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WO2003011859A2 - Derives oxazolidinones utilises en tant qu'agents antibacteriens - Google Patents

Derives oxazolidinones utilises en tant qu'agents antibacteriens Download PDF

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Publication number
WO2003011859A2
WO2003011859A2 PCT/GB2002/003404 GB0203404W WO03011859A2 WO 2003011859 A2 WO2003011859 A2 WO 2003011859A2 GB 0203404 W GB0203404 W GB 0203404W WO 03011859 A2 WO03011859 A2 WO 03011859A2
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WO
WIPO (PCT)
Prior art keywords
compound
formula
alkyl
group
produce
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/GB2002/003404
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English (en)
Other versions
WO2003011859A3 (fr
Inventor
Yusuf Khwaja Hamied
Vithal Madhvarao Kulkarni
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.)
Cipla Ltd
Original Assignee
Cipla 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 Cipla Ltd filed Critical Cipla Ltd
Publication of WO2003011859A2 publication Critical patent/WO2003011859A2/fr
Publication of WO2003011859A3 publication Critical patent/WO2003011859A3/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
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—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
    • 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

  • the present invention relates to novel oxazolidinone derivatives useful as antibacterial agents, and to their preparation.
  • antibacterial agents include penicillins, cephalosporins, monobactams, carbapenems), a inoglycosides, tetracyclines, sulphonamides, macrolides (such as erythromycin), quinolones and glycopeptides (e.g. vancomycin).
  • the totally synthetic oxazolidinones typified by eperezolid (1) and linezolid (2) are one such class of antibacterial agents with potent activity against gram-positive organisms including MRS A, MRSE and VRE. They have been shown to selectively and uniquely bind to the 50S ribosomal subunit and inhibit bacterial translation at the initiation phase of protein synthesis (Lin et al, 1997, Antimicrob. Agents Chemother. (41) 2127-2131 and Shinabarger et al 1997, Antimicrob. Agents Chemother. (41) 2132-2136).
  • oxazolidinones have excellent potential to address the imminent critical need for new antibacterial agents.
  • 3D-QSAR predictive three-dimensional quantitative structure-activity relationship
  • GFA genetic function approximation algorithm
  • R 1 comprises at least one substituted or unsubstituted phenyl group and at least one substituted or unsubstituted unsaturated heterocyclic group having two or more heteroatoms
  • R 3 is C r C 4 alkyl or SO 2 (C r C 4 )alkyl and R 4 is as defined above.
  • Preferred compounds of the invention include those of formula
  • R 1 comprises a phenyl group condensed with an unsaturated heterocyclic group
  • R 1 comprises a group of formula
  • R 1 comprises
  • R 5 is H 3 CH 2 CH 2 CS-
  • R 1 comprises a phenyl group and an unsaturated heterocyclic group which are not condensed.
  • the phenyl and unsaturated heterocyclic groups of R 1 are separated by an NHSO 2 group.
  • R 1 groups include those represented by the formula
  • R 2 is -OH and R 1 is as defined above.
  • the carbamate can be produced by deprotonating the carbamate of formula R l -NHCOOCH 2 CH 3 with, for example, sodium methoxide and reacting the deprotonated carbamate with an (R)- glycidyl ester.
  • the carbamate can be produced from its corresponding amine of formula R'-NH 2 by reaction with ethylchloroformate.
  • ethyl chloroformate and sodium methoxide instead of benzyl chloroformate and butyl lithium, has made production of the (5R)-(hydroxymethyl)-2-oxazolidinone economical.
  • This conversion proceeds by means of a step-wise process, as set out in Scheme 1.
  • the alkylsulphonate can be displaced by reaction with an azide such as NaN 3 to produce an azide of formula
  • the N 3 group of this latter compound can be converted to an amine group by catalytic hydrogenation (step f).
  • the amine can be alkylated to produce a compound of formula
  • Examples The compounds VMRG 1 through VMRG 19 were synthesised as described below and are shown in Table 1. Melting points were determined in capillary tubes and are uncorrected. Infrared spectra was recorded in KBr disks with Buck Scientific M-500 spectrophotometer and are reported in reciprocal centimeters. 1H-NMR spectra were determined in the indicated solvent on a Varian 60 MHz NMR spectrometer and are reported in ⁇ units (parts per million downf ⁇ eld from tetramethyl silane as the internal reference). Splitting patterns are designated as follows: s, singlet; d, doublet; t , triplet; q, quartet; m, multiplet; br, broad. Thin layer chromatography was performed on pre- coated aluminium sheets coated with Silica Gel 60 F 254 , 0.2 mm thickness.
  • the compounds (VMRG 1-VMRG 19) were screened for antibacterial activity against Staphylococcus aureus ATCC 29213.
  • the biological activity data is summarised in Table 1.
  • a stock solution of the compound was prepared using dimethyl sulphoxide and sterile water.
  • the volume of dimethyl sulphoxide used varied from 0.1 ml to 0.5 ml depending upon the solubility of the compound.
  • the concentration of the stock solution was 1000 ⁇ g/ml.
  • Different dilutions of the sample solution were prepared by serial dilution of the stock solution.
  • the compounds were tested at 100, 10, 1 and 0.1 ⁇ g/ml concentrations in duplicate.
  • the tubes were incubated at 37 °C for 48 hours. A set of negative and positive control of growth was also kept for incubation along with the sample tubes. In the tube for negative growth, 1 ml of sterile water was added instead of the sample solution and no culture was added while in the tube representing maximum growth (positive control) 1 ml of sterile water was added followed by 0.1 ml of the culture.
  • the optical densities of the solutions were measured using negative control as the blank at ⁇ 490 and 520, after 24 and 48 hours of incubation. Minimum inhibitory concentration was taken as the minimum concentration of the compound at which the optical density is the same as the negative control indicating complete inhibition of growth. Summary

