WO2005082897A1 - Agents antibacteriens oxazolidinone - Google Patents

Agents antibacteriens oxazolidinone Download PDF

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Publication number
WO2005082897A1
WO2005082897A1 PCT/IB2005/000102 IB2005000102W WO2005082897A1 WO 2005082897 A1 WO2005082897 A1 WO 2005082897A1 IB 2005000102 W IB2005000102 W IB 2005000102W WO 2005082897 A1 WO2005082897 A1 WO 2005082897A1
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Prior art keywords
methyl
oxo
benzo
oxazolidin
oxazin
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PCT/IB2005/000102
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English (en)
Inventor
Mikhail Fedorovich Gordeev
Rama Jain
Vara Prasad Venkata Nagendra Josyula
Gary Wayne Luehr
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Pharmacia & Upjohn Company Llc
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Publication of WO2005082897A1 publication Critical patent/WO2005082897A1/fr

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    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a new class of amidoxime and amidine oxazolidinone derivatives, to their use as antibacterial agents, to pharmaceutical compositions containing these compounds and to methods for their preparation.
  • oxazolidinone compounds are the most recent synthetic class of antimicrobials active against a number of pathogenic microorganisms. This invention provides novel amidoxime derivatives of oxazolidinones, and their preparation.
  • PCT publication WO 9964416 discloses oxazolidinone derivatives.
  • PCT publication WO 9964417 discloses oxazolidinone derivatives.
  • PCT publication WO 200021960 discloses heterocyclyl aminomethyl oxazolidinone derivatives.
  • PCT publication WO 200029409 discloses oxazolidinone derivatives.
  • PCT publication WO 200181350 discloses oxazolidinone derivatives and their salts or in vivo hydrolysable esters.
  • PCT publication WO 200281470 discloses oxazolidinone compounds and their salts or in vivo hydrolysable esters.
  • X is a structure of the following formula i, ii, iii, or iv
  • Y 1 , Y 2 and Y 3 are independently (a) CH, (b) N, (c) N + -O ⁇ or (d) CF;
  • G is -(CR 3 R 4 ) literal-;
  • R 2 is H or Ci- alkyl, optionally substituted with 1-3 fuloro;
  • R 3 and R 4 are independently (a) H (b) Ci- 6 alkyl, or (c) R 3 and R 4 taken together with the carbon atom to which they attach form C 3 - 7 cycloalkyl;
  • V is N, or C;
  • R 5 and R 6 are independently (a) H, or (b) Ci- alkyl, optional aryl is phenyl, biphenyl, or naphthyl, optionally substituted with halo, OR 5 , SR 5 , CN,
  • het is a five- (5) or six- (6) membered heterocyclic ring having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen within the ring, wherein each carbon atom in het is optionally substituted with halo, OR 5 , SR 5 , CN,
  • 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 microbial infections.
  • the invention may also provide novel intermediates and novel processes that are useful for preparing compounds of formula I.
  • C - 7 cycloalkyl refers to a cyclic saturated monovalent hydrocarbon group of three to seven carbon atoms, e.g., cyclopropyl, cyclohexyl, and the like.
  • halo refers to fluoro (F), chloro (CI), bromo (Br), or iodo (I).
  • 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, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, is
  • het includes, but are not limited to, pyridine, thiophene, furan, 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-o
  • 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.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-
  • 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.
  • 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.
  • 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”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • 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 arnino 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
  • alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, and their isomeric forms thereof.
  • alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, and their isomeric forms thereof.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and their isomeric forms thereof.
  • halo is fluoro (F), chloro (CI).
  • R 1 is Ci- 4 alkyl, optionally substituted with one, two or three fluoro (F), or chloro (CI).
  • R 1 is CH 3 , or CH 2 CH 3 .CHF 2 , CF 3 , or CHC1 2 .
  • R 1 is CHF 2 , CF 3 , or CHC1 2 .
  • W is CH het.
  • W is 1,2,3-triazole-l-yl methyl, or tetrazole- 1-yl methyl.
  • Y 1 , Y 2 , or Y 3 is CH.
  • one of the Y 1 , Y 2 and Y 3 is N, the other two are CH.
  • Y 1 is CF
  • Y 2 and Y 3 are CH.
  • G is CH 2 .
  • U is CH 2 .
  • U is O ir S.
  • R 2 is CH 3 .
  • R 2 is CH 2 F or CHF 2 .
  • V is N.
  • Z is CN.
  • Z is OCi. 6 alkyl, optionally substituted with OH, or O ⁇ alkyl.
  • Z is substituted with OC ⁇ - alkyl which may may be further substituted with a phenyl.
  • Z is OH or OCH 3 .
  • X is a structure of formula ii
  • Examples of the present invention include: a. (5S)-N-[3-(3-Methoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide, b. (5S)-N-[3-(3-Methoxyimino-4-methyl-3, 4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-propionamide, c.
  • R 1 , R 2 , Y 1 , Y 2 and Y 3 are as described previously), conveniently prepared as described by Bartel et al. in WO 9937641, is protected as a carbamate and converted to the thione using various thionation reagents, such as Lawesson, Davy, Yokahama or Belleau reagents, Na 2 P 4 S ⁇ ,
  • the reaction is most conveniently conducted using Lawesson' s reagent in a suitable organic solvent, such as dioxane or tetrahydrofuran, and is typically performed at temperatures in a range of from 25 °C to about 100 °C.
