Crystalline forms of a bromodomain and extraterminal protein inhibitor drug, processes for preparation thereof, and use thereof
Inventors
Chen, Minhua • Zhang, Yanfeng • ZHAI, Xiaoting • YAN, Kaiqiang • Zhang, Xiaoyu
Assignees
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Publication Number
US-10752595-B2
Publication Date
2020-08-25
Expiration Date
Abstract
The present disclosure relates to novel crystalline forms of a bromodomain protein inhibitor 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxyquinazolin-4(3H)-one and processes for preparation and use thereof, relating to pharmaceutical industry. Form CS2, Form CS8, Form CS13, Form CS20, Form CS1, Form CS7, Form CS9, Form CS11 and Form CS4 of the present disclosure can be used for preparing drugs treating cardiovascular, cholesterol or lipid-related disorders.
Core Innovation
The document discloses crystalline forms of apabetalone, identified by assigned form codes including CS1, CS2, CS4, CS7, CS8, CS9, CS11, CS13, and CS20. The crystalline forms are defined using X-ray powder diffraction patterns showing characteristic peaks, reported using CuKα radiation with specified 2theta values and an angular uncertainty of ±0.2°.
For each crystalline form, the XRPD characteristic peaks function as a fingerprint to distinguish and identify solid forms, including hydrate and anhydrate forms and a solvate form. The document further reports stability against polymorphic transition and hygroscopic behavior using tests including DVS, and provides stability durations described as stable for weeks-to-months for the reported forms.
The document also discloses pharmaceutical compositions comprising the crystalline forms and therapeutic use by administering a therapeutically effective amount of a selected crystalline form. The therapeutic context is directed to cardiovascular, cholesterol, and lipid-related disorders, including atherosclerosis and acute coronary syndrome, and also references predecessor diabetes.
Claims Coverage
The independent claims cover multiple crystalline forms of apabetalone (CS1, CS2, CS4, CS7, CS8, CS9, CS11, CS13, and CS20) by requiring XRPD characteristic peak positions measured with CuKα radiation. The claims focus on material solid-form definitions, and some families further tie the selected form to therapeutic treatment using a therapeutically effective amount for specified disorder categories. Overall, the inventive features center on XRPD fingerprint-based identification of each crystalline form and, for some families, therapeutic administration of the specified form.
Crystalline form CS1 defined by XRPD CuKα characteristic peaks
A crystalline form CS1 of apabetalone, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 6.1°±0.2°, 12.3°±0.2°, 26.1°±0.2° and 26.8°±0.2° using CuKα radiation.
Crystalline form CS2 defined by XRPD CuKα characteristic peaks
A crystalline form CS2 of apabetalone, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 11.5°±0.2°, 6.6°±0.2° and 8.8°±0.2° using CuKα radiation.
Crystalline form CS4 defined by XRPD CuKα characteristic peaks
A crystalline form CS4 of apabetalone, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 9.1°±0.2°, 14.5°±0.2°, 23.5°±0.2° and 24.2°±0.2° using CuKα radiation.
Crystalline form CS7 defined by XRPD CuKα characteristic peaks
A crystalline form CS7 of apabetalone, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 5.9°±0.2°, 6.7°±0.2°, 10.7°±0.2° and 12.5°±0.2° using CuKα radiation.
Crystalline form CS8 defined by XRPD CuKα characteristic peaks
A crystalline form CS8 of apabetalone, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 23.9°±0.2°, 13.5°±0.2°, 7.8°±0.2°, 22.5°±0.2° and 11.4°±0.2° using CuKα radiation.
Crystalline form CS9 defined by XRPD CuKα characteristic peaks
A crystalline form CS9 of apabetalone, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 7.3°±0.2°, 9.9°±0.2° and 17.0°±0.2° using CuKα radiation.
Crystalline form CS11 defined by XRPD CuKα characteristic peaks
A crystalline form CS11 of apabetalone, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 7.8°±0.2°, 8.8°±0.2°, 9.7°±0.2° and 13.6°±0.2° using CuKα radiation.
Crystalline form CS13 defined by XRPD CuKα characteristic peaks
A crystalline form CS13 of apabetalone, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 5.1°±0.2°, 12.5°±0.2° and 17.1°±0.2° using CuKα radiation.
Crystalline form CS20 defined by XRPD CuKα characteristic peaks
A crystalline form CS20 of apabetalone, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 8.4°±0.2°, 18.9°±0.2° and 13.5°±0.2° using CuKα radiation.
Across the independent claims, the inventive coverage is the definition of specific apabetalone crystalline forms (CS1, CS2, CS4, CS7, CS8, CS9, CS11, CS13, and CS20) via XRPD CuKα characteristic peak positions at specified 2theta values. The claim families further include dependent refinements to the diffraction peak sets, and in some families dependent claims additionally use the defined crystalline form in therapeutic treatment by administering a therapeutically effective amount for cardiovascular, cholesterol, or lipid-related disorders.
Stated Advantages
Good solubility in SGF/FeSSIF.
Low hygroscopicity.
For CS1 and CS4, mechanical stability under grinding.
Stability against polymorphic transition, reported as stable for weeks-to-months across multiple forms.
Documented Applications
Therapeutic use by administering a therapeutically effective amount of a selected crystalline form of apabetalone for cardiovascular, cholesterol, or lipid-related disorders, including atherosclerosis and acute coronary syndrome.
Therapeutic use for predecessor diabetes as described in the document.
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