WO2006051408A1 - Derives d'oxazolidinone comme antimicrobiens - Google Patents

Derives d'oxazolidinone comme antimicrobiens Download PDF

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Publication number
WO2006051408A1
WO2006051408A1 PCT/IB2005/003390 IB2005003390W WO2006051408A1 WO 2006051408 A1 WO2006051408 A1 WO 2006051408A1 IB 2005003390 W IB2005003390 W IB 2005003390W WO 2006051408 A1 WO2006051408 A1 WO 2006051408A1
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formula
compound
alkyl
aryl
cycloalkyl
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PCT/IB2005/003390
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English (en)
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Biswajit Das
Ajay Singh Yadav
Shahadat Ahmed
Arti Gujrati
Soma Ghosh
Ashok Rattan
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Ranbaxy Laboratories Limited
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Publication of WO2006051408A1 publication Critical patent/WO2006051408A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • novel substituted phenyloxazolidinones and to processes for the synthesis thereof.
  • pharmaceutical compositions comprising one or more compounds described herein.
  • the compounds described can be useful antimicrobial agents, which can be effective against a number of human and veterinary pathogens, including gram- positive aerobic bacteria, such as multiple-resistant staphylococci, streptococci and enterococci, as well as, anaerobic organisms, such as Bacterioides spp. and Clostridia spp. species, and acid fast organisms, such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
  • Oxazolidinones are a new class of synthetic antimicrobial agents, which kill gram- positive pathogens by inhibiting a very early stage of protein synthesis. Oxazolidinones inhibit the formation of ribosomal initiation complex involving 3OS and 5OS ribosomes leading to prevention of initiation complex formation. Due to their novel mechanism of action, these compounds are active against pathogens resistant to other clinically useful antibiotics.
  • novel phenyloxazolidinones derivatives that exhibit antibacterial activity, than available with the present compounds against gram positive pathogens, for example, methicilline resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae (PRSP), multiple drug- resistant tuberculosis (MDR-TB) and MAI sirens; and gram negative pathogens, for example, morazella catarrhalis and haemophilus influenza, to provide safe and effective treatment of bacterial infection.
  • MRSA methicilline resistant Staphylococcus aureus
  • VRE Vancomycin-resistant Enterococci
  • PRSP penicillin-resistant Streptococcus pneumoniae
  • MDR-TB multiple drug- resistant tuberculosis
  • MAI sirens gram negative pathogens
  • morazella catarrhalis and haemophilus influenza to provide safe and effective treatment of bacterial infection.
  • phenyloxazolidinone derivatives which can be used as active agents against multiple resistant gram-positive pathogens, for example, MRSA, VRE, Streptococcus pneumonia and others.
  • Compounds described herein can have activity against MDR-TB strain, as well as activity against anaerobic bacteria.
  • U and V can independently be selected from hydrogen, fluorine or lower (Q-C ⁇ alkyl, wherein both U and V cannot simultaneously be hydrogen;
  • R q can be hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl, and
  • R s can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroarylalkyl or heterocyclylalkyl;
  • Xi-X 2 Q can be * 3 x " , wherein
  • X 1 , X 2 , X 3 and X 4 can be independently selected from -CH-, -CF- or -N- wherein X 1 , X 2 , X 3 and X 4 cannot be the same simultaneously with the exception of -CH-; and
  • R can be aryl, heterocyclyl, heteroaryl or cycloalkyl.
  • compounds selected from: N- ⁇ [(5,S)-3-(3-fluoiO-4- ⁇ 4-[3-fluoro-4-(lH-pyrrol-l-yl)phenyl]piperazm-l- yl ⁇ phenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl ⁇ acetamide (Compound No. 1);
  • compositions comprising a therapeutically effective amount of a compound of Formula I
  • the methods can include one or more of the following embodiments.
  • the microbial infections can be caused by gram-positive and gram-negative bacteria.
  • the gram-positive bacteria can be selected from staphylococcus spp., streptococcus spp., bacillus spp., corynebacterum spp., Clostridia spp., peptostreptococcus spp., listeria spp. or legionella spp.
  • kits for treating or preventing aerobic and anaerobic bacterial infections in a mammal comprising administering to mammal in need thereof a therapeutically effective amount of a compound of Formula I
  • the compound of Formula II can be deprotected to form a compound of Formula III in the presence of hydrochloric acid in ethanol or trifluoroacetic acid in dichloromethane.
