WO2004009587A1 - Derives de l'oxazolidinone, agents antibacteriens - Google Patents

Derives de l'oxazolidinone, agents antibacteriens Download PDF

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Publication number
WO2004009587A1
WO2004009587A1 PCT/IB2003/002841 IB0302841W WO2004009587A1 WO 2004009587 A1 WO2004009587 A1 WO 2004009587A1 IB 0302841 W IB0302841 W IB 0302841W WO 2004009587 A1 WO2004009587 A1 WO 2004009587A1
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formula
compound
alkyl
ylmethyl
alkoxy
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PCT/IB2003/002841
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English (en)
Inventor
Shiv Kumar Agarwal
Satya Surya Visweswara Srinivas Akella
Matte Marianna Samuel
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Orchid Chemicals & Pharmaceuticals Ltd
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Priority to AU2003281526A priority Critical patent/AU2003281526A1/en
Publication of WO2004009587A1 publication Critical patent/WO2004009587A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention provides novel compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them.
  • the present invention more particularly provides novel oxazolidinone derivatives of the general formula (I).
  • the present invention also provides a process for the preparation of the above said novel oxazolidinone derivatives of the formula (I) their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them.
  • the novel oxazolidinone derivatives of the present invention are useful as antibacterial agents and hence useful in the treatment of conditions such as nosocomial pneumoniae, community acquired pneumoniae, vancomycin resistance enterococci (NRE) paused by methicillin resistance staphylococcus aureus (MRSA) and penicillin resistance streptococcus pneumoniae.
  • the compounds of the present invention are effective against a number of human or animal pathogens, clinical isolates, including Vancomycin resistant organisms, methicillin resistant organisms.
  • R 1 is a hydrogen, (CrC 6 )alkyl optionally substituted with one or more OH, CN, or halo or R 1 is -(CH 2 ) h -aryl, -COR 1"1 , COOR 1"2 , -CO-CCHa -COR 1"1 , (C r C 6 )alkylsulfonyl, -S0 2 -(CH 2 ) h -aryl or -(CO) r Het; R 2 is hydrogen, (C C 6 )alkyl, -(CH 2 ) h -aryl or halo; R 3 and R 4 are the same or different and are hydrogen or halo; R 5 is hydrogen, (C 1 -C 12 )alkyl optionally substituted with one or more halo, (C 3 -C 12 )cycloalkyl, (C ⁇ -C 6 )alkoxy
  • R 1 is a radical of the formula D-R 2 , -CO-R 3 or -CO-NR 4 R 5 , wherein D is the C0 2 or S0 2 group, R is phenyl or linear or branched alkyl having up to 7 carbon atoms, R is trifluoromethyl or linear or branched alkyl having up to 6 carbon atoms which is substituted by halogen or trifluoromethyl, and R 4 and R 5 are identical or different and are hydrogen, phenyl or linear or branched alkyl having up to 5 carbon atoms;
  • A is a 6-membered aromatic heterocycle having at least one nitrogen atom and directly bonded via a carbon atom, or a 6-membered bicyclic or tricyclic aromatic radical having at least one nitrogen-containing ring and directly bonded via a carbon atom, or ⁇ -carbolin-3- yl or indolizinyl directly bonded via the 6-membered ring, or a 5-membered aromatic heterocycle having
  • novel oxazolidinone derivatives of the formula (I) may be useful as antibacterial agents and hence are useful in the treatment of conditions such as nosocomial pneumoniae, community acquired pneumoniae, vancomycin resistance enterococci (NRE) caused by methicillin resistance staphylococcus aureus (MRSA) and penicillin resistance streptococcus pneumoniae.
