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WO1996036636A1 - Procede de preparation de derives de 4-arylpiperidine - Google Patents

Procede de preparation de derives de 4-arylpiperidine Download PDF

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Publication number
WO1996036636A1
WO1996036636A1 PCT/DK1996/000185 DK9600185W WO9636636A1 WO 1996036636 A1 WO1996036636 A1 WO 1996036636A1 DK 9600185 W DK9600185 W DK 9600185W WO 9636636 A1 WO9636636 A1 WO 9636636A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
treatment
alkyl
defined above
Prior art date
Application number
PCT/DK1996/000185
Other languages
English (en)
Inventor
John Bondo Hansen
Svend Treppendahl
Mogens Engelstoft
Bjørn BENTZEN
Søren LEHMANN
Original Assignee
Novo Nordisk A/S
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 Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to NZ307479A priority Critical patent/NZ307479A/xx
Priority to JP8534464A priority patent/JPH11505229A/ja
Priority to EP96914861A priority patent/EP0828735A1/fr
Priority to BR9608471A priority patent/BR9608471A/pt
Priority to AU56845/96A priority patent/AU721257B2/en
Publication of WO1996036636A1 publication Critical patent/WO1996036636A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel process for preparing 4-aryl- piperidine derivatives.
  • R 1 represents hydrogen, alkyl having 1 -4 carbon atoms and F may be in any of the available positions.
  • US Patent No. 4,585,777 and US Patent No. 4, 593,036 describes a compound of the following formula B:
  • the compounds of formula A and B are described as inhibitors of reup- take of 5-hydroxytryptamine (5-HT) which induces a potentiation of 5- HT induced neurotransmission.
  • 5-HT 5-hydroxytryptamine
  • Paroxetine which is the pure enantiomer (3S,4R)-4-(4-fluorophenyl)-3- (3,4-methylenedioxyphenoxymethyl)piperidine has been found to be a potent inhibitor of serotonin reuptake and to be an effective antide- pressant in man [ S. M. Holliday and G. L. Plosker, Drugs and Aging 3: 278-299 (1993)].
  • the pharmacological activity resides in this isomer and the corresponding stereoisomer is considerably less potent with respect to inhibition of 5-HT uptake in vitro [P. Plenge, E. T. Mellerup, T. Honore, and P. L. Honore, J. Pharm. Pharmacol. 39: 877-882 (1987)].
  • the Grignard reaction involves the use of ether solvents and is further ⁇ more complicated by the use of the toxic starting material arecoline.
  • the intermediary D1 is prepared by reduction of the imide (F2), prepared from benzaldehyde and methyl N-methylamidomalonate.
  • the reduction involves the use of lithium aluminium hydride, aluminium hydride or diborane using ether solvents like diethyl ether, tetrahydrofurane and dimethoxyethane, scheme F:
  • the intermediate D1 is prepared by reacting methylamine, formaldehyde and ⁇ -methylstyrene (G 1 ). Intermediates in this synthesis is the oxazine derivative (G2) and the potent neurotoxic compound 1 -methyl-4-phenyl-1 ,2,3,6-tetrahydropyridine (MPTP) [USP 2,748, 140, C. J. Schmidle and R. C. Mansfield, J. Am. Chem. Soc. 11 5698-5700 (1955); C. J. Schmidle and R. C. Mansfield, J. Am. Chem. Soc.
  • MPTP has in primates and in humans been found to cause anatomical and behavioral changes analogous to those of Parkinson's disease [M. Gerlach, P. Riederer, H. Przuntek, and M. B. H. Youdin, EUR. J. Pharma ⁇ col. Mol. Pharm, 208, 273-286, (1991 ); S. P. Markey and N. R. Schnuff, Medicinal Res. /?ev.6.386, ( 1 986)]. It is known that the 1 -methyl group causes MPTP to be toxic and that substitution of the methyl group with longer alkyl groups will abolish the toxicity [S. K. Youngster, P. K. Sonsalla, and R. E. Heikkila, J. Neurochem. 48, 929- 934, (1987)], scheme G:
  • Paroxetine is one of four possible isomers, the use of the practi ⁇ cally and economically best procedure for the isolation of this isomer is of high importance.
  • the procedure will involve the use of the appropriate isomer of D1 in combination with the use of the right conditions for reaction as well as separations by recrystallizations using optically active acids, e.g. mandelic acid, tartaric acid, and dibenzoyltartaric acid.
  • optically active acids e.g. mandelic acid, tartaric acid, and dibenzoyltartaric acid.
  • R 1 can be C 2 . 5 -alkyl, phenyl-C ⁇ -alkyl, or substituted phenyl-C ⁇ -alkyl, preferentially ethyl.
  • R 1 can be C 2 . 5 -alkyl, phenyl-C ⁇ -alkyl, or substituted phenyl-C ⁇ -alkyl, preferentially ethyl.