  • the compound of Formula III can be coupled with a compound of Formula IV to form a compound of Formula V in the presence of one or more organic or inorganic bases selected from amines, pyridines, morpholines, Group I carbonates, Group II carbonates or mixtures thereof.
  • the one or more organic or inorganic bases can be selected from N,N-diisopropylethylamine, triethylamine, 4- dimethylaminopyridine, N-methyl morpholine, potassium carbonate or mixtures thereof.
  • the compound of Formula V can be reduced to form a compound of Formula VI using hydrazine hydrate.
  • the compound of Formula V can be reduced to form a compound of Formula VI in the presence of one or more catalysts selected from Raney nickel, platinum, platinum metal complexes, palladium catalysts or mixtures thereof.
  • the compound of Formula VI can be cyclized with 2,5-dimethoxytetrahydrofuran to form a compound of Formula VII in the presence of one or more reagents selected from one or more organic acids, one or more organic anhydrides or mixtures thereof.
  • the one or more reagents can be selected from acetic acid, acetic anhydride or mixtures thereof.
  • These processes can include one or more of the following embodiments.
  • the compound of Formula III can be coupled with the compound of Formula VIII in the presence of one or more organic or inorganic bases selected from amines, pyridines, morpholines, Group I carbonates, Group II carbonates or mixtures thereof.
  • the one or more organic or inorganic bases can be selected from triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, N-methyl morpholine, potassium carbonate or mixtures thereof.
  • the compound of Formula IX can be coupled with tosyl methyl isocyanide to yield a compound of Formula X in the presence of one or more bases selected from Group I carbonates, Group II carbonates or mixtures thereof.
  • the one or more bases can be selected from sodium carbonate, potassium carbonate, cesium carbonate or mixtures thereof.
  • the compound of Formula III can be coupled with the compound of Formula XI to form the compound of Formula XII in the presence of one or more organic or inorganic bases selected from amines, pyridines, morpholines, Group I carbonates, Group II carbonates or mixtures thereof.
  • the one or more organic or inorganic bases can be selected from triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, N-methyl morpholine, potassium carbonate or mixtures thereof.
  • the compound of Formula XII can be cyclized with sodium azide to form the compound of
  • Formula XIII in the presence of one or more salts selected from triethylamine hydrochloride, ammonium chloride, sodium chloride, or mixtures thereof.
  • the compound of Formula XIII can be rearranged to form the compound of Formula XIV in the presence of one or more reagents selected from one or more organic acids, one or more organic anhydrides or mixtures thereof.
  • the one or more reagents can be selected from acetic anhydride, acetic acid or mixtures thereof.
  • the compound of Formula III can be coupled with the compound of Formula XV to form the compound of Formula XVI in the presence of one or more bases selected from Group I carbonates, Group II carbonates or mixtures thereof.
  • the one or more bases can be selected from sodium carbonate, potassium carbonate, cesium carbonate or mixtures thereof.
  • the compound of Formula XVI can be coupled with the compound of Formula XVII to form the compound of Formula XVIII in the presence of one or more bases selected from Group I carbonates, Group II carbonates or mixtures thereof.
  • the one or more bases can be selected from sodium carbonate, potassium carbonate, cesium carbonate or mixtures thereof.
  • the compound of Formula XVI can be coupled with the compound of Formula XVII to form the compound of Formula XVIII in the presence of one or more palladium catalysts.
  • the one or more palladium catalysts can be selected from tetrakistriphenylphosphine palladium (0) or in a mixture palladium diacetate, triphenyl phosphine or mixtures thereof.
  • U and V are independently selected from hydrogen, fluorine or lower (C 1 -C 6 ) alkyl, wherein both U and V cannot be hydrogen at the same time;
  • Rj is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl,
  • R f is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl,
  • T is O, S, -N(CN), -N(NO 2 ), or -CH(NO 2 ),
  • R q is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl, and
  • R s is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroarylalkyl or heterocyclylalkyl;
  • Q is -D X3 X4 - , wherein X 1 , X 2 , X 3 and X 4 can be independently selected from -CH-, -CF- or -N- and X 1 , X 2 ,
  • R is aryl, heterocyclyl, heteroaryl or cycloalkyl.
  • U and V are independently selected from hydrogen, fluorine or lower (C 1 -C 6 ) alkyl, wherein both U and V cannot be hydrogen at the same time;
  • R 1 is azido, NCS, OR j;
  • Rj is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl,
  • T is O, S, -N(CN), -N(NO 2 ), or -CH(NO 2 ),
  • Rf is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl,
  • R q is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl,
  • X 1 , X 2 , X 3 and X 4 can be independently selected from -CH-, -CF- or -N- and X 1 , X 2 , X 3 and X 4 cannot simultaneously be the same with the exception of -CH-;
  • R is aryl, heterocyclyl, heteroaryl or cycloalkyl.
