Tetrapeptide compound and method for producing same

Patent metadata

Field	Value
Publication number	US-9982014-B2
Application number	US-201415031135-A
Country	US
Kind code	B2
Filing date	Oct 23, 2014
Priority date	Oct 23, 2013
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

The present invention is to provide a method for the efficient production on an industrial scale of SS-31 (D-Arg-Dmt-Lys-Phe-NH 2 ), which is an SS peptide. According to the present invention, the desired SS-31 is produced by efficiently synthesizing a tetrapeptide compound as a precursor of SS-31 and improving the tetrapeptide purity by crystallization.

First claim

The invention claimed is:

1. A tetrapeptide compound represented by the following formula (1)

where R is a hydrogen atom, benzyl group, or benzyloxycarbonyl group.

2. The tetrapeptide compound according to claim 1 , which is an intermediate for producing a peptide drug represented by the following formula (2)

3. The tetrapeptide compound according to claim 1 , where R is a hydrogen atom.

4. The tetrapeptide compound according to claim 1 , where compound (1) is an amorphous solid.

5. The tetrapeptide compound according to claim 1 , wherein the compound is in the form of a crystalline solid and exhibits one or more peaks at 2θ±0.1 selected from 5.4°, 10.5°, 15.6°, 17.6°, 18.0°, 18.6°, 20.1°, or 20.6° in a powder X-ray diffraction spectrum obtained using Cu-Kα radiation.

6. The tetrapeptide compound according to claim 1 , wherein compound (1) is in a form of an amorphous solid or a crystalline solid.

7. A method for producing a peptide pharmaceutical, characterized in that the tetrapeptide compound represented by the following formula (1)

is catalytically reduced in the presence of a palladium catalyst to produce a peptide pharmaceutical represented by the following formula (2)

wherein in formula (1), R is a hydrogen atom, benzyl group, or benzyloxycarbonyl group.

8. The production method according to claim 7 , characterized in that compound (1) is produced by condensation via a carbodiimide compound in the presence of a hydroxylamine compound or via a dehydrocondensation agent of Z-D-Arg(Z)2-OH represented by the following formula (3)

and the tripeptide compound represented by the following formula (4)

9. The production method according to claim 7 , wherein R is a hydrogen atom.

10. The production method according to claim 7 , wherein compound (1) is a solid precipitated from an aprotic polar solvent.

11. The production method according to claim 10 , wherein the aprotic solvent is at least one selected from tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, dimethylsulfoxide, N-methylpyrrolidone, and 1,3-dimethylpropylene urea.

Assignees

• Kaneka Corp
• Stealth Bio Therapeutics Corp
• Stealth Biotherapeutics Corp

Inventors

• Hirai Yoshinori
• Nishiyama Akira
• Mitsuda Masaru

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · 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

• C07K5/1021 Primary

  with the first amino acid being acidic · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07K5/1019 Primary

  with the first amino acid being basic · CPC title