  • a suitable organic solvent such as dioxane or tetrahydrofuran
  • the intermediate thione compound lb is reacted with an alkxoyamine or a salt thereof such as methoxylamine hydrochloride and a suitable base at temperatures ranging from 25 °C to about 100 °C to give the desired benzazinone oxime intermediate lc.
  • Solvents for this transformation may include pyridine, an alcohol such as methanol or ethanol, or dimethylformamide.
  • Suitable bases include inorganic bases such as potassium carbonate or organic bases such as pyridine, triethylamine or N,N- diisopropylethylamine.
  • the synthesis of Scheme I continues with construction of the requisite oxazolidinone substituent using known chemistry methods such as described in US Patent No. 6,107,519. It is further understood that the amidoxime syntheses described herein are generally applicable to amidoxime derivatives bearing other groups in place of the oxazolidinone substituent (such as isoxazoline, isoxazolinone, or butenolide groups).
  • the Boc-protected oxazolidinone derivatives Id can be deprotected to give the corresponding amine. It is convenient to remove the Boc group with 20 to 60% trifluoroacetic acid in dichloroethane or hydrogen chloride in dioxane at temperatures ranging from 0 °C to 24 °C.
  • the synthesis is then completed by an acylation of the penultimate amine intermediate using known art. Thus, acylations can be routinely performed by reactions of the amines with carboxylic acid anhydrides or esters.
  • the compound 2b is then converted to the thione 2c using various thionation reagents, such as Lawesson, Davy, Yokahama or Belleau reagents, Na 2 P 4 S ⁇ , Na 2 P 4 S 10 O, or alike known reagents capable of converting amides into thioamides.
  • the reaction is most conveniently conducted using Lawesson' s reagent in a suitable organic solvent, such as dioxane or tetrahydrofuran, and is typically performed at temperatures in a range of from 25 °C to about 100 °C.
  • the Boc-protected oxazolidinone intermediate 2c is then deprotected to give the corresponding amine.
  • the intermediate thione compound 2d is reacted with hydroxylamine or a salt thereof such as hydroxylamine hydrochloride and a suitable base, a protected source of hydroxylamine such as O-(trimethylsilyl)hydroxylamine or N,O-bis- (trimethylsilyl)hydroxylamine in a protic solvent to provide 2e.
  • Solvents for this transformation may include pyridine, an alcohol such as methanol or ethanol, or dimethylformamide.
  • Suitable bases include inorganic bases such as potassium carbonate or organic bases such as pyridine, triethylamine or N,N- diisopropylethylamine.
  • the amidoxime benzazinone oxazolidinone 2e may be converted to an amidoxime ether le by reaction with a suitable electrophilic alkylating agent such as an alkyl halide, sulfate or tosylate, or a reagent containing an electrophilic multiple bond such as acrylonitrile in the presence of a suitable inorganic or organic base, such as sodium hydride or lithium bis(trimethylsilyl)amide.
  • a suitable electrophilic alkylating agent such as an alkyl halide, sulfate or tosylate, or a reagent containing an electrophilic multiple bond such as acrylonitrile in the presence of a suitable inorganic or organic base, such as sodium hydride or lithium bis(trimethylsilyl)amide.
  • the amidoxime benzazine oxazolidinone 2e may be acylated using known art to provide O-acyloximes 2f.
  • Solvents for the transformations may include tetrahydrofuran or dimethylformamide, and the reaction is typically performed in the range of about 0 °C to about 80°C.
  • Scheme HI illustrates one general synthetic route to amidoxime triazoloylmethyl oxazolidinone derivatives.
  • Scheme IN illustrates a general synthetic route to amidoxime isoxazolylaminomethyl and isoxazolyl ether oxazolidinone derivatives.
  • the hydroxymethyl amidoxime benzazine derivative 3b is coupled with an appropriate amino-isoxazole or hydroxy-isoxazole, for example 3-(2,2,2- trichloroethoxycarbonyl-amino)isoxazole (may be prepared as described in PCT publication WO 0021960) or 3-hydroxyisoxazole (may be prepared as described in US Patent 3,687,968).
  • an appropriate amino-isoxazole or hydroxy-isoxazole for example 3-(2,2,2- trichloroethoxycarbonyl-amino)isoxazole (may be prepared as described in PCT publication WO 0021960) or 3-hydroxyisoxazole (may be prepared as described in US Patent 3,687,968).
  • a suitable coupling reagent such as diisopropylazo-dicarboxylate (DIAD).
  • the coupling reaction is typically conducted in a polar aprotic solvent, such as dimethylformamide, acetonitrile, tetrahydrofuran, or mixtures thereof, in the presence of organic base, such as triphenylphosphine.
  • a polar aprotic solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, or mixtures thereof
  • organic base such as triphenylphosphine.
  • the process is typically carried out at about 0 to about 50.
  • the resulting carbamic acid intermediate can then be reduced to the heteroaryl amine 4b.
  • Schemes V and VI illustrate general synthetic routes to cyanoimine and nitromethylene benzazine oxazolidinone derivatives.
  • amidino derivative 7a provides nitroamidino derivative 8a.
  • 7a may be acylated or sulfonylated to provide amidino amide, or sulfonamide derivative as shown in
  • Scheme VIE Schemes IX-XII describe the synthesis of aryl isoxazolinone, aryl isoxazoline and aryl butyrolactones bearing amidoxime groups.
  • Scheme IX describes the synthesis of aryl isoxazolinone amidoximes.