  • the compounds of the present invention are effective against a number of human or animal pathogens, clinical isolates, including Nancomycin resistant organisms, methicillin resistant organisms
  • the present invention relates to novel oxazolidinones of the formula (I)
  • R 1 represents halogen, azido, nitro, cyano, substituted or unsubstituted group selected from TR , wherein T represents O or S;
  • R represents hydrogen, formyl, substituted or unsubstituted groups selected from (C 1 -C 6 )alkyl, cycloalkyl, aryl, aralkyl, acyl, thioacyl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; or R 1 represents N(R 8a R 8b ) where R 8a and R 8b may be same or different and independently represent hydrogen, formyl, substituted or unsubstituted groups selected from (C ⁇ -C 6 )alkyl,
  • R 1 is of the formula -NHS(0) r (C r C 4 )alkyl, -NHS(0) r aralkyl or NHS(0) r heteroaralkyl, where r is 0 to 2; A and B are different arid represent CH or N; R 2 and R 3 may be same or different and independently represent hydrogen, halogen, hydroxy, alkyl, alkoxy; n is an integer of 0 or 1; m is an integer in the range of 1 to 4; D represents CH or N; E represents CH or N, with a proviso that both E and D are not CH; R and R 5 may be same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (C ⁇ -C 6 )alkyl, haloalkyl, (C 1 -C 6 )alkoxy, (C C 6 )
  • Suitable groups represented by R and R are selected from hydrogen, halogen atom such as fluorine, chlorine, bromine or iodine; hydroxyl, ( - C 6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t- butyl, n-pentyl, isopentyl, hexyl and the like; (C 1 -C 6 )alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like.
  • Suitable groups represented by R 4 , R 5 and R 6 are selected from hydrogen, cyano, nitro, amino, halogen, hydroxyl, (C ⁇ -C 6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; haloalkyl such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like; (C C 6 )alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; (C ⁇ -C 6 )allylthio group such as methylthio, ethylthio, n-propylthio, iso-propylthio and the like; (C 3
  • Suitable groups represented by R are selected from hydrogen, formyl, substituted or unsubstituted linear or branched (C ⁇ -C 6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; (C 3 -C 6 )cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, which may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl group such as phenylmethyl, phenylethyl, naphthylmethyl, naphthylethyl and the like, the aralkyl group may be substituted; acyl group such as -
  • Suitable groups represented by R a and R 8b are selected from hydrogen, formyl, substituted or unsubstituted linear or branched (C ⁇ -C 6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; aryl group such as phenyl, naphthyl and the like, which may be substituted; aralkyl group such as phenylmethyl, phenylethyl, naphthylmethyl, naphthylethyl and the like, which may be substituted; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl
  • Suitable ring systems formed by R 8a and R 8 together are selected from pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, thiazinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like,
  • Suitable groups represented by R 9 are selected from hydrogen, amino, substituted or unsubstituted linear or branched (C ⁇ -C 6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; (C C 6 )alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, butoxy and the like, which may be substituted; aryl group such as phenyl, naphthyl and the like, which may be substituted; (C 3 -C 6 )cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, which may be substituted; monoalkylamino group such as NHCH 3 , NHC 2 H 5
  • the substituents on R are selected from halogen, hydroxy, formyl, nitro, cyano, azido, amino, alkyl, aryl, alkylamino, alkylaminocarbonyl, haloalkyl, alkylthio, acylamino, alkoxy, acyl, carboxylic acid or its derivatives such as esters or amides and these substituents are as defined above.
  • Suitable n is an integer of 0 or 1.
  • Suitable m is an integer in the range of 1 to 4, preferably m represents 1 or 2.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9 are selected from halogen, hydroxy, formyl, nitro, cyano, azido, amino, alkyl, aryl, alkylamino, alkylaminocarbonyl, haloalkyl, alkylthio, acylamino, alkoxy, acyl, cycloalkylacyl, heteroarylacyl, carboxylic acid or its derivatives such as esters or amides and these substituents are as defined above.
  • salts of the present invention include alkali metal like Li, Na, and K, alkaline earth metal like Ca and Mg, salts of organic bases such as diethanolamine, ⁇ -phenylethylanrine, benzylamine, piperidine, mo ⁇ holine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc.
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • Representative compounds according to the present invention include:
  • P represents protecting group such as benzyl, benzyloxy carbonyl, tert- butoxycarbonyl, chloroethyl formate, Fmoc and all other symbols are as defined earlier to produce a compound of formula (IV)
  • L represents a leaving group such as mesylate, tosylate or triflate and all other symbols are as defined earlier, ii) converting the compound of formula (IV) to produce a compound of formula (V) where all symbols are as defined earlier, iii) reducing the compound of formula (V) to a compound of formula (VI)
  • the reaction may be carried out in the presence of solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o- dichlorobenzene and the like or a mixture thereof and a base selected from dimethylamino pyridine, triethylamine, pyridine and the like.
  • solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o- dichlorobenzene and the like or a mixture thereof and a base selected from dimethylamino pyridine, triethylamine, pyridine and the like.
  • the reaction may be carried out at a temperature in the range of -10 °C to room temperature.
  • the duration of the reaction may range from 1 to 12 hrs.
  • the conversion of compound of formula (IV) may be carried out in the presence of one or more equivalents of metal azide such as LiN 3 , NaN 3 or trialkyl silylazide.
  • the reaction may be carried out in the presence of solvent such as THF, acetone, DMF, DMSO and the like or mixtures thereof.
  • the reaction may be carried out in inert atmosphere, which may be maintained using N 2 or Ar.
  • the reaction may be carried out at a temperature in the range of ambient temperature to reflux temperature of the solvent, preferably at a temperature in the range of 60 °C to 120 °C.
  • the reaction time may range from 0.5 to 18 h.
  • the reduction of compound of formula (V) may be carried out in the presence of gaseous hydrogen and a catalyst such as Ru, Pd, Rh, Pt, Ni on solid beads such as charcoal, alumina, asbestos and the like.
  • the reduction may be conducted in the presence of a solvent such as dioxane, acetic acid, ethyl acetate, THF, alcohol such as methanol, ethanol, isopropanol and the like or mixtures thereof.
  • a pressure between atmospheric pressure to 60 psi may be used.
  • the reaction may be carried out at a temperature in the range of 25 to 60 °C, preferably at room temperature.
  • the reaction time ranges from 2 to 48 h.
  • the reduction may also be carried out by employing metal in mineral acids such as Sn/HCl, Fe/HCl, Zn/HCl, Zn CH 3 C0 2 H and the like.
  • Acylation of compound of formula (VI) may be carried out using acylating agents such as anhydrides like acetic anhydride, propionic anhydride, acid chlorides like acetyl chloride, propionyl chloride, thioacids such as thioacetic acid.
  • the reaction may be carried out in the presence of solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o- dichlorobenzene or a mixture thereof.
  • the reaction may be carried out in the presence of base selected from dimethylamino pyridine, triethylamine, pyridine and the like.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature.
  • the duration of the reaction may range from 2 to 24 hrs.
  • the deprotection of compound of formula (VII) may be carried out using phenol/trifluoroacetic acid, anisole /trifluoroacetic acid, formic acid, PTSA, hydrochloric acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like.
  • the reaction may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o- dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature.
  • the duration of the reaction may range from 1 to 6 hrs.
  • reaction of compound of formula (VIII) with the compound of formula (IX) may be carried out in the presence of molecular sieves, and reducing agents such as sodium borohydride, triacetoxy sodium borohydride, sodium cyano borohydride, lithium aluminium hydride.
  • reducing agents such as sodium borohydride, triacetoxy sodium borohydride, sodium cyano borohydride, lithium aluminium hydride.
  • the reaction may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at room temperature. The duration of the reaction may range from 12 to 24 hrs.
  • the conversion of compound of formula (VI) to produce compound of formula (X) may be carried out using thiophosgene gas in the presence of solvent such as tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • solvent such as tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out in the presence of a base selected from dimethylamino pyridine, triethylamine, pyridine and the like.
  • the reaction may be carried out at a temperature in the range of -10 °C to room temperature.
  • (VII) may be carried out using solvents such as THF, DCM, alcohol such as methanol, ethanol, propanol and the like.
  • the reaction may also be carried out using amines such as alkyl amines, anilines and the like.
  • the reaction may be carried out in the presence of a base selected from dimethylamino pyridine, triethylamine, pyridine and the like.
  • the reaction may be carried out at a temperature in the range of 30 °C to reflux temperature. The duration of the reaction may range from 6 to 18 hrs.
  • the deprotection of compound of formula (VII) may be carried out using phenol/trifluoroacetic acid, anisole /trifluoroacetic acid, formic acid, PTSA, hydrochloric acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like.
