WO2000011031A1 - Procede de production de biostatine (triacetate tt-232) et de ses analogues - Google Patents

Procede de production de biostatine (triacetate tt-232) et de ses analogues Download PDF

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Publication number
WO2000011031A1
WO2000011031A1 PCT/EP1998/005306 EP9805306W WO0011031A1 WO 2000011031 A1 WO2000011031 A1 WO 2000011031A1 EP 9805306 W EP9805306 W EP 9805306W WO 0011031 A1 WO0011031 A1 WO 0011031A1
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WO
WIPO (PCT)
Prior art keywords
peptide
dimethylformamide
fmoc
mmol
solid phase
Prior art date
Application number
PCT/EP1998/005306
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German (de)
English (en)
Inventor
Günther Braum
Axel Lifferth
Christian Birr
Original Assignee
Orpegen Pharma Gesellschaft Für Biotechnologische Forschung, Entwicklung Und Produktion Mbh
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 Orpegen Pharma Gesellschaft Für Biotechnologische Forschung, Entwicklung Und Produktion Mbh filed Critical Orpegen Pharma Gesellschaft Für Biotechnologische Forschung, Entwicklung Und Produktion Mbh
Priority to AU94362/98A priority Critical patent/AU9436298A/en
Priority to PCT/EP1998/005306 priority patent/WO2000011031A1/fr
Priority to PCT/EP1999/006131 priority patent/WO2000011032A2/fr
Priority to AU56234/99A priority patent/AU5623499A/en
Priority to HU0103196A priority patent/HUP0103196A3/hu
Priority to EP99942897A priority patent/EP1104439B1/fr
Priority to JP2000566304A priority patent/JP2002523425A/ja
Priority to DE59913712T priority patent/DE59913712D1/de
Publication of WO2000011031A1 publication Critical patent/WO2000011031A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/655—Somatostatins
    • C07K14/6555—Somatostatins at least 1 amino acid in D-form
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • BIOSTATIN TT-232 triacetate
  • the present invention relates to a method for the synthesis of biostatin by means of solid phase synthesis.
  • the peptide biostatin (TT-232) is an analogue of somatostatin and has strong in vitro and in vivo antitumor activity.
  • Somatostatin is a naturally occurring tetradecapeptide that inhibits the formation of growth hormone and the secretion of other endocrine molecules, such as glucagon, insulin and gastrin. Somatostatin inhibits or regulates some cell functions and has also been found to display important endogenous antiproiiferative activity. An inhibitory effect of somatostatin and its analogues on tumors has also been shown. In the past few years, some somatostatin analogues have been developed which have longer action times than the native hormone and better anti-tumor activity. A great deal of effort was therefore devoted to developing tumor-selective somatostatin analogs, the ease of manufacture also playing a role in particular.
  • One of these analogs is a molecule with a 5-ring structure with the following sequence:
  • the molecule was called TT-232 or Biostatin.
  • This somatostatin analog has practically no inhibitory effect on growth hormone release, but shows strong antitumor activity in vivo and in vitro and induces apoptosis.
  • the compound inhibits the tyrosine kinase activity of various human intestinal tumor cell lines, this inhibition being in very good agreement with the observed inhibition of cell proliferation.
  • the solid phase synthesis used in the process according to the invention can be carried out in a manner known per se to the person skilled in the art.
  • the suitable solid phase materials, the required reagents, buffers, reaction conditions and protective groups to be used for the amino acids are known to the person skilled in the art.
  • the method according to the invention is based on the finding that the spatial separation of the reaction centers in the formation of the disulfide bridges in biostatin is sufficiently ensured if the oxidation takes place as long as the peptide is still bound to the solid phase.
  • oxidizing agents for oxidation, all oxidizing agents that have already been known for processes carried out in solution can be used. Suitable oxidizing agents are therefore known to the person skilled in the art. Examples of such oxidizing agents are silver, mercury or thallium salts, iodine, peroxides or oxygen. These oxidizing agents are used in the presence of a suitable solvent or solvent mixture.
