Processes for preparing AG-10, its intermediates, and salts thereof
Inventors
Chand, Pooran • Gupta, Yogesh Kumar • Kumawat, Rakesh Kumar • Alhamadsheh, Mamoun • Zamboni, Robert
Assignees
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Publication Number
US-11919865-B2
Publication Date
2024-03-05
Expiration Date
Abstract
Provided herein are improved processes for the preparation of a compound of Formula IX (AG-10). Also provided herein are pharmaceutically acceptable salts of Formula I and Formula Ib as well as crystalline types of Formula IX (AG-10). The processes described herein provide improved yields and efficiency, while the pharmaceutically acceptable salts and crystalline forms provide unexpected pharmacokinetic properties. Other features and aspects of the present disclosure will be apparent to a person of skill in the art upon reading the remainder of the specification.
Core Innovation
The disclosed invention provides crystalline Form Type A of Formula IX as an HCl salt for use in treating a transthyretin (TTR) amyloid disease. Crystalline Form Type A is characterized by an X-ray powder diffraction pattern having peaks at 12.0, 21.8, 25.9, 26.7, and 27.9 degrees 2θ (±0.2 degrees 2θ).
The document also reports identification of multiple crystalline forms of Formula IX, including HCl salt forms and free base forms, as well as unidentified forms. The forms are characterized by XRPD peak sets, thermal gravimetry weight loss ranges, differential scanning calorimetry endotherm ranges, and dynamic vapor sorption water uptake or gain.
The disclosure further describes polymorph screening and conversion behavior among the crystalline forms, including an interconversion chart. Pharmacokinetic examples are included to show improved pharmacokinetic properties for the HCl salt of Formula I versus other forms, and the treated compound is discussed in the context of TTR amyloid disease.
Claims Coverage
The independent claim identified is directed to treating a TTR amyloid disease by administering Crystalline Form Type A of Formula IX as its HCl salt, with a defined XRPD peak set. Dependent claims add further solid-state characterization features and narrow the treated disease subtype to TTR amyloid cardiomyopathy or polyneuropathy.
Treatment of TTR amyloid disease with Crystalline Form Type A as HCl salt
A method of treating a transthyretin (TTR) amyloid disease comprising administering to a subject in need thereof Crystalline Form Type A of Formula IX as its HCl salt, characterized by an X-ray powder diffraction pattern comprising peaks at 12.0, 21.8, 25.9, 26.7, and 27.9 degrees 2θ (±0.2 degrees 2θ).
Additional XRPD peak characterization for Crystalline Form Type A as HCl salt
The method further characterizes Crystalline Form Type A of Formula IX, when present as its HCl salt, by an X-ray powder diffraction pattern with specified peak positions at 7.0, 10.4, 13.0, and 13.9 degrees 2θ within ±0.2 degrees 2θ.
TGA weight loss characterization for Crystalline Form Type A as HCl salt
The method further characterizes Crystalline Form Type A of Formula IX as an HCl salt by its weight loss of about 0.7% to about 1.9% upon heating to around 150°C, measured by thermal gravimetric analysis.
DSC endotherm temperature characterization for Crystalline Form Type A as HCl salt
The method includes that crystalline Form Type A of Formula IX, when present as its HCl salt, is further characterized by a differential scanning calorimetry thermogram with endothermic peaks at around 211–214 and 237–239°C.
DVS water uptake characterization for Crystalline Form Type A as HCl salt
The method further specifies that crystalline Form Type A of Formula IX, as its HCl salt, has a water uptake of about 1.6% at 25°C/80% relative humidity after a dynamic vapor sorption cycle including pre-equilibration at 0% RH.
TTR amyloid cardiomyopathy subtype treatment
The method is directed to TTR amyloid disease specifically when it is TTR amyloid cardiomyopathy.
Overall, the claims cover treating TTR amyloid disease by administering Crystalline Form Type A of Formula IX as its HCl salt. Dependent claims further refine the same solid form using additional XRPD peaks, TGA weight loss, DSC endotherm temperatures, and DVS water uptake, and they narrow the disease subtype to TTR amyloid cardiomyopathy or polyneuropathy.
Stated Advantages
Improved pharmacokinetic properties for the HCl salt of Formula I versus other forms.
Improved yield/efficiency.
Unexpected pharmacokinetic/bioavailability advantages.
Documented Applications
Treating a transthyretin (TTR) amyloid disease in a subject in need thereof by administering Crystalline Form Type A of Formula IX as its HCl salt.
Treating TTR amyloid disease specifically when it is TTR amyloid cardiomyopathy.
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