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Synthesis of BI 1584142 and BI 1810631 (Zongertinib), Two Potent HER2 Inhibitors, Labeled With Carbon-14 and With
1The Radiosynthesis Laboratory, Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA.
Abstract:
BI 1584142 (1) and BI 1810631 (2, zongertinib) are potent and selective HER2 tyrosine kinase inhibitors being developed for the treatment of non-small cell lung cancer. Carbon-14-labeled versions of these drug candidates were needed to study their absorption, distribution, metabolism, and excretion in animals and in humans. BI 1584142 and BI 1810631 differ in two moieties; the former contains a piperazine and the latter a 4-aminopiperidine. Therefore, a common carbon-14-labeled intermediate like the sulfoxide [14C]-8 was prepared in four radioactive steps and used to provide [14C]-1 and [14C]-2 in two and three extra steps, respectively. Deuterium-labeled 1 and 2 were also synthesized as internal standards, using piperazine-d8 and 4-aminopiperidine-d9 for bioanalytical studies and other studies.
Insights
Radiolabeled HER2 inhibitors BI 1584142 and BI 1810631 were synthesized for ADME studies in non-small cell lung cancer. A common carbon-14 labeled intermediate facilitated the preparation of these drug candidates and their deuterium-labeled counterparts.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Radiochemistry
Background:
- BI 1584142 and BI 1810631 are potent, selective HER2 tyrosine kinase inhibitors.
- These agents are under development for non-small cell lung cancer (NSCLC).
- Absorption, distribution, metabolism, and excretion (ADME) studies require radiolabeled compounds.
Purpose of the Study:
- To synthesize carbon-14 labeled BI 1584142 and BI 1810631 for ADME studies.
- To prepare deuterium-labeled analogs of BI 1584142 and BI 1810631 as internal standards.
Main Methods:
- A common carbon-14 labeled sulfoxide intermediate ([14C]-8) was synthesized in four radioactive steps.
- The intermediate was used to prepare [14C]-BI 1584142 ([14C]-1) in two steps and [14C]-BI 1810631 ([14C]-2) in three steps.
- Deuterium-labeled piperazine-d8 and 4-aminopiperidine-d9 were used to synthesize deuterium-labeled analogs.
Main Results:
- Efficient synthesis of [14C]-labeled BI 1584142 and BI 1810631 was achieved.
- Deuterium-labeled internal standards were successfully prepared.
- The synthetic strategy allowed for the preparation of both 14C and deuterium labeled compounds.
Conclusions:
- The developed synthetic routes provide essential radiolabeled and stable isotope-labeled compounds for preclinical and clinical studies.
- These labeled compounds are crucial for understanding the pharmacokinetic profile of novel HER2 inhibitors in NSCLC treatment.
- The common intermediate strategy offers an efficient approach for preparing related radiolabeled drug candidates.
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