WO2003106454A1 - Derives de 1h-isoquinoline-oxazolidinone, et leur utilisation comme agents antibacteriens - Google Patents

Derives de 1h-isoquinoline-oxazolidinone, et leur utilisation comme agents antibacteriens Download PDF

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WO2003106454A1
WO2003106454A1 PCT/IB2003/002602 IB0302602W WO03106454A1 WO 2003106454 A1 WO2003106454 A1 WO 2003106454A1 IB 0302602 W IB0302602 W IB 0302602W WO 03106454 A1 WO03106454 A1 WO 03106454A1
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oxo
oxazolidin
isoquinolin
dihydro
compound
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Shiv Kumar Agarwal
Mrinal Kanti Guha
Matte Marianna Samuel
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Orchid Pharma Ltd
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Orchid Chemicals and Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention provides novel compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them.
  • the present invention more particularly provides novel oxazolidinone derivatives of the general formula (I)
  • the present invention also provides a process for the preparation of the above said novel oxazolidinone derivatives of the formula (I) their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them.
  • novel oxazolidinone derivatives of the present invention may be useful as antibacterial agents.
  • the novel oxazolidinone derivatives of the present invention 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. BACKGROUND OF THE INVENTION
  • the oxazolidinone class of compounds represent totally synthetic antibacterials endowed with a mechanism different from the mode of action of known antibacterial compounds.
  • the oxazolidinone interact with 50S 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 (PRSE), vancomycin resistant Enterococci (NRE).
  • MRSA methicillin resistant Staphylococcus aureus
  • PRSE penicillin resistant Streptococcus pneumoniae
  • NRE vancomycin resistant Enterococci
  • the best represented compounds are linezolid and eperezolid, linezolid being approved by US FDA for treatment of severe bacterial infections.
  • WO publication No. 00/73301 discloses bicyclic oxazolidinones useful as antibacterials.
  • WO publication No. 01/42242 discloses a series of bicyclic heterocyclic substituted phenyl oxazolidinones useful as antibacterial agents.
  • WO publication No. 98/54161 discloses amides, thioamides useful as. antibacterial agents.
  • R is selected from the group consisting of OH, N 3 , -OR 1 , O-aryl, O- heteroaryl, OS0 2 R , -NR R , etc, wherein (i) R , is benzyl or C 2 - 6 acyl; (ii) is selected from the group consisting of phenyl, tolyl, and C ⁇ - 6 alkyl; and (iii) R 3 and R 4 are independently selected from the group consisting of hydrogen, C 3 - 6 cycloalkyl, phenyl, tert-butoxycarbonyl, fluorenyloxycarbonyl, benzyloxycarbonyl, -C0 2 -R 5 , -CO-R 5 , -CO-SR 5 , -CS-R 5 , P(0)(0R 6 )(0R 7 ), S0 2 -
  • R and - ⁇ alkyl optionally substituted with 1 to 3 members independently selected from the group consisting of C ⁇ - 5 alkoxycarbonyl, OH, cyano, and halogen, etc, wherein R 5 is selected from the group consisting of hydrogen, C 3 - 6 cycloalkyl, trifluoromethyl, phenyl, benzyl, etc, R 6 and R 7 are independently hydrogen or C ⁇ - alkyl; R 8 is phenyl or - 4 alkyl; X is 0 to 4 members independently selected from the group consisting of halogen, OH, mercapto, nitro, halo-C ⁇ - 6 , C ⁇ - 8 alkoxy, etc, Y is a radical of formula
  • R , R , R , R , and R are each independently selected from the group consisting of hydrogen, CN, nitro, C ⁇ _ 6 alkyl, halo- - 6 alkyl, formyl, carboxy, or R and R and/or R and R and/or R and R together form an oxo group;
  • the moiety W represents any five- to ten-membered aromatic or heteroaromatic ring, said heteroaromatic ring having 1 to 4 members selected from the group consisting of S, O, and N;
  • Z is selected from the group consisting of hydrogen, halogen, amino, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, CN, CHO, alkyl-CO-, alkoxy, etc.
  • 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.
