WO2004069816A1 - Derives d'oxazolidinones en tant qu'agents anitmicrobiens - Google Patents

Derives d'oxazolidinones en tant qu'agents anitmicrobiens Download PDF

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WO2004069816A1
WO2004069816A1 PCT/IB2003/000429 IB0300429W WO2004069816A1 WO 2004069816 A1 WO2004069816 A1 WO 2004069816A1 IB 0300429 W IB0300429 W IB 0300429W WO 2004069816 A1 WO2004069816 A1 WO 2004069816A1
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alkyl
methyl
formula
compound
cycloalkyl
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PCT/IB2003/000429
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English (en)
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Anita Mehta
Sonali Rudra
Ajjarapu Venkata Subrahmanya Raja Rao
Ajay Singh Yadav
Ashok Rattan
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Ranbaxy Laboratories Limited
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Priority to PCT/IB2003/000429 priority Critical patent/WO2004069816A1/fr
Priority to EP03701664A priority patent/EP1594852A1/fr
Priority to AU2003202753A priority patent/AU2003202753A1/en
Publication of WO2004069816A1 publication Critical patent/WO2004069816A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 certain substituted phenyl oxazolidinones and to the processes for the synthesis of the same.
  • This invention also relates to pharmaceutical compositions containing the compounds of the present invention as antimicrobials.
  • the compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacterioides spp. and Clostridia spp. species, and acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
  • Nancomycin which inspite of its various drawbacks, has become the drug of choice for
  • Streptococcus pneumoniae is a major pathogen causing pneumonia, sinusitis and meningitis. Until very recently it was highly susceptible to penicillin.
  • Oxazolidinones are a new class of synthetic antimicrobial agents which kill gram positive pathogens by inhibiting a very early stage of protein synthesis. Oxazolidinones inhibit the formation of ribosomal initiation complex involving 30S and 50S ribosomes leading to prevention of initiation complex formation. Due to their novel mechanism of action, these compounds are active against pathogens resistant to other clinically useful antibiotics.
  • WO 02/06278 application discloses phenyloxazolidinone derivatives as antimicrobials.
  • WO 01/46164 discloses piperidinyloxy and pyrrolidinyloxyphenyl oxazolidinones as antimicrobials.
  • WO 99/37630 discloses oxazolidinone combinatorial libraries.
  • WO 93/23384 application discloses phenyloxazolidinones containing a substituted diazine moiety and their uses as antimicrobials.
  • WO 93/09103 application discloses substituted aryl and heteroaryl- phenyloxazolidinones useful as antibacterial agents
  • WO 90/02744 application discloses 5-indolinyl-5 ⁇ -amidomethyloxazolidinones, 3- (fused ring substituted) phenyl-5 ⁇ -amidomethyloxazolidinones which are useful as antibacterial agents.
  • European Patent Publication 352,781 discloses phenyl and pyridyl substituted phenyl oxazolidinones.
  • European Patent Application 312,000 discloses phenylmethyl and pyridinylmethyl substituted phenyl oxazolidinones.
  • U.S. Patent No. 5,254,577 discloses nitrogen heteroaromatic rings attached to phenyloxazolidinone.
  • the invention involves the synthesis, identification and profiling of oxazolidinone molecules which have good activity against multiply resistant gram positive pathogens like MRSA, NRE and PRSP. Some of these molecules have activity against MDR-TB and MAI strains, while others have significant activity against important anaerobic bacteria.
  • the invention provides processes for phenyloxazolidinones derivatives which can exhibit significant antibacterial activity against multiply resistant gram positive pathogens like MRSA, VRE and P ⁇ ISP against MDR-TB and MAI strains, in order to provide safe and effective treatment of bacterial infections.
  • T is a five to seven membered heterocyclic ring, aryl, substituted aryl, bound to the ring C with a linker W.
