Methanesulfonate Crystal Forms for Soluble Stable VEGFR Inhibitors
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Solution Overview
Problem
Existing anticancer drugs targeting VEGF receptors suffer from poor selectivity, strong toxicity, and drug resistance, with a need for improved solubility, stability, and oral bioavailability.
Innovation Solution
Development of crystalline forms A, B, and C of N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate, characterized by specific X-ray powder diffraction patterns, to enhance physicochemical properties and drug efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cytotoxic anticancer drugs are used, then tumor inhibition effect is achieved, but selectivity is poor and toxicity is strong
Solution Approach 1:
The patent changes the chemical structure parameters by introducing a specific quinoline core with 6,7-dimethoxy substitution and fluorophenyl group, creating a molecule with optimized pharmacological properties that achieves selective VEGF receptor inhibition with reduced toxicity compared to conventional cytotoxic drugs
Solution Approach 2:
The patent applies local quality by creating a molecule with specific functional regions - the quinoline core provides tyrosine kinase inhibitory activity while the 6,7-dimethoxy and fluorophenyl groups provide selective binding to VEGF receptors, achieving localized pharmacological activity at the target site
2Reliability
If conventional anticancer inhibitors are used, then VEGF receptor inhibition is achieved, but selectivity among family members is insufficient
Solution Approach 1:
The patent creates local quality differentiation through the specific 6,7-dimethoxyquinoline core structure that provides preferential binding to VEGF receptors over other tyrosine kinases, achieving selective inhibition while maintaining activity against the target
Solution Approach 2:
The patent modifies molecular parameters by incorporating the fluorophenyl group and specific methoxy substitutions that create steric and electronic properties favorable for VEGF receptor binding, improving selectivity among tyrosine kinase family members
3Reliability
If free base form of the compound is used, then drug activity is maintained, but solubility and oral bioavailability are insufficient
Solution Approach 1:
The patent uses methanesulfonate as an intermediary salt form that bridges the free base compound and the physiological environment, improving solubility and oral bioavailability while maintaining drug activity through the salt's enhanced pharmacokinetic properties
Solution Approach 2:
The patent changes the physical chemical parameters by converting the free base to its methanesulfonate salt, which alters the molecule's solubility, permeability, and absorption characteristics to improve oral bioavailability while preserving biological activity
4Stability of the object's composition
If crystalline forms are developed, then stability and solubility are improved, but manufacturing complexity increases
Solution Approach 1:
The patent changes the physical state parameter by developing specific crystalline forms (Forms A, B, and C) with defined X-ray diffraction patterns, improving stability and solubility through controlled crystal structure while providing clear identification criteria for manufacturing
Solution Approach 2:
The patent replaces complex manufacturing process control with clear crystalline form identification through X-ray powder diffraction patterns, allowing quality control through characteristic peak matching (2θ values) rather than complex process monitoring
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 improve solubility, stability, and oral bioavailability, making them suitable for drug development and industrial production with enhanced clinical advantages.
Implementation Method 1
crystalline form A has characteristic peaks in an X-ray powder diffraction pattern at 2θ of 6.5°±0.2°, 10.0°±0.2°, 15.2°±0.2°, 17.2°±0.2°, 19.8°±0.2°, and 24.3°±0.2°
Data Source
AI summary
The present disclosure belongs to the technical field of medicinal chemistry, and in particular relates to crystalline forms A, B, and C of a compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate and preparation methods thereof. The three crystalline forms A, B, and C provided by the present disclosure can be prepared under various different conditions, a crystallization process has a good purification effect and has advantageous characteristics such as stable process and easy operation, the preparation methods for the crystalline forms are simple and has low cost, and different crystal forms of the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate with high purity, good solubility and good stability can be obtained.