WO2003093247A2 - Nouveaux agents antibacteriens - Google Patents

Nouveaux agents antibacteriens Download PDF

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Publication number
WO2003093247A2
WO2003093247A2 PCT/IB2003/001571 IB0301571W WO03093247A2 WO 2003093247 A2 WO2003093247 A2 WO 2003093247A2 IB 0301571 W IB0301571 W IB 0301571W WO 03093247 A2 WO03093247 A2 WO 03093247A2
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Prior art keywords
phenyl
methyl
oxo
fluoro
oxazolidin
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PCT/IB2003/001571
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English (en)
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WO2003093247A3 (fr
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Shiv Kumar Agarwal
Surendrakumar Satyanarayan Pandey
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Orchid Chemicals & Pharmaceuticals Ltd
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Priority to AU2003224345A priority Critical patent/AU2003224345A1/en
Publication of WO2003093247A2 publication Critical patent/WO2003093247A2/fr
Publication of WO2003093247A3 publication Critical patent/WO2003093247A3/fr

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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
    • 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
    • C07D417/02—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
    • C07D417/10—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 carbon chain containing aromatic rings

Definitions

  • the present invention provides novel oxazolidinone derivatives of the formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts and pharmaceutically acceptable compositions containing them.
  • the present invention more particularly provides novel oxazolidinone derivatives of the general formula (I).
  • the present invention also provides a process for the preparation of the above said novel oxazolidinone derivatives of the formula (I) their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them.
  • novel oxazolidinone derivatives of the present invention are useful as antibacterial agents and hence useful in the treatment of conditions such as nosocomial pneumoniae, community acquired pneumoniae, vancomycin resistance enterococci (VRE) caused by methicillin resistance staphylococcus aureus (MRSA) and penicillin resistant streptococcus pneumoniae.
  • VRE vancomycin resistance enterococci
  • MRSA methicillin resistance staphylococcus aureus
  • penicillin resistant 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 resistant organisms, methicillin resistant organisms. Background of Invention
  • R is a hydrogen, (C r C 8 )alkyl optionally substituted with one or more F, Cl, hydroxy, (C C 8 )alkoxy, (C C 8 )acyloxy, or -0-CH 2 -Ph; (C 3 -C 6 )cycloalkyl, amino, (C ⁇ -C 8 )alkylamino, (C C 8 )dialkylamino or (C ⁇ -C 8 )alkoxy; R 1 is hydrogen except when X is O then R 1 can be hydrogen, CH 3 , CN, C0 2 H, C0 2 R, or (CH 2 ) m R ⁇ (m is 1 or 2); R 2 is independently hydrogen, fluoro or chloro; R is hydrogen except when X is O and R 1 is CH 3 , then R 3 can be hydrogen or CH 3 ; R 10 is independently hydrogen, (C C )alkyl optionally substituted
  • each n is independently 1 to 3;
  • Y is selected from a-n as defined in the patent; wherein each occurrence of (C C 6 )alkyl may be substituted with one or more of fluoro, chloro, bromo, iodo, OR 1 , CO 2 R 1 , CN, SR 1 or R 1 (where R 1 is a hydrogen or (C r C 4 )alkyl);
  • U, V and W are independently (C ⁇ -C 6 )alkyl, fluoro, chloro, bromo, hydrogen or a (C ⁇ -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 C ⁇ 2 )alkyl, (C 3 -C ⁇ 2 )cycloalkyl, (C C 6 )alkoxy, (C ⁇ -C 6 )alkyl substituted with one or
  • novel oxazolidinone derivatives which are effective against resistant organisms.
  • Our sustained efforts have resulted in novel oxazolidinone derivatives of the formula (I).
  • the novel oxazolidinone derivatives of the present invention are useful as antibacterial agents and hence useful in the treatment of conditions such as nosocomial pneumoniae, community acquired pneumoniae, vancomycin resistance enterococci (VRE) caused by methicillin resistance staphylococcus aureus (MRSA) and penicillin resistant streptococcus pneumoniae.
