WO2005003087A2 - Oxazole derivatives as antibacterial agents - Google Patents
Oxazole derivatives as antibacterial agents Download PDFInfo
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- 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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- pyridin
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- piperazin
- oxooxazolidin
- ylmethyl
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- 0 CCC(C)=C[*@@](C)C=C(C)[C@]1C(C)CCC1 Chemical compound CCC(C)=C[*@@](C)C=C(C)[C@]1C(C)CCC1 0.000 description 7
Classifications
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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
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- 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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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
NEW COMPOUNDS 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).
Objective of the Invention We have focused our research to identify novel oxazolidinone derivatives, which are effective against resistant organisms. Our sustained efforts have resulted in novel oxazolidinone derivatives of the formula (I). The novel oxazolidinone derivatives of the present invention may be useful as antibacterial agents and hence are useful in the treatment of conditions such as nosocomial pneumoniae, community acquired pneumoniae, vancomycin resistance enterococci (NRE) caused by methicillin resistance staphylococcus aureus (MRSA) and penicillin resistance streptococcus pneumoniae. The compounds of the present invention are effective against a number of human or animal pathogens, clinical isolates, including Nancomycin resistant organisms, methicillin resistant organisms
Summary of the Invention The present invention relates to novel oxazolidinone derivatives of the formula (I)
Representative compounds according to the present invention include:
(S)-N-[3-[2-[4-(N-5-Nifrofuran-2-ylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(^-N-[3-[2-[4-(N-5-Nitrofuran-2-ylthiocarbonyl)piperazin-l-yl]pyridin-5-yl]-
2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-5-Nitrofuran-2-ylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[2-[4-(N-5-Nitrofuran-2-ylthiocarbonyl)piperazin- 1 -yl]pyridϊn-5-yl]-
2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(<S)-N-[3-[2-[4-(N-furan-2-ylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-furan-2-ylthiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N- [3 - [2- [4-(N-furan-2-ylcarbonyl)piperazin- 1 -yl]pyridin-5 -yl] -2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(N-furan-2-ylthiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[2-[4-(N-5-Nitropyrazol-2-ylthiocarbonyl)piperazin-l-yl]pyridin-5- yl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[2-[4-(N-5-Nitropyrazol-2-ylthiocarbonyl)piperazin- 1 -yl]pyridin-5- yl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(N-5-Nitropyrazol-2-ylthiocarbonyl)piperazin-l-yl]pyridin-5- yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-5-Nitropyrazol-2-ylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-pyrazine-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(N-pyrazine-2-yl-thiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[2-[4-(N-pyrazine-2-yl-carbonyl)piperazin- 1 -yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-pyrazine-2-yl-thiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-5-methylpyrazin-2-yl-carbonyl)piperazin-l-yl]pyridin-5- yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(5)-N-[3-[2-[4-(N-5-methylpyrazin-2-yl-thiocarbonyl)piperazin-l-yl]pyridin-
5-yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N- [3 - [2- [4-(N-pyrazine-2-yl-carbonyl)piperazin- 1 -yl]pyridin-5 -yl] -2- oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[2-[4-(N-pyrazine-2-yl-thiocarbonyl)piperazin- 1 -yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[2-[4-(N-l-methylpyrrolyl-2-yl-carbonyl)piperazin-l-yl]pyridin-5- yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-pyrrolyl-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-thien-2-yl-thiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ; (S)-N-[3-[2-[4-(N-furan-2-yl-propenoyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(N-fiιran-2-yl-propenoyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl] thiocarbamate ;
(ι-^-N-[3-[2-[4-(N-5-fluoroindol-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(N-piperid--rι-l-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(4-(4-acetylρhenyl- 1 -yl)piperazin- 1 -yl-carbonyl)piperazin- 1 - yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ; (S)-N- [3 - [2- [4-(4-(piperidin- 1 -yl)piperidin- 1 -yl-carbonyl)piperazin- 1 - yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(4-(4-nitrophenyl-l-yl)furan-2-yl-carbonyl)piperazin-l- yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(cyclopropylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(cyclopropylthiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N- [3 - [2- [4-(cyclopropylcarbonyl)piperazin- 1 -yl]pyridin-5 -yl] -2- oxooxazolidin-5-ylmethyl]acetamide ; N' -methyl thiourea ;
(S)-N- [3 - [2- [4-(cyclopropylcarbonyl)piperazin- 1 -yl]pyridin-5-yl] -2- oxooxazolidin-5-ylmethyl]-N'-methyl thiourea ;
(S)-N-[3-[2-[4-(cyclopropylthiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(cyclopropylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[2-[4-(cyclopropylthiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[2-[4-(N-pyrrolidin-2-yl-carbonyl)piperazin- 1 -yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(N-pyrrolidin-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ; (S)-N-[3-[2-[4-(N-thiazolidin-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate and
(^-N-[3-[2-[4-(N-quinoxalin-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate.
