WO2004113329A1 - Oxazole derivatives as antibacterial agents - Google Patents

Oxazole derivatives as antibacterial agents Download PDF

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Publication number
WO2004113329A1
WO2004113329A1 PCT/IB2004/001965 IB2004001965W WO2004113329A1 WO 2004113329 A1 WO2004113329 A1 WO 2004113329A1 IB 2004001965 W IB2004001965 W IB 2004001965W WO 2004113329 A1 WO2004113329 A1 WO 2004113329A1
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Prior art keywords
phenyl
oxooxazolidin
fluoro
ylmethyl
compound
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PCT/IB2004/001965
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French (fr)
Inventor
Satya Surya Visweswara Srinivas Akella
Shiv Kumar Agarwal
Ananta Dharma Shinde
Matte Marianna Samuel
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Orchid Chemicals And Pharmaceuticals Ltd.
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Publication of WO2004113329A1 publication Critical patent/WO2004113329A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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

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, com unity acquired pneumoniae, ⁇ ancomycin resistance enterococci (VRE) caused by methicillin resistance staphylococcus aureus (MRSA) and penicillin resistance streptococcus pneumoniae.
  • VRE ⁇ ancomycin resistance enterococci
  • MRSA 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.
  • R 1 is a hydrogen, (C 1 -C 6 )alkyl optionally substituted with one or more OH, CN, or halo or R 1 is -(CH 2 ) h -aryl, -COR 1"1 , COOR 1"2 , -CO-(CH 2 ) h -COR , (Ci-C alkylsulfonyl, -SO 2 -(CH 2 ) h -aryl or - (CO)i-Het; R 2 is hydrogen, (C r 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 12 )alkyl optionally substituted with one or more halo, (C -C 12 )cycloalkyl, ( - 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 (MRSA) and penicillin resistance streptococcus pneumoniae.
  • VRE vancomycin resistance enterococci
  • MRSA 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 o:ca_-olidinone derivatives of the formula (I)
  • X represents oxygen or sulfur
  • Suitable groups represented by R 2 and R 3 are selected from hydrogen, halogen atom such as fluorine, chlorine, bromine or iodine; hydroxyl, ( - C 6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t- butyl, n-pentyl, isopentyl, hexyl and the like; (C 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 ⁇ alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; haloalkyl such as chloromethyl, chloroethyl, trifluoromethyl, frifluoroethyl, 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 3 -C 6 )cycl
  • Suitable groups represented by R 6a and R 6b may be selected from hydrogen, formyl, substituted or unsubstituted groups selected from ( - 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 phenyhnethyl, 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 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 2 H 5 ), N(C 2 H 5 ) 2 and the like; arylamino group such as phenylamino or naphthylamino; alkylcarbonylamino group such
  • Suitable groups represented by A are selected from substituted or unsubstituted aryl such as phenyl, naphthyl, and the like, (C 3 -C 6 )cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzofuranyl, benzoxadiazolyl,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b and R 7 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.
  • salts of the present invention include alkali metal like Li, Na, and ft, alkaline earth metal like Ca and Mg, alts of organic bases such as diethanolamine, ⁇ -phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline and the like, ammonium or substituted ammonium salts, aluminum salts.
  • Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc.
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • Representative compounds according to the present invention include:
  • P represents protecting group such as benzyl, benzyloxy carbonyl, tert- butoxycarbonyl, chloroethyl formate, Fmoc and all other symbols are as defined earlier to produce a compound of formula (IN)
  • L represents a leaving group such as mesylate, tosylate or friflate and all other symbols are as defined earlier, ii) converting the compound of formula (IN) to produce a compound of formula (N)
  • the compound of formula (III) may be converted to a compound of formula (IN) using methane sulfonyl chloride, tosyl chloride, trifluoromethane sulfonyl chloride.
  • the reaction may be earned 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 firom 1 to 12 hrs.
  • the compound of formula (IN) may be carried out in the presence of one or more equivalents of metal azide such as Li ⁇ , 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 tetrahydroiuran, chloroform, dichloiOmethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out in the presence of base selected from dimethylamino pyridine, triethylamine, pyridine and the like.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature. The duration of the reaction may range from 6 to 24 hrs.
  • the deprotection of compound of formula (Nil) may be carried by reduction using a catalyst such as Ru, Pd, Rh, Pt, ⁇ i 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 (NIII) with the compound of formula (IX) may be carried out in the presence of molecular sieves, and reducing agents such as sodium borohydride, friacetoxy sodium borohydride, sodium cyano borohydride, lithium aluminium hydride.
  • reducing agents such as sodium borohydride, friacetoxy sodium borohydride, sodium cyano borohydride, lithium aluminium hydride.
  • the reaction may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromefhane, 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.
  • 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 (Nil) where all symbols are as defined earlier, if) deprotecting the compound of formula (Nil) to produce a, compound of formula (X),
  • 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, dichloroinethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out in the presence of base selected from dimethylamino pyridine, triethylamine, pyridine and the like.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature. The duration of the reaction may range from 6 to 24 hrs.
  • the deprotection of compound of formula (Nil) may be carried by using chloroethyl chloroformate in the presence of a solvent such as DCM, , dioxane, acetic acid, ethyl acetate, THF, alcohol such as methanol, ethanol, isopropanol and the like or mixtures thereof.
  • a solvent such as DCM, , dioxane, acetic acid, ethyl acetate, THF, alcohol such as methanol, ethanol, isopropanol and the like or mixtures thereof.
  • reaction of compound of formula (X) with the compound of formula (IX) may be carried out in the presence of molecular sieves, and reducing agents such as sodium borohydride, friacetoxy sodium borohydride, sodium cyano borohydride, lithium aluminium hydride.
  • reducing agents such as sodium borohydride, friacetoxy 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 represents a leaving group such as mesylate, tosylate or triflale with NH(R 6a R 6 ) where all symbols are as defined earlier.
  • the conversion of compounds of formula (XI) to a compound of formula (I) may be carried out by heating in the presence of base selected from NaH, KH, t-BuOK and the like and solvents such as DMF, THF, DCM, 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.
  • acylation of compound of formula (XII) 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
  • a process for the conversion of compound of formula (I) wherein any of Z , Z" represents O, to compounds of formula (I) wherein Z , Z " represents S is 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.
