c-Met Inhibitor Salt Forms for Solubility and Crystalline Stability
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Solution Overview
Problem
There is a need for new or improved kinase inhibitors, particularly targeting c-Met, to effectively treat cancer and other diseases associated with dysregulation of kinase pathways, as existing agents may not adequately address tumor formation, growth, and metastasis, and are often associated with resistance to chemotherapy and radiotherapy.
Innovation Solution
Development of dihydrochloric acid and dibenzenesulfonic acid salts of the kinase inhibitor 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, which can inhibit tyrosine kinase activity and disrupt the HGF/c-Met signaling pathway, thereby inhibiting tumor growth and metastasis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing kinase inhibitors are used to treat cancer, then tumor growth may be inhibited, but resistance to chemotherapy and radiotherapy develops
Solution Approach 1:
The patent modifies the chemical structure of kinase inhibitors by creating salt forms (dihydrochloric acid salt and dibenzenesulfonic acid salt) of the parent compound. This changes the physical and chemical parameters of the drug, including solubility, stability, and bioavailability, which can overcome resistance mechanisms while maintaining the core kinase inhibitory activity against c-Met and other targets
2Reliability
If new kinase inhibitors targeting c-Met are developed, then tumor formation and growth can be addressed, but the complexity of the drug development process increases
Solution Approach 1:
The patent focuses on a specific kinase inhibitor compound with defined activity against multiple kinases including c-Met, ABL, BCR-ABL, and others. By segmenting the approach to target specific kinase pathways involved in tumor formation and growth, the patent achieves effective cancer treatment while managing development complexity through targeted rather than broad-spectrum inhibition
3Ease of manufacture
If the kinase inhibitor is formulated as salts, then solubility and crystalline form are improved for pharmaceutical use, but the manufacturing process becomes more complex
Solution Approach 1:
The patent converts the parent kinase inhibitor compound into salt forms (specifically dihydrochloric acid salt and dibenzenesulfonic acid salt). This parameter change in the chemical form improves critical pharmaceutical properties including aqueous solubility and crystalline structure, which are essential for drug formulation, stability, and bioavailability. The salt formation process, while adding a step, uses well-established pharmaceutical techniques to achieve these improvements
Data Source
AI summary
The present invention is directed to dihydrochloric acid and dibenzenesulfonic acid salts of the c-Met kinase inhibitor 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)-imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, and pharmaceutical compositions thereof, useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways. The present invention further relates to processes and intermediates for preparing 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, and salts thereof.