Nitroxide modified non-steroidal anti-inflammatory compounds and uses thereof in the treatment and prevention of diseases or disorders
Inventors
Wink, David A. • Flores-Santana, Wilmarie • King, S. Bruce • Cherukuri, Murali Krishna • Mitchell, James B.
Assignees
Wake Forest University • US Department of Health and Human Services
Publication Number
US-9012647-B2
Publication Date
2015-04-21
Expiration Date
2032-04-05
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Abstract
Disclosed are nitroxide modified NSAID compounds of the formula (I) or a pharmaceutically acceptable salt or enantiomer thereof:in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and n are defined herein and pharmaceutical compositions thereof. Further disclosed is a method of treating or preventing various disorders, such as inflammation, cancer, diabetes, a cardiovascular disorder, weight gain, polyps, and/or chronic pain, in a patient comprising administering an effective amount of a compound or pharmaceutically acceptable salt or enantiomer of formula (I). A method of imaging the compound or pharmaceutically acceptable salt or enantiomer of formula (I) in the body of the animal is also provided.
Core Innovation
The invention provides nitroxide modified non-steroidal anti-inflammatory compounds (NSAIDs) having the formula (I) that comprise one or more NSAID moieties and at least one nitroxide moiety. These compounds and their pharmaceutical compositions can be used for treating or preventing a variety of disorders including inflammation, cancer, diabetes, cardiovascular disorders, weight gain, polyps, and chronic pain. Additionally, the invention includes methods for imaging the compound in the body of an animal using their paramagnetic nitroxide properties.
The compounds are redox modified NSAIDs characterized by reduced gut toxicity and thrombosis relative to conventional NSAIDs. They possess antioxidant properties and superoxide dismutase (SOD) mimetic activity, enhancing their therapeutic profile. The compounds contain at least one NSAID moiety optionally substituted and bonded to a nitroxide group, which contributes to their unique biological and chemical properties.
The background addresses the problem that although NSAIDs like aspirin and COX-2 selective drugs reduce certain cancers and inflammation, their long-term use can cause adverse effects such as gut ulceration and thrombosis. Current NSAIDs with reduced gut toxicity and thrombosis remain an unmet need. The invention aims to overcome these limitations by providing modified NSAID compounds exhibiting enhanced safety and efficacy profiles, including less gut toxicity and thrombosis while providing antioxidant benefits.
Claims Coverage
The patent includes four independent claims defining the composition of matter and pharmaceutical compositions encompassing the nitroxide modified NSAID compounds and their salts or enantiomers.
Nitroxide modified NSAID compound structure
A compound of formula (I) comprising defined substituents including at least one NSAID moiety optionally substituted with triphenylphosphinyl C1-C12 alkyl substituents and bonded to a nitroxide moiety, with specific chemical group definitions and structural conditions.
Compounds containing multiple NSAID moieties
Compounds of formula (I) comprising at least three NSAID moieties, each optionally substituted with one or more triphenylphosphinyl C1-C12 alkyl substituents, bonded thereto.
Specific NSAID moieties selection
Compounds wherein the NSAID moieties are selected from a defined group of known NSAID structures and substructures as explicitly recited in the claims.
An alternative compound embodiment
A separate compound of formula (I) as defined with specific substituents and configurations provided as an independent composition of matter claim.
Pharmaceutical compositions containing the compounds
Pharmaceutical compositions comprising the compound, salt, or enantiomer of the aforementioned compound claims and a pharmaceutically acceptable carrier.
The claims cover compositions of nitroxide modified NSAIDs with defined structural features, including multiple NSAID moieties, specific NSAID selections, and pharmaceutical compositions thereof, emphasizing the invention's chemical versatility and formulation aspects.
Stated Advantages
The compounds have little or reduced gut toxicity compared to conventional NSAIDs.
They exhibit little or reduced thrombosis, enhancing safety for long-term use.
The compounds possess antioxidant properties and superoxide dismutase (SOD) mimetic activity.
The modified NSAIDs show improved anti-inflammatory potency and decreased ulcerogenic side effects relative to parent NSAIDs.
Documented Applications
Treatment or prevention of inflammation, cancer, diabetes, cardiovascular disorders, weight gain, asthma, polyps, and chronic pain in patients.
Use as imaging agents for cells, tissues, or organs in animals through detection of their paramagnetic nitroxide moieties using electron paramagnetic resonance (EPR) or magnetic resonance imaging (MRI).
Reduction of adverse effects such as gut ulceration and thrombosis associated with long-term NSAID therapy.
Inducing weight loss in patients.
Treatment or prevention of polyps and prevention of their progression to cancer.
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