CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer
Inventors
Siddiqui-Jain, Adam • Flynn, Paul • Fujiwara, Yuji • Masumoto, Shuji • Tanaka, Hiroaki • Kurebayashi, Hirotaka • HASHIZUKA, Takahiko • Arikawa, Yuka
Assignees
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Publication Number
US-12077554-B2
Publication Date
2024-09-03
Expiration Date
Abstract
A crystalline form and/or polymorph of a compound having the following structure (I), including tautomeric and zwitterionic forms thereof, are provided: Methods associated with preparation and use of the polymorphs, and pharmaceutical compositions comprising the same are also provided. Also provided are methods for preparing a compound having formula (I), or a salt, tautomer or zwitterionic form thereof.
Core Innovation
The invention provides crystalline Form B of a compound having structure (I), including tautomers and zwitterions, and characterizes the crystalline form using X-ray powder diffraction. Crystalline Form B is defined by an X-ray powder diffraction pattern with at least three peaks at 2-theta angles selected from 4.8±0.2°, 10.8±0.2°, 13.7±0.2°, 14.9±0.2°, 20.0±0.2° and 24.6±0.2°.
The disclosure describes preparation and characterization of polymorphs of a compound having structure (I), including conversion among intermediates and the crystalline Form A/Form B. A key focus is the formation of crystalline Form B from amorphous Form A using lattice-forming acids under low-water solvent conditions, with solid-state analytical characterization including XRPD, DVS, DSC, and TGA.
The disclosure also links crystalline Form B to pharmaceutical concepts and treatment methods, including administering crystalline Form B or a zwitterionic form thereof to a mammal for treating cancer. Pharmaceutical composition embodiments include oral formulations in dose-unit forms such as capsules, with pharmaceutically acceptable carriers and excipients.
Claims Coverage
The claim coverage centers on treating cancer by administering crystalline Form B (or a zwitterionic form) of a structure (I) compound at a specified daily dose range, with Form B defined by an XRPD pattern containing at least three specified 2-theta peaks. Dependent claims refine the peak characterization, administration frequency, daily dose specificity, and cancer indication.
Cancer treatment by crystalline Form B defined by XRPD peaks
Treating a cancer in a mammal by administering crystalline Form B of a compound having structure (I) or a zwitterionic form thereof, wherein crystalline Form B is characterized by an x-ray powder diffraction pattern comprising at least three peaks at 2-theta angles selected from 4.8±0.2°, 10.8±0.2°, 13.7±0.2°, 14.9±0.2°, 20.0±0.2° and 24.6±0.2° and administering an amount of from about 1 mg to about 50 mg per day.
Renal cancer treatment dosage with defined XRPD peaks for crystalline Form B
A method for treating a renal cancer in a mammal in need thereof comprising administering crystalline Form B of a compound having structure (I) or a zwitterionic form thereof in an amount of from about 1 mg to about 50 mg per day, wherein crystalline Form B is characterized by an x-ray powder diffraction pattern comprising at least three peaks at 2-theta angles selected from 4.8±0.2°, 10.8±0.2°, 13.7±0.2°, 14.9±0.2°, 20.0±0.2° and 24.6±0.2°.
Once-per-day administration
Crystalline Form B of a compound having structure (I) or a zwitterionic form thereof is administered to a mammal once per day.
Fixed daily dose for crystalline Form B
Crystalline Form B of a compound having structure (I) or a zwitterionic form thereof is administered at about 32 mg per day to a mammal.
Prostate cancer indication
The method is applied to prostate cancer.
MCL-1 dependent cancer indication
The method is applied to a cancer that is MCL-1 dependent.
Coverage centers on administering crystalline Form B of structure (I) or a zwitterionic form for cancer treatment, with Form B defined by an XRPD pattern containing at least three specified 2-theta peaks. Dependent claims further define the peak set, dosing regimen, and cancer indications including prostate cancer, renal cancer, and MCL-1 dependent cancer.
Stated Advantages
Stability-related purity retention and reduced water content.
Capsule formulations show one-month stability at various temperatures and relative humidity, and dissolution meeting a criterion of Q=75% within 45 minutes.
High purity (≥99.5%) of Form B at initial and after storage conditions.
Documented Applications
Treatment of cancer in a mammal.
Treatment of renal cancer in a mammal.
Capsule formulations containing crystalline Form B.
A Phase I clinical study with dose-escalation cohorts using PK/PD, adverse events, and PK sampling.
A Phase II trial design in metastatic castrate-resistant prostate cancer with efficacy, toxicity, biomarker, ORR, DoR, CDK9-related gene, phospho-AR, phospho-RNAPol2, and serum PSA assessments.
Treating prostate cancer using crystalline Form B.
Treating an MCL-1 dependent cancer using crystalline Form B.
Treating a renal cancer in a mammal by administering crystalline Form B or a zwitterionic form thereof of a compound having structure (I).
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