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WO2007004032A1 - Oxazolidiones contenant du cyclobutane servant d'agents antibactériens - Google Patents

Oxazolidiones contenant du cyclobutane servant d'agents antibactériens Download PDF

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Publication number
WO2007004032A1
WO2007004032A1 PCT/IB2006/001827 IB2006001827W WO2007004032A1 WO 2007004032 A1 WO2007004032 A1 WO 2007004032A1 IB 2006001827 W IB2006001827 W IB 2006001827W WO 2007004032 A1 WO2007004032 A1 WO 2007004032A1
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Prior art keywords
alkyl
compound
phenyl
acetamide
mmol
Prior art date
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PCT/IB2006/001827
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English (en)
Inventor
Mikhail Fedorovich Gordeev
Vara Prasad Venkata Nagendra Josyula
Adam Robert Renslo
Original Assignee
Pharmacia & Upjohn Company Llc
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Publication of WO2007004032A1 publication Critical patent/WO2007004032A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms

Definitions

  • the present invention relates to novel oxazolidinones derivatives bearing cyclobutane rings, pharmaceutical compositions thereof, methods for their use, and methods for preparing these compounds. These compounds have potent activities against against gram-positive and/or gram-negative bacteria.
  • 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. Among newer antibacterial agents, oxazolidinone compounds are the most recent synthetic class of antimicrobials. This invention provides cyclobutane derivatives of oxazolidinones as inhibitors of bacterial protein synthesis for the treatment of serious infections caused by a number of human and veterinary pathogens, including multiple resistant strains of bacteria. INFORMATION DISCLOSURE
  • the present invention provides a compound of formula I
  • A is a structure of i, ii, iii, or iv:
  • W is O or S
  • Y 1 , Y 2 , Y 3 , Y 4 are independently CH or CF;
  • R 1 and R 2 are independently
  • R 3 and R 4 are independently
  • heteroaryl at each occurrence, C ⁇ alkyl, or C 3 .
  • the present invention also provides: a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I, a method for treating gram-positive 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 gram-positive or gram-negative microbial infections.
  • the invention may also provide novel intermediates and novel processes that are useful for preparing compounds of formula I. DETAILED DESCRIPTION OF THE INVENTION
  • C 1 ⁇ alkyl refers to alkyl of one to six carbon atoms, inclusive.
  • alkyl, or alkenyl, etc. refer to 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.
  • C 3 .scycloalkyl or “Ca ⁇ cycloalkyl” refers to a cyclic saturated monovalent hydrocarbon group of three to eight or three to six carbon atoms, e.g., cyclopropyl, cyclohexyl, and the like.
  • halo refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • heteroaryl is a five- (5) or six- (6) membered unsaturated ring having 1, 2 or 3 heteroatoms selected from the group consisting of non-peroxide oxygen, sulfur, and nitrogen within the ring.
  • 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.
  • 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.
  • the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric 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.
  • 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, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • 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.
  • 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.
  • the compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system.
  • alkyl is methyl or ethyl.
  • halo is fluoro (F).
  • Y 2 and Y 4 are CH; and Y*and Y 3 are independently CH or CF.
  • formula I is a structure of formula Ia:
  • Scheme I illustrates construction of the oxazolidinone ring when acetylaminomethyl substitution is desired at C-5 of the oxazolidinone.
  • the aniline intermediate 1 is first converted to an aryl carbamate using (wherein R may be -CH 2 phenyl) standard procedures that are well known to those skilled in the art, for example using benzyl chloroformate and pyridine in dichloromethane.
  • Step 2 involves formation of the oxazolidinone ring. This can be accomplished using a multi-step procedure as described in Angewandte Chemie 2003, 42, 2010 (and references therein).
  • this conversion can be accomplished in one step using (5)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester.
