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WO2003068791A2 - Macrolides actifs contre staphylococcus aureus resistant a la methicilline - Google Patents

Macrolides actifs contre staphylococcus aureus resistant a la methicilline Download PDF

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Publication number
WO2003068791A2
WO2003068791A2 PCT/US2003/004130 US0304130W WO03068791A2 WO 2003068791 A2 WO2003068791 A2 WO 2003068791A2 US 0304130 W US0304130 W US 0304130W WO 03068791 A2 WO03068791 A2 WO 03068791A2
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WIPO (PCT)
Prior art keywords
group
hydrogen
nhc
compounds
alkyl
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PCT/US2003/004130
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English (en)
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WO2003068791A3 (fr
Inventor
Zhenkun Ma
Robert Keyes
Stevan Djuric
Hong Yong
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Abbott Laboratories
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Priority claimed from US10/075,012 external-priority patent/US20030162729A1/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of WO2003068791A2 publication Critical patent/WO2003068791A2/fr
Publication of WO2003068791A3 publication Critical patent/WO2003068791A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • 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

Definitions

  • TECHNICAL FIELD This invention is directed to compounds with activity against methicillin-resistant staphylococcus aureus (MRSA) , processes for making the compounds and intermediates used in the processes, compositions containing the compounds, and methods for prophylaxis or treatment of MRSA infections using the compounds.
  • MRSA methicillin-resistant staphylococcus aureus
  • MRSA methicillin-resistant staphylococcus aureus
  • a first embodiment of the invention is directed to compounds, and salts, prodrugs, and salts of prodrugs thereof, which have activity against MRSA, the compounds having formula (I)
  • a 1 and D 1 , A 1 and E 1 , B 1 and D 1 , or B 1 and D 1 together are one- to five-membered alkylene or two- to five-membered heteroalkylene, and the remainder are hydrogen; or A and B together are one- to seven-membered alkylene or two- to seven-membered heteroalkylene, and D and E 1 are hydrogen; or
  • D and E together are one- to seven-membered alkylene or two- to seven-membered heteroalkylene, and A and B are hydrogen;
  • X is selected from the group consisting of hydrogen and fluoride
  • R is selected from the group consisting of hydrogen and Rp, in which Rp is a hydroxyl protecting moiety;
  • R is selected from the group consisting of alkyl and alkyl substituted with a substituent selected from the group consisting of halo and -OR 45;
  • R and R are independently selected alkyl
  • R 40 is selected from the group consisting of phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2 , 3-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 3-triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrrolidinyl, inidazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halo, -CN, -OH, -SH
  • R is alkyl; and R and R are independently selected alkyl.
  • a second embodiment of the invention is directed to processes for making the compounds.
  • a third embodiment of the invention is directed to intermediates which are useful in the second embodiment.
  • a fourth embodiment of the invention is directed to anti- methicillin-resistant staphylococcus aureus compositions comprising a therapeutically effective amount of a compound of the first embodiment.
  • a fifth embodiment of the invention is directed to methods for prophylaxis or treatment of methicillin-resistant staphylococcus aureus infections in a fish or a mammal comprising administering thereto a therapeutically effective amount of a compound of the first embodiment .
  • the beneficiary of prophylaxis or treatment of methicillin- resistant staphylococcus aureus infections is a mammal.
  • the beneficiary of prophylaxis or treatment of methicillin- resistant staphylococcus aureus infections is a human.
  • the compounds of the invention comprise both fixed and variable moieties, the latter of which are identified by a capital letter and accompanying numerical or alphabetical superscript, in which the term “alkenyl” means a monovalent, straight or branched hydrocarbon, having two to eight carbon atoms and at least one carbon-carbon double bond, attached through a carbon atom; the term “alkynyl” means a monovalent, straight or branched hydrocarbon, having two to eight carbon atoms and at least one carbon-carbon triple bond, attached through a carbon atom; the term “alkyl” means a monovalent, saturated, straight or branched hydrocarbon, having one to eight carbon atoms, attached through a carbon atom; the term “alkylene” means a divalent, saturated, straight or branched hydrocarbon, having one to eight carbon atoms, attached through carbon atoms; the term “aryl” means monovalent phenyl, attached through a carbon atom, unfused or fused with
