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WO2003093301A2 - Procede permettant de synthetiser des peptides - Google Patents

Procede permettant de synthetiser des peptides Download PDF

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Publication number
WO2003093301A2
WO2003093301A2 PCT/GB2003/001925 GB0301925W WO03093301A2 WO 2003093301 A2 WO2003093301 A2 WO 2003093301A2 GB 0301925 W GB0301925 W GB 0301925W WO 03093301 A2 WO03093301 A2 WO 03093301A2
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WO
WIPO (PCT)
Prior art keywords
carboxy
protected
nitrogen
amino acid
peptide
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/GB2003/001925
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English (en)
Other versions
WO2003093301A3 (fr
Inventor
David John Evans
Eric Atherton
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Avecia Ltd
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Avecia Ltd
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Filing date
Publication date
Application filed by Avecia Ltd filed Critical Avecia Ltd
Priority to AU2003224327A priority Critical patent/AU2003224327A1/en
Publication of WO2003093301A2 publication Critical patent/WO2003093301A2/fr
Publication of WO2003093301A3 publication Critical patent/WO2003093301A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/003—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by transforming the C-terminal amino acid to amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/042—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers characterised by the nature of the carrier
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
    • C07K1/067—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for sulfur-containing functions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes
    • 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

  • This invention relates to a process for the solid-phase synthesis of peptides and to supports for peptide synthesis.
  • Peptides may be synthesised by solid-phase synthesis that commences from the carboxy-terminal end of the peptide using an ⁇ -amino protected amino acid.
  • the two most widely used protocols employ -ert-butyloxycarbonyl (Boc) or 9- fluorenylmethoxycarbonyl (Fmoc) as amino protecting groups.
  • cysteine residue is very susceptible to the vigorous esterification conditions leading to chiral inversion.
  • the conditions required for Fmoc removal and thus peptide elongation have been shown to promote racemisation of the C ⁇ -cysteine residue following the first amino acid introduction.
  • the synthesis of C ⁇ -Cys terminal peptides via the Fmoc/Boc approach is problematic using established methodologies.
  • the present invention provides a process for the solid-phase synthesis of a peptide which comprises attaching an ⁇ -nitrogen protected ⁇ -carboxy modified amino acid to a solid support via its side chain, removing the ⁇ -nitrogen protecting group, and assembling a peptide chain on said ⁇ -nitrogen.
  • the assembled peptide is then cleaved from the solid support.
  • the ⁇ -nitrogen protecting group is preferably a base labile protecting group. More preferably the ⁇ -nitrogen protecting group is Fmoc.
  • a preferred embodiment provides a process for the solid-phase synthesis of a peptide which comprises attaching an ⁇ -nitrogen protected ⁇ -carboxy protected amino acid to a solid support via its side chain, removing the ⁇ -nitrogen protecting group, and assembling a peptide chain on said ⁇ -nitrogen.
  • the ⁇ -carboxy is protected by the formation of a carboxy ester group, more preferably by the formation of an alkyl ester especially a fe/f-butyl ester (tBu).
  • the ⁇ -carboxy protecting group is selected to be orthogonal to the ⁇ -nitrogen protecting group.
  • the ⁇ -nitrogen protecting group can therefore be removed without deprotection of the ⁇ -carboxy.
  • the ⁇ -nitrogen protected ⁇ -carboxy modified amino acid comprises a heteroatom, such as N, O or S, especially S, in its side chain. More preferably the ⁇ -nitrogen protected ⁇ -carboxy modified amino acid is derived from Cys, Arg, Ser, Tyr, Thr, Lys, Orn, Asp, Glu, Trp, His, Pen (penicillamine), Dpr (2,3-diaminopropionic Acid) and Dab (2,4-diaminobutyric acid).
