WO2005113518A1 - Process for preparing irbesartan - Google Patents
Process for preparing irbesartan Download PDFInfo
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- WO2005113518A1 WO2005113518A1 PCT/US2005/017953 US2005017953W WO2005113518A1 WO 2005113518 A1 WO2005113518 A1 WO 2005113518A1 US 2005017953 W US2005017953 W US 2005017953W WO 2005113518 A1 WO2005113518 A1 WO 2005113518A1
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- irbesartan
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- 0 CCCCC(NC12CCCC1)N(Cc(c([I](C)[Cn])c1)ccc1Br)C2=O Chemical compound CCCCC(NC12CCCC1)N(Cc(c([I](C)[Cn])c1)ccc1Br)C2=O 0.000 description 4
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Definitions
- the present invention relates to a process for preparing the compound 2-n- Butyl-3-[[2'-(1 H-tetrazol-5-yl) [1 ,1'-biphenyl]-4-yl]methyl]- 1 ,3-diazaspiro [4.4]non- 1-en-4-one, also named 2-butyl-3[p-(o-1 - -tetrazol-5-ylphenyl)benzyl]-1 ,3- diazaspiro[4,4]non-1-en-4-one, which is also known by the adopted name "irbesartan.”
- Pharmaceutical products containing irbesartan are being sold using the trademark AVAPRO, for treating hypertension.
- the compound can be represented by formula (I).
- U.S. Patent 5,352,788 disclosed and claimed certain N- substituted heterocyclic derivatives including 2-n-butyl-4-spirocylopentane-1-[(2-(tertrozol-5yl) biphenyl-4-yl)methyl]-2-imidazolin-5-one, commonly known as irbesartan, and pharmaceutical compositions containing them.
- Irbesartan is a non-peptide compound, which antagonizes the physiologic effects of angiotensin II by inhibiting the action of angiotensin II on its receptors; the compounds particularly prevent increases in blood pressure produced by the receptor interaction.
- the compound Irbesartan is useful in the treatment of cardiovascular conditions such as hypertension and heart failure, as well as in preventing disorders of central nervous system, glaucoma, diabetic retinopathy, and diabetic nephropathy.
- a process for preparing irbesartan has been described in U.S. Patents 5,270,317 and 5,352,788.
- irbesartan can be prepared by reacting 2-n-butyl-4-spirocylopentane-2-imidazolin-5-one with 4-bromomethyl- 2-cyanobiphenyl in the presence of NaOH, followed by a column chromatography separation to yield 1-[(2'-cyanobiphenyl-4-yl) methyl]-2-n-butyl-4- spirocyclopentane-2-imidazolin-5-one (II).
- This product compound is further reacted with tributyltin azide and the product treated with trityl chloride and separated by column chromatography.
- U.S. Patent 6,162,922 has described a process for the preparation of 4-[[2- butyl-4-oxo-1 , 3-diazaspiro [4,4] non-1 -ene-3yl] methyl] [1 ,1-biphenyl]-2- carbonitrile (IV) comprising reacting 2-butyl-1 ,3-diazaspiro[4,4] nonane-4-one hydrochloride with 4'-(bromomethyl)[1 ,1-biphenyl]-2-carbonitrile (III) in the presence of phase transfer catalyst.
- a process for preparing irbesartan comprises: (a) reacting a compound having the formula III:
- irbesartan is prepared by a process comprising: (a) reacting a compound having formula VII: with 4-bromobenzylbromide to form a compound having formula IX:
- the present invention provides simple processes for preparing irbesartan.
- One embodiment of the present invention comprises pentanoylation of cycloleucine (III) in the presence of sodium hydroxide to form n-pentanoyl cycloleucine (IV), condensing this product with 2-(4-aminomethyl phenyl) benzonitrile (V) using dicyclohexyl carbodiimide and 1-hydroxy benzotriazole as a catalyst to form the 4-( ⁇ -N-pentanoyl amino) cyclopentamido methyl-2'-cyano biphenyl (VI) compound, and then cyclizing using trifluroacetic acid in the presence of an aromatic solvent such as xylene or toluene to get cyano irbesartan (II).