  • 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.
  • 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-tetrahydropyridin-4-yl]phenyl]-2- oxooxazolidin-5-yl]methanol (14.2 g 5 0.03717 moles) dissolved in dichloromethane ( 100 ml) and triethyhmine (7.88 g, 0.07S06 moles) and (he 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).
  • 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- [ 1 -benzyl- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl]-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 RM mixture was diluted with ethylacetate and washed with sodium bicarbonate solution, water and brine solution. Dried over sodium sulphate and concentrated to dryness. Purified the residue over silica gel column using dichloromethane and methanol mixture as eluent to afford the title compound (80 mg) as gummy material.
  • the compounds of invention showed in vitro antibacterial activity when tested by the Agar Dilution Method as specified in documents published by the National Committee for Clinical Laboratory Standards (NCCLS), USA.
  • the compounds of invention were weighed, dissolved in Dimethyl Sulfoxide, serially diluted in the same solvent and then incorpoi te into molten Mueller Hinton Agar in a petridish before solidification, with each petridish containing a different concentration of a compound.
  • the Bacterial Inoculum was prepared by touching the tops of 3 to 5 well isolated bacterial colonies with the same morphological appearance from an 18 hour old culture with an inoculating loop, transferring the growth to a tube containing 5ml of normal saline and adjusting the turbidity of the saline suspension to 0.5 Macfarland Turbidity Standard equivalent to a bacterial population of 1.5 x 10 8 colony forming units (CFU) per milliliter of suspension.
  • CFU colony forming units
  • the bacterial inoculum prepared in the above manner was inoculated onto petri dishes containing Mueller Hinton Agar which had earlier been incorporated with different dilutions of the compounds of invention by a
  • Multipoint Inoculator with each inoculum spot containing approximately 1 x
  • CFU colony forming units
  • Coagulase Negative Staphylococci and Enterococci were incubated for 24 hours.
  • MIC Minimum Inhibitory Concentration

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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

OXAZOLE DERIVATIVES AS ANTIBACTERIAL AGENTS
Field of the Invention
The present invention provides novel compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them. The present invention more particularly provides novel oxazolidinone derivatives of the general formula (I).
Figure imgf000002_0001
The present invention also provides a process for the preparation of the above said novel oxazolidinone derivatives of the formula (I) their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them.
The novel oxazolidinone derivatives of the present invention are useful as antibacterial agents and hence are useful in the treatment of conditions such as nosocomial pneumoniae, com unity acquired pneumoniae, ^ancomycin resistance enterococci (VRE) caused by methicillin resistance staphylococcus aureus (MRSA) and penicillin resistance streptococcus pneumoniae. The compounds of the present invention are effective against a number of human or animal pathogens, clinical isolates, including Vancomycin resistant organisms, methicillin resistant organisms.
Background of Invention Several oxazolidinone derivatives have been reported in the literature some of which relevant are given here: International publication number 97/09328 discloses and claims compounds of formula
Figure imgf000003_0001
in which X is NR1, S(O)g or O; R1 is a hydrogen, (C1-C6)alkyl optionally substituted with one or more OH, CN, or halo or R1 is -(CH2)h-aryl, -COR1"1, COOR1"2, -CO-(CH2)h-COR , (Ci-C alkylsulfonyl, -SO2-(CH2)h-aryl or - (CO)i-Het; R2 is hydrogen, (CrC6)alkyl, -(CH2)h-aryl or halo; R3 and R4 are the same or different and are hydrogen or halo; R5 is hydrogen, (Cι-C12)alkyl optionally substituted with one or more halo, (C -C12)cycloalkyl, ( - C6)alkoxy; g is 0, 1 or 2; h is 1, 2, 3 or 4; i is 0 or 1; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4 or 5.
International publication number 97/30995 discloses and claims compounds of formula
Figure imgf000003_0002
wherein T is of the formula
R5- A—
Re-"^ B wherein R is chloro, fluoro, (CrC^alkanesulfonyloxy, azido, (Cι-C4)alkoxy, (CrC^alkylthio, (Cι-C4)alkylaminocarbonyloxy; or of the formula - NHC(=-O)R wherem R is hydrogen, (Cι-C )alkoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino, dimethylamino or (C -C4)alkyl; or of the formula -NHS(O)n(Cι-C4)alkyl where n is 0, 1 or 2; R and R are independently hydrogen or fluoro; >A-B- is >CH-CH2; R6 is (C C4)alkyl, (CrC4)alkanoylamino(CrC4)alkyl, hydroxy(Cr C4)alkyl, carboxy, (C C )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 (MRSA) and penicillin resistance streptococcus pneumoniae. The compounds of the present invention are effective against a number of human or animal pathogens, clinical isolates, including Vancomycin resistant organisms, methicillin resistant organisms
Summary of the Invention The present invention relates to novel o:ca_-olidinone derivatives of the formula (I)
Figure imgf000004_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their solvates, their pharmaceutically acceptable salts and their pharmaceutically acceptable compositions wherein X represents oxygen or sulfur; L is a linking group selectd from S, S(O)p, C(=Z1), wherem p is an integer of 1 or 2, Z1 represents O or S; R1 represents N(R aR6b), where R6a and R6b may be same or different and independently represent substituted or unsubstituted groups selected firom (C1-C6)alkyl, aryl, aralkyl, cycloalkyl, heteroaryl, heterocyclyl, heteroaralkyl or an aminoacid residue which is attached through acid moiety; or R1 represents -NHC(=Z2)R7 wherein Z2 represents oxygen or sulfur; R7 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 (C C6)alkyl, haloalkyl, (CrC6)alkoxy, (C C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; A represents substituted or unsubstituted aryl, cycloalkyl or 5 to 10 membered mono or bicyclic, saturated, partially saturated or aromatic ring system containing 1 to 4 heteroatoms selected from O, S, N, heteroaralkyl, heteroaralkenyl; n is an integer in the range of 0 to 3, m is an integer in the range of 1 to 2.
