WO2003097640A1 - Oxazolidinone derivatives as antibacterial agents - Google Patents

Oxazolidinone derivatives as antibacterial agents Download PDF

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Publication number
WO2003097640A1
WO2003097640A1 PCT/IB2003/001944 IB0301944W WO03097640A1 WO 2003097640 A1 WO2003097640 A1 WO 2003097640A1 IB 0301944 W IB0301944 W IB 0301944W WO 03097640 A1 WO03097640 A1 WO 03097640A1
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Prior art keywords
ylmethyl
formula
compound
phenyl
substituted
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PCT/IB2003/001944
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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 AU2003228008A priority Critical patent/AU2003228008A1/en
Publication of WO2003097640A1 publication Critical patent/WO2003097640A1/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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention 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.
  • novel oxazolidinone derivatives of the present invention are 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 (MRS A) and penicillin resistance streptococcus pneumoniae.
  • NRE vancomycin resistance enterococci
  • MRS A methicillin resistance staphylococcus aureus
  • penicillin resistance streptococcus pneumoniae 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
  • R 1 is a hydrogen, (C C 6 )alkyl optionally substituted with one or more OH, CN, or halo or R 1 is -(CH 2 ) ⁇ .-aryl, -COR 1"1 , COOR 1-2 , -CO- CHa -COR 1 - 1 , (C r C 6 )alkylsulfonyl, -SO 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 ⁇ -C ⁇ 2 )alkyl optionally substituted with one or more halo, (C 3 -C ⁇ 2 )cycloalkyl, (C C 6 )alkoxy;
  • 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 (VRE) caused by methicillin resistance staphylococcus aureus (MRS A) and penicillin resistance streptococcus pneumoniae.
  • VRE vancomycin resistance enterococci
  • MRS A methicillin resistance staphylococcus aureus
  • penicillin resistance streptococcus pneumoniae 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
  • the present invention relates to novel oxazolidinone derivatives of the formula (I) their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, wherein X represents oxygen or sulfur; R 1 represents halogen, azido, nitro, cyano; ZR 7 , where X represents O or S, R represents hydrogen, formyl, substituted or unsubstituted groups selected from (C C 6 )alkyl, aryl, aralkyl, acyl, heteroaryl, heterocyclyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, (C ⁇ -C 6 )alkylaminocarbonyl;
  • Suitable groups represented by R 1 are selected from halogen atom such as fluorine, chlorine, bromine or iodine; azido, nitro, cyano, ZR 7 , N(R 8a R 8b ), -
  • NHC( Y)R 9 or -NHS(O) p (C C 4 )alkyl, -NHS(O) r (C ! -C 4 )aryl or -NHS(O) r (C r
  • Suitable groups represented by R and R are selected from hydrogen, halogen atom such as fluorine, chlorine, bromine or iodine; hydroxyl, (Q- 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 and the like.
  • Suitable groups represented by R 4 and R 5 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, trifluorornethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like; (C ⁇ -C 6 )alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; (C ⁇ -C 6 )alkylthio group such as methylthio, ethylthio, n-propylthio, iso-propylthio and the like; (C
  • Suitable groups represented by R are selected from hydrogen, halogen, hydroxy, cyano, nitro, 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 and the like, which may be substituted; aryl such as phenyl, naphthyl and the like, which may be substituted.
  • Suitable groups represented by R 8a and R 8b may be selected from hydrogen, formyl, substituted or unsubstituted groups selected from (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 such as phenyl or naphthyl; aralkyl group such as phenylmethyl, phenylethyl, naphthylmethyl, naphthylethyl and the like; (C 3 -C 6 )cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl,
  • Suitable groups represented by R 9 may be selected from hydrogen, amino, substituted or unsubstituted groups selected from (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; monoalkylamino group such as NHCH 3 , NHC 2 H 5 , NHC 3 H 7; NHC 6 H 13 , and the like; dialkylamino group such as N(CH 3 ) 2 , NCH 3 (C H 5 ), N(C 2 H 5 ) 2 and the like; arylamino group such as phenylamino or naphthylamino; alkylcarbonyla
  • Suitable groups represented by A are selected from phenyl substituted by haloalkyl, alkylthio, aryl, heteroaryl, nitro, amino; substituted or unsubstituted group selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indole, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl and the like, wherein the substituents are selected from halogen,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 R 8a , R 8b and R 9 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 in the range of 0, 1, or 2, preferably n represents 1 or 2.
  • 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, ⁇ -phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidme, 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, benxyloxy carbonyl, tert- butoxycarbonyl, chloroethyl formate, Fmoc and all other symbols are as defined earlier to produce a compound of formula (IN)
  • 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 (IN) to produce a compound of formula (V)
  • the compound of formula (III) may be converted to a compound of formula (IV) using methane sulfonyl chloride, tosyl chloride, rrifluoromethane sulfonyl chloride.
  • the reaction may be carried out in the presence of appropriate 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 0 °C to room temperature. The duration of the reaction may range from 1 to 12 hrs.
  • the 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 80 °C to 100 °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 CO 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 appropriate solvents like 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 0 °C to room temperature. The duration of the reaction may range from 6 to 24 hrs.
  • the deprotection of compound of formula (VII) may be carried by reduction using 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 Sn/HCl, Fe/HCl, Zn/HCl, Zn/CH 3 CO 2 H and the like.
  • 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 0 °C to room temperature.
  • (VII) may be carried out using alcohol such as methanol, ethanol, propanol 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 by reduction using 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 CO 2 H and the like.
  • reaction of compound of formula (VIII) with the compound of formula (DC) 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 tefrahydrofuran, 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 reaction of compound of formula (III) with the compound of formula (XI) may be carried 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 deprotection of compound of formula (VII) may be carried by reduction using 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 Sn/HCl, Fe/HCl, Zn/HCl, Zn CH 3 CO 2 H and the like.
  • 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.
  • L 1 represents a leaving group such as mesylate, tosylate or triflate with R 7 XH or NH(R 8a R 8b ) where all symbols are as defined earlier.
  • the conversion of compounds of formula (XII) to a comppund 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, DMA and the like.
  • reaction temperature may range from 0 °C to room temperature.
  • duration of the reaction may range from 2 to 6 hrs.
  • R 1 represents - NHS(O) p (C C 4 )alkyl, -NHS(O) p aralkyl or -NHS(O) p heteroaralkyl group, which comprises reacting the compound of formula (XIII)
  • R 1 represents N(R 8a R 8b ) where R 8a and R 8b represent hydrogen, with R'SO 2 Cl where R' represents (C ⁇ -C 4 )alkyl, aralkyl or heteroaralkyl group.