(5)-N-[3-[2-[4-(N-5-nitrofuran-2-ylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5 -ylmethyl]-(N ' -4-cyanophenyl)thiourea ; (S)-N-[3-[2-[4-(N-Cyclopropyl-2-ylcarbonyl)piperazin- 1 -yl]pyridin-5-yl]-2- oxooxazolidin-5 -ylmethyl] -(N ' -methyl-N' -cy clopropanecarboxamide) thiourea ;
(S)-N-[3-[2-[4-(4-(pyridin-2-yl)piperazin- 1 -yl-carbonyl)piperazin- 1 - yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[2-[4-(4-(pyridin-2-yl)piperazin-l-yl-thiocarbonyl)piperazin-l- yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[2-[4-(4-(pyridin-2-yl)piperazin- 1 -yl-carbonyl)piperazin- 1 - yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(4-(pyridin-2-yl)piperazin- 1 -yl-thiocarbonyl)piperazin- 1 - yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-imidazol-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(5 -N-[3-[2-[4-(N-imidazol-2-yl-thiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[2-[4-(N-irnidazol-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate and
(S)-N-[3-[2-[4-(N-imidazol-2-yl-thiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
According to another embodiment of the present invention, there is provided a process for the preparation of novel oxazolidinone derivatives of the formula (I) where R1 represents NHC(=Z)R9, wherein R9 is as defined earlier, n is 1 and all other symbols are as defined earlier, which comprises (i) converting the compound of formula (III)
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 LiΝ3, NaN3 or trialkyl silylazide. The reaction may be carried out in the presence of solvent such as THF, acetone, DMF, DMSO and the like or mixtures thereof. The reaction may be carried out in inert atmosphere, which may be maintained using N2 or Ar. The reaction may be carried out at a temperature in the range of ambient temperature to reflux temperature of the solvent, preferably at a temperature in the range of 60 °C to 120 °C. The reaction time may range
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 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. 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 ΝHC(=Z)R9, wherein Z is S; R9 represents alkoxy or amino and all other symbols are as defined earlier, which comprises i) converting the compound of formula (VI)
R6-(C(=Y))p-L (IX) wherein all symbols are as defined earlier and L is a leaving group to produce a compound of formula (I), where R1 represents - ΝHC(=Z)R9. The conversion of compound of formula (VI) to produce compound of formula (X) may be carried out using thiophosgene gas in the presence of solvent such as tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof. The reaction may be carried out in the presence of a base selected from dimethylamino pyridine, triethylamine, pyridine and the like. The reaction may be carried out at a temperature in the range of -10 °C to room temperature.