  • iodine is particularly preferably used as the oxidizing agent, for example in acetic acid solution or in a solvent based on N, N-dimethylformamide.
  • the polymer-bound peptide is washed with various solvents or solvent mixtures.
  • solvents or solvent mixtures e.g. N, N-dimethylformamide, methanol, acetic acid and water or else solutions of complexing reagents or reducing agents, such as in particular thiosulfate or ascorbic acid, can be used.
  • the process according to the invention is advantageously carried out on a solid phase which has an acid labile anchoring bond (ALAB).
  • a polymer in particular polystyrene, is particularly preferably used as the solid phase. Modified resins such as aminomethyl polystyrene (AMPS), benzhydrylamine (BHA-PS) and methylbenzhydrolamino-polystyrene (MBHA-PS) can also be used advantageously.
  • the solid phase can be in the form customary for solid phase synthesis be used.
  • the solid phase is preferably used in the form of beads, so-called "beads".
  • Suitable anchor groups are anchors customary in solid-phase chemistry, which allow the peptide to be split off from the polymeric support in a simple manner. Within the scope of the invention, anchor groups are particularly preferred which enable the peptide to be split off as an amide.
  • Exemplary polymers derivatized with an acid labile anchor group (ALAB-P) are 5- (9-amino) xanthene-2yl-) oxyveryI-4'-methyl-benzhydrylamino-polystyrene and 4- (2 ', 4'-dimethoxyphenyl) aminomethyl- phenoxyacetyl-4 "- methyl benzhydrylamino polystyrene.
  • anchor groups are also 4-hydroxymethylbenzoic acid (HBMA), 9-amino-xanthenyl-3-hydrol (Xant) or p [(R, 5) - - (1 - (9H-fluoren-9-yl) methoxyformamido] -2,4-dimethoxybenzyl] phenoxyacetic acid [MEOBP]
  • HBMA 4-hydroxymethylbenzoic acid
  • Xant 9-amino-xanthenyl-3-hydrol
  • MEOBP p [(R, 5) - - (1 - (9H-fluoren-9-yl) methoxyformamido] -2,4-dimethoxybenzyl] phenoxyacetic acid
  • MEOBP Most preferred in the context of the invention are the Xant and MEOBP groups.
  • the synthesis in the process according to the invention is preferably carried out using the Fmoc / tert. Butyl strategy carried out. This means that the amino acids required to build up the peptide have an Fmoc protecting group on the amino group and tert on the side chain groups. Butyl groups are derivatized.
  • the Fmoc protective group is a temporary protective group since it is split off during the formation of the peptide and only one Fmoc group remains at the N-terminus of the synthesized, solid-phase-bound peptide.
  • the sulfhydryl groups of the cysteines are advantageously derivatized with trityl or Acm protective groups. It is also particularly preferred to use the N-terminal last amino acid in the sequence structure as an N-alpha Boc-protected amino acid derivative.
  • the peptides are also cleaved from the polymeric support by methods known per se.
  • the cleavage is acidic, particularly preferably with concentrated or dilute trifluoroacetic acid.
  • the protective groups of the peptides detached from the solid phase are usually also cleaved by adding acid, preferably again using trifluoroacetic acid. After the peptides have been split off, further purification and / or concentration steps can be carried out, if desired. Cleaning can advantageously be carried out by means of preparative HPLC.
  • the synthesis according to the process according to the invention starts from Fmoc-threonine (tert.butyl ether) amide, which is covalently bound to a polystyrene solid phase via an acid-labile xanthenyl anchor grouping.
  • the individual protected amino acids are subsequently added to form a solid-phase-bound protected peptide.
  • the heptapeptide is then oxidized on the solid phase by adding iodine / N, N-dimethylformamide or acetic acid and the cyclized heptapeptide is detached from the support by acid treatment.
  • all protective groups on side chains of the peptide are split off.
  • the Fmoc protective group is split off as described in step 1, the initial swelling process being dispensed with in the DMF-moist resin.
  • the Kaisertest shows incomplete conversion, a recoupling is carried out using the following solutions: 1 96.8 g (336 mmol) Fmoc-Cys (Trt) in 250 ml NN-dimethylformamide, 52.2 g (336 mmol) HOBt * H 2 0 in 1 25 ml of N.N-dimethylformamide and 1 07.9 g TBTU in 375 ml of NN-dimethylformamide. These solutions are added to the reaction vessel, then 1 1 4.3 ml DIEA is added. After a reaction time of 1 hour, a resin sample is taken, washed and free Amino groups examined. The Kaisertest shows complete conversion, 4 DMF washing steps (see above) are carried out.
