WO1993005057A1 - Procede de synthese de glucuronides d'epoxy-4,5 morphinanes - Google Patents
Procede de synthese de glucuronides d'epoxy-4,5 morphinanes Download PDFInfo
- Publication number
- WO1993005057A1 WO1993005057A1 PCT/FR1992/000846 FR9200846W WO9305057A1 WO 1993005057 A1 WO1993005057 A1 WO 1993005057A1 FR 9200846 W FR9200846 W FR 9200846W WO 9305057 A1 WO9305057 A1 WO 9305057A1
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- radical
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- compound
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- 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
Definitions
- the invention relates to a process for the synthesis of glucuronides of 4,5-epoxy morphinans.
- 4,5-epoxy morphinan glucuronide is meant the result of the reaction of glucuronic acid or one of its derivatives with an epoxy-4,5 morphinane, such as for example the morphine.
- glucuronides which are formed in the body during the metabolism of epoxy-4,5 morphinans, are three in number in the case of morphine, namely 3-, 3,6- and 6-glucuronide.
- morphine; derivative 3- which mainly forms during said metabolism is an antagonist thereof, that is to say does not exhibit the analgesic activity of morphine on the central nervous system and on gastrointestinal motility, and would even have an important role in the phenomenon of tolerance to morphine; derivatives 3,6- and 6- (the first being formed linearly with respect to the second) are not only agonists of morphine but even have a greater analgesic activity than this, which makes these derivatives 3,6- and 6- particularly interesting, especially for the treatment of pain.
- the invention aims to remedy the drawbacks of the prior art and to develop a process for the synthesis of glucuronides of 4,5-epoxy morphinans of the genus in question, the yield of which is compatible with industrial exploitation.
- R 1 represents a hydrogen atom, a hydroxyl radical, a lower alkoxy radical, an acyloxy radical or an oxy- ⁇ -D-glucopyranosyl radical
- one of the two may also represent an oxy- ⁇ -D-glucopyranosyl radical
- R 4 represents a hydrogen atom or a hydroxyl radical
- R 5 represents a hydrogen atom, a lower alkyl radical, a cycloalkyl radical substituted by a lower alkyl, an aryl radical substituted by a lower alkyl, a lower alkene or lower alkyne radical,
- lower alkyl is meant linear or branched C 1 to C 7 and preferably C 1 to C 4 hydrocarbon groups such as for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. , preferably the methyl radical.
- lower alkene is meant linear or branched C 2 -C 7 hydrocarbon groups in which at least one carbon-carbon bond is unsaturated such as allyl, butenyl, dimethylallyl and the like.
- lower alkyne is meant radicals such as the propargyl radical and the like.
- cycloalkyl is meant cyclic C 3 -C 7 hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and preferably the cyclopropyl radical.
- lower alkoxy is meant linear or branched C 1 -C 7 alkoxy radicals such as methoxy, ethoxy, propoxy, butoxy and the like, and preferably the methoxy radical.
- aryl organic radicals derived from an aromatic ring by the elimination of a hydrogen atom such as, for example, phenyl, pyridyl, thienyl or furyl radicals substituted by a halogen atom, a radical nitro, an amino radical, an azido radical, a lower alkyl or lower alkoxy radical.
- - X represents a halogen atom, preferably bromine
- the hydrolysis of the compound thus obtained for transforming acetyl radicals into hydroxyl radicals is characterized in that the compound resulting from the reaction is extracted using an acid, from the reaction medium obtained at the end of the first step reaction of a compound of formula I 'with a derivative of formula II, whereby said compound is obtained in the form of the salt of the acid in question.
- the extraction of the compound resulting from the reaction of a compound of formula I 'with a derivative of formula II is carried out using hydrochloric acid, consequently giving rise to the corresponding hydrochloride.
- the hydrolysis step subsequent to the above extraction is carried out by the action of at least one of the hydrolysis reagents from the group consisting of lithium carbonate, lithium methylate and lithium metal, lithium carbonate being preferred.
- the acetylation, if necessary, of the compound I ′ is carried out within a carbonate buffer, and preferably within the KHCO 3 + buffer.