  • Compounds described herein can be useful antimicrobial agents, and in particular effective against a number of human and veterinary pathogens, including aerobic and Gram- positive bacteria, for example, multiply-antibiotic resistant staphylococci and streptococci, as well as anaerobic organisms, for example, Mycobacterium tuberculosis and other mycobacterium species.
  • Pharmaceutical compositions for use in the methods described herein may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with pharmaceutically acceptable liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • Solid form preparations include powders, tablets, pills, dispersible granules, dragees, capsules, cachets, suppositories, troches, patches, gel caps, magmas, lozenges, creams, pastes, plasters, lotions, discs, or ointments.
  • Liquid form preparations include solutions, suspensions, emulsions, microemulsions, syrups, elixirs, aerosols, nasal spays or oral sprays.
  • Solid carriers can include one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or disintegrating agents. Solid carriers can also include finely divided solids, which can be in admixture with one or more finely divided compounds described herein. In preparing tablets, one or more compounds described herein can be mixed with one or more carriers having the necessary binding properties in suitable proportions and compacted into the desired shape and size. In some embodiments, powders and tablets can contain from about 5 to about 70 percent of one or more compounds described herein.
  • Suitable solid carriers include, for example, sucrose, glucose, lactose, pectin, mannitol, silicic acid, dextrin, starch, gelatin, tragacanth, low melting wax, cocoa butter sugars, sodium citrate, dicalcium phosphate, microcrystalline cellulose, granulating agents, lubricants, binders, disintegrating agents, absorption accelerators, wetting agents, adsorbents and the like.
  • Binders include, for example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, acacia; disintegrating agents include, for example, agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates and sodium carbonate; absorption accelerators include, for example, quaternary ammonium compounds; wetting agents include, for example, cetyl alcohol, glycerol mono stearate; adsorbents include, for example, Kaolin; lubricants include, for example, talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate and mixture thereof.
  • the dosage form may also comprise buffering agents.
  • a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with one or more binders, lubricants, inert diluents, surface active or dispersing agents.
  • Molded tablets may be made by molding, in a suitable machine, a mixture of a powdered form of one or more compounds moistened with one or more inert liquid diluents.
  • active compounds can be mixed with water or other solvent, solubilizing agents and emulsifiers, for example, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oil), glycerol, fatty acid esters of sorbitan or mixtures thereof.
  • solubilizing agents and emulsifiers for example, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oil), glycerol,
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents and thickening agents as desired.
  • Aqueous suspension suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, for example, natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and other suspending agents.
  • Other liquid form preparations include, for example, water or water- propylene glycol solutions for parenteral injection.
  • injectable preparations for example, sterile injections, injectable depot forms, aqueous suspensions may be formulated according to the art using suitable dispersing or wetting and suspending agent.
  • suitable dispersing or wetting and suspending agent include water, Ringer's solution and isotonic sodium chloride.
  • Such solutions are prepared so as to be acceptable to biological systems with respect to isotonicity, pH, and other parameters.
  • Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • Ointment preparations can contain one or more compounds described herein or salts thereof with a physiologically acceptable carrier.
  • Such salts can be heavy metal salts.
  • the carrier can desirably be a conventional water-dispersible hydrophilic or oil-in-water carrier, particularly a conventional semi-soft or cream-like water-dispersible or water soluble, oil-in- water emulsion infected surface with a minimum of discomfort.
  • Suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment.
  • Dosage forms for tropical or transdermal administration of one or more compounds described herein includes ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Active compounds can be admixed under sterile condition with one or more pharmaceutically acceptable carriers and any desired preservatives or buffers as may be required. Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also encompassed within the scope of this invention.
  • the pharmaceutical preparation can be in unit dosage form.
  • the preparation can be subdivided into unit doses containing appropriate quantities of the active component, i.e., one or more compounds described herein and optionally one or more other therapeutic agents.
  • Dosage forms can be a packaged preparation containing one or more discrete unit dosages, for example, capsules, tablets, powders in vials, capsules or ampoules, ointments, cachets, gels or gel caps, cream itself, dispersible granules, suppositories, troches, patches, magmas, lozenges, pastes, plasters, lotions, discs, ointments, solutions, suspensions, emulsions, syrups, elixirs, aerosols, nasal spays or oral sprays.
