WO2005003087A2 - Composes nouveaux utiles comme agents anti-bacteriens - Google Patents

Composes nouveaux utiles comme agents anti-bacteriens Download PDF

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Publication number
WO2005003087A2
WO2005003087A2 PCT/IB2004/002131 IB2004002131W WO2005003087A2 WO 2005003087 A2 WO2005003087 A2 WO 2005003087A2 IB 2004002131 W IB2004002131 W IB 2004002131W WO 2005003087 A2 WO2005003087 A2 WO 2005003087A2
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Prior art keywords
pyridin
formula
piperazin
oxooxazolidin
ylmethyl
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PCT/IB2004/002131
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English (en)
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WO2005003087A3 (fr
Inventor
Satya Surya Visweswara Srinivas Akella
Kasinathanan Mathiyazhagan
Matte Mariana Samuel
Shakti Singh Solanki
Vijayan Magesh
Shiv Kumar Agarwal
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Orchid Chemicals And Pharmaceuticals Ltd.
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Publication of WO2005003087A2 publication Critical patent/WO2005003087A2/fr
Publication of WO2005003087A3 publication Critical patent/WO2005003087A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention provides novel compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them.
  • the present invention more particularly provides novel oxazolidinone derivatives of the general formula (I).
  • the present invention also provides a process for the preparation of the above said novel oxazolidinone derivatives of the formula (I) their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them.
  • the novel oxazolidinone derivatives of the present invention are useful as antibacterial agents and hence 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.
  • 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
  • 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 ) h -aryl, -COR 1"1 , COOR 1"2 , -CO-CCH ⁇ h -COR 1"1 , (C r C 6 )alkylsulforiyl, -SO 2 -(CH 2 ) h -aryl or - (CO)j-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, (CrC 12 )alkyl optionally substituted with one or more halo, (C 3 -C 12 )cycloalkyl, ( - C 6 )alkoxy;
  • R 1 is a radical of the formula D-R 2 , -CO-R 3 or -CO-NR 4 R 5 , wherein D is the CO 2 or SO 2 group, R 2 is phenyl or linear or branched alkyl • having up to 7 carbon atoms, R 3 is trifluoromethyl or linear or branched alkyl having up to 6 carbon atoms which is substituted by halogen or trifluoromethyl, and R 4 and R 5 are identical or different and are hydrogen, phenyl or linear or branched alkyl having up to 5 carbon atoms;
  • A is a 6- membered aromatic heterocycle having at least one nitrogen atom and directly bonded via a carbon atom, or a 6-membered bicyclic or tricyclic aromatic radical having at least one nitrogen-containing ring and directly bonded via a carbon atom, or ⁇ -carbolin-3-yl or indolizinyl directly bonded via the 6- membered ring, or a 5-membered aromatic heterocycle having
  • novel oxazolidinone derivatives of the formula (I) may be useful as antibacterial agents and hence are useful in the treatment of conditions such as nosocomial pneumoniae, community acquired pneumoniae, vancomycin resistance enterococci (NRE) caused by methicillin resistance staphylococcus aureus (MRSA) and penicillin resistance streptococcus pneumoniae.
  • the compounds of the present invention are effective against a number of human or animal pathogens, clinical isolates, including Nancomycin resistant organisms, methicillin resistant organisms
  • the present invention relates to novel oxazolidinone derivatives of the formula (I)
  • R 1 represents halogen, azido, nitro, cyano, substituted or unsubstituted group selected from TR 7 , wherein T represents O or S;
  • R 7 represents hydrogen, formyl, substituted or unsubstituted groups selected from (CrC 6 )alkyl, cycloalkyl, aryl, aralkyl, acyl, thioacyl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; or R 1 represents N(R 8a R 8b ) where R 8a and R 8b may be same or different and independently represent hydrogen, formyl, substituted or unsubstituted groups selected from (C C 6 )alkyl, aryl, aralkyl,
  • 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; (CrC 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 1 -C 6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; haloalkyl such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like; (C 1 -C 6 )alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; ( - C 6 )alkylthio group such as methylthio, ethylthio, n-propylthio, iso-propylthio and the like; (C 3
  • Suitable groups represented by R 7 are selected from hydrogen, formyl, substituted or unsubstituted linear or branched (C 1 -C 6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; (C 3 -C 6 )cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, which may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl group such as phenylmethyl, phenylethyl, naphthylmethyl, naphthylethyl and the like, the aralkyl group may be substituted; acyl group such as
  • Suitable groups represented by R 8a and R 8 are selected from hydrogen, formyl, substituted or unsubstituted linear or branched (C 1 -C 6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; aryl group such as phenyl, naphthyl and the like, which may be substituted; aralkyl group such as phenylmethyl, phenylethyl, naphthylmethyl, naphthylethyl and the like, which may be substituted; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl
  • Suitable ring systems formed by R 8a and R 8 together are selected from pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, thiazinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like.