The conversion of compound of formula (X) to compound of formula (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. In yet another embodiment of the present invention, there is provided a process for the preparation of compounds of formula (I) where R1 represents TR7, Ν(R8aR8b), wherein R7, R8a and R8 are as defined earlier which comprises reacting the compound of formula (XI)
where L1 represents a leaving group such as mesylate, tosylate or trifiate with
R7YH or NH(R8aR8b) where all symbols are as defined earlier. The conversion of compounds of formula (XI) to a compound of formula (I) may be carried out by heating in the presence of base selected from
NaH, KH, t-BuOK and the like and solvents such as DMF, THF, DCM, DMA and the like. The reaction temperature may range from 0 °C to room temperature. The duration of the reaction may range from 2 to 6 hrs. In yet another embodiment of the present invention, there is provided a process for the preparation of compounds of formula (I) wherein R1 represents -NHS(O)r(C C4)alkyl, -NHS(O)raralkyl or -NHS(O)rheteroaralkyl group, which comprises reacting the compound of formula (XII)
R9 and all other symbols are as defined above, which comprises reacting the compound of formula (XIII)
In another embodiment of the present invention, there is provided a process for the conversion of compounds of formula (I) where R1 represents the formula - NHC(=Z)R9; where Z is O, R9 and all other symbols are as defined above to compounds of formula (I) where R1 represents the formula - NHC(=Z)R9; where Z is S, R9 and all other symbols are as defined earlier. The conversion may be carried out using Lawesson's reagent in the presence of base such as triethyl amine, pyridine and the like and solvents such as toluene, DCC, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof. The reaction may be
carried out at a temperature in the range of 20 °C to 120 °C. The duration of the reaction may range from 1 to 12 hrs.
According to another embodiment of the present invention, there is provided a process for the preparation of compounds of formula (III)
The pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases such as diethanolamine, α- phenylethylamine, benzylamine, piperidine, morpholine, pyridine, 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. Alternatively, acid addition salts wherever applicable are prepared by the treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran, dioxane etc. Mixture of solvents may also be used. The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like. Commonly used methods are compiled by laques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). More specifically the compound of formula (I) may be converted to a 1:1 mixture of diastereomeric amides by treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula (I) may be prepared by hydrolysing the pure diastereomeric amide.
Various polymorphs of compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques. Pharmaceutically acceptable solvates of the compounds of formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of formula (I) in solvents such as water, methanol, ethanol, mixture of solvents such as acetone: water, dioxane:water, N,N-dimethylformamide: water and the like, preferably water and recrystallizing by using different crystallization techniques. The compounds of the present invention are useful for the treatment of microbial infections in humans and other warm blooded animals, under both parenteral and oral administration. In addition to the compounds of formula (I) the pharmaceutical compositions of the present invention may also contain or be co-administered with one or more known drugs selected from other clinically useful antibacterial agents such as β-lactams or aminoglycosides. These may include penicillins such as oxacillin or flucloxacillin and carbapenems such as meropenem or imipenem to broaden the therapeutic effectiveness against, for example, methicillin-resistant staphylococci. Compounds of the formula (I) of the present invention may also contain or be co-administered with bactericidal/permeability-increasing-g protein product
(BPI) or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents. The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavoring agents, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Such compositions typically contain from 1 to 20 %, preferably 1 to 10 % by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents. The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.
Preparation 1
Synthesis of (S)-N-3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5- yl]-2-oxooxazolidin-5-ylmethyl amine
Step (i)
Preparation of 2-(piperazine-N-t-butoxycarbonyl)-5-nitro pyridine t-Boc-N 2 N — ' H=J BINAP [(R)-2,2'-Bis(diphenylphosphino)-l,r-binaphthyl] (2.5 g, 0.00394088 moles) and tris(dibenzylidene acetone)dipalladium(o) (7.2 g, 0.00788177 moles) were taken in dry toluene (400 ml) and stirred under argon atmosphere at room temperature for 15 minutes. 2-Bromo-5-nitro-pyridine (40 g, 0.197044 moles) was dissolved in toluene (200 ml) and added to the reaction mixture followed by N-t-butoxycarbonyl piperazine (44 g, 0.23645 moles). To this cesium carbonate (90 g, 0.275862 moles) was added at room temperature
under argon atmosphere. The reaction mixture was cooled to RT and filtered through celite. Washed the residue thoroughly with ethylacetate. The combined filtrates were washed with water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness and purified over silica gel column using dichloroformate and methanol as eluent to yield the ( title compound (42.4 g, yield 70%).
Step (ii)
Preparation of 2-(piperazine-N-t-butoxycarbonyl)-5-amino pyridine / \ t-Boc-N N- -NH, N^
2-(Piperazine-N-t-butoxycarbonyl)-5-nitro pyridine (82 g, 0.266233 moles) was dissolved in 1:1 mixture of methanol and ethylacetate (1L). This solution was cooled to -5° to -10 °C. To this, 8.2 g of 10% palladium carbon was added and hydrogenated the reaction mixture at 45 °C, 60 psi for 3 hours. Filtered the reaction mixture through celite and washed the residue thoroughly with methanol. Concentrated the filtrate to dryness and dried under high vacuum to give the title compound (74 g).