  • a prophylactic or therapeutic dose of one or more compounds described herein in the acute or chronic prevention, treatment, or management of a disorder or condition will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • Suitable total daily dose ranges can be readily determined by those skilled in the art. In general, the total daily dose range for one or more compounds described herein, for the conditions described herein, is from about 1 mg to about several grams administered in single or divided doses according to the particular application and the potency of the active ingredient.
  • Compounds described herein can also be administered at initial dosages of about 3 mg to about 40 mg per kilogram daily. Suitable dosage amounts can be determined using small dosages that are less than the optimum dose.
  • Dosage amounts may be divided and administered as divided doses if desired.
  • any suitable route of administration may be employed for providing the patient with an effective dosage of one or more compounds described herein according to the methods of the present invention.
  • oral, intraoral, rectal, parenteral, epicutaneous, transdermal, subcutaneous, intramuscular, intranasal, sublingual, buccal, intradural, intraocular, intrarespiratory, or nasal inhalation and like forms of administration may be employed.
  • Oral administration is generally preferred.
  • the compound for use in the methods of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598, 123; and 4,008,719, the disclosures of which are incorporated herein by reference.
  • compositions described herein may be formed with inorganic or organic acids by methods well-known in the art.
  • the present invention also includes within its scope prodrugs of the compounds of Formula I.
  • prodrugs will be functional derivatives of these compounds, which readily get converted in vivo into defined compounds.
  • Conventional procedures for the selection and preparation of suitable prodrugs are known to the artisan of ordinary skill in the art.
  • the invention also includes pharmaceutically acceptable salts, pharmaceutically acceptable solvates, the enantiomers, diastereomers, N-oxides, prodrugs, metabolites in combination with a pharmaceutically acceptable carrier and optionally included excipients.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms.
  • Alkyl groups can be optionally interrupted by atom(s) or group(s) independently selected from oxygen, sulfur, a phenylene, sulphinyl, sulphonyl group or -NR a -, wherein R a can be hydrogen, alkyl, alkenyl, alkynyl cycloalkyl or aryl.
  • This term can be exemplified by groups such as methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n- hexyl, n-decyl, tetradecyl, and the like.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans, or geminal geometry. It can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -NR a -, wherein R 3 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl. In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms.
  • R 3 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl. In the event that alkynyl is attached to a heteroatom, the triple bond cannot be alpha to the heteroatom.
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefmic bonds, unless otherwise constrained by the definition.
  • Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures, including adamantanyl, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like.
  • alkoxy denotes the group O-alkyl wherein alkyl is the same as defined above.
  • aryl herein refers to aromatic system having 6 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups.
  • the aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
  • Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
  • aryloxy denotes the group O-aryl wherein aryl is the same as defined above.
  • heteroaryl refers to an aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic or tricyclic aromatic group having from 8 to 14 ring atoms, with one or more heteroatom(s) independently selected from N, O or S.
  • the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring.
  • heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, or benzoxazolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl, quinazonyl, carbazolyl phenothiazinyl, phen
  • Such ring systems can be mono-, bi- or tricyclic. Carbonyl or sulfonyl group can replace carbon atom(s) of heterocyclyl. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s).
  • heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, benzoxazinyl, benzthiazinyl, imidazolyl, benzimidazolyl, tetrazolyl, carbaxolyl, indolyl, phenoxazinyl, phenothiazinyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, thiazolidinyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl, tetrahydropyranyl, piperazinyl, 3H-imidazo[4,5- bjpyridine, isoquinolinyl, lH-pyrrolo[2,3-b]pyridine, and the like.
  • Heteroarylalkyl refers to alkyl-heteroaryl group linked through alkyl portion, wherein the alkyl and heteroaryl are the same as defined earlier.
  • Heterocyclylalkyl refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are the same as defined earlier.
  • protecting groups refers to moieties that prevent chemical reaction at a location of a molecule intended to be left unaffected during chemical modification of such molecule. Unless otherwise specified, protecting groups may be used on groups, such as hydroxy, amino, or carboxy. Examples of protecting groups are found in T. W. Greene and P.G.M. Wuts, "Protective.Groups in Organic Synthesis", 2 nd Ed., John Wiley and Sons, New York, N. Y., which is incorporated herein by reference. The species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting groups employed are not critical, as long as the derivatized moieties/moiety is/are stable to conditions of subsequent reactions and can be removed without disrupting the remainder of the molecule.