- an aromatic solvent such as xylene or toluene
- Cyano irbesartan is converted to irbesartan (I) by reaction with tributyltin chloride and sodium azide in the presence of an aromatic solvent such as toluene or xylene. Finally a pure pharma grade crystalline Form A irbesartan is isolated by recrystallization from methyl isobutyl ketone solvent.
- the present invention relates to a novel and improved process for the preparation of 2-n-Butyl-3-[[2'-(1 H-tetrazol-5-yl ) [1 ,1 '-biphenyl]-4-yl]methyl]- 1 ,3- diazaspiro [4.4]non-1-en-4-one (commonly known as irbesartan).
- a process of the present invention is schematically represented as follows.
- a process of the present invention comprises: (1 ) reacting cycloleucine, or 1-amino-cyclopentanecarboxylic acid, (III) with valeryl chloride in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium hydride, or organic bases such as triethyl amine, preferably sodium hydroxide, to produce n-pentanoyl cycloleucine, or 1-[(1-oxopentyl)amino]- cyclopentanecarboxylic acid, (IV); (2) condensing the n-pentanoyl cycloleucine (IV) with 2-(4-aminomethyl phenyl) benzonitrile (V), using dicyclohexyl carbodimide and 1-hydroxy benzotriazole as a catalyst, in a solvent such as tetrahydrofuran or methylene chloride, to obtain 4-( ⁇ ) inorgan
- a more pure pharmaceutical grade material can be obtained by recrystallizing the irbesartan from a solvent such as acetone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, or mixtures of any two or more thereof.
- a solvent such as acetone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, or mixtures of any two or more thereof.
- the starting material cycloleucine, or 1-amino-1-cyclopentanecarboxylic acid is commercially available and was described at Z. Physiol. Chem., Vol. 75, page 350 (1912).
- this process for the preparation of 2-n-butyl-3- [ ⁇ -(I H- tetrazol-5-yl)[1 ,1 / -biphenyl]-4-yl]methyl]-1 ,3-diazaspiro[4.4]non-1-en-4-one of Formula (I) comprises: (a) reacting 2-Butyl-1 ,3-diazo spiro [4.4] non-1 -en-4-one monohydrochloride of Formula (VII) with 4-bromobenzyl bromide of Formula (VIII) in a solvent such as toluene or dimethyl formamide, preferably dimethyl formamide, using a base such as potassium hydroxide, potassium carbonate, triethylamine, or sodium carbonate, preferably potassium carbonate, to yield 3-[4- bromo benzyl]-2-butyl-1 ,3-diazaspiro[4.4]non-1-en-4-one of Formula (IX); (b) reacting 3-
- n-pentanoyl cycloleucine of Formula IV sodium hydroxide (68.2 grams, 1.7 moles) was added to water (275 ml) and cooled the solution cooled to 0-5°C, then there was added slowly a solution of cycloleucine (55 grams, 0.426 moles) and valeryl chloride (77 grams, 0.639 moles) in toluene (55 ml) over about 2-3 hours at 0-10°C. The reaction mass was maintained at 0-10°C for about 2-3 hours. Water (275 ml) and toluene (55 ml) were added to the reaction mass and the mixture was stirred for about 15 minutes.
- the aqueous layer was separated and washed with toluene (55 ml), then the aqueous layer pH was adjusted to 2.0-2.5 with 8% aqueous hydrochloric acid (95 ml) and stirred for 15 minutes as a solid formed.
- the solid was separated by filtration and washed with water (45 ml), then was dried at 70-80°C to get the desired compound of Formula IV, in an amount of 50 grams.
- the formed solid was filtered and washed with methylene chloride (30 ml) followed by washing the filtrate with saturated sodium bicarbonate solution (2x250 ml). The organic layer was separated and concentrated under reduced pressure. Cyclohexane (100 ml) was added to the residue and the mixture stirred for 15 minutes. Then the separated solid was removed by filtration, washed with cyclohexane (30 ml), and dried at 70-80°C to a constant weight to yield the desired compound (59 grams).
