WO2000011032A9 - 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

Info

Publication number
WO2000011032A9
WO2000011032A9 PCT/EP1999/006131 EP9906131W WO0011032A9 WO 2000011032 A9 WO2000011032 A9 WO 2000011032A9 EP 9906131 W EP9906131 W EP 9906131W WO 0011032 A9 WO0011032 A9 WO 0011032A9
Authority
WO
WIPO (PCT)
Prior art keywords
peptide
mmol
dimethylformamide
fmoc
protective groups
Prior art date
Application number
PCT/EP1999/006131
Other languages
German (de)
English (en)
Other versions
WO2000011032A2 (fr
WO2000011032A3 (fr
Inventor
Guenther Braum
Axel Lifferth
Christian Birr
Original Assignee
Orpegen Pharma Ges Fuer Biotec
Guenther Braum
Axel Lifferth
Christian Birr
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 Ges Fuer Biotec, Guenther Braum, Axel Lifferth, Christian Birr filed Critical Orpegen Pharma Ges Fuer Biotec
Priority to HU0103196A priority Critical patent/HUP0103196A3/hu
Priority to JP2000566304A priority patent/JP2002523425A/ja
Priority to EP99942897A priority patent/EP1104439B1/fr
Priority to AU56234/99A priority patent/AU5623499A/en
Priority to DE59913712T priority patent/DE59913712D1/de
Publication of WO2000011032A2 publication Critical patent/WO2000011032A2/fr
Publication of WO2000011032A3 publication Critical patent/WO2000011032A3/fr
Publication of WO2000011032A9 publication Critical patent/WO2000011032A9/fr