  • the intermediary 1 -alkyl-1 ,2,3,6-tetrahydro-4-phenylpyridine will in comparison with MPTP be non-toxic as described in:S. K. Youngster, P.
  • the present invention provides a process for the preparation of a compound of formula VIII,
  • R is C 2 . 5 -alkyl, phenyl-C ⁇ -alkyl, or substituted phenyl-C ⁇ -alkyl, by
  • R 1 is C 2 . 5 -alkyl, phenyl-C ⁇ -alkyl, or substituted phenyl-C ⁇ -alkyl, with a compound of formula (II)
  • X is halogen, preferably F, to form a compound of formula
  • R 1 and X are as defined above, c) by treatment of a compound of formula IV, wherein R 1 and X are as defined above with metal hydrides, preferably LiAIH 4 or NaAIH 4 , to form a compound of formula VI,
  • R 1 and X are as defined above, with benzene sulfonylchloride, or another suitable reagent, which reacts with the hydroxy group to trans ⁇ form it into a leaving group, which subsequently can be removed by treatment with 3,4-methylene dioxyphenolate, prepared by treatment of 3,4-methylenedioxyphenol with a base, preferably sodium methanolate to give a compound of formula VIII,
  • R 1 and X are as defined above with chlorethylchloroformate or another similar reagent, followed by decomposition of the intermediary carbamate by methanol to form a compound of formula IX,
  • Ethylamine hydrochloride 132.2 g was dissolved in formaldehyde (500 ml, 37 %) and the mixture heated to 70°C. 1 -methyl-4'-fluorostyrene (200 ml) was added over 1 hour keeping the temperature about 70°C.
  • the phases were separated and the toluene phase extracted with hydrochloric acid (1 6 times 100 ml, 0.5 M).
  • hydrochloric acid 1 6 times 100 ml, 0.5 M.
  • the toluene phases were pooled and evaporated to an oil (1 64 g). The oil was dissolved in 2-propanol (300 ml) and the hydrochloride of the title compound precipitated with con ⁇ centrated hydrochloric acid.
  • the aqueous phase was extracted with another portion of toluene (50 ml).
  • the combined toluene extract was washed with water (50 ml), dried over potassium carbonate and evaporated.
  • the aqueous phase was separated and extracted with another portion of toluene (100 ml) .
  • the combined toluene phase was dried over potassium carbonate and evaporated to an oil (47 g).
  • the oil was dissolved in acetone (900 ml) with ( + )-O,O'-ditoluoyltartaric acid (59 g).
  • Formic acid ( 2.2 g) was added and the mixture stirred until next day.
  • the precipitate was filtered off, washed with acetone and dried.
  • the aqueous phase was extracted with another portion of toluene (50 ml), washed with water (50 ml) and evaporated.
  • Lithium aluminium hydride (3 g) and sodium hydride 60 % (3 g) was dispersed in dry tetrahydrofuran (80 ml). The mixture was heated at 60°C for 1 hour and then cooled to 20°C. To this mixture was added a solution of ( + )-1 -ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1 , 2,3,6- tetrahydropyridine (20 g) in tetrahydrofuran (40 ml) over 1 hour. The mixture was stirred at 50°C for 1 hour.
  • Benzene sulfonyl ⁇ chloride (16.6 g) was added over 1 hour keeping the temperature between 20 and 30°C with external cooling with ice and water. After the addition the reaction mixture was stirred at ambient temperature for 3 hours. Water was added (50 ml) and the toluene phase was separated. A solution of 3,4-methylenedioxyphenol (17 g) in methylisobutylcarbinol (4-methyl-2-pentanol) (90 ml) was added to the toluene phase together with sodium hydroxide (17.2 g, 32.5 %). The mixture was refluxed for 4 hours and stirred overnight at ambient temperature.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'un composé de formule (VIII), dans laquelle R1 représente alkyle-C¿2-5?, phényle-alkyle-C1-5, ou phényle-alkyle-C1-5 à substitution.
PCT/DK1996/000185 1995-05-17 1996-04-25 Procede de preparation de derives de 4-arylpiperidine WO1996036636A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
NZ307479A NZ307479A (en) 1995-05-17 1996-04-25 A process for preparing 4-(4-halo substituted phenyl)-3-(3,4-methylenedioxy phenoxy methyl)piperidine derivatives
JP8534464A JPH11505229A (ja) 1995-05-17 1996-04-25 ４−アリール−ピペリジン誘導体を製造する方法
EP96914861A EP0828735A1 (fr) 1995-05-17 1996-04-25 Procede de preparation de derives de 4-arylpiperidine
BR9608471A BR9608471A (pt) 1995-05-17 1996-04-25 Processo para a preparação de um composto
AU56845/96A AU721257B2 (en) 1995-05-17 1996-04-25 Process for preparing 4-aryl-piperidine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK56395 1995-05-17
DK0563/95 1995-05-17

