Water-soluble acetaminophen analogs

Abstract

The present invention provides water-soluble acetaminophen prodrugs and formulations which may be suitable for parenteral administration. Methods of treating a disease or condition responsive to acetaminophen (such as fever and/or pain) using the acetaminophen prodrugs, as well as kits, unit dosages, and combinations with additional pharmaceutical agent(s) are also provided.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof or solvate of the foregoing. 
       
     
     
         2 . A compound of  claim 1 , wherein the compound is a disodium salt of formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         3 . (canceled) 
     
     
         4 . A formulation comprising an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, and a pharmaceutically acceptable carrier. 
     
     
         5 . The formulation of  claim 4 , wherein the carrier is saline. 
     
     
         6 . The formulation of  claim 4 , further comprising a compound selected from the group consisting of an opioid, non-steroidal anti-inflammatory drug (NSAID), benzodiazepine, and barbiturate. 
     
     
         7 . The formulation of  claim 4 , further comprising a compound selected from the group consisting of codeine, morphine, hydrocodone, hydromorphone, levorphanol, aspirin, ketorolac, ibuprofen, naproxen, caffeine, tramadol, dextropropoxyphene, methylhexital, diazepam, lorazepam, midazolam, propoxyphene, ketoprofen, flurbiprofen, etodolac, diclofenac, misoprostol, meloxicam, piroxicam, doxylamine, pamabrom, carisoprodol, and butalbital. 
     
     
         8 . A substantially pure form of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing. 
     
     
         9 . A method of treating a disease or condition that is responsive to acetaminophen, comprising administering to an individual an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing. 
     
     
         10 . The method of  claim 9 , wherein the method comprises administering a formulation comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, and a pharmaceutically acceptable carrier. 
     
     
         11 . The method according to  claim 9 , wherein the disease or condition is selected from the group consisting of pain, fever, inflammation, ischemic injury, and neuronal injury. 
     
     
         12 . The method according to any one of  claim 9 , wherein the compound, or a pharmaceutically acceptable salt thereof or solvate of the foregoing, is administered parenterally. 
     
     
         13 . The method according to  claim 12 , wherein the compound, or a pharmaceutically acceptable salt thereof or solvate of the foregoing, is administered intravenously. 
     
     
         14 . The method according to  claim 12 , wherein the compound, or a pharmaceutically acceptable salt thereof or solvate of the foregoing, is administered intramuscularly. 
     
     
         15 . The method according to  claim 12 , wherein the compound, or a pharmaceutically acceptable salt thereof or solvate of the foregoing, is administered subcutaneously. 
     
     
         16 . The method according to  claim 9 , wherein the dosage of the compound, or a pharmaceutically acceptable salt thereof or solvate of the foregoing, is about 300 mg to about 2.6 g. 
     
     
         17 . The method according to  claim 16 , wherein the dosage of the compound, or a pharmaceutically acceptable salt thereof or solvate of the foregoing, is about 1.3 g to about 1.9 g. 
     
     
         18 . The method according to  claim 16 , wherein the volume of the dosage is about 1 mL to about 25 mL. 
     
     
         19 . The method according to  claim 18 , wherein the volume of the dosage is about 10 mL to about 20 mL. 
     
     
         20 . The method according to  claim 18 , wherein the volume of the dosage is about 1 mL to about 10 mL. 
     
     
         21 . The method according to  claim 18 , wherein the volume of the dosage is about 5 mL to about 10 mL. 
     
     
         22 . The method according to  claim 16 , wherein the dosage is administered more than once a day. 
     
     
         23 . The method according to  claim 16 , wherein the dosage is administered once every other day or less. 
     
     
         24 - 26 . (canceled) 
     
     
         27 . A kit for the treatment or prevention of pain, fever, inflammation, ischemic injury, or neuronal injury, comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, and instructions for use in the treatment or prevention of pain, fever, inflammation, ischemic injury, or neuronal injury. 
     
     
         28 . The kit of  claim 27 , wherein the kit further comprises a pharmaceutically acceptable carrier. 
     
     
         29 . The formulation of  claim 4 , wherein the formulation is a low volume/high concentration formulation comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         30 . The formulation of  claim 4 , wherein the formulation comprises a disodium salt of the formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         31 . The method of  claim 9 , wherein the method comprises administering to an individual an effective amount of a disodium salt of the formula (II):