WO2005082900A2 - Amidoxines d'oxazolidinone utilisees en tant qu'agents antibacteriens - Google Patents

Amidoxines d'oxazolidinone utilisees en tant qu'agents antibacteriens Download PDF

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WO2005082900A2
WO2005082900A2 PCT/IB2005/000119 IB2005000119W WO2005082900A2 WO 2005082900 A2 WO2005082900 A2 WO 2005082900A2 IB 2005000119 W IB2005000119 W IB 2005000119W WO 2005082900 A2 WO2005082900 A2 WO 2005082900A2
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Prior art keywords
alkyl
dihydro
oxo
oxazolidin
methyl
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PCT/IB2005/000119
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English (en)
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WO2005082900A3 (fr
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Mikhail Fedorovich Gordeev
Vara Prasad Venkata Nagendra Josyula
Gary Wayne Luehr
Rama Jain
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Pharmacia & Upjohn Company Llc
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Publication of WO2005082900A3 publication Critical patent/WO2005082900A3/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
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • 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
    • 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

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 ⁇ Y 2 and Y 3 are independently (a) CH, (b) N, (c) N + -O-, or (d) CF;
  • U is (a) CR 3 R 4 , (b) O, or (c) S, SO, or SO 2 ;
  • Z is O-Ci_ 6 alkyl, optionally substituted with OH, or OC ⁇ . 2 alkyl;
  • R 2 is (a) Cj-ealkyl, (b) OCi- ⁇ alkyl, or (c) (CH 2 ) j 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 microbial infections.
  • the invention may also provide novel intermediates and novel processes that are useful for preparing compounds of formula I.
  • C 3 . 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 (T).
  • heterocyclic ring having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen within the ring.
  • An examples of het includes, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,3,4-triazole, oxazole, thiazole, isoxazole, isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,3-thiadiazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, quinoxaline, quinazoline, cinnoline, p
  • het includes, but are not limited to, pyridine, thiophene, 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.
  • enantiomers and those that are non-superimposable mirror images of each other are termed "enantiomers".
  • 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.
  • the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well- known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992).
  • the term “treating” or “treatment” of a disease includes: (1) preventing the disease, i.e.
  • 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. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g.
  • 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 C ⁇ an yl, 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 .
  • 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.
  • U is CH 2 .
  • U is O or S.
  • R 2 is CH 3 .
  • R 2 is cyclopenten.
  • R 2 is C 1 . 4 alkyl, optionally substituted with 1-3 with one, two or three fluoro (F), or chloro (CI).
  • R 3 and R 4 are independently H.
  • Z is OCi- ⁇ alkyl, optionally substituted with OH, or OC ⁇ alkyl.
  • Z is OC ⁇ alkyl substituted with O ⁇ alkyl which may be further substituted with a phenyl.
  • Z is OCH 3 , or OCH 2 CH 3 .
  • Z is OH. :
  • X is a structure of formula ii
  • the compounds of this invention can be prepared in accordance with one or more of the Schemes discussed below. All of the starting materials are either commercially available or can be prepared by procedures that would be well known to one of ordinary skill in organic chemistry.
  • the variables used in the Schemes are as defined below, or as in the summary of the invention or claims.
  • an appropriate leaving group A such as halogen or S ⁇ alkyl
  • alkylating agents include alkyl sulfates ((R'O) 2 SO 2 or R'OSO 2 CF 3 ), halides (R'X), tosylates, triflates (R'OSO 2 - tolyl) or trialkyloxonium salts ((R 2 ) 3 OBF 3 ), wherein R' is an alkyl group.
  • the reaction is typically conducted neat with excess alkylating agent or in an organic solvent such as dimethylformamide, dichloromethane or tetrahydrofuran at temperatures in a range of from 0 °C to about 100 °C.
  • the intermediate benzazolium salt lb is treated with an alkoxyamine (H 2 NOR') or its salt thereof such as methoxylamine hydrochloride and a suitable base according to the methods described in Chem. Pharm. Bull., 1996, vol. 24(5), pp. 1050-1058.
  • the reaction is most conveniently conducted in water with an inorganic base such as sodium hydroxide, but may also be conducted in an organic solvent such as methanol or dimethylformamide with an organic base such as sodium methoxide or triethylamine.
  • the reaction is performed at temperatures in a range of from 0 °C to about 100 °C.
  • the alkoxyimino substituted nitrobenzazole lc may be converted to aniline Id under a variety of mild conditions including catalytic hydrogenation, transfer hydrogenation using a hydrogen donor such as ammonium formate in the presence of palladium catalyst or a dissolving metal reduction with iron or tin.