Publications (1)

Publication Number Publication Date
WO1996036636A1 true WO1996036636A1 (fr) 1996-11-21

Family

ID=8094959

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1996/000185 WO1996036636A1 (fr) 1995-05-17 1996-04-25 Procede de preparation de derives de 4-arylpiperidine

Country Status (11)

Country Link
EP (1) EP0828735A1 (fr)
JP (1) JPH11505229A (fr)
CN (1) CN1068597C (fr)
AU (1) AU721257B2 (fr)
BR (1) BR9608471A (fr)
CA (1) CA2220963A1 (fr)
HU (1) HUP9900318A3 (fr)
IL (1) IL118294A0 (fr)
NZ (1) NZ307479A (fr)
WO (1) WO1996036636A1 (fr)
ZA (1) ZA963951B (fr)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997024323A1 (fr) * 1995-12-28 1997-07-10 Chirotech Technology Procede de preparation de piperidines a substitution 4-aryl-3-hydromethyle, optiquement enrichies destinees a etre utilisees comme intermediaires dans la synthese de la paroxetine
WO1997031915A1 (fr) * 1996-02-29 1997-09-04 Ferrer Internacional, S.A. NOUVEAU PROCEDE POUR PREPARER LA (-)-TRANS-N-p-FLUOROBENZOLYLMETHYL-4-(p-FLUOROPHENYL)-3-3,4-(METHYLENEDIOXY)PHENOXY METHYL PIPERIDINE
EP0812827A1 (fr) * 1996-06-13 1997-12-17 SUMIKA FINE CHEMICALS Co., Ltd. Dérivés de pipéridine comme intermédiaire pour la production de paroxétine et procédé pour leur préparation
WO1998052920A1 (fr) * 1997-05-17 1998-11-26 Knoll Aktiengesellschaft Procede chimique pour la reduction de substitues en 3-hydroxymethyl-4- (-4-fluorophenyl)tetrahydropyridines
US5874447A (en) * 1997-06-10 1999-02-23 Synthon B. V. 4-Phenylpiperidine compounds for treating depression
US6063927A (en) * 1998-07-02 2000-05-16 Smithkline Beecham Plc Paroxetine derivatives
WO2000032591A1 (fr) * 1998-11-28 2000-06-08 Smithkline Beecham Plc Procede de fabrication d'hydrochlorure de paroxetine
WO2000039090A1 (fr) * 1998-12-29 2000-07-06 Smithkline Beecham Plc Procede de preparation d'acetate de paroxetine et de ses analogues
WO2000050422A1 (fr) * 1999-02-23 2000-08-31 Recordati S.A. Chemical And Pharmaceutical Company Procede de production de paroxetine
US6153755A (en) * 1996-11-09 2000-11-28 Smithkline Beecham Plc Process for preparing pharmaceutically active compounds and intermediates thereof
US6172233B1 (en) 1997-01-15 2001-01-09 Smithkline Beecham Plc Process for making paroxetine
EP1074550A1 (fr) * 1999-08-02 2001-02-07 CHEMI S.p.A. Procédé de préparation de dérivés de 4-phényl-pipéridines 3-substitués
WO2001032178A1 (fr) * 1999-10-29 2001-05-10 Novo Nordisk A/S Utilisation de piperidines 3,4-substituees
