WO2005026122A1 - PROCESS FOR THE PREPARATION OF (1α, 5α, 6α)-6-AMINOMETHYL-3-BENZYL-3-AZBICYCLO[3.1.0]HEXANE - Google Patents

PROCESS FOR THE PREPARATION OF (1α, 5α, 6α)-6-AMINOMETHYL-3-BENZYL-3-AZBICYCLO[3.1.0]HEXANE Download PDF

Info

Publication number
WO2005026122A1
WO2005026122A1 PCT/IB2004/003037 IB2004003037W WO2005026122A1 WO 2005026122 A1 WO2005026122 A1 WO 2005026122A1 IB 2004003037 W IB2004003037 W IB 2004003037W WO 2005026122 A1 WO2005026122 A1 WO 2005026122A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
reaction
compound
carried out
hexane
Prior art date
Application number
PCT/IB2004/003037
Other languages
French (fr)
Inventor
Mohammad Salman
Pakala Kumara Savithru Sarma
Sankaranarayanan Dharmarajan
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
Priority to EP04769411A priority Critical patent/EP1675828A1/en
Publication of WO2005026122A1 publication Critical patent/WO2005026122A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered

Definitions

  • the present invention relates to a new and industrially advantageous process for the preparation of (l ⁇ , 5 ⁇ , 6 ⁇ )-6-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane of Formula I,
  • This compound is a key intermediate for the synthesis of azabicyclo quinolone derivatives as antimicrobials and for the synthesis of various azabicyclo[3.1.0]hexane derivatives as muscarinic receptor antagonists.
  • azabicyclo quinolone derivatives are known in U.S. Patent Nos. 5,164,402; 5,391,763; 5,229,396; 5,266,569 and European Patent Application No. 0413455 A2.
  • the azabicyclo quinolone derivatives are useful in the broad spectrum treatment of bacterial infections. They are particularly active against sensitive and resistant strains of gram-positive pathogens like methicillin resistant staphylococcus aureus (MRSA), methicillin resistant staphylococcus epidermidis (MRSE), quinolone resistant staphylococcus aureus (QRSA) and Vancomycin resistant enterococci (VRSE).
  • MRSA methicillin resistant staphylococcus aureus
  • MRSE methicillin resistant staphylococcus epidermidis
  • QRSA quinolone resistant staphylococcus aureus
  • VRSE Vancomycin resistant enterococci
  • WO 2004/052857 and WO 04/004629 disclose 3, 6-disubstituted azabicyclo [3.1.0] hexane derivatives useful as muscarinic receptor antagonists.
  • WO 04/005252 discloses azabicyclo derivatives as musacrinic receptor antagonists.
  • WO 04/014853, WO 04/067510 and WO 04/014363 disclose derivatives of 3, 6-disubstituted azabicyclohexane useful as muscarinic receptor antagonists.
  • WO 2004/056810 discloses xan bine derivatives as muscarinic receptor antagonists.
  • WO 2004/056811 discloses flaxavate derivatives as muscarinic receptor antagonists.
  • WO 2004/056767 discloses 1-substituted- 3-pyrrolidine derivatives as muscarinic receptor antagonists.
  • WO 2004/018422 disclose fluoro and sulphonylamino containing 3, 6-disubstituted azabicyclo[3.1.0] hexane derivatives as muscarinic receptor antagonists.
  • the processes require the use of oxalyl chloride, which is a corrosive, toxic, moisture-sensitive reagent and hence difficult to handle on commercial scale.
  • the processes require the use of lithium aluminum hydride, which is a very corrosive, air sensitive, hygroscopic and flammable reagent, which thus pose a handling problem.
  • the reaction conditions involve the use of tetrahydrofuran, which is unsafe and can involve the risk of explosion and fire due to peroxide formation. Tetrahydrofuran and lithium aluminum hydride are expensive reagents and add significant factor in the overall cost of preparation of final product. Removal of dimethylsulhoxide is difficult as it is high temperature evaporating solvent.
  • Formula V in the presence of a catalyst and an organic base in an organic solvent at a temperature ranging from 0-5°C.
  • the reaction can be carried out in the presence of a hypernucleophilic catalyst, such as, for example, N,N-dimethyl amino pyridine.
  • Trie organic base can be selected from for example triethylamine and pyridine.
  • the organic solvent can be selected from for example, dichloromethane, dichloroethane, chloroform and ethyl acetate.
  • the compound of Formula V is further reacted with aqueous ammonia solution to give a compound of Formula I in an organic solvent at a temperature ranging from 75-80°C.
  • the organic solvent can be selected from for example metlranol, ethanol, n-propanol and isopropyl alcohol in acetonitrile.
  • liquid ammonia solution can also be used in place of aqueous ammonia solution.
  • reaction mixture was diluted with dichloromethane and washed with saturated aqueous solution of sodium bicarbonate.
  • the organic layer was separated, washed with water and brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the title compound with a yield of 74%.
  • Step b Preparation of (l ⁇ ,5 ⁇ ,6 ⁇ )-6-aminomethyl-3-azabicyclo[3.1.0]hexane (Formula I) To a solution of a compound obtained from step a above (1 g) in methanol was added aqueous ammonia solution (25% w ⁇ v, 10 ml). The reaction mixture was placed in autoclave and sealed tightly and heated at 75-80°C for approx. 12 hours followed by cooling it to room temperature. The solvent was removed under vacuum and the residue was diluted with water. The pH of the solution was adjusted to 1-2 with 2N hydrochloric acid followed by washing with toluene. The pH of the aqueous layer was adjusted to 13- 14 with 2N sodium hydroxide.

