+

WO2006008160A1 - Sels d'amine tertiaire de l’acide 2-(2-aminothiazole-4-yl)-2-(acyloxyimino) acetique - Google Patents

Sels d'amine tertiaire de l’acide 2-(2-aminothiazole-4-yl)-2-(acyloxyimino) acetique Download PDF

Info

Publication number
WO2006008160A1
WO2006008160A1 PCT/EP2005/007958 EP2005007958W WO2006008160A1 WO 2006008160 A1 WO2006008160 A1 WO 2006008160A1 EP 2005007958 W EP2005007958 W EP 2005007958W WO 2006008160 A1 WO2006008160 A1 WO 2006008160A1
Authority
WO
WIPO (PCT)
Prior art keywords
acetic acid
aminothiazole
formula
acyloxyimino
tertiary amine
Prior art date
Application number
PCT/EP2005/007958
Other languages
English (en)
Inventor
Peter Kremminger
Herbert Silberberger
Original Assignee
Sandoz Ag
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 Sandoz Ag filed Critical Sandoz Ag
Priority to EP05778079A priority Critical patent/EP1786793A1/fr
Publication of WO2006008160A1 publication Critical patent/WO2006008160A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by 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, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom

Definitions

  • the present invention relates to tertiary amine salts of 2-(2-aminothiazole-4-yl)-2- (acyloxyimino)acetic acid in crystalline form and a process for their preparation as well as a process for the preparation of cefdinir wherein such tertiary amine salts are used.
  • a 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds e.g. syn-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)-acetic acid and its derivatives
  • cefdinir (6R ; 7R)-7-[[(2Z)-(2-Amino-4-thiazolyl)(hydroxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
  • a process for the production of cefdinir includes a reaction step wherein a 2-(2-aminothiazole-4-yl)-2-(acyioxyimino)acetic acid compound is converted into an activated form thereof such as a mercaptobenzothiazolylester, a mixed acid anhydride, an acid halide or another conventional activated form by a reaction with an activating agent.
  • a 2-(2-aminothiazole-4-yl)-2-(acyioxyimino)acetic acid compound is converted into an activated form thereof such as a mercaptobenzothiazolylester, a mixed acid anhydride, an acid halide or another conventional activated form by a reaction with an activating agent.
  • Any crystal water of 2-(2- aminothiazole-4-yl)-2-(acyIoxyimino)acetic acid also reacts with the activating agent and typically causes decreased yields in the activation step or/and the necessity of significantly increased amounts of activating agent, e.
  • halogenation agent such as phosphorous pentachloride (see ES 2 013 828). Therefore, it is highly desirable to use anhydrous derivatives of a 2-(2-aminothiazole-4-yl)-2-(acyIoxyimino)acetic acid compound for an activation reaction.
  • 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds for instance syn- 2-(2-aminothiazol-4-yl)-2-(acetoxyimino)-acetic acid
  • 2-(2-aminothiazol-4-yl)-2-(acetoxyimino)-acetic acid are typically prepared from e.g. syn-2- (2-aminothiazol-4-yl)-2-(hydroxyimino)-acetic acid by reaction with alkanoic carboxylic acid anhydrides such as acetic acid anhydride under aqueous conditions and are crystallised in a hydrated form, e.g. as mono- or dihydrates.
  • alkanoic carboxylic acid anhydrides such as acetic acid anhydride under aqueous conditions
  • the present invention is intended to provide novel crystalline tertiary amine salts of 2-(2- aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds which are useful in a reaction step with an activating agent in order to produce cefdinir. It has surprisingly been found now that crystalline tertiary amine salts of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds may be obtained in an anhydrous form.
  • the present invention relates therefore to tertiary amine salts of 2-(2- aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds of formula
  • R-i, R 2 and R 3 independently represents unsubstituted or substituted alkyl, cyclo-alkyl or aryl, and R 4 denotes acyl.
  • R 1 , R 2 and R 3 alkyl includes (C 1-12 )alkyl such as (C 1-8 )alkyl, in particular (C 1- 4 )alkyl, e.g. ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl.
  • Aryl includes (C 6- i 2 )aryl, e.g. phenyl or naphtyl, in particular phenyl.