  • Preferred A , B , D , and E moieties are hydrogen.
  • a preferred L moiety is C ⁇ C.
  • a preferred X moiety is hydrogen.
  • a preferred R moiety is hydrogen.
  • R moieties are 4- (furan-2-yl) phenyl, 4- (2-methyl-2H-tetraazol-5-yl) phenyl, pyrid-2-yl, 4- (pyridin-2-yl) phenyl, qu ⁇ nolin-3-yl, 4- (1, 2 , 3-thiadiazol- 5-yl) phenyl, 4- (1, 3-thiazol-2-yl) phenyl, 4-(thien-2- yl) phenyl, and 4- (vinyl) phenyl .
  • variable moieties combine with the parent moiety to form a preferred first embodiment of this invention, the preferred first embodiment comprising compounds, and salts, prodrugs, and salts of prodrugs thereof, having formula (I)
  • variable moieties also combine to form still yet another preferred first embodiment of the invention, the preferred first embodiment comprising compounds, and salts, prodrugs, and salts of prodrugs thereof, which are selected from the group consisting of (3aS, 4R, 7R, 9R, 10R, US, 13R, 15R, 15aR) -4-ethyl- 3a, 7, 9, 11, 13, 15-hexamethyl-2, 6, 8-trioxo-ll- ( (4-pyridin-2- ylbut-2-ynyl) oxy) dodecahydro-14, 1-
  • the compounds of the invention comprise asymmetrically substituted carbon atoms in the R or S configuration.
  • Asymmetric carbon atoms with equimolar amounts of R and S configurations are racemic. Atoms with an excess of one configuration over the other are assigned the configuration in the higher amount, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and still more preferably an excess greater than about 99%.
  • the compounds of the invention may also comprise carbon-carbon double bonds as being in the Z or E configuration, in which the term “Z” represents the larger two of the four substituents disposed on same side of a carbon-carbon double bond and the term “E” represents the larger two of the four substituents disposed on opposite sides of a carbon-carbon double bond.
  • the compounds may also exist as an equilibrium mixture comprising Z or E configurations .
  • the compounds of the invention containing hydroxyl, amino, or carboxylic acids may have attached thereto prodrug-forming moieties.
  • the prodrug-forming moieties are removed by metabolic processes and release the compounds having the freed hydroxyl, amino, or carboxylic acid in vivo.
  • Prodrugs are useful for adjusting such pharmacokinetic properties of the compounds as solubility and/or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration, and rate of clearance .
  • the compounds of the invention may be prepared by synthetic processes or metabolic processes. Metabolic processes include those processes occurring in vitro and in vivo.
  • the compounds of the invention may exist as acid addition salts, basic addition salts, or zwitterions .
  • Salts of the compounds are prepared during their isolation or following their purification.
  • Acid addition salts of the compounds are those derived from the reaction of the compounds with an acid.
  • the compounds of the invention may be administered with or without an excipient.
  • Excipients include encapsulating materials or formulation additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof.
  • Excipients for orally administered compounds in solid dosage forms include agar, alginic acid, cocoa butter, gelatin, isotonic saline, malt, powdered tragacanth, Ringer's solution, talc, water, aluminum hydroxide, magnesium hydroxide, sodium and potassium phosphate salts, cellulose, cellulose acetate, ethyl cellulose, sodium carboxymethyl cellulose, ethyl laureate, ethyl oleate, magnesium stearate, sodium lauryl sulfate, castor oil, corn oil, cottonseed oil, germ oil, groundnut oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, ethanol, ethyl acetate, ethyl carbonate, glycerol, isopropanol, propylene glycol, tetrahydrofurfuryl
  • Excipients for ophthalmically and orally administered compounds in liquid dosage forms include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, cottonseed oil, groundnut oil, corn oil, germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, and mixtures thereof.
  • Excipients for osmotically administered compounds include water, ethanol, isopropanol, chlorofluorohydrocarbons, and mixtures thereof.
  • Excipients for parenterally administered compounds include water, 1, 3-butanediol, Ringer's solution, U.S. P. or isotonic sodium chloride solution, oleic acid, castor oil, corn oil, cottonseed oil, germ oil, groundnut oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, liposomes, and mixtures thereof.