  • the Fmoc protecting group is split off as described under stage 3.
  • the Kaisertest shows incomplete conversion, a recoupling is carried out using the following solutions: 1 57.4 g (336 mmol) Fmoc-Lys (Boc) in 250 ml NN-dimethylformamide, 52.2 g (336 mmol) HOBt * H 2 0 in 1 25 ml NN-dimethylformamide and 1 07.9 g TBTU in 375 ml N. N-dimethylformamide. These solutions are added to the reaction vessel, then 1 1 4.3 ml DIEA is added. After a reaction time of 1 hour, a resin sample is taken, washed and examined for free amino groups. The Kaisertest shows complete turnover, 4 DMF washing steps (see above) are carried out.
  • the Fmoc protecting group is split off as described under stage 3. Stage 8, coupling of Fmoc-D-Trp
  • the following solutions are prepared during the last DMF washing steps of the Fmoc cleavage (stage 7): 286.8 g (672 mmol) of Fmoc-D-Trp in 500 ml of NN-dimethylformamide, 1 04.4 g (672 mmol) of HOBt * H 2 0 in 250 ml of NN-dimethylformamide and 21 5.8 g of TBTU in 750 ml of NN-dimethylformamide.
  • the prepared solutions are added to the reaction vessel to the deblocked linker polymer (step 7), then 228.7 ml DIEA is added. After a reaction time of 2 hours, a resin sample is taken, washed and examined for free amino groups.
  • the Kaisertest shows incomplete conversion, a subsequent coupling is carried out using the following solutions: 1 43.3 g (336 mmol) Fmoc-D-Trp in 250 ml NN-dimethylformamide, 52.2 g (336 mmol) HOBt * H 2 0 in 1 25 ml of NN-dimethylformamide and 107.9 g of TBTU in 375 ml of NN-dimethylformamide. These solutions are added to the reaction vessel, then 1 1 4.3 ml DIEA is added. After a reaction time of 1 hour, a resin sample is taken, washed and examined for free amino groups. The Kaisertest shows complete conversion, 4 DMF washing steps (see above) are carried out.
  • the Fmoc protecting group is split off as described under stage 3.
  • the Kaisertest shows incomplete conversion, a subsequent coupling is carried out using the following solutions: 1 54.4 g (336 mmol) Fmoc-Tyr (tBu) in 250 ml N. N-dimethylformamide, 52.2 g (336 mmol) HOBt * H 2 0 in 1 25 ml NN-dimethylformamide and 1 07.9 g TBTU in 375 ml NN-dimethylformamide. These solutions are added to the reaction vessel, then 1 1 4.3 ml DIEA is added. After a reaction time of 1 hour, a resin sample is taken, washed and examined for free amino groups. The Kaisertest shows complete conversion, 4 DMF washing steps (see above) are carried out.
  • the Fmoc protecting group is split off as described under stage 3.
  • the Kaisertest shows incomplete conversion, a subsequent coupling is carried out using the following solutions: 1 96.8 g (336 mmol) of Fmoc-Cys (Trt) in 250 ml of N. N-dimethylformamide, 52.2 g (336 mmol) of HOBt * H 2 0 in 1 25 ml NN-dimethylformamide and 1 07.9 g TBTU in 375 ml N. N-dimethylformamide. These solutions are added to the reaction vessel, then 1 1 4.3 ml DIEA is added. After 1 hour A reaction time sample is taken from a resin, washed and examined for free amino groups. The Kaisertest shows complete conversion, 4 DMF washing steps (see above) are carried out.
  • the Fmoc protecting group is split off as described under stage 3
  • stage 1 During the last DMF washing steps of the Fmoc cleavage (stage 1) the following solutions are prepared: 1 78.3 g (672 mmol) Boc-D-Phe in 500 ml NN-dimethylformamide, 1 04.4 g (672 mmol) HOBt * H 2 0 in 250 ml N. N-dimethylformamide and 21 5.8 g TBTU in 750 ml NN-dimethylformamide. The prepared solutions are added to the reaction vessel to the deblocked linker polymer (stage 11), then 228.7 ml of DIEA are added. After a reaction time of 2 hours, a resin sample is taken, washed and examined for free amino groups.
  • the Kaisertest shows incomplete conversion, a subsequent coupling is carried out using the following solutions: 89.1 g (336 mmol) Boc-D-Phe in 250 ml N. N-dimethylformamide, 52.2 g (336 mmol) HOBt * H 2 0 in 1 25 ml NN-dimethylformamide and 1 07.9 g TBTU in 400 ml NN-dimethylformamide. These solutions are added to the reaction vessel, then 1 1 4.3 ml DIEA is added. After a reaction time of 1 hour, a resin sample is taken, washed and examined for free amino groups. The Kaisertest shows complete turnover, 4 DMF washing steps (see above) are carried out.