Abstract

The present invention relates to a new and industrially advantageous process for the preparation of (1α , 5α , 6α )-6-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane, a key intermediate for the synthesis of azabicyclo quinolone derivatives as antimicrobials and for the synthesis of various azabicyclo[3.1.0]hexane derivatives.

Description

PROCESS FOR THE PREPARATION OF (lα, 5α, 6α)-6-AMINOMETHYL-3- BENZYL-3-AZABICYCLO[3.1.0]HEXANE
Technical Field of the Invention
The present invention relates to a new and industrially advantageous process for the preparation of (lα, 5α, 6α)-6-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane of Formula I,
Figure imgf000002_0001
This compound is a key intermediate for the synthesis of azabicyclo quinolone derivatives as antimicrobials and for the synthesis of various azabicyclo[3.1.0]hexane derivatives as muscarinic receptor antagonists. Background of the Invention
Various azabicyclo quinolone derivatives are known in U.S. Patent Nos. 5,164,402; 5,391,763; 5,229,396; 5,266,569 and European Patent Application No. 0413455 A2. The azabicyclo quinolone derivatives are useful in the broad spectrum treatment of bacterial infections. They are particularly active against sensitive and resistant strains of gram-positive pathogens like methicillin resistant staphylococcus aureus (MRSA), methicillin resistant staphylococcus epidermidis (MRSE), quinolone resistant staphylococcus aureus (QRSA) and Vancomycin resistant enterococci (VRSE). These compounds can be administered by either oral or parental routes.
WO 2004/052857 and WO 04/004629 disclose 3, 6-disubstituted azabicyclo [3.1.0] hexane derivatives useful as muscarinic receptor antagonists. WO 04/005252 discloses azabicyclo derivatives as musacrinic receptor antagonists. WO 04/014853, WO 04/067510 and WO 04/014363 disclose derivatives of 3, 6-disubstituted azabicyclohexane useful as muscarinic receptor antagonists. WO 2004/056810 discloses xan bine derivatives as muscarinic receptor antagonists. WO 2004/056811 discloses flaxavate derivatives as muscarinic receptor antagonists. WO 2004/056767 discloses 1-substituted- 3-pyrrolidine derivatives as muscarinic receptor antagonists. WO 2004/018422 disclose fluoro and sulphonylamino containing 3, 6-disubstituted azabicyclo[3.1.0] hexane derivatives as muscarinic receptor antagonists.
Methods for the synthesis of intermediate of Formula I were reported in U.S. Patent Nos. 5,164,402; 5,391,763; 5,229,396; 5,266,569 and European Patent Application No. 0413455 A2 which comprises (1) oxidizing [lα,5α,6α]-3-beιιzyl-6-hydroxymettryl-3- azabicyclo [3.1.0]hexane of Formula II
Figure imgf000003_0001
Formula II with a mixture of oxalyl chloride and dimethylsulphoxide in dichloromethane at -65° C to give [lα,5α,6α]-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxaldehyde of Formula III
Figure imgf000003_0002
Formula III followed by its purification by column chromatography, (2) reacting a compound of Formula III with hydroxylamine hydrochloride and sodium acetate in ethanol, for 18 hours to give [lα,5α,6α]-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxaldehyde oxime of Formula IV,
Figure imgf000004_0001
Formula IV (3) reacting a compound of Formula TV with lithium aluminum hydride in tetrahydrofuran followed by, refluxing for 12 hours to give (lα,5α,6α)-6-aminomethyl-3-benzyl-3- azabicyclo[3.1.0]hexane of Formula I.
The above-mentioned prior art methods for the manufacture of desired compound of Formula I suffer from the following limitations and for various reasons stated below are not suitable for commercial production.
