WO2002020515A1 - Agents antibacteriens a l'oxazolidinone - Google Patents

Agents antibacteriens a l'oxazolidinone Download PDF

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Publication number
WO2002020515A1
WO2002020515A1 PCT/US2001/028125 US0128125W WO0220515A1 WO 2002020515 A1 WO2002020515 A1 WO 2002020515A1 US 0128125 W US0128125 W US 0128125W WO 0220515 A1 WO0220515 A1 WO 0220515A1
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WIPO (PCT)
Prior art keywords
methyl
oxo
oxazolidin
acetamide
ylidene
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PCT/US2001/028125
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English (en)
Inventor
David J. Madar
Daisy Pireh
Hana Kopecka
Steven W. Djuric
Paul E. Wiedeman
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Abbott Laboratories
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Publication of WO2002020515A1 publication Critical patent/WO2002020515A1/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
    • C07D413/02—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
    • C07D413/10—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 aromatic 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention is directed to compounds useful for treating bacterial infections, psoriasis, arthritis, and toxicity due to chemotherapy; preparation of the compounds; chemotherapeutic compositions comprising the compounds; and methods for treating diseases using the compounds.
  • oxazolidinones exemplified by eperezolid and linezolid, which constitute a class of orally active, synthetic antibacterial agents with good activity against Gram-positive bacteria (Current Pharmaceutical Design, op. cit.).
  • U.S. Patent 6,040,306 the disclosure of which is hereinafter incorporated by reference into this specification, also teaches the use of oxazolidinones for treatment of psoriasis, arthritis, and toxicity due to chemotherapy.
  • Japanese Patent 7,173,159 also teaches a series of substituted oxazolidinones, although they are used as blood sugar-reducing agents.
  • the present invention provides an antibacterial agent of formula (I)
  • A is selected from phenyl and a five- or six-membered aromatic ring containing one to three atoms selected from N, O, and S, and the remaining atoms are carbon, wherein A is substituted through carbon atoms in the ring;
  • X is selected from the group consisting of O, S, S(O), SO 2 , and NR ;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, alkoxy, alkyl, amino, cycloalkyl, halo, haloalkyl, hydroxy, and perfluoroalkyl;
  • R is selected from the group consisting of hydrogen, alkoxy, alkyl, amino, aryl, cyano, halo, haloalkoxy, hydroxy, and nitro;
  • R is selected from the group consisting of alkanoyl, alkoxycarbonyl, amido, aryl, aryloyl, heteroaryl, and heteroaryloyl;
  • R is selected from the group consisting of hydrogen, alkyl, and arylalkyl; with the proviso that when B is 2,4-dioxo-l,3-thiazolidin-5-yl and X is O, R is other than phenyl.
  • the compounds of the present invention are substituted oxazolidinones which are useful for the treatment of bacterial infections.
  • the present invention provides compounds of formula (I)
  • the compounds of the invention comprise oxazolidinones connected to a substituted alkene through ring A.
  • Ring A is a stable, aromatic group substituted through carbon atoms in the ring.
  • ring A is phenyl, although heteroaryl rings such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl are within the scope of the invention.
  • Ring A can be further substituted by independent replacement of one or two
  • R is preferably hydrogen, although groups such as alkyl, amino, cyano, halo, and nitro are within the scope of the invention.
  • Ring B is a stable, non-aromatic mono- or bicyclic optionally substituted heterocycle group attached to the parent molecular moiety through a substitutable carbon atom in the ring.
  • ring B is dihydropyrazole, imidazolidine, indoline, pyrrolidine, or thiazolidine, although heterocycle groups such as dihydrobenzofuran, dihydrobenzimidazole, dihydrothiazole, dihydrobenzothiophene, octahydrobenzofuran, octahydroindole, oxathiolane, oxazolidine, and the like, are within the scope of the invention.
  • a preferred embodiment of compounds of formula (I) are compounds of formula (II)
  • B is heterocycle wherein the heterocycle is selected from the group consisting of
  • D is selected from phenyl and a five- or six-membered aromatic ring containing one or two atoms selected from N, O, and S, and the remaining atoms are carbon, wherein the N is optionally oxidized, and wherein D is fused through carbon atoms in the ring; 1 2
  • R and R are independently selected from the group consisting of alkoxy, alkyl, and halo; each R is independently selected from the group consisting of hydrogen, alkanoyl, alkoxycarbonyl, alkyl, amido, aminoalkyl, aminosulfonyl, aryl, heteroaryl, hydroxyalkyl, and a nitrogen protecting group; and
  • R -R are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, amido, amino, aminosulfonyl, azido, carboxy, cyano, halo, haloalkoxy, haloalkyl, mercapto, nitro, perfluoroalkoxy, perfluoroalkyl, and thioalkoxy.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • the present invention provides a method for treating bacterial infections in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of formula (I), or a therapeutically acceptable salt thereof.
