EP1819699A2 - Utilisation de diazepine oxazolidinones comme agents antibacteriens - Google Patents

Utilisation de diazepine oxazolidinones comme agents antibacteriens

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Publication number
EP1819699A2
EP1819699A2 EP05808372A EP05808372A EP1819699A2 EP 1819699 A2 EP1819699 A2 EP 1819699A2 EP 05808372 A EP05808372 A EP 05808372A EP 05808372 A EP05808372 A EP 05808372A EP 1819699 A2 EP1819699 A2 EP 1819699A2
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EP
European Patent Office
Prior art keywords
oxo
methyl
phenyl
diazepan
oxazolidine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05808372A
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German (de)
English (en)
Inventor
Prudencio Sancon Pfizer Global R & D HERRADURA
Vara P V N Pfizer Global R & D JOSYULA
Adam Robert Pfizer Global R & D RENSLO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co LLC
Original Assignee
Pharmacia and Upjohn Co LLC
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Filing date
Publication date
Application filed by Pharmacia and Upjohn Co LLC filed Critical Pharmacia and Upjohn Co LLC
Publication of EP1819699A2 publication Critical patent/EP1819699A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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

Definitions

  • the present invention relates to a new class of oxazolidinone derivatives, to their use as antibacterial agents, to pharmaceutical compositions containing these compounds and to methods for their preparation.
  • Antibacterial resistance is a global clinical and public health problem that has emerged with alarming rapidity in recent years and undoubtedly will increase in the near future. Resistance is a problem in the community as well as in health care settings, where transmission of bacteria is greatly amplified. Because multiple drug resistance is a growing problem, physicians are now confronted with infections for which there is no effective therapy. As result, structurally novel antibacterials with a new mode of action have become increasingly important in the treatment of bacterial infections.
  • oxazolidinone compounds are the most recent synthetic class of antimicrobials.
  • This invention provides a new class of oxazolidinone derivatives containing a diazepine ring, which are active against a number of human and veterinary pathogens, including multiple resistant strains of bacteria.
  • A is a structure of the following formula i, ii, iii, or iv
  • Y 2 and Y 3 are independently CH 5 or CF;
  • Q is O, or S; R 1 is H 5 or C ⁇ alkyl;
  • the present invention also provides: a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of formula I, a method for treating microbial infections in a mammal by administering to the subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating microbial infections.
  • the invention may also provide novel intermediates and novel processes that are useful for preparing compounds of formula I.
  • C 1 ⁇ alkyl refers to alkyl of one to six carbon atoms, inclusive.
  • halo refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • a pharmaceutically acceptable salt of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • heterocyclic ring having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen within the ring.
  • An examples of het includes, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,3,4-triazole, oxazole, thiazole, isoxazole, isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,3-thiadiazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, quinoxaline, quinazoline, cinnoline, p
  • het includes, but are not limited to, pyridine, thiophene, fiiran, pyrazole, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxaz-olyl, 4-is-oxaz-olyl, 5-isoxaz-olyl, 3-pyrazolyl, 4-pyrazolyl, 5- pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl, 1,2,3-oxathiazole, 1,2,3-oxadiazole, 1 ,2,4-oxadiazole, 1,2,5-
  • pharmaceutically acceptable carrier means a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use.
  • a pharmaceutically acceptable carrier as used in the specification and claims includes both one and more than one such carrier.
  • mamal refers to human or. warm-blooded animals including livestock and companion animals. Livestock refers to animals suitable for human meat consumption. Examples include pigs, cattle, chickens, fish, turkeys, rabbits, etc. Companion animals refer to animals kept as pets such as dogs, cats, etc.
  • the term “optional” or “optionally” means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • treating includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, Le., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • terapéuticaally effective amount means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulas, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • leaving group has the meaning conventionally associated with it in synthetic organic chemistry i.e., an atom or group capable of being displaced by a nucleophile and includes halogen, alkylsulfonyloxy, ester, or amino such as chloro, bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy, N,O- dimethylhydroxyl-amino, and the like.
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers".
  • stereoisomers that differ in the arrangement of their atoms in space are termed "stereoisomers". It will be appreciated by those skilled in the art that compounds, of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism.
  • the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomers form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine antiviral activity using the standard tests described herein, or using other similar tests which are well known in the art.
  • the compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system.
  • radicals, substituents, and ranges are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