The processes require the use of oxalyl chloride, which is a corrosive, toxic, moisture-sensitive reagent and hence difficult to handle on commercial scale. The processes require the use of lithium aluminum hydride, which is a very corrosive, air sensitive, hygroscopic and flammable reagent, which thus pose a handling problem. The reaction conditions involve the use of tetrahydrofuran, which is unsafe and can involve the risk of explosion and fire due to peroxide formation. Tetrahydrofuran and lithium aluminum hydride are expensive reagents and add significant factor in the overall cost of preparation of final product. Removal of dimethylsulhoxide is difficult as it is high temperature evaporating solvent. Very low temperature conditions need to be employed (e.g., -65°C), which are very difficult to maintain at commercial scale, as it require special equipment is required to maintain these conditions. The purification of an intermediate compound in the first step involves column chromatography, which is cumbersome, tedious and not practical on an industrial scale. Detailed Description of the Invention
Herein is provided a simple, commercially viable, and efficient process for the preparation of (lα,5α,6α)-6-aminomethyl-3-benzyl-3-azabicyclo[3.1.O]hexane of Formula I.
Figure imgf000005_0001
It is advantageous to avoid the use of hazardous, expensive, toxic and commercially difficult- to-handle raw materials.
More particularly is provided a process for the preparation of [1 α,5α,6α]-6- aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane of Formula I, comprising reacting (lα,5α,6α)-6-hydroxymethyl-3-benzyl-3-azabicyclo[3.1.0]hexane of Formula II (prepared by following the process described in EP 0413455) with methane sulphonyl chloride to give (lα,5α,6α)-6-(methylsulphonyloxy) methyl-3-benzyl-3-azabicyclo[3.1.0]hexane of Formula V,
Figure imgf000005_0002
Formula V in the presence of a catalyst and an organic base in an organic solvent at a temperature ranging from 0-5°C. The reaction can be carried out in the presence of a hypernucleophilic catalyst, such as, for example, N,N-dimethyl amino pyridine. Trie organic base can be selected from for example triethylamine and pyridine. The organic solvent can be selected from for example, dichloromethane, dichloroethane, chloroform and ethyl acetate. The compound of Formula V is further reacted with aqueous ammonia solution to give a compound of Formula I in an organic solvent at a temperature ranging from 75-80°C. The organic solvent can be selected from for example metlranol, ethanol, n-propanol and isopropyl alcohol in acetonitrile.
Alternatively, liquid ammonia solution can also be used in place of aqueous ammonia solution.
In the following section several preferred embodiments are described by way of examples to illustrate the progress of the invention. However, these do not limit the scope of the present invention.
Example 1: Preparation of (lα,5α,6αV6-ammomethyl-3-benzyl-3- azabicyclo 3.1.0]hexane (Formula I)
Step a: Preparation of (lα,5α,6α)-6-(methylsulphonyloxy)methyl-3-benzyl-3- azabicyclo [3.1.0]hexane (Formula V)
To a solution of (lα,5α,6α)-6-hydroxymethyl-3-azabicyclo[3.1.0]hexane (25 g, 123.2 miUimoles), triethylamine (35 ml, 246.4 miUimoles) in dichloromethane, was added 4-dimethylamino pyridine (0.3 g, 2.5 miUimoles) in dicliloromethane followed by the addition of methane sulphonyl chloride (14.5 ml, 185 miUimoles) dropwise at 0-30°C. The reaction mixture was stirred at same temperature followed by warming to 25-30°C with constant stirring for approx. 15 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with water and brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the title compound with a yield of 74%.
Step b: Preparation of (lα,5α,6α)-6-aminomethyl-3-azabicyclo[3.1.0]hexane (Formula I) To a solution of a compound obtained from step a above (1 g) in methanol was added aqueous ammonia solution (25% w\v, 10 ml). The reaction mixture was placed in autoclave and sealed tightly and heated at 75-80°C for approx. 12 hours followed by cooling it to room temperature. The solvent was removed under vacuum and the residue was diluted with water. The pH of the solution was adjusted to 1-2 with 2N hydrochloric acid followed by washing with toluene. The pH of the aqueous layer was adjusted to 13- 14 with 2N sodium hydroxide. The organic compound was extracted with ether. The combined ether layer was washed with water and brine solution, dried and concentrated under reduced pressure to yield the title compound with a yield of 95%. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

