WO2006043121A1 - Derives d'oxazolidinone servant d'antimicrobiens - Google Patents

Derives d'oxazolidinone servant d'antimicrobiens Download PDF

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WO2006043121A1
WO2006043121A1 PCT/IB2004/003439 IB2004003439W WO2006043121A1 WO 2006043121 A1 WO2006043121 A1 WO 2006043121A1 IB 2004003439 W IB2004003439 W IB 2004003439W WO 2006043121 A1 WO2006043121 A1 WO 2006043121A1
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compound
formula
alkyl
oxazolidin
methyl
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PCT/IB2004/003439
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English (en)
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Anita Mehta
Biswajit Das
Sonali Rudra
Ajay Singh Yadav
Sangita Kumari
Mohammad Salman
Ashok Rattan
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Ranbaxy Laboratories Limited
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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
    • C07D413/02—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
    • C07D413/12—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 chain containing hetero atoms as chain links
    • 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 certain substituted phenyl oxazolidinones and to processes for the synthesis of the same.
  • This invention also relates to pharmaceutical compositions containing the compounds of the present invention as antimicrobials.
  • the compounds are useful antimicrobial agents, 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 Bactericides spp. and Clostridia spp. species, and acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
  • Streptococcus pneumoniae is a major pathogen causing pneumonia, sinusitis and meningitis. Until very recently it was highly susceptible to penicillin. Recently though, different PBP 2' strains with different susceptibility to penicillin have been reported from across the globe.
  • Oxazolidinones are a 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 mechanism of action, these compounds are active against pathogens resistant to other clinically useful antibiotics.
  • WO 04/014392 discloses piperazinyl oxazolidinyl acetamide derivatives which are described as antimicrobials.
  • WO 03/008389 discloses substituted phenyl oxazolidinones, which are said to be useful antimicrobial agents, described as 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 Bactericides spp., Clostridium spp. and acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
  • WO 03/007870 discloses oxazolidinone derivatives, which are described as useful antimicrobials agents, said to be effective against number of human and veterinary pathogens.
  • WO 03/072575 discloses 3- cyclyl-5-(nitrogen containing 5-membered ring) methyl oxazolidinone derivatives and their use as antibacterial agents.
  • WO 02/06278 discloses phenyl oxazolidinone derivatives described as antimicrobial agents.
  • J Med. Chem. 2002,45,3953-3962 describes synthesis of conformationally constrained analogues of linezolid, and structure activity relationship (SAR) studies on selected tricyclic oxazolidinones.
  • WO 00/32599 discloses phenyl oxazolidinyl described as antimicrobial agents.
  • Bioorg. Med. Chem. Lett, 9, 2685-2690, (1999) disclose oxazolidinone derivatives, which are apparently active against Gram-positive strains including the resistant strains of Staphylococcus and Enterococcus.
  • WO 99/64416 and WO 99/64417 disclose substituted oxazolidinyl described as antimicrobials agents.
  • J Med. Chem. 4_i (1998), 3727-3735 describes pyridine, diazine, triazine, heteroaromatic rings directly attached to a piperazinyl oxazolidinone core.
  • WO 98/01446 describes 6-membered heteroaryl rings containing 2 or 3 ring nitrogen atoms, attached to a piperazinyl oxazolidinyl core.
  • WO 98/01447 discloses pyridyl rings (optionally- substituted) attached to a piperazinyl oxazolidinyl core.
  • WO 97/10223 describes aminoaryloxazolidinone N- oxides.
  • WO93/23384 application discloses phenyloxazolidinones containing a substituted diazine moieties and their uses as antimicrobial agents.
  • WO93/09103 application discloses substituted aryl and heteroaryl- phenyl ⁇ oxazolidinones said to be useful as antibacterial agents.
  • WO90/02744 application discloses 5-indolinyl-5 ⁇ -amidomethyloxazolidinones, 3-(fused ring substituted) phenyl-5 ⁇ - amidomethyloxazolidinones which are described as useful as antibacterial agents.
