Amino acid having functional group capable of intermolecular hydrogen bonding, peptide compound containing same and method for production thereof

A technology of peptide compounds and amino acids, applied in the field of amino acids

Pending Publication Date: 2021-09-28
CHUGAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] On the one hand, there is no report on the design of unnatural amino acids with protons and maskable proton functional groups on the side chains of amino acids, and the use of masking their proton functions to improve the membrane permeability of peptides

Method used

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  • Amino acid having functional group capable of intermolecular hydrogen bonding, peptide compound containing same and method for production thereof
  • Amino acid having functional group capable of intermolecular hydrogen bonding, peptide compound containing same and method for production thereof
  • Amino acid having functional group capable of intermolecular hydrogen bonding, peptide compound containing same and method for production thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0306] (usual preparation method)

[0307] The general production method of the amino acid capable of forming a hydrogen bond in the side chain and the peptide compound of the present invention will be described below.

[0308] (Method for preparing amino acid capable of forming intramolecular hydrogen bond)

[0309] In the production of amino acids having intramolecular hydrogen bonds in their side chains, amino acids having ether bonds in their side chains can be produced by the following two synthesis methods.

[0310] Method 1:

[0311] In the presence of a Lewis acid, the aziridine compound having a protected amino group and a carboxylic acid group is reacted with an alcohol having a corresponding suitable protecting group to carry out a ring-opening reaction, followed by deprotection of an undesired protecting group. In the following general formula, it can be used as P 1 Use Cbz group, Fmoc group, Alloc group, nosyl group (Ns group), etc., as P 2 Me group, allyl gro...

Embodiment 1

[0409] The chemical synthesis of embodiment 1 peptide compound

[0410] According to the peptide synthesis method based on the Fmoc method described in WO2013 / 100132, the peptide was elongated in the following basic route. That is, a five-step process: 1) a peptide elongation reaction by the Fmoc method starting from the N-terminal of Asp in which the carboxylic acid of the side chain of Asp is supported on 2-chlorotrityl resin, 2) from The process of cleavage of peptide by 2-chlorotrityl resin, 3) amide cyclization, which is based on the carboxylic acid of the Asp side chain generated from the cleavage process from the 2-chlorotrityl resin and the peptide chain N-terminal (triangle unit), 4) deprotection of the protective group of the side chain functional group contained in the peptide chain, 5) purification of the compound based on preparative HPLC. In addition, in the peptide compound containing an amino acid having an acidic functional group in the side chain, in order t...

Embodiment 2

[1183] Example 2 Membrane Permeability Evaluation of Amino Acids Having a Donor in the Side Chain and an Intramolecular Hydrogen Bond in the Donor Moiety

[1184] 2-1 Comparison of membrane permeability of those having an intramolecular hydrogen bond at the donor moiety, and those not having, among amino acids having a donor at the side chain

[1185] In order to confirm that among amino acids with donors in their side chains, those with intramolecular hydrogen bonds in the donor moiety have better membrane permeability than those without, 2 cyclic peptides containing each amino acid were synthesized by The improved method described in International Publication No. 2018 / 124162 compares membrane permeability. Several combinations of the two cyclic peptides described above were synthesized, and the generality was confirmed by evaluation. As a result, it was confirmed that in (1) Ser(EtOH) and Nle(6-OH), (2) Ser(1-CF3-EtOH) and Hnl(7-F3-6-OH), (3) Tyr(3- OMe) and Tyr, (4) combi...

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Abstract

The present inventor found that the membrane permeability of a peptide compound can be improved by employing at least one amino acid which has a side chain capable of forming an intermolecular hydrogen bond, as one of the amino acids constituting the peptide compound.

Description

technical field [0001] The present invention relates to amino acids capable of improving the membrane permeability of peptide compounds, peptide compounds containing the amino acids, and methods for their preparation. Background technique [0002] Middle-molecular-weight compounds (molecular weight: 500-2000) may be superior to low-molecular-weight compounds in making contacts with difficult targets (represented by inhibition of protein-protein interactions). In addition, mid-molecular-weight compounds may also be superior to antibodies in terms of their ability to move into cells. Among middle-molecular compounds with physiological activity, there are more than 40 types of peptide drugs that have been marketed and have relatively high value (Non-Patent Document 1). [0003] Typical examples of peptide drugs include cyclosporine A and polymyxin B. Focusing on their structures, as characteristic points, they are peptides containing some unnatural amino acids (represented by...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/22C07C235/06C07C271/22C07K7/00C07K11/02C07K14/00C40B40/08C40B40/10
CPCC07C229/22C40B40/08C40B40/10C07C229/36C07C237/20C07C311/51C07C239/18C07K7/56C07D455/03C07D498/14C07D471/14C07K11/02C07C237/30C07C311/02C07D271/07C07D207/10C07D211/34C07D213/55C07D265/30C07D277/30C07D309/10C07D413/12
Inventor 村冈照茂田中翔太
Owner CHUGAI PHARMA CO LTD
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