WO2004009587A1 - Oxazolidinone derivatives as antibacterial agents - Google Patents

Oxazolidinone derivatives as antibacterial agents 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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French (fr)
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/en

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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 :

Abstract

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).

Description

OXAZOLIDINONE DERIVATIVES AS ANTIBACTERIAL AGENTS
Field of the Invention
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).
Figure imgf000002_0001
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.
Background of Invention Several oxazolidinone derivatives have been reported in the literature some of which relevant are given here: International publication number 97/09328 discloses and claims compounds of formula
Figure imgf000003_0001
in which X is NR1, S(0)g or O; R1 is a hydrogen, (CrC6)alkyl optionally substituted with one or more OH, CN, or halo or R1 is -(CH2)h-aryl, -COR1"1, COOR1"2, -CO-CCHa -COR1"1, (CrC6)alkylsulfonyl, -S02-(CH2)h-aryl or -(CO)r Het; R2 is hydrogen, (C C6)alkyl, -(CH2)h-aryl or halo; R3 and R4 are the same or different and are hydrogen or halo; R5 is hydrogen, (C1-C12)alkyl optionally substituted with one or more halo, (C3-C12)cycloalkyl, (Cι-C6)alkoxy; g is 0, 1 or 2; h is 1, 2, 3 or 4; i is 0 or 1; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4 or 5.
International publication number 97/30995 discloses and claims compounds of formula
Figure imgf000003_0002
wherein T is of the formula
R5-N A— R6^-B wherein R1 is chloro, fluoro, (C1-C4)alkanesulfonyloxy, azido, (C1-C4)alkoxy, (CrC )alkylthio, (Cι-C )alkylaminocarbonyloxy; or of the formula -NHC(=ιO)Rb wherein R is hydrogen, (C1-C4)alkoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino, dimethylamino or (CrC4)alkyl; or of the formula -NHS(0)n(Cι-C4)aιkyl where n is 0, 1 or 2; R2 and R3 are independently hydrogen or fluoro; >A-B- is >CH-CH2; R6 is (Cr C )alkyl, (C1-C4)alkanoylamino(C1-C4)alkyl, hydroxy(Ci-C4)alkyl, carboxy, (Ci- C )alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl (where Ar is as defined in the specification) or independently as defined for R excluding hydrogen; R5 is of the formula R10CO-, R10SO2-, R10CS-, where R10 is AR.
US patent No. 5,922,708 discloses and claims compounds of formula (IV)
Figure imgf000004_0001
in which R1 is a radical of the formula D-R2, -CO-R3 or -CO-NR4R5, wherein D is the C02 or S02 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 R4 and R5 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 β-carbolin-3- yl or indolizinyl directly bonded via the 6-membered ring, or a 5-membered aromatic heterocycle having up to 3 heteroatoms from the group S, N and/or O and directly bonded via a carbon atom, which heterocycle can additionally have a fused benzene or naphthyl ring, all the rings optionally being substituted in each case by up to 3 identical or different substituents selected from carboxyl, halogen, cyano, mercapto, formyl, trifluoromethyl, nitro, linear or branched alkoxy, alkoxycarbonyl, alkylthio or acyl, each of which has up to 6 carbon atoms, and linear or branched alkyl having up to 6 carbon atoms, which in turn can be substituted by hydroxyl, by linear or branched alkoxy or acyl, each of which has up to 5 carbon atoms, or by a group of the formula -NR6 R7, wherein R6 and R7 are identical or different and are hydrogen, cycloalkyl having 3 to 6 carbon atoms, linear or branched alkyl having up to 5 carbon atoms or phenyl, or, together with the nitrogen atom, form a 5- or 6-membered saturated heterocycle optionally having another heteroatom from the group N, S and/or O, which heterocycle in turn can optionally be substituted, also on another nitrogen atom, by linear or branched alkyl or acyl, each of which has up to 3 carbon atoms etc.
Objective of the Invention
We have focused our research to identify novel oxazolidinone derivatives, which are effective against resistant organisms. Our sustained efforts have resulted in novel oxazolidinone derivatives of the formula (I). The novel oxazolidinone derivatives of the present invention 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
Summary of the Invention
The present invention relates to novel oxazolidinones of the formula (I)
Figure imgf000005_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymoφhs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein X represents oxygen or sulfur; R1 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 (C1-C6)alkyl, cycloalkyl, aryl, aralkyl, acyl, thioacyl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; or R1 represents N(R8aR8b) where R8a and R8b may be same or different and independently represent hydrogen, formyl, substituted or unsubstituted groups selected from (Cι-C6)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or an aminoacid residue which is attached through acid moiety; or R8a and R8b together with nitrogen may represent a mono or bicyclic saturated or unsaturated ring system which may contain one or more heteroatoms selected from O, S or N; or R1 represents the formula -NHC(=Z)R9 wherein Z represents O or S, R9 is hydrogen, substituted or unsubstituted groups selected from (Cι-C6)alkyl, (Cr C6)alkoxy, aryl, (C3-C6)cycloalkyl, amino, monoalkylamino, dialkylamino, cycloalkylamino, arylamino, aroylamino, alkylcarbonylamino, arylcarbonylamino,. heteroaryl, heterocyclyl, heteroaralkyl, heteroaroylamino, or R1 is of the formula -NHS(0)r(CrC4)alkyl, -NHS(0)raralkyl or NHS(0)rheteroaralkyl, where r is 0 to 2; A and B are different arid represent CH or N; R2 and R3 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 R5 may be same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (Cι-C6)alkyl, haloalkyl, (C1-C6)alkoxy, (C C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent, an oxo or thiooxo group; R6 represents hydrogen, cyano, nitro, amino, halogen, hydroxyl, ( - C6)alkyl, haloalkyl, (C C6)alkoxy, (CrC6)alkylthio, (C3-C6)cycloalkyl; m is an integer 1-4; G represents aryl, cycloalkyl, heteroaryl, heterocyclyl linked through carbon atom;
Detailed Description of the Invention Suitable groups represented by R1 are selected from halogen, azido, nitro, cyano, substituted or unsubstituted group selected from TR6, N(R7aR7b), - NHC(=Q)R8, -NHS(0)r(C C4)alkyl, -NHS(0)raralkyl or NHS(0)rheteroaralkyl.
Suitable groups represented by R and R are selected from hydrogen, halogen atom such as fluorine, chlorine, bromine or iodine; hydroxyl, ( - C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t- butyl, n-pentyl, isopentyl, hexyl and the like; (C1-C6)alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like.
Suitable groups represented by R4, R5 and R6 are selected from hydrogen, cyano, nitro, amino, halogen, hydroxyl, (Cι-C6)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 C6)alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; (Cι-C6)allylthio group such as methylthio, ethylthio, n-propylthio, iso-propylthio and the like; (C3- C6)cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like or either of R4 or R5 represent an oxo or thiooxo group.
Suitable groups represented by R are selected from hydrogen, formyl, substituted or unsubstituted linear or branched (Cι-C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; (C3-C6)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 -C(=0)CH3, - C(=0)C2H5, -C(=0)C3H7j -C(=0)C6H13, benzoyl and the like, the acyl group may be substituted; thioacyl group such as -C(=S)CH3, -C(=S)C2H5, -C(=S)C3H7] -C(=S)C6H13 and the like, the thioacyl group may be substituted; alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl and the like, which may be substituted; arylsulfonyl group such as phenylsulfonyl, naphthylsulfonyl and the like, which may be substituted; aralkylsulfonyl group such as phenylmethylsulfonyl, phenylethylsulfonyl, naphthylmethylsulfonyl, naphthylethylsulfonyl and the like, which may be substituted; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like, which may be substituted; heterocyclyl group such as pyrrolidinyl, moφholinyl, thiomoφholinyl, piperidinyl, piperazinyl, and the like, which may be substituted.