  • EP 352,781 discloses phenyl and pyridyl substituted phenyl oxazolidinones.
  • EP 312,000 discloses phenyl methyl and pyridinylmethyl substituted phenyl oxazolidinones.
  • U.S. Patent No. 5,254,577 discloses heteroaromatic nitrogen rings attached to phenyloxazolidinones.
  • U.S. Patent Nos. 5,547,950 and 5,700,799 also disclose phenyl piperazinyl oxazolidinones.
  • U.S. Patent No. 5,719,154 describes substituted or unsubstituted 2-pyrimidinyl, 4-pyrimidinyl, or 3-pyridazinyl rings directly attached to a piperazinyl oxazolidinyl core.
  • U.S. Patent No. 5,736,545 describes azolyl piperazinyl phenyl oxazolidinones which contain azolyl rings as f ⁇ ve-membered heterocyclic rings wherein the piperazine nitrogen atom is attached to the carbon atom of the carbon nitrogen double bond of the five-membered heterocyclic ring.
  • the heterocycle ring contains more than one heteroatom.
  • the f ⁇ ve- membered ring heterocycle (azolyl ring) is of the general formula:
  • A, B, and C are independently oxygen (O), nitrogen (N), sulfur (S) or carbon (C).
  • oxazolidinone molecules that have activity against multiply-resistant Gram-positive pathogens like MRSA, VRE and PRSP are provided. Some of these molecules have activity against MDR-TB and MEAI strains, while others have significant activity against important anaerobic bacteria.
  • U can be hydrogen, optionally substituted C 1-6 alkyl, F, Cl, Br, I, or C 1-12 alkyl substituted with one or more of F, Cl, Br, I.
  • n is an integer 0, 1, 2 or 3.
  • Q can be O, S or NR 11 (wherein R 11 is hydrogen, optionally substituted C 1-12 alkyl, C 3-12 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl carbonyl, C 1-6 alkylcarboxy, aryl or heteroaryl).
  • Compounds disclosed herein can be useful antimicrobial agents, effective against a number of human and veterinary pathogens, particularly aerobic and Gram-positive bacteria, including multiply-antibiotic resistant Staphylococci and Streptococci, as well as anaerobic organisms such as Mycobacterium tuberculosis and other Mycobacterium species.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories and ointments.
  • a solid carrier can be one or more substance which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablets disintegrating agents; it can also be as finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from about 5 to about 70 percent of the active ingredient.
  • suitable solid carriers are lactose, pectin, dextrin, starch, gelatin, tragacanth, low melting wax, cocoa butter and the like.
  • preparation is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it.
  • capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid form preparations include solutions suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems (isotonicity, pH, etc.). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
  • Aqueous suspensions 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 well-known suspending agents.
  • Ointment preparations can contain pharmaceutically acceptable salts of a compound of Formula I with a physiologically acceptable carrier.
  • the carrier is desirably 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.
  • the pharmaceutical preparation can be in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete capsules, powders in vials or ampoules and ointments capsule, cachet, tablet, gel, or cream itself or it can be the appropriate number of any of these packaged forms.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from less than 1 mg to several grams according to the particular application and the potency of the active ingredient.
  • the compounds utilised in the pharmaceutical method of this invention are administered at the initial dosage of about 3 mg to about 40 mg per kilogram daily.
  • the dosages may be varied dependirxg upon the requirements of the patient and the compound being employed. Determination! of the proper dosage for a particular situation is within the smaller dosages, which are less than the optimum dose. Small increments until the optimum effect under the daily dosage may be divided and administered in portions during the day if desired.
  • 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 compound of Formula IV is further deprotected and reacted in situ with compound of Formula V (path a') or VI (path b') to give compounds of Formulae " V 7 II and VIII, respectively (wherein G, Q and het are as defined earlier and hal is halogen selected from Cl, Br, or I).
