Deuterated forms of acetaminophen and uses thereof

Abstract

The present disclosure provides compositions comprising deuterated forms of acetaminophen. When administered to human subjects, such compositions form less of the toxic metabolite NAPQI, and therefore are useful in methods of treating various diseases and conditions with a reduced risk of liver injury or other side effects associated with non-deuterated forms of acetaminophen.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62 / 861,073, filed on Jun. 13, 2019, and U.S. Provisional Application No. 62 / 857,226, filed on Jun. 4, 2019, the entire contents of which are herein incorporated by reference.BACKGROUND OF THE INVENTION[0002]Acetaminophen (also known as paracetamol) was approved by the FDA in 1951 and is one of the most widely used drugs in the United States. Today, acetaminophen is found in hundreds of over-the-counter (OTC) and prescription medicines, including in Tylenol-brand products, as an intravenous formulation (OFIRMEV), and in prescription combination drug products such as Vicodin and Percocet.[0003]The chemical structure of acetaminophen, N-(4-Hydroxyphenyl)acetamide, is as follows:[0004]Acetaminophen is a pain reliever and fever reducer that is used to treat many conditions including headaches, muscle aches, arthritis, backache, toothaches, cold...

AI Technical Summary

Benefits of technology

[0009]Described herein is an invention that solves the significant, long felt need for safe and effective non-NSAID, non-opioid pain relievers and fever reducers. It has been surprisingly discovered that deuterated forms of acetaminophen may be safely and effectively administered to humans, and other mammals or subjects, for a number of diseases and conditions, including, but not limited to, treatment of pain and fever. It has also been surprisingly discovered that deuterated forms of acetaminophen, such as acetaminophen-d4 (shown below), when administered, unexpectedly form less of the toxic metabolite, NAPQI, and therefore may be used to treat pain and fever while reducing the risk of liver injury and other side effects associated with non-deuterated forms of acetaminophen.

[0012]It has been surprisingly discovered that the replacement of one or more hydrogen atoms with deuterium in a compound of Formula (I) results in a compound with unexpectedly different and superior properties, including avoidance or reduced incidence of life-threatening side effects related to hepatoxicity. These compounds, and compositions comprising them, are useful for preventing or treating a number of conditions, including pain and fever.

Problems solved by technology

Despite its widespread use, acetaminophen has been known for years to cause liver injury.

Notwithstanding the FDA's actions, acetaminophen overdose remains a significant problem, as it is the leading cause of acute liver failure in the United States.

Despite being on the market for more than sixty (60) years, scientists have been unsuccessful in developing and commercializing a safer, improved form of acetaminophen.

Unfortunately, alternatives to acetaminophen, such as NSAIDs and opioids, come with different, but serious, and in many cases life threatening, risks.

For example, NSAIDs, such as ibuprofen, today carry a “black box” warning of (a) an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, and (b) an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, both of which may be fatal.

Opioids, on the other hand, are widely known to lead to addiction, abuse, and misuse, which can result in overdose and death.

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