WO2014138905A1 - Formes de tosylate de sorafénib et procédés pour les préparer - Google Patents

Formes de tosylate de sorafénib et procédés pour les préparer Download PDF

Info

Publication number
WO2014138905A1
WO2014138905A1 PCT/CA2014/000235 CA2014000235W WO2014138905A1 WO 2014138905 A1 WO2014138905 A1 WO 2014138905A1 CA 2014000235 W CA2014000235 W CA 2014000235W WO 2014138905 A1 WO2014138905 A1 WO 2014138905A1
Authority
WO
WIPO (PCT)
Prior art keywords
sorafenib tosylate
hemi
form apo
dmso solvate
dmso
Prior art date
Application number
PCT/CA2014/000235
Other languages
English (en)
Inventor
Kevin W. Kells
Abbulu KANTE
Jenny L. GERSTER
Allan W. Rey
Original Assignee
Apotex Technologies Inc.
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 Apotex Technologies Inc. filed Critical Apotex Technologies Inc.
Publication of WO2014138905A1 publication Critical patent/WO2014138905A1/fr

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

Definitions

  • the present invention relates to a solvate of sorafenib tosylate and processes for the preparation thereof.
  • Sorafenib has the chemical name 4-[4-[[[[[4-chloro-3- (trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2- pyridinecarboxamide.
  • Sorafenib tosylate, 1 is marketed in the U.S. as Nexavar ® and is indicated for the treatment of primary kidney cancer and advanced primary liver cancer.
  • Patent publication US 2009/0215833 relates to a novel form
  • thermodynamically stable at room temperature of the tosylate salt of 4-[4-H[ ⁇ 4- chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2- pyridinecarboxamide, to processes for its preparation, to medicaments comprising it and to its use in the control of disorders.
  • Patent publication US 2009/0192200 relates to sorafenib hemi-tosylate, polymorphs thereof, polymorphs of sorafenib tosylate, preparation thereof and pharmaceutical compositions thereof.
  • Patent publication WO 2009/106825 relates to sorafenib or a
  • Patent publication WO 2010/079498 relates to a novel polymorph of sorafenib tosylate, process for its preparation and to pharmaceutical composition containing it.
  • sorafenib tosylate was added to water, the contents were stirred at room temperature, the solid obtained was collected by filtration and dried to give sorafenib tosylate polymorph III.
  • Patent publication WO 2010/142678 relates to polymorphs of 4-[4-[[4- chloro-3-(trifluoromethyl)phenyl]-carbamoylamino]phenoxy]-N-methyl-pyridine-2- carboxamide and pharmaceutical compositions comprising the same.
  • Patent publication WO 201 1/092663 provides dimethyl sulphoxide solvate of 4-(4- ⁇ 3-[4-chloro- 3-(trifluoromethyl)phenyl]ureido ⁇ phenoxy)-N2 - methylpyridine-2-carboxamide, a process for its preparation, a pharmaceutical composition comprising it and its use for the treatment of cancer.
  • the invention also provides a novel HPLC method for the identification, quantification and isolation of related substances of sorafenib.
  • the present invention relates, at least in part, to a crystalline DMSO solvate of sorafenib tosylate, termed herein Form APO-I, wherein the molar ratio of sorafenib tosylate to DMSO is approximately 1 :0.5 ('hemi-solvate').
  • the crystalline solvate of the present invention may have advantages relative to other known forms of sorafenib tosylate, such as solvated forms of sorafenib tosylate, including chemical stability, polymorphic stability, varying solubility and/or bioavailability.
  • the crystalline solvate of the present invention may be washed with a lower boiling solvent such as isopropanol without disruption of the solvate. As a result, the crystalline solvate may be easily filtered and dried.
  • Illustrative embodiments of the invention provide Form APO-I of sorafenib tosylate hemi-DMSO solvate characterized by a PXRD diffractogram comprising peaks, in degrees 2-theta, at 7.1 ⁇ 0.2, 9.9 ⁇ 0.2, 12.6 ⁇ 0.2, 14.3 ⁇ 0.2 and 20.4 ⁇ 0.2.
