EP1313742A1 - Procede de preparation d'hydrates d'olanzapine et de conversion de ceux-ci en formes cristallines d'olanzapine - Google Patents

Procede de preparation d'hydrates d'olanzapine et de conversion de ceux-ci en formes cristallines d'olanzapine

Info

Publication number
EP1313742A1
EP1313742A1 EP01916449A EP01916449A EP1313742A1 EP 1313742 A1 EP1313742 A1 EP 1313742A1 EP 01916449 A EP01916449 A EP 01916449A EP 01916449 A EP01916449 A EP 01916449A EP 1313742 A1 EP1313742 A1 EP 1313742A1
Authority
EP
European Patent Office
Prior art keywords
olanzapine
methyl
thieno
dichloromethane
process according
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.)
Withdrawn
Application number
EP01916449A
Other languages
German (de)
English (en)
Inventor
Robert Koprowski
Buchi Reddy Reguri
Ramesh Chakka
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.)
Dr Reddys Laboratories Ltd
Original Assignee
Dr Reddys Laboratories 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 Dr Reddys Laboratories Ltd filed Critical Dr Reddys Laboratories Ltd
Publication of EP1313742A1 publication Critical patent/EP1313742A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics

Definitions

  • the present invention relates to a method for the preparation of hydrates of 2- methyl-4-(4-methyl-l-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine (hereinafter referred to as Olanzapine).
  • the present invention also relates to a process for conversion of these hydrates into a pure crystalline form of olanzapine referred to as form-I.
  • the present invention also relates to a method of converting Olanzapine Form-2 to Form-1.
  • This invention more particularly relates to the preparation of hydrates of olanzapine and their conversion into crystalline form of Olanzapine Form-1 through recrystallization from a solvent.
  • Olanzapine is represented by the following structure.
  • Olanzapine is useful for treating psychotic patients and mild anxiety states.
  • Preparation of Olanzapine and its acid salts, having pharmaceutical properties particularly in the treatment of disorders ofthe central nervous system has been discussed in U.S. Patent No. 5,229,382.
  • U.S. Patent No. 5,229,382 does not refer to any specific polymorphic crystalline form of Olanzapine.
  • European patent specification No. 733635A1 claims Form-2 of Olanzapine. The process under this patent describes preparation of Form-2 from ethyl acetate. This patent also designated the product obtained according to the process described in U.S. Patent No. 5,229,382 as Form-1.
  • EP 733635 Al discloses the d values for Form-1 and Form-2 from their X-ray Diffractograms. The values are: d value d value
  • EP 0 831 098 A2 discloses the preparation of a series of dihydrates of olanzapine namely Dihydrate B, Dihydrate D and Dihydrate E.
  • the compound was dried to a constant weight in an oven (51.6g).
  • the present invention provides a novel method for preparation of hydrates of olanzapine, which are different from those reported in the literature. These hydrates are named Olanzapine monohydrate-I and Olanzapine dihydrate-I for convenience.
  • the present invention also provides a novel method for preparation of Olanzapine Form-1 by recrystallization of olanzapine or its hydrates in dichloromethane .
  • the present invention also provides a novel method for converting Olanzapine
  • the process for the preparation of olanzapine monohydrate-I comprises: a) refluxing a mixture of 4-amino-2-methyl-10H-thieno-[2,3-b] [l,5]benzodiazepine hydrochloride, N-methyl piperazine, dimethyl sulfoxide (DMSO) and toluene for 5 to 20 hours; b) cooling the mixture to 20 to 90°C; c) adding water; d) cooling the mixture to -5 to 25°C and stirring for 2-10 hours; e) filtering the mixture and washing with water; and f) drying at 30 to 50°C to a constant weight.
  • DMSO dimethyl sulfoxide
  • the process for the preparation of olanzapine dihydrate -I comprises: a) refluxing a mixture of 4-amino-2-methyl- 10H-thieno-[2,3-b] [l,5]benzodiazepine hydrochloride, N-methyl piperazine, dimethyl sulfoxide (DMSO) and toluene for 5 to 20 hours; b) cooling the mixture to 20 to 90°C; c) adding water; d) cooling the mixture to -5 to 25°C and stirring for 2-10 hours; e) filtering the mixture and washing with water; and f) drying at ambient temperature to a constant weight.
  • DMSO dimethyl sulfoxide
  • Olanzapine Form -I is prepared by heating to reflux a suspension of olanzapine or its hydrates in dichloromethane wherein the amount of dichloro-methane used is 4.5 to 13 volume/weight of Olanzapine to obtain a clear solution. The resultant solution is then treated with carbon followed by filtration. Upon completion of this step the filtrate is cooled to 0 to 5°C and stirred at the same temperature for 60-90 minutes. The separated solid was filtered and washed with dichloromethane.
  • the product obtained on drying in an oven at 60-70°C to a constant weight is Form-1 of Olanzapine.