  • alkyl denotes both straight and branched groups; but reference to an individual radical such as "propyl” embraces only the straight chain radical, a branched chain isomer such as "isopropyl” being specifically referred to.
  • alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, and their isomeric forms thereof.
  • alkenyl is vinyl, propenyl, allyl, butenyl, and their isomeric forms thereof.
  • halo is fluoro (F), or chloro (Cl).
  • Y 1 and Y 2 are independently. CH or. CF; and W. is CONHR 2 or CH 2 NHCO(NH)Ci. 6 alkyl,
  • Y 1 and Y 2 are independently CH or CF, R 1 is H or methyl; and R 2 is H, CH 3 , or OCH 3 .
  • Examples of the present invention are:
  • Scheme I describes the synthesis of the oxazolidinone ring with its C-5 carboxamide side chain, starting from commercially available aniline 1.
  • aniline 1 is reacted with an alkyl (2i?)-epoxypropanoate and a Lewis acid such as ithium triflate (as described in US Patent Application Publication No. US 2004/0044052) to provide amino alcohol 2.
  • a Lewis acid such as ithium triflate (as described in US Patent Application Publication No. US 2004/0044052) to provide amino alcohol 2.
  • the amino alcohol 2 is cyclized to give the aryl oxazolidinones 3 using methods known to one skilled in the art.
  • reaction of intermediate 2 with l,r-carbonyldiimidazole in a solvent such as acetonitrile or tetrahydrofuran at an appropriate temperature, typically in a range of 20 0 C to 80 0 C provides the oxazolidinone 3.
  • the product may be used as collected or may first be purified using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.
  • Scheme II describes the synthesis of aniline intermediates 9 bearing the diazepanone ring.
  • the diazepanone 5 (for synthesis see Scheme III) is reacted in a nucleophilic aromatic substitution reaction with a fluoronitrobenzene (for example, with 3,4,-difluoronitrobenzene) to provide intermediates such as 6.
  • a fluoronitrobenzene for example, with 3,4,-difluoronitrobenzene
  • transformations are generally performed at a temperature in a range from about 4O 0 C to about 90°C using polar aprotic solvents such as acetonitrile or dimethylformamide and in the presence of acid-scavenging bases such as triethylamine or N,N- diisopropylethylamine.
  • Intermediate 6 is then optionally alkylated on the nitrogen atom to form intermediate 7.
  • Intermediate 7 is then reduced to provide the aniline intermediate 8. This reduction is generally accomplished by reacting 7 with reducing metals (for example with iron powder).
  • the reaction is favorably carried out at temperatures in a range from about 60°C to about 9O 0 C in mixtures of water and alcohol (methanol, ethanol, etc.) as solvent, and in the presence of ammonium chloride to buffer the reaction mixture.
  • reductions of this type are conducted by reaction with other metals such as tin or zinc or by hydrogenation under palladium or platinum catalysis (see Rylander Hydrogenation Methods; Academic Press: New York, 1985, pp. 104-116).
  • the product may be used as collected or. may first be purified. using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like. Aniline intermediates such as 9 can then be converted to oxazolidinone analogs as described in Scheme I.
  • Scheme III describes the synthesis of the diazepanone heterocycle 5.
  • This compound may be prepared in three steps from commerically available piperidone compounds such as benzyl 4-oxopiperidine-l-carboxylate (10, commercially available) or tert-butyl 4-oxopiperidine-l-carboxylate. Reaction of 10 with hydroxylamine in the presence of molecular sieves (to remove water formed in the reaction) and in a solvent such as pyridine provides the oxime intermediate 11.
  • intermediate 11 is converted to the protected diazepanone intermediate 12.
  • This reaction known as the Beckmann rearrangement, is well known to those of ordinary skill in the art and may be accomplished under a variety of conditions (for a review see Gawley Organic Reactions, 1988, 35, pp 1-420).
  • the reaction is favorably carried out with tosyl chloride to activate the oxime, and in solvents such as acetone, water, or mixtures thereof and in the presence of an acid scavenging base such as sodium carbonate.
  • the product may be used as collected or may first be purified using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.
  • the protecting group e.g., Cbz or Boc
  • benzyl carbamate protection is favorably accomplished by hydrogenolysis, typically employing a palladium catalyst under an atmosphere of hydrogen gas and using solvents such as ethyl acetate, alcohols, or mixtures thereof.
  • Cleavage of tert-butyl carbamates is typically accomplished by treatment with acids such as hydrochloric acid or trifluoroacetic acid. If less harsh conditions are required, treatement with trimethylsilyltrifluoromethane sulfonate and 2,6-lutidine (as described by Ohfune, Y- and Sakaitani, M. J. Org. Chem. .1990, 55, 870-876) is also effective.
  • the diazepanone 5 may then be employed in the synthesis of final analogs as outlined in Schemes I and II.
  • Schemes V-VIII describe the synthesis of aryl isoxazolinone, aryl isoxazoline and aryl butyrolactone compounds bearing diazepanone and related heterocyclic rings of the type described in Schemes I- VII.
  • the following schemes describe general methods to prepare claimed structures in which A is (ii), (iii), or (iv).
  • the diazepanone and related heterocycles may be prepared as described above in Schemes I-VII but it will be understood by those of ordinary skill in the art that suitable, protecting groups may be required to protect and later reveal sensitive functional groups.
  • Scheme V summarizes the synthesis of the requisite substituted benzaldehyde intermediates.
  • the general methods described in the previous Schemes are applicable but with the use of fluorinated benzonitrile (29) or benzoate ester starting materials in the place of fluorinated nitrobenzenes.