  • Illustrative embodiments of the invention provide a Form APO-I of sorafenib tosylate hemi-DMSO solvate described herein wherein the PXRD diffractogram further comprises a peak, in degrees 2-theta, at 22.9 ⁇ 0.2.
  • Illustrative embodiments of the invention provide a Form APO-I of sorafenib tosylate hemi-DMSO solvate described herein wherein the PXRD diffractogram further comprises peaks, in degrees 2-theta, at 17.0 ⁇ 0.2, 19.2 ⁇ 0.2, 20.0 ⁇ 0.2, 20.8 ⁇ 0.2 and 21.5 ⁇ 0.2.
  • Illustrative embodiments of the invention provide a Form APO-I of sorafenib tosylate hemi-DMSO solvate described herein Form APO-I of sorafenib tosylate hemi-DMSO solvate characterized by a PXRD diffractogram substantially similar to the PXRD diffractogram as depicted in Figure 1.
  • Illustrative embodiments of the invention provide a Form APO-I of sorafenib tosylate hemi-DMSO solvate described herein characterized by a PXRD diffractogram as depicted in Figure 1.
  • thermogram indicating a weight loss of 5.8% ⁇ 0.6% at a temperature between approximately 140 °C and approximately 214 °C.
  • thermogram substantially similar to the TGA thermogram as depicted in Figure 2.
  • thermogram as depicted in Figure 2.
  • Illustrative embodiments of the invention provide a Form APO-I of sorafenib tosylate hemi-DMSO solvate described herein characterized by a 1 % KBr FTIR spectrum comprising peaks, in cm "1 , at 3279 ⁇ 5, 1707 + 5, 1698 + 5, 1464 + 5, 1314 ⁇ 5 and 1033 ⁇ 5.
  • Illustrative embodiments of the invention provide a Form APO-I of sorafenib tosylate hemi-DMSO solvate described herein wherein the 1% KBr FTIR spectrum further comprises peaks, in cm "1 , at 1551 + 5, 1507 ⁇ 5, 1486 ⁇ 5, and 1416 ⁇ 5.
  • Illustrative embodiments of the invention provide a Form APO-I of sorafenib tosylate hemi-DMSO solvate described herein characterized by a 1 % KBr FTIR spectrum substantially similar to the FTIR spectrum as depicted in Figure 3.
  • Illustrative embodiments of the invention provide a Form APO-I of sorafenib tosylate hemi-DMSO solvate described herein characterized by a 1 % KBr FTIR spectrum as depicted in Figure 3.
  • Illustrative embodiments of the invention provide a pharmaceutical formulation comprising Form APO-I sorafenib tosylate hemi-DMSO solvate described herein and a pharmaceutically acceptable excipient.
  • Illustrative embodiments of the invention provide a process for preparation of Form APO-I sorafenib tosylate hemi-DMSO solvate comprising: i. preparing a solution of sorafenib tosylate in DMSO; ii. adding propylene glycol to the solution, thereby forming a suspension; and iii. isolating Form APO-I sorafenib tosylate hemi-DMSO solvate from the suspension.
  • Illustrative embodiments of the invention provide a process described herein wherein the suspension is diluted with isopropanol prior to isolating Form APO-I sorafenib tosylate DMSO solvate.
  • Figure 1 is a powder X-ray diffraction (PXRD) diffractogram of Form APO-I sorafenib tosylate hemi-DMSO solvate.
  • Figure 2 is a Thermogravimetric Analysis (TGA) thermogram of Form APO-I sorafenib tosylate hemi-DMSO solvate.
  • Figure 3 is a Fourier Transform Infrared (FTIR) spectrum of Form APO-I sorafenib tosylate hemi-DMSO solvate.
  • FTIR Fourier Transform Infrared
  • the term "substantially similar" means that the subject diffractogram, spectrum and/or data presented in a graph encompasses all diffractograms, spectra and/or data presented in graphs that vary within acceptable boundaries of experimentation that are known to a person of skill in the art. Such boundaries of experimentation will vary depending on the type of the subject diffractogram, spectrum and/or data presented in a graph, but will nevertheless be known to a person of skill in the art.
  • the term “approximately” means that the peak may vary by ⁇ 0.2 degrees 2-theta of the subject value.