Links

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 antiproliferative 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.
  • Another object was to enable the production of biostatin in such a way that the product obtained can be easily worked up.
  • 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 aminomethylpolystyrene (AMPS), can also be used advantageously.
  • AMPS aminomethylpolystyrene
  • BHA-PS Benzhydrylamine
  • MBHA-PS methylbenzhydrolamino-polystyrene
  • the solid phase can be used in the form customary for solid phase synthesis.
  • 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-) oxyveryl-4'-methyl-benzhydrylamino-polystyrene and 4- (2 ', 4'-dimethoxyphenyl) aminomethyl- phenoxyacetyl-4 "- methyl benzhydrylamino polystyrene.
  • anchor groups are also 4-hydroxymethyl benzoic 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-hydroxymethyl benzoic 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 that the N- terminally used 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 or / and concentration steps can be carried out if desired. Cleaning can advantageously be carried out by means of preparative HPLC.
  • 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 present invention further provides a process for the synthesis of biostatin (TT-232) by means of peptide synthesis in solution by stepwise construction of the peptide using amino acids derivatized with protective groups, the disulfide bridge being formed by oxidation of the fully or partially built up peptide in the presence of a suitable one Solvent is closed and the biostatin is obtained after removing the solvent and optionally washing the product.
  • biostatin TT-232
  • the process according to the invention enables biostatin to be prepared very effectively and simply by means of peptide synthesis in solution compared to the prior art.
  • Ddz 3-dimethoxybenzyl- ⁇ , ⁇ -dimethyl-oxycarbonyl or 2 [(3,5-dimethoxyphenyl) -2-oxycarbonyl] -propyl
  • Ddz 5-dimethoxybenzyl- ⁇ , ⁇ -dimethyl-oxycarbonyl or 2 [(3,5-dimethoxyphenyl) -2-oxycarbonyl] -propyl
  • Yields of the product can be obtained in a simple manner.
  • the process according to the invention also has the advantage that the oxidation can easily take place after the peptide structure has been completed. In the context of the present invention, it is preferred to carry out the oxidation before all protective groups have been split off, but the procedure is to remove the protective groups before the oxidation also possible, even if the yields are slightly lower with this variant.
  • a particular advantage of the process according to the invention is that after the oxidation and thus intramolecular ring closure has taken place, the reaction solution can be evaporated off via the two cysteine residues and the product is obtained in this way. If necessary, the product is still washed, e.g. with ether, and then suction filtered and dried.
  • 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: 196.8 g (336 mmol) Fmoc-Cys (Trt) in 250 ml NN-dimethylformamide, 52.2 g (336 mmol) HOBt * H 2 O in 125 ml NN-dimethylformamide and 107.9 g TBTU in 375 ml NN-dimethylformamide. These solutions are added to the reaction vessel, then 14.3 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 recoupling is carried out using the following solutions: 157.4 g (336 mmol) Fmoc-Lys (Boc) in 250 ml NN-dimethylformamide, 52.2 g (336 mmol) HOBt * H 2 O in 125 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 14.3 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. Stage 7, splitting off the Fmoc protecting group
  • the Fmoc protecting group is split off as described under stage 3.
  • 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, 104.4 g (672 mmol) of HOBt * H 2 O in 250 ml NN-dimethylformamide and 215.8 g TBTU in 750 ml 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 recoupling is carried out using the following solutions: 143.3 g (336 mmol) Fmoc-D-Trp in 250 ml NN-dimethylformamide, 52.2 g (336 mmol) HOBt * H 2 O in 125 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 14.3 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: 154.4 g (336 mmol) Fmoc-Tyr (tBu) in 250 ml NN-dimethylformamide, 52.2 g (336 mmol) HOBt * H 2 0 in 125 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 14.3 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.
  • stage 1 During the last DMF washing steps of the Fmoc cleavage (stage 1) the following solutions are prepared: 393.6 g (672 mmol) Fmoc-Cys (Trt) in 500 ml NN-dimethylformamide, 104.4 g (672 mmol) HOBt * H 2 O in 250 ml NN-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 recoupling is carried out using the following solutions: 196.8 g (336 mmol) Fmoc-Cys (Trt) in 250 ml NN-dimethylformamide, 52.2 g (336 mmol) HOBt * H 2 O in 125 ml NN-dimethylformamide and 107.9 g TBTU in 375 ml NN-dimethylformamide. These solutions are added to the reaction vessel, then 14.3 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: 89.1 g (336 mmol) Boc-D-Phe in 250 ml NN-dimethylformamide, 52.2 g (336 mmol) HOBt * H 2 O in 125 ml NN-dimethylformamide and 107.9 g TBTU in 400 ml NN-dimethylformamide. These solutions are added to the reaction vessel, then 14.3 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. Level 15, implementation with Boc 2 O
  • the product resulting from stage 14 is mixed with 4 l of NN-dimethylformamide and agitated for 20 minutes. Then 400 g of Boc 2 O are added, after 5 minutes 3 portions of DIEA a 200 ml are added at 5 minute intervals. After 1000 minutes, the product is suctioned off, followed by 5 DMF washing steps (see above) of 3 I and 3 analog MeOH washing steps, 2.5 I of MeOH being used in each case. After drying for 16 hours under high vacuum, 833 g of polymer-bound peptide are obtained.
  • a solution of 416.5 g of iodine in 6 l of NN-dimethylformamide is added to 833 g of polymer-bound peptide (0.37 mmol peptide / g peptide-carrier conjugate) from stage 15. After 60 minutes, the product is filtered off with suction and mixed with 8 l of NN-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 of NN-dimethylformamide and 2 I of 10% Na 2 S 2 0 3 solution are added.
  • a solution of 120 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 16 and shaken for 30 minutes at room temperature. Then it is suctioned off and the resin is again mixed with a releasing reagent. The first post-splitting is suctioned off after 30 minutes, followed by post-splitting of one or two hours in duration.
  • 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 drying in a high vacuum for 16 hours, a total of 231.85 g of peptide are obtained.
  • stage 1 During the last DMF washing steps of the Fmoc cleavage (stage 1), 2.39 g (6 mmol) of Fmoc-Thr (tBu), 1, 12 g (7.2 mmol) of HOBt * H 2 O and 2, 12 g (6.6 mmol) of TBTU dissolved in 15 ml of NN-dimethylformamide. This solution is added to the reaction vessel to the deblocked linker polymer (step 1), then 2.04 ml (12 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.
  • 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.
  • 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 peptide / g peptide-carrier conjugate) from stage 14.
  • the product is filtered off with suction and mixed with 50 ml of NN-dimethylformamide.
  • the mixture is suctioned off, followed by 4 DMF washing steps (see above) of 50 ml.
  • the following procedure is carried out 3 times: 16 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).
  • 0.25 ml of triethylsilane is mixed with 10 ml of trifluoroacetic acid (cleaving reagent).
  • cleaving reagent Trifluoroacetic acid
  • 0.4 g of polymer-bound peptide are shaken with 3 ml of cleaving reagent for 30 minutes, then it is suctioned off and 2.5 ml of cleaving 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 under high vacuum for 16 hours, a total of 11 mg peptide are obtained.
  • Thr-NH 2 are slowly added with vigorous stirring.
  • the solution is degassed with argon.
  • a solution of 92 mg (0.36 mmol) of iodine in 6 mL MeOH is slowly added dropwise at 22 ° C. through a dropping funnel until the reaction solution has a permanent, slightly orange color.
  • a solution of 53 mg (0.3 mmol) of ascorbic acid in 5 mL deionized water is added until the reaction solution is decolorized.
  • the solution is evaporated on a rotary evaporator at 40 ° C. water bath temperature, the residue is triturated with 5 mL ether after drying in a high vacuum, washed with suction and dried in a high vacuum. 280 mg of solid are obtained (HPLC comparison with a reference shows a content of 53%).
  • Example 5 The procedure is as in Example 4, but the disulfide bridge is formed on the protected peptide. 1 . tert butyl-protected TT232

