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WO2008010070A2 - Nouveaux dérivés d'oxazolidinone - Google Patents

Nouveaux dérivés d'oxazolidinone Download PDF

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Publication number
WO2008010070A2
WO2008010070A2 PCT/IB2007/002019 IB2007002019W WO2008010070A2 WO 2008010070 A2 WO2008010070 A2 WO 2008010070A2 IB 2007002019 W IB2007002019 W IB 2007002019W WO 2008010070 A2 WO2008010070 A2 WO 2008010070A2
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WIPO (PCT)
Prior art keywords
groups
methyl
oxo
oxazolidin
fluorophenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2007/002019
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English (en)
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WO2008010070A3 (fr
Inventor
Uma Ramachandran
Mrinal Kanti Guha
Ravikumar Tadiparthi
Ganesh Prabhu
Vijayalakshmi Vadarevu
Simi Pushpan
Veenaa Anantharaman
Santhosh Subramanian
Shakti Singh Solanki
Matte Marianna Samuel
Kesavan Koppolu
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Orchid Research Laboratories Ltd
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Orchid Research Laboratories Ltd
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Publication of WO2008010070A2 publication Critical patent/WO2008010070A2/fr
Anticipated expiration legal-status Critical
Publication of WO2008010070A3 publication Critical patent/WO2008010070A3/fr
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof.
  • 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 Oxazolidinones of the formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof.
  • novel Oxazolidinone derivatives of the present invention are expected to be more soluble and can be easily formulated in an appropriate vehicle for the purpose of intravenous delivery. Also the present invention provides methods and exemplary compounds with enhanced solubility, which might be useful for the design of better compounds with improved therapeutic index towards second-generation Oxazolidinone antibacterials.
  • novel Oxazolidinone derivatives of the present invention may be useful as antibacterial agents, particularly for intravenous injections and are also useful in the treatment of conditions such as nosocomial pneumoniae, community acquired pneumoniae, Vancomycin resistant enterococci (VRE) caused by Methicillin resistant
  • MRSA Staphylococcus Aureus
  • Streptococcus Pneumoniae penicillin resistant Streptococcus Pneumoniae
  • the compounds of the present invention are effective against a number of human or animal pathogens, clinical isolates, including Vancomycin and Methicillin resistant organisms.
  • the Oxazolidinone class of compounds represents totally synthetic antibacterials endowed with a mechanism different from the mode of action of known antibacterial compounds.
  • the Oxazolidinones interact with 5OS ribosomal subunit to form an initiation complex and thus prevent the bacterial translation necessary for the replication of the bacteria.
  • These compounds had shown antibacterial activity against gram +ve organisms and a host of opportunistic pathogens such as Methicillin resistant Staphylococcus Aureus (MRSA), penicillin resistant Streptococcus Pneumoniae (PRSP) and Vancomycin resistant Enterococci (VRE).
  • MRSA Methicillin resistant Staphylococcus Aureus
  • PRSP penicillin resistant Streptococcus Pneumoniae
  • VRE Vancomycin resistant Enterococci
  • the best-represented compounds are Linezolid and Eperezolid, Linezolid being approved by the US FDA for treatment of severe bacterial infections.
  • C 6 )alkyl fluoro, chloro, bromo, hydrogen or a (Ci-C 6 )alkyl substituted with one or more of fluoro, chloro, bromo or iodo, preferably U and V are fluoro and W is hydrogen;
  • R is hydrogen, (C 1 -Ci 2 )alkyl, (C 3 -Ci 2 )cycloalkyl, (Ci-C6)alkoxy, (Cr C ⁇ )alkyl substituted with one or more of fluoro, chloro, bromo, iodo or hydroxy and q is 0 to 4 inclusive.
  • WO 02/06278 describes a series of Oxazolidinone derivatives useful as antimicrobial agents, of the formula (I),
  • T is a five to seven membered heterocyclic ring, aryl, substituted aryl; R is a substituent on T;
  • X is CH 2 , CH-S, CH-O and N;
  • Y and Z are independently selected from hydrogen, alkyl, cycloalkyl;
  • U and V are independently selected from alkyl, halogen;
  • W is selected from group CH 2 , CO, CH 2 NH, CH 2 NHCH 2 , S, CH 2 CO etc;
  • A represents a Oxazolidinone ring and the like;
  • Y is NH, O, or S;
  • R 1 is H, NH 2 , NHC r4 alkyl, Ci- 4 alkenyl, etc;
  • R 2 and R 3 are independently H, F, Cl or Ci- 2 alkyl;
  • R 5 is H;
  • R 6 is phenyl, benzyl, etc,
  • R 7 is H, CH 3 or Ci- 4 alkanoyl;
  • R 8 is H, Cp 4 alky
  • Z 2 is SO 2 -, -O-, -(NR 107 )-OS-, -S-, and the like;
  • R 107 is -R 108 CO- etc,
  • R 108 is H, alkyl, aryl etc.