  • Suitable groups represented by R 9 are selected from substituted or unsubstituted linear or branched (C 1 -C 10 )alkyl group such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; (C 1 -C 1 o)alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, butoxy and the like, which may be substituted; aryl group such as phenyl, naphthyl and the like, which may be substituted; (C 3 -C 6 )cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, which may be substituted; heteroaryl group such as thienyl, pyridyl,
  • Suitable groups represented by R 10 and R are selected from hydrogen, substituted or unsubstituted linear or branched (C 1 -C 10 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; aryl group such as phenyl, naphthyl and the like, which may be substituted; (C 3 -C 6 )cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, which may be substituted; alkylcarbonyl group such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl and the like, which may be substituted; arylcarbonyl group such as pheny
  • Suitable groups represented by R 6 are selected from aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl group such as phenylmethyl, phenylethyl, naphthylmethyl, naphthylethyl and the like, the aralkyl group may be substituted; (C 3 -C 6 )cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; heteroaryl group such as thienyl, pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidin
  • the substituents on R 6 are selected from halogen, hydroxy, formyl, nitro, cyano, azido, amino, alkyl, alkylamino, alkylaminocarbonyl, haloalkyl, alkylthio, acylamino, alkoxy, acyl, carboxylic acid or its derivatives such as esters or amides, aryl, heteroaryl, heterocyclyl, substituted aryl, wherein the substituent is selected from nitro, halogen, cyano, hydroxy, amino, alkyl, alkoxy, acyl, and the like; and these substituents are as defined above.
  • Suitable n is an integer of 0 or 1.
  • Suitable n is an integer in the range of 1 to 4, preferably n represents 1 or 2.
  • the substituents on any of the groups represented by R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 8b , R 9 R 10 , R 11 are selected from halogen, hydroxy, formyl, nitro, cyano, azido, amino, alkyl, aryl, alkylamino, alkylaminocarbonyl, haloalkyl, alkylthio, acylamino, alkoxy, acyl, cycloalkylcarbonyl, heteroarylcarbonyl, carboxylic acid or its derivatives such as esters or amides and these substituents are as defined above.
  • salts of the present invention include alkali metal like Li, Na, and K, alkaline earth metal like Ca and Mg, salts of organic bases such as diethanolamine, ⁇ -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, 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 (N)
  • R6— (C( Y))p-L (IX) wherein L is a leaving group and all other symbols are as defined earlier to produce a compound of formula (I).
  • the compound of formula (III) may be converted to a compound of formula (IN) using methane sulfonyl chloride, tosyl chloride, trifluoromethane sulfonyl chloride.
  • the reaction may be carried out in the presence of solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene and the like or a mixture thereof and a base selected from dimethylamino pyridine, triethylamine, pyridine and the like.
  • the reaction may be carried out at a temperature in the range of -10 °C to room temperature.
  • the duration of the reaction may range from 1 to 12 hrs.
  • the conversion of compound of formula (IN) may be carried out in the presence of one or more equivalents of metal azide such as Li ⁇ 3 , NaN 3 or trialkyl silylazide.
  • the reaction may be carried out in the presence of solvent such as THF, acetone, DMF, DMSO and the like or mixtures thereof.
  • the reaction may be carried out in inert atmosphere, which may be maintained using N 2 or Ar.
  • the reaction may be carried out at a temperature in the range of ambient temperature to reflux temperature of the solvent, preferably at a temperature in the range of 60 °C to 120 °C.
  • the reaction time may range
  • 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 solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out in the presence of base selected from dimethylamino pyridine, triethylamine, pyridine and the like.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature.
  • the duration of the reaction may range from 2 to 24 hrs.
  • the deprotection of compound of formula (Nil) may be carried out using strong acids such as trifluoroacetic acid, hydrochloric acid, sulfuric 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 1 to 6 hrs.
  • 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, 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.
  • a process for the preparation of novel oxazolidinone derivatives of the formula (I) where R 1 represents ⁇ HC( Z)R 9 , wherein Z is S; R 9 represents alkoxy or amino and all other symbols are as defined earlier, which comprises i) converting the compound of formula (VI)
  • the conversion of compound of formula (VI) to produce compound of formula (X) may be carried out using thiophosgene gas in the presence of solvent such as tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out in the presence of a base selected from dimethylamino pyridine, triethylamine, pyridine and the like.
  • the reaction may be carried out at a temperature in the range of -10 °C to room temperature.
  • the conversion of compound of formula (X) to compound of formula (Nil) may be carried out using solvents such as THF, DCM, alcohol such as methanol, ethanol, propanol and the like.
  • the reaction may be carried out in the presence of a base selected from dimethylamino pyridine, triethylamine, pyridine and the like.
  • the reaction may be carried out at a temperature in the range of 30 °C to reflux temperature.
  • the duration of the reaction may range
  • the deprotection of compound of formula (Nil) may be carried out using strong acids such as trifluoroacetic acid, hydrochloric acid, sulfuric 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 1 to 6 hrs.
  • 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, triacetoxy sodium borohydride, sodium cyano borohydride, lithium aluminium hydride.