  • the present invention provides a method for treating psoriasis in a patient comprising administering to the patient a therapeutically acceptable amount of a compound of formula (I), or a therapeutically acceptable salt thereof.
  • the present invention provides a method for treating arthritis in a patient comprising administering to the patient a therapeutically acceptable amount of a compound of formula (I), or a therapeutically acceptable salt thereof.
  • the present invention provides a method for treating toxicity due to chemotherapy in a patient comprising administering to the patient a therapeutically acceptable amount of a compound of formula (I), or a therapeutically acceptable salt thereof.
  • the present invention provides a composition comprising a compound of formula (II), or a therapeutically acceptable salt thereof, and a therapeutically acceptable carrier.
  • the present invention provides a method for treating bacterial infections in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of formula (II), or a therapeutically acceptable salt thereof.
  • the present invention provides a method for treating psoriasis in a patient comprising administering to the patient a therapeutically acceptable amount of a compound of formula (II), or a therapeutically acceptable salt thereof.
  • the present invention provides a method for treating arthritis in a patient comprising administering to the patient a therapeutically acceptable amount of a compound of formula (II), or a therapeutically acceptable salt thereof.
  • the present invention provides a method for treating toxicity due to chemotherapy in a patient comprising administering to the patient a therapeutically acceptable amount of a compound of formula (II), or a therapeutically acceptable salt thereof.
  • the invention contemplates stereoisomers and thereof.
  • Individual stereoisomers of compounds are prepared by synthesis from starting materials containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns.
  • Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well known in the art.
  • the present compounds may exhibit the phenomena of tautomerism or structural isomerism.
  • the compounds described herein may adopt an E or Z conformation about the double bond connecting the A ring to the B ring, or may be mixtures of E and Z isomers.
  • the drawings within this specification can only represent one possible tautomeric or structural isomeric form, it should be understood that the invention encompasses any tautomeric or structural isomeric form, or mixtures thereof, which possess the ability to inhibit bacterial growth, and is not limited to any one tautomeric or structural isomeric form utilized within the drawings.
  • the term "E” represents higher order substituents on opposite sides of a carbon-carbon double bond
  • the term "Z" represents higher order substituents on the same side of a carbon- carbon double bond.
  • the invention is further directed, where applicable, to unsolvated as well as solvated forms of the compounds (e.g. hydrated forms) having the ability to inhibit bacterial growth.
  • additive means a catalyst or reagent which advances the course of the reaction.
  • additives include H 3 PO 4 , pyridinium trifluoroacetate, silica gel, TEA, pyridine, and quinoline.
  • additive also means dehydrating agents such as magnesium sulfate, silica gel, and molecular sieves.
  • additive also means monodentate phosphorus-containing ligands of formulas P(R°) 3 (phosphines), P(OR ) 3 (phosphites) and As(R c ) 3 (arsines), wherein each R c is independently hydrogen; alkyl such as methyl, ethyl, and tert-butyl; cycloalkyl such as cyclopropyl and cyclohexyl; optionally substituted aryl such as phenyl, naphthyl, and ortho-tolyl; and optionally substiuted heteroaryl such as furyl and pyridyl; and wherein each R is independently alkyl such as methyl, ethyl, and tert-butyl; cycloalkyl such as cyclopropyl and cyclohexyl; optionally substituted aryl such as phenyl, naphthyl, and ortho-tolyl; and optionally substituted heteroary
  • additives include tri(aIkyl)phosphines such as trimethylphosphine, triethylphosphine, tributylphosphine, and the like; tri(cycloalkyl)phosphines such as tricyclopropylphosphine, tricyclohexylphosphine, and the like; tri(aryl)phosphines such as triphenylphosphine, trinaphthylphosphine, and the like; tri(heteroaryl)phosphines such as tri(fur-2-yl)phosphine, tri(pyrid-3-yl)phosphine, and the like; tri(alkyl)phosphites such as trimethylphosphite, triethylphosphite, tributylphosphite, and the like; tri(cycloalkyl)- phosphites such as tricyclopropylphosphite, tricycloalky
  • additive also means bidentate phosphines such as l,4-bis(diphenylphosphino)butane (DPPB), l,2-bis(diphenyl- phosphino)ethane (DPPE), l,l-bis(diphenylphosphino)methane (DPPM), 1,2- bis(dimethyl-phosphino)ethane (DMPE), l,l'-bis(diphenylphosphino)ferrocene (DPPF), and the like.