  • the aldehyde group is conveniently protected as an acetal or other suitable protecting group and the benzazinone converted to the thione using various thionation reagents as previously described.
  • the intermediate thione compound 9c is reacted with an alkoxyamine or a salt thereof as described previously to give the desired benzazinone oxime intermediate 9d.
  • the acetal protecting group is removed using various reaction conditions that are well known in the art (see “Protecting Groups” by Philip J. Kocienski; publisher : Georg Thieme Nerlag: Stuttgart, 1994).
  • Benzaldehyde intermediate 9e may be reacted with ethyl diazoacetate (as described by Mahmood, et al. in J. Org. Chem., 1998, Vol. 63, pp. 3333-3336) to provide ester aldehyde intermediate If.
  • Scheme X describes the synthesis of aryl isoxazoline amidoximes.
  • Aldehyde 9e is reacted with hydroxylamine hydrochlori.de in a polar protic solvent, such as methanol, in the presence of a base, such as pyridine, to afford oxime 10a.
  • the oxime is oxidized with N-chlorosuccinimide in a suitable solvent, such as dichloromethane, to give the intermediate N-hydroxyoximidoyl chloride 10b.
  • N-hydroxyoximidoyl chloride is reacted with an allylic compound such as allyl alcohol or N-acetylamine, in the presence of a base, such as triethylamine, in a solvent such as dichloromethane, to provide the hydroxymethyl or acetamidomethyl substituted isoxazolines.
  • the resulting D-hydroxyacid is cyclized with catalytic p-toluenesulfonic acid to provide lactone lib as a mixture of diastereomers.
  • the Z-group functionality may be introduced by a known sequence of hydrogenolytic benzyl deprotection, mesylate formation, nucleophilic substitution by azide ion, hydrogenolytic reduction and acetyl formation with acetic anhydride.
  • the saturated butyrolactone is then brominated with N-bromosuccinimde, and the double bond introduced by elimination with pyridine in a suitable solvent such as pyridine to provide lid.
  • Medical and Veterinary Uses 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.
  • anaerobic organisms such as bacteroides and clostridia species
  • 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.
  • Antibacterial activity 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.
  • 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.
  • Pharmaceutical 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.
  • concentrated sugar solutions 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.
  • Pharmaceutical 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.
  • 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.
  • 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.
  • suitable non-irritating excipient 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. Additionally, the compounds may be delivered using a sustained-release system. Various 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 Pharmaceutical 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.
  • 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. Generally, 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.
  • the dosages may vary depending upon the requirements of each subject and the severity of the bacterial infection being treated.
  • 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.
  • Step 1 Preparation of 7-nitro-4H-benzo[l,4]oxazin-3-one.
  • 2-amino-5-nitrophenol (10 g, 0.065 M) and potassium carbonate (23 g, 0.162 M) in DMF (30 ml) are heated at 90 °C for 24 h.
  • the reaction mixture is allowed to cool and diluted with water.
  • the resulting precipitate is collected by filtration and dried under vacuum to give the title compound as a brown solid. (11.5g, 91%); HPLC r.t. 4.23 rnin.
  • Step 2 Preparation of 4-methyl-7-nitro-4H-benzo[l,4]oxazin-3-one.
  • 7- ⁇ itro-4H-benzo[l,4]oxazin-3-one (6.0 g, 0.031 mol), iodomethane (5.8 ml, 0.093 mol) and potassium carbonate (4.3 g, 0.031 mol) in DMF (30 ml) are stirred for 24 h at room temperature.
  • the reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na 2 SO 4 ) and evaporated to give the title compound as a brown solid (6.2 g, 96.8%); HPLC r.t. 4.78 rnin.
  • Step 3 Preparation of 7-amino-4-methyl-4H-benzo[l,4]oxazin-3-one.
  • Iron powder (6.45 g, 0.11 mol) is added in small portions to 4-methyl-7-nitro- 4H-benzo[l,4]oxazin-3-one (6.0 g, 0.0288 mol) and ammonium chloride (15.4 g, 0.288 mol) in ethanol (150 ml) and water (75 ml) at 90 °C.
  • the reaction mixture is stirred vigorously and heated for 1 hour, allowed to cool to room temperature, and diluted with dichloromethane (500 ml).
  • Step 4 Preparation of (4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- carbamic acid benzyl ester.
  • Benzyl chloroformate (4.37ml, 0.031M) is added dropwise to 7-amino-4- methyl-4H-benzo[l,4]oxazin-3-one (5.0g, 0.028M) and pyridine (4.53ml, 0.056M) in dichloromethane (50ml) at 0 °C.
  • the reaction mixture is stirred at 0 °C for 30 rnin, allowed to warm at room temperature and then diluted with water.
  • Step 4 Preparation of (4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- carbamic acid benzyl ester.
  • Step 6 Preparation of (5S)-[3-(3-methoxyimino-4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Lithium t-butoxide (1.0 M solution in THF, 4.38 ml, 4.38 mmol) is added at 0 °C to 3-methoxyimino-4-methyl-3, 4-dihydro-2H-benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (0.5 g, 1.46 mmol) and (3-chloro-2-hydroxy-propyl)-carbamic acid tert-butyl ester (0.45 g, 2.2 mmol) in DMF (5 ml). The reaction mixture is allowed to warm at room temperature and stirred for 24h. The reaction is quenched with saturated aqueous ammonium chloride, diluted with water and extracted with dichloromethane.