  • This reagent is prepared from (S)-epichlorohydrin in three steps (epoxide ring opening with benzaldehyde imine, imine hydrolysis, and peracylation with acetic anhydride) according to the procedure described in US Patent No. 6,833,453.
  • the reaction is performed in the presence of an organic base such as lithium tert- butoxide, in a polar organic solvent such as dimethylformamide or acetonitrile, at temperatures of about 0 0 C to 25 0 C.
  • the product may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.
  • R 3 alkyl, O-alkyl, or NH-alkyl, etc.
  • the aryl carbamate 1 (wherein R may be -CH 2 phenyl) is reacted with (S)-(3-chloro-2-hydroxy-propyl)-carbamic acid tert-butyl ester (prepared as described in US Patent No. 6,833,453) using conditions analogous to those described for Scheme I, step 2.
  • the product of this reaction is intermediate 2 bearing a tert-butyl carbamate (Boc protected amine) at the C-5 position.
  • step 2 the amine is deprotected by treatment with acids such as hydrochloric acid or trifluoric acid. If less harsh conditions are required, treatement with trimethylsilyltrifluoromethane sulfonate and 2,6-lutidine (as described by Ohfune, Y. and Sakaitani, M. /. Org. Chem. 1990, 55, 870-876) is also effective.
  • the amine can be converted to various amides using well-known coupling reactions (for example by treatment with acid chlorides) or to ureas and carbamates by reaction with isocyanates or alkyl chloroformates, respectively.
  • the products may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.
  • the intermediate 2 can be prepared in a single step involving the transition metal catalyzed reaction of a 4-bromo benzaldehyde starting material (1) with an alkyl carbamate, for example benzyl carbamate. Reactions of this type are well known to those skilled in the art (see for example Buchwald et.al. /. Am. Chem. Soc. 2002, 124, 7421-7428) and are typically carried out with palladium or copper catalysts and employing ligands such as BINAP or related phosphine or arsine ligands.
  • ligands such as BINAP or related phosphine or arsine ligands.
  • the reaction is favorably carried out in solvents such as toluene or benzene and at temperatures of about 50 0 C up to 110 0 C.
  • the product may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.
  • Step 2 of Scheme 5 involves the conversion of benzaldehyde intermediate 2 to the styrene 3.
  • Olefination of 2 is accomplished under conditions well-known to those of ordinary skill in organic chemistry, for example by reaction of the aldehyde with a phophorus ylide (generated by the reaction of a methyltriphenylphosphonium salt with a base such as sodium hydride or potassium bis(trimethylsilyl)amide).
  • the reaction is typically carried out in solvents such as THF or DMF and at temperatures of about -50 0 C up to 25 °C.
  • the product may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.
  • step 3 of Scheme 5 the cyclobutanone ring is formed by the reaction of the styrene intermediate 3 with dichlorocarbene followed by a dechlorination step to provide 4.
  • the generation and [2+2] cycloaddition of dichlorocarbene with olefins is well known and review articles describing these reactions are available (for example, see Brady, W. T. Tetrahedron 1981, 17, 2949-2966).
  • the dichlorocyclobutanone intermediate formed in the cycloaddition reaction is then dechlorinated by reaction with reducing metals (for example with Zn-Cu couple) to form the desired cyclobutanone intermediate.
  • Such reduction reactions are well known and are discussed in review articles, including that referenced above.
  • the products of these reactions may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.
  • Step 4 of Scheme 5 represents one or more steps required for the protection, reduction, or otherwise conversion of the azetidinone ring to a more highly functionalized state. This may involve, for example, reduction, protection of the alcohol thus formed as a silyl ether, fluorination, olefination reactions, oxime formation, or reaction with nucleophiles.
  • the product may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like. Medical and Veterinary Uses
  • the compounds of the present invention may be used for the treatment of infectious, Gram-positive bacterial infections caused by a variety of bacterial organisms, including those that require long-term therapy (>28 days).
  • 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. coll 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 for bacteria that grow aerobically, Approved Standard (6 th ed), M7-A6, NCCLS, Wayne, PA; (2) National Committee for Clinical Laboratory Standards (Mar.
  • 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