  • additive also means copper salts such as copper(I) iodide and copper(I) chloride. It should be understood that multiple additives may be added to a reaction to promote the progress thereof.
  • a transition metal coupling reaction can employ a copper salt, such as copper(I) iodide, and also a bidentate phospine ligand, such as DPPE.
  • alkanoyl represents an alkyl group attached to the parent molecular moiety through a carbonyl group.
  • alkoxy represents an alkyl group attached to the parent molecular moiety through an oxygen atom.
  • alkoxycarbonyl represents an alkoxy group attached to the parent molecular moiety through a carbonyl group.
  • alkyl represents a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom.
  • amino represents an amino group attached to the parent molecular moiety through a carbonyl group.
  • amino represents -NR R , wherein R and R are independently selected from the group consisting of hydrogen, alkanoyl, alkyl, cycloalkyl,
  • aminoalkyl represents an amino group attached to the parent molecular moiety through an alkyl group.
  • aminosulfonyl represents an amino group attached to the parent molecular moiety through a sulfonyl group.
  • aryl represents dihydronaphthyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • Aryl groups having an unsaturated or partially saturated ring fused to an aromatic ring can be attached through the saturated or the unsaturated part of the group.
  • aryl groups of this invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, amido, amino, aminosulfonyl, azido, carboxy, cyano, halo, haloalkoxy, haloalkyl, mercapto, nitro, perfluoroalkyl, and thioalkoxy.
  • arylalkyl represents an aryl group attached to the parent molecular moiety through an alkyl group.
  • Representative arylalkyl groups are benzyl, 4- methoxybenzyl, 2,4-dimethoxybenzyl, and the like.
  • aryloyl represents an aryl group attached to the parent molecular moiety through a carbonyl group.
  • azido represents -N 3 .
  • carbonyl represents -C(O)-.
  • cyano represents -CN
  • cycloalkyl represents a saturated cyclic, bicyclic, or tricyclic hydrocarbon ring system having three to twelve carbon atoms.
  • Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, bicyclo[3.1.1]heptyl, adamantyl, and the like.
  • the cycloalkyl groups of this invention can be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, azido, carboxy, cyano, halo, haloalkoxy, haloalkyl, nitro, and thioalkoxy.
  • (cycloalkyl)alkyl represents a cycloalkyl group attached to the parent molecular moiety through an alkyl group.
  • halo represents F, CI, Br, or I.
  • haloalkoxy represents a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl represents an alkyl group substituted by one, two, three, or four halogen atoms.
  • heteroaryl represents a cyclic aromatic group having five or six ring atoms wherein at least one ring atom is selected from the group consisting of oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon.
  • the five- membered rings have two double bonds, and the six-membered rings have three double bonds.
  • heteroaryl also includes bicyclic groups in which the heteroaryl ring is fused to an aryl group.
  • heteroaryl groups include furyl, imidazolyl, thienyl, pyridinyl, pyrimidinyl, indolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, and quinolinyl.
  • the heteroaryl groups of the present invention are connected to the parent molecular moiety through a carbon atom in the ring or, as exemplified by imidazolyl, indolyl, and benzimidazolyl, through either a carbon atom or nitrogen atom in the ring.
  • heteroaryl groups of this invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, amido, amino, aminosulfonyl, azido, carboxy, cyano, halo, haloalkoxy, haloalkyl, mercapto, nitro, perfluoroalkyl, and thioalkoxy.
  • heteroaryloyl represents a heteroaryl group attached to the parent molecular moiety through a carbonyl group.
  • heterocycle represents a non-aromatic five- or six- membered ring having two or three heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the nitrogen and the sulfur are optionally oxidized.
  • the five- membered ring has zero to one double bond and the six-membered ring has zero to two double bonds.
  • the heterocycle groups of the present invention are connected to the parent molecular moiety through a substitutable carbon atom in the ring.
  • Heterocycle groups can be optionally fused to a ring selected from the group consisting of aryl, heteroaryl, heterocycle, and cycloalkyl to provide a bicyclic group which is attached to the parent molecular moiety through a substitutable carbon atom on the heterocycle part of the group.
  • heterocycle also represents a non-aromatic five-or six-membered ring having one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen, wherein the ring is fused to a second ring selected from the group consisting of aryl, heteroaryl, heterocycle, and cycloalkyl to provide a bicyclic group, which is attached to the parent molecular moiety through a carbon atom on the heterocycle part of the group.
  • heterocycle groups of this invention can be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, amido, amino, aminoalkyl, aminosulfonyl, aryl, azido, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, hydroxy, hydroxyalkyl, mercapto, nitro, a nitrogen protecting group, oxo, perfluoroalkyl, thioalkoxy, and (thio)oxo.