Step (iii) Preparation of 2-(piperazine-N-t-butoxycarbonyl)-5-(benzyIoxycarbonyI) aminopyridine t-Boc-N N→ V-NHCBz N — f N^
To a solution of 2-(piperazine-N-t-butoxycarbonyl)-5-amino pyridine (70 g,
0.251798 moles) dissolved in acetone (700 ml), sodium bicarbonate (42.3 g, 0.503597 moles) dissolved in water (350 ml), was added and cooled to 0 °C.
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 %).
Step (iv) Preparation of (<S)-N-3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yI]pyridin- 5-yl]-2-oxooxazoIidin-5-yImethanol
A solution of 2-(piperazine-N-t-butoxycarbonyl)-5-(benzyloxycarbonyl) aminopyridine (30 g, 0.0728155 moles) dissolved in dry tetrahydrofuran (600 ml) was cooled to -78 °C. To this n-butyl lithium (23.3 g, 0.3640776 moles, 15% solution in hexane) was added at -78 °C dropwise with out raising the temperature. After complete addition, continued the stirring at —78 °C for 1 hour. Then, (R)-glycidylbutyrate (15.73 g, 0.1092232 moles) was added to the reaction mixture at -78 °C and kept the reaction mixture at -78 °C -> 0 °C -^ RT for 16 hours. Quenched the RM by adding ammonium chloride solution followed by water. The RM was extracted with ethyl acetate (3 x 500 ml), dried over anhydrous sodium sulphate and concentrated to dryness and purified over silica gel, using DCM and methanol as eluent. The pure compound was eluted in 1 to 2% methanol / DCM, to obtained the title compound (16.5 g, yield 60%).
Step (v)
Preparation of (S)-N-[3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-
5-yl] -2-oxooxazolidin-5-ylmethyI] mesylate
Step (vi)
Preparation of (S)-N-[3-[2-[4-(N-t-butoxycarbonyI)piperazin-l-yI]pyridin- 5-y 1] -2-oxooxazoIidin-5-yImethy I] azide
To a solution of (S)-N-[3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5- yl]-2-oxooxazolidin-5-ylmethyl]mesylate (25 g, 0.0548245 moles) dissolved in DMF (300 ml), sodium azide (14.25 g, 0.21929 moles) was added. The reaction mixture was heated at 85-90 °C for 4 hours. Cooled the reaction mixture to RT and water (200 ml) was added and extracted the reaction mixture with ethyl acetate (3 x 300 ml). The ethyl acetate layer was washed with water and brine solution. Dried over anhydrous sodium sulphate and
concentrated the solution and dried the mass under high vacuum to give the title compound (22 g, yield 100 %).
Step (vi!) Synthesis of (S)-N-[3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5- yl] -2-oxooxazolidin~5-ylmethy 1] amine
(S)-N-[3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]azide (17 g, 0.04218 moles) was taken in methanol (200 ml) and 10% palladium-carbon (1.7 g) was added under N2 atmosphere. Hydrogenated the reaction mixture using par hydrogenation apparatus at 40 °C under 80 psi pressure for 6 hours. Filtered the RM through celite and washed the residue thoroughly with methanol. The filtrate was concentrated to dryness and washed with hexane. Dried the compound under high vacuum to give the title compound (11 g, yield 70%).
Preparation 2
Synthesis of (S)-N-[3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5- yl] -2-oxooxazolidin-5-ylmethyl] acetamide
(S)-N-[3-[2-[4-(N-t-Butoxycarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]amine (5.8 g, 0.0153846 moles) was dissolved in dry DCM (50 ml) and cooled to 0 °C. To this solution pyridine (1.82 g,
0.0230769 moles) and acetic anhydride (6.27 g, 0.06153846 moles) was added at 0 °C. Allowed the RM to stir at RT for 4 hours and poured the RM over ice and extracted with DCM (3 x 100 ml). Washed the organic layer with sodium bicarbonate, water and brine solution. Dried over anhydrous sodium sulphate, and concentrated to dryness. Purified the crude material on silica gel using DCM and CH3OH as eluent to yield the title compound (4.6 g, yield 72%).