- a process for the preparation of 1 -[(2'-Cyanobiphenyl-4-yl) methyl] -2-n- butyl-4-spirocyclopentane-2- imidazolin-5-one of Formula (II) involved charging 4- [(alpha-N-pentanoyl amino) cyclopentamido methyl]-2'-cyano biphenyl (140 ml, 0.347 moles) toluene (1400 ml) and trifluoroacetic acid (40.1 ml) to a vessel, heating to reflux temperature and maintaining until completion of the reaction.
- reaction mass was stirred at 30-35°C for 35-45 minutes, then filtered and the solid washed with toluene (150 ml). The aqueous layer was separated and extracted with toluene (150 ml). The organic layers were combined and concentrated under reduced pressure.
- Xylene (50 ml) was added to the residue followed by tributyltin chloride (77.1 grams, 0.237 moles) and sodium azide (15.4 grams, 0.2369 moles), and the reaction mass heated to reflux until the reaction completed.
- the reaction mass was cooled to 25-35°C and water (500 ml) and acetone (400 ml) were added.
- Reaction mass pH was adjusted to 4.0 to 4.5 with a 1 :3 solution of acetic acid and water (140 ml), then cyclohexane (500 ml) was added and the mixture stirred for 2 hours. A solid was isolated by filtering the reaction mass and was washed with cyclohexane (250 ml). After drying the solid at 70-80°C the desired compound was obtained (48 grams).
- Irbesartan was purified by recrystallization from methyl isobutyl ketone.
- a mixture of irbesartan (11 grams) and methyl isobutyl ketone (330.0 ml) was heated to reflux.
- Decolorizing carbon powder was added to the reaction solution and maintained at reflux for 35-45 minutes. Carbon was removed by filtering the mixture in a hot condition and washing the carbon with methyl isobutyl ketone (11 ml). The filtrate was cooled to 25-30 °C and stirred for 45 minutes and then further cooled to 0-5°C and stirred for 45 minutes to produce a solid.
- the solid was isolated by filtration and washed with methyl isobutyl ketone (11 ml). After drying at 70-80°C, the desired compound was obtained (8.8 grams).
- Irbesartan (30 grams) and isopropyl alcohol (600 ml) were mixed and heated to reflux. After 15 minutes, the solution was filtered and the solid washed with isopropyl alcohol (30 ml). The filtrate was cooled to 20-25 °C with stirring for 30 minutes to produce a solid. The solid was isolated by filtration and washed with water (60 ml). The obtained solid was dried at 70-80°C to yield the desired compound (20.9 grams).
- EXAMPLE 7 3-[4-bromo benzyl]-2-butyl-1 ,3-diazaspiro [4.4]non-1 -en-4-one was prepared by adding a mixture of 2— Butyl— 1 ,3-diazo spiro [4. 4] non -1- en -4- one Hydrochloride (50 grams), potassium carbonate (74.8 grams), 4-bromobenzyl bromide (67.8 grams) at a temperature of 25-35°C to dimethylformamide (400 ml), heating to a temperature of 50-55°C, and then stirring gently and maintaining at temperature until TLC analysis indicated reaction completion. Subsequently, the reaction mixture was cooled to a temperature of 25-35 ° C.
- Tetrakis(triphenyl phosphine)palladium (0.4 grams) was added to the above reaction mixture at a temperature of 25-35°C, and the reaction mixture was heated to a temperature of 80-85°C and stirred until completion of the reaction as shown by TLC analysis.
- the reaction mixture was cooled to a temperature of 25-35°C and water (50 ml) was added and stirred for 30 minutes at a temperature of 25-35°C.
- the resultant reaction mixture was filtered and washed with toluene (20 ml), then the organic layer was separated and washed with water (20 ml). Solvent was distilled from the organic layer under reduced pressure.
- the aqueous layer was washed with toluene (3 X 15 ml) at a temperature of 10-15°C, then the aqueous layer was separated and its pH was adjusted to 5 using dilute acetic acid. Upon stirring for 1-2 hours at a temperature of 25-35°C the produced solid mass was filtered and washed with water (25 ml) to afford the desired compound. (Yield: 1.3 grams, 22%).