  • the reaction may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o- dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature. The duration of the reaction may range from 1 to 6 hrs.
  • reaction of compound of formula (VIII) with the compound of fonnula (IX) may be carried out in the presence of molecular sieves, and reducing agents such as sodium borohydride, triacetoxy sodium borohydride, sodium cyano borohydride, lithium aluminium hydride.
  • reducing agents such as sodium borohydride, triacetoxy sodium borohydride, sodium cyano borohydride, lithium aluminium hydride.
  • the reaction may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, benzene, xylene, THF, o- dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at room temperature. The duration of the reaction may range from 12 to 24 hrs.
  • L 1 represents a leaving group such as mesylate, tosylate or triflate with R 7 TH or NH(R 8a R 8b ) where all symbols are as defined earlier.
  • (I) may be carried out by heating in the presence of base selected from NaH, KH, t-BuOK and the like and solvents such as DMF, THF, DCM, DMAc and the like.
  • the reaction temperature may range from 0 °C to room temperature.
  • the duration of the reaction may range from 2 to 6 hrs.
  • R 1 represents - NHS(0) r (C ⁇ -C 4 )alkyl, -NHS(0) r aralkyl or -NHS(0) r heteroaralkyl group, which comprises reacting the compound of formula (XII)
  • R 1 represents N(R 8a R 8b ) where R 8a and R 8b represent hydrogen, with R'S0 2 C1 where R' represents (C ⁇ -C 4 )alkyl, aralkyl or heteroaralkyl group.
  • the reaction of compounds of formula (XII) may be carried out by heating in the presence of base selected from pyridine, triethylamine and the like and solvents such as DMF, DCM, ethyl acetate and the like.
  • base selected from pyridine, triethylamine and the like and solvents such as DMF, DCM, ethyl acetate and the like.
  • the reaction temperature may range from 0 °C to room temperature.
  • the duration of the reaction may range from 4 to 12 hrs.
  • acylation of compound of formula (XIII) may be carried out using acylating agents such as thioacetic acid.
  • the reaction may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature. The duration of the reaction may range from 6 to 12 hrs.
  • the reaction of compound of formula (III) with the compound of formula (XIV) may be carried out using triphenyl phosphine, l,l'-azodicarbonyl dipiperidine, dicyclohexyl carbodiimide, dimethylamino pyridine, N,N'- carbodiimidazole or triethylamine, or pyridine.
  • the reaction may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of room temperature to reflux temperature of the solvent. The duration of the reaction may range from 6 to 12 hrs.
  • the deprotection of compound of formula (XV) may be carried out using phenol/trifluoroacetic acid, anisole /trifluoroacetic acid, formic acid, PTSA, hydrochloric acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like.
  • the reaction may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o- dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature. The duration of the reaction may range from 1 to 6 hrs.
  • reaction of compound of formula (XVI) with the compound of formula (IX) may be carried out in the presence of molecular sieves, and reducing agents such as sodium borohydride, triacetoxy sodium borohydride, sodium cyano borohydride, lithium aluminium hydride.
  • reducing agents such as sodium borohydride, triacetoxy sodium borohydride, sodium cyano borohydride, lithium aluminium hydride.
  • the reaction may be carried out in the presence of appropriate solvents like tetrahydiOfuran, chloroform, dichloromethane, dichloroethane, ethylacetate, benzene, xylene, THF, o- dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at room temperature. The duration of the reaction may range from 12 to 24 hrs.
  • the deprotection of compound of formula (III) may be ca ied out using phenol/trifluoroacetic acid, anisole /trifluoroacetic acid, formic acid, PTSA, hydrochloric acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like.
  • the reaction may be canied out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o- dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature. The duration of the reaction may range from 1 to 6 hrs.
  • reaction of compound of formula (XVII) with the compound of formula (XIV) may be canied out using triphenyl phosphine, l,l '-azodicarbonyl dipiperidine, dicylcohexyl carbodiimide, dimethylamino pyridine, N,N'- carbodiimidazole or triethylamine, or pyridine.
  • the reaction may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of room temperature to reflux temperature of the solvent.
  • the duration of the reaction may range from 6 to 12 hrs.
