Crystalline CFTR Modulators via Segmented Synthesis
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Solution Overview
Problem
Current treatments for cystic fibrosis, particularly those targeting the CFTR protein, face challenges in effectively addressing mutations like ΔF508, which impede protein folding and trafficking, leading to reduced anion transport and severe disease symptoms.
Innovation Solution
Development of crystalline forms of Compound 1, synthesized through specific coupling reactions using agents like 2-chloro-1,3-dimethyl-2-imidazolium tetrafluoroborate, to modulate CFTR activity, potentially improving protein function and reducing disease severity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule drugs (potentiators) are developed to increase CFTR channel opening probability, then anion transport function is improved, but the complexity of drug synthesis and manufacturing increases
Solution Approach 1:
The patent segments the complex CFTR modulation problem into distinct chemical building blocks (compounds of Formula I) with specific structural features that can be synthesized through modular coupling reactions. This segmentation allows for systematic development of potentiators with improved anion transport function while managing synthesis complexity through structured molecular design
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters (substituents R1-R6, core structures) in the compound molecules to optimize CFTR binding affinity and channel opening probability. This approach enables tuning of drug properties to achieve reliable CFTR modulation while maintaining feasible synthesis pathways
2Manufacturing precision
If crystalline forms of Compound 1 are synthesized using specific coupling agents, then manufacturing precision is improved, but the ease of manufacture decreases
Solution Approach 1:
The patent applies preliminary action by pre-selecting and optimizing specific coupling agents (2-chloro-1,3-dimethyl-2-imidazolium tetrafluoroborate and others) and reaction conditions before full-scale synthesis. This preliminary optimization ensures high manufacturing precision for crystalline forms while documenting procedures to facilitate ease of manufacture in subsequent production
Solution Approach 2:
The patent uses coupling agents as intermediaries to mediate the formation of Compound 1 with high precision. These intermediaries enable controlled chemical reactions that produce pure crystalline forms while the detailed characterization of intermediate steps provides a roadmap for simplifying the overall manufacturing process
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 forms of Compound 1 demonstrate potential in treating a wide range of diseases associated with CFTR mutations by enhancing CFTR activity, thereby alleviating symptoms of cystic fibrosis and other conditions.
Implementation Method 1
reacting Compound 2 with Compound 3 in the presence of a coupling agent wherein the coupling agent is selected from the group consisting of 2-chloro-1,3-dimethyl-2-imidazolium tetrafluoroborate, HBTU, HCTU, 2-chloro-4,6-dimethoxy-1,3,5-triazine, HATU, HOBT/EDC, and T3P
Data Source
AI summary
The present invention relates to processes for preparing solid state forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, including Compound 1 Form A, Compound 1 Form A-HCl, Compound 1 Form B, and Compound 1 Form B-HCl, any combination of these forms, pharmaceutical compositions thereof, and methods of treatment therewith.