a jacketed 1 L reactor vessel was equipped with an overhead stirrer and connected to a recirculating water bath calibrated to 65° C.
  • N,N-Dimethylacetamide 160 mL
  • DIPEA 6.8 mL, 39.0 mmol, 2.92 equivalents
  • vancomycin HCl (19.8 g, 13.38 mmol, 1.00 equivalents) was added to the reactor vessel.
  • the reaction mixture was cooled to RT and sodium borohydride was added to convert residual aldehyde reagent to the corresponding alcohol.
  • the pH was adjusted to between 7-8 using either acetic acid or 0.1M NaOH and volatile solvents were removed by blowing N 2 (g) with gentle heat.
  • To the reaction mixture was added acetonitrile to precipitate the crude product as an off-white solid.
  • the reaction mixture was centrifuged and the liquid was decanted. The solid was dissolved in 10% MeCN/H 2 O containing 0.1% phosphoric acid to decomplex the copper at which point the solution briefly turned purple and then took on a yellow tinge.
  • Preparatory HPLC was used to purify final product and LCMS was used to confirm compound identity and purity.
  • FIG. 1 A diagram of the reaction is provided at FIG. 1 , bottom.
  • Glycopeptide compounds were dissolved in 100% DMSO. In vitro activities were determined using CLSI-guided broth susceptibility testing to measure drug minimum inhibitory concentrations (MICs) of the compounds against the quality control strain ATCC 29213 (MSSA) and the MRSA isolate ATCC BAA-1556. The minimal inhibitory concentrations MICs are summarized in Table 2. Glycopeptides are defined as compounds of Formula (I), and their respective R 1 , R 2 , R 3 and R 4 groups. X is —O— for each compound in Table 2.
  • MRSA methicillin-resistant
  • VISA vancomycin-intermediate
  • Broth microdilution MIC testing was conducted in accordance with guidelines from the Clinical and Laboratory Standards Institute (CLSI; 1, 2) and included the comparators telavancin (TLV), vancomycin (VAN), tigecycline (TGC), and linezolid (LNZ).
  • CLSI Clinical and Laboratory Standards Institute
  • TLV telavancin
  • VAN vancomycin
  • TGC tigecycline
  • LNZ linezolid
  • Test compounds The 6 test agents and the comparators are detailed in Table 3 below.
  • test organisms were originally received from clinical sources, the American Type Culture Collection (ATCC, Manassas, Va.), and the Network on Antimicrobial Resistance in S. aureus (NARSA; BEI Resources, Manassas, Va.). Upon receipt, the organisms were sub-cultured onto an appropriate agar medium. Following incubation, colonies were harvested from these plates and cell suspensions prepared and frozen at ⁇ 80° C. with a cryoprotectant. On the day prior to the assay, frozen stocks of isolates were streaked onto Trypticase Soy Agar with 5% sheep blood (Remel, Lenexa, Kans.; Lot No. 964323) and incubated overnight at 35° C.
  • aureus MMX MRSA 3 0.5 0.185 0.12 0.06 0.06 0.008 3982 S . aureus MMX MRSA 1.5 1 0.12 0.06 0.06 0.06 0.008 4675ATCC BAA-1556 S . aureus MMX MRSA 1 1 0.25 0.12 0.06 0.06 0.015 5717 ATCC 33591 S . aureus MMX MRSA 2.5 0.5 0.185 0.03 0.06 0.06 0.008 5985 S . aureus MMX MRSA 1.5 0.5 0.12 0.12 0.06 0.06 0.008 5999 S . aureus MMX MRSA 1.5 0.5 0.12 0.12 0.06 0.06 0.008 7899 S .
  • aureus MMX MRSA 2 0.5 0.185 0.12 0.12 0.06 0.008 7900 S . aureus MMX MRSA 2 0.5 0.12 0.5 0.06 0.03 0.008 7901 S . aureus MMX MRSA 2 1 0.12 0.5 0.25 0.06 0.015 7902 S . aureus MMX MRSA 1.5 1 0.12 0.06 0.06 0.06 0.008 7903 S . aureus MMX hVISA 1.5 4 0.25 0.5 0.5 0.25 0.03 4665 S . aureus MMX Mu3; hVISA 1.5 1 0.75 0.12 0.06 0.12 0.015 5989 S .
