[go: up one dir, main page]

WO2007117053A1 - Nouveaux dérivés hétérocycliques pontés diaza et leur procédé de préparation en phase solide - Google Patents

Nouveaux dérivés hétérocycliques pontés diaza et leur procédé de préparation en phase solide Download PDF

Info

Publication number
WO2007117053A1
WO2007117053A1 PCT/KR2006/001714 KR2006001714W WO2007117053A1 WO 2007117053 A1 WO2007117053 A1 WO 2007117053A1 KR 2006001714 W KR2006001714 W KR 2006001714W WO 2007117053 A1 WO2007117053 A1 WO 2007117053A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
aryl
halogen
alkoxy
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2006/001714
Other languages
English (en)
Inventor
Seung Bum Park
Sung-Chan Lee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Seoul National University Industry Foundation
Original Assignee
Seoul National University Industry Foundation
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 Seoul National University Industry Foundation filed Critical Seoul National University Industry Foundation
Publication of WO2007117053A1 publication Critical patent/WO2007117053A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a new diaza-bridged heterocycle derivative and a solid-phase preparation method thereof, and more specifically the present invention is characterized by using a solid-phase bromoacetal resin as a starting material to react with amino acids and various derivatives thereof, and then subjecting the product to solid-phase cleavage in a one -pot reaction by means of the Pictet-Spengler mechanism under acidic conditions to obtain the objective compound.
  • a solid-phase bromoacetal resin as a starting material to react with amino acids and various derivatives thereof, and then subjecting the product to solid-phase cleavage in a one -pot reaction by means of the Pictet-Spengler mechanism under acidic conditions to obtain the objective compound.
  • the libraries in the combinatorial chemistry are simply a collection of the molecules. These libraries vary depending on the method for generating the members of the libraries, or the method used to identify the member which reacts with a biological target of interest, as well as the chemical species in the libraries. The methods for generating the libraries and screening them in this field have been already diversified and complicated. For example, the articles published in recent years, relating to various libraries in the combinatorial chemistry, disclose a number of technologies (Dolle, J. Com. Chem., 2(3): 383-433, 2000), including the use of all the labeled or unlabeled members of the libraries (Janda, Proc. Natl. Acad. Sci. USA 91: 10779-10785, 1994).
  • the compound library is a basic element for rapidly exploring the lead materials in the initial step of drug discovery, as well as for HTS (high throughput screening). Accordingly, the researches for the construction of the unique compound libraries having drug properties by means of a combinatorial chemistry technology, which is a highly efficient synthesis method, can be said to a basic research field which is critical to the improvement of the probability of exploration of the lead materials for new drugs.
  • the combinatorial chemistry synthesis belongs to a new technical field involving the synthesis for discovering new substances and new materials. It can be said that it is a high-efficiency method for the synthesis of the chemical products, allowing a wide variety of many compounds to be synthesized at the same time and also allowing automation of a multi-step synthesis process, while the conventional organic synthesis allows only one compound to be synthesized. Also, the synthesis technology in the combinatorial chemistry has advantages that since the reaction process is largely maintained in the solid support, continuous multi-step reactions and automated reaction processes can be allowed, and that since the process for separating and purifying the products is very simple, high-efficiency, massive assays can be allowed.
  • the synthesis technology in the combinatorial chemistry is a new synthesis method which overcame the problems such as poor economy and efficiency in the conventional synthesis technologies, however this could not be easily applied to the organic synthesis field.
  • One of the reasons therefore is that since the chemical reaction on the solid support requires that most of the reaction reagents should be used in excessive amounts, and thus, in some cases, undesired side reactions occur and the range for the selection of the reaction conditions is extremely narrow due to the limitation of the solvent which can be used according to the physical properties of the selectively used solid support. Accordingly, it can be said that in the synthesis of the compound library employing the solid-phase synthesis, the selection of proper solid- phase supporters and the establishment of proper reaction conditions which can minimize the chemical reactions and side reactions applicable in the solid phase are important elements.