Detailed Description of the Invention Suitable groups represented by R1 are selected from N(R6aR6b), - NHC(=Z2)R7. Suitable groups represented by R2 and R3 are selected from hydrogen, halogen atom such as fluorine, chlorine, bromine or iodine; hydroxyl, ( - C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t- butyl, n-pentyl, isopentyl, hexyl and the like; (C 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, ( -C^alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; haloalkyl such as chloromethyl, chloroethyl, trifluoromethyl, frifluoroethyl, dichloromethyl, dichloroethyl and the like; (Cι-C6)alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; (C 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 R6a and R6b may be selected from hydrogen, formyl, substituted or unsubstituted groups selected from ( - 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 phenyhnethyl, 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, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridadnyl, ben*ropyranyl, indolyl, indolinyl, benzimidazol l, ben∑ acolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl, benzodioxolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl 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 R 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; (C 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(C2H5), 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, isooxazoly oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyraziny pyridazinyl, benzopyranyl, indolyl, indolinyl, benzimidazolyl, benzoxazoly' benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazoly benzodioxolyl, quinolinyl, dihydiOquinolinyl, tetrahydroquinoliny' isoquinolinyl dihydroisoquinolinyl, tetrahydroisoquinolin l and the like; heteroaralkyl group wherem 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 substituted or unsubstituted aryl such as phenyl, naphthyl, and the like, (C3-C6)cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzofuranyl, benzoxadiazolyl, benzothiadiazolyl, benzodioxolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl and the like; heteroaralkyl and heteroaralkenyl, wherein the heteroaryl is as defined above; wherein the substituents are selected from halogen, hydroxy, formyl, nitro, cyano, azido, amino, alkyl, aryl, substituted aryl, aralkyl, monoalkylamino, dialkylamino, alkylaminocarbonyl, haloalkyl, alkylthio, acylamino, alkoxy, acyl, heteroaryl, heterocyclyl, cycloalkyl, 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, R6a, R6b and R7 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 ft, alkaline earth metal like Ca and Mg, alts of organic bases such as diethanolamine, α-phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
Representative compounds according to the present invention include:
(S)-N-[3-[3-Fluoro-4-[l-(N-pyrazine-2-yl-carbonyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(6)-N-[3-[3-Fluoro-4-[l-(N-pyrazine-2yl-thiocarbonyl) piperidin-4-yl]phenyl]-
2-oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N- [3 - [3 -Fluoro-4- [ 1 -(N-5 -nifrofuran-2-yl-thiocarbonyl)piperidin-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[ 1 -(N-ρyrazine-2-yl-thiocarbonyl)- 1 ,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-5-methylpyrazine-2-yl-thiocarbonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-5-nitrofuran-2-yl-thiocarbonyl)-l,253,6- tetrahydropyridin-4-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[ 1 -(N-thiomorpholin-4-yl-thiocarbonyl)- 1 ,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ; ( S )-N-[3-[3-Fluoro-4-[ 1 -(N-piperidine- 1 -yl-thiocarbonyl)- 1 ,2,3,6- tetrahydiOpyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-4-(pyrύrιidine-2-yl)piperazin-l-ylthiocarbonyl)-
1,2,3, 6-tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl] thioacetamide ; (S)-N-[3-[3-Fluoro-4-[l-(N-benzofuran-2-yl-thiocarbonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-(l-methylpyrrolyl-2-yl)thiocarbonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[3-Fluoro-4-[ 1 -(N-pyrazine-2-yl-carbonyl)- 1 ,2,3,6- tetrahydropyridm-4-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-cyclopropylcarbonyl)-l,2,3,6-tetrahydropyridin-4- yl]phenyl] -2-oxooxazolidin-5-ylmethyl] acetamide ; (S)-N-[3-[3-Fluoro-4-[l-(N-thien-3-yl-carbonyl)-l,2,3,6-tetrahydropyridin-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-5-nifrofuran-2-yl-carbonyl)-l,2,3,6- tetrahydropyridin-4-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-pyrrolidin-3-yl-carbonyl)-l,2,3,6- tetrahydropyridin-4-yl]phenyl] -2-oxooxazolidin-5 -ylmethyl] acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-l-methylpyrrol-2-yl-carbonyl)-l,2,3,6- tetrahydropyridin-4-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(■S)-N-[3-[3-Fluoro-4-[l-(N-quinoxalin-2-yl-carbonyl)-l,2,3,6- tetrahydropyridin-4-yl]phenyl]-2-oxooxazolidm-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[l-(N-5-methylpyrazine-2-yl-carbonyl)-l,2,3,6- tetrahydropjτidin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-p} azol-5-yl-caι*bonyl)-l,2,3,6-tetrahydropyridin-
4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-benzimidazol-5-yl-carbonyl)-l, 2,3,6- tetrah3/dropyiidin-4yl]phenyl]-2-o:fooxaz;olidin-5-ylmethyl]acetamide ;
(S)-M-[3-[3-Fluoro-4-[l-(N-indol-2-yl-carbonyl)-l,2,3,6-tetrahydropyridin-
4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[ 1 -(N-furan-2-yl-propenoyl)- 1 ,2,3,6-tetrahydropyridin-
4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[l-(N-morρholin-4-yl-carbonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-thiomorpholin-4-yl-carbonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[ 1 -(N-4-(pyridin-2-yl)piperazin- 1 -yl-carbonyl)-l ,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[ 1 -(N-4-(piρeridin- 1 -yl)ρiperidin- l-yl-carbonyl)- 1 ,2,3,6- tefrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[ l-(N-4-(pyrrolidin- 1 -yl)piperidin- 1 -yl-carbonyl)-
1,2,3, 6-tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-4-(pyrimidin-2-yl)piperazin-l-yl-carbonyl)-
1,2,3, 6-tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[ 1 -(N-ρiρeridine- 1 -yl-carbonyl)- 1 ,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[ 1 -(N-benofuran-2-yl-carbonyl)- 1 ,2,3,6- tetralιydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-5-nifrofuran-2-yl-carbonyl)piperidin-4-yl]phenyl]-
2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[ 1 -(N-benzimidazol-5-yl-carbonyl)piperidine-4- yl]phenyl]-2-oxooxazolidin-5-ylmefhyl]acetamide ;