  • the deprotection of Formula IV can be carried out in the presence of solvent such as dichloromethane, diethyl ether or chloroform in the presence of a reagent such as trifluoroaceticacid or ethanolic hydrochloric acid.
  • reaction of the deprotected compound with a compound of Formula V can be carried out in the presence of a base such as disopropyl-ethylamine or potassium carbonate in a solvent such as acetonitrile or dimethylformarnide to give a compound of Formula VII.
  • a base such as disopropyl-ethylamine or potassium carbonate
  • a solvent such as acetonitrile or dimethylformarnide
  • reaction of the deprotected compound with a compound of Formula VI can be carried out in the presence of a reducing agent such as triacetoxy sodium borohydr ⁇ de or sodium cyanoborohydride and in a solvent such as tetrahydrofuran, ethyl acetate, isopropyl alcohol, dichloromethane or the like, to give compound of Formula VIII.
  • a reducing agent such as triacetoxy sodium borohydr ⁇ de or sodium cyanoborohydride
  • a solvent such as tetrahydrofuran, ethyl acetate, isopropyl alcohol, dichloromethane or the like
  • a compound of Formula I ⁇ can be reacted with compound of Formula IX (where R a is alkyl or aryl)(path b).
  • the reaction can be carried out in presence of a base such as sodium hydride or lithium hydride and in an organic solvent such as dimethyl formamide, acetonitrile, dimethylsufoxide or ethylene glycol to give compound o Jf Formula X, which can be deprotected in the presence of a solvent such as dichloromethane or chloroform in presence of a reagent such as trifluoroaceticacid and ethanolic hydrochloric acid.
  • the deprotected compound is further reacted with a compound of Formula " V
  • Path a A compound of Formula XII (wherein U is as defined earlier) is reacted with a compound of Formula XIII (wherein Rb can be O-het or het and het is as defined earlier) to give a compound of Formula XIV 5 , in the presence of a coupling agent such as diethyl azodicarboxylate or disopropyl azodicarboxylate, and a suitable catalyst such as triphenylphospine, trimethyl phosphine, tributyl phosphine or di-1- adamantyl(butyl)phospbine in a solvent such as tetrahydrofuran or dimetfrylforrnamide.
  • a coupling agent such as diethyl azodicarboxylate or disopropyl azodicarboxylate
  • a suitable catalyst such as triphenylphospine, trimethyl phosphine, tributyl phosphine or di-1
  • Path b A compound of Formula II is reacted with a compound of Formula XIII( where R b is as defined earlier) to give a compound of Formula XIV, in the presence of a base such as sodium hydride or lithium hydride and an organic solvent such as dimethyl formamide, acetonitrile, dimethylacetamide, dimethylsufoxide or ethylene glycol.
  • a base such as sodium hydride or lithium hydride
  • an organic solvent such as dimethyl formamide, acetonitrile, dimethylacetamide, dimethylsufoxide or ethylene glycol.
  • the compound of Formula XIV can be deprotected in the presence of a solvent such as with dichloromethane or chloroform in the presence of reagents such as trifluoroaceticacid and reacted with a compound of Formula VI (wherein G, Q & hal are as defined earlier) in presence of a base such as diisopropoylethylamiine or potassium carbonate and organic solvents such as acetonitrile or dimethylformamide to obtain a compound of Formula XV (wherein G, Q & Rb are as defined earlier).
  • a solvent such as with dichloromethane or chloroform
  • reagents such as trifluoroaceticacid
  • a compound of Formula VI wherein G, Q & hal are as defined earlier
  • a base such as diisopropoylethylamiine or potassium carbonate
  • organic solvents such as acetonitrile or dimethylformamide
  • amine of Formula XVII is converted to corresponding isothiocyanate of Formula XX (Path b), by reacting with carbon disulfide and ethyl chloroformate in the presence of a base such as triethylamine, diisopropoylethylamine or pyridine and an organic solvent such as dichloromethane, dichloroethane or chloroform.
