Inhibitors of glucocorticoid receptor
Inventors
Sun, Daqing • McGee, Lawrence R. • Du, Xiaohui • Zhu, Liusheng • Yan, Xuelei • Rew, Yosup • Eksterowicz, John • Medina, Julio C. • Zhou, Haiying • BALBAS, Minna Delarae • Fantin, Valeria R.
Assignees
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Publication Number
US-11208432-B2
Publication Date
2021-12-28
Expiration Date
Abstract
The present invention relates generally to compositions and methods for treating cancer and hypercortisolism. Provided herein are substituted steroidal derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of glucocorticoid receptors. Furthermore, the subject compounds and compositions are useful for the treatment of cancer and hypercortisolism.
Core Innovation
The patent discloses a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The compound includes ring A selected from heteroaryl, aryl, cycloalkyl, or heterocyclyl, together with multiple substituent positions defined by variables R1 through R13 and n. The substituent framework is specified using broad lists of allowable functional group types and ring-forming options at the nitrogen atom and other positions.
The core innovation includes variable definitions for alkyINR4R5 and other substituent classes, and permits formation of substituted or unsubstituted heterocycles via R4 and R5 being taken together with the same N atom. The disclosed structural scope also includes alternative structural representations including Formula (Ia) through Formula (Id), together with stereochemical and isotopic forms such as enantiomers, E/Z, tautomers, and deuterium-enriched isotopic variants.
The disclosed compounds are described in a glucocorticoid receptor (GR) modulating/inhibiting context, including GR antagonism/inhibition to reduce cortisol activity while minimizing off-target receptor activation. The partial content also relates to reduced androgen receptor (AR) signaling inhibition, non-modulation of progesterone receptor (PR), and reduced GR agonism or partial agonism in the GR inhibitory/modulating context.
Claims Coverage
The independent claim set centers on a Formula (I) compound, with dependent refinements narrowing ring-A class selections, constraining selected substituents and heterocycle formation, and including a pharmaceutical composition embodiment. Across the merged claim family, the inventive coverage is anchored by the Formula (I) scaffold and its pharmaceutically acceptable salt, solvate, and prodrug forms, with broad substituent definitions across R1–R13 and n.
Formula (I) compound scaffold
A compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, with ring A selected from heteroaryl, aryl, cycloalkyl, or heterocyclyl and substituents R1 through R13 and n defined by the provided substitution options and constraints.
Ring A narrowed to specific classes
A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
Heterocycle formation from R4 and R5
R4 and R5 attached to the same N atom are taken together with the N atom to form a substituted or unsubstituted heterocycle, where the heterocycle contains 0–3 additional heteroatoms selected from O, NH, NR6, S, and S(O)2.
Specific substituent pattern including R12=methyl and n=0
A compound of Formula (I) having specified substituent values including R8=H, R9=H, R10=H, R11=H, and R12=methyl, together with any pharmaceutically acceptable salt, solvate, or prodrug thereof, including an embodiment with R1=—NR4R5 and n=0.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition that includes the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug form, together with at least one pharmaceutically acceptable excipient.
Claim coverage is centered on a Formula (I) steroid scaffold with ring-A selection and broad substituent options across R1–R13 and n. Dependent refinements narrow ring A to named aromatic/heteroaromatic options, constrain the heterocycle formed by R4 and R5, specify exemplified substitution patterns including R12=methyl and n=0, and include pharmaceutical compositions containing a pharmaceutically acceptable excipient.
Stated Advantages
GR antagonism/inhibition with reduced off-target receptor activation, including reduced AR/PR activity and avoidance of GR agonism or partial agonism.
Documented Applications
Treatment or use in cancer indications, including cancer, prostate cancer, castration-resistant prostate cancer (CRPC), breast cancer, triple-negative breast cancer (TNBC), ovarian cancer, non-small cell lung cancer (NSCLC), chemoresistant, radioresistant, refractory, and relapsed recurrent prostate cancer, and high-grade serous or platinum-resistant ovarian cancer.
Treatment or use in hypercortisolism/Cushing’s disease.
Treating cancer.
Treating hypercortisolism, including Cushing’s syndrome.
Cancer settings such as cancer-resistance and recurrence.
Using combinations optionally including androgen receptor signaling inhibitors, chemotherapeutics, and immunotherapy agents such as anti–PD-L1 and anti–PD1.
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