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WO1999026902A1 - Technologie en phase solide pour l'elaboration de bibliotheques combinatoires par via ancrage par liaison amide - Google Patents

Technologie en phase solide pour l'elaboration de bibliotheques combinatoires par via ancrage par liaison amide Download PDF

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Publication number
WO1999026902A1
WO1999026902A1 PCT/GB1998/003523 GB9803523W WO9926902A1 WO 1999026902 A1 WO1999026902 A1 WO 1999026902A1 GB 9803523 W GB9803523 W GB 9803523W WO 9926902 A1 WO9926902 A1 WO 9926902A1
Authority
WO
WIPO (PCT)
Prior art keywords
linker
resin
compounds
scheme
general formula
Prior art date
Application number
PCT/GB1998/003523
Other languages
English (en)
Inventor
Tony Johnson
Martin Quibell
Joanne Howe
Original Assignee
Peptide Therapeutics Limited
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
Priority claimed from GBGB9724853.8A external-priority patent/GB9724853D0/en
Priority claimed from GBGB9808744.8A external-priority patent/GB9808744D0/en
Application filed by Peptide Therapeutics Limited filed Critical Peptide Therapeutics Limited
Priority to AU13420/99A priority Critical patent/AU734992B2/en
Priority to CA002311490A priority patent/CA2311490A1/fr
Priority to EP98956988A priority patent/EP1034154A1/fr
Priority to JP2000522063A priority patent/JP2001524457A/ja
Publication of WO1999026902A1 publication Critical patent/WO1999026902A1/fr

Links

Classifications

    • 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
    • C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/74—Unsaturated compounds containing —CHO groups
    • 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
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • 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