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05752192A EP1751123A4 (en) | 2004-05-20 | 2005-05-20 | Process for preparing irbesartan |
US11/569,380 US20090286990A1 (en) | 2004-05-20 | 2005-05-20 | Process for preparing irbesartan |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN472/CHE/2004 | 2004-05-20 | ||
IN472CH2004 | 2004-05-20 | ||
US57991404P | 2004-06-15 | 2004-06-15 | |
US60/579,914 | 2004-06-15 |
Publications (1)
Publication Number | Publication Date |
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WO2005113518A1 true WO2005113518A1 (en) | 2005-12-01 |
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ID=35428367
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2005/017953 WO2005113518A1 (en) | 2004-05-20 | 2005-05-20 | Process for preparing irbesartan |
Country Status (3)
Country | Link |
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US (1) | US20090286990A1 (en) |
EP (1) | EP1751123A4 (en) |
WO (1) | WO2005113518A1 (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2259909A1 (en) * | 2005-02-28 | 2006-10-16 | Inke, S.A. | Method for obtaining a pharmaceutically active compound (irbesartan) and its synthesis intermediate |
WO2007039117A2 (en) * | 2005-09-20 | 2007-04-12 | Krka, D.D., Novo, Mesto | A process for the preparation of sartan derivatives and intermediates useful in such process |
WO2007049293A1 (en) * | 2005-10-28 | 2007-05-03 | Alembic Limited | An improved process for preparation of irbesartan |
WO2007122508A2 (en) * | 2006-04-24 | 2007-11-01 | Aurobindo Pharma Limited | An improved process for the preparation of irbesartan |
WO2007134136A2 (en) * | 2006-05-09 | 2007-11-22 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
EP1918288A1 (en) | 2006-11-02 | 2008-05-07 | Cadila Pharmaceuticals Limited | A novel and improved process for the preparation of Irbesartan, an angiotensin-II receptor antagonist for the treatment of hypertension |
ES2300175A1 (en) * | 2006-02-14 | 2008-06-01 | Inke, S.A. | Method for obtaining intermediate, particularly candesartan used in preparation of active pharmaceutical compound, particularly candesartan cilexetil for treatment of hypertension or heart failure, involves forming diphenyl bond |
WO2008107799A2 (en) * | 2007-03-06 | 2008-09-12 | Actavis Group Ptc Ehf | Improved process for preparing irbesartan |
EP2194050A1 (en) | 2008-12-08 | 2010-06-09 | KRKA, tovarna zdravil, d.d., Novo mesto | A new process for the preparation of irbesartan |
US7858611B2 (en) | 2006-05-09 | 2010-12-28 | Braincells Inc. | Neurogenesis by modulating angiotensin |
US8080670B2 (en) | 2010-05-04 | 2011-12-20 | Divi's Laboratories, Ltd. | Process for the preparation of irbesartan |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5352788A (en) * | 1990-03-20 | 1994-10-04 | Elf Sanofi | N-substituted heterocyclic derivatives |
US6162922A (en) * | 1998-01-30 | 2000-12-19 | Bristol-Myers Squibb Co. | Method for preparing N-substituted heterocyclic derivatives using a phase-transfer catalyst |
US6800761B1 (en) * | 1998-06-24 | 2004-10-05 | Sanofi-Synthelabo | Form of irbesartan, methods for obtaining said form and pharmaceutical compositions containing same |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL99372A0 (en) * | 1990-09-10 | 1992-08-18 | Ciba Geigy Ag | Azacyclic compounds |
SI1509517T1 (en) * | 2003-01-16 | 2008-10-31 | Teva Pharma | Novel synthesis of irbesartan |
-
2005
- 2005-05-20 WO PCT/US2005/017953 patent/WO2005113518A1/en active Application Filing
- 2005-05-20 EP EP05752192A patent/EP1751123A4/en not_active Withdrawn
- 2005-05-20 US US11/569,380 patent/US20090286990A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5352788A (en) * | 1990-03-20 | 1994-10-04 | Elf Sanofi | N-substituted heterocyclic derivatives |
