EP3390360A1 - Procédé de préparation d'un agent pharmaceutique - Google Patents

Procédé de préparation d'un agent pharmaceutique

Info

Publication number
EP3390360A1
EP3390360A1 EP16828991.6A EP16828991A EP3390360A1 EP 3390360 A1 EP3390360 A1 EP 3390360A1 EP 16828991 A EP16828991 A EP 16828991A EP 3390360 A1 EP3390360 A1 EP 3390360A1
Authority
EP
European Patent Office
Prior art keywords
acid
formula
reaction
apremilast
salt
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP16828991.6A
Other languages
German (de)
English (en)
Inventor
Dominika PODWYSOCKA
Arkadiusz Majewski
Marcin Szulc
Monika Oracz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zaklady Farmaceutyczne Polpharma SA
Original Assignee
Zaklady Farmaceutyczne Polpharma SA
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 Zaklady Farmaceutyczne Polpharma SA filed Critical Zaklady Farmaceutyczne Polpharma SA
Publication of EP3390360A1 publication Critical patent/EP3390360A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide

Definitions

  • the present invention relates to a process for the preparation of a pharmaceutical agent, and particularly to a process for preparing apremilast.
  • Arthritis represents a major global health problem, for example, arthritis is the most common cause of disability in the United States of America, affecting 20 million people and placing severe restrictions on their physical capabilities.
  • the term "arthritis” encompasses a variety of disease states which typically involve inflammation of one or more joints. Patients most typically present with joint pain that is a direct result of inflammation occurring around the joint. The pain is often localised to the affected joint and provides a constant source of physical distress for patients.
  • Psoriasis is a chronic inflammatory skin disease that can lead to significant physical and psychological distress for patients.
  • Inflammation is an omnipresent symptomatic feature of both arthritis and psoriasis. Aside from sharing this common symptom the disease states overlap further in that a particular form of arthritis exists which is directly attributable to psoriasis.
  • Psoriatic arthritis is known to develop in approximately 30% of people who already suffer from psoriasis. The disease impacts upon the patients' range of motion, and patients typically present with swelling, stiffness and pain within and around the joints. Physical fatigue is also a common complaint among sufferers. Although the exact cause of the disease has not been elucidated, it has been postulated that the prolonged skin inflammation experienced by psoriasis sufferers can inflict proximal damage to neighbouring joints, which then manifests as arthritis.
  • arthritic conditions e.g. psoriatic arthritis
  • NSAIDS nonsteroidal anti-inflammatory drugs
  • ibuprofen and naproxen for mild symptomatic pain
  • diclofenac and indomethacin in more serious circumstances.
  • ibuprofen and naproxen for mild symptomatic pain
  • diclofenac and indomethacin in more serious circumstances.
  • ibuprofen and naproxen for mild symptomatic pain
  • diclofenac and indomethacin in more serious circumstances.
  • More recent studies have investigated the pathogenesis of psoriasis and psoriatic arthritis at the molecular level.
  • TNFa tumour necrosis factor alpha
  • PDE4 phosphodiesterase IV
  • Apremilast is named ⁇ /-[2-[ ⁇ 1 S)-1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyi)ethyl]-1 ,3-dioxo-2,3- dihydro-1 H-isoindol-4-yl]acetamide. Apremilast is represented structurally by the formulae below.
  • Apremilast is indicated for the treatment of patients presenting with moderate to severe plaque psoriasis and psoriatic arthritis.
  • the drug is commercially marketed by Celgene Ltd under the trade name Otezla® and is formulated as an oral film-coated tablet in a size amount of 10, 20 or 30 mg.
  • WO 03/080049 details a synthesis of apremilast:
  • the present invention provides a process for preparing apremilast
  • the present invention entails a condensation reaction between an amino-substituted phthaltc anhydride derivative and a primary amine.
  • protic acid should be understood as encompassing acids that can be described by both, or either of the Arrhenius acid and Bransted-Lowry acid definitions.
  • An Arrhenius acid is a substance that, when added to water, increases the concentration of protons (H + ) ions in the water.
  • H + protons
  • a Bransted-Lowry acid is a species that donates a proton to a Bransted-Lowry base (a proton acceptor). The following equations demonstrate the use and applicability of each of the Arrhenius and Bronsted-Lowry definitions, the protic acid exemplified being acetic acid:
  • Equation (b) CH3COOH + NH 3 CH 3 COCf + NH 4 + Equation (a) can be described by both definitions of protic acid.
  • acetic acid can be said to act as an Arrhenius acid, because following addition to, or reaction with water, the concentration of l-bO "1" increases.
