WO2006018682A2 - Derives d'oxazolidinone comme antimicrobiens - Google Patents

Derives d'oxazolidinone comme antimicrobiens Download PDF

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Publication number
WO2006018682A2
WO2006018682A2 PCT/IB2005/002226 IB2005002226W WO2006018682A2 WO 2006018682 A2 WO2006018682 A2 WO 2006018682A2 IB 2005002226 W IB2005002226 W IB 2005002226W WO 2006018682 A2 WO2006018682 A2 WO 2006018682A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
tetrazol
oxazolidin
acetamide
Prior art date
Application number
PCT/IB2005/002226
Other languages
English (en)
Other versions
WO2006018682A3 (fr
Inventor
Biswajit Das
Shahadat Ahmed
Ajay Singh Yadav
Soma Ghosh
Ashok Rattan
Original Assignee
Ranbaxy Laboratories Limited
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 Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2006018682A2 publication Critical patent/WO2006018682A2/fr
Publication of WO2006018682A3 publication Critical patent/WO2006018682A3/fr

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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
    • C07D413/10—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
    • 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
    • C07D413/14—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

Definitions

  • the present invention relates to certain substituted phenyl oxazolidinones and to processes for the synthesis of the same.
  • This invention also relates to pharmaceutical compositions containing the compounds of the present invention as antimicrobials.
  • the compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiple-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacterioides spp. and Clostridia spp. species, and acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
  • Streptococcus pneumoniae is a major pathogen causing pneumonia, sinusitis and meningitis. Until very recently it was highly susceptible to penicillin. Recently though, different PBP 2' strains with different susceptibility to penicillin have been reported from across the globe.
  • Oxazolidinones are a new class of synthetic antimicrobial agents, which kill gram- positive pathogens by inhibiting a very early stage of protein synthesis. Oxazolidinones inhibit the formation of ribosomal initiation complex involving 3OS and 5OS ribosomes leading to prevention of initiation complex formation. These compounds are active against pathogens resistant to other clinically useful antibiotics.
  • WO 04/14392 discloses substituted phenyl oxazolidinone derivatives which are described as antimicrobials.
  • WO 03/97059 discloses polymorphic forms of phenyl oxazolidinone derivatives.
  • WO 03/08389 discloses substituted phenyl oxazolidinone derivatives described as potential antimicrobials.
  • WO 03/07870 discloses oxazolidinone derivatives which are described as antimicrobials.
  • WO 04/14392 discloses substituted phenyl oxazolidinone derivatives which are described as antimicrobials.
  • WO 93/09103 discloses substituted aryl and heteroaryl phenyl oxazolidinone said to be useful as antibacterial agents.
  • WO 98/54161 and US 6255304 disclose oxazolidinone antibacterial agents having a thiocarbonyl functionality.
  • WO 00/29396 discloses substituted phenyloxazolidione derivatives for producing antibacterial medicament for treating human being and animals.
  • WO 01/80841 discloses use of thioamide oxazolidinones allegedly useful for the treatment of bone resorption and osteoporosis.
  • WO 01/94342 and US6, 689,779 disclose oxazolidinone derivatives having pyridine or pyrimidine moieties and a process for the preparation thereof.
  • WO 03/022824 discloses oxazolidione and/or isoxazoline described as antibacterial agents.
  • 03/072553 discloses N-aryl-2-oxazolidinone-5-carboxamides and their derivatives and their use as antibacterial agents.
  • WO 03/006447 discloses oxazolidione compounds having thiocarbonyl functionality which are described as antibacterial agents.
  • Oxazolidinone derivatives which have a good activity against multiple resistant gram positive pathogens like methicilline resistant Staphylococcus aureus (MRSA), Vancomycin- resistant Enterococci (VRE) and Streptococcus pneumonia are disclosed.
  • MRSA methicilline resistant Staphylococcus aureus
  • VRE Vancomycin- resistant Enterococci
  • Streptococcus pneumonia is disclosed.
  • MDR- TB multiple drug resistant tuberculosis
  • Phenyloxazolidinone derivatives exhibiting good antibacterial activity against Gram-positive pathogens like MRSA, VRE and PRSP against MDR-TB and MAI strains and Gram-negative pathogens like morazella catarrhalis and Haemophilus influenza in order to provide safe and effective treatment of bacterial infection are provided.
  • V can be hydrogen or fluorine
  • A can be
  • Compounds disclosed herein can be useful antimicrobial agents, effective against a number of human and veterinary pathogens, particularly aerobic and Gram-positive bacteria, including multiply-antibiotic resistant Staphylococci and Streptococci, as well as anaerobic organisms such as Mycobacterium tuberculosis and other Mycobacterium species.
  • compositions comprising the compounds disclosed herein, their enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, N-oxides or metabolites in combination with pharmaceutically acceptable carriers and optionally included excipients are also provided herein.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories and ointments.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablets disintegrating agents; it can also be as finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from about 5 to about 70 percent of the active ingredient.