  • Excipients for rectally and vaginally administered compounds include cocoa butter, polyethylene glycol, wax, and mixtures thereof.
  • the compounds of the invention may be administered parenterally (subcutaneously, intravenously, intramuscularly, and intrasternally) , orally, osmotically, ophthalmically, rectally, topically, and vaginally.
  • Orally administered compounds in solid dosage forms may be administered as capsules, dragees, granules, pills, powders, and tablets .
  • Ophthalmically and orally administered compounds in liquid dosage forms may be administered as elixirs, emulsions, microemulsions, solutions, suspensions, and syrups.
  • Osmotically and topically administered compounds may be administered as creams, gels, inhalants, lotions, ointments, pastes, powders, solutions, and sprays.
  • Parenterally administered compounds may be administered as aqueous or oleaginous solutions or aqueous or oleaginous suspensions, the latter of which contains crystalline, amorphous, or otherwise insoluble forms of the compounds. Rectally and vaginally administered compounds may be administered as creams, gels, lotions, ointments, and pastes .
  • Dosage forms for the compounds of the invention depend on the species being treated, the disorder being treated and the severity thereof, the composition comprising the compounds, the time of administration, the route of administration, the duration of treatment, the potency of the compounds, and the rate of excretion of the compounds.
  • the daily therapeutically effective amount of the compounds administered to a patient in single or divided doses range from about 0.1 to about 200 mg/kg body weight, preferably from about 0.25 to about 100 mg/kg body weight.
  • Single dose compositions contain these amounts of the compounds or combinations of submultiples thereof.
  • MIC minimum inhibitory concentration
  • the compounds tested displayed activity against MRSA superior to their respective controls.
  • the compounds demonstrated MIC's in a range of about 2 ⁇ g/mL to about 64 ⁇ g/mL; and in a more preferred range, the compounds demonstrated MIC's in a range of about 2 ⁇ g/mL to about 8 ⁇ g/mL.
  • the compounds are therefore useful as antibacterials against methicillin-resistant staphylococcus aureus .
  • the following schemes illustrate representative processes by which the compounds of the invention may be prepared with the understanding that the order of the steps in the processes may be varied, other reagents may be substituted for those specifically mentioned, and vulnerable substituents may be protected and deprotected during the process .
  • Abbreviations used are: DME for 1, 2-dimethoxyethane; DMF for N, N-dimethylformamide; and THF for tetrahydrofuran .
  • Compounds having formula (1) may be converted to p compounds having formula (2), in which R is acetyl (CH 3 C(0)), benzoyl (C 6 H 5 C(0)), or trimethylsilyl, by reacting the former, a hydroxyl protecting reagent, a first base, and, optionally, N,N-dimethylaminopyridine .
  • Hydroxyl protecting reagents include acetic anhydride, acetyl chloride, benzoic anhydride, benzoyl chloride, and trimethylsilyl chloride.
  • First bases include triethylamine, diisopropylethylamine, pyridine, and lutidine.
  • the reaction is typically conducted at about 0 °C to 60 °C, over about 4 to 24 hours, in solvents such as dichloromethane, chloroform, THF, DME, and tert-butyl methylether.
  • Compounds having formula (2) may be converted to compounds having formula (3) by reacting the former, carbonyldiimidazole, a second base, and, optionally, N,N- dimethylaminopyridine.
  • Second bases include 1,8- diazabicyclo- [5.4.0] undec-7-ene, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide .
  • the reaction is typically conducted at about 25 °C, over about 6 to 24 hours, in solvents such as THF, DMF, 1,4-dioxane, and N-methylpyrrolidine .
  • Compounds having formula (3) may be converted to compounds having formula (4) by (a) reacting the former and a compound having formula (i)
  • First acids include hydrochloric acid, triflic acid, para-toluenesulfonic acid, and trifluoroacetic acid.
  • Step (a) is typically conducted at about 25 °C, over about
  • Step (b) is typically conducted at about 70 °C to 100 °C, over about 12 hours to about 24 hours, in solvents such as benzene, toluene, xylene, and mixtures thereof.
  • Second acids include hydrochloric acid, triflic acid, para-toluenesulfonic acid, and trifluoroacetic acid.
  • the reaction is typically conducted at about 60 °C, over about 12 to 24 hours, in solvents such as ethanol, acetone, THF, water, and mixtures thereof.
