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US-20260125442-A1 - PROCESS FOR PREPARING A GIP/GLP1 DUAL AGONIST

US20260125442A1US 20260125442 A1US20260125442 A1US 20260125442A1US-20260125442-A1

Abstract

The present invention provides novel intermediates and processes useful in the manufacture of tirzepatide, or a pharmaceutically acceptable salt thereof.

Inventors

  • Michael E. Kobierski
  • Michael E. Kopach

Assignees

  • ELI LILLY AND COMPANY

Dates

Publication Date
20260507
Application Date
20250926

Claims (10)

  1. 1 - 8 . (canceled)
  2. 9 . A compound comprising the amino acid sequence of SEQ ID NO: 5, wherein the threonine amino acid at position 5 is D-threonine, the aspartic acid amino acid at position 9 is D-aspartic acid, and/or the aspartic acid amino acid at position 15 is D-aspartic acid.
  3. 10 . The compound of claim 9 , wherein the threonine amino acid at position 5 is D-threonine and the aspartic acid amino acid at position 9 is D-aspartic acid.
  4. 11 . The compound of claim 9 , wherein the aspartic acid amino acid at position 15 is D-aspartic acid.
  5. 12 . A composition comprising: (a) the compound of claim 9 ; and) (b) a compound comprising the amino acid sequence of SEQ ID NO: 5 (tirzepatide).
  6. 13 . The composition of claim 12 , wherein the composition comprises: (a) from about 0.1% to about 1.0%, by weight of the composition, of the compound of claim 9 ; and (b) from about 99% to about 99.9%, by weight of the composition, of tirzepatide.
  7. 14 . A composition comprising: (a) the compound of claim 10 ; and) (b) a compound comprising the amino acid sequence of SEQ ID NO: 5 (tirzepatide).
  8. 15 . The composition of claim 14 , wherein the composition comprises: (a) from about 0.1% to about 1.0%, by weight of the composition, of the compound of claim 10 ; and (b) from about 99% to about 99.9%, by weight of the composition, of tirzepatide.
  9. 16 . A composition comprising: (a) the compound of claim 11 ; and) (b) a compound comprising the amino acid sequence of SEQ ID NO: 5 (tirzepatide).
  10. 17 . The composition of claim 16 , wherein the composition comprises: (a) from about 0.1% to about 1.0%, by weight of the composition, of the compound of claim 11 ; and (b) from about 99% to about 99.9%, by weight of the composition, of tirzepatide.

Description

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file titled “30310_US.xml,” created Nov. 1, 2024, and is 63,013 bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety. The present invention provides improved processes and intermediates for making a GIP/GLP1 dual agonist peptide, tirzepatide, or a pharmaceutically acceptable salt thereof. Diabetes mellitus is a chronic disorder characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. In type 2 diabetes mellitus (“T2D”), the combined effects of impaired insulin secretion and insulin resistance are associated with elevated blood glucose levels. The GIP/GLP1 dual agonist, tirzepatide is described and claimed in U.S. Pat. No. 9,474,780 (“780 Patent”). Tirzepatide can be useful in the treatment of T2D. U.S. Pat. No. 9,474,780 generally describes peptides and a method for making a GIP/GLP1 dual agonist. WO2020/159949 describes methods of making tirzepatide; however, there is a need for linear process improvements to facilitate large scale commercial production. There is a need for processes and intermediates to enable improved technology for production of tirzepatide having a combination of advantages including commercially desired purity and efficiency. Similarly, there is a need for efficient and environmentally “green” processes, including stable intermediates to provide tirzepatide with fewer purification steps. Improved technology is also needed to provide tirzepatide manufacturing processes producing minimal waste streams for both environmental and operator enhanced safety. The preparation of large-scale, pharmaceutically-elegant tirzepatide presents a number of technical challenges that may affect the overall yield and purity. There is a need for processes to avoid the use of transition metals and/or harsh reaction conditions that are incompatible with peptide synthesis. The present invention seeks to meet these needs by providing novel intermediates and processes useful in the manufacture of tirzepatide (SEQ ID NO:5), or a pharmaceutically acceptable salt thereof. The improved tirzepatide manufacturing processes of the present invention provide intermediates and process reactions embodying a combination of advances, including an efficient route having fewer steps, while at the same time maintaining high quality and purity. Importantly, the improved processes and intermediates decrease resource intensity and minimize waste streams. The improved processes described herein provide various embodiments of intermediates useful for production of tirzepatide. The present invention provides a compound of SEQ ID NO:1, or a pharmaceutically acceptable salt thereof. The present invention provides a compound of SEQ ID NO:2, or a pharmaceutically acceptable salt thereof. The present invention provides a compound of SEQ ID NO:3, or a pharmaceutically acceptable salt thereof. The present invention provides a process to prepare tirzepatide, comprising preparing the protected compound, or pharmaceutically acceptable salt, of a compound of SEQ ID NO:1. The present invention provides a process to prepare tirzepatide, comprising deprotecting a compound, or pharmaceutically acceptable salt, of a compound of SEQ ID NO:1. The present invention provides a process to prepare tirzepatide, comprising cleaving a compound from a resin, or pharmaceutically acceptable salt, of a compound of SEQ ID NO:2. The present invention provides a process to prepare tirzepatide, comprising deprotecting a compound, or pharmaceutically acceptable salt, of a compound of SEQ ID NO:3. The present invention provides a process to prepare tirzepatide (SEQ ID NO:5), comprising acylating a lysine to form a compound, or pharmaceutically acceptable salt, of a compound of SEQ ID NO:4 and then deprotecting to form tirzepatide. Provided is a process to prepare the mtt protected epsilon amino group of a lysine amino acid of a resin bound protected peptide of SEQ ID NO:1. Provided is a process to selectively deprotect a mtt protected epsilon amino group of a lysine amino acid of a resin bound protected peptide of SEQ ID NO: 1 to form a protected peptide of SEQ ID NO:2. Provided is a process to selectively cleave the resin bound protected peptide of SEQ ID NO: 2 to form the the compound of SEQ ID NO:3. Provided is a process to acylate an unprotected epsilon amino group of a lysine of SEQ ID NO:3 with Compound 1 to form the compound of SEQ ID NO:4. Provided is a process for determining the chiral purity for the preparation of a peptide by SPPS by using a chiral high-performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS/MS) method. In an embodiment is a process to prepare tirzepatide (SEQ ID NO:5) comprising a) deprotecting a compound of SEQ ID NO:1 to provide a compound of SEQ ID NO: 2