  • the required starting materials e.g., 3,4,5- trifluorobenzonitrile
  • Conversion of these starting materials to intermediate 30 is accomplished in a series of steps using the same methods described in Schemes II-IV for the preparation of aniline intermediates.
  • Intermediate 30 is then converted to the benzaldehyde intermediate 31 using methods that are well known to those of ordinary skill in the art, for example by reduction to the imine with SnCl 2 /HCl followed by hydrolysis (Stephen aldehyde synthesis).
  • Scheme VII describes a general method for preparing aryl isoxazoline compounds bearing diazepanone or related heterocycles of the type described in the Schemes above.
  • the benzaldehyde intermediate 31 is reacted with hydroxylamine hydrochloride in a polar protic solvent, such as methanol, in the presence of a base, such as pyridine, to afford the oxime intermediate 35.
  • the oxime 35 is then oxidized with TV-chlorosuccinimide (NCS) in an appropriate solvent, such as dichloromethane, to give the hydroximinoyl chloride intermediate 36.
  • NCS TV-chlorosuccinimide
  • This material is then reacted with an alkene, for example with allyl alcohol, in the presence of a base such as triethylamine and in a solvent such as dichloromethane, to provide the hydroxymethyl-substituted isoxazoline 37.
  • the hydroximinoyl chloride intermediate may be formed in situ as described above and then directly treated with the alkenes to generate the isoxazoline intermediates directly from 35. SCHEME VII
  • Scheme VIII describes the synthesis of aryl butyrolactone analogs such as 42.
  • the synthesis of the saturated (as in 41) and unsaturated (as in 42) 3-arylbutyrolactone ring system is described in the literature (for example, see Bioorganic & Medicinal Chemistry Letters, 1994, 4, 1925-1930).
  • Aldehyde intermediate 31 is converted to phenyl acetic acid intermediate 39 using established procedures (for example as described by Hester, et al. in US Patent 5,708,169). The dianion of 39 is then reacted with i?-benzyloxymethyloxirane in THF.
  • the resulting hydroxyacid is cyclized under acid catalysis (for example, using p-toluenesulfonic acid) to provide lactone 40.
  • the butyrolactone is oxidized using a two-step protocol involving bromination (using for example N- bromosuccinimide) and subsequent elimination by treatment with a suitable base such as pyridine or DBU to provide 42.
  • the compounds of the present invention may be used for the treatment of infectious diseases caused by a variety of bacterial organisms.
  • Examples include gram-positive bacteria such as multiple resistant staphylococci, for example S. aureus and S. epidermidis; multiple resistant streptococci, for example S. pneumoniae and S. pyogenes; and multiple resistant Enterococci, for example E. faecalis; gram negative aerobic bacteria such as Haemophilus, for example H. influenzae and Moraxella, for example M. catarrhalis; as well as anaerobic organisms such as bacteroides and Clostridia species, and acid-fast organisms such as Mycobacteria, for example M. tuberculosis; and/or Mycobacterium avium.
  • Other examples include Escherichia, for example E. coli. intercellular microbes, for example Chlamydia and Rickettsiae.
  • infections examples include central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients.
  • infectious diseases that may be treated with the compounds of the present invention are gram-positive infections such as osteomyelitis, endocarditis and diabetic foot.
  • the in vitro antibacterial activity of the compounds of the present invention may be assessed by following procedures recommended in (1) National Committee for Clinical Laboratory Standards (Jan. 2003), Methods for dilution antimicrobial tests or bacteria that grow aerobically, Approved Standard (6 th ed), M7-A6, NCCLS, Wayne, PA; (2) National Committee for Clinical Laboratory Standards (Mar. 2001), Methods for antimicrobial susceptibility testing of anaerobic bacteria, Approved Standard (5 th ed), Ml 1-A4, NCCLS, Wayne, PA; (3) National Committee for Clinical
  • the compound of formula I may be used in its native form or as a salt. In cases where forming a stable nontoxic acid or base salt is ' desired, administration of the compound as a pharmaceutically acceptable salt may be appropriate.
  • pharmaceutically acceptable salts of the present invention include inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, bicarbonate, carbonate salts, and organic salts such as tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, etoglutarate, and glycerophosphate. .
  • salts may be obtained using standard procedures well known in the art, for example, reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically, acceptable, anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically, acceptable, anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • a compound of the present invention or its pharmaceutical compositions can be administered orally, parenterally, topically, rectally, transmucosally, or intestinally.
  • Parenteral administrations include indirect injections to generate a systemic effect or direct injections to the afflicted area. Examples of parenteral administrations are subcutaneous, intravenous, intramuscular, intradermal, intrathecal, intraocular, intranasal, intravetricular injections or infusions techniques.
  • Topical administrations include the treatment of infectious areas or organs readily accessibly by local application, such as, for example, eyes, ears including external and middle ear infections, vaginal, open wound, skins including the surface skin and the underneath dermal structures, or other lower intestinal tract. It also includes transdermal delivery to generate a systemic effect.
  • the rectal administration includes the form of suppositories.