We Claim: 1. A process for the preparation of (lα,5α,6α)-6-aminomethyl-3-benzyl-3- azabicyclo[3.1.0]hexane of Formula I,
Figure imgf000008_0001
as shown in the accompanied drawings, comprising reacting (lα,5α,6α)-6- hydroxymethyl-3-benzyl-3-azabicyclo[3.1.0] hexane of Formula II,
with methane sulphonyl chloride in an organic solvent in the presence of organic base and
Figure imgf000008_0002
Formula II a catalyst to give (lα,5α,6α)-6-(methylsulphonyloxy)methyl-3-benzyl-3-azabicyclo [3.1.0] hexane of Formula V,
Figure imgf000009_0001
Formula V which on reaction with aqueous ammonia solution in an organic solvent yields the compound of Formula I.
2. The process of claim 1 wherein the reaction of a compound of Formula II
Figure imgf000009_0002
Formula II with methane sulphonyl chloride to give a compound of Formula V
Figure imgf000009_0003
Formula V is carried out in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform and ethyl acetate.
3. The process of claim 2 wherein the reaction is carried out in dichloromethane.
4. The process of claim 1 wherein the reaction of a compound of Formula II
Figure imgf000010_0001
Formula II with methane sulphonyl chloride is carried out in the presence of an organic base selected from a group consisting of triethylamine and pyridine.
5. The process of claim 4 wherein the reaction is carried out in triethylamine.
6. The process of claim 1 wherein the reaction of a compound of Formula II
Figure imgf000010_0002
Formula II with methane sulphonyl chloride is carried out in the presence of a catalyst.
7. The process of claim 6 wherein the reaction is carried out in 4-dimethyl amino pyridine.
8. The process of claim 1 wherein the reaction of a compound of Formula II
Figure imgf000011_0001
Formula II with methane sulphonyl chloride is carried out at a temperature ranging from about 0 to • about 30°C.
9. The process of claim 1 wherein the reaction of a compound of Formula V
Figure imgf000011_0002
Formula V with aqueous ammonia solution to give a compound of Formula I,
Figure imgf000011_0003
is carried out in a organic solvent selected from the group consisting of methanol, ethanol, propanol and isopropyl alcohol in acetonitrile.
10. The process of claim 9, wherein the reaction is carried out in methanol.
11. The process of claim 1 wherein the reaction of a compound of Formula V
Figure imgf000012_0001
Formula V with aqueous ammonia solution is carried out at a temperature ranging from about 75 to about 80°C.
PCT/IB2004/003037 2003-09-18 2004-09-17 PROCESS FOR THE PREPARATION OF (1α, 5α, 6α)-6-AMINOMETHYL-3-BENZYL-3-AZBICYCLO[3.1.0]HEXANE WO2005026122A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP04769411A EP1675828A1 (en) 2003-09-18 2004-09-17 PROCESS FOR THE PREPARATION OF (1alpha, 5alpha, 6alpha)-6-AMINOME THYL-3-BENZYL-3-AZBICYCLO [3.1.0] HEXANE

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1169/DEL/2003 2003-09-18
IN1169DE2003 2003-09-18

Publications (1)

Publication Number Publication Date
WO2005026122A1 true WO2005026122A1 (en) 2005-03-24

Family

ID=34308047

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2004/003037 WO2005026122A1 (en) 2003-09-18 2004-09-17 PROCESS FOR THE PREPARATION OF (1α, 5α, 6α)-6-AMINOMETHYL-3-BENZYL-3-AZBICYCLO[3.1.0]HEXANE

Country Status (2)

Country Link
EP (1) EP1675828A1 (en)
WO (1) WO2005026122A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007039884A1 (en) 2005-10-05 2007-04-12 Ranbaxy Laboratories Limited 3 -azabicyclooctane derivatives as muscarinic receptor antagonists
WO2007110782A1 (en) 2005-12-30 2007-10-04 Ranbaxy Laboratories Limited Muscarinic receptor antagonists
WO2009068876A1 (en) * 2007-11-30 2009-06-04 Summit Corporation Plc Compositions for the treatment of skin disorders

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5164402A (en) * 1989-08-16 1992-11-17 Pfizer Inc Azabicyclo quinolone and naphthyridinone carboxylic acids

