WO2005014590A2 - Procedure for preparing 11-(4`2-(2-hydroxyethoxy )ethyl!-1-piperazinyl!-dibenzo`b,f!`1,4!thiazepine - Google Patents
Procedure for preparing 11-(4`2-(2-hydroxyethoxy )ethyl!-1-piperazinyl!-dibenzo`b,f!`1,4!thiazepine Download PDFInfo
- Publication number
- WO2005014590A2 WO2005014590A2 PCT/IB2004/002527 IB2004002527W WO2005014590A2 WO 2005014590 A2 WO2005014590 A2 WO 2005014590A2 IB 2004002527 W IB2004002527 W IB 2004002527W WO 2005014590 A2 WO2005014590 A2 WO 2005014590A2
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- WIPO (PCT)
- Prior art keywords
- procedure according
- formula
- compound
- alkaline
- base
- Prior art date
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- 0 *OCCOCC*(CCC1)CC*C1C1=*c(cccc2)c2Nc2c1cccc2 Chemical compound *OCCOCC*(CCC1)CC*C1C1=*c(cccc2)c2Nc2c1cccc2 0.000 description 2
- JSGJXCXXTHQKEF-UHFFFAOYSA-N OCCN(CC1)C=CN1C1NC(CCC=C2)=C2Sc2c1cccc2 Chemical compound OCCN(CC1)C=CN1C1NC(CCC=C2)=C2Sc2c1cccc2 JSGJXCXXTHQKEF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D417/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/18—Eight-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D281/16—[b, f]-condensed
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This invention relates to a new procedure for the preparation of a pharmaceutically active compound-
- Patent EP 240228 describes a dibenzothiazepine compound of formula (I) :
- the said patent describes the obtaining of the compound of formula (I) by reaction of an imino chloride, specifically 11-chloro-dibenzo [b, f] [1, ] thiazepine, or of its corresponding imino ether, with 2- (2-piperazine-l-il- ethoxy) ethanol .
- EP 282236 describes the preparation of the compound of formula (I) by reaction of the same imino chloride with piperazine, followed by reaction of the product obtained in hydrochlorate form with chloro- ethoxyethanol.
- this invention discloses a new procedure for obtaining the
- X means a leaving group and P a protective group of alcohols resistant to alkaline conditions, in the presence of a base, followed by a step of deprotection and, eventually, obtaining a pharmaceutically acceptable salt thereof.
- a protective group of alcohols resistant to alkaline conditions is taken to mean a protective group of alcohols resistant to a pH > 10 under aqueous conditions. See also “Protective Groups in Organic Synthesis, 3 rd edition, T.W. Greene, Wiley Interscience, chapter 2" on protective groups of alcohols.
- a base in the presence of a base is taken to mean in the presence of an alkaline or alkaline-earth organic or inorganic base, such as alkaline or alkaline- earth hydroxides or carbonates.
- the use of the intermediate of formula (III) which has the hydroxyl group protected prevents, without addition of an excess of reagent, the undesired disubstitution reactions taking place.
- the leaving group X (see M.B. Smith, J. March. March's Advanced Organic Chemistry, 5 th Edition, New York (USA) : John Wiley & Sons; 2001, pp 446) , can be halogen or an alkylsulphonyloxy group, such as mesylate, triflate, nonaflate and tresylate, or an arylsulphonyloxy group, such as tosylate, brosylate, nosylate.
- X is chloro or a p-toluenesulphonyloxy group (tosylate) .
- the protective group P is of ether type, such as methyl-, ethyl- or benzylether, all of them optionally replaced.
- the protective group P is a tetrahydropyranyl, benzyl or trithyl (triphenylmethyl) group. More preferably still, P is a trithyl group.
- the reaction can be carried out within a wide range of temperatures between 0°C and 130°C. Preferably, in a range of 25-70°C when P is tetrahydropyranyl, 40 to 70°C when P is benzyl and 80-120°C when P is trithyl.
- the procedure according to the invention is carried out by phase-transfer reaction between the compound of formula (II) and a compound of formula (III) in the presence of a phase- transfer catalyst.