US6162922A (en) * | 1998-01-30 | 2000-12-19 | Bristol-Myers Squibb Co. | Method for preparing N-substituted heterocyclic derivatives using a phase-transfer catalyst |
US6800761B1 (en) * | 1998-06-24 | 2004-10-05 | Sanofi-Synthelabo | Form of irbesartan, methods for obtaining said form and pharmaceutical compositions containing same |
Non-Patent Citations (1)
Title |
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See also references of EP1751123A4 * |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2259909A1 (en) * | 2005-02-28 | 2006-10-16 | Inke, S.A. | Method for obtaining a pharmaceutically active compound (irbesartan) and its synthesis intermediate |
WO2007039117A2 (en) * | 2005-09-20 | 2007-04-12 | Krka, D.D., Novo, Mesto | A process for the preparation of sartan derivatives and intermediates useful in such process |
WO2007039117A3 (en) * | 2005-09-20 | 2007-06-21 | Krka D D Novo Mesto | A process for the preparation of sartan derivatives and intermediates useful in such process |
US7868180B2 (en) | 2005-09-20 | 2011-01-11 | Krka, D.D. Novo Mesto | Process for the preparation of sartan derivatives and intermediates useful in such process |
EA014691B1 (en) * | 2005-09-20 | 2010-12-30 | КРКА, д.д., НОВО МЕСТО | A process for the preparation of sartan derivatives and intermediates useful in such process |
US7652147B2 (en) | 2005-10-28 | 2010-01-26 | Alembic Limited | Process for preparation of Irbesartan |
WO2007049293A1 (en) * | 2005-10-28 | 2007-05-03 | Alembic Limited | An improved process for preparation of irbesartan |
ES2300175A1 (en) * | 2006-02-14 | 2008-06-01 | Inke, S.A. | Method for obtaining intermediate, particularly candesartan used in preparation of active pharmaceutical compound, particularly candesartan cilexetil for treatment of hypertension or heart failure, involves forming diphenyl bond |
WO2007122508A2 (en) * | 2006-04-24 | 2007-11-01 | Aurobindo Pharma Limited | An improved process for the preparation of irbesartan |
US8106216B2 (en) * | 2006-04-24 | 2012-01-31 | Aurobindo Pharma Ltd. | Process for the preparation of Irbesartan |
WO2007122508A3 (en) * | 2006-04-24 | 2008-03-06 | Aurobindo Pharma Ltd | An improved process for the preparation of irbesartan |
US20100056797A1 (en) * | 2006-04-24 | 2010-03-04 | Korrapati Venkata Vara Prasada Rao | Process for the Preparation of Irbesartan |
US7858611B2 (en) | 2006-05-09 | 2010-12-28 | Braincells Inc. | Neurogenesis by modulating angiotensin |
WO2007134136A3 (en) * | 2006-05-09 | 2008-08-28 | Braincells Inc | Neurogenesis by modulating angiotensin |
WO2007134136A2 (en) * | 2006-05-09 | 2007-11-22 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
EP1918288A1 (en) | 2006-11-02 | 2008-05-07 | Cadila Pharmaceuticals Limited | A novel and improved process for the preparation of Irbesartan, an angiotensin-II receptor antagonist for the treatment of hypertension |
WO2008107799A3 (en) * | 2007-03-06 | 2008-11-06 | Actavis Group Ptc Ehf | Improved process for preparing irbesartan |
WO2008107799A2 (en) * | 2007-03-06 | 2008-09-12 | Actavis Group Ptc Ehf | Improved process for preparing irbesartan |
EP2194050A1 (en) | 2008-12-08 | 2010-06-09 | KRKA, tovarna zdravil, d.d., Novo mesto | A new process for the preparation of irbesartan |
US8080670B2 (en) | 2010-05-04 | 2011-12-20 | Divi's Laboratories, Ltd. | Process for the preparation of irbesartan |
Also Published As
Publication number | Publication date |
---|---|
EP1751123A4 (en) | 2010-06-30 |
EP1751123A1 (en) | 2007-02-14 |
US20090286990A1 (en) | 2009-11-19 |
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