Method for producing peptide compound comprising highly sterically hindered amino acid

Patent metadata

Field	Value
Publication number	US-12404299-B2
Application number	US-202017773734-A
Country	US
Kind code	B2
Filing date	Nov 5, 2020
Priority date	Nov 7, 2019
Publication date	Sep 2, 2025
Grant date	Sep 2, 2025

Abstract

It was found that a peptide compound that has an N-substituted-α,α-disubstituted amino acid residue at the N-terminus and containing a dipeptide residue in which the N-substituted-α,α-disubstituted amino acid residue and an N-substituted amino acid residue are linked together, can be efficiently produced by linking an N-unsubstituted-α,α-disubstituted amino acid whose amino group is protected with an electron-withdrawing protecting group to an N-substituted amino acid or a peptide compound having an N-substituted amino acid residue at the N-terminus, and then allowing a substituent-introducing agent to act in the presence of a specific base to selectively introduce a substituent to the amino group at the N-terminus.

First claim

The invention claimed is:

1. A method for producing a peptide compound having an N-substituted-α,α-disubstituted amino acid residue at the N-terminus and comprising a dipeptide residue in which the N-substituted-α,α-disubstituted amino acid residue is linked to an N-substituted amino acid residue, a salt thereof, or a solvate of these, the method comprising the following steps of:
Step A: reacting (1) an N-substituted amino acid, a salt thereof, or a solvate of these, or a peptide compound having an N-substituted amino acid residue at the N-terminus, a salt thereof, or a solvate of these, wherein the main-chain amino group of the N-substituted amino acid or the N-substituted amino acid residue is represented by —NHR, wherein R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, and optionally substituted cycloalkyl, or R represents a carbon chain bonded to the N atom, which together with the carbon atom at the α-position form an optionally substituted ring,

with (2) an α,α-disubstituted amino acid having an amino group protected with an electron-withdrawing protecting group, a salt thereof, a dehydrated product thereof, or a solvate of these, wherein the amino group is the amino group on the main chain of the α,α-disubstituted amino acid and is represented by the formula —NHR′, wherein R′ is the electron-withdrawing protecting group, wherein the electron-withdrawing protecting group is a protecting group with which the pKa in water of the NH group to which the protecting group is bonded is 6 to 11,
in the presence or absence of a condensing reagent to obtain a peptide compound having an α,α-disubstituted amino acid residue having an amino group protected with an electron-withdrawing protecting group at the N-terminus and comprising a dipeptide residue in which the α,α-disubstituted amino acid residue is linked to an N-substituted amino acid residue, a salt thereof, or a solvate of these; and
Step B: introducing a substituent to the amino group of the α,α-disubstituted amino acid residue protected with the electron-withdrawing protecting group at the N-terminus in the presence of a base and a substituent-introducing agent to obtain a peptide compound having an α,α-disubstituted amino acid residue having an amino group on the main chain of the α,α-disubstituted amino acid substituted with the substituent and protected with the electron-withdrawing protecting group at the N-terminus and comprising a dipeptide residue in which the α,α-disubstituted amino acid residue is linked to the N-substituted amino acid residue, a salt thereof, or a solvate of these.

2. The method of claim 1 , wherein the pKa in acetonitrile of the conjugate acid of the base is 18 to 31.

3. The method of claim 1 , wherein the N-substituted amino acid or the peptide compound having an N-substituted amino acid residue at the N-terminus is loaded on a resin for solid-phase synthesis.

4. The method of claim 1 , wherein the N-substituted amino acid or the peptide compound having an N-substituted amino acid residue at the N-terminus is represented by formula (2):

wherein
P 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 7 -C 14 aralkyl;
R 2 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylsulfonylC 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl optionally substituted with one or more halogens, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, or C 7 -C 14 aralkyl;
R 3 is hydroxy, O-PG 2 , an arbitrary amino acid residue, or an arbitrary peptide residue; and
PG 2 is a protecting group for a carboxyl group.

5. The method of claim 1 , wherein the α,α-disubstituted amino acid having an amino group protected with an electron-withdrawing protecting group is represented by formula (3):

wherein
PG 1 is the electron-withdrawing protecting group; and
R 1 and Q 1 are independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, and optionally substituted C 7 -C 14 aralkyl, or
R 1 and Q 1 together with the carbon atom to which they are bonded form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.

6. The method of claim 1 , wherein the peptide compound obtained in step A is represented by formula (4):

wherein
PG 1 is the electron-withdrawing protecting group;
R 1 and Q 1 are independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, and optionally substituted C 7 -C 14 aralkyl, or
R 1 and Q 1 together with the carbon atom to which they are bonded form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring;
P 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 7 -C 14 aralkyl;
R 2 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylsulfonylC 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 , alkoxyC 1 -C 6 alkyl optionally substituted with one or more halogens, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, or C 7 -C 14 aralkyl; and
R 3 is hydroxy, O-PG 2 , an arbitrary amino acid residue, or an arbitrary peptide residue, wherein PG 2 is a protecting group for a carboxyl group.

7. The method of claim 6 , wherein the substituent-introducing agent in step B is P 1 X, wherein P 1 is the same as P 1 in formula (1), and X is a leaving group, and the peptide compound obtained in step B is represented by formula (1):

wherein
P 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 7 -C 14 aralkyl; and
PG 1 , R 1 , Q 1 , P 2 , R 2 , and R 3 are the same as PG 1 , R 1 , Q 1 , P 2 , R 2 , and R 3 in formula (4), respectively.

8. A method for producing a peptide compound comprising a structure in which two amino acid residues are connected as represented by formula (1), a salt thereof, or a solvate of these:

wherein
PG 1 is a protecting group for an amino group;
P 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 7 -C 14 aralkyl;
R 1 and Q 1 am independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, and optionally substituted C 7 -C 14 aralkyl, or
R 1 and Q 1 together with the carbon atom to which they are bonded form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring;
P 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 7 -C 14 aralkyl;
R 2 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylsulfonylC 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl optionally substituted with one or more halogens, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, or C 7 -C 14 aralkyl;
R 3 is hydroxy, O-PG 2 , an arbitrary amino acid residue, or an arbitrary peptide residue; and
PG 2 is a protecting group for a carboxyl group,

the method comprising the following steps of:
Step A: reacting a compound represen

Assignees

• Chugai Pharmaceutical Co Ltd

Inventors

• Nomura Kenichi
• Morita Yuya
• Hashimoto Satoshi

Classifications

• C07K1/026

  by fragment condensation in solution · CPC title

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · CPC title

• C07K1/04 Primary

  on carriers {(C07K1/003, C07K1/006 take precedence)} · CPC title

• C07K5/0808

  the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu · CPC title

• C07K1/063 Primary

  for alpha-amino functions · CPC title