  • the process described in U.S. 5,229,382 was used to prepare olanzapine crude and the process described in EP 733 635 Al was used to prepare olanzapine Form-2 for our studies.
  • other methods may be used to prepare olanzapine crude and olanzapine Form-2 and any other methods that can be used to prepare olanzapine crude and olanzapine Form 2 can be used in the processes of this invention.
  • Fig.l is a characteristic X-ray powder diffraction pattern of Form-2 obtained on recrystallization with acetonitrile (Nertical axis: Intensity (CPS); Horizontal axis:
  • Fig. 2 is a characteristic X-ray powder diffraction pattern of Olanzapine monohydrate-I (Nertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).
  • Fig. 3 is a characteristic infrared absorption spectrum in potassium bromide of
  • Olanzapine monohydrate-I (Nertical axis, Tramission (%); Horizontal axis: Wave number (cm )).
  • Fig. 4 is a characteristic of differential scanning calorimetry thermogram of Olanzapine monohydrate-I. (Nertical axis: mW; Horizontal axis: Temperature (°C)).
  • Fig. 5 is a characteristic X-ray powder diffraction pattern of Olanzapine dihydrate-I (Nertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).
  • Fig. 6 is a characteristic infrared absorption spectrum in potassium bromide of
  • Olanzapine dihydrate-I (Nertical axis, Tramission (%); Horizontal axis: Wave number (cm " )).
  • Fig. 7 is a characteristic of differential scanning calorimetry thermogram of
  • Fig. 8 is a characteristic X-ray powder diffraction pattern of Form-1 produced by recrystallizing crude Olanzapine in dichloromethane. (Nertical axis: Intensity
  • Fig.9 is a characteristic infrared absorption spectrum in potassium bromide of Form-1 produced by recrystallizing crude Olanzapine in dichloromethane. (Nertical axis, Tramission (%); Horizontal axis: Wave number (cm "1 )).
  • Fig.10 is a characteristic of differential scanning calorimetry thermogram of Form-1 produced by recrystallizing crude Olanzapine in dichloromethane. [Nertical axis: mW; Horizontal axis: Temperature (°C))].
  • Fig.11 is a characteristic X-ray powder diffraction pattern of Form-I obtained on conversion of Form-2 to Form-1 Olanzapine in dichloromethane (Nertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).
  • Fig.12 is a characteristic infrared absorption spectrum in potassium bromide of Form-1 obtained on conversion of Form-2 to Form-1 Olanzapine in dichloromethane (Nertical axis, Tramission (%); Horizontal axis: Wave number (cm "1 ))].
  • Fig.13 is a characteristic of differential scanning calorimetry thermogram of Form-1 obtained on conversion of Form-2 to Form-1 Olanzapine in dichloromethane (Nertical axis: mW; Horizontal axis: Temperature (°C))].
  • Fig.14 is a characteristic X-ray powder diffraction pattern of Form-1 obtained on conversion of olanzapine monohydrate-I to Form-1 Olanzapine in dichloromethane (Nertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).
  • Fig.15 is a characteristic infrared absorption spectrum in potassium bromide of Form-1 obtained on conversion of olanzapine monohydrate-I to Form-1 Olanzapine in dichloromethane (Nertical axis, Tramission (%); Horizontal axis: Wave number (cm "1 )).
  • Fig.16 is a characteristic of differential scanning calorimetry thermogram of
  • Form-1 obtained on conversion of olanzapine monohydrate-I to Form-1
  • Fig.17 is a characteristic X-ray powder diffraction pattern of Form-1 obtained on conversion of olanzapine dihydrate-I to Form-1 Olanzapine in dichloromethane
  • Fig.18 is a characteristic infrared absorption spectrum in potassium bromide of Form-1 obtained on conversion of olanzapine dihydrate-I to Form-1 Olanzapine in dichloromethane. ([Vertical axis, Tramission (%); Horizontal axis: Wave number
  • Fig.19 is a characteristic of differential scanning calorimetry thermogram of Form-1 obtained on conversion of olanzapine dihydrate-I to Form-1 Olanzapine in dichloromethane. (Nertical axis: mW; Horizontal axis: Temperature (°C)).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Psychiatry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'hydrates de 2-méthyl-4-(4-méthyl-1-pipérazinyl)-10H-thiéno [2,3-b] [1,5] benzodiazépine (ci-après dénommés olanzapine), ainsi qu'un procédé de conversion de ces hydrates en une forme cristalline pure dénommée forme 1. L'invention concerne encore un procédé de conversion d'olanzapine forme 2 en Olanzapine forme 1.
EP01916449A 2000-08-31 2001-03-07 Procede de preparation d'hydrates d'olanzapine et de conversion de ceux-ci en formes cristallines d'olanzapine Withdrawn EP1313742A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
INMU070900 2000-08-31
IN709CH2000 2000-08-31
INMU071100 2000-08-31
IN711CH2000 2000-08-31
PCT/US2001/007258 WO2002018390A1 (fr) 2000-08-31 2001-03-07 Procede de preparation d'hydrates d'olanzapine et de conversion de ceux-ci en formes cristallines d'olanzapine