WO2002006275A1 (fr) * 2000-07-17 2002-01-24 Smithkline Beecham P.L.C. Nouveaux procedes de preparation de derives 4-phenylpiperidine
WO2002018337A1 (fr) * 2000-08-30 2002-03-07 Basf Aktiengesellschaft Processus de racemisation d'un intermediaire utile dans la preparation de paroxetine
WO2002018338A1 (fr) * 2000-08-30 2002-03-07 Basf Aktiengesellschaft Procede de racemisation de 1-benzyl-4-(4-fluorophenyl)-3-hydroxymethyl-1,2,3,6-tetrahydropyridine utilise comme produit intermediaire dans la synthese de la paroxetine
WO2002028834A1 (fr) * 2000-10-06 2002-04-11 Smithkline Beecham P.L.C. Procede de preparation de carbonols d'aryl-piperidine et produits intermediaires de ces derniers
WO2002053537A1 (fr) * 2001-01-04 2002-07-11 Ferrer Internacional, S.A. Procede de preparation de (?)-trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine
US6489347B1 (en) 1997-05-29 2002-12-03 Smithkline Beecham Plc Process
EP1242378A4 (fr) * 1999-12-23 2003-01-15 Smithkline Beecham Corp Nouveaux procedes
US6521758B2 (en) 2000-05-12 2003-02-18 Synthon Bv Tosylate salts of 4-(p-fluorophenyl)-piperidine-3-carbinols
US6657062B1 (en) * 1996-07-08 2003-12-02 Richter Gedeon Vegyesseti Gyar Rt. N-benzylpiperidine and tetrahydropyridine derivatives
WO2015071831A1 (fr) * 2013-11-18 2015-05-21 Piramal Enterprises Limited Procédé amélioré permettant de réduire au minimum la formation de sous-produits déshalogénés

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4007196A (en) * 1973-01-30 1977-02-08 A/S Ferrosan 4-Phenylpiperidine compounds
US4593036A (en) * 1984-02-07 1986-06-03 A/S Ferrosan (-)-Trans-4-(4-fluorophenyl)-3-[(4-methoxyphenoxy)methyl]-1-methylpiperidine useful as 5-HT potentiator
EP0266574A2 (fr) * 1986-11-03 1988-05-11 Novo Nordisk A/S Dérivés de la pipéridine, leur préparation et leur utilisation
EP0374674A2 (fr) * 1988-12-22 1990-06-27 A/S Ferrosan Etherification et désalcoylation de dérivés de pipéridine et intermédiaires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4007196A (en) * 1973-01-30 1977-02-08 A/S Ferrosan 4-Phenylpiperidine compounds
US4593036A (en) * 1984-02-07 1986-06-03 A/S Ferrosan (-)-Trans-4-(4-fluorophenyl)-3-[(4-methoxyphenoxy)methyl]-1-methylpiperidine useful as 5-HT potentiator
EP0266574A2 (fr) * 1986-11-03 1988-05-11 Novo Nordisk A/S Dérivés de la pipéridine, leur préparation et leur utilisation
EP0374674A2 (fr) * 1988-12-22 1990-06-27 A/S Ferrosan Etherification et désalcoylation de dérivés de pipéridine et intermédiaires

