+

WO2006018703A2 - Procedes de preparation de la narwedine et son utilisation dans la synthese de galantamine - Google Patents

Procedes de preparation de la narwedine et son utilisation dans la synthese de galantamine Download PDF

Info

Publication number
WO2006018703A2
WO2006018703A2 PCT/IB2005/002431 IB2005002431W WO2006018703A2 WO 2006018703 A2 WO2006018703 A2 WO 2006018703A2 IB 2005002431 W IB2005002431 W IB 2005002431W WO 2006018703 A2 WO2006018703 A2 WO 2006018703A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
salt
narwedine
acid
ketal
Prior art date
Application number
PCT/IB2005/002431
Other languages
English (en)
Other versions
WO2006018703A3 (fr
Inventor
Saswata Lahiri
Mohan Prasad
Nitin Maheshwari
Yatendra Kumar
Original Assignee
Ranbaxy Laboratories Limited
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 Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2006018703A2 publication Critical patent/WO2006018703A2/fr
Publication of WO2006018703A3 publication Critical patent/WO2006018703A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to processes for the preparation of narwedine, and the use thereof in the synthesis of pure galantamine or salt thereof.
  • the present invention further relates to an acid addition salt of narwedine isopropylene glycol ketal (Formula I), which is a useful intermediate in the synthesis of narwedine and galantamine.
  • narwedine is a tertiary amaryllidaceae alkaloid which is useful as an intermediate in the synthesis of (-)-galantamine (Formula III).
  • Galantamine is a 6-hydroxy derivative of narwedine and is indicated in the treatment of Alzheimer's disease, dementia, mania, fatigue syndrome, schizophrenia and for inhibiting acetyl cholinesterase activity.
  • Narwedine is isolated from bulbs of nineteen species of trumpet narcissus, twelve species of cup narcissus, and eight species of filled narcissus (doubles) by an extraction process followed by chromatographic purification of the fractions to get crystalline narwedine (hereinafter referred to as Form A of narwedine) having a melting point of 188°C -190°C.
  • Galantamine can be isolated from daffodils ⁇ Narcissus pseudonarciss us L.) by an extraction process, but this method is quite expensive for pharmaceutical grade material, even when taking into account large-scale production efficiencies.
  • Narwedine may be isolated from the reaction mass by several different column chromatography techniques.
  • One such technique uses 95% ethanol, wherein racemic narwedine having a melting point range of 187°- 19O 0 C is obtained.
  • a similar melting point for narwedine was observed when it was isolated by column chromatography using ethyl acetate and benzene as an eluent.
  • the product so obtained after sublimation gave racemic narwedine having a melting point in the range of 178°C - 186 0 C. However, when sublimation was carried out under a vacuum, the melting point of 186°C -190°C is observed again.
  • IP ketal is formed by reducing the N-formyl isopropylene glycol ketal (Formula IV), wherein the N-formyl group is reduced to a N-methyl group and debromo- hydrogenation is simultaneously achieved.
  • IP ketal is isolated and then hydrolyzed using an acid to get narwedine (Formula II).
  • the IP ketal formed via this process is unstable in acidic conditions and should not be stored for a long time before converting to narwedine.
  • IP ketal (Formula I) can be isolated as its acid addition salt by treating it with an acid. This provides a method for purification of the IP ketal in spite of having poor stability in acidic conditions.
  • the salt of IP ketal that is formed is stable for about five to six days when stored under anhydrous conditions.
  • the inventors have also found that it is possible to prepare a highly pure narwedine or salt thereof having a purity above 98% as measured by HPLC. This form of narwedine may then be used in the production of galantamine.
  • a hydrobromide salt of IP ketal (Formula I).
  • a process for the preparation of an acid addition salt of IP ketal (Formula I). The process includes reducing with a reducing agent N-formyl ispropylene glycol ketal (Formula IV) to get IP ketal (Formula I);
  • IP ketal to its acid addition salt by treating it with a suitable acid at a pH of about 3.2 to 4.0; and isolating the acid addition salt of IP ketal from the reaction mass thereof.
  • Embodiments of the process may include one or more of the following features.
  • the reducing agent may include metal hydrides and metal borohydrides.
  • the acid may include one or more of hydrobromic acid, hydroiodic acid, acetic acid, propionic acid, methensulphonic acid, and p-toluenesulphonic acid.
  • the process may further include hydrolyzing the acid addition salt of IP ketal using an acid; and isolating narwedine (Formula II) from the reaction mixture thereof.