  • a base such as triethylamine, diisopropoylethylamine or pyridine
  • an organic solvent such as dichloromethane, dichloroethane or chloroform.
  • g can be selected from hydrogen or alkyl group) gives a compound of Formula XXI, in trxe presence of a base such as triethylamine or diisopropoylethylamine and an organic solvent such as dichloromethane, dichloroethane or methanol.
  • a base such as triethylamine or diisopropoylethylamine
  • an organic solvent such as dichloromethane, dichloroethane or methanol.
  • the amine of Formula XVII is converted to (un)substituted thiourea of Formula XXTV(Path c), on reaction with (un)substituted isothiocyanate of Formula X)CIII (R d is alkyl or aryl), in the presence of a base such as triethylamine, diisopropylethyl amine or sodium hydride.
  • the compound of Formula XVII (wherein G, Q, U and n are as defined earlier) can be reacted with the acid of Formula XXV (wherein R ⁇ is a substituted heterocyclic group) to give a compound of Formula XXVI (Path a) in the presence of a coupling agent like 1,3-dicyclohexylcarbodimide (DCC) or l-ethyl-3-(3'- dimethylaminopropyl)carbodimide hydrochloride (EDC) in the presence of an additive such as 1-hydroxybenzotriazole (HOBt)or l-hydroxy-7-azabenzotriazole (HOAt) and a base such as N-methylmorpholine, diisopropoylethylamine, or collidine in solvent such as dimethylformamide, tetrahydrofuran or acetonitrile.
  • the compound of Formula XXVII is prepared by reacting a compound of Formula XVII with e
  • the compound of Formula XXX can be reacted with a compound of Formula V in the presence of a base such as diisopropoylethylamine, triethylamine or potassium carbonate and an organic solvent such as acetonitrile or dimethylformamide to yield a compound of Formula XXXI (where G, Q & R x are as defined earlier) which is hydrolysed with hydrochloric acid to give compound of Formula XXXII (where G & Q are as defined earlier).
  • a base such as diisopropoylethylamine, triethylamine or potassium carbonate
  • an organic solvent such as acetonitrile or dimethylformamide
  • Path a The compound of Formula XXXII (wherein G, Q and U are as defined earlier) can be reacted with a compound of Formula XXXIII in the presence of a base such as sodium hydride or lithium hydride and an organic solvent such as dimethyl
  • a compound of Formula XXXVI can be prepared by reacting a compound of Formula XXXII with compound of Formula XXXV (where Rpalkyl/aryl & hal is as defined earlier) in the presence of a base such as sodium hydride or lithium hydride and an
  • a compound of Formula XXXVIII can be prepared by reacting a compound of Formula XXXII with a compound of Formula XXXVII (where R, is alkyl/aryl) in the presence of a coupling agent such as diethyl azodicarboxylate and a catalyst such as triphenylphospine, trimethyl phosphine, tributyl phosphine or di-1- adamantyl(butyl)phosphine in a solvent such as dimethylformamide, toluene or tetrahydrofuran.
  • a coupling agent such as diethyl azodicarboxylate
  • a catalyst such as triphenylphospine, trimethyl phosphine, tributyl phosphine or di-1- adamantyl(butyl)phosphine in a solvent such as dimethylformamide, toluene or tetrahydrofuran.
  • Example 1 Analogues of (5S)-3-(3-fluoro-4- ⁇ 4-r(5-nitro-2-thienyl)rriethyl1piperazm-l- yl ⁇ phenyiy5-r(isoxazol-3-ylammo)methyri-l ,3-oxazolidin-2-one (Core 1)
  • (5S)-3-C3-fluoro-4- ⁇ 4-f(5-nitm-2-thienyl)methylJpiperazin-l-yl ⁇ phenyl)-5-f(isoxazol-3- ylamino)methyl]-l,3-oxazolidin-2-one Compound No. 1
  • Step a Synthesis of (S)-N-(3- ⁇ 3-Fluoro-4-[4-N-(tert-butoxycarbonyl)-piperazin- 1 - ylJphenyll-l-oxo-oxazolidin-S-ylmethy ⁇ -N-Isoxazol-S-yl-N-tert-butoxycarboxamide .