  • S. aureus ATCC 29213 was included during the testing of S. aureus for purposes of quality control (Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing: Twenty-Seventh Informational Supplement.
  • aureus MMX MRSA 1 1 0.25 0.12 0.06 0.06 0.015 5717 ATCC 33591 S . aureus MMX MRSA 2.5 0.5 0.185 0.03 0.06 0.06 0.008 5985 S . aureus MMX MRSA 1.5 0.5 0.12 0.12 0.06 0.06 0.008 5999 S . aureus MMX MRSA 1.5 0.5 0.12 0.12 0.06 0.06 0.008 7899 S . aureus MMX MRSA 2 0.5 0.185 0.12 0.12 0.06 0.008 7900 S . aureus MMX MRSA 2 0.5 0.12 0.5 0.06 0.03 0.008 7901 S .
  • aureus MMX MRSA 2 1 0.12 0.5 0.25 0.06 0.015 7902 S . aureus MMX MRSA 1.5 1 0.12 0.06 0.06 0.06 0.008 7903
  • agalactiae MMX 4088 1 0.25 0.03 0.12 0.015 0.06 0.008 S .
  • agalactiae MMX 4115 erm R 1 0.25 0.03 0.25 0.015 0.06 0.008 S .
  • dysgalactiae MMX 5121 1 0.25 0.06 0.05 0.015 0.12 0.008 S .
  • dysgalactiae MMX 5124 1 0.25 0.12 1 0.015 0.03 0.015 S .
  • anginosus MMX 1201 0.5 0.5 0.008 0.5 0.03 0.06 0.015 (AGS) ATCC 33397 S . constellatus MMX 5677 — 0.5 0.25 0.03 ⁇ 0.008 0.03 0.03 0.008 (AGS) S .
  • mitis (MGS) MMX 1205 — 0.5 — 0.03 0.03 0.06 0.008 ATCC 49456 S .
  • MMX 8351 — 0.5 0.12 0.015 0.06 0.015 0.015 ATCC 13124 P .
  • micros MMX 3546 — 0.5 0.015 0.03 0.12 0.06 0.015 P .
  • anaerobius MMX 1208 — — 0.25 0.03 0.03 0.03 0.03 0.008 ATCC 27337 P .
  • acnes MMX 7942 — 0.25 0.03 ⁇ 0.008 0.06 0.03 0.008 ATCC 6919 P . acnes MMX 7946 — 0.25 0.03 ⁇ 0.008 0.06 0.015 0.008 ATCC 11827 E . lenta MMX 1287 — — — 0.25 — 0.12 — — ATCC 43055
  • the medium employed for the MIC assay was cation-adjusted Mueller-Hinton Broth (MHBII; BD; Lot No. 6117994), excluding C. difficile which were tested in supplemented Brucella Broth (SBB).
  • MHBII Mueller-Hinton Broth
  • the MHBII was supplemented with 3% Laked Horse Blood (Cleveland Scientific; Bath, Ohio; Lot No. 333835).
  • Brucella Broth (BD; Lot No. 6155858) was supplemented with vitamin K (Sigma, St. Louis, Mo.; Lot No. 108K1088), hemin (Sigma; Lot No. SLB14685V), and 5% Laked Horse Blood.
  • Test media was prepared fresh on each day of testing and was supplemented with 0.002% polysorbate-80 (v/v) for the testing of telavancin per CLSI (Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing: Twenty - Seventh Informational Supplement .
  • MIC values were determined using a broth microdilution procedure described by CLSI (Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing: Twenty - Seventh Informational Supplement .
  • Automated liquid handlers Multidrop 384, Labsystems, Helsinki, Finland; Biomek 2000 and Biomek FX, Beckman Coulter, Fullerton Calif. were used to conduct serial dilutions and liquid transfers.
  • the wells of columns 2-12 of standard 96-well microdilution plates (Costar 3795) were filled with 150 ⁇ L of the designated diluent for each row of drug.