  • Compounds having formula (5) may be converted to compounds having formula (6) by reacting the former, a first oxidizing agent, and, optionally, a first additive.
  • First oxidizing agents include dimethylsulfide/N- chlorosuccinimide, dimethylsulfoxide/1- (3- dimethylaminopropyl) -3-ethylcarbodiimide, and dimethylsulfoxide/oxalyl chloride.
  • First additives include phosphoric acid, pyridinium trifluoroacetate, silica gel, triethylamine, and pyridine. The reaction is typically conducted at about -10 °C to 25 °C, over about 3 to 24 hours, in solvents such as THF, DMSO, and dichloromethane .
  • Compounds having formula (6) may be converted to compounds of formula (7) by reacting the former, a fluorinating agent and, optionally, a second base.
  • Fluorinating agents include 3, 5-dichloro-l-fluoropyridinium tetrafluoroborate, N-fluorobenzenesulfonimide, 3, 5-dichloro- 1-fluoropyridinium triflate, N-fluoro-N-methyl-para- toluenesulfonamide, N-fluoropyridinium triflate, and N- fluoroperfluoropiperidine .
  • Second bases include sodium hydride, potassium hydride, lithium diisopropylamide, triethylamine, and N,N-diisopropylethylamine .
  • the reaction is typically conducted at about -78 °C to 0 °C, over about 2 to 24 hours, in solvents such as DMF, THF, diethyl ether, and mixtures thereof.
  • Compounds having formula (8) may be converted to compounds having formula (9) by reacting the former, a stannylating agent and, optionally, a coupling catalyst.
  • Stannylating agents include tributyltin ethoxide, tributyltin methoxide, hexamethyldistannane, and hexabutyldistannane .
  • Coupling catalysts include tetrakis (triphenylphosphine) palladium(O) , and tris (dibenzylideneacetone) dipalladium(O) .
  • the reaction is typically conducted neat at about 80 °C to 150 °C, over about 8 to 48 hours, or in solvents such as toluene, xylenes, 1,4- dioxane, and THF.
  • Coupling catalysts include tetrakis (triphenylphosphine) palladium (0) , tris (dibenzylideneacetone) dipalladium(O) , and dichlorobis (triphenylphosphine) palladium (II) .
  • Third bases include sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, and diisopropylethylamine. The reaction is typically conducted in a sealed vessel at about 80 °C to 150 °C, over about 2 to
  • R is aryl or heteroaryl, under the same conditions described for the conversion of compounds having formula (9) to compounds having formula (I) -a in SCHEME 4.
  • Compounds having formula (10) may be converted to compounds having formula (I) -a by reacting the former, a compound having formula (iv)
  • Compounds having formula (I) -a may be converted to compounds having formula (I)-c by reacting the former, hydrogen gas, a hydrogenation catalyst, and, optionally, quinoline.
  • Hydrogenation catalysts include Lindlar catalyst and palladium on barium sulfate. The reaction is typically conducted at 25 °C, over about 1 to 6 hours, in solvents such as methanol, ethanol, propanol, butanol, iso-propanol, tert-butanol, acetonitrile, THF, ethyl acetate, and mixtures thereof.
  • reaction is typically conducted at about -20 °C to 25 °C, over about 1 to 6 hours, in solvents such as THF, DME, and diethyl ether.
  • Compounds having formula (11) may be converted to compounds having formula (I)-c by reacting the former and compounds having formula (vi)
  • Compounds having formula (I), in which R A is R P , and R P is trimethylsilyl, may be converted to compounds having formula (I), in which R is hydrogen, by reacting the former and a fluoride-donating agent.
  • Fluoride-donating agents include tetrabutylammonium fluoride, polymer-bound ammonium fluoride, tetrabutylammonium fluoride, pyridine-HF, and triethylamine • trihydrofluoride .
  • the reaction is typically conducted at about 0 °C to 50 °C, over about 1 to 24 hours, in solvents such as THF and 1,4-dioxane.
  • EXAMPLE 1 This example was prepared as described in commonly owned US 6,075,133, EXAMPLE 246, step 246c.
  • EXAMPLE 3 A solution of EXAMPLE 2 (9.8 g) , carbonyldiimidazole (4.05 g) , N 'N-dimethylaminopyridine (122 mg) , and 1, 8-diazabicyclo[5. .0] undec-7-ene (2.24 mL) in THF (45 mL) and DMF (13 mL) was stirred for 12 hours, diluted with ethyl acetate, washed with water and brine, and dried (Na 2 S0 4 ), filtered, and concentrated.
  • EXAMPLE 4 A solution of EXAMPLE 3 (11.09 g) and ethylenediamine (6.67 mL) in acetonitrile (50 mL) and water (5 mL) at ambient temperature was stirred for 3 days and concentrated. The concentrate was dissolved in toluene (140 mL) and acetic acid (7 mL) , and this solution was heated at 80 °C for 12 hours then cooled, stirred for 12 hours, diluted with dichloromethane, washed with saturated potassium carbonate, and dried (Na 2 S0 4 ) , filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with 95:5:0.5 dichloromethane/methanol/concentrated ammonium hydroxide.