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés d'oxazolidine représentés par la formule générale suivante, dans laquelle R1 comprend au moins un groupe phényle substitué ou non et au moins un groupe hétérocyclique insaturé substitué ou non, possédant au moins deux hétéroatomes ; et R2 représente un groupe imide, alkylidène, alkyle, halogène, alcanoyloxy, phosphate, arylsulphonate substitué ou ammonium, un hétérocycle saturé ou insaturé, H, OR3, N3 ou NHR4, R3=H, alkyle C¿1?-C4, SO2(C1-C4)alkyle ; R?4¿=H, alkyle C¿1?-C4, C(=O)(C1-C4)alkyle.
PCT/GB2002/003404 2001-07-27 2002-07-25 Derives oxazolidinones utilises en tant qu'agents antibacteriens Ceased WO2003011859A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0118407.6A GB0118407D0 (en) 2001-07-27 2001-07-27 Oxazolidinone derivatives as antibacterial agents
GB0118407.6 2001-07-27

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/719,232 Continuation US6908013B2 (en) 2001-05-25 2003-11-20 Tamper-evident device

Publications (2)

Publication Number Publication Date
WO2003011859A2 true WO2003011859A2 (fr) 2003-02-13
WO2003011859A3 WO2003011859A3 (fr) 2003-04-03

Family

ID=9919346

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2002/003404 Ceased WO2003011859A2 (fr) 2001-07-27 2002-07-25 Derives oxazolidinones utilises en tant qu'agents antibacteriens

Country Status (2)

