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WO1996030366A1 - Polimorfos a y b de 1-(difenilmetil)-4-[3-(2-fenil-1,3-dioxolan-2-il)propil]piperazina - Google Patents

Polimorfos a y b de 1-(difenilmetil)-4-[3-(2-fenil-1,3-dioxolan-2-il)propil]piperazina Download PDF

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Publication number
WO1996030366A1
WO1996030366A1 PCT/ES1995/000033 ES9500033W WO9630366A1 WO 1996030366 A1 WO1996030366 A1 WO 1996030366A1 ES 9500033 W ES9500033 W ES 9500033W WO 9630366 A1 WO9630366 A1 WO 9630366A1
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WO
WIPO (PCT)
Prior art keywords
polymorph
piperazine
phenyl
diphenylmethyl
dioxolan
Prior art date
Application number
PCT/ES1995/000033
Other languages
English (en)
French (fr)
Inventor
Rafael Foguet Ambros
Lluis Anglada Burniol
José A. ORTIZ HERNANDEZ
Aurelio SACRISTAN MUÑOZ
Josep María CASTELLO BARENYS
Manuel Mauricio RAGA CARREÑO
Original Assignee
Ferrer Internacional, S.A.
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
Priority to US08/750,131 priority Critical patent/US5852021A/en
Priority to ES95913177T priority patent/ES2149353T3/es
Priority to PCT/ES1995/000033 priority patent/WO1996030366A1/es
Priority to EP95913177A priority patent/EP0785196B1/en
Priority to DK95913177T priority patent/DK0785196T3/da
Priority to AT95913177T priority patent/ATE194004T1/de
Priority to DE69517593T priority patent/DE69517593T2/de
Priority to AU20740/95A priority patent/AU690974B2/en
Priority to PT95913177T priority patent/PT785196E/pt
Priority to NZ282827A priority patent/NZ282827A/en
Application filed by Ferrer Internacional, S.A. filed Critical Ferrer Internacional, S.A.
Priority to JP8528964A priority patent/JPH10501555A/ja
Priority to KR1019960706754A priority patent/KR970703337A/ko
Publication of WO1996030366A1 publication Critical patent/WO1996030366A1/es
Priority to FI964653A priority patent/FI964653A0/fi
Priority to NO965050A priority patent/NO965050L/no
Priority to GR20000402152T priority patent/GR3034463T3/el

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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
    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/28—Radicals substituted by nitrogen atoms
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents

Definitions

  • the present invention relates to novel polymorphs A and B of 1- (Diphenylmethyl) -4- [3- (2-phenyl-1, 3-dioxolan-2- yl) propyl] piperazine, a compound known as Dotarizine (WHO) ).
  • Figure 1 represents the IR Spectrum of Dotarizine polymorph A in the range of 4000 to 400 cm "1 .
  • Figure 2 represents the IR Spectrum of Dotarizine polymorph A in the range of 2000 to 400 cm '1 .
  • Figure 3 represents the "Differential Scanning Calorimetry" (DSC) Thermogram of Dotarizine Polymorph A.
  • Figure 4 represents the X-ray diffractogram of Dotarizine polymorph A.
  • Figure 5 represents the IR Spectrum of Dotarizine polymorph B in the range of 4000 to 400 cm "1.
  • Figure 6 represents the IR Spectrum of Dotarizine polymorph B in the range of 2000 to 400 c " 1 .
  • Figure 7 depicts the "Differential Scanning Calorimetry" (DSC) Thermogram of Dotarizine polymorph B.
  • Figure 8 depicts the X-ray Difractogram a of Dotarizine polymorph B.
  • the compound 1- (Diphenylmethyl) -4- [3- (2-phenyl-l, 3- dioxolan-2-yl) propyl] piperazine has antiserotoninergic action (5HT 1C and 5HT 2 ) and calcium antagonist. It is effective in the prophylaxis of migraine and in the treatment of vertigo.
  • the preparation of this compound is described in EP 97340, assigning a melting point of 93-97 ° C therein.
  • Dotarizina presents two new polymorphs, A and B, whose melting points are both between 100 and 103 ° C.
  • the "Differential Scanning Calorimetry" (DSC) thermograms of both polymorphs do not show significant differences, as illustrated in Figures 3 and 7.
  • IR spectra do show significant differences especially in the 1100 range. - 900 cm '1 as can be seen in the extended IR spectra of Figures 2 and 6.
  • Dotarizine polymorph A is characterized by having bands at 2962, 2949, 2808, 2767, 1446, 1040, 1025, 1002, 993, 970, 960, 761 and 707 cm “1
  • polymorph B is characterized by presenting bands at 2961, 2883, 2812, 2777, 2760, 1448, 1283, 1058, 1042, 1029, 1006, 978, 951, 758 and 703 cm '1 ( Figures 1 and 5)
  • the present application presents a procedure for selectively obtaining the two polymorphic forms of Dotarizine. Indeed, form A it is obtained by crystallization in methanol, while form B is obtained by crystallization in n-hexane.
  • polymorph A is recommended for the preparation of pharmaceutical compositions in the form of drops (suspensions), while it is preferable to use polymorph B to prepare capsules and other solid forms.
  • Dotarizine polymorphs A and B mixed with pharmaceutically acceptable excipients, can be administered at daily doses between 50 and 150 mg.
  • the following examples illustrate the obtaining of polymorphs A and B of Dotarizine and of pharmaceutical formulations containing them. The examples are not intended to limit the scope of the invention, as defined, or as claimed below.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Se han identificado dos polimorfos A y B de 1-(difenilmetil)-4-[3-(2-fenil-1,3-dioxolan-2-il)propil]piperazina. Se describe un procedimiento para la obtención de ambos y su uso posterior.