  • the reaction of compound of formula (XVIII) with the compound of formula (IX) may be carried out in the presence of molecular sieves, and reducing agents such as sodium borohydride, triacetoxy sodium borohydride, sodium cyano borohydride, lithium aluminium hydride.
  • the reaction may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, benzene, xylene, THF, o- dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at room temperature.
  • the duration of the reaction may range from 12 to 24 hrs.
  • the reaction may be canied out in the presence of solvents such as toluene, DCC, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • solvents such as toluene, DCC, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction is canied out at temperature in the range of 20 to 60 °C.
  • the reduction of compound of formula (IIIc) may be canied out in the presence of gaseous hydrogen and a catalyst such as Ru, Pd, Rh, Pt, Ni on solid beads such as charcoal, alumina, asbestos and the like.
  • the reduction may be conducted in the presence of a solvent such as dioxane, acetic acid, ethyl acetate, THF, alcohol such as methanol, ethanol, isopropanol and the like or mixtures thereof.
  • a solvent such as dioxane, acetic acid, ethyl acetate, THF, alcohol such as methanol, ethanol, isopropanol and the like or mixtures thereof.
  • a pressure between atmospheric pressure to 60 psi may be used.
  • the reaction may be carried out at a temperature in the range of 25 to 60 °C, preferably at room temperature.
  • the reaction time ranges from 2 to 48 h.
  • the reduction may also be canied out by employing metal in mineral acids such as Sn/HCl, Fe/HCl, Zn/HCl, Zn/CH 3 C0 2 H and the like.
  • the conversion of compound of formula (Hid) to compound of formula (Hie) may be canied out using benzyloxycarbonyl chloride and sodium bicarbonate, in the presence of solvents such as acetone, DMF, water, THF and the like or mixtures thereof.
  • the reaction temperature may range from —20 °C to room temperature.
  • the duration of the reaction may range from 3 to 18 hrs.
  • the cyclization of compound of formula (Hie) may be carried out in the presence of base such as n-butyl lithium, LDA, potassium bis(trimethylsilyl)amide, lithium-bis(trimethylsilyl)amide and the like.
  • the reaction may be carried out in the presence of solvent such as THF, DMF and the like.
  • the reaction is carried out using chiral ester such as R-(-)-glycidyl butyrate.
  • the reaction is carried out at a temperature in the range of -80 °C to -50 °C.
  • the duration of the reaction may range from 2 to 12 hrs.
  • X represents halogen atom and all other symbols are as defined earlier using 1,2- bis (chloro dimethylsilyl) ethane or benzyl chloro formate to produce a compound of formula (Illg) or (Illh)
  • the protection of the compound of formula (Illf) using benzyloxy carbonyl chloride or 1,2-bis (chloro dimethylsilyl) ethane may be canied out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature or at refiuxing temperature. The duration of the reaction may range from 24 to 36 hrs.
  • the condensation of compound of formula (Illg) or (Illh) with N-benzyl piperidone may be carried out using a base selected from n-butyl lithium.
  • the reaction may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o- dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of -80 °C to room temperature.
  • the duration of the reaction may range from 6 to 12 hrs.
  • the dehydration of compound of formula (Illi) to produce a compound of formula (IIIj) may be carried out using a mineral acid selected from hydrochloric acid, sulphuric acid.
  • the reaction may be canied out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of room temperature to reflux temperature of the solvent.
  • the duration of the reaction may range from 12 to 24 hrs.
  • the simultaneous debenzylation and reduction of the compound of formula (Illk) may be earned out using Pd/C in alcohol such as methanol, ethanol or isopropanol or mixtures thereof.
  • the reaction may be carried out at room temperature.
  • the pressure of the reaction may be maintained at 40 psi to 100 psi.
  • the duration of the reaction may range from 6 to 12 hrs.
  • the protection of the compound of formula (III1) may be carried out using benzyloxy carbonyl chloride, tert-butoxycarbonyl chloride, Fmoc may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be canied out at a temperature in the range of 0 °C to room temperature.
  • the duration of the reaction may range from 4 to 6 hrs.
  • reaction of compound of formula (III1) with R-glycidyl butyrate may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of -80 °C to room temperature.