  • suitable solid carriers are lactose, pectin, dextrin, starch, gelatin, tragacanth, low melting wax, cocoa butter and the like.
  • preparation is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it.
  • capsules can be used, as solid dosage forms suitable for oral administration.
  • Liquid form preparations include solutions suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems (isotonicity, pH, etc.). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
  • Aqueous suspension suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and other well-known suspending agents.
  • Ointment preparations contain heavy metal salts of a compound of Formula I with a physiologically acceptable carrier.
  • the carrier is desirably a conventional water- dispersible hydrophilic or oil-in-water carrier, particularly a conventional semi-soft or cream-like water-dispersible or water soluble, oil-in-water emulsion infected surface with a minimum of discomfort.
  • Suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment.
  • the pharmaceutical preparation can be in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete capsules, powders in vials or ampoules and ointments capsule, cachet, tablet, gel, or cream itself or it can be the appropriate number of any of these packaged forms.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from less than 1 mg to several grams according to the particular application and the potency of the active ingredient.
  • the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 3 mg to about 40 mg per kilogram daily.
  • the dosages may be varied depending upon the requirements of the patient and the compound being employed.
  • Determination of the proper dosage for a particular situation is within the smaller dosages, which are less than the optimum dose. Small increments until the optimum effect under the daily dosage may be divided and administered in portions during the day if desired.
  • Prodrugs of the compounds of Formula I are also included. In general, such prodrugs will be functional derivatives of these compounds, which readily get converted in vivo into defined compounds. Conventional procedures for the selection and preparation of suitable prodrugs are known to the artisan of ordinary skill in the art.
  • the compounds of Formula I can be prepared, for example, following Scheme I.
  • a compound of Formula II, wherein V is same as defined earlier (prepared as per the procedure described in WO 93/09103) is reacted with a compound of Formula III (wherein A is same as defined earlier) to yield a compound of Formula I.
  • reaction of a compound of Formula II with a compound of Formula III to yield a compound of Formula I is carried out in an organic solvent for example dimethyl formamide, acetonitrile, dimethylacetamide or dimethylsulfoxide and an organic base for example triethylamine, diisopropoylethylamine, pyridine or 1 ,2-ethylenediamine in the presence of a palladium catalyst for example tetrakistriphenylphosphine palladium (0) or dichlorobistriphenylphosphine palladium (II).
  • organic solvent for example dimethyl formamide, acetonitrile, dimethylacetamide or dimethylsulfoxide
  • an organic base for example triethylamine, diisopropoylethylamine, pyridine or 1 ,2-ethylenediamine
  • a palladium catalyst for example tetrakistriphenylphosphine palladium (0) or dichlorobistriphenylphosphine
  • S.aureus ATCC 29213 Staphylococcus aureus ATCC 29213; MIC was 0.25 - 4 ⁇ g/ml, with linezolid 2 ⁇ g/ml and vancomycin 1 ⁇ g/ml.
  • S.aureus MRSA ATCC 562 Metal-oxide Resistant Staphylococcus aureus ATCC562; MIC was 0.25 - 2 ⁇ g/ml, with linezolid 2 ⁇ g/ml and vancomycin 1 ⁇ g/ml.
  • E. faecalis SP 346 A Vancomycin-Resistant enterococci SP 346A; MIC was 0.125 - 1 ⁇ g/ml, with linezolid 2 ⁇ g/ml, and vancomycin >16 ⁇ g/ml.
  • S.aureus MRSA 32 Metal-oxide Resistant Staphylococcus aureus 32; MIC was 2 - 8 ⁇ g/ml, with linezolid >64 ⁇ g/ml, and vancomycin 0.5 ⁇ g/ml.
  • E.faecalis 427 Enterococcus faecalis 427; MIC was 1 - 16 ⁇ g/ml, with linezolid >64 ⁇ g/ml, and vancomycin 1 ⁇ g/ml.
  • E.faecalis 303 Enterococcus faecalis 303; MIC was 0.125 - 4 ⁇ g/ml, with linezolid >64 ⁇ g/ml, and vancomycin 1 ⁇ g/ml.
  • -S. pneum. ATCC 6303 -Streptococcus pneumoniae ATCC 6303; MIC was 1 - 32 ⁇ g/ml, with linezolid >16 ⁇ g/ml, and vancomycin 0.5 ⁇ g/ml.
  • the in vitro antibacterial activity of the compounds was demonstrated by the agar dilution method (NCCLS M 7-A5 and M 100-S8 documents). Briefly, the compounds were dissolved in dimethylsulphoxide and doubling dilution of the compounds was made in distilled water/ dimethylsulphoxide as per NCCLS method, dilutions were incorporated into Muller Hinton agar before solidification. Inoculum was prepared by direct colony suspension in normal saline solution and adjusting the turbidity to 0.5 McFarland turbidity and subsequently diluting as per NCCLS guidelines in order to obtain 10 ⁇ CFU/spot. CFU/ml of few randomly selected cultures was performed.
  • the cultures were replicated on agar plates using Denley's multipoint replicator.
  • the agar plates were incubated for 18 hours-24 hours (24 hours for MRSA studies) at 35+ 2 0 C. Q. C. strains were also included in each run of the study.