Suitable groups represented by R a and R8b are selected from hydrogen, formyl, substituted or unsubstituted linear or branched (Cι-C6)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, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like, which may be substituted; heteroaralkyl group wherein the heteroaryl moiety is as defined above; an aminoacid residue group selected from glycine, alanine, lysine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, iso-leucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine.
Suitable ring systems formed by R8a and R8 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 R9 are selected from hydrogen, amino, substituted or unsubstituted linear or branched (Cι-C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; (C C6)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; (C3-C6)cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, which may be substituted; monoalkylamino group such as NHCH3, NHC2H5, NHC3H7> NHC6H13, and the like, which may be substituted; dialkylamino group such as N(CH3)2, NCH3(C2H5), N(C2H5)2 and the like, which may be substituted; arylamino group such as phenylamino or naphthylamino, which may be substituted; alkylcarbonylamino group such as methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, iso-propylcarbonylamino and the like, which may be substituted; arylcarbonylamino group such as phenylcarbonylamino or naphthylcarbonylamino, which may be substituted; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like, which may be substituted; heteroaroylamino wherein the heteroaryl group is as defined above; heteroaralkyl group wherein the heteroaryl moiety is as defined above; heterocyclyl group such as pyrrolidinyl, moφholinyl, thiomoφholinyl, piperidinyl, piperazinyl, and the like, which may be substituted; cycloalkyl amino group such as cyclopropyl amino, cyclobutylamino, cyclopentylamino, cyclohexylamino and the like, which may be substituted; Suitable groups represented by G are selected from aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; (C3- C6)cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, which may be substituted; heteroaryl group such as thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indole, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like; heterocyclyl group such as pyrrolidinyl, moφholinyl, thiomoφholinyl, piperidinyl, piperazinyl and the like. 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.
The substituents on any of the groups represented by R1, R2, R3, R4, R5, R6, R7, R8a, R8b, R9 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.
Pharmaceutically acceptable 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, α-phenylethylanrine, benzylamine, piperidine, moφholine, 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:
(5)-N-[3-[2-[4-(5-Nitrothiophen-2-ylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(5 -N-[3-[2-[4-(5-Nitrothiophen-2-ylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(^-N-[3-[2-[4-(5-Nitτofuran-2-ylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl] acetamide ; («S)-N- [3 - [2- [4-(5 -Nitrofuran-2-ylmethyl)piρerazin- 1 -yl]pyridin-5 -yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ; (^)-N-[3-[2-[4-(4-Methylsulfanylphenylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(5)-N- [3 - [2- [4-(4-Methylsulfanylphenylmethyl)piperazin- 1 -yl]pyridin-5-yl] -2- oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N- [3 - [2- [4-(4-Trifluoromethylphenylmethyl)piperazin- 1 -yl]pyridin-5-yl] -2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N- [3 - [2- [4-(4-Trifluoromethylphenylmethyl)piperazin- 1 -yl]pyridin-5 -yl]-2- oxooxazolidin- 5 -ylmethyl] thioacetamide ;
( )-N-[3-[2-[4-(2,4,6-Trifluorophenylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(5)-N-[3-[2-[4-(2,4,6-Trifluorophenylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(<S)-N- [3 - [2- [4-(5 -Nitrothiophen-2-ylmethyl)piperazin- 1 -yl]pyridin-5-yl] -2- oxooxazolidin-5-ylmethyl]thiocarbamate ; (S)-N-[3-[2-[4-(5-Nitrofuran-2-ylmethyl)ρiρerazin- 1 -yl]pyridin-5-yl]-2- oxooxazolidin- 5 -ylmethyljthiocarbamate ;
(S)-N- [3 - [2- [4-(4-Trifluoromethylphenylmethyl)piperazin- 1 -yl]pyridm-5-yl] -2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N- [3 - [2- [4-(4-Trifluoro phenyl -2-ylmethyl)piperazin- 1 -yl]pyridin-5 -yl]-2- oxooxazolidin-5-ylmethyl]-N'-methyl thiourea ;
(S)-N-[3-[2-[4-(5-Nitrothiophen-2-ylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]-N'-methyl thiourea ;
( )-N-[3-[2-[4-(5-Nitτofuran-2-ylmethyl)ρiperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]-N'-methyl thioure ; (S)-N-[3-[2-[4-(4-pyrazin-2-ylmethyl)ρiρerazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ; 0S)-N- [3 - [2- [4-(4-pyrazin-2-ylmethyl)piperazin- 1 -yl]pyridin-5 -yl] -2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(1S)-N-[3-[2-[4-(4-pyrazin-2-ylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate and ()S)-N-[3-[2-[4-(4-pyrazin-2-ylmethyl)piperazin-l-yl]ρyridin-5-yl]-2- oxooxazolidin- 5 -ylmethyl] -N ' -methyl thiourea.
According to another embodiment of the present invention, there is provided a process for the preparation of novel oxazolidinone derivatives of the formula (I) where R1 represents NHC(=Z)R9, wherein R9 is as defined earlier and all other symbols are as defined earlier, which comprises (i) converting the compound of formula (III)
Figure imgf000013_0001
where 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)
Figure imgf000013_0002
where 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)
Figure imgf000014_0001
where all symbols are as defined earlier, iii) reducing the compound of formula (V) to a compound of formula (VI)
Figure imgf000014_0002
where all symbols are as defined earlier, iv) acylating the compound of formula (VI) to produce a compound of formula (VII)
Figure imgf000014_0003
where all symbols are as defined earlier, v) deprotecting the compound of formula (VII) to produce a compound formula
Figure imgf000014_0004
where all symbols are as defined earlier, vi) reacting the compound of formula (VIII) with a compound of formula (IX) G-(CHR6)o— L (IX) wherein L is a leaving group and all other symbols are as defined earlier to produce a compound of formula (I). The compound of formula (III) may be converted to a compound of formula (IV) using methane sulfonyl chloride, tosyl chloride, trifluoromethane sulfonyl chloride. 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. 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 LiN3, NaN3 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 N2 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 CH3C02H 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.
The 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. 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. According to another embodiment of the present invention, there is provided a process for the preparation of novel oxazolidinone derivatives of the formula (I) where R1 represents NHC(=Z)R9, wherein Z is S; R9 represents alkoxy, amino, monoalkylamino, dialkylamino; and all other symbols are as defined earlier, which comprises i) converting the compound of formula (VI)
Figure imgf000017_0001
to produce a compound of formula (X)
Figure imgf000017_0002
where all symbols are as defined earlier, ii) converting the compound of formula (X) to produce a compound of formula (VII)
Figure imgf000017_0003
wherein R1 is NHC(=Z)R9, wherein Z is S; and all other symbols are as defined earlier and iii) deprotecting the compound of formula (VII) to produce a compound formula (VIII),
Figure imgf000017_0004
wherein R1 is NHC(=Z)R9, wherein Z is S; and all other symbols are as defined earlier and iv) reacting the compound of formula (VIII) with a compound of formula
(IX) G-(CHR6)o-L (IX) wherein all symbols are as defined earlier and L is a leaving group to produce a compound of formula (I), where R1 represents - NHC(=Z)R9.
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. 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. The conversion of compound of formula (X) to compound of formula
(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.
The 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. 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.
