Derivatives of piperlongumine and uses thereof
Inventors
Protter, Andrew Asher • Green, Michael John • CHANG, Hak Jin • Pham, Son Minh • Chakravarty, Sarvajit • Luedtke, Gregory R. • Lum, Pek Yee
Assignees
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Publication Number
US-11485725-B2
Publication Date
2022-11-01
Expiration Date
Abstract
The present invention relates to a group of 1-[(E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoyl]-2,3-dihydropyridin-6-one (piperlongumine) derivatives, analogs and pharmaceutically acceptable salts thereof. The present invention also relates to processes for preparing the same; a pharmaceutical composition and formulation containing a derivative of piperlongumine; and use of the derivatives and analogs for treating cancer.
Core Innovation
The disclosure relates to compounds of Formula I or pharmaceutically acceptable salts thereof, including piperlongumine derivatives and substituted 5,6-dihydropyridin-2(1H)-one derivatives. The framework constrains n and independently chosen X or Y as C(O) or S(O)2, and defines selections for R1, R2, R3, R4, and R5 through specified cycloalkyl, heteroaryl, heterocyclyl, and polycyclic heteroaryl group classes with optional substitution patterns.
The described subject matter further includes compound families in which at least one of X or Y is S(O)2 and at least one of R2, R3, or R4 is not hydrogen, together with families in which R1 is a branched C3 alkyl group, a saturated or partially unsaturated C3-C9 cycloalkyl group having no heteroatom, or a 3-13 member heterocyclyl group having 1-5 heteroatom(s) selected from N, O, and S. Additional disclosed examples include pyrimidinyl, quinazolinyl, pyridazinyl, pyrazole, benzoyl, p-fluorobenzoyl, phenylsulfonyl, and p-fluorophenylsulfonyl variants, with LCMS and 1H NMR characterization reported for examples.
The disclosure also provides pharmaceutical compositions comprising the compounds and pharmaceutically acceptable carriers and/or excipients, including sustained release or controlled release formulations. It further describes treatment of cancer by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, with combination therapy with other anticancer agents.
Claims Coverage
The consolidated independent claim coverage includes three Formula I compound families. Across these claims, the inventive features center on the selection of n, X or Y as C(O) or S(O)2, and constrained selections for R1 through R5, including specific ring classes, heteroatom counts, optional substitution, and the condition that at least one of R2, R3, or R4 is not hydrogen in one claim family.
Formula I scaffold with constrained n and X or Y
A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein n is an integer within the claimed range and X or Y is independently C(O) or S(O)2, with the structure further defined by R1, R2, R3, R4, and R5 selections.
Cycloalkyl, heteroaryl, and heterocyclyl R1 selection
R1 is selected from specified saturated cycloalkyl groups, monocyclic heteroaryl groups, monocyclic unsaturated cycloheteroalkyl groups, polycyclic heteroaryl groups, branched C3 alkyl groups, or 3-13 member heterocyclyl groups having 1-5 heteroatom(s) selected from N, O, and S, depending on the claim family.
S(O)2 and non-hydrogen substituent requirement
In one claim family, at least one of X or Y is S(O)2 and at least one of R2, R3, or R4 is not hydrogen, with the remaining substituent positions defined by the stated optional substitution and group-selection rules.
Pharmaceutical composition and cancer treatment
Dependent coverage includes pharmaceutical compositions comprising the Formula I compound or salt, and therapeutic methods for treating cancer by administering a therapeutically effective amount of the compound, with enumerated cancer types in the claim set.
The claim coverage is unified by Formula I compound definitions and the stated substituent constraints on n, X/Y, and R1-R5, with one claim family adding an explicit S(O)2 and non-hydrogen substituent requirement. Dependent coverage adds pharmaceutical composition context and cancer-treatment use for enumerated cancer types.
Stated Advantages
The disclosure states that piperlongumine derivatives display ROS-driven antitumor activity and that prior analogs have limitations, motivating the development of improved piperlongumine derivatives.
Documented Applications
Treating cancer by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt.
Pharmaceutical compositions comprising the compounds and pharmaceutically acceptable carriers and/or excipients, including sustained release or controlled release formulations.
Combination therapy with other anticancer agents.
Cancer types enumerated in the claims and disclosure, including lymphoma, osteosarcoma, melanoma, breast cancer, renal cancer, prostate cancer, colorectal cancer, thyroid cancer, ovarian cancer, pancreatic cancer, neuronal cancer, lung cancer, uterine cancer, and gastrointestinal cancer.
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