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Publication Number
US-11746102-B2
Publication Date
2023-09-05
Expiration Date
Abstract
The present invention relates to crystalline forms of the compound represented by Structural Formula I, and compositions comprising crystalline forms of the compound represented by Structural Formula I described herein. The crystalline forms of the compound of Structural Formula I and compositions comprising the crystalline forms of the compound of Structural Formula I provided herein, in particular, single crystalline Form A, can be incorporated into pharmaceutical compositions, which can be used to treat various disorders associated with CRM1 activity, including cancer. Also described herein are methods for preparing the compound of Structural Formula I and its single crystalline forms.
Core Innovation
The disclosure defines crystallization-related inducing formation and maturing processes for crystallizing Structural Formula I into specified crystalline polymorphic forms, including Form A, Form B, Form C, and Form D. The description characterizes transitions among these forms in a solvent-dependent manner and includes defined solvent-system selections used during the inducing formation and maturing processes, with X-ray powder diffraction peak sets used for characterization.
The disclosed crystallization process includes selecting and applying cooling, heating, aging, cycling, and drying/desolvation behaviors to obtain and control particular crystalline forms. The document reports conversion behavior between forms, including that Form D can convert to Form A under described conditions, and it further describes multi-step sequences to obtain single crystalline Form A, including solvent exchange to acetonitrile followed by crystallization/thermal treatment.
The embodiments emphasize specific single crystalline forms, especially Form D, using XRPD peak position sets including peaks at 2θ values of 3.7, 7.3, 10.9, 18.3, and 21.9. Form A is characterized by an XRPD peak set including 4.4, 19.9, 21.3, and 22.0, and the disclosure also describes pharmaceutical formulations comprising pharmaceutically acceptable carriers and single-crystal Form A particles with unimodal particle size distributions.
Claims Coverage
The provided independent claims cover two treatment claims, one for multiple myeloma and one for diffuse large B-cell lymphoma, each requiring administration of an effective amount of a crystalline form of Structural Formula I. The crystalline form is defined by at least three XRPD peaks at 2θ angles selected from 4.4°, 19.9°, 21.3°, and 22.0°, with dependent claims adding further XRPD and optional DSC characterization.
X-ray powder diffraction peak-defined crystalline form
A crystalline form characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 4.4°, 19.9°, 21.3° and 22.0°.
Treatment of multiple myeloma with Structural Formula I crystalline form
Administering to a subject in need thereof an effective amount of a crystalline form of a compound represented by Structural Formula I, wherein the crystalline form is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 4.4°, 19.9°, 21.3° and 22.0°.
Treatment of diffuse large B-cell lymphoma with Structural Formula I crystalline form
Administering to a subject in need thereof an effective amount of a crystalline form of a compound represented by Structural Formula I, wherein the crystalline form is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 4.4°, 19.9°, 21.3° and 22.0°.
Across the independent claims, the shared inventive concept is using a Structural Formula I crystalline form defined by XRPD peak positioning as the administered pharmaceutical form for cancer treatment. The claim sets further refine the crystalline-form characterization by specifying exact XRPD peak sets and optional DSC endothermic peak characterization, and the multiple myeloma claim set also mentions dexamethasone and/or bortezomib.
Stated Advantages
Form A is thermodynamically most stable.
Single-crystal Form D purity and yield translate to highly pure Form A suitable for pharmaceutical manufacture.
Documented Applications
Treating multiple myeloma by administering an effective amount of a crystalline form of a compound represented by Structural Formula I characterized by specified XRPD peaks.
Treating diffuse large B-cell lymphoma by administering an effective amount of a crystalline form of a compound represented by Structural Formula I characterized by specified XRPD peaks.
Therapeutic use via CRM1 inhibition in a cancer context.
Wound healing context for CRM1 inhibition by selinexor.
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