  • the resulting aniline Id is protected as the carbamate le and converted to the Boc-protected oxazolidinone If using known chemistry methods described in US Patent publication No. 6,107,519.
  • Acylations can be routinely performed by reactions of amines with carboxylic acid anhydrides or esters. These transformations are generally performed at 0 °C to 50 °C using polar solvents, such as acetonitrile, dimethylformamide, tetrahydrofuran and methanol or mixtures thereof with optional apolar solvents, such as dichloromethane. These reactions are preferably conducted in the presence of an organic or inorganic base, such as pyridine, triethylamine, or potassium carbonate. In this reaction it is often convenient to employ an excess of the tertiary amine base with the amine salt prepared by Boc deprotection without first isolating the free base. Solvents such as tetrahydrofuran, methylene chloride or preferably methanol and temperatures in the range of about 24 °C to about 50 °C can be used for this reaction.
  • polar solvents such as acetonitrile, dimethylformamide, tetrahydrofuran and
  • 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 ranging from 25 °C to about 100 °C.
  • the intermediate thione compound 2b is reacted with an alkoxyamine or a salt thereof, such as methoxylamine hydrochloride and a suitable base at temperatures ranging from 25 °C to about 100 °C to give alkoxyimino intermediate 2c.
  • the alkoxyimino substituted nitrooxindole 2c may be converted to aniline 2d under a variety of mild conditions including catalytic hydrogenation, transfer hydrogenation using a hydrogen donor such as ammonium formate in the presence of palladium catalyst or a dissolving metal reduction with iron or tin.
  • the resulting aniline 2d is protected as the carbamate 2e and converted to the Boc-protected oxazolidinone 2f using known chemistry methods described in US Patent publication No. 6,107,519.
  • known oxazolidinone benzazolium salt intermediates 3a described in US Patent Publication No. 6,069,160 may be reacted with hydroxylamine or a salt thereof such as hydroxylamine hydrochloride and a suitable base, or a protected source of hydroxylamine such as O-(trimethylsilyl) hydroxylamine or N,O-bis(trimethylsilyl)hydroxylamine in a protic solvent to provide
  • the reaction is most conveniently conducted in water with an inorganic base such as sodium hydroxide, but may also be conducted in an organic solvent such as methanol or dimethylformamide with an organic base such as sodium methoxide or triethylamine.
  • the reaction is performed at temperatures in a range of from 0 °C to about 24 °C.
  • hydroxyimino benzazole 3b may be further converted to alkoxyimino benzazole lg 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. Solvents for this transformation may include tetrahydrofuran or dimethylformamide, and the reaction is typically performed in the range of about 0 °C to 80 °C.
  • Schemes IN- VI describe the synthesis of aryl isoxazolinone, aryl isoxazoline and aryl butyrolactones bearing amidoxime groups.
  • the aldehyde group is conveniently protected as an acetal or other suitable protecting group and the benzazole 4b reacted with an appropriate alkylating agent as described previously.
  • the intermediate benzazolium salt 4c is then reacted with an alkoxyamine or a salt thereof as described previously to give the desired alkoxyimino intermediate 4d.
  • the acetal protecting group is removed using various reaction conditions that are well known in the art (see “Protecting Groups" by Philip J.
  • Benzaldehyde intermediate 4e 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 4f.
  • ethyl diazoacetate as described by Mahmood, et al. in J. Org. Chem., 1998, Vol. 63, pp. 3333-3336
  • This intermediate is then converted to the corresponding methylacetamide 4h by reaction with N-(hydroxymethyl)acetamide acetate (prepared as described by Barnes et al. in US Patent 5,284,863) in a polar aprotic solvent such as dimethylformamide.
  • oxime 4e is reacted with hydroxylamine hydrochloride in a polar protic solvent, such as methanol, in the presence of a base, such as pyridine, to afford oxime 5a.
  • a polar protic solvent such as methanol
  • a base such as pyridine
  • the oxime is oxidized with N-chlorosuccinimide in a suitable solvent, such as dichloromethane, to give the intermediate N-hydroxyoximidoyl chloride 5b.
  • the 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.
  • Scheme VI describes the synthesis of aryl butyrolactone amidoximes.
  • Aldehyde intermediate 4e is conveniently converted to phenyl acetic acid intermediate 6a following methods described by Hester, et al. in US Patent 5,708,169.
  • the synthesis of the saturated and unsaturated 3-arylbutyrolactone system parallels that described in Biorganic & Medicinal Chemistry Letters, 1994, Vol. 4, No. 16, pp. 1925-1930.