  • acetic acid is also acting as a Br0nsted-Lowry acid by donating a proton to water.
  • Equation (b) highlights a similar situation wherein acetic acid donates a proton to ammonia and thus again behaves like a Bransted-Lowry acid, however equation (b) cannot be described by the Arrhenius definition, because the reaction is occurring in the absence of water.
  • protic acid is intended to cover protic acids that when added to water in an amount sufficient to form a 1 molar aqueous solution at 25°C, the resulting solution will have a pH less than 7 when measured by conventional methods e.g. a pH meter.
  • protic acids examples include acetic acid, formic acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, methanesuifonic acid, trifluoromethanesuifonic acid, trifiuoroacetic acid, phosphoric acid, benzoic acid, citric acid, tartaric acid, nitric acid, hydrobromic acid, hydrofluoric acid, carbonic acid, potassium bisulfate, anthranilic acid, ethylenediaminetetraacetic acid, fumaric acid, giycolic acid, lactic acid, maleic acid, malonic acid, oxalic acid, peracetic acid, propionic acid, phthalic acid, salicyclic acid, succinic acid and sulfamic acid.
  • acetic acid formic acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, methanesuifonic acid, trifluoromethanesuifonic acid
  • the present invention is performed in the absence of protic acid, for example in the absence of typical protic acids listed above. It should also be noted that the list is not exhaustive and is not in any way intended to be limiting upon the scope of the invention.
  • the term "acidic proton” is a term of the art and is used to describe protons which have the ability to act as acids in a given chemical environment. Generally, and in accordance with the present invention, “acidic protons” should be understood as being inherently more acidic in comparison to alkyl protons i.e. protons directly bonded to a carbon atom in an sp3, sp2 or sp hybridisation state. Protons that are generally considered “acidic protons” are typically directly bonded to an oxygen or nitrogen atom.
  • a molecule containing one or more protons in such an environment e.g. an amide proton could lead to an interpretation that the molecule per se is a protic acid.
  • a process for the preparation of apremilast comprising reacting compounds of formula I and formula H or a salt thereof in the absence of a protic acid, it should be understood that molecules possessing protons in the aforementioned environments, that is, environments in which a proton is considered an "acidic proton", are not considered to be protic acids.
  • the process for preparing apremilast is preferabably conducted in a solvent (i.e. an organic solvent) or a mixture of solvents.
  • water- or air-sensitive transformations require the use of non-aqueous, non-protic solvents such as acetonitrile, tetrahydrofuran, dioxane, dimethylsulfoxide dichloromethane, chloroform or W-methylpyrrolidine.
  • non-aqueous, non-protic solvents such as acetonitrile, tetrahydrofuran, dioxane, dimethylsulfoxide dichloromethane, chloroform or W-methylpyrrolidine.
  • water- or air- sensitive reactions may also require an atmosphere of inert gas (to prevent atmospheric water from compromising a transformation) typical inert gases include nitrogen and argon.
  • reactions requiring the use of an aqueous reagent e.g.
  • aqueous hydrochloric acid or aqueous sodium hydroxide may require the use of one or more organic co-solvents.
  • an organic co- solvent is added to aid the dissolution, or partial dissolution of a less polar organic reagent.
  • Typical organic co-solvents for use with such aqueous reagents include, toluene, alcohols (methanol, ethanol, propanoi), tetrahydrofuran and dimethylsulfoxide.
  • reaction efficacy when using organic co-solvents with aqueous solvents is the requirement for some degree of miscibility of the organic co-solvent with water.
  • phase transfer catalyst e.g. tetrabutylammonium bromide.
  • Solvents are traditionally categorised into two categories, polar and non-polar. More specifically solvents are allocated into each category according to their dielectric constant. It is generally accepted that solvents displaying a dielectric constant of less than 15 are considered to be non-polar solvents, and solvents displaying a dielectric constant of greater than or equal to 15 are considered to be polar solvents.
  • Preferred solvents for use in preparing apremilast according to the present invention are polar solvents.
  • Particularly preferred solvents for use in preparing apremilast are aikylacetamide-containing solvents.
  • A!ky!acetamides are solvents that comprise carbon, hydrogen, oxygen and nitrogen only, and whereas the term acetamide represents solvents wherein the amine ⁇ -NH2) group is unsubsituted, alkyiacetamide represents solvents wherein the amine group is mono- (-NR1H) or di- (NR1R2) substituted with one or more alkyl groups, wherein the alkyl groups (Ri) and (R2) can be identical or different.
