FIELD OF THE INVENTION

The present invention relates to methods and compositions for the production and use of pro-drug analogs of the analgesic acetaminophen. This invention relates to a method for the production of a broad group of novel glycoside derivatives of acetaminophen. The invention also importantly relates to the resulting glycosides as novel compounds of diverse application having desired properties including pharmacodynamic properties; and to medicaments containing the pro-drug compounds.

BACKGROUND OF THE INVENTION

Acetaminophen is a widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer). It is commonly used for the relief of fever, headaches, and other minor aches and pains, and is a major ingredient in numerous cold and flu remedies. In combination with non-steroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics, acetaminophen is used also in the management of more severe pain (such as postoperative pain).

One of the problems in the development of an injectable acetaminophen is its poor solubility in water. One approach to improve solubility is to glycosylate acetaminophen. For example, glycosylated acetaminophen pro-drug analogs that with an olefin at the 2,3 position of the carbohydrate are described in U.S. Pat. No. 5,693,767 [1] shown in FIG. 1.

Acetaminophen is most stable at pH 6, and the analogs with the olefin at the 2,3 position, will hydrolyze easily at this and lower pH's. Thus, new acetaminophen analogs that are more stable to pH's lower than 7 are needed.

SUMMARY OF THE INVENTION

In one embodiment, the invention relates to a pro-drug 2,3-hydroxy-glycoside derivative of acetaminophen, methods of making the same, and methods for administering the same to a subject. In one embodiment, the invention relates to a compound of the formula:

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wherein R₁is an alkyl, alkyl alkanoate, alkenyl, alkynyl, acyl, alkanediyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl oximes (Râ• CHâ• NOH), alkyl hydrazones (Râ• CHâ• NHNHR), alkyl amines, or a substituted version of any of these groups or a protecting group, phosphates [R=â€”OP(O)(OH)₂]v, sulfonates [Râ• OS(O)₂OH], sugar, OH, or H; and R₂is an alkyl, alkyl alkanoate, alkenyl, alkynyl, acyl, alkanediyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl oximes (Râ• CHâ• NOH), alkyl hydrazones (Râ• CHâ• NHNHR), alkyl amines or a substituted version of any of these groups or a protecting group, phosphates [R=â€”OP(O)(OH)₂], sulfonates [Râ• OS(O)₂OH], sugar, or H. In one embodiment, said compound comprises a monosaccharide derivative of acetaminophen. In one embodiment, said compound comprises disaccharide derivative of acetaminophen. In one embodiment, said compound, further comprising a pharmaceutically effective carrier. In one embodiment, the invention relates to a compound of the formula:

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