(S)-N-[3-[3-FluoiO-4-[l-(N-qumoxalin-2-yl-carbonyi)-piperidin-4-yl]phenyl]-
2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-FluoiO-4-[l-(N-cyclopropylcarbonyl)-piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-benzofuran-2-yl-carbonyl)-piperidin-4yl]phenyl]-
2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-quinolinyl-8-sulphonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl] -2-oxooxazolidin-5 -ylmethy 1] acetamide ; (S)-N-[3-[3-Fluoro-4-[ 1 -(N-naphthyl- 1 -sulphonyl)- 1 ,2,3,6-tetrahydropyridin-
4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-4-dimethylaminonaphthyl-lyl-carbonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5 -ylmethy 1] acetamide ; (S)-N-[3-[3-Fluoro-4-[l-(N-4-(N-(4-acetylphenyl-2yl)piperazin-l-yl- carbonyl)-l,2,3,6-tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl] acetamide ;
(S)-N-[3-[3-Fluoro-4-[l -(N-naphthyl- 1 -sulphonyl)- 1 ,2,3,6-tetrahydropyridin- 4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(<S)-N-[3-[3-Fluoro-4-[l-(N-pyrazine-2-yl-carbonyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[3-Fluoro-4-[l-(N-pyrazine-2yl-thiocarbonyl)piperidin-4-yl]phenyl]-
2-oxooxazolidin-5-ylmethyl]thiocarbamate ; (<S)-N- [3 - [3 -Fluoro-4- [ 1 -(N-5 -nitrofuran-2-yl-thiocarbonyl)piperidin-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N- [3 - [3 -Fluoro-4- [ 1 -(N-5 -nitrofuran-2-yl-carbonyl)piperidin-4-yl]phenyl] -
2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[3-Fluoro-4-[l-(N-benzofuran-2-yl-thiocarbonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[3-Fluoro-4-[l-(N-benzofuran-2-yl-carbonyl)-piperidin-4yl]phenyl]-
2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[3-Fluoro-4-[l-(N-thien-3-yl-carbonyl)-l,2,3,6-tetrahydropyridin-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ; (S)-N-[3-[3-Fluoro-4-[l-(lT-quinolinyl-C-sulphonyl)- 1 ,2,3,6- tetrahydrop5πridin-4yl]plιenyl]-2-oxooxazolidin-5-ylmethyi]thiocarbamate ;
(S)-N-[3-[3-Fluoro-4-[l-(N-pyrazine-2-yl-carbonyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]-N' -methyl thiourea ;
(S)-N-[3-[3-Fluoro-4-[l-(N-pyrazine-2yl-thiocarbonyl)piperidin-4-yl]phenyl]- 2-oxooxazolidin-5-ylmethyl]-N'-methyl thiourea and
(6)-N-[3-[3-Fluoro-4-[l-(N-5-nifrofuran-2-yl-thiocarbonyl)piperidin-4- yljphenyl] -2-oxooxazolidin-5-ylmethyl] -N ' -methyl thiourea. According to another embodiment of the present invention, there is provided a process for the preparation of novel oxazolidinone derivatives of the formula (I) where R1 represents NHC(=Z2)R7, wherein Z2 represents O, n is 1 and all other symbols are as defined earlier, which comprises : (i) converting the compound of formula (HI)
Figure imgf000013_0001
where P represents protecting group such as benzyl, benzyloxy carbonyl, tert- butoxycarbonyl, chloroethyl formate, Fmoc and all other symbols are as defined earlier to produce a compound of formula (IN)
Figure imgf000013_0002
where L represents a leaving group such as mesylate, tosylate or friflate and all other symbols are as defined earlier, ii) converting the compound of formula (IN) to produce a compound of formula (N)
Figure imgf000013_0003
iii) reducing the compound of formula (N) to a compound of formula (NI)
Figure imgf000013_0004
where all symbols are as defined earlier, iv) acylating the compound of formula (VI) to produce a compound of formula (VII)
Figure imgf000014_0001
where all symbols are as defined earlier, v) deprotecting the compound of formula (Nil) to produce a compound of formula (NIII),
Figure imgf000014_0002
where all symbols are as defined earlier, vi) reacting the compound of formula (VIII) with a compound of formula
(IX)
A-L-L, (|χ) wherein A and L are as defined earlier and L1 is a leaving group to produce a compound of formula (I) as defined above.
The compound of formula (III) may be converted to a compound of formula (IN) using methane sulfonyl chloride, tosyl chloride, trifluoromethane sulfonyl chloride. The reaction may be earned 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 firom 1 to 12 hrs.
The compound of formula (IN) may be carried out in the presence of one or more equivalents of metal azide such as LiΝ , 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 tetrahydroiuran, chloroform, dichloiOmethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof. The reaction may be carried out in the presence of base selected from dimethylamino pyridine, triethylamine, pyridine and the like. The reaction may be carried out at a temperature in the range of 0 °C to room temperature. The duration of the reaction may range from 6 to 24 hrs.
The deprotection of compound of formula (Nil) may be carried by reduction using a catalyst such as Ru, Pd, Rh, Pt, Νi 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 (NIII) with the compound of formula (IX) may be carried out in the presence of molecular sieves, and reducing agents such as sodium borohydride, friacetoxy sodium borohydride, sodium cyano borohydride, lithium aluminium hydride. The reaction may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromefhane, 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 " — " represents a bond; R1 represents ΝHC(=Z2)R7, wherein X represents U, n is 1 and all other symbols are as defined earlier, which comprises : i) acylating the compound of formula (VI)
Figure imgf000016_0001
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 (Nil)
Figure imgf000017_0001
where all symbols are as defined earlier, if) deprotecting the compound of formula (Nil) to produce a, compound of formula (X),
Figure imgf000017_0002
where all symbols are as defined earlier, iii) reacting the compound of formula (X) with a compound of formula
(IX)
A~L-L1 (|χ) wherein A and L are as defined earlier and L1 is a leaving group to produce a compound of formula (I) as defined above.
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, dichloroinethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof. The reaction may be carried out in the presence of base selected from dimethylamino pyridine, triethylamine, pyridine and the like. The reaction may be carried out at a temperature in the range of 0 °C to room temperature. The duration of the reaction may range from 6 to 24 hrs.
The deprotection of compound of formula (Nil) may be carried by using chloroethyl chloroformate in the presence of a solvent such as DCM, , dioxane, acetic acid, ethyl acetate, THF, alcohol such as methanol, ethanol, isopropanol and the like or mixtures thereof.
