WO2014007326A1 - Procédé de préparation de mésylate de nafamostat - Google Patents

Procédé de préparation de mésylate de nafamostat Download PDF

Info

Publication number
WO2014007326A1
WO2014007326A1 PCT/JP2013/068360 JP2013068360W WO2014007326A1 WO 2014007326 A1 WO2014007326 A1 WO 2014007326A1 JP 2013068360 W JP2013068360 W JP 2013068360W WO 2014007326 A1 WO2014007326 A1 WO 2014007326A1
Authority
WO
WIPO (PCT)
Prior art keywords
nafamostat
salt
mesylate
solvent
producing
Prior art date
Application number
PCT/JP2013/068360
Other languages
English (en)
Japanese (ja)
Inventor
宣博 山中
弘明 吉崎
俊博 松沢
Original Assignee
味の素株式会社
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 味の素株式会社 filed Critical 味の素株式会社
Priority to JP2014523782A priority Critical patent/JP6252991B2/ja
Publication of WO2014007326A1 publication Critical patent/WO2014007326A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/06—Purification or separation of guanidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a method for producing nafamostat mesylate.
  • Nafamostat mesylate is an effective compound for preventing coagulation of perfused blood during extracorporeal circulation in patients with pancreatic diseases such as pancreatitis, generalized intravascular blood coagulation, hemorrhagic lesions or bleeding tendency.
  • a sodium bicarbonate aqueous solution was added to a solution containing nafamostat to isolate nafamostat bicarbonate as a solid, and this nafamostat bicarbonate was mixed with methane.
  • Patent Documents 1 and 2 There is known a production method through a step of adding sulfonic acid to induce formation into nafamostat mesylate.
  • Non-patent Document 1 a method of converting to nafamostat mesylate by adding 10 equivalents of sodium methanesulfonate to nafamostat hydrochloride is also known (Non-patent Document 1).
  • Non-Patent Document 1 Since degradation products such as acid and 6-amidino-2-naphthol are known to occur (Pharmaceutical Journal 105 (5), 512-516 (1985)), the problem of degradation of the purity of nafamostat due to degradation There was also. On the other hand, the method disclosed in Non-Patent Document 1 has a problem that quality deteriorates because sodium methanesulfonate is mixed. Further, it is known that crystallization of nafamostat mesylate from water alone results in a gel-like lump, which makes it difficult to separate nafamostat mesylate by filtration (Japanese Patent No. 3796481, JP2012-87099). . Therefore, the method disclosed in Non-Patent Document 1 is not suitable for mass production.
  • the present invention has been made in view of the above-mentioned problems, and nafamostat mesylate without passing through nafamostat bicarbonate having poor filterability and stability and without being mixed with sodium mesylate.
  • An object of the present invention is to provide a method of producing
  • the present inventor has intensively studied a method for producing nafamostat mesylate, and as a result, nafamostat bicarbonate and nafamostat salt other than nafamostat mesylate are used as anion exchange resins.
  • anion exchange resin whose anion is mesylate ion in the presence of a solvent
  • nafamostat mesylate without passing through nafamostat bicarbonate and without being mixed with sodium mesylate Has been found to be able to be produced, and the present invention has been completed. That is, the present invention has the following configuration.
  • nafamostat salt other than nafamostat bicarbonate and nafamostat mesylate in the presence of a solvent
  • Salt exchange to mostat mesylate (3) a step of crystallizing the nafamostat mesylate obtained in step (2),
  • a process for producing nafamostat mesylate comprising:
  • nafamostat mesylate can be produced without going through nafamostat bicarbonate and without mixing sodium mesylate. Therefore, a highly pure nafamostat mesylate can be produced in a shorter time than before. It is also suitable for mass production. Moreover, when manufactured by a batch method, in addition to the above effects, the production amount of nafamostat mesilic acid per batch can be greatly increased, and therefore, it is more suitable for mass production. Moreover, since the amount of the solvent used in the anion exchange step and the amount of the solvent discarded after use can be greatly reduced, the influence on the environment can be kept low.
  • Nafamostat mesylate is the generic name for 6′-amidino-2′-naphthyl 4-guanidinobenzoate dimethanesulfonate, represented by the following formula:
  • the method for producing nafamostat mesylate of the present invention comprises (1) a step of preparing an anion exchange resin in which the anion of the anion exchange resin is a mesylate ion, and (2) an anion obtained in step (1)
  • an anion exchange resin in which the anion of the anion exchange resin is a mesylate ion is used to salt-exchange nafamostat salt other than nafamostat bicarbonate and nafamostat mesylate to nafamostat mesylate. Used for.
  • an anion exchange resin in which the anion of the anion exchange resin is a mesylate ion is used to salt-exchange nafamostat salt other than nafamostat bicarbonate and nafamostat mesylate to nafamostat mesylate.
  • mesylic acid methanesulfonic acid
  • Examples of basic ion exchange resins include strong basic anion exchange resins having quaternary ammonium groups and weak basic anion exchange resins having primary to tertiary amino groups as functional groups.
  • a strongly basic anion exchange resin is particularly preferable, and a reaction product of chloromethylated product and trimethylamine of copolymerization of styrenedivinylbenzene is more preferable.
  • the replacement may be performed by a conventionally used method.
  • mesylic acid methanesulfonic acid
  • it can be substituted by a method such as adding methanesulfonic acid to a strong ionic exchange resin substituted with hydroxide ions.
  • an anion exchange resin in which the anion of the anion exchange resin is a mesylate ion hereinafter sometimes referred to as a mesylated anion exchange resin
  • nafamostat bicarbonate nafamostat mesylate
  • nafamostat salt other than the salt is contacted in the presence of a solvent to exchange the nafamostat salt with nafamostat mesylate.
  • This salt exchange to nafamostat mesylate may be carried out by any method that can be assumed by those skilled in the art, for example, nafamostat salts other than nafamostat bicarbonate and nafamostat mesylate, and mesylated anion.
  • nafamostat salts other than nafamostat bicarbonate and nafamostat mesylate and mesylated anion.
  • Use a batch method in which an ion exchange resin is mixed in a reaction vessel in the presence of a solvent or a column method in which a solution containing nafamostat salt is passed through a column / resin tower packed with an anion exchange resin substituted with mesylate ions. Salt exchange.
  • salt exchange is performed by mixing a mesylated anion exchange resin and a nafamostat salt other than nafamostat bicarbonate and nafamostat mesylate in the presence of a solvent.
  • the batch method is not particularly limited as long as a mesyl-oxidized anion exchange resin is used.
  • Salt exchange can be performed by mixing using a solvent such as 50 vol% acetone aqueous solution.
  • Nafamostat salt concentration The molecular weight of nafamostat is 347.37, the molecular weight of nafamostat hydrochloride is 420.29, and the molecular weight of nafamostat mesylate is 539.58. Even though the amount of nafamostat molecule itself is the same, The mass (concentration) of nafamostat salt contained in the solution changes. Therefore, the Nafamostat salt concentration is defined as follows as a unified index.