  • heterocyclic groups of the present invention include, but are not limited to, dihydropyrazole, imidazolidine, indoline, pyrrolidine, thiazolidine, dihydrobenzofuran, dihydrobenzimidazole, dihydrothiazole, dihydrobenzothiophene, octahydrobenzofuran, octahydroindole, oxathiolane, oxazolidine, and the like.
  • hydroxy represents -OH.
  • hydroxyalkyl represents a hydroxy group attached to the parent molecular moiety through an alkyl group.
  • mercapto represents -SH.
  • nitro represents -NO 2 .
  • nitrogen protecting group represents groups intended to protect an amino group against undesirable reactions during synthetic procedures.
  • Common N-protecting groups comprise acyl groups such as acetyl, benzoyl, 2- bromoacetyl, 4-bromobenzoyl, tert-butylacetyl, carboxaldehyde, 2-chloroacetyl, 4- chloroberrzoyl, ⁇ -chlorobutyryl, 4-nitrobenzoyl, o-nitrophenoxyacetyl, phthalyl, pivaloyl, propionyl, trichloroacetyl, and trifluoroacetyl; sulfonyl groups such as benzenesulfonyl, and p-toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl, benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc),
  • perfluoroalkoxy represents an perfluoroalkyl group attached to the parent molecular moiety through an oxygen atom.
  • perfluoroalkyl represents an alkyl group wherein each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical.
  • sulfonyl represents -SO 2 -.
  • thioalkoxy represents an alkyl group attached to the parent molecular moiety through a sulfur atom.
  • the compounds of the present invention can exist as therapeutically acceptable salts.
  • therapeutically acceptable salt represents salts or zwitterionic forms of the compounds of the present invention which are water or oil- soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response; which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate,
  • amino groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • the cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • the present compounds can also exist as therapeutically acceptable prodrugs.
  • therapeutically acceptable prodrug refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • prodrug refers to compounds which are rapidly transformed in vivo to parent compounds of formula (I) for example, by hydrolysis in blood.
  • the compounds can be administered alone or in combination with other antibacterial agents.
  • the specific therapeutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drugs used in combination with or coincidently with the compound used.
  • the compounds can be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof.
  • parenteral includes infusion as well as subcutaneous, intravenous, intramuscular, and intrasternal injection.
  • Parenterally administered aqueous or oleaginous suspensions of the compounds can be formulated with dispersing, wetting, or suspending agents.
  • the injectable preparation can also be an injectable solution or suspension in a diluent or solvent.
  • acceptable diluents or solvents employed are water, saline, Ringer's solution, buffers, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.
  • the antibacterial effect of parenterally administered compounds can be prolonged by slowing their absorption.
  • One way to slow the absorption of a particular compound is administering injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound.
  • the rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state.
  • Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension.
  • injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or poly anhydrides.
  • biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or poly anhydrides.
  • the rate of drug release can be controlled.
  • Transdermal patches can also provide controlled delivery of the compounds.
  • the rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers can be used to increase absorption.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or macrocrystalline cellulose.
  • Capsules, tablets and pills can also comprise buffering agents, and tablets and pills can be prepared with enteric coatings or other release-controlling coatings.
  • Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or substitutes therefor.
  • Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.
  • Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches.
  • the compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers.
  • These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Suppositories for rectal or vaginal administration can be prepared by mixing the compounds with a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
  • a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina.
  • Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • the total daily dose of the compounds administered to a host in single or divided doses can be in amounts from about 0.1 to about 200 mg/kg body weight or preferably from about 0.25 to about 100 mg/kg body weight.
  • Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.
  • MIC's The minimum inhibitory concentrations (MIC's) of the compounds for the microorganisms listed in Table 1 were determined by the procedure described in National Committee for Clinical Laboratory Standards. 2000. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, 5th ed. Approved Standard: M7- A5 (NCCLS, Wayne, PA). Briefly, the compounds were dissolved in DMSO to 2 mg/mL and diluted in the appropriate susceptibility test medium to a concentration of 256 ⁇ g/mL. Serial two-fold dilutions were made in microtiter plates to achieve a final volume of 50 ⁇ L.
  • Inocula for each organism were prepared by making a standard suspension in sterile saline with turbidity equivalent to that of a 0.5 McFarland Standard from an 18 to 24 hour culture grown on agar plates at 35 °C.
  • the standard suspension of each organism was diluted 100-fold in the appropriate medium and further diluted 2-fold by adding 50 ⁇ L to the medium containing antibiotic to achieve a final density of 5 x 10 CFU/mL.