Preparation 3
Synthesis of (S)-N-[3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yI]pyridin-5- yI]-2-oxooxazoIidin-5-ylmethyI]isothiocyanate
(S)-N-[3-[2-[4-(N-t-Butoxycarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]amine (8 g, 0.02122 moles) was dissolved in dry DCM (40 ml) and cooled to 0 °C. Triethyl amine (7.5 g, 0.074271 moles ) was added to the RM at 0 °C. Thiophosgene (2.9 g, 0.0254641 moles) was added to the RM at 0 °C. Stirred the RM at room temperature for 3 hours. Removed the solvent from the reaction mixture over Buchi rotary evaporator and dissolved the mass in ethyl acetate (500 ml). Washed the ethyl acetate layer with sodium bicarbonate, water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness. Dried the compound under high vacuum, to give the title compound (8 g, yield 90%).
Preparation 4
Synthesis of (5 -N-[3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5- yl]-2-oxooxazolidin-5-yImethyl]thiocarbamate
A solution of (S)-N-[3-[2-[4-(TSr-t-butoxycarbonyl)piperazin-l-yl]pyridin-5- yl]-2-oxooxazolidin-5-ylmethyl]isothiocyanate (8 g, 0.019093 moles) dissolved in methanol (80 ml) was heated to reflux temperature for 6 hours. After completion of the reaction, the solvent was removed and purified the RM over silica gel column using hexane and ethylacetate mixture as eluent to yield the title compound (5.2 g, yield 60%).
Preparation 5 Synthesis of (S)-N-[3-[2-[4-(N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5- yl]-2-oxooxazolidin-5-ylmethyl]-N'-methyl thiourea
(S)-N-[3-[2-[4-(N-t-Butoxycarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]isothiocyanate (5 g, 0.011933 moles) was dissolved in dry THF (50 ml). To this solution triethylamine (0.6 g, 0.005966 moles) and methyl amine hydrochloride (1.2 g, 0.017899 moles) were added at room temperature and heated the reaction mixture to reflux temperature for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethylacetate. Washed the ethyl acetate layer with water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness. Purified the crude material over silica gel using hexane and ethylacetate mixture as eluent to yield the title compound (3.6 g, yield 68%).
Preparation 6
Synthesis of (S)-N-[3-[2-(piperazin-l-yl)pyridin-5-yI]-2-oxooxazolidin-5- ylmethyl] acetamide
Preparation 7
Synthesis of (S)-N- [3- [2-(piperazin-l-yl)pyridin-5-yI] -2-oxooxazolidin-5- ylmethyl]thiocarbamate
The title compound (1.55 g, yield 100%) was prepared from (S)-N-[3-[2-[4- (N-t-butoxycarbonyl)piperazin- 1 -yl]pyridin-5-yl]-2-oxooxazolidin-5- ylmethyljthiocarbamate (2 g, 0.004434 moles) (obtained according to the procedure given in preparation 4) and trifluoro acetic acid (3.032 g, 0.026604 moles) by following the procedure described in preparation 6.
Preparation 8
Synthesis of (S)-N-[3-[2-(piperazin-l-yl)pyridin-5-yl]-2-oxooxazolidin-5- ylmethyl]-N'-methyl thiourea
The title compound (1.55 g, yield 100%) was prepared from (S)-N-[3-[2-[4- (N-t-butoxycarbonyl)piperazin-l-yl]pyridin-5-yl]-2-oxooxazolidin-5- ylmethyl]-N' -methyl thiourea (2 g, 0.004444 moles) (obtained according to the procedure given in preparation 5) and trifluoroacetic acid (3.0399 g, 0.02666 moles) by following the procedure described in preparation 6.