  • the reaction of compounds of formula (XIII) 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.
  • the acylation of compound of formula (XIV) 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 conversion may be carried 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.
  • base such as triethyl amine, pyridine and the like and solvents
  • 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 0 °C to room temperature. The duration of the reaction may range from 1 to 2 hrs.
  • R 4 or R 5 represent an oxo or thiooxo group
  • q is an integer 1 to 4
  • R 6 represents hydrogen, halogen, hydroxy, cyano, nitro, amino or substituted or unsubstituted groups selected from alkyl, alkoxy or aryl
  • A represents a substituted or unsubstituted 5 to 10 membered ring system, which may be mono or bicyclic, saturated, partially saturated or aromatic containing 1 to 4 heteroatoms selected from O, S, N; n is an integer in the range of 0 to 3, m is an integer in the range of 1 to 4.
  • 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.
  • Organic bases such as diethanolamine, ⁇ - phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidme, 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 preferred 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 formula (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 formula (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 carriers 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 carriers, diluents or solvents.
  • the compounds of the invention displayed antibacterial activity when tested by the agar incorporation method.
  • the in vitro antibacterial activity of the compounds were demonstrated by the agar inco ⁇ oration method (NCCLS). Briefly, the compounds were dissolved in DMSO and doubling dilution of the compounds were inco ⁇ orated into Meuller Hilton agar before solidification. Inoculum was prepared by suspending 4 to 5 colonies into 5 ml of normal saline solution and adjusting the turbidity to 0.5 Macfarland turbidity standard tables (1.5.times.l0 8 CFU/ml), after appropriate dilutions, 10 4 CFU/spot was transferred into the surface of dried plate and incubated for 18 hours. The concentration showing no growth of the inoculated culture was recorded as the MIC. Appropriate ATCC standard strains were simultaneously tested and result recorded.

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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 DERIVATES 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 are useful in the treatment of conditions such as nosocomial pneumoniae, community acquired pneumoniae, vancomycin resistance enterococci (NRE) caused by methicillin resistance staphylococcus aureus (MRS A) 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 which are relevant are given here:
International publication number 97/09328 discloses and claims compounds of formula
Figure imgf000003_0001
in which X is NR1, S(O)g or O; R1 is a hydrogen, (C C6)alkyl optionally substituted with one or more OH, CN, or halo or R1 is -(CH2)ι.-aryl, -COR1"1, COOR1-2, -CO- CHa -COR1-1, (CrC6)alkylsulfonyl, -SO2-(CH2)h-aryl or -(CO)r Het; R2 is hydrogen, (Cι-C6)alkyl, -(CH2)h-aryl or halo; R3 and R4 are the same or different and are hydrogen or halo; R5 is hydrogen, (Cι-Cι2)alkyl optionally substituted with one or more halo, (C3-Cι2)cycloalkyl, (C C6)alkoxy; g is 0, 1 or 2; h is 1, 2, 3 or 4; i is 0 or l; 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, (Cι-C4)alkanesulfonyloxy, azido, (Cι-C )alkoxy, (C C4)alkylthio, (Cι-C4)alkylaminocarbonyloxy; or of the formula -NHC(=O)Rb wherein Rb is hydrogen, (Cι-C4)alkoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino, dimethylamino or (CrC4)alkyl; or of the formula -NHS(O)n(CrC4)alkyl where n is 0, 1 or 2; R2 and R3 are independently hydrogen or fluoro; >A-B- is >CH-CH2; R6 is (C C4)alkyl, (Cι-C4)alkanoylamino(Cι-C4)alkyl, hydroxy(Cι-C4)alkyl, carboxy, ( - C4)alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl (where Ar is as defined in the specification) or independently as defined for R5 excluding hydrogen; R5 is of the formula R10CO-, R10SO2-, R10CS-, where R10 is AR.
Objective of the Invention
We have focussed 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 (VRE) caused by methicillin resistance staphylococcus aureus (MRS A) 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
Summary of the Invention
The present invention relates to novel oxazolidinone derivatives of the formula (I)
Figure imgf000005_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, wherein X represents oxygen or sulfur; R1 represents halogen, azido, nitro, cyano; ZR7, where X represents O or S, R represents hydrogen, formyl, substituted or unsubstituted groups selected from (C C6)alkyl, aryl, aralkyl, acyl, heteroaryl, heterocyclyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, (Cι-C6)alkylaminocarbonyl;
N(R8 R8b), 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, cycloalkyl, heteroaryl, heterocyclyl, heteroaralkyl or an aminoacid residue which is attached through acid moiety; or R1 represents - NHC(=Y)R9 wherein Y represents O or S, R9 is hydrogen, amino, substituted or unsubstituted groups selected from (Cι-C6)alkyl, (Cι-C6)alkoxy, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, alkylcarbonylamino, arylcarbonylamino, cycloalkyl, heteroaryl, heterocyclyl, heteroaralkyl or R1 is of the formula -NHS(O)r(C C4)alkyl, -NHS(O)r(C C4)aryl or -NHS(O)r(Cι-C4)heteroaryl, where r is 0 to 2; R2 and R3 may be same or different and independently represent hydrogen, halogen, hydroxy, alkyl, alkoxy; " — " represents a bond or no bond; R and R5 may be same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (CrC6)alkyl, haloalkyl, (d- C6)alkoxy, (Cι-C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; q is an integer 1 to 4; R6 represents hydrogen, halogen, hydroxy, cyano, nitro, amino or substituted or unsubstituted groups selected from alkyl, alkoxy or aryl; A represents a substituted phenyl or substituted or unsubstituted 5 to 10 membered ring system, which may be mono or bicyclic, saturated, partially saturated or aromatic containing 1 to 4 heteroatoms selected from O, S, N; n is an integer in the range of 0 to 3, m is an integer in the range of 1 to 4, with a proviso that when A represents phenyl substituted by alkylthio, Y does not represent O.
Detailed Description of the Invention
Suitable groups represented by R1 are selected from halogen atom such as fluorine, chlorine, bromine or iodine; azido, nitro, cyano, ZR7, N(R8aR8b), -
NHC(=Y)R9 or -NHS(O)p(C C4)alkyl, -NHS(O)r(C!-C4)aryl or -NHS(O)r(Cr
C )heteroaryl.
Suitable groups represented by R and R are selected from hydrogen, halogen atom such as fluorine, chlorine, bromine or iodine; hydroxyl, (Q- C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t- butyl, n-pentyl, isopentyl, hexyl and the like; (Cι-C6)alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like.