  • the reaction may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, benzene, xylene, THF, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at room temperature. The duration of the reaction may range from 12 to 24 hrs.
  • reaction temperature may range from 0 °C to room temperature.
  • duration of the reaction may range from 2 to 6 hrs.
  • R 1 represents N(R 8a R 8b ) where R 8a and R 8b represent hydrogen, with R'SO 2 Cl where R' represents (CrC 4 )alkyl, aralkyl or heteroaralkyl group.
  • the reaction of compounds of formula (XII) may be carried out by heating in the presence of base selected from pyridine, friethylamine 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.
  • a process for the preparation of novel oxazolidinone derivatives of the formula (I) where R 1 represents the formula - NHC( Z)R 9 where Y is S,
  • acylation of compound of formula (XIII) may be carried out using acylating agents such as thioacetic acid.
  • the reaction may be carried out in the presence of appropriate solvents like tefrahydrofuran, 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 20 °C to 120 °C.
  • the duration of the reaction may range from 1 to 12 hrs.
  • reaction of compound of formula (Ilia) with compound of formula (Hlb) may be carried out in the presence of BINAP [(R)-2,2' ⁇ Bis(diphenylphosphino)-l,r-binaphthyl] and tris(dibenzylidene acetone)dipalladium(o).
  • BINAP (R)-2,2' ⁇ Bis(diphenylphosphino)-l,r-binaphthyl] and tris(dibenzylidene acetone)dipalladium(o).
  • the reaction may be carried out using inert gases such as N 2 , argon and the like.
  • the reaction may be carried out in the presence of solvents such as toluene, DCC, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • solvents such as toluene, DCC, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction is carried out at temperature in the range of 20 to 60 °C.
  • the reduction of compound of formula (IIIc) 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 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.
  • the conversion of compound of formula (Hid) to compound of formula (Ille) may be carried out using benzyloxycarbonyl chloride and sodium bicarbonate, in the presence of solvents such as acetone, DMF, water, THF and the like or mixtures thereof.
  • solvents such as acetone, DMF, water, THF and the like or mixtures thereof.
  • the reaction temperature may range from -20 °C to room temperature.
  • the duration of the reaction may range from 3 to 18 hrs.
  • the cyclization of compound of formula (Ille) may be carried out in the presence of base such as n-butyl lithium, LDA, potassium bis(trimethylsilyl)amide, lithium-bis(trimethylsilyl)amide and the like.
  • the reaction may be carried out in the presence of solvent such as THF, DMF and the like.
  • the reaction is carried out using chiral ester such as R-(-)-glycidyl butyrate.
  • the reaction is carried out at a temperature in the range of -80 °C to -50 °C.
  • the duration of the reaction may range from 2 to 12 hrs. 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.
  • a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like
  • solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used.
  • Organic bases such as diethanolamine, ⁇ - phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, 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.
  • 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.
  • 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.
  • 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
  • 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.
  • drugs selected from other clinically useful antibacterial agents such as ⁇ -lactams or aminoglycosides.
  • drugs selected from other clinically useful antibacterial agents such as ⁇ -lactams or aminoglycosides.
  • penicillins such as oxacillin or flucloxacillin
  • 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
  • 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.
  • Benzylchloroformate (85.8 g, 0.503597 moles) was added to the reaction mixture at 0 °C dropwise. After complete addition, the reaction mixture was kept at room temperature for 12 hours. Acetone was removed from the reaction mixture and diluted further with ethylacetate (2L). Washed the ethylacetate layer with water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness. The crude compound was crystallized using ethylacetate and hexane to yield the title compound (67.4 g, yield 65 %).
  • the compounds of invention showed in vitro antibacterial activity when tested by the Agar Dilution Method as specified in documents published by the National Committee for Clinical Laboratory Standards (NCCLS), USA. Briefly, the compounds of invention were weighed, dissolved in Dimethyl Sulfoxide, serially diluted in the same solvent and then incorporated into molten Mueller Hinton Agar in a petridish before solidification, with each petridish containing a different concentration of a compound.
  • the Bacterial Inoculum was prepared by touching the tops of 3 to 5 well isolated bacterial colonies with the same morphological appearance from an 18 hour old culture with an inoculating loop, transferring the growth to a tube containing 5ml of normal saline and adjusting the turbidity of the saline suspension to 0.5 Macfarland Turbidity Standard equivalent to a bacterial population of 1.5 x 10 8 colony forming units (CFU) per milliliter of suspension.
  • the bacterial inoculum prepared in the above manner was inoculated onto petri dishes containing Mueller Hinton Agar which had earlier been incorporated with different dilutions of the compounds of invention by a
  • Multipoint Inoculator with each inoculum spot containing approximately 1 x 10 4 colony forming units (CFU) of bacteria.
  • CFU colony forming units
  • Nancomycin and Oxacillin and inoculated with Staphylococcus aureus are Nancomycin and Oxacillin and inoculated with Staphylococcus aureus