  • the transmucosal administration includes nasal aerosol or inhalation applications.
  • the preferred routes of administration are oral and parenteral.
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulation, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying.
  • compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to. be formulated. as tablets, pills, lozenges, dragees, capsules, liquids, solutions, emulsions, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient.
  • a carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent.
  • Such carriers or excipients include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, sucrose, pectin, dextrin, mannitol, sorbitol, starches, gelatin, cellulosic materials, low melting wax, cocoa butter or powder, polymers such as polyethylene glycols and other pharmaceutical acceptable materials.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, liquid polyethylene glycols, cremophor, capmul, medium or long chain mono-, di- or triglycerides.
  • Liquid form compositions include solutions, suspensions and emulsions.
  • solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.
  • the compounds may also be formulated for parenteral administration, e.g., by injections, bolus injection or continuous infusion.
  • Formulations for parenteral administration may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating materials such as suspending, stabilizing and/or dispersing agents.
  • the compounds of the invention may be formulated in aqueous solution, preferably in physiologically compatible buffers or physiological saline buffer.
  • Suitable buffering agents include trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine.
  • Parenteral administrations also include aqueous solutions of a water soluble form, such as, without limitation, a salt, of the active compound.
  • suspensions of the active compounds may be prepared in a lipophilic vehicle.
  • Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water
  • the compounds may also be formulated by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • Such materials include cocoa butter, beeswax and other glycerides.
  • compounds of the present invention can be conveniently delivered through an aerosol spray in the form of solution, dry powder, or suspensions.
  • the aerosol may use a pressurized pack or a nebulizer and a suitable propellant.
  • the dosage unit may be controlled by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin for use in an inhaler may be formulated containing a power base such as lactose or starch.
  • the pharmaceutical composition may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion such as suspensions, emulsion, or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, ceteary alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as a benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • the compounds may also be formulated as depot preparations. Such long acting formulations may be in the form of implants.
  • a compound of this invention may be formulated for this route of administration with suitable polymers, hydrophobic materials, or as a sparing soluble derivative such as, without limitation, a sparingly soluble salt.
  • the compounds may be delivered using a sustained-release system.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for 24 hours or for up to several days. Dosage
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose, i.e., the treatment or prevent of infectious diseases. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • the quantity of active component, that is the compound of this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the manner of administration, the potency of the particular compound and the desired concentration. Determination of a therapeutically effective amount is well within the capability of those skilled in the art. Generally, .the quantity of active component will range between 0.5% to 90% by weight of the composition.
  • a therapeutically effective amount of dosage of active component will be in the range of about 0.1 to about 400 mg/kg of body weight/day, more preferably about 1.0 to about 50 mg/kg of body weight/day. It is to be understood that the dosages may vary depending upon the requirements of each subject and the severity of the bacterial infection being treated. In average, the effective amount of active component is about 200 mg to 800 mg and preferable 600 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired plasma concentration.
  • the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation.
  • the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day.
  • the effective local concentration of the drug may not be related to plasma concentration and other procedures know in the art may be used to determine the desired dosage amount.
  • Boc tert-butoxycarbonyl
  • reaction mixture is cooled to 23°C, concentrated, and the residue purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 2% to 5% MeOH in dichloromethane. Relevant fractions are combined and concentrated to afford the title compound.
  • the resulting mixture is stirred at 50°C overnight, cooled to 23 °C, and concentrated in vacuo.
  • the residue is taken into ethyl acetate (300 mL), washed with 0.5 M aqueous HCl, brine, and dried (Na 2 SO 4 ), filtered, and concentrated.
  • the residue is purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 2% to 5% MeOH in dichloromethane. Relevant fractions are combined and concentrated to afford the title compound.
  • the reaction mixture is cooled to 23°C, concentrated, and taken into ethyl acetate and water. The layers are separated and the organic phase washed with brine, dried (MgSO 4 ), filtered, and concentrated.
  • the crude residue is purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 0% to 10% MeOH in dichloromethane. Relevant fractions are combined and concentrated to afford the title compound.