Suitable groups represented by R4 and R5 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, trifluorornethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like; (Cι-C6)alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; (Cι-C6)alkylthio 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, halogen, hydroxy, cyano, nitro, amino, substituted or unsubstituted linear or branched (C C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t- butyl, n-pentyl, isopentyl, hexyl and the like; (Cι-C6)alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like, which may be substituted; aryl such as phenyl, naphthyl and the like, which may be substituted.
Suitable groups represented by R7 are selected from hydrogen, formyl, substituted or unsubstituted groups selected from (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 or naphthyl; aralkyl group such as phenylmethyl, phenylethyl, naphthylmethyl, naphthylethyl and the like; acyl group such as -C(=0)CH3, -C(=O)C2H5, -C(=O)C3H7, -C(0)C6H13, -C(=S)CH3, -C(=S)C2H5, -C(=S)C3H7j -C(=S)C6Hi3, benzoyl and the like; (Cr C6)alkylaminocarbonyl group such as -C(=O)NHCH3, -C(=O)NHC2H5, - C(=O)NHC3H7, -C(=O)NHC6H13, and the like; alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl and the like; arylsulfonyl group such as phenylsulfonyl or naphthylsulfonyl; aralkylsulfonyl group such as phenylmethylsulfonyl, phenylethylsulfonyl, naphthylmethylsulfonyl or naphthylethylsulfonyl; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like; heterocyclyl group such as pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, and the like.
Suitable groups represented by R8a and R8b may be selected from hydrogen, formyl, substituted or unsubstituted groups selected from (Cι-C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n- pentyl, isopentyl, hexyl and the like; aryl such as phenyl or naphthyl; aralkyl group such as phenylmethyl, phenylethyl, naphthylmethyl, naphthylethyl and the like; (C3-C6)cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like; 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 groups represented by R9 may be selected from hydrogen, amino, substituted or unsubstituted groups selected from (Cι-C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; (Cι-C6)alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, butoxy and the like; monoalkylamino group such as NHCH3, NHC2H5, NHC3H7; NHC6H13, and the like; dialkylamino group such as N(CH3)2, NCH3(C H5), N(C2H5)2 and the like; arylamino group such as phenylamino or naphthylamino; alkylcarbonylamino group such as methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, iso-propylcarbonylamino and the like, arylcarbonylamino group such as phenylcarbonylamino or naphthylcarbonylaminol; (C3-C6)cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; cycloalkyl amino group such as cyclopropyl amino, cyclobutylamino, cyclopentylamino, cyclohexylamino and the like; heteroaryl group such as pyridyl, 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; heteroaralkyl group wherein the heteroaryl moiety is as defined above; heterocyclyl group such as pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, and the like.
Suitable groups represented by A are selected from phenyl substituted by haloalkyl, alkylthio, aryl, heteroaryl, nitro, amino; substituted or unsubstituted group selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indole, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl and the like, wherein the substituents 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.
The substituents on any of the groups represented by R1, R2, R3, R4, R5, R6, R7 R8a, R8b and R9 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 in the range of 0, 1, or 2, preferably n represents 1 or 2. 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-phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidme, 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:
(S)-N-[3-[3-Fluoro-4-[N-(furan-2-ylmethyl)ρiρeridin-4-yl]ρhenyl]-2- oxooxazolidin- 5 -ylmethyl] acetamide ; (S)-N-[3-[3-Fluoro-4-[N-(furan-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrofuran-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl] acetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrofuran-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacβtamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nifrofuran-2-ylmethyl)-l,2,3,6-tetrahydropyridin-4- yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrofuran-2-ylmethyl)-l,2,3,6-tetrahydropyridin-4- yl)phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[3-Fluoro-4-[N-(5-nitrothien-2-ylmethyl)piρeridin-4-yl]ρhenyl]-2- oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[N-(5-nitrothien-2-ylmethyl)piperidin-4-yl]ρhenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(thien-2-ylmethyl)piρeridin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl] acetamide ; (S)-N-[3-[3-Fluoro-4-[N-(thien-2-ylmethyl)ρiperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrothien-2-ylmethyl)-l;2,3,6-tetrahydropyridin-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrothien-2-ylmethyl)-l,2,3,6-tetrahydropyridin-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]mioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitropyrazin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitropyrazin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[3-Fluoro-4-[N-(pyrazin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(pyrazin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(pyrirnidin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(ρyrimidin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N- [3 - [3 -Fluoro-4- [N-(pyrazin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N'-cyclopropyl thiourea ; (S)-N-[3-[3-Fluoro-4-[N-(ρyrazin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N'-methyl thiourea ; (S)-N-[3-[3-Fluoro-4-[N-(furan-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N'-cyclopropyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[N-(furan-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N'-methyl thiourea ; (S)-N-[3-[3-Fluoro-4-[N-(5-nifrofuran-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N'-cyclopropyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrofuran-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin- 5 -ylmethyl]-N' -methyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrothien-2-ylmethyl)piρeridin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N' -cyclopropyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrothien-2-ylmethyl)piρeridin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N'-methyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[N-(thien-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N'-cyclopropyl thiourea ; (S)-N-[3-[3-Fluoro-4-[N-(thien-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N'-methyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrofuran-2-ylmethyl)piρeridin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[3-Fluoro-4-[N-(furan-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrofuran-2-ylmethyl)piρeridin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]carbamate;
(S)-N- [3 -[3 -Fluoro-4-[N-(furan-2-ylmethyl)piρeridin-4-yl]phenyl] -2- oxooxazolidin- 5-ylmethyl] carbamate ; (S)-N-[3-[3-Fluoro-4-[N-(4-sulfamylphenylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[3-Fluoro-4-[N-(4-trifluoromethylphenylmethyl)piperidin-4-yl]phenyl]- 2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(4-trifluoromethylphenylmethyl)piperidin-4-yl]phenyl]- 2-oxooxazolidin- 5 -ylmethyl] acetamide ; (S)-N-[3-[3-Fluoro-4-[N-(indol-3-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5 -ylmethyl] acetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(indol-3-ylmethyl)ρiρeridin-4-yl]ρhenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitroindol-3-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide and
(S)-N-[3-[3-Fluoro-4-[N-(5-nitroindol-3-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide.
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(=Y)R9, m is 1, — represents no bond 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, benxyloxy carbonyl, tert- butoxycarbonyl, chloroethyl formate, Fmoc and all other symbols are as defined earlier to produce a compound of formula (IN)
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 (IN) to produce a compound of formula (V)
Figure imgf000014_0001
wherein all symbols are as defined above, 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 (NI) to produce a compound of formula (Nil)
Figure imgf000014_0003
where all symbols are as defined earlier, v) deprotecting the compound of formula (Nil) to produce a compound formula (NIII),
where all symbols are as defined earlier and vi) reacting the compound of formula (NIII) with a compound of formula (IX) A— CHO (IX) wherein A is as defined earlier to produce a compound of formula (I), where R1 represents -NHC(=Y)R9.