  • a heteroatom such as N, O or S, especially S, in its side chain. More preferably the ⁇ -nitrogen protected ⁇ -carboxy modified amino acid is derived from Cys, Arg, Ser, Tyr, Thr, Lys, Orn, Asp, Glu, Trp, His, Pen (penicillamine), Dpr (2,3-diaminopropionic Acid) and Dab (2,4-diaminobutyric acid).
  • the ⁇ -nitrogen protected ⁇ -carboxy modified amino acid is derived from cysteine.
  • an especially preferred ⁇ -nitrogen protected ⁇ -carboxy modified amino acid is Fmoc-Cys-O-tBu.
  • Fmoc-Cys-O-tBu may be prepared by reacting the commercially available disulphide (H-Cys-OtBu) 2 .2HCI with Fmoc to yield (Fmoc-Cys-O-tBu) 2 which may be hydrolysed to yield Fmoc-Cys-O-tBu.
  • the process comprises attaching Fmoc-Cys-O-tBu to a solid support by its thiol side chain.
  • the solid support may be any support known in the art which is suitable for use in solid-phase peptide synthesis, optionally with a linker group, able to react with a side chain of an amino acid, more preferably a nucleophilic amino acid side chain, to form a bond which is stable during the acylation and deprotection cycles involved in assembling a peptide.
  • the solid support comprises a polystyrene or polydimethylacrylamide polymer. More preferably the support comprises a copolymer of styrene with about 0.5 to 2% divinyl benzene as a cross-linking agent or a polydimethylacrylamide polymer comprising N,N-dimethylacrylamide, N,N-bisacryloylethylenediamine and acryloylsarcosine methyl ester monomers. Details of these preferred supports and other suitable supports may be found in Chan and White "Fmoc Solid-Phase Peptide Synthesis" Oxford University Press, 2000 which are included herein by reference.
  • the preferred linker group on the solid support comprises a trityl moiety, more preferably a 4-methoxytrityl moiety.
  • a particularly preferred solid support is 4- methoxytrityl polystyrene.
  • a preferred process for the solid-phase synthesis of a peptide comprises the steps of:
  • Step (f) removing the ⁇ -carboxy protecting group and any side chain protecting groups.
  • Step (a) may be carried out under the same conditions and in the same solvents as are commonly used in linking amino acids via their C ⁇ -carboxyl to solid supports in peptide solid-phase synthesis.
  • step (a) typically comprises dissolving Fmoc-Cys-O-tBu in a suitable solvent such as N,N-dimethylformamide then adding, with mixing, N,N-diisopropylethylamine. This solution is then added to the resin and allowed to react before collecting the resin and washing with a suitable solvent such as N,N-dimethylformamide.
  • a suitable solvent such as N,N-dimethylformamide
  • steps (b), (c) and (d) may be carried out using any standard conditions for peptide solid-phase synthesis well known to one skilled in the art.
  • any standard conditions for peptide solid-phase synthesis well known to one skilled in the art.
  • reference is made, for example, to Atherton and Sheppard, "Solid-Phase Peptide Synthesis A Practical Approach", IRL Press at Oxford University Press, 1989 and Chan and White “Fmoc Solid-Phase Peptide Synthesis” Oxford University Press, 2000 which are incorporated herein by reference.
  • Fmoc removal is effected by treating with a solution of piperidine in N,N-dimethylformamide, more preferably 20%v/v piperidine in N,N-dimethylformamide.
  • Amino acid activation is preferably carried out in N,N-dimethylformamide in the presence of 1-hydroxybenzotriazole and diisopropylcarbodiimide.
  • steps (b), (c) and (d) side chain protecting groups may be used to protect susceptible side chains which could otherwise be modified in the coupling and deprotection cycles.
  • Examples of amino acids with susceptible side chains in steps (b) and (c) are Cys, Asp, Glu, Ser, Arg, Har, Tyr, Thr, Lys, Orn, Pen, Trp, Asn and Gin.
  • a post solid-phase synthesis chemical modification of the peptide may be carried out to yield a desired side chain.
  • the precise conditions required to cleave the peptide from the solid support vary with the nature of the side chain of the ⁇ -nitrogen protected ⁇ -carboxy modified amino acid and the linker group on the support and are similar to those known in the art.