  • the term “approximately” means that the weight loss may vary by ⁇ 10% from the subject value. For example, a weight loss of 5.8% is understood to include values between 5.2% and 6.4%.
  • the term "peak” refers to a feature that one skilled in the art would recognize as not attributing to background noise.
  • an intensity of a peak obtained may vary quite dramatically. For example, it is possible to obtain a relative peak intensity of 1 % when analyzing one sample of a substance, but another sample of the same substance may show a much different relative intensity for a peak at the same position. This may be due, in part, to the preferred orientation of the sample and its deviation from the ideal random sample orientation, sample preparation and the methodology applied. Such variations are known and understood by a person of skill in the art.
  • the present invention encompasses the solvates isolated in pure form or when admixed with other materials, for example other isomers and/or
  • Solvates have some variability in the exact molar ratio of their components depending on a variety of conditions understood to a person of skill in the art.
  • a molar ratio of components within a solvate provides a person of skill in the art information as to the general relative quantities of the components of the solvate and in many cases the molar ratio may vary by about plus or minus 30% from a stated range.
  • a molar ratio of 1 :1 is understood to include the ratio 1 :0.7 as well as 1 :1.3 as well as all of the individual ratios in between.
  • the present invention comprises Form APO-I sorafenib tosylate hemi-DMSO solvate wherein the molar ratio of sorafenib tosylate to DMSO is approximately 1 :0.5.
  • FIG. 1 An illustrative PXRD diffractogram of Form APO-I sorafenib tosylate hemi- DMSO solvate obtained according to the conditions given in Example 2 is shown in Figure 1.
  • the Form APO-I sorafenib tosylate hemi- DMSO solvate may have a reflection ("peak") at any one or more of the values expressed in degrees 2-theta given in Table 1.
  • the solvate may be defined by the claimed peaks and a particular claim may be limited to one peak only, or several peaks.
  • the Form APO-I sorafenib tosylate hemi-DMSO solvate does not have to include all or even many of the peaks listed in Table 1.
  • Form APO-I sorafenib tosylate hemi- DMSO solvate obtained according to the conditions given in Example 1 is shown in Figure 3.
  • the Form APO-I sorafenib tosylate hemi- DMSO solvate may have an absorption band ("peak") at any one or more of the values expressed in cm "1 given in Table 2.
  • the present invention provides a process for preparation of Form APO-I sorafenib tosylate hemi-DMSO solvate comprising:
  • the solution of sorafenib tosylate in DMSO may be prepared by dissolving sorafenib base in DMSO and adding p-toluene sulfonic acid. Alternately, the solution may be prepared by dissolving sorafenib tosylate salt in DMSO.
  • the suspension formed by adding propylene glycol to the solution may or may not be diluted with isopropanol prior to isolating Form APO-I from the suspension.
  • Powder X-Ray Diffraction Analysis The data were acquired on a
  • PANanalytical X-Pert Pro MPD diffractometer with fixed divergence slits and an X-Celerator RTMS detector.
  • the diffractometer was configured in Bragg- Brentano geometry; data was collected over a 2-theta range of 3 to 40 degrees using CuKa radiation at a power of 40 mA and 45 kV. CuK radiation was removed using a divergent beam nickel filter. A step size of 0.017 degrees was used.
  • Thermogravimetric Analysis (TGA): The TGA thermogram was collected on a Mettler Toledo TGA/SDTA851. Sample (5.6 mg) was weighed into a 100 pL aluminum pan and was crimped closed with a lid having a ca. 1 mm pinhole.
  • the sample was analyzed under a flow of nitrogen (ca. 85 mL/min) at a heating rate of 10°C/minute from 25°C-360°C.
