N-substituted indenoisoquinolines and syntheses thereof
Inventors
Cushman, Mark S. • Morrell, Andrew E. • Nagarajan, Muthukaman • Pommier, Yves George • Antony, Smitha • Agama, Keli K. • BECK, Daniel E.
Assignees
Purdue Research Foundation • National Institutes of Health NIH
Publication Number
US-9388211-B2
Publication Date
2016-07-12
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
The invention relates to N-substituted indenoisoquinoline compounds, specifically substituted 11H-indeno[1,2-c]isoquinoline compounds, including dimers formed with a divalent linker. These compounds are described as potentially useful for treating cancer in mammals. The invention also covers pharmaceutical compositions comprising these compounds, processes for preparing them, and methods for treating cancer by administrating therapeutically effective amounts of these compounds either alone or in formulations.
The compound structures are defined by formulae involving variable substituents such as R6, Ra, Rd, and a divalent linker X in dimers. The substituents include a wide range of chemical groups, including haloalkyls, amino derivatives, heteroaryl, alkylamino groups, and others. Processes for producing these compounds include reactions of benz[d]indeno[1,2-b]pyran-5,11-dione intermediates with primary amines or polyamines, and condensation with homophthalic anhydrides and Schiff bases followed by ring closure. Various embodiments account for symmetrical and unsymmetrical bisindenoisoquinolines, with substituent variations affecting their chemical and biological properties.
The problem addressed is the need for effective anticancer agents capable of targeting cancer cells through mechanisms such as topoisomerase I inhibition, which disrupts DNA replication in rapidly proliferating cancer cells. Existing agents like camptothecin suffer from drawbacks including instability and reversible inhibition, limiting their clinical efficacy. Given cancer’s heterogeneity, there is a need for compounds that are chemically stable and have selective cytotoxicity against diverse cancer types, including slower growing solid tumors. The invention responds to this by providing novel indenoisoquinoline compounds that are inhibitors of topoisomerase I, potentially exhibiting longer-lasting activity and unique DNA binding selectivity compared to camptothecin.
Claims Coverage
The patent includes one independent claim directed to a compound of a specified formula and independent claims directed to pharmaceutical compositions and methods for treating cancer using the compounds. The main inventive features focus on the chemical structure and use of these compounds.
N-substituted indenoisoquinoline compounds of specific formula
Compounds defined by a formula wherein R6 is selected from amino, alkylamino, dialkylamino, trialkylammonium, bis(hydroxyalkyl)amino, and hydroxyalkylaminoalkylamino. Substituents Ra and Rd include alkoxy groups, alkylenedioxy groups, and nitro groups at specified positions. The integer m is specifically 3 in one embodiment.
Pharmaceutical compositions comprising the compounds
Pharmaceutical compositions containing the compounds of the defined formula or their pharmaceutically acceptable salts, hydrates, or solvates, combined with pharmaceutically acceptable carriers, diluents, and excipients.
Methods for treating cancer by administering the compounds
Methods involving administering therapeutically effective amounts of the compounds of the formula or their pharmaceutically acceptable salts, hydrates, or solvates to patients in need of treatment for cancer.
Methods for treating cancer using compounds of specified structural formulas
Administration of therapeutically effective amounts of specific indenoisoquinoline compounds defined by structural formulae to treat cancer.
The claims cover the chemical entities of N-substituted indenoisoquinoline compounds with specific substituents, pharmaceutical compositions containing them, and methods for treating cancer by administering these compounds. The inventive features emphasize the structural definitions, the inclusion of particular substituents, and the therapeutic application of these compounds.
Stated Advantages
The compounds may be chemically more stable than camptothecin due to the absence of a lactone ring.
Compounds exhibit potent inhibitory activity against topoisomerase I, stabilizing DNA-topoisomerase I cleavage complexes and potentially causing longer in vitro and in vivo activity.
The compounds may have unique DNA binding site selectivities relative to camptothecin.
The compounds demonstrate selective cytotoxicity against a broad range of human cancer cell lines, including leukemias, lymphomas, and slower growing solid tumors.
Pharmaceutical compositions can be administered via various routes including parenteral and oral, allowing conventional pharmaceutical formulations for cancer treatment.
Documented Applications
Treatment of cancer in mammals by administering therapeutically effective amounts of N-substituted indenoisoquinoline compounds or pharmaceutical compositions thereof.
Use as antineoplastic agents exhibiting cytotoxic activity in vitro against human cancer cell lines of diverse tumor origins.
Administration in vivo as anticancer agents demonstrated by hollow fiber assays in animal models bearing multiple human tumor cell lines.
Inhibition of the topoisomerase I enzyme, disrupting DNA cleavage and religation, effective against various human cancers responsive to topoisomerase I inhibition.
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