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WO2004058732A1 - Derive d'oxazolidine, technique de preparation et d'utilisations - Google Patents

Derive d'oxazolidine, technique de preparation et d'utilisations Download PDF

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Publication number
WO2004058732A1
WO2004058732A1 PCT/CN2002/000928 CN0200928W WO2004058732A1 WO 2004058732 A1 WO2004058732 A1 WO 2004058732A1 CN 0200928 W CN0200928 W CN 0200928W WO 2004058732 A1 WO2004058732 A1 WO 2004058732A1
Authority
WO
WIPO (PCT)
Prior art keywords
fluoro
oxo
substituted
phenyl
piperazinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2002/000928
Other languages
English (en)
Chinese (zh)
Inventor
Yushe Yang
Yingjie Cui
Ruyun Ji
Kaixian Chen
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.)
Shanghai Institute of Materia Medica of CAS
Nanjing Changao Pharmaceutical Science and Technology Co Ltd
Original Assignee
Shanghai Institute of Materia Medica of CAS
Nanjing Changao Pharmaceutical Science and Technology Co 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 Shanghai Institute of Materia Medica of CAS, Nanjing Changao Pharmaceutical Science and Technology Co Ltd filed Critical Shanghai Institute of Materia Medica of CAS
Priority to AU2002357561A priority Critical patent/AU2002357561A1/en
Priority to PCT/CN2002/000928 priority patent/WO2004058732A1/fr
Publication of WO2004058732A1 publication Critical patent/WO2004058732A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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