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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne une nouvelles classe de dérivés d'oxazolidinone, leur utilisation comme agents antibactériens, des compositions pharmaceutiques contenant ces composés et leurs méthodes de préparation.
EP05808372A 2004-11-29 2005-11-17 Utilisation de diazepine oxazolidinones comme agents antibacteriens Withdrawn EP1819699A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US63147504P 2004-11-29 2004-11-29
PCT/IB2005/003559 WO2006056877A2 (fr) 2004-11-29 2005-11-17 Utilisation de diazepine oxazolidinones comme agents antibacteriens

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EP1819699A2 true EP1819699A2 (fr) 2007-08-22

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EP (1) EP1819699A2 (fr)
JP (1) JP2008521792A (fr)
CA (1) CA2589250A1 (fr)
WO (1) WO2006056877A2 (fr)

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Publication number Priority date Publication date Assignee Title
US8020889B2 (en) 2005-09-21 2011-09-20 Tk Holdings, Inc. Passive airbag venting
EP2233484A3 (fr) * 2007-10-02 2012-04-04 Research Foundation Itsuu Laboratory Dérivés de oxazolidone ayant un cycle hétérocyclique à sept membre

Family Cites Families (3)

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Publication number Priority date Publication date Assignee Title
CA2303959A1 (fr) * 1997-11-12 1999-05-20 Pharmacia & Upjohn Company Derives d'oxazolidinone et compositions pharmaceutiques
IL150348A0 (en) * 1999-12-21 2002-12-01 Upjohn Co Oxazolidinones having a sulfoximine functionality and their use as antimicrobial agents
AR038536A1 (es) * 2002-02-25 2005-01-19 Upjohn Co N-aril-2-oxazolidinona-5- carboxamidas y sus derivados

Non-Patent Citations (1)

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Title
See references of WO2006056877A2 *

Also Published As

Publication number Publication date
CA2589250A1 (fr) 2006-06-01
WO2006056877A2 (fr) 2006-06-01
JP2008521792A (ja) 2008-06-26
WO2006056877A3 (fr) 2006-07-20

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