Prodrugs of Neuraminidase Inhibitors

Abstract

A new class of neuramidase inhibitor prodrugs is provided characterized by a prodrug moiety of a carboxyl group modified to form a carbonyl ethoxy amino acid, a carbonyl ethoxy dipeptide or a carbonyl ethoxy tripeptide, a guanidine group modified to form a carbonyl ethoxy amino acid, a carbonyl ethoxy dipeptide, a carbonyl ethoxy tripeptide; a primary alcohol modified to form an esterified single amino acid, dipeptide or tripeptide of zanavimir of the unaltered therapeutic agent. Exemplary therapeutic agents so modified to form prodrugs include zanavimir, oseltamivir and peramivir. The prodrug has increased oral bioavailability relative to the unaltered neuraminidase inhibitor and is effective in the inhibition of viral infections involving neuraminidase in the viral reproductive cycle.

1 . A prodrug of a neuraminidase inhibitor having the formula (I): 
       
         
           
           
               
               
           
         
         where R 1  is an amino acid residue having the formula —C(O)CH(R′)NH 2 , a dipeptide residue having the formula —C(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)NH 2 , a tripeptide residue having the formula —C(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)N(H)C(O) (CH 2 ) n CH(R′″)NH 2 , —H, —COC(CH 3 ) 2 CH 2 R*, —COCH 2 CH 2 R* or —COCH 3 ; n is zero, one or two; R 2  is a nullity or CR*R**, O or CR*(OH); R* is —H, —C 1 -C 8  alkyl, or —C 1 -C 6  alkyl having a heteroatom substituent of hydroxyl, carboxyl, or primary amine; R** is R* or an electron of covalent bond; R 3  is an sp 2  hybridized C or CR*; R 4  is CR*R** when R 3  is CR* and an sp 2  hybridized C when R 3  is the sp 2  hybridized C forming an ethylenic unsaturation therebetween, R 4  is CH; R 5  is CR*R** and R** is the electron of a covalent bond when bonded to R 2  or R 7  to form a 5- or 6-member cyclic structure; R 6  is —NH—C(O)—CH 2 R*, R 7  is a nullity, —CR*R** and R 8  is —CR*(OR 11 )CR*(OR 12 )CHR*(OR 13 ); R 11 , R 12  and R 13  are each independently an amino acid residue having the formula —C(O)(CH 2 ) n CH(R′)NH 2 , a dipeptide residue having the formula —C(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)NH 2 , a tripeptide residue having the formula —C(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)N(H)C(O)(CH 2 ) n CH(R′″)NH 2 , —H, —COC(CH 3 ) 2 CH 2 R*, —COCH 2 CH 2 R*, or —COCH 3 ; R 9  and R 10 , are each independently an amino acid residue having the formula —C(O)(CH 2 ) n CH(R′)NH 2 , a dipeptide residue having the formula —C(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)NH 2 , a tripeptide residue having the formula —C(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)N(H)C(O)CH(R′″)NH 2  or —H; L 1  is a nullity, —[(CH 2 ) n CH(CH 2 R*)O] m , or —[(CH 2 ) n CH 2 O] m , with the proviso that L 1  is —[(CH 2 ) n CH(CH 2 R*)O] m  or —[(CH 2 ) n CH 2 O] m  when R 1  is a single amino acid residue, a dipeptide residue or a tripeptide residue; m is 1; L 2  is a nullity, —C(O)(CH 2 ) n CH(CH 2 R*)O or —C(O)O(CH 2 ) n CH 2 O with the proviso that L 2  is —C(O)[(CH 2 ) n CH(CH 2 R*)O] m  or —C(O)O[(CH 2 ) n CH 2 O] m  when R 9  or R 10  is a single amino acid residue or a dipeptide residue; R′, R″ and R′″, in each occurrence, is an independently selected amino acid side chain; with the proviso that at least one of R 1 , R 9 , R 10 , R 11 , R 12  or R 13  is a single α, β or γ amino acid residue, a dipeptide residue or a tripeptide residue. In a specific preferred embodiment of the prodrug of formula (I) n is zero in each occurrence and R* is H in each occurrence. 
       
     
     
         2 . The prodrug of a neuraminidase inhibitor of  claim 1 , having formula (III): 
       
         
           
           
               
               
           
         
         where R 14  is —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)NH 2 , —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)NH 2 , —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)N(H)C(O)(CH 2 ) n CH(R′″)NH 2 , —H, —COC(CH 3 ) 2 CH 2 R*, —COCH 2 CH 2 R*, or —COCH 3 ; n is zero or one; R* is —H, —C 1 -C 8  alkyl, or —C 1 -C 6  alkyl having a heteroatom substituent of hydroxyl, carboxyl, or primary amine; R 15  is in each occurrence independently —C(O)OCH(CH 3 )OC(O)(CH 2 ) n CH(R′)NH 2 , —C(O)OCH(CH 3 )OC(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)NH 2 , —CH(CH 3 )O—C(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)N(H)C(O) (CH 2 ) n CH(R′″)NH 2 , —H, —COC(CH 3 ) 2 CH 2 R*, —COCH 2 CH 2 R*, or —COCH 3 ; R 16  and R 17  are each independently —H, an amino acid residue having the formula C(O)(CH 2 ) n CH(R′)NH 2 , a dipeptide residue having the formula C(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)NH 2 , or a tripeptide residue —CH(CH 3 )O—C(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)N(H)C(O) (CH 2 ) n CH(R′″)NH 2 , where R′, R″ and R′″ are each an independently selected amino acid side chain; and where at least one of R 14 , R 15 , R 16  and R 17  includes an amino acid, dipeptide or tripeptide residue. 
       
