Citrate salt, pharmaceutical compositions, and methods of making and using the same
Inventors
Gu, Chong-Hui • Waetzig, Joshua D.
Assignees
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Publication Number
US-11767330-B2
Publication Date
2023-09-26
Expiration Date
Abstract
The present disclosure features citrate salts and pharmaceutical compositions useful for the treatment of BAF complex-related disorders. Also disclosed are methods for preparing compounds.
Core Innovation
The invention concerns citrate salts of the compound of Formula I. The compound is defined by structural features including a BRD9 binding moiety and linker options, and the disclosed embodiments specify Formula III and related structural templates with variable substituents and ring-system parameters. The disclosure also provides structural definitions for substituent options and representative linker chemistries with attachment points.
The invention further relates to BRD9 modulating embodiments in a synovial sarcoma context. The document associates BRD9 depletion and effects on growth and apoptosis in synovial sarcoma cells with BRD9 degrader embodiments, and identifies BRD9 as a component of SS18-SSX1-containing BAF complexes. It also describes in-cell epimerization between Enantiomer 1 and Enantiomer 2, where Enantiomer 2 is the active enantiomer for BRD9 degradation in cells and in SYO-1 synovial sarcoma xenografts.
The disclosure additionally includes formulation-related characterization for the citrate salt form, including pharmaceutical composition features such as pH, isotonic saline, citrate buffer, and a cyclodextrin-based solubilizer. It also describes forced-degradation and stability/solubility investigations, pH-dependent stability in citrate/phosphate buffer, and formulation feasibility via dissolution and lyophilized formulations.
Claims Coverage
The independent claim is directed to a citrate salt of the compound of Formula I. The claim set includes five inventive features centered on the citrate salt form, pharmaceutical composition constraints, a cyclodextrin-based solubilizer, and treatment of synovial sarcoma.
Citrate salt of the compound of Formula I
A citrate salt of the compound of Formula I.
Pharmaceutical composition with a specified pH range
A pharmaceutical composition comprising the citrate salt, wherein the pH is in the range of 3.5 to 5.5.
Pharmaceutical composition with isotonic saline
A pharmaceutical composition wherein the saline component is isotonic saline.
Pharmaceutical composition with a cyclodextrin-based solubilizer
The pharmaceutical composition wherein the cyclodextrin-based solubilizer is sulfobutylether-β-cyclodextrin.
Method of treating synovial sarcoma by administering the citrate salt
A method for treating a subject with synovial sarcoma by administering an effective amount of the citrate salt.
Overall, claim coverage centers on the citrate salt of Formula I, with dependent refinements for pH range, isotonic saline, sulfobutylether-β-cyclodextrin, and treatment of synovial sarcoma by administering an effective amount of the citrate salt.
Stated Advantages
Provides crystalline free-base solid forms characterized by PXRD peaks.
Supports treatment of BAF complex-related disorders by associating BRD9 depletion with reduced SS18-SSX fusion protein.
Documented Applications
Treating synovial sarcoma by administering an effective amount of the citrate salt.
Treating cancers associated with BAF/BRD9/SS18-SSX.
Treating viral infections related to BAF/BRD9/SS18-SSX.
In-cell epimerization leading to conversion between Enantiomer 1 and Enantiomer 2, with Enantiomer 2 identified as the active enantiomer for BRD9 degradation in cells.
In vivo pharmacodynamic testing in SYO-1 synovial sarcoma xenografts, reporting BRD9 degradation up to 72 h post-dose for Enantiomer 2 while Enantiomer 1 is inactive.
Cancer treatment in a synovial sarcoma context via BRD9/BAF complex modulation, including BRD9 depletion and associated growth inhibition and apoptosis effects in synovial sarcoma cells.
Forced-degradation and stability evaluation for compound D1/S-D1 under acid/base/oxidation/photolysis/thermal/humidity stress, and pH-dependent stability in citrate/phosphate buffer.
Solubility and formulation investigations for IV formulation stability/precipitation effects of SBECD concentration, and feasibility of dissolution and lyophilized formulations with product testing.
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