Abuse-resistant amphetamine prodrugs

Abstract

The invention describes compounds, compositions, and methods of using the same comprising a chemical moiety covalently attached to amphetamine. These compounds and compositions are useful for reducing or preventing abuse and overdose of amphetamine. These compounds and compositions find particular use in providing an abuse-resistant alternative treatment for certain disorders, such as attention deficit hyperactivity disorder (ADHD), ADD, narcolepsy, and obesity. Oral bioavailability of amphetamine is maintained at therapeutically useful doses. At higher doses bioavailability is substantially reduced, thereby providing a method of reducing oral abuse liability. Further, compounds and compositions of the invention decrease the bioavailability of amphetamine by parenteral routes, such as intravenous or intranasal administration, further limiting their abuse liability.

1 .- 15 . (canceled) 
     
     
         16 . A method of preparing lisdexamphetamine dimesylate comprising the step of:
 reacting a di-amine protected 1-lysine-d-amphetamine with methane sulfonic acid in a solvent to produce lisdexamphetamine dimesylate.   
     
     
         17 . The method of  claim 16 , wherein the di-amine protected l-lysine-d-amphetamine is Boc-L-Lys(Boc)-D-amphetamine. 
     
     
         18 . The method of  claim 16 , wherein the reaction is performed at a temperature ranging from about 60 to about 70° C. and optionally at reduced pressure. 
     
     
         19 . The method of  claim 18 , further comprising the sequential steps of:
 (a) cooling to the lisdexamphetamine dimesylate to from about 20 to about 25° C.;   (b) heating the lisdexamphetamine dimesylate to from about 50 to about 70° C.; and   (c) cooling to the lisdexamphetamine dimesylate to from about 20 to about 25° C.   
     
     
         20 . A method of preparing lisdexamphetamine or a salt thereof comprising the steps of:
 (a) protecting the amine groups of L-lysine or a salt thereof,   (b) subjecting the protected L-lysine to an acid activated amidation reaction with d-amphetamine to form a di-amine protected lisdexamphetamine, and   (c) deprotecting the di-amine protected lisdexamphetamine and optionally converting the lisdexamphetamine to a salt.   
     
     
         21 . The method of  claim 20 , wherein the amine protecting groups are Boc (—C(O)OC(CH 3 ) 3 ). 
     
     
         22 . The method of  claim 20 , wherein step (a) comprises reacting L-lysine or a salt thereof with di-tert-butyl dicarbonate. 
     
     
         23 . The method of  claim 20 , wherein step (b) comprises (i) activating the acid group on the protected L-lysine, and (ii) subjecting the activated L-lysine to a substation reaction to form a di-amine protected lisdexamphetamine. 
     
     
         24 . The method of  claim 20 , wherein step (c) comprises reacting the di-amine protected lisdexamphetamine with methanesulfonic acid to form a mesylate salt of lisdexamphetamine. 
     
     
         25 .- 67 . (canceled)