Publications (1)

Publication Number Publication Date
EP1313742A1 true EP1313742A1 (fr) 2003-05-28

Family

ID=26324874

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01916449A Withdrawn EP1313742A1 (fr) 2000-08-31 2001-03-07 Procede de preparation d'hydrates d'olanzapine et de conversion de ceux-ci en formes cristallines d'olanzapine

Country Status (12)

Country Link
EP (1) EP1313742A1 (fr)
JP (1) JP2004507548A (fr)
AU (1) AU2001243475A1 (fr)
BR (1) BR0114031A (fr)
CA (1) CA2420987A1 (fr)
CZ (1) CZ2003566A3 (fr)
HU (1) HUP0300875A3 (fr)
IL (1) IL154688A0 (fr)
NO (1) NO20030926L (fr)
RU (1) RU2003108745A (fr)
SK (1) SK2502003A3 (fr)
WO (1) WO2002018390A1 (fr)

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002340328A1 (en) * 2001-10-29 2003-05-12 Janet I. Cord Olanzapine dihydrate-ii a process for its preparation and use thereof
AU2003243153A1 (en) * 2002-04-23 2003-11-10 Dr. Reddy's Laboratories Limited Novel crystalline polymorph form-vi of olanzapine and a process for preparation thereof
AU2002251329A1 (en) * 2002-04-25 2003-11-10 Generics (Uk) Limited Novel crystalline forms of celecoxib and other compounds
PL196814B1 (pl) 2002-05-17 2008-02-29 Inst Farmaceutyczny Sposób wytwarzania odmiany polimorficznej I olanzapiny i jej solwaty
SI1513846T1 (sl) 2002-05-31 2011-11-30 Sandoz Ag Postopek za pripravo olanzapina form I
SI21270A (sl) 2002-07-15 2004-02-29 Krka, Tovarna Zdravil, D.D., Novo Mesto Kristalne oblike olanzapina in postopki za njihovo pripravo
PL202856B1 (pl) * 2002-12-20 2009-07-31 Adamed Spo & Lstrok Ka Z Ogran Sposób otrzymywania farmaceutycznie czystej polimorficznej postaci I olanzapiny
EP1575962A1 (fr) * 2002-12-24 2005-09-21 Teva Pharmaceutical Industries Limited Nouvelles formes cristallines d'olanzapine, procedes pour les preparer et procede pour preparer des formes cristallines d'olanzapine connues
DE602004014264D1 (de) 2003-12-22 2008-07-17 Teva Pharma Verfahren zur herstellung von olanzapin
AR047460A1 (es) * 2004-01-27 2006-01-18 Synthon Bv Proceso para la fabricacion de acetato de 2-metil-4-(4-metil-1-piperazinil)-10h-tieno[2,3-b][1,5]benzodiazepina (acetato de olanzapina)
EP1709053B1 (fr) 2004-01-27 2011-04-06 Synthon B.V. Sels stables d'olanzapine
WO2005080401A1 (fr) * 2004-02-19 2005-09-01 Neuland Laboratories Limited Procede ameliore de preparation de la forme 1 de l'olanzapine utile en tant que medicament psychotique