In yet another embodiment of the present invention, there is provided a
1 7 process for the preparation of compounds of formula (I) where R represents TR , N(R8aR8b), wherein R7, R8a and R8b are as defined earlier which comprises reacting the compound of formula (XI)
Figure imgf000019_0001
where L1 represents a leaving group such as mesylate, tosylate or triflate with R7TH or NH(R8aR8b) where all symbols are as defined earlier. The conversion of compounds of formula (XI) to a compound of formula
(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. In yet another embodiment of the present invention, there is provided a process for the preparation of compounds of formula (I) wherein R1 represents - NHS(0)r(Cι-C4)alkyl, -NHS(0)raralkyl or -NHS(0)rheteroaralkyl group, which comprises reacting the compound of formula (XII)
Figure imgf000020_0001
where all symbols are as defined earlier which represents compounds of formula
(I), R1 represents N(R8aR8b) where R8a and R8b represent hydrogen, with R'S02C1 where R' represents (Cι-C4)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. The reaction temperature may range from 0 °C to room temperature. The duration of the reaction may range from 4 to 12 hrs.
According to another embodiment of the present invention, there is provided a process for the preparation of novel oxazolidinone derivatives of the formula (I) where R1 represents the formula - NHC(=Z)R9 where Z is S, R9 and all other symbols are as defined above, which comprises reacting the compound of formula (XIII)
G-
Figure imgf000020_0002
where all symbols are as defined earlier which represents compound of formula (I) where R1 represents azido with thioacetic acid to produce compound of formula (I) as defined above. The 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.
According to another embodiment of the present invention, there is provided a process for the preparation of novel oxazolidinone derivatives of the formula (I) where E represents N, D represents CH, R1 represents TR7 where R7 and all other symbols are as defined earlier, which comprises : i) reacting the compound of formula (III)
Figure imgf000021_0001
with a compound of formula (XIV) R7TH (XIV) to produce a compound of formula (XV)
Figure imgf000021_0002
where all symbols are as defined earlier, ii) deprotecting the compound of formula (XV) to produce a compound of formula (XVI),
Figure imgf000022_0001
where all symbols are as defined earlier, iii) reacting the compound of formula (XVI) with a compound of formula
G-(CHR6)o— L (IX) wherein all symbols are as defined earlier and L is a leaving group to produce a
1 7 compound of formula (I), where R represents TR ,
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. The 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. 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.
According to another embodiment of the present invention, there is provided a process for the preparation of novel oxazolidinone derivatives of the
1 7 7 formula (I) where E represents N, D represents CH, R represents TR where R and all other symbols are as defined earlier, which comprises : i) deprotecting the compound of formula (III)
Figure imgf000023_0001
to produce a compound of formula (XVII),
Figure imgf000023_0002
ii) reacting the compound of formula (XVII) with a compound of fonnula (XIV)
R7TH (XIV) to produce a compound of fonnula (XVIII) (XVIII)
Figure imgf000024_0001
where all symbols are as defined earlier, iii) reacting the compound of formula (XVIII) with a compound of formula
(IX)
G-(CHR6)o— L (IX) wherein all symbols are as defined earlier and L is a leaving group to produce a compound of formula (I), where R represents TR .
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.
The 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.
According to another embodiment of the present invention, there is provided a process for the preparation of compounds of formula (III)
Figure imgf000025_0001
where all symbols are as defined earlier, which comprises : i) reacting the compound of formula (Ilia)
Figure imgf000025_0002
where X represents halogen atom and all other symbols are as defined earlier, with compound of formula (Illb)
Figure imgf000025_0003
where P represents protecting group and all other symbols are as defined earlier, to produce compound of formula (IIIc)
Figure imgf000026_0001
ii) reducing the compound of formula (IIIc) to produce a compound of formula (Hid)
Figure imgf000026_0002
wherein all symbols are as defined earlier, iii) converting the compound of formula (Hid) to produce compound of formula (Hie)
Figure imgf000026_0003
where P represents protecting group all symbols are as defined earlier, iv) cyclizing the compound of formula (Hie) with R-(-)-glycidyl butyrate to produce a compound of formula (III) where all symbols are as defined earlier.
The reaction of compound of formula (Ilia) with compound of fonnula
(Illb) may be canied out in the presence of BINAP [(R)-2,2'-
Bis(diphenylphosphino)-l,l'-binaρhthyl] and tris(dibenzylidene acetone)dipalladium(o). The reaction may be carried out using inert gases such as
N2, argon and the like. 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. 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 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/CH3C02H 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.
According to another embodiment of the present invention, there is provided a process for the preparation of novel oxazolidinone derivatives of the formula (III)
Figure imgf000027_0001
where E represents N, D represents CH, and all other symbols are as defined earlier, which comprises : i) protecting compound of formula (Illf)
Figure imgf000028_0001
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)
Figure imgf000028_0002
ii) condensing the compound of formula (Illg) or (Illh) with N-benzyl piperidone to produce a compound of formula (Illi)
Figure imgf000028_0003
iii) dehydrating the compound of formula (Illi) using a mineral acid to produce a compound of formula (IIIj)
Figure imgf000028_0004
(iv) simultaneously reducing and debenzylating the compound of formula (IIIj) to produce a compound of formula (Illk)
Figure imgf000029_0001
iv) protecting the compound of formula (Illk) using conventional nitrogen protecting groups to produce a compound of formula (III1)
Figure imgf000029_0002
v) cyclizing the compound of fonnula (III1) with R-(-)-glycidyl butyrate to produce a compound of formula (III) where all symbols are as defined earlier.
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. The 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. According to another embodiment of the present invention, there is provided a process for the preparation of compounds of formula (XVII)
Figure imgf000031_0001
where all symbols are as defined earlier, which comprises : i) protecting compound of formula (Illf)
Figure imgf000031_0002
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)
Figure imgf000031_0003
ii) condensing the compound of formula (Illg) or (Illh) with a compound of formula (Illm)
Figure imgf000031_0004
to produce a compound of formula (IHn)
Figure imgf000031_0005
(iii) protecting compound of formula (IHn) using conventional nitrogen protecting groups to produce a compound of formula (IIIo)
Figure imgf000032_0001
(vi) reacting the compound of fonnula (IIIo) with R-glycidyl butyrate to produce a compound of formula (XVII).
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 (IΙ)acetate in BINAP and Cs2C03. 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.
The 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. 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.
In another embodiment of the present invention, there is provided a process for the conversion of compounds of formula (I) where R1 represents the formula - NHC(=Z)R ; where Z is O, R and all other symbols are as defined above to compounds of formula (I) where R1 represents the formula -
NHC(=Z)R ; where Z is S, R and all other symbols are as defined earlier. 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. It is appreciated that in any of the above-mentioned reactions, 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. Organic bases such as diethanolamine, α- 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. Alternatively, 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.
The 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. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). More specifically 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.
Various 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.
Pharmaceutically acceptable 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.
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. In addition to the compounds of formula (I) 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 β-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.
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.
Preparation 1 Synthesis of (-S)-N-3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5-yl]- 2-oxooxazoIidin-5-ylmethyl amine
Figure imgf000036_0001
Step (ϊ) Preparation of 2-(N-t-butoxycarbonyIpiperazine)-5-nitro pyridine
Figure imgf000037_0001
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). To this cesium carbonate (90 g, 275,862 mmoles) was added at room temperature under argon atmosphere. The reaction mixture was heated to 80 °C for 1-2 hours under argon atmosphere and was cooled to RT and filtered through celite. Washed the residue thoroughly with ethylacetate. The combined filtrates were washed with water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness and purified over silica gel column using dichloromethane and methanol as eluent to yield the title compound (42.4 g, yield 70%).
Step (ii)
Preparation of 2-(N-t-butoxycarbonylpiperazine)-5-amino pyridine
t-Boc-N N— ^ NH 2
\ — N=/ 2-(N-t-Butoxycarbonylpiperazine)-5-nitro pyridine (82 g, 266.233 mmoles) was dissolved in 1:1 mixture of methanol and ethylacetate (1L). This solution was cooled to -5° to -10 °C. To this, 8.2 g of 10% palladium carbon was added and hydrogenated the reaction mixture at 45 °C, 60 psi for 3 hours. Filtered the reaction mixture through celite and washed the residue thoroughly with methanol. Concentrated the filtrate to dryness and dried under high vacuum to give the title compound (74 g).