- the salts can be obtained by adding compounds of the genus in question with an equimolar amount of an alkali metal, for example sodium, potassium or lithium, or of an amino acid such as for example lysine, or d 'an organic or mineral acid such as hydrochloric acid, tallow acid, tartaric acid and its esters, fumaric acid or salicylic acid.
- an alkali metal for example sodium, potassium or lithium
- an amino acid such as for example lysine
- d 'an organic or mineral acid such as hydrochloric acid, tallow acid, tartaric acid and its esters, fumaric acid or salicylic acid.
- the anhydrous forms can be obtained by drying the compounds of the genus in question, for example at 70 ° C for about 3 hours or under a high vacuum using a vane or membrane pump.
- the solvated and polymorphic forms can be obtained by crystallization of the compounds of the genus in question with a solvent such as, for example, ether or ethyl acetate.
- the dihydrate forms can be obtained by drying at room temperature the compounds of the genus in question and the hemihydrate forms can be obtained by drying the compounds of the genus in question under vacuum using a water pump.
- the process in accordance with the invention applies equally to the synthesis of glucuronides of epoxy4,5 dextrorotatory or levorotatory morphines depending on whether the starting product is in the dextrorotatory or levorotatory form.
- the process according to the invention essentially uses two raw materials, namely an epoxy-4,5 morphine, such as for example morphine, and a protected derivative of glucuronic acid.
- the 4,5-epoxy morphinans are stable compounds whose conservation does not pose any particular problem; it is not the same for the protected derivative of glucuronic acid.
- the Applicant has found that, surprisingly and unexpectedly, it was possible to make the latter product capable of being stored for a period of more than one year, as soon as it is prepared in crystallized form by crystallization in strict absence of alcohol, for example in the presence of ether; this conservation being preferably ensured at a temperature of -20 to -80 ° C.
- the shelf life can be further increased to reach approximately 2 years, by addition to the protected derivative of glucuronic acid, after its crystallization in strict absence of alcohol, barium carbonate (BaCO 3 ) or calcium carbonate ( CaCO 3 ) at a rate of 1 to 10% by weight relative to the weight of the total mixture.
- barium carbonate BaCO 3
- CaCO 3 calcium carbonate
- a solution of 140 g of bromo-1 ⁇ deoxy-1 tri-O-acetyl-2,3,4 methyl dglucopyranuronate in 400 ml of benzene is added dropwise to a mixture of 33 g of acetyl-3 morphine and 70 g of silver carbonate in 500 ml of benzene.
- the reaction mixture is then heated at reflux for 5 hours.
- the mineral salts are removed from the benzene solution containing the base obtained by the above reaction; this benzene solution is concentrated under vacuum to 200 ml and the above-mentioned base is extracted from this solution in 3 times with dilute hydrochloric acid, which gives rise to the formation of the corresponding hydrochloride.
- the combined acid extracts are in turn extracted 4 times with methylene chloride.
- the organic layer based on methylene chloride which contains the acid extracts is washed with water, dried over sodium sulfate and evaporated to dryness under vacuum.
- the resulting viscous residue is crystallized with a mixture of ethyl acetate / ether (1/6), filtered and recrystallized with a mixture of ethanol / ethyl acetate (5/95) to obtain pale yellow crystals.
- the residue is dissolved in 50 ml of water and purified by HPLC on a column loaded with octadecyl silica particles (ODS-silica) with a particle size of 1-10 ⁇ m and eluted with 25% methanol or acetonitrile in 10 mM sodium dihydrogen phosphate buffer at pH 2.1, (adjusted with phosphoric acid) containing 1 mM dodecylsulphate as a counterion. 0.49 g of 6 ⁇ Dglucuronide of morphine is obtained, ie a yield of 71%.
