Process Research and Development for a Tetrazole-Based Growth Hormone Secretagogue (GHS) Pharmaceutical Development Candidate

Abstract

BMS-317180 (1) is a potent, orally active agonist of the human growth hormone secretagogue (GHS) receptor. This manuscript details the process research and development efforts that enabled the synthesis of the phosphate salt of 1 on a multi-kilogram scale. Key considerations in the development of this process focused on safe execution and the requirement for telescoped synthetic transformations (i.e., without isolation of intermediate products) to contend with a lack of suitably crystalline products.

Synthesis of Novel bis-1,5-Disubstituted-1H-Tetrazoles by an Efficient Catalyst-Free Ugi-Azide Repetitive Process

“…For example, the 1,5-DS-1H-T 1 showed antifungal activity against Candida albicans, Cryptococcus neoformans and Aspergillus niger comparable to the most potent commercially available antimycotics, such as fluconazole and itraconazole [2]. In the same context, the in-clinical phase drug, BMS-317180 (2), is a potent orally agonist of the human growth hormone, secretagogue [3] (Figure 1). It is noteworthy that the most used methods toward the synthesis of the 1,5-DS-1H-T are both click [3 + 2] dipolar cycloadditions of organic azides with cyanides [4][5][6][7] and the Ugi-azide reaction between amines, aldehydes, isocyanides and hydrazoic acid [8].…”

Five‐Membered Heterocycles with Four Heteroatoms: Tetrazoles

“…In a recent development, an interesting methodology was reported for the synthesis of tetrazole ring compounds starting from an amide [10]. The amide substrate was first converted into an oxazoline and then treated with hydrazine hydrochloride in methanol to yield an amidrazone.…”

Expedient Access to Novel Bis‐tetrazolopiperazines via Ugi‐azide Reactions

“…Moreover, 1,5‐DS‐1 H ‐T is the core of the in clinical phase drug BMS‐317180 (Fig. b) as a potent orally available ligand of the growth hormone secretagogue . On the other hand, heterocycles present in widely used losartan and valsartan are known with angiotensin receptor blocker properties (Fig.…”