  • Microdilution plates were incubated for 16 to 20 hours at 35 °C in ambient air. Each plate was visually inspected, and MIC's were recorded as the lowest concentration of drug which yielded no growth, a slight haze, or sparsely isolated colonies on the inoculum spot as compared to the growth control.
  • the compounds are useful for treating bacterial infections including, but not limited to, those shown in Table 1.
  • a transition metal coupling reaction can employ a copper salt, such as copper(I) iodide, and also a bidentate phospine ligand, such as DPPE, in addition to the required transition metal catalyst, such as tris(dibenzylideneacetone)dipalladium(0).
  • a copper salt such as copper(I) iodide
  • a bidentate phospine ligand such as DPPE
  • Scheme 1 shows the synthesis of compounds of formula (la) where R is hydrogen, alkoxy, alkyl, aryl, or haloalkoxy.
  • Compounds of formula (3) where X is O and R is hydrogen can be converted to compounds of formula (3) where X is O, S, S(O), SO 2 , or NR and R is alkanoyl, aryl, aryloyl, heteroaryl, and heteroaryloyl by methods known to those of ordinary skill in the art. These compounds can be reacted with compounds of
  • a palladium catalyst and base to provide compounds of formula (5) where R is hydrogen, alkoxy, alkyl, aryl, hydroxy, or haloalkoxy.
  • Representative palladium catalysts include Pd 2 (dba) 3 with BINAP, (DPPF)PdCl 2 , and (o-tolyl 3 P) 2 PdCl 2
  • representative bases include CS 2 CO 3 and NaOt-Bu.
  • solvents used in these reactions include toluene, THF, and dioxane. The reaction is conducted at about 80 °C to about 110 °C and reaction times are typically about 12 to about 36 hours.
  • Scheme 2 shows the synthesis of compounds of formula (8).
  • Compounds of formula (7) can be prepared from compounds of formula (5), wherein R is hydroxy or alkoxy, using methods known to those of ordinary skill in the art.
  • Compounds of formula (7) can be reacted with a chlorinating reagent to provide compounds of formula (8).
  • Representative chlorinating reagents include POCI 3 and PCI 5 .
  • R 13 is alkyl or haloalkyl by treatment with an appropriately substituted alcohol in the presence of base.
  • Representative bases include triethylamine and diisopropylethylamine.
  • compounds of formula (8) can be converted to compounds of formula (10) by a palladium-catalyzed coupling with Zn(CN) 2 -
  • Representative palladium catalysts include Pd(PPh 3 ) 4 , Pd(PPh 3 ) Cl 2 , and Pd 2 (dba) 3 with TFP.
  • Compounds of formula (11) where R 11 and R 12 are hydrogen can be oxidized to compounds of formula (12) by a variety of methods known to those of ordinary skill in the art.
  • compounds of formula (12) may be obtained by treatment of a nitromethylphenyl compound of formula (5-a) with a dicarbonyl compound of formula (6- a), for example isatin, and a base in an appropriate solvent.
  • Example 1A ((5R)-2-oxo-l ,3-oxazolidin-5-yl)methyl 2-nitrobenzenesulfonate
  • a solution of (5R)-5-(hydroxymethyl)-l,3-oxazolidin-2-one (1.2 g, prepared as described in Tetrahedron: Asymmetry 1995, 6, 1181-1190) in pyridine (5 mL) at -10 °C was treated with a solution of 2-nitrobenzensulfonyl chloride (2.75 g) in pyridine (3 mL), warmed to -5 °C, stirred for 2.5 hours, treated with water, and extracted with ethyl acetate.
  • Example IB N-(2,4-dimethoxyphenyl)-N-(((5R)-2-oxo-l,3-oxazolidin-5-yl)methyl)acetamide
  • the reaction mixture was concentrated, dissolved in dichloromethane (20 mL), treated with pyridine (13.0 mL) and acetic anhydride (12.5 mL), stirred for 20 hours, and concentrated.
  • Example 1C N-(2,4-dimethoxybenzyl)-N-(((5S)-3-(3-fluoro-4-((Z)-(2-oxo-l,2-dihydro-3H-pyrrolo(2,3- b)pyridin-3-ylidene)methyl)phenyl)-2-oxo-l,3-oxazolidin-5-yl)methyl)acetamide
  • a suspension of Example 1C (200 mg) in ethanol (3 mL) was treated with 1,3- dihydro-2H-pyrrolo(2,3-b)pyridin-2-one (81 mg), and piperidine (15 ⁇ L), sealed, heated to 100 °C for 24 hours, cooled to room temperature, and concentrated. .