  • WO 04/018439 describes a series of Oxazolidinone derivatives useful as antimicrobial agents, of the formula (I),
  • Oxazolidinone derivatives may be useful as antibacterial agents and hence are useful in the treatment of conditions such as nosocomial pneumoniae, community acquired pneumoniae, Vancomycin resistant enterococci (VRE) caused by Methicillin resistant Staphylococcus Aureus (MRSA) and penicillin resistant Streptococcus pneumoniae.
  • VRE Vancomycin resistant enterococci
  • MRSA Methicillin resistant Staphylococcus Aureus
  • Streptococcus pneumoniae penicillin resistant Streptococcus pneumoniae.
  • the compounds of the present invention are effective against a number of human or animal pathogens, clinical isolates, including Vancomycin and Methiciliin resistant organisms.
  • the present invention relates to novel Oxazolidinone derivatives of the formula
  • Ri is selected from hydrogen, alkyl, haloalkyl, O-alkyl, S- alkyl, NH 2 , NH-alkyl or N(alkyl) 2 , O-het, S-het or -NH-het;
  • R 2 and R 3 may be same or different and independently represent hydrogen, halogen, hydroxy, haloakyl, alkyl or alkoxy;
  • R 4 and R 5 may be same or different and independently represent hydrogen, cyano, nitro, amino, halogen, hydroxy, haloalkyl, alkylthio, alkyl, alkoxy or benzyl;
  • Z represents S, O and NR 6 ;
  • R 6 represents hydrogen, hydroxy, cyano, alkyl, alkoxy, -O-(C 3 - C 7 ) cycloalkyl, -O-aryl, -O-heteroaryl or -O-heterocyclyl ;
  • R represents a five to seven membered heterocyclic ring, aryl, alkyl, aralkyl, aralkylamino, aralkylthio group and is further substituted by a group selected from halogen, cyano, nitro, alkoxy, acyl, phenyl, aralkyl, heteroaryl, heterocyclyl, amino groups or substituted or unsubstituted groups selected from alkyl, -O-alkoxyalkyl, alkoxy, acyl, aralkyl, cycloalkyl groups, -OCH 2 R 7 ;
  • R 7 represents hydrogen, halogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, amino, arylakylamino, heteroaryl and heterocyclyl groups.
  • n is an integer of 0-1, with the condition that when n is 1 then Z is not S, and when n is 0 then Z is S,
  • X represents O
  • R represents -OCH 2 R 7 , -O-alkoxyalkyl, - CH 2 OCH 2 -R 8 , -CH 2 OH, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and
  • Ri represents substituted or unsubstituted haloalkyl group.
  • n 0 then Z is O and X represents O, R represents -OCH 2 R 7, -O- alkoxyalkyl, -CH 2 OCH 2 -R 8 , -CH 2 OH, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and Ri represents substituted or unsubstituted haloalkyl group.
  • Z is N-R 6 and X represents O, R represents -OCH 2 R 7j -O- alkoxyalkyl, -CH 2 OCH 2 -Rs, -CH 2 OH, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and Ri represents substituted or unsubstituted haloalkyl group, wherein Rs represents hydrogen, halogen, hydroxyl, alkyl, cycloalkyl, aryl, aralkyl, amino, aralkylamino, heteroaryl and heterocyclyl group.
  • the present invention relates to novel Oxazolidinone derivatives of the formula
  • X may be selected from O or S
  • Ri represents substituted or unsubstituted groups selected from hydrogen, (Ci- C 4 ) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like; haloalkyl groups such as dichloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl and the like; O-alkyl, S- alkyl, NH 2 , NHalkyl or N(alkyl) 2 , O-het, S-het or -NH-het, wherein het is a C-linked five or six membered saturated or unsaturated heterocyclic
  • R 2 and R 3 represents substituted or unsubstituted groups selected from hydrogen, halogen atoms such as fluorine, chlorine, bromine or iodine; hydroxy, (Ci- C ⁇ )alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like; (Ci-Ce)alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like.