WO2005107375A2 (fr) * 2004-05-06 2005-11-17 Matrix Laboratories Ltd Procede pour la preparation de forme i d'olanzapine
DE05783995T1 (de) * 2004-07-14 2007-10-11 Shasun Chemicals and Drugs Ltd., Chennai Verbessertes verfahren zur herstellung von form i aus olanzapin
EP1778649A4 (fr) 2004-07-14 2008-09-10 Jubilant Organosys Ltd Procede permettant de produire une forme pure de 2-methyl-4-(4-methyl-1-piperazinyl)-10h-thieno[2,3-b][1,5]benzodiazepine
ES2253091B1 (es) 2004-07-27 2007-02-01 Inke, S.A. Solvato mixto de olanzapina, procedimiento para su obtencion y procedimiento de obtencion de la forma i de olanzapina a partir del mismo.
WO2006025065A1 (fr) * 2004-08-31 2006-03-09 Lee Pharma Private Limited Procédé pour la préparation de chlorhydrate d'olanzapine anhydre de forme 1
US7829700B2 (en) 2004-09-06 2010-11-09 Shasun Chemicals And Drugs Limited Process for preparation of a pharmaceutically pure polymorphic form I of Olanzapine
SI1838716T1 (sl) * 2005-01-05 2011-10-28 Lilly Co Eli Olanzapin pamoat dihidrat
WO2006102176A2 (fr) * 2005-03-21 2006-09-28 Dr. Reddy's Laboratories Ltd. Procede de preparation d'une forme cristalline i d'olanzapine
HUP0501046A2 (en) * 2005-11-11 2007-08-28 Egis Gyogyszergyar Nyilvanosan Process for the preparation of olanzapine
US7834176B2 (en) 2006-01-26 2010-11-16 Sandoz Ag Polymorph E of Olanzapine and preparation of anhydrous non-solvated crystalline polymorphic Form I of 2-methyl-4(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine (Olanzapine Form I) from the polymorphic Olanzapine Form E
PL381564A1 (pl) 2007-01-22 2008-08-04 Koźluk Tomasz Nobilus Ent Sposób wytwarzania zasadniczo czystej odmiany polimorficznej I olanzapiny
EP2185566A2 (fr) * 2007-05-15 2010-05-19 Generics Ýuk¨Limited Procédé de purification d`olanzapine
EP2292624A1 (fr) 2009-07-20 2011-03-09 LEK Pharmaceuticals d.d. Processus de purification d'olanzapine
CN102093386B (zh) * 2011-01-05 2016-06-01 浙江华海药业股份有限公司 一种制备奥兰扎平晶型ⅱ的方法
JP6008734B2 (ja) * 2012-12-20 2016-10-19 株式会社トクヤマ オランザピンｉｉ型結晶の製造方法
FI3466934T3 (fi) 2016-05-31 2024-04-23 Taiho Pharmaceutical Co Ltd Sulfonamidiyhdisteitä tai niiden suola ribonukleotidireduktaasin inhibiittoreina syövän hoitamiseksi

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0454436B1 (fr) 1990-04-25 1995-09-13 Lilly Industries Limited Composés pharmaceutiques

