Salts and polymorphic forms of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine
Inventors
LOUGHREY, Jonathan • KELK, Natalie • KREINER, Michaela • HALBERT, Gavin
Assignees
Ellipses Pharma Ltd • Institute of Cancer Research Royal Cancer Hospital
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Publication Number
US-12624027-B2
Publication Date
2026-05-12
Expiration Date
Abstract
The present invention relates to salts and polymorphic forms of Compound A (6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine), an inhibitor of Aurora kinase and FMS-like tyrosine kinase 3 (FLT3) activity. The present invention also relates to processes for the preparation of the salts and polymorphic forms of the compound, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which Aurora kinase and/or FLT3 activity is implicated.
Core Innovation
The disclosed invention relates to salts and polymorphic or crystalline forms of dual Aurora kinase/FLT3 inhibitor Compound A, including Compound A fumarate and multiple other fumarate-associated crystalline variants. The disclosure defines specific crystalline forms using solid-state characterization, including XRPD patterns and unit cell parameters at 298 K, with distinct space group and crystal system characterizations.
A primary problem addressed is that the solid state of Compound A fumarate is characterized by measurable properties relevant to formulation and performance, including aqueous solubility, hygroscopicity, stability, and processability. The disclosure further notes minimal hERG/P450 interaction in the context of advantages, and it provides comparative and illustrative characterization across the different salt and polymorphic/crystalline forms using XRPD, DTA/TGA, DSC, DVS, and PLM.
The document enumerates multiple salt forms and polymorphic/crystalline forms, including fumarate variants and additional forms such as mesylate, hydrochloride, malate, sulfate, and L-tartrate. Within the defined fumarate crystalline forms, Form 1 is specifically highlighted as advantageous, with an unexpected balance of stability and solubility and low hygroscopicity, supported by example characterization and stability observations for selected forms.
The disclosure additionally characterizes solvate or unsolvated status for named forms, including examples with dioxane solvate and benzyl alcohol solvate, and it describes how some forms can convert upon drying. It provides thermodynamic solubility comparisons across biorelevant media and includes stated stability results for selected forms to support the selection of crystalline forms for use.
Claims Coverage
The partial claims content includes two independent claims defining crystalline solid forms of Compound A fumarate (Form 1 and Forms 2, 3, 4, 5, or 8). Each independent claim is anchored to XRPD-based identification and, where specified, unit cell parameters at 298 K, with subsequent dependent claims using those forms in therapeutic methods for disease states linked to Aurora kinase activity and/or FLT3.
Crystalline Form 1 defined by XRPD peaks and monoclinic unit cell parameters
A crystalline Form 1 of Compound A fumarate characterized by XRPD peaks at approximately 12.9, 20.5, 21.2, 22.9, and 23.4, by an XRPD pattern matching FIG. 1, and/or by unit cell parameters at 298 K with a monoclinic P system.
Crystalline Forms 2, 3, 4, 5 or 8 defined by XRPD peaks and unit cell parameters at 298 K
A crystalline Form 2, Form 3, Form 4, Form 5 or Form 8 of Compound A fumarate characterized by XRPD peak sets and, for Forms 2, 3, and 8, by unit cell parameters at 298 K with triclinic or monoclinic P systems, and matching FIGS. 2, 3, 4, 5, or 8.
Across the provided independent claims, the key inventive coverage is the specification of crystalline identities for Compound A fumarate forms using XRPD peak sets and matching XRPD figures, and in several instances unit cell parameters at 298 K tied to the stated crystal systems and space groups. The partial dependent claim summaries further indicate therapeutic method coverage using these defined crystalline forms for diseases linked to Aurora kinase activity and/or FLT3, including proliferative disorders, cancer, and acute myeloid leukemia (AML).
Stated Advantages
Improved aqueous solubility.
Improved or reduced hygroscopicity.
Improved solid-state stability.
Improved processability.
An unexpected balance of stability, solubility, and low hygroscopicity for Form 1.
Minimal hERG/P450 interaction is noted.
Documented Applications
Treating a disease or condition linked to Aurora kinase activity and/or FLT3 by administering a crystalline form of Compound A fumarate to a human or animal subject.
Treating a proliferative disorder by administering crystalline forms of Compound A fumarate, including Form 1 and alternative forms.
Treating cancer by administering the crystalline forms of Compound A fumarate.
Treating acute myeloid leukemia (AML) by administering the crystalline forms of Compound A fumarate.
Manufacturing and formulation use of salts and polymorphic/crystalline forms of Compound A, including pharmaceutical compositions.
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