  • the compounds of the present invention are effective against a number of human or animal pathogens, clinical isolates, including Vancomycin resistant organisms, methicillin resistant organisms
  • the present invention relates to novel oxazolidinone derivatives of the formula (I)
  • Y is O or S
  • Suitable groups represented by R 1 may be selected from hydrogen, (C r C ) alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n- pentyl, isopentyl, hexyl and the like; (C 3 -C 6 )cycloa_kyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; aryl group such as phenyl or naphthyl.
  • Suitable aminoacid residue represented by R may be selected from glycine, alanine, lysine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, iso-leucine, leucine, methionine, phenyl alanine, proline, serine, threonine, tryptophan, tyrosine or valine.
  • Suitable groups represented by R and R may be selected from hydrogen or halogen atom such as fluorine or chlorine.
  • Suitable groups represented by R 5 and R may be selected from hydrogen, cyano, nitro, amino, oxo, thioxo, hydroxyl, (C ⁇ -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; (C C 6 )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.
  • Suitable groups represented by Z may be selected from hydrogen, hydroxyl, halogen such as chlorine, fluorine, bromine or iodine; substituted or unsubstituted, linear or branched (C ⁇ -C 6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; aryl group such as phenyl or naphthyl, the aryl group may be substituted; heteroaryl group may be mono or bicyclic system such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyridazine, pyrazin
  • (d-C 8 )alkylthio group such as methylthio, ethylthio, n- propylthio, iso-propylthio and the like, the alkylthio group may be substituted;
  • (C C 8 )alkylsulfonyl group such as methyl sulfonyl, ethylsulfonyl, n-propylsulfonyl, iso- propylsulfonyl and the like, the alkylsulfonyl group may be substituted; arylsulfonyl group such as phenylsulfonyl or naphthylsulfonyl, the arylsulfonyl group may be substituted; sulfamyl, (C]-C 8 )alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-prop
  • the substituents on the group Z may be selected from halogen, hydroxy, nitro, cyano, azido, amino, formyl, alkyl, aryl, cycloalkyl, alkoxy, aryloxy, aralkoxy and these substituents are as defined above.
  • Suitable n is an integer in the range of 0, 1, or 2, preferably n represents 1 or 2.
  • salts of the present invention include alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, 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: (S) N-[(3-(3-F_uoro-4-(mo ⁇ holin-4-yl)phenyl)-2-oxo-oxazolidin-5-yl)methyl]-2- amino propionamide or its salts ;
  • R 1 represents hydrogen and all other symbols are as defined earlier, with protected amino acid and deprotecting to yield the compound of formula (I) as defined earlier.
  • the protecting groups used in this reaction are conventional protecting groups such as t-butoxy carbonyl (t-Boc), acetyl, trityl, trifluoroacetyl, benzyloxy, 9-fluorenyl methylcarbonate (Fmoc), vinyl carbamate, benzyloxy carbonyl (Cbz), 2,2,2-trichloroethyl carbamate (Troc), allyl carbamate.
  • the reaction of compound of formula (la) with protected amino acid residue may be carried out using carbodiimides such as dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-[3-dimethylarninopropyl]-3- ethylcarbodiimide hydrochloride (EDCI), l-[3-dimethylaminopropyl]-3- ethylcarbodiimide and the like, in the presence of a solvent selected from acetonitrile, dichloromethane, dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N-dimethyl acetamide.
  • the reaction may be carried out at a temperature in the range of -10 to 60 °C. The duration of the reaction may range from 6 to 10 h.
  • the deprotection is carried out using conventional deprotecting agents selected from 4-(aminornethyl)piperidine, mo ⁇ holine, piperidine, tris(2- aminoethyl)amine, hydrazine hydrate, tris(2-arninoethyl)amine polymer supported 5 % Pd/C, 10 % Pd/C or the deprotection may be carried out by passing HC1 gas in the presence of solvent selected from acetonitrile, dichloromethane, dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran, 1 -methyl -2- pyrrolidinone, N,N-dimethylacetamide.
  • the reaction may be carried out at a temperature in the range of -10 to 20 °C.
  • the protecting groups used in this reaction are conventional protecting groups such as t-butoxy carbonyl (t-Boc), acetyl, trityl, trifluoroacetyl, benzyloxy, 9-fluorenyl methylcarbonate (Fmoc), vinyl carbamate, benzyloxy carbonyl (Cbz), 2,2,2-trichloroethyl carbamate (Troc), allyl carbamate.