Description

POLIMORFOS A Y B DE 1- (DIFENILMETIL) -4- [3- (2-FENIL-1.3- DIOXOLA -2-IL)PROPIL]PIPERAZINA
La presente invención se refiere a nuevos polimorfos A y B de 1- (Difenilmetil) -4- [3- (2-fenil-l,3-dioxolan-2- il)propil]piperazina, compuesto que se conoce como Dotarizina (OMS) .
Breve descripción de las figuras
La Figura 1 representa el Espectro de IR del polimorfo A de Dotarizina en el rango de 4000 a 400 cm"1.
La Figura 2 representa el Espectro de IR del polimorfo A de Dotarizina en el rango de 2000 a 400 cm'1.
La Figura 3 representa el Termograma de "Differential Scanning Calorimetry" (DSC) del polimorfo A de Dotarizina. La Figura 4 representa el Difractograma de Rayos X del polimorfo A de Dotarizina.
La Figura 5 representa el Espectro de IR del polimorfo B de Dotarizina en el rango de 4000 a 400 cm"1. La Figura 6 representa el Espectro de IR del polimorfo B de Dotarizina en el rango de 2000 a 400 c "1.
La Figura 7 representa el Termograma de "Differential Scanning Calorimetry" (DSC) del polimorfo B de Dotarizina. La Figura 8 representa el Difractogra a de Rayos X del polimorfo B de Dotarizina.
Descripción detallada de la Invención
El compuesto 1- (Difenilmetil) -4- [3- (2-fenil-l,3- dioxolan- 2 - il ) propil ] piperazina tiene acción antiserotoninérgica (5HT1C y 5HT2) y antagonista del calcio. Es eficaz en la profilaxis de la migraña y en el trabamiento del vértigo. La obtención de este compuesto está descrita en la patente EP 97340, asignándosele en ella un punto de fusión de 93-97°C. Los solicitantes han descubierto que Dotarizina presenta dos nuevos polimorfos, A y B, cuyos puntos de fusión están ambos entre 100 y 103°C. Los termogramas de "Differential Scanning Calorimetry" (DSC) de ambos polimorfos no presentan diferencias significativas, según se ilustra en las Figuras 3 y 7. No obstante, los solicitantes han descubierto que los espectros de IR sí presentan diferencias significativas especialmente en el rango 1100 - 900 cm'1 según puede apreciarse en los espectros de IR ampliados de las Figuras 2 y 6. El polimorfo A de Dotarizina se caracteriza por presentar bandas a 2962, 2949, 2808, 2767, 1446, 1040, 1025, 1002, 993, 970, 960, 761 y 707 cm"1 y el polimorfo B se caracteriza por presentar bandas a 2961, 2883, 2812, 2777, 2760, 1448, 1283, 1058, 1042, 1029, 1006, 978, 951, 758 y 703 cm'1 (Figuras 1 y 5) . La presente solicitud presenta un procedimiento para obtener selectivamente las dos formas polimórficas de la Dotarizina. En efecto, la forma A se obtiene por cristalización en metanol, en tanto que la forma B se obtiene por cristalización en n-hexano.
Es recomendable el empleo del polimorfo A para la preparación de composiciones farmacéuticas en forma de gotas (suspensiones) , en tanto que es preferible el uso del polimorfo B para preparar cápsulas y otras formas sólidas.
Los polimorfos A y B de Dotarizina, mezclados con los excipientes farmacéuticamente aceptables, pueden administrarse a dosis diarias comprendidas entre 50 y 150 mg. Los siguientes ejemplos ilustran la obtención de los polimorfos A y B de Dotarizina y de formulaciones farmacéuticas que los contienen. Los ejemplos no se orientan a limitar la amplitud de la invención, según se ha definido, o como se reivindica más adelante.
Ejemplo 1 PolimorfoAde 1- (Difenilmetil) -4- [3- (2-fenil-l, 3-dioxolan-2- il)propil]piperazina
Se disuelven 11,2 g de Dotarizina en 56 mi de metanol a reflujo. Se filtra la disolución formada y se deja cristalizar a temperatura entre 20 y 25°C con agitación suave. Se forma un sólido cristalino que una vez seco pesa 9,9 g (rendimiento 88,5 %) . Espectro de IR (KBr) , rango de 4000 a 400 c "1: Figura 1
Espectro de IR (KBr) , rango de 2000 a 400 cm"1: Figura 2 Termograma de "Differential Scanning Calorimetry" (DSC) : Figura 3 Difractograma de Rayos X: Figura 4
Ejemplo 2
PolimorfoBdel- (Difenilmetil) -4- [3- (2-fenil-1,3-dioxolan-2- il)propil]piperazina
Se disuelven 10 g de Dotarizina en 100 mi de n-hexano a reflujo. Se filtra la disolución formada y se deja cristalizar a temperatura entre 20 y 25°C con agitación. Se forma un sólido cristalino que una vez seco pesa 7,6 g
(rendimiento 76 %) .
Espectro de IR (KBr) , rango de 4000 a 400 cm"1: Figura 5
Espectro de IR (KBr), rango de 2000 a 400 cm"1: Figura 6
Termograma de "Differential Scanning Calorimetry" (DSC) : Figura 7 Difractograma de Rayos X: Figura 8
Ejemplo 3
Gotas
Fórmula por 100 mi: Polimorfo A de Dotarizina 7,50 g
Sacarosa 30,00 g
Celulosa microcristalina RC-581 1,00 g
Carboximetilcelulosa sódica 0, 10 g
Sacarina sódica 3,50 g p-Hidroxibenzoato de metilo 0,15 g p-Hidroxibenzoato de propilo 0, 03 g
Polisorbato 80 0,20 g
Agua destilada c.s.h 100,00 mi
Ejemplo 4
Cápsulas Fórmula por cápsula:
Polimorfo B de Dotarizina 50,0 mg
Dióxido de silicio 2,0 mg Croscaramelosa sódica 8,0 mg
Almidón de maíz 50,0 mg
Talco 8,0 mg
Estearato de magnesio 1,5 mg
Celulosa microcristalina c.s.h 210,0 mg