  • NRE vancomycin resistance enterococci
  • MRSA methicillin resistance staphylococcus aureus
  • penicillin resistance streptococcus pneumoniae penicillin resistance streptococcus pneumoniae.
  • the compounds of the present invention are effective against a number of human or animal pathogens, clinical isolates, including Nancomycin resistant organisms, methicillin resistant organisms.
  • R and R may be same or different and independently represent hydrogen, halogen, hydroxy, alkyl, alkoxy;
  • R 3 , R 4 and R 5 may be same or different and independently represent hydrogen, cyano, nitro, amino, hydroxyl, substituted or unsubstituted groups selected from (C ⁇ -C 6 )alkyl, (C ⁇ -C 6 )alkoxy, acyl, (C ⁇ -C 6 )alkylthio, (C 3 - C 6 )cycloalkyl, carboxylic acid or its esters; or R 4 and R 5 when present on adjacent carbon atoms may also form methylenedioxy group, aromatic ring, 5 or 6 membered heterocyclic ring.
  • Suitable groups represented by R and R are selected from hydrogen, halogen atom such as fluorine, chlorine, bromine or iodine; hydroxyl, ( - C 6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t- butyl, n-pentyl, isopentyl, hexyl and the like; (C ⁇ -C 6 )alkoxy group,, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like.
  • Suitable groups represented by R 3 , R 4 and R 5 are selected from hydrogen, cyano, nitro, amino, hydroxyl, (CrC 6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; ( - C 6 )alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; (C !
  • alkylthio group such as methylthio, ethylthio, n-propylthio, iso-propylthio and the like; (C 3 -C 6 )cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like or together represent methylenedioxy group; aromatic group such as phenylene; heterocyclic group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl; carboxylic acid or its esters.
  • Suitable groups represented by R 6 are selected from amino, (C 2 - C 6 )alkenyl, alkoxyalkyl such as methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl and the like; (C C 6 )alkylthio; NHCH 3 , NHC 2 H 5 , NHC 3 H 7, NHC 6 H 13 , N(CH 3 ) 2 , NCH 3 (C 2 H 5 ), N(C 2 H 5 ) 2 ; arylamino group such as phenylamino or naphthylamino, which may be substituted; (C 2 -C 6 )alkenylamino, heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, thiazolin, oxazolin, imidazolyl, isooxazolyl, oxadiazolyl, tri
  • Suitable groups represented by R 8 and R 8b may be selected from heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and the like; heterocyclyl group such as pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, and the like; heteroaralkyl group wherein the heteroaryl moiety is as defined above; an aminoacid residue group selected from glycine,
  • the substituents on any of the groups represented by R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b are selected from halogen, hydroxy, formyl, nitro, cyano, azido, amino, alkyl, aryl, alkylamino, alkylaminocarbonyl, haloalkyl, alkylthio, acylamino, alkoxy, acyl, carboxylic acid or its derivatives such as esters or amides and these substituents are as defined above.
  • salts of the present invention include salts of the 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:
  • N-(-S)- [3 - [4-(3 ,4-Dihydro- 1 H-isoquinolin-2-yl)-3 -fluorophenyl] -2-oxo- oxazolidin- 5 -ylmethyl] -N 1 -phenylthiourea ; N-(6)- [3 - [4-(3 ,4-Dihydro- 1 H-isoquinolin-2-yl)-3 -fluorophenyl]-2-oxo- oxazolidin-S-ylmethyl -N ⁇ allylthiourea ;
  • compound of formula (Ila) may be carried out using sulfonyl chlorides in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out in the presence of base selected from dimethylamino pyridine, triethylamine, pyridine and the like.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature. The duration of the reaction may range from 1 to 4 hrs.
  • the conversion of compound of formula (lib) may be carried out in the presence of one or more equivalents of metal azide such as LiN 3 , NaN 3 or trialkyl silylazide.
  • the reaction may be carried out in the presence of solvent such as THF, acetone, DMF, DMSO and the like or mixtures thereof.
  • the reaction may be carried out in inert atmosphere, which may be maintained using N 2 or Ar.