  • the duration of the reaction may range from 12 to 24 hrs.
  • X represents halogen atom and all other symbols are as defined earlier using 1,2- bis (chloro dimethylsilyl) ethane or benzyl chloro formate to produce a compound of formula (Illg) or (Illh)
  • the protection of the compound of formula (Illf) using benzyloxy carbonyl chloride or 1,2-bis (chloro dimethylsilyl) ethane may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature or at refluxing temperature.
  • the duration of the reaction may range from 24 to 36 hrs.
  • the condensation of compound of formula (Illg) or (Illh) with the compound of formula (Illm) may be carried out using palladium catalysts like Tris(dibenzylidineacetone)dipalladium(0), 1 ,3-Bis(diphenyl phosphino)propane, Palladium (I ⁇ )acetate in BINAP and Cs 2 C0 3 .
  • the reaction may be carried out in the presence of appropriate solvents like toluene, dioxane, THF or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of room temperature to refluxing temperature. The duration of the reaction may range from 12 to 24 hrs.
  • the protection of the compound of formula (Illn) may be carried out using benzyloxy carbonyl chloride, tert-butoxycarbonyl chloride, Fmoc may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature. The duration of the reaction may range from 1 to 4 hrs.
  • reaction of compound of formula (IIIo) with R-glycidyl butyrate may be canied out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of room temperature to reflux temperature of the solvent.
  • the duration of the reaction may range from 6 to 12 hrs.
  • the conversion may be canied out using Lawesson's reagent in the presence of base such as triethyl amine, pyridine and the like and solvents such as toluene, DCC, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o- dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 20 °C to 120 °C. The duration of the reaction may range from 1 to 12 hrs.
  • any reactive group in the substrate molecule may be protected according to conventional chemical practice.
  • Suitable protecting groups in any of the above-mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used.
  • a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like
  • solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used.
  • Organic bases such as diethanolamine, ⁇ - phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpynolidine, hydroxyethylpiperidine, choline and the like, ammonium or substituted ammonium salts, aluminum salts.
  • Amino acid such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc may be used for the preparation of amino acid salts.
  • acid addition salts wherever applicable are prepared by the treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p- toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p- toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynap
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the prefened methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like.
  • the compound of formula (I) may be converted to a 1:1 mixture of diastereomeric amides by treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula (I) may be prepared by hydrolysing the pure diastereomeric amide.
  • polymorphs of compound of general fonnula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • solvates of the compounds of formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of fonnula (I) in solvents such as water, methanol, ethanol, mixture of solvents such as acetone:water, dioxane: water, N,N- dimethylformamide:water and the like, preferably water and recrystallizing by using different crystallization techniques.
  • solvents such as water, methanol, ethanol, mixture of solvents such as acetone:water, dioxane: water, N,N- dimethylformamide:water and the like, preferably water and recrystallizing by using different crystallization techniques.
  • the compounds of the present invention are useful for the treatment of microbial infections in humans and other warm blooded animals, under both parenteral and oral administration.
  • the pharmaceutical compositions of the present invention may also contain or be co-administered with one or more known drugs selected from other clinically useful antibacterial agents such as ⁇ -lactams or aminoglycosides. These may include penicillins such as oxacillin or flucloxacillin and carbapenems such as meropenem or imipenem to broaden the therapeutic effectiveness against, for example, methicillin-resistant staphylococci.
  • Compounds of the formula (I) of the present invention may also contain or be co-administered with bactericidal/permeability-increasing-g protein product (BPI) or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.
  • BPI bactericidal/permeability-increasing-g protein product
  • efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavoring agents, sweeteners etc. in suitable solid or liquid caniers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • Such compositions typically contain from 1 to 20 %, preferably 1 to 10 % by weight of active compound, the remainder of the composition being pharmaceutically acceptable caniers, diluents or solvents.
  • the present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.
  • BINAP (R)-2,2'-Bis(diphenylphosphino)-l,r-binaphthyl] (2.5 g, 3.94088 mmoles) and tris(dibenzylidene acetone)dipalladium(o) (7.2 g, 7.88177 mmoles) were taken in dry toluene (400 ml) and stined under argon atmosphere at room temperature for 15 minutes. 2-Bromo-5-nitro-pyridine (40 g, 197.044 mmoles) was dissolved in toluene (200 ml) and added to the reaction mixture followed by N-t-butoxycarbonyl piperazine (44 g, 236.45 mmoles).
