Crystalline SHP2 Inhibitor Forms for Stable Therapeutic Use
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Solution Overview
Problem
Current therapies lack effective small molecules to inhibit the activity of Src homology region 2-containing protein tyrosine phosphatase (SHP2), which is implicated in various human diseases such as Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia, and cancers of the breast, lung, and colon.
Innovation Solution
Development of crystalline solid forms of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, or its pharmaceutically acceptable salts, which act as potent SHP2 inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If crystalline solid forms of the SHP2 inhibitor compound are developed, then the reliability and therapeutic effectiveness are improved, but the manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline polymorphs (Forms A, B, C, and D) of the SHP2 inhibitor compound, each with distinct crystal structures characterized by different X-ray powder diffraction patterns. This allows optimization of therapeutic effectiveness and stability by selecting appropriate crystal forms while managing manufacturing complexity through systematic structure characterization.
Solution Approach 2:
The patent utilizes phase transitions by identifying and characterizing different solid-state phases (polymorphs) of the compound. Each polymorph represents a distinct phase with unique properties, enabling selection of the most suitable form for therapeutic application while providing multiple options for manufacturing optimization.
2Adaptability or versatility
If multiple crystalline forms are characterized and prepared, then the adaptability for different therapeutic applications is improved, but the loss of time in development increases
Solution Approach 1:
The patent applies preliminary action by proactively characterizing multiple crystalline polymorphs and their interconversion relationships during the development phase. By establishing the stability relationships and transition conditions between Forms A, B, C, and D in advance, the patent enables rapid selection of the most appropriate form for specific therapeutic applications without requiring additional development time later.
Solution Approach 2:
The patent applies dynamics by investigating the interconversion relationships between different polymorphs under various conditions. Understanding the dynamic behavior and stability relationships between crystal forms enables flexible adaptation to different therapeutic requirements while streamlining the development process through predicted conversion pathways.
Data Source
AI summary
The present disclosure relates to crystalline solid forms of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, or a pharmaceutically acceptable salt thereof, the process of preparing the forms, and pharmaceutical compositions and methods of use thereof.