Step (iii)
Preparation of 2-(N-t-butoxycarbonylpiperazine)-5-(benzyIoxycarbonyI) aminopyridine
Figure imgf000038_0001
To a solution of 2-(N-t-butoxycarbonylpiperazine)-5-amino pyridine (70 g, 251.798 mmoles) dissolved in acetone (700 ml), sodium bicarbonate (42.3 g, 503.597 mmoles) dissolved in water (350 ml), was added. and cooled to 0 °C. Benzylchloroformate (85.8 g, 503.597 mmoles) was added to the reaction mixture at 0 °C drop wise. After complete addition, the reaction mixture was kept at room temperature for 12 hours. Acetone was removed from the reaction mixture and diluted further with ethylacetate (2L). Washed the ethylacetate layer with water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness. The crude compound was crystallized using ethylacetate and hexane to yield the title compound (67.4 g, yield 65 %).
Step (iv) Preparation of (5)-N-3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5- yl]-2-oxooxazolidin-5-ylmethanol
Figure imgf000038_0002
A solution of 2-(N-t-butoxycarbonylpiperazine)-5-(benzyloxycarbonyl) aminopyridine (30 g, 72.8155 mmoles) dissolved in dry tetrahydrofuran (600 ml) was cooled to -78 °C. To this n-butyl lithium (23.3 g, 364.0776 mmoles, 15% solution in hexane) was added at -78 °C drop wise with out raising the temperature. After complete addition, continued the stirring at -78 °C for 1 hour. Then, (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%).
Step (v)
Preparation of (1S -N-[3-[2-[4-(N-t-butoxycarbonyI)piperazin-l-yl]pyridin-5- yl] -2-oxooxazolidin-5-ylmethyI] mesylate
Figure imgf000039_0001
To a solution of (S)-N-3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5-yl]- 2-oxooxazolidin-5-ylmethanol (10 g, 26.455 mmoles) dissolved in DCM (100 ml) cooled to 0 °C, triethylamine (5.66 g, 56.0846 mmoles) was added. To this reaction mixture methane sulphonylchloride (5.36 g, 46.825 mmoles) was added at 0 °C. The reaction mixture was stined for 3 hours at room temperature. Diluted the reaction mixture with ethyl acetate (1L) and the ethylacetate layer was washed with sodium bicarbonate, water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness to yield the title compound (12 g, yield 100%). Step (vi)
Preparation of (.S)-N-[3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yI]pyridin-5- yl] -2-oxooxazolidin-5-ylmethyI] azide
Figure imgf000040_0001
To a solution of (S)-N-[3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5-yl]- 2-oxooxazolidin-5-ylmethyl]mesylate (25 g, 54,8245 mmoles) dissolved in DMF (300 ml), sodium azide (14.25 g, 219.29 mmoles) was added. The reaction mixture was heated at 85-90 °C for 4 hours. Cooled the reaction mixture to RT and water (200 ml) was added and extracted the reaction mixture with ethyl acetate (3 x 300 ml). The ethyl acetate layer was washed with water and brine solution. Dried over anhydrous sodium sulphate and concentrated the solution and dried the mass under high vacuum to give the title compound (22 g, yield 100 %).
Step (vii)
Synthesis of (lS -N-[3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yI]pyridin-5-yI]- 2-oxooxazoIidin-5-ylmethyl]amine
Figure imgf000040_0002
(S)-N- [3 - [2- [4-(N-t-butoxycarbonyl)piperazin- 1 -yl]ρyridin-5-yl] -2- oxooxazolidin-5-ylmethyl]azide (17 g, 42.18 mmoles) was taken in methanol (200 ml) and 10% palladium-carbon (1.7 g) was added under N2 atmosphere. Hydrogenated the reaction mixture using par hydrogenation apparatus at 40 °C under 80 psi pressure for 6 hours. Filtered the RM through celite and washed- the residue thoroughly with methanol. The filtrate was concentrated to dryness and washed with hexane. Dried the compound under high vacuum to give the title compound (11 g, yield 70%).
Preparation 2
S nthesis of (-S)-N- [3- [2- [4-(N-t-butox carbonyι)piperazin-l-yl] p ridin-5-yl] -
2-oxooxazolidin-5-yImethyl]acetamide
Figure imgf000041_0001
(S)-N-[3-[2-[4-(N-t-Butoxycarbonyl)ρiperazin-l-yl]ρyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]amine (5.8 g, 15.3846 mmoles) was dissolved in dry DCM (50 ml) and cooled to 0 °C. To this solution pyridine (1.82 g, 23.0769 mmoles) and acetic anhydride (6.27 g, 61.53846 mmoles) was added at 0 °C. Allowed the RM to stir at RT for 4 hours and poured the RM over ice and extracted with DCM (3 x 100 ml). Washed the organic layer with sodium bicarbonate, water and brine solution. Dried over anhydrous sodium sulphate, and concentrated to dryness. Purified the crude material on silica gel using DCM and CH3OH as eluent to yield the title compound (4,6 g, yield 72%).
Preparation 3
Synthesis of (5 -N-[3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5-yl]- 2-oxooxazolidin-5-ylmethyI]isothiocyanate
Figure imgf000042_0001
(<S)-N- [3 - [2- [4-(N-t-Butoxycarbonyl)piperazin- 1 -yljpyridin- 5 -yl]-2- oxooxazolidin-5-ylmethyl]amine (8 g, 21.22 mmoles) was dissolved in dry DCM (40 ml) and cooled to 0 °C. Triethyl amine (7.5 g, 74.271 mmoles ) was added to the RM at 0 °C. Thiophosgene (2.9 g, 25.4641 mmoles) was added to the RM at 0 °C. Stined the RM at room temperature for 3 hours. Removed the solvent from the reaction mixture over Buchi rotary evaporator and dissolved the mass in ethyl acetate (500 ml). Washed the ethyl acetate layer with sodium bicarbonate, water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness. Dried the compound under high vacuum, to give the title compound (8 g, yield 90%).
Preparation 4
Synthesis of (S)-N- [3- [2- [4-(N-t-butoxycarbony l)piper azin-1-yl] pyridin-5-yl] - 2-oxooxazolidin-5-ylmethyl]thiocarbamate
Figure imgf000042_0002
A solution of («S)-N-[3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]isothiocyanate (8 g, 19.093 mmoles) dissolved in methanol (80 ml) was heated to reflux temperature for 6 hours. After completion of the reaction, the solvent was removed and purified the RM over silica gel column using hexane and ethylacetate mixture as eluent to yield the title compound (5.2 g, yield 60%). Preparation 5
Synthesis of (5)-N-[3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5-yl]-
2-oxooxazolidin-5-ylmethyI]-N'-methyl thiourea
Figure imgf000043_0001
(5)-N-[3-[2-[4-(N-t-Butoxycarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]isothiocyanate (5 g, 11,933 mmoles) was dissolved in dry THF (50 ml). To this solution triethylamine (0,6 g, 5.966 mmoles) and methyl amine hydrochlori.de (1.2 g, 17.899 mmoles) were added at room temperature and heated the reaction mixture to reflux temperature for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethylacetate. Washed the ethyl acetate layer with water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness. Purified the crude material over silica gel using hexane and ethylacetate mixture as eluent to yield the title compound (3.6 g, yield 68%).