  • X is H, CH, CH-S, CH-O, N, CHNRn, wherein R ⁇ is hydrogen, optionally substituted Ci. 2 alkyl, C 3 . 12 cycloalkyl, C ⁇ - 6 alkoxy, C ⁇ - 6 alkyl, C ⁇ _ 6 alkylcarbonyl, C ⁇ - 6 alkyl carboxy, aryl or heteroaryl;
  • X 2 CH or N; Y and Z are independently selected from hydrogen, C-_ 6 alkyl, C 3 12 cycloalkyl or C 0 _ 3 bridging group;
  • U and V are independently selected from hydrogen, optionally substituted C alkyl, F, Cl, Br, C._ 12 alkyl substituted with one or more of F, Cl, Br, I, preferably U and V are hydrogen or fluoro;
  • W is selected from CH 2 , CO, CH 2 NH, -NHCH 2 , -CH 2 NHCH 2 , -CH 2 N(R ⁇ )CH 2 -, CH 2 ( R ⁇ )N-, CH(R n ), CH 2 (CO), NH, O, S, N(R ⁇ ), (CO)CH 2 , N(R ⁇ )CON(Rn), N(Rn)CSN(Rii), SO 2 , SO, wherein R n is the same as defined above; and
  • U and V are independently selected from hydrogen, optionally substituted C ⁇ - 6 alkyl, F, Cl, Br, Ci- 12 alkyl substituted with one or more of F, Cl, Br, I; preferably U and V are hydrogen and fluoro;
  • Y and Z are independently selected from hydrogen, C ⁇ - 6 alkyl, C . ⁇ 2 cycloalkyl, Co- bridging group;
  • X is selected from H, CH, CH-S, CH-O or N;
  • X 2 CH or N
  • Qi is selected from O, S or NR ⁇ , wherein R ⁇ is as defined above;
  • G, J, L are independently selected from H, C ⁇ . 6 alkyl, F, Cl, Br,I, -CN, COR 5 ,COOR 5 ,
  • R 5 are independently selected from H, C ⁇ - 12 alkyl, C 3 _ ⁇ 2 cycloalkyl, C ⁇ - 6 alkoxy, C ⁇ - 6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl;
  • Rg and R are independently selected from H, optionally substituted C -n alkyl, C3-12 cycloalkyl, C ⁇ - 6 alkoxy;
  • R 8 and R 9 are independently selected from H, C ⁇ - 6 alkyl, F, Cl, Br, I, C 1 - 1 2 alkyl substituted with one or more of F, Cl, Br, I, OR 5 , SRj, N(Re,R 7 );
  • ring C may be 6-8 membered in size and the ring may have either two or three carbon atoms between each nitrogen atom, for example:
  • the ring C may be bridged to form a bicyclic system as shown below:
  • ring C is optionally substituted at positions Y and Z with alkyl groups, cycloalkyl groups, fluoro group, carboxylic and corresponding esters, amides, substituted alkyls or bridging alkyl groups are as shown below:
  • ring C also includes the following structures:
  • U and V are independently selected from hydrogen, optionally substituted C ⁇ - 6 alkyl, F, Cl, Br, C ⁇ _ ⁇ 2 alkyl substituted with one or more of F, Cl, Br, I; preferably U and V are hydrogen and fluoro;
  • Y and Z are independently selected from hydrogen, C ⁇ . 6 alkyl, C 3 - ⁇ 2 cycloalkyl, Co- 3 bridging group;
  • X is selected from H, CH, CH-S, CH-O or N;
  • R 6 and R 7 are independently selected from H, optionally substituted - 12 alkyl, C -i 2 cycloalkyl, C ⁇ - 6 alkoxy;
  • R 8 and R 9 are independently selected from H, C ⁇ - 6 alkyl, F, Cl, Br, I, C ⁇ - ⁇ 2 alkyl substituted with one or more of F, Cl, Br, I, OR 5 , SR- t , N(R 6 ,R 7 );
  • R ⁇ o H, optionally substituted C ⁇ - ⁇ 2 alkyl, G 3 - 12 cycloalkyl, C ⁇ _ 6 alkoxy, C ⁇ _ 6 alkyl, aryl, heteroaryl; and
  • n is an integer in the range from 0 to 3;
  • Particular G, J and L substitutions can include nitro, aldehydes and halides.