  • the process may also include purifying narwedine to obtain substantially pure narwedine or a salt thereof and it may include reducing with a reducing agent the substantially pure narwedine or salt thereof having a purity above 98% in presence of an organic solvent to get racemic galantamine or salt thereof; treating the racemic product of step a) with a chiral auxiliary to get (-)-isomer (Formula V),
  • CHI represents the chiral auxiliary used; and converting (-)-isomer (Formula V) to galantamine or salt thereof.
  • a process for the preparation of narwedine includes hydrolyzing the acid addition salt of IP ketal (Formula I) using an acid; and isolating narwedine (Formula II) from the reaction mixture thereof.
  • the acid may include a mineral acid and the mineral acid may be hydrochloric acid.
  • substantially pure narwedine or salt thereof having a purity above 98% as measured by HPLC.
  • a process for the preparation of substantially pure narwedine or salt thereof includes reducing N-formyl propylene glycol ketal (Formula FV) with a reducing agent to get narwedine propylene glycol ketal (Formula I);
  • FORMULA IV optionally converting the narwedine propylene glycol ketal to its salt at a pH of about 3.2 to 4.0; and hydrolyzing the narwedine propylene glycol ketal or salt thereof to get substantially pure narwedine or salt thereof.
  • Embodiments of the process may include one or more of the following features.
  • reducing agent may include metal hydrides and metal borohydrides.
  • a process for the preparation of (-)- galantamine or salt thereof includes reducing substantially pure narwedine or salt thereof having a purity above 98% with a reducing agent in presence of an organic solvent to get racemic galantamine or salt thereof; treating the racemic product of step a) with a chiral auxiliary to get (-)-isomer (Formula V),
  • CHI represents the chiral auxiliary used; and converting (-)-isomer (Formula V) to galantamine or salt thereof.
  • Embodiments of the process may include one or more of the following features.
  • the reducing agent may include metal hydrides and metal borohydrides and may be one or more of L-selectride, lithium aluminium hydride, lithium borohydride, vitride.
  • the organic solvent may include one or more of tetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether, N-methylpyrrolidine, and N,N-dimethylformamide.
  • the chiral auxiliary may be di-4-toluoyl-D-tartaric acid.
  • the process may further, include purifying galantamine or salt thereof and incorporating the galantamine into a pharmaceutical dosage form.
  • the present invention provides for an acid addition salt of IP ketal (Formula I).
  • a hydrobromide salt of IP ketal (Formula I) may be formulated.
  • the hydrobromide salt of IP ketal is stable for about five to six days when stored in suitable anhydrous conditions.
  • the process includes: a) reducing N-formyl isopropylene glycol ketal (Formula IV) with a reducing agent to get IP ketal (Formula I);
  • FORMULA I b) converting the IP ketal to its acid addition salt by treating it with suitable acid at a pH of about 3.2 to about 4.0; and c) isolating the acid addition salt of IP ketal from the resulting reaction mass.
  • N-Formyl propylene glycol ketal (Formula IV) used in the process may be prepared by the process described in Kueenburg et al., Organic Process Research & Development. 3(6), 425-431 (1999) and U.S. Patent No. 6,407,229.
  • the N-formyl isopropylene glycol ketal (Formula IV) is dissolved in a suitable organic solvent and reduced using a suitable reducing agent.
  • suitable reducing agents capable of reducing a formyl group to a methyl group are known to a person of ordinary skills in the art through several literature references.
  • metal hydrides and metal borohydrides such as lithium aluminum hydride, lithium borohydride, Vitride®, and L-selectride® may be used as reducing agents.
  • Suitable organic solvents include Tetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether, N-methylpyrrolidine and N,N-dimethylformamide.
  • the reduction is carried out at temperature of between about - 20°C to about 60°C.
  • reaction mass is diluted with toluene and quenched by adding saturated sodium sulphate solution.
  • the resultant mass is filtered and the organic layer is concentrated to get residue of IP ketal (Formula I).
  • the residue is treated with a suitable acid at a pH of about 3.2 to about 4.0 to get a novel acid addition salt of IP ketal.
  • suitable acids include hydrobromic acid, hydroiodic acid, acetic acid, propionic acid, methensulphonic acid, and p-toluenesulphonic acid.
  • hydrobromic acid may be used to produce the hydrobromide salt of IP ketal.
  • the hydrobromide salt has been studied for its stability under different storage conditions. It was found that when the hydrobromide salt is stored at 35% relative humidity at about 15°C to 2O 0 C, it is stable for a minimum of five to six days. The stability samples were analyzed by HPLC method.