  • the alkyl groups present upon the solvent used in conjunction with the present invention are C1-C10 alkyl groups.
  • alkyiacetamide solvents that can be used in conjunction with the present invention are, W.N-dimethylacetarnide, ⁇ /, ⁇ -dimethylformamide, W-methylacetamide, N- methylform amide, A/-methyl-2-pyrro!idone and pyrrolidone. It is particularly preferred wherein the solvent used in conjunction with the present invention is /V,A/-dimethylacetamide or N,N- dimethylformamide. It is most preferred wherein the solvent used in conjunction with the present invention is /V,W-dimethylacetamide.
  • the process for preparing apremilast comprising reacting compounds of formula I and formula II or a salt thereof where neither acetic nor formic acid are present, is conducted in an alkyiacetamide solvent.
  • the process for preparing apremilast comprising reacting compounds of formula I and formula II or a salt thereof in the absence of a protic acid, is conducted in an alkyiacetamide solvent.
  • the process for preparing apremilast comprising reacting compounds of formula I and formula N or a salt thereof where neither acetic nor formic acid are present, is conducted in a A/,W-dimethylacetamide or N,W-dirnethylformamide solvent. It is particularly preferred when the solvent is W.W-dimethylacetamide.
  • the process for preparing apremilast comprising reacting compounds of formula I and formula II or a salt thereof in the absence of a protic acid, is conducted in a N,N- dimethylacetamide or W,W-dimethylformamide solvent. It is particularly preferred when the solvent is /V.W-dimethylacetamide.
  • the process for preparing apremilast is advantageously conducted at a temperature obtainable by the application of simple and non-expensive heating technologies.
  • the process of the present invention is conducted at a temperature of from 90°C to 150°C.
  • the present invention requires non-expensive heating technologies in order to obtain the most preferred reaction temperature of from 110°C to 120°C.
  • the process for preparing apremilast requires a relatively short reaction time.
  • the process for preparing apremilast comprising reacting compounds of formula I and formula II or a salt thereof, where neither acetic nor formic acid are present and wherein the solvent is an alkylacetamide solvent, that the reaction is conducted at a temperature of from 110°C to 120°C and the duration of the reaction is 1 to 5 hours. It is more preferred wherein the duration of the reaction is 3 hours. It is also preferred where the process for preparing apremilast, comprising reacting compounds of formula I and formula II or a salt thereof, in the absence of a protic acid and wherein the solvent is an alkylacetamide solvent, that the reaction is conducted at a temperature of from 110°C to 120°C and the duration of the reaction is 1 to 5 hours. It is more preferred wherein the duration of the reaction is about 3 hours, or is 3 hours.
  • the process for preparing apremilast comprising reacting compounds of formula I and formula !l or a salt thereof, where neither acetic nor formic acid are present and wherein the solvent is W.W-dimethylacetamide or A/,A -dimethylformamide, that the reaction is conducted at a temperature of from 110°C to 120°C and the duration of the reaction is 1 to 5 hours. It is more preferred where the duration of the reaction is 3 hours and wherein the solvent is N,N ⁇ dimethylacetamide.
  • the process for preparing apremilast comprising reacting compounds of formula I and formuia II or a salt thereof, in the absence of a protic acid and wherein the solvent is N,W-dimethylacetamide or N,W-dimethylformamide, that the reaction is conducted at a temperature of from 110°C to 120 C C and the duration of the reaction is 1 to 5 hours. It is more preferred where the duration of the reaction is 3 hours and wherein the solvent is N,N- dimethylacetamide.
  • a salt thereof used in conjunction with a compound of formula II means any pharmaceutically acceptable salt thereof, and for example, typically refers to and includes at least the N-acetyl-L-leucine salt of a compound of formula II.
  • N-acetyl-L-leucine salt of a compound of formula II is represented structurally below.
  • a process for the preparation of apremilast comprising reacting compounds of formula I and formula II or a salt thereof in the absence of a protic acid.
  • a salt of formula II it is most preferred that the salt of formula II is the N-acetyl-L-leucine salt. In such circumstances the N-acetyl-L-leucine salt is not to be understood as a protic acid.
  • protic acid present is generated from protons (1 ), (2), (3) and (4).
  • the process for preparing apremilast comprising reacting compounds of formula I and formula II or a salt thereof, wherein the only protic acid present is generated from protons (1), (2), (3) and (4) and wherein the solvent is an alkylacetamide solvent, that the reaction is conducted at a temperature of from 110°C to 120°C and the duration of the reaction is 1 to 5 hours. It is more preferred wherein the duration of the reaction is 3 hours.
