WO2007069264A2 - Nouveaux composes - Google Patents

Nouveaux composes Download PDF

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Publication number
WO2007069264A2
WO2007069264A2 PCT/IN2006/000356 IN2006000356W WO2007069264A2 WO 2007069264 A2 WO2007069264 A2 WO 2007069264A2 IN 2006000356 W IN2006000356 W IN 2006000356W WO 2007069264 A2 WO2007069264 A2 WO 2007069264A2
Authority
WO
WIPO (PCT)
Prior art keywords
telithromycin
compound
sample
purity
diluent
Prior art date
Application number
PCT/IN2006/000356
Other languages
English (en)
Other versions
WO2007069264A3 (fr
Inventor
Pandurang Balwant Deshpande
Parven Kumar Luthra
Rajesh Nautiyal
Bhushan Sahasrabuddhey
Manish Kanchanbhai Patel
Mahesh Pravinchandra Davadra
Original Assignee
Alembic 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 Alembic Limited filed Critical Alembic Limited
Publication of WO2007069264A2 publication Critical patent/WO2007069264A2/fr
Publication of WO2007069264A3 publication Critical patent/WO2007069264A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N2030/022—Column chromatography characterised by the kind of separation mechanism
    • G01N2030/027—Liquid chromatography

Definitions

  • the present invention relates to novel compounds useful as reference markers for the analysis of Telithromycin of formula (I) and pharmaceutical formulations thereof. It also discloses method of testing the purity of a sample of Telithromycin or a pharmaceutical dosage form comprising Telithromycin.
  • Telithromycin is chemically known as l l,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3- O-methyl- ⁇ -L-ribohexopyranosyl)oxy]-6-O-methyl-3-oxo-12,ll-(oxycarbonyl[4-[4-(3- pyridinyl)-lH-imidazol-l-yl]butyl]imino)-erythromycin. It is marketed under brand name "Ketek" and is indicated for the treatment of bacterial infections.
  • Telithromycin of formula (I) is a ketolide which differs chemically from the macrolide group of antibacterials by the lack of ⁇ -L-cladinose at position 3 of the erythronolide A ring, resulting in a 3-keto function. It is further characterized by a C 11 -C 12 carbamate substituted by an imidazolyl and pyridyl ring through a butyl chain. Telithromycin exhibits antibacterial activity and is used for treatment of community acquired pneumonia, acute exacerbation of chronic bronchitis, acute sinusitis, tonsillitis/pharyngitis.
  • This data include analytical data which shows that (i) drug is free from impurities or impurities are present only in negligible amount and (ii) shelf-life or storage stability of drug is acceptable. In order to generate this data the drug is tested against an external standard or reference marker.
  • Impurities generally found in pharmaceutically active agents and formulations containing them include residual amounts of synthetic precursors to the active agent, by-products which arise during synthesis of the active agent, residual solvent, isomers of the active agent, contaminants which were present in materials used in the synthesis of the active agent or in the preparation of the pharmaceutical formulation, and unidentified adventitious substances.
  • Other impurities which may appear on storage include substances resulting from degradation of the active agent, for instance by oxidation or hydrolysis.
  • Another object of the present invention is to provide a method of testing the purity of a sample of Telithromycin or a pharmaceutical dosage form comprising Telithromycin.
  • Yet another object of the present invention is to provide novel compounds, Compound A, B and D, which are useful as reference markers for the analysis of Telithromycin and pharmaceutical formulations thereof.
  • Further object of the present invention is to provide Telithromycin having purity greater than about 98%, more preferably greater than about 98.5%.
  • novel compounds A, B and D which are useful as reference markers for the analysis of Telithromycin and pharmaceutical composition thereof. Also, there is provided process for preparation of these novel compounds.
  • the present invention also provides method of testing the purity of a sample of Telithromycin or a pharmaceutical dosage form comprising Telithromycin comprising assaying the said sample for the presence of a compound selected form Compounds A, B and D.
  • Another aspect of the present invention provides Telithromycin having purity greater than about 98%, more preferably greater than about 98.5%.
  • Compound A is prepared by carrying out hydrolysis of 2'-O-benzoyl-l 1-amino-l l-N-[4- [4-(3-pyridyl)imidazol-l-yl]butyl]-ll-deoxy-5-0-desosaminyl-6-0-methylerythronolide A 11,12-cyclic carbamate of formula (VI) in alcohol.