Example 1
Synthesis of (S)-N-[3-[2-[4-(N-5-nitrofuran-2-ylcarbonyI)piperazin-l- yl] py ridin-5-y 1] -2-oxooxazolidin-5-y lmethyl] thiocarb amate
To a solution of (S)-N-[3-[2-(piperazin-l-yl)pyridin-5-yl]-2-oxooxazolidin-5- ylmethyl]thiocarbamate (300 mg, 0.0008547 moles) (obtained from preparation 7) in dry THF (10 ml), 5-nitro-furan-2-carbonylchloride [which was prepared by reacting 5-nitro-2-furoic acid (201 mg, 0.001282 moles) with thionylchloride (5 ml) and triethylamine (388 mg, 0.003846 moles)] was added at 0 °C and stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution, water and brine. Dried over anhydrous sodium sulphate, concentrated
005 0
37 to dryness and purified the residue over silica gel column using dichloromethane and methanol mixture as eluent to afford the title compound (167 mg, yield 40%), mp : 148-149 °C. 1HNMR (CDC13) δ : 3.66 (s, 4H), 3.84-3.86 (t, 4H), 3.88 (s, 3H), 3.95-3.97 (t, IH), 3.99-4.01 (m, 2H), 4.07-4.09 (t, IH), 4.93 (bs, IH), 6.71-6.73 (d, IH), 7.23-7.25 (t, IH), 7.37-7.38 (d, IH), 7.93-7.95 (d, IH), 7.97-7.98 (bs, IH), 8.15 (s, IH). Mass (M++l) : 491 The following compounds were prepared according to the procedure given in example 1.
Antimicrobial Testing The compounds of invention showed in vitro antibacterial activity when tested by the Agar Dilution Method as specified in documents published by the National Committee for Clinical Laboratory Standards (NCCLS), USA. Briefly, the compounds of invention were weighed, dissolved in Dimethyl Sulfoxide, serially diluted in the same solvent and then incorporated into molten Mueller Hinton Agar in a petridish before solidification, with each petridish containing a different concentration of a compound. The Bacterial Inoculum was prepared by touching the tops of 3 to 5 well isolated bacterial colonies with the same morphological appearance from an 18 hour old culture with an inoculating loop, transferring the growth to a tube containing 5ml of normal saline and adjusting the turbidity of the saline suspension to 0.5 Macfarland Turbidity Standard equivalent to a bacterial population of 1.5 x 108 colony forming units (CFU) per milliliter of suspension.
The bacterial inoculum prepared in the above manner was inoculated onto petri dishes containing Mueller Hinton Agar which had earlier been incorporated with different dilutions of the compounds of invention by a
Multipoint Inoculator with each inoculum spot containing approximately 1 x 104 colony forming units (CFU) of bacteria. The inoculated pefridishes were incubated at 35°Celsius in an ambient atmosphere for 20 hours. Pefridishes containing different concentrations of
Nancomycin and Oxacillin and inoculated with Staphylococcus aureus,
Coagulase Negative Staphylococci and Enterococci were incubated for 24 hours. The petridishes after incubation, were placed on a dark non reflecting surface and the Minimum Inhibitory Concentration (MIC) recorded as the concentration which showed no growth of the inoculated culture. The minimum inhibitory concentrations (μg/ml) were obtained for representative compounds of the invention are given in the table 1 :
S. aureus - Staphylococus aureus Ent. Faecalis - Enterococcus faecalis E. faecium - Enterococcus faecium ATCC — American Type Culture Collection MRO - Microbial Resource Orchid
Table 1
Table 1 (Contd.)
t
Table 1 (Contd.)
Table 1 (Contd.)
KJ
Claims
1. A compound of formula (I)
2. The compound as heteroaryl group represented by R6 are substituted or unsubstituted phenyl, naphthyl, phenylmethyl, phenylethyl, naphthylmethyl, naphthylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thienyl, 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, thiazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, heteroaralkyl, heterocycloalkyl, hetero(C2-C6)aralkenyl, heterocyclo(C2- C6)alkenyl.