  • Cycloalkyl includes (C 3-8 )cycloalkyl, preferably C 3 , C 5 or C 6 -cycloalkyl such as cyclohexyl.
  • any alkyl, cycloalkyl or aryl group of R 1 , R 2 and R 3 may be unsubstituted or one to three times substituted, e.g. one times substituted by halogen or alkyl.
  • Aryl and cycloalkyl may be also one to five times substituted by alkyl, e.g. (C 1-4 )alkyl or halogen.
  • R 1 , R 2 and R 3 each denote n-butyl, ethyl, phenyl or n-octyl.
  • Ri and R 2 denote iso-propyl and R 3 denotes ethyl.
  • Particularly preferred are compounds wherein R 1 , R 2 and R 3 each denote n-butyl.
  • R 4 denotes acyl such as (C 1-6 )acyl, e.g. formyl, acetyl, propanoyl or butanoyl. In a preferred embodiment R 4 denotes C 2 -acyl, i.e. acetyl.
  • acyl includes (C 1-6 )acyl, e.g. formyl, acetyl, propanoyl or butanoyl, preferably acetyl.
  • An anhydrous form of a crystalline tertiary amine salt of formula I may contain less than 1.0% (w/w) of water, i.e. from about 0% to below 1.0% (w/w), e.g. from about 0.01 % to about 0.5% (w/w) such as from about 0.05% to about 0.2% (w/w) or even less than about 0.1% (w/w).
  • Crystalline tertiary amine salts of formula I may be produced by contacting 2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid dissolved or suspended in a solvent with an amine of formula R 1
  • the amount of added amine of formula Ii is not critical.
  • An equimolar amount of a 2-(2- aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid compound dissolved or suspended in a solvent and of the amine of formula Il may be used, whereby a slight molar excess of the amine of formula II, e.g. around 1.01 to around 1.50 molar equivalents of an amine of formula Il per equivalent of 2-(2-aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid compound may be of advantage.
  • a higher excess for example about 1.5 to about 5 molar equivalents of an amine of formula Il per equivalent of the 2-(2-aminothiazol-4-yl)-2- (acylcarbonyloxyimino)-acetic acid compound may also be used.
  • reaction temperature is not critical for the crystallization of a tertiary amine salt of formula I. Suitable reaction temperatures are from -3O 0 C to 7O 0 C, e.g. -2O 0 C to 35°C, particularly from -10°C to 25°C such as at ambient room temperature.
  • a salt of formula I is crystallized under mild temperature conditions such as at or below ambient room temperature because that would result in a very mild and gentle dehydration process leading to high yields and very high purities of the cefdinir to be prepared from a tertiary amine salt of formula I.
  • Suitable solvents for the crystallisation of a tertiary amine salt of formula I are solvents which may typically be used for crystallisation of amine salts of beta-lactam compounds.
  • Suitable solvents may include ketones, e.g. (C 3 . 6 )-ketones, nitriles, such as (C 1-6 )-nitriles, ethers, for example (C 2- 8)alkyl(C 2- 8)alkylethers or tetrahydrofuran (THF), amides such as dimethylacetamide or dimethylformamide and chlorinated hydrocarbons such as methylenechloride , and mixtures of two or more of said solvents.
  • ketones e.g. (C 3 . 6 )-ketones
  • nitriles such as (C 1-6 )-nitriles
  • ethers for example (C 2- 8)alkyl(C 2- 8)alkylethers or tetrahydrofuran (
  • Preferred solvents are acetone, THF and N,N-dimethylformamide.
  • a - Counter-solvents which may optionally be added to facilitate crystallisation are liquids which, if added, decrease the solubility of a tertiary amine salts of formula I.
  • Suitable counter- solvents are aliphatic, alicyclic or aromatic hydrocarbons such as (C 5-16 )alkanes, (C 5-10 )cycloalkanes or benzene that may be unsubstituted or substituted by (C 1-6 )alkyl, e.g. toluene, xylene, mesitylene or carboxylic acid esters such as acetic acid-(Ci- 4 )-alkyl esters, e.g. n-butylacetate or ethylacetate.
  • the starting 2-(2-aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid compounds e.g. in the form of hydrates may be produced by known methods.
  • the present invention relates to a process for the production of cefdinir comprising the steps a. preparing a tertiary amine salt of formula I in crystalline form, preferably in an anhydrous form, as described above, b. reacting the crystalline amine salt obtained from step a. with an activating agent to obtain a 2-(2-aminothiazole-4-yl)-2-acyloxyimino acetic acid compound in an activated form, c. reacting the activated 2-(2-aminothiazole-4-yl)-2-acyloxyimino acetic acid compound obtained from step b. with a 7-amino-3-vinyl-3-cephem-4- carboxylic acid compound to obtain a 7-[2-(2-aminothiazole-4-yl)-2-
