3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dione derivatives and compositions comprising and methods of using the same
Inventors
Assignees
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Publication Number
US-9540340-B2
Publication Date
2017-01-10
Expiration Date
Abstract
The invention provides 3-deuterium-enriched 3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-diones, deuterated derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salt forms thereof, and methods of treatment using the same, such as in the treatment of cancer, an immune-related disease, or an inflammatory disease.
Core Innovation
The invention relates to deuterium-enriched, enantiomerically enriched 3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-diones, wherein Z is D at the C–Z carbon. The compounds are described as having an enantiomeric excess of at least 90%, and include stereoisomers, isolated or purified deuterated compounds, mixtures of deuterated compounds, pharmaceutically acceptable salts, and pharmaceutical compositions comprising a carrier and a therapeutically effective amount of the deuterium-enriched compound.
The disclosure defines stereochemical purity using enantiomeric excess and exantiomeric excess around the C–Z carbon, and states that the compounds resist racemization at the stereogenic center. This resistance is tied to deuterium incorporation at Z and to the stronger C–D bond at the 3-position, while additional deuteration at exchangeable positions is described as providing enrichment beyond the 3-position.
Representative compound examples are provided across Formula I, sub-formulae I-A through I-G, and extended Formula II through IV embodiments with variable substituents. The substituent options R1 through R10 are described across Formula II, Formula III, and Formula IV embodiments, including IIa/IIb, IIIa/IIIb, and IVa/IVb sets.
Claims Coverage
The provided claim set includes one independent claim focused on a deuterium-enriched compound having Z = D and an enantiomeric excess of at least 90%, with coverage of pharmaceutically acceptable salts. The claim set includes 3 main inventive features, with dependent refinements increasing the enantiomeric excess threshold to at least 95% and defining pharmaceutical compositions containing a carrier.
Deuterium-enriched compound with Z = D and enantiomeric excess at least 90%
A deuterium-enriched compound in which Z is D and the compound has an enantiomeric excess of at least 90%, or a pharmaceutically acceptable salt thereof.
Deuterium-enriched compound with enantiomeric excess at least 95%
The deuterium-enriched compound has an enantiomeric excess of at least 95%.
Pharmaceutical composition comprising carrier and the deuterium-enriched compound
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as defined for the deuterium-enriched compound.
Overall, the claim coverage centers on deuterium-enriched 3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dione derivatives defined by Z = D and high enantiomeric excess, with refinement to at least 95% and to pharmaceutical compositions that include a pharmaceutically acceptable carrier.
Stated Advantages
Resists racemization at the stereogenic center.
Slows racemization of the stereogenic center via a stronger C–D bond at the 3-position.
Provides deuterium enrichment beyond the 3-position.
Documented Applications
Treating cancer.
Treating cytokine- and/or angiogenesis-related disorders.
Treating immune-related diseases including lymphocytic and B- and T-cell related conditions.
Treating inflammatory diseases.
Angiogenesis-related disorders.
Cytokine- and TNF-α-related disorders, including IL-1β, IL-12, IL-18, GM-CSF, IL-6, IL-10, and IFN-γ-related contexts.
In vivo multiple myeloma xenograft model efficacy, including differential potency comparisons between the deuterated enantiomer(s) and a non-deuterated racemate as stated in the provided partial content.
Plasma stability assessment in mouse and human contexts using D/H exchange and degradation rate constants, with reported half-lives in mouse and human plasma as stated in the provided partial content.
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