WO2005113520A1 - 2,3,5-trifluorphenyl oxazolidinones substitues a utiliser en tant qu'agents antibacteriens - Google Patents

2,3,5-trifluorphenyl oxazolidinones substitues a utiliser en tant qu'agents antibacteriens Download PDF

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Publication number
WO2005113520A1
WO2005113520A1 PCT/IB2005/001294 IB2005001294W WO2005113520A1 WO 2005113520 A1 WO2005113520 A1 WO 2005113520A1 IB 2005001294 W IB2005001294 W IB 2005001294W WO 2005113520 A1 WO2005113520 A1 WO 2005113520A1
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compound
mmol
compounds
mixture
reduced pressure
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PCT/IB2005/001294
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Michael Robert Barbachyn
Christina Renee Harris
Vara Prasad Venkata Nagendra Josyula
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Pharmacia & Upjohn Company Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • 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

  • the present invention relates to substituted trifluorphenyl oxazolidinones and 5 to the processe for the synthesis of the same.
  • the compounds of the present invention are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci, and enterococci as well as anaerobic organisms such as bacteroides spp. and clostridia spp. species, and acid-fast organisms such as 10 Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
  • This invention also relates to a novel combination therapy for treating infective diseases caused by bacteria in human or animal.
  • oxazolidinone compounds are the most recent synthetic class of antimicrobials active against a number of pathogenic microorganisms, including pathogens resistant to other clinically useful antibiotics. 20 It is also known that as a chemical compound class, oxazolidinones generally inhibit to some extent monoamine oxidase (MAO), the enzyme responsible for preventing acute blood pressure elevation by the endogenous and dietary amine, tyramine, and other sympathomimetic amines.
  • MAO monoamine oxidase
  • the present invention provides sulfur-containing heterocyclic trifluorphenyl oxazolidinones of formula I. These compounds has unexpectedly weak MAO inhibitory activity, which indicates that these compounds possess the capacity to minimize or eliminate potential drug-drug interactions since strong inhibition of monoamine oxidase can result in altered clearance rates for other compounds 30 normally metabolized by it.
  • Many classes of antibiotic compounds, including quinolones, have been described for the treatment of infectious diseases, particularly bacterial infections. The development of bacterial resistance to currently available antibacterial agents is a growing global health problem.
  • MRS A methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant Enterococci
  • GISA glycopeptide-intermediate Staphylococcus aureus
  • VISA vancomycin-intermediate Staphylococcus aureus
  • the present invention may be used in a combination therapy for treating bacterial infections which comprises administration to a mammal a compound of present invention and a second antibiotic agent to achieve broad coverage and synergistic interactions.
  • WO 03/063862 discloses that a wide variety of oxazolidinones may be used in combination with B vitamins in the treatment of bacterial infections.
  • US Patent 6,239,152 discloses oxazolidinones and methods for their synthesis.
  • US Patent No 6,605,609 discloses a thizaine oxazolidinone useful as antimicrobial agent and a new antimicrobial combination therapy for infective diseases.
  • US Patent No 5,700,799 discloses oxazolidinone derivatives possessing a substituted diazine moiety bonded to an N-aryl ring.
  • US Patent No 6,605,609 discloses thiopyran oxazolidinones useful as antimicrobial agents.
  • 5,880,118 discloses substituted oxazine and thiazine oxazolidinone antimicrobials.
  • US Patent No. 6,968,962 discloses phenyloxazolidinones having a C-C bond to 4-8 membered heterocyclic rings.
  • US Patent No. 5,981,528 discloses antibiotic oxazolidinone derivatives.
  • International Patent Publication No. WO 01/34128 A2 discloses admixture of linezolid and other antibacterial agents.
  • International Patent Publication No. WO 03/093247 A discloses oxazolidinone derivatives for treating or preventing infectious disorder caused by bacteria in human or animal.
  • WO 03/0007870 A2 discloses certain substituted phenyl oxazolidinones and processes for the synthesis of the same.
  • US Patents 4,382,892, 4,670,444, 4,670,444, 4,703,047, 4,758,567, 4,820,716, 4,889,857, 5,039,683, 5,077429, 5,262,417, and 5,385,906 disclose quinolone antibiotics that may be used in combination with the compounds of the present invention. None of the references cited above specifically contemplates the compound of the present invention, its combination therapy and its novel compositions.
