WO2017042839A1 - Nouveau sel d'eltrombopag et préparation de celui-ci - Google Patents

Nouveau sel d'eltrombopag et préparation de celui-ci Download PDF

Info

Publication number
WO2017042839A1
WO2017042839A1 PCT/IS2016/050013 IS2016050013W WO2017042839A1 WO 2017042839 A1 WO2017042839 A1 WO 2017042839A1 IS 2016050013 W IS2016050013 W IS 2016050013W WO 2017042839 A1 WO2017042839 A1 WO 2017042839A1
Authority
WO
WIPO (PCT)
Prior art keywords
eltrombopag
tromethamine salt
tromethamine
ray diffraction
crystalline
Prior art date
Application number
PCT/IS2016/050013
Other languages
English (en)
Inventor
Nasir Ali Shafakat ALI
Vijay Hariprasad SHARMA
Ashutosh Vijay Joshi
Parven Kumar Luthra
Original Assignee
Actavis Group Ptc Ehf.
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 Actavis Group Ptc Ehf. filed Critical Actavis Group Ptc Ehf.
Publication of WO2017042839A1 publication Critical patent/WO2017042839A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
    • C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the invention generally relates to a pharmaceutical compound, and more specifically an eltrombopag salt and the preparation thereof.
  • the present invention also relates to methods of treatment, in particular the treatment of thrombocytopenia.
  • Thrombocytopenia is a disorder in which there is an abnormally low amount of platelets.
  • Thrombopoietin has been shown to be the main humoral regulator in situations involving thrombocytopenia.
  • TPO was shown to increase platelet counts, increase platelet size, and increase isotope incorporation into platelets of recipient animals. Because platelets are necessary for blood clotting and when their numbers are low, a patient is at risk of death from catastrophic haemorrhage. TPO is thus considered to have potential useful applications in both the diagnosis and the treatment of various hematological disorders, for example, diseases primarily due to platelet defects.
  • Eltrombopag also known as (Z)-3'-(2-(l-(3,4-dimethylphenyl)-3-methyl-5-oxo-lH-pyrazol- 4(5H)-ylidene)hydrazinyl)-2'-hydroxybiphenyl-3-carboxylic acid, is a compound having the following chemical structure:
  • TPO thrombopoitin
  • Eltrombopag is marketed under the trade name Promacta® by GlaxoSmithKline and Ligand Pharmaceuticals as a bisethanolamine salt of the following chemical structure for the treatment of conditions leading to thrombocytopenia.
  • Eltrombopag is the first FDA approved small molecule drug in the hematopoietic growth factor field for the treatment of thrombocytopenia. Instead of competing with endogenous thrombopoietin (TPO) for the same binding site of TPO receptor, eltrombopag activates the TPO receptor interacts with the transmembrane domain of the TPO receptor, leading to increased platelet production by initiating signalling cascades that induce proliferation and differentiation of megakaryocytes from bone marrow progenitor cells.
  • TPO endogenous thrombopoietin
  • Eltrombopag has been disclosed in U.S. Patent Nos. 7,332,481 and 7,160,870, as well as WO 01/89457; and in EP Patent No. 1,294,378.
  • Eltrombopag bisethanolamine salt and eltrombopag olamine salt has been disclosed in WO 03/098992 and U.S. Patent No. 8,052,994, respectively.
  • the present invention provides a novel crystalline form of eltrombopag:
  • the present invention provides eltrombopag tromethamine salt and processes for preparing the novel salt form.
  • Tromethamine (2-Amino-2-hydroxymethyl-propane-l,3-diol) is an organic amine proton acceptor, generally used as an alkalizer or emulsifying agent, biological buffer, as well as in the synthesis of surface-active agents and pharmaceuticals. It has been found that crystalline eltrombopag tromethamine salt as described herein has advantageous properties.
  • eltrombopag tromethamine salt has HPLC purity more than 99.5%, it is non-hygroscopic, has a low content of residual solvent and is stable at ambient temperature for at least up to 9 months.
  • Novel eltrombopag salt form according to the invention has been characterized by powder X- ray diffraction (XRD) as shown in Figure 1 and Table 2 herein.
  • Table 1 shows the main peaks as 2-theta values:
  • the novel salt form according to the present invention can be characterized by at least one, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or all 10 of X-ray diffraction peaks with 2-theta values of about 8.49°, about 12.5°, about 15.9°, about 18.09°, about 20.14°, about 20.82°, about 21.7°, about 22.48°, about 25.2° and/or about 26.12°.