  • FTIR Fourier Transform Infrared Analysis: The FTIR spectrum was collected at 4 cm-1 resolution using a Perkin Elmer Paragon 1100 single beam FTIR instrument. The sample was intimately mixed in an approximately 1 :100 ratio (w/w) with potassium bromide using an agate mortar and pestle to a fine consistency; the mixture was compressed in a pellet die at a pressure of 5 tonnes for a time period of about 2 minutes. The resulting disk was scanned 4 times versus a collected background. Data was baseline corrected and normalized. Sorafenib free base may be prepared according to US7235576 B1.
  • the sorafenib free base used in the following embodiments was substantially pure by 1 H NMR.
  • sorafenib base (2.00 g) followed by DMSO (3 ml_), and the mixture was stirred at room temperature under a nitrogen atmosphere to obtain a solution.
  • DMSO 3 ml_
  • p-toluenesulphonic acid monohydrate (0.82 g)
  • sorafenib base (1.00 g) followed by DMSO (1.5 mL), and the mixture was stirred at room temperature under a nitrogen atmosphere to obtain a solution.
  • DMSO DMSO
  • p-toluenesulphonic acid monohydrate (0.41 g)
  • Propylene glycol (3.5 mL) was added to the stirring solution, and the resulting solution was stirred at room temperature under a nitrogen atmosphere.
  • the resulting suspension was diluted with isopropanol (10 mL), stirred at room temperature for
  • DMSO solvate was obtained (0.80 g).
  • the total residual solvent (propylene glycol, isopropanol) estimated by 1 H NMR was less than 0.5 wt%.
  • the initial KF of the sample was 0.27%. The KF of the sample remained essentially
  • Figures 1 and 2 set out a PXRD and TGA, respectively, that were obtained from material prepared by this procedure.
  • sorafenib base (1.00 g) followed by DMSO (2.5 mL), and the mixture was stirred at room temperature under a nitrogen atmosphere to obtain a clear solution.
  • DMSO dimethyl sulfoxide
  • p-toluenesulphonic acid monohydrate 0.41 g
  • Propylene glycol 3.5 mL was added to the stirring solution, and the resulting solution was stirred at room temperature under a nitrogen atmosphere. After stirring at room temperature for approximately 22 hours, the resulting suspension was diluted with isopropanol (10 mL), stirred at room temperature for approximately 20 minutes, and then filtered.
  • the filter cake was washed with isopropanol (2 x 5 mL) and dried under suction until solvent ceased dripping from the end of the funnel. The filter cake was then dried under vacuum at room temperature for 3 hours to yield Form APO-I sorafenib tosylate hemi-DMSO solvate (0.25 g, molar ratio of sorafenib tosylate to DMSO, 1 :0.5) containing less than 0.1 wt % isopropanol and negligible levels of propylene glycol by 1 H NMR.
  • sorafenib base (4.00 g) followed by DMSO (10.0 mL), and the mixture was stirred at room temperature under a nitrogen atmosphere to obtain a clear solution.
  • DMSO dimethyl methacrylate
  • p-toluenesulphonic acid monohydrate 1.64 g
  • Propylene glycol (14.0 mL) was added to the stirring solution, and the resulting solution was stirred at room temperature under a nitrogen atmosphere. Seed crystals of Form APO-I sorafenib tosylate hemi-DMSO solvate were added.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le solvate de semi-DMSO du tosylate de sorafénib, un procédé permettant de le préparer et une formulation pharmaceutique le contenant. Le procédé comprend la préparation d'une solution de tosylate de sorafénib dans le DMSO, par ajout de DMSO à une base de sorafénib, puis l'ajout d'acide p-toluènesulfonique monohydraté, ou l'ajout de DMSO au tosylate de sorafénib, puis l'ajout de propylène glycol au mélange pour former une suspension, à partir de laquelle le solvate de semi-DMSO est isolé avec ou sans dilution avec de l'isopropanol.
PCT/CA2014/000235 2013-03-14 2014-03-14 Formes de tosylate de sorafénib et procédés pour les préparer WO2014138905A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361784127P 2013-03-14 2013-03-14
US61/784,127 2013-03-14