  • Nafamostat equivalent concentration of nafamostat salt When all the nafamostat salt dissolved in the solution containing the nafamostat salt and the solvent (the solution containing the nafamostat salt) is replaced with nafamostat (molecular weight: 347.37), the solution is dissolved in the solution. The ratio (% by mass) of the nafamostat.
  • the concentration of the nafamostat salt in the solution containing the nafamostat salt is preferably 3% by mass to 10% by mass, more preferably 4% by mass to 9% by mass, and further preferably 5% by mass to 8% by mass. .
  • nafamostat salts other than nafamostat mesylate have low solubility in water and solvents such as N, N-dimethylformamide (at most about 0.1 to 2% by mass), and the nafamostat salt is dissolved in the solvent. This requires a large amount of solvent.
  • the salt exchange by the batch method is preferably performed with stirring under a temperature condition within a range of ⁇ 10 ° C. to 45 ° C., more preferably 0 ° C. to 40 ° C., and even more preferably 10 ° C. to 35 ° C.
  • a temperature condition within a range of ⁇ 10 ° C. to 45 ° C., more preferably 0 ° C. to 40 ° C., and even more preferably 10 ° C. to 35 ° C.
  • the stirring time in the batch method is not particularly limited as long as salt exchange is performed, and may be appropriately determined, but is preferably 1 minute to 1 week, more preferably 10 minutes to 1 day, and further preferably 30 minutes to 1 hour 30 minutes. It is. When the stirring time is within the above range, ion exchange is facilitated.
  • the salt exchange step using an anion exchange resin may be performed using a column method in addition to the batch method.
  • salt exchange is carried out by passing a solution containing mesilnafamostat salt other than nafamostat bicarbonate and nafamostat mesylate through a column / resin tower packed with mesylated anion exchange resin.
  • the column method is not particularly limited as long as a column filled with mesyl-oxidized anion exchange resin is used.
  • a glass column is filled with mesyl-oxidized strong basic ion-exchange resin and washed with a solvent such as 50 vol% acetone aqueous solution. And it can carry out by letting the solution which melt
  • the salt exchange using the anion exchange resin may be performed only once, but is preferably repeated twice or more, more preferably three or more times.
  • salt exchange can be repeated 1 to 10 times, preferably 2 to 8 times, more preferably 3 to 6 times.
  • the ratio (mass%) of nafamostat mesylic acid in the total nafamostat salt contained after the salt exchange can be increased.
  • the salt exchange is repeated twice or more, either the batch method or the column method may be used, or a combination of these may be used.
  • at least the first salt exchange is performed by a batch method. More preferably, all salt exchange is performed by a batch method.
  • a large amount of nafamostat salt can be dissolved in the solution, so that nafamostat mesylate can be obtained efficiently.
  • the amount of solvent used during salt exchange and the amount of solvent discarded after use can be reduced.
  • the form of the salt of nafamostat other than nafamostat bicarbonate and nafamostat mesylate used in the production method of the present invention is preferably a chemically acceptable salt of a strong acid or weak acid, more preferably a strong acid salt. is there.
  • strong acid salts include hydrochloride, bromate, iodate, paratoluenesulfonate, and benzenesulfonate. Among these, hydrochloride (dihydrochloride) is preferable.
  • Each of the above nafamostat salts may be a commercially available salt or may be produced by synthesis.
  • nafamostat salt in the nafamostat salt-containing solution is preferably 0.5% by mass to 10% by mass.
  • concentration of nafamostat salt in the nafamostat salt-containing solution is preferably 0.5% by mass to 10% by mass.
