Azaindenoisoquinoline topoisomerase I inhibitors
Inventors
Cushman, Mark S. • Kiselev, Evgeny A. • Morrell, Andrew E. • Pommier, Yves George
Assignees
Purdue Research Foundation • National Institutes of Health NIH
Publication Number
US-9034870-B2
Publication Date
2015-05-19
Expiration Date
2032-07-13
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Abstract
The invention described herein pertains to substituted azaindenoisoquinoline compounds, in particular 7-, 8-, 9-, and 10-azaindenoisoquinoline compounds, which are inhibitors of topoisomerase I, processes and intermediates for their syntheses, pharmaceutical compositions of the compounds, and methods of using them in the treatment of cancer.
Core Innovation
The invention pertains to substituted azaindenoisoquinoline compounds, specifically 7-, 8-, 9-, and 10-azaindenoisoquinoline compounds, which act as inhibitors of topoisomerase I (Top1). The invention further encompasses processes and intermediates for synthesizing these compounds, pharmaceutical compositions containing them, and their use in treating cancer.
The problem being solved relates to limitations of existing Top1 inhibitors, such as camptothecin and its derivatives, which suffer from poor water solubility, chemical instability, equilibrium between active and inactive forms at physiological pH, reduced bioavailability due to plasma protein binding, and rapid reversibility of the Top1-DNA cleavage complex leading to the need for long infusion times. The azaindenoisoquinolines described demonstrate improved water solubility without decreasing Top1 inhibitory activity or cytotoxicity, addressing these issues.
Claims Coverage
The claims include one independent chemical compound claim and an independent pharmaceutical composition claim, a method of treatment claim, and a process claim for compound preparation. The inventive features encompass structural definitions of the compounds, pharmaceutical compositions, methods of cancer treatment, and synthetic processes.
Chemical compound structure defining substituted azaindenoisoquinolines
Defines a compound of a specific azaindenoisoquinoline formula wherein W, X, Y, Z represent nitrogen or carbon atoms with specified substitution patterns; RA, RB, RC, RD independently represent hydrogen or other specified substituents; RE represents (1-6C) alkyl or —(CH2)nRN with RN being various nitrogen-containing groups; and specific substituent constraints apply.
Pharmaceutical compositions containing the compounds
Compositions comprising the defined azaindenoisoquinoline compounds or their pharmaceutically acceptable salts together with a diluent, excipient, or carrier.
Method of treating cancer using the compounds
Methods of treatment involving administering a therapeutically effective amount of the compounds or their pharmaceutically acceptable salts to a patient in need, specifically targeting cancers such as ovarian, small-cell lung, cervical, colon, and rectal cancer.
Process for preparing substituted azaindenoisoquinolines
A synthetic process involving steps including treating homophthalic anhydrides with cyanopyridines, oxidations, and alkylations, with specified substituents and leaving groups, to furnish the azaindenoisoquinoline compounds or their salts.
The claims collectively cover the specific substituted azaindenoisoquinoline compounds, their pharmaceutical formulations, therapeutic use for cancer treatment, and defined synthetic routes, emphasizing novel structural features and biological applications.
Stated Advantages
Improved water solubility of azaindenoisoquinolines compared to earlier Top1 inhibitors without loss of inhibitory activity or cytotoxicity.
Enhanced chemical stability relative to camptothecin derivatives, overcoming issues of rapid reversibility and poor bioavailability.
Ability of compounds to intercalate into DNA and Top1-DNA cleavage complexes with varying substituent sizes influencing binding properties and efficacy.
Documented Applications
Treatment of cancer, specifically ovarian cancer, small-cell lung cancer, cervical cancer, colon cancer, and rectal cancer using the azaindenoisoquinoline compounds or their pharmaceutical compositions.
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