  • R 1 is -CH 3
  • X is -N-
  • R 1 is -CH 3
  • X is -N-
  • Y is -O-.
  • R 1 is -CH 3
  • X is -N-
  • Y is -SO 2 -.
  • the present invention further provides a method for treating bacterial infections which comprises administration to a mammal being treated a pharmaceutically effective amount of the compound of formula I, either individually, or in combination with at least one second antibiotics.
  • the present invention further provides compositions for treating bacterial infections wherein the compositions comprise a pharmaceutically effective amount of the compound of formula I and a pharmaceutically acceptable carrier.
  • a “pharmaceutically acceptable carrier” refers to a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable carrier” as used in the specification and claims includes both one and more than one such carrier.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable, non-toxic bases and acids.
  • Pharmaceutically acceptable, non-toxic bases and acids include inorganic bases, inorganic acids, organic acids, and inorganic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, ferric, ferrous, lithium, magnesium, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable, organic, non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, such as arginine, betaine, caffeine, choline, N, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and the like.
  • cyclic amines such as arginine, betaine, caffeine, choline, N
  • Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, mineral acids, sulfonic acids, phosphoric acid, phosphorous acid, and the like.
  • Salts derived from pharmaceutically acceptable, organic, non-toxic acids include salts of C 1-6 alkyl carboxylic acids, di- carboxylic acids, and tri-carboxylic acids such as acetic acid, propionic acid, fumaric acid, succinic acid, tartaric acid, maleic acid, adipic acid, and citric acid.
  • Other salts may be derived from aryl and alkyl sulfonic acids such as toluene sulfonic acids and the like.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the present invention provides compounds, which are in a prodrug form.
  • prodrug denotes a derivative of a known direct acting drug, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic, for example by hydrolysis in blood, or chemical process [see T. Higuchi and V.
  • prodrug is any covalently bonded carrier that releases in vivo the active parent drug according to the Formula I when such prodrug is administered to the subject.
  • Prodrugs of the compounds of Formula I are prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include, but are not limited to, compounds derived from compounds of Formula I wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to the subject, cleaves to form the free hydroxyl, amino or sulfhydryl group, respectively.
  • Selected examples include, but are not limited to, biohydrolyzable amides and biohydrolyzable esters and biohydrolyzable carbamates, carbonates, acetate, formate and benzoate derivatives of alcohol and amine functional groups.
  • prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of Formula I and Formula ⁇ .
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4- hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.
  • treating or “treatment” of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • therapeutically effective amount refers to the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the "therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • the term “combination therapy” refers to a treatment regimen wherein the compounds of the present invention and the second antibiotics are administered individually or together in such a way as to provide a beneficial effect from co-action of these therapeutic agents.
  • Such beneficial effect can include, but is not limited to, pharmacokinetic or pharmacodynamic co-action of the therapeutic agents.
  • Combination therapy can, for example, enable administration of a lower dose of one or both agents than would normally be administered during monotherapy, thus decreasing risk or incidence of adverse effects associated with higher doses.
  • combination therapy can result in increased therapeutic effect at the normal dose of each agent in monotherapy.
  • combination therapy can maximize the therapeutic effect at higher doses.
  • mammal refers to human or warm-blooded animals including livestock and companion animals.
  • Methods for Preparation The compound of the present invention can be prepared according to the procedures described herein below. As shown in Scheme I, alkylation of 2,3,4,5- tetrafluoronitrobenzene a with thiomorpholine in an appropriate solvent such as
  • DMSO provides 4-(2,3,6-trifluoro-4-nitrophenyl)thiomorpholine b.
  • the compound b is then treated with stannous chloride dihydrate (SnCl 2 ) at a temperature in the range of about 25 C to about 100 C followed by protection of the aniline as the CBz- carbamate afforded the desired intermediate c.
  • SnCl 2 stannous chloride dihydrate
  • R 2 is tert-butyl
  • treatment with trifluoroacetic acid (neat or in dichloromethane) or hydrochloric acid in dioxane affords the corresponding 5- (aminomethyl)oxazolidinone intermediate which can be reacted with a variety of acetylating agents to provide the targeted compounds d.
  • the starting material 2,3,5-trifluoroaniline a is converted to the protected silylated derivative b as described, for example, in Grega, K. C; et al. in J. Org. Chem. 1995, 60, 5255-5261 and Hutchinson, D. K.; et al. PCT Int. Appl. WO 9709328.