The compound of formula (III) may be converted to a compound of formula (IV) using methane sulfonyl chloride, tosyl chloride, rrifluoromethane sulfonyl chloride. The reaction may be carried out in the presence of appropriate 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 0 °C to room temperature. The duration of the reaction may range from 1 to 12 hrs.
The 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 80 °C to 100 °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/CH3CO2H 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 appropriate solvents like 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 0 °C to room temperature. The duration of the reaction may range from 6 to 24 hrs.
The deprotection of compound of formula (VII) may be carried by reduction using 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 Sn/HCl, Fe/HCl, Zn/HCl, Zn/CH3CO2H and the like.
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(=S)R9 where R9 represent alkoxy, m is 1 , — - represents no bond 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
where R1 is as defined above and all other symbols are as defined earlier and iii) deprotecting the compound of formula (VII) to produce a compound formula (VIII),
Figure imgf000018_0001
where all symbols are as defined earlier and iv) reacting the compound of formula (VIII) with a compound of formula (IX) A — CHO (IX) wherein A is as defined earlier to produce a compound of formula (I), where R1 represents -NHC(=Y)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 0 °C to room temperature. The conversion of compound of formula (X) to compound of formula
(VII) may be carried out using alcohol such as methanol, ethanol, propanol 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 by reduction using 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/CH3CO2H and the like.
The reaction of compound of formula (VIII) with the compound of formula (DC) 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 tefrahydrofuran, 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.
In another embodiment of the present invention, there is provided a process for the preparation of compound of formula (I) where m is 1, — represents no bond, R1 represents ZR7 where R7 and all other symbols are as defined earlier, which comprises i) reacting the compound of formula (III)
Figure imgf000019_0001
with a compound of formula (XI)
R7-XH (XI) where R7 is as defined earlier to produce a compound formula (VII)
Figure imgf000019_0002
where all symbols are as defined earlier, ii) deprotecting the compound of formula (VII) to produce a compound formula (VIII),
Figure imgf000020_0001
where all symbols are as defined earlier and iii) reacting the compound of formula (VIII) with a compound of formula (IX)
A— CHO (IX) wherein A is as defined earlier to produce a compound of formula (I), where R1 represents ZR7.
The reaction of compound of formula (III) with the compound of formula (XI) may be carried 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 deprotection of compound of formula (VII) may be carried by reduction using 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 Sn/HCl, Fe/HCl, Zn/HCl, Zn CH3CO2H and the like.
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.
In yet another embodiment of the present invention, there is provided a process for the preparation of compounds of formula (I) where R1 represents ZR7, N(R8aR8b) where R7, R8a and R8b are as defined earlier which comprises reacting the compound of formula (XII)
Figure imgf000021_0001
where L1 represents a leaving group such as mesylate, tosylate or triflate with R7XH or NH(R8aR8b) where all symbols are as defined earlier.
The conversion of compounds of formula (XII) to a comppund 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, DMA 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(O)p(C C4)alkyl, -NHS(O)paralkyl or -NHS(O)pheteroaralkyl group, which comprises reacting the compound of formula (XIII)
Figure imgf000022_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'SO2Cl where R' represents (Cι-C4)alkyl, aralkyl or heteroaralkyl group.
The reaction of compounds of formula (XIII) 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(=Y)R9; where Y is S, R9 and all other symbols are as defined above, which comprises reacting the compound of formula (XIV)
Figure imgf000022_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 (XIV) 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.
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(=Y)R9; where Y is O, R9 and all other symbols are as defined above to compounds of formula (I) where Rl represents the formula — NHC(=Y)R9; where Y is S, R9 and all other symbols are as defined earlier. The conversion may be carried 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 0 °C to room temperature. The duration of the reaction may range from 1 to 2 hrs.
In yet another embodiment of the present invention, there is provided a novel intermediate of formula (XII)
Figure imgf000024_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, wherein L1 represents a leaving group such as mesylate, tosylate or triflate; X represents oxygen or sulfur; R2 and R3 may be same or different and independently represent hydrogen, halogen, hydroxy, alkyl, alkoxy; " — " represents a bond or no bond; R4 and R5 may be same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (Q-
C6)alkyl, haloalkyl, (Cι-C6)alkoxy, (C C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; q is an integer 1 to 4; R6 represents hydrogen, halogen, hydroxy, cyano, nitro, amino or substituted or unsubstituted groups selected from alkyl, alkoxy or aryl; A represents a substituted or unsubstituted 5 to 10 membered ring system, which may be mono or bicyclic, saturated, partially saturated or aromatic containing 1 to 4 heteroatoms selected from O, S, N; n is an integer in the range of 0 to 3, m is an integer in the range of 1 to 4.
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, hydroxyethylpyrrolidme, 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 preferred 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 formula (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 formula (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 carriers 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 carriers, 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
(S)-[3-[3-Fluoro-4-[l-benzyl-l,2,3,6-tetrahydropyridin-4-yl]phenyl]-2- oxooxazolidin-5-yl) methyl mesylate
Figure imgf000027_0001
Methane sulphonyl chloride (6.38 g, 0.05575 moles) was added to a solution of (S)-[3-[3-fluoro-4-[l-benzyl-l,2,3,6-tetrahydroρyridin-4-yl]ρhenyl]-2- oxooxazolidin-5-yl]methanol (14.2 g, 0.03717 moles) dissolved in dichloromethane (100 ml) and triethylamine (7.88 g, 0.07806 moles) and the mixture was stirred at RT for 6 hours. Water was added to the reaction mixture and the DCM layer was separated, washed with sodium bicarbonate solution, water, brine solution and dried over anhydrous sodium sulphate and concentrated to afford the title compound (17 g, yield 100%).
Preparation 2
(S)-N-[3-[3-Fluoro-4-[l-benzyl-l,2,3,6-tetrahydropyridin-4-yl]phenyI]-2- oxooxazolidin-5-ylmethy 1] azide
Figure imgf000028_0001
Sodium azide (9.4 g, 0.1478 moles) was added to a DMF (100 ml) solution of (S)- [3-[3-fluoro-4-[l-benzyl-l,2,3,6-tetrahydropyridin-4-yl]phenyl]-2-oxooxazolidin-
5-yl]methyl mesylate (17 g, 0.03695 moles) at room temperature and the mixture was stirred at 80 °C for 6 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, water was added and the reaction mixture was extracted with ethylacetate. The organic layer was washed with water and brine solution, dried over anhydrous sodium sulphate. The solvent was evaporated and the residue was dried under vacuum to afford the title compound
(15 g).