Preparation 6
Synthesis of (_S)-N- [3-[2-(piperazin-l -yl)pyridin~5-yl] -2-oxooxazoIidin-5- ylmethyl] acetamide
Figure imgf000043_0002
(iS)-N-[3-[2-[4-(N-t-Butoxycarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide (0.6 g, 1.43 mmoles) (obtained according to the procedure given in preparation 2) was taken in dry DCM (10 ml) and cooled to 0 °C. Trifluoroacetic acid (0.978 g, 8.58 mmoles) was added to the reaction mixture and stirred the RM at room temperature for 3 hours. Excess sodium' bicarbonate was added to the RM and stined for 15 minutes. Filtered the solid and washed thoroughly with ethyl acetate. The filtrate was concentrated to dryness and dried under vacuum to afford the title compound (0.45 g, yield 100%).
Preparation 7 Synthesis of (S)-N-[3-[2-(piperazin-l-yl)pyridin-5-yl]-2-oxooxazolidin-5- ylmethyl] thiocarbamate
Figure imgf000044_0001
The title compound (1.55 g, yield 100%) was prepared from (_S)-N-[3-[2-[4-(N-t- butoxycarbonyl)piperazin- 1 -yl]pyridin-5-yl]-2-oxooxazolidin-5- ylmethyl]thiocarbamate (2 g, 4.434 mmoles) (obtained according to the procedure given in preparation 4) and trifluoro acetic acid (3.032 g, 26.604 mmoles) by following the procedure described in preparation 6.
Preparation 8 Synthesis of (iS)-N-[3-[2-(piperazin-l-yl)pyridin-5-yl]-2-oxooxazolidin-5- ylmethyl]-N'-methyl thiourea
Figure imgf000044_0002
The title compound (1.55 g, yield 100%) was prepared from (S)-N-[3-[2-[4-(N-t- butoxycarbonyl)piperazin-l-yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]-N'- methyl thiourea (2 g, 4.444 mmoles) (obtained according to the procedure given in preparation 5) and trifluoroacetic acid (3.0399 g, 26.66 mmoles) by following the procedure described in preparation 6.
Example 1
Synthesis of . (5)-N-[3-[2-[4-(5-nitrothiophen-2-ylmethyI)piperazin-l- yl] py ridin-5-y 1] -2-oxooxazolidin-5-yImethyl] acetamide
Figure imgf000045_0001
(S)-N-[3-[2-(Piperazin-l-yl)pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl] acetamide
(obtained according to the procedure given in preparation 6) (300 mg, 0.9404 mmoles) was taken in benzene (100 ml) and 5-nitro-2-thiophene carboxaldehyde
(221 mg, 1.4106 mmoles) was added and heated the reaction contents using Dean-stark apparatus at 80 - 85 °C for 1 hour. The reaction mixture was cooled to room temperature and triacetoxy sodium borohydride (797 mg, 3.7616 mmoles) Was added and continued the stirring 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 (173 mg, yield 40%). Mass M+1 : 461 !HNMR (CDCI3) δ : 2.03 (s, 3H), 2.64-2.67 (t, 4H), 3.55-3.57 (t, 4H), 3.60-3.61 (m, IH), 3.70-3.72 (t, 2H), 3.73-3.75 (m, IH), 4.03 (s, 2H), 4.78 (bs, IH), 6.01(s, IH, D20 exchangeable), 6.66-6.68 (d, IH), 6.89-6.90 (s, IH), 7.80-7.81 (d, IH), 7.83-7.84 (d, IH), 8.12 - 8.13 (s, IH).
The following compounds were prepared according to the procedure given in example 1.
Figure imgf000046_0001
Figure imgf000047_0001
Example 6
S nthesis of (-S)-N- [3- [2- [4-(5-nitrothiophen-2-ylmethyl)piperazin-l- yl] pyridin-5-yl] -2-oxooxazolidin-5-ylmethyl] thioacetamide
Figure imgf000048_0001
To a solution of (»S)-N-[3-[2-[4-(5-nitrothiophen-2-ylmethyl)piperazin-l- yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]acetamide (obtained from example 1) (100 mg, 0.2173 mmoles ) in dry toluene (10 ml), Lawessons reagent (96 mg, 0.2391 mmoles ) was added and heated the reaction contents at 100 °C for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness and purified over silica gel column using chloroform and methanol mixture as eluent to afford the title compound as gummy material (72 mg, yield 70%).
Mass M+1 : 477
1HNMR (CDC13) δ : 2.15 (bs, 3H), 2.71 (s, 4H), 3,60-3.62 (t, 4H), 3.64-3.65 (m, IH), 3.71-3.73 (t, 2H), 3.78-3.80 (m, IH), 4.12 (s, 2H), 4.98 (bs, IH), 6.68-6.70 (d, IH), 6.93-6.94 (bs, IH, D20 exchangeable), 7.80-7.81 (d, IH), 7.90-7.92 (d, IH), 8.08-8.14 (m, 2H).
Example 7
Synthesis of (5 -N-[3-[2-[4-(5-nitrothiophen-2-ylmethyl)piperazin-l- yl]pyridin-5-yl]-2~oxooxazolidin-5-ylmethyl] thiocarbamate
Figure imgf000048_0002
(S)-N- [3 - [2-(Piperazin- 1 -yl)pyridin-5 -yl] -2-oxooxazolidin-5-ylmethyl] thiocarbamate (obtained according to the procedure given in preparation 7) (230mg, 0.655 mmoles) was taken in benzene (100 ml) and 5-nitro-2-thiophene carboxaldehyde (310 mg, 1.9726 mmoles) was added and heated the reaction contents using Dean-stark apparatus at 80 - 85 °C for 1 hour. The 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%).
1HNMR (CDC13) δ : 2.65-2.67 (bs, 4H), 3.56-3.58 (t, 4H), 3.76 (s, 3H), 3.86-3.88 (t, IH), 4.01- 4.04 (m, 2H), 4.06-4.08 (t, IH), 4.12 (s, 2H), 4.97 (s, IH), 6.67- 6.69 (d, 2H), 6.91 (s, IH), 7.81-7.82 (s, IH), 7.85-7.86 (d, IH), 8.12 (s, IH). M+l at 493.
The following compounds were prepared according to the procedure given in example 7.
Figure imgf000049_0001
Figure imgf000050_0002
Example 10
Synthesis of (S)-N-[3-[2-[4-(4-trifluoro phenyl -2-ylmethyl)piperazin-l- yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl] N'-methyl thiourea
Figure imgf000050_0001
(S)-N-[3-[2-(Piperazin-l-yl)pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]-N'-methyl thiourea (obtained according to the procedure given in preparation 8) (389 mg, 1.111 mmoles) was taken in benzene (100 ml) and 4- trifluoromethyl benzaldehyde (380 mg, 2.1824 mmoles) was added and heated the reaction contents using Dean-stark apparatus at 80 - 85 °C for 1 hour. The reaction mixture was cooled to room temperature and triacetoxy sodium borohydride (940 mg, 4.434 mmoles) was added and continued the stirring 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 crystalline solid (237 mg, 42% yield), mp : 170-172 °C. 1HNMR (CDC13) δ : 2.53-2.56 (t, 4H), 2.98 (s, 3H), 3.51-3.54 (t, 4H), 3.60 (s, 2H), 4.01-4.03 (m, 3H), 4.24-4.25 (t, IH), 4.92 (bs, IH), 6.61-6.64 (d, 2H), 6.65 (bs, IH, D20 exchangeable), 7.47-7.49 (d, 2H), 7.58-7.60 (d, IH), 7.68-7.69 (bs, IH, D20 exchangeable), 7.91-7.92 (s, IH), 8.16-8.17(s, IH). Mass : M+l at 509.
Antimicrobial Testing
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.
Briefly, 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 108 colony forming units (CFU) per milliliter of suspension.
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.
The inoculated 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.
The petridishes after incubation, were placed on a dark non reflecting surface and the Minimum Inhibitory Concentration (MIC) recorded as the concentration which showed no growth of the inoculated culture.