  • Combinatorial chemistry techniques which are methods for the parallel preparation of many molecules compared to traditional single serial techniques, have the potential to play a pivotal role in the design and development of drug-like molecules.
  • International Application No. WO 97/40065 describes a combinatorial library technology which has been developed as a tool to accelerate the development of inhibitors of proteolytic enzymes.
  • a protease is screened against a large addressable library of potential protease substrates, swiftly providing an assay for proteolytic activity based upon internally quenched fluorescence.
  • a wealth of substrate structure-activity data is gathered which may be used in the design of an inhibitor.
  • International Application No. WO 98/17628 describes a novel solid-phase methodology allowing flexible variation of the N and C termini of a discrete target compound, or a combinatorial approach leading to parallel preparation of many analogues of a target compound. This approach allows for great flexibility in the primary sequence assembly of many chemical classes of compound libraries.
  • a potential limitation to International Application No. WO 98/17628 may be encountered when considering a further level of complexity in library synthesis - the absolute chiral integrity of all chiral centres in the target molecules. Under certain circumstances the C terminal amino acid of an assembled sequence can undergo epimerisation with the resulting loss of chiral integrity.
  • Solid phase based syntheses utilise a cross-linked polymer (a resin support) which is functionalised with a chemically reactive unit (a linker).
  • a functional group (carboxylic acid, amine, hydroxyl, sulphydryl etc) from an initial intermediate of the final desired compound is reversibly and covalently attached to the resin through the linker.
  • Sequential chemical transformations of this now resin-bound intermediate to the final compound are then performed.
  • excess and spent reagents are removed from the growing resin-bound product by simple filtration and washing - this being the overriding factor providing expedient synthesis compared to solution based synthesis.
  • the fully assembled product is released from the solid support by cleavage of the covalent bond between the linker and product functional group.
  • peptidyl acyloxymethyl ketones a potent class of inhibitor of the cysteinyl protease Derp I, a major allergen of the house dust mite contain no obvious functional group by which a linker can attach an intermediate to a resin. Therefore current solid phase techniques cannot prepare many types of potential drug candidates as single discrete compounds let alone defined libraries of analogues.
  • the only functional element that is always required to be present in the target molecule is a single secondary amide group.
  • the attachment of initial intermediates through the conserved secondary amide group to a resin support provides a unique route to any class of linear compounds.
  • the covalent bond between the linker and now tertiary amide is cleaved to regenerate the conserved secondary amide.
  • Coupling reactions the addition of a new chemical moiety providing a part of the final product
  • each coupling stage may be performed using chemical mixtures, providing a combinatorial library of final products in which both the N and C terminal residues have been varied. This latter route greatly expands the number and range of drug-like molecules that may be accessed in an overall drug discovery programme.
  • backbone amide protecting groups which generate amides upon acidolytic treatment described in the literature.
  • Johnson, Quibell and Sheppard have described the development of a backbone amide protection system.
  • This system (not a linker in its own right) was designed to protect the backbone amide of a peptide (previously attached to the resin through a C-terminal residue- linker moiety) during synthesis.
  • the group was removed as a final step along with side-chain deprotection and peptide- linker cleavage by trifluoroacetic acid (TFA).
  • TFA trifluoroacetic acid
  • this linker has the limitation that under certain circumstances a C ⁇ terminal amino acid can undergo epimerisation with the resulting loss of chiral integrity.
  • loss of chiral integrity may occur.
  • An example of this is the preparation of backbone cyclised peptides.
  • the C-terminal amino acid residue of a peptide sequence is activated, without urethane protection, facilitating closure to a cyclic peptide and may give significant epimersiation of the C ⁇ of the activated amino acid residue.
  • This problem severely restricts the fully flexible synthesis of cyclic peptides. with full chiral integrity, to a method of preparation which relies on the activation of a glycine (achiral), or proline (good chiral stability) respectively.
  • the present invention provides the means to suppress epimerisation of the C ⁇ terminal amino acid of a protected peptide sequence during coupling by using the protection moiety shown in (1) which is referred to as a "'precursor linker * ' by virtue of having the aldehyde group.
  • This moiety has a number of features; the functional group R and the 2- hydroxyl function lie in a para position relative to each other while the ether residue lies in a para position relative to the aldehyde residue.