  • the reaction may be carried out at a temperature in the range of ambient temperature to reflux temperature of the solvent, preferably at a temperature in the range of 80 °C to 100 °C.
  • the reaction time may range from 0.5 to 18 h.
  • the reduction of compound of formula (lie) 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 C0 2 H and the like.
  • Acylation of compound of formula (lid) may be carried out using acylating agents such as anhydrides like acetic anhydride, propionic anhydride, acid chlorides like acetyl chloride, propionyl chloride, thioacids such as thioacetic acid.
  • the reaction may be carried out in the presence of appropriate solvents like tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o- dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature. The duration of the reaction may range from 6 to 12 hrs.
  • R represents SR 7 , wherein R 7 is as defined earlier which comprises reacting the compound of formula (lib)
  • R SH where R is as defined earlier.
  • the conversion of compounds of formula (lib) 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.
  • 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.
  • reaction of a compound of the general formula (He) with a compound of formula (Ilf) may be carried out in the presence of a solvent selected from acetonitrile, DMF, dimethyl acetamide and the like or mixtures thereof.
  • the reaction may be carried out in the presence of base such as diethylamine, triethylamine, DIE A and the like.
  • the reaction temperature may range from 40 °C to reflux temperature.
  • the duration of the reaction may range from 6 to 10 h.
  • the reduction of compound of formula (Ilg) 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 earned out by employing metal in mineral acids such as Sn/HCl, Fe/HCl, Zn/HCl, Zn/CH 3 C0 2 H and the like.
  • the conversion of compound of formula (Ilh) to compound of formula (Hi) 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.
  • the reaction temperature may range from -20 °C to room temperature.
  • the duration of the reaction may range from 3 to 6 hrs.
  • the cyclization of compound of formula (Hi) 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 from -78 °C to -50 °C.
  • the duration of the reaction may range from 2 to 12 hrs.
  • the conversion may be carried out using Lawesson's reagent in the presence of base such as triethyl amine, pyridine and the like and solvents such as toluene, DCC, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o- dichlorobenzene or a mixture thereof.
  • base such as triethyl amine, pyridine and the like and solvents
  • solvents such as toluene, DCC, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o- dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to room temperature. The duration of the reaction may range from 1 to 2 hrs.
  • any reactive group in the substrate molecule may be protected according to conventional chemical practice.
  • Suitable protecting groups in any of the above-mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc.
  • Organic bases such as diethanolamine, ⁇ - phenylethylamine, benzylamine, piperidine, morpholine, pyridine, 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, dibenzoyl 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 hydrolyzing the pure diastereomeric amide.
  • polymorphs of compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe ira-r spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • solvates of the compounds of formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of formula (I) in solvents such as water, methanol, ethanol, mixture of solvents such as acetone: water, dioxane:water, N,N- dimethylformamide:water and the like, preferably water and recrystallizing by using different crystallization techniques.
  • solvents such as water, methanol, ethanol, mixture of solvents such as acetone: water, dioxane:water, N,N- dimethylformamide:water and the like, preferably water and recrystallizing by using different crystallization techniques.
  • the present invention provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable hydrates and solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful 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 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 earners, diluents or solvents.
  • N-(-S)-[3-[4-(3,4-dihydro-(lH)-isoquinolin-2-yl)-3-fluoiOphenyl]- 2-oxo-oxazolidin-5-yl]methylamine prepared according to the procedure described in preparation 7) (103 mg, 0.30 mmoles) in dry dichloromethane (15 ml), pyridine (49 ⁇ l, 0.60 mmoles) was added and the reaction mixture was stirred at 0-4 °C in an ice bath. Then methacryloyl chloride (37.5 ⁇ l, 0.39 mmoles) dissolved in DCM (2 ml) was added under N 2 .
  • the title compound was prepared from N-(-S)-[3-[4-(3,4-dihydro-(lH)- isoquinolin-2-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methylamine (100 mg, 0.29 mmoles) (obtained in preparation 7) and (0.34 mmoles) crotonyl chloride by following the procedure described in example 2 ( 81 mg, yield 68%), mp : 197.9 °C.
