Synthesis of hydantoin containing peptide products

Patent metadata

Field	Value
Publication number	US-10087221-B2
Application number	US-201414778496-A
Country	US
Kind code	B2
Filing date	Mar 19, 2014
Priority date	Mar 21, 2013
Publication date	Oct 2, 2018
Grant date	Oct 2, 2018

Abstract

The present invention relates to a method of synthesizing a peptide product comprising at least one hydantoin group. The peptide product may be used as a reference material for the quality control of pharmaceutical peptides, particularly for the quality control of exendin peptides. Further, the invention relates to hydantoin building blocks, a method for manufacturing such building blocks and their use for the synthesis of peptide products.

First claim

The invention claimed is:

1. A method of synthesizing a peptide product comprising an N-terminal hydantoin group of formula:

or a salt or solvate thereof, wherein
P is a peptidic residue Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH 2 (SEQ ID NO: 2), and
(*) in each case independently denotes an optionally asymmetric C-atom,

comprising the steps:
(a) coupling a hydantoin building block of formula (II)

wherein
R 1′ is an optionally protected Gin side chain,
R 2′ is an optionally protected Met side chain,
Z is a carboxy group, and
each (*) independently denotes an optionally asymmetric C-atom,

to a peptide of formula (III)
H 2 N—P′  (III)

wherein
P′ is a peptidic residue P comprising optionally protected amino acid side chains or optional′ coupled to a solid phase carrier,

(b) optionally cleaving off protecting groups from protected amino acid side chains, and
(c) isolating and optionally purifying the peptide product.

2. The method of claim 1 , wherein R 1′ and/or R 2′ are protected with an acid-labile protecting group, a base-labile protecting group, or another protecting group.

3. The method of claim 1 , wherein P′ is a peptidic residue P coupled to a solid phase carrier.

4. The method of claim 1 , wherein the coupling in step s carried out using a coupling reagent and an organic base.

5. The method of claim 4 , wherein the coupling reagent is TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate), HBTU (2-(1H-benzotrialzole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate); or HOBT (1-hydroxybenzotriazole)/DIC (diisopropylcarbodiimide).

6. The method of claim 4 , wherein the organic base is diisopropylethylamine (DIPEA).

7. The method of claim 4 , wherein the coupling in step (a) is carried out in dimethylformamide (DMF).

8. The method of claim 1 , wherein R 1′ is a protected Gin side chain.

9. The method of claim 1 , wherein R 2′ is an unprotected Met side chain.

10. A method for the quality control of a composition comprising a pharmaceutical exendin peptide product, comprising quantitatively determining the amount of a peptide product with a hydantoin group according to claim 1 , in said composition.

Assignees

• Sanofi Aventis Deutschland

Inventors

• Henkel Bernd

Classifications

• C07K1/107

  by chemical modification of precursor peptides · CPC title

• C07K1/04

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

• C07D233/78 Primary

  Radicals substituted by oxygen atoms · CPC title

• C07K14/47 Primary

  from mammals · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title