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997024323A1 (fr) * 1995-12-28 1997-07-10 Chirotech Technology Procede de preparation de piperidines a substitution 4-aryl-3-hydromethyle, optiquement enrichies destinees a etre utilisees comme intermediaires dans la synthese de la paroxetine
WO1997031915A1 (fr) * 1996-02-29 1997-09-04 Ferrer Internacional, S.A. NOUVEAU PROCEDE POUR PREPARER LA (-)-TRANS-N-p-FLUOROBENZOLYLMETHYL-4-(p-FLUOROPHENYL)-3-3,4-(METHYLENEDIOXY)PHENOXY METHYL PIPERIDINE
US6815548B2 (en) 1996-06-13 2004-11-09 Sumika Fine Chemicals Co., Ltd. Process for preparing a piperidine derivative
EP0812827A1 (fr) * 1996-06-13 1997-12-17 SUMIKA FINE CHEMICALS Co., Ltd. Dérivés de pipéridine comme intermédiaire pour la production de paroxétine et procédé pour leur préparation
US6610851B1 (en) 1996-06-13 2003-08-26 Sumika Fine Chemicals Co., Ltd. Process for preparing a piperidine derivative
US5948914A (en) * 1996-06-13 1999-09-07 Sumika Fine Chemicals Co., Ltd. Piperidine derivative and process for preparing the same
US6476227B1 (en) 1996-06-13 2002-11-05 Sumika Fine Chemicals Co., Ltd. Piperidine derivative and process for preparing the same
US6657062B1 (en) * 1996-07-08 2003-12-02 Richter Gedeon Vegyesseti Gyar Rt. N-benzylpiperidine and tetrahydropyridine derivatives
US6153755A (en) * 1996-11-09 2000-11-28 Smithkline Beecham Plc Process for preparing pharmaceutically active compounds and intermediates thereof
US6172233B1 (en) 1997-01-15 2001-01-09 Smithkline Beecham Plc Process for making paroxetine
WO1998052920A1 (fr) * 1997-05-17 1998-11-26 Knoll Aktiengesellschaft Procede chimique pour la reduction de substitues en 3-hydroxymethyl-4- (-4-fluorophenyl)tetrahydropyridines
US6326496B1 (en) 1997-05-17 2001-12-04 Knoll Aktiengesellschaft Process for preparing an intermediate in the production of paroxetine
CN1121386C (zh) * 1997-05-17 2003-09-17 克诺尔有限公司 还原1－取代－3－羟甲基－4－(4－氟苯基)四氢吡啶的化学方法
US6716985B2 (en) 1997-05-29 2004-04-06 Smithkline Beecham P.L.C. Process for making paroxetine
US6489347B1 (en) 1997-05-29 2002-12-03 Smithkline Beecham Plc Process
US7598271B1 (en) 1997-06-10 2009-10-06 Noven Therapeutics, Llc Crystalline paroxetine methane sulfonate
US6900327B2 (en) 1997-06-10 2005-05-31 Synthon Bct Technologies, Llc 4-phenylpiperidine compounds
US5874447A (en) * 1997-06-10 1999-02-23 Synthon B. V. 4-Phenylpiperidine compounds for treating depression
US6063927A (en) * 1998-07-02 2000-05-16 Smithkline Beecham Plc Paroxetine derivatives
WO2000032591A1 (fr) * 1998-11-28 2000-06-08 Smithkline Beecham Plc Procede de fabrication d'hydrochlorure de paroxetine
WO2000039090A1 (fr) * 1998-12-29 2000-07-06 Smithkline Beecham Plc Procede de preparation d'acetate de paroxetine et de ses analogues