  • the aniline a can be converted to the protected dimethylpyrrole derivative c.
  • Treatment of either b or c with n-BuLi in THF affords an intermediate lithiated phenyl ring which can be added to tetrahydrothiopyran-4-one (d) to give an intermediate adduct.
  • the silyl protecting group can be removed by stirring with methanolic potassium carbonate or the like. Subsequent reaction with an appropriate alkyl chloroformate then affords the carbamate e.
  • Scheme HI illustrates the preparation of compounds wherein Y is oxygen and X is nitrogen.
  • Alkylation of 2,3,4,5-tetrafluoronitrobenzene a with morpholine in an appropriate solvent such as DMSO provides 4-(2,3,6-trifluoro-4- nitrophenyl)morpholine b.
  • the compound b is then treated with stannous chloride dihydrate (SnCl 2 ) at a temperature in the range of about 25 C to about 100 C followed by protection of the aniline as the CBz-carbamate afforded the desired intermediate c.
  • the nitro group of b can be reduced by hydrogenation with hydrogen gas in the presence of a suitable palladium catalyst such as 5-10% palladium on carbon. It will be apparent to one skilled in the art that these reduction conditions are merely representative and that other variations are possible.
  • the aniline a can be converted to the protected dimethylpyrrole derivative j.
  • Treatment of either i or j with n-BuLi in THF affords an intermediate lithiated phenyl ring which can be added to tetrahydrothiopyran-4-one (k) to give an intermediate adduct.
  • the silyl protecting group can be removed by stirring with methanolic potassium carbonate or the like. Subsequent reaction with an appropriate alkyl chloroformate then affords the carbamate 1.
  • Step 1 Preparation of 4-(2,3 ,6-trifluoro-4-nitrophenyl)thiomorpholine
  • Step 2 Preparation of 4-[4-(benzyloxycarbonyl)amino-2,3,6-trifluorophenyl] thiomorpholine
  • the intermediate aniline is dissolved in THF (100 mL), cooled to 0 °C, and treated 2M NaOH (20 mL, 35.0 mmol) and then benzyloxychloroformate (3.58 g, 3.0 mL, 21.0 mmol). The cooling bath is then removed and the mixture allowed to reach ambient temperature over an 8 hour period. After additional time at room temperature the reaction is judged to be essentially complete by TLC (50% EtOAc / hexanes). The mixture is poured into H 2 O and extracted with EtOAc. Combined organic extracts are washed with H 2 O, brine, dried over Mg 2 SO 4 , filtered, concentrated under reduced pressure and triturated with Et 2 O to give the title compound.
  • Step 3 Preparation of tert-butyl (5)-N-[[3-[2,3,5-trifluoro-4-(thiomorpholin-4- yl)phenyl]-2-oxo-5-oxazolidinonyl] methyljcarbamate
  • the starting material, 4-[4-(benzyloxycarbonyl)amino-2,3,6-trifluorophenyl] thiomorpholine (10.95 mmol) is dissolved in DMF (20 mL) and the mixture cooled to 0 °C.
  • Lithium tert-butoxide 33.0 mL of a 1.0M solution in hexane, 32.85 mmol is added dropwise via an addition funnel.
  • tert-butyl (S)- N-(3-chloro-2-hydroxyprop-l-yl)carbamate (21.9 mmol) is added in one portion.
  • the cooling bath is then removed and the mixture allowed to warm to ambient temperature over 8 hour and then left overnight at ambient temperature.
  • TLC analysis (1:1 EtOAc / hexane) revealed the reaction to be nearly complete.
  • the reaction mixture is quenched with 0. IN aqueous HCl.
  • An aqueous workup with EtOAc afforded a crude product which is chromatographed on a Biotage silica gel column (40M), eluting with 1:1 EtOAc / hexane. Appropriate fractions are combined and concentrated under reduced pressure.
  • Step 4 Preparation of (5)-N-[[3-[2,3,5-trifluoro-4-(thiomorpholin-4- yl)phenyl]-2-oxo-5-oxazolidinonyl]methyl]acetamide
  • the starting material l-(benzyloxycarbonyl)-4-[4-(benzyloxycarbonyl)amino- 2,3,6-trifluorophenyl]piperazine (11.16 g, 22.3 mmol), is dissolved in DMF (40 mL) and the mixture cooled to 0 °C.