  • novel eltrombopag tromethamine according to the invention can also be characterized by at least one, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or all of the X-ray diffraction peaks having 2-theta values as indicated in Table 2 and/or as shown in Figure 1.
  • the term "about” refers to a range of values + 10% of a specified value.
  • the phrase “about 95” includes ⁇ 10% of 95 and 95 as such. It should be appreciated and is well known to the skilled person that the powder x-ray diffraction pattern can have 2- theta values that show a slight deviation from the above recited values.
  • eltrombopag tromethamine salt obtained or obtainable by the present invention can be characterized by at least one, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or all of X-ray diffraction peaks with 2-theta values 8.49+/- 0.1°, 12.5+/- 0.1°, 15.9+/- 0.1°, 18.09+/- 0.1°, 20.14+/- 0. ⁇ , 20.82+/- 0. ⁇ , 21.7+/- 0. ⁇ , 22.48+/- 0. ⁇ , 25.2+/- 0. ⁇ and/or 26.12+/- ⁇ . ⁇ .
  • Eltrombopag tromethamine salt obtained or obtainable by the present invention can be additionally characterized by at least one of X-ray diffraction peaks with 2-theta values 4.54+/- 0. ⁇ , 5.64+/- 0. ⁇ , 10.00+/- 0. ⁇ , 11.51+/- 0. ⁇ , 14.12+/- 0. ⁇ , 16.70+/- 0. ⁇ , 18.83+/- 0. ⁇ , 24.04+/- 0. ⁇ , 27.82+/- 0. ⁇ , 30.22+/- 0. ⁇ , 33.90+/- 0. ⁇ , 38.40+/- 0. ⁇ or 42.01+/- ⁇ . ⁇ .
  • crystalline eltrombopag tromethamine salt can be characterized by the X- ray diffraction peaks with 2 theta values of 8.49+/- 0. ⁇ , 12.5+/- 0. ⁇ , 15.9+/- 0. ⁇ , 18.09+/- 0. ⁇ , 20.14+/- 0. ⁇ , 20.82+/- 0. ⁇ , 21.7+/- 0. ⁇ , 22.48+/- 0. ⁇ , 25.2+/- 0. ⁇ and 26.12+/- 0.1°.
  • Eltrombopag tromethamine according to the invention can also be characterized by the X-ray diffraction peaks with 2 theta values of 8.49°, 12.5°, 15.9°, 18.09°, 20.14°, 20.82°, 21.7°, 22.48°, 25.2° and 26.12°.
  • Eltrombopag tromethamine may optionally also have an IR spectrum substantially similar to an IR spectrum as depicted in Fig. 2, and/or a differential scanning calorimetric (DSC) thermogram with an endothermic peak at about 136.9+/-3°C or a differential scanning calorimetric thermogram as depicted in Fig. 3.
  • substantially similar means an analytical spectrum, such as XRD pattern, 1H- MR spectrum, FT-IR spectrum, Raman spectrum, TGA thermogram, DSC thermogram etc., which resembles the reference spectrum to a great degree in both the peak locations and their intensity.
  • the eltrombopag tromethamine according to the invention is characterized by (i) at least one of the X-ray diffraction peaks with 2 theta values of 8.49+/- 0.1°, 12.5+/- 0.1°, 15.9+/- 0.1°, 18.09+/- 0.1°, 20.14+/- 0.1°, 20.82+/- 0.1°, 21.7+/- 0.1°, 22.48+/- 0.1°, 25.2+/- 0.1° and/or 26.12+/- 0.1°; and (ii) a differential scanning calorimetric thermogram with an endothermic peak at about 136.9+/-3°C.
  • eltrombopag tromethamine according to the invention is characterized by (i) at least one of the X-ray diffraction peaks with 2 theta values of 8.49°, 12.5°, 15.9°, 18.09°, 20.14°, 20.82°, 21.7°, 22.48°, 25.2° and 26.12°; and (ii) a differential scanning calorimetric thermogram with an endothermic peak at about 136.9°C.
  • the crystalline eltrombopag tromethamine compound of the invention can be synthesized from readily available starting materials, such as eltrombopag as described below in the Examples.
  • room temperature can be taken to mean a temperature within the range commonly associated with the ambient temperature in a laboratory environment, and will typically be in the range of about 25°C to about 50°C. In other instances, reactions or crystallizations were conducted at room temperature and the temperature was actually measured and recorded.
  • the starting material can be readily prepared from commercially available eltrombopag or other starting materials and reagents using the procedures that are well known in the art, for example as described in U.S. Patent Nos. 7,332,481 and 7,160,870 or examples provided herein.
  • the crystallization is conducted in a suitable solvent, including tetrahydrofuran, ethyl acetate, acetone, methyl ethyl ketone, dichloromethane, chloroform, dioxane, diethyl ether, diary 1 ether and the like, or mixtures thereof, by an addition of tromethamine.
