JP-7856703-B2 - Process for preparing GIP/GLP1 dual agonists

Inventors

• コフィン，ステファニー ルース
• フレデリック，マイケル オリバー
• ジャラン，アンクル
• コールマン，ニール ジョン
• コパック，マイケル ユージーン
• サイバート，ケビン デイル
• ツカノフ，セルゲイ ヴラディミロヴィチ

Assignees

• イーライ リリー アンド カンパニー

Dates

Publication Date

20260511

Application Date

20240802

Priority Date

20190129

Claims (3)

1. Compound of Sequence ID No. 10: or a pharmaceutically acceptable salt thereof.
2. Compound of Sequence ID No. 16: or a pharmaceutically acceptable salt thereof.
3. Compound of Sequence ID No. 26: or a pharmaceutically acceptable salt thereof.

Description

Detailed description of the invention This invention provides a process and intermediates for producing GIP/GLP1 dual agonist peptides, tilzepatides, or pharmaceutically acceptable salts thereof. Diabetes mellitus is a chronic disease characterized by hyperglycemia resulting from deficiencies in insulin secretion, insulin action, or both. In type 2 diabetes mellitus ("T2D"), the combined effects of insulin deficiency and insulin resistance are associated with elevated blood glucose levels. Tilzepatide, a GIP/GLP1 dual agonist, is described and claimed in U.S. Patent No. 9,474,780 ("780 Patent"). Tilzepatide may be useful in the treatment of T2D. US9474780 generally describes methods for preparing peptides and GIP/GLP1 dual agonists. Processes and intermediates are needed to enable improved techniques for producing tylzepatide with a combination of advantages, including commercially desirable purity. Similarly, an efficient and environmentally "green" process is needed, including stable intermediates to provide tylzepatide with fewer purification steps. Improved techniques are also required to provide a tylzepatide production process that minimizes waste flow to enhance safety for both the environment and operators. Large-scale preparation of pharmaceutically superior tylzepatide presents several technical challenges that can affect overall yield and purity. Processes are needed to avoid the use of transition metals and/or harsh reaction conditions that are incompatible with peptide synthesis. This invention aims to satisfy these needs by providing novel intermediates and processes useful for the production of tirzepatide (SEQ ID NO: 1) or its pharmaceutically acceptable salts. The improved tirzepatide production process of this invention provides intermediates and process reactions that embody a combination of advancements, including an efficient route with fewer steps while maintaining high quality and purity. Importantly, the improved process and intermediates reduce resource intensity and minimize waste flow. The improved processes described herein provide various embodiments of intermediates useful for the production of tilzepitide. This invention provides the compound of SEQ ID NO: 17, or a pharmaceutically acceptable salt thereof. This invention provides the compound of SEQ ID NO: 11, or a pharmaceutically acceptable salt thereof. This invention provides the compound of SEQ ID NO: 22, or a pharmaceutically acceptable salt thereof. This invention provides the compound of SEQ ID NO: 21, or a pharmaceutically acceptable salt thereof. This invention provides the compound of SEQ ID NO: 20, or a pharmaceutically acceptable salt thereof. This invention provides the compound of SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof. This invention provides the compound of SEQ ID NO: 4, or a pharmaceutically acceptable salt thereof. This invention provides the compound of SEQ ID NO: 7, or a pharmaceutically acceptable salt thereof. This invention provides the compound of SEQ ID NO: 14, or a pharmaceutically acceptable salt thereof. This invention provides the compound of SEQ ID NO: 33, or a pharmaceutically acceptable salt thereof. This invention provides the compound of SEQ ID NO: 32, or a pharmaceutically acceptable salt thereof. This invention provides the compound of SEQ ID NO: 34, or a pharmaceutically acceptable salt thereof. This invention provides the compound of SEQ ID NO: 35, or a pharmaceutically acceptable salt thereof. This invention provides the compound of SEQ ID NO: 36, or pharmaceutically acceptable salts thereof. This invention provides the compound of SEQ ID NO: 38, or pharmaceutically acceptable salts thereof. This invention provides the compound of SEQ ID NO: 39, or pharmaceutically acceptable salts thereof. The compound of the following formula: or provide a pharmaceutically acceptable salt thereof. The compound of the following formula: or provide a pharmaceutically acceptable salt thereof. This invention provides a process for preparing tilzepatide using nanofiltration. The present invention provides a process for preparing tilzepatide, comprising deprotecting a compound of the compound of SEQ ID NO: 22, or a pharmaceutically acceptable salt thereof. The present invention provides a process for selectively acylating lysine amino acids and lysine amino acids with a protected N-terminus. The present invention provides a process for selectively acylating lysine amino acids in a peptide, comprising coupling a resin-bound peptide-lysine- NH2 with t-butyl-eicosanedioyl-Glu-(O-tert-butyl)-(8-amino-3,6-dioxaoctanoic acid)-(8-amino-3,6-dioxaoctanoic acid)-OH). The present invention provides a process for preparing tilzepatide, comprising deprotecting the compound of SEQ ID NO: 22 or a pharmaceutically acceptable salt thereof. The deprotection solution provides a process for deprotecting tilzepatide, comprising dithiothreitol, triisopropylsilane, and trifluoroacetic acid. The peptide-lysin