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EG23659A (en) * 1995-03-24 2007-03-26 Lilly Co Eli Process and crystal forms of methyl-thieno-benzodiazepine
ZA978515B (en) * 1996-09-23 1999-03-23 Lilly Co Eli Intermediates and process for preparing olanzapine
AU720366B2 (en) * 1996-09-23 2000-06-01 Eli Lilly And Company Olanzapine dihydrate D

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0454436B1 (fr) 1990-04-25 1995-09-13 Lilly Industries Limited Composés pharmaceutiques

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BREWSTER R.Q.; VANDERWERF C.A.; MCEWEN W.E.: "Initized Experiments in Organic Chemistry", vol. 2, June 1965, D. VAN NOSTRAND COMPANY, INC., TORONTO, article "EXPERIMENT 4 - Chrystallization", pages: 18 - 23, XP002970932
FIESER L.F.: "ORGANIC EXPERIMENTS", part 7 1964, D.C. HEATH AND COMPANY, BOSTON, article "Crystallization", pages: 41 - 51, XP002970931
See also references of WO0218390A1

Also Published As

Publication number Publication date
CZ2003566A3 (cs) 2004-01-14
WO2002018390A1 (fr) 2002-03-07
AU2001243475A1 (en) 2002-03-13
BR0114031A (pt) 2003-09-09
HUP0300875A3 (en) 2005-09-28
CA2420987A1 (fr) 2002-03-07
SK2502003A3 (en) 2004-03-02
IL154688A0 (en) 2003-09-17
NO20030926D0 (no) 2003-02-27
JP2004507548A (ja) 2004-03-11
RU2003108745A (ru) 2005-01-10
NO20030926L (no) 2003-04-24
HUP0300875A2 (hu) 2003-12-29

Similar Documents

Publication Publication Date Title
WO2002018390A1 (fr) Procede de preparation d'hydrates d'olanzapine et de conversion de ceux-ci en formes cristallines d'olanzapine
JP2009242407A (ja) オランザピンの製造方法および中間体
EP3077375B1 (fr) Procédé pour la production de 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1h-indole dimesylate monohydrate à grande échelle
EP0733634B1 (fr) Procédé de préparation d'un dérivé de thieno(2,3-B)(1,5)benzodiazepine
EP1551414B1 (fr) Procede de preparation de forme i de l'olanzapine
WO2006006185A1 (fr) Procede ameliore de fabrication de forme i de l'olanzapine .
US20040067936A1 (en) Process for preparation of hydrates of olanzapine and their conversion into crystalline forms of olanzapine
CA2395774C (fr) Nouvelles formes polymorphes d'olanzapine
ZA200301640B (en) Process for preparation of hydrates of Olanzapine and their conversion into cystalline forms of Olanzapine.
US7829700B2 (en) Process for preparation of a pharmaceutically pure polymorphic form I of Olanzapine
WO2007102167A1 (fr) Procédé de synthèse de la forme polymorphique anhydre de l'olanzapine
MXPA03001827A (es) Proceso para la preparacion de hidratos de olanzapina y su conversion a formas cristalinas de olanzapina.
EP1730153B1 (fr) Solvate isopropanol-eau d'olanzapine
US3567745A (en) 2-(2-azido-n-methylacetamido)-5-chloro-benzophenone
KR101489062B1 (ko) 고순도의 올란자핀 및 이의 결정형 ii의 제조방법
AU2005230922A1 (en) Crystalline forms of 5,11-dihydro-11-ethyl-5-methyl-8-{2-{(1-oxido-4-quinolinyl)oxy}ethyl}-6H-dipyrido[3,2-B:2',3'-E][1,4]diazepin-6-one
RU2521595C2 (ru) Кристаллическая форма ii тилорона и способ ее получения (варианты)
EP1716154A1 (fr) Procede ameliore de preparation de la forme 1 de l'olanzapine utile en tant que medicament psychotique
AU2003249262A1 (en) Process for the preparation of imidazo(1,2-a)pyridine-3-acetamides
PL81442B1 (fr)

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20030326

AK Designated contracting states

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17Q First examination report despatched

Effective date: 20030924

TPAC Observations filed by third parties

Free format text: ORIGINAL CODE: EPIDOSNTIPA

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20050618