  • the lithiated dianion of the phenyl acetic acid intermediate 6a is reacted with R-benzyloxymethyloxirane in THF.
  • the resulting ⁇ -hydroxyacid is cyclized with catalytic p-toluenesulfonic acid to provide lactone 6b 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 compounds of the present invention may be used for the treatment of infectious diseases caused by a variety of bacterial organisms.
  • gram-positive bacteria such as multiple resistant staphylococci, for example S. aureus and S. epidermidis; multiple resistant streptococci, for example S. pneumoniae and S. pyogenes; and multiple resistant Enterococci, for example E. faecalis; gram negative aerobic bacteria such as
  • Haemophilus for example H. influenzae and Moraxella, for example M. catarrhalis; as well as anaerobic organisms such as bacteroides and clostridia species, and acid- fast organisms such as Mycobacteria, for example M. tuberculosis', and/or Mycobacterium avium.
  • Other examples include Escherichia, for example E. coli. intercellular microbes, for example Chlamydia and Rickettsiae.
  • infections examples include central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients.
  • infectious diseases that may be treated with the compounds of the present invention are gram-positive infections such as osteomyelitis, endocarditis and diabetic foot.
  • the in vitro antibacterial activity of the compounds of the present invention may be assessed by following procedures recommended in (1) National Committee for Clinical Laboratory Standards (Jan. 2003), Methods for dilution antimicrobial tests or bacteria that grow aerobically, Approved Standard (6 th ed), M7-A6, NCCLS, Wayne, PA; (2) National Committee for Clinical Laboratory Standards (Mar. 2001), Methods for antimicrobial susceptibility testing of anaerobic bacteria, Approved
  • 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. Additionally, 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 carboxymefhyl 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.
  • 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.
  • suitable non-irritating excipient include cocoa butter, beeswax and other glycerides.
  • 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
  • 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. 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 3-methyl-2-methylsulfanyl-6-nitro-benzothiazol-3-ium methyl sulfate 2-Methylsulfanyl-6-nitro-benzothiazole (5.00 g, 0.0221 mol) and dimethyl sulfate (10 ml) are heated at 100 °C for 20 hours. The reaction mixture is cooled and diluted with ether (50 ml). The resulting white precipitate is filtered, washed thoroughly with ether and dried under vacuum (10 g, 98%).
  • Step 2 Preparation of 3-methyl-6-nitro-3H-benzothiazol-2-one O-methyl-oxime Methoxylamine hydrochloride (0.676 g, 8.09 mmol) is added in one portion to 3-methyl-2-methylsulfanyl-6-nitro-benzothiazol-3-ium methyl sulfate (2.50 g, 5.39 mmol) in pyridine (10 ml) and heated at 65 °C for 20 hours.
  • Step 3 Preparation of 6-amino-3-methyl-3H-benzothiazol-2-one O-mefhyl-oxime 3-Methyl-6-nitro-3H-benzothiazol-2-one O-methyl-oxime (1.20 g, 5.02 mmol) and palladium on carbon (10%, wet Degussa type E101 NE/W, 0.250 g) are suspended in ethyl acetate (20 ml) and placed under a hydrogen atmosphere (balloon) overnight. The catalyst is filtered and the clear colorless filtrate evaporated under vacuum to give the title compound as a white solid (1.05 g, 99%), ⁇ PLC r.t. 2.837 min; MS for C 9 ⁇ n N 3 OS m/z 210 (M+H) + .
  • Step 4 Preparation of (2-methoxyimino-3-methyl-2,3-dihydro-benzothiazol-6-yl)- carbamic acid benzyl ester
  • Benzyl chloroformate (0.75 ml, 5.26 mmol) is added dropwise to 6-amino-3- methyl-3H-benzothiazol-2-one O-methyl-oxime (1.00 g, 4.78 mmol) and pyridine (0.64 ml, 7.89 mmol) in dichloromethane (10 ml) at 0 °C. The mixture is allowed to warm to room temperature and stirred for 15 minutes.
  • Step 5 Preparation of (5S)-[3-(2-methoxyimino-3-methyl-2,3-dihydro-benzothiazol- 6-yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester
  • Lithium t-butoxide 1.0 M solution in THF, 13.1 ml, 13.1 mmol
  • Step 6 Preparation of (5R)-6-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-3-methyl-3H- benzothiazol-2-one O-methyl-oxime (5S)-[3-(2-Methoxyimino-3-methyl-2,3-dihydro-benzothiazol-6-yl)-2-oxo- oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester (0.65 g, 1.59 mmol) is stirred with 50% TFA/DCM (10 ml) for 1 h at room temperature. The solvent is evaporated to give the title compound as the TFA salt (0.68 g, 99%); MS for C 13 H 16 N 4 O 3 S m/z 309 (M+H) + .