  • Step 7 Preparation of (5R)-7-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l,4]oxazin-3-one O-methyl-oxime.
  • 3-(3-Methoxyimino-4-methyl-3 ,4-dihydro-2H-benzo [ 1 ,4]oxazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester (0.35 g, 0.86 mmol) is stirred with 50% TFA/DCM (4 ml) for 1 h at room temperature. The solvent is evaporated to give the title compound as the TFA salt (0.36 g, 99%); HPLC r.t. 3.54 min; MS for C 14 H 18 N 4 O 4 m/z 307.0(M+H) + .
  • Step 8 Preparation of (5S)-N-[3-(3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[ 1 ,4] oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl] -acetamide.
  • Acetic anhydride (0.163 ml, 1.71 mmol) is added dropwise at 0 °C to (5R)-7- (5-aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4 ⁇ -benzo[l ,4]oxazin-3-one O- methyl-oxime (0.35 g, 1.14 mmol) and diisopropylethylamine (0.6 ml, 3.42 mmol) in dichloromethane (5 ml). The reaction mixture is stirred at 0 °C for 30 min. then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water, citric acid and brine, dried ( ⁇ a 2 SO 4 ) and evaporated to give the title compound as an off white solid (0.3 g, 75%); HPLC r.t.
  • Methyl chloroformate (0.177 ml, 2.28 mmol) is added at 0 °C to 7-(5- aminomethyl-2-oxo-oxazolidin-3 -yl)-4-methyl-4H-benzo [ 1 ,4] oxazin-3 -one O-methyl- oxime (Example 1, Step 7, 0.35 g, 1.14 mmol) and diisopropylethylamine (0.6 ml, 3.42 mmol) in dichloromethane (5 ml). The reaction mixture is allowed to warm at room temperature and stirred for 1 h.
  • reaction mixture is diluted with dichloromethane, washed with water, citric acid and brine, dried ( ⁇ a 2 SO ), and evaporated to give the title compound as an off white solid solid (0.31 g, 74%); HPLC r.t.
  • Methyl isocyanate (0.036 ml, 0.636 mmol) was added to (5R)-7-(5-aminomethyl-2- oxo-oxazolidin-3-yl)-4-methyl-4H-benzo [1,4] oxazin-3-one O-methyl-oxime (Example 1, Step 7, 0.134 g, 0.318 mmol) and diisopropylethylamine (0.33ml, 1.908mmol) in dichloromethane (5ml) at 0 °C. The mixture was allowed to warm at room temperature and stirred for 1 hour.
  • Step 1 Preparation of 7-(5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l ,4]oxazin-3-one O-methyl-oxime.
  • Lithium bis(trimethylsilyl)amide (1.0 M in THF, 3.21 ml, 0.00321 mol) is added dropwise at -78 °C to (3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (1.0 g, 0.00292 mol) in THF (10 ml).
  • Step 2 Preparation of (5R)-methanesulfonic acid 3-(3-methoxyimino-4-methyl-3,4- dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl ester.
  • Methanesulfonyl chloride (0.162 ml, 2.1 mmol) is added dropwise at 0 °C to
  • Step 3 Preparation of (5R)-7-(5-azidomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l,4]oxazin-3-one O-methyl-oxime.
  • Step 4 Preparation of (5R)-4-methyl-7-(2-oxo-5-[l,2,3]triazol-l-ylmethyl- oxazolidin-3-yl)-4H-benzo [ 1 ,4]oxazin-3-one O-methyl- 1 -oxime.
  • Step 1 Preparation of [3-(4-methyl-3-oxo-3, 4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2- oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Lithium t-butoxide (1.0 M solution in THF, 42.2 ml, 42.24 mmol) is dropwise at 0 °C to 4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (5.5 g, 17.6 mmol) and (3-chloro-2-hydroxy-propyl)-carbamic acid tert- butyl ester (4.58 g, 22.18 mmol) in DMF (50 ml). The reaction mixture is allowed to warm to room temperature and stirred for 24 h.
  • Step 2 Preparation of (5S)-[3-(4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin- 7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Step 3 Preparation of (5R)-aminomethyl-3-(4-methyl-3-thioxo-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-oxazolidin-2-one.
  • Step 4 Preparation of (5S)-N-[3-(4-methyl-3-thioxo-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • Acetic anhydride (0.585 ml, 6.12 mmol) is added at 0 °C to (5R)- aminomethyl-3-(4-methyl-3-thioxo 3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- oxazolidin-2-one (1.2 g, 4.08 mmol) and diisopropylethylamine (2.13 ml, 12.2 mmol) in dichloromethane (15 ml). The reaction mixture is stirred at 0 °C for 30 min, allowed to warm at room temperature and diluted with dichloromethane. The organic layer is separated, washed with water, citric acid and brine, dried ( ⁇ a 2 SO 4 ) and evaporated. The residue is purified to give the title compound as a light brown solid (1.3 g, 95%); HPLC r.t. 4.28 min; MS for C 15 H ⁇ 7 N 3 O 4 S m/z 336.0(M+H) + .
  • Step 5 Preparation of (5S)-N-[3-(3-ethoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide. N-[3-(4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo- oxazolidin-5-ylmethyl]-acetamide (50 mg, 0.15 mmol) and O-ethyl hydroxylamine (88.5 mg, 0.90 mmol) in pyridine (2 ml) are heated overnight at 70 °C.