  • U and V are independently selected from hydrogen, optionally substituted C ⁇ - 6 alkyl, F, Cl, Br, C ⁇ - 12 alkyl substituted with one or more of F, Cl, Br, I; preferably U and V are hydrogen and fluoro;
  • Y and Z are independently selected from hydrogen, C ⁇ _ 6 alkyl, C 3 _i2 cycloalkyl, C0-3 bridging group;
  • X is selected from C, CH, CH-S, CH-O or N;
  • Another particular compound of Formula IN is as follows:
  • Y and Z are independently selected from hydrogen, C ⁇ _ 6 alkyl, C -i 2 cycloalkyl, Co- 3 bridging group;
  • X is selected from H, CH, CH-S, CH-O, or N;
  • a particular compound of Formula V is as follows: (S)-N-[[3-[3-Fluoro-4-[ J- ⁇ 2-furyl-(5-nitro)-methyl ⁇ piperidmyl-4-oxy]phenyl]-2-oxo-5- oxozolidinyljmethyl] acetamide.
  • Compounds of the present invention can be useful antimicrobial agents, effective against a number of human and veterinary pathogens, particularly aerobic Gram-positive bacteria, including multiply-antibiotic resistant staphylococci and streptococci, as well as anaerobic organisms such as Mycobacterium tuberculosis and other mycobacterium species.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories, and ointments.
  • a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, or tablets disintegrating agents; it can also be as finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from about 5 to about 70 percent of the active ingredient.
  • suitable solid carriers are lactose, pectin, dextrin, starch, gelatin, tragacanth, low melting wax, cocoa butter, and the like.
  • preparation is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it.
  • capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid form preparations include solutions, suspensions, and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems
  • Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing, and thickening agents as desired.
  • Aqueous suspension suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
  • Ointment preparations contain heavy metal salts of a compound of Formula I with a physiologically acceptable carrier.
  • the carrier is desirably a conventional water- dispersible hydrophilic or oil-in-water carrier, particularly a conventional semi-soft or cream-like water-dispersible or water soluble, oil-in-water emulsion infected surface with a minimum of discomfort.
  • Suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment.
  • the pharmaceutical preparations can be in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete capsules, powders in vials or ampoules, and ointments capsule, cachet, tablet, gel, or cream itself or it can be the appropriate number of any of these packaged forms.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from less than 1 mg to several grams according to the particular application and the potency of the active ingredient.
  • the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 3 mg to about 40 mg per kilogram daily.
  • the dosages may be varied depending upon the requirements of the patient and the compound being employed. Determination of the proper dosage for a particular situation is within the smaller dosages which are less than the optimum dose. Small increments until the optimum effect under the daily dosage may be divided and administered in portions during the day if desired.
  • the invention provides processes for the synthesis of compounds of Formulae I, II, III, IN and V.
  • Pharmaceutically acceptable non-toxic acid addition salts of the compounds of the present invention of Formulae I, II, III, TV and N may be formed with inorganic or organic acids, by methods well known in the art.
  • the present invention also includes within its scope prodrugs of the compounds of
  • prodrugs will be functional derivatives of these compounds which readily get converted in vivo into defined compounds.
  • the invention also includes pharmaceutically acceptable salts, the enantiomers, diastereomers, N-oxides, prodrugs, metabolites in combination with a pharmaceutically acceptable carrier and optionally included excipients.
