Solid forms of (S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine and salts thereof
Inventors
Li, Qun • Wu, Wenxue • Zhao, Matthew Mangzhu
Assignees
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Publication Number
US-12344596-B2
Publication Date
2025-07-01
Expiration Date
Abstract
Salts of the AAK1 inhibitor (S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine and solid forms thereof are disclosed, as are pharmaceutical formulations comprising them and methods of their preparation.
Core Innovation
The invention relates to a crystalline compound defined as crystalline (S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-aminium dihydrogen phosphate (Compound K). The crystalline compound is characterized by an XRPD pattern comprising peaks at one or more of about 4.81, 5.99, 7.44, 7.89, 11.66, 14.85, 15.77, 19.19, 20.86, 21.65, 23.96, 24.48, or 24.73 degrees 2-theta. Crystallinity and purity are confirmed using XRPD and DSC, with reported purity of 98.7–99.9 area%.
Crystalline Form I of Compound K is described with a melting point of about 184° C and stability under 40° C/75% RH for up to 4 weeks. Recrystallization upon melting is described, and the solid form is presented as having improved water solubility compared with a hydrochloride salt. The solid form is presented as a preferred pharmaceutically acceptable salt/solid form for an AAK1 inhibitor based on solid-form properties such as stability, manufacturability, and characterization by XRPD/DSC/TGA.
The disclosure additionally describes preparation and characterization of multiple intermediates and crystalline active compound, including conversion of Compound L4-phosphate to Compound Q, DAST fluorination to yield Compound H, preparation of a chiral amino alcohol (Compound D-benzoate) with XRPD, and further transformations to free base Compound J and HCl salt Compound S, followed by formation of the phosphoric acid salt Compound K with crystallinity confirmed by XRPD/DSC. The tablet examples are presented as formulations tied to the crystalline Compound K and include a high-level description of process steps.
Claims Coverage
The claims cover six inventive features centered on Compound K as a crystalline material identified by specified XRPD peaks, with dependent refinements for melting point, pharmaceutical composition elements, impurity limits, tablet dosage strengths, and a therapeutic method for pain.
XPRD-defined crystalline dihydrogen phosphate salt
A crystalline compound of crystalline (S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-aminium dihydrogen phosphate (Compound K) having an XPRD pattern comprising peaks at one or more of about 4.81, 5.99, 7.44, 7.89, 11.66, 14.85, 15.77, 19.19, 20.86, 21.65, 23.96, 24.48, or 24.73 degrees 2-theta.
Melting point of the crystalline compound
The crystalline compound of claim 1 has a melting point of about 184° C.
Pharmaceutical composition with API, excipient, and lubricant
A pharmaceutical composition comprises an active pharmaceutical ingredient (API), an excipient, and a lubricant, wherein the API is the crystalline compound of claim 1.
Impurity or variant content threshold relative to Table 2
The composition comprises less than 0.05 weight percent of at least one compound listed in Table 2.
Tablet dosage strength for the API
The tablet of claim 5 comprises 10, 20, or 50 mg of the API.
Method for treating or managing pain by administering the crystalline compound
A method of treating or managing pain in a patient comprises administering to a patient in need a therapeutically effective amount of a compound of claim 1.
Overall, the claim coverage centers on Compound K as a crystalline material identified by specified XRPD peaks, optionally further constrained by melting point and impurity limits, and linked to pharmaceutical compositions and tablet formulations with defined API selection and dosage strengths. The scope also includes a method of treating or managing pain through administration of a therapeutically effective amount of the claimed crystalline compound.
Stated Advantages
Improved water solubility of Compound K compared with the hydrochloride salt.
Stability under 40° C/75% RH for up to 4 weeks.
Recrystallization upon melting is described for the crystalline form, supporting solid-form characterization and retention of a crystalline form.
Crystallinity of Compound K is confirmed by XRPD/DSC.
Purity of Compound K is reported as 98.7–99.9 area%.
Documented Applications
Therapeutic use for AAK1 inhibition, including methods to treat or manage diseases or conditions mediated by AAK1 activity.
Pain treatment or management in a patient, including neuropathic pain.
Viral infections mediated by AAK1 activity, including coronaviruses.
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