  • the bromoacetal polystyrene resin is generally not a frequently used solid support, but can serve as an important element for generating cleavage in the solid phase under acidic conditions as a feature of the solid support, and the intramolecular cyclization reaction by the reaction of the active aldehyde generated during said cleavage with amide and amine.
  • USA Molecumetics demonstrated the usefulness of a bromoacetal polystyrene resin by employing the bromoacetal polystyrene resin in the production of a double-ring peptidomimetic compound library as a beta-turn analogues (J. Med. Chem. 2002, 45. 7. 1395-1398, PCT WO 01/00210).
  • the compounds as illustrated above exhibit the anti-cancer effect and the activity on the nervous system, and ET-743 as one example thereof is a drug which is approved as an anti-cancer drug in the market.
  • the compounds have the structure which can be commonly shown in alkaloids which are frequently found in natural products, and the substances having biological activity. Accordingly, many researchers have tried to synthesize the natural product mimetics having the biological activity as described above.
  • the methods for synthesizing the natural product mimetics which are largely classical organic synthesis methods, required considerable amount of labors and presented difficulties in preparing the derivatives other than the objective compounds.
  • 1,4-benzodiazepine a number of peptides, natural products and natural product mimetics libraries have been synthesized, however the range thereof was significantly limited.
  • the present inventors have investigated the efficient and massive synthesis methods of the natural product mimetics having the biological activity for the treatment of diseases in the human bodies, in particular the anti-cancer effect and the activity on the nervous system, and during the investigation, have analyzed the structure as illustrated above, which can be commonly seen in the alkaloid often found in the natural products and the materials having biological activity, to obtain a clue for configuring its key structure, and thus have prepared a library of various compounds by using a solid-phase bromoacetal resin as a starting material to react with amino acids and various derivatives thereof. Thus, they confirmed that this synthesis method allows more rapid and massive production of a variety of lead compounds for drug discovery, thus completing the present invention.
  • Technical Solution
  • the present invention aims to provide a new diaza-bridged heterocycle derivative.
  • the present invention aims to provide a solid-phase preparation method of the above-described diaza-bridged heterocycle derivative. Best Mode for Carrying Out the Invention
  • the present invention provides a diaza-bridged heterocycle derivative represented by the following chemical formula 1 :
  • R is hydrogen
  • 1 8 J one group selected from the group consisting of halogen, hydroxy, mercapto, amino, C
  • C -C alkenyl which is unsubstituted or substituted with at least one group selected from the group consisting of halogen, hydroxy, mercapto, amino, C -C alkylamino, C -C dialkylamino, C -C alkylthio, C -C alkylsulfinyl, C -C alkylsulfonyl, C -C alkoxy, C -C cycloalkyl, C -C aryl, C -C cycloheterocycle, and C -C aryl
  • C -C alkynyl which is unsubstituted or substituted with at least one group selected from the group consisting of halogen, hydroxy, mercapto, amino, C -C alkylamino, C -C dialkylamino, C -C alkylthio, C -C alkylsulfinyl, C -C alkylsulfonyl, C -C alkoxy, C -C cycloalkyl, C -C aryl, C -C cycloheterocycle, and C -C aryl
  • R is hydrogen or -(X)-R ,
  • R is C -C linear or branched alkyl; C -C alkenyl; C -C alkynyl; C -C cycloalkyl;
  • a and A may each be independently same or different, and represent hydrogen; C -C linear or branched alkyl which is unsubstituted or substituted with phenyl; C -C alkenyl; or C -C aryl which is unsubstituted or substituted with r J 2 8 J 6 20 J halogen, C -C alkyl or C -C alkoxy, and [28] Ar is C -C aryl which is unsubstituted or substituted with halogen, hydroxy,
  • R is hydrogen
