3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dione derivatives and compositions comprising and methods of using the same
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Publication Number
US-10202316-B2
Publication Date
2019-02-12
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 compounds of the 3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione scaffold, including stereoisomers, pharmaceutically acceptable salts, and solvates. The described structures use Z as H or D and are characterized by an abundance of deuterium in Z of at least 30%, together with an enantiomeric excess with respect to the C-Z carbon.
The invention emphasizes improved resistance to racemization at a stereogenic center by introducing deuterium via a 3-deuterium substitution at Z. The disclosure also refers to structural substituent variables for the Formula IIIb compounds, including R6 = CH3 and R10b = NH2, and maintains the defined isotopic and stereochemical constraints.
The compounds and stereoisomers are presented as therapeutically useful agents for therapy of disorders linked to angiogenesis and cytokine related activity. Treatment indications explicitly described include angiogenesis, multiple myeloma, angiogenesis/cytokine-related disorders, cancer, immune-related diseases, and inflammatory diseases.
Claims Coverage
The provided claim coverage contains one independent method claim directed to treating a disorder selected from angiogenesis and multiple myeloma by administering a deuterium-enriched compound of Formula IIIb. The independent claim includes four inventive features that define the scope.
Treating angiogenesis or multiple myeloma with deuterium-enriched Formula IIIb
A method for treating a disorder selected from the group consisting of angiogenesis and multiple myeloma by administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula IIIb, or a pharmaceutically acceptable salt or solvate thereof.
Enantiomeric excess at the C-Z carbon of at least 90%
The deuterium-enriched compound of Formula IIIb has an enantiomeric excess with respect to the C-Z carbon of at least 90%.
Deuterium abundance in Z of at least 30%
Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
Specified substituent constraints in Formula IIIb
R1, R2, R3, R4, R5, R7, R8, and R9 are independently selected from H and D; R6 = CH3; and R10b = NH2.
Coverage centers on a therapeutic method for angiogenesis and multiple myeloma using deuterium-enriched Formula IIIb, with Z being H or D at a deuterium abundance of at least 30% and an enantiomeric excess at the C-Z carbon of at least 90%, together with specified R-group constraints.
Stated Advantages
A stronger C-D bond slows racemization at the 3-position and supports maintenance of stereochemical integrity.
Improved resistance to racemization due to a 3-deuterium substitution.
Documented Applications
Therapy of disorders selected from angiogenesis and multiple myeloma by administering a therapeutically effective amount of a deuterium-enriched compound of Formula IIIb.
Treatment applications explicitly described include angiogenesis/cytokine-related disorders, cancer, immune-related diseases, and inflammatory diseases.
Nonclinical efficacy is documented in a human multiple myeloma H929 tumor xenograft model.
Plasma stability modeling and deuterium/protonation-related stability characterization are documented in mouse plasma and human plasma.
Pharmacokinetics are documented in mice with chiral analysis by LC/MS-MS.
Pharmaceutical dosage and formulation concepts are documented, including dosage ranges, pharmaceutical compositions with excipients, lactose-free and anhydrous formulations, controlled release, and kit concepts.
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