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 . A compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein 
         A is a bond or a substituted or unsubstituted amino acid moiety; 
         B is —H, acetyl, or a substituted or unsubstituted amino acid moiety; 
         R 1  is —H, —CH 3 , an alkylene-phosphate moiety, a substituted or unsubstituted amino acid moiety, or a substituted or unsubstituted nucleoside moiety;
 or wherein B is taken together with R 1  to form a substituted or unsubstituted heterocycloalkyl; 
 
         x is 1 or 2; and 
         m is 0 or 1; wherein 
         when A is a bond, x is 1 and R 1  is —H, B is a substituted or unsubstituted amino acid moiety; and 
         when A is a bond, x is 2 and R 1  is methyl, B is —H or a substituted or unsubstituted amino acid moiety; 
         or a pharmaceutically acceptable salt thereof or solvate of the foregoing. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, provided that when A is a bond, and R 1  is methyl or —H, B is a substituted or unsubstituted amino acid moiety. 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein A is a bond. 
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein A is a substituted or unsubstituted amino acid moiety. 
     
     
         5 . (canceled) 
     
     
         6 . The compound of  claim 4 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein A is an unsubstituted glycine moiety. 
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein B is —H or acetyl. 
     
     
         8 . The compound of  claim 7 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein B is acetyl. 
     
     
         9 . The compound of  claim 7 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein B is —H. 
     
     
         10 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein B is a substituted or unsubstituted amino acid moiety. 
     
     
         11 . The compound of  claim 10 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein B is a substituted or unsubstituted glutamate moiety. 
     
     
         12 . (canceled) 
     
     
         13 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein x is 1. 
     
     
         14 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein x is 2. 
     
     
         15 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein m is 0. 
     
     
         16 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein m is 1. 
     
     
         17 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein R 1  is —H, —CH 3 , or a substituted or unsubstituted amino acid moiety. 
     
     
         18 . The compound of  claim 17 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein R 1  is —H, or —CH 3 . 
     
     
         19 . The compound of  claim 18 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein R 1  is —H. 
     
     
         20 . The compound of  claim 18 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein R 1  —CH 3 . 
     
     
         21 . The compound of  claim 17 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein R 1  is a substituted or unsubstituted amino acid moiety. 
     
     
         22 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein R 1  is a substituted or unsubstituted cysteine moiety. 
     
     
         23 - 25 . (canceled) 
     
     
         26 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein R 1  is an alkylene-phosphate moiety. 
     
     
         27 . The compound of  claim 26 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein R 1  is —CH 2 —OPO 3 H 2 . 
     
     
         28 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein R 1  is a substituted or unsubstituted nucleoside moiety. 
     
     
         29 . The compound of  claim 28 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         30 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein B is taken together with R 1  to form a substituted or unsubstituted heterocycloalkyl. 
     
     
         31 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein B is taken together with R 1  to form an unsubstituted 5-thiazolidinonyl. 
     
     
         32 . A compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof or solvate of the foregoing; 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof or solvate of the foregoing; 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof or solvate of the foregoing; 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof or solvate of the foregoing; 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof or solvate of the foregoing; 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof or solvate of the foregoing; 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof or solvate of the foregoing; 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof or solvate of the foregoing; and 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof or solvate of the foregoing. 
     
     
         33 - 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 . The compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein at least one of A and D is a bond. 
     
     
         43 . The compound of  claim 42 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein each of A and D is a bond. 
     
     
         44 . The compound of  claim 42 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein one of A and D is a bond and the other of A and D is a substituted or unsubstituted amino acid moiety. 
     
     
         45 . The compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein at least one of A and D is a substituted or unsubstituted amino acid moiety. 
     
     
         46 . The compound of  claim 45 , 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 . The compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein A and D are each independently a bond or a substituted or unsubstituted moiety selected from the group consisting of glycine, cysteine, and methionine. 
     
     
         48 . The compound of  claim 47 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein A and D are each independently a substituted or unsubstituted moiety selected from the group consisting of glycine, cysteine, and methionine. 
     
     
         49 . The compound of  claim 48 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein A and D are each independently a substituted or unsubstituted glycine. 
     
     
         50 . The compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein at least one of B and C is H. 
     
     
         51 . The compound of  claim 50 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein each of B and C is H. 
     
     
         52 . The compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein at least one of B and C is acetyl. 
     
     
         53 . The compound of  claim 52 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein each of B and C is acetyl. 
     
     
         54 . The compound of  claim 50 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein one of B and C is H and the other of B and C is acetyl. 
     
     
         55 . The compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein B and C are each independently H, acetyl, or a substituted or unsubstituted amino acid moiety selected from the group consisting of glutamate, cysteine, and methionine. 
     
     
         56 . 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 amino acid moiety selected from the group consisting of glutamate, cysteine, and methionine. 
     
     
         57 . The compound of  claim 56 , 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 . The compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein x and y are each 2. 
     
     
         60 . The compound of  claim 41 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, wherein one of x and y is 1 and the other of x and y is 2. 
     
     
         61 . A compound of  claim 41 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof or solvate of the foregoing or 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof or solvate of the foregoing. 
     
     
         62 .- 69 . (canceled) 
     
     
         70 . 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. 
     
     
         71 . (canceled) 
     
     
         72 . The formulation of  claim 70 , further comprising a compound selected from the group consisting of an opioid, non-steroidal anti-inflammatory drug (NSAID), benzodiazepine, and barbiturate. 
     
     
         73 . The formulation of  claim 70 , further comprising 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, or midazolam. 
     
     
         74 . (canceled) 
     
     
         75 . 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. 
     
     
         76 . The method according to  claim 75 , wherein disease or condition is selected from the group consisting of pain, fever, inflammation, ischemic injury, and neuronal injury. 
     
     
         77 - 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 - 92 . (canceled) 
     
     
         93 . A kit 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. 
     
     
         94 - 98 . (canceled) 
     
     
         99 . The formulation of  claim 70 , wherein the formulation is a low volume/high concentration formulation comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof or solvate of the foregoing, and a pharmaceutically acceptable carrier. 
     
     
         100 . (canceled)