Preparation 3 (S)-N-[3-[3-FIuoro-4-[l-benzyi-l,2,3,6-tetrahydropyridin-4-yI]phenyl]-2- oxooxazoIidin-5-ylmethyl] amine
Figure imgf000029_0001
(S)-N-[3-[3-Fluoro-4-[l-benzyl-l,2,3,6-tetrahydropyridin-4-yl]phenyl]-2- oxooxazolidin- 5 -ylmethyl] azide. (15 g, 0.03685 moles) and triphenyl phosphene (12.5 g, 0.04791 moles) were taken in THF (100 ml) at room temperature and stirred at RT for 10 hours. Then added water (3 to 5 ml) to the RM and heated the reaction contents at 60-70 °C for 12 hours. The solvent was removed under vacuum and purified the reaction mixture over silica gel column using chloroform and methanol mixture to afford the title compound (8.2 g, yield 58%).
Preparation 4
(S)-N-[3-[3-FIuoro-4-[l-benzyi-l,2,3,6-tetrahydropyridin-4-yI]phenyI]-2- oxooxazoIidin-5-ylmethyl]acetamide
Figure imgf000029_0002
Acetic anhydride (1.07 g, 0.01049 moles) and pyridine (0.31 g, 0.003937 moles) were added to a chloroform (20 ml) solution of (S)-N-[3-[3-fluoro-4-[l-benzyl-
1 ,2,3,6-tetrahydropyridin-4-yl]ρhenyl]-2-oxooxazolidin-5-ylmethyl]amine (1 g,
0.00262 moles) at 0 °C and stirred the RM at room temperature for 12 hours. Water was added to the RM and extracted with chloroform (3 x 100 ml). The organic layer was separated, washed with sodium carbonate solution, water, brine solution and dried over anhydrous sodium sulphate and concentrated. This product was purified on silica gel column chromatography using chloroform and methanol (1% CH3OH / CHC13) to afford the title compound (800 mg, yield 72%).
Preparation 5
(S)-N-[3-[3-Fluoro-4-(piperidin-4-yl)phenyl]-2-oxooxazoiidin-5- y lmethy 1] acetamide
Figure imgf000030_0001
(S)-N-[3-[3-Fluoro-4-[l-benzyl-l,2,3,6-tetrahydropyridin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]acetamide (0.8 gm, 0.00189 moles) was debenzylated followed by reduction of the double bond with 10% palladium carbon (160 mg) in methanol (30 ml) at 60 psi at RT using Parr hydrogenation apparatus for 24 hours. The catalyst was filtered and washed the residue thoroughly with methanol. The filtrate was concentrated and dried under vacuum to afford the title compound (633 mg, yield 100%).
Example 1
Synthesis of (S)-N-[3-[3-fluoro~4-[N-(5-nitrofuran-2-ylmethyl)piperidin-4- yl]phenyl]-2-oxooxazo!idin-5-ylmethyI]acetamide
Figure imgf000030_0002
(S)-N- [3 - [3-Fluoro-4-(piperidin-4-yl)phenyl] -2-oxooxazolidin-5- ylmethyl] acetamide (150 mg, 0.4477 mmoles) and 5-nitro-2-furaldehyde (189 mg, 1.3432 mmoles) were taken in dry benzene (100 ml) and refluxed the reaction contents using Dean-stock apparatus for 1 hour. The reaction mixture was cooled to room temperature and triacetoxy sodium hydride (379 mg, 1.79104 mmoles) was added and stirred at RT for 12 hours. Water was added and extracted with ethylacetate (3 x 100 ml). The organic layer was washed with water, brine solution and dried over anhydrous sodium sulphate and concentrated. The residue was purified over silica gel column using chloroform and methanol mixture to afford the title compound (84 mg), as gummy material. !HNMR (CDCI3) δ : 1.80 - 1.83 (m, 4H), 2.01 (s, 3H), 2.25 (bs, 2H), 2.80-2.81 (m, IH), 3.02-3.05 ( t, 2H), 3.61-3.62 (m, IH), 3.63 (s, 2H), 3.70 - 3.76 (m, 2H), 4.00-4.05 (t, IH), 4.78-4.79 (m, IH), 5.96 (bs, IH, D2O exchangeable), 6.49-6.50 (d, IH), 7.13 (s, IH), 7.19-7.21 (d, IH), 7.29-7.30 (s, IH), 7.37-7.41 (d, IH). M S at 461.
The following compounds were prepared according to the procedure given in example 1.
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0002
Example 5
Synthesis of (S)-N-[3-[3-fluoro-4-[N-(5-nitrofuran-2-ylmethyl)piperidin-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide
Figure imgf000033_0001
To a solution of (S)-N-[3-[3-fluoro-4-[N-(5-nitrofuran-2-ylmethyl)piperidin-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (150 mg, 0.000326 moles) in dry toluene (10 ml) and Lawssons reagent (263 mg, 0.000652 moles) was added and heated the reaction contents at 100 °C for 3 hours. The reaction mixture was diluted with ethylacetate and washed with water, brine solution and dried over anhydrous sodium sulphate and concentrated to dryness. The product was purified using chloroform and methanol mixture as eluent to afford the title compound as a gummy solid (60 mg). !HNMR (CDC13) δ : 1.78-1.81 (m, 4H), 2.24 (s, 2H), 2.61 (s, 3H), 2.81-2.82 (m, IH), 3.07-3.09 (t, 2H), 3.62-3.63 (m, IH), 3.65-3.66 (d, 2H), 3.71-3.74 (m, 2H), 4.01-4.04 (t, IH), 4.77-4.79 (m, IH), 6.51-6.52 (d, IH), 6.88 (s, IH), 7.17-7.19 (d, IH), 7.20-7.22 (s, IH), 7.24-7.25 (d, IH), 7.27-7.29 (bs, IH, D2O exchangeable). M/S at 477. The following compounds were prepared according to the procedure given in example 6.
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Pharmacological Testing
The compounds of the invention displayed antibacterial activity when tested by the agar incorporation method. The in vitro antibacterial activity of the compounds were demonstrated by the agar incoφoration method (NCCLS). Briefly, the compounds were dissolved in DMSO and doubling dilution of the compounds were incoφorated into Meuller Hilton agar before solidification. Inoculum was prepared by suspending 4 to 5 colonies into 5 ml of normal saline solution and adjusting the turbidity to 0.5 Macfarland turbidity standard tables (1.5.times.l08 CFU/ml), after appropriate dilutions, 104 CFU/spot was transferred into the surface of dried plate and incubated for 18 hours. The concentration showing no growth of the inoculated culture was recorded as the MIC. Appropriate ATCC standard strains were simultaneously tested and result recorded.