  • pharmaceutically acceptable salts refers to derivatives of compounds that can be modified by forming their corresponding acid or base salts.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acids salts of basic residues (such as amines), or alkali or organic salts of acidic residues (such as carboxylic acids), and the like.
  • the present invention encompasses all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • Isotopes of carbon include C- 13 and C- 14.
  • the compounds describe herein can contain one or more asymmetric carbon atoms and thus can occur as racemates/racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention.
  • Each stereogenic carbon may be of the R or S configuration.
  • the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are envisioned as part of the invention.
  • amino acids and amino acid side chains may be depicted in a particular configuration, both natural and unnatural forms are envisioned as part of the invention.
  • the compounds described herein may be prepared by techniques well-known in the art. In addition, the compounds described herein may be prepared by the following reaction sequences depicted in Schemes I, II, III and FV below.
  • Compounds of Formula VII can be prepared following Scheme I.
  • compounds of Formula II can be deprotected to form compounds of Formula III, wherein U, V and R 1 are as defined earlier.
  • Compounds of Formula III can be coupled with compounds of Formula IV to yield compounds of Formula V, wherein Hal can be Cl, F or Br; and U, V, R 1 and Q are same as defined earlier.
  • Compounds of Formula V can be reduced to form compounds of Formula VI, wherein U, V, Q and R 1 are as defined earlier.
  • Compounds of Formula VI can be reacted with 2,5-dimethoxytetrahydofuran to form compounds of Formula VII, wherein U, V, Q and R 1 are as defined earlier.
  • Compounds of Formula II can be deprotected to form compounds of Formula III in the presence of one or more acids.
  • acids include inorganic acids, for example, hydrochloric acid or organic acids, for example, trifluoroacetic acid.
  • the deprotection reactions can be carried out in the presence of, for example, hydrochloric acid in ethanol or trifluoroacetic acid in dichloromethane.
  • Compounds of Formula III can be coupled with compounds of Formula IV to form compounds of Formula V in the presence of one or more organic or inorganic bases, for example, amines, pyridines (substituted or unsubstituted), morpholines, Group I or Group II carbonates, or mixtures thereof.
  • bases include N 5 N- diisopropylethylamine, triethylamine, 4-dimethylammopyridine, N-methyl morpholine, potassium carbonate or mixtures thereof.
  • organic solvents for example, dimethylsulphoxide, dimethylformamide, N-methyl-2- pyrrolidone or mixtures thereof.
  • Compounds of Formula V can be reduced to form compounds of Formula VI with hydrazine hydrate.
  • the reduction reaction can also be carried out in the presence of one or more catalysts, for example, Raney nickel, platinum or platinum metal complexes, palladium catalysts (e.g. Pd/C) or mixtures thereof.
  • catalysts for example, Raney nickel, platinum or platinum metal complexes, palladium catalysts (e.g. Pd/C) or mixtures thereof.
  • Pd/C palladium catalysts
  • organic solvents for example, alcohols, e.g., methanol, ethanol or mixtures thereof.
  • Compounds of Formula V can also be reduced to form compounds of Formula VI using one or more reducing agents known in the art, for example, amalgamated magnesium and titanium tetrachloride in tetrahydrofuran/tert-butanol, zinc-hydrazinium monoformate, ferrous hydroxide, one or more palladium catalysts or mixtures thereof.
  • reducing agents known in the art, for example, amalgamated magnesium and titanium tetrachloride in tetrahydrofuran/tert-butanol, zinc-hydrazinium monoformate, ferrous hydroxide, one or more palladium catalysts or mixtures thereof.
  • Compounds of Formula VI can be cyclized with 2,5-dimethoxytetrahydrofuran to form compounds of Formula VII in the presence of one or more reagents, for example, organic acids, organic anhydrides (e.g., acetic acid, acetic anhydride or mixtures thereof) or mixture thereof.
  • one or more reagents for example, organic acids, organic anhydrides (e.g., acetic acid, acetic anhydride or mixtures thereof) or mixture thereof.
  • Formula III can be coupled with compounds of Formula VIII to form compounds of Formula IX, wherein Hal can be fluorine, chlorine or bromine and U, V, Q and R 1 are as defined earlier.
  • Compounds of Formula IX can be reacted with tosyl methyl isocyanide to form compounds of Formula X, wherein Q, U, V and R 1 are as defined earlier.