- phase-transfer reaction permits the reaction to be carried out under softer temperature conditions, with shorter reaction times.
- phase-transfer reaction between the compound of formula (II) and the compound of formula (III) can be carried out in the absence of organic solvent, thereby avoiding the use of toxic solvents .
- the phase-transfer catalyst used is selected from among tetrabutyl ammonium bisulphate, Aliquat 336, tetrabutyl ammonium iodide, and ether 18-corona-6.
- the base is an alkaline hydroxide, such as sodium hydroxide or potassium hydroxide, in solid form or in aqueous solution.
- alkaline hydroxide such as sodium hydroxide or potassium hydroxide
- the intermediate of formula (IV) can later be isolated by extraction with an organic solvent, preferably toluene.
- the step of deprotection is then carried out, which can be by conventional methods .
- the deprotection is carried out by hydrolysis of the intermediate (IV) in acid medium to yield the compound of formula (I) .
- the intermediate of formula (IV) is preferably not isolated, and the hydrolysis is carried out directly in the presence of an aqueous mineral acid.
- the intermediate is preferably isolated, and the deprotection is carried out by means of acid hydrolysis, for example, with a solution of 33% hydrobromic acid in acetic acid.
- the intermediate of formula (IV) obtained is a crystalline solid. This allows it to be purified by recrystallisation in organic solvents, such as methanol, ethylmethylketone or a mixture thereof. A high purity of this product is thereby obtained.
- said recrystallised intermediate is later hydrolysed to the final compound of formula (I) in the presence of an acid such as acetic acid, trifluoroacetic acid, p- toluenesulphonic acid or hydrochloric acid, preferably p- toluenesulphonic acid, in an organic solvent such as toluene, methanol, isopropanol or a mixture thereof and, if wished, in the presence of water.
- an acid such as acetic acid, trifluoroacetic acid, p- toluenesulphonic acid or hydrochloric acid, preferably p- toluenesulphonic acid
- organic solvent such as toluene, methanol, isopropanol or a mixture thereof
- the compound of formula (I) is obtained in the form of a pharmaceutically acceptable salt.
- the he ifumarate is obtained.
- the intermediate of formula (II) can be obtained as described in patent CH 422793, by reaction of the aforesaid imino chloride with 2-piperazinyl-l-ethanol.
- X is CI or p-toluenesulphonyloxy
- the phases are separated and the organic phase is washed with water (2 x 26 mL) .
- 32 L of water and 5 mL of 35% hydrochloric acid 35% are added and the two-phase mixture is stirred at 20-25°C for 3 hours.
- the phases are separated and the aqueous phase is washed successively with n-butanol (10 mL) and toluene (10 mL) .
- 45 mL of toluene and 10% aqueous solution of potassium carbonate are added until the aqueous phase pH 10 is reached.
- the phases are separated and the aqueous phase is extracted with toluene (10 mL) .
- the combined organic phases are evaporated to dryness under vacuum, yielding 4.80 g (85%) of the product of the title as a light yellow oil.
- Example 1 The mixture is heated at 60- 65°C for 8 hours with thorough stirring.
- the synthesis proceeds as in Example 1, yielding 5.08 g (90%) of the product of the title as a light yellow oil, having IR and 10 -"-H-RMN spectra identical to those of the product obtained in Example 1.
- aqueous phase is extracted with dichloromethane (25 mL) and the combined organic phases are dried with anhydrous sodium sulphate and evaporated to dryness under vacuum, yielding 0.8 g (89%) of 2-[2-(4- dibenzo [b, f] [1.4] thiazepine-ll-il-piperazine-1- il) ethoxy] ethylo acetate as a yellow oil.
- a mixture of 40 g (0.12 mols) of 2- (4- 30 dibenzo[b,f] [1, 4] thiazepine-11-il-piperazine-l-il) ethanol and 44 g (0.14 mols) of trityl- (2-chloroethyl) -ether are heated slowly to 100-110°C until the mixture has fused completely. Stirring is started, and 4 fractions of 5 g of powdered potassium hydroxide are added over the course of 35 45-60 min, while keeping the temperature at 110-115°C. 1.6 g of 18-corona-6 catalyst are added and the mixture kept under stirring at 110-115°C for 2 hours.
