Compounds, compositions and methods
Inventors
Mazhari, Reza • Mezaache, Djelila • Paterson, Blake M. • Vornov, James • Garner, Rachel M. • Nelson, Todd
Assignees
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Publication Number
US-11479542-B2
Publication Date
2022-10-25
Expiration Date
Abstract
The disclosed subject matter provides certain polymorphic forms of Compound (I) as well as pharmaceutical compositions comprising Compound (I) or such polymorphic forms, and methods of using or making such compounds and pharmaceutical compositions. It has now been discovered that Compound (I) can exist in multiple crystalline forms (polymorphs). One particular crystalline form, Form II, has been found to be more thermodynamically stable and, thus, likely more suitable for bulk preparation and handling than other polymorphic forms. Efficient and economic methods have been developed to prepare Compound (I) and Form II in high purity on a large scale. In animal studies, Form II has demonstrated safety and efficacy in treating depressive disorders and, when micronized, improved absorption compared to non-micronized Form II.
Core Innovation
The invention provides crystalline Form II of Compound (I) and methods of treating a condition responsive to an NR2B antagonist by administering crystalline Form II to a patient in need thereof. Crystalline Form II is an anhydrate and is characterized using copper Kα radiation and an X-ray powder diffraction pattern comprising a peak of 2-theta angle of about 5.9 degree, together with an infrared spectrum substantially as shown in FIG. 3, a thermogravimetric analysis curve substantially as shown in FIG. 6, and a differential scanning calorimetry thermogram substantially as shown in FIG. 7.
The disclosure relates to polymorphic forms of Compound (I), including crystalline Form I and crystalline Form II, with emphasis on crystalline Form II. Comparative conversion and characterization work distinguishes Form I and Form II, including conversion between forms and particle-size co-milling to obtain Form II with defined particle-size characteristics.
The disclosed Compound (I) as crystalline Form II is also supported by receptor pharmacology and functional assays demonstrating NMDA GluN2B-selective antagonism, including radioligand binding Ki values for GluN1a/GluN2B and a calcium-influx functional assay IC50. Nonclinical PK/efficacy and safety pharmacology are described, together with antidepressant behavioral models and additional safety-related assays including neurotoxicity profiling and hERG evaluation.
Claims Coverage
The independent claims cover treatment by administering crystalline Form II of Compound (I), with the compound defined by four inventive characterization features.
Treating an nr2b-antagonist responsive condition with crystalline form ii
A method of treating a condition responsive to an NR2B antagonist by administering to a patient an effective amount of crystalline Form II of Compound (I).
Xrpd-defined crystalline form ii using copper kα radiation peak
The crystalline Form II exhibits an X-ray powder diffraction pattern obtained using copper Kα radiation comprising a peak of 2-theta angle of about 5.9 degree.
Infrared-spectrum-defined crystalline form ii
The crystalline Form II exhibits an infrared spectrum substantially as shown in FIG. 3.
Thermogravimetric-analysis-defined crystalline form ii
The crystalline Form II exhibits a thermogravimetric analysis curve substantially as shown in FIG. 6.
Differential scanning calorimetry thermogram-defined crystalline form ii
The crystalline Form II exhibits a differential scanning calorimetry thermogram substantially as shown in FIG. 7.
Overall, claim coverage centers on administering crystalline Form II of Compound (I) for treating an NR2B-antagonist responsive condition, where the compound is specified through XRPD, IR, TGA, and DSC characteristics substantially as shown in the cited figures.
Stated Advantages
Crystalline Form II is more thermodynamically stable for bulk preparation.
Jet-milled Form II increases AUC versus unmilled Form II (fed monkeys).
Documented Applications
Treating NR2B-antagonist-responsive depressive disorders, including major depressive disorder, treatment-resistant major depressive disorder, and suicidal ideation, by targeting GluN2B/NR2B.
Use for a defined set of neurological, pain, psychiatric, and related disorders responsive to an NR2B antagonist.
Use as an adjunct to a serotonin reuptake inhibitor or to a serotonin and norepinephrine reuptake inhibitor.
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