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne des composés nouveaux de formule générale (I), leurs dérivés, leurs analogues, leurs formes tautomères, leurs stéréoisomères, leurs polymorphes, leurs hydrates, leurs solvates, leurs sels pharmaceutiquement acceptables et des compositions pharmaceutiquement acceptables qui les contiennent. L'invention concerne notamment des dérivés nouveaux d'oxazolidinone de formule générale (I).
PCT/IB2004/002131 2003-07-01 2004-06-28 Composes nouveaux utiles comme agents anti-bacteriens WO2005003087A2 (fr)

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US6969726B2 (en) * 2003-06-03 2005-11-29 Rib X Pharmaceuticals Inc Biaryl heterocyclic compounds and methods of making and using the same
WO2006034440A3 (fr) * 2004-09-20 2006-08-10 Xenon Pharmaceuticals Inc Derives heterocycliques et leur utilisation en tant qu'agents therapeutiques
US7129259B2 (en) 2003-12-17 2006-10-31 Rib-X Pharmaceuticals, Inc. Halogenated biaryl heterocyclic compounds and methods of making and using the same
WO2006130986A1 (fr) * 2005-06-09 2006-12-14 Merck Frosst Canada Ltd. Derives d'azacyclohexane comme inhibiteurs de la stearoyl-coenzyme a delta-9 desaturase
WO2008029266A1 (fr) * 2006-09-08 2008-03-13 Glenmark Pharmaceuticals S.A. Inhibiteurs de la stéaroyl coa désaturase
WO2009084614A1 (fr) * 2007-12-27 2009-07-09 Daiichi Sankyo Company, Limited Composé carbonyle d'imidazole
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
US7919496B2 (en) 2004-09-20 2011-04-05 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
US8026360B2 (en) 2004-09-20 2011-09-27 Xenon Pharmaceuticals Inc. Substituted pyridazines as stearoyl-CoA desaturase inhibitors
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US8324398B2 (en) 2003-06-03 2012-12-04 Rib-X Pharmaceuticals, Inc. Process for the synthesis of biaryl oxazolidinones
US8399660B2 (en) 2005-06-08 2013-03-19 Rib-X Pharmaceuticals, Inc. Process for the synthesis of triazoles
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
US8841306B2 (en) 2008-11-20 2014-09-23 Panacea Biotec Ltd. Antimicrobials
US8906913B2 (en) 2009-06-26 2014-12-09 Panacea Biotec Limited Azabicyclohexanes
WO2018170664A1 (fr) * 2017-03-20 2018-09-27 Merck Sharp & Dohme Corp. Composés d'oxazolidinone et leurs procédés d'utilisation en tant qu'agents antibactériens