  • R 4 and R 5 represent substituted or unsubstituted groups selected from hydrogen, cyano, nitro, amino, hydroxy; halogen atoms such as fluorine, chlorine, bromine or iodine; (C]-C 4 ) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and the like; haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like; (Q- C 4 )alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; (Ci- Cg)alkylthio groups such as methylthio, ethylthio, n-propylthio, iso-propylthio and the like; benz
  • Re represents substituted or unsubstituted groups selected from hydrogen, hydroxyl, cyano, linear or branched (Ci-C 4 ) alkyl groups; -O-alkyl groups in which the alkyl groups are such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like; -0-(C 3 - C 7 ) cycloalkyl groups in which the cylcoalkyl groups are such as cyclopropyl, cyclobutyl, cyclopentyl, and the like; -O-aryl groups in which the aryl groups are such as phenyl, naphthyl and the like; -O-heteroaryl groups in which heteraoaryl groups are such as pyrldyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imi
  • R 7 represents substituted or unsubstituted groups selected from hydrogen, halogen, hydroxy, linear or branched (Ci-C 4 ) alkyl groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, t-butyl, and the like; (C 4 -Cs) cycloalkyl groups such as cyclobutyl, cyclopentyl, cyclohexyl and the like; aryl groups such as phenyl, naphthyl and the like; aralkyl groups such as phenylmethyl, phenylethyl, naphthylmethyl, naphthylethyl and the like; the amino group; aralkylamino groups such as benzylamino and the like; heteroaryl groups such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazo
  • Rs represents substituted or unsubstituted groups selected from hydrogen, halogen, hydroxyl, linear or branched (C 1 -C 4 ) alkyl groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, t-butyl, and the like; (C 3 - C 7 ) cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and the like; aryl groups such as phenyl, naphthyl and the like; aralkyl groups such as phenylmethyl, phenylethyl, naphthylmethyl, naphthylethyl and the like; the amino group; aralkylamino groups such as benzylamino and the like; heteroaryl groups such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl,
  • Z is selected from O, S and NR 6 ; n is an integer of 0-1, with the condition that when n is 1 then Z is not S, and when n is O then Z is S, X represents O, R represents -OCH 2 R 7; -O-alkoxyalkyl, - CH 2 OCH 2 -Rs, -CH 2 OH, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and Ri represents substituted or unsubstituted haloalkyl.
  • n O
  • Z O
  • X represents O
  • R represents -OCH 2 R 7 , -O-alkoxyalkyl, -CH 2 OCH 2 -R 8 , -CH 2 OH, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl
  • Ri represents substituted or unsubstituted haloalkyl.
  • Z is N-R 6
  • X represents O
  • R represents -OCH 2 R 7 , -O-alkoxyalkyl, -CH 2 OCH 2 -R 8 , -CH 2 OH, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl
  • Ri represents substituted or unsubstituted haloalkyl.
  • L represents a suitable leaving group selected from fluoro, chloro, bromo, carboxylic hydroxyl groups and similar leaving groups.
  • R, R 1 , R 2 , R3, R 4 , R5, R 6 , R 7 and R 8 are selected from halogen, hydroxy, formyl, nitro, cyano, azido, amino, alkyl, aryl, alkylamino, alkylaminocarbonyl, haloalkyl, acylamino, alkoxy, acyl and these substituents are as defined above.
  • the compounds of this invention may be useful in their natural form or as their salts.
  • the salt when required for infusion may be formulated in its stable non-toxic and non-allergic acceptable form.
  • the acceptable salts are those formed with acids which form under physiological conditions as anion or conjugate base, for example tosylate, mesylate, acetate, tartarate, succinate, malonate, base of phosphate, citrate and lactate.
  • suitable inorganic salts such as hydrochloride, hydroiodide, methyl iodide, sulfate, nitrate, carbonate, bicarbonate and bisulphate.
  • the pharmacologically acceptable salts of the present invention include alkali metals like Li, Na, and K, alkaline earth metals 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:
  • the compounds of general formula (I) may be prepared by one or more schemes or combinations of reactions given below.
  • Scheme II a) Converting the compound of the formula (Ia) to produce the compound of formula (Ic) with Lawesson's reagent and all the other symbols are as defined earlier.
  • Compounds of the general formula (I) may be obtained from the compound of general formula (Ia) by deprotecting the compound of formula (Ia) where P is the protecting group and all other groups are as defined earlier to produce the compound of formula (Ib) with suitable reagents such as TFA and the like in the presence of solvents such as DCM and the like.