  • Crystallization can be done by commonly used techniques such as solvent evaporation; slow cooling of the solution, solvent/ non-solvent, diffusion, vapour diffusion and sublimation.
  • the crystalline compound can be isolated from the reaction mixture by any conventional means such as precipitation, concentration, centrifugation and the like.
  • tromethamine can be added to the solution of eltrombopag in tetrahydrofuran to form crystalline, which is then filtered, washed and dried.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising eltrombopag tromethamine and optionally a pharmaceutically acceptable excipient.
  • pharmaceutically acceptable refers to a material that is not biologically or otherwise unacceptable when used in the invention.
  • pharmaceutically acceptable excipient refers to a material that can be incorporated into a composition and administered to a patient without causing unacceptable biological effects or interacting in an unacceptable manner with other components of the composition.
  • Such pharmaceutically acceptable materials typically have met the required standards of toxicological and manufacturing testing, and include those materials identified as suitable inactive ingredients by the U.S. Food and Drug Administration.
  • the present invention also provides a method of treating thrombocytopenia comprising administering a therapeutically effective amount of eltrombopag tromethamine, preferably eltrombopag tromethamine characterized in the present application, such as eltrombopag tromethamine salt characterized by the X-ray diffraction peaks with 2 theta values of 8.49+/- 0.1°, 12.5+/- 0.1°, 15.9+/- 0.1°, 18.09+/- 0.1°, 20.14+/- 0. ⁇ , 20.82+/- 0. ⁇ , 21.7+/- 0. ⁇ , 22.48+/- 0. ⁇ , 25.2+/- 0.
  • eltrombopag tromethamine preferably eltrombopag tromethamine characterized in the present application, such as eltrombopag tromethamine salt characterized by the X-ray diffraction peaks with 2 theta values
  • Eltrombopag tromethamine for the treatment of thrombocytopenia may optionally also have an IR spectrum substantially similar to an IR spectrum as depicted in Fig. 2, and/or a differential scanning calorimetric thermogram with an endothermic peak at about 136.9+/-3°C or a differential scanning calorimetric thermogram as depicted in Fig. 3.
  • the term "therapeutically effective amount” means an amount sufficient to effect treatment when administered to a patient in need thereof, i.e., the amount of drug needed to obtain the desired therapeutic effect.
  • an "effective amount" according to the present invention may be the amount needed to activate TPO receptor.
  • treating means the treating or treatment of a disease or medical condition in a patient, such as a mammal (particularly a human), that includes one or more of the following: (a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient; (b) ameliorating the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in a patient; (c) suppressing the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in a patient; or (d) alleviating the symptoms of the disease or medical condition in a patient.
  • the patient is with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
  • ITP chronic immune
  • patient is intended to include those mammals, such as humans, that are in need of treatment or disease prevention, that are presently being treated for disease prevention or treatment of a specific disease or medical condition, as well as test subjects in which compounds of the invention are being evaluated or being used in an assay, for example an animal model. All other terms used herein are intended to have their ordinary meaning as understood by those of ordinary skill in the art to which they pertain.
  • Figure 1 shows structural analysis of eltrombopag tromethamine by X-ray diffraction (XRD), as obtained according to the invention.
  • Figure 2 shows an Infrared Spectrum (IR) of eltrombopag tromethamine, as obtained by according to the invention.
  • IR Infrared Spectrum
  • Figure 3 shows results of Differential Scanning Calorimetry (DSC) of eltrombopag tromethamine, as obtained according to the invention.
  • Figure 2 shows an Infrared Spectrum (IR) of the eltrombopag tromethamine, as obtained by the above process.
  • Figure 3 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l- oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t- butyl amine salt, as obtained by the above process.
  • DSC Differential Scanning Calorimetry