  • the concentrate was purified by flash column chromatography on silica gel with 2:98 methanol/dichloromethane to provide the desired product.
  • Example 3 N-(((5S)-2-oxo-3-(4-((E)-(2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyl)phenyl)-l,3- oxazolidin-5 -yl)methyl)acetamide
  • the desired product was prepared as a 2:1 mixture of E and Z isomers by substituting l,3-dihydro-2H-indol-2-one for 4,5-dimethyl-l,3-dihydro-2H-indol-2-one in Example 2.
  • Example 4 N-(((5S)-3-(4-((E)-(5-chloro-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyl)phenyl)-2- oxo- 1 ,3 -oxazolidin-5-yl)methyl)acetamide
  • the desired product was prepared as a 2:1 mixture of E and Z isomers by substituting 5-chloro-l,3-dihydro-2H-indol-2-one for 4,5-dimethyl-l,3-dihydro-2H-indol- 2-one in Example 2.
  • Example 5 N-(((5S)-3-(4-((E)-(5-nitro-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyl)phenyl)-2-oxo- l,3-oxazolidin-5-yl)methyl)acetamide
  • the desired product was prepared as a 2:1 mixture of E and Z isomers by substituting 5-nitro-l,3-dihydro-2H-indol-2-one for 4,5-dimethyl-l,3-dihydro-2H-indol-2- one in Example 2.
  • Example 7 N-(((5S)-3-(4-((E)-(3-methyl-2,5-dioxo-4-imidazolidinylidene)methyl) ⁇ henyl)-2-oxo-l,3- oxazolidin-5-yl)methyl)acetamide
  • the desired product was prepared by substituting l-methyl-2,4-imidazolidinedione for 4,5-dimethyl-l,3-dihydro-2H-indol-2-one in Example 2.
  • MS (ESI(+)) m/e 359 (M+H) + ;
  • Example 8 N-(((5 S)-3 -(4-((Z)- (2,4-dioxo- 1 ,3-thiazolidin-5-ylidene)methyl)phenyl)-2-oxo- 1,3- oxazolidin-5-yl)methyl)acetamide
  • N-(((5S)-3-(4-formylphenyl)-2-oxo-l,3-oxazolidin-5- yl)methyl)acetamide (0.03 g, prepared as described inJ. Med. Chem.
  • Example 9 N-(((5S)-3-(4-((Z)-(3-tert-butyl-l-methyl-5-oxo-1.5-dihydro-4H-pyrazol-4- ylidene)methyl)phenyl)-2-oxo-l,3-oxazolidin-5-yl)methyl)acetamide
  • the desired product was prepared by substituting 5-tert-butyl-2-methyl-2,4- dihydro-3H-pyrazol-3-one for 4,5-dimethyl-l,3-dihydro-2H-indol-2-one in Example 2.
  • the desired product was prepared by substituting 5-tert-butyl-2-phenyl-2,4- dihydro-3H-pyrazol-3-one for 4,5-dimethyl-l,3-dihydro-2H-indol-2-one in Example 2. mp: 70 °C;
  • Example 11 N-(((5S)-3-(4-((Z -(2,4-dioxo-l,3-thiazolidin-5-ylidene)methyl -3-fluorophenyl)-2-oxo- l,3-oxazolidin-5-yl)methyl)acetamide
  • the desired product was prepared by substituting l,3-thiazolidine-2,4-dione for l,3-dihydro-2H-pyrrolo(2,3-b)pyridin-2-one in Example 1.
  • MS (APCI(+)) m/e 380 (M+H) + ;
  • Example 12 N-(((5S)-3-(3-fluoro-4-((Z)-(l-methyl-2-oxo-l,2-dihydro-3H-indol-3- ylidene)methyl)phenyl)-2-oxo-l,3-oxazolidin-5-yl)methyl)acetamide
  • the desired product was prepared by as a 1 : 1 mixture of E and Z isomers by substituting 1 -methyl- l,3-dihydro-2H-indol-2-one for l,3-dihydro-2H-pyrrolo(2,3- b)pyridin-2-one in Example 1.
  • Example 13 N-(((5SV3-(3-fluoro-4-((E)-(l-methyl-5-nitro-2-oxo-l,2-dihydro-3H-indol-3- ylidene)methyl)phenyl)-2-oxo-l,3-oxazolidin-5-yl)methyl)acetamide
  • the desired product was prepared as a 5:1 mixture of E and Z isomers by substituting l-methyl-5-nitro-l,3-dihydro-2H-indol-2-one for l,3-dihydro-2H-pyrrolo(2,3- b)pyridin-2-one in Example 1.
