EP2170874A2 - Nouveaux composés et leur utilisation - Google Patents

Nouveaux composés et leur utilisation

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Publication number
EP2170874A2
EP2170874A2 EP08762934A EP08762934A EP2170874A2 EP 2170874 A2 EP2170874 A2 EP 2170874A2 EP 08762934 A EP08762934 A EP 08762934A EP 08762934 A EP08762934 A EP 08762934A EP 2170874 A2 EP2170874 A2 EP 2170874A2
Authority
EP
European Patent Office
Prior art keywords
methyl
piperazin
methylcarbamothioate
oxooxazolidin
groups
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.)
Withdrawn
Application number
EP08762934A
Other languages
German (de)
English (en)
Other versions
EP2170874A4 (fr
Inventor
Simi Pushpan
Uma Ramachandran
Mrinalkanti Kundu
Veenaa Anantharaman
Santhosh Subramanian
Radhakrishnan Viswanathan
Ravikumar Tadiparthi
Maneesh Paul-Sathyaseela
Shakti Singh Solanki
Kesavan Koppolu
Sathishkumar Devarajan
Martin Gnanamuthu
Thanga Mariappan
Narayanan Surendran
Sriram Rajagopal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Orchid Research Laboratories Ltd
Original Assignee
Orchid Research Laboratories Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Orchid Research Laboratories Ltd filed Critical Orchid Research Laboratories Ltd
Publication of EP2170874A2 publication Critical patent/EP2170874A2/fr
Publication of EP2170874A4 publication Critical patent/EP2170874A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • 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
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • novel compounds of the general formula (I) their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and 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 oxazolidinone derivatives of the formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof.
  • This invention also relates to intermediates useful in the preparation of such compounds.
  • novel oxazolidinone derivatives of the present invention are useful as antibacterial agents in the treatment of conditions such as nosocomial pneumonia, community acquired pneumonia, infections caused by vancomycin resistant enterococci (VRE), methicillin resistant Staphylococcus aureus (MRSA), Heamophilus influenzae (HI) and penicillin resistant Streptococcus pneumoniae (PRSP).
  • VRE vancomycin resistant enterococci
  • MRSA methicillin resistant Staphylococcus aureus
  • HI Heamophilus influenzae
  • PRSP penicillin resistant Streptococcus pneumoniae
  • the compounds of the present invention are effective against a number of human or animal pathogens including PRSP, VRE, MRSA and HI.
  • WO 97/09328 discloses compounds of formula (II) in which X is NR 1 , S(O) g or O; R 1 is a hydrogen, (Ci-C 6 )alkyl optionally substituted with one or more OH, CN, or halo or R 1 is -(CH 2 ) h -aryl, -COR 1"1 , COOR 1'2 , -CO- (CH 2 ) H -COR 1'1 , (Ci-C 6 )alkylsulfonyl, -SO 2 -(CH 2 ) h -aryl or -(CO), -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, (C[-Ci 2 )alkyl optionally substituted with one or more halo, (C 3
  • R 6 ⁇ -B wherein R 1 is chloro, fluoro, (C
  • -C 4 )alkylaminocarbonyloxy; or of the formula -NHC( O)R b wherein R b is hydrogen, (C] ⁇ C 4 )alkoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino, dimethylamino or (Cr C 4 )alkyl; or of the formula -NHS(O) n (C ⁇ -C 4 )alkyl where n is 0, 1 or 2; R 2 and R 3 are independently hydrogen or fluoro; >A-B- is >CH-CH 2 ; R 6 is (Ci-C 4 )alkyl, (C r C i)
  • 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
  • R] represents an alkyl group which may be substituted, or a cycloalkyl group which may be substituted; and R 2 , R 3 and R 4 independently represent hydrogen atom, a halogen atom, substituted or unsubstituted an alkyl, alkoxyl, amino, alkanoyl, cycloalkyloxy or a saturated heterocyclic group.
  • WO 2005003087 discloses oxazolidinone derivatives as antibacterial agents of formula (VIl)
  • R 9 is hydrogen, substituted or unsubstituted groups selected from (C]-C 6 ) alkyl, (Ci-C 6 ) alkoxy, aryl, X and Y represent oxygen or sulfur
  • a and B are different and represent CH or N
  • R 2 and R 3 may be same or different and independently represent hydrogen, halogen, hydroxy, alkyl and 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
  • R 4 and R 5 represent hydrogen, cyano, nitro, amino, halogen and hydroxy!