  • Step 1 Preparation of (3-Hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin- 7-yl)-carbamic acid benzyl ester 4-Methyl-3-thioxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl)- carbamic acid benzyl ester (1.2 g, 3.65 mmol)(Example 1, step 5) and N, O-bis(trimethylsilyl) hydroxylamine (1.4 ml, 6.55 mmol) in ethanol (25 ml) were heated overnight at 70 °C.
  • Step 2 Preparation of [4-Methyl-3-(tetrahydro-pyran-2yloxyimino)-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (3-Hydroxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (0.93 g, 2.84 mmol), 3,4-dihydro-2H-pyran (0.57 ml, 6.25 mmol) and p-toluene sulfonic acid (0.108 g, 0.568 mmol) in DMF (6 ml) were stirred at room temperature for 72 hours.
  • Step 3 Preparation of (5S)- ⁇ 3-[4-Methyl-3-(tetrahydro-pyran-2yloxyimino)-3,4- dihydro-2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl ⁇ -carbamic acid tert- butyl ester Lithium t-butoxide (1.0 M solution in THF, 5.82 ml, 5.82 mmol) was added at 0 °C to [4-methyl-3-(tetrahydro-pyran-2yloxyimino)-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (0.80 g, 1.94 mmol) and (3-chloro- 2-hydroxy-propyl)-carbamic acid tert-butyl ester (0.609 g, 2.91 mmol) in DMF (7 ml
  • Step 4 Preparation of (5R)-7-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l,4]oxazin-3-one oxime.
  • Step 5 (5S)-[3-(3-Hydroxyimino -4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- 2-oxo-oxazolidin-5-ylmethyl] -carbamic acid methyl ester Methyl chloroformate (0.046 ml, 0.588 mmol) was added to (5R)-7-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H-benzo [ 1 ,4] oxazin-3-one oxime.
  • Step 1 Preparation of (5S)-N-[3-(3-hydroxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • Step 2 Preparation of (5S)-N-[3-(3-isopropoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • reaction is quenched with sat. ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried ( ⁇ a 2 SO 4 ) and evaporated.
  • residue is purified by PTLC (10% MeO ⁇ /DCM) to give product as a white solid (0.45 g, 64%); ⁇ PLC r.t.
  • Step 1 Preparation of (4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-7-yl)- carbamic acid benzyl ester.
  • Benzyl chloroformate (4.01 mL, 28.08 mmol) is added at 0 °C to a stirred solution of 7-amino-4-methyl-4H-benzo[l,4]thiazin-3-one (prepared accordind to the method described in WO/03072553) (3.41 g, 17.55 mmol) and pyridine (3.12 mL, 38.62 mmol) in dry DCM (20 ml).
  • the reaction mixture is allowed to warm to room temperature and then washed with 2N HC1.
  • Step 2 Preparation of (5S)-[3-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Lithium t-butoxide (1.0 M solution in THF, 35.45 ml, 35.45 mmol) is added dropwise at 0 °C to (4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]thiazin-7-yl)- carbamic acid benzyl ester (3.88g, 11.8 mmol) and (3-chloro-2-hydroxy-propyl)- carbamic acid tert-butyl ester (3.714 g, 17.7 mmol) in DMF (9 ml). The reaction mixture is allowed to warm at room temperature and stirred for 16 h.
  • Step 3 Preparation of (5S)-[3-(4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]thiazin- 7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Step 4 Preparation of (5S)-N-[3-(4-methyl-3-thioxo-3,4-dihydro-2H- benzo[l,4]thiazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • Step 5 Preparation of (5S)-N-[3-(3-hydroxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]thiazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • Step 1 Preparation of (l-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester.
  • Benzyl chloroformate (0.171 mL, 1.2 mmol) is added at 0 °C to a stirred solution of 6-amino-l-methyl-3,4-dihydro-lH-quinolin-2-one (prepared according to the method described in WO/03072553) (0.176 g, 1.00 mmol) and pyridine (0.194 mL, 2.40 mmol) in dry DCM (5 ml).
  • the reaction mixture is allowed to warm to room temperature and then washed with 2 ⁇ HCl.
  • Step 2 Preparation of (5S)-[3-(l-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl)-2- oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Lithium t-butoxide (1.0 M solution in THF, 2.3 ml, 2.33 mmol) is added dropwise at 0 °C to (l-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester (2.0 g, 6.41 mmol) and (3-chloro-2-hydroxy-propyl)-carbamic acid tert- butyl ester (0.300 g, 0.97 mmol) in DMF (2 ml). The reaction mixture is allowed to warm at room temperature and stirred overnight. The reaction is quenched with saturated aqueous ammonium chloride, diluted with water and extracted with dichloromethane.
  • Step 3 Preparation of (5S)-[3-(l-methyl-2-thioxo-l,2,3,4-tetrahydro-quinolin-6-yl)-2- oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Step 4 Preparation of (5S)-N-[3-(l-methyl-2-thioxo-l,2,3,4-tetrahydro-quinolin-6- yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • TFA (1.50 ml) in dichloroethane (2 ml) is added to [3-(l-Methyl-2-thioxo- 1 ,2,3,4-tetrahydro-quinolin-6-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert- butyl ester (0.39 g, 4.0 mmol).
  • Step 5 Preparation of (5S)-N-[3-(2-Hydroxyimino-l-methyl-l,2,3,4-tetrahydro- quinolin-6-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • Step 1 Preparation of (l-Methyl-2-thioxo-l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester.