  • Mi is NH, NHRi 4 , CH 2 NHR ⁇ 4 , CH-CH 2 NHR ⁇ 4 , -CCH 2 -NHR ⁇ 4 wherein R 14 is H, ethyl, methyl, isopropyl, acetyl, cyclopropyl, or alkoxy and
  • X 2 CH or N
  • Y and Z are independently selected from hydrogen, Q, alkyl, C 3 _ 12 cycloalkyl or C 0 _ 3 bridging group;
  • U and V are independently selected from hydrogen, optionally substituted C._ 6 alkyl, F, Cl, Br, C . alkyl substituted with one or more of F, Cl, Br, I, preferably U and V are hydrogen or fluoro; and
  • W is selected from CH 2 , CO, CH 2 NH, -NHCH 2 , -CH 2 NHCH 2 , -CH 2 N(R ⁇ )CH 2 -, CH 2 ( R ⁇ )N-, CH(R ⁇ ), CH 2 (CO), NH, O, S, N(R ⁇ ), (CO)CH 2 , N(R ⁇ )CON(R ⁇ ), N(R ⁇ )CSN(R ⁇ ), SO 2 , SO, wherein R is the same as defined above; and
  • R 1 2 is a suitable leaving group well known to one of ordinary skill in the art such as fluoro, chloro, bromo, iodo, SCH 3 , -SO 2 CH 3 , -SO 2 CF 3 , Tos or OC 6 H 5 etc.
  • the reaction can be carried out in a suitable solvent in the presence of a suitable base selected from the group consisting of potassium carbonate, N-ethyldiisopropylamine and dipotassium hydrogen phosphate.
  • a suitable base selected from the group consisting of potassium carbonate, N-ethyldiisopropylamine and dipotassium hydrogen phosphate.
  • the corresponding aldehyde can be used through a process of reductive amination and is attached to the amine of Formula VI.
  • the corresponding acid can be used and the amino compound of Formula VI can be acylated through activated esters in the presence of condensing agents such as 1,3- dicyclohexylcarbodiimide (DCC) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlori.de (EDC).
  • DCC 1,3- dicyclohexylcarbodiimide
  • EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlori.de
  • Other methods of acylation can also be employed.
  • the compounds having carbonyl link can also be made by reacting heteroaromatic compound of the Formula VII (wherein G, J, L, Qi & R ⁇ 2 are the same as defined earlier),
  • Formula VII such as N-methyl pyrrole, with the intermediate amine of Formula VI in the presence of triphosgene or phosgene.
  • the carbonyl linkers may also be introduced between heteroaromatic compound, such as 3-bromothiophene and the amine of Formula VI with carbon monoxide in the presence of a catalyst such as Pd (PPli 3 ) 2 Cl .
  • the extended chain pyrroles having dicarbonyl linkers can also be obtained from treatment with oxalyl chloride and the amine of the Formula VI.
  • the heteroaromatic compound of the Formula VII such as 2-bromo-thiophene is reacted with the intermediate amine of Formula VI in the presence of ligands such as palladium dibenzylidene acetone Pd 2 (dba) 3 or Pd(OAc) 2 with 2,2'-bis-(di ⁇ henylphosphino)-l,l'-bina ⁇ hthyl (BINAP) and bases such as cesium carbonate or sodium t-butoxide (Ref: J. Org. Chem. 1999, 64, 6019- 6022 and J. Org. Chem. 2000, 65, 1144-1157).
  • ligands such as palladium dibenzylidene acetone Pd 2 (dba) 3 or Pd(OAc) 2 with 2,2'-bis-(di ⁇ henylphosphino)-l,l'-bina ⁇ hthyl (BINAP) and bases such as cesium carbonate or sodium t-butoxide
  • the compounds having carbonyl link can also be made by reacting heteroaromatic compound of the Formula VII, (wherein G, J, L, Qi and R ⁇ 2 are as defined earlier) such as N- methyl pyrrole with the intermediate amine of Formula VI in the presence of triphosgene or phosgene.
  • the carbonyl linkers may also be introduced between heteroaromatic compound, such as 3-bromothiophene and the amine of Formula VI with carbon monoxide in the presence of a catalyst such as Pd (PPh 3 ) 2 Cl 2 .
  • the extended chain pyrroles having dicarbonyl linkers can also be obtained from treatment with oxalyl chloride and the amine of the Formula VI.
  • the reaction can be carried out in a suitable solvent such as dimethylformamide, dimethylacetamide, ethanol, dimethylsulfoxide, acetonitrile, or ethylene glycol at a suitable temperature in the range of about -70°C to 180° C to afford compounds of Formula II.