  • p is an integer of 1
  • R 6 represents a substituted or unsubstituted groups selected from aryl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclyl, hetero
  • WO 20000332599 discloses oxazolidinone antibacterial agents having a thiocarbonyl functionality of formula (VIII)
  • Ri is H, NH 2 , NHalkylC, -4 ; N(alkylC M ) 2 ; alkylC M ; OalkylC l-4 ; SalkylCu; alkylC ⁇ , R 23 and R 24 are same or different and are H 5 F, Cl, Ci -2 alkyl, CN, OH, nitro and amino; W represents 0, I, 2 or 3; Z 2 is -O 2 S-, -O-, ⁇ N(Rio7)-,-OS-, or -S-; Rio?
  • novel oxazolidinone derivatives of the formula (I) are useful as antibacterial agents, 0 useful in the treatment of conditions such as nosocomial pneumonia, community acquired pneumonia, infections caused by vancomycin resistant enterococci (VRE), methicillin resistant Staphylococcus aureus (MRSA), Heamophilus influenzae (HI) and penicillin resistant Streptococcus pneumoniae (PRSP).
  • VRE vancomycin resistant enterococci
  • MRSA methicillin resistant Staphylococcus aureus
  • HI Heamophilus influenzae
  • PRSP penicillin resistant Streptococcus pneumoniae
  • the compounds of the present invention are effective against a number of human or animal pathogens including VRE, 5 PRSP, HI and MRSA.
  • the present invention relates to novel oxazolidinone derivatives of the formula
  • R 8 represents substituted or unsubstituted groups selected from (Ci-C 6 )alkyl; haloalkyl; (C 3 - C6)cycloalkyl; alkylamine; aryl; aralkyl; heterocyclyl; heteroaryl; alkylsulfonyl; arylsulfonyl and aralkylsulfonyl; n is an integer of 0 or 1.
  • the present invention relates to novel oxazolidinone derivatives of the formula 0),
  • R ! suitable groups represented by R ! are selected from hydrogen; (Ci- Ce)alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, /-butyl, n- pentyl, isopentyl, hexyl and the like, which may be substituted; haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichioromethyl, dichloroethyl and the like, which may be substituted; (C 3 -C6)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, which may be substituted;
  • Suitable groups represented by R 2 and R 3 are selected from hydrogen; halogen atoms such as fluorine, chlorine, bromine or iodine; hydroxyl; (Ci-C 6 ) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, /-butyl, n-pentyl, isopentyl, hexyl and the like, which may be substituted; (Ci-C 6 ) alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy and the like, which may be substituted.
  • Suitable groups represented by R 4 and R 5 are selected from hydrogen; cyano; nitro; amino; halogen; hydroxyl; (Ci-C 6 ) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, /-butyl, n-pentyl, isopentyl, hexyl and the like, which may be substituted; haloalkyl such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like, which may be substituted; (C]-C 6 ) alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy and the like, which may be substituted; (C)-C6)alkylthio groups such as methylthio, ethylthio, n- propylthio, iso
  • Suitable groups represented by R 6 are selected from a (C 1 -C 6 ) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, /-butyl, n-pentyl, isopentyl, hexyl and the like, which may be substituted; mono or dihydroxyalkyloxymethyl groups like HO-CH 2 -CH 2 -O-CH 2 -, HO-CH 2 -CH(OH)-CH 2 -O-CH 2 -; haloalkyl such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like, which may be substituted; (C 3 -C O ) cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl,
  • X and Y independently represent oxygen or sulfur; Z represent oxygen or sulphur or N(O) n R 7 , wherein suitable groups represented by R 7 are selected from hydrogen; hydroxyl; substituted or unsubstituted linear or branched (Ci-C 6 )alkyl groups such as methyl, ethyl, n-propyl, isopropy), n-butyl, isobuty], /-butyl, n-pentyl, hexyl and the like, which may be substituted; (C 3 -C 6 ) cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, which may be substituted; haloalkyl groups such as chloromethyl, chioroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like, which may be substituted;
  • the substituents on any of the groups represented by R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are selected from one or more groups represented by halogen; hydroxy; formyl; nitro; cyano; azido; amino; alkyl; aryl; alkylamino; alkylsulfonylamino; aralkoxy; airylthio; alkylaminocarbonyl; haloalkyl; alkylthio; acylamino; alkoxy; acyl; cycloalkylacyl; heteroarylacyl; N-hydroxyimidamide; carboxylic acid and its derivatives such as esters and amides and these substituents are as defined above.