  • step 1 4 The product resulting from step 1 4 is mixed with 4 l of NN-dimethylformamide and agitated for 20 minutes. Then 400 g of Boc 2 0 are added, after 5 minutes, 3 portions of DIEA a 200 ml are added every 5 minutes. After 1,000 minutes, the product is suctioned off, followed by 5 DMF washing steps (see above) of 3 l and 3 analogous MeOH washing steps, each using 2.5 l of MeOH. After drying under high vacuum for 16 hours, 833 g of polymer-bound peptide are obtained.
  • a solution of 41 6.5 g of iodine in 6 l of NN-dimethylformamide is added to 833 g of polymer-bound peptide (0.37 mmol of peptide / g of peptide-carrier conjugate) from stage 15. After 60 minutes, the product is filtered off with suction and mixed with 8 l of N.N-dimethylformamide. After 60 minutes, the product is suctioned off, followed by 4 DMF washing steps (see above) of 8 I. The following procedure is carried out 3 times: 8 I N. N-dimethylformamide and 2 I 1 0% Na 2 S 2 0 3 solution admitted.
  • a solution of 1 20 ml each of m-cresol and water in 6 l of trifluoroacetic acid (cleaving reagent) is added to 672.4 g of polymer-bound peptide from stage 1 6 and shaken at room temperature for 30 minutes. Then it is suctioned off and the resin is again mixed with a releasing reagent. The first post-splitting is aspirated after 30 minutes, followed by post-splitting lasting one or two hours. The respective filtrates are evaporated on a rotary evaporator at 30 ° C water bath temperature in a water jet vacuum. The residue is stirred with 3 l of ether, suction filtered through a P3 frit and washed 3 times with 1.5 l of ether. After 1 6 hourly drying in a high vacuum gives a total of 231.85 g of peptide.
  • the Fmoc protective group is split off as described in step 1, the initial swelling process being dispensed with in the DMF-moist resin.
  • the Fmoc protecting group is split off as described under stage 3.
  • the Fmoc protecting group is split off as described under stage 3.
  • the Fmoc protecting group is split off as described under stage 3.
  • stage 9 During the last DMF washing steps of the Fmoc cleavage (stage 9), 2.76 g (6 mmol) of Fmoc-Tyr (tBu), 1, 1 2 g (7.2 mmol) HOBt * H 2 0 and 2, 1 2 g (6, 6 mmol) TBTU dissolved in 1 5 ml of NN-dimethylformamide. This solution is added to the reaction vessel to the deblocked linker polymer (step 9), then 2.04 ml (1 2 mmol) DIEA is added. After a reaction time of 2 hours, a resin sample is taken, washed and examined for free amino groups. The Kaisertest shows complete conversion, 5 DMF washing steps (see above) are carried out. Stage 1 1, splitting off the Fmoc protective group
  • the Fmoc protecting group is split off as described under stage 3.
  • the Fmoc protecting group is split off as described under stage 3.
  • a solution of 2.5 g of iodine in 50 ml of NN-dimethylformamide is added to 5 g of polymer-bound peptide (0.30 mmol of peptide / g of peptide-carrier conjugate) from stage 1 4.
  • the product is filtered off with suction and mixed with 50 ml of N. N-dimethylformamide.
  • the product is suctioned off, followed by 4 DMF washing steps (see above) of 50 ml.
  • the following procedure is carried out 3 times: 1 6 ml of NN-dimethylformamide and 4 ml of 10% Na 2 S 2 0 3 solution are added .
  • suction is carried out, followed by 3 DMF washing steps. It is then washed 3 times with water, methanol, water and methanol and dried overnight under high vacuum. Weigh out 4.1 g (0.34 mmol peptide / g peptide-carrier conjugate).
  • Example 3 Disulfide oxidation with thallium trifluoroacetate
  • 136 mg TI (TFA) 3 are dissolved in 1 ml NN-dimethylformamide (oxidation solution), 0.5 g polymer-bound peptide (0.38 mmol peptide / g peptide carrier conjugate) are mixed with 3 ml NN-dimethylformamide for 5 minutes shaken, then 0.725 ml of oxidizing solution are added.
  • 0.25 ml of triethylsilane is mixed with 10 ml of trifluoroacetic acid (cleavage reagent).
  • cleavage reagent Trifluoroacetic acid
  • 0.4 g of polymer-bound peptide is shaken for 30 minutes with 3 ml of cleavage reagent, then it is suctioned off and 2.5 ml of cleavage reagent is added.
  • the product is filtered off with suction and the resin is treated for 1 and 2 hours with 2.5 ml of cleaving reagent.
  • the filtrates are evaporated, triturated with 3 ml of ether each time, the precipitates obtained are suction filtered through a P3 frit and washed 3 times with 2 ml of ether each time. After drying in a high vacuum for 16 hours, a total of 119 mg of peptide are obtained.