  • Step 7 Preparation of (5S)-N-[3-(2-methoxyimino-3-methyl-2,3-dihydro- benzothiazol-6-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide
  • Acetic anhydride (0.133 ml, 1.30 mmol ) is added to (5R)-6-(5-aminomethyl- 2-oxo-oxazolidin-3-yl)-3-methyl-3H-benzothiazol-2-one
  • O-methyl-oxime (0.500 g, 1.19 mmol) and pyridine (0.290 ml, 3.55 mmol) in dichloromethane (5 ml) at 0 °C.
  • Step 1 Preparation of 3-methyl-6-nitro-3H-benzothiazol-2-one O-ethyl-oxime O-Ethylhydroxylamine hydrochloride (0.789 g, 8.09 mmol) is added in one portion to 3-methyl-2-methylsulfanyl-6-nitro-benzothiazol-3-ium methyl sulfate (2.50 g, 5.39 mmol) in pyridine (10 ml) and heated at 65 °C for 20 hours.
  • Step 2 Preparation of 6-amino-3-methyl-3H-benzothiazol-2-one O-ethyl-oxime 3-Methyl-6-nitro-3H-benzothiazol-2-one O-ethyl-oxime (1.25 g, 4.94 mmol) and palladium on carbon (10%, wet Degussa type E101 NE/W, 0.250 g) are suspended in ethyl acetate (20 ml) and placed under a hydrogen atmosphere (balloon) overnight. The catalyst is filtered and the clear colorless filtrate evaporated under vacuum to give the title compound as a white solid (1.10 g, 99%); MS for C 10 ⁇ 13 N 3 OS m/z 224 (M+H) + .
  • Step 3 Preparation of (2-ethoxyimino-3-methyl-2,3-dihydro-benzothiazol-6-yl)- carbamic acid benzyl ester
  • Benzyl chloroformate (0.74 ml, 5.17 mmol) is added dropwise to 6-amino-3- methyl-3H-benzothiazol-2-one O-ethyl-oxime (1.05 g, 4.70 mmol) and pyridine (0.57 ml, 7.05 mmol) in dichloromethane (10 ml) at 0 °C. The mixture is allowed to warm to room temperature and stirred for 15 minutes.
  • Step 4 Preparation of (5S)-[3-(2-ethoxyimino-3-methyl-2,3-dihydro-benzothiazol-6- yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester
  • Lithium t-butoxide 1.0 M solution in THF, 13.0 ml, 13.0 mmol
  • Step 5 Preparation of (5R)-6-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-3-methyl-3H- benzothiazol-2-one O-ethyl-oxime (5S)-[3-(2-Ethoxyimino-3-methyl-2,3-dihydro-benzothiazol-6-yl)-2-oxo- oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester (0.70 g, 1.66 mmol) is stirred with 50% TFA/DCM (10 ml) for 1 h at room temperature. The solvent is evaporated to the title compound as the TEA salt (0.72 g, 99%); MS for C 14 H 18 N 4 O 3 S m/z 323 (M+H) + .
  • Step 6 Preparation of (5S)-N-[3-(2-ethoxyimino-3-methyl-2,3-dihydro-benzothiazol- 6-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide
  • Acetic anhydride 0.112 ml, 1.11 mmol
  • O-ethyl-oxime 0.436 g, 1.00 mmol
  • pyridine 0.245 ml, 3.00 mmol
  • Propionic anhydride (0.129 ml, 1.01 mmol ) is added to (5R)-6-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-3-methyl-3H-benzothiazol-2-one O-ethyl-oxime (0.400 g, 0.917 mmol) and pyridine (0.224 ml, 2.75 mmol) in dichloromethane (5 ml) at 0 °C. The reaction is stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture is diluted with dichloromethane, washed with water, citric acid and brine, dried ( ⁇ a 2 S ⁇ ), and evaporated.
  • Step 1 Preparation of 3-ethyl-2-methylsulfanyl-6-nitro-benzothiazol-3-ium ethyl sulfate 2-Methylsulfanyl-6-nitro-benzothiazole (5.00 g, 0.0221 mol) and diethyl sulfate (10 ml) are heated at 100 °C for 20 hours. The reaction mixture is cooled and diluted with ether (50 ml). The resulting white precipitate is filtered, washed thoroughly with ether and dried under vacuum (8.9 g, 82%); mp.