  • Rl is an electron donating alkyl group.
  • the R group is a moiety that may readily be interconverted between electron- withdrawing and electron donating. This is based on the safety catch principle. The principle, that a stable bond is smoothly converted to a labile one at a convenient point during a synthesis, has been applied in peptide chemistry for the development of linkers and protecting groups. One approach has been to exploit the facile reductive conversion of a sulphoxide to sulphide. This approach when applied to the precursor linker (1) provides the functional protection moieties which are referred to as "linker compounds".
  • the present invention provides a resin linked compound of the general formula:
  • X is (CH 2 ) n R3 where R3 is an -CO- group for attachment to the terminal NH group of the solid phase through a standard bond eg carboxyl amide;
  • Rl is methyl or another such suitable alkyl known in the art; n is between 2 and 12, preferably 4;
  • Y is H or an N ⁇ functional group protective moiety such as Fmoc;
  • R2 is a variable residue
  • R2 1 is an intermediate form of R2 which is subsequently chemically transformed to give the desired R2.
  • the present invention provides an alternative presentation of the linker whereby the attachment to the solid phase via X is through the ether residue of (B), as shown in (C).
  • X is (CH 2 ) ⁇ R3, where R3 is an -CO- group for attachment to the terminal NH group of the solid phase through a standard bond eg carboxyl amide;
  • Rl is methyl or another such suitable alkyl known in the art; and n is between 2 and 12, preferably 4.
  • the invention provides a methodology for producing the compounds above as well as providing for the compounds which are the products of the said methods.
  • X is (CH 2 ) n R3
  • (CH 2 ) is selected from: (a) a linear alkyl group; (b) a branched alkyl group; and (c) a non-aromatic ring system which may optionally be attached to a linear or branched alkyl group.
  • Analytical HPLC was performed using a Phenomenex Jupiter C4 reversed phase column (250 x 4.6 mm id). Solvent system used: solvent A: 0.1% aqueous TFA. Solvent B: 90% acetonitrile, 10% solvent A. Analytical gradient used 10% solvent B, to 90% solvent B over 27 min. Mass spectra were recorded using a Fisons VG single platform spectrometer in either positive ES (electrospray) or APCI (Atmospheric Pressure Chemical Ionisation) mode. 400MHz NMR were acquired at the University of Cambridge NMR service. Chemical shifts are reported in parts per million and were referenced to residual solvent peaks within deuterated solvents.
  • DEPT disortionless enhancement through polarization transfer
  • (0); CH or CH 3 (positive) and (1); C or CH; (negative) signals (0); CH or CH 3 (positive) and (1); C or CH; (negative) signals.
  • Analytical thin-layer chromatography (TLC) was conducted on prelayered silica gel Plates. Visualisaxion of plates was accomplished using a 254 nm UV light (for chromophores). Flash chromatography was conducted upon Kieselgel 60, 230-400 mesh and was run under a slight positive pressure.
  • Solvents used were either reagent or HPLC grade. Reactions were carried out at ambient temperature under nitrogen unless otherwise noted. Solvent mixtures are expressed as volume: volume ratios. All starting materials were commercially available unless otherwise stated.
  • Resorcinol 0.1 mmol, 11s
  • copper sulphate 0.2mmol, 3 l.Sg
  • Ammonium thiocyanate 0.4mmol, 31g
  • the resultant white suspension was filtered through celite; and washed with a further 50mL of water.
  • the resultant filtrate was stirred vigorously with the addition of sodium carbonate (0.5mmol, 5.3g) in water (50mL) in one portion.
  • 6-(tert-butoxy)-2H-l,3-benzoxathiol-2- ⁇ ne (2) (l lmmol, 2.49g) was dissolved in dioxane (105mmol, 9.60mL) with vigorous stirring at 5°C. A 2N solution of NaOH (10.56mL) was added in a dropwise manor over 10 minutes with vigorous stirring. Cooling was maintained for 10 minutes further then the solution was allowed to warm to room temperature for 1 hour. Dioxane was removed in vacuo, the remaining slurry was taken up in water (lOmL) and washed with tert-butyl ether (20mL).
  • the resultant resin-handle complex was washed with DMF (5 x 2 min), CH2CI2 (5 x 2 min), MeOH (3 x 2 min) and TBDME ( 5 2 min).
  • the resin was dried imtially under a positive nitrogen pressure and then in vacuo.
  • Linker-resin complex (10) was allowed to eqilibrate in trimethylorthoformate (15mL) containing H-L-Leu-CTMA (28mmol, 4.62g). The reaction is allowed to proceed in a capped syringe for 5 hours. The resultant resin-complex was washed with dry THF (5 x 2 min) and dried under a positive pressure of nitrogen. The resin was then suspended in dry THF/ acetic acid/water (90:5:5, v/v/v, 20mL) containing sodium cyanoborohydride (14mmol, 882mg) for 14 hours.
  • the resultant resin conjugate was washed with DMF/water (9:1, v/v, 20mL x 9), MeOH (20mL x 9) and tert-butyl ether (30mL x 1) allowing the solvent to percolate through the resin bed for 30 seconds.
  • the resin conjugate was dried under a positive nitrogen pressure and in vacuo for 2 hours.
  • the resin-linker-AA-OCTMA complex was initially reated with Fmoc-Cl and DIEA to protect the the secondary amine mtrogen prior to oxidation of the sulfide.