- ODS-silica octadecyl silica particles
- methyl uronate is added to a solution of 3.0 g of [2,3,4-triacetyl-2,3,4 ⁇ Dglucopyranoside) -3 yl-3 morphine] in 100 ml of benzene redistilled over sodium, 3, 18 g of silver carbonate then 6.42 g of bromo-l ⁇ deoxy-1-2,3-triacetyl-2,3,4 methyl Oglucopyranuronate in 150 ml of benzene redistilled over sodium. The mixture is heated at reflux for 5 hours. After cooling, the silver salts are removed by filtration and then the benzene is concentrated to 50 ml by evaporation under vacuum.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP92919332A EP0602151A1 (fr) | 1991-09-04 | 1992-09-04 | Procede de synthese de glucuronides d'epoxy-4,5 morphinanes |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9110927A FR2680786B1 (fr) | 1991-09-04 | 1991-09-04 | Procede de synthese de glucuronides d'epoxy-4,5 morphinanes. |
FR91/10927 | 1991-09-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993005057A1 true WO1993005057A1 (fr) | 1993-03-18 |
Family
ID=9416616
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1992/000846 WO1993005057A1 (fr) | 1991-09-04 | 1992-09-04 | Procede de synthese de glucuronides d'epoxy-4,5 morphinanes |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0602151A1 (fr) |
AU (1) | AU2555592A (fr) |
FR (1) | FR2680786B1 (fr) |
WO (1) | WO1993005057A1 (fr) |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995016050A1 (fr) * | 1993-12-07 | 1995-06-15 | Salford Ultrafine Chemicals And Research Limited | Procede enzymatique de fabrication de morphine-6-glucuronide ou de morphine-6-glucuronide substitue |
WO1997013775A1 (fr) * | 1995-10-11 | 1997-04-17 | Nycomed Imaging As | Nouvelle forme cristalline de morphine-6-glucuronide |
DE19541921A1 (de) * | 1995-11-10 | 1997-05-15 | Nycomed Arzneimittel Gmbh | Neue Kristallform von Morphin-6-glucuronid |
WO1997021416A2 (fr) * | 1995-11-29 | 1997-06-19 | Rolabo Sl | Glycoconjugues de substances opiacees |
US5705186A (en) * | 1994-02-07 | 1998-01-06 | Lts Lohmann Therapie-Systeme Gmbh | Pharmaceutical composition for the systemic transdermal administration having the active substance morphine-6-glucuronide |
EP0597915B1 (fr) * | 1991-08-06 | 1998-11-11 | Salford Ultrafine Chemicals And Research Limited | Procede de preparation de morphine-6-glycuroconjuguee ou de morphine-6-glycuroconjuguee substituee |
WO1998054196A1 (fr) * | 1997-05-29 | 1998-12-03 | Rolabo Sl | Glycoconjugues de substances opiacees |
US5908927A (en) * | 1996-05-22 | 1999-06-01 | High Standard Products Corporation | Synthesis of deuterated opiate glucuronides |
WO1999038876A1 (fr) * | 1998-02-02 | 1999-08-05 | Cenes Limited | Glycosidation de 4,5-epoxymorphinane-6-ols |
US5977326A (en) * | 1991-08-06 | 1999-11-02 | Salford Ultrafine Chemicals And Research Limited | Process for making morphine-6-glucuronide or substituted morphine-6-glucuronide |
WO1999058545A1 (fr) * | 1998-05-13 | 1999-11-18 | Cenes Limited | Procede de preparation de 4,5 epoxymorphinan-6-oxyglucuronides |
WO1999064430A2 (fr) * | 1998-06-06 | 1999-12-16 | Cenes Limited | Synthese de morphine-6-glucuronide |