  • (R)-glycidylbutyrate (15.73 g, 109.2232 mmoles) was added to the reaction mixture at -78 °C and kept the reaction mixture to attain RT for 16 hours. Quenched the RM by adding ammonium chloride solution followed by water. The RM was extracted with ethyl acetate (3 x 500 ml), dried over anhydrous sodium sulphate and concentrated to dryness and purified over silica gel, using DCM and methanol as eluent. The pure compound was eluted in 1 to 2% methanol / DCM, to obtain the title compound (16,5 g, yield 60%).
  • reaction mixture was cooled to room temperature and triacetoxy sodium borohydride (560 mg, 2.6415 mmoles) was added and continued the stining at room temperature for 24 hours. Filtered the reaction mixture and washed the residue thoroughly with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulphate and concentrated to dryness. The residue was purified over silica gel column using methanol / dichloromethane as eluent to afford the title compound as gummy material (145 mg, yield 45%).
  • the compounds of invention showed in vitro antibacterial activity when tested by the Agar Dilution Method as specified in documents published by the National Committee for Clinical Laboratory Standards (NCCLS), USA.
  • the compounds of invention were weighed, dissolved in Dimethyl Sulfoxide, serially diluted in the same solvent and then incorporated into molten Mueller Hinton Agar in a petridish before solidification, with each petridish containing a different concentration of a compound.
  • the Bacterial Inoculum was prepared by touching the tops of 3 to 5 well isolated bacterial colonies with the same morphological appearance from an 18 hour old culture with an inoculating loop, transferring the growth to a tube containing 5ml of normal saline and adjusting the turbidity of the saline suspension to 0.5 Macfarland Turbidity Standard equivalent to a bacterial population of 1.5 x 10 8 colony forming units (CFU) per milliliter of suspension.
  • CFU colony forming units
  • the bacterial inoculum prepared in the above manner was inoculated onto petri dishes containing Mueller Hinton Agar which had earlier been incorporated with different dilutions of the compounds of invention by a Multipoint Inoculator with each inoculum spot containing approximately 1 x 10 colony forming units (CFU) of bacteria.
  • CFU colony forming units
  • Petridishes were incubated at 35°Celsius in an ambient atmosphere for 20 hours. Petridishes containing different concentrations of Vancomycin and Oxacillin and inoculated with Staphylococcus aureus, Coagulase Negative Staphylococci and Enterococci were incubated for 24 hours.
  • MIC Minimum Inhibitory Concentration
  • the compounds of the present invention are also active against gram negative bacterial. Given below is the activity of the representative compounds of the invention active against gram negative bacteria :

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Abstract

L'invention porte: sur des nouveaux composés de formule générale (I) , leurs dérivés, leurs analogues, leurs tautomères, leurs stéréoisomères, leurs polymorphes, leurs hydrates, leurs solvates, leurs sels pharmacocompatibles, et sur des préparations pharmacocompatibles les contenant, et plus particulièrement sur de nouveaux dérivés de l'oxazolidinone de formule générale (I).
