Method for preparing amg 416

Patent metadata

Field	Value
Publication number	US-2017190739-A1
Application number	US-201515300209-A
Country	US
Kind code	A1
Filing date	Apr 3, 2015
Priority date	Apr 3, 2014
Publication date	Jul 6, 2017
Grant date	—

Abstract

A method for preparing AMG 416, or a pharmaceutically acceptable salt thereof, is provided. AMG 416 is a synthetic, eight amino-acid selective peptide agonist of the calcium sensing receptor. It is being developed as an intravenous treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients with chronic kidney disease—mineral and bone disorder (CKD-MBD).

First claim

What is claimed is:

1 . A method for preparing AMG 416 comprising:
providing a resin-bound peptide having a structure selected from the group consisting of Fmoc- D -Cys(Trt)- D -Ala- D -Arg(Pbf) - D -Arg(Pbf) - D -Arg(Pbf)- D -Ala- D -Arg(Pbf)-[Resin] (SEQ ID NO:2) and 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); cleaving the peptide from the solid support; and activating the side chain of the D -Cys residue.

2 . The method of claim 1 , wherein the cleavage and the activation occur in the same vessel.

3 . The method of claim 1 , wherein the resin-bound peptide is contacted with a solution comprising water, trifluoroacetic acid, triisopropylsilane and dipyridyldisulfide.

4 . A method for preparing AMG 416 comprising:
providing a peptide having the structure of Ac- D -Cys(SPy)- D -Ala- D -Arg- D -Arg- D -Arg- D -Ala- D -Arg-NH 2 (SEQ ID NO:4); and contacting the peptide with L -Cys to produce a conjugated product.

5 . The method of claim 4 , wherein the peptide is contacted with an aqueous solution comprising L -Cys and trifluoroacetic acid.

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

7 . The method of claim 4 , further comprising contacting the conjugated product with an aqueous solution comprising IPA and HCl, thereby producing a precipitate comprising AMG 416 HCl (SEQ ID NO:1).

8 . The method of claim 7 , further comprising purifying the precipitate by HPLC.

9 . A method for preparing AMG 416 comprising:
providing a peptide having the structure Ac- D -Cys(SPy)- D -Ala- D -Arg- D -Arg- D -Arg- D -Ala- D -Arg-NH 2 (SEQ ID NO:4) in a solution of TFA; purifying the peptide by HPLC; performing solvent exchange by azeotropic distillation; and contacting the peptide with L -Cys to produce a conjugated product.

10 . The method of claim 9 , wherein the peptide is contacted with an aqueous solution of L -Cys and water in IPA.

11 . The method of claim 10 , further comprising contacting the conjugated product with an aqueous solution comprising IPA and HCl, thereby producing a precipitate comprising AMG 416 HCl (SEQ ID NO:1).

12 . A method for synthesizing D -Arg(Pbf)-OH comprising:
converting Boc- D -Arg-OH to Boc- D -Arg(Pbf)-OH by mixing the Boc- D -Arg-OH with PbfCl, NaOH and NaI.

13 . The method of claim 12 , further comprising:
Converting the Boc- D -Arg(Pbf)-OH to D -Arg(Pbf)-OH by mixing the Boc- D -Arg(Pbf)-OH with HCl and IPAc.

Assignees

• Amgen Inc

Inventors

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

Classifications

• C07K1/02

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

• C07K1/1075 Primary

  by covalent attachment of amino acids or peptide residues · 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

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title

• A61P5/20

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