US6740641B2 (en) * | 2001-07-27 | 2004-05-25 | Euro-Celtique, S.A. | Sugar derivatives of hydromorphone, dihydromorphine and dihydromorphine, compositions thereof and uses for treating or preventing pain |
JP2006500360A (ja) * | 2002-08-14 | 2006-01-05 | セネス リミティド | モルヒネ−6−グルクロニドの塩 |
CN103421063A (zh) * | 2012-05-23 | 2013-12-04 | 宜昌人福药业有限责任公司 | 一种合成吗啡-6-β-D-葡萄糖醛酸苷的方法 |
WO2018075979A1 (fr) | 2016-10-21 | 2018-04-26 | Somniferum Labs LLC | Compositions, méthodes et kits pour l'administration par inhalation sûre d'opioïdes ciblés pour le traitement de la douleur et de la dépendance |
CN108727444A (zh) * | 2017-04-19 | 2018-11-02 | 宜昌人福药业有限责任公司 | 吗啡-6-β-D-葡萄糖醛酸苷的合成方法及其中间体化合物 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0324212A1 (fr) * | 1988-01-12 | 1989-07-19 | Baker Norton Pharmaceuticals, Inc. | Dérivés de l'acide glucuronique des antagonistes d'opiöides |
-
1991
- 1991-09-04 FR FR9110927A patent/FR2680786B1/fr not_active Expired - Fee Related
-
1992
- 1992-09-04 EP EP92919332A patent/EP0602151A1/fr not_active Ceased
- 1992-09-04 WO PCT/FR1992/000846 patent/WO1993005057A1/fr not_active Application Discontinuation
- 1992-09-04 AU AU25555/92A patent/AU2555592A/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0324212A1 (fr) * | 1988-01-12 | 1989-07-19 | Baker Norton Pharmaceuticals, Inc. | Dérivés de l'acide glucuronique des antagonistes d'opiöides |
Non-Patent Citations (3)
Title |
---|
CHEMICAL AND PHARMACEUTICAL BULLETIN. vol. 37, no. 4, Avril 1989, TOKYO JP pages 955 - 957 K. OGURI, C.K. KUO AND H YOSHIMURA 'Synthesis and analgesic effect of normorphine-3- and -6-glucuronides' * |
JOURNAL OF MEDICINAL CHEMISTRY. vol. 34, no. 4, Avril 1991, WASHINGTON US pages 1272 - 1275 CARRUPT P. A. ET AL 'Morphine 6-glucuronide and morphine 3-glucuronide as molecular chameleons with unexpected lipophilicity' * |
TETRAHEDRON LETTERS no. 4, 1968, OXFORD, UK pages 483 - 486 H. YOSHIMURA ET AL 'The synthesis of codeine and morphine D-glucuronides' * |
Cited By (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6046313A (en) * | 1991-08-06 | 2000-04-04 | Salford Ultrafine Chemicals And Research Limited | Process for making morphine-6-glucuronide or substituted morphine-6-glucuronide |
EP0597915B1 (fr) * | 1991-08-06 | 1998-11-11 | Salford Ultrafine Chemicals And Research Limited | Procede de preparation de morphine-6-glycuroconjuguee ou de morphine-6-glycuroconjuguee substituee |
US5977326A (en) * | 1991-08-06 | 1999-11-02 | Salford Ultrafine Chemicals And Research Limited | Process for making morphine-6-glucuronide or substituted morphine-6-glucuronide |
WO1995016050A1 (fr) * | 1993-12-07 | 1995-06-15 | Salford Ultrafine Chemicals And Research Limited | Procede enzymatique de fabrication de morphine-6-glucuronide ou de morphine-6-glucuronide substitue |
US5705186A (en) * | 1994-02-07 | 1998-01-06 | Lts Lohmann Therapie-Systeme Gmbh | Pharmaceutical composition for the systemic transdermal administration having the active substance morphine-6-glucuronide |
