Formulations of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
Inventors
Reynolds, Mark • Eary, Charles Todd
Assignees
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Publication Number
US-11963950-B2
Publication Date
2024-04-23
Expiration Date
Abstract
6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt, amorphous form, polymorph form, or pharmaceutical composition (including solid formulations or liquid formulations) thereof and the use thereof for treating diseases and disorders which can be treated with a RET kinase inhibitor, such as RET-associated diseases and disorders, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors, and gastrointestinal disorders such as IBS are disclosed.
Core Innovation
The invention relates to solid pharmaceutical formulations comprising a compound of Formula (I) and pharmaceutically acceptable salt, amorphous form or polymorph form thereof. The formulations include the compound of Formula (I) in a defined amount together with one or more excipients, and the excipients are selected to provide a solid dosage formulation.
The disclosure focuses on specific excipient types and named excipients for the solid formulation. Excipients include diluent or filler, glidant, dispersing agent, disintegrant, lubricant, binding agent, dispersing or wetting agent, and examples such as microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, mannitol, and fumed silica. The document also enumerates polymorphs and solid forms of the compound of Formula (I), including amorphous form, polymorph forms, and salts.
The document characterizes solid-state forms using XRPD/XRD patterns, DSC endotherms, and TG/DTA weight loss behavior, and includes an example phosphate salt with XRPD. It also describes solid dosage forms such as powder, tablets, gelatin hard capsule, capsule, spray dried dispersions, and other solid dosage formulation needs.
Claims Coverage
The independent claims cover solid formulations comprising a compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form or polymorph form thereof, at about 20 wt % to about 50 wt % or about 30 wt % to about 50 wt %, together with defined excipient selections. The inventive features are the compound loading range and the required excipient package or specific excipient identities, with four independent formulation claims represented across the items.
Solid formulation with formula (I) at 20-50 wt % plus one or more excipients
A solid formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form or polymorph form thereof, in an amount from about 20 wt % to about 50 wt % and one or more excipients.
Solid formulation with formula (I) at 30-50 wt % and specified excipient set
A solid formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form or polymorph form thereof, in an amount from about 30 wt % to about 50 wt %, and one or more excipients, wherein the one or more excipients comprise diluents or fillers, a disintegrant, a lubricant and a binding agent.
Solid formulation with formula (I) and specific excipients microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose
A solid formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form or polymorph form thereof, in an amount from about 20 wt % to about 50 wt %, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose.
Solid formulation with formula (I) and specific excipients plus mannitol and a lubricant
A solid formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form or polymorph form thereof, in an amount from about 20 wt % to about 50 wt %, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, mannitol and a lubricant.
The claims collectively cover solid pharmaceutical formulations of Formula (I) compounds, including pharmaceutically acceptable salts and amorphous or polymorph forms, with defined wt % ranges and specified excipient compositions. The core inventive coverage is the compound loading range together with excipient selection, from broad excipient classes to named ingredients such as microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, mannitol, and a lubricant.
Stated Advantages
Nanomolar potency against RET kinase.
Selectivity over other kinases, including KDR/VEGFR2.
Inhibition activity against RET activating and inhibitor-resistance mutants.
Inhibition activity against RET fusion proteins, including KIF5B-RET.
Selective cytotoxicity to RET-mutant cells.
Potential brain/CNS penetration.
Improved pharmacokinetic properties, including high GI absorption.
Improved pharmacokinetic properties, including low clearance.
Improved pharmacokinetic properties, including low drug-drug interaction potential.
Documented Applications
Treating RET-associated cancers, including solid and hematological cancers.
Treatment use cases that include pediatric populations.
Administration in relation to dysphagia, including liquid formulations.
Treatment contexts involving brain/CNS with potential BBB/CNS penetration.
Therapeutic use of the disclosed RET kinase inhibitors, with pharmaceutically acceptable salts and solvates of representative RET inhibitor compounds.
Treating RET-associated diseases.
Treating IBS.
Treatment of RET-associated cancers, including reduction of metastasis risk.
Diagnostic detection of RET kinase dysregulation/fusion proteins, including KIF5B-RET.
Combined therapy approaches using additional RET inhibitors such as crizotinib and osimertinib.
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