WO2000064865A1 - Monomeres et peptidomimetiques d'oligo-uree, et leur procede de preparation - Google Patents

Monomeres et peptidomimetiques d'oligo-uree, et leur procede de preparation Download PDF

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Publication number
WO2000064865A1
WO2000064865A1 PCT/EP2000/003735 EP0003735W WO0064865A1 WO 2000064865 A1 WO2000064865 A1 WO 2000064865A1 EP 0003735 W EP0003735 W EP 0003735W WO 0064865 A1 WO0064865 A1 WO 0064865A1
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WO
WIPO (PCT)
Prior art keywords
protected
monomers
mmol
nmr
oligourea
Prior art date
Application number
PCT/EP2000/003735
Other languages
English (en)
Inventor
Astrid Boeijen
Rob M. J. Liskamp
Jack A. J. Den Hartog
Original Assignee
Solvay Pharmaceuticals B.V.
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 Solvay Pharmaceuticals B.V. filed Critical Solvay Pharmaceuticals B.V.
Priority to AU44030/00A priority Critical patent/AU4403000A/en
Publication of WO2000064865A1 publication Critical patent/WO2000064865A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/52—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups

Definitions

  • the invention relates to novel protected monomers, the preparation thereof and their use for the preparation of oligourea peptidomimetics.
  • the backbone in each repeating unit of oligourea peptidomimetics is generally extended by one carbon atom in comparison with the natural amino acid
  • the extra carbon atom may also increase the lipophilicity and flexibility of the compounds which makes it easier to pass barriers like the cell wall and the blood-brain barrier.
  • the hydrogen-bond-forming capacity of the urea unit on the other hand might help in rendering the urea compounds more water soluble than the natural peptide.
  • an appropriately placed hydrogen-bonding unit may cause additional affinity in interaction with a receptor. Examples of solid-phase synthesis of oligourea peptidomimetics in the literature have been described by the groups of Burgess and Schultz. (Angew. Chem. Int. Ed. Engl. (1995), M., 907-909; Angew. Chem.
  • the invention relates to a procedure for the synthesis of oligourea peptidomimetics using more usual protective-groups, instead of the phthalimido and azido groups (vide supra) which could be easily implemented on commercial peptide or robot synthesizers.
  • the aim of the invention is the preparation of the C-terminal free acids, since a carboxyl terminus is often essential for the biological activity of peptides and peptidomimetics.
  • novel monomer building blocks are t.butoxycarbonyl (Boc)-protected monomers of the formula (I)
  • R represents a side-chain of a natural or unnatural, common or uncommon amino acid wherein optionally present functional groups are protected.
  • Preferred building blocks of the formula (I) are monomers wherein R represents the side-chain of a natural or unnatural amino acid, especially the side-chain of one of the following amino acids: phenylalanine, O-protected tyrosine, leucine, O- protected serine, N-protected lysine or glycine.
  • the monomers having formula (I) can be prepared as indicated in Schemel.
  • a further objective of the invention is the solid phase synthesis of a oligourea peptidomimetics having a free carboxyl terminus.
  • PCL means photocleavable linker (linked to the resin), R 1 is the side-chain of an amino acid, R has the meaning given above, and n is the number of monomers (which can be the same or different) in the oligourea peptidomimetic.
  • urea monomers can be incorporated in a simple manner into peptides and peptidomimetics, even using automated procedures, with minimum adjustments of the protocol and reagents needed for coupling and deprotection.
  • Hydroxyethyl Photolinker Novasyn ® TG resin (5) was purchased from NovaBiochem, La ⁇ felfingen, Switzerland. All protected amino acids were purchased from Advanced Chemtech (Belgium). THF, NMP and DCM were purchased from Biosolve, the Netherlands. THF was distilled immediately prior to use from LiAIH 4 . NMP and DCM were stored on molecular sieves (4 A). Hexanes had a boiling range of 60-80 °C. DiPEA and TEA were distilled from ninhydrin and KOH. Pyridine was distilled from KOH.
  • Elution was effected using an appropriate gradient from 0.1% TFA in water to 0.085% TFA in acetonitrile/water (95/5, v/v), at a flow rate of 11.5 mL min -1 .
  • UV lamp Vilber Lourmat TFP-35L UV table.
  • IR Bio-RAD FTS-25.
  • Polarimeter Jasco P-1010.
  • Example 2 Preparation of starting compound (4) as used in Example 1
  • Phenylalanine Amide 2a Yield 2.52 g (9.5 mmol, 95%) white solid; m.p. 144-
  • Phenylalanine Nitrile 3a 1.14 g (4.6 mmol, 93%) white solid was obtained from 2a (1.32 g, 5.0 mmol) after column chromatography (silica, 1.5%
  • Tyrosine Nitrile 3b 3.35 g (9.9 mmol, 99%) white solid was obtained from 2b (3.55 g, 10,0 mmol) after column chromatography (silica, 1% MeOH/DCM); m.p.
  • Urea Dimer 13 To resin 9 (250 mg, 0.19 mmol/g), THF (10 mL) was added. The reaction vessel was evacuated and filled with Argon (3 ⁇ ), and suspended above the UV lamp in a shaking device. The set up was covered with aluminium foil and irradiated for 24 h, under continuous shaking. Samples were taken after 10 min, 1 , 2, 3, 4, 5, 6, 7, 8, 22, 23 and 24 h, and analyzed by HPLC. Cleavage was complete after 24 h. The resin was filtrated and washed with THF (3 x). The filtrate was evaporated. This yielded 21.1 mg (>100%) of the crude product.
  • the Boc group in 11 mg of the crude product was removed directly with 30% TFA/DCM at 0 °C, and the product was purified by preparative HPLC.
  • the pure product 13 was obtained after lyophilisation as a white solid (6.1 mg, 0.0199 mmol, 80%).
  • Urea Pentamer 14 To resin 12 (500 mg, 0.20 mmol/g), THF (10 mL) was added. The reaction vessel was evacuated and filled with Argon (3 x), and suspended above the UV lamp in a shaking device. The set up was covered with aluminium foil and irradiated for 24 h, under continuous shaking. After 24 h, the resin was filtrated and washed with THF (3 x), and the filtrate was evaporated. The benzyl group in the tyrosine side chain of the crude product was removed by catalytic hydrogenation with 5% Pd/C. Preparative HPLC and subsequential lyophilisation gave the pure product 14 as a white solid (27 mg, 0.040 mmol, 40%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne de nouveaux motifs structuraux monomères protégés de formule (I), dans laquelle R représente une chaîne latérale d'un acide aminé naturel ou artificiel, commun ou peu fréquent, les groupes fonctionnels éventuellement présents étant protégés. Cette invention concerne également un procédé de préparation de ces monomères, ainsi que leur utilisation dans la synthèse en phase solide de peptidomimétiques d'oligo-urée.
PCT/EP2000/003735 1999-04-23 2000-04-19 Monomeres et peptidomimetiques d'oligo-uree, et leur procede de preparation WO2000064865A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU44030/00A AU4403000A (en) 1999-04-23 2000-04-19 Monomers and oligourea peptidomimetics and process for the prepa ration thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP99201268 1999-04-23
NL1011878 1999-04-23
NL1011878 1999-04-23
EP99201268.2 1999-04-23