  • Step b Synthesis of tert-butyl 4-(2-fluoro-4- ⁇ (5S)-5-[(isoxazol-3-yla3nmo)methyl]-2-oxo- l,3-oxazolidin-3-yl ⁇ phenyl)piperazine-l-carboxylate:
  • Step c Synthesis of (5S)-3-(3-fluoro-4- ⁇ 4-[(5-nitro-2-thienyl)methyl]piperazin-l- yl ⁇ phenyl)-5-[(isoxazol-3-ylamino)methyl]-l,3-oxazolidin-2-one:
  • Step a Synthesis of tert-butyl 4-f4- ⁇ f5R)-5-rfethylthio)methyl1-2-oxo-L 3-oxazolidin-3- yl ⁇ -2-fluorophenyl)piperazine-l-carboxylate
  • Step b Synthesis of (5RV5-rrethylthio)methyll-3- ⁇ 3-fluoro-4-r4-r5-nitro-2- thienvDpiperazin- 1 -yl]phenyl> - 13 -oxazoridin-2-one
  • Step a Synthesis of tert-butyl 4- ⁇ -fluoro-4- ⁇ (5R)-5-rChe ⁇ tylthio)methyll-2-oxo-l,3- oxazolidm-3-yl ⁇ phenyl)piperazme-l-carboxylate.
  • Step b Synthesis of (5R)-3-(3-fluoro-4-r4-(5-nitro-2-thienyl)piperazin-l-vnphenvU-5- [(heptylthio)methyli - 1 ,3-oxazolidin-2-one
  • Step a Synthesis of tert-butyl 4-(2-fluoro-4- ⁇ (5RV5-r(2-naphthylthio)methyll-2-oxo-L3- oxazolidin-3-vUphenvDpiperazme-l-carboxylate.
  • Step b Synthesis of (5R)-3- ⁇ 3-fluoro-4-r4-( ' 5-nitro-2-thienvnpiperazin-l-yllphenvU-5- r(2-naphthylthio)methyl]-l,3-oxazolidin-2-one
  • tert-butyl 4-(2-fluoro-4- ⁇ (5R)-5-[(2-na ⁇ hthylthio)methyl]-2-oxo- l,3-oxazolidin-3-yl ⁇ phenyl)piperazine-l-carboxylate To a solution of tert-butyl 4-(2-fluoro-4- ⁇ (5R)-5-[(2-na ⁇ hthylthio)methyl]-2-oxo- l,3-oxazolidin-3-yl ⁇ phenyl)piperazine-l-carboxylate.
  • Step a Synthesis of tert-butyl 4-(4- ⁇ (5S)-5-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl] -2-oxo-l, 3-oxazolidin-3-yl ⁇ -2-fluorophenyl)piperazine-l-carboxylate.
  • Step b Synthesis of 5-F4-f4- ⁇ (5SV5-
  • Step a Synthesis of tert-butyl 4- ⁇ 2-fluoro-4-r(5R)-5-(lH-imidazol-l-vhnethvn-2-oxo- l,3-oxazolidin-3-yl]pfaenyl ⁇ piperazine-l-carboxylate.
  • Step b Synthesis of (5R)-3-f3-fluoro-4-f4-( ' 5-nitro-2-thienyl)piperazin-l-vnplienyl>-5- (lH-imidazol-l-ylmethyl)-l,3-oxazolidin-2-one
  • Example 5 Analogues of phenyl [rr5S)-3- ⁇ 3-fluoro-4-r4-(5-nitro-2-thienyl)piperazin-l- yl]phenyl ⁇ -2-oxo-l,3-oxazolidin-5-yl)methyl]carbarnate (Core 5) phenyl [((5S)-3- ⁇ 3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl ⁇ -2-oxo-l,3- oxazolidin-5-yl)methyl] carbamate (Compound No. 18).