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Pharmacology & Pharmacy (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 l'obtention et la caractérisation d'un sel de trométhamine d'eltrombopag. Des compositions pharmaceutiques comprenant cette forme de sel de trométhamine d'elthrombopag peuvent être utilisées pour le traitement de maladies, y compris une thrombocytopénie chez des patients présentant un purpura thrombopénique immunitaire chronique (idiopathique) (ITP) et pour qui la réponse à des corticostéroïdes, des immunoglobulines ou à une splénectomie s'est avérée insuffisante. L'invention concerne également un procédé de préparation de la forme de sel de trométhamine d'elthrombopag.
PCT/IS2016/050013 2015-09-08 2016-09-08 Nouveau sel d'eltrombopag et préparation de celui-ci WO2017042839A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2813/DEL/2015 2015-09-08
IN2813DE2015 2015-09-08

Publications (1)

Publication Number Publication Date
WO2017042839A1 true WO2017042839A1 (fr) 2017-03-16

Family

ID=57124071

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IS2016/050013 WO2017042839A1 (fr) 2015-09-08 2016-09-08 Nouveau sel d'eltrombopag et préparation de celui-ci

Country Status (1)

Country Link
WO (1) WO2017042839A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019071111A1 (fr) 2017-10-06 2019-04-11 Teva Pharmaceuticals Usa, Inc. Formes à l'état solide d'eltrombopag choline
WO2022039701A1 (fr) * 2020-08-21 2022-02-24 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Composition orale solide comprenant de l'eltrombopag choline

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001089457A2 (fr) 2000-05-25 2001-11-29 Smithkline Beecham Corporation Mimiques de thrombopoietine
WO2003098992A2 (fr) 2002-05-22 2003-12-04 Smithkline Beecham Corporation Acide 3'-[(2z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4h-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylique bis-(monoethanolamine)
US8052994B2 (en) 2007-05-03 2011-11-08 Glaxosmithkline Llc 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine)
EP2441457A1 (fr) * 2009-06-11 2012-04-18 Jiangsu Hengrui Medicine Co., Ltd. Sels de dérivés azoïques de pyrazolone substituée par un substituant bicyclique, leur procédé de préparation et leur utilisation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001089457A2 (fr) 2000-05-25 2001-11-29 Smithkline Beecham Corporation Mimiques de thrombopoietine
EP1294378A2 (fr) 2000-05-25 2003-03-26 Smithkline Beecham Corporation Mimiques de thrombopoietine
US7160870B2 (en) 2000-05-25 2007-01-09 Smithkline Beecham Corporation Thrombopoietin mimetics
US7332481B2 (en) 2000-05-25 2008-02-19 Smithkline Beecham Corporation Thrombopoietin mimetics
WO2003098992A2 (fr) 2002-05-22 2003-12-04 Smithkline Beecham Corporation Acide 3'-[(2z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4h-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylique bis-(monoethanolamine)
US8052994B2 (en) 2007-05-03 2011-11-08 Glaxosmithkline Llc 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine)
EP2441457A1 (fr) * 2009-06-11 2012-04-18 Jiangsu Hengrui Medicine Co., Ltd. Sels de dérivés azoïques de pyrazolone substituée par un substituant bicyclique, leur procédé de préparation et leur utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"SALTS AND POLYMORPHS OF (Z)-3'-(2-(1-(3,4-DIMETHYLPHENYL)-3- METHYL-5-OXO-1H-PYRAZOL-4(5H)-YLIDENE)HYDRAZINYL)-2'- HYDROXYBIPHENYL-3-CARBOXYLIC ACID", IP.COM JOURNAL, IP.COM INC., WEST HENRIETTA, NY, US, 2 March 2011 (2011-03-02), XP013144170, ISSN: 1533-0001 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019071111A1 (fr) 2017-10-06 2019-04-11 Teva Pharmaceuticals Usa, Inc. Formes à l'état solide d'eltrombopag choline
US11072586B2 (en) 2017-10-06 2021-07-27 Assia Chemical Industries Ltd. Solid state forms of eltrombopag choline
WO2022039701A1 (fr) * 2020-08-21 2022-02-24 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Composition orale solide comprenant de l'eltrombopag choline