Claims

Reivindicaciones
Ia) - Polimorfo A de 1- (Difenilmetil) -4- [3- (2-fenil-l,3- dioxolan-2-il)propil]piperazina caracterizado por presentar bandas de IR a 2962, 2949, 2808, 2767, 1446, 1040, 1025, 1002, 993, 970, 960, 761 y 707 cm"1 según las Figuras 1 y 2.
2*) - Polimorfo B de 1- (Difenilmetil) -4- [3- (2-fenil-1,3- dioxolan-2-il)propil]piperazina caracterizado por presentar bandas de IR a 2961, 2883, 2812, 2777, 2760, 1443, 1283,
1058, 1042, 1029, 1006, 978, 951, 758 y 703 cm"1 según las
Figuras 5 y 6.
3*) - Un procedimiento para la obtención del polimorfo A de i- (Difenilmetil) -4- [3- (2-fenil-l, 3-dioxolan-2- il)propil]piperazina por cristalización del compuesto en metanol.
4') - Un procedimiento para la obtención del polimorfo B de l- (Difenilmetil) -4- [3- (2-fenil-l, 3-dioxolan-2- iDpropil]piperazina por cristalización del compuesto en n- hexano.
5*) - Una composición farmacéutica que comprende una cantidad del polimorfo, según las reivindicaciones l y 3, eficaz en la profilaxis de la migraña y en el tratamiento del vértigo, y los excipientes farmacéuticamente aceptables. 61) - Una composición farmacéutica que comprende una cantidad del polimorfo, según las reivindicaciones 2 y 4, eficaz en la profilaxis de la migraña y en el tratamiento del vértigo, y los excipientes farmacéuticamente aceptables. 7*) - Un método para la profilaxis de la migraña y el tratamiento del vértigo, que consiste en administrar al enfermo una cantidad efectiva del compuesto de las reivindicaciones l, 3 y 5 para aliviar tales condiciones. 8*) - Un método para la profilaxis de la migraña y el tratamiento del vértigo, que consiste en administrar al enfermo una cantidad efectiva del compuesto de las reivindicaciones 2, 4 y 6 para aliviar tales condiciones.
PCT/ES1995/000033 1995-03-28 1995-03-28 Polimorfos a y b de 1-(difenilmetil)-4-[3-(2-fenil-1,3-dioxolan-2-il)propil]piperazina WO1996030366A1 (es)

Priority Applications (15)

Application Number Priority Date Filing Date Title
PT95913177T PT785196E (pt) 1995-03-28 1995-03-28 Polimorfos a e b de 1-(difenilmetil)-4-¬3-(2-fenil-1,3-dioxolano-2-il)propil|piperazina