  • R is C -C linear or branched alkyl; C -C cycloheterocycle; phenyl substituted with F, Cl or Br; C 1 -C 8 linear or branched alkyl substituted with at least one group selected from the group consisting of phenyl, naphthyl, and phenyl substituted with F, Cl or Br; C 2 -C 8 alkenyl substituted with at least one group selected from the group consisting of phenyl, naphthyl, and phenyl substituted with F, Cl or Br; C -C alkynyl substituted with at least one group selected from the group consisting of phenyl, naphthyl, and phenyl substituted with F, Cl or Br; or NA A ,
  • a and A may each be independently same or different, and represent hydrogen; C -C linear or branched alkyl which is unsubstituted or substituted with
  • Ar is indole or dihydroxyphenyl.
  • the present invention provides a solid-phase preparation method of the diaza-bridged heterocycle derivative represented by the above chemical formula 1.
  • the solid-phase preparation method of the diaza-bridged heterocycle derivative according to the present invention comprises: [42] 1) a step for preparing a secondary amine compound (3) by reacting a bromoacetal resin (2) with a primary amine compound, [43] 2) a step for preparing a compound (4) by subjecting the secondary amine compound (3) and an amino acid derivative having a protecting group to condensation reaction, [44] 3) a step for removing a protecting group by reacting the compound (4) prepared in the 2) step with piperidine, and preparing a compound (5) by reacting the compound (4) with a R compound, and [45] 4) a step for intramolecular cyclization by reacting the compound (5) with formic acid,
  • the bromoacetal resin (2) used as a starting material is commercially available or directly synthesized for use.
  • HATU (2-(7-aza- lH-benzotriazol- 1-yl)- 1 , 1 ,3,3-tetramethyluronium hexafluo- rophosphate) and DIPEA (N,N'-diisopropylethanolamine) are dissolved in DMF, and after 30 minutes, the reaction mixture is distributed into the reaction vessel, followed by loading it into each of 96 wells. The reaction mixture is subjected to reaction in a rotating oven at room temperature for 12 hours. The resulting resins are washed sequentially three times each with DMF, MeOH and DCM, and then vacuum-dried. HATU is the most effective reagent in terms of yield and purity.
  • step 3 the compound (4) prepared in the step 2) is reacted with piperidine in DMF to remove a protecting group (Fmoc functional group) and is condensed with a R compound (carboxylic acid, isocyanate, sulfonamide or aldehyde).
  • a protecting group Fmoc functional group
  • R compound carboxylic acid, isocyanate, sulfonamide or aldehyde
  • a mixed solvent of 25% piperidine/DMF is distributed into the reaction vessel, and the reaction mixture is reacted with shaking at room temperature for 1 hour to remove an Fmoc functional group.
  • the resulting resins are then washed in the same manner as described above. 3 equivalents of each of 8 carboxylic acids are added to each well, DIC (diisopropylcarbodiimide, 3 equivalents) and HOBt (N-hydroxybenzotriazole, 3 equivalents) are added thereto.
  • the resulting mixture is dissolved in DMF to react with each other and then is distributed into a 96-well reactor.
  • the reaction mixture is shaken in a rotating oven at room temperature for 12 hours.
  • the resulting resins are washed sequentially three times each with DMF, MeOH and DCM, and then vacuum-dried.
  • the solid-phase cleavage/cyclization reaction is performed using the Pictet-Spengler mechanism in a one-pot reaction under acidic conditions.
  • the resins are put into the 96-well reaction vessel which had been sufficiently vacuum-dried and 100% formic acid is distributed into 96 wells to react the resins with shaking at room temperature for 18 hours. After the completion of the reaction, the resins are removed by filtration, the compound obtained is concentrated and freeze- dried using a parallel evaporation device (SpeedVac) to obtain solid-phase products. The products are isolated, and the purity thereof and whether or not the desired products are present by LC/MS are observed.
  • SpeedVac parallel evaporation device
  • C2 attack can provide 3,9-diazabicyclo[3.3.1]non-6-en-2-one derivative (Ia) as a single diastereomer.
  • C3 attack it is speculated that a spiro-five-membered intermediate is generated, followed by cationic migration and hydride elimination, because the compound (Ia) is a single regioisomer and diastereomer in this reaction.
  • the diaza-bridged heterocycle derivative according to the present invention comprises a structure which is commonly shown in alkaloids which are frequently discovered in natural products, and the substances having biological activity, and thus it is expected that it has anti-cancer effect, anti- virus effect, anti-inflammatory effect, or pharmacological activity in heart circulating system disease, immune system disease, central nervous system disease or the like.