  • the alcohol is selected from group comprising of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol or mixtures thereof, preferably methanol.
  • the reaction is carried out at a temperature of 0 0 C to 100°C and preferably at 20 0 C to 7O 0 C.
  • the reaction can also be carried out in presence of mineral acid selected from group comprising of HCl, H 2 SO 4 and like.
  • Compound A can be further purified by recrystallization from a solvent preferably acetone. .
  • Compound A is substantially pure and having purity at least 99%.
  • Compound B is isolated by carrying of preparative HPLC of the crude Telithromycin.
  • Compound B obtained by this method is substantially pure and has purity at least 95%.
  • N-oxide Telithromycin (Compound D) is also formed due to side reactions occurring during the synthesis of Telithromycin.
  • Telithromycin obtained in accordance with Scheme-I is further purified by treating Telithromycin with halogenated solvent to obtain solution and adding an anti-solvent to said solution to obtain pure Telithromycin.
  • the halogenated solvent is selected from group comprising of methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride or like, preferably methylene dichloride.
  • the anti-solvent is selected from group comprising of methyl tertbutyl ether, diethyl ether, diisopropyl ether, cyclohexane, n-heptane, n-hexane or like, preferably methyl tertbutyl ether.
  • Ethereal solvents usually contain some content of peroxide in it. Thus when used for purification of Telithromycin, it causes oxidation of Telithromycin resulting in Compound D.
  • Compound D can thus easily be prepared by reacting Telithromycin with oxidizing agent, preferably hydrogen peroxide in a suitable solvent, preferably methanol.
  • oxidizing agent preferably hydrogen peroxide
  • suitable solvent preferably methanol.
  • the reaction is carried out in temperature range of 2O 0 C to reflux temperature of the solvent for about 10 to 20 hours.
  • Compound D obtained by method described above is substantially pure and has purity at least 99%.
  • test sample of drug substance (Telithromycin) or drug product (pharmaceutical dosage form of Telithromycin) to be analyzed may be assayed by one or more conventional analytical techniques.
  • the analytical technique includes high performance liquid chromatography (HPLC). The results obtained are compared with the results obtained from testing a substantially pure reference sample of compound A or B and D.
  • the content or each compound in the test sample can then be determined.
  • Telithromycin by determination of Related Compounds comprises steps of: (i) dissolving a sample of reference standard (compound A and D) in a solvent
  • the method for testing the purity of a sample of Telithromycin by Assay comprises steps of:
  • Diluent Use buffer of pH:7.0 # and acetonitrile in ratio(53: 47).
  • Buffer Preparation pH:7.0 # Dissolve accurately weighed about 2.28g of KH2PO4 and
  • Diluent Use buffer of pH:7.0 # and acetonitrile in ratio(53: 47).
  • Buffer Preparation pH 7.0 : Dissolve accurately weighed about 2.28g of KH 2 PO 4 and
  • the product had the following characteristics: Molecular formula: C 4S He 7 NsOjO Molecular mass: 814.02 TLC (silica gel with ethyl acetate: toluene: methanol; ammonia: 40:25:20:2) IR (in KBr): 3479, 2971,2939,1551,1455,1110,1167,1733 cm "1 .
  • Assay for Telithromycin by HPLC comprises following steps:
  • test solution Accurately weigh and transfer about 125mg of test into a 50ml volumetric flask, dissolve in 15 ml of diluent and sonicate it for 2 min.; make up the volume with diluent and mix for 2 min. Further dilute 5mL of this solution to 5OmL with diluent and mix well. Prepare test solution in duplicate.
  • Diluent Use buffer of pH: 7.0 # and acetonitrile in ratio (55: 45).
  • Buffer Preparation pH:7.0 # Dissolve accurately weighed about 2.28g of KH 2 PO 4 and 0.103Og of NH 4 Cl, adjust pH 7.0 by diluted KOH solution and filter through 0.45 ⁇ membrane filter paper. Injection Procedure
  • a stable baseline was obtained the system suitability solution were injected six replicate and the relative standard deviation was calculated and it should not be more than 1.0%.
  • WtXAs weight (mg) of Telithromycin standard taken
  • % of individual reference marker in drug by HPLC comprises following steps:
  • Buffer Preparation pH:7.0 # Dissolve accurately weighed about 2.28g of KH 2 PO 4 and 0.103Og of NH 4 Cl, adjust pH 7.0 by diluted KOH solution and filter through 0.45 ⁇ membrane filter paper.
  • Ai area of peak for Individual compound in sample solution injection
  • Wt weight (mg) of Telithromycin sample taken RRF - relative response factor