  • Step 2 Preparation of 3-ethyl-6-nitro-3H-benzothiazol-2-one O-methyl-oxime Methoxylamine hydrochloride (0.638 g, 7.64 mmol) is added in one portion to
  • Step 3 Preparation of 6-amino-3-ethyl-3H-benzothiazol-2-one O-methyl-oxime 3-Ethyl-6-nitro-3H-benzothiazol-2-one O-methyl-oxime (1.25 g, 4.94 mmol) and palladium on carbon (10%, wet Degussa type E101 NE/W, 0.250 g) are suspended in ethyl acetate (20 ml) and placed under a hydrogen atmosphere (balloon) overnight. The catalyst is filtered and the clear colorless filtrate evaporated under vacuum to give the title compound as a white solid (1.00 g, 91%); MS for C 10 H 13 N 3 OS m/z 224 (M+H) + .
  • Step 4 Preparation of (3-ethyl-2-methoxyimino-2,3-dihydro-benzothiazol-6-yl)- carbamic acid benzyl ester
  • Benzyl chloroformate (0.70 ml, 4.93 mmol) is added dropwise to 6-amino-3- ethyl-3H-benzothiazol-2-one O-methyl-oxime (1.00 g, 4.48 mmol) and pyridine (0.54 ml, 6.72 mmol) in dichloromethane (10 ml) at 0 °C. The mixture is allowed to warm to room temperature and stirred for 15 minutes.
  • Step 5 Preparation of (5S)-[3-(3-ethyl-2-methoxyimino-2,3-dihydro-benzothiazol-6- yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester Lithium t-butoxide (1.0 M solution in THF, 11.8 ml, 11.8 mmol) is added at 0
  • Step 6 Preparation of (5R)-6-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-3-ethyl-3H- benzothiazol-2-one O-methyl-oxime (5S)-[3-(3-Ethyl-2-methoxyimino-2,3-dihydro-benzothiazol-6-yl)-2-oxo- oxazolidin-5-ylmethyl] -carbamic acid tert-butyl ester (0.60 g, 1.42 mmol) is stirred with 50% TFA/DCM (10 ml) for 1 h at room temperature. The solvent is evaporated to give the title compound as the TFA salt (0.62 g, 99%); MS for C 1 ⁇ 18 N 4 O 3 S m/z
  • Step 7 Preparation of (5S)-N-[3-(3-ethyl-2-methoxyimino-2,3-dihydro-benzothiazol- 6-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide
  • Acetic anhydride (0.129 ml, 1.26 mmol ) is added to (5R)-6-(5-aminomethyl- 2-oxo-oxazolidin-3-yl)-3-ethyl-3H-benzofhiazol-2-one
  • O-methyl-oxime (0.50 g, 1.15 mmol
  • pyridine 0.280 ml, 3.44 mmol
  • Propionic anhydride (0.129 ml, 1.01 mmol ) is added to (5R)-6-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-3-ethyl-3H-benzothiazol-2-one O-methyl-oxime (0.400 g, 0.917 mmol) and pyridine (0.224 ml, 2.75 mmol) in dichloromethane (5 ml) at 0 °C. The reaction is stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture is diluted with dichloromethane, washed with water, citric acid and brine, dried ( ⁇ a 2 S ⁇ 4 ), and evaporated.
  • Step 1 Preparation of 3-ethyl-6-nitro-3H-benzothiazol-2-one O-ethyl-oxime O-Ethylhydroxylamine hydrochloride (0.744 g, 7.64 mmol) is added in one portion to 3-ethyl-2-methylsulfanyl-6-nitro-benzothiazol-3-ium ethyl sulfate (2.50 g, 5.09 mmol) in pyridine (10 ml) and heated at 65 °C for 20 hours.
  • Step 2 Preparation of 6-Amino-3-ethyl-3H-benzothiazol-2-one O-ethyl-oxime 3-Ethyl-6-nitro-3H-benzothiazol-2-one O-ethyl-oxime (1.25 g, 4.68 mmol) and palladium on carbon (10%, wet Degussa type E101 NE/W, 0.250 g) are suspended in ethyl acetate (20 ml) and placed under a hydrogen atmosphere (balloon) overnight. The catalyst is filtered and the clear colorless filtrate evaporated under vacuum to give the title compound as a white solid (1.10 g, 99%); MS for C ⁇ ⁇ 15 N 3 OS m/z 238 (M+H) + .