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 imgf000037_0001
1) E. faecium ATCC 700221- Enterococcus faecium ATCC 700221
2) E. faecalis ATCC 29212-Enterococcus faecalis ATCC 29212
3) S. Epidermis MRO 02046 - Staphylococus epidermis Microbial Resource Orchid 02046 4) S. Epidermis MRO 02002 - Staphylococus epidermis Microbial Resource Orchid 02002

Claims

Claims :
1. A compound of formula (I)
Figure imgf000038_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymoφhs, their pharmaceutically acceptable salts, wherein X represents oxygen or sulfur; R1 represents halogen, azido, nitro, cyano; ZR7, where X represents O or S, R7 represents hydrogen, formyl, substituted or unsubstituted groups selected from (Cι-C6)alkyl, aryl, aralkyl, acyl, heteroaryl, heterocyclyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, (C Cg^lkylaminocarbonyl; N(R8aR8 ), where R8 and R8b may be same or different and independently represent hydrogen, formyl, substituted or unsubstituted groups selected from (C -C6)alkyl, aryl, aralkyl, cycloalkyl, heteroaryl, heterocyclyl, heteroaralkyl or an aminoacid residue which is attached through acid moiety; or R1 represents - NHC(=Y)R9 wherein Y represents O or S, R9 is hydrogen, amino, substituted or unsubstituted groups selected from (Cι-C6)alkyl, (C C6)alkoxy, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, alkylcarbonylamino, arylcarbonylamino, cycloalkyl, heteroaryl, heterocyclyl, heteroaralkyl or R1 is of the formula -NHS(O)r(C C4)alkyl, -NHS(O)r(C C4)aryl or -NHS(O)r(Cι-C4)heteroaryl, where r is 0 to 2; R2 and R3 may be same or different and independently represent hydrogen, halogen, hydroxy, alkyl, alkoxy; " — " represents a bond or no bond; 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, (C C6)alkoxy, (Cι-C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; q is an integer 1 to 4; R6 represents hydrogen, halogen, hydroxy, cyano, nitro, amino or substituted or unsubstituted groups selected from alkyl, alkoxy or aryl; A represents a substituted phenyl or substituted or unsubstituted 5 to 10 membered ring system, which may be mono or bicyclic, saturated, partially saturated or aromatic containing 1 to 4 heteroatoms selected from O, S, N; n is an integer in the range of 0 to 3, m is an integer in the range of 1 to 4, with a proviso that when A represents phenyl substituted by alkylthio, Y does not represent O.
2. A compound as claimed in claim 1, wherein the groups represented by A are selected from phenyl substituted by haloalkyl, alkylthio, aryl, heteroaryl, nitro, amino; substituted or unsubstituted group selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indole, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl, pyrrolidinyl, moφholinyl, thiomoφholinyl, piperidinyl or piperazinyl.
3. A compound of formula (I) as claimed in claim 1, which is selected from : (S)-N-[3-[3-Fluoro-4-[N-(furan-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[N-(furan-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin- 5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrofuran-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin- 5-ylmethyl] acetamide ; (S)-N-[3-[3-Fluoro-4-[N-(5-nitromran-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nifrofuran-2-ylmethyl)-l,2,3,6-tetrahydropyridin-4- yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[N-(5-nitrofuran-2-ylmethyl)-l,2,3,6-tetrahydropyridin-4- yl)phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitτothien-2-ylmethyl)ρiperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[N-(5-nitrothien-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(thien-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl] acetamide ;
(S)-N-[3 - [3 -Fluoro-4- [N-(thien-2-ylmethyl)ρiρeridin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrothien-2-ylmethyl)-l,2,3,6-tetrahydropyridin-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrothien-2-ylmethyl)-l,2,3,6-tetrahydropyridin-4- yl]phenyl] -2-oxooxazolidin- 5-ylmethyl]thioacetamide ; (S)-N-[3-[3-Fluoro-4-[N-(5-nitropyrazin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitropyrazin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(pyrazin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin- 5 -ylmethyl] acetamide ;
(S)-N- [3 - [3 -Fluoro-4- [N-(pyrazin-2-ylmethyl)piperidin-4-yl]phenyl] -2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(pyrimidin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]acetamide ; (S)-N- [3 - [3 -Fluoro-4- [N-(pyrimidin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin- 5 -ylmethyljthioacetamide ; (S)-N-[3-[3-Fluoro-4-[N-(pyrazin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N'-cyclopropyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[N-(pyrazin-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N'-methyl thiourea ; (S)-N-[3-[3-Fluoro-4-[N-(furan-2-ylmethyl)ρiperidin-4-yl]ρhenyl]-2- oxooxazolidin-5-ylmethyl]-N'-cyclopropyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[N-(furan-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N'-methyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrofuran-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N'-cyclopropyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrofuran-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N' -methyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitrothien-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N'-cyclopropyl thiourea ; (S)-N-[3-[3-Fluoro-4-[N-(5-nitrothien-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin- 5 -ylmethyl] -N' -methyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[N-(thien-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N'-cyclopropyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[N-(thien-2-ylmethyl)piρeridin-4-yl]phenyl]-2- oxooxazolidin- 5 -ylmethyl] -N' -methyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nifrofuran-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[3-Fluoro-4-[N-(furan-2-ylmethyl)piρeridin-4-yl]ρhenyl]-2- oxooxazolidin- 5 -ylmethyl]thiocarbamate ; (S)-N-[3-[3-Fluoro-4-[N-(5-nitrofuran-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]carbamate; (S)-N-[3-[3-Fluoro-4-[N-(furan-2-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]carbamate ;
(S)-N-[3-[3-Fluoro-4-[N-(4-sulfamylphenylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[3-Fluoro-4-[N-(4-trifluoromethylphenylmethyl)piperidin-4-yl]phenyl]-
2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N- [3 - [3 -Fluoro-4- [N-(4-trifluoromethylphenylmethyl)piperidin-4-yl]phenyl] -
2-oxooxazolidin- 5 -ylmethyl] acetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(indol-3-ylmethyl)ρiperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(indol-3-ylmethyl)piperidin-4-yl]ρhenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[N-(5-nitroindol-3-ylmethyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thioacetamide and (S)-N- [3 - [3 -Fluoro-4- [N-(5-nitroindol-3 -ylmethyl)piperidin-4-yl]phenyl] -2- oxooxazolidin-5-ylmethyl]thioacetamide.