  • the batch method is used, as described above, it is preferably 3% by mass to 10% by mass, more preferably 4% by mass to 9% by mass, and still more preferably 5% by mass to 8% by mass.
  • the pH of the solution containing nafamostat bicarbonate other than nafamostat bicarbonate and nafamostat mesylate used in the salt exchange step is preferably in the range of 1 to 5, more preferably 1 to 3. Even more preferred is 5-2.5. Most preferably it is about pH2.
  • the pH can be adjusted by adding an acid or a base to the solution.
  • the pH is adjusted by adding acid, more preferably mesylic acid (methanesulfonic acid) to the solution.
  • the solvent used in the salt exchange step is preferably water or a mixed solvent of a water-soluble solvent and water. More preferred is a mixed solvent of a water-soluble solvent and water.
  • the water-soluble solvent include acetone, tetrahydrofuran (THF), 2-propanol, acetonitrile, and 2-butanol. Among these, acetone and THF are preferable. That is, the mixed solvent of the water-soluble solvent and water is preferably a mixed solvent of acetone and water or a mixed solvent of THF and water.
  • the mixing ratio of the water-soluble solvent and water is preferably 1: 9 to 9: 1, more preferably 3: 7 to 7: 3, still more preferably Is 4: 6 to 6: 4 (volume ratio). If it is in the said range, the amount of solvent required for melt
  • the amount of mesylated anion exchange resin used in the batch process is preferably 2 to 20 equivalents, more preferably 2.3 to nafamostat salts other than nafamostat bicarbonate and nafamostat mesylate. Equivalent to 16 equivalents, more preferably 2.3 to 13 equivalents.
  • nafamostat mesylate is crystallized from a solution containing nafamostat mesylate obtained through the salt exchange step.
  • the crystallization step may be performed using the solution containing nafamostat mesylate obtained in the salt exchange step as it is, or may be performed after concentrating the solution under reduced pressure.
  • nafamostat mesylate there is no particular limitation on the crystallization method of nafamostat mesylate, and it is possible to crystallize nafamostat mesylate using a generally known crystallization apparatus and method.
  • a water-soluble solvent or a mixed solution of water and a water-soluble solvent is added to a solution containing nafamostat mesylate, and the crystals are precipitated by adding nafamostat mesylate as a seed crystal and stirring.
  • nafamostat mesylate By separating and drying the crystals thus obtained, a highly pure nafamostat mesylate can be obtained.
  • water-soluble solvent used in this case examples include THF, acetone, acetonitrile, 2-butanol, and 2-propanol.
  • THF is preferably used.
  • the content ratio after adding a mixture of water and a water-soluble solvent to a solution containing nafamostat mesylate is preferably 1: 1 to 1:50, and preferably 1: 3 to 1:15. More preferably, it is more preferably 1: 8 (water: water-soluble solvent (volume ratio)).
  • the crude nafamostat mesylate can be crystallized by dissolving in water at high temperature and cooling (see, for example, Non-Patent Document 1, JP-A 2012-87099, etc.). be able to.).
  • Example 1 ⁇ Column method> A glass column (inner diameter 0.8-0.9 cm, height 6 cm) was packed with 29.26 g of strong ionic exchange resin substituted with hydroxide ions (2.3 equivalents relative to the following Nafamostat hydrochloride). After washing with water, the solution was methanesulfonated through a solution obtained by diluting 18.5 ml of methanesulfonic acid with 288 ml of water, and washed with 160 ml of 50 vol% acetone aqueous solution.
  • nafamostat hydrochloride net amount 8.0 g, HPLC purity: 99.8%
  • the pH was adjusted to 2.0 by adding 3.8 ml of 0 mol / L methanesulfonic acid aqueous solution.
  • the nafamostat solution was passed through the column and washed with 160 ml of 50 vol% acetone aqueous solution.