  • Step 2 Preparation of (2-Methoxyimino-l-methyl-l,2,3,4-tetrahydro-quinolin-6-yl)- carbamic acid benzyl ester.
  • Methoxylamine hydrochloride (3.157 g, 37.8 mmol) and (l-methyl-2-thioxo- l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester (3.00 g , 9.22 mmol) in pyridine (45 mL), was added) was heated for 48 hours at 70 °C. The reaction was evaporated, diluted with dichloromethane, washed with water and brine, dried (MgSO ) and evaporated.
  • Step 3 Preparation of (5S)-[3-(2-Methoxyimino-l-methyl-l,2,3,4-tetrahydro-quinolin- 6-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Lithium t-butoxide (1M in THF, 7.13 mL, 7.13 mmol) was added at 0 °C to (2- methoxyimino-l-methyl-l,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid benzyl ester (1.10 g , 3.24 mmol) and (3-chloro-2-hydroxy-propyl)-carban ic acid tert-butyl ester (1.024 g, 4.884 mmol)in DMF (10 mL). The mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane.
  • Propionic anhydride (0.325 ml, 2.538 mmol) was added to (5R)-6-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-l-methyl-3,4-dihydro-lH-quinolin-2-one O- methyl-oxime (0.531 g , 1.27 mmol) and diisopropylethylamine (0.629 ml, 3.081 mmol) in dichloromethane (5 ml) was added) at 0 °C. The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature.
  • Step 1 Preparation of 2-amino-3-fluoro-5-nitro-phenol.
  • 4-Fluoro-6-nitro-l, 3-benzoxazol-2 (3H)-one (prepared according to the method described in WO/03072553) (5.0 g, 0.02 mol) and sodium hydroxide (5.05 g, 0.126 mol) in water (125 ml) is heated at 100 °C for 3 h.
  • the reaction mixture is cooled to room temperature and carefully neutralized with 6 ⁇ hydrochloric acid.
  • the resulting precipitate is filtered, washed with water and dried under vacuum to provide pure the title compound as orange solid (3.1 g, 72%); HPLC r.t. 4.05 min.
  • Step 3 Preparation of 5-fluoro-4-methyl-7-nitro-4H-benzo[l,4]oxazin-3-one.
  • Iodomethane (1.65 ml, 0.0283 mol)
  • 5-fluoro-7-nitro-4H-benzo[l,4]oxazin-3- one 2.0 g, 0.0094 mol
  • potassium carbonate 1.3 g, 0.0094 mol
  • the reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na 2 SO ) to give the title compound as a brown solid suitable for use directly in the next step (1.8 g, 84.5%); HPLC r.t. 4.82 min.
  • Step 4 Preparation of 7-amino-5-fluoro-4-methyl-4H-benzo[l,4]oxazin-3-one.
  • Iron powder (2.27 g, 0.0406 mol) is added in small portion to a mixture of 5- fluoro-4-methyl-7-nitro-4H-benzo[l,4]oxazin-3-one (2.3 g, 0.010 mol) and ammonium chloride (5.41 g , 0.102 mol) in ethanol (100 ml) and water (50 ml) at 90 °C.
  • the reaction mixture is stirred vigorously and heated for 1 hour, cooled to room temperature and diluted with dichloromethane (200 ml).
  • the mixture is filtered through celite, washed with water and brine, dried over sodium sulfate and evaporated to give the title compound as a brown solid (1.77 g, 89%); HPLC r.t. 2.47min.
  • Step 5 Preparation of (5-fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7- yl)-carbamic acid benzyl ester.
  • Benzyl chloroformate (1.38 ml, 0.00981 mol) is added dropwise to a mixture of 7-amino-5-fluoro-4-methyl-4H-benzo[l,4]oxazin-3-one (1.75 g, 0.00892 mol) and pyridine (1.44 ml, 0.0178 mol) in dichloromethane (15 ml) at 0 °C.
  • Step 6 Preparation of (5-fluoro-4-methyl-3-thioxo-3, 4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester.
  • 5-Fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (2.2 g, 0.0066 mol) and Lawesson's reagent (2.04 g, 0.005 mol) in dioxane (15 ml) are heated overnight at 70 °C.
  • Step 7 Preparation of (5-fluoro-3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester.
  • 5-Fluoro-4-methyl-3-thioxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- carbamic acid benzyl ester (0.85 g, 2.45 mmol) and methoxylamine hydrochloride (1.22 g, 14.7 mmol) in pyridine (8 ml) are heated overnight at 70 °C. The reaction mixture is evaporated to dryness.
  • Step 8 Preparation of (5S)-[3-(5-fluoro-3-methoxyimino-4-methyl-3, 4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Lithium t-butoxide (1.0 M solution in THF, 7.35 ml, 7.35 mmol) is added dropwise at 0 °C to 5-fIuoro-3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (0.8g, 2.4mmol) and (3-chloro-2- hydroxy-propyl)-carbamic acid tert-butyl ester (0.77 g, 3.67 mmol) in DMF (10 ml). The reaction mixture is allowed to warm at room temperature and stirred for 144 h.
  • Step 9 Preparation of (5S)-7-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-5-fluoro-4- methyl-4H-benzo [ 1 ,4] oxazin-3 -one O-methyl-oxime.