  • the reaction of compound of formula (la) with protected amino acid residue may be carried out using carbodiimides such as dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-[3-dimethylaminopropyl]-3- ethylcarbodiimide hydrochloride (EDCI), l-[3-dimethylaminopropyl]-3- ethylcarbodiimide and the like, in the presence of a solvent selected from acetonitrile, dichloromethane, dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide.
  • the reaction may be carried out at a temperature in the range of -10 to 60 °C. The duration of the reaction may range from 6 to 10 h.
  • the deprotection of compound of formula (lb) is carried out using conventional deprotecting agents selected from ammonium formate, 4- (aminomethyl)piperidine, mo ⁇ holine, piperidine, tris(2-aminoethyl)amine, hydrazine hydrate, tris(2-aminoethyl)amine polymer supported 5 % Pd/C, 10 % Pd/C or the deprotection may be carried out by passing HC1 gas in the presence of solvent selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N- dimethylacetamide and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of -10 to 20 °C.
  • the reaction in step (iii) is carried out in the presence of solvent selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, N,N- dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N- dimethylacetamide and the like or mixtures thereof and a base such as triethylamine, pyridine and the like.
  • solvent selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, N,N- dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N- dimethylacetamide and the like or mixtures thereof and a base such as triethylamine, pyridine and the like.
  • solvent selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, N,N- dimethylformamide, tetrahydrofuran, l-
  • the deprotection of compound of formula (Id) is carried out using conventional deprotecting agents selected from ammonium formate, 4- (aminomethyl)piperidine, mo ⁇ holine, piperidine, tris(2-aminoethyl)amine, hydrazine hydrate, tris(2-aminoethyl)amine polymer supported 5 % Pd/C, 10 % Pd/C or the deprotection may be carried out by passing HCl gas in the presence of solvent selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N- dimethylacetamide and the like or mixtures thereof.
  • solvent selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrol
  • reaction may be carried out at a temperature in the range of -10 to 20 °C.
  • a process for the preparation of novel oxazolidinone derivatives of the formula (I) wherein X represents NR 7 , wherein R 7 represents-(C 0) rn -(CH 2 )
  • the protecting groups used in this reaction are conventional protecting groups such as t-butoxy carbonyl (t-Boc), acetyl, trityl, trifluoroacetyl, benzyloxy, 9-fluorenyl methylcarbonate (Fmoc), vinyl carbamate, benzyloxy carbonyl (Cbz), 2,2,2-trichloroethyl carbamate (Troc), allyl carbamate.
  • the deprotection of compound of formula (Ie) is carried out using conventional deprotecting agents selected from ammonium formate, 4- (aminomethyl)piperidine, mo ⁇ holine, piperidine, tris(2-aminoethyl)amine, hydrazine hydrate, tris(2-aminoethyl)amine polymer supported 5 % Pd/C, 10 % Pd/C or the deprotection may be carried out by passing HCl gas in the presence of solvent selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N- dimethylacetamide and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of -10 to 20 °C.
  • the reaction in step (ii) is carried out in the presence of solvent selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, N,N- dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N- dimethylacetamide and the like or mixtures thereof and a base such as triethylamine, pyridine and the like.
  • solvent selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, N,N- dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N- dimethylacetamide and the like or mixtures thereof and a base such as triethylamine, pyridine and the like.
  • the reaction may be carried out at a temperature in the range of-10 to 20 °C.
  • the reduction of compound of formula (Ig) may be carried out in the presence of gaseous hydrogen and a catalyst
  • the reduction may be conducted in the presence of a solvent such as dioxane, acetic acid, ethyl acetate, THF, alcohol such as methanol, ethanol and the like or mixtures thereof.
  • a solvent such as dioxane, acetic acid, ethyl acetate, THF, alcohol such as methanol, ethanol 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 PPh 3 in water.
  • reaction of compound of formula (Ih) with protected amino acid residue may be carried out using carbodiimides such as dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1 -[3-dimethylaminopropyl]-3- ethylcarbodiimide hydrochloride (EDCI), l-[3-dimethylaminopropyl]-3- ethylcarbodiimide and the like, in the presence of a solvent selected from acetonitrile, dichloromethane, dimethylsulfoxide, N.N-dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide.
