EP1212351A1 - Procede de production de peptidomimetiques cycliques - Google Patents

Procede de production de peptidomimetiques cycliques

Info

Publication number
EP1212351A1
EP1212351A1 EP00963949A EP00963949A EP1212351A1 EP 1212351 A1 EP1212351 A1 EP 1212351A1 EP 00963949 A EP00963949 A EP 00963949A EP 00963949 A EP00963949 A EP 00963949A EP 1212351 A1 EP1212351 A1 EP 1212351A1
Authority
EP
European Patent Office
Prior art keywords
peptide
peptidomimetic
nucleophilic
cyclization
functionality
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.)
Withdrawn
Application number
EP00963949A
Other languages
German (de)
English (en)
Inventor
Dirk Scharn
Lothar Germeroth
Holger Wenschuh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chemotopix GmbH
Original Assignee
Chemotopix GmbH
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 Chemotopix GmbH filed Critical Chemotopix GmbH
Publication of EP1212351A1 publication Critical patent/EP1212351A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • 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
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
    • C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • 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
    • 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

  • peptides are limited for the following reasons: (i) Under physiological conditions, peptides are degraded by many specific and non-specific peptidases, (ii) peptides are only moderately absorbed and quickly excreted again. (iii) The conformational flexibility of peptides can lead to binding to more than one receptor and thus to undesirable side effects, (iv) peptides can be immunogenic.
  • the resulting conformationally restricted peptide analogs can not only lead to increased avidity and affinity for the receptor [Ladner, CL TIBTECH 1995, 13, 426] but also have a significantly reduced lability towards proteases and a significantly increased membrane passage [Hruby, VJ et al. Life Be. 1982, 31, 189].
  • the object is to produce peptides or peptidomimetics which no longer have the aforementioned disadvantageous properties of peptides for clinical applications.
  • cyclic peptides and peptidomimetics are to be synthesized, the backbone of which is modified by aromatic or heteroaromatic residues.
  • the object is achieved by a process for the synthesis of cyclic peptides or peptidomimetics by sequential nucleophilic substitutions on polyhalogenated aromatics with the following formula: (i) 2,4,6-trihalo-S-triazine or 2,4,6-trihalo-1 , 3,5-triazine; (see.
  • a linear peptide or peptidomimetic with a free nucleophilic functionality wherein the nucleophilic functionality is an alcohol, thiol or amine, and wherein the nucleophilic functionality is either at one end, in the side chain or on the backbone of the peptide or peptidomimetic implemented with the aromatic in the sense of a simple nucleophilic aromatic substitution, the peptide or peptidomimetic being in solution or in a state bound to a solid phase
  • the protective group of a further nucleophilic functionality on the same peptide or peptidomimetic is selectively cleaved, the nucleophilic functionality released being an alcohol, thiol or amine, and the nucleophilic functionality being at either end in which
  • the present method is a valuable tool for the synthesis of new bioactive compounds.
  • the following invention describes a new, versatile procedure for the production of such, not previously described, conformationally restricted connections.
  • a process according to the invention is preferred, the polyhalogenated aromatic being a cyanuric chloride or fluoride.
  • a cyanuric chloride is more preferred.
  • a method according to the invention is advantageous in which the remaining halogen atoms are reacted in further nucleophilic aromatic substitution reactions, the nucleophile being an alcohol, a thiol or an amine.
  • the nucleophile can be part of the same peptide or peptidomimetic or part of another molecule. This creates intramolecular or intermolecularly linked compounds.
  • the present invention relates to a process for the preparation of novel cyclic peptidomimetics by means of successive nucleophilic substitution on cyanuric chloride and other polyhalogenated aromatic compounds.
  • peptides or peptidomimetic oligomers which are built up by means of solid-phase or solution synthesis and initially have only one free nucleophilic functional group are reacted with cyanuric chloride.
  • cyanuric chloride The temperature-dependent tendency of substitution of the chlorine atoms present is exploited [Thurston, JT et al. J. Am. Chem. Soc. 1951, 73, 2981].
  • the complete reaction of amino, hydroxy, or thiol functions with excess cyanuric chloride at room temperature initially leads exclusively to dichloro-1, 3,5-triazinylpeptides (Scheme II) without the formation of 1,3,5-triazine-bridged peptide dimers.
  • the method according to the invention makes a large variety of conformationally restricted compounds accessible.
  • both the ring size and the molecular weight can be gradually changed.
  • Figure 1 shows possible ring closure reactions in peptides and peptidomimetics.
  • Figure 2 shows the schematic representation of the production of cyclic peptidomimetics by means of sequential aromatic substitution using the example of
  • Figure 3 shows a solid phase cyclization using cyanuric chloride to cycles of different ring sizes and molecular weights.
  • FIG. 4 shows the increase in the diversity of the cyclized compounds by nucleophilic substitution of the remaining chlorine atom on the ring system.
  • FIG. 5 shows the cyclization of dipeptides by means of cyanuric chloride in FIG.