  • MS (ESI(+)) m/e 455 (M+H) + ;
  • Example 14 N-(((5S -3-(4-((E -(6-chloro-2-oxo-l,2-dihydro-3H-indol-3-ylidene)meth ⁇ l)-3- fluorophenyl)-2-oxo-l,3-oxazolidin-5-yl)methyl)acetamide
  • the desired product was prepared by substituting 6-chloro-l,3-dihydro-2H-indol- 2-one for l,3-dihydro-2H-pyrrolo(2,3-b)pyridin-2-one in Example 1.
  • MS (ESI(+)) m/e 430 (M+H) + ;
  • Example 15 N-(((5S)-3-(4-r(E)-(5-methoxy-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyl)-3- fluorophenyl)-2-oxo- 1 ,3-oxazolidin-5-yl)methyl)acetamide
  • the desired product was prepared by substituting 5-methoxy-l,3-dihydro-2H- indol-2-one for l,3-dihydro-2H-pyrrolo(2,3-b)pyridin-2-one in Example 1.
  • MS (ESI(+)) m/e 426 (M+H) + ;
  • Example 16 N-(((5S)-3-(4-((Z)-(5-chloro-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyl)-3- fluorophenyl)-2-oxo- 1 ,3-oxazolidin-5-yl)methyl)acetamide
  • the desired product was prepared as a 7:1 mixture of Z and E isomers by substituting 5-chloro-l,3-dihydro-2H-indol-2-one for l,3-dihydro-2H-pyrrolo(2,3- b)pyridin-2-one in Example 1.
  • Example 17 N-(((5S)-3-(4-((E)-(l-methyl-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyl)phenyl)-2- oxo-l,3-oxazolidin-5-yl)methyl)acetamide
  • the desired product was prepared as a 3:2 mixture of E and Z isomers by substituting 1 -methyl- l,3-dihydro-2H-indol-2-one for 4,5-dimethyl-l,3-dihydro-2H-indol- 2-one in Example 2.
  • Example 18 N-r((5S)-3- ⁇ 4-r(E)-(6-chloro-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyllphenyl ⁇ -2- oxo- 1 ,3-oxazolidin-5-yl)methyl]acetamide
  • the desired product was prepared as a 2:1 mixture of E and Z isomers by substituting 6-chloro-l,3-dihydro-indol-2-one for 4,5-dimethyl-l,3-dihydro-2H-indol-2- one in Example 2.
  • MS (ESI(+)) m/e 412 (M+H) + ;
  • Example 19 N-r((5S)-3- ⁇ 4-r(E)-(5,6-dimethoxy-2-oxo-l,2-dihydro-3H-indol-3-ylidene)methyn-3- fluorophenyl ⁇ -2-oxo-l,3-oxazolidin-5-yl)methyllacetamide
  • the desired product was prepared as a 2:1 mixture of E and Z isomers by substituting 5,6-dimethoxy-l,3-dihydro-indol-2-one for l,3-dihydro-2H-pyrrolo(2,3- b)pyridin-2-one in Example 1.
  • MS (ESI(+)) m/e 456 (M+H) + ;
  • Example 20 N-r((5S)-2-oxo-3- ⁇ 4-r(Z)-(4-oxo-2-thioxo-l,3-thiazolidin-5-ylidene)methyl1phenyl>-l,3- oxazolidin-5-yl)methyllacetamide
  • the desired product was prepared by substituting 2-thioxo-4-thiazolidinone for 4,5-dimethyl-l,3-dihydro-2H-indol-2-one in Example 2.
  • MS (ESI(+)) m/e 377 (M+H) + ;
  • Example 21 N-
  • the desired product was prepared as a 2:1 mixture of Z and E isomers by substituting 5-methoxy-l,3-dihydro-indol-2-one for 4,5-dimethyl-l,3-dihydro-2H-indol-2- one in Example 2.
  • MS (ESI(+)) m/e 408 (M+H) + ;
  • the desired product was prepared as a 2: 1 mixture of E and Z isomers by substituting l-acetyl-l,3-dihydro-indol-2-one for l,3-dihydro-2H-pyrrolo(2,3-b)pyridin-2- one in Example 1.
  • Example 23 N-r((5S)-3- ⁇ 4-r(Z)-(4,7-dimethyl-2-oxo-l,2-dih ⁇ dro-3H-indol-3-ylidene)methyn-3- fluorophenyl ⁇ -2-oxo-l,3-oxazolidin-5-yl)methyl1acetamide
  • the desired product was prepared by substituting 4,7-dimethyl-l,3-dihydro-indol- 2-one for l,3-dihydro-2H-pyrrolo(2,3-b)pyridin-2-one in Example 1.