  • Lithium tert-butoxide (67.0 mL of a 1.0M solution in hexane, 66.9 mmol) is added dropwise via an addition funnel.
  • tert-butyl ( ⁇ S)-N-(3-chloro-2-hydroxyprop-l-yl)carbamate (9.35 g, 44.6 mmol) is added in one portion.
  • Step 4 (5 -N-[[3-[2,3,5-trifluoro-4-[4-(benzyloxycarbonyl)piperazin-l- yl]phenyl]-2-oxo-5-oxazolidinonyl]methyl]acetamide
  • Step 5 Preparation of ( 1 S)-N-[[3-[2,3,5-trifluoro-4-(4-piperazin-l-yl)phenyl]-2- oxo-5-oxazolidinonyl]methyl]acetamide
  • the material is suspended in 3: 1 MeOH / H 2 O (10 mL), cooled to 0 °C and treated with lithium hydroxide (0.03 g, 0.64 mmol). After 4 hours the reaction mixture is quenched with IN aqueous HCl (10 mL). The methanol is removed by rotary evaporation under reduced pressure and the aqueous layer extracted with dichloromethane. The combined organic extracts are washed with H O, brine, dried over Mg 2 SO , filtered and concentrated under reduced pressure.
  • the starting material 4-[4-(benzyloxycarbonyl)amino-2,3,6- trifluorophenyl]morpholine (4.01 g, 10.95 mmol), was dissolved in DMF (20 mL) and the mixture cooled to 0 °C. Lithium tert-butoxide (33.0 mL of a 1.0M solution in hexane, 32.85 mmol) was added drop wise via an addition funnel. When the addition was complete, tert-butyl (S N-(3-chloro-2-hydroxyprop-l-yl)carbamate (4.59 g, 21.9 mmol) was added in one portion.
  • the in vitro activity of the compound of this invention can be assessed by standard testing procedures such as the determination of minimum inhibitory concentration (MIC) by agar dilution as described in "Approved Standard. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically", 3rd. ed., published 1993 by the National Committee for Clinical Laboratory Standards, Villanova, Pennsylvania, USA.
  • the activity of compounds of this invention against Staphylococcus aureus is shown in Table 1.
  • Oxazolidinones with weak or no ability to inhibit MAO-A have the potential to minimize or eliminate potential drug-drug interactions.
  • the compound of the present invention is tested for their MAO inhibitory activity by using the procedures below.
  • the enzyme assay for human MAO-A relies on the formation of a colored reaction product by the enzyme. This product is detected by a spectrophotometer at 421 nm.
  • the chromogenic substrate is l-methyl-4-(l-methyl-2-pyrryl)-l,2,3,6- tetrahydropyridine.
  • Membrane bound, human placental MAO-A is solubilized and purified as described and used as a concentrated solution (5 nmoles per ml). See: Flaherty P, Castagnoli K, Wang Y-X, Castagnoli Jr. N., JMed Chem. Vol. 39, p. 4756, (1996).
  • Stock Solutions- Sodium phosphate is prepared as a 50 mM stock solution, pH 7.3 at 37°C.
  • Stock solutions (50 mM) of the test compounds are prepared in DMSO.
  • Serial dilutions of the 50 mM stocks are made in DMSO to form additional stock solutions ranging from 20 mM to 0.3125 mM. These stocks are then frozen until needed.
  • the stocks are diluted 1/100 into the final enzyme assay volume at the time of assay.
  • a 10 mM stock solution of the chromogenic substrate is prepared in the 50 mM phosphate buffer, aliquoted and then frozen until time of use.
  • Enzyme Assay- Initial velocity assays are run in a SPECTRAmax 250 microplate spectrophotometer (Molecular Devices Corp., Sunnyvale, CA.). The final composition of the assay solution is 0.05 M sodium phosphate, pH 7.3, 80 mM substrate, inhibitor concentrations ranging up to 500 mM, 1% DMSO, and sufficient enzyme to produce an absorbency change at 421 nm of 0.0015-0.002/ min. The reactions are run at 37 °C. The reaction is followed by recording the increase in absorbency at 421 nm. Inhibitors are pre-incubated with the MAO-A in the reaction mixture for 15 min. prior to starting the reaction. Ki values are determined from the initial velocity data using the following equation.
