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Publication Number
US-9969722-B2
Publication Date
2018-05-15
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 invention relates to fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate forms, including crystalline salts and polymorphs of the benzenesulfonic acid salt corresponding to Formula I and the hydroxynaphthoic acid salt corresponding to Formula II. The benzenesulfonic acid salt is identified as having polymorphs Form I, Form II, Form III, and Form IV, and the hydroxynaphthoic acid salt is identified as Form A.
Each polymorphic form is characterized by X-ray powder diffraction peak positions measured with Cu Kα radiation, with supporting thermal characterization by DSC and TG/DTA. The document also describes stability, purity, and thermal behavior, including high purity retention under temperature and relative humidity conditions.
The benzenesulfonic acid salt and its polymorphs are described as more stable than the free base and hemi-tartrate forms, and as suitable robust intermediates. The salt is used as an intermediate for polymer-conjugated derivatives and is described in connection with MetAP2 inhibition and cancer-related diseases, including lymphoma and myeloma.
Claims Coverage
The claim coverage centers on a polymorphic form of fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate benzenesulfonic acid salt defined by an X-ray powder diffraction pattern measured with Cu Kα radiation. Dependent coverage adds further XRPD peak sets, thermal characterization, purity limits, pharmaceutical and therapeutic use, MetAP2 inhibition, and a preparation refinement involving seed-crystal loading.
Polymorphic form defined by specific X-ray powder diffraction peaks
A polymorphic form of fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate benzenesulfonic acid salt characterized by an X-ray powder diffraction pattern including peaks at 6.0, 9.0, 12.3, 12.5, 16.1, and 18.0 2θ using Cu Kα radiation.
Expanded XRPD peak pattern for further polymorph distinction
A polymorphic form characterized by an X-ray powder diffraction pattern with specified peak positions using Cu Kα radiation.
Thermal characterization by DSC exothermic onset and peak
A polymorphic form characterized by an exothermic event onset at 178°C and a peak at 188°C as measured by differential scanning calorimetry.
High purity polymorphic form
The polymorphic form characterized by having a purity greater than 98%.
Therapeutic treatment of myeloma and lymphoma by administration
A method for treating selected diseases, myeloma and lymphoma, in a subject by administering a therapeutically effective amount of the compound of the polymorphic form.
Polymorph preparation via seed crystal loading
The process configured such that the seed crystal is about 1 weight percent of the fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate dissolved in the solution in Step (1).
Claim coverage is primarily directed to a benzenesulfonic acid salt polymorph of fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate defined by an XRD peak pattern measured with Cu Kα radiation. The dependent features further refine the polymorph by XRPD, DSC, purity, therapeutic use for myeloma and lymphoma, MetAP2 inhibition, and seed-crystal loading.
Stated Advantages
Enables identification of specific polymorphs via XRPD peak patterns using Cu Kα radiation and thermal characterization by DSC and TG/DTA.
High purity is described, including purity greater than 98%.
Describes stability under temperature and relative humidity conditions.
More stable than the free base fumagill-6-yl N-(trans-4-aminocyclohexyl)carbamate and the hemi-tartrate forms.
Contains higher impurity levels in the free base and hemi-tartrate forms, whereas the benzenesulfonic acid salt and its polymorphs are described as suitable robust intermediates.
High purity retention under temperature and relative humidity storage conditions is reported for the described benzenesulfonic acid salt polymorphs.
Documented Applications
Use as stable intermediates for polymer-conjugated fumagillol derivatives.
Use as direct therapeutic agents in connection with MetAP2 inhibition and cancer-related diseases.
Method for treating selected diseases, myeloma and lymphoma, in a subject by administering a therapeutically effective amount of the compound of the polymorphic form.
Use as an intermediate for polymer-conjugated derivatives (Formula III) including derivatives involving an HPMA copolymer with a leaving group.
MetAP2 inhibition activity, including cancer cell activity examples reported with IC50 values and figures.
Therapeutic treatment by administering a therapeutically effective amount to treat diseases selected from myeloma and lymphoma in a subject.
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