Morphic forms of 4-amino-7-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide and uses thereof
Inventors
Ware, Roy W. • LAKSHMANAN, Venkat • Downey, Aaron Leigh
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11111264-B2
Publication Date
2021-09-07
Expiration Date
Abstract
The present disclosure relates to crystalline morphic forms of 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide. The morphic form can be a stable hemihydrate crystalline form.
Core Innovation
The document describes crystalline 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide hemihydrate, including the crystalline hemihydrate solid form designated as Form A. Form A is characterized by a powder X-ray diffraction pattern comprising a peak at a diffraction angle (2θ) of about 26.2° measured using Cu Kα1 X-rays at a wavelength of 1.5406 Å. It is described as a stable hemihydrate with the least hygroscopic behavior among the disclosed forms and low adsorption/desorption behavior.
The disclosure compares Form A with other crystalline morphic forms, including methanol hemisolvate Form B, ethanol hemisolvate Form C, substantially anhydrous or hemisolvate-derived Forms D and E, 2-propanol solvate Form F, and Form G. Forms B–E are stated to convert to Form A under humidity, and the forms are described as suitable for formulation and use.
The document further links Form A to solid-state characterization and impurity control, including PXRD identification, particle morphology by microscopy, residual 1-propanol by 1H-NMR, and additional thermal and mass-loss characterization. It reports strong reductions of benzoic acid and Impurity No. 1, and includes a crystallization optimization study for Compound 1 Form A with improved robustness, avoidance of spontaneous crystallization, and improved control of deposits above suspension.
The disclosure also includes broad methods of use for treating and preventing viral infections with Formula I compounds, including norovirus, Ebola, Marburg, and influenza, and describes pharmaceutical compositions and medicaments for administering a therapeutically effective amount of the crystalline hemihydrate form.
Claims Coverage
The independent claims identified are directed to the specific crystalline hemihydrate, the crystalline hemihydrate Form A defined by PXRD, a method for preparing the crystalline hemihydrate using a water-activity-conditioned recrystallization, and uses in pharmaceutical compositions and treatment of viral infection. Across the independent claims, the inventive features primarily cover the defined crystalline hemihydrate identity, preparation conditioned by water activity, and administration for treating viral infection.
Crystalline hemihydrate of the named compound
Crystalline 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide hemihydrate.
Form A defined by PXRD peak at about 26.2° (2θ) with Cu Kα1
A crystalline hemihydrate form (Form A) wherein the powder X-ray diffraction pattern comprises a peak at a diffraction angle (2θ) of about 26.2° obtained using Cu Kα1 X-rays at a wavelength of 1.5406 Å.
Recrystallization from solvent having water activity at least about 0.18
A method of preparing a crystalline hemihydrate form comprising recrystallizing the named compound from a solvent having a water activity of at least about 0.18.
Therapeutically effective amount administration for treating a viral infection
A method of treating a viral infection by administering a therapeutically effective amount of the crystalline hemihydrate compound to a subject in need.
Pharmaceutical composition with a pharmaceutically acceptable carrier
A pharmaceutical composition comprising the crystalline hemihydrate of the specified compound and a pharmaceutically acceptable carrier.
The claim coverage centers on defining the crystalline hemihydrate identity of the specified compound as Form A by a characteristic PXRD peak, preparing that crystalline hemihydrate by recrystallization under a solvent water-activity condition, and using the crystalline hemihydrate in pharmaceutical compositions and by administration to treat a viral infection.
Stated Advantages
Described as stable hemihydrate Form A that is least hygroscopic among the disclosed forms.
Low adsorption/desorption behavior is described for Form A (DVS).
High yields are reported, including about 87–89% in iterative trials and about 87–88% in a stated 20 g/medium-scale trial.
High HPLC purity is reported, including strong reductions of benzoic acid and Impurity No. 1.
Residual 1-propanol is reported to be reduced to a stated low level.
Robustness is reported, including avoidance of spontaneous crystallization and improved control of deposits above suspension.
Documented Applications
Formulation and use in treating viral infections with medicaments and pharmaceutical compositions, by administering a therapeutically effective amount of the crystalline hemihydrate form.
Treating a viral infection by administering a therapeutically effective amount of the crystalline hemihydrate form to a subject in need.
Preventing viral infections using Formula I compounds, including norovirus, Ebola virus, Marburg virus, and influenza, with oral administration.
Pharmaceutical composition comprising the crystalline hemihydrate with a pharmaceutically acceptable carrier.
Interested in licensing this patent?