  • Compounds of Formula III can be coupled with compounds of Formula VIII in the presence of one or more organic or inorganic bases, for example, amines, pyridines (substituted or unsubstituted), morpholines, Group I or Group II carbonates, or mixtures thereof.
  • bases include N,N-diisopropylethylamine, triethylamine, 4- dimethylaminopyridine, N-methyl morpholine, potassium carbonate or mixtures thereof.
  • the coupling reactions can also be carried out in one or more organic solvents, for example, dimethylsulphoxide, dimethyl formamide, N-methyl-2-pyrrolidone or mixtures thereof.
  • Compounds of Formula IX can be reacted with tosyl methyl isocyanide to form compounds of Formula X in the presence of one or more organic or inorganic bases, for example, sodium carbonate, potassium carbonate, cesium carbonate or mixtures thereof. This reaction can also be carried out in one or more organic solvents, for example, methanol, n- propanol, 1,4-dioxane, acetone or mixtures thereof.
  • organic or inorganic bases for example, sodium carbonate, potassium carbonate, cesium carbonate or mixtures thereof.
  • organic solvents for example, methanol, n- propanol, 1,4-dioxane, acetone or mixtures thereof.
  • Compounds of Formula XIV can be prepared following Scheme III.
  • compounds of Formula III can be coupled with compounds of Formula XI to obtain compounds of Formula XII, wherein Hal can be fluorine, chlorine or bromine and U, V, Q and R 1 are as defined earlier.
  • Compounds of Formula XII can be reacted with sodium azide to form compounds of Formula XIII, wherein U, V, Q and R 1 are as defined earlier.
  • Compounds of Formula XIII can be reacted with acetic anhydride to form compounds of Formula XIV, wherein U, V, Q and R 1 are as defined earlier.
  • Compounds of Formula III can be coupled with compounds of Formula XI to form compounds of Formula XII in the presence of one or more organic or inorganic bases, for example, amines, pyridines, morpholines, Group I or Group II carbonates or mixtures thereof.
  • organic or inorganic bases for example, amines, pyridines, morpholines, Group I or Group II carbonates or mixtures thereof.
  • bases include N,N-diisopropylethylamine, triethylamine, 4- dimethylaminopyridine, N-methyl morpholine, potassium carbonate or mixtures thereof.
  • the coupling reaction can also be carried out in one or more organic solvents, for example, dimethylsulphoxide, dimethylformamide or mixtures thereof.
  • Compounds of Formula XII can be cyclized with sodium azide to form compounds of Formula XIII in the presence of one or more salts, for example, hydrochloride or chloride salts.
  • Suitable salts include, for example, triethylamine hydrochloride, ammonium chloride, sodium chloride or mixtures thereof.
  • the cyclization reactions can also be carried out in one or more organic solvents, for example, benzene, toluene, dimethyl formamide or mixtures thereof.
  • Compounds of Formula XIII can be rearranged to form compounds of Formula XIV in the presence of one or more reagents, for example, organic acids, organic anhydrides (e.g., acetic anhydride, acetic acid or mixtures thereof) or mixtures thereof.
  • reagents for example, organic acids, organic anhydrides (e.g., acetic anhydride, acetic acid or mixtures thereof) or mixtures thereof.
  • Compounds prepared following Scheme III include, for example:
  • Compounds of Formula XVIII can be prepared following Scheme IV.
  • compounds of Formula III can be coupled with compounds of Formula XV to form compounds of Formula XVI, wherein Hal can be fluorine, chlorine or bromine and U, V, Q and R 1 are as defined earlier.
  • Compounds of Formula XVI can be coupled with compounds of Formula XVII to form compounds of Formula XVIII, wherein R 3 can be aryl or heteroaryl, and U, V, Q and R 1 are as defined earlier.
  • Compounds of Formula III can be coupled with compounds of Formula XV to form compounds of Formula XVI in the presence of one or more bases, for example, Group I carbonates and Group II carbonates, e.g., sodium carbonate, potassium carbonate, cesium carbonate or mixtures thereof.
  • the coupling reaction can also be carried out in one or more organic solvents, for example, N-methyl pyrrolidinone, dimethylformamide or mixtures thereof.
  • Compounds of Formula XVI can be coupled with compounds of Formula XVII to form compounds of Formula XVIII in the presence of one or more bases, for example, amines, Group I carbonates or Group II carbonates, e.g., triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, and in the presence of one or more catalysts, for example, palladium catalysts, e.g., tetrakistriphenylphosphine palladium (0) or in a mixture palladium diacetate and triphenyl phosphine.