  • the above substituents, which in turn are further substituted by the groups, selected from alkyl; halogen; amino; nitro; hydroxy and the like.
  • 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 diethanolami ⁇ e, ⁇ -phe ⁇ ylethylamine, benzylamine, piperidi ⁇ e, 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, perch lorates, 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: 1. (5)-0-Mcthyl(3-(4-(4-(benzofuran-2-carbonyl)piperazin-l-yl)-3-fluorophenyl)-2- oxooxazolidin-5-yl)methylcarbamothioate;
  • a process for the preparation of novel oxazolidinone derivatives of the formula (I) where X and Y represents O or S, and all other symbols are as defined earlier, which comprises (i) Converting the compound of formula (II) wherein P represents protecting groups such as benzyl, benzyloxy carbonyl, t- butyloxycarbonyl, chloroethyl formate, 9H-(f)luoren-9-yl(m)eth(o)xy(c)arbonyl and all other symbols are as defined earlier to produce a compound of formula (III)
  • the compound of formula (II) may be converted to a compound of formula (III) using methane sulfonyl chloride, tosyl chloride, and trifluoromethane sulfonyl chloride.
  • the reaction may be carried out in 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 0 C to room temperature. The duration of the reaction may range from l to 12 hours.
  • the conversion of compound of formula (III) 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 a 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 used, preferably at a temperature in the range of 60 0 C to 120 0 C.
  • the reaction time may range from 0.5 to 18 hours.
  • the reduction of compound of formula (IV) may be carried out in the presence of gaseoug, 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, alcohols such as methanol, ethanol, isopropanol and the like or mixtures thereof.
  • a pressure between atmospheric pressure to 80 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 hours.
  • the reduction may also be carried out by employing metals in mineral acids such as Sn/HCl, Fe/HCl, Zn/HCl, Zn/CH 3 CO 2 H, Zn- HCO 2 H/HCOONH 4 and the like.
  • mineral acids such as Sn/HCl, Fe/HCl, Zn/HCl, Zn/CH 3 CO 2 H, Zn- HCO 2 H/HCOONH 4 and the like.
  • VJ may be carried out using thiophosgene or phosgene gas in the presence of a solvent such as tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • a 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 0 C to room temperature.
  • the conversion of compound of formula (VI) to compound of formula (VII) may be carried out using alcohols 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 0 C to reflux temperature. The duration of the reaction may range from 6 to 18 hours.
  • the conversion of compound of formula (V) to produce compound of formula (VII) may be carried out using alkylhaloformates such as chloroethylchloroformate, arylchloroformates such as benzylchloroformates, heteroarylchloroformates in presence of organic bases selected from dimethylamino pyridine, triethylamine, pyridine and the like or in presence of inorganic bases selected from sodium bicarbonate, sodium carbonate and cesium carbonate and the like, in presence of solvents such as dichloromethane, acetone, DMF, water, THF and the like or mixtures thereof.
  • the reaction temperature may range from -20 0 C to room temperature.
  • the duration of the reaction may range from 3 to 18 hours.
  • the deprotection of compound of formula (VII) may be carried out using an inorganic acid such as trifluoroacetic acid, hydrochloric acid and sulfuric acid.
  • the reaction may be carried out in 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 0 C to 40 0 C.
  • the duration of the reaction may range from 1 to 6 hours.
  • reaction of compound of formula (VIII) with compound of formula (IX) may be carried out in solvents such as toluene, dimethylformamide, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, dioxane, ethylacetate, o-dichlorobenzene or a mixture thereof with or without organic or inorganic bases such as triethyl amine, pyridine, dimethylaminopyridine, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and the like in the absence or presence of reagents such as (DCC) dicyclohexylcarbodiimide, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), benzotriazole- 1 -yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphat
  • reaction may be carried out at a temperature in the range of 0 0 C to 40 0 C.
  • duration of the reaction may range from 1 to 2 hours.
  • L) represents a leaving group such as mesylate, tosylate or triflate with azides to produce a compound of formula (XI) i) Converting the compound of formula (X) to produce a compound of formula (XI) wherein all symbols are as defined earlier,
  • the conversion of compound of formula (X) 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 a solvent such as THF, acetone, DMF,
  • the reaction may be carried out in an 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 used, preferably at a temperature in the range of 60 0 C to 120 0 C.
  • the reaction time may range from 0.5 to 18 hours.
  • a process for the conversion of compounds of formula (I) where X or Z represents the O and all other symbols are as defined above to compounds of formula (I) where X or Z is S, and all other symbols are as defined earlier.
