A2A Receptor Antagonist Crystal Forms for Solubility and Tumor Targeting
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Solution Overview
Problem
Existing treatments for A2A receptor-related diseases, particularly in the context of solid tumors, fail to effectively inhibit the adenosine signaling pathway, leading to immune suppression and uncontrolled tumor growth due to high adenosine concentrations activating A2A receptors, which suppress the immune system.
Innovation Solution
Development of specific crystal forms of adenosine A2A receptor antagonists, such as crystal forms A, B, C, D, E, and F, which exhibit improved solubility and pharmacokinetic properties, allowing for better tumor targeting and synergistic effects when combined with CS1003, a PD-1 antibody, to enhance immune function and inhibit tumor growth.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adenosine signaling pathway is activated by high adenosine concentrations in solid tumors, then immune suppression occurs and tumor growth is promoted, but blocking this pathway requires effective A2A receptor antagonists which have limited availability with poor solubility and pharmacokinetic properties
Solution Approach 1:
The patent applies parameter changes by developing multiple crystal forms (Forms A-F) of the A2A receptor antagonist, each with distinct X-ray diffraction patterns and physical properties. This polymorphic approach modifies the physical state parameters of the compound to achieve improved solubility and pharmacokinetic properties while maintaining the biological activity of blocking the adenosine signaling pathway and enhancing immune function
2Reliability
If existing A2A receptor antagonists are used, then some immune suppression effect is achieved, but their poor solubility and pharmacokinetic properties limit their effectiveness and tumor targeting capability
Solution Approach 1:
The patent modifies physical parameters by crystallizing the A2A receptor antagonist in six different crystal forms with distinct lattice structures and solubility characteristics. These parameter changes enable better drug delivery and tumor targeting while maintaining the reliable immune function enhancement through A2A receptor blockade
Solution Approach 2:
The patent creates composite crystalline structures by forming solvates and hydrates of the A2A receptor antagonist with various solvents. These composite material forms combine the pharmacological activity of the antagonist with specific solvent molecules in the crystal lattice, resulting in improved solubility and pharmacokinetic properties that enhance tumor targeting capability
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 crystal forms of the adenosine A2A receptor antagonists demonstrate enhanced stability and solubility, providing effective tumor targeting and a synergistic anti-tumor effect when combined with CS1003, thereby improving immune function and inhibiting tumor growth.
Implementation Method 1
The present disclosure also provides a crystal form A of the compound of formula (I), wherein the X-ray powder diffraction pattern thereof has characteristic diffraction peaks at the following 2θ angles: 7.16±0.2°, 9.66±0.2°, 19.66±0.2°
Data Source
AI summary
Provided are a salt form and a crystal form of adenosine A2A receptor antagonist, and preparation method therefor. Also provided is an application of the salt form or crystal form in the preparation of a medicine for A2A receptor-related diseases, the maleate salt in the salt form has a structure of formula (I).