The following minimum inhibitory concentrations (μg/ml) were obtained for representative compounds of the invention which are given in the following table : Antimicrobial Screening (MIC) (μg/ml)
Figure imgf000052_0001
Figure imgf000053_0001
"S.aureus - Staphylococus aureus
Ent. Faecalis - Enterococcus faecalis
E. faecium - Enterococcus faecium
ATCC - American Type Culture Collection
MRO - Microbial Resource Orchid
S. epidermidis - Staphylococus epidermidis
S. haemolyticus - Staphylococus haemolyticus
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 :
Figure imgf000053_0002
M. catarrhalis - Moraxella catarrhalis

Claims

Claims :
1. A compound of formula (I)
Figure imgf000054_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein X represents oxygen or sulfur; R1 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 (C1-C6)alkyl, cycloalkyl, aryl, aralkyl, acyl, thioacyl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; or R1 represents N(R8aR8 ) where R8a and R8b are same or different and independently represent hydrogen, formyl, substituted or unsubstituted groups selected from (CrC6)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or an aminoacid residue which is attached through acid moiety; or R8a and R8b together with nitrogen represent a mono or bicyclic saturated or unsaturated ring system which contain one or more heteroatoms selected from O, S or N; or R1 represents the formula -NHC(=Z)R9 wherein Z represents O or S, R9 is hydrogen, substituted or unsubstituted groups selected from (CrC6)alkyl, (C1-C6)alkoxy, aryl, (C3-C6)cycloalkyl, amino, monoalkylamino, dialkylamino, cycloalkylamino, arylamino, aroylamino, alkylcarbonylamino, arylcarbonylamino, heteroaryl, heterocyclyl, heteroaralkyl, heteroaroylamino, or R1 is of the formula - NHS(0)r(CrC4)alkyl, -NHS(0)raralkyl or -NHS(0)rheteroaralkyl, where r is 0 to 2; A and B are different and represent CH or N; R and R are 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; R4 and R are same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (Cι-C6)alkyl, haloalkyl, (d-C6)aιkoxy, (CrC6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; R6 represents hydrogen, cyano, nitro, amino, halogen, hydroxyl, (Cι-C6)aιkyl, haloalkyl, ( -C^alkoxy, (CrC6)alkylthio, (C3- C6)cycloalkyl; m is an integer 1-4; G represents aryl, cycloalkyl, heteroaryl, heterocyclyl linked through carbon atom.
2. A compound as claimed in claim 1, wherein the groups represented by G are selected from phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indole, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopynolyl, benzoxadiazolyl, benzothiadiazolyl, pynolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl.
3. A compound of formula (I) as claimed in claim 1 , which is selected from : (S)-N- [3 - [2- [4-(5-Nitrothiophen-2-ylmethyl)piper.azin- 1 -yl]pyridin- 5 -yl] -2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(5-Nitrothiophen-2-ylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[2-[4-(5-Nifrofuran-2-ylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin- 5 -ylmethyl] acetamide ;
(S)-N- [3 - [2- [4-(5 -Nitrofuran-2-ylmethyl)piperazin- 1 -yl]pyridin-5-yl] -2- oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N- [3 - [2- [4-(4-Methylsulfanylphenylmethyl)ρiperazin- 1 -yl]pyridin-5-yl] -2- oxooxazolidin-5-ylmethyl]acetamide ; (>S)-N- [3 - [2- [4-(4-Methylsulfanylphenylmethyl)piperazin- 1 -yl]pyridin-5 -yl] -2- oxooxazolidin-5-ylmethyl]thioacetamide ;
()S)-N-[3-[2-[4-(4-Trifluoromethylphenylmethyl)piperazin-l-yl]ρyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ; (5)-N-[3-[2-[4-(4-Trifluoromethylphenylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(5)-N-[3-[2-[4-(2,4,6-Trifluorophenylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(^)-N-[3-[2-[4-(2,4,6-Trifluorophenylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(ιS)-N- [3 - [2- [4-(5 -Nitrothiophen-2-ylmethyl)piperazin- 1 -yl]pyridin-5-yl] -2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(5-Nitrofuran-2-ylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ; (<S)-N- [3 - [2- [4-(4-Trifluoromethylphenylmethyl)piperazin- 1 -yl]pyridin-5-yl] -2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(4-Trifluoro phenyl -2-ylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]-N'-methyl thiourea ;
(5)-N-[3-[2-[4-(5-Nitrothiophen-2-ylmethyl)piperazin-l-yl]ρyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]-N'-methyl thiourea ;
(ιS)-N- [3 - [2- [4-(5-Nitrofuran-2-ylmethyl)piperazin- 1 -yl]pyridin-5 -yl] -2- oxooxazolidin-5-ylmethyl]-N'-methyl thiourea ;
(S)-N-[3-[2-[4-(4-pyrazin-2-ylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin- 5 -ylmethyl] acetamide ; (5)-N-[3-[2-[4-(4-ρyrazin-2-ylmethyl)piperazin- 1 -yι]ρyridin-5-yl]-2- oxooxazolidin- 5 -ylmethyl] thioacetamide ; (>S)-N- [3 - [2- [4-(4-pyrazin-2-ylmethyl)piperazin- 1 -yl]pyridin- 5 -yl] -2- oxooxazolidin-5-ylmethyl]thiocarbamate and (-S)-N-[3-[2-[4-(4-pyrazin-2-ylmethyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]-N'-methyl thiourea.
4. The compound as claimed in claim 3, wherein the salt is selected from hydrochloride or hydrobromide.
5. A process for the preparation of compound of the formula (I)
Figure imgf000057_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein X represents oxygen or sulfur; R1 represents NHC(=Z)R9, wherein Z is O or S; R9 is hydrogen, substituted or unsubstituted groups selected from (Cι-C6)alkyl, (Cι-C6)alkoxy, aryl, (C3-C6)cycloalkyl, amino, monoalkylamino, dialkylamino, cycloalkylamino, arylamino, aroylamino, alkylcarbonylamino, arylcarbonylamino, heteroaryl, heterocyclyl, heteroaralkyl, heteroaroylamino; A and B are different and represent CH or N; R2 and R3 are 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; R4 and R5 are same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (CrC6)alkyl, haloalkyl, (CrC6)alkoxy, (CrC6)alkylthio, (C3- C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; R6 represents hydrogen, cyano, nitro, amino, halogen, hydroxyl, ( -C^alkyl, haloalkyl, (Cι-C6)alkoxy, (C Ce^lkylthio, (C3-C6)cycloalkyl; m is an integer 1- 4; G represents aryl, cycloalkyl, heteroaryl, heterocyclyl linked through carbon atom; which comprises :
(i) converting the compound of formula (III)
( ,l'l"h)
Figure imgf000058_0001
where P represents protecting group and all other symbols are as defined above to produce a compound of formula (IV)
Figure imgf000058_0002
where L represents a leaving group such as mesylate, tosylate or triflate and all other symbols are as defined above, ii) converting the compound of formula, (IV) to produce a compound of formula (V)
Figure imgf000058_0003
where all symbols are as defined above, iii) reducing the compound of formula (V) to a compound of fonnula (VI)
Figure imgf000058_0004
where all symbols are as defined above, iv) acylating the compound of formula (VI) to produce a compound of formula (VII)
Figure imgf000059_0001
where all symbols are as defined above, v) deprotecting the compound of formula (VII) to produce a compound formula
(VIII),
Figure imgf000059_0002
where all symbols are as defined above and vi) reacting the compound of formula (VIII) with a compound of formula (IX)
G-(CHR6)o— L (IX) wherein L is a leaving group and all other symbols are as defined above to produce a compound of formula (I) .