  • Example 2 ⁇ Batch method> (Methanesulfonated resin preparation) After adding 220 ml of water to 133.14 g of strong basic ion exchange resin substituted with hydroxide ions (12 equivalents to the following nafamostat hydrochloride), 14.3 ml of methanesulfonic acid was added dropwise at 20 ° C. And stirred at 20 ° C. for 1 hour and 10 minutes. This resin was separated and washed, then suspended in 213 ml of 50 vol% acetone aqueous solution and stirred at 20 ° C. for 20 minutes. This resin was separated and washed to obtain 124.50 g of methanesulfonated resin.
  • Example 3 ⁇ Batch method> (Methanesulfonated resin preparation) After adding 157 ml of water to 94.36 g of strongly basic ion exchange resin substituted with hydroxide ions (12 equivalents to the following nafamostat hydrochloride), 15.09 g of methanesulfonic acid was added dropwise at 25 ° C. , And stirred at 25 ° C. for 1 hour or longer. This resin was separated and washed, then suspended in 151 ml of 50 vol% THF aqueous solution and stirred at 25 ° C. for 10 minutes. This resin was separated and washed to obtain 87.38 g of methanesulfonated resin.
  • the ion exchange resin was separated by filtration, and the resin was washed with 40 ml of 50 vol% THF aqueous solution.
  • To the obtained filtrate 30.19 g of methane sulfonated resin was added. After this suspension was stirred at 25 ° C. for 1 hour or longer, the ion exchange resin was separated, and the resin was washed with 40 ml of 50 vol% THF aqueous solution. This process was repeated once more, and 140.27 g of the obtained filtrate was concentrated under reduced pressure to 23.3 g. After the completion of concentration, 3 ml of water and 20 ml of THF were added and cooled to 8 ° C.
  • nafamostat mesylate After adding 0.05 g of nafamostat mesylate as a seed crystal to the cooled solution, the solution was stirred for 30 minutes, and further 200 ml of THF was added over 2.5 hours. After stirring for 3 hours, the precipitated crystals were filtered and dried with a Kiriyama funnel having an inner diameter of 40 mm over 30 minutes to obtain 6.03 g of nafamostat mesylate (HPLC purity: 99.9%, residual chloride ion: 0 .018%).
  • the method of the present invention compared with the methods of Comparative Examples 1 and 2, the filtration time was short, and the purity of the obtained nafamostat mesylate was very high (Examples 1 to 3). Furthermore, when the batch method was used, the amount of solvent required to dissolve the nafamostat salt other than nafamostat bicarbonate and nafamostat mesylate could be greatly reduced (Example 2). ⁇ 3). Therefore, the method for producing nafamostat mesylate of the present invention is superior to the conventional method, and is suitable for mass production of nafamostat.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de mésylate de nafamostat sans passer par le bicarbonate de nafamostat tout en évitant l'inclusion de mésylate de sodium. Le procédé de préparation de mésylate de nafamostat comprend (1) une étape dans laquelle une résine échangeuse d'anions, l'anion étant un ion d'acide mésylique, est préparée, (2) une étape dans laquelle la résine échangeuse d'anions obtenue dans l'étape (1) est amenée en contact avec un sel de nafamostat qui n'est ni un bicarbonate nafamostat ni un mésylate de nafamostat, en présence d'un solvant en vue de convertir ainsi le sel de nafamostat en mésylate de nafamostat par échange de sel et (3) une étape dans laquelle le mésylate de nafamostat obtenu dans l'étape (2) est cristallisé.
PCT/JP2013/068360 2012-07-04 2013-07-04 Procédé de préparation de mésylate de nafamostat WO2014007326A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2014523782A JP6252991B2 (ja) 2012-07-04 2013-07-04 ナファモスタットメシル酸塩の製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2012-150686 2012-07-04
JP2012150686 2012-07-04