  • the nitrogen dried resin conjugate (500mg) was suspended in a solution of MCPBA (250mg in 25mL DCM). The reaction was allowed to proceed in a capped syringe for 5 hours.
  • the resultant resin-complex was washed with DCM (2 x 20mL), DMF (2 x 20mL), methanol (2 x 20mL) and finally tert-butyl ether (2 x 20mL).
  • the resin conjugate was dried under a positive nitrogen pressure and finally in a vacuum desicator overnight. Acylation of resin conjugate (11) via symmetrical anhydrides. (A general case)
  • Fmoc-amino acid (20eq excess to resin loading) is dissolved / suspended in dichloromethane (5mL / mmol amino acid) with stirring and ice cooling in a 50mL Falcon tube. If the amino acid appears insoluble , then DMF (500 ⁇ L) is added to aid dissolution. Diisopropylcarbodiimide(l ⁇ eq) in DCM (lmL) is added over a few minutes, and the mixture stirred at 0°C for 30 minutes. Resin conjugate (11) was added to the anhydride solution, sealed and left to react for the appropriate time. The fully acylated resin cojugate is filtered and washed with DMF (5 x 50mL), methanol (5 x 50mL) and tert-butyl ether (2 x 50mL).
  • Solid phase peptide chemistry was carried out using standard solid phase Fmoc-AA-Opfp / HOBt couplings.
  • the C-terminal protecting group chosen was the in house developed Fmoc-AA-OCTMA derivatives. These Fmoc amino acid derivatives are stable throughout Fmoc-polyamide peptide synthesis, and can be removed using weak solutions of TFA in conjunction with the appropriate scavengers (TFA / TES).
  • Pepti de-resin conjugate (lOOmg) was suspended in a solution of 2%TFA / 1%TES in DCM (lOmL) for 15 minute x 2. The resin was filtered, washed with DMF (5 x lOmL), methanol (5 x lOmL) and tert butyl ether (5 x lOmL) and dried under a positive nitrogen pressure. Cvclization to give cvclo A AAi - AA?- AAi- AA.- AA*- A ⁇ A-
  • Peptide-resin 50mg, 0.24mmol / g, was treated with suspended in 1ml of a solution of DMF containing BOP (16mg, 0.036mmol), HOBt (6mg, 0.036mmol) and NMM (4 ⁇ L, 0.036mmol).
  • the resin was aggitated for 24 hours, removal of reagents occurred via filtration, followed by washing with DMF (2 x 2mL), methanol (2 x 2mL) and tert-butyl ether (2 x 2mL). The resin was dried under a positive pressure of nitrogen prior to cleavage.
  • Peptide-resin 50mg, 0.24mmol / g, was treated with suspended in 1ml of a solution of DMF containing BOP (16mg, 0.036mmol). HOBt (6mg, 0.036mmol) and NMM (4 ⁇ L, 0.036mmol) and H-AA-AMC (0.036mmol). The resin was aggitated for 2 hours, removal of reagents occurred via filtration, followed by washing with DMF (2 x 2mL), methanol (2 x 2mL) and tert-butyl ether (2 x 2mL). The resin was dried under a positive pressure of nitrogen prior to cleavage.
  • Peptide-resin conjugate (50mg, 0.24mmol g "1 substitution) was suspended in TFA / TES / DMS / H 2 0 (90/1/1/8) containing 1 mol % of NELL The suspension was aggitated at room temperature for 2 hours. The resin was filtered, the resultant filtrate was sparged down under a stream of nitrogen and the peptide precipitated via the slow addition of cold ten butyl ether, spun down via centrifugation and air dried prior to HPLC analysis.
  • Linear peptide sequence prepared via Fmoc polyamide synthesis Compound of general formula cyclo XAAi-TL i-AArAAj-AAs-AAe)- H-Leu-Tyr-Leu-Ser-Gln-Leu-OH, C 35 H 37 N 7 O ⁇ o ; calculated 735.89, found 736.5 (MET). HPLC retention 12.78 minutes.
  • Combinatorial libraries of peptidyl cyclic compounds which can be cyclised from linear compounds of general formula (D) and cleaved to provide cyclic compounds of the general formula (E) in which AA r AA 3 are independently combinatorially variable.
  • the class of compound (D) can utilise any available residue, be it a peptide, peptidomimetic or other, as during the synthesis the chiral integrity of the C ⁇ is protected. Therefore, the need to include specialised residues in this position, such as proline or glycine, which cannot easily be epimerised in the reaction, is eliminated.
  • the present invention can be used to produce combinatorial libraries useful for designing appropriate peptide-based substrates and inhibitors for proteases (and other enzymes).
  • a known class of compounds having three variable amino acid residues X of general formula Ac-X-X-X-Asp-aminomethylcoumarin have been proposed for investigating protease specificities of interleukin-l ⁇ converting enzyme (ICE) - ref: Rans et al, Chem. & Biol., 1997, Vol. 4, No. 2.
  • ICE interleukin-l ⁇ converting enzyme
  • the present invention allows for the production of a general library class of compounds -X-X-X-X-AMC which have four variable amino acid residues X. Such compounds are referred to hereafter as "4X-AMC".
  • the compounds can be synthesised according to the present invention and libraries of the compounds can be used to rapidly and accurately assess enzymatic specificity.
  • Scheme 5 provides a generic synthetic route to 4X-AMC compoimds
  • Scheme 6 provides a specific example of the synthesis of the compound Ac-Tyr-Leu-Leu-Lys- AMC.
  • step A the compound prior to step A could be chosen to have tha-SOMe rather than the -SMe substituent.
  • the reductive amination of step A would reduce -SOMe to -SMe followed by re-oxidation to -SOMe in step B.