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 imgf000042_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymoφhs, their pharmaceutically acceptable salts, wherein X represents oxygen or sulfur; R1 represents -NHC(=Y)R9 wherein Y represents O or S, R9 is hydrogen, amino, substituted or unsubstituted groups selected from (Cι-C6)alkyl, (Cι-Cg)alkoxy, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, alkylcarbonylamino, arylcarbonylamino, cycloalkyl, heteroaryl, heterocyclyl, heteroaralkyl; " — " represents no bond; R4 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, ( - C6)alkoxy, (Cι-C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; q is an integer 1 to 4; R represents hydrogen, halogen, hydroxy, cyano, nitro, amino or substituted or unsubstituted groups selected from alkyl, alkoxy or aryl; A represents a substituted phenyl or substituted or unsubstituted 5 to 10 membered ring system, which may be mono or bicyclic, saturated, partially saturated or aromatic containing 1 to 4 heteroatoms selected from O, S, N; n is an integer in the range of 0 to 3, m is 1, with a proviso that when A represents phenyl substituted by alkylthio, Y does not represent O, which comprises : (i) converting the compound of formula (III)
Figure imgf000043_0001
where P represents protecting group and all other symbols are as defined above to produce a compound of formula (IV)
Figure imgf000043_0002
where L represents a leaving group and all other symbols are as defined above, ii) converting the compound of formula (IV) to produce a compound of formula (V)
Figure imgf000044_0001
wherein all symbols are as defined above, iii) reducing the compound of formula (V) to a compound of formula (VI)
Figure imgf000044_0002
wherein all symbols are as defined above, iv) acylating the compound of formula (VI) to produce a compound of formula (VII)
Figure imgf000044_0003
wherein all symbols are as defined above, v) deprotecting the compound of formula (VII) to produce a compound formula (VIII),
Figure imgf000044_0004
where all symbols are as defined above and vi) reacting the compound of formula (VIII) with a compound of formula (IX) A— CHO (IX) wherein A is as defined above to produce a compound of formula (I) defined above.
6. A process for the preparation of compound of the formula (I)
Figure imgf000045_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymoφhs, their pharmaceutically acceptable salts, wherein X represents oxygen or sulfur; R1 represents NHC(=S)R9 where R9 represent alkoxy; R2 and R3 may be same or different and independently represent hydrogen, halogen, hydroxy, alkyl, alkoxy; " — " represents no bond; R4 and R5 may be same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (C C6)alkyl, haloalkyl, (Cι-C6)alkoxy, (C C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; q is an integer 1 to 4; R represents hydrogen, halogen, hydroxy, cyano, nitro, amino or substituted or unsubstituted groups selected from alkyl, alkoxy or aryl; A represents a substituted phenyl or substituted or unsubstituted 5 to 10 membered ring system, which may be mono or bicyclic, saturated, partially saturated or aromatic containing 1 to 4 heteroatoms selected from O, S, N; n is an integer in the range of 0 to 3, m is 1, with a proviso that when A represents phenyl substituted by alkylthio, Y does not represent O, which comprises : i) converting the compound of formula (VI)
Figure imgf000045_0002
to produce a compound of formula (X)
Figure imgf000046_0001
where all symbols are as defined above, ii) converting the compound of formula (X) to produce a compound of formula (VII)
p-%xXXN ? R1 m R5 i3 ^ where all symbols are as defined above, iii) deprotecting the compound of formula (VII) to produce a compound formula (VIII),
Figure imgf000046_0002
where all symbols are as defined above and iv) reacting the compound of formula (VIII) with a compound of formula (IX)
A — CHO (IX) wherein A is as defined above to produce a compound of formula (I) defined above.
7. A process for the preparation of compound of the formula (I)
Figure imgf000046_0003
their derivatives, their analogs,^ their tautomeric forms, their stereoisomers, their polymoφhs, their pharmaceutically acceptable salts, wherein X represents oxygen or sulfur; R1 represents ZR7, where X represents O or S, R7 represents hydrogen, formyl, substituted or unsubstituted groups selected from (Cι-C6)alkyl, aryl, aralkyl, acyl, heteroaryl,. heterocyclyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, (C C6)alkylaminocarbonyl; R2 and R3 may be same or different and independently represent hydrogen, halogen, hydroxy, alkyl, alkoxy; " — " represents no bond; R4 and R5 may be same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from (C C6)alkyl, haloalkyl, (Cι-C6)alkoxy, ( - C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; q is an integer 1 to 4; Rδ represents hydrogen, halogen, hydroxy, cyano, nitro, amino or substituted or unsubstituted groups selected from alkyl, alkoxy or aryl; A represents a substituted phenyl or substituted or unsubstituted 5 to 10 membered ring system, which may be mono or bicyclic, saturated, partially saturated or aromatic containing 1 to 4 heteroatoms selected from O, S, N; n is an integer in the range of 0 to 3, m is 1, with a proviso that when A represents phenyl substituted by alkylthio, Y does not represent O, which comprises i) reacting the compound of formula (III)
Figure imgf000047_0001
with a compound of formula (XI)
R7-XH (XI) where R7 is as defined above to produce a compound formula (VII)
Figure imgf000048_0001
where all symbols are as defined above, ii) deprotecting the compound of formula (VII) to produce a compound formula (VIII),
Figure imgf000048_0002
where all symbols are as defined above and iii) reacting the compound of formula (VIII) with a compound of formula (IX)
A— CHO (IX) wherein A is as defined above to produce a compound of formula (I) defined above.
8. A process for the preparation of compound of the formula (I)
Figure imgf000048_0003
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymoφhs, their pharmaceutically acceptable salts, wherein X represents
1 7 7 oxygen or sulfur; R represents ZR , where X represents O or S, R represents hydrogen, formyl, substituted or unsubstituted groups selected from (Cι-C6)alkyl, aryl, aralkyl, acyl, heteroaryl, heterocyclyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, (C C6)alkylaminocarbonyl; 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, cycloalkyl, heteroaryl, heterocyclyl, heteroaralkyl or an aminoacid residue which is attached through acid moiety; R and R may be same or different and independently represent hydrogen, halogen, hydroxy, alkyl, alkoxy; " — " represents bond or no bond; R4 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, (Cι-C6)alkoxy, (Cι-C6)alkylthio, (C3- C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; q is an integer 1 to 4; R represents hydrogen, halogen, hydroxy, cyano, nitro, amino or substituted or unsubstituted groups selected from alkyl, alkoxy or aryl; A represents a substituted phenyl or substituted or unsubstituted 5 to 10 membered ring system, which may be mono or bicyclic, saturated, partially saturated or aromatic containing 1 to 4 heteroatoms selected from O, S, N; n is an integer in the range of 0 to 3, m is an integer in the range of 1 to 4, with a proviso that when A represents phenyl substituted by alkylthio, Y does not represent O, which comprises, reacting the compound of formula (XII)
Figure imgf000049_0001
where L1 represents a leaving group with R7XH or NH(R8aR8b) where all symbols are as defined above.
