Monoclinic FGFR4 Inhibitor Crystal Form for Stability
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Solution Overview
Problem
There is an urgent need for selective FGFR4 inhibitors to treat various cancers, particularly liver cancer, as existing FGFR inhibitors can cause toxicity due to non-specific inhibition of FGFR subtypes.
Innovation Solution
Development of a crystalline form of an FGFR4 selective inhibitor, compound of formula B, with specific X-ray diffraction peaks and monoclinic crystal system, providing improved pharmacokinetic properties and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing FGFR inhibitors are used to treat cancers, then tumor proliferation can be inhibited, but toxicity increases due to non-specific inhibition of FGFR subtypes
Solution Approach 1:
The patent applies local quality by designing a crystalline form with specific molecular arrangement and packing that confers selective FGFR4 inhibition properties. The crystal structure creates localized molecular interactions that enhance affinity for FGFR4 while reducing off-target effects on other FGFR subtypes, thereby achieving selectivity without increasing toxicity.
Solution Approach 2:
The patent utilizes parameter changes by transforming the compound into a specific crystalline form with defined lattice parameters and molecular orientation. This structural parameter change enhances the pharmacokinetic properties and selectivity of the FGFR4 inhibitor, allowing for improved therapeutic index and reduced toxicity compared to the amorphous form.
2Reliability
If compound of formula B is developed as an FGFR4 inhibitor, then selective inhibition is achieved, but stability and pharmacokinetic properties need optimization
Solution Approach 1:
The patent applies phase transitions by converting the amorphous compound of formula B into a crystalline form. This phase change from amorphous to crystalline state significantly improves the stability, solubility, and pharmacokinetic properties of the FGFR4 inhibitor, while maintaining the selective inhibition activity.
Solution Approach 2:
The patent uses segmentation by identifying and isolating specific crystalline forms (Form I, Form II, Form III) with distinct molecular arrangements. Each crystalline form represents a segmented version of the compound with optimized properties, allowing selection of the most stable and pharmacologically active form for therapeutic use.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The crystalline form of compound B offers enhanced stability and druggability, addressing the need for selective FGFR4 inhibition with reduced toxicity, suitable for treating cancers and other FGFR4-related diseases.
Implementation Method 1
the crystalline form of compound B, particularly the preferred crystalline form, has stable quality, stable thermodynamics, and desirable druggability
Implementation Method 2
the crystalline form I of the compound of formula B has characteristic peaks at 2θ angles of 7.4±0.2° and 25.0±0.2° by X-ray powder diffraction using Cu-Kα radiation
Data Source
AI summary
A crystalline form of an FGFR4 inhibitor and use thereof are provided. A compound of formula B is in crystalline form, which has excellent FGFR4 kinase inhibitory activity and Huh-7 tumor cell proliferation inhibition. The pharmacokinetic effect of the compound is better than that of its enantiomers or its racemates.