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Publication Number
US-11753401-B2
Publication Date
2023-09-12
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 invention provides crystalline polymorphs of selinexor defined as single-crystal Forms A, B, C, and D, each characterized by specific X-ray powder diffraction (XRPD) 2θ peak sets. Form A is described as thermodynamically most stable, and Form D is described as particularly advantageous as an intermediate enabling high-yield and high-purity conversion to Form A.
Crystalline solid-form characterization is supported by XRPD with defined 2θ peak angles, and also by thermal characterization including differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Compositions and pharmaceutical compositions are disclosed that contain one of the crystalline forms, including particle-size specifications for Form A based on a unimodal particle size distribution with d(0.9) within specified ranges.
The disclosed crystalline forms are used for inhibiting CRM1, including exportin 1 (XPO1) activity, with treatment context extending to cancer and other CRM1-associated disorders. The disclosure also includes methods for preparing and selecting solid forms, including conversion between forms via solvent-mediated processes and crystallization/solvatoformation, including an acetonitrile solvate associated with Form D.
Claims Coverage
The consolidated claim set contains three independent claims. They cover a pharmaceutical composition defined by XRPD peak characterization of a Structural Formula I crystalline form, treating multiple myeloma using that composition, and treating diffuse large B-cell lymphoma using that composition.
Crystalline form pharmaceutical composition defined by XRPD peaks
A pharmaceutical composition comprising 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°, and a pharmaceutically acceptable carrier.
Treating multiple myeloma with an XRPD-defined crystalline form composition
A method for treating multiple myeloma comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a crystalline form of a compound represented by Structural Formula I and a pharmaceutically acceptable carrier, 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°.
Treating diffuse large B-cell lymphoma with an XRPD-defined crystalline form composition
A method for treating diffuse large B-cell lymphoma comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a crystalline form of a compound represented by Structural Formula I and a pharmaceutically acceptable carrier, 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 core inventive concept is using selinexor (Structural Formula I) in a crystalline form defined by XRPD 2θ peak characterization, formulated with a pharmaceutically acceptable carrier, and administering the resulting pharmaceutical composition to treat multiple myeloma or diffuse large B-cell lymphoma. Dependent claims further narrow the crystalline-form definition via additional XRPD peak sets and/or DSC endothermic peak characterization and/or XRPD pattern agreement with a referenced figure.
Stated Advantages
Form D is particularly advantageous as an intermediate enabling high-yield and high-purity conversion to Form A.
Form A is described as thermodynamically most stable.
Documented Applications
Inhibiting CRM1, including exportin 1 (XPO1) activity, with treatment context including cancer and other CRM1-associated disorders.
Treating multiple myeloma by administering an effective amount of a pharmaceutical composition comprising the specified XRPD-defined crystalline form of a compound represented by Structural Formula I.
Treating diffuse large B-cell lymphoma by administering an effective amount of a pharmaceutical composition comprising the specified XRPD-defined crystalline form of a compound represented by Structural Formula I.
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