Publications (1)

Publication Number Publication Date
WO2000064865A1 true WO2000064865A1 (fr) 2000-11-02

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/003735 WO2000064865A1 (fr) 1999-04-23 2000-04-19 Monomeres et peptidomimetiques d'oligo-uree, et leur procede de preparation

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AU (1) AU4403000A (fr)
WO (1) WO2000064865A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10464920B2 (en) 2015-07-06 2019-11-05 Inserm (Institute National De La Santé Et De La Recherche Médicale Vicinal primary diamines associated with metal and/or free radical chelation motifs, and active against carbonyl and oxidative stress, and use thereof
CN111094238A (zh) * 2017-07-31 2020-05-01 杰资制药爱尔兰有限公司 氨基甲酰基苯丙氨醇类似物及其用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KEVIN BURGESS ET AL.: "Solid phase syntheses of Oligoureas", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 119, no. 7, 19 February 1997 (1997-02-19), DC US, pages 1556 - 1564, XP002115550 *
KRUIJTZER J A W ET AL: "Approaches to the Synthesis of Ureapeptoid Peptidomimetics", TETRAHEDRON LETTERS, vol. 38, no. 30, 28 July 1997 (1997-07-28), pages 5335-5338, XP004083313, ISSN: 0040-4039 *
WILSON M E ET AL: "An Efficient Synthesis of N,N'-Linked Oligoureas", TETRAHEDRON LETTERS, vol. 39, no. 37, 10 September 1998 (1998-09-10), pages 6613-6616, XP004132559, ISSN: 0040-4039 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10464920B2 (en) 2015-07-06 2019-11-05 Inserm (Institute National De La Santé Et De La Recherche Médicale Vicinal primary diamines associated with metal and/or free radical chelation motifs, and active against carbonyl and oxidative stress, and use thereof
CN111094238A (zh) * 2017-07-31 2020-05-01 杰资制药爱尔兰有限公司 氨基甲酰基苯丙氨醇类似物及其用途
JP2020530837A (ja) * 2017-07-31 2020-10-29 ジャズ ファーマシューティカルズ アイルランド リミテッド カルバモイルフェニルアラニノール類縁体およびその使用
US11413264B2 (en) 2017-07-31 2022-08-16 Jazz Pharmaceuticals Ireland Limited Carbamoyl phenylalaninol analogs and uses thereof
AU2018312328B2 (en) * 2017-07-31 2022-12-15 Jazz Pharmaceuticals Ireland Limited Carbamoyl phenylalaninol analogs and uses thereof
US20220401401A1 (en) * 2017-07-31 2022-12-22 Axsome Malta Ltd. Carbamoyl phenylalaninol analogs and uses thereof
CN111094238B (zh) * 2017-07-31 2023-06-09 杰资制药爱尔兰有限公司 氨基甲酰基苯丙氨醇类似物及其用途
JP7366002B2 (ja) 2017-07-31 2023-10-20 ジャズ ファーマシューティカルズ アイルランド リミテッド カルバモイルフェニルアラニノール類縁体およびその使用

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