Publications (1)

Publication Number Publication Date
WO2014007326A1 true WO2014007326A1 (fr) 2014-01-09

Family

ID=49882077

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2013/068360 WO2014007326A1 (fr) 2012-07-04 2013-07-04 Procédé de préparation de mésylate de nafamostat

Country Status (2)

Country Link
JP (1) JP6252991B2 (fr)
WO (1) WO2014007326A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113999145A (zh) * 2021-11-12 2022-02-01 开封明仁药业有限公司 一种甲磺酸萘莫司他的合成方法
JP2022109243A (ja) * 2021-01-14 2022-07-27 デボン エルエス カンパニー，リミテッド メシル酸ナファモスタットの共結晶多形及びその製造方法
WO2023144830A1 (fr) 2022-01-30 2023-08-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Inhibiteurs de la protéine zika m utilisés en tant qu'agents anti-virus zika

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0672981A (ja) * 1992-06-01 1994-03-15 Biogal Gyogyszergyar 高純度デフェロキサミン塩の製造法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5753454A (en) * 1980-09-16 1982-03-30 Torii Yakuhin Kk Guanidinobenzoate and anticomplementary agent
JPS6133173A (ja) * 1984-07-25 1986-02-17 Torii Yakuhin Kk アミジン化合物
JPS61286361A (ja) * 1985-06-14 1986-12-16 Torii Yakuhin Kk アミジン誘導体
JP5649909B2 (ja) * 2010-10-21 2015-01-07 桂化学株式会社 ナファモスタットメシル酸塩の晶析方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0672981A (ja) * 1992-06-01 1994-03-15 Biogal Gyogyszergyar 高純度デフェロキサミン塩の製造法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AOYAMA T. ET AL.: "Synthesis and Structure- Activity Study of Protease Inhibitors. IV. Amidinonaphthols and Related Acyl Derivatives", CHEM. PHARM. BULL., vol. 33, no. 4, 1985, pages 1458 - 1471 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022109243A (ja) * 2021-01-14 2022-07-27 デボン エルエス カンパニー，リミテッド メシル酸ナファモスタットの共結晶多形及びその製造方法
CN113999145A (zh) * 2021-11-12 2022-02-01 开封明仁药业有限公司 一种甲磺酸萘莫司他的合成方法
CN113999145B (zh) * 2021-11-12 2023-02-03 开封明仁药业有限公司 一种甲磺酸萘莫司他的合成方法
WO2023144830A1 (fr) 2022-01-30 2023-08-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Inhibiteurs de la protéine zika m utilisés en tant qu'agents anti-virus zika

Also Published As

Publication number Publication date
JP6252991B2 (ja) 2017-12-27
JPWO2014007326A1 (ja) 2016-06-02

Similar Documents

Publication Publication Date Title
AU2007206681B2 (en) Process for the crystallisation of mesotrione
SG174982A1 (en) L-ornithine phenyl acetate and methods of making thereof
KR20010042078A (ko) 피리다지논 염산염 화합물 및 그 제조방법
JP6252991B2 (ja) ナファモスタットメシル酸塩の製造方法
CA2813563A1 (fr) Procedes de fabrication d'acetate de phenyle de l-ornithine
CN105348209A (zh) 一种抗心衰药lcz696的制备方法
BR102022003820A2 (pt) Processo para preparação de sulfentrazona com compatibilidade de mistura em tanque
ES2873828T3 (es) Preparación y cristalización innovadoras de iosimenol
CN109988094A (zh) 一种乙磺酸尼达尼布的制备方法
JPS5843939A (ja) マンデル酸塩及びその製法
CA2980224C (fr) Forme cristalline de ahu377, procede de preparation et utilisation de cette derniere
WO2012089238A1 (fr) Procédé de fabrication de cristaux de chlorhydrate de fingolimod
JP2017095453A (ja) 高純度フルオレセインナトリウム
EP1708990A1 (fr) Preparation de r-5-(2-(2-ethoxyphenoxyetylamino)propyl)-2- methoxybenzenesulphonamide chlorhydrate a purete chimique elevee
BR112013010115B1 (pt) processo de separação de enantiômeros derivados de triazina utilizando ácido tartárico
JPWO2003011886A1 (ja) ５’−グアニル酸ジナトリウム・５’−イノシン酸ジナトリウム混晶の製造法
JP3312452B2 (ja) 光学活性トランス−１，２−ジアミノシクロヘキサン製造法
EP3068746B1 (fr) Procédé de préparation de 1-aminoindane énantiomériquement pur
CN116178274A (zh) 氯比普兰硫酸盐晶型及其制备方法
CN114524746B (zh) 拉考沙胺晶型的制备方法
RU2779668C1 (ru) Способ получения калькобутрола
TWI729370B (zh) 一種二苯碸衍生物的組成物及其製法
JP5200245B2 (ja) Ｄｌ−バリンラセミ化合物の光学分割方法。
CN108892677B (zh) 一种头孢地尼的粒度控制方法
AU2008298402B2 (en) Method for producing N-methacryloyl-4-cyano-3-trifluoromethylaniline

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: 13813255

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2014523782

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13813255

Country of ref document: EP

Kind code of ref document: A1