  • FIG. 6 shows the representation of the solid phase cyclization of dipeptides in FIG.
  • FIG. 7 shows the “head to backbone” cyclization on peptomers.
  • FIG. 8 shows the representation of the nucleophilic substitution on cyclic monochloro-1,3,5-triazinylpeptides.
  • FIG. 9 shows a “head-to-tail” cyclization in solution.
  • FIG. 10 shows the aromatics of the process according to the invention, a chlorine atom being used as an example for the halogen.
  • the chlorine atom is to be replaced by halogen in the general formulas.
  • All peptides and peptidomimetics can optionally include protecting groups.
  • the protective group at the N terminus can consist of: alkyl, aryl, alkylaryl, arylalkyl, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,
  • Carbon atoms preferably fluorenylmethoxycarbonyl, tert. butyloxycarbonyl,
  • the protecting group C - terminus can consist of: An alkoxy or aryloxy group with 1 to 10 carbon atoms or one
  • Peptide In the context of the present application, the term “peptide” also includes peptide derivatives and analogs which contain at least one peptide bond.
  • Oligo-N-alkyl-glycine in which formally the side chains of the peptides are transferred from the ⁇ -carbon atom of the amino acids to the amide function.
  • the side chain protecting groups were cleaved for 2.5 hours with a solution of 5% water, 5% phenol, 2.5% triisopropylsilane in TFA.
  • the orthogonal lysine protecting group (Mtt) could be cleaved in 1h using a solution of 1% TFA and 5% triisopropylsilane in DCM without affecting the other acid labile protecting groups.
  • Example 3 Studies on the solid phase cyclization of dipeptides using cyanuric chloride
  • the diverse application possibilities of the new method can be expanded if the cyclization is transferred to peptide-related oligomers.
  • the synthesis of peptomers (hybrids of peptides and peptoids) or peptoids, which leads to N-alkylated compounds also opens up the possibility of carrying out cyclizations on the backbone of the peptidomimetic (see scheme I) [Gilon, C. et al. Biopolymers 1991, 31, 745].
  • the peptomers shown in Figure 6 were synthesized. For this purpose, as described in the general synthesis strategy, the cellulose membrane was first modified with the photolinker.
  • the BOC protecting groups of the amino functions of the peptoid building blocks could be removed by bathing the membrane for 30 minutes in a solution of 5% water in 90% TFA / DCM. After washing again, the cyclization with 30% DIEA in DMF at room temperature was achieved within 30 minutes. After washing the membrane (5xDMF, 3xMeOH, 1xDCM) and drying, the cyclized compounds were cleaved from the cellulose surface by UV irradiation at 365 nm (120 min). LC-MS analysis of the compounds showed that the desired product was obtained in all cases.
  • Example 5 Studies on the substitution of the chlorine atom on cyclic monochloro-1, 3,5-triazinyl peptides bound to the solid phase.
  • Example 6 Testing of different multi-halogenated azaaromatic compounds for solid phase cycling
  • the linear tripeptide AFK was synthesized as described in Example 1.
  • the excess of reagent was removed by washing with DMF, methanol and DCM (3 ⁇ 5 min each).
  • the membrane (5xDMF, 3xMeOH, 1xDCM)
  • the BOC protecting group of the ⁇ -amino function was removed from the lysine by bathing the membrane in a solution of 5% water in 90% TFA / DCM for 30 minutes.
  • Termini are anchored to the carrier, a "head to tail" cyclization must be carried out in solution.
  • the following example describes such a ring closure on one
  • the dichloro-triazine derivative thus obtained was cleaved from the membrane with 80% TFA in DCM for 30 min at RT (FIG. 9, compound 1).
  • the excess TFA and DCM were removed in vacuo and taken up in 50 ul of a 50% solution of acetonitrile in water. 10 ⁇ l of these were analyzed by LC-MS.
  • the cyclization was achieved by adding 2 ⁇ l DIEA and shaking at RT for 30 min (FIG. 9, compound 2).
  • the mixture was then evaporated to dryness again in vacuo and taken up in 50 ⁇ l of a 50% strength solution of acetonitrile in water and the reaction product was analyzed by means of LC-MS.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Analytical Chemistry (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne un procédé de synthèse de peptides ou de peptidomimétiques cycliques par substitutions séquentielles nucléophiles au niveau d'aromatiques polyhalogénés. Ledit procédé comprend les étapes suivantes: (i) on fait réagir un peptide ou un peptidomimétique linéaire présentant une fonctionnalité nucléophile libre, laquelle peut être un alcool, un thiol ou une amine, avec l'aromatique pour obtenir une substitution simple nucléophile aromatique; (ii) une autre fonctionnalité nucléophile est séparée de façon sélective au niveau du même peptide ou du même peptidomimétique, la fonctionnalité nucléophile libérée étant un alcool, un thiol ou une amine; et (iii) on procède à une cyclisation par addition d'une amine tertiaire ou d'une autre base, cette cyclisation se faisant par substitution nucléophile aromatique d'un autre atome d'halogène de l'aromatique halogéné lié au peptide, par la fonctionnalité nucléophile libérée.
EP00963949A 1999-08-28 2000-08-28 Procede de production de peptidomimetiques cycliques Withdrawn EP1212351A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19942624A DE19942624A1 (de) 1999-08-28 1999-08-28 Verfahren zur Herstellung von zyklischen Peptidomimetika
DE19942624 1999-08-28
PCT/DE2000/002982 WO2001016162A1 (fr) 1999-08-28 2000-08-28 Procede de production de peptidomimetiques cycliques

