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Publication Number
US-10287277-B2
Publication Date
2019-05-14
Expiration Date
Abstract
The present disclosure relates to salts and polymorphs of aminoalkylfumagillol carbamates (e.g., fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate benzenesulfonic acid salt and fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate hydroxynaphthoic acid salt). The polymorphs are characterized by X-ray powder diffraction, differential scanning calorimetry, and thermogravimetric analysis, among other methods. The polymorphs and salts can be used as intermediates in the production of fumagillol derivatives (e.g., polymer-conjugated fumagillol derivatives) as well as therapeutic agents for the treatment of various diseases and conditions such as cancer.
Core Innovation
The disclosed subject matter identifies and stabilizes polymorphic forms of fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate salts, including fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate benzenesulfonic acid salt and fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate hydroxynaphthoic acid salt. Formula I is defined by specific polymorphs, including Forms I-IV, and Formula II is defined by Form A, with X-ray powder diffraction characteristics measured with Cu Kα radiation.
The document further associates polymorph identification with thermal characterization, including DSC thermal events and TG/DTA thermal event characteristics. Analytical characterization is described as including XRPD, DSC, TG/DTA, HPLC, and NMR to support characterization and purity/stability assertions.
The document states that benzenesulfonic acid salts and polymorphs are more stable than the fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate free base and hemi-tartrate. The polymorphic forms are positioned as stable intermediates for polymer-conjugated fumagillol derivatives and as therapeutic MetAP2 inhibitors for diseases including cancer, lymphoma, and myeloma.
Claims Coverage
The claim coverage centers on defining specific polymorphic forms of fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate salts by Cu Kα X-ray powder diffraction peak patterns. Across the provided claim set, the inventive features also include thermal characterization by DSC and TGA/DTA, and medical-use coverage for MetAP2 inhibition and treatment of lymphoma and/or myeloma.
XRPD-defined polymorphic form of fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate 1-hydroxy-2-naphthoic acid salt
A polymorphic form of fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate 1-hydroxy-2-naphthoic acid salt characterized by an X-ray powder diffraction pattern comprising peaks at 5.6, 8.9, 11.5, 12.1, 15.4, and 20.9 degrees 2θ using Cu Kα radiation.
Expanded XRPD peak pattern with Cu Kα radiation
A polymorphic form characterized by an X-ray powder diffraction pattern with Cu Kα radiation containing diffraction peaks at specified 2θ angles.
TGA/DTA-defined thermal events
A polymorphic form characterized by defined endothermic and exothermic thermal events at specified temperatures, as measured by thermogravimetric analysis/differential thermal analysis.
DSC-defined thermal events
A polymorphic form characterized by differential scanning calorimetry thermal events with an endothermic onset at 182°C and a peak at 186°C.
Method of inhibiting MetAP2 by administering an effective amount
A method for inhibiting MetAP2 in a subject by administering an effective amount of the polymorphic form.
Treatment of lymphoma or myeloma
A method of treating lymphoma or myeloma in a subject by administering an effective amount of the polymorphic form described in claim 1.
The claim coverage is anchored to Cu Kα XRPD-defined polymorphic forms of fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate salts. Dependent features refine polymorph identification through additional diffraction peaks and thermal characterization, and extend the scope to MetAP2 inhibition and treatment of lymphoma and/or myeloma by administration of an effective amount.
Stated Advantages
Benzenesulfonic acid salts and polymorphs are more stable than the fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate free base and hemi-tartrate.
Documented Applications
Use as stable intermediates for polymer-conjugated fumagillol derivatives.
Therapeutic use as MetAP2 inhibitors for diseases including cancer, lymphoma, and myeloma.
Use in lymphoma and myeloma contexts, including B-cell lymphoma and myeloma cell contexts.
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