  • Reacting the compound of formula (Ib) with the compound of the formula (2a) is carried out in the presence of an organic base such as triethylamine, pyridine, dimethylamine and the like or in the presence of an inorganic base such as potassium carbonate, sodium carbonate and the like and in solvents selected from toluene, trifluoroacetic acid, DMF, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethyl acetate or a mixture thereof or by using conventional coupling procedures employed in the carboxylic acid and amine couplings .
  • the reaction may be carried out at a temperature in the range of 0 0 C to 50 0 C.
  • the duration of the reaction may range from 4 to 24 hours, to produce the compound of the general formula (3a).
  • the compound of formula (3a) is converted to the respective oxime of formula (3b) by treatment with substituted or unsubstit ⁇ ted hydroxylamine hydrochloride in the presence of a inorganic bases such as sodium acetate, ammonium acetate, potassium carbonate, cesium carbonate and the like or in the presence of organic bases such as pyridine, diisopropylethylamine and the like, and in the presence of solvents such as methanol, ethanol and the like or the mixture thereof.
  • the reaction may be carried out at a temperature in the range of 10 0 C to 100 0 C.
  • the reaction time ranges from 1 to 12 hours.
  • Compounds of general formula (I) may be obtained by converting the compound of formula (Ia) to the thioamides by using Lawesson's reagent in the presence of a base such as triethylamine, pyridine and the like and solvents such as toluene, benzene, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethyl acetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a. temperature in the range of 80 ° to 120 0 C.
  • the duration of the reaction may range from 4 to 8 hours to produce the compound of formula (Ic).
  • the reaction of the compound of formula (Ic) with suitable reagents such as
  • the reaction of the compound of formula (Id) with the compound of the formula (2a) is carried out in the presence of an organic base such as triethylamine, pyridine, dimethylamine and the like or in the presence of an inorganic base such as potassium carbonate, sodium carbonate and the like and in solvents selected from toluene, trifluoroacetic acid, DMF, tetrahydrofuran, chloroform,' dichloromethane, dichloroethane, ethyl acetate or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 0 0 C to 50 0 C.
  • the duration of the reaction may range from 4 to 24 hours to produce the compound of the general formula (3a).
  • the compound of formula (3a) is converted to the oxime of formula (3b) by treatment with substituted or unsubstituted hydroxylamine hydrochloride in the presence of a inorganic base such as sodium acetate, ammonium acetate, potassium carbonate, cesium carbonate and the like or in the presence of organic bases such as pyridine, diisopropylethylamine and the like, in the presence of solvents such as methanol, ethanol, tetrahydrofuran, pyridine, N,N-dimethylformamide and the like or the mixture thereof.
  • the reaction may be carried out at a temperature in the range of 10 to 100 °C.
  • the reaction time ranges from 1 to 12 hours.
  • Compounds of the general formula (3d) may be obtained by converting the compound of formula (3c) to the carbothioate ester by treatment with R 7 CH 2 OH in the presence of base such as sodium acetate, potassium carbonate, cesium carbonate and the like and in the presence or absence of a suitable solvent such as dimethylformamide, dichloromethane, toluene, acetonitrile, dioxane, methyl ethyl ketone and the like or the mixture thereof.
  • the reaction may be carried out at a temperature in the range of 10 to 100 0 C.
  • the reaction time ranges from 1 to 36 hours.
  • the protecting groups P used in the invention are conventional protecting groups such as t-butoxy carbonyl (t-Boc), trityl, trifluoroacetyl, benzyloxy, benzyloxy carbonyl (Cbz) and the like.
  • any reactive group in the substrate molecule may be protected according to the 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 pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, aerosols, 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.
  • the compositions may be prepared by processes known in the art.
  • the amount of the active ingredient in the composition may be less than 70% by weight.
  • compositions typically contain from 1 to 20 %, preferably 1 to 10 % by weight of the active compound, the remainder of the composition being the pharmaceutically acceptable carriers, diluents or solvents.
  • reaction mixture was poured on to ice-water mixture.
  • the solid obtained was extracted with ethyl acetate (100ml) and the organic layer was washed with cold water (50ml), and dried over anhydrous Na 2 SO 4 .
  • the solvent was distilled off under vacuum to yield the crude product, which was purified by column chromatography using silica gel and ethyl acetate rhexane mixture as eluent, to yield the title compound (0.2g, 19.8 % yield).