  • Step 3 Preparation of (2-ethoxyimino-3-ethyl-2,3-dihydro-benzothiazol-6-yl)- carbamic acid benzyl ester
  • Benzyl chloroformate (0.66 ml, 4.64 mmol) is added dropwise to 6-amino-3- ethyl-3H-benzothiazol-2-one O-ethyl-oxime (1.00 g, 4.21 mmol) and pyridine (0.51 ml, 6.31 mmol) in dichloromethane (10 ml) at 0 °C. The mixture is allowed to warm to room temperature and stirred for 15 minutes.
  • Step 4 Preparation of (5S)-[3-(2-ethoxyimino-3-ethyl-2,3-dihydro-benzothiazol-6- yl)-2-oxo-oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester Lithium t-butoxide (1.0 M solution in THF, 11.3 ml, 11.3 mmol) is added at 0 °C to (2-ethoxyimino-3-ethyl-2,3-dihydro-benzothiazol-6-yl)-carbamic acid benzyl ester (1.40 g, 3.77 mmol) and (3-chloro-2-hydroxy-propyl)-carbamic acid tert-butyl ester (1.22 g, 5.66 mmol) in DMF (10 ml).
  • Step 5 Preparation of (5R)-6-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-3-ethyl-3H- benzothiazol-2-one O-ethyl-oxime (5S)-[3-(2-Ethoxyimino-3-ethyl-2,3-dihydro-benzothiazol-6-yl)-2-oxo- oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester (0.60 g, 1.37 mmol) is stirred with 50% TFA/DCM (10 ml) for 1 h at room temperature. The solvent is evaporated to give the title compound as the TFA salt (0.62 g, 99%); MS for C 15 ⁇ 20 N 4 O 3 S m/z 337 (M+H) + .
  • Step 6 Preparation of (5S)-N-[3-(2-ethoxyimino-3-ethyl-2,3-dihydro-benzothiazol-6- yl)-2-oxo-oxazolidin-5-ylmethyl] -acetamide
  • Acetic anhydride (0.125 ml, 1.22 mmol ) is added to (5R)-6-(5-aminomethyl- 2-oxo-oxazolidin-3-yl)-3-ethyl-3H-benzothiazol-2-one
  • O-ethyl-oxime (0.500 g, 1.11 mmol) and pyridine (0.270 ml, 3.33 mmol) in dichloromethane (5 ml) at 0 °C.
  • Propionic anhydride (0.128 ml, 0.99 mmol ) is added to (5R)-6-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-3-ethyl-3H-benzothiazol-2-one O-ethyl-oxime (0.400 g, 0.908 mmol) and pyridine (0.222 ml, 2.72 mmol) in dichloromethane (5 ml) at 0 °C. The reaction is stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture is diluted with dichloromethane, washed with water, citric acid and brine, dried ( ⁇ a 2 S ⁇ 4 ), and evaporated.
  • Step 1 Preparation of 3,3-difluoro-l-methyl-5-nitro-l,3-dihydro-indol-2-one (Diethylamino)sulfur trifluoride (4.04 ml, 30.6 mmol) is added dropwise to 1- methyl-5-nitro-lH-indole-2,3-dione (3.00 g, 14.6 mmol) in dichloromethane (50 ml) at -78 °C. The reaction is allowed to warm to room temperature and stirred for 48 hours. The mixture is poured into cold saturated sodium bicarbonate solution and the product extracted with dichloromethane. The extract is washed with brine, dried (Na.
  • Step 2 Preparation of 5-amino-3,3-difluoro-l-methyl-l,3-dihydro-indol-2-one Iron powder (1.56 g, 28.05 mmol) is added in small portions to 3,3-difluoro 1- methyl-5-nitro-l, 3-dihydro-indol-2-one (1.60 g, 7.01 mmol) and ammonium chloride (3.72 g, 70.1 mmol) in ethanol (70 ml) and water (35 ml) at 90 °C.
  • reaction mixture is stirred vigorously and heated for 30 minutes, cooled to room temperature, and diluted with dichloromethane (150 ml).
  • the mixture is filtered through celite, the organic layer separated and washed with water and brine, dried (Na 2 SO ), and evaporated to give the title compound as a brown solid (1.30 g, 93.5%); HPLC r.t. 1.96min; MS for C 9 H 8 F 2 N 2 O m/z 199.1(M+H) + .
  • Step 3 Preparation of (3,3-difluoro-l-methyl-2-oxo-2,3-dihydro-lH-indol-5-yl)- carbamic acid benzyl ester
  • Benzyl chloroformate (0.547ml, 3.89mmol) is added dropwise to a mixture of 5-amino-3,3-difluoro-l-methyl-l,3-dihydro-indol-2-one (0.70 g, 3.53 mmol) and pyridine (0.571 ml, 7.06 mmol) in dichloromethane (6 ml) at 0 °C.