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)

Abstract

L'invention concerne un procédé permettant de tester la pureté d'un échantillon de télithromycine ou d'une forme dosifiée contenant de la télithromycine, ce procédé consistant à analyser ledit échantillon afin de détecter la présence de composés A, B et D, le composé A étant représenté par la formule générale (I), le composé B étant représenté par la formule générale (II) et le composé D étant représenté par la formule générale (III). L'invention concerne également les composés A, B et D, ainsi que leurs utilisations en tant que marqueurs de référence pour l'analyse de la pureté d'un échantillon de télithromycine ou d'une forme dosifiée contenant de la télithromycine.
PCT/IN2006/000356 2005-12-15 2006-09-11 Nouveaux composes WO2007069264A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1576/MUM/2005 2005-12-15
IN1576MU2005 2005-12-15

Publications (2)

Publication Number Publication Date
WO2007069264A2 true WO2007069264A2 (fr) 2007-06-21
WO2007069264A3 WO2007069264A3 (fr) 2007-11-29

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2006/000356 WO2007069264A2 (fr) 2005-12-15 2006-09-11 Nouveaux composes

Country Status (1)

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WO (1) WO2007069264A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009009153A1 (fr) * 2007-07-12 2009-01-15 Teva Pharmaceutical Industries Ltd. Purification de l'intermédiaire de la rosuvastatine par évaporation en film mince et procédé chimique

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997031929A1 (fr) * 1996-02-28 1997-09-04 Hoechst Marion Roussel Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments
EP1170588A1 (fr) * 1998-06-10 2002-01-09 The Wellcome Foundation Limited Procédé de vérifier la pureté ou stabilité de 'lamotrigine' en utilisant d'un dérivé de 1,2,4-triazine comme marqueur de référence
WO2002054062A2 (fr) * 2000-12-29 2002-07-11 Pfizer Limited Standards de reference destines a la determination de la purete ou de la stabilite de maleate d'amlodipine et procedes correspondants
WO2005105821A2 (fr) * 2004-04-28 2005-11-10 Alembic Limited Procede de preparation de telithromycine
WO2005108984A2 (fr) * 2004-05-06 2005-11-17 Chiron Corporation Procedes et systemes de detection, d'identification et de quantification de macrolides et de leurs impuretes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997031929A1 (fr) * 1996-02-28 1997-09-04 Hoechst Marion Roussel Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments
EP1170588A1 (fr) * 1998-06-10 2002-01-09 The Wellcome Foundation Limited Procédé de vérifier la pureté ou stabilité de 'lamotrigine' en utilisant d'un dérivé de 1,2,4-triazine comme marqueur de référence
WO2002054062A2 (fr) * 2000-12-29 2002-07-11 Pfizer Limited Standards de reference destines a la determination de la purete ou de la stabilite de maleate d'amlodipine et procedes correspondants
WO2005105821A2 (fr) * 2004-04-28 2005-11-10 Alembic Limited Procede de preparation de telithromycine
WO2005108984A2 (fr) * 2004-05-06 2005-11-17 Chiron Corporation Procedes et systemes de detection, d'identification et de quantification de macrolides et de leurs impuretes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KANFER I ET AL: "Analysis of macrolide antibiotics" JOURNAL OF CHROMATOGRAPHY A, ELSEVIER, AMSTERDAM, NL, vol. 812, no. 1-2, 3 July 1998 (1998-07-03), pages 255-286, XP004127049 ISSN: 0021-9673 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009009153A1 (fr) * 2007-07-12 2009-01-15 Teva Pharmaceutical Industries Ltd. Purification de l'intermédiaire de la rosuvastatine par évaporation en film mince et procédé chimique
US7884226B2 (en) 2007-07-12 2011-02-08 Teva Pharmaceutical Industries, Ltd. Purification of rosuvatatin intermediate by thin film evaporation and chemical method

Also Published As

Publication number Publication date
WO2007069264A3 (fr) 2007-11-29

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