WO2000050422A1 (fr) * 1999-02-23 2000-08-31 Recordati S.A. Chemical And Pharmaceutical Company Procede de production de paroxetine
JP2002537394A (ja) * 1999-02-23 2002-11-05 レコーダチ エス．エイ．ケミカル アンド ファルマチェウティカル カンパニー パロキセチンの製造方法
US6583287B1 (en) 1999-02-23 2003-06-24 Recordati S.A. Chemical And Pharmaceutical Company Process for the production of paroxetine
US6444822B1 (en) 1999-08-02 2002-09-03 Chemi S.P.A. Process for the preparation of 3-substituted 4-phenyl-piperidine derivative
EP1074550A1 (fr) * 1999-08-02 2001-02-07 CHEMI S.p.A. Procédé de préparation de dérivés de 4-phényl-pipéridines 3-substitués
WO2001032178A1 (fr) * 1999-10-29 2001-05-10 Novo Nordisk A/S Utilisation de piperidines 3,4-substituees
EP1242378A4 (fr) * 1999-12-23 2003-01-15 Smithkline Beecham Corp Nouveaux procedes
US6521758B2 (en) 2000-05-12 2003-02-18 Synthon Bv Tosylate salts of 4-(p-fluorophenyl)-piperidine-3-carbinols
WO2002006275A1 (fr) * 2000-07-17 2002-01-24 Smithkline Beecham P.L.C. Nouveaux procedes de preparation de derives 4-phenylpiperidine
WO2002018337A1 (fr) * 2000-08-30 2002-03-07 Basf Aktiengesellschaft Processus de racemisation d'un intermediaire utile dans la preparation de paroxetine
WO2002018338A1 (fr) * 2000-08-30 2002-03-07 Basf Aktiengesellschaft Procede de racemisation de 1-benzyl-4-(4-fluorophenyl)-3-hydroxymethyl-1,2,3,6-tetrahydropyridine utilise comme produit intermediaire dans la synthese de la paroxetine
US6949650B2 (en) 2000-08-30 2005-09-27 Aesica Pharmaceuticals Ltd. Process for the racemization of 1-benzyl-4-(4-fluorophenyl)-3-hydroxymethyl-1,2-3,6-tetrahydropyridine to be used as intermediate in the synthesis of paroxetine
WO2002028834A1 (fr) * 2000-10-06 2002-04-11 Smithkline Beecham P.L.C. Procede de preparation de carbonols d'aryl-piperidine et produits intermediaires de ces derniers
US6881845B2 (en) 2001-01-04 2005-04-19 Ferrer Internacional, S.A. Process for preparing (±)trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine
WO2002053537A1 (fr) * 2001-01-04 2002-07-11 Ferrer Internacional, S.A. Procede de preparation de (?)-trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine
WO2015071831A1 (fr) * 2013-11-18 2015-05-21 Piramal Enterprises Limited Procédé amélioré permettant de réduire au minimum la formation de sous-produits déshalogénés

Also Published As

Publication number Publication date
CN1184476A (zh) 1998-06-10
NZ307479A (en) 1999-08-30
ZA963951B (en) 1997-01-21
AU721257B2 (en) 2000-06-29
AU5684596A (en) 1996-11-29
IL118294A0 (en) 1996-09-12
JPH11505229A (ja) 1999-05-18
HUP9900318A2 (hu) 1999-09-28
EP0828735A1 (fr) 1998-03-18
HUP9900318A3 (en) 2001-09-28
CA2220963A1 (fr) 1996-11-21
BR9608471A (pt) 1998-12-29
CN1068597C (zh) 2001-07-18

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