  • MS (APCI/NH 3 ) m/e 424 (M+H) + ;

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Abstract

La présente invention concerne des composés représentés par la formule (I) ou des sels de ces derniers acceptables du point de vue thérapeutique. Dans la formule, A est sélectionné entre phényle et un anneau aromatique à cinq ou six chaînons contenant de un à trois atomes sélectionnés entre N, O et S, les atomes restants étant des atomes de carbone, A étant substitué par les atomes de carbone présents dans l'anneau; B est un hétérocycle. Ces composés sont utiles pour traiter les infections bactériennes. Formule (I)
PCT/US2001/028125 2000-09-08 2001-09-07 Agents antibacteriens a l'oxazolidinone WO2002020515A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7132434B2 (en) 2001-11-07 2006-11-07 Astrazeneca Ab Metalloproteinase inhibitors
US7354940B2 (en) 2002-08-27 2008-04-08 Astrazeneca Ab 2,5-dioxoimidazolidin-4-yl acetamines and analogues as inhibitors of metalloproteinase mmp12
US7368465B2 (en) 2001-03-15 2008-05-06 Astrazeneca Ab Metalloproteinase inhibitors
US7691889B2 (en) 2002-09-20 2010-04-06 Lupin Limited Antimycobacterial compounds
AU2006254336B2 (en) * 2005-06-01 2012-10-04 Ucb Pharma, S.A. 2 -oxo-I -pyrrolidine derivatives/ processes for preparing them and their therapeutic use on the central nervous system
CN103848814A (zh) * 2012-12-06 2014-06-11 山东亨利医药科技有限责任公司 作为酪氨酸激酶抑制剂的取代吲哚满酮衍生物

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EP0316594A1 (fr) * 1987-10-21 1989-05-24 The Du Pont Merck Pharmaceutical Company Dérivés d'aminométhyl-oxo-oxazolidinyl éthénylbenzène comme agents antibactériens
WO1993009103A1 (fr) * 1991-11-01 1993-05-13 The Upjohn Company Aryl- et heteroarylphenyloxazolidinones substituees, utilisees comme agents antibacteriens
JPH07173159A (ja) * 1993-12-17 1995-07-11 Taiho Yakuhin Kogyo Kk オキサゾリジノン誘導体又はその塩
US5521202A (en) * 1993-04-07 1996-05-28 Taiho Pharmaceutical Co., Ltd. Thiazolidine derivatives and pharmaceutical compositions containing the same

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Publication number Priority date Publication date Assignee Title
EP0316594A1 (fr) * 1987-10-21 1989-05-24 The Du Pont Merck Pharmaceutical Company Dérivés d'aminométhyl-oxo-oxazolidinyl éthénylbenzène comme agents antibactériens
WO1993009103A1 (fr) * 1991-11-01 1993-05-13 The Upjohn Company Aryl- et heteroarylphenyloxazolidinones substituees, utilisees comme agents antibacteriens
US5521202A (en) * 1993-04-07 1996-05-28 Taiho Pharmaceutical Co., Ltd. Thiazolidine derivatives and pharmaceutical compositions containing the same
JPH07173159A (ja) * 1993-12-17 1995-07-11 Taiho Yakuhin Kogyo Kk オキサゾリジノン誘導体又はその塩

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DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002185947, Database accession no. 1995:842591 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7368465B2 (en) 2001-03-15 2008-05-06 Astrazeneca Ab Metalloproteinase inhibitors
US7132434B2 (en) 2001-11-07 2006-11-07 Astrazeneca Ab Metalloproteinase inhibitors
US7354940B2 (en) 2002-08-27 2008-04-08 Astrazeneca Ab 2,5-dioxoimidazolidin-4-yl acetamines and analogues as inhibitors of metalloproteinase mmp12
US7691889B2 (en) 2002-09-20 2010-04-06 Lupin Limited Antimycobacterial compounds
AU2006254336B2 (en) * 2005-06-01 2012-10-04 Ucb Pharma, S.A. 2 -oxo-I -pyrrolidine derivatives/ processes for preparing them and their therapeutic use on the central nervous system
AU2006254336B9 (en) * 2005-06-01 2013-02-28 Ucb Pharma, S.A. 2 -oxo-I -pyrrolidine derivatives/ processes for preparing them and their therapeutic use on the central nervous system
CN103848814A (zh) * 2012-12-06 2014-06-11 山东亨利医药科技有限责任公司 作为酪氨酸激酶抑制剂的取代吲哚满酮衍生物
CN103848814B (zh) * 2012-12-06 2016-08-17 山东亨利医药科技有限责任公司 作为酪氨酸激酶抑制剂的取代吲哚满酮衍生物

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