  • Step a. e.g. in anhydrous form
  • Step b. may be carried out in analogy, e.g. according to methods known in the art, e.g. in analogy to a process as described in WO 2004/016623.
  • An activated form includes a mercaptobenzothiazolylester, a mixed acid anhydride, an acid halide such as an acid chloride or other conventional activated forms.
  • activating agents are bis-(benzothiazol-2-yl)-disulphide/triethy!phosphite, bis-(benzothiazol-2-yl)-di- sulphide/triphenylphosphine, phosphorous pentachloride, pivaloyl chloride/triethylamine etc.
  • Step c. may be carried out in analogy, e.g. according to known methods.
  • Step d. may be effected in analogy to, e.g. according to methods known in the art, for instance by hydrolysis or alcoholysis with a strong acid. If step d. is performed by alcoholysis, it is desirous to use water-free strong acids.
  • Suitable strong acids include strong organic acids such as trifluoroacetic acid, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid or a toluene sulfonic acid, a sulfamic acid and water-free anorganic acids, e.g. sulphuric acid.
  • Cleavage of the acetyl-group is usually carried out in a solvent which does not adversely affect the reaction.
  • Suitable solvents include alcohols such as methanol, ethanol, propanols, butanols.
  • the reaction is carried out at temperatures from -20 to 3O 0 C, preferably between -5 and +10 0 C.
  • an excess of anhydrous acid e.g. from 1.1 to 5.0 molar equivalents are used.
  • the present invention relates to a process for the production of an activated form of 2-(2-aminothiazole-4-yl)-2-acyloxyimino acetic acid compounds comprising the steps of preparing a tertiary crystalline amine salt of formula I, e.g. in an anhydrous form, as defined above and reacting the obtained crystalline tertiary amine salt of formula I with an activating agent in order to obtain a 2-(2-aminothiazole-4-yl)-2-acyloxyimino acetic acid compound in an activated form.
  • An activated form of 2-(2-aminothiazole-4-yl)-2-acylimino acetic acid compounds includes for example an acid halide such as an acid chloride, a mixed acid anhydride and a mercaptobenzothiazolyl ester or other conventional activated forms resulting from reactions with activating agents such as those listed above.
  • the present invention relates in another aspect to the use of a tertiary amine salt of formula I in crystalline form, e.g. in an anhydrous form, in the preparation of an activated form of 2-(2-aminothiazole-4-yi)-2-acyloxyimino acetic acid compounds.
  • a tertiary amine salt of formula I in crystalline form, preferably in an anhydrous form, e.g. prepared by a process as set out above, is useful as an intermediate in the production of cefdinir.
  • the present invention relates in a further aspect to the use of a tertiary amine salt of formula I in crystalline form, e.g. in an anhydrous form, in the production of cefdinir.
  • the mixture is cooled to 0 0 C and stirred at this temperature for 30 minutes.
  • the crystalline material is filtered, washed with a small portion of cold acetone and dried in vacuum.
  • syn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid dihydrate are suspended in 100 ml of acetone at ambient temperature and 9.7ml of tri-(n-octyl)amine is added. The material dissolves and the mixture is cooled to -20 0 C for crystallisation and stirred at this temperature. The crystalline material is filtered, washed with a small portion of cold acetone and dried in vacuum.
  • the mixture is stirred for 2.0 h at 30 0 C, cooled to 0 0 C and the reaction mixture added dropwise at O 0 C to a solution of 7.0ml 85% phosphoric acid in 53.6ml MeOH and 11.2ml water, on which a thick crystalline suspension is formed.
  • the suspension is diluted with 257ml methylenechloride, stirred for 1h at 0 0 C and filtered.
  • the filter cake is washed once with a mixture of 90ml methylenechloride and 17ml MeOH, and then twice more, each time with 107ml methylenechloride, followed by vacuum drying at ambient room temperature.