Country Link
GB (1) GB0118407D0 (fr)
WO (1) WO2003011859A2 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7160912B2 (en) 2000-12-26 2007-01-09 Dr.Reddy's Laboratories Ltd. Heterocyclic compounds having antibacterial activity: process for their preparation and pharmaceutical compositions containing them
US7183301B2 (en) 2000-12-26 2007-02-27 Dr. Reddy's Research Foundation Heterocyclic compounds having antibacterial activity: process for their preparation and pharmaceutical compositions containing them
WO2007114326A1 (fr) 2006-03-31 2007-10-11 Research Foundation Itsuu Laboratory Nouveau composé ayant un hétérocycle
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
WO2009044777A1 (fr) 2007-10-02 2009-04-09 Research Foundation Itsuu Laboratory Dérivé d'oxazolidinone avec hétérocycle à 7 chaînons
US7538107B2 (en) 2006-08-15 2009-05-26 Wyeth Oxazinan-2-one derivatives useful as PR modulators
US7618990B2 (en) 2006-08-15 2009-11-17 Wyeth Oxazolidone derivatives as PR modulators
US7618989B2 (en) 2006-08-15 2009-11-17 Wyeth Tricyclic oxazolidone derivatives useful as PR modulators
US7649007B2 (en) 2006-08-15 2010-01-19 Wyeth Llc Oxazolidine derivatives as PR modulators
US7652018B2 (en) 2006-08-15 2010-01-26 Wyeth Llc Imidazolidin-2-one derivatives useful as PR modulators
CN116423599A (zh) * 2023-05-29 2023-07-14 德华兔宝宝装饰新材股份有限公司 抗菌阻燃木单板及其制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU617871B2 (en) * 1988-09-15 1991-12-05 Pharmacia & Upjohn Company In position 3 substituted-5-beta-amidomethyl-oxazolidin-2- ones
DE4425613A1 (de) * 1994-07-20 1996-01-25 Bayer Ag 5-gliedrige Heteroaryl-oxazolidinone
ZA969622B (en) * 1995-12-13 1998-05-15 Upjohn Co Oxazolidinone antibacterial agents having a six-membered heteroaromatic ring.
WO1999002525A1 (fr) * 1997-07-11 1999-01-21 Pharmacia & Upjohn Company Agents antibacteriens de type phenyloxazolidinones de thiadiazolyle et d'oxadiazolyle

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7160912B2 (en) 2000-12-26 2007-01-09 Dr.Reddy's Laboratories Ltd. Heterocyclic compounds having antibacterial activity: process for their preparation and pharmaceutical compositions containing them
US7183301B2 (en) 2000-12-26 2007-02-27 Dr. Reddy's Research Foundation Heterocyclic compounds having antibacterial activity: process for their preparation and pharmaceutical compositions containing them
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
WO2007114326A1 (fr) 2006-03-31 2007-10-11 Research Foundation Itsuu Laboratory Nouveau composé ayant un hétérocycle
US8785625B2 (en) 2006-03-31 2014-07-22 Research Foundation Itsuu Laboratory Compound having heterocyclic ring
US8148362B2 (en) 2006-03-31 2012-04-03 Research Foundation Itsuu Laboratory Compound having heterocyclic ring
EP2181994A1 (fr) 2006-03-31 2010-05-05 Research Foundation Itsuu Laboratory Composés antimicrobiens
US7649007B2 (en) 2006-08-15 2010-01-19 Wyeth Llc Oxazolidine derivatives as PR modulators
US7618989B2 (en) 2006-08-15 2009-11-17 Wyeth Tricyclic oxazolidone derivatives useful as PR modulators
US7652018B2 (en) 2006-08-15 2010-01-26 Wyeth Llc Imidazolidin-2-one derivatives useful as PR modulators
US7618990B2 (en) 2006-08-15 2009-11-17 Wyeth Oxazolidone derivatives as PR modulators
US7538107B2 (en) 2006-08-15 2009-05-26 Wyeth Oxazinan-2-one derivatives useful as PR modulators
EP2233484A2 (fr) 2007-10-02 2010-09-29 Research Foundation Itsuu Laboratory Dérivés de oxazolidone ayant un cycle hétérocyclique à sept membre
US8530646B2 (en) 2007-10-02 2013-09-10 Research Foundation Itsuu Laboratory Oxazolidinone derivative having 7-membered hetero ring
EP2669283A1 (fr) 2007-10-02 2013-12-04 Shionogi&Co., Ltd. Dérivé dýoxazolidinone doté dýune bague hétéro composée de 7 éléments
WO2009044777A1 (fr) 2007-10-02 2009-04-09 Research Foundation Itsuu Laboratory Dérivé d'oxazolidinone avec hétérocycle à 7 chaînons
CN116423599A (zh) * 2023-05-29 2023-07-14 德华兔宝宝装饰新材股份有限公司 抗菌阻燃木单板及其制备方法

Also Published As

Publication number Publication date
WO2003011859A3 (fr) 2003-04-03
GB0118407D0 (en) 2001-09-19

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