  • ⁇ ICgo minimum inhibitory concentration required to inhibit 90% of the isolates (lower number is better). 2 Ki for human monoamine oxidase A (higher number is better).
  • the compound of the present invention, or the combination therapy has useful activity against a number of human and veterinary bacterial pathogens.
  • Representative organisms include, but are not limited to, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Streptococcus pyogenes, Chlamydophila pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Clostridium spp., Peptostreptococcus spp., Bacteroides spp, Listeria monocytogenes, Corynebacterium jeikeium, methicillin- resistant Staphylococcus aureus (MRS A), vancomycin-resistant Enterococci (VRE), glycopeptide-intermediate Staphylococcus aureus (GISA), and vancomycin- intermediate Staphylococcus aureus (VISA
  • Skin disease that may be treated using the compounds of the present invention include cutaneous anthrax, cellulites, necrotizing fasciitis, scalded skin syndrome, toxic epidermal necrolysis, furuncles, and erythrasma.
  • Infectious diseases of the eye that may be treated using compounds of the present invention include orbital cellulites, dacrocystitis, blepharitis, hordeolum, bacterial conjunctivitis, and trachoma.
  • an antibacterially effective amount of dosage of the compound of formula I of the present invention will be in the range of about 0.1 to about 400, more preferably about 1.0 to about 50 mg/kg of body weight/day. It is to be understood that the dosages of active component(s) may vary depending upon the requirements of each subject being treated and the severity of the bacterial infection. The desired dose may conveniently be presented in a single dose or as divided into multiple doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired plasma concentration.
  • the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation.
  • compositions of the compound of formula I either individually or may be prepared by methods well known in the art, e.g., by means of conventional mixing, dissolving, granulation, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying.
  • Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the compounds of formula I may be administered parenterally, orally, topically, transdermally, and rectally (e.g., as a suppository).
  • Formulations for systemic administration may be in the form of aqueous solutions and suspensions, in addition to solid tablet and capsule formulations.
  • the aqueous solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Other adjuvants are well and widely known in the pharmaceutical art.
  • the suspensions or solutions for systemic administration may include ⁇ -cyclodextrins, such as Captisol®, as a solubilizing agent.
  • the compositions may, for example, be administered parenterally, e.g., intravascularly, intraperitoneally, subcutaneously, or intramuscularly.
  • parenteral administration e.g., saline solution, dextrose solution, or water may be used as a suitable carrier.
  • Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions.
  • compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound or a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3.5-6.
  • a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3.5-6.
  • Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine to name but a few representative buffering agents.
  • the compound of this invention generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg/mL to about 400 mg/mL of solution.
  • the resulting liquid pharmaceutical composition will be administered so as to obtain the above-mentioned antibacterially effective amount of dosage.
  • the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, solutions, emulsions, gels, syrups, slurries, suspensions, and the like for oral ingestion by a patient.
  • the pharmaceutical composition for therapeutic use may also comprise one or more non-toxic, pharmaceutically acceptable carrier materials or excipients.
  • carrier material or excipient herein means any substance, not itself a therapeutic agent, used as a carrier and/or diluent and/or adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule or tablet suitable for oral administration.
  • Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, glidants, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition.
  • Acceptable excipients include stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, magnesium carbonate, talc, gelatin, acacia gum, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starches, gelatin, cellulosic materials, such as cellulose esters of alkanoic acids and cellulose alkyl esters, low melting wax, cocoa butter or powder, polymers such as polyvinyl- pyrrolidone, polyvinyl alcohol, and polyethylene glycols, and other pharmaceutical acceptable materials.
  • the components pharmaceutical composition can be encapsulated or tableted for convenient administration.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension, or liquid. If desired, other active ingredients may be included in the composition.
  • the suspension or liquid may include other additives such as ⁇ -cyclodextrins, such as Captisol®, which may act as a solubilizing agent.
  • Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Pharmaceutical compositions which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, liquid polyethylene glycols, cremophor, capmul, medium or long chain mono-, di- or triglycerides.
  • suitable liquids such as fatty oils, liquid paraffin, liquid polyethylene glycols, cremophor, capmul, medium or long chain mono-, di- or triglycerides.
  • Stabilizers may be added in these formulations, also.
  • Liquid form compositions include solutions, suspensions and emulsions.
  • solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.
  • the compound of formula I may be in a powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water
  • the compounds may also be formulated by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • Such materials include cocoa butter, beeswax and other glycerides.