Landscapes

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

Abstract

La présente invention porte sur des sels d'amine tertiaire cristallins des composés de l'acide 2-(2-aminothiazole-4-yl)-2-(acyloxyimino) acétique de formule (I) dans laquelle R1, R2 et R3 représentent, indépendamment, alkyle non substitué ou substitué, cyclo-alkyle ou aryle, et R4 représente acyle qui peut être obtenu sous forme anhydre. Des composés cristallins de formule (I) sont utiles dans une étape où ils réagissent avec un agent d'activation afin de produire cefdinir. L'invention porte également sur un procédé de préparation des composés de formule (I).
PCT/EP2005/007958 2004-07-22 2005-07-21 Sels d'amine tertiaire de l’acide 2-(2-aminothiazole-4-yl)-2-(acyloxyimino) acetique WO2006008160A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP05778079A EP1786793A1 (fr) 2004-07-22 2005-07-21 Sels d'amine tertiaire de l'acide 2-(2-aminothiazole-4-yl)-2-(acyloxyimino) acetique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0416379A GB0416379D0 (en) 2004-07-22 2004-07-22 Organic compounds
GB0416379.6 2004-07-22

Publications (1)

Publication Number Publication Date
WO2006008160A1 true WO2006008160A1 (fr) 2006-01-26

Family

ID=32922625

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2005/007958 WO2006008160A1 (fr) 2004-07-22 2005-07-21 Sels d'amine tertiaire de l’acide 2-(2-aminothiazole-4-yl)-2-(acyloxyimino) acetique

Country Status (3)

Country Link
EP (1) EP1786793A1 (fr)
GB (1) GB0416379D0 (fr)
WO (1) WO2006008160A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7173126B2 (en) * 2002-12-20 2007-02-06 Antibioticos S.P.A. Crystalline cefdinir salts
US7250508B2 (en) * 2002-08-13 2007-07-31 Sandoz Ag Cefdinir intermediate
CN100448854C (zh) * 2006-06-26 2009-01-07 山东金城医药化工股份有限公司 一种制备氨噻肟酸的方法
KR101058135B1 (ko) 2008-04-04 2011-08-24 대웅바이오 주식회사 세프디니르 합성에 유용한 중간체 및 이를 이용하여세프디니르를 제조하는 방법
US20130017156A1 (en) * 2009-12-25 2013-01-17 Mahmut Bilgic Cefdinir and cefixime formulations and uses thereof
US9139542B2 (en) 2013-03-13 2015-09-22 Theravance Biopharma Antibiotics Ip, Llc Crystalline form of a substituted thiazolylacetic acid triethylamine salt
CN107892676A (zh) * 2017-12-21 2018-04-10 山东金城柯瑞化学有限公司 头孢地尼活性硫酯的制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR201000686A1 (tr) 2010-01-29 2011-08-22 B�Lg�� Mahmut Bakteriyel enfeksiyonların tedavisinde suda çözünebilir sefdinir ve klavulanik asit formülasyonları.@

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0185220A2 (fr) * 1984-12-19 1986-06-25 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Intermédiaires pour la préparation de céphalosporines
ES2013828A6 (es) * 1988-01-07 1990-06-01 Fujisawa Pharmaceutical Co Procedimiento para la preparacion de compuestos de 7-(2-(2-aminotiazol-4-il)-2-hidrociiminoacetamino)-3-cefem.
EP0531981A1 (fr) * 1991-09-10 1993-03-17 Bristol-Myers Squibb Company Procédé de préparation d'une céphalosporine antibiotique
EP1340751A1 (fr) * 2000-12-04 2003-09-03 Fujisawa Pharmaceutical Co., Ltd. Procede de production d'anhydride d'un derive d'aminothiazole
WO2004016623A1 (fr) * 2002-08-13 2004-02-26 Sandoz Ag Intermediaire de cefdinir