3. A compound of formula (I) as claimed in claim 1, which is selected
(S)-N-[3-[2-[4-(N-5-Nitrofuran-2-ylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3 - [2- [4-(N-5-Nitrofuran-2-ylthiocarbonyl)piperazin- 1 -yl]pyridin-5 -yl] - 2-oxooxazolidin-5-ylmethyl]thiocarbamate ; (S)-N-[3-[2-[4-(N-5-Nifrofuran-2-ylcarbonyl)piρerazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(N-5-Nifrofuran-2-ylthiocarbonyl)piperazin-l-yl]pyridin-5-yl]-
2-oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[2-[4-(N-furan-2-ylcarbonyl)piperazin- 1 -yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-furan-2-ylthiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-fiιran-2-ylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(^-furan-2-ylthiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[2-[4-(N-5-Nitropyrazol-2-ylthiocarbonyl)piperazin-l-yl]pyridin-5- yl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[2-[4-(N-5-Nitropyrazol-2-ylthiocarbonyl)piperazin- 1 -yl]pyridin-5- yl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(N-5-Nifropyrazol-2-ylthiocarbonyl)piperazin-l-yl]pyridin-5- yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(5)-N-[3-[2-[4-(N-5-Nitropyrazol-2-ylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-pyrazine-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(N-pyrazine-2-yl-thiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[2-[4-(N-pyrazine-2-yl-carbonyl)piperazin- 1 -yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(»S)-N-[3-[2-[4-(N-pyrazine-2-yl-thiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ; (S)-N-[3-[2-[4-(N-5-methylpyrazm-2-yl-carbonyl)piperazin-l-yl]pyridin-5- yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
( )-N-[3-[2-[4-(N-5-methylpyrazin-2-yl-thiocarbonyl)piperazin-l-yl]pyridin-
5-yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ; (S)-N-[3-[2-[4-(N-pyrazine-2-yl-carbonyl)piperazin- 1 -yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[2-[4-(N-pyrazine-2-yl-thiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(^-N-[3-[2-[4-(N-l-methylpyrrolyl-2-yl-carbonyl)piperazin-l-yl]pyridin-5- yl] -2-oxooxazolidin-5 -ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-pyrrolyl-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-thien-2-yl-thiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ; (S)-N-[3-[2-[4-(N-furan-2-yl-propenoyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(5)-N-[3-[2-[4-(N-furan-2-yl-propenoyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl] thiocarbamate ;
(S)-N-[3-[2-[4-(^-5-fluoroindol-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(N-piperidin- 1 -yl-carbonyl)piperazin- 1 -yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(4-(4-acetylphenyl- 1 -yl)piperazin- l-yl-carbonyl)piρerazin- 1 - yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ; (S)-N-[3-[2-[4-(4-(piperidin- 1 -yl)piperidin- 1 -yl-carbonyl)piperazin- 1 - yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(4-(4-nitrophenyl- 1 -yl)furan-2-yl-carbonyl)piperazin- 1 - yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]acetamide ; (S)-N-[3-[2-[4-(cyclopropylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(cyclopropylthiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ; (S)-N-[3-[2-[4-(cyclopropylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
N' -methyl thiourea ;
(S)-N-[3 -[2-[4-(cyclopropylcarbonyl)piperazin- 1 -yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]-N'-methyl thiourea ; (S)-N-[3-[2-[4-(cyclopropylthiocarbonyl)piperazin- 1 -yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(cyclopropylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[2-[4-(cyclopropylthiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N-[3-[2-[4-(N-pyrrolidin-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-( -pyrrolidin-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ; (S)-N-[3-[2-[4-(N-thiazolidin-2-yl-carbonyl)piperazin- 1 -yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate and
(S)-N-[3-[2-[4-(N-quinoxalin-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate.