  • As a topical treatment an effective amount of formula I is admixed in a pharmaceutically acceptable gel or cream vehicle that can be applied to the patient's skin at the area of treatment.
  • the compound of formula I can be administrated by inhalation provided that the compounds pass into the blood stream.
  • pharmaceutical compositions containing the compound of formula I can be conveniently delivered through an aerosol spray in the form of solution, dry powder, or cream.
  • the aerosol may use a pressurized pack or a nebulizer and a suitable propellant.
  • the dosage unit may be controlled by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin for use in an inhaler may be formulated containing a power base such as lactose or starch. Additionally, the compound of formula I may be delivered using a sustained- release system. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for 24 hours up to several days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed. The compound of formula I may also be delivered by controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropyl- methyl cellulose, or other methods known to those skilled in the art.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention se rapporte à des trifluorphenyl oxazolidinones représentés par la formule (I) ainsi qu'au procédé de synthèse associé. Les composés de l'invention sont des agents antimicrobiens utiles, efficaces contre un certain nombre de troubles pathogènes humains et vétérinaires.
PCT/IB2005/001294 2004-05-20 2005-05-09 2,3,5-trifluorphenyl oxazolidinones substitues a utiliser en tant qu'agents antibacteriens WO2005113520A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US57273804P 2004-05-20 2004-05-20
US57279904P 2004-05-20 2004-05-20
US57280204P 2004-05-20 2004-05-20
US57273904P 2004-05-20 2004-05-20
US60/572,802 2004-05-20
US60/572,739 2004-05-20
US60/572,799 2004-05-20
US60/572,738 2004-05-20

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008038092A2 (fr) 2006-09-25 2008-04-03 Wockhardt Research Centre Pipéridinophényloxazolidinones substituées
WO2009020616A1 (fr) * 2007-08-06 2009-02-12 Micurx Pharmaceuticals, Inc. Orthofluorophényle oxazolidinones antimicrobiennes pour le traitement d'infections bactériennes
WO2009001192A3 (fr) * 2007-06-22 2010-05-27 Orchid Research Laboratories Limited Nouveaux composés et leur utilisation
CN103649081A (zh) * 2011-06-14 2014-03-19 浙江华海药业股份有限公司 合成利伐沙班中间体4-{4-[(5s)-5-(氨基甲基)-2-氧代-1,3-恶唑烷-3-基]苯基}吗啉-3-酮的新方法
JP2014530232A (ja) * 2011-10-11 2014-11-17 カウンシル オブ サイエンティフィク アンド インダストリアル リサーチ オキサゾリジノン誘導体のシラアナログ及びその合成
US9382276B2 (en) 2014-02-21 2016-07-05 Micurx Pharmaceuticals, Inc. Water-soluble O-carbonyl phosphoramidate prodrugs for therapeutic administration
US10947205B2 (en) 2015-10-22 2021-03-16 Merck Sharp & Dohme Corp. Oxazolidinone compounds and methods of use thereof as antibacterial agents
WO2021188606A1 (fr) * 2020-03-20 2021-09-23 Merck Sharp & Dohme Corp. Composé d'oxazolidinone et procédés d'utilisation de celui-ci en tant qu'agent antibactérien

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WO1993023384A1 (fr) * 1992-05-08 1993-11-25 The Upjohn Company Oxazolidinones contenant une fraction diazine substituee et leur utilisation comme antimicrobiens
WO1995007271A1 (fr) * 1993-09-09 1995-03-16 The Upjohn Company Agents antimicrobiens oxazolidinone a substitution oxazine et thiazine
WO2001098297A2 (fr) * 2000-06-16 2001-12-27 Pharmacia & Up John Company Thiazine oxazolidinone