  • the conversion may be carried out in presence of acid or 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, dichioromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 20 0 C to 120 0 C.
  • the duration of the reaction may range from 1 to 12 hours.
  • the reaction of compound of formula (Ha) with the compound of formula (lib) may be carried out in the presence of BINAP [(R)-2,2'-Bis(diphenylphosphino)-l,l'- 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.
  • the reaction is carried out at temperature in the range of 20 0 C to 60 0 C.
  • 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 80 psi may be used.
  • the reaction may be carried out at a temperature in the range of 25 to 60 0 C, preferably between 30 0 C and 40 0 C.
  • the reaction time ranges from 2 to 48 hours.
  • the reduction may also be carried out by employing metals in mineral acids such as Sn/HCl, Fe/HCl, Zn/HCl, Zn/CH 3 CO 2 H, Zn/HCO 2 H/HCOONH 4 and the like.
  • the conversion of compound of formula (Hd) to compound of formula (He) may be carried out using benzyloxycarbonyl chloride in the presence of inorganic or organic base such as sodium bicarbonate, caesium carbonate, potassium carbonate, triethylamine, diisopropylamine, N,N-dimethylaniline, lutidine and the like, in solvents such as acetone, DMF, water, THF and the like or mixtures thereof.
  • the reaction temperature may range from -20 0 C to 40 0 C.
  • the duration of the reaction may range from 2 to 18 hours.
  • the cyclization of compound of formula (He) 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 i?-(-)-glycidyl butyrate.
  • the reaction is carried out at a temperature in the range of -80 0 C to -50 0 C.
  • the duration of the reaction may range from 2 to 12 hours.
  • 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 /-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, tetrahydrofuran, methanol, /-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, jo-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, jo-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 treatment with chiral amines, aminoacids, aiminoaicohols derived from aminoacids; conventional reaction conditions may be employed to convert the 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.
  • 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 gradual or fast cooling of compound after heating or melting. 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 (1) 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.
  • compounds of the invention may contain groups that may exist in tautomeric forms, and though one form is named, described, displayed and/or claimed herein, all the forms are intended to be inherently included in such name, description, display and/or claim.
  • Prodrugs of the compounds of formula (I), are also contemplated by this invention.
  • a prodrug is an active or inactive compound that is modified chemically through in-vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • the suitability and techniques involved in making and using prodrugs are well known to those skilled in the art.
  • the present invention also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I), as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like.
  • the derivatives provided by the present invention can be employed as pharmaceutical compositions, for example, in the form of pharmaceutical compositions containing the derivatives together with appropriate, pharmaceutically acceptable carriers.
  • the products in accordance with the invention can be administered, for example, perorally, such as in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, or rectally, such as in the form of suppositories, etc.
  • the compositions may be sterilized and may contain auxiliary agents generally employed in the pharmaceutical art, such as sodium hydrogen carbonate, citric acid, propylene glycol, tween 80, etc.
  • the compounds can be used orally or parenteral Iy.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, 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, such as by combining the ingredients into a dosage form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and if desired, the usual pharmaceutical adjuvants.
  • the amount of the active ingredient in the composition may be less than 70% by weight.
  • Such compositions typically contain from 1 to 25%, preferably 1 to 15% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents, excipients or solvents.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
  • the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-aeceptable acid addition salts or alkali or alkaline earth metal salts of the compounds.
  • the injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the effective dose for treating a particular condition in a patient may be readily determined and adjusted by the physician during treatment to alleviate the symptoms or indications of the condition or disease.
  • a daily dose of active compound in the range of about 0.01 to 1000 mg/kg of body weight is appropriate for administration to obtain effective results.
  • the daily dose may be administered in a single dose or divided into several doses. In some cases, depending upon the individual response, it may be necessary to deviate upwards or downwards from the initially prescribed daily dose.
  • Typical pharmaceutical preparations normally contain from about 0.2 to about 500 mg of active compound of formula I and/or its pharmaceutically active salts or solvates per dose.
  • the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents.
  • the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
  • the term "therapeutically effective amount” or “effective amount” refers to that aimount of a compound or mixture of compounds of Formula I that is sufficient to effect treatment, as defined below, when administered alone or in combination with other therapies to a mammal in need of such treatment.
  • animal as used herein is meant to include all mammals, and in particular humans. Such animals are also referred to herein as subjects or patients in need of treatment.
  • the therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound of Formula I chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.