  • a suitable base such as tri ethylamine, N-ethyldiisopropyl amine, potassium carbonate, sodium bicarbonate, dipotassium hydrogen phosphate is useful in some cases to improve the yield of the reaction.
  • Formula VI identified as three different cores, namely
  • optically pure amines of Formula VI could be obtained either by one of a number of assymetric synthesis or alternatively by resolution from a racemic mixture by selective crystallization of a salt prepared, with an appropriate optically active acid such as dibenzoyl tartarate or 10-camphorsulfonic acid, followed by treatment with base to afford the optically pure amine.
  • an appropriate optically active acid such as dibenzoyl tartarate or 10-camphorsulfonic acid
  • the title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl] acetamide and 4-(N-4-methyl-piperazin- 1 -yl)-5-nitro-2- thiophenecarboxaldehyde using Method A.
  • the title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl]acetamide and 2-nitro-3-thiophenecarboxaldehyde using Method A.
  • the reaction is carried out in a suitable solvent such as dimethylformamide, dimethylacetamide, ethanol or ethylene glycol at a suitable temperature in the range of - 78°C to 180°C to afford compounds of Formula II.
  • a suitable base such as triethylamine, diisopropyl amine, potassium carbonate, sodium bicarbonate is useful in some cases to improve the yield of the reaction.
  • the tiltle compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5 -oxozolidinyl]methyl] acetamide and 5-nitro-2-( - trifluoromethylsulfonate)ethylfuran using Method B.
  • DCC 1,3- dicyclohexylcarbodiimide
  • EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Other methods of acylation can also be employed.
  • the following compounds were prepared using this method:
  • reaction mixture was quenched with water and extracted with ethyl acetate (100 ml).
  • organic layer was dried over anhydrous sodium sulfate and concentrated to get the crude product which was purified by column chromatography using 2-3% methanol in dichloromethane as eluent to yield 150 mg of the title compound.
  • the title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl]acetamide and 5-nitro-2-thiophenecarboxylic acid using Method C.
  • Step-c Preparation of 3- fluoro- 4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tert-butoxycarbonyl-3-azabicyclo- [3.1.0]hexan-6-yl ⁇ -methyloxy]mtrobenzene:
  • Step-d Preparation of 3-Fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl ⁇ methyloxy]aniline: To a solution of 3-fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tert-butoxycarbonyl-3-azabicyclo- [3.1.0]hexan-6-yl ⁇ -methyloxy]nitrobenzene obtained in step-c (6gm) in methanol (100), 5% wet Pd/C (8gm) was added and shaken in a parr hydrogenation apparatus under 50 psi of hydrogen gas for 3h . Then the rection mixture was filtered over celite bed and washed with 50 ml of methanol. The filtrate was evaporated in vacuo to yield 5.5 gm of the title compound.
  • Step-e Preparation of 3-Fluoro-4-[ ⁇ (l ,5 ⁇ ,6 ⁇ )-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0]-hexan-6-yl ⁇ methyloxy] benzyloxy carbonyl aniline: To a solution of 3-Fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl ⁇ methyloxy]aniline obtained in step-d (D, 5.0 gm, 0.015 mole) in THF (150ml) cooled to 5°C, sodium bicarbonate (3.92 gm, 0.046 mole), was added and then benzylchloroformate (3.94 gm, 0.02 mole) was added dropwise at the same temperature .
  • reaction mixture was stirred at room temperature for 4 hrs and then filtered, washed with THF (50 ml). The filtrate was evaporated in vacuo. The residue obtained was triturated with hexane. The solid was filtered and dried to get the 5.0 gm of the title compound.
  • Step-f Preparation of R(-)-3-[3-fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl ⁇ methyloxy]phenyl]5-hydroxymethyl-2-oxazolidinone :
  • reaction mixture was stirred at -78°C for 1.5hr, then R-glycidyl butyrate (1.70 gm, 0.0118 mole) was added and the reaction mixture was stirred at -78°C for lhr and then at RT for 18 hr.
  • the reaction mixture was quenched with saturated ammonium chloride solution (25 ml) and the organic layer was separated. The aqueous layer was again extracted with 200ml of ethyl acetate. The combined organic layer was dried over anhydrous Na SO 4 and evaporated in vacuo.