  • the process for preparing apremilast comprising reacting compounds of formula I and formula II or a salt thereof, wherein the only protic acid present is generated from protons (1 ), (2), (3) and (4) and wherein the solvent is ⁇ ,/V-dimethylacetamide or N,N- dimethylformamide, that the reaction is conducted at a temperature of from 110°C to 120'C and the duration of the reaction is 1 to 5 hours. It is more preferred where the duration of the reaction is 3 hours and wherein the solvent is W,W-dimethylacetamide.
  • the process of the present invention is performed in one pot.
  • the term "one pot” should be understood as referring to a single operational step, i.e. where reagents are added consecutively into one pot, and no intermediate is isolated.
  • the process of the present invention provides a one pot synthesis, minimising both the requirement for multiple purification steps and for example the amount of solvent needed and used in multistep syntheses.
  • the process also reduces the operational complexity associated with chemical reactions conducted using multiple steps in multiple different reaction vessels.
  • Purification of apremilast is preferably simplified following the removal of the reaction solvent by, for example, reduced pressure evaporation or distillation. Purification of apremilast can be performed using methods known in the art. Compounds can be purified by, for example, normal phase liquid chromatography, reversed phase and normal phase high-performance liquid chromatography and recrystallisation or salt formation. Furthermore, the purity of apremilast can be analysed and measured using high-performance liquid chromatography or chiral high-performance liquid chromatography. Preferred solvents for HPLC analysis and purification are hkO/MeCN (water/acetonitrile).
  • HPLC analysis can be performed using a 100 x 2.1 mm Waters Acquity C18 BEH column, where detection is set at 230nm, and wherein elution is conducted using a hfeO/MeCN gradient (97/3 to 20/80) over a period of 15 minutes.
  • the apremilast obtained is crystallised from a mixture of acetone and ethanoi.
  • the apremilast obtained is crystallised from a mixture of acetone and ethanoi to afford pure apremilast. It is preferred that apremilast is dissolved in a mixture of acetone and ethanoi, at a temperature at which the mixture is boiling. Upon dissolution, the mixture is allowed to cool to ambient temperature (about 25°C or room temperature) and stirred for 3 to 6 hours.
  • apremilast is dissolved in a solution of boiling acetone, and following dissolution a solution of boiling ethanoi is added thereto, to form a mixture of boiling acetone and ethanoi.
  • the mixture is allowed to cool to ambient temperature (about 25°C or room temperature) and stirred for 3 to 6 hours.
  • This invention provides a process for preparing apremilast, comprising reacting compounds of formula I and formula II or a salt thereof where neither acetic nor formic acid are present. Accordingly, it can be seen that the present invention provides a one-pot process for providing apremilast, the process comprises a condensation reaction between an amino-substituted phthalic anhydride derivative and a primary amine where neither acetic nor formic acid are present.
  • Example 2 The residue obtained in Example 1 ⁇ 10 g was dissolved in a mixture of acetone (30 mL) and ethanol (60 mL) at boiling temperature and charcoal ⁇ 1 g) was added. The mixture was allowed to stir for 30 minutes at boiling temperature. The charcoal was filtered off and washed with a mixture of acetone ⁇ 5mL) and ethanol (10 mL). The mixture was allowed to cool to a designated temperature (A, B, C, D - see table below) and stirred for 3-6 hours. The solid obtained in each case was filtered under reduced pressure and the filter cake was washed with ethanol (2 x 20 mL).
  • Example 2 The residue obtained in Example 1 was dissolved in acetone (30 mL) at boiling temperature and charcoal (1 g) was added. The mixture was allowed to stir for 30 minutes at boiling temperature. The charcoal was filtered off and washed with acetone (5 mL). A solution of boiling ethanol (70 mL) was then added to the solution. The mixture was allowed to cooi to a designated temperature (A, B, C, D - see table below) and stirred for 3-6 hours. The solid obtained was filtered under reduced pressure and the filter cake was washed with ethanol (2 x 20 mL).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'aprémilast, consistant à faire réagir des composés de formule I et de formule II, ou un sel de ceux-ci, en l'absence d'acide acétique et d'acide formique.
EP16828991.6A 2015-12-17 2016-12-14 Procédé de préparation d'un agent pharmaceutique Withdrawn EP3390360A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15460122.3A EP3181549A1 (fr) 2015-12-17 2015-12-17 Procédé de préparation de l'apremilast
PCT/PL2016/000148 WO2017105263A1 (fr) 2015-12-17 2016-12-14 Procédé de préparation d'un agent pharmaceutique