  • N-(S)-[3-[4-(3,4-dihydro-(lH)-isoquinolin-2-yl)-3-fluorophenyl]-2-oxo- oxazolidin-5-yl]methylamine (126 mg, 0.36 mmoles) (prepared according to the procedure described in preparation 7) was added and the reaction was allowed to stir at ambient temperature overnight. The reaction mixture was poured in to water and the product was extracted with ethyl acetate. The organic layer was separated and dried over Na 2 S0 and solvent evaporated off under reduced pressure.
  • the title compound was prepared from N-(S)-[3-[4-(3,4-dihydro-(lH)- isoquinolin-2-yl)-3 -fluorophenyl] -2-oxo-oxazolidin-5 -yl]methyl methanesulphonate (100 mg (0.24 mmoles) (prepared according to the procedure described in preparation 5) and 2-mercapto pyridine (32 mg, 0.29 mmoles) by following the procedure described in example 8 (97 mg, yield 93%).
  • the title compound was prepared from N-(-S)-[3-[4-(3,4-dihydro-(lH)- isoquinolin-2-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl methanesulphonate (100 mg, 0.24 mmoles) (prepared according to the procedure described in preparation 5) and 3-mercapto-l,2,4-triazole (29 mg, 0.29 mmoles) by following the procedure described in example 8 (66 mg, yield 65%), mp : 120 °C.
  • the title compound was prepared from N-(S)-[3-[4-(3,4-dihydro-(lH)- isoquinolin-2-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl methanesulphonate (150.6 mg, 0.36 mmoles) (prepared according to the procedure described in preparation 5) and 4-mercapto pyridine (47.8 mg, 0.43 mmoles) by following the procedure described in example 8 (57 mg, yield 36%), mp : 135.9 °C.
  • the title compound was prepared from N-(S)-[3-[4-(3,4-dihydro-(lH)- isoquinolin-2-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl methanesulphonate (105.4 mg, 0.25 mmoles) (prepared according to the procedure described in preparation 5) and thiophenol (70 mg, 0.64 mmoles) by following the procedure described in example 8 (35 mg, yield 33%), mp : 249 °C.
  • the title compound was prepared from N-(S)-[3-[4-(3,4-dihydro-(lH)- isoquinolin-2-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl methanesulphonate (152.2 mg, 0.36 mmoles) (prepared according to the procedure described in preparation 5) and 2-mercapto thiazoline (106.7 mg, 0.89 mmoles) by following the procedure described in example 8 (70 mg, yield 44 % yield), mp : > 250 °C.
  • the title compound was prepared from N-(-S)-[3-[4-(3,4-dihydro-(lH)- isoquinolin-2-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl methanesulphonate (125 mg, 0.30 mmoles) (prepared according to the procedure described in preparation 5) and 2-mercapto pyrimidine (40 mg, 0.36 mmoles) by following the procedure described in example 8 (97 mg, yield 75%).
  • the title compound was prepared from N-( )-[3-[4-(3,4-dihydro-(lH)- isoquinolin-2-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl methanesulphonate (150 mg, 0.36 mmoles) (prepared according to the procedure described in preparation 5) and 2-mercapto thiazole (48 mg, 0.41 mmoles) by following the procedure described in example 8 (21 mg, yield 13%), mp : 106.1 °C.
  • the title compound was prepared from N-(-S)-[3-[4-(3,4-dihydro-(lH)- isoquinolin-2-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl methanesulphonate (151 mg, 0.36 mmoles) (prepared according to the procedure described in preparation 5) and 2-mercapto- 1, 3 -benzothiazole (72.3 mg, 0.42 mmoles) by following the procedure described in example 8 (20 mg, yield 12%), mp : > 250 °C.
  • the title compound was prepared from N-(S)-[3-[4-(3,4-dihydro-(lH)- isoquinolin-2-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl methanesulphonate (150.6 mg, 0.36 mmoles) (prepared according to the procedure described in preparation 5) and 5-methyl-2-mercapto-l,3,4-thiadiazole (88 mg, 0.67 mmoles) by following the procedure described in example 8 (40 mg, yield 25%), mp : 186.8 °C.