  • the peptide may be released by treating the peptide resin with 10% (v/v) ethanedithiol in trifluoroacetic acid.
  • step (f) Suitable conditions for the removal of various carboxy protecting groups in step (f) are described in Chan and White “Fmoc Solid-Phase Peptide Synthesis” Oxford University Press, 2000 on pages 20-21 which is incorporated herein by reference and in Atherton and Sheppard, “Solid-Phase Peptide Synthesis A Practical Approach", IRL Press at Oxford University Press, 1989 which is also incorporated herein by reference.
  • Step (f) removal of the ⁇ -carboxy protecting group, may be carried out before or after step (e), cleavage of the peptide from the resin. However, preferably step (e) and (f) are carried out as a single process.
  • step (d) does not involve reaction with a non-amino acid N-terminal residue that: the ⁇ -nitrogen protecting group is removed from the N-terminus, the link between the solid support and peptide (step (e)) and removal of the ⁇ -carboxy protecting group and any side chain protecting groups is carried out by a single process (step(f)).
  • Isolation and purification of the peptide may be achieved using standard procedures and techniques that would be well known to one skilled in the art. These methods include precipitation of the peptide in a solvent that will not affect the integrity of the peptide.such as diisopropylether, followed by preparative HPLC and salt exchange.
  • the peptide isolated may be subjected to further processing, either before or after purification
  • the processes of the present invention may use batch or continuous flow synthesis techniques or any automated synthesizer following the instructions provided by the manufacturer.
  • a second aspect of the invention provides a support for solid-phase synthesis which comprises an ⁇ -nitrogen protected ⁇ -carboxy modified amino acid attached to a solid phase support through the side chain of the amino acid.
  • the solid phase support is as described in the first aspect of the invention and preferably is based on a polystyrene or polydimethylacrylamide polymer with a trityl linker.
  • the ⁇ -nitrogen protecting group on the attached ⁇ -nitrogen protected ⁇ -carboxy protected amino acid is preferably a base labile protecting group. More preferably the ⁇ - nitrogen protecting group is Fmoc.
  • the ⁇ -carboxy is modified by a protecting group.
  • the ⁇ -carboxy is protected by the formation of a carboxy ester group, more preferably by the formation of an alkyl ester especially a te/ -butyl ester (t-Bu).
  • a preferred support for solid-phase synthesis in the second aspect of the invention comprises a polystyrene or polydimethylacrylamide polymer with a trityl linker to which a Fmoc- ⁇ -nitrogen-C ⁇ -carboxy -erf-butyl ester amino acid is attached by its side chain wherein the amino acid is selected from the group consisting of Cys, Arg, Ser, Tyr, Thr, Lys, Orn, Asp, Glu, Trp, His, Pen, Dpr and Dab, especially Cys.
  • An especially preferred support for solid-phase synthesis in the second aspect of the invention comprises a polystyrene or polydimethylacrylamide polymer with a trityl linker to which Fmoc-Cys-O-tBu is attached by its thiol side chain.
  • an ⁇ -nitrogen protected ⁇ -carboxy protected cysteine wherein the ⁇ -nitrogen protecting group is a base labile protecting group, preferably Fmoc and the ⁇ -carboxy is protected by the formation of a carboxy ester group, more preferably by the formation of an alkyl ester especially a -erf-butyl ester (t-Bu).
  • the ⁇ -nitrogen protecting group is a base labile protecting group, preferably Fmoc and the ⁇ -carboxy is protected by the formation of a carboxy ester group, more preferably by the formation of an alkyl ester especially a -erf-butyl ester (t-Bu).
  • the ⁇ -nitrogen protected ⁇ -carboxy protected cysteine is of formula Fmoc-Cys-O-tBu.
  • ⁇ -nitrogen protected ⁇ -carboxy protected cysteine disulphide linked dimer wherein the ⁇ -nitrogen protecting group is a base labile protecting group, preferably Fmoc and the ⁇ -carboxy is protected by the formation of a carboxy ester group, more preferably by the formation of an alkyl ester especially a terf-butyl ester (t-Bu).