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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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)
  • Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)

Abstract

L'invention concerne une technique permettant d'éliminer l'épimérisation de l'acide aminé terminal Cα dans une séquence peptidique protégée, durant le couplage, en utilisant la fraction de protection représentée en (1), que l'on appelle 'lieur précurseur'. Cette fraction a un certain nombre de caractéristiques. Ainsi, le groupe fonctionnel R et la fonction 2-hydroxyle sont en position para l'un vis-à-vis de l'autre, et le résidu éther est en position para vis-à-vis du résidu aldéhyde. R1 est un groupe alkyle donneur d'électrons. Le groupe R est une fraction capable de passer facilement d'un rôle de retrait d'électrons à un rôle donneur d'électrons et vice versa. Cela repose sur la notion de mécanisme de sécurité. Le principe selon lequel une liaison stable passe aisément à l'état de liaison instable en un point approprié durant une synthèse a été appliqué à la chimie des peptides pour l'élaboration de lieurs et de groupes de protection. Une approche a consisté à exploiter la facilité de conversion réductrice d'un sulfoxyde en sulfure. Lorsqu'elle est appliquée au lieur précurseur (1), cette approche permet d'obtenir des fractions de protection fonctionnelles appelées 'composés lieurs'.
PCT/GB1998/003523 1997-11-26 1998-11-26 Technologie en phase solide pour l'elaboration de bibliotheques combinatoires par via ancrage par liaison amide WO1999026902A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU13420/99A AU734992B2 (en) 1997-11-26 1998-11-26 A solid-phase technology for the preparation of combinatorial libraries through amide-bond anchoring
CA002311490A CA2311490A1 (fr) 1997-11-26 1998-11-26 Technologie en phase solide pour l'elaboration de bibliotheques combinatoires par via ancrage par liaison amide
EP98956988A EP1034154A1 (fr) 1997-11-26 1998-11-26 Technologie en phase solide pour l'elaboration de bibliotheques combinatoires par via ancrage par liaison amide
JP2000522063A JP2001524457A (ja) 1997-11-26 1998-11-26 アミド結合固着による混成ライブラリー調製のための固相技術

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB9724853.8A GB9724853D0 (en) 1997-11-26 1997-11-26 A solid-phase technology for the preparation of combinatorial libraries through amide-bond anchoring
GB9724853.8 1998-04-25
GB9808744.8 1998-04-25
GBGB9808744.8A GB9808744D0 (en) 1998-04-25 1998-04-25 A solid-phase technology for the preparation of combinatorial libraries through amide-bond anchoring