  • Step 4 Preparation of (3,3-difluoro-l-methyl-2-thioxo-2,3-dihydro-lH-indol-5-yl)- carbamic acid benzyl ester (3,3-Difluoro-l-methyl-2-oxo-2,3-dihydro-lH-indol-5-yl)-carbamic acid benzyl ester (1.10 g, 3.3 mmol) and Lawesson's reagent (1.0 g, 2.48 mmol) in dioxane (7 ml) are heated overnight at 65 °C.
  • Step 5 Preparation of (3,3-difluoro-2-methoxyimino-l-methyl-2,3-dihydro-lH-indol- 5-yl)-carbamic acid benzyl ester (3,3-Difluoro-l-methyl-2-thioxo-2,3-dihydro-lH-indol-5-yl)-carbamic acid benzyl ester (0.50 g, 1.43 mmol) and methoxylamine hydrochloride (0.48 g, 5.74 mmol) in pyridine (5 ml) are heated overnight at 70 °C.
  • Step 6 Preparation of (5R)-N-[3-(3,3-difluoro-2-methoxyimino-l-methyl-2,3- dihydro-lH-indol-5-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide
  • Lithium t-butoxide (1M solution in THF, 0.83 ml, 0.828 mmol) is added dropwise to (3,3-difluoro-2-methoxyimino-l-methyl-2,3-dihydro-lH-indol-5-yl)- carbamic acid benzyl ester (0.100 g, 0.276 mmol) and methanol (0.0225 ml, 0.558 mmol) in DMF (1ml) at 0°C.
  • Step 1 Preparation of (5R)-N-[3-(3,3-difluoro-2-methoxyimino-l-methyl-2,3- dihydro-lH-indol-5-yl)-2-oxo-oxazolidin-5-ylmethyl] -carbamic acid tert-butyl ester Lithium t-butoxide (1M solution in THF, 1.41ml, 1.41mmol) is added dropwise to (3,3-difluoro-2-methoxyimino-l-methyl-2,3-dihydro-lH-indol-5-yl)- carbamic acid benzyl ester (0.17 g, 0.470 mmol) and (3-chloro-2-hydroxy-propyl)- carbamic acid tert-butyl ester (0.147 g, 0.705 mmol) in DMF (5ml) at 0°C.
  • Step 2 Preparation of (5R)-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-3,3-difluoro-l- methyl- 1 ,3-dihydro-indol-2-one O-methyl-oxime (5R)-[3-(3,3-Difluoro-2-methoxyimino-l-methyl-2,3-dihydro-lH-indol-5-yl)-2-oxo- oxazolidin-5-ylmethyl]-carbamic acid tert-butyl ester (0.15 g, 0.35 mmol) is treated with 50% TFA / DCM (2 ml) for 30 minutes at room temperature. The reaction mixture is evaporated under vacuum to give product as the TFA salt. (0.093g, 60%); HPLC r.t. 3.65 min; MS for C 14 H 16 F 2 N 4 O 3 m/z 327.3 (M+H) + .
  • Step 3 Preparation of (5R)-N-[3-(3,3-difluoro-2-methoxyimino-l-methyl-2,3- dihydro- 1 H-indol-5-yl)-2-oxo-oxazolidin-5-ylmethyl] -propionamide
  • Propionic anhydride (0.0295 ml, 0.231 mmol is added to (5R)-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-3 ,3-difluoro- 1 -methyl- 1 ,3-dihydro-indol-2-one O-methyl-oxime (0.042 g, 0.115 mmol) and diisopropyl ethylamine (0.080 ml, 0.463 mmol) in dichloromethane (2 ml) at 0 °C.
  • Methyl chloroformate (0.054 ml, 0.70 mmol) is added to (5R)-(5- aminomethyl-2-oxo-oxazolidin-3-yl)-3,3-difluoro-l-methyl-l,3-dihydro-indol-2-one O-methyl-oxime (0.155 g, 0.352 mmol) and diisopropyl ethylamine (0.365 ml, 2.11 mmol) in dichloromethane (3ml) at 0 °C and stirred for 30 minutes at 0 °C.
  • reaction mixture is diluted with dichloromethane, washed with water, citric acid and brine, dried (Na 2 S ⁇ 4 ), and evaporated.
  • the residue is purified by PTLC (5% MeOH / DCM) to give the title compound as an off white solid (0.05 g, 37%); HPLC r.t. 4.75 min; %).