Abstract

L'invention concerne certaines oxazolidinones de phényle substituées ainsi que leur procédé de synthèse. L'invention concerne également des compositions pharmaceutiques renfermant ces composés comme antimicrobiens. Lesdits composés sont des agents antimicrobiens utiles et efficaces contre un certain nombre de pathogènes humains et vétérinaires, notamment des bactéries aérobies gram positif telles que des staphylocoques, streptocoques et entérocoques polyrésistants ainsi que des organismes anaérobies tels que les espèces Bacterioides spp. et Clostridia spp. et les organismes résistant aux acides tels que Mycobacterium tuberculosis, Mycobacterium avium et Mycobacterium spp.
PCT/IB2005/002226 2004-08-11 2005-07-27 Derives d'oxazolidinone comme antimicrobiens WO2006018682A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US60049504P 2004-08-11 2004-08-11
US60/600,495 2004-08-11

Publications (2)

Publication Number Publication Date
WO2006018682A2 true WO2006018682A2 (fr) 2006-02-23
WO2006018682A3 WO2006018682A3 (fr) 2006-07-06

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102276595A (zh) * 2010-04-16 2011-12-14 山东轩竹医药科技有限公司 含有五元杂环的噁唑烷酮抗菌素
US20120157434A1 (en) * 2007-03-02 2012-06-21 CSO of MicuRx Pharmaceuticals, Inc. Antimicrobial heterocyclic compounds for treatment of bacterial infections

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5654435A (en) * 1991-11-01 1997-08-05 Pharmacia & Upjohn Company Substituted arylphenyloxazolindinones
WO2001094342A1 (fr) * 2000-06-05 2001-12-13 Dong A Pharm. Co., Ltd. Nouveaux derives oxazolidinone et processus de preparation de ces derives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5654435A (en) * 1991-11-01 1997-08-05 Pharmacia & Upjohn Company Substituted arylphenyloxazolindinones
WO2001094342A1 (fr) * 2000-06-05 2001-12-13 Dong A Pharm. Co., Ltd. Nouveaux derives oxazolidinone et processus de preparation de ces derives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120157434A1 (en) * 2007-03-02 2012-06-21 CSO of MicuRx Pharmaceuticals, Inc. Antimicrobial heterocyclic compounds for treatment of bacterial infections
CN102276595A (zh) * 2010-04-16 2011-12-14 山东轩竹医药科技有限公司 含有五元杂环的噁唑烷酮抗菌素

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Publication number Publication date
WO2006018682A3 (fr) 2006-07-06

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