  • the crude product was purified by column chromatography (eluent is 2% methanol in dichloromethane) to yield 3.5 gm of the title compound.
  • Step-g Preparation of R(-)-3-[3-fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0] hexan-6-yl ⁇ methyloxy]phenyl]5-methanesulphonyloxy-methyl-2- oxazolidinone:
  • Step-h Preparation of S(-)-3-[3-fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tert-butoxycarbonyl-3- azabicyclo[3.1.0]hexa-6-yl ⁇ methyloxy]phenyl]5-azidomethyl-2-oxazolidinone:
  • Step-i Preparation of S(-)-3-[3-fluoro-4-[ ⁇ (l ,5 ⁇ ,6 ⁇ )-3-tert-butoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl]phenyl]-5-aminomethyl-2-oxazolidinone: To a solution of S(-)-3-[3-fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tert-butoxycarbonyl-3- azabicyclo[3.1.0]hexa-6-yl ⁇ methyloxy]phenyl]5-azidomethyl-2-oxazolidinone (2.0 gm, 0.0045 mole) in THF, triphenylphosphine was added and stirred for 2hr at RT.
  • Step-j Preparation of (S)-N-[[3-[3-Fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-t-butoxycarbonyl-3- azabicyclo [3.1.0]hexan-6-yl ⁇ -methyloxy]phenyl] -2-oxo-5 -oxozolidinyl]methyl] acetamide.
  • reaction mixture was diluted with dichloromethane (25 ml) and washed with saturated sodium bicarbonate, followed by brine. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under vacuo to get the 1.3 gm of the title compound.
  • Step-k Preparation of (S)-N-[[3-[3-Fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-azabicyclo[3.1.0]hexan-6- yl ⁇ -methyloxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide.
  • the title compound was prepared from (S)-N-[[3-[3-Fluoro-4-[ ⁇ (l ,5 ⁇ ,6 )-3- azabicyclo[3.1.0]hexan-6-yl ⁇ -methyloxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide and 5-nitro-2-thiophenecarboxaldehyde using Method A.
  • the title compound was prepared from (S)-N-[[3-[3-Fluoro-4-[N-l-(N-l- piperazinylcarbonyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide Trifluorocaetate and 5-nitro-2-thiophenecarboxaldehyde using Method A.
  • the title compound was prepared from (S)-N-[[3-[3-Fluoro-4-[N-l-(N-l- pi ⁇ erazinylcarbonyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide trifluoroacetate and 5-nitro-2-bromothiophene using Method B.
  • the compounds of the invention display antibacterial activity when tested by the agar incorporation method.
  • the following minimum inhibitory concentrations ( ⁇ g/ml) were obtained for representative compounds of the invention which are given below in Table- 1.
  • MRSA 15187 Metalicillin Resistant Staphylococcus aureus 3
  • MRSA 15187 Metalicillin Resistant Staphylococcus aureus 3
  • ATCC 6303 Streptococcus pneumoniae ATCC 6303

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Abstract

La présente invention a trait à certains oxazolidinones phényliques substitués de formule (I), dans laquelle : T est un noyau et des procédés pour leur synthèse. Les composés sont des agents antimicrobiens utiles, efficaces contre un certain nombre d'agents pathogènes humains et vétérinaires, y compris les bactéries aérobies gram positif telles que les staphylococci, streptococci et enterococci polyrésistants ainsi que des organismes aérobies tels que les espèces Bactérioïdes spp. et Clostridia spp, et des organismes acido-résistants tels que le bacille de Koch, Mycobacterium avium et Mycobacterium spp.