6. A process for the preparation of compound of the formula (I)
Figure imgf000059_0003
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein X represents oxygen or sulfur; R1 represents NHC(=Z)R9, where Z is S; R9 represents alkoxy, amino, monoalkylamino, dialkylamino; A and B are different and represent CH or N; R and R are 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; R4 and R5 are same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (CrC6)alkyl, haloalkyl, (C C6)alkoxy, (C C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; R represents hydrogen, cyano, nitro, amino, halogen, hydroxyl, (C C6)alkyl, haloalkyl, (C1-C6)alkoxy, (C C6)alkylthio, (C - C6)cycloalkyl; m is an integer 1-4; G represents aryl, cycloalkyl, heteroaryl, heterocyclyl linked through carbon atom; which comprises : i) converting the compound of formula (VI)
Figure imgf000060_0001
to produce a compound of formula (X)
Figure imgf000060_0002
where all symbols are as defined above, ii) converting the compound of formula (X) to produce a compound of formula (VII)
Figure imgf000060_0003
wherein R1 is NHC(=Z)R9, wherein Z is S; and all other symbols are as defined above, iii) deprotecting the compound of formula (VII) to produce a compound formula (VIII), (VIII)
Figure imgf000061_0001
wherein R1 is NHC(=Z)R9, wherein Z is S; and all other symbols are as defined above and iv) reacting the compound of formula (VIII) with a compound of formula
(IX)
G-(CHR6)o— L (IX) wherein all symbols are as defined earlier and L is a leaving group to produce a compound of formula (I).
7. A process for the preparation of compound of the formula (I)
Figure imgf000061_0002
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymoφhs, their pharmaceutically acceptable salts, their pharmaceutically
1 — -. 7 acceptable solvates, wherein X represents oxygen or sulfur; R represents TR , wherein T represents O or S; R represents hydrogen, formyl, substituted or unsubstituted groups selected from (C C6)alkyl, cycloalkyl, aryl, aralkyl, acyl, thioacyl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; or R1 represents N(R8aR8b) where R8a and R8b are same or different and independently represent hydrogen, formyl, substituted or unsubstituted groups selected from (Cι-C6)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or an aminoacid residue which is attached through acid moiety; or R8a and R8b together with nitrogen represent a mono or bicyclic saturated or unsaturated ring system which contain one or more heteroatoms selected from O, S or N; A and B are different and represent CH or N; R2 and R3 are 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; R4 and R5 are same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (Cι-C6)alkyl, haloalkyl, (CrC6)alkoxy, (CrC6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; R represents hydrogen, cyano, nitro, amino, halogen, hydroxyl, (Cι-C6)alkyl, haloalkyl, (CrC6)alkoxy, (C C6)alkylthio, (C3- C6)cycloalkyl; m is an integer 1-4; G represents aryl, cycloalkyl, heteroaryl, heterocyclyl linked through carbon atom, which comprises reacting the compound of formula (XI)
Figure imgf000062_0001
where L1 represents a leaving group such as mesylate, tosylate or triflate with R7TH or NH(R8aR8b) where all symbols are as defined above.
8. A process for the preparation of compound' of the formula (I)
Figure imgf000062_0002
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein X represents oxygen or sulfur; R1 is of the formula - NHS(0)r(CrC4)alkyl, -NHS(0)raralkyl or -NHS(0)rheteroaralkyl, where r is 0 to 2; A and B are different and represent CH or N; R2 and R3 are 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; R4 and R5 are same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (CrC6)alkyl, haloalkyl, (Cι-C6)alkoxy, (C C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; R6 represents hydrogen, cyano, nitro, amino, halogen, hydroxyl, (CrC6)alkyl, haloalkyl, (C C6)alkoxy, (C C6)alkylthio, (C3- C6)cycloalkyl; m is an integer 1-4; G represents aryl, cycloalkyl, heteroaryl, heterocyclyl linked through carbon atom, which comprises reacting the compound of formula (XII)
Figure imgf000063_0001
where all symbols are as defined above with R'S02C1 where R' represents (Cr
C4)alkyl, aralkyl or heteroaralkyl group.
9. A process for the preparation of compound of the formula (I)
Figure imgf000063_0002
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein X represents oxygen or sulfur; R1 represents NHC(=Z)R9, where Z is S; R9 represents alkoxy, amino, monoalkylamino, dialkylamino; A and B are different and represent CH or N; R2 and R3 are 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; R4 and R5 are same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (Cι-C6)alkyl, haloalkyl, (CrC6)alkoxy, (C C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; R6 represents hydrogen, cyano, nitro, amino, halogen, hydroxyl, (C C6)alkyl, haloalkyl, (C C6)alkoxy, (C1-C6)alkylthio, (C3- C6)cycloalkyl; m is an integer 1-4; G represents aryl, cycloalkyl, heteroaryl, heterocyclyl linked through carbon atom; which comprises reacting the compound of formula (XIII)
Figure imgf000064_0001
where all symbols are as defined above which represents compound of formula (I) where R1 represents azido with thioacetic acid to produce compound of formula (I) as defined above.
10. A process for the preparation of compound of the formula (I)
Figure imgf000064_0002
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically
• " 1 acceptable solvates, wherein X represents oxygen or sulfur; R represents TR , wherein T represents O or S; R represents hydrogen, formyl, substituted or unsubstituted groups selected from (Cι-C6)alkyl, cycloalkyl, aryl, aralkyl, acyl, thioacyl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; A and B are different and represent CH or N; R and R are 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; E represents N, D represents CH; R4 and R5 are same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (CrC6)alkyl, haloalkyl, (C C6)alkoxy, (C C6)alkylthio,
(C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; R6 represents hydrogen, cyano, nitro, amino, halogen, hydroxyl, (CrC6)alkyl, haloalkyl, (C C6)alkoxy, (Cι-C6)alkylthio, (C3-C6)cycloalkyl; m is an integer 1-
4; G represents aryl, cycloalkyl, heteroaryl, heterocyclyl linked through carbon atom, which comprises : i) reacting the compound of formula (III)
Figure imgf000065_0001
with a compound of formula (XIV)
R7TH (XIV) to produce a compound of formula (XV)
Figure imgf000065_0002
where all symbols are as defined above, ii) deprotecting the compound of formula (XV) to produce a compound of formula (XVI),
Figure imgf000065_0003
where all symbols are as defined above and iii) reacting the compound of formula (XVI) with a compound of formula (IX)
G-(CHR6)o— L (IX) wherein all symbols are as defined above and L is a leaving group to produce a
1 compound of formula (I), where R represents TR . 11. A process for the preparation of compound of the formula (I)
Figure imgf000066_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically
1 1 acceptable solvates, wherein X represents oxygen or sulfur; R represents TR , wherein T represents O or S; R7 represents hydrogen, formyl, substituted or unsubstituted groups selected from (C C6)alkyl, cycloalkyl, aryl, aralkyl, acyl, thioacyl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; A
7 o and B are different and represent CH or N; R and R are 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; E represents N, D represents CH; R4 and R5 are same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (Cι-C6)alkyl, haloalkyl, (CrC6)alkoxy, (CrC6)alkylthio, (C3-C6)cycloaιkyl or either of R4 or R5 represent an oxo or thiooxo group; R6 represents hydrogen, cyano, nitro, amino, halogen, hydroxyl, (C1-C6)alkyl, haloalkyl, (CrC6)alkoxy, (Cι-C6)alkylthio, (C3-C6)cycloalkyl; m is an integer 1- 4; G represents aryl, cycloalkyl, heteroaryl, heterocyclyl linked through carbon atom, which comprises : i) deprotecting the compound of formula (III)
Figure imgf000067_0001
where all symbols are as defined above to produce a compound of formula (XVII),
Figure imgf000067_0002
ii) reacting the compound of formula (XVII) with a compound of formula
(XIV)
R7TH (XIV) to produce a compound of formula (XVIII)
(XVIII)
Figure imgf000067_0003
where all symbols are as defined above and iii) reacting the compound of formula (XVIII) with a compound of formula
(IX)
G-(CHR6)o— L (IX) wherein all symbols are as defined above and L is a leaving group to produce a
1 7 compound of formula (I), where R represents TR .