  • 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.
  • an oxazolidinone prodrug 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.
  • 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.
  • Stabilizers may be added in these formulations, also.
  • Liquid form compositions include solutions, suspensions and emulsions.
  • solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.
  • the 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.
  • the 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.
  • 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.
  • HATU N-[(dimethylamino)-lH-l ,2,3-triazolo-[4,5-b]pyridin
  • TBS tributylsilyl
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • Boc te/t-butoxycarbonyl
  • Hydrogen fluoride triethylamine complex (0.9 mL, 5.5 mmol) is added to a THF (18.0 mL) solution of ⁇ -( ⁇ (5S)-3-[3-fluoro-4-(3- ⁇ tert-butyldimethylsilyloxy ⁇ - cyclobutyOphenyll ⁇ -oxo-l ⁇ -oxazolidin-S-ylJmethyOacetamide (0.8 g, 1.83 mmol) at room temperature. After 4 hours, the solution is treated with dilute NaHC ⁇ 3 dropwise and extracted with 5% MeOH / dichloromethane. The organic extracts are washed with brine, dried (MgSO 4 ), filtered, and concentrated. Purification by column chromatography (0-8% MeOH-dichloromethane) afforded the title compound.
  • the resulting suspension is stirred at 95°- 100 0 C for 24 hours and cooled down to 23 0 C.
  • the reaction mixture is diluted with aqueous NH 4 Cl (1 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers are washed (brine), 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 0 to 20% ethyl acetate in hexane. Relevant fractions are combined to afford the title compound.
  • Potassium bis(trimethylsilyl)amide solution (64.4 mL of a 0.5M toluene solution, 32.2 mmol) is added to a cooled ( 0 0 C) solution of methyltriphenyphosphoniu ⁇ i bromide ( 11.5 g, 32.2 mmol) in THF (64.4 mL). After stirring at room temperature for 2 h, the mixture is cooled (-78 0 C) and benzyl 3-fluoro-4-formylphenylcarbamate (4.4 g, 16.1 mmol) is added as a solution in THF (23.0 mL). After warming up to -10 0 C, saturated aqueous ammonium chloride is added, along with H 2 O and brine.
  • Trichloroacetyl chloride (3.02 mL, 26.9 mmol) is added to a suspension of benzyl 3- fluoro-4-vinylphenylcarbamate (2.7 g, 9.95 mmol), Zn-Cu couple (2.0 g) and 1,2- dimethoxyethane (5.0 mL) in dry ether (37.0 mL). After refuxing for 16 h, the mixture is filtered and the filtrate is concentrated and taken into dichloromethane. The organic solution is washed with saturated aqueous NaHCO 3 , brine, and dried (MgSO 4 ), filtered, and concentrated.
  • Benzyl 3-fluoro-4-(3-oxocyclobutyl)phenylcarbamate (3.6 g, 11.5 mmol) in THF (88 mL) is cooled (-78 0 C) and treated with diisobutylaluminum hydride solution (34.5 mL of IM solution in THF, 34.5 mmol). After 1.5 h, the mixture is warmed up to room temperature and quenched with saturated aqueous ammonium chlroride and treated with dilute citric acid.
  • Lithium butoxide solution (11.2 mL of a 1.0 M THF solution, 11.2 mmol) is added to a cooled (0 0 C) solution of benzyl 3-fluoro-4-(3- ⁇ tert-butyldimethylsilyloxy ⁇ - cyclobutyOphenylcarbamate (1.2 g, 2.79 mmol) in DMF (1.8 mL) and MeOH (0.226 mL, 5.58 mmol).
  • Solid (S ⁇ -acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (1.18 g, 5.58 mmol) is then added and the solution allowed to warm to room temperature and stirred for 16 h.
  • Lithium butoxide solution (1.59 mL of a 1.0 M THF solution, 11.2 mmol) is added to a cooled (0 0 C) solution of benzyl 3-fluoro-4-(3-methoxycyclobutyl)phenyl- carbamate (0.13 g, 0.39 mmol) in DMF (0.26 mL) and MeOH (0.032 mL, 0.78 mmol).
  • Solid (5)-acetic acid 2- acetylamino-1-chloromethyl-ethyl ester (0.15 g, 0.78 mmol) is then added and the solution allowed to warm to room temperature and stirred for 18 h.
  • Lithium butoxide solution (2.62 mL of a 1.0 M THF solution, 2.62 mmol) is added to a cooled (0 0 C) solution of benzyl 4-(3,3-difluorocyclobutyl)-3-fluorophenylcarbamate (0.22 g, 0.66 mmol) in DMF (0.44 mL) and MeOH (0.053 mL, 1.32 mmol).
  • Solid (S)-acetic acid 2-acetylamino-l-chloromethyl- ethyl ester (0.26 g, 1.32 mmol) is then added and the solution allowed to warm to room temperature and stirred for 72 h.
  • Hydrogen fluoride tr ethylamine complex (0.11 mL Y, 0.66 mmol) is added to a THF (2.2 mL) solution of ⁇ -( ⁇ (5S)-3-[3,5-difluoro-4-(3- ⁇ rert-butyldimethylsilyloxy ⁇ - cyclobutyOphenylJ ⁇ -oxo-l ⁇ -oxazolidin-S-ylJmethyOacetamide ⁇ .l g, 0.22 mmol) at room temperature. After 3 hours, the solution is treated with saturated aqueous NaHCO 3 dropwise and extracted with chloroform.