  • the ⁇ -nitrogen protected ⁇ -carboxy protected cysteine disulfide linked dimer is of formula (Fmoc-Cys-O-tBu) 2 .
  • Fmoc-Cys-O-tBu (0.503g, 1.31 mmoles) from stage 2 was dissolved, with stirring, in DMF (3 ml). DIPEA (0.457ml, 2.63 mmoles) was added to the resultant solution and mixed for one minute. The Fmoc-Cys-O-tBu solution so formed was then added to 4- methoxytrityl polystyrene resin (0.500g, scale of assembly 0.875 mmoles) (supplied from CBL-Patros, Greece) as a single aliquot. The reaction mixture was mixed for two hours and then charged to a reactor vessel that allowed removal of the solvent by filtration.
  • the resin with Fmoc-Cys-O-tBu attached was then washed seven times with DMF (7 x 10ml).
  • the washed resin was suspended in 10% v/v DIPEA in methanol (10ml) for 5 minutes before filtration and subsequent washing 7 times with DMF (7 x10ml).
  • the Fmoc protecting group was then removed by treating the resin twice with 20% v/v piperidine in DMF (2 x 10ml).
  • the resin and piperidine/DMF mixture were agitated gently for 3 minutes before removing the piperidine/DMF by filtration.
  • the resin and piperidine/DMF mixture was agitated gently for 7 minutes before removing the piperidine/DMF by filtration.
  • the resin was then washed 7 times with DMF (7 x 10ml) removing the solvent by filtration.
  • Fmoc-Pro-OH (0.443g, 1.31 mmoles) and HOBt (0.402g, 2.63 mmoles) were dissolved in DMF (5 ml) and cooled to less than 10°C in an ice bath. DIC (0.272ml, 1.75 mmoles) was added to the reaction mixture as a single aliquot. The mixture was then agitated for 6 minutes before being charged to the damp resin from stage 3. The coupling reaction was allowed to proceed for 6 hours at ambient temperature. Coupling efficiency was tested by the Kaiser test. The peptide -resin was then washed with DMF (10ml) and the protecting Fmoc-group removed in an identical manner to that as described previously.
  • Fmoc-Har-OH (0.598g, 1.31 mmoles) was coupled using the same protocol as Fmoc-Pro-OH except that additional HOBt (0.603g, 3.94 mmoles) was used to protonate the unprotected guanidino group.
  • additional HOBt 0.03g, 3.94 mmoles
  • [Mpr-OH] 2 (0.276g, 1.31 mmoles) was coupled using the same protocol as for Fmoc-Pro-OH except that the volume of DMF used in the washes was increased from 10 to 12ml. Upon completion of the assembly the peptidyl resin was collapsed using DCM (5 x 20ml). The resin was then air dried for 1 hour (resin yield 1.096g)
  • a premixed solution of 90% TFA /10% EDT (7.5ml) was added to a sample of the peptide resin (0.500g) from stage 4. Thirty minutes after the initial charge the crude linear peptide solution was filtered from the resin. The resin was washed 3 times with TFA (3 x 5ml). The combined filtrates were pooled and concentrated to a thin oil by rotary evaporation (bath temperature ⁇ 35°C). The resultant oil was gradually added drop wise to a stirred media of IPP (20ml). The mixture was agitated for a further 10 minutes and the resultant precipitated peptide filtered through a 0.65 ⁇ m DVPP membrane (Millipore).
  • a sample of peptide (10.1 mg) from stage 5 was suspended in CH 3 CN (1 ml), and water (1ml) was added with agitation to provide a solution. This solution was then added to water (8.1ml) with mixing. A solution of ammonia in water (3.5%w/v, 0.1 ml) was added to the peptide solution to adjust the pH to 9.0 ⁇ 0.25. The amount of ammonia required was approximately 1.0ml/g crude peptide. If the pH exceeded pH 9.25 acetic acid was added to bring the pH value into the required range. The resultant solution was stirred in air and monitored by RP-HPLC until the reaction was deemed complete (18 hours).
  • the elution profile clearly indicated the absence of the linear starting material and the formation of a new single entity (purity 92%) assumed cyclic peptide acid.
  • the sample was then co-injected with a standard of the peptide acid affording a single peak confirming the identity of the crude peptidic product. Additional confirmation to the identity of the crude peptidic material was achieved by electrospray MS (theoretical 833.0, found 832.8).