  • narwedine Forma II
  • the process includes: a) hydrolyzing the acid addition salt of IP ketal (Formula I) using an acid; and b) isolating the narwedine (Formula II) from the resulting reaction mixture.
  • the acid addition salt of IP ketal is hydrolyzed in aqueous conditions using a suitable mineral acid.
  • the reaction is carried out at a temperature of about 25 0 C to 7O 0 C.
  • the pH of the reaction mass is adjusted to above 9, preferably 9.2, using an aqueous ammonia solution.
  • the separated solid is filtered and washed with water to get narwedine.
  • narwedine is then crystallized from a suitable organic solvent to yield narwedine having a purity above 98% as measured by HPLC.
  • suitable organic solvents for crystallization include lower alkanols, ketones, esters, polar aprotic solvents, aromatic hydrocarbons, chlorinated hydrocarbons or mixtures thereof.
  • the narwedine of Formula II thus obtained can then be converted to its salt by treating with suitable acid.
  • the process includes: a) reducing N-formyl propylene glycol ketal (Formula IV) with a reducing agent to get IP ketal (Formula I);
  • IP ketal (Formula I) to its salt at a pH of about 3.2 to about 4.0, c) hydrolyzing the IP ketal or salt thereof to get a substantially pure narwedine or salt thereof.
  • the present invention also provides a novel polymorphic form of narwedine (herein after designated as Form B of narwedine).
  • Form B of narwedine has a characteristic X-Ray Diffraction (XRD) pattern as depicted in Figure 1.
  • the XRD of Form B of narwedine shows characteristic 2 theta values of 10.44, 11.70, 13.85, 14.56, 17.32, 18.28, 19.64, 20.50, 21.05, 21.70, 22.94, 23.50, 25.18, 26.04, 26.86, 28.44, 29.00, 29.48, 30.28, 30.92, 31.42, 32.30, 33.12, 38.46 and 39.46.
  • the polymorphic Form B of narwedine may be prepared by: a) stirring narwedine with a Ci -4 primary, secondary or tertiary alkanol; b) optionally heating the reaction mass to reflux temperature; and c) isolating the narwedine polymorphic Form B from the reaction mass.
  • narwedine used as the starting material may be prepared by any conventional process known in the art.
  • Suitable Ci -4 primary, secondary and tertiary alkanols include one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and t- butanol.
  • the reaction mass may be optionally heated to about reflux temperature of the alkanol used and then subsequently cooled to about -20°C to 35°C.
  • the precipitated product is filtered and washed with a small quantity of alkanol and then dried to get Form B of narwedine having the XRD as depicted in Figure 1.
  • the XRD of the samples were determined by using X-Ray Diffractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.
  • (-)-Galantamine or salt thereof may be produced from the substantially pure narwedine or salt thereof.
  • the process includes; a) reducing the substantially pure narwedine or salt thereof having a purity above 98% with a reducing agent in the presence of an organic solvent to get racemic galantamine or salt thereof; b) treating the racemic product of step a) with a chiral auxiliary to get the (-)- isomer of Formula VI
  • CHI represents the chiral auxiliary used; and " c) converting the (-)-isomer (Formula VI) to galantamine or salt thereof and then optionally purifying.
  • the preparation of the substantially pure narwedine or salt thereof having purity above 98% as measured by HPLC is described above.
  • the substantially pure narwedine is added in lots to a pre-cooled solution of reducing agent in an organic solvent.
  • the suitable reducing agent may include metal hydrides and metal borohydrides, wherein the metal may be lithium, aluminum or sodium.
  • the reducing agent may be Vitride ®, L-selectride®, lithium aluminium hydride, or lithium borohydride.
  • Suitable organic solvents include tetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether, N-methylpyrrolidine and N,N-dimethylformamide.
  • the reduction is carried out at a temperature of between about -70°C to 10 0 C. After completion of the reduction, the temperature of the reaction mass may be raised to about 20°C and the excess reducing agent, as well as side products formed, can be quenched by addition of ethanol.
  • racemic galantamine which may be isolated by converting it to a salt.
  • the racemic galantamine may be treated with hydrobromic acid thus producing the hydrobromide salt of galantamine.
  • the solid salt may be filtered from the reaction mass and dried suitably.
  • Racemic galantamine or its salt obtained is then dissolved in a suitable organic solvent, water or mixtures thereof. If salt is used then it is first converted to free base by treating with dilute alkali solution.
