Crystalline forms of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making
Inventors
Waetzig, Joshua D. • Wilkie, Gordon
Assignees
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Publication Number
US-11999744-B2
Publication Date
2024-06-04
Expiration Date
Abstract
Crystalline Forms of Compound (I): pharmaceutically acceptable salts thereof and solvates of any of the foregoing are disclosed. Pharmaceutical compositions comprising the same, methods of treating disorders and conditions associated with oncogenic KIT and PDGFRA alterations using the same, and methods for making Compound (I) and crystalline forms thereof are also disclosed.
Core Innovation
The disclosure describes solid-state crystalline forms of Compound (I), including crystalline Form A and other crystalline forms, including crystalline Form B, crystalline Form C (hydrate), crystalline Form O (anhydrous), crystalline Form T (tosylate), crystalline Form Tr (tartrate), and crystalline Form H (hydrochloride mono-salt), as well as pharmaceutical salts and solvates/hydrates. The forms are characterized by X-ray powder diffractogram, DSC, TGA, dynamic vapor sorption, and NMR, with specific analytical signatures used to identify the forms.
Crystalline Form A is characterized by an X-ray powder diffractogram comprising at least three peaks at 2θ angles chosen from 11.5±0.2, 15.4±0.2, 16.7±0.2, 20.0±0.2, and 21.6±0.2, and the disclosure also refers to additional peak content and DSC thermogram endothermic-event characterization in some embodiments. For Form A and the other crystalline forms, the document provides identification and distinguishing criteria using XRPD, DSC, TGA, dynamic vapor sorption, stability, and solubility notes.
The disclosure emphasizes substantially pure, low-impurity crystalline API forms and links the crystalline characterization to manufacturing/formulation stability. It also includes chemistry/process and purification information directed to forming and purifying chiral Compound (I) intermediates and the final active pharmaceutical ingredient, including purification from an undesired enantiomer by salt formation with D-quinic acid in THF followed by recrystallization using acetone/water.
The invention relates to a method of treating systemic mastocytosis by administering a therapeutically effective amount of crystalline Form A of Compound (I), and the disclosure also states use as selective KIT and/or PDGFRA inhibitors for KIT/PDGFRA-alteration-associated diseases, including mastocytosis such as systemic mastocytosis (SM), indolent systemic mastocytosis (ISM), and smoldering systemic mastocytosis (SSM), and other KIT/PDGFRA-driven cancers.
Claims Coverage
The independent claim coverage centers on treating systemic mastocytosis by administering crystalline Form A of Compound (I) defined by specific X-ray powder diffractogram peak criteria. The provided claim coverage includes six inventive features, with further refinements involving patient selection, DSC characterization, additional XRPD peak requirements, and a specified dosing regimen for an advanced subtype.
Treating systemic mastocytosis with crystalline Form A of Compound (I)
A method of treating systemic mastocytosis comprising administering to a patient in need thereof a therapeutically effective amount of crystalline Form A of Compound (I).
X-ray powder diffractogram-based identification of crystalline Form A
Crystalline Form A is characterized by an X-ray powder diffractogram which comprises at least three peaks at 2θ angles chosen from 11.5±0.2, 15.4±0.2, 16.7±0.2, 20.0±0.2, and 21.6±0.2.
Additional diffractogram peak requirement for crystalline Form A
Crystalline Form A has an X-ray powder diffractogram with at least seven peaks at selected 2θ angles.
DSC thermogram endothermic-event characterization of crystalline Form A
Crystalline Form A is characterized by a DSC thermogram with an endothermic event within a specified temperature range or with a specified onset temperature.
Patient selection by KIT exon 17 mutation (D816V)
The patient has a mutation in Exon 17 in KIT, wherein the D816 mutation is D816V.
Dosing regimen for an advanced subtype
For an advanced subtype, 200 mg of crystalline Form A of Compound (I) is administered to a patient once daily.
The claim coverage centers on administering crystalline Form A of Compound (I) for systemic mastocytosis, where the crystalline material is defined by specific X-ray powder diffractogram peak criteria and can be further constrained by DSC endothermic-event characterization, patient selection based on KIT exon 17 mutations including D816V, and a specified once-daily 200 mg regimen for an advanced subtype.
Stated Advantages
Supports substantially pure, low-impurity crystalline API forms for manufacturing/formulation stability.
Enables identification of crystalline Form A using XRPD and DSC-based characterization parameters as described in the document.
Provides crystalline Form A of Compound (I) that is characterized for use in treating systemic mastocytosis.
Documented Applications
Treatment of systemic mastocytosis, including indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM), using crystalline Form A of Compound (I) as a selective KIT and/or PDGFRA inhibitor.
Treatment of KIT/PDGFRA-alteration-associated diseases, including other KIT/PDGFRA-driven cancers, described as use of selective KIT and/or PDGFRA inhibitors.
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