Solid forms of a compound for modulating kinases
Inventors
Ibrahim, Prabha N. • Rezaei, Hamid • Nespi, Marika • POWELL, BEN • PATEL, RASHMIN
Assignees
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Publication Number
US-10717735-B2
Publication Date
2020-07-21
Expiration Date
Abstract
Forms of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid (Compound I) were prepared and characterized in the solid state: Also provided are processes of manufacture and methods of using the forms of Compound I.
Core Innovation
The invention relates to solid-state forms of bromodomain-modulating Compound I, specifically a free acid amorphous form of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid. The free acid amorphous form is characterized by an X-ray powder diffractogram as substantially shown in FIG. 18, and the document also describes additional solid-state forms and solid-form characterization results.
Additional solid-state embodiments include crystalline polymorphs (Forms A–D and additional Materials E–G) and a sodium salt (Compound I sodium Material A). The solid-state characterizations are supported using XRPD peak sets together with thermal metrics including thermogravimetric analysis and differential scanning calorimetry.
The invention further relates to pharmaceutical compositions and therapeutic uses of the bromodomain-modulating Compound I forms. Pharmaceutical compositions include the free acid amorphous form together with pharmaceutically acceptable carriers, and therapeutic methods are directed to modulating bromodomain proteins and BET proteins.
Claims Coverage
The partial claim set provided includes one independent claim. The inventive features cover an amorphous free acid solid form defined by XRPD substantially as shown in FIG. 18, with further features that refine characterization by TGA and DSC and define formulation and use embodiments.
X-ray powder diffractogram-defined free acid amorphous form
A free acid amorphous form of Compound I characterized by an X-ray powder diffractogram as substantially shown in FIG. 18.
TGA weight-loss characteristic
The free acid amorphous form is characterized by a thermogravimetric analysis profile showing about 17% weight loss up to about 250°C.
DSC exotherm peak maximum
The free acid amorphous form is characterized by a DSC exotherm with a peak maximum at about 237°C.
Molecular dispersion in a polymer matrix
The free acid amorphous form is molecularly dispersed within a polymer matrix.
Pharmaceutical composition with pharmaceutically acceptable carriers
A pharmaceutical composition that includes one or more pharmaceutically acceptable carriers and the free acid amorphous form of Compound I.
Combination treatment for CLL or Richter’s Syndrome with a BTK inhibitor
A method for treating chronic lymphocytic leukemia (CLL) or Richter's Syndrome by administering an effective amount of the free acid amorphous form of Compound I in combination with an effective amount of a Bruton's Tyrosine Kinase (BTK) inhibitor.
Overall, the claim coverage anchors the invention in an XRPD-defined free acid amorphous form of Compound I, with refinements using TGA and DSC characterization and embodiments that specify molecular dispersion, pharmaceutical compositions, and an example combination treatment use.
Stated Advantages
Documented Applications
Modulating bromodomain proteins and BET proteins (BRD4 indicated in the provided context).
Treating chronic lymphocytic leukemia (CLL) or Richter's Syndrome using the free acid amorphous form of Compound I in combination with a BTK inhibitor.
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