  • the solid-phase preparation method of the diaza-bridged heterocycle derivative according to the present invention comprises using a solid-phase bromoacetal resin as a starting material to react with amino acids and various derivatives thereof, and then subjecting the product to solid-phase cleavage and intramolecular cyclization reaction in a one-pot reaction by means of the Pictet-Spengler mechanism under acidic conditions to obtain the objective compound. Therefore, a library of various compounds can be prepared at the same time, and this preparation method allows more rapid and massive production of a variety of lead compounds for drug discovery.
  • Mode for the Invention comprises using a solid-phase bromoacetal resin as a starting material to react with amino acids and various derivatives thereof, and then subjecting the product to solid-phase cleavage and intramolecular cyclization reaction in a one-pot reaction by means of the Pictet-Spengler mechanism under acidic conditions to obtain the objective compound. Therefore, a library of various compounds can be prepared at the same time, and this preparation method allows more rapid and massive
  • Example 1 Solid-phase preparation method of diaza-bridged heterocycle derivative according to the present invention
  • a bromoacetal resin (40 mg, 1.6 mmol/g, 0.064 mmol) was loaded into each well of a Robbins 96-well reactor, and 12 different primary amines (20 equivalents in DMSO 1.2 mL) were distributed into the previously designated wells.
  • the reaction mixture was heated with shaking in a rotating oven at 6O 0 C for 12 hours.
  • the resins were washed sequentially three times each with DMF, MeOH and DCM, and then vacuum- dried.
  • a mixed solvent of 25% piperidine/DMF was distributed into the reaction vessel, and the reaction mixture was reacted with shaking at room temperature for 1 hour.
  • the resins were washed sequentially three times each with DMF, MeOH and DCM and then again with DMF.
  • 3 equivalents of each of 8 carboxylic acids were added to each reaction well, DIC (3 equivalents) and HOBt (3 equivalents) were dissolved in DMF to react with each other for 30 minutes.
  • the reaction mixture was distributed into the 96-well reactor, and the reaction mixture was shaken in a rotating oven at room temperature for 12 hours.
  • the resins were washed sequentially three times each with DMF, MeOH and DCM, and then vacuum-dried.
  • Boc-L-DOPA-OH (3.5 g, 11.78 mmol) was dissolved in dichloromethane (250 rnL), diisopropylcarbodiimide (1.9 mL, 11.78 mmol), hydroxybenzotriazole (1.8 g, 11.78 mmol) and diisopropylethylamine (4 mL, 23.56 mmol) were added thereto, and the resulting mixture was stirred at room temperature for 30 minutes. Aminoacetaldehyde (1.71 mL, 11.78 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours.
  • the organic layer was washed with a 10% aqueous citric acid solution, and then organic layer was dehydrated over sodium sulfate. After the mixed solvent was concentrated, the compound was added to neat formic acid, and then the mixture was stirred for 15 hours to complete the reaction. Then, formic acid was removed by concentration. The resulting compound was purified with silica gel to obtain 1.1 g of the objective compound as a solid.
  • the diaza-bridged heterocycle derivative according to the present invention can be obtained as the objective compound by using a solid-phase bromoacetal resin as a starting material to react with amino acids and various derivatives thereof, and then subjecting the product to solid-phase cleavage and intramolecular cyclization reaction in a one -pot reaction by means of the Pictet-Spengler mechanism under acidic conditions. Therefore, the effect that a library of various compounds can be prepared at the same time is obtained, and this preparation method allows more rapid and massive production of a variety of lead compounds for drug discovery.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne un nouveau dérivé hétérocyclique ponté diaza et son procédé de préparation en phase solide. L'invention consiste plus particulièrement à utiliser une résine au brome acétal comme matériau de départ que l'on met en réaction avec des acides aminés et plusieurs dérivés de ces derniers, et à soumettre le produit à un clivage en phase solide dans une réaction monotope en utilisant le mécanisme de type Pictet-Spengler dans des conditions d'acidité de manière à obtenir le composé désiré.
PCT/KR2006/001714 2006-04-11 2006-05-08 Nouveaux dérivés hétérocycliques pontés diaza et leur procédé de préparation en phase solide Ceased WO2007117053A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2006-0032908 2006-04-11
KR1020060032908A KR100712667B1 (ko) 2006-04-11 2006-04-11 신규한 디아자 헤테로고리 유도체 및 그의 고체상 제조방법