Publications (1)

Publication Number Publication Date
WO1999026902A1 true WO1999026902A1 (fr) 1999-06-03

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PCT/GB1998/003523 WO1999026902A1 (fr) 1997-11-26 1998-11-26 Technologie en phase solide pour l'elaboration de bibliotheques combinatoires par via ancrage par liaison amide

Country Status (5)

Country Link
EP (1) EP1034154A1 (fr)
JP (1) JP2001524457A (fr)
AU (1) AU734992B2 (fr)
CA (1) CA2311490A1 (fr)
WO (1) WO1999026902A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1115739A1 (fr) * 1998-09-25 2001-07-18 The University Of Queensland Auxiliaire pour la formation de liaisons amides
US7589170B1 (en) 1998-09-25 2009-09-15 The University Of Queensland Synthesis of cyclic peptides
CN117924235A (zh) * 2024-01-19 2024-04-26 王叔和生物医药(武汉)有限公司 硫氰酸钠在氧化间苯二酚合成制备噻克索酮中的应用及噻克索酮的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992018144A1 (fr) * 1991-04-12 1992-10-29 Michal Lebl Benzhydrylamines substituees utilisees comme elements d'espacement bifonctionnels de liaison pour la synthese de peptides en phase solide
WO1996000378A1 (fr) * 1994-06-23 1996-01-04 Affymax Technologies N.V. Compose photolabiles et procedes pour leur utilisation
WO1998017628A2 (fr) * 1996-10-22 1998-04-30 Peptide Therapeutics Limited Technique en phase solide pour la preparation d'amides

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6528275B1 (en) * 1996-04-24 2003-03-04 Peptide Therapeutics Limited Substrates and inhibitors of proteolytic enzymes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992018144A1 (fr) * 1991-04-12 1992-10-29 Michal Lebl Benzhydrylamines substituees utilisees comme elements d'espacement bifonctionnels de liaison pour la synthese de peptides en phase solide
WO1996000378A1 (fr) * 1994-06-23 1996-01-04 Affymax Technologies N.V. Compose photolabiles et procedes pour leur utilisation
WO1998017628A2 (fr) * 1996-10-22 1998-04-30 Peptide Therapeutics Limited Technique en phase solide pour la preparation d'amides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CALMES M ET AL: "USE OF A NEW SONICALLY CLEAVABLE AND ACIDO-LABILE HANDLE FOR SOLID-PHASE PEPTIDE AMIDE SYNTHESIS", INTERNATIONAL JOURNAL OF PEPTIDE AND PROTEIN RESEARCH, vol. 44, no. 1, 1 July 1994 (1994-07-01), pages 58 - 60, XP000451983 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1115739A1 (fr) * 1998-09-25 2001-07-18 The University Of Queensland Auxiliaire pour la formation de liaisons amides
EP1115739A4 (fr) * 1998-09-25 2004-10-27 Univ Queensland Auxiliaire pour la formation de liaisons amides
US7589170B1 (en) 1998-09-25 2009-09-15 The University Of Queensland Synthesis of cyclic peptides
US7718598B1 (en) 1998-09-25 2010-05-18 The University Of Queensland Auxiliary for amide bond formation
CN117924235A (zh) * 2024-01-19 2024-04-26 王叔和生物医药(武汉)有限公司 硫氰酸钠在氧化间苯二酚合成制备噻克索酮中的应用及噻克索酮的制备方法
CN117924235B (zh) * 2024-01-19 2024-08-06 王叔和生物医药(武汉)有限公司 硫氰酸钠在氧化间苯二酚合成制备噻克索酮中的应用及噻克索酮的制备方法

Also Published As

Publication number Publication date
AU1342099A (en) 1999-06-15
AU734992B2 (en) 2001-06-28
CA2311490A1 (fr) 1999-06-03
EP1034154A1 (fr) 2000-09-13
JP2001524457A (ja) 2001-12-04

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