PCT/IB2003/000429 2003-02-07 2003-02-07 Derives d'oxazolidinones en tant qu'agents anitmicrobiens WO2004069816A1 (fr)

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PCT/IB2003/000429 WO2004069816A1 (fr) 2003-02-07 2003-02-07 Derives d'oxazolidinones en tant qu'agents anitmicrobiens
EP03701664A EP1594852A1 (fr) 2003-02-07 2003-02-07 Derives d'oxazolidinones en tant qu'agents antimicrobiens
AU2003202753A AU2003202753A1 (en) 2003-02-07 2003-02-07 Oxazolidinone derivatives as antimicrobials

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WO2005023801A1 (fr) * 2003-09-03 2005-03-17 Morphochem Aktiengesellschaft für kombinatorische Chemie Produits intermediaires destines a la fabrication d'hybrides oxazolidinone-chinolone
WO2006024955A1 (fr) * 2004-09-01 2006-03-09 Pfizer Products Inc. Antagonistes des recepteurs d'amine histamine-3 azabicycliques
JP2009057299A (ja) * 2007-08-30 2009-03-19 Nippon Soda Co Ltd 置換フェノキシアザビシクロオクタン誘導体およびその製造方法
US7638531B2 (en) * 2005-12-21 2009-12-29 Schering Corporation Phenoxypiperidines and analogs thereof useful as histamine H3 antagonists
US7858644B2 (en) 2003-01-29 2010-12-28 Asterand Uk Limited EP4 receptor antagonists
US8158797B2 (en) 2003-12-18 2012-04-17 Morphochem Aktiengesellschaft Fur Kombinatorische Chemie Oxazolidinone-quinolone hybrid antibiotics
US8268812B2 (en) 2003-04-30 2012-09-18 Morphochem Aktiengesellschaft fül Kombinatorische Chemie Use of oxazolidinone-quinoline hybrid antibiotics for the treatment of anthrax and other infections
US8329908B2 (en) 2001-10-04 2012-12-11 Morphochem Aktiengesellschaft Fur Kombinatorische Chemie Dual action antibiotics
EP2565182A1 (fr) * 2010-04-27 2013-03-06 Mitsubishi Tanabe Pharma Corporation Nouveau dérivé d'amide et emploi dudit dérivé au titre de médicament
RU2487124C2 (ru) * 2008-10-27 2013-07-10 Мицубиси Танабе Фарма Корпорейшн Новое амидное производное и его использование в качестве лекарственного средства
US8501774B2 (en) 2003-12-18 2013-08-06 Morphochem Aktiengesellschaft für kombinatorische Chemie Oxazolidinone-quinolone hybrid antibiotics
US9611251B2 (en) 2013-03-13 2017-04-04 Janssen Pharmaceutica Nv Substituted piperidine compounds and their use as orexin receptor modulators
US9611262B2 (en) 2014-09-11 2017-04-04 Janssen Pharmaceutica Nv Substituted 2-azabicycles and their use as orexin receptor modulators
US9611277B2 (en) 2013-03-13 2017-04-04 Janssen Pharmaceutica Nv Substituted 2-azabicycles and their use as orexin receptor modulators
US9637496B2 (en) 2013-03-13 2017-05-02 Janssen Pharmaceutica Nv Substituted 7-azabicycles and their use as orexin receptor modulators
WO2023061617A1 (fr) * 2020-12-21 2023-04-20 F. Hoffmann-La Roche Ag Composés de sulfonylpipérazinyle pour le traitement d'infections bactériennes

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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8329908B2 (en) 2001-10-04 2012-12-11 Morphochem Aktiengesellschaft Fur Kombinatorische Chemie Dual action antibiotics
US7858644B2 (en) 2003-01-29 2010-12-28 Asterand Uk Limited EP4 receptor antagonists
US8268812B2 (en) 2003-04-30 2012-09-18 Morphochem Aktiengesellschaft fül Kombinatorische Chemie Use of oxazolidinone-quinoline hybrid antibiotics for the treatment of anthrax and other infections
US8513231B2 (en) 2003-04-30 2013-08-20 Morphochem Aktiengesellschaft fü Kombinatorische Chemie Use of oxazolidinone-quinoline hybrid antibiotics for the treatment of anthrax and other infections
