N-substituted indenoisoquinolines and syntheses thereof
Inventors
Cushman, Mark S. • Pommier, Yves George • LU, Peng-Cheng • Marchand, Christophe • AGAMA, Keli
Assignees
Purdue Research Foundation • National Institutes of Health NIH
Publication Number
US-9399660-B2
Publication Date
2016-07-26
Expiration Date
2026-11-13
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Abstract
N-Substituted indenoisoquinoline compounds, and pharmaceutical formulations of N-substituted indenoisoquinoline compounds are described. Also described are processes for preparing N-substituted indenoisoquinoline compounds. Also described are methods for treating cancer in mammals using the described N-substituted indenoisoquinoline compounds or pharmaceutical formulations thereof.
Core Innovation
N-substituted indenoisoquinoline compounds, including substituted 11H-indeno[1,2-c]isoquinoline compounds and dimers thereof formed with a divalent linker, are described along with pharmaceutical formulations and processes for their preparation. These compounds are proposed for treating cancer in mammals by administering therapeutically effective amounts, either alone or as pharmaceutical compositions.
The problem being addressed is the need for effective anticancer agents that overcome complications in the treatment of cancer, especially given that chemotherapy is an indispensable therapy for inoperable or metastatic disease, yet low clinical efficacy against slower growing solid tumors remains a serious concern. Existing chemotherapeutics such as camptothecin, which inhibit topoisomerase I, have drawbacks including toxic side effects, molecular instability, and reversible inhibition allowing cancer cell recovery.
The invention focuses on developing indenoisoquinoline compounds that act as topoisomerase I inhibitors (top1 poisons) which stabilize DNA-topoisomerase 1 cleavage complexes through intercalation at the DNA cleavage site, resulting in inhibition of the religation reaction. These compounds may offer advantages such as chemical stability, unique DNA binding site selectivities relative to camptothecin, and biological and pharmacological activity in inhibiting cancer cell growth through enzyme inhibition.
Claims Coverage
This patent includes one independent claim with several dependent claims, focusing on the structure and pharmaceutical use of novel N-substituted indenoisoquinoline compounds.
Novel N-substituted indenoisoquinoline compounds with defined substituents
The compounds have a core formula comprising an indenoisoquinoline scaffold with N-substitution characterized by a variable integer m from 0 to about 6 and substituent R6 selected from a comprehensive group of functional moieties including haloalkyl, heteroaryl, amino derivatives, and others, with Ra and Rd representing independently selected substituents that may form optionally substituted heterocycles.
Pharmaceutical compositions containing said compounds
Pharmaceutical compositions comprising the N-substituted indenoisoquinoline compounds or their pharmaceutically acceptable salts, hydrates, or solvates, along with pharmaceutically acceptable carriers, diluents, and excipients.
Methods of treating cancer with the compounds
Methods comprising administering therapeutically effective amounts of the described N-substituted indenoisoquinoline compounds or pharmaceutical compositions thereof to treat cancer in mammals.
The claims broadly encompass the chemical structure of novel N-substituted indenoisoquinoline compounds, their pharmaceutical compositions, and their therapeutic application in cancer treatment, emphasizing specific substituent variations and formulations.
Stated Advantages
The compounds may be chemically more stable than camptothecin, owing to the absence of a lactone ring, enhancing potential therapeutic efficacy.
They may have unique DNA binding site selectivities relative to camptothecin, allowing differing or improved mechanisms of action.
The compounds exhibit potent inhibition of topoisomerase I, stabilizing the cleavage complexes and inhibiting DNA religation, leading to antiproliferative activity against cancer cells.
Certain compounds additionally inhibit TDP1 enzyme activity, potentially providing dual enzyme inhibition.
Documented Applications
Treatment of cancer in mammals, wherein the compounds act as topoisomerase I poisons to inhibit tumor cell proliferation.
Administration of the compounds in pharmaceutical compositions by various routes including parenteral injection and oral administration for anticancer therapy.
Use in in vitro screening assays for antineoplastic activity against diverse human cancer cell lines and in vivo hollow fiber assays assessing anticancer efficacy.
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