  • the test articles and comparator compounds (300 ⁇ L at 100 ⁇ the highest concentration to be tested) were dispensed into the appropriate wells in column 1.
  • the Biomek 2000 was then used to make 2-fold serial dilutions in the mother plates from column 1 through column 11.
  • the wells of Column 12 contained no drug and served as the organism growth control wells for the assay.
  • the daughter plates were loaded with 190 ⁇ L per well of the appropriate test medium containing 0.002% polysorbate-80 (v/v) for telavancin, oritavancin, Compound 40, and Compound 5, using the Multidrop 384.
  • the daughter plates were prepared on the Biomek FX instrument which transferred 2 ⁇ L of drug solution from each well of a mother plate to the corresponding well of each daughter plate in a single step.
  • the daughter plates for C. difficile were placed in the anaerobe chamber and allowed to reduce for one hour prior to inoculation.
  • CLSI CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically;
  • the inoculum for each organism was dispensed into sterile reservoirs (Beckman Coulter 372788), and the Biomek 2000 was used to deliver 10 ⁇ L of standardized inoculum into each well resulting in a final test concentration of approximately 5 ⁇ 10 5 CFU/mL.
  • Daughter plates were placed on the Biomek 2000 work surface reversed so that inoculation took place from low to high drug concentration.
  • inoculum preparation and the inoculation of the daughter plates was carried out by hand in the anaerobe chamber.
  • Plates were stacked 3 high, covered with a lid on the top plate, placed in plastic bags, and incubated at 35° C. in ambient atmosphere for approximately 18-20 hr for telavancin, Compound 40, Compound 5, oritavancin, linezolid, and tigecycline, or 24 hr for vancomycin with the exception of C. difficile plates which were incubated at 35° C. anaerobically for 48 h. Following incubation, the microplates were removed from the incubator and viewed from the bottom using a plate viewer. For each of the test compounds, an un-inoculated solubility control plate for each test medium was observed for evidence of drug precipitation. The MIC was read and recorded as the lowest concentration of drug that inhibited visible growth.
  • CLSI Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Tenth Edition. CLSI document M07-A10. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pa. 19087-1898 USA, 2015).
  • Vancomycin Vancomycin
  • TLV telavancin
  • oritivancin oritivancin
  • RV40 compound of Formula (I) or (II) where R 1 is (CH 2 )—NH—(CH 2 ) 9 —CH 3 , R 2 is OH, R 3 and R 4 are H and X is O) were tested for their ability to eradicate MRSA 1556 biofilm.
  • RV40 was more potent to kill MRSA 1556 biofilm developed in a co-culture with CFBE cells compared to vancomycin, telavancin and oritavancin with >3 log CFU/ml reduction at 20 ⁇ g/ml ( FIG. 11 ).
  • mice Male Sprague Dawley rats (179-200 g) were rendered neutropenic through a series of cyclophosphamide injections (IP) at 150 mg/kg (Day ⁇ 4) and 100 mg/kg (Day ⁇ 1). They were then challenged with Methicillin-Resistant Staphylococcus aureus (MRSA) (ATCC-BAA-1556; TPPS 1062) at 8 log 10 via intranasal (IN) instillation on study Day 0.
  • MRSA Methicillin-Resistant Staphylococcus aureus
  • Rats were treated with vehicle control (bicine; pH 9.2) or RV40 (compound 40) (in bicine; pH 9.2) via nebulization using CH Technologies 12 Port Module Oral-Nasal Aerosol and Respiratory Exposure Systems (ONARES) connected to an Aeroneb Pro nebulizer at 12 h and 24 h post-challenge. At 36 hours, post-challenge lungs were collected for CFU enumeration. The results are shown in FIG. 12 .

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US11857597B2 (en) 2017-05-22 2024-01-02 Insmed Incorporated Lipo-glycopeptide cleavable derivatives and uses thereof
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IL270686B (he) 2022-09-01
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US11071769B2 (en) 2021-07-27
AU2018271873A1 (en) 2019-11-28
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GB201917677D0 (en) 2020-01-15
EP3634464A4 (en) 2021-04-07
CN110996984A (zh) 2020-04-10
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