Publications (1)

Publication Number Publication Date
EP3390360A1 true EP3390360A1 (fr) 2018-10-24

Family

ID=55174523

Family Applications (2)

Application Number Title Priority Date Filing Date
EP15460122.3A Withdrawn EP3181549A1 (fr) 2015-12-17 2015-12-17 Procédé de préparation de l'apremilast
EP16828991.6A Withdrawn EP3390360A1 (fr) 2015-12-17 2016-12-14 Procédé de préparation d'un agent pharmaceutique

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP15460122.3A Withdrawn EP3181549A1 (fr) 2015-12-17 2015-12-17 Procédé de préparation de l'apremilast

Country Status (2)

Country Link
EP (2) EP3181549A1 (fr)
WO (1) WO2017105263A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107698485A (zh) * 2017-11-23 2018-02-16 中山奕安泰医药科技有限公司 一种高纯度阿普斯特的精制制备工艺
CN110467557B (zh) * 2018-05-11 2021-02-26 北京大学 阿普斯特的三组分一锅煮合成法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6962940B2 (en) 2002-03-20 2005-11-08 Celgene Corporation (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
US20150290171A1 (en) * 2012-11-09 2015-10-15 Celgene Corporation Methods for the treatment of bone loss
CN104529869B (zh) * 2014-12-19 2017-06-13 苏州亚宝药物研发有限公司 一种 (s)‑2‑[1‑(3‑乙氧基‑4‑甲氧基苯基)‑2‑甲磺酰基乙基]‑4‑乙酰基氨基异吲哚啉‑1,3‑二酮异构体的制备方法
WO2016174685A1 (fr) * 2015-04-27 2016-11-03 Mylan Laboratories Limited Procédé de résolution énantiomérique d'intermédiaires d'aprémilast

