Aryl phosphate derivatives of D4T with potent anti-viral activity

Abstract

Methods for increasing the elimination half-life of key metabolites such as d4T by administering an aryl phosphate derivative of d4T having an electron withdrawing substituent on the aryl group and an amino acid substituent on the phosphate group are described. A preferred aryl phosphate derivative of d4T is HI-113 (d4T-5′-[p-bromophenyl methoxyalaninyl phosphate]). The administration of HI-113 results in more prolonged systemic exposure to the key metabolites, Ala-d4T-MP and d4T, than administration of an equimolar dose of either metabolite. Each metabolite has a significantly longer elimination half life when formed in vivo from the administration of HI-113 than when the metabolite is administered directly.

1 - 13 . (canceled)  
     
     
         14 . A method for extending the half-life of a compound of formula I in a mammal comprising administering to the mammal: 
 an esterase inhibitor; and    a compound of formula I;    wherein the compound of formula I is:                          where R 1  is an aryl group substituted with an electron withdrawing group and R 2  is an amino acid residue or an ester of the amino acid residue, or a pharmaceutically acceptable salt thereof.    
     
     
         15 . The method of  claim 14 , wherein the aryl group is selected from the group consisting of phenyl, naphthyl, and anthryl.  
     
     
         16 . The method of  claim 14 , wherein the aryl group is phenyl.  
     
     
         17 . The method of  claim 14 , wherein the electron-withdrawing group is halo.  
     
     
         18 . The method of  claim 14 , wherein R 1  is para-bromophenyl.  
     
     
         19 . The method of  claim 14 , wherein R 2  is an α-amino acid or ester thereof.  
     
     
         20 . The method of  claim 14 , wherein R 2  is —NHCH(CH 3 )COOCH 3 .  
     
     
         21 . The method of  claim 14 , wherein R 1  is para-bromophenyl and R 2  is —NHCH(CH 3 )COOCH 3 .  
     
     
         22 . The method of  claim 14 , wherein the compound of formula I is administered intraveneously.  
     
     
         23 . The method of  claim 14 , wherein the compound of formula I is administered orally.  
     
     
         24 . The method of  claim 14 , wherein the esterase inhibitor is selected from the group of an inhibitor of cholinesterase, an inhibitor of carboxylesterase, or a combination thereof.  
     
     
         25 . The method of  claim 24 , wherein the inhibitor of cholinesterase is paraoxon.  
     
     
         26 . The method of  claim 24 , wherein the inhibitor of cholinesterase is phyostigmine.  
     
     
         27 . The method of  claim 21 , wherein the inhibitor of cholinesterase is selected from paraoxon and phyostigmine.  
     
     
         28 . The method of  claim 14 , wherein the compound of formula I and the esterase inhibitor are administered concurrently.  
     
     
         29 . The method of  claim 14 , wherein the compound of formula I and the esterase inhibitor are administered in a single dosage form.  
     
     
         30 . The method of  claim 29 , wherein the a single dosage form is a parenteral dosage form.  
     
     
         31 . A pharmaceutical composition comprising: 
 an esterase inhibitor; and    a compound of formula I:                          where R 1  is an aryl group substituted with an electron withdrawing groups and R 2  is an amino acid residue or an ester of the amino acid residue, or a pharmaceutically acceptable salt thereof.    
     
     
         32 . The composition of  claim 31 , wherein the aryl group is selected from the group consisting of phenyl, naphthyl, and anthryl.  
     
     
         33 . The composition of  claim 31 , wherein the aryl group is phenyl.  
     
     
         34 . The composition of  claim 31 , wherein the electron-withdrawing group is halo.  
     
     
         35 . The composition of  claim 31 , wherein R 1  is para-bromophenyl.  
     
     
         36 . The composition of  claim 31 , additionally comprising a pharmaceutically acceptable carrier or diluent.  
     
     
         37 . The composition of  claim 31 , wherein R 2  is —NHCH(CH 3 )COOCH 3 .  
     
     
         38 . The composition of  claim 31 , wherein R 1  is para-bromophenyl and R 2  is —NHCH(CH 3 )COOCH 3 .  
     
     
         39 . The composition of  claim 31 , wherein the esterase inhibitor is selected from the group of an inhibitor of cholinesterase, an inhibitor of carboxylesterase, or a combination thereof.  
     
     
         40 . The composition of  claim 39 , wherein the inhibitor of cholinesterase is paraoxon.  
     
     
         41 . The composition of  claim 39 , wherein the inhibitor of cholinesterase is phyostigmine.  
     
     
         42 . The composition of  claim 38 , wherein the inhibitor of cholinesterase is selected from paraoxon and phyostigmine.  
     
     
         43 . The composition of  claim 31 , wherein the composition is adapted for intravenous administration.  
     
     
         44 . The composition of  claim 31 , wherein the composition is adapted for intravenous oral administration.  
     
     
         45 . A method for extending the half-life of a compound of formula I comprising administering the pharmaceutical composition of  claim 31 .  
     
     
         46 . The method of  claim 45 , wherein the composition of  claim 31  comprises an esterase inhibitor is an inhibitor of cholinesterase, an inhibitor of carboxylesterase, or a combination thereof.  
     
     
         47 . The method of  claim 46 , wherein the inhibitor of cholinesterase is paraoxon.  
     
     
         48 . The method of  claim 46 , wherein the inhibitor of cholinesterase is phyostigmine.