N-substituted indenoisoquinolines and syntheses thereof
Inventors
Cushman, Mark S. • Morrell, Andrew E. • Nagarajan, Muthukaman • Pommier, Yves G. • Agama, Keli K. • Antony, Smitha
Assignees
Purdue Research Foundation • US Department of Health and Human Services
Publication Number
US-8829022-B2
Publication Date
2014-09-09
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 describes N-substituted indenoisoquinoline compounds, specifically substituted 11H-indeno[1,2-c]isoquinoline compounds, including dimers formed with a divalent linker. Also disclosed are processes for preparing these compounds, pharmaceutical formulations thereof, and methods for treating cancer by administering therapeutically effective amounts of these indenoisoquinoline compounds or pharmaceutical compositions containing them.
The problem addressed is the need for effective anticancer agents, especially for cancers that are difficult to treat with conventional chemotherapy. Existing anticancer agents such as camptothecin, a topoisomerase I inhibitor, have limitations including toxic side effects, molecular instability, and reversible inhibition, which reduce their clinical effectiveness. The invention aims to provide new compounds with potent anticancer activity, improved chemical stability, unique DNA binding selectivities, and efficacy against various types of human cancers.
Claims Coverage
The claims include three independent claims covering novel N-substituted indenoisoquinoline compounds, pharmaceutical compositions containing these compounds, and processes for preparing the compounds.
N-substituted indenoisoquinoline compounds with specific substituents
Novel compounds of substituted 11H-indeno[1,2-c]isoquinoline structure with defined substituents at positions Ra, Rd, and R6, including variants where R6 includes various functionalities such as haloalkyl, amino, heteroaryl, and others, and m is an integer from 0 to about 6.
Pharmaceutical compositions comprising the compounds and carriers
Pharmaceutical compositions for treating cancer comprising a compound of the specified formula or pharmaceutically acceptable salts, hydrates, or solvates thereof, combined with pharmaceutically acceptable carriers, diluents, or excipients.
Processes for preparing the compounds involving cyclization
Processes for preparing the N-substituted indenoisoquinoline compounds including the cyclization of intermediates such as 2-carboxybenzaldehyde and phthalide compounds, with cyclizing agents including acids or dicyclohexylcarbodiimide, and steps for reacting intermediates to introduce the N-substituted moieties.
The claims cover the chemical entities of N-substituted indenoisoquinoline compounds with specific substitutions, their pharmaceutical formulations for cancer treatment, and multiple synthetic processes to prepare these compounds, highlighting novel structures, compositions, and methods of preparation.
Stated Advantages
The compounds may be chemically more stable than camptothecin owing to the absence of the lactone ring.
They exhibit potent anticancer activity, including inhibition of topoisomerase I, and may provide longer in vitro and in vivo activity due to formation of more stable ternary complexes with DNA and topoisomerase I.
These compounds have unique DNA binding site selectivities relative to camptothecin.
Documented Applications
Treatment of cancer in mammals by administering therapeutically effective amounts of the N-substituted indenoisoquinoline compounds or pharmaceutical compositions thereof.
Use as inhibitors of topoisomerase I, acting as top1 poisons by stabilizing DNA-topoisomerase I cleavage complexes and inhibiting the DNA religation reaction.
Antineoplastic agents effective across various human cancer cell lines, including leukemia, lymphoma, solid tumors such as lung, colon, breast, skin, kidney, ovarian, prostate, and melanoma cells, as demonstrated through COMPARE screening.
Use in pharmaceutical compositions delivered via parenteral injections or oral dosage forms for anticancer therapy.
In vivo anticancer efficacy demonstrated in animal models using hollow fiber assays with various human tumor cell lines.
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