  • Step a Synthesis of (5S)-5-(aminomethylV3-(3-fluoro-4-[ " 4-(5-nitro-2-thienyl)piperazin- 1 -vilphenyl) - 1 ,3-oxazolidin-2-one.
  • Step b Synthesis of phenyl f((5S)-3- ⁇ 3-fluoro-4-[ " 4-( ' 5-mtro-2-thienyl)piperazm-l- yl]phenvU -2-oxo-l ,3-oxazolidin-5-yl)methyl]carbamate.
  • Example 7 Analogues of N'-[(C5S)-3- ⁇ 3-fluoro-4-( ' 4-( ' 5-nitro-2-thienyl)piperazm-l- yl]phenyl ⁇ -2-oxo-l ,3-oxazolidin-5-yDmethyll-N,N-dimethylthiourea (Core 7) N'-[((5S)-3- ⁇ 3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl ⁇ -2-oxo-l,3- oxazolidin-5-yl)methyl]-N,N-dimethylthiourea (Compound No. 25).
  • Step a Synthesis of (5R)-3- ⁇ 3-fluoro-4-[4-(5-nitro-2-thienyl ' )piperazin-l-yl]phenyl)-5- (isothiocvanatomethylVl,3-oxazolidin-2-one
  • Step b Synthesis of N'-[(( " 5S)-3- ⁇ 3-fluoro-4-r4-r5-nitro-2-thienyl)piperazin-l-yl]phenvU- 2-oxo- 13 -oxazolidin-5 -vDmethyll -N,N-dimethylthiourea To a solution of (5R)-3- ⁇ 3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl ⁇ -
  • Step b N- ⁇
  • reaction mixture was stirred at the same temperature for 1.5 hrs, and then l-ethyl-3-(3'-dimethylammopropyl)carbodimide hydroch.loride (0.25g) was added to it and stirred at room temperature for 17 hrs.
  • the reaction mixture was quenched with water and extracted with dichloromethane.
  • the organic laryer was dried on sodium sulphate and concentrated under reduced pressure.
  • the crude product obtained was purified by column chromatography using 1% methanol in dichloromethane to get the title compound (75mg).
  • Trie reaction mixture was stirred at the same temperature for 1.5 hrs, then l-ethyl-3-(3'-dirnethylaminopropyl) carbodimide hydrochloride (0.25g) was added to it and then stirred at room temperature for 17 hrs.
  • the reaction mixture was quenched with water and extracted with dichloromethane.
  • the organic layer was dried on sodium sulphate and concentrated under reduced pressure.
  • the crude product obtained was purified by column chromatography using 1% methanol in dichloromethane to get the title compound (80mg).
  • Example 10 Analogues of ((5RV3- ⁇ 3-fluoro-4-r4-(5-nitro-2-thienyl)piperazin-l- yl1phenyl
  • Step a Synthesis of tert-butyl 4-(4- ⁇ ( " 5R)-5-[(acetyloxy)methyll-2-oxo-L3-oxazolidin-3- yl> - ⁇ -fluorophenvDpiperazine- 1 -carboxylate
  • tert-butyl 4- ⁇ 2-fluoro-4-[(5i?)-5-(hydroxymethyl)-2-oxo-l,3- oxazolidm-3-yl] ⁇ henyl ⁇ piperazine-l-carboxylate (10.8 g), prepared as per described in WO 93/23384) in pyridine (22.09 mL) was added acetic anhydride (3.9 ml) and stirred for 17 hrs.