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Abstract

L'invention concerne un procédé de synthèse de biostatine (TT232), consistant à effectuer une synthèse en phase solide sur un support polymère par formation par étapes du peptide, au moyen d'aminoacides dérivatisés avec des groupes de protection, ces groupes de protection étant ensuite éliminés et le peptide séparé de la face solide. Le pont disulfure est fermé par oxydation du peptide complètement ou partiellement formé, en présence d'un solvant approprié, tant que le peptide reste lié à la phase solide.
PCT/EP1998/005306 1998-08-20 1998-08-20 Procede de production de biostatine (triacetate tt-232) et de ses analogues WO2000011031A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
AU94362/98A AU9436298A (en) 1998-08-20 1998-08-20 Method for producing biostatin (tt-232 triacetate) and the analogs thereof
PCT/EP1998/005306 WO2000011031A1 (fr) 1998-08-20 1998-08-20 Procede de production de biostatine (triacetate tt-232) et de ses analogues
PCT/EP1999/006131 WO2000011032A2 (fr) 1998-08-20 1999-08-20 Procede de production de biostatine (triacetate tt-232) et de ses analogues
AU56234/99A AU5623499A (en) 1998-08-20 1999-08-20 Method for producing biostatin (tt-232 triacetate) and analogs thereof
HU0103196A HUP0103196A3 (en) 1998-08-20 1999-08-20 Method for producing biostatin (tt-232 triacetate) and analogs thereof
EP99942897A EP1104439B1 (fr) 1998-08-20 1999-08-20 Procede de production de biostatine (triacetate tt-232) et de ses analogues
JP2000566304A JP2002523425A (ja) 1998-08-20 1999-08-20 ビオスタチン（ｔｔ−２３２トリアセテート）およびその類似体の製造方法
DE59913712T DE59913712D1 (de) 1998-08-20 1999-08-20 Verfahren zur herstellung von biostatin (tt-232 triacetat) und seine analoga