  • a solvent selected from acetonitrile, dichloromethane, dimethylsulfoxide, N.N-dimethylformamide, tetrahydrofuran, l-methyl-2-pyr
  • the reaction may be carried out at a temperature in the range of -10 to 60 °C.
  • the duration of the reaction may range from 6 to 10 h.
  • the deprotection of compound of formula (Ii) is carried out using conventional deprotecting agents selected from ammonium formate, 4- (aminomethyl)piperidine, mo ⁇ holine, piperidine, tris(2-aminoethyl)amine, hydrazine hydrate, tris(2-aminoethyl)amine polymer supported 5 % Pd/C, 10 % Pd/C or the deprotection may be carried out by passing HCl gas in the presence of solvent selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N- dimethyl acetamide and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of -10 to 20 °C.
  • the compounds of formula (I) where X represents S is oxidized to a compound of formula (I) where X represents SO using sodium metaperiodate in a mixture of water and methanol.
  • R represents hydrogen, (Cj-C 6 )alkyl, aryl or (C 3 -C 6 )cycloalkyl; R 3 and R 4 may be same or different and independently represent hydrogen or halogen; R 5 and R 6 may be same or different and independently represent hydrogen, cyano, nitro, amino, oxo, thioxo, hydroxyl, (C C 6 )alkyl, (C C 6 )alkoxy, (C C 6 )alkylthio, (C 3 -C 6 )cycloalkyl and n is 0, 1 or 2.
  • R ' is protected amino acid residue
  • Y is O or S
  • R 1 represents hydrogen, (C C 6 )alkyl, aryl or (C 3 -C 6 )cycloalkyl
  • R and R 4 may be same or different and independently represent hydrogen or halogen
  • R and R may be same or different and independently represent hydrogen, cyano, nitro, amino, oxo, thioxo, hydroxyl, (C ⁇ - C 6 )alkyl, (C r C 6 )alkoxy, (C C 6 )alkylthio, (C 3 -C 6 )cycloalkyl and n is 0, 1 or 2.
  • any reactive group in the substrate molecule may be protected according to conventional chemical practice.
  • Suitable protecting groups in any of the above-mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used.
  • a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like
  • solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used.
  • Organic bases such as diethanolamine, ⁇ -phenylethylamine, benzylamine, piperidine, mo ⁇ holine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline and the like, ammonium or substituted ammonium salts, aluminum salts.
  • Amino acid such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc may be used for the preparation of amino acid salts.
  • acid addition salts wherever applicable are prepared by the treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynap
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like.
  • the compound of formula (I) may be converted to a 1 : 1 mixture of diastereomeric amides by treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula (I) may be prepared by hydrolysing the pure diastereomeric amide.
  • polymo ⁇ hs 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. Polymo ⁇ hs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymo ⁇ hs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • solvates of the compounds of formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of formula (I) in solvents such as water, methanol, ethanol, mixture of solvents such as acetone:water, dioxane:water, N.N- dimethylformamide:water and the like, preferably water and recrystallizing by using different crystallization techniques.
  • solvents such as water, methanol, ethanol, mixture of solvents such as acetone:water, dioxane:water, N.N- dimethylformamide:water and the like, preferably water and recrystallizing by using different crystallization techniques.
  • 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.
  • 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.
  • drugs selected from other clinically useful antibacterial agents such as ⁇ -lactams or aminoglycosides.
  • drugs 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) of the present invention may also contain or be co-administered with bactericidal/permeability-
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavoring agents, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • Such compositions typically contain from 1 to 20 %, preferably 1 to 10 % by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
  • step (i) obtained in step (i) by following the procedure as described in step (ii) of example 1 (68mg, 75%).
  • the title compound was prepared from (_S)-5-(aminomethyl)-3-(3-fluoro-4- (mo ⁇ holin-4-yl)-phenyl)-l,3-oxazolidin-2-one (200mg, 67mmol) and N-t- butoxycarbonylamino-4-rnethylthiobutyric acid (202mg, ⁇ lmmol) by following the procedure as described in step (i) of example 1 (185mg, 51%).