  • treatment means any treatment of a disease in a mammal, including: a) Preventing the disease, that is, causing the clinical symptoms of the disease not to develop; b) Inhibiting the disease, that is, slowing or arresting the development of clinical symptoms; and/or c) Relieving the disease, that is, causing the regression of clinical symptoms.
  • 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.
  • 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 ⁇ -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) 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
  • efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.
  • Tri fluoroacetic acid (16.4ml, 0.2mmol) was added to a cold (0 0 C) solution of G'?)-r-butyl-4-(2-fluoro-4-(5-((methoxycarbonothioylamino)methyl)-2-oxooxazoIidin-3- yljphenyl) piperazine-l-carboxylate (5.0g, 10.6mmol), obtained according to the procedure given in the step 2, in dry DCM (100ml) under stirring. After completion of the addition the reaction mixture was allowed to stir at room temperature for 3 hours.
  • Example 56 (5)-S-Methyl(3-(3-fluoro-4-(4-(morpholine-4-carbonothioyl) piperazin-l-yl)phenyl)-2-oxooxazolidin-5-y.I)inethylcarbamothioate:
  • the precipitate (0.49g, 1.03mmol) was then suspended in DCM (5ml) and the reaction mixture and it was cooled to 10 0 C, into which triethyl amine (0.6ml, 4.28mmol) and thiophosgene (0.08ml, 1.03mmol) were added under stirring over 30 minutes.
  • the reaction mass was allowed to attain ambient temperature and was further slirred for another 90 minutes.
  • Morpholine (0.3ml, 3.21mmol) was added into the reaction mixture and was allowed to stir for another 15 hours. On completion of the reaction, the resulting mixture was diluted with DCM (30ml) and washed with water wash thrice.
  • the organic layer was separated, dried over anhydrous Na 2 SO 4 and solvent was removed under vacuum to yield a yellow residue.
  • the crude product obtained was purified by flash chromatography on silica gel using a Biotage SP-I system (12+M) cartridge using ethyl acetate and hexane as eluent to afford the title compound (0.04 g, 8.0%).
  • Example 57 (5)-S-Methyl (3-(4-(4-(2-(2,5-dichlorophenylthio)acetyl) piperazin-1- yl)-3-fluorophenyI)-2-oxooxazolidin-5-yl)methyIcarbamothioate
  • Compound 53 (0.25g, 0.56mmol) was dissolved in DMF (2 ml) and the reaction mixture was cooled to -20 0 C into which 2,6-lutidine (0.28 ml, 0.67 mmol) was added dropwise and stirred for 10 minutes.
  • 2,5-dichlorothiophenol (0.12g, 0.67mmol) was added into the chilled mixture and it was stirred for another 30 minutes, subsequently the temperature of the reaction mixture was raised to 0 0 C and stirred for another 3 hours. After completion of reaction, the mixture was poured into 100ml of ice-cold water and stirred for 10 minutes. The white precipitate thus obtained was filtered, dried and purified by flash chromatography on silica gel using a Biotage SP-I system (12+M) cartridge using ethyl acetate and hexane as eluent to afford the title compound (0.042 g, 13%).
  • the crude product was purified by flash chromatography on silica gel using a Biotage SP-I system (12+M) cartridge using ethyl acetate and hexane as eluent to afford the title compound (0.08g, 11.6%).
  • the crude reaction material was purified by flash chromatography on silica gel using a Biotage SP-I system (12+M) cartridge using ethyl acetate and hexane as eluent to afford the title compound (0.03g, 6.1%).
  • Example 76 Synthesis of (S)-O-methyl (3-(4-(4-(lH-imidazoIe-l-carbonothioyI) piperazin-l-yl)-3-fluorophenyl)-2-oxooxazoIidin-5-yI)methyl carbamothioate To a stirred solution of O-methyl-(iS)-N-[3-[3-fluoro-4-[piperazin-l-yl]pheny!]-
  • 2-oxo-oxazolidin-5-ylmethyl]thiocarbamate (2.35g, 6.4mmol), prepared according to the procedure described in the step 3 of example 1 in DMF (10ml), was added 1,1*- thiocarbonyl diimidazole (1.37g, 7.68mmol) and triethyl amine (3.56ml, 25.6mmol) at ambient temperature, and the stirring was continued for another 15 hours.
  • the crude product was partitioned between EtOAc and water, the ethyl acetate layer was then separated, dried over anhydrous Na 2 SO 4 and the solvent was removed under vacuurn.