PCT/ES1995/000033 WO1996030366A1 (es) 1995-03-28 1995-03-28 Polimorfos a y b de 1-(difenilmetil)-4-[3-(2-fenil-1,3-dioxolan-2-il)propil]piperazina
EP95913177A EP0785196B1 (en) 1995-03-28 1995-03-28 Polymorphs a and b of 1-(diphenylmethyl)-4-[3-(2-phenyl-1,3-dioxolan-2-yl) propyl]piperazine
DK95913177T DK0785196T3 (da) 1995-03-28 1995-03-28 Polymorfer A og B af 1-(diphenylmethyl)-4-[3-(2-phenyl-1,3-dioxolan-2-yl)propyl]piperazin
AT95913177T ATE194004T1 (de) 1995-03-28 1995-03-28 Polymorphe a und b des 1-(piphenylmethyl)-4-(3-(2-phenyl-dioxolan-2-yl propyl)piperazins
DE69517593T DE69517593T2 (de) 1995-03-28 1995-03-28 Polymorphe a und b des 1-(piphenylmethyl)-4-[3-(2-phenyl-dioxolan-2-yl)propyl]piperazins
AU20740/95A AU690974B2 (en) 1995-03-28 1995-03-28 Polymorphs A and B of 1-(diphenylmethyl)-4- 3-(2-phenyl-1,3- dioxolan-2-yl)propyl piperazine
US08/750,131 US5852021A (en) 1995-03-28 1995-03-28 Polymorph B of 1-(diphenylmethyl)-4- 3-(2-phenyl-1,3-dioxolan-2-YL) propyl! piperazine
ES95913177T ES2149353T3 (es) 1995-03-28 1995-03-28 Polimorfos a y b de 1-(difenilmetil)-4-(3-(2-fenil-1,3-dioxolan-2-il)propil)piperazina.
NZ282827A NZ282827A (en) 1995-03-28 1995-03-28 Polymorphs of 1-(diphenylmethyl)-4-[3-(2-phenyl-1,3-dioxolan-2-yl) propyl] piperazine
JP8528964A JPH10501555A (ja) 1995-03-28 1995-03-28 １−（ジフェニルメチル）−４−［３−（２−フェニル−１，３−ジオキソラン−２−イル）プロピル］ピペラジンの多形体ａおよびｂ
KR1019960706754A KR970703337A (ko) 1995-03-28 1995-03-28 1-(디페닐메틸)-4-[3-(2-페닐-1,3-디옥솔란-2-yl)프로필]피페라진의 동형이상 a형 및 b형(polymorphs a and b of 1-(diphenylmethyl)-4-[3-(2-phenyl-1,3-dioxolan-2-yl)propyl]piperazine)
FI964653A FI964653A0 (fi) 1995-03-28 1996-11-21 1-(difenyylimetyyli)-4-(3-(2-fenyyli-1,3-dioksolan-2-yyli)propyyli)piperatsiinin A- ja B-polymorfit
NO965050A NO965050L (no) 1995-03-28 1996-11-27 A- og B-polymorfene av 1-(difenylmetyl)-4- 3-(2-fenyl-1,3-dioksolan-2-yl)propyl -piperazin
GR20000402152T GR3034463T3 (en) 1995-03-28 2000-09-21 Polymorphs a and b of 1-(diphenylmethyl)-4-[3-(2-phenyl-1,3-dioxolan-2-yl) propyl]piperazine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/ES1995/000033 WO1996030366A1 (es) 1995-03-28 1995-03-28 Polimorfos a y b de 1-(difenilmetil)-4-[3-(2-fenil-1,3-dioxolan-2-il)propil]piperazina

