Use of imipramine blue and analogs thereof in treating cancers
Inventors
Assignees
Emory University • US Department of Veterans Affairs
Publication Number
US-8435979-B2
Publication Date
2013-05-07
Expiration Date
2028-12-29
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are triphenyl methane analogs. The compounds and compositions can be used to treat and/or prevent a wide variety of cancers, including drug resistant cancers, inflammatory, degenerative and vascular diseases, and parasitic infections. The compounds are triphenyl methane analogs of imipramine blue and analogs thereof, as defined herein. The compounds are believed to function by inhibiting tNOX expression, the effects of ROS, and/or the production of HIF2. Thus, the compounds are novel therapeutic agents for a variety of cancers and other diseases.
Core Innovation
The invention relates to novel methods and compositions for treating primary and metastatic cancers and other proliferative disorders using specific triaryl amine compounds named imipramine blue and analogs thereof. These compounds, which are triphenylmethane analogs, along with pharmaceutical compositions including them, demonstrate utility particularly in treating primary and metastatic cancers in humans, with various modes of administration encompassed.
The background identifies a significant problem in cancer treatment arising from the increased levels of reactive oxygen species (ROS) linked with cancer growth and angiogenesis, with particular reference to NAD(P)H oxidases (Nox) enzymes, such as Nox1-Nox5 and tNox, which contribute to ROS production and tumorigenicity. Conventional chemotherapeutic agents lack selectivity, producing adverse effects. Thus, there remains a need for cancer treatments that minimize adverse effects and additional treatments for inflammatory, degenerative, and vascular diseases involving ROS.
The compounds of the invention, including imipramine blue and its analogs, are synthesized by reacting diaryl ketones (e.g., Mischler's ketone) with imipramine or analogs in the presence of Lewis acids, generating triphenylmethane structures. These compounds can also be prepared as prodrugs, which are less colored, more lipophilic, and reoxidized in vivo to active forms. It is believed that the compounds act by various mechanisms: inhibiting all forms or specific forms of Nox enzymes including tNox prevalent in cancer cells, inhibiting ROS effects, promoting scavengers of ROS, and inducing G2/M cell cycle arrest. The compounds selectively kill cancer cells, including metastasized tumors, without significantly affecting healthy cells. Additionally, the compounds inhibit hypoxia inducible factor 2 (HIF2) production, contributing to anti-angiogenic and anticancer effects. These mechanisms provide a novel, selective therapeutic approach to cancer and ROS-related diseases.
Claims Coverage
The patent contains two independent claims covering the chemical structures of novel compounds central to the invention. The claims define the inventive chemical entities and their specific structures.
Compound of specific triphenylmethane formula
A compound characterized by a defined chemical structure involving a triphenylmethane core, with specific substituents R, X, Z, and Xʹ as described, encompassing various substitutions such as alkyl, aryl, amino, hydroxy, and others, including pharmaceutically acceptable salts, prodrugs, racemic mixtures, stereoisomers, and polymorphs.
Compound of an optimized chemical structure
A compound having a more specific triphenylmethane formula with defined substituents and motifs, including particular heteroaryl and functional groups, tailored for therapeutic activity against cancers and related diseases.
The independent claims cover chemical compounds of the triphenylmethane class, including imipramine blue and its analogs, characterized by detailed substitution patterns and prodrug forms, which form the basis for their selective anticancer and therapeutic activities.
Stated Advantages
The compounds selectively kill cancer cells, including metastasized tumors, without killing healthy cells, providing a selective anti-cancer therapy.
Prodrug forms of the compounds are less colored, more lipophilic, and more readily taken up by cells, potentially reducing irritation and improving delivery.
The compounds inhibit reactive oxygen species and HIF2, enabling treatment of inflammatory, degenerative, and vascular diseases where ROS are implicated.
Complexation with proteins allows targeted delivery, reducing toxicity and enhancing therapeutic specificity.
Combination therapy with various chemotherapeutic agents allows additive or synergistic anti-cancer effects.
Documented Applications
Treatment and prevention of a wide variety of cancers, including melanoma, leukemia, non-small cell lung, colon, CNS, renal, ovarian, breast and prostate cancers, and particularly drug resistant and metastatic cancers.
Treatment of inflammatory disorders such as psoriasis, atopic dermatitis, asthma, arthritis, inflammatory bowel diseases, lupus, multiple sclerosis, and others wherein reactive oxygen species play a role.
Treatment of degenerative diseases including macular degeneration, Alzheimer's disease, Parkinson's disease, dementia, prion-caused disorders, emphysema, osteoporosis, and hypertension.
Treatment of vascular disorders like erectile dysfunction, migraines, and prevention of atherosclerosis.
Treatment of parasitic infections including malaria, trypanosomiasis (sleeping sickness), and leishmaniasis.
Use as adjunct therapy in combination with surgery, radiation, and other anticancer drugs to enhance therapeutic outcomes.
Interested in licensing this patent?