WO2004014897A1 (fr) * 2002-08-12 2004-02-19 Pharmacia & Upjohn Company Llc N-aryl-2-oxazolidinones et leurs derives
WO2004087697A1 (fr) * 2003-04-01 2004-10-14 Pharmacia & Upjohn Company Llc Derives de n-aryl-2-oxazolidinone-5-carboxamide a activite antibacterienne
WO2005028473A1 (fr) * 2003-09-23 2005-03-31 Pharmacia & Upjohn Company Llc Bioprecurseurs acyloxymethylcarbamate des oxazolidinones

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Publication number Priority date Publication date Assignee Title
WO1993023384A1 (fr) * 1992-05-08 1993-11-25 The Upjohn Company Oxazolidinones contenant une fraction diazine substituee et leur utilisation comme antimicrobiens
WO1995007271A1 (fr) * 1993-09-09 1995-03-16 The Upjohn Company Agents antimicrobiens oxazolidinone a substitution oxazine et thiazine
WO2001098297A2 (fr) * 2000-06-16 2001-12-27 Pharmacia & Up John Company Thiazine oxazolidinone
WO2004014897A1 (fr) * 2002-08-12 2004-02-19 Pharmacia & Upjohn Company Llc N-aryl-2-oxazolidinones et leurs derives
WO2004087697A1 (fr) * 2003-04-01 2004-10-14 Pharmacia & Upjohn Company Llc Derives de n-aryl-2-oxazolidinone-5-carboxamide a activite antibacterienne
WO2005028473A1 (fr) * 2003-09-23 2005-03-31 Pharmacia & Upjohn Company Llc Bioprecurseurs acyloxymethylcarbamate des oxazolidinones

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008038092A2 (fr) 2006-09-25 2008-04-03 Wockhardt Research Centre Pipéridinophényloxazolidinones substituées
WO2008038092A3 (fr) * 2006-09-25 2009-08-27 Wockhardt Research Centre Pipéridinophényloxazolidinones substituées
US8288416B2 (en) 2006-09-25 2012-10-16 Wockhardt Ltd. Substituted piperidinophenyl oxazolidinones
WO2009001192A3 (fr) * 2007-06-22 2010-05-27 Orchid Research Laboratories Limited Nouveaux composés et leur utilisation
WO2009020616A1 (fr) * 2007-08-06 2009-02-12 Micurx Pharmaceuticals, Inc. Orthofluorophényle oxazolidinones antimicrobiennes pour le traitement d'infections bactériennes
US8178683B2 (en) 2007-08-06 2012-05-15 Micurx Pharmaceuticals, Inc. Antimicrobial ortho-fluorophenyl oxazolidinones for treatment of bacterial infections
CN103649081B (zh) * 2011-06-14 2016-06-01 浙江华海药业股份有限公司 合成利伐沙班中间体4-{4-[(5s)-5-(氨基甲基)-2-氧代-1,3-恶唑烷-3-基]苯基}吗啉-3-酮的方法
CN103649081A (zh) * 2011-06-14 2014-03-19 浙江华海药业股份有限公司 合成利伐沙班中间体4-{4-[(5s)-5-(氨基甲基)-2-氧代-1,3-恶唑烷-3-基]苯基}吗啉-3-酮的新方法
JP2014530232A (ja) * 2011-10-11 2014-11-17 カウンシル オブ サイエンティフィク アンド インダストリアル リサーチ オキサゾリジノン誘導体のシラアナログ及びその合成
US9382276B2 (en) 2014-02-21 2016-07-05 Micurx Pharmaceuticals, Inc. Water-soluble O-carbonyl phosphoramidate prodrugs for therapeutic administration
US10947205B2 (en) 2015-10-22 2021-03-16 Merck Sharp & Dohme Corp. Oxazolidinone compounds and methods of use thereof as antibacterial agents
WO2021188606A1 (fr) * 2020-03-20 2021-09-23 Merck Sharp & Dohme Corp. Composé d'oxazolidinone et procédés d'utilisation de celui-ci en tant qu'agent antibactérien
CN115605208A (zh) * 2020-03-20 2023-01-13 默沙东有限责任公司（Us） 噁唑烷酮化合物及其作为抗菌剂的使用方法
JP2023507683A (ja) * 2020-03-20 2023-02-24 メルク・シャープ・アンド・ドーム・エルエルシー オキサゾリジノン化合物および抗細菌剤としてのその使用方法
JP7241984B2 (ja) 2020-03-20 2023-03-17 メルク・シャープ・アンド・ドーム・エルエルシー オキサゾリジノン化合物および抗細菌剤としてのその使用方法
TWI799814B (zh) * 2020-03-20 2023-04-21 美商默沙東有限責任公司 噁唑啶酮化合物及其做為抗菌劑之使用方法
AU2021239937B2 (en) * 2020-03-20 2023-10-26 Merck Sharp & Dohme Llc Oxazolidinone compound and methods of use thereof as an antibacterial agent

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