Solid forms of an sGC stimulator
Inventors
SETHURAMAN, Vasu • Hashash, Ahmad • Xue, Song • Livingston, Robert C. • Nti-Addae, Kwame Wiredu
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10889577-B2
Publication Date
2021-01-12
Expiration Date
Abstract
The present disclosure relates to crystalline solid forms of a stimulator of soluble guanylate cyclase (sGC), Compound I: Also provided herein are methods for the preparation of these solid forms. The invention also relates to pharmaceutical formulations and dosage forms comprising these solid forms and their uses thereof, alone or in combination with one or more additional agents, for treating and/or preventing various diseases or disorders; these diseases or disorders are ones that may benefit from sGC stimulation or from an increase in the concentration of nitric oxide (NO) and/or cyclic guanosine monophosphate (cGMP).
Core Innovation
The disclosure relates to solid forms of Compound I, including crystalline polymorphs and a hydrochloric acid salt. The free base of Compound I is identified as having seven neat crystalline forms designated as Forms A, B, D, E, F, G, and H, together with solvates including hydrates and salts.
A crystalline solid form is characterized by physicochemical analytical criteria. The disclosure uses XRPD, FT-Raman, and IR spectral comparisons to define particular crystalline free forms, including substantially similar spectra to those shown in specific figures.
The document also describes fluorinated heterocycle intermediates and their conversion toward Compound I, including formation of an intermediate from another intermediate using methoxide/methanol, followed by hydrogenation of a fluorinated intermediate with Pd/C to a further intermediate. It further describes acid demethylation to another intermediate, subsequent chlorination to a Formula IV intermediate, and coupling to yield Compound I.
The solid forms are further related to pharmaceutical compositions and dosage forms. Therapeutic use is described for diseases and conditions that benefit from sGC stimulation and/or increased NO and cGMP, including delivery with a stent and a drug-eluting stent.
Claims Coverage
The independent claims define crystalline solid forms of Compound I by specifying which crystalline free form applies, with seven alternative inventive feature sets corresponding to Forms E, A, D, B, F, G, and H. The core inventive features are the XRPD, FT-Raman, and IR characterization criteria used to distinguish the crystalline free forms of Compound I.
Crystalline free form Form E identification by XRPD/FT-Raman/IR
Crystalline free form Form E characterized by peaks in the XRPD spectrum comprising specified 2θ values; an XRPD spectrum substantially similar to that shown in FIG. 2 or FIG. 6; a FT-Raman spectrum substantially similar to that shown in FIG. 10; and an IR spectrum exhibiting either peak maximums or band maxima at specified wavenumbers.
Crystalline free form Form A identification by XRPD/FT-Raman/IR
Crystalline free form Form A characterized by specified XRPD peak sets including 2θ positions and relative intensity patterns; an XRPD spectrum substantially similar to that shown in FIG. 2 or FIG. 3A; an XRPD spectrum substantially similar to that shown in FIG. 3C; a FT-Raman spectrum substantially similar to that shown in FIG. 10; and an IR spectrum exhibiting a band maximum at a specified wavenumber or a specified band maximum set.
Crystalline free form Form D identification by XRPD/FT-Raman/IR
Crystalline free form Form D characterized by specified XRPD peak sets including 2θ positions; an XRPD spectrum substantially similar to that shown in FIG. 2 or FIG. 5A; an XRPD spectrum substantially similar to that shown in FIG. 5C; a FT-Raman spectrum substantially similar to that shown in FIG. 10; and an IR spectrum exhibiting specified band maxima at specified wavenumbers, either individually or in combination.
Crystalline free form Form B identification by XRPD/FT-Raman/IR
Crystalline free form Form B characterized by specified XRPD peak sets including 2θ positions and relative intensity patterns; an XRPD spectrum substantially similar to that shown in FIG. 2 or FIG. 4A; an XRPD spectrum substantially similar to that shown in FIG. 4C; a FT-Raman spectrum substantially similar to that shown in FIG. 10; and an IR spectrum exhibiting a peak maximum at a specified wavenumber.
Crystalline free form Form F identification by XRPD
Crystalline free form Form F characterized by peaks in the XRPD spectrum comprising specified 2θ values and relative intensity patterns, or an XRPD spectrum substantially similar to that shown in FIG. 7.
Crystalline free form Form G identification by XRPD
Crystalline free form Form G characterized by peaks in the XRPD spectrum comprising specified 2θ values and relative intensity patterns, or an XRPD spectrum substantially similar to that shown in FIG. 8.
Crystalline free form Form H identification by XRPD/IR
Crystalline free form Form H characterized by specified XRPD peak sets with 2θ positions and relative intensity patterns; and by an XRPD spectrum substantially similar to that shown in FIG. 9, with the characterization additionally including the specified XRPD peak set option enumerations.
Overall, the independent claims cover crystalline solid forms of Compound I by defining, through XRPD, FT-Raman, and IR characterization profiles, which crystalline free form the solid is (Forms E, A, D, B, F, G, and H), using substantially similar spectral comparisons to specific figures and specified spectral peak maxima and band maxima.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of sickle cell disease by administering a therapeutically effective amount of the crystalline solid form of Compound I to a subject in need of treatment.
Pharmaceutical compositions and dosage forms comprising the crystalline solid forms for diseases and conditions benefitting from sGC stimulation and/or increased NO and cGMP.
Delivery including delivery with a stent, including a drug-eluting stent (DES).
Interested in licensing this patent?