WO2005023801A1 (fr) * 2003-09-03 2005-03-17 Morphochem Aktiengesellschaft für kombinatorische Chemie Produits intermediaires destines a la fabrication d'hybrides oxazolidinone-chinolone
US7557214B2 (en) 2003-09-03 2009-07-07 Morphochem Aktiengesellschaft für kombinatorische Chemie Intermediate products for producing oxazolidinone-quinolone hybrids
AU2004270379B2 (en) * 2003-09-03 2011-03-31 Morphochem Aktiengesellschaft Fuer Kombinatorische Chemie Intermediate products for producing oxazolidinone-quinolone hybrids
EP2374806A1 (fr) * 2003-09-03 2011-10-12 Morphochem Aktiengesellschaft Für Kombinatorische Chemie OXAZOLIDINON-QUINOLON HYBRIDes et intermédiaires pour leur préparation
US8124772B2 (en) 2003-09-03 2012-02-28 Morphochem Aktiengesellschaft für kombinatorische Chemie Intermediate products for producing oxazolidinone-quinolone hybrids
US9133213B2 (en) 2003-12-18 2015-09-15 Morphochem Aktiengesellschaft für kombinatorische Chemie Oxazolidinone-quinolone hybrid antibiotics
US8501774B2 (en) 2003-12-18 2013-08-06 Morphochem Aktiengesellschaft für kombinatorische Chemie Oxazolidinone-quinolone hybrid antibiotics
US8158797B2 (en) 2003-12-18 2012-04-17 Morphochem Aktiengesellschaft Fur Kombinatorische Chemie Oxazolidinone-quinolone hybrid antibiotics
WO2006024955A1 (fr) * 2004-09-01 2006-03-09 Pfizer Products Inc. Antagonistes des recepteurs d'amine histamine-3 azabicycliques
US7638531B2 (en) * 2005-12-21 2009-12-29 Schering Corporation Phenoxypiperidines and analogs thereof useful as histamine H3 antagonists
JP2009057299A (ja) * 2007-08-30 2009-03-19 Nippon Soda Co Ltd 置換フェノキシアザビシクロオクタン誘導体およびその製造方法
RU2487124C2 (ru) * 2008-10-27 2013-07-10 Мицубиси Танабе Фарма Корпорейшн Новое амидное производное и его использование в качестве лекарственного средства
EP2565182A1 (fr) * 2010-04-27 2013-03-06 Mitsubishi Tanabe Pharma Corporation Nouveau dérivé d'amide et emploi dudit dérivé au titre de médicament
EP2565182A4 (fr) * 2010-04-27 2014-01-01 Mitsubishi Tanabe Pharma Corp Nouveau dérivé d'amide et emploi dudit dérivé au titre de médicament
US8816079B2 (en) 2010-04-27 2014-08-26 Mitsubishi Tanabe Pharma Corporation Amide derivative and use thereof as medicine
US9611251B2 (en) 2013-03-13 2017-04-04 Janssen Pharmaceutica Nv Substituted piperidine compounds and their use as orexin receptor modulators
US9611277B2 (en) 2013-03-13 2017-04-04 Janssen Pharmaceutica Nv Substituted 2-azabicycles and their use as orexin receptor modulators
US9637496B2 (en) 2013-03-13 2017-05-02 Janssen Pharmaceutica Nv Substituted 7-azabicycles and their use as orexin receptor modulators
US9695183B2 (en) 2013-03-13 2017-07-04 Janssen Pharmaceutica Nv Substituted 7-azabicycles and their use as orexin receptor modulators
US9845333B2 (en) 2013-03-13 2017-12-19 Janssen Pharmaceutica Nv Substituted 2-azabicycles and their use as orexin receptor modulators
US10183953B2 (en) 2013-03-13 2019-01-22 Janssen Pharmaceutica Nv Substituted 2-azabicycles and their use as orexin receptor modulators
US9611262B2 (en) 2014-09-11 2017-04-04 Janssen Pharmaceutica Nv Substituted 2-azabicycles and their use as orexin receptor modulators
WO2023061617A1 (fr) * 2020-12-21 2023-04-20 F. Hoffmann-La Roche Ag Composés de sulfonylpipérazinyle pour le traitement d'infections bactériennes

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