Definitions

  • the invention relates to the fields of medicinal chemistry and chemotherapeutics, in particular to the synthesis of oxazolidinone compounds and its use in the preparation of a medicament for the treatment of infectious diseases, especially infectious diseases caused by multidrug-resistant bacteria. Background technique
  • Oxazolidone represents a very promising class of new synthetic antibacterial agents. Its mechanism of inhibiting early bacterial protein synthesis is different from all currently known antibiotics, meaning that the possibility of cross-resistance is less likely.
  • the focus of the new generation of oxazolidone drugs is to increase antibacterial activity and expand the antibacterial spectrum, including activity against Gram-negative bacteria.
  • Another object of the present invention is to provide a method for preparing a novel oxazolidinone compound having antibacterial activity, particularly anti-multidrug resistance, and a pharmaceutically acceptable salt thereof.
  • Yet another object of the present invention is to provide the use of such compounds and pharmaceutically acceptable salts thereof in the preparation of a medicament for treating infectious diseases, especially infectious diseases caused by multidrug-resistant bacteria.
  • the present invention provides an oxazolidinone compound having the structure of the following formula (I) and a pharmaceutically acceptable salt thereof:
  • R 3 H or alkyl.
  • the present invention also provides two methods for preparing the oxazolidinone compound and the salt thereof having the structure of the formula (I).
  • the first preparation method includes the following steps ⁇
  • the second preparation method includes the following steps:
  • the present invention further provides an application of the oxazolone compound and its salt represented by formula ((I)) in the preparation of a medicament for treating an infectious disease, especially an infectious disease caused by a multidrug-resistant bacteria.
  • Alkyl means a saturated or unsaturated, substituted or unsubstituted straight-chain, branched alkane chain, and specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary Butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylpropyl, hexyl, isohexyl, 1-methylpentyl, 2- Methylpentyl, 3-methylpentyl, 2-methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2 , 3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2 -Trimethylpropyl, 1-ethy
  • fluorenyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, and butyl are preferred, and methyl, ethyl, and propyl are more preferred. Methyl and ethyl are the best.
  • Aryl means an aromatic hydrocarbon group, preferably an aryl group of 6 to 14 carbon atoms, specifically phenyl, tolyl, xylyl, biphenyl, naphthyl, indenyl, anthracenyl, phenanthryl , More preferably phenyl or naphthyl, and most preferably phenyl.
  • Aromatic heterocyclyl means a five- or six-membered heteroaryl group containing 1-4 heteroatoms selected from oxygen, nitrogen or sulfur atoms, furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl , Pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, and the like. Of these groups, thienyl, furyl, oxazolyl, isoxazolyl and thiazolyl are preferred, and thienyl, oxazolyl and isoxazolyl are more preferred.
  • Substitutable fluorenyl "substitutable aryl”, and “substitutable aromatic heterocyclic group” respectively represent the above-mentioned “alkyl”, “aryl” and “aromatic heterocyclic group” are optional They are selected from atoms, alkyl, alkoxy, acyloxy, - 0H, _NH 2, N0 2, - NHAc substituent group.
  • the "sulfonylating agent" is selected from the group consisting of a sulfonyl chloride which may be substituted with an alkyl group or an aryl group, a sulfonyl bromide which may be substituted with an alkyl group or an aryl group, and a sulfonic anhydride which may be substituted with a carbaryl group or an aryl group.
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid, and formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, and succinic acid.
  • Fumaric acid maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid and other organic acids and acid such as aspartic acid and glutamic acid
  • Addition salts, or salts with bases such as salts of inorganic bases such as sodium, potassium, calcium, aluminum, ammonium salts, methylamine salts, ethylamine salts, ethanolamine salts, etc., or with lysine, arginine, Salt formed from basic amino acids such as ornithine.
  • oxazolone compounds or salts thereof of the present invention can be made into various preparations containing 0.01 to 99.9% by weight of the active ingredient and an appropriate amount of a pharmaceutically acceptable carrier, such as suitable for oral, injection or intestinal Formulations used for oral administration.
  • a pharmaceutically acceptable carrier such as suitable for oral, injection or intestinal Formulations used for oral administration.
  • the medicine containing a therapeutically effective amount of the compound of the present invention can be administered to a subject according to the subject's age (months or weeks), general health, disease severity and duration, route of administration, individual sensitivity to the drug, etc. preparation.
  • the oxazolidinone compound represented by the formula (I) of the present invention and a salt thereof are prepared according to the following scheme.
  • Compounds 6-8 use methanol, ethanol, acetic acid, etc. as solvents, and use palladium / carbon or other metal catalysts containing palladium or nickel as catalysts.
  • Compounds 10-12 are obtained by catalytic hydrogenation at normal temperature and pressure. The best conditions for the reaction are methanol as the solvent, 5% or 10% palladium / carbon as the catalyst, and catalytic hydrogenation at normal temperature and pressure. 4.
  • Compounds 26-27 use methanol, ethanol, acetic acid, etc. as solvents, and use palladium / carbon or other palladium-containing catalysts to react in the range of 0 ° to room temperature for 8-24 hours. 10% palladium / carbon was used as a catalyst to catalyze hydrogenation under normal temperature and pressure to obtain compounds 28-29. ⁇
  • Test method ⁇ Determine the minimum inhibitory concentration (MIC) of the compound against the test strain by agar dilution method. That is, 1 ml of the test compound is pipetted into a sterilized plate, and then 19 ml of M-H agar medium (thaw to 50 ° C) is added to the plate, so that the final concentration of the compound in each plate is 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0. 254 g / ml, and then inoculated the bacteria on the surface of each dish with a multi-point inoculation device (Denley A400), the final concentration of the bacterial solution was 10 FU / ml. Incubate at 37 ° C for 20 hours. Observe the results. The lowest concentration of the drug in the bacteria-free growth plate is the minimum inhibitory concentration (MIC) of the bacteria.
  • MIC minimum inhibitory concentration
  • Test strains All the test strains used were clinically isolated pathogenic bacteria collected in Sichuan in 2001 and used after re-identification by conventional methods. After the test compound was solubilized with CH 3 0H or DMS0, a mother liquor of 256 g / ml was prepared with sterilized distilled water for use.
  • the oxazolidone derivatives and pharmaceutically acceptable salts thereof used in the present invention can be used to treat infectious diseases, especially infectious diseases caused by multidrug-resistant bacteria.
  • Example 32 (S) -N-3- (3-fluoro-4-o-acetoxybenzenesulfonylaminophenyl) -2-oxo-5-oxazolidinylmethylacetamide (32)
  • Compound (S)-N-3- (3-fluoro-4-aminophenyl) -2-oxo-5-oxazolidinylmethylacetamide (59.0 mg, 0.221 mmol) was dissolved in dry tetrahydrofuran (8.0 mL), under ice-water cooling and stirring, 2-acetoxybenzoyl chloride (0.70 mL) and 3 drops of triethylamine were added dropwise and reacted overnight.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne un dérivé d'oxazolidine représenté par la formule (I) ou des sels de celui-ci. Dans cette formule R est F (I) Or NR2R3, R1 est éventuellement substitué par alkylsulfortyle, arylsulfonyle, hétéroarylsulfonyle, alkylcarbonyle derivé d'acide aminé, arylcarbonyle, arylaminocarbonyle, arylaminothiocarbonyle; R2 est éventuellement substitué par alkylsulfonyle, arylsulfonyle, arylcarbonyle, hétéroarylsunlfonyle; R3 est H ou alkyle. Cette invention concerne aussi la technique de préparation de ces composés et l'utilisation de production de produits médicinaux qui conviennent pour le traitement et la prévention d'une pathologie infectieuse en particulier, induite par des bactéries résistantes aux médicaments.
PCT/CN2002/000928 2002-12-30 2002-12-30 Derive d'oxazolidine, technique de preparation et d'utilisations Ceased WO2004058732A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2002357561A AU2002357561A1 (en) 2002-12-30 2002-12-30 Oxazolidine derivative, methods of preparation and uses
PCT/CN2002/000928 WO2004058732A1 (fr) 2002-12-30 2002-12-30 Derive d'oxazolidine, technique de preparation et d'utilisations