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

Abstract

L'invention concerne un procédé permettant de réaliser la synthèse en phase solide d'un peptide qui consiste à fixer un acide aminé à α-azote et à α-carboxy protégé sur un support solide via sa chaîne latérale, à supprimer le groupe protecteur de α-azote et à assembler une chaîne peptidique sur ledit α-azote. L'invention concerne également de nouveaux analogues d'acide aminé et des supports en phase solide.
PCT/GB2003/001925 2002-05-03 2003-05-02 Procede permettant de synthetiser des peptides Ceased WO2003093301A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003224327A AU2003224327A1 (en) 2002-05-03 2003-05-02 Process for the synthesis of peptides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0210183.0 2002-05-03
GBGB0210183.0A GB0210183D0 (en) 2002-05-03 2002-05-03 Process

Publications (2)

Publication Number Publication Date
WO2003093301A2 true WO2003093301A2 (fr) 2003-11-13
WO2003093301A3 WO2003093301A3 (fr) 2004-01-08

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GB (1) GB0210183D0 (fr)
WO (1) WO2003093301A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006119388A3 (fr) * 2005-05-03 2007-06-28 Novetide Ltd Methode d'obtention de derives peptidiques
CN101628929A (zh) * 2009-08-27 2010-01-20 中国人民解放军防化指挥工程学院 一种固相合成侧链保护肽链的新方法
US10087221B2 (en) 2013-03-21 2018-10-02 Sanofi-Aventis Deutschland Gmbh Synthesis of hydantoin containing peptide products
US10450343B2 (en) 2013-03-21 2019-10-22 Sanofi-Aventis Deutschland Gmbh Synthesis of cyclic imide containing peptide products

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4119856A1 (de) * 1991-06-17 1992-12-24 Hoechst Ag N-acyl-s-(2-hydroxyalkyl)-cysteine, deren herstellung sowie deren verwendung als zwischenprodukte zur herstellung von synthetischen immunadjuvantien und synthetischen impfstoffen
US6008058A (en) * 1993-06-18 1999-12-28 University Of Louisville Cyclic peptide mixtures via side chain or backbone attachment and solid phase synthesis

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006119388A3 (fr) * 2005-05-03 2007-06-28 Novetide Ltd Methode d'obtention de derives peptidiques
EP2119724A1 (fr) * 2005-05-03 2009-11-18 Novetide Ltd. Procédé en phase solide pour la préparation de la goséréline
EP2119725A1 (fr) * 2005-05-03 2009-11-18 Novetide Ltd. Méthode de préparation de la leuprolide
CN101628929A (zh) * 2009-08-27 2010-01-20 中国人民解放军防化指挥工程学院 一种固相合成侧链保护肽链的新方法
CN101628929B (zh) * 2009-08-27 2014-09-17 中国人民解放军防化学院 一种固相合成侧链保护肽链的新方法
US10087221B2 (en) 2013-03-21 2018-10-02 Sanofi-Aventis Deutschland Gmbh Synthesis of hydantoin containing peptide products
US10450343B2 (en) 2013-03-21 2019-10-22 Sanofi-Aventis Deutschland Gmbh Synthesis of cyclic imide containing peptide products

Also Published As

Publication number Publication date
WO2003093301A3 (fr) 2004-01-08
AU2003224327A1 (en) 2003-11-17
GB0210183D0 (en) 2002-06-12
AU2003224327A8 (en) 2003-11-17

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