- the above crude product is purified by recrystallisation of a mixture at reflux of 125 mL of ethylmethylketone and 200 mL of methanol. It is cooled slowly to 20-25°C and the
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006523068A JP2007501837A (en) | 2003-08-08 | 2004-07-27 | Method for producing pharmaceutically active compound |
US10/566,413 US7807827B2 (en) | 2003-08-08 | 2004-07-27 | Procedure for preparing 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazineyl)-dibenzo[b,f] [1,4]thiazepine |
DE602004007670T DE602004007670T2 (en) | 2003-08-08 | 2004-07-27 | PROCESS FOR PREPARING 11- (4-Ä2- (2-HYDROXYETHOXY) ETHYLÜ-1-PIPERAZINYL) DIBENZOÄB, FÜÄ1,4ÜTHIAZEPIN |
EP04744176A EP1660468B1 (en) | 2003-08-08 | 2004-07-27 | Procedure for preparing 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine |
PL04744176T PL1660468T3 (en) | 2003-08-08 | 2004-07-27 | Procedure for preparing 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES200301922A ES2223294B2 (en) | 2003-08-08 | 2003-08-08 | PREPARATION PROCEDURE FOR A PHARMACEUTICALLY ACTIVE COMPOUND. |
ESP-200301922 | 2003-08-08 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2005014590A2 true WO2005014590A2 (en) | 2005-02-17 |
WO2005014590A3 WO2005014590A3 (en) | 2005-05-06 |
Family
ID=34130558
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2004/002527 WO2005014590A2 (en) | 2003-08-08 | 2004-07-27 | Procedure for preparing 11-(4`2-(2-hydroxyethoxy )ethyl!-1-piperazinyl!-dibenzo`b,f!`1,4!thiazepine |
Country Status (10)
Country | Link |
---|---|
US (1) | US7807827B2 (en) |
EP (1) | EP1660468B1 (en) |
JP (1) | JP2007501837A (en) |
KR (1) | KR100864799B1 (en) |
AT (1) | ATE367383T1 (en) |
DE (1) | DE602004007670T2 (en) |
ES (2) | ES2223294B2 (en) |
PL (1) | PL1660468T3 (en) |
PT (1) | PT1660468E (en) |
WO (1) | WO2005014590A2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1958617A1 (en) | 2007-02-14 | 2008-08-20 | Laboratorios Lesvi, S. L. | Pharmaceutical compositions containing quetiapine fumarate |
US7687622B2 (en) | 2005-04-14 | 2010-03-30 | Teva Pharmaceutical Industries, Ltd | Process for preparing quetiapine fumarate |
US8420807B2 (en) | 2008-01-31 | 2013-04-16 | Fermion Oy | Process for the preparation of quetiapine |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL164155A0 (en) * | 2002-03-20 | 2005-12-18 | Teva Pharma | Crystalline forms of quetiapine hemifumarate |
DE602004024798D1 (en) * | 2003-09-23 | 2010-02-04 | Fermion Oy | PREPARATION OF QUETIAPINE |
CN101610774B (en) * | 2006-11-03 | 2012-04-04 | 萨斯喀彻温大学 | Method of treating demyelination diseases |
US20080241949A1 (en) * | 2007-03-29 | 2008-10-02 | Vinod Kumar Kansal | Process for preparing quetiapine fumarate |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0240228A1 (en) * | 1986-03-27 | 1987-10-07 | Ici Americas Inc. | Thiazepine compounds |
EP0282236A1 (en) * | 1987-03-10 | 1988-09-14 | Imperial Chemical Industries Plc | Process for the preparation of a thiazepine compound |
WO2001055125A1 (en) * | 2000-01-25 | 2001-08-02 | EGIS Gyógyszergyár Rt. | A process for the preparation of quetiapine and intermediates therefor |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH422793A (en) | 1961-07-20 | 1966-10-31 | Wander Ag Dr A | Process for the preparation of 11-basic substituted dibenzo (b, f) (1,4) thiazepines |