WO1997013775A1 (fr) * | 1995-10-11 | 1997-04-17 | Nycomed Imaging As | Nouvelle forme cristalline de morphine-6-glucuronide |
US6172206B1 (en) | 1995-10-11 | 2001-01-09 | Cenes Ltd. | Crystalline form of morphine-6-glucuronide |
EA000755B1 (ru) * | 1995-10-11 | 2000-04-24 | Никомед Имеджинг Ас | Новая кристаллическая форма морфин-6-глюкуронида |
DE19541921A1 (de) * | 1995-11-10 | 1997-05-15 | Nycomed Arzneimittel Gmbh | Neue Kristallform von Morphin-6-glucuronid |
WO1997021416A2 (fr) * | 1995-11-29 | 1997-06-19 | Rolabo Sl | Glycoconjugues de substances opiacees |
WO1997021416A3 (fr) * | 1995-11-29 | 1997-09-12 | Farmhispania | Glycoconjugues de substances opiacees |
US5908927A (en) * | 1996-05-22 | 1999-06-01 | High Standard Products Corporation | Synthesis of deuterated opiate glucuronides |
WO1998054196A1 (fr) * | 1997-05-29 | 1998-12-03 | Rolabo Sl | Glycoconjugues de substances opiacees |
WO1999038876A1 (fr) * | 1998-02-02 | 1999-08-05 | Cenes Limited | Glycosidation de 4,5-epoxymorphinane-6-ols |
US6555665B1 (en) | 1998-02-02 | 2003-04-29 | Cenes Limited | Glycosidation of 4,5-epoxymorphinan-6-ols |
WO1999058545A1 (fr) * | 1998-05-13 | 1999-11-18 | Cenes Limited | Procede de preparation de 4,5 epoxymorphinan-6-oxyglucuronides |
US6737518B1 (en) | 1998-05-13 | 2004-05-18 | Cenes Limited | Process for preparation of 4,5-epoxymorphinan-6-oxyglucuronides |
WO1999064430A3 (fr) * | 1998-06-06 | 2000-02-03 | Cenes Ltd | Synthese de morphine-6-glucuronide |
WO1999064430A2 (fr) * | 1998-06-06 | 1999-12-16 | Cenes Limited | Synthese de morphine-6-glucuronide |
US6566510B1 (en) | 1998-06-06 | 2003-05-20 | Genes Limited | Morphine-6-glucuronide synthesis |
US6693179B2 (en) * | 1998-06-06 | 2004-02-17 | Cenes Limited | Morphine-6-glucuronide synthesis |
US6740641B2 (en) * | 2001-07-27 | 2004-05-25 | Euro-Celtique, S.A. | Sugar derivatives of hydromorphone, dihydromorphine and dihydromorphine, compositions thereof and uses for treating or preventing pain |
JP2005500357A (ja) * | 2001-07-27 | 2005-01-06 | ユーロ−セルティーク,エス.エイ. | ヒドロモルホン、ジヒドロモルフィンおよびジヒドロイソモルフィンの糖誘導体、これらの組成物および痛みを治療あるいは予防するための使用 |
JP4679055B2 (ja) * | 2001-07-27 | 2011-04-27 | ユーロ−セルティーク エス.エイ. | ヒドロモルホン、ジヒドロモルフィンおよびジヒドロイソモルフィンの糖誘導体、これらの組成物および痛みを治療あるいは予防するための使用 |
JP2006500360A (ja) * | 2002-08-14 | 2006-01-05 | セネス リミティド | モルヒネ−6−グルクロニドの塩 |
JP4727990B2 (ja) * | 2002-08-14 | 2011-07-20 | セネス リミティド | モルヒネ−6−グルクロニドの塩 |
CN103421063A (zh) * | 2012-05-23 | 2013-12-04 | 宜昌人福药业有限责任公司 | 一种合成吗啡-6-β-D-葡萄糖醛酸苷的方法 |
CN103421063B (zh) * | 2012-05-23 | 2016-04-06 | 宜昌人福药业有限责任公司 | 一种合成吗啡-6-β-D-葡萄糖醛酸苷的方法 |
WO2018075979A1 (fr) | 2016-10-21 | 2018-04-26 | Somniferum Labs LLC | Compositions, méthodes et kits pour l'administration par inhalation sûre d'opioïdes ciblés pour le traitement de la douleur et de la dépendance |
CN108727444A (zh) * | 2017-04-19 | 2018-11-02 | 宜昌人福药业有限责任公司 | 吗啡-6-β-D-葡萄糖醛酸苷的合成方法及其中间体化合物 |
Also Published As
Publication number | Publication date |
---|---|
FR2680786B1 (fr) | 1995-03-10 |
FR2680786A1 (fr) | 1993-03-05 |
AU2555592A (en) | 1993-04-05 |
EP0602151A1 (fr) | 1994-06-22 |
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