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-10710976-B2
Publication Date
2020-07-14
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 concerns crystalline Form II of Compound I, defined by an X-ray powder diffraction pattern substantially as shown in FIG. 1A. Form II is described as a polymorphic form obtained by conversion from Form I, which has an X-ray powder diffraction pattern as shown in FIG. 1B, and is also characterized as an anhydrate with a melting point of 123–124°C.
The disclosure characterizes Form II by analytical data including an X-ray powder diffraction pattern with defining peaks at approximately 5.9° and 8.8° 2θ, together with UV, IR, NMR, and thermal analysis data. Form II is described as substantially pure, and the specification presents it as a thermodynamically stable crystalline form.
The invention also relates to routes for obtaining crystalline Form II by converting Form I into Form II, including suspension of Form I in water and heating of solid Form I. In one preparative route, Compound (8) is reacted with triflic anhydride to yield a triflate, the triflate is reacted with ammonia to yield Compound (9), Compound (9) is reacted with 2-chloropyrimidine to yield a crude form of Compound I, and the crude form is purified to collect Form I before conversion to Form II by suspension in water.
Claims Coverage
The independent claims cover two inventive features: crystalline Form II of Compound I defined by conversion from Form I using X-ray powder diffraction patterns, and a method of preparing crystalline Form II that includes intermediate reactions, purification, and conversion by suspending purified Form I in water.
Crystalline Form II obtained by converting X-ray diffraction-defined Form I
Crystalline Form II of Compound I is obtained by converting Form I of Compound I having an X-ray powder diffraction pattern as shown in FIG. 1B to Form II having an X-ray powder diffraction pattern substantially as shown in FIG. 1A.
Method preparing crystalline Form II via intermediate reactions, purification, and water suspension
A method of preparing crystalline Form II of Compound I where Form II has an X-ray powder diffraction pattern substantially as shown in FIG. 1A comprising reacting Compound (8) with triflic anhydride to yield a triflate; reacting the triflate with ammonia to yield Compound (9); reacting Compound (9) with 2-chloropyrimidine to yield a crude form of Compound I; purifying the crude form by dissolving in ethyl acetate at a temperature above 35°C and partially or completely replacing ethyl acetate with heptane; collecting purified Form I of Compound I having an X-ray powder diffraction pattern as shown in FIG. 1B; and suspending the purified Form I in water to obtain crystalline Form II.
The claims focus on obtaining crystalline Form II of Compound I with a defined X-ray powder diffraction pattern, either by conversion from Form I or by a preparative route that yields purified Form I followed by suspension in water to produce Form II.
Stated Advantages
Crystalline Form II is thermodynamically stable.
Form II is suitable for bulk handling.
Improved bioavailability is associated with particle-size controlled formulations.
Reducing absorption effects is described via food timing.
Documented Applications
Treatment of NR2B antagonist-responsive conditions, including depressive disorders and suicidal ideation.
Targeting GluN2B using the disclosed NMDA GluN2B/NR2B antagonist Compound (I) and its crystalline forms.
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