  • 3-(5-Fluoro-3-methoxyimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin-7- yl)-2-oxo-oxazolidin-5-ylmethyl] -carbamic acid tert-butyl ester (0.47 g, 1.11 mmol) is stirred with 50% TFA/DCM (4 ml) for 1 h at room temperature.
  • Step 10 Preparation of (5S)-N-[3-(5-fluoro-3-methoxyimino-4-methyl-3, 4-dihydro- 2H-benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • Acetic anhydride (0.156 ml, 1.64 mmol) is added dropwise at 0 °C to (5R)-7- (5-aminomethyl-2-oxo-oxazolidin-3-yl)-5-fluoro-4-methyl-4H-benzo[l,4]oxazin-3- one O-methyl-oxime (0.355 g, 1.09 mmol) and diisopropylethylamine (0.57 ml, 3.27 mmol) in dichloromethane (5 ml). The reaction mixture is stirred at 0 °C for 30 min then allowed to warm at room temperature.
  • Methyl chloroformate (0.12 ml, 1.55 mmol) was added dropwise to (5R)-7-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-5-fluoro-4-methyl-4H-benzo [1,4] oxazin-3-one O-methyl-oxime (0.34 g, 0.775 mmol) (from Example 21, step 9) and diisopropyl ethylamine (0.80 ml, 4.65 mmol) in dichloromethane (5 ml) at 0 °C. The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature.
  • Step 1 Preparation of 7-nitro-4H-benzo [1,4] oxazin-3 -thione 7-Nitro-4H-benzo [1,4] oxazin-3-one (5.0 g, 25.75 mmol) and Lawesson's reagent (7.78 g, 19.31mmol) in tetrahydrofuran (50 ml) was heated 3 hours at 55 °C. The mixture was evaporated and residue triturated with dichloromethane and dried under vacuum to give product as a greenish yellow solid (5.3 g, 97.9%); HPLC r.t. 4.87 min; MS for C 8 H 6 N 2 O 3 S m/z 209.0 (M-H) " .
  • Step 2 Preparation of 7-nitro-4H-benzo [1,4] oxazin-3-one O-methyl-oxime 7-Nitro-4H-benzo [1,4] oxazin-3 -thione (2.5 g, 11.89 mmol) and methoxylamine hydrochloride (2.97 g, 35.67 mmol) in pyridine (15 ml) was heated overnight at 70°C. The mixture was evaporated and the residue diluted with ethyl acetate, washed with 5% aqueous citric acid, water and brine, dried (Na 2 SO 4 ) and evaporated to give product as a yellow solid (2.55 g, 96%); HPLC r.t. 4.59 min; MS for C 9 H 9 N 3 O 4 m/z 222.2 (M-H) " .
  • Step 3 Preparation of 7-Amino-4H-benzo [1,4] oxazin-3-one O-methyl-oxime
  • Iron powder (1.18g, 21.5mmol) was added in small portion to a mixture of 7- nitro-4H-benzo [1,4] oxazin-3-one O-methyl-oxime (1.2 g, 5.37 mmol) and ammonium chloride (2.82 g, 53.7 mmol) in ethanol (50 ml) and water (25 ml) at 90 °C.
  • the reaction mixture was stirred vigorously and heated for 1 hour, cooled to room temperature and diluted with dichloromethane (200 ml).
  • Step 4 Preparation of (3-Methoxyimino-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) - carbamic acid benzyl ester
  • Benzyl chloroformate (0.497 ml, 3.53 mmol) was added dropwise to a mixture of 7-amino-4H-benzo [1,4] oxazin-3-one O-methyl-oxime (0.62 g, 3.21 mmol) and pyridine (0.52 ml, 6.42 mmol) in dichloromethane (10 ml) at 0 °C.
  • the reaction mixture was stirred at 0 °C for 30 minutes, allowed to warm at room temperature and then poured into water.
  • Step 5 Preparation of (5S)-[3-(3-Methoxyimino-3,4-dihydro-2H-benzo [1,4] oxazin- 7-yl) -2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester Lithium t-butoxide (1.0 M, 4.2 ml, 4.2 mmol) was added to (3-methoxyimino-
  • Step 7 Preparation of (5S)-[3-(3-Hydroxyimino -4-methyl-3,4-dihydro-2H- benzo[ 1 ,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid methyl ester.
  • Lithium bis(trimethylsilyl)amide (1.0 M in T ⁇ F, 3.21 ml, 0.00321 mol) is added dropwise at -78 °C to (3-methoxyimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-carbamic acid benzyl ester (1.0 g, 0.00292 mol) in T ⁇ F (10 ml).
  • the reaction mixture is stirred at -78 °C for lh and then (R)-glycidyl butyrate (0.46 ml, 0.00321 mol) added dropwise.
  • the mixture is allowed to warm to room temperature and stirred overnight.
  • Step 1 Preparation of 4-Methyl-7-nitro-4H-benzo[l,4]oxazin-3-ylidene-cyanamide.
  • Methyl trifilate (0.50 ml, 4.44 mmol) was added to 4-methyl-7-nitro-4H- benzo[l, 4] oxazine-3 -thione (0.50 g, 2.22 mmol) in dichloromethane (10 ml) at 0 °C. The mixture was allowed to warm to room temperature and stirred overnight to provide a solution of 4-methyl-3-methylsulfanyl-7-nitro-2H-benzo[l,4]oxazin-4-ium triflate in dichloromethane.