Publications (1)

Publication Number Publication Date
EP1212351A1 true EP1212351A1 (fr) 2002-06-12

Family

ID=7921062

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00963949A Withdrawn EP1212351A1 (fr) 1999-08-28 2000-08-28 Procede de production de peptidomimetiques cycliques

Country Status (5)

Country Link
EP (1) EP1212351A1 (fr)
JP (1) JP2003508408A (fr)
AU (1) AU7506100A (fr)
DE (1) DE19942624A1 (fr)
WO (1) WO2001016162A1 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2528375C (fr) 2003-06-18 2013-11-19 Tranzyme Pharma, Inc. Antagonistes macrocycliques du recepteur de motiline
US7259258B2 (en) 2003-12-17 2007-08-21 Illumina, Inc. Methods of attaching biological compounds to solid supports using triazine
TWI640541B (zh) 2011-12-28 2018-11-11 中外製藥股份有限公司 Peptide compound having an annular portion and pharmaceutical composition thereof
US10815489B2 (en) 2015-03-13 2020-10-27 Chugai Seiyaku Kabushiki Kaisha Modified aminoacyl-tRNA synthetase and use thereof
US12391971B2 (en) 2017-01-31 2025-08-19 Chugai Seiyaku Kabushiki Kaisha Method for synthesizing peptides in cell-free translation system
KR20250007021A (ko) 2017-06-09 2025-01-13 추가이 세이야쿠 가부시키가이샤 N-치환 아미노산을 포함하는 펩타이드의 합성 방법
CN111479819B (zh) 2017-12-15 2024-06-14 中外制药株式会社 制备肽的方法和处理碱的方法
EP3878836B1 (fr) 2018-11-07 2025-07-23 Chugai Seiyaku Kabushiki Kaisha Procédé de production d'un dérivé de sérine o-substitué
WO2020111238A1 (fr) 2018-11-30 2020-06-04 中外製薬株式会社 Procédé de déprotection et procédé d'élimination de résine dans une réaction en phase solide d'un composé peptidique ou d'un composé amide, et procédé de production d'un composé peptidique
CN113692401A (zh) 2019-03-15 2021-11-23 中外制药株式会社 芳香族氨基酸衍生物的制备方法
JP6880352B1 (ja) 2019-11-07 2021-06-02 中外製薬株式会社 Ｋｒａｓ阻害作用を有する環状ペプチド化合物