The reaction of compound of formula (X) with the compound of formula (IX) may be carried out in the presence of molecular sieves, and reducing agents such as sodium borohydride, friacetoxy 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 N(R aR ) where R a and R6b are as defined earlier which comprises reacting the compound of formula (XI)
Figure imgf000018_0001
where L represents a leaving group such as mesylate, tosylate or triflale with NH(R6aR6 ) where all symbols are as defined earlier. The conversion of compounds of formula (XI) to a compound of formula (I) may be carried out by heating in the presence of base selected from NaH, KH, t-BuOK and the like and solvents such as DMF, THF, DCM, 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. 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(-=Z2)R7; where Z2 represents S, R7 and all other symbols are as defined above, which comprises reacting the compound of formula (XII)
Figure imgf000019_0001
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 (XII) 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
In yet another embodiment of the present invention, there is provided a process for the conversion of compound of formula (I) wherein any of Z , Z" represents O, to compounds of formula (I) wherein Z , Z" represents S, is 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. 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 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
Preparation of (S)-[3-[3-fluoro-4-[l-benzyl-l,2,3,6-tetrahydropyridin-4- yl] phenyl] -2-oxooxazolidin-5-yl] methyl mesylate
Figure imgf000020_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-tetrahydropyridin-4-yl]phenyl]-2- oxooxazolidin-5-yl]methanol (14.2 g5 0.03717 moles) dissolved in dichloromethane ( 100 ml) and triethyhmine (7.88 g, 0.07S06 moles) and (he 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).
Preparation 2 Preparation of (S)-N-[3-[3-fluoro-4-[l-benzyl-l,2,3,6-tetrahydropyridin-4- yl] phenyl] -2-oxooxazolidin-5-ylmethyl] azide
Figure imgf000021_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
Preparation of («S)-N-[3-[3-fluoro-4-[l-benzyl-l,2,3,6-tetrahydropyridin-4- yl] phenyl] -2-osoosasolidin-5-ylmethyl] amine
Figure imgf000021_0002
(!?)-!" f-[3-[3-Fluoro- -[l-benr:yl-l ,2,3,ό-lelrahydrop- ridin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl] zide (15 g, 0.03685 moles) and triphenyl phosphine (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
Preparation of (S)-N-[3-[3-fluoro-4-[l-benzyl-l,2,3,6-tetrahydropyridin-4- yl] phenyl] -2-oxooxazolidin-5-ylmethyl] acetamide
Figure imgf000022_0001
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- [ 1 -benzyl- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl]-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
Preparation of (5)AT-[3-[3-llιιoro-4-(piperidiιι-4-yI phenyl]-2- osoosa_solidin-5-ylmethyljaeetamide
Figure imgf000022_0002
(S)-N-[3-[3-Fluoro-4-[ 1 -benzyl- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]acetamide (0.8 g, 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%).
Preparation 6
Preparation of (S)-N-[3-[3-fIuoro-4-[l,2,3,6-tetrahydropyridin-4- yl] phenyl] -2-oxooxazolidin-5-y lmethyl] acetamide
Figure imgf000023_0001
A solution of (S)-N-[3-[3-Fluoro-4-[l-benzyl-l,2,3,6-tetralιydropyridin-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (1 g, 0.002364 moles) in DCM (20 ml) was cooled to 0 °C under nitrogen atmosphere. To this 1- chloroethyl chloroformate (0.4 gm, 0.0083 moles) was added drop wise. The resulting solution was stirred at ice temperature for 1 hr. The solvent was removed under high vacuum and the residue was dried. The gummy material obtained was taken in methanol (20 ml) and refluxed for 1 hr and evaporated the solvent and purified the residue over silica gel column to yield the title compound (0.5 g, yield 65%).
Example 1 Synthesis of (<S}-N-[3-[3-fluoro-4-[l-(N-pyrazine-2-yl-carbonyl)piperidin- 4-yl]phenyl]-2-oxooxasolidin-5-ylmethyl] acetamide
Figure imgf000023_0002
To a solution of (S)-N-[3-[3-fluoro-4-(piperidin-4-yl)phenyl]-2-oxooxazolidin- 5-ylmethyl]acetamide (150 mg, 0.4477 mmoles) (prepared according to the procedure described in our WO publication No. 03/097640) dissolved in dry THF (5 ml), pyrazine-2-carbonyl chloride (which was prepared by reacting pyrazine-2-carboxylic acid (168 mg, 1.3432 mmoles) with thionyl chloride and triethylamine (136 mg, 1.34328 mmoles) at 0 °C and stirred at RT under Nitrogen atmosphere for 4 hours. The RM mixture was diluted with ethylacetate and washed with sodium bicarbonate solution, water and brine solution. Dried over sodium sulphate and concentrated to dryness. Purified the residue over silica gel column using dichloromethane and methanol mixture as eluent to afford the title compound (80 mg) as gummy material. 1HNMR (CDC13) δ : 1.80-1.84 (m, 4H), 2.01 (s, 3H), 2.02-2.03 (s, 2H), 3.07- 3.09 (t, 2H), 3.62-3.69 (m, IH), 3.71-3.77 (t, 2H), 4.02-4.06 (m, 2H), 4.78- 4.79 (m, IH), 5.97 (bs, IH, D2O exchangeable), 7.12-7.14 (d, IH), 7.21-7.23 (t, IH), 7.42-7.45 (d, IH), 8.56-8.57 (t, IH), 8.64-8.65 (d, IH), 8.94- 8.95 (d, IH).
The following compounds were prepared according to the procedure given in example 1.