  • Step 2 Preparation of 7- Amino-4-methyl-4H-benzo[ 1,4] oxazin-3 -ylidene-cyanamide Iron powder (0.182 g, 3.27 mmol) was added in small portions to 4-methyl-7- nitro-4H-benzo[ 1,4] oxazin-3 -ylidene-cyanamide (0.19 g, 0.818 mmol) and ammonium chloride (0.433 g, 8.18 mmol) in ethanol (20 ml) and water (10 ml) at 90 °C. The reaction mixture was stirred vigorously and heated for 30 minutes, allowed to cool to room temperature, and diluted with dichloromethane (50 ml).
  • Step 3 Preparation of [3-(3-Cyanoimino-4-methyl-3,4-dihydro-2H-benzo[l,4]oxazin- 7-ylamino)-(2R)-hydroxy- ⁇ ropyl]-carbamic acid tert-butyl ester.
  • Step 4 Preparation of (5S)-[3-(3-Cyanoimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester.
  • Step 5 Preparation of (5R)-7-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-4-methyl-4H- benzo[l,4]oxazin-3-ylidene-cyanamide.
  • Step 6 Preparation of (5S)-N-[3-(3-Cyanoimino-4-methyl-3,4-dihydro-2H- benzo[l,4]oxazin-7-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
  • Acetic anhydride (0.014ml, 0.144mmol) was added to (5R)-7-(5-aminomethyl- 2-oxo-oxazolidin-3-yl)-4-methyl-4H-benzo[l,4]oxazin-3-ylidene-cyanamide (0.040 g, 0.096 mmol) and diisopropylethylamine (0.066 ml, 0.384 mmol) in dichloromethane (3 ml) at 0°C. The reaction mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with dichloromethane, washed with water, citric acid and brine, dried ( ⁇ a 2 SO 4 ), and evaporated.

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Abstract

La présente invention concerne de nouvelles amidoximes et amidines oxazolidinones de la formule (I) dans laquelle R2, Y1, Y 2, Y3, X, W, G et U ont la notation définie dans la description. Les composés de la présente invention possèdent des activités puissantes contre les bactéries gram positif.
PCT/IB2005/000102 2004-01-28 2005-01-17 Agents antibacteriens oxazolidinone WO2005082897A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007093904A1 (fr) * 2006-02-14 2007-08-23 Pfizer Products Inc. Oxazolidinones benzoxazinone et benzoxazépinone en tant qu'agents antibactériens
CN102584738A (zh) * 2011-01-07 2012-07-18 浙江九洲药业股份有限公司 一种合成利伐沙班中间体的新工艺
CN103420933A (zh) * 2012-05-26 2013-12-04 鲁南制药集团股份有限公司 一种利奈唑胺的制备方法
US8841306B2 (en) 2008-11-20 2014-09-23 Panacea Biotec Ltd. Antimicrobials
US8906913B2 (en) 2009-06-26 2014-12-09 Panacea Biotec Limited Azabicyclohexanes
CN104693139A (zh) * 2011-01-07 2015-06-10 浙江九洲药业股份有限公司 一种合成利伐沙班中间体的新工艺
CN115073458A (zh) * 2022-07-04 2022-09-20 山东致泰医药技术有限公司 一种阿维巴坦钠的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0738726A1 (fr) * 1995-04-21 1996-10-23 Bayer Ag Hétérobenzocyclopentane oxazolidinones ayant une activité antibactérienne
DE19604223A1 (de) * 1996-02-06 1997-08-07 Bayer Ag Neue substituierte Oxazolidinone
WO2000029409A1 (fr) * 1998-11-17 2000-05-25 Bayer Aktiengesellschaft Nouveaux derives d'oxazolidone substitues par un heterocyclyle

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0738726A1 (fr) * 1995-04-21 1996-10-23 Bayer Ag Hétérobenzocyclopentane oxazolidinones ayant une activité antibactérienne
DE19604223A1 (de) * 1996-02-06 1997-08-07 Bayer Ag Neue substituierte Oxazolidinone
WO2000029409A1 (fr) * 1998-11-17 2000-05-25 Bayer Aktiengesellschaft Nouveaux derives d'oxazolidone substitues par un heterocyclyle

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007093904A1 (fr) * 2006-02-14 2007-08-23 Pfizer Products Inc. Oxazolidinones benzoxazinone et benzoxazépinone en tant qu'agents antibactériens
US8841306B2 (en) 2008-11-20 2014-09-23 Panacea Biotec Ltd. Antimicrobials
US8906913B2 (en) 2009-06-26 2014-12-09 Panacea Biotec Limited Azabicyclohexanes
CN102584738A (zh) * 2011-01-07 2012-07-18 浙江九洲药业股份有限公司 一种合成利伐沙班中间体的新工艺
CN104693139A (zh) * 2011-01-07 2015-06-10 浙江九洲药业股份有限公司 一种合成利伐沙班中间体的新工艺
CN104693139B (zh) * 2011-01-07 2017-04-19 浙江九洲药业股份有限公司 一种合成利伐沙班中间体的新工艺
CN103420933A (zh) * 2012-05-26 2013-12-04 鲁南制药集团股份有限公司 一种利奈唑胺的制备方法
CN103420933B (zh) * 2012-05-26 2016-03-02 鲁南制药集团股份有限公司 一种利奈唑胺的制备方法
CN115073458A (zh) * 2022-07-04 2022-09-20 山东致泰医药技术有限公司 一种阿维巴坦钠的制备方法

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