  • Step II Synthesis of 2,2-difluoro-iV-( ⁇ 3-[3-fluoro-4-(3,5-dimethyIpiperazin-l-yI) phenyl]-2- oxo-l,3-oxazolidin ⁇ 5(iS)-yI ⁇ methyl)acetamide
  • Dry palladium carbon (0.05g) was added to the solution of 2,2-difluoro-N-( ⁇ 3- [3-fluoro-4- ⁇ (3,5-dimethyl-4-[(benzyloxy)acetyl]piperazin-l-yl ⁇ phenyl)]-2-oxo-l,3- oxazolidin-5(5)-yl ⁇ methyl)acetamide (0.2g, 0.3mmol, obtained according to the procedure described in the example 20) in methanol :ethyl acetate (1:1 mixture, 10ml) with vigorous shaking.
  • reaction mass was stirred until completion of the reaction as confirmed by TLC after 15 hours of stirring.
  • the reaction mass was poured on to the water and then the product was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na 2 SO 4 and the solvent was removed under vacuum.
  • the product was purified by column chromatography using ethyl acetate and hexane mixture (35:65) as an eluent to afford the title compound (0.055g, yield 1.25%).
  • the compounds of the present 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 (now CLSI).
  • the compounds of the invention were weighed, dissolved in dimethyl sulfoxide (DMSO), serially two fold 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.
  • DMSO dimethyl sulfoxide
  • the bacterial inoculum was prepared by picking 3 to 5 well isolated bacterial colonies with the same morphological appearance from an 18-24 hours old culture with an inoculating loop, then transferring the growth to a tube containing 3 mL of normal saline and adjusting the turbidity of the saline suspension to 0.5 McFarland Turbidity Standard equivalent to a bacterial population of 1.5 x 10 8 colony forming units (CFU) per mL of the suspension.
  • the suspension was diluted 1:10 in saline (i.e. 0.5 mL suspension + 4.5 mL saline) to get a bacterial population of 1.5 x 10 7 .CFU/mL as inoculum.
  • 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
  • Petridishes were incubated at 35°C in an ambient atmosphere for 16-20 j hours. Petridishes containing different concentrations of Vancomycin and Oxacillin and inoculated with Staphylococcus aureus, Coagulase Negative Staphylococci and Enterococci were incubated for 24 hours.
  • mice infected with Oxacillin resistant S. aureus ATCC 43300 were challenged by the intraperitoneal injection of bacterial suspensions in 0.5 ml of hog gastric mucin (usu.100 x 50% lethal dose).
  • Four or five dose levels of the compound of invention was administered orally at 0.75 h and 4 h post infection. All the untreated control animals died within 36 to 48 h of infection.
  • in- house Linezolid was used as a comparator in four doses.
  • Median (50%) effective dose (ED50) were determined by applying the Reed and Muench's method of the 7-day survival ratios.
  • EDso of the Example 23 against ORSA is 16.31 mg/kg b.w.

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Abstract

La présente invention concerne de nouveaux composés de formule générale (I) et les dérivés, analogues, formes tautomères, stéréoisomères, polymorphes, hydrates, solvates, sels acceptables du point de vue pharmaceutique, compositions pharmaceutiques, métabolites et promédicaments de ceux-ci. La présente invention concerne plus particulièrement de nouveaux dérivés d'oxazolidinone de formule générale (I). Les nouveaux dérivés d'oxazolidinone de la présente invention peuvent être utiles en tant qu'agents antibactériens, en particulier pour des injections intraveineuses, et ils sont également utiles dans le traitement d'affections telles que les pneumonies nosocomiales, les pneumonies extrahospitalières, les entérocoques résistants à la vancomycine (ERV) provoqués par le staphylocoque doré (Staphylococcus aureus) résistant à la méthicilline (SARM) et les pneumonies à streptocoque résistant à la pénicilline. Les composés de la présente invention sont efficaces contre un certain nombre d'isolats cliniques pathogènes humains ou animaux, dont des organismes résistants à la vancomycine et à la méthicilline.
PCT/IB2007/002019 2006-07-19 2007-07-18 Nouveaux dérivés d'oxazolidinone Ceased WO2008010070A2 (fr)

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IN1253/CHE/2006 2006-07-19

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WO2008010070A3 WO2008010070A3 (fr) 2010-02-11

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SK283420B6 (sk) * 1992-05-08 2003-07-01 Pharmacia & Upjohn Company Antimikrobiálne oxazolidinóny obsahujúce substituované diazínové skupiny
JPH11322729A (ja) * 1998-03-09 1999-11-24 Hokuriku Seiyaku Co Ltd ジチオカルバミド酸誘導体
JP2000204084A (ja) * 1998-11-11 2000-07-25 Hokuriku Seiyaku Co Ltd チオカルバミド酸誘導体

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