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WO2002006278A1 (fr) * 2000-07-17 2002-01-24 Ranbaxy Laboratories Limited Derives d'oxazolidinone utilises en tant qu'antimicrobiens
WO2004009587A1 (fr) * 2002-07-22 2004-01-29 Orchid Chemicals & Pharmaceuticals Ltd Derives de l'oxazolidinone, agents antibacteriens

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WO2000021960A1 (fr) * 1998-10-09 2000-04-20 Astrazeneca Ab Heterocyclyl amino methyloxa zolidinones comme agents antibacteriens
WO2002006278A1 (fr) * 2000-07-17 2002-01-24 Ranbaxy Laboratories Limited Derives d'oxazolidinone utilises en tant qu'antimicrobiens
WO2004009587A1 (fr) * 2002-07-22 2004-01-29 Orchid Chemicals & Pharmaceuticals Ltd Derives de l'oxazolidinone, agents antibacteriens

Cited By (30)

* Cited by examiner, † Cited by third party
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US7705026B2 (en) 2003-06-03 2010-04-27 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US8324398B2 (en) 2003-06-03 2012-12-04 Rib-X Pharmaceuticals, Inc. Process for the synthesis of biaryl oxazolidinones
US6969726B2 (en) * 2003-06-03 2005-11-29 Rib X Pharmaceuticals Inc Biaryl heterocyclic compounds and methods of making and using the same
US7148219B2 (en) 2003-06-03 2006-12-12 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US9550783B2 (en) 2003-06-03 2017-01-24 Melinta Therapeutics, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US8895741B2 (en) 2003-06-03 2014-11-25 Melinta Therapeutics, Inc. Process for the synthesis of biaryl oxazolidinones
US7456206B2 (en) 2003-06-03 2008-11-25 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US7129259B2 (en) 2003-12-17 2006-10-31 Rib-X Pharmaceuticals, Inc. Halogenated biaryl heterocyclic compounds and methods of making and using the same
WO2006034440A3 (fr) * 2004-09-20 2006-08-10 Xenon Pharmaceuticals Inc Derives heterocycliques et leur utilisation en tant qu'agents therapeutiques
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
EP2266569A2 (fr) 2004-09-20 2010-12-29 Xenon Pharmaceuticals Inc. Dérivés hétérocycliques et leur utilisation en tant qu'inhibiteurs de la stearoyl-coa desaturase
EP2266569A3 (fr) * 2004-09-20 2011-03-09 Xenon Pharmaceuticals Inc. Dérivés hétérocycliques et leur utilisation en tant qu'inhibiteurs de la stearoyl-coa desaturase
US7919496B2 (en) 2004-09-20 2011-04-05 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
US8026360B2 (en) 2004-09-20 2011-09-27 Xenon Pharmaceuticals Inc. Substituted pyridazines as stearoyl-CoA desaturase inhibitors
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7767677B2 (en) 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
US8796465B2 (en) 2005-06-08 2014-08-05 Melinta Therapeutics, Inc. Process for the syntheses of triazoles
US8399660B2 (en) 2005-06-08 2013-03-19 Rib-X Pharmaceuticals, Inc. Process for the synthesis of triazoles
US9376400B2 (en) 2005-06-08 2016-06-28 Melinta Therapeutics, Inc. Process for the synthesis of triazoles
WO2006130986A1 (fr) * 2005-06-09 2006-12-14 Merck Frosst Canada Ltd. Derives d'azacyclohexane comme inhibiteurs de la stearoyl-coenzyme a delta-9 desaturase
WO2008029266A1 (fr) * 2006-09-08 2008-03-13 Glenmark Pharmaceuticals S.A. Inhibiteurs de la stéaroyl coa désaturase
WO2009084614A1 (fr) * 2007-12-27 2009-07-09 Daiichi Sankyo Company, Limited Composé carbonyle d'imidazole
JP2014196369A (ja) * 2007-12-27 2014-10-16 第一三共株式会社 イミダゾールカルボニル化合物
US8841306B2 (en) 2008-11-20 2014-09-23 Panacea Biotec Ltd. Antimicrobials
US8906913B2 (en) 2009-06-26 2014-12-09 Panacea Biotec Limited Azabicyclohexanes
WO2018170664A1 (fr) * 2017-03-20 2018-09-27 Merck Sharp & Dohme Corp. Composés d'oxazolidinone et leurs procédés d'utilisation en tant qu'agents antibactériens
US10752621B2 (en) 2017-03-20 2020-08-25 Merck Sharp & Dohme Corp. Oxazolidinone compounds and methods of use thereof as antibacterial agents

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