7-benzyl-4-(methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5 (1h)-one, salts thereof and methods of using the same in combination therapy
Inventors
Stogniew, Martin • Allen, Joshua E.
Assignees
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Publication Number
US-10045992-B2
Publication Date
2018-08-14
Expiration Date
Abstract
This disclosure relates, at least in part, to a method of treatment. In one embodiment, the method of treatment comprises administering to a subject in need of such treatment a first therapeutic agent including compound (1): or a pharmaceutically acceptable salt thereof in combination with a second therapeutic agent, wherein the first therapeutic agent and the second therapeutic agent are administered either simultaneously or sequentially.
Core Innovation
The invention relates to compound (1), identified as ONC201, and pharmaceutically acceptable salts thereof, including a dihydrochloride salt and mono/di-salts. The disclosure defines the relevant compounds and salts and presents scheme-based transformations that connect intermediates to compound (1) and then to compound (2).
The disclosure further defines derivative and analog structures in which substituents such as R1 and R2 vary among specified groups, and describes related variants where additional substitution patterns, including R3/R4 and alternative core N substitution, are varied. Schemes 3–5 describe how analogs with different R1/R2 are accessed by converting key intermediates (6)/(7) to (9)/(10), using alkylation (R2X) or deprotection/alkylation for variation of R1.
Claims Coverage
The independent claims cover administering compound (1) (ONC201) or a pharmaceutically acceptable salt for treatment of genitourinary cancer, with one independent claim additionally limiting use to salvage therapy. Across the independent claims, the inventive feature set centers on treatment administration for genitourinary cancer and, for one claim, salvage therapy context.
Salvage therapy for genitourinary cancer
A method of treatment comprising administering to a subject having genitourinary cancer in need of such treatment a pharmaceutically acceptable amount of compound (1) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable amount of compound (1) is administered as a salvage therapy.
Genitourinary cancer treatment with compound (1)
A method of treatment comprising administering to a subject in need of such treatment a therapeutic agent comprising compound (1) or a pharmaceutically acceptable salt thereof, wherein the treatment is for a genitourinary cancer.
Both independent claims require administration of compound (1) (ONC201) or a pharmaceutically acceptable salt for genitourinary cancer; one claim specifically requires that the administration is as salvage therapy.
Stated Advantages
Mitigation of combined toxic effects during combination therapy via timing and conditional dosing based on pharmacokinetic monitoring and expected half-life.
Selectivity/differential viability observation between tumor cells and normal cells in cell assays.
Cell recovery after drug removal.
Documented Applications
Salvage therapy for genitourinary cancer.
Treatment of genitourinary cancer.
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