     
     
         3 . The prodrug of a neuraminidase inhibitor of  claim 1 , having formula (VI) 
       
         
           
           
               
               
           
         
         where R 18  is —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)NH 2 , —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)NH 2 , —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)N(H)C(O)(CH 2 ) n CH(R′″)NH 2 , —COC(CH 3 ) 2 CH 2 R*, —COCH 2 CH 2 R*, or —COCH 3 ; n is zero or one; R* is —H, —C 1 -C 8  alkyl, or —C 1 -C 6  alkyl having a heteroatom substituent of hydroxyl, carboxyl, or primary amine; and R′, R″ and R′″ are each independently an amino acid side chain. 
       
     
     
         4 . The prodrug of a neuraminidase inhibitor of  claim 1 , having formula (VII): 
       
         
           
           
               
               
           
         
         where R 19  is —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)NH 2 , —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)NH 2 , —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)N(H)C(O)(CH 2 ) n CH(R′″)NH 2 , —H, —COC(CH 3 ) 2 CH 2 R*, —COCH 2 CH 2 R*, or —COCH 3 ; n is zero or one; R* is —H, —C 1 -C 8  alkyl, or —C 1 -C 6  alkyl having a heteroatom substituent of hydroxyl, carboxyl, or primary amine; R 20  is in each occurrence independently —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)NH 2 , —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)NH 2 , —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)N(H)C(O)(CH 2 ) n CH(R′″)NH 2 , or —H; R′, R″ and R′″ are each an independently an amino acid side chain; and where at least one R 19  or R 20  includes an amino acid residue, dipeptide residue or tripeptide residue. 
       
     
     
         5 . The prodrug of a neuraminidase inhibitor of  claim 1 , having formula (IX) 
       
         
           
           
               
               
           
         
         where R 21  is —CH(CH 3 )OC(O)(CH 2 ) n CH(R)NH 2 , —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)NH 2 , —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)N(H)C(O)(CH 2 ) n CH(R′″)NH 2 , —H, —COC(CH 3 ) 2 CH 2 R*, —COCH 2 CH 2 R*, or —COCH 3 ; n is zero or one; R* is —H, —C 1 -C 8  alkyl, or —C 1 -C 6  alkyl having a heteroatom substituent of hydroxyl, carboxyl, or primary amine; R 22  is in each occurrence independently —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)NH 2 , —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)NH 2 , —CH(CH 3 )OC(O)(CH 2 ) n CH(R′)N(H)C(O)(CH 2 ) n CH(R″)N(H)C(O)(CH 2 ) n CH(R′″)NH 2 , or —H; R′, R″ and R′″ are each an independently selected amino acid side chain; and where at least one R 21  or R 22  includes an amino acid residue, dipeptide residue or tripeptide residue. 
       
     
     
         6 . A prodrug comprising:
 a prodrug moiety of: a carboxyl group modified to form, a carbonyl ethoxy amino acid, a carbonyl ethoxy dipeptide, a carbonyl ethoxy tripeptide, a guanidine group modified to form a carbonyl ethoxy amino acid, a carbonyl ethoxy dipeptide, or a carbonyl ethoxy tripeptide of a therapeutic agent of zanavimir, oseltamivir, or peramivir.   
     
     
         7 . The prodrug of  claim 6  wherein the prodrug moiety is the guanidine group modified to form the carbonyl ethoxy amino acid and the therapeutic agent is oseltamivir. 
     
     
         8 . The prodrug of  claim 6  wherein the prodrug moiety is the carboxyl group modified to form the carbonyl ethoxy amino acid and the therapeutic agent is oseltamivir. 
     
     
         9 . A prodrug of zanavimir, comprising:
 a prodrug moiety of: a carboxyl group modified to form a carbonyl ethoxy amino acid, a carbonyl ethoxy dipeptide or a carbonyl ethoxy tripeptide, a guanidine group modified to form a carbonyl ethoxy amino acid, a carbonyl ethoxy dipeptide, a carbonyl ethoxy tripeptide; a primary alcohol modified to form an esterified single amino acid, dipeptide or tripeptide of zanavimir.   
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . A commercial package comprising a prodrug having the formula (I) according to  claim 1  as an active ingredient together with instructions for the use thereof as a neuraminidase inhibitor. 
     
     
         14 . A method of inhibiting a viral infection in a subject, comprising:
 administering a neuraminidase inhibitor prodrug of  claim 1  to a subject.   
     
     
         15 . The method of  claim 14  wherein the viral infection is an influenza virus infection. 
     
     
         16 . The method of  claim 14  wherein the subject is human. 
     
     
         17 . The prodrug of  claim 1  wherein L 2  is a nullity, R 9  is H, and R 10  is H. 
     
     
         18 . The prodrug of  claim 1  wherein L 1  is —[(CH 2 ) n CH(CH 2 R*)O] m . 
     
     
         19 . The prodrug of  claim 18  wherein R 1  is —C(O)CH(R″)NH 2 . 
     
     
         20 . The prodrug of  claim 19 , wherein L 2  is a nullity, R 9  is H, and R 10  is H.