  • bases for example, amines, Group I carbonates or Group II carbonates, e.g., triethylamine, sodium carbonate, potassium carbonate, cesium carbonate
  • catalysts for example, palladium catalysts, e.g., tetrakistriphenylphosphine palladium (0) or in a mixture palladium diacetate and triphenyl phosphine.
  • the coupling reaction can also be carried out in one or more organic solvents, for example, polar solvents, e.g., methanol, ethanol, n-propanol, 1,4-dioxane, acetone or mixtures thereof.
  • organic solvents for example, polar solvents, e.g., methanol, ethanol, n-propanol, 1,4-dioxane, acetone or mixtures thereof.
  • polar solvents e.g., methanol, ethanol, n-propanol, 1,4-dioxane, acetone or mixtures thereof.
  • Step b Synthesis of N-
  • Step c Synthesis of N-rfr5SV3- ⁇ 4-r4-( " 4-amino-3-fluorophenvDpiperazin-l-yl1-3- fluorophenyl
  • Raney nickel 0.5 g in methanol was added to a solution of the compound obtained from step b above (850 mg) in methanol (50 mL) followed by dropwise addition of a solution of hydrazine hydrate (1.0 mL) in methanol over a period of about 1 h.
  • the reaction mixture was stirred at room temperature for 4 h and filtered through a celite pad. The resulting filtrate was evaporated under vacuum to yield the title compound (800 mg).
  • Step d Synthesis of N- ⁇ [(5S)-3-(3-fluoro-4- ⁇ 4-f3-fluoro-4-('lH-pyrrol-l-yl)phenyllpiperazin-
  • Step a Synthesis of N-[((5SV3- ⁇ 3-fluoro-4-r4-(3-fluoro-4-formylphenyl)piperazin-l- yl1phenvU-2-oxo-l,3-oxazolidin-5-vDmethyl]acetamide.
  • Step b Synthesis of N- ⁇ rr5SV3-r3-fluoro-4- ⁇ 4-r3-fluoro-4-n,3-oxazol-5- yl)phenyl]piperazin- 1 -yl ⁇ phenylV2-oxo- 1 ,3-oxazolidin-5-yllmethyl
  • Step a Synthesis of N-
  • Step b Synthesis of N-([r5SV3-f3-fluoro-4-i4-r3-fluoro-4-(lH-tetrazol-l- vDphenyllpiperazm-l-yllphenylV2-oxo-l,3-oxazolidin-5-yl "
  • Sodium azide (0.428 g) and ammonium chloride (0.352 g) was added to a solution of compound obtained from step a above (1.2 g) in dimethylformamide (10 mL). The reaction mixture was stirred at 100-110 0 C for about 6 h and filtered and washed with dimethylformamide (10 mL).
  • Step c Synthesis of N4rf5SV3-f3-fluoro-4-(443-fluoro-4-f5-methyl-1.3.4-oxadiazol-2- yDphenylipiperazin-l-yllphenvD- ⁇ -oxo-l.S-oxazolidin-S-yllmethyllacetamide
  • step b above The compound (0.450 g) obtained from step b above was refluxed with acetic anhydride (10 niL) for about 4h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product thus obtained was purified through column chromatography using 3 % methanol in dichloromethane as eluant and the solvent was evaporated in vacuo. The compound thus obtained was triturated with ether to yield the title compound (0.060 g).
  • Step a Synthesis of N-
  • Step b Synthesis of N- ⁇ r(5SV3-( ' 3-fluoro-4-(4-r5-( ' 3-furv ⁇ pyrimidin-2-yllpiperazin-l- yllphenylV2-oxo-L3-oxazolidin-5-yl]methyl ⁇ acetamide
  • a solution of the compound obtained from step a above (250 mg) and furan-3-boronic acid (101 mg) in «-propanol (30 mL) was degassed with argon for 15 minutes.
  • Palladium diacetate (40.2 mg) and triphenyl phosphine (142.5 mg) were added and the reaction mixture was degassed with argon for 15 minutes.
  • the in vitro antibacterial activity of the compounds was demonstrated by the agar dilution method (NCCLS M 7-A5 and M 100-S8 documents). Briefly, the compounds were dissolved in dimethylsulphoxide and doubling dilution of the compounds was incorporated into Muller Hilton agar before solidification. Inoculum was prepared by direct colony suspension in normal saline solution and adjusting the turbidity to 0.5 Macfarland turbidity and subsequently diluting as per NCCLS guidelines in order to obtain 10 ⁇ CFU/spot.