12. A process for the preparation of compound of the formula (III)
Figure imgf000067_0004
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein X represents oxygen or sulfur; A and B are different and represent CH or N; R and R are 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; R4 and R5 are same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (Cι-C6)alkyl, haloalkyl, ( - C6)alkoxy, (Cι-C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; P represents protecting group, which comprises : i) reacting the compound of formula (Ilia)
Figure imgf000068_0001
where X represents halogen atom and all other symbols are as defined above, with compound of formula (Illb)
Figure imgf000068_0002
where P represents protecting group and all other symbols are as defined above, to produce compound of formula (IIIc)
(IIIC)
Figure imgf000068_0003
ii) reducing the compound of formula (IIIc) to produce a compound of formula (Hid)
Figure imgf000069_0001
wherein all symbols are as defined earlier, iii) converting the compound of formula (Hid) to produce compound of formula (Hie)
Figure imgf000069_0002
where P represents protecting group and all symbols are as defined above and iv) cyclizing the compound of formula (Hie) with R-(-)-glycidyl butyrate to produce a compound of formula (III) where all symbols are as defined above.
13. A process for the preparation of compound of the formula (III)
Figure imgf000069_0003
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein X represents oxygen or sulfur; A and B are different
9 ^ and represent CH or N; R and R are 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; E represents N, D represents CH; R4 and R5 are same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (C C6)alkyl, haloalkyl, (C C6)alkoxy, (C C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; P represents protecting group, which comprises : i) protecting compound of formula (Illf)
Figure imgf000070_0001
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)
Figure imgf000070_0002
ii) condensing the compound of formula (Illg) or (Illh) with N-benzyl piperidone to produce a compound of formula (Illi)
Figure imgf000070_0003
iii) dehydrating the compound of formula (Illi) using a mineral acid to produce a compound of formula (IIIj)
Figure imgf000070_0004
(iv) simultaneously reducing and debenzylating the compound of formula (IIIj) to produce a compound of formula (Illk)
Figure imgf000071_0001
iv) protecting the compound of formula (Illk) using conventional nitrogen protecting groups to produce a compound of formula (III1) and
Figure imgf000071_0002
where all symbols are as defined above and v) cyclizing the compound of formula (III1) with R-(-)-glycidyl butyrate to produce a compound of formula (III) where all symbols are as defined earlier.
14. A process for the preparation of compounds of formula (XVII)
Figure imgf000071_0003
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymoφhs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein X represents oxygen or sulfur; A and B are different
9 "\ and represent CH or N; R and R are 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 R5 are same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (C C6)alkyl, haloalkyl, ( - C6)alkoxy, (C C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; which comprises : i) protecting compound of formula (Illf)
Figure imgf000072_0001
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)
Figure imgf000072_0002
ii) condensing the compound of formula (Illg) or (Illh) with a compound of formula (Illm)
Figure imgf000072_0003
to produce a compound of formula (Illn)
Figure imgf000072_0004
(iii) protecting compound of formula (Illn) using conventional nitrogen protecting groups to produce a compound of formula (IIIo)
Figure imgf000072_0005
where all symbols are as defined above, (vi) reacting the compound of formula (IIIo) with R-glycidyl butyrate to produce a compound of formula (XVII).
15. A process for the preparation of compound of the formula (I)
Figure imgf000073_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein X represents oxygen or sulfur; R1 represents halogen, azido, nitro, cyano, substituted or unsubstituted group selected from
7 7
TR , wherein T represents O or S; R represents hydrogen, formyl, substituted or unsubstituted groups selected from (CrC6)alkyl, cycloalkyl, aryl, aralkyl, acyl, thioacyl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; or R represents N(R R ) where R and R are same or different and independently represent hydrogen, formyl, substituted or unsubstituted groups selected from (Cι-C6)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or an aminoacid residue which is attached through acid moiety; or R8a and R8b together with nitrogen represent a mono or bicyclic saturated or unsaturated ring system which contain one or more heteroatoms selected from O, S or N; or R1 represents the formula -NHC(=Z)R9 wherein Z represents S, R9 is hydrogen, substituted or unsubstituted groups selected from (Cι-C6)alkyl, (Cι-C6)alkoxy, aryl, (C3- C6)cycloalkyl, amino, monoalkylamino, dialkylamino, cycloalkylamino, arylamino, aroylamino, alkylcarbonylamino, arylcarbonylamino, heteroaryl, heterocyclyl, heteroaralkyl, heteroaroylamino, or R1 is of the formula - NHS(0)r(CrC4)alkyl, -NHS(0)raralkyl or -NHS(0)rheteroaralkyl, where r is 0
9 " to 2; A and B are different and represent CH or N; R and R are 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; R4 and R5 are same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (CrC6)alkyl, haloalkyl, (CrC6)alkoxy, (C C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; R represents hydrogen, cyano, nitro, amino, halogen, hydroxyl, (CrC6)alkyl, haloalkyl, (Cι-C6)alkoxy, (C C6)alkylthio, (C3- C6)cycloalkyl; m is an integer 1-4; G represents aryl, cycloalkyl, heteroaryl, heterocyclyl linked through carbon atom, which comprises converting the compound of formula (I) where R1 represents formula -NHC(=Z)R9; where Z is O and R9 is as defined above using Lawesson's reagent in the presence of base.
16. A pharmaceutical composition, which comprises a compound of formula
(I)
Figure imgf000074_0001
as defined in claim 1 and a pharmaceutically acceptable carrier, diluents, excipient or solvate.
17. A pharmaceutical composition as claimed in claim 16, in the form of a tablet, capsule, powder, syrup, solution, aerosol or suspension.
18. Use of compound of formula (I) claimed in claim 1, for treating or preventing an infectious disorder in a human or animal.
19. Use of compound as claimed in claim 18, wherein the infectious disorder is caused by bacteria.
20. Use of compound claimed in claim 3, for treating or preventing an infectious disorder in a human or animal.
21. Use of compound as claimed in claim 20, wherein the infectious disorder is caused by bacteria.
22. Use of pharmaceutical composition as claimed in claim 16, for treating or preventing an infectious disorder in a human or animal.
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WO2005003087A2 (en) * 2003-07-01 2005-01-13 Orchid Chemicals And Pharmaceuticals Ltd. Oxazole derivatives as antibacterial agents
WO2007000644A1 (en) 2005-06-29 2007-01-04 Pharmacia & Upjohn Company Llc Homomorpholine oxazolidinones as antibacterial agents
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US7919496B2 (en) 2004-09-20 2011-04-05 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes
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Publication number Priority date Publication date Assignee Title
WO2005003087A2 (en) * 2003-07-01 2005-01-13 Orchid Chemicals And Pharmaceuticals Ltd. Oxazole derivatives as antibacterial agents
WO2005003087A3 (en) * 2003-07-01 2005-03-17 Orchid Chemicals & Pharm Ltd Oxazole derivatives as antibacterial agents
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 (en) 2004-09-20 2010-12-29 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors
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 (en) * 2005-06-20 2007-03-01 Wockhardt Limited Oxazolidinones bearing antimicrobial activity composition and methods of preparation
WO2007023507A3 (en) * 2005-06-20 2007-07-12 Milind D Sindkhedkar Oxazolidinones bearing antimicrobial activity composition and methods of preparation
WO2007000644A1 (en) 2005-06-29 2007-01-04 Pharmacia & Upjohn Company Llc Homomorpholine oxazolidinones as antibacterial agents
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 (en) * 2017-03-20 2018-09-27 Merck Sharp & Dohme Corp. Oxazolidinone compounds and methods of use thereof as antibacterial agents
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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