  • EXAMPLE 5 A solution of EXAMPLE 4 (5.95 g) and 2M HC1 (5 mL) in ethanol (5 mL) was stirred at 55°C for 12 hours and concentrated. The concentrate was dissolved in water, and this solution was washed with diethyl ether, treated with concentrated ammonium hydroxide, and extracted with dichloromethane; and the extract was concentrated.
  • EXAMPLE 7 A solution of EXAMPLE 6 (3.825 g) and tributyltin ethoxide (1.76 mL) was heated at 110°C for 48 hours, with an additional tributyltin ethoxide (1.76 mL) treatment after 24 hours, and concentrated; and the concentrate was dissolved in acetonitrile and treated with hexane .
  • EXAMPLE 8 A solution of EXAMPLE 7 (2.11 g), l-bromo-4- (bromomethyl) benzene (797 mg) , and tetrakis (triphenylphosphine) palladium (0) (116 mg) in toluene (10 mL) was heated at 90 °C in a sealed tube for 3 hours and concentrated; and the concentrate was flash chromatographed on silica gel with 97:3:0.5 dichloromethane/methanol/ concentrated ammonium hydroxide.
  • EXAMPLE 9 A solution of EXAMPLE 7 (220 mg) , 2-bromomethylpyridine (84 mg) , and tetrakis (triphenylphosphine) palladium(O) (11 mg) in toluene (2 mL) was heated at 80°C in a sealed tube for 12 hours, diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, and dried (Na 2 S0 4 ) , filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with 97:3:0.5 dichloromethane/ methanol/concentrated ammonium hydroxide.
  • EXAMPLE 10 A solution of EXAMPLE 9 in methanol was heated at 65°C for 3 hours and concentrated; and the concentrate was flash chromatographed on silica gel with 95:5:0.5 dichloromethane/methanol/concentrated ammonium hydroxide.
  • EXAMPLE 11 This example was prepared by substituting 5- (4- (bromomethyl) phenyl) -1, 2, 3-thiadiazole for 2- bromomethylpyridine in EXAMPLES 9 and 10.
  • EXAMPLE 1 A solution of EXAMPLE 13 in methanol at 65°C was stirred for 3 hours and concentrated; and the concentrate was flash chromatographed on silica gel with 95:5:0.5 dichloromethane/methanol/concentrated ammonium hydroxide.
  • EXAMPLE 17 This example was prepared by substituting vinyltributylstannane for 2- (tributylstannyl) thiophene in EXAMPLES 13 and 14.
  • EXAMPLE 18 This example was prepared by substituting 2- (tributylstannyl) pyridine for 2- (tributylstannyl) thiophene in EXAMPLES 13 and 14.
  • EXAMPLE 19 This example was prepared by substituting 2-methyl-5- (tributylstannyl) -2H-tetrazole for 2- (tributylstannyl) thiophene in EXAMPLES 13 and 14.
  • EXAMPLE 20 A solution of EXAMPLE 6 (672 mg) in DMF (5 mL) at 0°C was treated with 60% oily sodium hydride (70 mg) , stirred for 40 minutes, treated with N-fluorobenzenesulphonimide (314 mg) , stirred for 3 hours, diluted with ethyl acetate, washed with water and brine, and dried (Na 2 S0 ) , filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with 95:5:0.5 dichloromethane/ methanol/concentrated ammonium hydroxide.
  • EXAMPLE 18 13 3 ,C NMR (CDCI 3 ) 5204.9, 169.4, 156.1, 149.6, 137.5, 136.6, 131.5, 129.7, 128.4, 127.0, 121.9, 120.4, 103.5, 83.5, 81.6, 80.0, 76.7, 70.3, 69.6, 65.9, 60.2, 51.1, 51.0, 49.5, 47.0, 42.8, 42.1, 40.2, 38.2, 36.3, 28.2, 27.8, 27.1, 25.1, 22.4, 21.3, 20.1, 19.7, 15.6, 14.8, 14.6, 13.6, 13.1, 11.1, 10.7.

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Abstract

L'invention concerne des composés actifs contre des staphylocoques dorés résistants à la méthicilline (MRSA), ces composés étant représentés par la formule (I). Elle concerne aussi des sels, des promédicaments de ces composés, des procédés de fabrication de ces composés et des intermédiaires utilisés dans les procédés, des compositions contenant ces composés, et des méthodes de prophylaxie et de traitement d'infections dues aux staphylocoques dorés résistants à la méthicilline, au moyen de ces composés.
PCT/US2003/004130 2002-02-13 2003-02-11 Macrolides actifs contre staphylococcus aureus resistant a la methicilline WO2003068791A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US10/075,012 US20030162729A1 (en) 2002-02-13 2002-02-13 Macrolides with activity against methicillin-resistant staphylococcus aureus
US10/075,012 2002-02-13
US36147103A 2003-02-10 2003-02-10
US10/361,471 2003-02-10

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WO2003068791A2 true WO2003068791A2 (fr) 2003-08-21
WO2003068791A3 WO2003068791A3 (fr) 2004-01-22

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CA2367431C (fr) * 1999-03-15 2008-06-10 Abbott Laboratories Macrolides substitues en 6-o a activite antibacterienne

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