  • Step b Synthesis of ((5RV3- ⁇ 3-fluoro-4-[4-(5-nitro-2-thienyl) ⁇ iperazm-l-yl1phenvU-2- oxo-1 ,3-oxazolidm-5-yr)methyl acetate
  • 3-yl ⁇ -2-fluorophenyl)piperazine-l-carboxylate (0.5g) was added ethanolic-HCl (60 ml, 0.296 N) at 0 0 C and stirred for 6 hrs allowing the reaction mixture to warm to room temperature. The reaction mixture was evaporated and dried. The residue was taken in acetonitrile (20 mL) and to it was added N-ethyl-diisopropylamine (2 mL), 2-bromo-5- nitro-thiophene (0.27 g) and heated at 60 0 C for 30 hrs.
  • Examplel2 Preparation of (5R)-3- ⁇ 3-fluor ⁇ -4-[4-( " 5-m ' tro-2-thienyl)piperazin-l- yliphenyl ⁇ -5-(methoxymethyl)-l ,3-oxazolidin-2-one.
  • the compounds of the invention displayed antibacterial activity when tested by the agar incorporation method.
  • Minimum inhibitory concentrations ( ⁇ g/ml) obtained for representative compounds provided herein were in the ranges given below.
  • Staphylococcus aureus ATCC 25923 from about 0.1 ⁇ g/ml to about 16 ⁇ g/ml.
  • Methicilline Resistant Staphylococcus aureus ATCCl 5187 from about 0.1 ⁇ g/ml to about
  • Methicilline Resistant Staphylococcus aureus ATCC562 from about O.I ⁇ g/ml to about 16 ⁇ g/ml.
  • Methicilline Resistant Staphylococcus aureus ATCC33 from about O.I ⁇ g/ml to about 16 ⁇ g/ml.
  • Enterococcus faecalis ATCC 29212 from about 0.1 ⁇ g/ml to about S ⁇ g/ml.
  • Vancomycin-Resistant enterococci 6 A from about 0.1 ⁇ g/ml to about 8 ⁇ g/ml.
  • Streptococcus pneumoniae ATCC 6303 from about 0.1 ⁇ g/ml to aboTit 4 ⁇ g/ml.
  • Streptococcus pneumoniae AB34 DRSP from about 0.1 ⁇ g/ml to about 8 ⁇ g/ml.
  • Streptococcus pyogenes ATCC 19615 from about 0.1 ⁇ g/ml to about 4 ⁇ g/ml.
  • ICH CFU/spot was transferred into the surface of dried plate and incubated for 1 8 hours (24 hours for MRSN studies). 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.

Abstract

L'invention concerne certaines oxazolidinones phényle substituées et des procédés pour la synthèse de celles-ci. L'invention concerne également des compositions pharmaceutiques contenant les composés de l'invention, servant d'antimicrobiens. Ces composés constituent des agents antimicrobiens utiles, ils sont efficaces contre un certain nombre de pathogènes humains et vétérinaires, notamment des bactéries aérobies Gram positives, notamment des staphylocoques, des streptocoques et des entérocoques multirésistants, ainsi que des organismes anaérobies, notamment les espèces Bacterioides spp. et Clostridia spp., et des organismes rapides acides, notamment Mycobacterium tuberculosis, Mycobacterium avium et Mycobacterium spp.
PCT/IB2004/003439 2004-10-20 2004-10-20 Derives d'oxazolidinone servant d'antimicrobiens WO2006043121A1 (fr)

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WO2011014774A1 (fr) * 2009-07-31 2011-02-03 Global Alliance For Tb Drug Development Nitroimidazooxazines et leurs utilisations en thérapie antituberculeuse
CN103420997A (zh) * 2013-09-07 2013-12-04 吉首大学 吡咯酮-胺甲基-噁唑烷酮型化合物及其制法和用途
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US8841306B2 (en) 2008-11-20 2014-09-23 Panacea Biotec Ltd. Antimicrobials
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WO2015127316A1 (fr) 2014-02-21 2015-08-27 Micurx Pharmaceuticals, Inc. Promédicaments à base de o-carbonyl phosphoramidate pour l'administration thérapeutique
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