ATM Inhibitor Crystal Forms for Brain-Penetrant Drug Delivery
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Solution Overview
Problem
Existing ATM inhibitors struggle to effectively cross the blood-brain barrier to reach therapeutic drug concentrations, and the free base amorphous form of 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c] quinolin-2-one derivatives are not conducive to pharmaceutical processing and compositions.
Innovation Solution
Development of a novel 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c] quinolin-2-one derivative with R chirality and specific XRPD patterns for both free base and fumarate salt crystal forms, enhancing their ability to cross the blood-brain barrier and improve pharmaceutical processing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If the free base amorphous form of 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c] quinolin-2-one derivatives is used, then the drug can be synthesized, but it is not conducive to pharmaceutical processing and compositions
Solution Approach 1:
The patent transforms the amorphous free base form into crystalline forms (free base crystal form and fumarate salt crystal form) by changing the physical state parameters. This crystallization process improves pharmaceutical processing properties including stability, solubility, and bioavailability while maintaining the core molecular structure of the ATM kinase inhibitor.
2Reliability
If existing ATM inhibitors are used, then they can inhibit ATM kinase, but they cannot effectively cross the blood-brain barrier to reach therapeutic drug concentrations
Solution Approach 1:
The patent introduces a fluorinated piperidine moiety with specific stereochemistry (R-configuration) to the ATM kinase inhibitor structure. This local structural modification at the piperidine ring enhances blood-brain barrier penetration capability while preserving the core imidazo[4,5-c]quinolin-2-one structure that provides ATM kinase inhibition activity.
Solution Approach 2:
The patent creates a composite molecular structure combining the imidazo[4,5-c]quinolin-2-one core with a 3,3-difluoropiperidin-4-yl group. This composite structure integrates both the ATM kinase binding capability and the blood-brain barrier penetration properties in a single molecule, achieving dual functionality.
Data Source
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Figure 4B~5A
AI summary
A substituted 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c] quinolin-2-one derivative (represented by the formula (I)) free base's crystal form and salt's crystal form, a preparation method and application are provided; specifically, the free base crystal form and fumarate salt crystal form of the 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c] quinolin-2-one derivative represented by formula (I). The free base crystal form and salt crystal form provided by the present invention have good stability, which can be used in the treatment of cancers, cancers with CNS metastasis, meningeal metastasis, primary brain cancer or glioma, etc., especially combination with DNA double strand break inducing agents, and have good bioavailability and half-life, which are of great significance for further research on the efficacy of such solid drugs.