  • Potassium bis(trimethylsilyl)amide solution (25.0 mL of a 0.5 M toluene solution, 12.4 mmol) is added to a cooled (0 0 C) solution of methyltriphenyphosphonium bromide (4.4 g, 12.4 mmol) in THF (25 mL). After stirring at room temperature for 3 hours, the mixture is cooled (-78 0 C) and benzyl 3,5-difluoro-4-formylphenylcarbamate (1.8 g, 6.2 mmol) is added as a solution in THF (8.3 mL). After stirring at room temperature for 16 hours, saturated aqueous ammonium chloride is added, along with H 2 O and brine.
  • THF (10.5 mL) is cooled (-78 0 C) and treated with diisobutylaluminum hydride solution (4.0 mL of IM solution in THF, 4.0 mmol). After 1.5 hours, the mixture is warmed up to room temperature and quenched with saturated aqueous ammonium chloride and dilute citric acid.
  • Lithium butoxide solution (1.79 mL of a 1.0 M THF solution, 1.79 mmol) is added to a cooled (0 0 C) solution of benzyl 3,5-difluoro-4 ⁇ (3- ⁇ t ⁇ 7f-butyldirnethylsilyloxy ⁇ - cyclobutyOphenylcarbamate (0.2 g, 0.45 mmol) in DMF (0.3 mL) and MeOH (0.036 mL, 0.9 mmol).
  • Solid (5)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (0.174 g, 0.9 mmol) is then added and the solution allowed to warm to room temperature and stirred for 16 hours.
  • Trimethylsilyltrifluorome anesulfonate (0.18 mL Y, 1.0 mmol) is added to a cooled (0 0 C) solution of tert-butyl ⁇ (5S)-3-[3,5-difluoro-4-(3-hydroxy-3-methylcyclobutyl)phenyl]-2- oxo-l,3-oxazolidin-5-yl ⁇ methylcarbamate (0.16 g, 0.39 mmol) in dichloromethane (1.6 mL) and 2,6-lutidine (0.097 mL, 0.84 mmol).
  • Methylmagenesium bromide (1.51 mL of 3.0 M solution in diethyl ether, 4.53 mmol) is taken in THF (2.0 mL) and cooled (-78 0 C). To this solution is added a solution of benzyl 3,5-difluoro-4-(3-oxocyclobutyl)phenylcarbamate (0.75 g, 2.26 mmol) in THF (2.5 mL). After stirring at room temperature for 2 hours, the reaction mixture is quenched with saturated aqueous NH 4 Cl, followed by addition of water and brine. The mixture is extracted with dichloromethane and the organic layer is washed with brine and dried (MgSO 4 ), filtered, and concentrated. Purification by column chromatography (0-4% MeOH-dichloromethane) afforded the title compound.
  • Lithium butoxide solu on (1.5 mL of a 1.0 M TH VF solution, 1.5 mmol) is added to a cooled (0 0 C) solution benzyl 3,5-difluoro-4-(3-fluoro-3-methylcyclobutyl)- phenylcarbamate (0.13 g, 0.37 mmol) in DMF (0.25 mL) and MeOH (0.03 mL, 0.74 mmol).
  • Solid (5)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (0.143 g, 0.74 mmol) is then added and the solution allowed to warm to room temperature and stirred for 60 hours.
  • reaction mixture After stirring at - 78°C for another hour, the reaction mixture is allowed to warm to room temperature and quenched with 1 M aqueous K 2 CO 3 , followed by addition of water and brine.
  • Lithium butoxide solution (0.8 mL of a 1.0 M THF solution, 0.8 mmol) is added to a cooled (0 0 C) solution of benzyl 3,5-difluoro-4-(3-methoxy-3- methylcyclobutyl)phenylcarbamate (0.07 g, 0.2 mmol) in DMF (0.13 mL) and MeOH (0.016 mL, 0.4 mmol).
  • Solid (5)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (0.077 g, 0.4 mmol) is then added and the solution allowed to warm to room temperature and stirred for 16 hours.
  • Trimethyloxonium tetrafluoroborate (0.072 g, 0.49 mmol) is added to a cooled (0 0 C) solution of benzyl 3,5-difluoro-4-(3-hydroxy-3-methylcyclobutyl)phenylcarbamate (0.17 g, 0.49 mmol) and 2,6-di-t ⁇ /t-butyl-4-methyl pyridine (0.2 g, 0.98 mmol) in dichloromethane (3.0 mL). After stirring at 4°C for 60 hours, the reaction mixture is allowed to warm to room temperature and washed with saturated aqueous NaHC ⁇ 3 , brine, and dried (MgSO 4 ), filtered, and concentrated.
  • Lithium butoxide solution (2.8 mL of a 1.0 M THF solution, 2.8 mmol) is added to a cooled (0 0 C) solution of the intermediate I (0.3 g, 0.7 mmol) in DMF (0.47 mL) and MeOH (0.057 mL, 1.4 mmol).
  • Solid (S)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (0.27 g, 1.4 mmol) is then added and the solution allowed to warm to room temperature and stirred for 16 hours. Saturated aqueous ammonium chloride is added, along with H 2 O and brine.
  • Diisopropyl azodicarboxylate (0.28 niL, 1.43 mmol) is added to a solution of benzyl 3-fluoro-4-(3-hydroxycyclobutyl)phenylcarbamate (0.3 g, 0.95 mmol; prepared as described for Example 1), benzoic acid (0.17 g, 1.43 mmol) and triphenylphospine (0.38 g, 1.43 mmol) in diethyl ether (3.5 mL). After stirring at room temperature for 16 hours, the reaction mixture is washed with saturated aqueous NaHC ⁇ 3 , brine, and dried (MgSO 4 ), filtered, and concentrated.