Similar Documents

Publication Publication Date Title
JP6946194B2 (ja) キナーゼを調節する化合物の固体形態
EP2244712B1 (fr) Études in vivo de formes cristallines de méloxicam
AU2014351486B2 (en) Crystalline forms of lesinurad and its sodium salt
JP2022553479A (ja) （ｓ）－２－（（（ｓ）－６，８－ジフルオロ－１，２，３，４－テトラヒドロナフタレン－２－イル）アミノ）－ｎ－（１－（２－メチル－１－（ネオペンチルアミノ）プロパン－２－イル）－１ｈ－イミダゾール－４－イル）ペンタンアミドの固体状態形態およびその使用
WO2011047767A1 (fr) Nouvelles formes polymorphes de sel mésylate de (s)-2-[-4-(3-fluorobenzyloxy)-benzylamino]-propionamide et leurs procédés de fabrication
WO2017042839A1 (fr) Nouveau sel d'eltrombopag et préparation de celui-ci
EP2496079A1 (fr) Nouvelles formes cristallines du (1s,2r)-2-(aminométhyl)-n,n-diéthyl-1-phénylcyclopropanecarboxamide
CN117843645A (zh) 一种pde9抑制剂的一水合物和结晶形态
US20120165260A2 (en) Crystalline ezatiostat hydrochloride ansolvate
CN102234265A (zh) 兰索拉唑化合物
JP2020500936A (ja) ピリジノイルピペリジン５−ｈｔ１ｆアゴニストに関する組成物および方法
US20230151015A1 (en) The crystalline forms of a compound
CN104321323B (zh) 碳环核苷及其医药用途和组合物
CZ20011417A3 (cs) Sklovitá forma 8-(3-(N-((E)-3-(6-acetamidopyridin-3-yl)-akryloylglycyl)-N-methylamino)-2,6-dichlorbenzyloxy)-2-methylchinolinu
EP2576591A2 (fr) Formulation d'ezatiostat en comprimés
CN110028497A (zh) 一种血小板生成素模拟物的乙醇胺盐的结晶形式及制备方法
JP7322151B2 (ja) 医薬化合物、その製造方法、及び薬剤としての使用
WO2021009509A1 (fr) Monotosylate d'umbralisib amorphe
CN102245606A (zh) 新化合物
WO2019246479A1 (fr) Forme de ponatinib
JP2015027983A (ja) 結晶及び該結晶を含有してなる医薬製剤
CN110950835A (zh) 稳定的鲁格列净化合物
ES2717254T3 (es) Formas en estado sólido de sofosbuvir
WO2021209477A1 (fr) Formes cristallines de 4-[(7-chloro-2-méthoxybenzo[b][1,5]naphtyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylméthyl)phénol et leurs sels
JP2024038059A (ja) ４－フェニルチアゾール誘導体の結晶形およびその調製方法

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: 16779191

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: 16779191

Country of ref document: EP

Kind code of ref document: A1