PDE3/PDE4 Dual Inhibitor Crystal Form for COPD Solubility and Stability
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Solution Overview
Problem
Existing PDE3/PDE4 inhibitors, such as RPL554 and RPL565, exhibit poor solubility, high plasma clearance, and insufficient anti-inflammatory effects, necessitating the development of a compound with improved PDE3/4 inhibitory activity and favorable physicochemical properties for effective treatment of chronic obstructive pulmonary disease (COPD).
Innovation Solution
A crystalline form of a compound with specific X-ray diffraction peaks and thermal properties is developed, providing enhanced PDE3/PDE4 inhibitory activity, stability, and solubility, suitable for inhalational administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing PDE3/PDE4 inhibitors (RPL554, RPL565) are used, then bronchodilation effect is achieved, but solubility is poor and plasma clearance is high
Solution Approach 1:
The patent modifies the molecular structure of PDE3/PDE4 inhibitors by changing chemical parameters (introducing specific substituents at positions 2 and 6 of the pyridine ring, adjusting the R1-R6 groups) to improve solubility while maintaining bronchodilation activity. This structural parameter change enables better dissolution and reduced plasma clearance.
2Reliability
If existing PDE3/PDE4 inhibitors (RPL554, RPL565) are used, then bronchodilation effect is achieved, but anti-inflammatory effect is insufficient
Solution Approach 1:
The patent designs a dual-targeting inhibitor that simultaneously activates both PDE3 (for bronchodilation) and PDE4 (for anti-inflammatory effects). The compound structure incorporates multiple functional groups that enable interaction with both enzyme targets, achieving multi-functionality in a single agent to address both bronchodilation and inflammation.
3Reliability
If combination therapy is used to achieve therapeutic effect, then efficacy is improved, but administration complexity increases
Solution Approach 1:
The patent merges the functions of separate PDE3 and PDE4 inhibitors into a single dual-targeting compound. This consolidation eliminates the need for combination therapy, simplifying administration while maintaining the synergistic therapeutic effect of targeting both enzymes simultaneously.
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 form addresses the limitations of existing inhibitors by offering improved bronchodilation and anti-inflammatory effects, enhancing therapeutic efficacy for COPD treatment.
Implementation Method 1
having diffraction peaks in an X-ray powder diffraction pattern using Cu Kα radiation at the following 2θ angles: 4.14±0.2°, 6.98±0.2°, 8.20±0.2° and 11.50±0.2°
Implementation Method 2
the crystalline form A has endothermic peaks in a differential scanning calorimetry curve at 146.23±2 °C and/or 162.19±2 °C
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
Provided are a crystal of a tricyclic compound as shown in formula (I) or a pharmaceutically acceptable salt thereof and a preparation method therefor, and the use thereof in preparing a drug for treating PDE3- and/or PDE4-related diseases.