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2002/000928 WO2004058732A1 (fr) 2002-12-30 2002-12-30 Derive d'oxazolidine, technique de preparation et d'utilisations

Publications (1)

Publication Number Publication Date
WO2004058732A1 true WO2004058732A1 (fr) 2004-07-15

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AU (1) AU2002357561A1 (fr)
WO (1) WO2004058732A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007020888A1 (fr) * 2005-08-12 2007-02-22 Takeda Pharmaceutical Company Limited Agent protegeant des cellules du cerveau/neuronales et agent therapeutique pour des troubles du sommeil
US7825122B2 (en) 2005-12-14 2010-11-02 Amgen Inc. Diaza heterocyclic sulfonamide derivatives and their uses
CN103450174A (zh) * 2013-09-07 2013-12-18 吉首大学 苯并吡喃酮-苯基-噁唑烷酮型化合物及其制法和用途
CN107365359A (zh) * 2017-07-17 2017-11-21 昆明理工大学 一种万古霉素手性功能单体合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1079964A (zh) * 1992-05-08 1993-12-29 厄普约翰公司 含取代二嗪基的唑烷酮类抗菌剂
WO1995014684A1 (fr) * 1993-11-22 1995-06-01 The Upjohn Company Esters d'hydroxyacetyl-piperazine-phenyl-oxazolidinones substituees
WO1999037630A1 (fr) * 1998-01-23 1999-07-29 Versicor, Inc. Banques combinatoires d'oxazolidinones, compositions a base de tels composes et procedes de preparation
WO2001009107A1 (fr) * 1999-07-28 2001-02-08 Pharmacia & Upjohn Company Oxazolidinones et leur utilisation comme anti-infectieux

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1079964A (zh) * 1992-05-08 1993-12-29 厄普约翰公司 含取代二嗪基的唑烷酮类抗菌剂
WO1995014684A1 (fr) * 1993-11-22 1995-06-01 The Upjohn Company Esters d'hydroxyacetyl-piperazine-phenyl-oxazolidinones substituees
WO1999037630A1 (fr) * 1998-01-23 1999-07-29 Versicor, Inc. Banques combinatoires d'oxazolidinones, compositions a base de tels composes et procedes de preparation
US6239152B1 (en) * 1998-01-23 2001-05-29 Pharmacia & Upjohn Company Oxazolidinone combinatorial libraries, compositions and methods of preparation
WO2001009107A1 (fr) * 1999-07-28 2001-02-08 Pharmacia & Upjohn Company Oxazolidinones et leur utilisation comme anti-infectieux

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DRUG METABOLISM AND BISPOSITION, vol. 27, no. 9, 1999, pages 992 - 998 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007020888A1 (fr) * 2005-08-12 2007-02-22 Takeda Pharmaceutical Company Limited Agent protegeant des cellules du cerveau/neuronales et agent therapeutique pour des troubles du sommeil
US7812025B2 (en) 2005-08-12 2010-10-12 Takeda Pharmaceutical Company Limited Brain/neuronal cell-protecting agent and therapeutic agent for sleep disorder
US7825122B2 (en) 2005-12-14 2010-11-02 Amgen Inc. Diaza heterocyclic sulfonamide derivatives and their uses
CN103450174A (zh) * 2013-09-07 2013-12-18 吉首大学 苯并吡喃酮-苯基-噁唑烷酮型化合物及其制法和用途
CN107365359A (zh) * 2017-07-17 2017-11-21 昆明理工大学 一种万古霉素手性功能单体合成方法
CN107365359B (zh) * 2017-07-17 2021-06-04 昆明理工大学 一种万古霉素手性功能单体合成方法

Also Published As

Publication number Publication date
AU2002357561A8 (en) 2004-07-22
AU2002357561A1 (en) 2004-07-22

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