GB9716161D0 (en) | 1997-08-01 | 1997-10-08 | Zeneca Ltd | Process |
US20050080072A1 (en) * | 2003-09-01 | 2005-04-14 | Orchid Chemicals & Pharmaceuticals Ltd. | Process for the preparation of a thiazepine derivative |
-
2003
- 2003-08-08 ES ES200301922A patent/ES2223294B2/en not_active Expired - Fee Related
-
2004
- 2004-07-27 ES ES04744176T patent/ES2290734T3/en active Active
- 2004-07-27 AT AT04744176T patent/ATE367383T1/en not_active IP Right Cessation
- 2004-07-27 US US10/566,413 patent/US7807827B2/en not_active Expired - Fee Related
- 2004-07-27 KR KR1020067002638A patent/KR100864799B1/en not_active IP Right Cessation
- 2004-07-27 EP EP04744176A patent/EP1660468B1/en active Active
- 2004-07-27 PT PT04744176T patent/PT1660468E/en unknown
- 2004-07-27 WO PCT/IB2004/002527 patent/WO2005014590A2/en active IP Right Grant
- 2004-07-27 JP JP2006523068A patent/JP2007501837A/en active Pending
- 2004-07-27 DE DE602004007670T patent/DE602004007670T2/en active Active
- 2004-07-27 PL PL04744176T patent/PL1660468T3/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0240228A1 (en) * | 1986-03-27 | 1987-10-07 | Ici Americas Inc. | Thiazepine compounds |
EP0282236A1 (en) * | 1987-03-10 | 1988-09-14 | Imperial Chemical Industries Plc | Process for the preparation of a thiazepine compound |
WO2001055125A1 (en) * | 2000-01-25 | 2001-08-02 | EGIS Gyógyszergyár Rt. | A process for the preparation of quetiapine and intermediates therefor |
Non-Patent Citations (2)
Title |
---|
LAMBERT, T.N. ET AL.: "Synthesis of 3-Hydroxy-2-pyridinone Derivatives of 4-tert-Butylcalix[4]arenes: A New Class of Selective Extractants of Actinide(IV) Ions" JOURNAL OF ORGANIC CHEMISTRY, vol. 64, 1999, pages 6097-6101, XP002317244 * |
WARAWA E J ET AL: "Behavioral approach to nondyskinetic dopamine antagonists: Identification of Seroquel" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 44, 1 February 2001 (2001-02-01), pages 372-389, XP002213291 ISSN: 0022-2623 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7687622B2 (en) | 2005-04-14 | 2010-03-30 | Teva Pharmaceutical Industries, Ltd | Process for preparing quetiapine fumarate |
EP1958617A1 (en) | 2007-02-14 | 2008-08-20 | Laboratorios Lesvi, S. L. | Pharmaceutical compositions containing quetiapine fumarate |
US8420807B2 (en) | 2008-01-31 | 2013-04-16 | Fermion Oy | Process for the preparation of quetiapine |
Also Published As
Publication number | Publication date |
---|---|
WO2005014590A3 (en) | 2005-05-06 |
ATE367383T1 (en) | 2007-08-15 |
KR20060087506A (en) | 2006-08-02 |
JP2007501837A (en) | 2007-02-01 |
PL1660468T3 (en) | 2007-12-31 |
KR100864799B1 (en) | 2008-10-23 |
DE602004007670T2 (en) | 2008-04-30 |
US7807827B2 (en) | 2010-10-05 |
DE602004007670D1 (en) | 2007-08-30 |
EP1660468B1 (en) | 2007-07-18 |
ES2290734T3 (en) | 2008-02-16 |
PT1660468E (en) | 2007-10-12 |
EP1660468A2 (en) | 2006-05-31 |
US20060189594A1 (en) | 2006-08-24 |
ES2223294B2 (en) | 2005-10-01 |
ES2223294A1 (en) | 2005-02-16 |
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