  • CFU/mL of few randomly selected cultures was performed.
  • the cultures were replicated on agar plate using Denley's multipoint replicator.
  • the agar plates were incubated for 18 hours- 24 hours (24 hours for MRSA studies) at 35+ 2 0 C. Q.C. strains were also included in each run of the study.
  • NCCLS method Inoculum was prepared by direct colony suspensions in normal saline and adjusted to 1 McFarland turbidity and subsequently diluted in broth 100 times as per NCCLS guidelines in order to obtain 105 CFU/spot.
  • the concentration showing no growth of the inoculated culture was recorded as the MIC.
  • Appropriate ATCC standard strains were simultaneously tested and result recorded only when the MICs against standard antibiotics were within the acceptable range.
  • S.aureus MRSA ATCC33 Metal-reactive Staphylococcus aureus ATCC33; MIC was 0.5-2 ⁇ g/mL and even 0.5-1 ⁇ g/mL with Linezolid 2 ⁇ g/mL.
  • Ent. faecalis ATCC 29212 Enter oco ecus faecalis ATCC 29212; MIC was 0.5-2 ⁇ g/mL and even 0.5-1 ⁇ g/mL with Linezolid 2 ⁇ g/mL.
  • VRE Vancomycin-resistant enterococci ATCC 6A; MIC was 0.5-2 ⁇ g/mL and even 0.5-1 ⁇ g/mL with Linezolid 2 ⁇ g/mL. Strep.pyog. ATCC 19615 -Streptococcus pyogenes ATCC 19615; MIC was 0.25-8 ⁇ g/mL, 0.25-2 ⁇ g/mL, and even 0.25-1 ⁇ g/mL with Linezolid 2 ⁇ g/mL. iS ⁇ rep. /wem.
  • M.c ⁇ tf. Moraxella catarrhalis ATCC 8176; MIC was 2-16 ⁇ g/mL and even 2-4 ⁇ g/mL with Linezolid 2 ⁇ g/mL.

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Abstract

L'invention concerne des phényloxazolidinones substituées et des procédés pour leur synthèse, ainsi que des compositions pharmaceutiques renfermant un ou plusieurs composés décrits, lesquels peuvent être utiles comme agents antimicrobiens, c'est-à-dire efficaces contre un certain nombre de pathogènes humains et vétérinaires, y compris les bactéries aérobies gram-positives du type staphylocoques, streptocoques et entérocoques multi-résistants, ainsi que les organismes anaérobies du type espèces Bacterioides spp. et Clostridia spp., et les organismes acido-résistants tels que Mycobacterium tuberculosis, Mycobacterium avium et Mycobacterium spp.
PCT/IB2005/003390 2004-11-11 2005-11-10 Derives d'oxazolidinone comme antimicrobiens WO2006051408A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11555033B2 (en) 2020-06-18 2023-01-17 Akagera Medicines, Inc. Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof
US12116361B2 (en) 2022-12-01 2024-10-15 Akagera Medicines, Inc. Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0883611A1 (fr) * 1996-02-26 1998-12-16 PHARMACIA & UPJOHN COMPANY Antimicrobiens a base d'azolyl piperazinyl phenyl oxazolidone
WO2004014392A1 (fr) * 2002-07-29 2004-02-19 Ranbaxy Laboratories Limited Derives d'oxazolidinone utilises comme agents antimicrobiens
WO2004089944A1 (fr) * 2003-04-07 2004-10-21 Ranbaxy Laboratories Limited Derives d'oxazolidinone comme antimicrobiens

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0883611A1 (fr) * 1996-02-26 1998-12-16 PHARMACIA & UPJOHN COMPANY Antimicrobiens a base d'azolyl piperazinyl phenyl oxazolidone
WO2004014392A1 (fr) * 2002-07-29 2004-02-19 Ranbaxy Laboratories Limited Derives d'oxazolidinone utilises comme agents antimicrobiens
WO2004089944A1 (fr) * 2003-04-07 2004-10-21 Ranbaxy Laboratories Limited Derives d'oxazolidinone comme antimicrobiens

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11555033B2 (en) 2020-06-18 2023-01-17 Akagera Medicines, Inc. Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof
US11566023B2 (en) 2020-06-18 2023-01-31 Akagera Medicines, Inc. Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof
US12116361B2 (en) 2022-12-01 2024-10-15 Akagera Medicines, Inc. Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof

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