  • the title compound was prepared from N-(S)-[3-[4-(3,4-dihydro-(lH)- isoquinolin-2-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methylamine (108.4 mg, 0.32 mmoles) (prepared according to the procedure described in preparation 7) and phenyl isothiocyanate (76 ⁇ l, 0.64 mmoles) by following the procedure described in example 19 (120 mg, yield 79%), mp : > 250 °C.
  • the title compound was prepared from N-(jS)-[3-[4-(3,4-dihydro-(lH)- isoquinolin-2-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methylamine (115.4 mg 0.33 mmoles) (prepared according to the procedure described in preparation 7) and allyl isothiocyanate 80 ⁇ l (0.82 mmoles) by following the procedure described in example 19 (107 mg, yield 72%), mp : 162 °C.
  • the compounds of invention showed in vitro antibacterial activity when tested by the Agar Dilution Method as specified in documents published by the National Committee for Clinical Laboratory Standards (NCCLS), USA.
  • the compounds of invention were weighed, dissolved in Dimethyl Sulfoxide, serially diluted in the same solvent and then 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 colony forming units (CFU) per milliliter of suspension.
  • CFU colony forming units
  • the bacterial inoculum prepared in the above manner was inoculated onto petri dishes containing Mueller Hinton Agar which had earlier been incorporated with different dilutions of the compounds of invention by a Multipoint Inoculator with each inoculum spot containing approximately 1 x 10 4 colony forming units
  • Petridishes were incubated at 35°Celsius in an ambient atmosphere for 20 hours. Petridishes containing different concentrations of Nancomycin and Oxacillin and inoculated with Staphylococcus aureus, Coagulase Negative Staphylococci and Enterococci were incubated for 24 hours.
  • MIC Minimum Inhibitory Concentration

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Abstract

L'invention concerne des composés nouveaux représentés par la formule générale (I), y compris leurs dérivés, analogues, formes tautomères stéréo-isomères, polymorphes, hydrates, solvates, sels pharmaceutiquement acceptables et compositions pharmaceutiquement acceptables les renfermant. L'invention concerne plus particulièrement des dérivés d'oxazolidinone représentés par la formule générale (I)
PCT/IB2003/002602 2002-06-12 2003-06-10 Derives de 1h-isoquinoline-oxazolidinone, et leur utilisation comme agents antibacteriens Ceased WO2003106454A1 (fr)

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WO2008037482A1 (fr) 2006-09-27 2008-04-03 Julius-Maximilians-Universität Würzburg Effet d'entravement des biofilms ainsi qu'activité anti-infectieuse des arylisoquinoléines n,c-liées et leur utilisation
ITMI20081233A1 (it) * 2008-07-07 2010-01-08 Dipharma Francis Srl Sali di linezolid e loro uso nella preparazione di forme cristalline di linezolid
US7960436B2 (en) 2006-06-05 2011-06-14 Valeant Pharmaceuticals International Substituted arylamino-1,2,3,4-tetrahydro naphthalenes and-2,3-dihydro-1H-indenes as potassium channel modulators
US8211918B2 (en) 2007-08-13 2012-07-03 Valeant Pharmaceuticals International Derivatives of 5-amino-4,6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators
US8293911B2 (en) * 2006-08-23 2012-10-23 Valeant Pharmaceuticals International Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators
US8367684B2 (en) 2007-06-13 2013-02-05 Valeant Pharmaceuticals International Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators
US8563566B2 (en) 2007-08-01 2013-10-22 Valeant Pharmaceuticals International Naphthyridine derivatives as potassium channel modulators
US8722929B2 (en) 2006-10-10 2014-05-13 Valeant Pharmaceuticals International N-[2-amino-4-(phenylmethoxy)phenyl] amides and related compounds as potassium channel modulators