(S)-N-[3-[2-[4-(N-5-nitrofuran-2-ylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]-(N'-4-cyanophenyl)thiourea ;
(S)-N-[3-[2-[4-(N-Cyclopropyl-2-ylcarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]-(N'-methyl-N'-cyclopropanecarboxamide) thiourea ; (S)-N-[3-[2-[4-(4-(pyridin-2-yl)piperazin- 1 -yl-carbonyl)piperazin- 1 - yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]acetamide ;
(S)-N-[3-[2-[4-(4-(pyridin-2-yl)piperazin-l-yl-thiocarbonyl)piperazin-l- yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]thioacetamide ; (S)-N-[3-[2-[4-(4-(pyridin-2-yl)piperazin- 1 -yl-carbonyl)piperazin- 1 - yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(4-(pyridin-2-yl)piperazin-l-yl-thiocarbonyl)piperazin-l- yl]pyridin-5-yl]-2-oxooxazolidin-5-ylmethyl]thiocarbamate ;
(S)-N-[3-[2-[4-(N-imidazol-2-yl-carbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]acetamide ;
(5)-N-[3-[2-[4-(N-imidazol-2-yl-thiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thioacetamide ;
(S)-N- [3 - [2- [4-(N-imidazol-2-yl-carbonyl)piperazin- 1 -yl]pyridin-5-yl] -2- oxooxazolidin-5-ylmethyl]thiocarbamate and (5)-N-[3-[2-[4-(N-imidazol-2-yl-thiocarbonyl)piperazin-l-yl]pyridin-5-yl]-2- oxooxazolidin-5-ylmethyl]thiocarbamate ;
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)
R6— (C(=Y))p- X) wherein L is a leaving group and all other symbols are as defined earlier to produce a compound of formula (I).
6. A process for the preparation of compound of the formula (I)
(Cι-C6)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; p is an integer of 1; R6 represents a substituted or unsubstituted groups selected from aryl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclyl, heterocycloalkyl, heterocycloalkenyl, which comprises, i) converting the compound of formula (NI)
R6-(C(=Y))p-L (IX) wherein all symbols are as defined earlier and L is a leaving group to produce a compound of formula (I), where R1 represents - ΝHC(=Z)R9.
7. A process for the preparation of compound of the formula (I)
8. A process for the preparation of compound of the formula (I)
NHS(O)rar alkyl or -NHS(O)rheteroaralkyl, where r is 0 to 2; A and B are different and represent CH or N; R2 and R3 may be same or different and independently represent hydrogen, halogen, hydroxy, alkyl, alkoxy; n is an integer of 0 or 1; m is an integer in the range of 1 to 4; D represents CH or N; E represents CH or N; 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-Cg)alkylthio, (C3-C6)cycloalkyl or either of R4 or R5 represent an oxo or thiooxo group; p is an integer of 1; R represents a substituted or unsubstituted groups selected from aryl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclyl, heterocycloalkyl, heterocycloalkenyl, which comprises reacting the compound of formula (XII)
9. A process for the preparation of compound of the formula (I)
10. A process for the preparation of compound of the formula (I)
11. A process for the preparation of compound of the formula (III)
12. A pharmaceutical composition, which comprises a compound of formula (I)
13. A pharmaceutical composition as claimed in claim 12, in the form of a tablet, capsule, powder, syrup, solution, aerosol or suspension.
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 1 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 an effective amount of a compound of claim 3 to human or animal in need thereof.
17. A method as claimed in claim 16, wherein the infectious disorder is caused by bacteria.
18. A method of treating or preventing an infectious disorder in a human or animal, comprising administering a composition as claimed in claim 12 to human or animal in need thereof.
19. A method as claimed in claim 18, wherein the infectious disorder is caused by bacteria.
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| 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 |
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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 |
| US7148219B2 (en) | 2003-06-03 | 2006-12-12 | Rib-X Pharmaceuticals, Inc. | Biaryl heterocyclic compounds and methods of making and using the same |
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| US8071603B2 (en) | 2004-09-20 | 2011-12-06 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors |
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| US8541457B2 (en) | 2005-06-03 | 2013-09-24 | Xenon Pharmaceuticals Inc. | Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors |
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| WO2006130986A1 (en) * | 2005-06-09 | 2006-12-14 | Merck Frosst Canada Ltd. | Azacyclohexane derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase |
| WO2008029266A1 (en) * | 2006-09-08 | 2008-03-13 | Glenmark Pharmaceuticals S.A. | Stearoyl coa desaturase inhibitors |
| WO2009084614A1 (en) * | 2007-12-27 | 2009-07-09 | Daiichi Sankyo Company, Limited | Imidazole carbonyl compound |
| JP2014196369A (en) * | 2007-12-27 | 2014-10-16 | 第一三共株式会社 | Imidazolecarbonyl compound |
| 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 (en) * | 2017-03-20 | 2018-09-27 | Merck Sharp & Dohme Corp. | Oxazolidinone compounds and methods of use thereof as antibacterial agents |
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