  • Suitable organic solvent may be water-miscible or immiscible and may include ethyl acetate, methyl formate, methyl acetate, n-butyl acetate, tetrahydrofuran, methanol, ethanol, isopropanol, n-butanol, dichloromethane, chloroform, carbon tetrachloride, acetone, methyl isobutyl ketone, ethyl methyl ketone, diisobutyl ketone and acetonirile.
  • the separated base is then extracted in a water immiscible organic solvent.
  • Suitable water immiscible organic solvents include ethyl acetate, methyl formate, methyl acetate, n-butyl acetate, dichloromethane, chloroform and carbon tetrachloride.
  • the organic extract is concentrated and the residue obtained is re-dissolved in an alcoholic solvent, such as methanol, ethanol, isopropanol, n-butanol and n-propanol.
  • an alcoholic solvent such as methanol, ethanol, isopropanol, n-butanol and n-propanol.
  • a chiral auxiliary is added and the resultant mass is stirred for sufficient time at lower temperature to induce crystallization of the desired (-)-isomer of galantamine as its salt of chiral auxiliary (Formula V).
  • the chiral auxiliary may be di-4- toluoyl-D-tartaric acid.
  • the precipitated product is filtered, washed with cold alcoholic organic solvent and recrystallized if required to get desired purity.
  • the chiral auxiliary salt (Formula V) is then converted to (-)-galantamine by treating it with a dilute alkali solution.
  • the alkali solution may be ammonia.
  • (-)-Galantamine is then isolated from the reaction mass by an extractive work-up.
  • the solution of (-)-galantamine may then optionally be treated with an acid thus producing the salt of galantamine.
  • the salt or the free base may also be optionally recrystallized to get galantamine or salt thereof.
  • (-)-Galantamine or a salt thereof may also be prepared from the polymorphic Form B of narwedine.
  • the process includes: a) reducing Form B of narwedine with a reducing agent in the presence of an organic solvent to get racemic galantamine or salt thereof; b) treating the racemic product of step a) with a chiral auxiliary to get (-)- isomer (Formula V)
  • CHI represent the chiral auxiliary used; and c) converting the (-)-isomer (Formula V) to produce galantamine or salt thereof, which may be optionally purified.
  • Figure 1 depicts XRD pattern of Form B of narwedine.
  • Powder XRD of the samples were determined by using X-Ray Difractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.
  • Narwedine (20 gm) was stirred in denatured spirit (60 ml) at a temperature of about 60°C-65°C for 30 minutes. The resultant mass was cooled to about 0 0 C-IO 0 C and filtered after stirring for 30 minutes. The product was washed with denatured spirit (20 ml) and dried under a vacuum to get the title compound.
  • L-Selectride lithium tri-sec-butylborohydride, 1.0 M solution in tetrahydrofuran
  • THF 100 ml
  • narwedine 100 g
  • Tetrahydrofuran 25 ml was used to wash the addition vessel and the reaction mixture was stirred for 30 minutes at -15 0 C to -2O 0 C. It was heated to 20 0 C and ethanol (400 ml) was added.
  • Racemic galantamine hydrobromide (100 gm) was dissolved in water (3200 ml) and the solution was filtered through a celite bed. The celite bed was washed with water (300 ml) and washings were combined with the filtrate. The combined aqueous layer was washed with dichloromethane (300 ml) and the organic layer was discarded. To the aqueous layer was charged dichloromethane (1000 ml) and adjusted the pH of the aqueous layer to 8.9 to 9.1 using aqueous ammonia at O 0 C - 5°C. The aqueous layer was separated and extracted with dichloromethane (1000 ml).
  • Galantamine tartarate 100 grams was taken in a mixture of dichloromethane (600 ml) and water (400 ml), and the pH of the mixture was adjusted to 8.9 to 9.1 using aqueous ammonia at 5°C - 10°C. The organic layer was separated and the aqueous layer was extracted with dichloromethane (600 ml). The combined organic layer was washed with water (2 x 300 ml). A mixture of ethanol and -48% aqueous hydrobromic acid (1:1, 1 ml) was added to the organic layer and the mass was concentrated at 30°C - 35°C under reduced pressure. The free base obtained was dissolved in a mixture of ethanol (1260 ml) and water (110 ml).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés de préparation de la narwedine et son utilisation dans la synthèse de galantamine pure et de ses sels. La présente invention concerne également un nouveau sel d'addition acide de narwedine isopropylène glycol cétal (de la formule I) qui est un intermédiaire utile dans la synthèse de la narwedine et de la galantamine.
PCT/IB2005/002431 2004-08-16 2005-08-15 Procedes de preparation de la narwedine et son utilisation dans la synthese de galantamine WO2006018703A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
IN1505/DEL/2004 2004-08-16
IN1504DE2004 2004-08-16
IN1505DE2004 2004-08-16
IN1504/DEL/2004 2004-08-16
IN1551DE2004 2004-08-19
IN1551/DEL/2004 2004-08-19