  • the compounds of invention showed in vitro antibacterial activities when tested by the Agar Dilution Method as specified in documents published by the National Committee for Clinical Laboratory Standards (NCCLS, now CLSI), USA.
  • the compounds of invention were weighed, dissolved in dimethyl sulfoxide, serially two fold diluted in the same solvent and then incorporated into molten Mueller Hinton Agar (MHA) in a petridish just before solidification, with each petridish containing a different concentration of a compound.
  • MHA Mueller Hinton Agar
  • 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, transferring the growth to a tube containing 3mL of normal saline and adjusting the turbidity of the saline suspension to 0.5 Mc Farland Turbidity Standard equivalent to a bacterial population of 1.5 x 10 8 colony forming units (CFU) per mL of suspension.
  • the suspension was diluted 1 : 10 in saline (i.e. 0.5mL suspension + 4.5mL saline) to get a bacterial population of 1.5 x 10 7 CFU/mL as in
  • the bacterial inoculum prepared in the above manner was inoculated onto MHA which had earlier been incorporated with different concentration of the compounds of invention by a Multipoint Inoculator with each inoculum spot containing approximately 1 x 10 4 CFU of bacteria.
  • the inoculated petridishes were incubated at 35 0 C in an ambient atmosphere for 16-20 hours. Following incubation, the petridishes were placed on a dark non- reflecting surface and the Minimum Inhibitory Concentration (MIC) was recorded as the concentration that showed no growth of.the inoculated culture.
  • MIC Minimum Inhibitory Concentration
  • the novel compounds synthesized have shown MIC values ranging from ⁇ 0.03 to >32 ⁇ g/ml against gram-positive and gram-negative pathogens including MRSA, PRSP, VRE, M. catarrhal ⁇ and H. influenza

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Abstract

La présente invention concerne de nouveaux composés représentés par la formule générale (i), leurs dérivés, analogues, formes tautomères, stéréoisomères, polymorphes, hydrates, solvates, sels pharmaceutiquement acceptables ainsi que leurs compositions, métabolites et promédicaments. Les nouveaux composés se révèlent utiles en tant qu'agents antibactériens pour le traitement de pathologies telles qu'une pneumonie nosocomiale, une pneumonie acquise dans la collectivité, des infections causées par des entérocoques résistants à la vancomycine (ERV) et des bactéries telles que Staphylococcus aureus résistant à la méthicilline (SARM), Heamophilus influenzae (HI) et Streptococcus pneumoniae résistant à la pénicilline (SPRP). Les composés de la présente invention se révèlent efficaces contre un certain nombre de pathogènes humains ou animaux, notamment ERV, SPRP, HI et SARM.
EP08762934A 2007-06-22 2008-06-20 Nouveaux composés et leur utilisation Withdrawn EP2170874A4 (fr)

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KR20110092309A (ko) * 2008-11-20 2011-08-17 파나세아 바이오테크 리미티드 신규 항균제
WO2013054275A1 (fr) * 2011-10-11 2013-04-18 Council Of Scientific & Industrial Research Sila-analogues de dérivés d'oxazolidinone et synthèse de ceux-ci
WO2017156519A1 (fr) * 2016-03-11 2017-09-14 The Board Of Trustees Of The University Of Illinois Petites molécules actives contre les bactéries à gram négatif
US11274106B2 (en) 2017-06-23 2022-03-15 The Board Of Trustees Of The University Of Illinois Topoisomerase inhibitors with antibacterial and anticancer activity
CN115466253B (zh) * 2021-06-16 2024-08-20 沈阳药科大学 含二硫代氨基甲酸酯结构的噁唑烷酮类化合物及其制备方法

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US20010041728A1 (en) * 1997-05-30 2001-11-15 Hester Jackson B. Oxazolidinone antibacterial agents having a thiocarbonyl functionality
WO2001044212A1 (fr) * 1999-12-14 2001-06-21 Pharmacia & Upjohn Company Esters d'acide benzoique d'oxazolidinones presentant un substituant d'hydroxyacetylpiperazine
US20020137754A1 (en) * 2000-02-10 2002-09-26 Hester Jackson B. Oxazolidinone thioamides with piperazine amide substituents
WO2004045616A1 (fr) * 2002-11-21 2004-06-03 Pharmacia & Upjohn Company Llc Derives de n-(4-(piperazine-1-yl)-phenyl-2-oxazolidinone-5-carboxamides et composes associes servant d'agents antibacteriens
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