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2636066B1 (fr) * 1988-09-02 1991-10-25 Centre Nat Rech Scient Derives de cyclopeptides, utilisables comme inhibiteurs selectifs vis-a-vis de proteases a serine active
US5656645A (en) * 1994-12-13 1997-08-12 Corvas International, Inc. Aromatic heterocyclic derivatives as enzyme inhibitors
US5672584A (en) * 1995-04-25 1997-09-30 The University Of Kansas Cyclic prodrugs of peptides and peptide nucleic acids having improved metabolic stability and cell membrane permeability
JP2000501068A (ja) * 1995-09-12 2000-02-02 フィテラ シンビオン エイピーエス アクチノマイシンｄ類似体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0116162A1 *

Also Published As

Publication number Publication date
DE19942624A1 (de) 2001-03-08
AU7506100A (en) 2001-03-26
JP2003508408A (ja) 2003-03-04
WO2001016162A1 (fr) 2001-03-08

Similar Documents

Publication Publication Date Title
EP0285562B1 (fr) Résine synthétique
DE69429542T2 (de) Selektiv spaltbare verbindungen, die auf iminodiessigsäure-ester-bindungen basieren
DE69132914T2 (de) Substanzbibliotheken ABGEÄNDERTER, PROTEASE-RESISTENTER PEPTIDE
DE69936322T2 (de) Polyamideketten von genauer Länge und deren Konjugate mit Proteinen
DE60208684T2 (de) Verbesserte native chemische ligation mit drei oder mehreren komponenten
DE3788910T2 (de) Methode für die Synthese eines Peptides, das eine nicht peptidartige Bindung enthält.
TW201915009A (zh) 合成依特卡肽（Ｅｔｅｌｃａｌｃｅｔｉｄｅ）或其鹽類之方法
WO2001016162A1 (fr) Procede de production de peptidomimetiques cycliques
DE3884976T2 (de) Verfahren zur enzymatischen Herstellung von Dipeptiden.
DE3782010T2 (de) Vom calcitonin-gen abgeleitete peptidderivate.
DE3177306T2 (de) Verfahren und Verbindungen zur Herstellung von H-ARG-X-Z-Y-TYR-R.
DE69225597T2 (de) Peptide mit einer lanthionin-brücke
US7691968B2 (en) Process for the synthesis of peptides amides by side-chain attachment to a solid phase
DE69604759T2 (de) N alpha-2-(4-nitrophenylsulfonyl)ethoxycarbonyl-aminosäuren
DE4119544C1 (fr)
DE60124376T2 (de) Funktionalisierter festträger zur organischen synthese von peptiden und kleinen molekülen
EP1373190A2 (fr) Procede pour la production d'amides d'acide carboxylique
EP0051205A1 (fr) Tridécapeptide, procédé pour sa préparation et son utilisation
Arai et al. Synthesis of (Hexafluorovalyl1, 1) gramicidin S.
US6277958B1 (en) Method for preparing peptide thiol ester
CN107383054B (zh) 一种含二硫键长臂生物素及其制备方法
HU185238B (en) Process for preparing peptides containing guanidino-group
DE2751026A1 (de) Verfahren zur herstellung von peptiden, die tyrosinsulfat enthalten
HU221619B1 (hu) Eljárás peptidek előállítására és intermedierek
EP0443598B1 (fr) Peptides inhibant la coagulation du sang, leur procédé de préparation et leur emploi

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020327

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20030204