9. A process for the preparation of compound of the formula (I)
Figure imgf000049_0002
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymoφhs, their pharmaceutically acceptable salts, wherein X represents oxygen or sulfur; R1 represents -NHS(O)p(C C4)alkyl, -NHS(O)paralkyl or - NHS(O)pheteroaralkyl group; R2 and R3 may be same or different and independently represent hydrogen, halogen, hydroxy, alkyl, alkoxy; " — " represents a bond or no bond; R4 and R5 may be 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, (Cι-C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; q is an integer 1 to 4; R6 represents hydrogen, halogen, hydroxy, cyano, nitro, amino or substituted or unsubstituted groups selected from alkyl, alkoxy or aryl; A represents a substituted phenyl or substituted or unsubstituted 5 to 10 membered ring system, which may be mono or bicyclic, saturated, partially saturated or aromatic containing 1 to 4 heteroatoms selected from O, S, N; n is an integer in the range of 0 to 3, m is an integer in the range of 1 to 4, with a proviso that when A represents phenyl substituted by alkylthio, Y does not represent O, which comprises reacting the compound of formula (XIII)
Figure imgf000050_0001
where all symbols are as defined above, which represents compounds of formula (I), R1 represents N(R8aR8b) where R8a and R8b represent hydrogen, with R'SO2Cl where R' represents (Cι-C4)alkyl, aralkyl or heteroaralkyl group.
10. A process for the preparation of compound of the formula (I)
Figure imgf000051_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymoφhs, their pharmaceutically acceptable salts, wherein X represents oxygen or sulfur; R1 represents -NHC(=Y)R9 wherein Y represents S, R9 is hydrogen, amino, substituted or unsubstituted groups selected from (C C6)alkyl,
(Cι-C6)alkoxy, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, alkylcarbonylamino, arylcarbonylamino, cycloalkyl, heteroaryl, heterocyclyl, heteroaralkyl; R and R may be same or different and independently represent hydrogen, halogen, hydroxy, alkyl, alkoxy; " — " represents a bond or no bond; R4 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, (Cι-C6)alkoxy, (Cι-C6)alkylthio, (C3- C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; q is an integer 1 to 4; R6 represents hydrogen, halogen, hydroxy, cyano, nitro, amino or substituted or unsubstituted groups selected from alkyl, alkoxy or aryl; A represents a substituted phenyl or substituted or unsubstituted 5 to 10 membered ring system, which may be mono or bicyclic, saturated, partially saturated or aromatic containing 1 to 4 heteroatoms selected from O, S, N; n is an integer in the range of 0 to 3, m is an integer in the range of 1 to 4, with a proviso that when A represents phenyl substituted by alkylthio, Y does not represent O, which comprises reacting the compound of formula (XIV)
Figure imgf000052_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.
11. A process for the preparation of compound of the formula (I)
Figure imgf000052_0002
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymoφhs, their pharmaceutically acceptable salts, wherein X represents oxygen or sulfur; R1 represents -NHC(=Y)R9 wherein Y represents S, R9 is hydrogen, amino, substituted or unsubstituted groups selected from (C C6)alkyl, (Cι-C6)alkoxy, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, alkylcarbonylamino, arylcarbonylamino, cycloalkyl, heteroaryl, heterocyclyl, heteroaralkyl; R2 and R3 may be same or different and independently represent hydrogen, halogen, hydroxy, alkyl, alkoxy; " — " represents a bond or no bond; R4 and R5 may be 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; q is an integer 1 to 4; R6 represents hydrogen, halogen, hydroxy, cyano, nitro, amino or substituted or unsubstituted groups selected from alkyl, alkoxy or aryl; A represents a substituted phenyl or substituted or unsubstituted 5 to 10 membered ring system, which may be mono or bicyclic, saturated, partially saturated or aromatic containing 1 to 4 heteroatoms selected from O, S, N; n is an integer in the range of 0 to 3, m is an integer in the range of 1 to 4, with a proviso that when A represents phenyl substituted by alkylthio, Y does not represent O, which comprises converting the compound of formula (I) where R1 represents formula - NHC(=Y)R9; where Y is O and R9 is as defined above using Lawesson's reagent in the presence of base.
12. A compound of formula (XII)
Figure imgf000053_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymoφhs, their pharmaceutically acceptable salts, wherein L1 represents a leaving group such mesylate, tosylate or triflate; X represents oxygen or sulfur; R2 and R3 may be same or different and independently represent hydrogen, halogen, hydroxy, alkyl, alkoxy; " — " represents a bond or no bond; R4 and R5 may be same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxyl, substituted or unsubstituted groups selected from ( - C6)alkyl, haloalkyl, (Cι-Cg)alkoxy, (C C6)alkylthio, (C -C6)cycloallcyl or either of R4 or R5 represent an oxo or thiooxo group; q is an integer 1 to 4; R6 represents hydrogen, halogen, hydroxy, cyano, nitro, amino or substituted or unsubstituted groups selected from alkyl, alkoxy or aryl; A represents a substituted or unsubstituted 5 to 1 membered ring system, which may be mono or bicyclic, saturated, partially saturated or aromatic containing 1 to 4 heteroatoms selected from O, S, N; n is an integer in the range of 0 to 3, m is an integer in the range of 1 to 4.
13. A pharmaceutical composition, which comprises a compound of formula (I)
Figure imgf000054_0001
as defined in claim 1 and a pharmaceutically acceptable carrier, diluents, excipient or solvate.
14. A pharmaceutical composition as claimed in claim 13, in the form of a tablet, capsule, powder, syrup, solution, aerosol or suspension.
15. Use of compound of formula (I) claimed in claim 1, for treating or preventing an infectious disorder in a human or animal.
16. Use of compound as claimed in claim 15, wherein the infectious disorder is caused by bacteria.
17. Use of compound claimed in claim 3, for treating or preventing an infectious disorder in a human or animal.
18. Use of compound as claimed in claim 17, wherein the infectious disorder is caused by bacteria.
19. Use of pharmaceutical composition as claimed in claim 13, for treating or preventing an infectious disorder in a human or animal.
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