Publications (1)

Publication Number Publication Date
WO2007117053A1 true WO2007117053A1 (fr) 2007-10-18

Family

ID=38269241

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2006/001714 Ceased WO2007117053A1 (fr) 2006-04-11 2006-05-08 Nouveaux dérivés hétérocycliques pontés diaza et leur procédé de préparation en phase solide

Country Status (2)

Country Link
KR (1) KR100712667B1 (fr)
WO (1) WO2007117053A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10457676B2 (en) 2014-08-29 2019-10-29 The Board Of Regents Of The University Of Texas System Capsazepine analogs for the treatment of cancer and other proliferative diseases

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS632991A (ja) * 1986-06-23 1988-01-07 Akinori Kubo 新規イソキノリン誘導体
US4837149A (en) * 1984-08-30 1989-06-06 Tadashi Arai Novel saframycin A derivatives and process for producing the same
WO2003031448A1 (fr) * 2001-10-12 2003-04-17 Choongwae Pharma Corporation Mimetiques de coudes inverses et procede associe
US20030083495A1 (en) * 2000-02-11 2003-05-01 President And Fellows Of Harvard College Synthetic process for an intermediate for ecteinascidin and phthalascidin compounds
EP1287004B1 (fr) * 2000-05-15 2005-07-27 Pharma Mar, S.A. Procede de synthese destine a la fabrication d'un compose d'ecteinascidine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY130271A (en) 1999-05-14 2007-06-29 Pharma Mar Sa Hemisynthetic method and new compounds
US7420051B2 (en) 2000-05-15 2008-09-02 Pharma Mar, S.A. Synthetic process for the manufacture of an ecteinaschidin compound

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4837149A (en) * 1984-08-30 1989-06-06 Tadashi Arai Novel saframycin A derivatives and process for producing the same
JPS632991A (ja) * 1986-06-23 1988-01-07 Akinori Kubo 新規イソキノリン誘導体
US20030083495A1 (en) * 2000-02-11 2003-05-01 President And Fellows Of Harvard College Synthetic process for an intermediate for ecteinascidin and phthalascidin compounds
EP1287004B1 (fr) * 2000-05-15 2005-07-27 Pharma Mar, S.A. Procede de synthese destine a la fabrication d'un compose d'ecteinascidine
WO2003031448A1 (fr) * 2001-10-12 2003-04-17 Choongwae Pharma Corporation Mimetiques de coudes inverses et procede associe

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10457676B2 (en) 2014-08-29 2019-10-29 The Board Of Regents Of The University Of Texas System Capsazepine analogs for the treatment of cancer and other proliferative diseases
US12358909B2 (en) 2014-08-29 2025-07-15 Board Of Regents Of The University Of Texas System Capsazepine analogs for the treatment of cancer and other proliferative diseases

Also Published As

Publication number Publication date
KR100712667B1 (ko) 2007-05-02

Similar Documents

Publication Publication Date Title
US6150416A (en) Nanomolar, non-peptide inhibitors of cathepsin D
AU704183B2 (en) Systematic modular production of aminimide- and oxazolone-based molecules having selected properties
CA2183428A1 (fr) Derives de sulfonamide et leur utilisation
JP4012145B2 (ja) ピロール−イミダゾールポリアミドの固相合成法
Dallinger et al. Creating chemical diversity space by scaffold decoration of dihydropyrimidines
HK1052703A1 (en) Salts of bicyclic, n-acylated imidazo-3-amines and imidazo-5-amines
CN107810189B (zh) 用于制备氮芥衍生物的方法
JP2019501188A (ja) ヘテロアリール含有大環状化合物のライブラリならびにその製造方法および使用方法
WO2007117053A1 (fr) Nouveaux dérivés hétérocycliques pontés diaza et leur procédé de préparation en phase solide
US6872825B2 (en) Peptide β-turn mimetic compounds and processes for making them
JP6638016B2 (ja) シクロペプチド、それを含む医薬または化粧用組成物、及びその製造方法
US6566520B2 (en) Support for synthesis and purification of compounds
US6274383B1 (en) Methods for synthesizing libraries of dihydro-quinazolinones
JP2000508664A (ja) 置換チオフェン及び置換チオフェンのアレイの固相及び組合せ合成
US5962412A (en) Method of making polymers having specific properties
JP2002507617A (ja) 化合物および化合物のライブラリの合成
Maiden et al. A convergent strategy towards febrifugine and related compounds
US8674020B2 (en) Process for preparing polyamides
US20060252093A1 (en) Heterocyclic organic molecules through intramolecular formation of n-acyliminium ions
Boeglin et al. Efficient solid-phase synthesis of 4, 5-dihydro-1, 2, 4-triazin-6 (1H)-ones
Rodriguez Target-oriented and diversity-oriented organic synthesis
Raghavulu et al. Synthesis of novel unnatural α-amino acids (UAAs) containing 7-hydroxy-2, 2-dimethyl-chroman using isoxazole as a linker
CN114341134B (zh) 用于制备包含环氧己烷环的药物的方法
Abdelbaky et al. Synthesis of α-(R)-/γ-(S)-Dimethyl Substituted Peptide Nucleic Acid Submonomer Using Mitsunobu Reaction
WO2001046197A1 (fr) Composes mimetiques du virage-beta peptidique et procedes de fabrication de ces derniers

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: 06757661

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: 06757661

Country of ref document: EP

Kind code of ref document: A1