Quaternary Fused Ring Salt Crystals for Resistant BCR-ABL1 Inhibition
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Solution Overview
Problem
Existing drugs like imatinib, nilotinib, and dasatinib are ineffective against drug-resistant BCR-ABL1 mutants in chronic myeloid leukemia (CML), necessitating the development of new compounds to inhibit tyrosine kinase activity effectively.
Innovation Solution
Development of a crystal form of a quaternary fused ring compound in the form of acid salts, such as ethylsulfonate, mesylate, sulfate, hydrochloride, p-tosylate, besylate, isethionate, or 1,5-napadisylate, to enhance solubility, stability, and bioavailability, thereby targeting the ATP and myristoyl binding sites of BCR-ABL1.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing drugs like imatinib, nilotinib, and dasatinib are used to inhibit BCR-ABL1 tyrosine kinase activity, then the drug may be effective in treating CML, but some patients relapse due to the emergence of drug-resistant clones
Solution Approach 1:
The patent modifies the chemical structure of quaternary fused ring compounds by changing parameters such as substituting hydrogen atoms with deuterium atoms (kinetic isotope effect), adjusting molecular weight, and modifying functional groups to create compounds that can overcome drug resistance while maintaining therapeutic efficacy
Solution Approach 2:
The patent creates composite salt forms by combining the quaternary fused ring compound with various acids (e.g., p-toluenesulfonic acid, mesitic acid, benzoic acid) to form salt crystals that exhibit enhanced solubility, stability, and bioavailability, thereby improving therapeutic performance against resistant mutants
2Duration of action of stationary object
If salt crystal forms of quaternary fused ring compounds are developed to improve solubility and stability, then the product life cycle is prolonged, but the complexity of the preparation process increases
Solution Approach 1:
The patent performs preliminary crystallization and salt formation steps during the synthesis process itself, rather than as separate post-processing operations. The quaternary fused ring compound is formed with the appropriate salt form already integrated into the molecular structure, simplifying downstream processing and storage
Solution Approach 2:
The patent optimizes crystallization parameters such as temperature, pH, and solvent composition to facilitate the formation of stable salt crystal forms with desired properties. By controlling these parameters, the patent achieves prolonged product life cycle while maintaining relatively simple preparation processes
Data Source
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AI summary
The present invention relates to a salt crystal form of a quaternary fused ring compound, and a preparation method therefor and the use thereof. Specifically, the present invention relates to a salt crystal form of the quaternary fused ring compound of a compound as represented by formula (I), a preparation method therefor, a pharmaceutical 5 composition comprising a therapeutically effective amount of the compound or the crystal form thereof, and the use thereof as a tyrosine kinase inhibitor drug.