Heterocyclic compounds and uses thereof
Inventors
Ibrahim, Prabha N. • Spevak, Wayne • Zhang, Jiazhong • Shi, Songyuan • POWELL, BEN • Ma, Yan
Assignees
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Publication Number
US-10647716-B2
Publication Date
2020-05-12
Expiration Date
Abstract
Provided herein are heterocyclic compounds of Formula (I), pharmaceutical compositions containing such a compound and their therapeutic uses, methods for their preparation, intermediate compounds, pharmaceutical compositions containing such a compound, and their therapeutic uses.
Core Innovation
The invention relates to heterocyclic bromodomain-modulating compounds of Formula (I) and (II). The compounds include pharmaceutically acceptable salts, solvates, tautomers, isomers, and deuterated analogs, and are differentiated by a required di(pyridin-2-yl)methylene moiety with an R1 substituent as defined and by the defined substituent pattern.
The disclosure addresses bromodomain activity metrics and bromodomain modulation and inhibition in connection with administration of the Formula (I)/(II) compounds. Pharmaceutical compositions containing the compounds of Formula (I)/(II) are described for bromodomain modulation and inhibition, and the disclosure states that the compounds provide unexpectedly improved pharmacokinetic properties.
The document also describes representative compounds and Table I of specific compounds, including P-001, P-004, and P-006, with example substitutions. It further includes intermediate compounds for synthesis and synthetic examples that yield specific compounds such as P-001, P-002, P-003, P-004, P-005, and P-006.
Claims Coverage
The provided independent claims cover 5 inventive features across chemical synthesis processes and treatment methods. These claims include specified multi-step processes of making compound 13, P-002, and P-001, and combination-treatment methods for acute myeloid leukemia and ovarian cancer using a formula-defined bromodomain modulator compound (or its pharmaceutically acceptable salt) with specified co-therapeutics.
Synthesis of compound 13 from compound 12
A process comprising contacting compound 12 with potassium tert-butoxide and iodomethane under conditions sufficient to form compound 13.
Synthesis of P-002 using palladium catalysis
A process comprising contacting compound 13 with compound 13b in the presence of [1,1′-Bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) under conditions sufficient to form P-002.
Synthesis of P-001 from P-002 with lithium hydroxide
A process comprising contacting compound P-002 with lithium hydroxide under conditions sufficient to form P-001.
Treating acute myeloid leukemia with bromodomain modulator plus azacitidine
A method for treating acute myeloid leukemia comprising administering to a subject in need thereof an effective amount of a compound of formula (or a pharmaceutically acceptable salt thereof), and azacitidine.
Treating ovarian cancer with bromodomain modulator plus carboplatin
A method for treating ovarian cancer comprising administering to a subject in need thereof an effective amount of a compound of formula (or a pharmaceutically acceptable salt thereof), and carboplatin.
Across the independent claims, the inventive features comprise specified contacting-based synthetic transformations to make compound 13, P-002, and P-001, and treatment methods for acute myeloid leukemia and ovarian cancer using an effective amount of a formula-defined compound (or its pharmaceutically acceptable salt) administered in combination with azacitidine or carboplatin, respectively.
Stated Advantages
Unexpectedly improved pharmacokinetic properties are stated.
Substantially higher rat pharmacokinetic exposure for P-001 than for Compound Z.
Improved rat IV AUC/half-life and PO exposure/parameters for P-001 versus Compound Z.
Stronger antitumor response in the IPC298 xenograft model versus Compound Z, indicated by smaller tumor volumes and higher TGI.
Acceptable tolerability in the IPC298 xenograft model.
Significantly improved toxicity profile versus Compound Z in the Ba/F3 IL-3-dependent/factor-independent xenograft toxicity model.
Minimal or no observed toxicity for P-001 at 10 mg/kg in the toxicity model.
Documented Applications
Treating acute myeloid leukemia using a compound of the recited formula or a pharmaceutically acceptable salt thereof in combination with azacitidine.
Treating ovarian cancer using a compound of the recited formula or a pharmaceutically acceptable salt thereof in combination with carboplatin.
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