PCT/IB2003/002841 2002-07-22 2003-07-18 Derives de l'oxazolidinone, agents antibacteriens WO2004009587A1 (fr)

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005003087A2 (fr) * 2003-07-01 2005-01-13 Orchid Chemicals And Pharmaceuticals Ltd. Composes nouveaux utiles comme agents anti-bacteriens
WO2007000644A1 (fr) 2005-06-29 2007-01-04 Pharmacia & Upjohn Company Llc Oxazolidinones d'homomorpholine en tant qu'agents antibacteriens
WO2007023507A2 (fr) * 2005-06-20 2007-03-01 Wockhardt Limited Composition a activite antimicrobienne supportant des oxazolidinones ainsi que procedes de preparation associes
US7767677B2 (en) 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
US7919496B2 (en) 2004-09-20 2011-04-05 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
US8026360B2 (en) 2004-09-20 2011-09-27 Xenon Pharmaceuticals Inc. Substituted pyridazines as stearoyl-CoA desaturase inhibitors
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US8288373B2 (en) 2008-11-04 2012-10-16 Chemocentryx, Inc. Modulators of CXCR7
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
US8841306B2 (en) 2008-11-20 2014-09-23 Panacea Biotec Ltd. Antimicrobials
US8853202B2 (en) 2008-11-04 2014-10-07 Chemocentryx, Inc. Modulators of CXCR7
US8906913B2 (en) 2009-06-26 2014-12-09 Panacea Biotec Limited Azabicyclohexanes
WO2018170664A1 (fr) * 2017-03-20 2018-09-27 Merck Sharp & Dohme Corp. Composés d'oxazolidinone et leurs procédés d'utilisation en tant qu'agents antibactériens
US11464786B2 (en) 2018-12-12 2022-10-11 Chemocentryx, Inc. CXCR7 inhibitors for the treatment of cancer
US11834452B2 (en) 2012-11-29 2023-12-05 Chemocentryx, Inc. CXCR7 antagonists

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EP0694543A1 (fr) * 1994-07-20 1996-01-31 Bayer Ag N-hétéroaryloxazolidinones à six chaînes

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EP0694543A1 (fr) * 1994-07-20 1996-01-31 Bayer Ag N-hétéroaryloxazolidinones à six chaînes
US5843967A (en) * 1994-07-20 1998-12-01 Bayer Aktiengesellschaft 6-membered nitrogen-containing heteroaryl-oxazolidinones

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005003087A2 (fr) * 2003-07-01 2005-01-13 Orchid Chemicals And Pharmaceuticals Ltd. Composes nouveaux utiles comme agents anti-bacteriens
WO2005003087A3 (fr) * 2003-07-01 2005-03-17 Orchid Chemicals & Pharm Ltd Composes nouveaux utiles comme agents anti-bacteriens
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
US8026360B2 (en) 2004-09-20 2011-09-27 Xenon Pharmaceuticals Inc. Substituted pyridazines as stearoyl-CoA desaturase inhibitors
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7767677B2 (en) 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
EP2266569A2 (fr) 2004-09-20 2010-12-29 Xenon Pharmaceuticals Inc. Dérivés hétérocycliques et leur utilisation en tant qu'inhibiteurs de la stearoyl-coa desaturase
US7919496B2 (en) 2004-09-20 2011-04-05 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
WO2007023507A2 (fr) * 2005-06-20 2007-03-01 Wockhardt Limited Composition a activite antimicrobienne supportant des oxazolidinones ainsi que procedes de preparation associes
WO2007023507A3 (fr) * 2005-06-20 2007-07-12 Milind D Sindkhedkar Composition a activite antimicrobienne supportant des oxazolidinones ainsi que procedes de preparation associes
WO2007000644A1 (fr) 2005-06-29 2007-01-04 Pharmacia & Upjohn Company Llc Oxazolidinones d'homomorpholine en tant qu'agents antibacteriens
US8288373B2 (en) 2008-11-04 2012-10-16 Chemocentryx, Inc. Modulators of CXCR7
US8853202B2 (en) 2008-11-04 2014-10-07 Chemocentryx, Inc. Modulators of CXCR7
US8841306B2 (en) 2008-11-20 2014-09-23 Panacea Biotec Ltd. Antimicrobials
US8906913B2 (en) 2009-06-26 2014-12-09 Panacea Biotec Limited Azabicyclohexanes
US11834452B2 (en) 2012-11-29 2023-12-05 Chemocentryx, Inc. CXCR7 antagonists
WO2018170664A1 (fr) * 2017-03-20 2018-09-27 Merck Sharp & Dohme Corp. Composés d'oxazolidinone et leurs procédés d'utilisation en tant qu'agents antibactériens
US10752621B2 (en) 2017-03-20 2020-08-25 Merck Sharp & Dohme Corp. Oxazolidinone compounds and methods of use thereof as antibacterial agents
US11464786B2 (en) 2018-12-12 2022-10-11 Chemocentryx, Inc. CXCR7 inhibitors for the treatment of cancer

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