Water-soluble acetaminophen analogs
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 process for preparing a compound of formula (I)
or a pharmaceutically acceptable salt thereof,
comprising the steps of:
(a) reacting a compound of formula SI-A:
with a halomethyl sulfide to provide a compound of the formula
(b) reacting the compound of the formula
with dibenzylphosphate to provide a compound of the formula
wherein Bn is benzyl;
(c) deprotecting the compound of the formula
to provide the compound of formula (I); and
(d) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt thereof.
2. The process of claim 1 , wherein the halomethyl sulfide of step (a) is chloromethyl methyl sulfide.
3. The process of claim 1 , wherein step (a) is performed using HMPA as a solvent.
4. The process of claim 1 , wherein step (a) further comprises NaH.
5. The process of claim 1 , wherein step (b) is performed using THF as a solvent.
6. The process of claim 1 , wherein step (b) further comprises NIS or NBS.
7. The process of claim 1 , wherein step (c) is performed under reducing conditions.
8. The process of claim 1 , wherein step (c) is performed using Pd(OH) 2 /H 2 .
9. The process of claim 1 , wherein step (c) is performed using acidic conditions.
10. The process of claim 9 , wherein step (c) comprises treatment with acetic acid.
11. The process of claim 1 , wherein step (c) is performed using a protic solvent.
12. The process of claim 11 , wherein the protic solvent is methanol.