Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06086—Dipeptides with the first amino acid being basic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06086—Dipeptides with the first amino acid being basic
  • C07K5/06095—Arg-amino acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/10—Tetrapeptides
  • C07K5/1019—Tetrapeptides with the first amino acid being basic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2299/00—Coordinates from 3D structures of peptides, e.g. proteins or enzymes

Definitions

• Elamipretide (MTP-131) is a mitochondria-targeting peptide compound with therapeutic potential for treating diseases associated with mitochondrial dysfunction.
• Elamipretide contains four-amino acid residues and has been synthesized according to typical linear and convergent solution phase peptide synthesis methods.
• the synthetic routes to generate elamipretide that have been used to date require the preparation of various differentially protected peptides, such that certain protecting groups are selectively removed in order to subject the deprotected compound to peptide coupling, while other protecting groups remain to prevent unwanted side reactions. Even with protecting groups such coupling reactions and related steps generate impurities.
• Crystallization of the desired reaction products are one method of achieving the necessary purification.
• Figure 1 is the XRPD pattern of crystalline L-Lys(Boc)-Phe-NH2.
• Figure 2 is the XRPD pattern crystalline Boc-D-Arg-DMT.
• Elamipretide has been shown to have various therapeutic effects in diseases related to mitochondrial dysfunction.
• Previous synthetic routes to elamipretide presented challenges with respect to scale-up due to reliance on chromatographic separations to enrich levels of desired intermediates.
• Herein are disclosed crystalline forms of L-Lys(Boc)-Phe-NH2 and Boc-D-Arg-DMT, which can be used as purified intermediates in the synthesis of elamipretide.
• One aspect of the present invention relates to crystalline forms of Compound (I):
• a crystalline form of Compound (I) can be used in the synthesis of elamipretide.
• a polymorph of the crystalline form is characterized by powder X-ray diffraction (XRD).
• Q represents the diffraction angle, measured in degrees.
• the diffractometer used in XRD measures the diffraction angle as two times the diffraction angle Q.
• the diffraction patterns described herein refer to X-ray intensity measured against angle 2Q.
• a crystalline form of Compound (I) is not solvated (e.g., the crystal lattice does not comprise molecules of a solvent).
• a crystalline form of Compound (I) is solvated.
• the solvent is water.
• the invention features a crystalline form of Compound (I) which has characteristic peaks in the powder X-ray diffraction (XRPD) pattern as shown in Figure 1.
• the invention features a crystalline form of Compound (I) which has characteristic peaks in the powder X-ray diffraction (XRPD) pattern at values of two theta (° 2Q) as shown in Table 1.
• the invention features a crystalline form of Compound (I) which has characteristic peaks in the powder X-ray diffraction (XRPD) pattern at values of two theta (° 2Q) of: 4.7, 6.2, 12.4, 15.8, 16.5, 18.0, 18.2, 18.8, and 19.8.
• XRPD powder X-ray diffraction
• the invention features a crystalline form of Compound (I) which has characteristic peaks in the powder X-ray diffraction (XRPD) pattern at values of two theta (° 2Q) of: 4.7, 6.2, 11.3, 12.4, 13.3, 15.0, 15.8, 16.5, 17.0, 17.7, 18.0, 18.2, 18.8, 19.8, 22.0, and 22.8.
• XRPD powder X-ray diffraction
• the relative intensity, as well as the two theta value, of each peak in Table 1, as well as in Figure 1 may change or shift under certain conditions, although the crystalline form is the same.
• One of ordinary skill in the art should be able to determine readily whether a given crystalline form is the same crystalline form as described in Table 1, as well as in Figure 1, by comparing their XRPD data.
• One aspect of the present invention relates to a crystalline form of Compound (II):
• Boc-D-Arg-DMT which compound is also known as Boc-D-Arg-DMT, and may also be drawn in the form of a zwitterion.
• a crystalline form of Compound (II) can be used in the synthesis of elamipretide.
• a polymorph of the crystalline form is characterized by powder X-ray diffraction (XRD).
• Q represents the diffraction angle, measured in degrees.
• the diffractometer used in XRD measures the diffraction angle as two times the diffraction angle Q.
• the diffraction patterns described herein refer to X-ray intensity measured against angle 2Q.
• a crystalline form of Compound (II) is not solvated (e.g., the crystal lattice does not comprise molecules of a solvent). In certain alternative embodiments, a crystalline form of Compound (II) is solvated. In some cases, the solvent is water.
• the invention features a crystalline form of Compound (II) which has characteristic peaks in the powder X-ray diffraction (XRPD) pattern as shown in Figure 2.
• the invention features a crystalline form of Compound (II) which has characteristic peaks in the powder X-ray diffraction (XRPD) pattern at values of two theta (° 2Q) as shown in Table 2.
• the invention features a crystalline form of Compound (II) which has characteristic peaks in the powder X-ray diffraction (XRPD) pattern at values of two theta (° 2Q) of : 9.3, 12.1, 16.6, 17.6, 18.0, 18.8, and 19.4.
• the invention features a crystalline form of Compound (II) which has characteristic peaks in the powder X-ray diffraction (XRPD) pattern at values of two theta (° 2Q) of : 9.3, 12.1, 13.7, 16.3, 16.6, 17.6, 18.0, 18.8, 19.4, 21.3, 23.0, 24.2, and 25.1.
• the suspension is heated to 45 ⁇ 50°C.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Genetics & Genomics (AREA)
• Biochemistry (AREA)
• Biophysics (AREA)
• General Health & Medical Sciences (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Molecular Biology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Life Sciences & Earth Sciences (AREA)
• Peptides Or Proteins (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2019
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