  • the title compound was prepared from ( ⁇ S)-5-(aminomethyl)-3-(3-fluoro-4- (mo ⁇ holin-4-yl)phenyl)-l,3-oxazolidin-2-one (200mg, 67mmol) and N-t- butoxycarbonyl pyrrolidine carboxylic acid (175mg, 81mmol) by following the procedure as described in step (i) of example 1 (172mg, 51%).
  • the title compound was prepared from ( ⁇ S)-5-(aminomethyl)-3-(3-fh ⁇ oro-4- (mo ⁇ holin-4-yl)-phenyl)-l,3-oxazolidin-2-one (200mg, 67mmol) and N-t- butoxycarbonylamino pentanoic acid (187mg, 80mmol) by following the procedure as described in step (i) of example 1 (137mg, 39%).
  • the title compound was prepared from (S)-5-(aminomethyl)-3-(3-fluoro-4-(N-4-t- butoxycarbonylpiperazin-l-yl-phenyl)-l,3-oxazolidin-2-one (250mg, 0.634mmol) and N-t-butoxycarbonylamino-3-phenyl propionic acid (168mg, 0.634mmol) by following the procedure as described in step (i) of example 1 (240mg, 59 %).
  • Step (iii) (5 -N-[(3-(3-Fluoro-4-((N-4-benzyloxyacetyl)piperazin-l-yl)phenyl)-2-oxo- oxazolidin-5-yl)methyl]-2-t-butoxycarbonylamino propionamide
  • a solution of (5)-N-[(3-(3-fluoro-4-(piperazin-l-yl)phenyl)-2-oxo-oxazolidin-5- yl)methyl]-2-t-butoxycarbonylam_no propionamide (135mg.
  • step (ii) obtained in step (ii) and triethylamine (87mg, 0.87mmol) in dichloromethane (15ml) was stirred for 15 minutes at 0 °C.
  • Benzyloxy acetyl chloride 64mg, 0.34mmol was added and stirring was continued for 30 minutes at 0 °C and for 30 minutes at ambient temperature.
  • Aqueous NaHC ⁇ 3 solution (5%, 15ml) was added and stirred for 10 minutes. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (160mg, 90%).
  • the compounds of the invention displayed antibacterial activity when tested by the agar inco ⁇ oration method.
  • the in vitro antibacterial activity of the compounds were demonstrated by the agar inco ⁇ oration method (NCCLS). Briefly, the compounds were dissolved in DMSO and doubling dilution of the compounds were inco ⁇ orated into Meuller Hilton agar before solidification. Inoculum was prepared by suspending 4 to 5 colonies into 5 ml of normal saline solution and adjusting the turbidity to 0.5 Macfarland turbidity standard tables ( 1.5. times.10 8 CFU/ml), after appropriate dilutions, 10 4 CFU/spot was transferred into the surface of dried plate and incubated for 18 hours. The concentration showing no growth of the inoculated culture was recorded as the MIC. Appropriate ATCC standard strains were simultaneously tested and result recorded.
  • NCLS agar inco ⁇ oration method
  • the compounds were dissolved in DMSO and doubling dilution of the compounds were inco ⁇ orated into Meuller Hilton agar before solidification.
  • Inoculum was prepared by suspending 4 to 5 colonies into 5 ml of normal saline solution and adjusting the turbidity to 0.5 Macfarland turbidity standard tables (1.5. times.10 CFU/ml), after appropriate dilutions, 10 4 CFU/spot was transferred into the surface of dried plate and incubated for 18 hours. The concentration showing no growth of the inoculated culture was recorded as the MIC. Appropriate ATCC standard strains were simultaneously tested and result recorded.

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Abstract

La présente invention concerne de nouveaux dérivés de l'oxazolidinone de la formule (1), leurs dérivés, leurs analogues, leurs formes tautomères, leurs stéréoisomères, leurs polymorphes, leurs hydrates, leurs solvates, leurs sels pharmaceutiquement acceptables et des compositions pharmaceutiquement acceptables les contenant. L'invention se rapporte en particulier à de nouveaux dérivés de l'oxazolidinone de la formule générale (1).