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Example 31
Synthesis of (S)-N-[3-[3-fluoro-4-[l-(N-pyrazine-2yl-thiocarbonyl) piperidin-4-yl]phenyl]-2-oxooxazoIidin-5-ylmethyl]thioacetamide
Figure imgf000037_0002
To a solution of (S)-N-[3-[3-fluoro-4-[l-(N-pyra^ine-2-yl-carbonyl)piperidin- -yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetanιide (100 mg, 0.2262 mmoles) obtained in example 1, in dry toluene (10 ml) and Lawessons reagent (137 mg, 0.3393 mmoles) was added and heated the reaction contents at 100 °C for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness. Purified the reaction mixture using chloroform and methanol mixture as eluent to afford the title compound as a gummy material (60 mg). 1HNMR (CDCI3) δ : 1.98-2.01 (m, 4H), 2.59 (s, 3H), 3.25 - 3.26 (t, 2H), 3.52 - 3.53 (m, IH), 3.81 - 3.84 (d, 2H), 4.08 - 4.12 (m, 3H), 4.46 - 4.48 (t, IH), 5.08 - 5.10 (m, IH), 6.96 - 6.97 (d, IH), 7.14-7.15 (t, IH), 7.21-7.25 (d, IH), 7.43-7.46 (d, IH), 8.47 (s, IH), 8.53-8.54 (d, IH), 8.89 (s, IH, D2O exchangeable). Mass (M++l) : 474
The following compounds were prepared according to the procedure given in example 31.
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Antimicrobial Testing
The compounds of invention showed in vitro antibacterial activity when tested by the Agar Dilution Method as specified in documents published by the National Committee for Clinical Laboratory Standards (NCCLS), USA.
Briefly, the compounds of invention were weighed, dissolved in Dimethyl Sulfoxide, serially diluted in the same solvent and then incorpoi te into molten Mueller Hinton Agar in a petridish before solidification, with each petridish containing a different concentration of a compound.
The Bacterial Inoculum was prepared by touching the tops of 3 to 5 well isolated bacterial colonies with the same morphological appearance from an 18 hour old culture with an inoculating loop, transferring the growth to a tube containing 5ml of normal saline and adjusting the turbidity of the saline suspension to 0.5 Macfarland Turbidity Standard equivalent to a bacterial population of 1.5 x 108 colony forming units (CFU) per milliliter of suspension.
The bacterial inoculum prepared in the above manner was inoculated onto petri dishes containing Mueller Hinton Agar which had earlier been incorporated with different dilutions of the compounds of invention by a
Multipoint Inoculator with each inoculum spot containing approximately 1 x
IO4 colony forming units (CFU) of bacteria.
The inoculated petridishes were incubated at 35°Celsius in an ambient atmosphere for 20 hours. Petridishes containing different concentrations of Nancomycin and Oxacillin and inoculated with Stapliylococcus aureus,
Coagulase Negative Staphylococci and Enterococci were incubated for 24 hours.
The petridishes after incubation, were placed on a dark non reflecting surface and the Minimum Inhibitory Concentration (MIC) recorded as the concentration which showed no growth of the inoculated culture.
The minimum inhibitory concentrations (μg/ml) were obtained for representative compounds of the invention which are given in the table 1:
1) S. aureus - Staphylococus aureus 2) Ent. Faecalis - Einerococcm faecalis 3).E. faecium - Enterococcus faecium ATCC - American Type Culture Collection MRO - Microbial Resource Orchid
Table I (Cont)
4i-
Figure imgf000044_0001
Figure imgf000044_0002
Table I (Contd.)
Figure imgf000045_0001
Figure imgf000045_0002
Table I
4=>
Figure imgf000046_0001
Figure imgf000046_0002

Claims

We claim :
1. A compound of formula (I)
Figure imgf000047_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their solvates, their pharmaceutically acceptable salts and their pharmaceutically acceptable compositions wherein X represents oxygen or sulfur; L is a linking group selected from S, S(O)p, C(=Z ), wherein p is an integer of 1 or 2, Z1 represents O or S; R1 represents N(R6aR6b), where R6a and R6b may be same or different and independently represent 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(=Z )R7 wherein Z2 represents oxygen or sulfur; R is hydrogen, amino, substituted or unsubstituted groups selected from (C- -Chalky 1, (C--C6)alko y, 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 (Cι-C6)alkyl, haloalkyl, (Cι-C6)alkoxy, (C1-C6)alkylthio, (C3-C6)cycloalkyl or either of R or R5 represent an oxo or thiooxo group; A represents substituted or unsubstituted aryl, cycloalkyl or 5 to 10 membered mono or bicyclic, saturated, partially saturated or aromatic ring system containing 1 to 4 heteroatoms selected from O, S, N, heteroaralkyl, heteroaralkenyl; n is an integer in the range of 0 to 3, m is an integer in the range of 1 to 2.
2. The compound as heteroaryl group represented by A are selected from substituted or unsubstituted phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzofuranyl, benzoxadiazolyl, benzothiadiazolyl, benzodioxolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl or piperazinyl.