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5164402A (en) * 1989-08-16 1992-11-17 Pfizer Inc Azabicyclo quinolone and naphthyridinone carboxylic acids

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANQUETIN, G. ET AL: "Synthesis of new fluoroquinolones and evaluation of their in vitro activity on Toxoplasma gondii and Plasmodium spp.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS , 14(11), 2773-2776 CODEN: BMCLE8; ISSN: 0960-894X, 2004, XP009041042 *
BRIGHTY, KATHERINE E. ET AL: "Synthesis of (1.alpha.,5.alpha.,6.alpha.)-6-amino-3- azabicyclo[3.1.0]hexane, a novel achiral diamine", SYNLETT , (11), 1097-1099 CODEN: SYNLES; ISSN: 0936-5214, 1996, XP009041061 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007039884A1 (en) 2005-10-05 2007-04-12 Ranbaxy Laboratories Limited 3 -azabicyclooctane derivatives as muscarinic receptor antagonists
WO2007110782A1 (en) 2005-12-30 2007-10-04 Ranbaxy Laboratories Limited Muscarinic receptor antagonists
WO2009068876A1 (en) * 2007-11-30 2009-06-04 Summit Corporation Plc Compositions for the treatment of skin disorders

Also Published As

Publication number Publication date
EP1675828A1 (en) 2006-07-05

Similar Documents

Publication Publication Date Title
US20190202814A1 (en) Processes for preparation of empagliflozin
WO2016180275A1 (en) Ahu-377 intermediates and method for preparing ahu-377 and ahu-377 intermediates
CN108440330A (en) A kind of preparation method of Doxycycline Hyclate
CN112574190B (en) Method for synthesizing chlorantraniliprole
ZA200407018B (en) Method for preparing benzisoxazole methane sulfonyl chloride and its amidation to form zonisamide
WO2005026122A1 (en) PROCESS FOR THE PREPARATION OF (1α, 5α, 6α)-6-AMINOMETHYL-3-BENZYL-3-AZBICYCLO[3.1.0]HEXANE
WO2009157525A1 (en) Method for producing 3-methyl-2-thiophenecarboxylic acid
EP2850064B1 (en) Process for preparation of montelukast sodium
CN108558785B (en) 5-aryl-2-arylseleno-1, 3-oxazole compound and preparation method thereof
WO2009047797A2 (en) Process for the preparation of perhydroisoindole derivative
CN107540575B (en) Preparation method of sitagliptin intermediate
WO2012060232A1 (en) 5-trifluoromethyl-4-nitro-2-isoxazoline compounds and preparing process therefor
EP1670759A1 (en) PROCESS FOR THE PREPARATION OF (1a, 5a, 6a)-6-AMINOME THYL-3-BENZYL-3-AZABICYCLO 3.1.0 HEXANE
US20230382887A1 (en) Process for the preparation of chlorantraniliprole
JP2006528978A (en) Method for the synthesis of β-lactamase inhibitor intermediates
WO2010000197A1 (en) A method for preparing 5h-cyano-imido stilbene
JP2015533142A (en) Production of ertapenem intermediate
CN115490728B (en) Synthesis method of allyl phosphine derivative
WO2007013323A1 (en) 4,5-di(5-tetrazolyl)-[1,2,3]triazole compound and process for producing the same
JP2001019689A (en) Production of indene carbonate
CN109970681A (en) A kind of synthetic method of Repaglinide
CN116730939A (en) Preparation method of famoxadone characteristic impurities
JPH0987288A (en) Purification method for 1,3-bis(3-aminopropyl)-1,1,3,3-tetraorganodisiloxane
KR100310936B1 (en) A process for preparing N-(4-methylbenzenesulfonyl)-N'-(3-azabicyclo[3,3,0]octane)urea
CN116813517A (en) Vinyl sulfonyl fluoride compound, intermediate thereof, preparation method and application

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BW BY BZ CA CH CN CO CR CU CZ DK DM DZ EC EE EG ES FI GB GD GE GM HR HU ID IL IN IS JP KE KG KP KZ LC LK LR LS LT LU LV MA MD MK MN MW MX MZ NA NI NO NZ PG PH PL PT RO RU SC SD SE SG SK SY TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SZ TZ UG ZM ZW AM AZ BY KG MD RU TJ TM AT BE BG CH CY DE DK EE ES FI FR GB GR HU IE IT MC NL PL PT RO SE SI SK TR BF CF CG CI CM GA GN GQ GW ML MR SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2004769411

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2004769411

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 2004769411

Country of ref document: EP