Hepatoprotectant acetaminophen mutual prodrugs

Abstract

The present invention provides hepatoprotectant acetaminophen mutual prodrugs, which have an acetaminophen moiety covalently linked to a second moiety that may act as a hepatoprotectant against acetaminophen hepatotoxicity. Additionally, acetaminophen mutual prodrugs may have improved water solubility which may provide better suitability for parenteral and other dosage forms relative to administration of acetaminophen. Also provided are methods of treating a disease or condition that is responsive to acetaminophen (such as fever, pain and ischemic injury) using hepatoprotectant acetaminophen mutual prodrugs, as well as kits and unit dosages.

1 - 40 . (canceled) 
     
     
         41 . A compound of formula (III): 
       
         
           
           
               
               
           
         
         wherein A and D are each independently a bond or a substituted or unsubstituted amino acid moiety; 
         B and C are each independently —H, acetyl, or a substituted or unsubstituted amino acid moiety; and 
         x and y are each independently 1 or 2; wherein 
         when A and D are each a bond, x and y are each 1, and B is acetyl, then C is —H, or a substituted or unsubstituted amino acid moiety; 
         or a pharmaceutically acceptable salt thereof or solvate of the foregoing. 
       
     
     
         42 . (canceled) 
     
     
         43 . The compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein each of A and D is a bond. 
     
     
         44 - 45 . (canceled) 
     
     
         46 . The compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein each of A and D is a substituted or unsubstituted amino acid moiety. 
     
     
         47 - 48 . (canceled) 
     
     
         49 . The compound of  claim 46 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein A and D are each independently a substituted or unsubstituted glycine. 
     
     
         50 . (canceled) 
     
     
         51 . The compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein each of B and C is H. 
     
     
         52 - 54 . (canceled) 
     
     
         55 . The compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein B and C are each independently a substituted or unsubstituted amino acid moiety. 
     
     
         56 . (canceled) 
     
     
         57 . The compound of  claim 55 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein B and C are each independently a substituted or unsubstituted glutamate. 
     
     
         58 . The compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein x and y are each 1. 
     
     
         59 - 60 . (canceled) 
     
     
         61 . The compound of  claim 41 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof or solvate of the foregoing. 
       
     
     
         62 . The compound of  claim 41 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof or solvate of the foregoing. 
     
     
         63 - 68 . (canceled) 
     
     
         69 . A formulation comprising the compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, and a pharmaceutically acceptable carrier. 
     
     
         70 - 71 . (canceled) 
     
     
         72 . A formulation comprising the compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, and a compound selected from the group consisting of an opioid, non-steroidal anti-inflammatory drug (NSAID), benzodiazepine, and barbiturate. 
     
     
         73 . A formulation comprising the compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, and a compound selected from the group consisting of codeine, morphine, hydrocodone, hydromorphone, levorphanol, propoxyphene, aspirin, ketorolac, ibuprofen, ketoprofen, flurbiprofen, etodolac, diclofenac, misoprostol, meloxicam, piroxicam, naproxen, caffeine, doxylamine, pamabrom, tramadol, dextropropoxyphene, methylhexital, carisoprodol, butalbital, diazepam, lorazepam, and midazolam. 
     
     
         74 . (canceled) 
     
     
         75 . A method of treating pain, fever, ischemic injury, or neuronal injury, comprising administering to an individual an effective amount of the compound of  claim 41  or a pharmaceutically acceptable salt thereof or solvate of the foregoing. 
     
     
         76 - 83 . (canceled) 
     
     
         84 . The method according to  claim 75 , wherein the compound is administered orally. 
     
     
         85 . The method according to  claim 75 , wherein the compound is administered parenterally. 
     
     
         86 . The method according to  claim 75 , wherein the dosage of the compound is about 300 mg to about 3.6 g. 
     
     
         87 . (canceled) 
     
     
         88 . The method according to  claim 75 , wherein the dosage of the compound is about 1 nmol to about 10 mmol. 
     
     
         89 - 92 . (canceled) 
     
     
         93 . A kit for treatment or prevention of pain, fever, ischemic injury, or neuronal injury, comprising the compound of  claim 41  or a pharmaceutically acceptable salt thereof or solvate of the foregoing; and instructions for use in the treatment or prevention of pain, fever, ischemic injury, or neuronal injury. 
     
     
         94 - 98 . (canceled) 
     
     
         99 . A low volume/high concentration formulation comprising the compound of  claim 41  or a pharmaceutically acceptable salt thereof or solvate of the foregoing and a pharmaceutically acceptable carrier. 
     
     
         100 . (canceled)