Publications (1)

Publication Number Publication Date
WO1996030366A1 true WO1996030366A1 (es) 1996-10-03

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/ES1995/000033 WO1996030366A1 (es) 1995-03-28 1995-03-28 Polimorfos a y b de 1-(difenilmetil)-4-[3-(2-fenil-1,3-dioxolan-2-il)propil]piperazina

Country Status (14)

Country Link
US (1) US5852021A (es)
EP (1) EP0785196B1 (es)
JP (1) JPH10501555A (es)
KR (1) KR970703337A (es)
AT (1) ATE194004T1 (es)
AU (1) AU690974B2 (es)
DE (1) DE69517593T2 (es)
DK (1) DK0785196T3 (es)
ES (1) ES2149353T3 (es)
FI (1) FI964653A0 (es)
GR (1) GR3034463T3 (es)
NO (1) NO965050L (es)
PT (1) PT785196E (es)
WO (1) WO1996030366A1 (es)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998050065A3 (de) * 1997-05-05 1999-06-10 Marion Sangster Eckmiller Verwendung biologisch aktiver wirkstoffe zum beeinflussen des extrazellulär-raumes von sinneszellen und verfahren zur wirkstoff-administrationssteuerung und vorrichtung hierzu

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006012536A2 (en) * 2004-07-22 2006-02-02 Ritter Andrew J Methods and compositions for treating lactose intolerance

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0097340A2 (en) * 1982-06-17 1984-01-04 Ferrer Internacional, S.A. Piperazine derivatives, a process for preparing them and pharmaceutical compositions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0097340A2 (en) * 1982-06-17 1984-01-04 Ferrer Internacional, S.A. Piperazine derivatives, a process for preparing them and pharmaceutical compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
S. GUBERT ET AL.: "Synthesis of Some N-Benzhydrylpiperazine Derivatives as Calcium Antagonists", ARZNEIMITTEL FORSCHUNG. DRUG RESEARCH, vol. 37, no. 10, 1987, AULENDORF DE, pages 1103 - 1107 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998050065A3 (de) * 1997-05-05 1999-06-10 Marion Sangster Eckmiller Verwendung biologisch aktiver wirkstoffe zum beeinflussen des extrazellulär-raumes von sinneszellen und verfahren zur wirkstoff-administrationssteuerung und vorrichtung hierzu

Also Published As

Publication number Publication date
DE69517593T2 (de) 2001-03-08
DE69517593D1 (de) 2000-07-27
AU690974B2 (en) 1998-05-07
FI964653L (fi) 1996-11-21
ATE194004T1 (de) 2000-07-15
KR970703337A (ko) 1997-07-03
EP0785196B1 (en) 2000-06-21
NO965050D0 (no) 1996-11-27
EP0785196A1 (en) 1997-07-23
PT785196E (pt) 2000-12-29
JPH10501555A (ja) 1998-02-10
GR3034463T3 (en) 2000-12-29
DK0785196T3 (da) 2000-10-16
US5852021A (en) 1998-12-22
AU2074095A (en) 1996-10-16
FI964653A0 (fi) 1996-11-21
ES2149353T3 (es) 2000-11-01
NO965050L (no) 1996-11-27

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