Also Published As

Publication number Publication date
EP3181549A1 (fr) 2017-06-21
WO2017105263A1 (fr) 2017-06-22

Similar Documents

Publication Publication Date Title
JP3775796B2 (ja) 抗炎症活性及び／又は鎮痛活性を有する硝酸エステル類及びそれらの製造方法
JP5363312B2 (ja) ピロール誘導体のアトロプ異性体
EP2418200A1 (fr) Dérivés phtalimidiques de composés antiinflammatoires non stéroïdiens et/ou de modulateurs du tnf- , procédé pour leur obtention, compositions pharmaceutiques les contenant et leurs utilisations dans le traitement de maladies inflammatoires
EP2057139B1 (fr) Dérivés de sulfure d'hydrogène d'anti-inflammatoires non stéroïdiens
NO331775B1 (no) Modifisert Pictet-Spengler-reaksjon og produkt fremstilt ved denne
SU1156593A3 (ru) Способ получени производных бензамида или их кислотно-аддитивных солей,или оптических изомеров
BE1003848A3 (fr) Nouveaux derives de la thiouree, leur preparation et leur utilisation comme medicaments.
JPH02209848A (ja) ナフチルメチルアミン誘導体およびそれを有効成分とする抗真菌剤
EP3390360A1 (fr) Procédé de préparation d'un agent pharmaceutique
JP2014511881A (ja) 高純度塩酸ベニジピンの調製方法
RU2622105C2 (ru) Кристаллическая форма соединения, используемая в качестве антагониста минералокортикоидного рецептора, и способ ее получения
CN111018738A (zh) 丹皮酚衍生物、药物制剂、制备方法与应用
NO328064B1 (no) Ny fremgangsmate ved syntese av N-[(S)-1-karboksybutyl]-(S)-alaninestere og anvendelse i syntese av perindopril
Jiang et al. An expedient route for the practical preparation of optically active (−)-gossypol
CN115105503A (zh) 一种trpv1拮抗/cox抑制双靶点药物或其药学上可接受的盐、药物制剂和应用
TW201028377A (en) Atropisomers of (hydroxyalkyl) pyrrole derivatives
CN110981934B (zh) 一种阿加曲班水合物的合成方法
CA2856607C (fr) Formes cristallines du [(s)-1-carbamoyl-2-(phenylpyrimidin-2-ylamino)ethyl]amide de l'acide 2-(2-methylaminopyrimidin-4-yl)-1h-indole-5-carboxylique
CN101759665B (zh) 取代苯基哌嗪芳烷醇衍生物及其在制备镇痛药物中的应用
RU2740503C1 (ru) Производные 3-гидроксихиназолин-4(3Н)-она в качестве ингибиторов гистондеацетилазы и способ их получения
CH658786A5 (fr) Medicaments qui contiennent d'alpha-(n-pyrrolyl)-acides ou de leurs sels ou esters.
US11840517B2 (en) Lappaconitine derivative with analgesic activity, and preparation and application thereof
RU2779981C1 (ru) Гидроксамовые кислоты, производные 4-аминохиназолин-7-карбоновой кислоты как ингибиторы гистондеацетилазы и способ их получения
RU2744750C1 (ru) Способ получения гидроксамовых кислот, производных 2-арил-2,3-дигидрохиназолин-4(1Н)-онов
CN115433166B (zh) 一种选择性丁酰胆碱酯酶抑制剂及其制备方法和应用

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20180709

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20190723

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20200903