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0185220A2 (fr) * 1984-12-19 1986-06-25 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Intermédiaires pour la préparation de céphalosporines
ES2013828A6 (es) * 1988-01-07 1990-06-01 Fujisawa Pharmaceutical Co Procedimiento para la preparacion de compuestos de 7-(2-(2-aminotiazol-4-il)-2-hidrociiminoacetamino)-3-cefem.
EP0531981A1 (fr) * 1991-09-10 1993-03-17 Bristol-Myers Squibb Company Procédé de préparation d'une céphalosporine antibiotique
EP1340751A1 (fr) * 2000-12-04 2003-09-03 Fujisawa Pharmaceutical Co., Ltd. Procede de production d'anhydride d'un derive d'aminothiazole
WO2004016623A1 (fr) * 2002-08-13 2004-02-26 Sandoz Ag Intermediaire de cefdinir

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7250508B2 (en) * 2002-08-13 2007-07-31 Sandoz Ag Cefdinir intermediate
US7825241B2 (en) 2002-08-13 2010-11-02 Sandoz Ag Cefdinir intermediate
US7173126B2 (en) * 2002-12-20 2007-02-06 Antibioticos S.P.A. Crystalline cefdinir salts
CN100448854C (zh) * 2006-06-26 2009-01-07 山东金城医药化工股份有限公司 一种制备氨噻肟酸的方法
KR101058135B1 (ko) 2008-04-04 2011-08-24 대웅바이오 주식회사 세프디니르 합성에 유용한 중간체 및 이를 이용하여세프디니르를 제조하는 방법
US20130017156A1 (en) * 2009-12-25 2013-01-17 Mahmut Bilgic Cefdinir and cefixime formulations and uses thereof
US8614315B2 (en) * 2009-12-25 2013-12-24 Mahmut Bilgic Cefdinir and cefixime formulations and uses thereof
US9139542B2 (en) 2013-03-13 2015-09-22 Theravance Biopharma Antibiotics Ip, Llc Crystalline form of a substituted thiazolylacetic acid triethylamine salt
CN107892676A (zh) * 2017-12-21 2018-04-10 山东金城柯瑞化学有限公司 头孢地尼活性硫酯的制备方法
CN107892676B (zh) * 2017-12-21 2019-11-29 山东金城柯瑞化学有限公司 头孢地尼活性硫酯的制备方法

Also Published As

Publication number Publication date
GB0416379D0 (en) 2004-08-25
EP1786793A1 (fr) 2007-05-23

Similar Documents

Publication Publication Date Title
EP1554289B1 (fr) Intermediaire de cefdinir
EP1786793A1 (fr) Sels d'amine tertiaire de l'acide 2-(2-aminothiazole-4-yl)-2-(acyloxyimino) acetique
JP2004155793A (ja) 精製方法
KR20030007548A (ko) 티아졸리딘디온 유도체의 신규한 안정한 결정 및 이의제조방법
KR870001332B1 (ko) 세펨 유도체의 간단한 제조방법
FI109127B (fi) Menetelmä kefepiimidihydrokloridihydraattiantibiootin valmistamiseksi
JP4022070B2 (ja) 新規チアゾール化合物およびその製造方法
FI109126B (fi) Menetelmä kefepiimidihydrokloridihydraattiantibiootin valmistamiseksi
JPH069647A (ja) 新規なセファロスポリン中間体
GB2421024A (en) Cefdinir crystalline form C
WO2006008161A1 (fr) Solvates alcanoyle amide d'acide 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetique
US5594130A (en) Preparation of a cephalosporin antibiotic using the syn-isomer of a thiazolyl intermediate
JP3514495B2 (ja) ハロゲン化アミノチアジアゾリル酢酸誘導体の製造法
GB2195334A (en) 1-Methanesulfonyloxy-6-trifluoromethyl-1H-benzotriazole and its use in preparing cephalosporin derivatives
IT8922575A1 (it) Procedimento per la preparazione dell'acido 7-(d-2-amino-2-fenilacetam ido)-3-cloro-3-cefem-4-carbossilico monoidrato e intermedio
KR101278359B1 (ko) Ｎｐｙｙ5 수용체 길항 작용을 갖는 화합물의 제조 방법 및 유용한 결정
KR0174432B1 (ko) 신규한 결정성 세프디니르 중간체 및 그의 제조방법
US5138049A (en) Cephalosporin derivative
KR20020038112A (ko) 세펨 유도체 또는 그 염의 신규한 제조방법

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

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: A1

Designated state(s): BW GH 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

WWE Wipo information: entry into national phase

Ref document number: 2005778079

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2005778079

Country of ref document: EP

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