Abstract

L'invention se rapporte à de nouvelles amidoximes d'oxazolidinone représentées par la formule (I) dans laquelle R2, Y1, Y2, Y3, X, W, et Z sont définis ci-après dans le descriptif. Les composés de l'invention possèdent une activité puissante contre les bactéries gram positifs.
PCT/IB2005/000119 2004-01-28 2005-01-17 Amidoxines d'oxazolidinone utilisees en tant qu'agents antibacteriens WO2005082900A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8841306B2 (en) 2008-11-20 2014-09-23 Panacea Biotec Ltd. Antimicrobials
KR101456730B1 (ko) * 2006-12-19 2014-10-31 바스프 에스이 코일 코팅 방법을 위한 코팅 물질 및 코팅된 코일의 제조를 위한 시클로헥산 폴리카르복실산 에스테르의 용도
US8906913B2 (en) 2009-06-26 2014-12-09 Panacea Biotec Limited Azabicyclohexanes

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5164510A (en) * 1988-09-15 1992-11-17 The Upjohn Company 5'Indolinyl-5β-amidomethyloxazolidin-2-ones
EP0738726A1 (fr) * 1995-04-21 1996-10-23 Bayer Ag Hétérobenzocyclopentane oxazolidinones ayant une activité antibactérienne
EP0785201A1 (fr) * 1996-01-18 1997-07-23 Bayer Ag Oxazolidinones substituées avec cyclopantopyridyl contenant des hétéroatomes
EP0789025A1 (fr) * 1996-02-06 1997-08-13 Bayer Ag Oxazolidinones substituées et leur utilisation comme médicaments antibactériens
WO1998007708A1 (fr) * 1996-08-21 1998-02-26 Pharmacia & Upjohn Company Derives d'isoxazoline utiles comme agents antimicrobiens
WO1998054161A1 (fr) * 1997-05-30 1998-12-03 Pharmacia & Upjohn Company Agents antibacteriens oxazolidinone ayant une fonctionnalite thiocarbonyle
WO2000010566A1 (fr) * 1998-08-24 2000-03-02 Bristol-Myers Squibb Company Nouveaux agents antibacteriens a base d'isoxazolinone
WO2000029409A1 (fr) * 1998-11-17 2000-05-25 Bayer Aktiengesellschaft Nouveaux derives d'oxazolidone substitues par un heterocyclyle
WO2002059115A1 (fr) * 2000-11-17 2002-08-01 Pharmacia & Upjohn Company Oxazolidinones a cycle benzenique comportant un heterocycle a six ou sept elements accole, utilisees comme agents antibacteriens
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

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5164510A (en) * 1988-09-15 1992-11-17 The Upjohn Company 5'Indolinyl-5β-amidomethyloxazolidin-2-ones
EP0738726A1 (fr) * 1995-04-21 1996-10-23 Bayer Ag Hétérobenzocyclopentane oxazolidinones ayant une activité antibactérienne
EP0785201A1 (fr) * 1996-01-18 1997-07-23 Bayer Ag Oxazolidinones substituées avec cyclopantopyridyl contenant des hétéroatomes
EP0789025A1 (fr) * 1996-02-06 1997-08-13 Bayer Ag Oxazolidinones substituées et leur utilisation comme médicaments antibactériens
WO1998007708A1 (fr) * 1996-08-21 1998-02-26 Pharmacia & Upjohn Company Derives d'isoxazoline utiles comme agents antimicrobiens
WO1998054161A1 (fr) * 1997-05-30 1998-12-03 Pharmacia & Upjohn Company Agents antibacteriens oxazolidinone ayant une fonctionnalite thiocarbonyle
WO2000010566A1 (fr) * 1998-08-24 2000-03-02 Bristol-Myers Squibb Company Nouveaux agents antibacteriens a base d'isoxazolinone
WO2000029409A1 (fr) * 1998-11-17 2000-05-25 Bayer Aktiengesellschaft Nouveaux derives d'oxazolidone substitues par un heterocyclyle
WO2002059115A1 (fr) * 2000-11-17 2002-08-01 Pharmacia & Upjohn Company Oxazolidinones a cycle benzenique comportant un heterocycle a six ou sept elements accole, utilisees comme agents antibacteriens
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

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101456730B1 (ko) * 2006-12-19 2014-10-31 바스프 에스이 코일 코팅 방법을 위한 코팅 물질 및 코팅된 코일의 제조를 위한 시클로헥산 폴리카르복실산 에스테르의 용도
US8841306B2 (en) 2008-11-20 2014-09-23 Panacea Biotec Ltd. Antimicrobials
US8906913B2 (en) 2009-06-26 2014-12-09 Panacea Biotec Limited Azabicyclohexanes

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