Method for preparing AMG 416 (etelcalcetide)

Patent metadata

Field	Value
Publication number	US-11377474-B2
Application number	US-201916532344-A
Country	US
Kind code	B2
Filing date	Aug 5, 2019
Priority date	Apr 3, 2014
Publication date	Jul 5, 2022
Grant date	Jul 5, 2022

Abstract

A method for preparing AMG 416, or a pharmaceutically acceptable salt thereof, is provided.

First claim

What is claimed is:

1. A method for preparing etelcalcetide, as set forth in formula (1):

or a pharmaceutically acceptable salt thereof, the method comprising:
contacting a peptide having the structure of Ac-D-Cys(SPy)-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH2 (SEQ ID NO:4) with L-Cys to produce a conjugated product of formula (1).

2. The method of claim 1 , wherein said contacting comprises dissolving the peptide in an aqueous solution comprising L -Cys and trifluoroacetic acid (TFA).

3. The method of claim 2 , wherein said contacting occurs at room temperature for about 15 minutes.

4. The method of claim 1 , further comprising lyophilizing the conjugated product.

5. The method of claim 4 , further comprising contacting the conjugated product with an aqueous solution comprising isopropyl alcohol and hydrochloride (HCl), thereby producing a precipitate comprising etelcalcetide HCl (SEQ ID NO:1).

6. The method of claim 5 , further comprising washing the precipitate comprising etelcalcetide HCl (SEQ ID NO:1) with isopropyl alcohol.

7. The method of claim 6 , further comprising dissolving the isopropyl alcohol washed precipitate in water to produce a dissolved precipitate.

8. The method of claim 7 , further comprising concentrating the dissolved precipitate via distillation.

9. The method of claim 5 , further comprising purifying the precipitate by HPLC.

10. The method of claim 1 , wherein the conjugated product is represented by a formula Ac-D-Cys(L-Cys-OH)-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH 2 (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 , further comprising contacting the conjugated product with an aqueous solution comprising isopropyl alcohol (IPA) and HCl, thereby producing a precipitate comprising a HCl salt of SEC ID NO: 1.

12. The method of claim 4 , wherein the method further comprises deriving the peptide having structure Ac-D-Cys(SPy)-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH 2 (SEQ ID NO:4) from a resin-bound peptide having a structure of Ac-D-Cys(Trt)-D-Ala-D-Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-[Resin] (SEQ ID NO:3).

13. The method of claim 12 , wherein the deriving comprises contacting the resin-bound peptide with a solution comprising water, trifluoroacetic acid, triisopropylsilane and dipyridyldisulfide.

14. The method of claim 1 , wherein the peptide comprises a TFA salt of Ac-D-Cys(SPy)-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH 2 (SEQ ID NO:4).

Assignees

• Amgen Inc

Inventors

• Bezemer Jeroen
• Chen Ying
• Crockett Richard
• Crossley Kevin
• Cui Sheng
• Huang Liang
• Jones Sian
• Lower Asher
• Ranganathan Krishnakumar

Classifications

• C07K1/1075 Primary

  by covalent attachment of amino acids or peptide residues · CPC title

• C07K1/02

  in solution {(C07K1/003, C07K1/006 take precedence)} · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61P5/20

  for decreasing, blocking or antagonising the activity of PTH · CPC title

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title