Monohydrate and crystalline forms of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one
Inventors
Buttar, Suzanne • PITAK, MATEUSZ • PATTERSON, ADAM ROSS • STRATFORD, Samuel Alexander • SOVAGO, IOANA • Xu, Jun • Zhou, Peng • WEI, HAOJUAN • DAI, Kuangchu
Assignees
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Publication Number
US-12006319-B2
Publication Date
2024-06-11
Expiration Date
Abstract
The present disclosure relates to crystalline polymorph forms of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazol[1,5-a]pyrazin-8-one.
Core Innovation
The disclosure describes two newly discovered monohydrate polymorphic crystalline forms of the PDE9 inhibitor Compound 1: Monohydrate Form 1 (MH1) and Monohydrate Form 2 (MH2). The monohydrate crystalline forms are characterized and identified using X-ray powder diffraction (XRPD) peak positions, IR/FTIR characteristic absorption bands, DSC transitions, and TGA dehydration/weight-loss behavior, together with purity ranges.
The disclosure further relates the monohydrate forms to an anhydrous form (AH) by describing polymorphic relationships, including conversion and rehydration behavior under heating, vacuum, and ambient moisture. The document states that MH1 is more stable at ambient conditions and supports use of the analytical signatures to monitor or confirm the form identity across these conditions.
The disclosure also encompasses pharmaceutical composition embodiments containing a therapeutically effective amount of the PDE9 inhibitor as the monohydrate crystalline form, including oral dosage forms and excipients, with content and purity thresholds described for the monohydrate forms. Method concepts are described for preparing and using the polymorphs for treatment of sickle cell disease and related conditions via PDE9 inhibition.
Claims Coverage
The partial content provides two independent claims covering two distinct monohydrate crystalline forms of Compound 1: Monohydrate Form 1 (MH1) and Monohydrate Form 2 (MH2). Each independent claim defines the relevant monohydrate form by an XRPD pattern consisting of specified 2θ peak angles with a tolerance, and the dependent claim content further characterizes each form using DSC, TGA, and IR/FTIR features and composition/purity-related limitations.
Monohydrate form 1 defined by XRPD peaks
A monohydrate crystalline form of Compound 1 wherein the monohydrate crystalline form is Monohydrate Form 1 (MH1), having an XRPD pattern comprising peaks of 2θ angles at 9.1, 11.5, 16.2, 16.7, 18.2, 18.9, 19.8, 22.6, and 26.4 degrees 2θ, each ±0.2 degrees 2θ.
Monohydrate form 2 defined by XRPD peaks
A monohydrate crystalline form of Compound 1 wherein the monohydrate crystalline form is Monohydrate Form 2 (MH2), having an XRPD pattern comprising peaks of 2θ angles at 9.0, 11.6, 15.0, 16.0, 18.6, 19.1, 20.4, or 20.6 degrees 2θ, each ±0.2 degrees 2θ.
Across the independent claims, the principal claim coverage is directed to two polymorphic monohydrate crystalline forms of Compound 1, each uniquely defined by an XRPD peak pattern with specified 2θ peak angles and ±0.2° tolerances. The provided dependent claim content indicates further refinement by additional analytical signatures and by pharmaceutical composition content/purity ranges.
Stated Advantages
MH1 is more stable at ambient conditions.
Documented Applications
Treating sickle cell disease and related conditions via PDE9 inhibition.
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