JP-2022534886-A5 -

Dates

Publication Date

20230518

Application Date

20200515

Description

[0004] Endocrine therapy is at the forefront of treatment methods used to treat or cure breast cancer. Endocrine therapy is a treatment that involves promoting or inhibiting the expression or function of hormones in the body to treat specific diseases. Endocrine therapy targeting ERα has been shown to be ineffective as a long-term treatment method for breast cancer because 20% to 40% of all breast cancers expressing ERα acquire mutations after long-term endocrine therapy, and these mutations cause the receptor to become unresponsive to conventional endocrine therapy (Robinson, D.R., Nat. Genet. 2013; 45: 1446-1451). Therefore, there is a need in the field of chemotherapy to develop novel therapeutic methods that can effectively target mutated ERα isoforms that make cancer resistant to endocrine therapy. While pursuing the development of novel treatments for endocrine-resistant breast cancer, a novel class of ERα inhibitors called selective estrogen receptor covalent antagonists (SERCAs) was discovered. SERCAs inactivate ER signaling by targeting cysteine residues on the ER that are not present in other nuclear hormone receptors (Puyang, X., Cancer Discov. 2018, 8(9): 1176-1193). One of the SERCAs identified during this period is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazole-5-yl)-2-phenylbuta-1-enyl]pyridine-2-yl]oxyethylamino]buta-2-enamide , which is given by the following formula I: This is shown by [the following]. [0005] The free base form of (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazole-5-yl)-2-phenylbuta-1-enyl]pyridine-2-yl]oxyethylamino]buta-2-enamide is sometimes referred to as H3B-6545. H3B-6545 is a covalent small molecule inhibitor that inactivates both wild-type ERα (ERα-WT) and mutant ERα (ERα-mut) without degrading the receptor. H3B-6545 can interact with the Cys530 residue of ERα, thereby inducing a unique structure in which the receptor inhibits its ability to promote ligand-independent ERα signaling transduction (Puyang, X., Cancer Discov. 2018, 8(9): 1176-1193). H3B-6545 has been shown to exhibit potent chemotherapeutic properties in various breast cancer cell lines and patient-derived xenograft models in nude mice (Smith, P.G., et al., Cancer Res. 2017). [0007] Embodiments may provide an oral dosage form comprising, for example, a compound represented by formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazole-5-yl)-2-phenylbuta-1-enyl]pyridine-2-yl]oxyethylamino]buta-2-enamide , and the oral dosage form is formulated to achieve an average Cmax of about 1 ng/mL to about 4 ng/mL when administered once daily to human subjects, measured for each mg of formula I in the dosage form. In some embodiments, the average Cmax is about 2 ng/mL to about 4 ng/mL for each mg of formula I in the dosage form. In some embodiments, the average C max is about 3 ng/mL to about 4 ng/mL for each mg of formula I in the dosage form. In some embodiments, the average C max is in the range of 80% to 125% of 3 ng/mL to 80% to 125% of 3.5 ng/mL for each mg of formula I in the dosage form. [0010] Further embodiments provide an oral dosage form comprising a compound represented by formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazole-5-yl)-2-phenylbuta-1-enyl]pyridine-2-yl]oxyethylamino]buta-2-enamide , and the oral dosage form is formulated to achieve an average AUC 0-24 of about 16 h*ng/mL to about 44 h*ng/mL for each mg of formula I in the dosage form when administered orally once daily to human subjects. In some embodiments, the average AUC 0-24 is about 27 h*ng/mL to about 44 h*ng/mL for each mg of formula I in the dosage form. In some embodiments, the average AUC 0–24 is in the range of 80%–125% of 30 h*ng/mL to 80%–125% of 44 h*ng/mL for each mg of formula I in the dosage form. In some embodiments, the dosage form contains a total equivalent of about 100 mg to about 600 mg of formula I. In some embodiments, the dosage form contains a total equivalent of about 450 mg of formula I. [0011] Further embodiments provide an oral dosage form comprising a compound represented by formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the compound represented by formula I is (E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazole-5-yl)-2-phenylbuta-1-enyl]pyridine-2-yl]oxyethylamino]buta-2-enamide , and the oral dosage form is formulated to achieve an average t 1/2 of formula I in the dosage form of about 8 hours to about 22 hours when administered orally once daily to human subjects. In further embodiments, the average t 1/2 is about 8 hours to about 12 hours. In further embodiments, the average t 1/2 is a