US8993593B2 (en) 2006-08-23 2015-03-31 Valeant Pharmaceuticals International N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide as potassium channel modulators
CN109641836A (zh) * 2016-06-10 2019-04-16 赛弗卢尔生命科学公司 氟化的2-氨基-4-(取代的氨基)苯基氨基甲酸酯衍生物
US12171759B1 (en) 2021-02-09 2024-12-24 Xenon Pharmaceuticals Inc. Methods and uses for treating anhedonia
US12178811B2 (en) 2019-11-08 2024-12-31 Xenon Pharmaceuticals Inc. Methods of treating depressive disorders

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WO2001042242A1 (fr) * 1999-08-12 2001-06-14 Ortho-Mcneil Pharmaceutical, Inc. Phenyl-oxazolidinones substitutees heterobicycliques antibacteriennes
WO2002064574A2 (fr) * 2001-02-07 2002-08-22 Ortho-Mcneil Pharmaceutical, Inc. Antibactériens à base de pyridoarylphényle oxazolidinone, compositions et procédés associés

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WO2001042242A1 (fr) * 1999-08-12 2001-06-14 Ortho-Mcneil Pharmaceutical, Inc. Phenyl-oxazolidinones substitutees heterobicycliques antibacteriennes
WO2002064574A2 (fr) * 2001-02-07 2002-08-22 Ortho-Mcneil Pharmaceutical, Inc. Antibactériens à base de pyridoarylphényle oxazolidinone, compositions et procédés associés

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7960436B2 (en) 2006-06-05 2011-06-14 Valeant Pharmaceuticals International Substituted arylamino-1,2,3,4-tetrahydro naphthalenes and-2,3-dihydro-1H-indenes as potassium channel modulators
US8338487B2 (en) 2006-06-05 2012-12-25 Valeant Pharmaceuticals International, Inc. Substituted arylamino-1,2,3,4-tetrahydro naphthalenes and -2,3-dihydro-1H-indenes as potassium channel modulators
US8993593B2 (en) 2006-08-23 2015-03-31 Valeant Pharmaceuticals International N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide as potassium channel modulators
US8293911B2 (en) * 2006-08-23 2012-10-23 Valeant Pharmaceuticals International Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators
WO2008037482A1 (fr) 2006-09-27 2008-04-03 Julius-Maximilians-Universität Würzburg Effet d'entravement des biofilms ainsi qu'activité anti-infectieuse des arylisoquinoléines n,c-liées et leur utilisation
EP2074100B1 (fr) * 2006-09-27 2013-08-28 Julius-Maximilians-Universität Würzburg Effet d'entravement des biofilms ainsi qu'activité anti-infectieuse des arylisoquinoléines n,c-liées et leur utilisation
US8722929B2 (en) 2006-10-10 2014-05-13 Valeant Pharmaceuticals International N-[2-amino-4-(phenylmethoxy)phenyl] amides and related compounds as potassium channel modulators
US8367684B2 (en) 2007-06-13 2013-02-05 Valeant Pharmaceuticals International Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators
US8563566B2 (en) 2007-08-01 2013-10-22 Valeant Pharmaceuticals International Naphthyridine derivatives as potassium channel modulators
US8211918B2 (en) 2007-08-13 2012-07-03 Valeant Pharmaceuticals International Derivatives of 5-amino-4,6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators
ITMI20081233A1 (it) * 2008-07-07 2010-01-08 Dipharma Francis Srl Sali di linezolid e loro uso nella preparazione di forme cristalline di linezolid
CN109641836A (zh) * 2016-06-10 2019-04-16 赛弗卢尔生命科学公司 氟化的2-氨基-4-(取代的氨基)苯基氨基甲酸酯衍生物
EP3468947A4 (fr) * 2016-06-10 2020-01-08 SciFluor Life Sciences, Inc. Dérivés fluorés 2-amino-4-(amino substitué)phényl carbamate
US11858900B2 (en) 2016-06-10 2024-01-02 Ocuterra Therapeutics, Inc. Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives
US12178811B2 (en) 2019-11-08 2024-12-31 Xenon Pharmaceuticals Inc. Methods of treating depressive disorders
US12171759B1 (en) 2021-02-09 2024-12-24 Xenon Pharmaceuticals Inc. Methods and uses for treating anhedonia

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