3. A compound of formula (I) as claimed in claim 1, which is selected
(S)-N-[3-[3-Fluoro-4-[l-(N-pyrazine-2-yl-carbonyl)piperidm-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-pyτazine-2yl-thiocarbonyl) piperidin-4-yl]phenyl]-
2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(>S)-N-[3-[3-Fluoro-4-[l-(N-5-nitiOfuran-2-yl-thiocarbonyl)piperidin-4- yl]phenyl]-2-or:ooxa^olidin-5-ylmelhyl]thioaeetanιide ;
(S)-N-[3-[3-FluoiO-4-[l-(N-pyτazine-2-yl-thiocarbonyl)-l, 2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-5-methylpyrazine-2-yl-thiocarbonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl] -2-oxooxazolidin-5 -ylmethy l]thioacetamide ; (S)-N-[3-[3-Fluoro-4-[l-(N-5-nitrofuran-2-yl-thiocarbonyl)-l,2,3,6- tetrahydropyridin-4-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-thiomorpholin-4-yl-thiocarbonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[3-Fluoro-4-[ 1 -(N-piperidine- 1 -yl-thiocarbonyl)- 1 ,2,3,6- tefrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[3-Fluoro-4-[ 1 -(N-4-(pyrimidine-2-yl)piperazin- 1 -ylthiocarbonyl)- l,2,3,6-tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl] thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[ 1 -(N-benzofuran-2-yl-thiocarbonyl)- 1 ,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[3-Fluoro-4-[l-(N-(l-methylpyrrolyl-2-yl)thiocarbonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[3-Fluoro-4-[ 1 -(N-pyrazine-2-yl-carbonyl)- 1 ,2,3,6- tetrahydropyridin-4-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[ 1 -(N-cyclopropylcarbonyl)- 1 ,2,3,6-tetrahydropyridin-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[ 1 -(N-thien-3-yl-carbonyl)- 1 ,2,3,6-tetrahydropyridin-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(fS)-N-[3-[3-Fluoro-4-[l-(N-5-nitrofuran-2-yl-carbonyl)-l, 2,3,6- tetrahydropyridin-4-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[ 1 -(N-ρyrrolidin-3-yl-carbonyl)- 1 ,2,3,6- tetrahydropyridin-4-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (_Sp)-N-[3-[3-Fluoro-4 -[ 1 -(11- 1 -methylpyτrol-2-yAcarborryl )- 1 ,2,3,6- tetrahydropyridin-4-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[ 1 -(N-quinoxalin-2-yl-carbonyl)- 1 ,2,3,6- tetrahydropyridin-4-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[l-(N-5-methylpyrazine-2-yl-carbonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-pyrazol-5-yl-carbonyl)-l,2,3,6-tetrahydropyridin- 4yl]phenyl] -2-oxooxazolidin-5 -ylmethy 1] acetamide ; (S)-N-[3-[3-Fluoro-4-[l-(N-benzimidazol-5-yl-carbonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[l-( -indol-2-yl-carbonyl)-l,2,3,6-tetrahydropyridin-
4yl]phenyl] -2-oxooxazolidin-5 -ylmethyl] acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-fVn-aιι-2-yl-propenoyl)-l,2,3,6-tetrahydropyridin-
4yl]phenyl] -2-oxooxazolidin-5 -ylmethyl] acetamide ; (S)-N-[3-[3-Fluoro-4-[l-(N-morpholin-4-yl-carbonyl)-l,2,3,6- tefrahydropyridin-4yl]phenyl] -2-oxooxazolidin-5 -ylmethyl] acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-thiomorpholin-4-yl-carbonyl)-l,2,3,6- tefrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-4-(pyridin-2-yl)piperazin-l-yl-carbonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[ 1 -(N-4-(piperidin- 1 -yl)piperidin- 1 -yl-carbonyl)- 1 ,2,3,6- tetrahydropyridin-4yl]phenyl] -2-oxooxazolidin-5 -ylmethyl] acetamide ;
(S)-N-[3-[3-Fluoro-4-[ 1 -(N-4-(pyrrolidin- 1 -yl)piperidin- 1 -yl-carbonyl)-
1,2,3, 6-tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[ 1 -(N-4-(pyrimidin-2-yl)piperazin- 1 -yl-carbonyl)- l,2,3,6-tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-piperidine-l-yl-carbonyl)-l,2,3,6- tefrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-benofuran-2-yl-carbonyl)-l,2,3,6- tetrah'ydropyi*idin-4yl]phenyl]-2-o>:ooxai;olidin-5-ylmethyl]acetamide ;
(5)-N-[3-[3-Fluoro-4-[l-(N-5-nitrofuran-2-yl-carbonyl)piperidin-4-yl]phenyl]-
2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-benzimidazol-5-yl-carbonyl)piperidine-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N- [3 -[3 -Fluoro-4- [ 1 -(N-quinoxalin-2-yl-carbonyl)-piperidin-4-yl]phenyl]-
2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-cyclopropylcarbonyl)-piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[3-Fluoro-4-[l-(N-benzofuran-2-yl-carbonyl)-piperidin-4yl]phenyl]-
2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[ 1 -(N-quinolinyl-8-sulphonyl)- 1 ,2,3,6- tetrahydropyridin-4yl]phenyl] -2-oxooxazolidin-5 -ylmethyl] acetamide ; (S)-N-[3-[3-Fluoro-4-[ 1 -(N-naphthyl- 1 -sulphonyl)- 1 ,2,3,6-tetrahydropyridin-
4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[3-Fluoro-4-[ 1 -(N-4-dimethylaminonaphthyl-lyl-carbonyl)- 1 ,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5 -ylmethyl] acetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-4-(N-(4-acetylphenyl-2yl)piperazin-l-yl- carbonyl)-l,2,3,6-tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl] acetamide ;
(S)-N-[3-[3-Fluoro-4-[ 1 -(N-naphthyl- 1 -sulphonyl)- 1 ,2,3,6-tetrahydropyridin-
4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[3-Fluoro-4-[l-(N-pyrazine-2-yl-carbonyl)piperidin-4-yl]phenyl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[3-FluoiO-4-[l-(N-p5τazine-2yl-thiocarbonyl)piperidin-4-yl]phenyl]-
2-oxooxazolidin-5 -ylmethyl]thiocarbamate ;
(jS)-N-[3-[3-Fluoro-4-[l-(N-5-nifrofuran-2-yl-thiocarbonyl)piperidin-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ; (ly)-^I-[3-[3-Fluol^-4-[l-(^I-5-nit^^fur^n-2-} l-carbonyl)piperielin-4-yl]phenyl]-
2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[3-Fluoro-4-[l-(N-benzofuran-2-yl-thiocarbonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[3-Fluoro-4-[l-(N-benzofuran-2-yl-carbonyl)-piperidin-4yl]phenyl]- 2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[3-Fluoro-4-[l-(N-thien-3-yl-carbonyl)-l,2,3,6-tefrahydropyridin-4- yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[3-Fluoro-4-[l-(N-quinolinyl-8-sulphonyl)-l,2,3,6- tetrahydropyridin-4yl]phenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ; (■S)-N-[3-[3-Fluoro-4-[l-(N-pyrazine-2-yl-carbonyl)piperidin-4-yl]ρhenyl]-2- oxooxazolidin-5 -ylmethyl] -N' -methyl thiourea and
(S)-N-[3-[3-Fluoro-4-[l-(N-pyrazine-2yl-thiocarbonyl)ρiperidin-4-yl]phenyl]- 2-oxooxazolidin-5-ylmethyl]-N'-methyl thiourea. (S)-N-[3-[3-Fluoro-4-[l-(N-5-nifrofuran-2-yl-thiocarbonyl)piperidin-4- yl]phenyl]-2-oxooxazolidin-5 -ylmethyl] -N' -methyl thiourea ;