Publications (2)

Publication Number Publication Date
WO2006018703A2 true WO2006018703A2 (fr) 2006-02-23
WO2006018703A3 WO2006018703A3 (fr) 2006-07-20

Family

ID=35788180

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/IB2005/002431 WO2006018703A2 (fr) 2004-08-16 2005-08-15 Procedes de preparation de la narwedine et son utilisation dans la synthese de galantamine
PCT/IB2005/002429 WO2006046096A2 (fr) 2004-08-16 2005-08-15 Forme polymorphe de la narwedine et son utilisation dans la synthese de la galantamine

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/IB2005/002429 WO2006046096A2 (fr) 2004-08-16 2005-08-15 Forme polymorphe de la narwedine et son utilisation dans la synthese de la galantamine

Country Status (1)

Country Link
WO (2) WO2006018703A2 (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RO118419B1 (ro) * 1994-10-21 2003-05-30 Waldheim Pharmazeutika Gmbh Procedeu de obtinere a derivatilor de 4a, 5, 9, 10, 11, 12-hexahidro-6h-benzofuro 3a, 3, 2- ef 2 benzazepina si intermediari care intervin in procedeu
GB9610887D0 (en) * 1996-05-24 1996-07-31 N H S Trust Process
GB9707413D0 (en) * 1997-04-11 1997-05-28 Chiroscience Ltd Process
AT405051B (de) * 1997-05-21 1999-05-25 Sanochemia Ltd Reduktion aromatischer halogenide

Also Published As

Publication number Publication date
WO2006018703A3 (fr) 2006-07-20
WO2006046096A2 (fr) 2006-05-04
WO2006046096A3 (fr) 2006-08-24

Similar Documents

Publication Publication Date Title
US8178670B2 (en) Method of synthesizing tetrahydrobiopterin
US20140228575A1 (en) Process for the Preparation of Solifenacin and Salts Thereof
JP6081450B2 (ja) アセナピンの結晶塩
WO2012081031A1 (fr) Procédé de préparation de tétrabénazine
JP2003513974A (ja) イミダゾリジノン系αｖ−インテグリン拮抗薬の製造方法および製造用中間体
WO2010056656A2 (fr) Synthèse de chlorhydrate de palonosétron cristallin
EP3424908A1 (fr) Procédé de préparation de levosimendan
US20100311969A1 (en) Process For Preparation of Paliperidone
WO2009010987A1 (fr) Procédé amélioré pour la préparation de chlorhydrate de palonosétron pur
US7547785B2 (en) Process for preparing topotecan
WO2009139002A2 (fr) Procédé perfectionné de fabrication de solifénacine et de ses sels pharmaceutiquement acceptables
WO2019167085A1 (fr) Procédé de préparation de méthanesulfonate de (s)-2-[[4-[(3-fluorophényl)méthoxy]phényl]méthyl]amino propanamide
Brine et al. An improved resolution of (±)‐cis‐N‐normetazocine
US20080306257A1 (en) Syntheses and Preparations of Narwedine and Related Novel Compounds
CZ300692B6 (cs) Zpusob prípravy solifenacinu
WO2006018703A2 (fr) Procedes de preparation de la narwedine et son utilisation dans la synthese de galantamine
KR920007272B1 (ko) 라세미 반-에스테르의 분리방법
CN108586450B (zh) 一种胆碱m受体抗结剂的重结晶纯化方法
CA3097628A1 (fr) Intermediaires et procedes pour la preparation de linagliptine et de ses sels
WO2006013546A2 (fr) Procede de preparation de galantamine pure
US7223882B2 (en) Process for producing triterpene derivative
US20120267533A1 (en) Processes for the preparation of form i and form ii of palonosetron hydrochloride
WO2006013550A2 (fr) Procede d'elaboration d'acide carboxylique de piperidine
US20120259116A1 (en) Novel Process for the Preparation of Paliperidone
WO2015177801A1 (fr) Nouveau procede pour la preparation d'un compose contenant du lactame

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载