Publications (1)

Publication Number Publication Date
WO2014138905A1 true WO2014138905A1 (fr) 2014-09-18

Family

ID=51535668

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2014/000235 WO2014138905A1 (fr) 2013-03-14 2014-03-14 Formes de tosylate de sorafénib et procédés pour les préparer

Country Status (1)

Country Link
WO (1) WO2014138905A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106336377A (zh) * 2015-07-17 2017-01-18 苏州亚宝药物研发有限公司 一种甲苯磺酸索拉非尼晶型ⅱ的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006034797A1 (fr) * 2004-09-29 2006-04-06 Bayer Healthcare Ag Forme thermodynamiquement stable de tosylate de bay 43-9006
US20090192200A1 (en) * 2008-01-17 2009-07-30 Ales Gavenda Polymorphs of sorafenib tosylate and sorafenib hemi-tosylate, and processes for preparation thereof
WO2011092663A2 (fr) * 2010-01-29 2011-08-04 Ranbaxy Laboratories Limited Solvate de diméthylsulfoxyde du 4-(4-{3-[4-chloro-3-(trifluorométhyl)phényl]uréido}phénoxy)-n2-méthylpyridine-2-carboxamide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006034797A1 (fr) * 2004-09-29 2006-04-06 Bayer Healthcare Ag Forme thermodynamiquement stable de tosylate de bay 43-9006
US20090192200A1 (en) * 2008-01-17 2009-07-30 Ales Gavenda Polymorphs of sorafenib tosylate and sorafenib hemi-tosylate, and processes for preparation thereof
WO2011092663A2 (fr) * 2010-01-29 2011-08-04 Ranbaxy Laboratories Limited Solvate de diméthylsulfoxyde du 4-(4-{3-[4-chloro-3-(trifluorométhyl)phényl]uréido}phénoxy)-n2-méthylpyridine-2-carboxamide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106336377A (zh) * 2015-07-17 2017-01-18 苏州亚宝药物研发有限公司 一种甲苯磺酸索拉非尼晶型ⅱ的制备方法

Similar Documents

Publication Publication Date Title
US10669275B2 (en) Methods of preparing co-crystals of ibrutinib with carboxylic acids
JP2018520205A (ja) レンバチニブメシル酸塩の新規結晶形及びその製造方法
WO2017008773A1 (fr) Formes cristallines d'acide obéticholique
DE10339862A1 (de) 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester-Methansulfonat und dessen Verwendung als Arzneimittel
JP2018501289A (ja) ネラチニブマレイン酸塩の新規な結晶形及びその製造方法
TW201206948A (en) Production method for a salt-form of optically active diamine
EP2907812B1 (fr) Procédé de préparation d'une forme amorphe du dexlansoprazole
CA2888002A1 (fr) Formes solides du chlorhydrate de nilotinib
EP3327012B1 (fr) Formes cristallines de la bilastine et procédés pour leur préparation
EP3564224A2 (fr) Forme cristalline de vortioxetine hydrobromide comme médicament antidepresseur
WO2014138905A1 (fr) Formes de tosylate de sorafénib et procédés pour les préparer
AU2015379251A1 (en) Crystalline forms of efinaconazole
WO2016058564A1 (fr) Sels de bédaquiline
WO2016155560A1 (fr) Sel d'acide p-toluènesulfonique de lenvatinib, forme cristalline et méthode de préparation de cette dernière
WO2014147504A2 (fr) Procédé de préparation de formes solides de 2-chloro-n-(4-chloro-3-(pyridin-2-ylphényl)-4-méthylsulfonylbenzamide
EP2573084A1 (fr) Nouvelles formes cristallines de rivaroxaban et leurs procédés de préparation
EP3063151B1 (fr) Polymorphe stable du sel de (2r)-4-oxo-4-[3-(trifiuorométhyl)-5,6- dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8h)-yl]-1-(2,4,5-trifluorophényl)butan-2-amine avec du l-acide tartrique
US9382233B2 (en) Forms of vilazodone and processes for the preparation thereof
US10016423B2 (en) Solid forms of nilotinib hydrochloride
WO2013082302A1 (fr) Complexe agomélatine-urée et formes cristallines de celui-ci
US20220380348A1 (en) Axl inhibitor formulations
CA3197026A1 (fr) Sels et co-cristaux de siponimod
JP2004512282A (ja) １−［６−クロロ−５−（トリフルオロメチル）−２−ピリジニル］ピペラジン塩酸塩の結晶形態
WO2016127962A1 (fr) Forme solide amorphe de suvorexant avec acide sulfurique
EP3357909A1 (fr) 4-[3-(méthylsulfonyl)phényl]-1-propyl-pipéridine cristalline

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14765562

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14765562

Country of ref document: EP

Kind code of ref document: A1