PCT/IB2003/001571 2002-04-30 2003-04-25 Nouveaux agents antibacteriens WO2003093247A2 (fr)

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WO2004018439A1 (fr) * 2002-08-22 2004-03-04 Orchid Chemicals & Pharmaceuticals Ltd Nouveaux agents antibacteriens
WO2006091731A2 (fr) * 2005-02-24 2006-08-31 Teva Pharmaceutical Industries Ltd. Procedes de preparation d'intermediaire linezolid
WO2007000644A1 (fr) 2005-06-29 2007-01-04 Pharmacia & Upjohn Company Llc Oxazolidinones d'homomorpholine en tant qu'agents antibacteriens
WO2008090570A1 (fr) * 2007-01-25 2008-07-31 Panacea Biotec Ltd Nouveaux antimicrobiens
JP2010523645A (ja) * 2007-04-11 2010-07-15 アクテリオン ファーマシューティカルズ リミテッド オキサゾリジノン抗生物質誘導体
CN107382893A (zh) * 2017-07-18 2017-11-24 郑州大学 具有抗菌活性的利奈唑胺碱阳离子两亲性化合物及其制备方法
JP2018524406A (ja) * 2015-07-17 2018-08-30 ザ グローバル アライアンス フォー ティービー ドラッグ デベロップメント， インコーポレイテッド 抗微生物治療のための置換フェニルオキサゾリジノン
US10995097B2 (en) * 2016-03-11 2021-05-04 The Board Of Trustees Of The University Of Illinois Small molecules active against gram-negative bacteria
US11274106B2 (en) 2017-06-23 2022-03-15 The Board Of Trustees Of The University Of Illinois Topoisomerase inhibitors with antibacterial and anticancer activity

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004018439A1 (fr) * 2002-08-22 2004-03-04 Orchid Chemicals & Pharmaceuticals Ltd Nouveaux agents antibacteriens
WO2006091731A2 (fr) * 2005-02-24 2006-08-31 Teva Pharmaceutical Industries Ltd. Procedes de preparation d'intermediaire linezolid
WO2006091731A3 (fr) * 2005-02-24 2006-10-19 Teva Pharma Procedes de preparation d'intermediaire linezolid
US7291614B2 (en) 2005-02-24 2007-11-06 Teva Pharmaceutical Industries Ltd. Processes for the preparation of linezolid intermediate
JP2008530028A (ja) * 2005-02-24 2008-08-07 テバ ファーマシューティカル インダストリーズ リミティド リネゾリッド中間体の調製方法
WO2007000644A1 (fr) 2005-06-29 2007-01-04 Pharmacia & Upjohn Company Llc Oxazolidinones d'homomorpholine en tant qu'agents antibacteriens
WO2008090570A1 (fr) * 2007-01-25 2008-07-31 Panacea Biotec Ltd Nouveaux antimicrobiens
JP2010523645A (ja) * 2007-04-11 2010-07-15 アクテリオン ファーマシューティカルズ リミテッド オキサゾリジノン抗生物質誘導体
JP2020122016A (ja) * 2015-07-17 2020-08-13 ザ グローバル アライアンス フォー ティービー ドラッグ デベロップメント， インコーポレイテッド 抗微生物治療のための置換フェニルオキサゾリジノン
US11964949B2 (en) 2015-07-17 2024-04-23 The Global Alliance For Tb Drug Development, Inc. Substituted phenyloxazolidinones for antimicrobial therapy
JP2018524406A (ja) * 2015-07-17 2018-08-30 ザ グローバル アライアンス フォー ティービー ドラッグ デベロップメント， インコーポレイテッド 抗微生物治療のための置換フェニルオキサゾリジノン
US10995097B2 (en) * 2016-03-11 2021-05-04 The Board Of Trustees Of The University Of Illinois Small molecules active against gram-negative bacteria
US11858946B2 (en) 2016-03-11 2024-01-02 The Board Of Trustees Of The University Of Illinois Small molecules active against gram-negative bacteria
US11274106B2 (en) 2017-06-23 2022-03-15 The Board Of Trustees Of The University Of Illinois Topoisomerase inhibitors with antibacterial and anticancer activity
CN107382893B (zh) * 2017-07-18 2020-04-28 郑州大学 具有抗菌活性的利奈唑胺碱阳离子两亲性化合物及其制备方法
CN107382893A (zh) * 2017-07-18 2017-11-24 郑州大学 具有抗菌活性的利奈唑胺碱阳离子两亲性化合物及其制备方法

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