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1998/005306 WO2000011031A1 (fr) 1998-08-20 1998-08-20 Procede de production de biostatine (triacetate tt-232) et de ses analogues

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WO2000011031A1 true WO2000011031A1 (fr) 2000-03-02

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PCT/EP1998/005306 WO2000011031A1 (fr) 1998-08-20 1998-08-20 Procede de production de biostatine (triacetate tt-232) et de ses analogues
PCT/EP1999/006131 WO2000011032A2 (fr) 1998-08-20 1999-08-20 Procede de production de biostatine (triacetate tt-232) et de ses analogues

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Application Number Title Priority Date Filing Date
PCT/EP1999/006131 WO2000011032A2 (fr) 1998-08-20 1999-08-20 Procede de production de biostatine (triacetate tt-232) et de ses analogues

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JP (1) JP2002523425A (fr)
AU (2) AU9436298A (fr)
DE (1) DE59913712D1 (fr)
HU (1) HUP0103196A3 (fr)
WO (2) WO2000011031A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0505680A1 (fr) * 1991-01-25 1992-09-30 BIOSIGNAL Kutato-Fejleszto Kft. Octapeptidyl et heptepeptidyl dérivés, procédé pour les préparer aussi comme médicaments qui les contiennent et leur utilisation
JPH1067796A (ja) * 1996-08-27 1998-03-10 Sumitomo Pharmaceut Co Ltd 環状ペプチドの合成法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2451915A1 (fr) * 1979-03-23 1980-10-17 Clin Midy Nouveau procede de preparation de la somatostatine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0505680A1 (fr) * 1991-01-25 1992-09-30 BIOSIGNAL Kutato-Fejleszto Kft. Octapeptidyl et heptepeptidyl dérivés, procédé pour les préparer aussi comme médicaments qui les contiennent et leur utilisation
JPH1067796A (ja) * 1996-08-27 1998-03-10 Sumitomo Pharmaceut Co Ltd 環状ペプチドの合成法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
C GARCIA-ECHEVERRIA ET AL.: "Convenient synthesis of a cyclic peptide disulfide: a type II beta-turn structural model", TETRAHEDRON LETTERS., vol. 30, no. 18, 1989, OXFORD GB, pages 2441 - 2444, XP002103314 *
CHEMICAL ABSTRACTS, vol. 128, no. 19, 11 May 1998, Columbus, Ohio, US; abstract no. 230702, H UNO & S KANAOKA: "preparation of cyclic peptides" XP002103315 *
M KAKIUCHI ET AL.: "Amino acids and peptides. XXVII. Solid phase synthesis of fibrinogen-related peptides with disulfide bond formed on solid support", CHEMICAL AND PHARMACEUTICAL BULLETIN., vol. 44, no. 5, May 1996 (1996-05-01), TOKYO JP, pages 1107 - 1110, XP002103313 *

Also Published As

Publication number Publication date
JP2002523425A (ja) 2002-07-30
WO2000011032A3 (fr) 2000-09-14
WO2000011032A9 (fr) 2000-10-26
WO2000011032A2 (fr) 2000-03-02
AU5623499A (en) 2000-03-14
AU9436298A (en) 2000-03-14
HUP0103196A2 (hu) 2002-02-28
HUP0103196A3 (en) 2002-05-28
DE59913712D1 (de) 2006-09-07

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