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne un procédé de synthèse de biostatine (TT-232) consistant à effectuer une synthèse en phase solide sur un support polymère, par la formation graduelle du peptide au moyen d'aminoacides dérivatisés par des groupes protecteurs. Selon l'invention, les groupes protecteurs sont séparés et le peptide est détaché de la phase solide. Le pont disulfure est fermé par oxydation du peptide synthétisé complètement ou partiellement, en présence d'un solvant approprié, aussi longtemps que le peptide reste attaché à la phase solide.
PCT/EP1999/006131 1998-08-20 1999-08-20 Procede de production de biostatine (triacetate tt-232) et de ses analogues WO2000011032A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
HU0103196A HUP0103196A3 (en) 1998-08-20 1999-08-20 Method for producing biostatin (tt-232 triacetate) and analogs thereof
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
EP99942897A EP1104439B1 (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
DE59913712T DE59913712D1 (de) 1998-08-20 1999-08-20 Verfahren zur herstellung von biostatin (tt-232 triacetat) und seine analoga

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EPPCT/EP98/05306 1998-08-20
PCT/EP1998/005306 WO2000011031A1 (fr) 1998-08-20 1998-08-20 Procede de production de biostatine (triacetate tt-232) et de ses analogues

Publications (3)

Publication Number Publication Date
WO2000011032A2 WO2000011032A2 (fr) 2000-03-02
WO2000011032A3 WO2000011032A3 (fr) 2000-09-14
WO2000011032A9 true WO2000011032A9 (fr) 2000-10-26

Family

ID=8167037

Family Applications (2)

Application Number Title Priority Date Filing Date
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

Family Applications Before (1)

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

Country Status (5)

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

Family Cites Families (3)

* 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
HU207104B (en) * 1991-01-25 1993-03-01 Biosignal Kutato Fejlesztoe Kf Process for producing new somatostatin analogs inhibiting tumour growth and pharmaceutical compositions comprising such compounds
JPH1067796A (ja) * 1996-08-27 1998-03-10 Sumitomo Pharmaceut Co Ltd 環状ペプチドの合成法

Also Published As

Publication number Publication date
AU5623499A (en) 2000-03-14
HUP0103196A2 (hu) 2002-02-28
WO2000011032A2 (fr) 2000-03-02
HUP0103196A3 (en) 2002-05-28
DE59913712D1 (de) 2006-09-07
JP2002523425A (ja) 2002-07-30
WO2000011031A1 (fr) 2000-03-02
AU9436298A (en) 2000-03-14
WO2000011032A3 (fr) 2000-09-14

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