4. The compound as claimed in claim 3, wherein the salt is selected from hydrochloride or hydrobromide.
5. A process for the preparation of compound of the formula (I)
Figure imgf000052_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their solvates, their pharmaceutically acceptable salts and their pharmaceutically acceptable compositions wherein X represents oxygen or sulfur; L is a linking group selectd from S, S(0)p, C(=Z ), wherein p is .an integer of 1 or 2, Z1 represents O or S; R1 represents N(R6aR6 ), where R6a and R6 may be same or different and independently represent 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(=Z2)R7 wherein Z2 represents oxygen or sulfur; R7 is hydrogen, amino, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C1-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, (Cι-C6)al lthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; A represents substituted or unsubstituted aryl, cycloalkyl or 5 to 10 membered mono or bicyclic, saturated, partially saturated or aromatic ring system containing 1 to 4 heteroatoms selected from O, S, N, heteroaralkyl, heteroaralkenyl; n is an integer in the range of 0 to 3, m is an integer in the range of 1 to 2, which comprises : (i) converting the compound of formula (III)
Figure imgf000053_0001
where P represents protecting group and all other symbols are as defined above to produce a compound of formula (IN)
Figure imgf000053_0002
where L represents a leaving group such as mesylate, tosylate or friflate and all other symbols are as defined above, ii) converting the compound of formula (IV) to produce a compound of formula (N)
Figure imgf000053_0003
iii) reducing the compound of formula (N) to a compound of formula (NI)
Figure imgf000053_0004
where all symbols are as defined above, iv) acylating the compound of formula (NI) to produce a compound of formula (Nil)
Figure imgf000054_0001
where all symbols are as defined above, v) deprotecting the compound of formula (Nil) to produce a compound of formula (NIII),
Figure imgf000054_0002
where all symbols are as defined above, vi) reacting the compound of formula (NIII) with a compound of formula
A-L-L1 (|χ) wherein A and L are as defined earlier and L1 is a leaving group to produce a compound of formula (I) as defined above.
6. A process for the preparation of compound of the formula (I)
Figure imgf000054_0003
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their solvates, their pharmaceutically acceptable salts and their pharmaceutically acceptable compositions wherein X represents oxygen or sulfur; L is a linking group selectd from S, S(O)p, C(=Z1), wherein p is an integer of 1 or 2, Z1 represents O or S; R1 represents N(R6aR6 ), where R6a and R6 may be same or different and independently represent 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(=Z2)R7 wherein Z2 represents oxygen or sulfur; R7 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; 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 (Cι-C6)alkyl, haloalkyl, (Cι-C6)alkoxy, (C1-C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; A represents substituted or unsubstituted aryl, cycloalkyl or 5 to 10 membered mono or bicyclic, saturated, partially saturated or aromatic ring system containing 1 to 4 heteroatoms selected from O, S, N, heteroaralkyl, heteroaralkenyl; n is an integer in the range of 0 to 3, m is an integer in the range of 1 to 2, which comprises : i) acylating the compound of formula (VI)
Figure imgf000055_0001
wherein P represents protecting group and all other symbols are as defined above to produce a compound of formula (Nil)
Figure imgf000055_0002
where all symbols are as defined above, ii) deprotecting the compound of formula (Nil) to produce a compound of formula (X),
Figure imgf000056_0001
where all symbols are as defined earlier, iii) reacting the compound of formula (X) with a compound of formula (IX)
A-L-L1 (|χ) wherein A and L are as defined earlier and L1 is a leaving group to produce a compound of formula (I) as defined above.
7. A process for the preparation of compound of the formula (I)
Figure imgf000056_0002
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, wherein X represents α.i gen or sulfur; R represents 11(R aR' ) where R and P " and all other symbols are as defined in claim 1, which comprises reacting the compound of formula (XI)
Figure imgf000056_0003
where L represents a leaving group such as mesylate, tosylate or friflate with NH(R6aR6 ) where all symbols are as defined in claim 1.
8. A process for the preparation of compound of the formula (I)
Figure imgf000057_0001
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, wherein X represents oxygen or sulfur; R1 represents the formula -NHC(=Z1)R7; where R7 and all other symbols are as defined in claim 1, which comprises reacting the compound of formula (XIV)
Figure imgf000057_0002
where all symbols are as defined earlier which represents compound of formula (I) where R represents azido with thioacetic acid to produce compound of formula (I) as defined above.
9. A process for the preparation of compound of formula (I)
Figure imgf000057_0003
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their solvates, their pharmaceutically acceptable salts and their pharmaceutically acceptable compositions wherein X represents oxygen or sulfur; L is a linking group selected from S, S(O)p, C(=Z1), wherein p is an integer of 1 or 2, Z1 represents S; R1 represents N(R6aR6b), where R6a and R6b may be same or different and independently represent 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(=Z2)R7 wherein Z2 represents sulfur; R 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; 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)alkylfhio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group;- q is an integer 1 to 4; A represents substituted or unsubstituted aryl, cycloalkyl or 5 to 10 membered mono or bicyclic, saturated, partially saturated or aromatic ring system containing 1 to 4 heteroatoms selected from O, S, N, heteroaralkyl, heteroaralkenyl; n is an integer in the range of 0 to 3, m is an integer in the range of 1 to 2, comprising converting the compound of formula (I) wherein Z1 or Z2 represent O using Lawessons reagent.
10. A pharmaceutical composition, which comprises a compound of formula (I)
Figure imgf000058_0001
as defined in claim 1 and a pharmaceutically acceptable carrier, diluent, excipient or solvate.
11. A pharmaceutical composition as claimed in claim 10, in the form of a tablet, capsule, powder, syrup, solution, aerosol or suspension.
12. A method of treating or preventing an infectious disorder in a human or animal, comprising administering an effective amount of a compound of claim
1 to human or animal in need thereof.
13. A method as claimed in claim 12, wherein the infectious disorder is caused by bacteria.
14. A method of treating or preventing an infectious disorder in a human or animal, comprising administering an effective amount of a compound of claim 3 to human or animal in need thereof.
15. A method as claimed in claim 14, wherein the infectious disorder is caused by bacteria.
16. A method of treating or preventing an infectious disorder in a human or animal, comprising administering a composition as claimed in claim 9 to human or animal in need thereof.
17. A method as claimed in claim 16, wherein the infectious disorder is caused by bacteria.
PCT/IB2004/001965 2003-06-20 2004-06-15 Oxazole derivatives as antibacterial agents WO2004113329A1 (en)

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