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Abstract

La présente invention concerne un composé selon la formule (I) ou un sel pharmaceutiquement acceptable servant d'agent antibactérien.
PCT/IB2006/001827 2005-07-06 2006-06-26 Oxazolidiones contenant du cyclobutane servant d'agents antibactériens WO2007004032A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108239098A (zh) * 2016-12-26 2018-07-03 中国医学科学院药物研究所 含四氢吡啶的苯并噁嗪噁唑烷酮类化合物及其制备方法和用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003027083A1 (fr) * 2001-04-17 2003-04-03 Merck & Co., Inc. Antibiotiques oxazolidinone contenant du bicyclo[3.1.0] hexane et derives de ces derniers
WO2003072553A1 (fr) * 2002-02-25 2003-09-04 Pharmacia & Upjohn Company N-aryl-2-oxazolidinone-5-carboxamides et leurs derives et utilisation de ces composes comme antibacteriens
WO2005019214A1 (fr) * 2003-08-25 2005-03-03 Warner-Lambert Company Llc Nouveaux composes d'aryloxazolidinone antimicrobiens

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003027083A1 (fr) * 2001-04-17 2003-04-03 Merck & Co., Inc. Antibiotiques oxazolidinone contenant du bicyclo[3.1.0] hexane et derives de ces derniers
WO2003072553A1 (fr) * 2002-02-25 2003-09-04 Pharmacia & Upjohn Company N-aryl-2-oxazolidinone-5-carboxamides et leurs derives et utilisation de ces composes comme antibacteriens
WO2005019214A1 (fr) * 2003-08-25 2005-03-03 Warner-Lambert Company Llc Nouveaux composes d'aryloxazolidinone antimicrobiens

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108239098A (zh) * 2016-12-26 2018-07-03 中国医学科学院药物研究所 含四氢吡啶的苯并噁嗪噁唑烷酮类化合物及其制备方法和用途

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